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IJBMeISSN 1724-6008
Int J Biol Markers 2016; 31(4): e332-e367
© 2016 Wichtig Publishing
GUIDELINES
DOI: 10.5301/jbm.5000251
Circulating tumor markers: a guide to their appropriate clinical use Comparative summary of recommendations from clinical practice guidelines (PART 1)
Massimo Gion1, Chiara Trevisiol2, Anne W.S. Rutjes3, Giulia Rainato2, Aline S.C. Fabricio1
1 Regional Center and Program for Biomarkers, Department of Clinical Pathology and Transfusion Medicine, Azienda ULSS 12 Veneziana, Venice - Italy
2 Istituto Oncologico Veneto IOV - IRCCS, Padova - Italy3 Institute of Social and Preventive Medicine, University of Bern, Bern - Switzerland
Endorsed byAGENAS National Agency for Regional Health Services, Rome, ItalyRegional Center for Biomarkers, Azienda ULSS 12 Veneziana, Venice, Italy
On behalf of and in collaboration withRegione del Veneto, IOV - Istituto Oncologico Veneto - I.R.C.C.S., AIOM (Associazione Italiana di Oncologia Medica), SIBioC - Medicina di Laboratorio (Società Italiana di Biochimica Clinica e Biologia Molecolare Clinica), AIRO (Associazione Italiana di Radioterapia Oncologica), ELAS-Italia (European Ligand Assay Society Italia), FADOI (Federazione delle Associazioni dei Dirigenti Ospedalieri Internisti), SICO (Società Italiana di Chirurgia Oncologica), SIGO (Società Italiana di Ginecologia e Ostetricia), SIMG (Società Italiana di Medicina Generale), SIUrO (Società Italiana di Urologia Oncologica), AVAPO Venezia Onlus (Associazione Volontari per l’Assistenza di Pazienti Oncologici)
Steering CommitteeMario Braga, Massimo Gion, Carmine Pinto, Bruno Rusticali, Holger Schünemann, Tommaso TrentiFor complete contributors' affiliations see end of article (pp. e364-e367)
Scientific CommitteeAline S.C. Fabricio, Evaristo Maiello, Anne W.S. Rutjes, Valter Torri, Quinto Tozzi, Chiara TrevisiolFor complete contributors' affiliations see end of article (pp. e364-e367)
Received: October 30, 2016Accepted: December 15, 2016Published online: December 20, 2016
Corresponding author:Dr. Massimo GionCentro Regionale BiomarcatoriAzienda ULSS12 VenezianaOspedale Civile30122 Venice, Italymassimo.gion@ulss12.ve.it
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Contributions of panel members(1) Search and selection of guidelines (2) Appraisal of guidelines through the AGREE II tool (3) Assessment of the rate of utilization of a subset of guidance documents in clinical practice (4) Synthesis of recommendations and other information concerning tumor markers into summary tables (5) Assessment of correctness and completeness of the information summarized in the tables
External validationInterregional Biomarkers Working Group, instituted by the Health Commission of the Italian Permanent Conference for Relations between State, Regions and the Autonomous Provinces of Trento and Bolzano. Antonino Iaria (Calabria), Vincenzo Montesarchio (Campania), Tommaso Trenti (Emilia Romagna), Laura Conti (Lazio), Luigina Bonelli and Gabriella Paoli (Liguria), Mario Cassani (Lombardia), Lucia Di Furia (Marche), Emiliano C. Aroasio (Piemonte), Mario Brandi (Puglia), Marcello Ciaccio and Antonio Russo (Sicilia), Gianni Amunni (Toscana), Emanuela Toffalori (P.A. Trento), Basilio Ubaldo Passamonti (Umbria), Claudio Pilerci and Francesca Russo (Veneto), Annarosa Del Mistro (IOV IRCCS, Veneto)
Executive secretaryOrnella Scattolin
FundingAGENAS Agenzia Nazionale per i Servizi Sanitari Regionali Azienda ULSS 12 VenezianaIOV - Istituto Oncologico Veneto - I.R.C.C.S.AIOM (Associazione Italiana di Oncologia Medica)SIBioC - Medicina di Laboratorio (Società Italiana di Biochimica Clinica e Biologia Molecolare Clinica)ELAS-Italia (European Ligand Assay Society Italia)SIUrO (Società Italiana di Urologia Oncologica) AVAPO Venezia Onlus (Associazione Volontari per l’Assistenza di Pazienti Oncologici)
This study was helpful in the exploration of unmet needs in tumor marker application in the frame of an AIRC 5x1000 research project, from which it was partially supported (Italian Association for Research on Cancer - AIRC; Grant Special Program Molecu-lar Clinical Oncology, 5x1000, No. 12214).
The authors would like to thank the following cultural associations in Venice for their supportAssociazione “Un amico a Venezia”, “Chiostro Tintorettiano di Venezia”, “I ragazzi di don Bepi”, SKÅL International Venezia for their support.
AcknowledgmentsThe authors would like to thank the following researchers for their collaboration: Mauro Antimi (Roma), Alessandro Battaggia (Padova), Nicola L. Bragazzi (Genova), Massimo Brunetti (Modena), Michele Cannone (Canosa di Puglia), Antonette E. Leon (Venezia).
This guide is published in Italian as:Gion M, Trevisiol C, Rainato G, Fabricio ASC. Marcatori circolanti in oncologia: guida all'uso clinico appropriato. I Quaderni di Monitor. Roma, IT: AGENAS, Agenzia Nazionale per i Servizi Sanitari Regionali, 2016.
Multidisciplinary panel of experts Salvatore Alfieri(5), Emiliano Aroasio(3,5), Alessandro Bertaccini(3,5), Francesco Boccardo(3,5), Roberto Buzzoni(3,5), Maurizio Cancian(5), Ettore D. Capoluongo(5), Elisabetta Cariani(5), Vanna Chiarion Sileni(3,5), Michela Cinquini(1,3,5), Giuseppe Civardi(5), Renzo Colombo(3,5), Mario Correale(3,5), Gaetano D’Ambrosio(5), Bruno Daniele(3,5), Marco Danova(3,5), Giovanna Del Vecchio Blanco(3,5), Francesca Di Fabio(3,5), Massimo Di Maio(3,5), Ruggero Dittadi(3,5), Massimo Falconi(3,5), Andrea Fandella(3,5), Tommaso Fasano(5), Simona Ferraro(3,5), Antonio Fortunato(3,5), Bruno Franco Novelletto(5), Angiolo Gadducci(3,5), Luca Germagnoli(3,5), Maria Grazia Ghi(3,5), Davide Giavarina(3,5), Marién González Lorenzo(2,5), Stefania Gori(3,5), Fiorella Guadagni(3,5), Cinzia Iotti(3,5), Tiziana Latiano(1,3,5), Lisa Licitra(3,5), Tiziano Maggino(5), Gianluca Masi(5), Paolo Morandi(3,5), Maria Teresa Muratore(3,5), Gianmauro Numico(5), Valentina Pecoraro(2,5), Paola Pezzati(3,5), Silvia Pregno(5), Giulia Rainato(4), Stefano Rapi(3,5), Francesco Ricci(3,5), Lorena Fabiola Rojas Llimpe(3,5), Laura Roli(1,5), Giovanni Rosti(3,5), Tiziana Rubeca(3,5), Giuseppina Ruggeri(5), Gian Luca Salvagno(5), Maria Teresa Sandri(5), Giovanni Scambia(3,5), Mario Scartozzi(3,5), Vincenzo Scattoni(3,5), Giuseppe Sica(3,5), Alessandro Terreni(3,5), Marcello Tiseo(3,5), Paolo Zola(5)
For complete contributors' affiliations see end of article (pp. e364-e367)
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Contents Introduction e335
Methodology e336
Take-home messages
Users’ instructions e340
Biliary cancer e341
Colorectal cancer e342
Esophageal cancer e344
Gastric cancer e345
Hepatocellular carcinoma e346
Pancreatic cancer e348
Detailed summary tables
Users’ instructions e349
Biliary cancer e350
Colorectal cancer e352
Esophageal cancer e355
Gastric cancer e356
Hepatocellular carcinoma e357
Pancreatic cancer e359
Selected guidelines (by cancer site) e361
Contributors e364
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Introduction
Some studies have recently shown that the number of tumor markers (TMs) requested is considerably higher than expected based on cancer prevalence (1,2), and that many factors may contribute to overordering of laboratory tests (3). These findings are in agreement with studies performed in case series showing that TMs are frequently requested inap-propriately (4). The high rate of overutilization is related to an increased risk of both overdiagnosis and false positive results, with significant repercussions both on individual patients and health care systems (5).
The pathway of knowledge translation of TM research re-sults to clinical practice has changed over the years. Until a couple of decades ago, primary studies were considered the major source of information for clinical practice; studies re-porting promising results were frequently advocated to sus-tain the utilization of the marker. Over the last 2 decades – also because of a progressive shrinkage of resources allotted to the health care sector – clinical practice guidelines (CPGs) have been more and more frequently considered the refer-ence evidence to support clinical choices. However, it should be noted that the primary studies concerning TMs frequently lack design requirements needed to provide good-level evi-dence according to criteria set for therapeutic intervention trials. Randomization and blinding methods are applied in only few studies where a TM is used as a predictive marker to select patients for a given therapy. The majority of stud-ies on TMs evaluate the diagnostic or prognostic information provided by the markers in a nonrandomized manner; in the case of determination of circulating tumor markers, which-ever the result may be, it has no immediate impact on clinical decision-making. As a result, panels preparing CPGs typically lack high-level evidence on TMs according to standard re-quirements for intervention trials; they frequently either do not produce recommendations, or opt for formulating nega-tive recommendations.
Nevertheless, in spite of either available negative recom-mendations or the absence of recommendations, TM overor-dering persists and tends to increase over time, demonstrat-ing the poor adherence of clinicians to CPGs. Many barriers may prevent clinicians from following guideline recommen-dations, including discrepancies between promising results of primary studies and the cautious position of CPGs, and the frequent poor consistency between recommendations pre-pared by different CPGs on the same clinical question.
Diagnostic randomized controlled trials are still infre-quently performed, and although the number of comparative diagnostic test accuracy studies is increasing, the vast majori-ty of the available evidence comes from single test evaluation studies. The latter studies do not measure patient-relevant outcomes directly, and cannot be equated to pharmacologi-cal clinical trials due to intrinsic differences in both design and endpoints. Although a framework of “linked evidence” has been in place for years, which strives to use evidence on true positive, true negative, false positive and false negative test results to deduct therapeutic and other patient-relevant consequences of testing, the application of this framework has been shown to be challenging (6). While awaiting the dis-
tillation of higher quality evidence into comprehensive guide-lines with possibly an application of the linked-evidence or related frameworks (7), efforts should be made to improve the adherence to existing guidelines.
Harmonization of different CPGs is a current strategy to handle uncertainties or discrepancies between different CPGs in settings where the clinical questions are complex, e.g., screening programs or disease prevention campaigns. Studies on the harmonization of recommendations for circu-lating cancer biomarkers have not been published so far.
The aim of the present research project is to develop a tool to summarize the recommendations and supplementary information on circulating TMs offered by available CPGs on solid tumors. The tool is intended to provide all possible evi-dence-based choices concerning TMs for people facing a clin-ical question in which the use of a TM could be contemplated.
Diligence was adopted to develop the tool according to a structured and rigorous methodology in order to guarantee the accurate extraction of relevant information including rec-ommendations from selected guidelines as well as the valid-ity of the synthesis of information from different sources.
Recommendations and supplementary information ex-tracted from CPGs were clustered and summarized applying 4 increasing levels of synthesis, summarizing and simplifying the information to make it explicit, verifiable, valid and re-producible. The first 2 levels of clustering and synthesis are available for consultation upon request. The last 2 levels of synthesis are reported in the present article. They are the Detailed Summary Tables and Take-Home Messages, which represent the levels of synthesis suitable for practical use. The Take-Home Messages are intended for use by health care providers in clinical practice with the goal of improving the appropriateness of TM use. The Detailed Summary Tables can be used by policy makers for potential adaptation to their own context and by educators to design teaching programs consistent with the available evidence.
The tabulation of the information has been structured by individual malignancies. Within each malignancy, we clus-tered the information according to a set of clinical questions established as being common to all malignancies. A parallel assessment of the quality of the included CPGs has been per-formed and the results are shown alongside the Take-Home Messages in order to inform the reader about the quality of the source (CPGs) from which the recommendations were distilled.
The purpose of this project was to provide an accurate and synthetic reproduction of the available evidence on the clinical use of circulating TMs. We endeavored to avoid any interpretation of the content of CPGs and used verbatim re-porting of the original sentences whenever possible.
Likewise, the expert panel intentionally avoided express-ing its own opinion in cases where different CPGs showed discrepant positions on a clinical question. Dissimilar recom-mendations of diverse CPGs may be due to different causes; in fact, CPG panels have to interpret the primary TM evidence in different local contexts with possibly dissimilar available resources or patient preferences. Our panel deemed that the complete presentation of clinical questions in which the consistency between guidelines seemed poor represents a
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strength of the present project for 2 reasons; firstly, it pro-vides an inventory of all possible recommendations after the application of evidence synthesis frameworks; secondly, it should help identify areas in which primary studies are es-pecially needed to answer clinical questions concerning TMs.
References1. Gion M, Peloso L, Trevisiol C, et al. An epidemiology-based mod-
el as a tool to monitor the outbreak of inappropriateness in tu-mor marker requests: a national scale study. Clin Chem Lab Med. 2016;54:473-482.
2. Franceschini R, Trevisiol C, Dittadi R, et al. Tumour markers re-questing pattern with regards to different organizational settings in Italy: a survey of hospital laboratories. Ann Clin Biochem. 2009;46:316-321.
3. Sood R, Sood A, Ghosh AK. Non-evidence-based variables affect-ing physicians’ test-ordering tendencies: a systematic review. Neth J Med. 2007;65:167-177.
4. Zhi M, Ding EL, Theisen-Toupal J, et al. The landscape of inap-propriate laboratory testing: a 15-year meta-analysis. PLoS One. 2013;8:e78962. doi: 10.1371/journal.pone.0078962
5. Moynihan R, Henry D, Moons KG. Using evidence to combat overdiagnosis and overtreatment: evaluating treatments, tests, and disease definitions in the time of too much. PLoS Med. 2014;11:e1001655. doi: 10.1371/journal. pmed.1001655.
6. Merlin T, Lehman S, Hiller JE, Ryan P. The "linked evidence ap-proach" to assess medical tests: a critical analysis. Int J Technol Assess Health Care. 2013;29:343-350.
7. Schünemann HJ, Mustafa R, Brozek J, et al; GRADE Working Group. GRADE Guidelines: 16. GRADE evidence to decision frameworks for tests in clinical practice and public health. J Clin Epidemiol. 2016;76:89-98.
Methodology
Scope
CPGs are critical for translating evidence to application in medical decision-making. Trustworthy guidelines are based on a systematic review of the clinical evidence (1, 2). The num-ber of CPGs has grown considerably and their quality is often heterogeneous. The objective of the project was to provide an easy-to-use but complete synthesis of TM recommendations distilled from evidence-based CPGs. The ultimate aim was to improve the appropriate use of TMs in clinical practice.
For the synthesis document to be useful it had to have the following characteristics:− to be developed with sound and structured methodology− to include all recommendations and information on circu-
lating biomarkers reported in CPGs on solid tumors− to synthesize recommendations and information in easy-to-
use tables at 2 decreasing levels of complexity− to be useful for the following target audience: (i) health care
providers, (ii) policy makers for potential adaptation to spe-cific settings, and (iii) staff developing educational material informed by available evidence.
Panel composition and project planning
The participating institutions and scientific societies sug-gested 74 delegates to be enrolled in the expert panel. The panel comprised a multidisciplinary group of medical oncolo-gists, radiation oncologists, clinical pathologists, general prac-titioners, internists, gynecologists, urologists, and experts in evidence-based methodology.
The project was organized in work packages (WPs) with dedicated tasks and milestones:WP1 – Definition of the primary objectives of the project and management strategiesWP2 – Search and selection of guidelinesWP3 – Appraisal of guidelines through the AGREE II toolWP4 – Assessment of the rate of utilization of a subset of guidance documents in clinical practiceWP5 – Synthesis into “Detailed Summary Tables” and “Take-Home Messages” regarding the recommended use of TMsWP6 – Assessment of the correctness and completeness of the information summarized in the summary tables by our expert panel (n=74)WP7 – External and independent verification of the correct-ness and completeness of the information summarized in the tables by an independent external committee (n=18).
WP1 was jointly managed by the Steering Committee and the Scientific Committee of the project. The activities of WPs 2 to 6 were carried out by working groups composed of mem-bers of the expert panel, in which oncologists and other cli-nicians, laboratory staff, methodologists and other research staff participated (see p. e364-e367). WP7 was realized by the members of the Interregional Biomarkers Working Group, in-stituted by the Health Commission of the Italian Permanent Conference for Relations between State, Regions and the Au-tonomous Provinces of Trento and Bolzano.
Search and selection process
We performed a systematic search for CPGs in the fol-lowing databases: PubMed, the National Guidelines Clear-inghouse and the GIN library. The search for guidance docu-ments included the following search terms, their synonyms, and associated MESH terms: "guideline OR recommendation OR consensus OR consensus development conference" AND "neoplasms OR carcinoma OR cancer OR tumor". We in-cluded guidance documents published from January 2009 to July 2015 in English or Italian. The search identified a total of 8,266 citations. In addition to searching bibliographic data-bases, we searched 11 websites of state or local government agencies and 61 websites of pertinent professional organiza-tions in Italy.
We used a standardized set of selection criteria to identify potentially relevant publications. The identified documents were assessed for pertinence according to shared criteria es-tablished by a selected group of 4 members of the expert panel to select guidelines that fit the objectives of the project.
Only documents containing recommendations for clinical practice were included. Reviews, technology assessments, commentaries to CPGs, and service documents were ex-
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cluded. The types of biomarker considered were circulating biomarkers measured in body fluids (blood derivatives of serum or plasma/urine) with commercially available assay methods. Fecal blood tests, laboratory tests aimed at moni-toring metabolism, organ damage and blood cell counts were not considered, as these do not present a direct relationship with the tumor. Circulating tumor cells, cell-free circulating DNA, and microRNA were also excluded from the assess-ment. Guidance papers limited to rare tumors, sarcomas, he-matological malignancies, the pediatric population, pregnant women, and specific aspects of specialized topics (i.e., imag-ing techniques, radiotherapy procedures, drug administra-tion modalities) were excluded. We did not consider health care procedures established by the Italian National Health Service at the national and regional level (i.e., hereditary tu-mors other than those of the ovary and thyroid), nor did we consider screening programs currently provided by the Italian National Health Service (i.e., screening for colorectal cancer, uterine cervix cancer and breast cancer), as the latter do not include circulating TMs. Details on the search strategy and se-lection criteria will be described in a dedicated report on the systematic review process (in preparation and available from the corresponding author of the present article).
Selection of CPGs was independently performed by 3 ex-aminers on the basis of the titles and abstracts of the 8,266 identified documents. A guidance document was considered potentially relevant when 2 of the 3 examiners opted for in-clusion. Documents included by a single examiner were dis-cussed until consensus for inclusion or exclusion was reached.
A total of 1,181 potentially relevant documents were se-lected, for which full-text reports were obtained. The result-ing set was then screened for inclusion and the included re-ports were grouped by guideline, allowing multiple reports on a single guideline. If several versions of a specific guideline were found, we included the most recently updated version.
We included a final set of 559 CPGs concerning 20 dif-ferent malignancies: carcinomas of the breast, biliary tract, colon-rectum, endometrium, esophagus, head and neck, kid-ney, liver, lung, stomach, ovary, pancreas, prostate, uterine cervix, urinary bladder, differentiated and medullary thyroid cancer, germ cell testicular cancer, melanoma, mesothelioma and neuroendocrine tumors.
Quality appraisal of guidelines
The selected guidance documents were further appraised to determine their adherence to the IOM standards, which require CPGs to be based on systematic reviews of existing evidence (1). The 559 guidance documents were clustered into 2 groups: 127 documents in which systematic reviews were essential to generate recommendations (CPGs) and 432 guidance documents without evidence of systematic review methodology (other guidance documents – OGDs). How-ever, authoritative institutions or medical societies typically produce guidance documents without applying systematic review methods. We also knew up front that these docu-ments are currently used by clinicians in their daily practice. The Steering Committee therefore decided to provide all guidance documents to the panel members with a request
to judge which of the OGDs were used by our target audi-ence. Whenever 25% or more of the panel members declared that a given guidance document was used in clinical practice, the guidance document was retained. In all, 111 of 432 OGDs qualified for inclusion.
The development process
The detailed process of document development was agreed upon by the Steering Committee and the Scientific Committee (report in preparation and available from the cor-responding author of the present article). The basic steps in the process are summarized below:– classifying the clinical questions (e.g., screening, diagnosis,
therapy)– choosing the biomarkers of interest– developing the specific queries on TM use within the clinical
questions – retrieving and tagging information concerning every clinical
question– data extraction from both types of guidance documents,
with quality assessment of CPGs and assessment of clinical use of OGDs
– clustering and synthesizing information at decreasing levels of complexity
– final write-up.
Classifying the clinical questionGiven that the role of TMs may differ widely in the dif-
ferent clinical phases of the disease, we decided to consider the clinical questions separately: (i) screening, (ii) differential diagnosis, (iii) preoperative workup, (iv) reassessment after curative treatment, (v) early detection of recurrence or pro-gression, and (ii) monitoring of treatment response in ad-vanced disease. Details of the considered clinical questions are reported elsewhere (in preparation and available from the corresponding author of the present article).
Developing specific queries within the clinical questions The information related to the following specific queries
were found in the selected guidance documents:1. Is the use of TM(s) explicitly recommended or not recom-
mended?2. Which TM(s) is/are recommended or not recommended?3. In which type of patients is/are TM(s) recommended or not
recommended?4. Can TM(s) be used autonomously or should they be used in
association with other tests?5. Are rules to interpret the result of TM determination pro-
vided?6. Do the TM results have an impact on treatment decisions
or, more broadly, on the clinical management of the pa-tient?
7. Is information on possible causes of false positive and false negative results provided?
8. Is information on preanalytical or analytical issues that can influence the reliability of the TM result provided?
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Retrieving and tagging information concerning every clinical question
For every malignancy, all information concerning TMs in the different clinical questions was identified in the selected guidance documents. For each guidance document, the rel-evant information was tagged, extracted (whenever possible as a verbatim transcription) and classified as follows:– Recommendation: part of text explicitly defined and clearly
recognizable as recommendation– Supplementary information: (i) implicit advice for clinical
practice not recognizable as explicit recommendation; (ii) additional information concerning the application and in-terpretation of TMs
– Supporting evidence: reporting and conclusions of the evi-dence used by the author team that developed the pub-lished guidance document to draw up recommendations.
All information extracted from guidance documents was clustered and synthesized in 4 rounds (levels) of increasing simplification as described elsewhere (report in preparation and available from the corresponding author of the present article) and briefly summarized below. – Level 1: The parts pertaining to TMs were retrieved from ev-
ery guidance document and transcribed verbatim, preserv-ing the textual structure – e.g., paragraph, complete clause – in which they were included, in a Master table (first-level tabulation)
– Level 2: Portions of text strictly referring to TMs were ex-tracted, clustered as recommendations and supplementary information, and transcribed verbatim in a table (second-level tabulation). Information from different guidelines was summarized separately
– Level 3: Similar recommendations and supplementary in-formation from different guidelines were summarized as a single entry, followed by the acronyms of the CPGs and/or ODGs formulating them (third-level tabulation: Detailed Summary Table)
– Level 4: Essential information to support decision-making in clinical practice was distilled and summarized in a further simplified table (fourth-level tabulation: Take-Home Mes-sage).
The present article reports the Detailed Summary Tables and Take-Home Messages, which represent the levels of syn-thesis suitable for practical use.
Managing information of CPGs and OGDsRecommendations provided by CPGs are displayed in
Detailed Summary Tables and Take-Home Messages. Recom-mendations from OGDs are embedded in both tables when-ever they were consistent with those of CPGs. Recommenda-tions reported exclusively by OGDs are not included in the Take-Home Messages, but are provided as supplementary information in the Detailed Summary Tables. CPGs and OGDs are labeled as such in all tables in order to allow the reader to track the source of the reported information.
WordingThe terms used to formulate recommendations were
found to be highly heterogeneous among the included guide-lines, reflecting (i) the variable quality of the supporting evi-dence, (ii) the different weight given to the trade-off between the benefits and harms of an intervention in different con-texts, and (iii) the uneven methodological rigor used to de-velop the guidance documents. In agreement with the scope of the project, the Scientific Committee settled on maintain-ing the original terms used by different CPGs, thus avoiding any attempt towards harmonization of the terms. When the same recommendation was provided by more than one CPG, the less stringent term (e.g., should rather than have to) was chosen in the synthesis.
Indications concerning TMs can be grouped into 3 catego-ries: positive recommendation (CPG recommends to use TM), negative recommendation (CPG recommends not to use the marker), and no explicit recommendation available. The third category (no explicit recommendation available) encompass-es different circumstances in relation to either the availabil-ity and quality of evidence or the assessment of benefit and harms, or both.
The following sentences were used in the synthesis to represent the different circumstances in which no recom-mendations were provided:1. Clinical question considered, but TMs not addressed: The
clinical question (screening, differential diagnosis, initial workup, etc.) is comprehensively considered by the CPG, but circulating TMs are not mentioned.
2. Clinical question considered, no explicit recommendations on TMs provided: TMs are mentioned and discussed with reference to the clinical question, but the panel that de-veloped the CPG deemed the available evidence or the as-sessment of benefit and harms, or both, not adequate to support a positive or negative recommendation.
3. Clinical question considered, but criteria to monitor treat-ment response (including TMs) not addressed: Response rates to different therapeutic regimens and survival ben-efits are the most frequently addressed topics by guidance documents in the clinical question “Monitoring of treat-ment response in advanced disease”. If the guidance docu-ment does not mention criteria to monitor the response, it cannot be assumed that a systematic search of the primary literature on TMs in this setting was performed. Therefore, a sentence different from the first one was used since it could not be appraised whether the clinical question had been comprehensively considered.
These 3 sentences are used in the Detailed Summary Ta-bles to provide comprehensive information on how different guidelines considered TMs in different clinical questions. In the Take-Home Messages a more general sentence indicating that there are no recommendations on TMs was preferred (Recommendations on TMs not available), given the practical purpose of this level of synthesis.
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Agreeing on the synthesis process and resultsThe process of synthesis was agreed upon within the Sci-
entific Committee. The Detailed Summary Tables and Take-Home Messages were submitted to the expert panel for eval-uation (internal evaluation) and approval of the synthesis, or for suggestions. Comments and suggestions were discussed and accepted when appropriate. The Detailed Summary Ta-bles and Take-Home Messages were then submitted to the members of the Interregional Biomarkers Working Group, in-stituted by the Health Commission of the Italian Permanent Conference for Relations between State, Regions and the Au-tonomous Provinces of Trento and Bolzano for external and independent verification of the correctness and complete-ness of the information summarized in the tables.
Assessment of CPGs with the AGREE II instrument
CPGs were assessed with the Appraisal of Guidelines for Research & Evaluation (AGREE II) tool, in order to facilitate comparison of the quality of the summarized CPGs on the basis of an objective, standardized method (3). The instru-ment comprises 23 key items organized into 6 domains. Each domain captures a distinct dimension of guideline quality: 1. Scope and purpose; 2. Stakeholder involvement; 3. Rigor of development; 4. Clarity of presentation; 5. Applicability; 6. Editorial independence. An AGREE quality score is calcu-lated for each of the 6 AGREE domains using a 7-point scoring system. A higher score indicates a better quality of the do-main. The 6 domain scores are independent and should not be combined into a single score.
Each CPG was rated by 2 evaluators independently. If the CPG addressed multiple diseases, the evaluators considered the documents as many times as the number of diseases ad-dressed. The evaluators achieved high interrater reliability. The scores of the 6 domains were subdivided into quartiles and marked in different colors for easier comprehension of the score (4).
References 1. IOM (Institute of Medicine). Clinical Practice Guidelines We Can
Trust. Washington, DC: The National Academies Press, 2011.2. Qaseem A, Forland F, Macbeth F, et al; Board of Trustees of the
Guidelines International Network. Guidelines International Net-work: toward international standards for clinical practice guide-lines. Ann Intern Med. 2012;156:525-531.
3. Brouwers M, Kho ME, Browman GP, et al; for the AGREE Next Steps Consortium. AGREE II: Advancing guideline develop-ment, reporting and evaluation in healthcare. Can Med Assoc J. 2010;182:E839-842.
4. http://www.snlg-iss.it/banca_dati_comparativa. (Accessed No-vember 24, 2016).
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AGREE evaluation
CPGs concerning every malignancy were also assessed with the Appraisal of Guidelines for Research & Evaluation (AGREE II) tool. A higher score equals a better quality of the domain. The results are reported after the Take-Home Message tables.
Additional notes
▪ Take-Home Messages are reported in alphabetical order.
▪ Information from OGDs on a specific clinical question were only reported in the Take-Home Messages if the clinical question was considered by CPGs. Descriptions regarding these OGDs can, however, be found in the Detailed Summary Tables.
▪ References concerning both CPGs and OGDs are reported after the Detailed Summary Tables, divided by type of malignancy and cited with the acronyms used in the Tables.
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AGREE evaluation
CPGs concerning every malignancy were also assessed with the Appraisal of Guidelines for Research & Evaluation (AGREE II) tool. A higher score equals a better quality of the domain. The results are reported after the Take-‐Home Message tables.
Acronym Domain 1 Scope and purpose
Domain 2 Stakeholder involvement
Domain 3 Rigor of development
Domain 4 Clarity of
presentation
Domain 5 Applicability
Domain 6 Editorial
independence
Acronyms of CPGs
Scores concerning the overall aim of the guideline, the specific health questions, and the target population are reported for every CPG
Scores concerning the extent to which the guideline was developed by the appropriate stakeholders and represents the views of its intended users are reported for every CPG
Scores concerning the process used to gather and synthesize the evidence, and the methods to formulate the recommendations and update them are reported for every CPG
Scores concerning the language, structure, and format of the guideline are reported for every CPG
Scores concerning the likely barriers and facilitators to implementation, strategies to improve uptake, and resource implications of applying the guideline are reported for every CPG
Scores concerning the formulation of recommendations not being unduly biased with competing interests are reported for every CPG
The scores of the 6 domains were subdivided into quartiles and marked in different colors as shown in the following table:
0-‐25th percentile 26th-‐50th percentile 51st-‐75th percentile
76th-‐100th percentile Additional notes − Take-‐Home Message tables are reported in alphabetical order − Information from OGDs on a specific clinical question were only reported in the Take-‐Home Message table if the clinical question was considered by CPGs. Descriptions regarding these OGDs
can, however, be found in the Detailed Summary Tables. − References concerning both GPGs and OGD are reported after the Detailed Summary Tables, divided by type of malignancy and cited with the acronyms used in the Tables
Take-home messages
Users' instructions
Definition and target audience
Take-Home Messages are presented in table format for every tumor type, summarizing essential information to support decision-making in clinical practice. They are intended for use by health care providers.
14
TAKE-‐HOME MESSAGES -‐ Users’ instructions
Definition and target audience Take-‐Home Messages are presented in table format for every tumor type, summarizing essential information to support decision-‐making in clinical practice. They are intended for use by health care providers. Structure
Total number of selected documents (number of CPGs, number of OGDs)
Clinical question
Summary of recommendations
Recommended tumor marker(s)
CPG/total CPG (CPG acronyms)
OGD/total OGD
(OGD acronyms)
The different clinical questions are reported
The symbol denotes that CPGs formulated inconsistent recommendations on TMs in the clinical question
Recommendations and information from CPGs that consider the clinical question are summarized
The sentence “Recommendations on TMs not available” is reported when the clinical question was considered by CPGs, but either TMs were not addressed or no explicit recommendations on TMs were provided
The recommended TM(s) are reported
When CPGs explicitly recommend against TM(s), the word “None” is reported
The symbol ∅ is shown when the examined CPGs either do not address TMs or, if TMs are addressed, CPGs do not formulate explicit recommendations
Number of CPGs reporting the summarized information in proportion to the total number of CPGs that consider the clinical question (acronyms of the CPGs in parenthesis)
Number of ODGs reporting the summarized information in proportion to the total number of CPGs that consider the clinical question (acronyms of the OGDs in parenthesis)
STRUCTURE
Total number of selected documents (number of CPGs, number of OGDs)
Gion et al e341
© 2016 Wichtig Publishing
16
Bilia
ry c
ance
r
Exam
ined
doc
umen
ts: 7
(2 C
PGs,
5 O
GD
s)
Clin
ical
que
stio
n Su
mm
ary
of re
com
men
datio
ns
Reco
mm
ende
d
tum
or m
arke
r(s)
CP
G/t
otal
CPG
(1)
(CPG
acr
onym
s)
OG
D/t
otal
OG
D (2
)
(OG
D a
cron
yms)
Scre
enin
g of
peo
ple
at
incr
ease
d ris
k ( s
cler
osin
g ch
olan
gitis
) Re
com
men
datio
ns o
n TM
s not
ava
ilabl
e
∅
1/1
(ACG
201
4)
1/2
(AAS
LD 2
010)
Diff
eren
tial d
iagn
osis
Re
com
men
datio
ns o
n TM
s not
ava
ilabl
e
∅
2/2
(ACG
201
4, N
ICE
2015
)
4/5
(AIR
O 2
012,
ESM
O 2
011,
N
CCN
201
5, S
IGE
2010
)
Preo
pera
tive
wor
kup
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
1/
1 (A
CG 2
014)
1/
3 (S
IGE
2010
)
Reas
sess
men
t aft
er in
itial
cu
rativ
e tr
eatm
ent
Clin
ical
que
stio
n no
t add
ress
ed b
y CP
Gs
-‐-‐-‐
-‐-‐-‐
-‐-‐-‐
Early
det
ectio
n of
re
curr
ence
or p
rogr
essi
on
Clin
ical
que
stio
n no
t add
ress
ed b
y CP
Gs
-‐-‐-‐
-‐-‐-‐
-‐-‐-‐
Mon
itorin
g of
trea
tmen
t re
spon
se in
adv
ance
d di
seas
e Cl
inic
al q
uest
ion
not a
ddre
ssed
by
CPG
s -‐-‐-‐
-‐-‐-‐
-‐-‐-‐
(1) C
PG/t
otal
CPG
: CPG
s rep
ortin
g th
e su
mm
arize
d in
form
atio
n/to
tal n
umbe
r of C
PGs t
hat c
onsid
er th
e cl
inic
al q
uest
ion.
(2
) OG
D/t
otal
OG
D: O
GDs
repo
rtin
g th
e su
mm
arize
d in
form
atio
n/to
tal n
umbe
r of O
GDs
that
con
sider
the
clin
ical
que
stio
n.
∅ T
he e
xam
ined
CPG
s th
at c
onsid
er th
e cl
inic
al q
uest
ion
eith
er d
o no
t add
ress
TM
s or,
if TM
s are
add
ress
ed, C
PGs d
o no
t pre
sent
exp
licit
reco
mm
enda
tions
. Ac
rony
ms
of C
PGs
Dom
ain
1 S c
ope
and
purp
ose
Dom
ain
2 St
akeh
olde
r in
volv
emen
t
Dom
ain
3 Ri
gor o
f de
velo
pmen
t
Dom
ain
4 Cl
arity
of
pres
enta
tion
Dom
ain
5 Ap
plic
abili
ty
Dom
ain
6 Ed
itoria
l in
depe
nden
ce
ACG
201
4 58
36
67
92
25
88
N
ICE
2015
93
88
96
93
72
81
BIL
IAR
Y C
AN
CER
Ta
ke-h
ome
mes
sage
Exam
ined
doc
umen
ts: 7
(2 C
PGs,
5 O
GD
s)
Circulating tumor markers: a guide to their appropriate clinical usee342
© 2016 Wichtig Publishing
17
Colo
rect
al c
ance
r
Exam
ined
doc
umen
ts: 1
9 (1
0 CP
Gs,
9 O
GD
s)
Clin
ical
que
stio
n
Sum
mar
y of
reco
mm
enda
tions
Reco
mm
ende
d tu
mor
mar
ker(
s)
CPG
/tot
al C
PG (1
) (C
PG a
cron
yms)
O
GD
/tot
al O
GD
(2)
(OG
D a
cron
yms)
Scre
enin
g of
peo
ple
at
incr
ease
d ris
k
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
4/4
(AG
A 20
10, N
ICE
2011
-‐SU
, SIG
N 2
011,
U
SMST
F 20
12)
3/3
(AIO
M 2
015,
ESM
O 2
013-‐
C,
NCC
N 2
015-‐
C)
Diff
eren
tial d
iagn
osis
Re
com
men
datio
ns o
n TM
s not
ava
ilabl
e ∅
5/
5 (A
SCRS
201
2-‐C,
CCO
201
4-‐CR
C,
NIC
E 20
14, N
ICE
2015
, SIG
N 2
011)
4/4
(AIO
M 2
015,
ESM
O 2
012-‐
CRC,
ES
MO
201
3-‐C,
ESM
O 2
013-‐
R)
Preo
pera
tive
wor
kup
CEA
shou
ld b
e as
sess
ed b
efor
e el
ectiv
e su
rger
y fo
r the
es
tabl
ishm
ent o
f bas
elin
e va
lues
CE
A ∅
3/6
(ASC
RS 2
012-‐
C, A
SCRS
201
3-‐R,
CC
O 2
014-‐
R)
7/7
(AIO
M 2
015,
EG
TM 2
013,
ESM
O 2
012-‐
CRC,
ESM
O 2
013-‐
C, E
SMO
201
3-‐R,
N
CCN
201
5-‐C,
NCC
N 2
015-‐
R)
At p
rese
nt th
ere
is in
suffi
cien
t evi
denc
e to
supp
ort t
he
rout
ine
use
of o
ther
TM
s suc
h as
CA1
9.9
in a
dditi
on to
CEA
2/
6 (A
SCRS
201
2-‐C,
ASC
RS 2
013-‐
R)
1/7
(AIO
M 2
015)
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
3/6
(AG
A 20
10, N
ICE
2014
, SIG
N 2
011)
0/
7
Reas
sess
men
t aft
er in
itial
cu
rativ
e tr
eatm
ent
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
1/1
(SIG
N 2
011)
2/
3 (E
SMO
201
3-‐C,
ESM
O 2
013-‐
R)
Early
det
ectio
n of
re
curr
ence
or p
rogr
essi
on
CEA
shou
ld b
e re
gula
rly a
sses
sed
at le
ast i
n th
e fir
st 3
-‐5
year
s dur
ing
follo
w-‐u
p to
mon
itor f
or si
gns o
f rec
urre
nce
CEA
4/4
(ASC
RS 2
012-‐
C, A
SCRS
201
3-‐R,
N
ICE
2014
, SIG
N 2
011)
7/8
(AIO
M 2
015,
ASC
O 2
013,
EG
TM 2
013,
ES
MO
201
2-‐CR
C, E
SMO
201
3-‐C,
N
CCN
201
5-‐C,
NCC
N 2
015-‐
R)
A co
nfirm
ed ri
se in
pos
tope
rativ
e CE
A le
vels
durin
g su
rvei
llanc
e sh
ould
pro
mpt
furt
her i
nves
tigat
ion
for
recu
rren
t dise
ase
2/4
(ASC
RS 2
012-‐
C, A
SCRS
201
3-‐R)
5/
8 (A
IOM
201
5, E
GTM
201
3, E
SMO
201
3-‐C,
N
CCN
201
5-‐C,
NCC
N 2
015-‐
R)
At p
rese
nt th
ere
is in
suffi
cien
t evi
denc
e to
supp
ort t
he
rout
ine
use
of o
ther
TM
s suc
h as
CA1
9.9
in a
dditi
on to
CEA
2/
4 (A
SCRS
201
2-‐C,
ASC
RS 2
013-‐
R)
1/8
(ESM
O 2
013-‐
C)
Mon
itorin
g of
trea
tmen
t re
spon
se in
adv
ance
d di
seas
e Re
com
men
datio
ns o
n TM
s not
ava
ilabl
e ∅
3/
3 (A
SCRS
201
2-‐C,
NIC
E 20
14, S
IGN
201
1)
3/7
(AIO
M 2
015,
ESM
O 2
012-‐
CRC,
ES
MO
201
3-‐R)
(1
) CPG
/tot
al C
PG: C
PGs r
epor
ting
the
sum
mar
ized
info
rmat
ion/
tota
l num
ber o
f CPG
s tha
t con
sider
the
clin
ical
que
stio
n.
(2) O
GD
/tot
al O
GD
: OG
Ds re
port
ing
the
sum
mar
ized
info
rmat
ion/
tota
l num
ber o
f OG
Ds th
at c
onsid
er th
e cl
inic
al q
uest
ion.
∅
The
exa
min
ed C
PGs
that
con
sider
the
clin
ical
que
stio
n ei
ther
do
not a
ddre
ss T
Ms o
r, if
TMs a
re a
ddre
ssed
, CPG
s do
not p
rese
nt e
xplic
it re
com
men
datio
ns.
COLO
REC
TAL
CA
NC
ER
Tak
e-ho
me
mes
sage
Exam
ined
doc
umen
ts: 1
9 (1
0 CP
Gs,
9 O
GD
s)
Gion et al e343
© 2016 Wichtig Publishing
18
Acro
nym
s of
CPG
s
Dom
ain
1 Sc
ope
and
purp
ose
Dom
ain
2 St
akeh
olde
r in
volv
emen
t
Dom
ain
3 Ri
gor o
f de
velo
pmen
t
Dom
ain
4 Cl
arity
of
pres
enta
tion
Dom
ain
5 Ap
plic
abili
ty
Dom
ain
6 Ed
itoria
l in
depe
nden
ce
AGA
2010
72
33
49
78
21
54
AS
CRS
2012
-‐C
58
33
67
83
25
33
ASCR
S 20
13-‐R
53
36
59
81
19
38
CC
O 2
014-‐
CRC
94
53
77
75
35
100
CCO
201
4-‐R
97
50
83
81
38
67
NIC
E 20
11-‐S
U
97
92
93
97
79
88
NIC
E 20
14
100
94
97
94
88
92
NIC
E 20
15
94
92
95
94
88
83
SIG
N 2
011
86
81
78
89
73
63
USM
STF
2012
67
36
67
69
19
50
COLO
REC
TAL
CA
NC
ER
Tak
e-ho
me
mes
sage
Exam
ined
doc
umen
ts: 1
9 (1
0 CP
Gs,
9 O
GD
s)
Circulating tumor markers: a guide to their appropriate clinical usee344
© 2016 Wichtig Publishing
19
Esop
hage
al c
ance
r
Ex
amin
ed d
ocum
ents
: 9 (5
CPG
s, 4
OG
Ds)
Clin
ical
que
stio
n
Sum
mar
y of
reco
mm
enda
tions
Reco
mm
ende
d
tum
or m
arke
r(s)
CP
G/t
otal
CPG
(1)
(CPG
acr
onym
s)
OG
D/t
otal
OG
D (2
)
(OG
D a
cron
yms)
Scre
enin
g of
peo
ple
at
incr
ease
d ris
k
(Bar
rett
's e
soph
agus
) Re
com
men
datio
ns o
n TM
s not
ava
ilabl
e
∅
3/3
(AHS
201
4, m
ep 2
012,
N
HMRC
201
4)
0/0
Diff
eren
tial d
iagn
osis
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
5/5
(AHS
201
4, m
ep 2
012,
N
HMRC
201
4, N
ICE
2015
, ST
S 20
13)
3/3
(AIO
M 2
015,
ESM
O 2
013,
N
CCN
201
5)
Preo
pera
tive
wor
kup
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
3/
3 (A
HS 2
014,
NHM
RC 2
014,
ST
S 20
13)
4/4
(AIO
M 2
015,
AIR
O 2
012,
ES
MO
201
3, N
CCN
201
5)
Reas
sess
men
t aft
er in
itial
cu
rativ
e tr
eatm
ent
Clin
ical
que
stio
n no
t add
ress
ed b
y CP
Gs
-‐-‐-‐
-‐-‐-‐
-‐-‐-‐
Early
det
ectio
n of
re
curr
ence
or p
rogr
essi
on
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
1/1
(AHS
201
4)
4/4
(AIO
M 2
015,
AIR
O 2
012,
ES
MO
201
3, N
CCN
201
5)
Mon
itorin
g of
trea
tmen
t re
spon
se in
adv
ance
d di
seas
e Re
com
men
datio
ns o
n TM
s not
ava
ilabl
e ∅
1/
1 (S
TS 2
013)
4/
4 (A
IOM
201
5, A
IRO
201
2,
ESM
O 2
013,
NCC
N 2
015)
(1) C
PG/t
otal
CPG
: CPG
s rep
ortin
g th
e su
mm
arize
d in
form
atio
n/to
tal n
umbe
r of C
PGs t
hat c
onsid
er th
e cl
inic
al q
uest
ion.
(2
) OG
D/t
otal
OG
D: O
GDs
repo
rtin
g th
e su
mm
arize
d in
form
atio
n/to
tal n
umbe
r of O
GDs
that
con
sider
the
clin
ical
que
stio
n.
∅ T
he e
xam
ined
CPG
s th
at c
onsid
er th
e cl
inic
al q
uest
ion
eith
er d
o no
t add
ress
TM
s or,
if TM
s are
add
ress
ed, C
PGs d
o no
t pre
sent
exp
licit
reco
mm
enda
tions
. Ac
rony
ms
of C
PGs
Dom
ain
1 S c
ope
and
purp
ose
Dom
ain
2 St
akeh
olde
r in
volv
emen
t
Dom
ain
3 Ri
gor o
f de
velo
pmen
t
Dom
ain
4 Cl
arity
of
pres
enta
tion
Dom
ain
5 Ap
plic
abili
ty
Dom
ain
6 Ed
itoria
l in
depe
nden
ce
AHS
2014
92
44
68
67
58
79
m
ep 2
012
72
67
65
75
33
67
NH
MRC
201
4 83
67
68
81
44
75
N
ICE
2015
89
97
90
92
73
79
ST
S 20
13
58
44
69
69
25
50
ESO
PHA
GEA
L C
AN
CER
Ta
ke-h
ome
mes
sage
Exam
ined
doc
umen
ts: 9
(5 C
PGs,
4 O
GD
s)
Gion et al e345
© 2016 Wichtig Publishing
20
Gas
tric
can
cer
Ex
amin
ed d
ocum
ents
: 8 (3
CPG
s, 5
OG
Ds)
Clin
ical
que
stio
n
Sum
mar
y of
reco
mm
enda
tions
Reco
mm
ende
d tu
mor
mar
ker(
s)
CPG
/tot
al C
PG (1
) (C
PG a
cron
yms)
O
GD
/tot
al O
GD
(2)
(OG
D a
cron
yms)
Scre
enin
g of
peo
ple
at
incr
ease
d ris
k
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
1/
1 (A
CCC
2009
) 1/
1 (N
CCN
201
5)
Diff
eren
tial d
iagn
osis
Re
com
men
datio
ns o
n TM
s not
ava
ilabl
e
∅
1/1
(NIC
E 20
15)
2/2
(AIO
M 2
015,
ESM
O 2
013)
Preo
pera
tive
wor
kup
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
1/
1 (A
CCC
2009
) 4/
5 (A
IOM
201
5, E
GTM
201
3,
ESM
O 2
013,
NCC
N 2
015)
Reas
sess
men
t aft
er in
itial
cu
rativ
e tr
eatm
ent
Clin
ical
que
stio
n no
t add
ress
ed b
y CP
Gs
-‐-‐-‐
-‐-‐-‐
-‐-‐-‐
Early
det
ectio
n of
re
curr
ence
or p
rogr
essi
on
Dete
rmin
ing
TMs f
or th
e fo
llow
-‐up
of p
atie
nts o
pera
ted
on fo
r gas
tric
ca
rcin
oma
is no
t wor
thw
hile
bec
ause
it d
oes n
ot le
ad to
clin
ical
ben
efit
N
one
1/1
(ACC
C 20
09)
0/4
Mon
itorin
g of
trea
tmen
t re
spon
se in
adv
ance
d di
seas
e Re
com
men
datio
ns o
n TM
s not
ava
ilabl
e ∅
2/2
(ACC
C 20
09, C
CO 2
014)
4/
4 (A
IOM
201
5, A
IRO
201
2,
ESM
O 2
013,
NCC
N 2
015)
(1
) CPG
/tot
al C
PG: C
PGs r
epor
ting
the
sum
mar
ized
info
rmat
ion/
tota
l num
ber o
f CPG
s tha
t con
sider
the
clin
ical
que
stio
n.
(2) O
GD
/tot
al O
GD
: OG
Ds re
port
ing
the
sum
mar
ized
info
rmat
ion/
tota
l num
ber o
f OG
Ds th
at c
onsid
er th
e cl
inic
al q
uest
ion.
∅
The
exa
min
ed C
PGs
that
con
sider
the
clin
ical
que
stio
n ei
ther
do
not a
ddre
ss T
Ms o
r, if
TMs a
re a
ddre
ssed
, CPG
s do
not p
rese
nt e
xplic
it re
com
men
datio
ns.
Acro
nym
s of
CPG
s
Dom
ain
1 S c
ope
and
purp
ose
Dom
ain
2 St
akeh
olde
r in
volv
emen
t
Dom
ain
3 Ri
gor o
f de
velo
pmen
t
Dom
ain
4 Cl
arity
of
pres
enta
tion
Dom
ain
5 Ap
plic
abili
ty
Dom
ain
6 Ed
itoria
l in
depe
nden
ce
ACCC
200
9 83
61
71
75
33
50
CC
O 2
014
83
56
81
75
42
71
NIC
E 20
15
89
97
91
89
71
83
GA
STR
IC C
AN
CER
Ta
ke-h
ome
mes
sage
Exam
ined
doc
umen
ts: 8
(3 C
PGs,
5 O
GD
s)
Circulating tumor markers: a guide to their appropriate clinical usee346
© 2016 Wichtig Publishing
21
Hep
atoc
ellu
lar c
arci
nom
a (H
CC)
Exam
ined
doc
umen
ts: 1
2 (6
CPG
s, 6
OG
Ds)
Clin
ical
que
stio
n
Sum
mar
y of
reco
mm
enda
tions
Reco
mm
ende
d tu
mor
mar
ker(
s)
CPG
/tot
al C
PG (1
) (C
PG a
cron
yms)
O
GD
/tot
al O
GD
(2)
(OG
D a
cron
yms)
Scre
enin
g of
peo
ple
at
incr
ease
d ris
k
Surv
eilla
nce
of p
atie
nts i
n th
e hi
gh-‐r
isk g
roup
is b
ased
on
perio
dic
ultr
ason
ogra
phy
com
bine
d w
ith m
easu
rem
ent o
f AFP
AFP ∅
2/3
(JSH
2013
, NIC
E 20
13-‐H
BV)
1/6
(NCC
N 2
015)
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
1/3
(MCC
201
1)
1/6
(ESM
O 2
012)
Supp
lem
enta
ry in
form
atio
n: S
cree
ning
for H
CC sh
ould
use
ul
tras
onog
raph
y al
one.
AFP
(and
oth
er T
Ms)
not
indi
cate
d fo
r su
rvei
llanc
e st
rate
gy b
ecau
se o
f low
sens
itivi
ty (l
ower
than
ul
tras
onog
raph
y) a
nd lo
w sp
ecifi
city
1/3
(MCC
201
1)
5/6
(AIO
M 2
015,
AIR
O 2
012,
AI
SF 2
013,
EAS
L-‐EO
RTC
2012
, ES
MO
201
2)
Diff
eren
tial d
iagn
osis
R eco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
4/4
(ACG
201
4-‐FL
L, JS
H 20
13,
MCC
201
1, N
ICE
2015
)
3/6
(AIO
M 2
015,
AIR
O 2
012,
EA
SL-‐E
ORT
C 20
12)
Supp
lem
enta
ry in
form
atio
n n.
1: T
he d
iagn
ostic
wor
kup
of a
pat
ient
w
ith su
spec
ted
HCC
incl
udes
seru
m A
FP m
easu
rem
ent
1/4
(ACG
201
4-‐FL
L)
2/6
(AIO
M 2
015,
ESM
O 2
012)
Supp
lem
enta
ry in
form
atio
n n.
2: N
o pr
imar
y ca
re e
vide
nce
was
id
entif
ied
pert
aini
ng to
the
diag
nost
ic a
ccur
acy
of A
FP in
pat
ient
s with
su
spec
ted
liver
can
cer w
here
the
clin
ical
resp
onsib
ility
was
reta
ined
by
prim
ary
care
1/4
(NIC
E 20
15)
0/6
Preo
pera
tive
wor
kup
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
2/2
(JSH
2013
, MCC
201
1)
3/6
(AIR
O 2
012,
EAS
L-‐EO
RTC
2012
, ES
MO
201
2)
Live
r tra
nspl
ant p
riorit
y an
d de
listin
g po
licie
s Pe
riodi
c w
aitin
g-‐lis
t mon
itorin
g sh
ould
be
perf
orm
ed b
y im
agin
g an
d AF
P m
easu
rem
ent
AFP ∅
1/3
(OLT
4HCG
201
2)
2/4
(AIS
F 20
13, E
ASL-‐
EORT
C 20
12)
Incr
ease
d AF
P le
vels
and/
or c
hang
es in
seru
m A
FP o
ver t
ime
may
pr
edic
t the
risk
of d
ropo
ut fr
om li
ver t
rans
plan
t wai
ting
list
1/3
(OLT
4HCG
201
2)
2/4
(AIS
F 20
13, E
ASL-‐
EORT
C 20
12)
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
2/3
(JSH
2013
, MCC
201
1)
2/4
(AIO
M 2
015,
NCC
N 2
015)
Reas
sess
men
t aft
er in
itial
cu
rativ
e tr
eatm
ent
Clin
ical
que
stio
n no
t add
ress
ed b
y CP
Gs
-‐-‐-‐
-‐-‐-‐
-‐-‐-‐
Early
det
ectio
n of
re
curr
ence
or p
rogr
essi
on
Mon
itorin
g af
ter l
iver
tran
spla
nt a
nd p
allia
tive
trea
tmen
ts m
ay in
clud
e pe
riodi
c AF
P m
easu
rem
ents
AF
P 1/
1 (O
LT4H
CG 2
012)
3/
5 (A
ISF
2013
, ESM
O 2
012,
N
CCN
201
5)
HEP
ATO
CEL
LULA
R C
AR
CIN
OM
A (H
CC)
Take
-hom
e m
essa
ge
Exam
ined
doc
umen
ts: 1
2 (6
CPG
s, 6
OG
Ds)
to b
e co
ntinu
ed
Gion et al e347
© 2016 Wichtig Publishing
22
Clin
ical
que
stio
n
Sum
mar
y of
reco
mm
enda
tions
Reco
mm
ende
d tu
mor
mar
ker(
s)
CPG
/tot
al C
PG (1
) (C
PG a
cron
yms)
O
GD
/tot
al O
GD
(2)
(OG
D a
cron
yms)
Mon
itorin
g of
trea
tmen
t re
spon
se in
adv
ance
d
dise
ase
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
2/2
(JSH
2013
, MCC
201
1)
5/6
(AIO
M 2
015,
AIR
O 2
012,
AI
SF 2
013,
EAS
L-‐EO
RTC
2012
, N
CCN
201
5)
(1) C
PG/t
otal
CPG
: CPG
s rep
ortin
g th
e su
mm
ariz
ed in
form
atio
n/to
tal n
umbe
r of C
PGs t
hat c
onsid
er th
e cl
inic
al q
uest
ion.
(2
) OG
D/t
otal
OG
D: O
GDs
repo
rtin
g th
e su
mm
ariz
ed in
form
atio
n/to
tal n
umbe
r of O
GDs
that
con
sider
the
clin
ical
que
stio
n.
∅ T
he e
xam
ined
CPG
s th
at c
onsid
er th
e cl
inic
al q
uest
ion
eith
er d
o no
t add
ress
TM
s or,
if TM
s are
add
ress
ed, C
PGs d
o no
t pre
sent
exp
licit
reco
mm
enda
tions
.
Inco
nsist
ent r
ecom
men
datio
ns o
n TM
s in
the
clin
ical
que
stio
n ar
e re
port
ed b
y di
ffere
nt C
PGs.
Ac
rony
ms
of C
PGs
Dom
ain
1 Sc
ope
and
purp
ose
Dom
ain
2 St
akeh
olde
r in
volv
emen
t
Dom
ain
3 Ri
gor o
f de
velo
pmen
t
Dom
ain
4 Cl
arity
of
pres
enta
tion
Dom
ain
5 Ap
plic
abili
ty
Dom
ain
6 Ed
itoria
l in
depe
nden
ce
ACG
201
4-‐FL
L 58
42
70
89
33
88
JS
H 2
013
75
44
60
81
40
29
MCC
201
1 56
44
63
72
33
58
N
ICE
2013
-‐HBV
94
89
97
97
81
88
N
ICE
2015
89
97
91
86
73
83
O
LT4H
CG 2
012
56
61
68
75
31
50
HEP
ATO
CEL
LULA
R C
AR
CIN
OM
A (H
CC)
Take
-hom
e m
essa
ge
Exam
ined
doc
umen
ts: 1
2 (6
CPG
s, 6
OG
Ds)
Circulating tumor markers: a guide to their appropriate clinical usee348
© 2016 Wichtig Publishing
23
Panc
reat
ic c
ance
r
Exam
ined
doc
umen
ts: 7
(4 C
PGs,
3 O
GD
s)
Clin
ical
que
stio
n
Sum
mar
y of
reco
mm
enda
tions
Reco
mm
ende
d tu
mor
mar
ker(
s)
CPG
/tot
al C
PG (1
) (C
PG a
cron
yms)
O
GD
/tot
al O
GD
(2)
(OG
D a
cron
yms)
Scre
enin
g
Clin
ical
que
stio
n no
t add
ress
ed b
y CP
Gs
-‐-‐-‐
-‐-‐-‐
-‐-‐-‐
Diff
eren
tial d
iagn
osis
Re
com
men
datio
ns o
n TM
s not
ava
ilabl
e
∅
2/2
(ISG
PS 2
014-‐
A, N
ICE
2015
) 3/
3 (A
IOM
201
5, E
SMO
201
2,
NCC
N 2
015)
Supp
lem
enta
ry in
form
atio
n: C
A 19
.9 m
ay b
e fa
lsel
y po
sitiv
e in
ca
ses o
f bili
ary
obst
ruct
ion
(reg
ardl
ess o
f etio
logy
) and
in
case
s of i
nfec
tion
or in
flam
mat
ion
of th
e bi
liary
trac
t (N
CCN
201
5)
1/2
(ISG
PS 2
014-‐
A)
3/3
(AIO
M 2
015,
ESM
O 2
012,
N
CCN
201
5)
Preo
pera
tive
wor
kup
CA19
.9 m
ay b
e in
clud
ed in
stan
dard
pre
oper
ativ
e di
agno
stic
s fo
r pat
ient
s with
borderline re
sectab
le pan
creatic can
cer
CA19
.9
∅
1/3
(ISG
PS 2
014-‐
B)
0/3
Supp
lem
enta
ry in
form
atio
n: E
leva
ted
preo
pera
tive
CA19
.9
may
hav
e ne
gativ
e pr
ogno
stic
val
ue
2/3
(ISG
PS 2
014-‐
B, S
3 20
14)
3/3
(AIO
M 2
015,
ESM
O 2
012,
N
CCN
201
5)
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
2/
3 (IS
GPS
201
4-‐A,
S3
2014
) 1/
3 (E
SMO
201
2)
Reas
sess
men
t aft
er in
itial
cu
rativ
e tr
eatm
ent
Clin
ical
que
stio
n no
t add
ress
ed b
y CP
Gs
-‐-‐-‐
-‐-‐-‐
-‐-‐-‐
Early
det
ectio
n of
re
curr
ence
or p
rogr
essi
on
Clin
ical
que
stio
n no
t add
ress
ed b
y CP
Gs
-‐-‐-‐
-‐-‐-‐
-‐-‐-‐
Mon
itorin
g of
trea
tmen
t re
spon
se in
adv
ance
d
dise
ase
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
1/
1 (S
3 20
14)
2/3
(ESM
O 2
012,
NCC
N 2
015)
(1) C
PG/t
otal
CPG
: CPG
s rep
ortin
g th
e su
mm
ariz
ed in
form
atio
n/to
tal n
umbe
r of C
PGs t
hat c
onsid
er th
e cl
inic
al q
uest
ion.
(2
) OG
D/t
otal
OG
D: O
GDs
repo
rtin
g th
e su
mm
ariz
ed in
form
atio
n/to
tal n
umbe
r of O
GDs
that
con
sider
the
clin
ical
que
stio
n.
∅ T
he e
xam
ined
CPG
s th
at c
onsid
er th
e cl
inic
al q
uest
ion
eith
er d
o no
t add
ress
TM
s or,
if TM
s are
add
ress
ed, C
PGs d
o no
t pre
sent
exp
licit
reco
mm
enda
tions
. PA
NC
REA
TIC
CA
NC
ER
Ta
ke-h
ome
mes
sage
Exam
ined
doc
umen
ts: 7
(4 C
PGs,
3 O
GD
s)
24
Acro
nym
s of
CPG
s
Dom
ain
1 Sc
ope
and
purp
ose
Dom
ain
2 St
akeh
olde
r in
volv
emen
t
Dom
ain
3 Ri
gor o
f de
velo
pmen
t
Dom
ain
4 Cl
arity
of
pres
enta
tion
Dom
ain
5 Ap
plic
abili
ty
Dom
ain
6 Ed
itoria
l in
depe
nden
ce
ISG
PS 2
014-‐
A 81
44
58
67
27
42
IS
GPS
201
4-‐B
81
44
59
67
27
42
NIC
E 20
15
89
97
91
89
73
88
S3 2
014
58
44
60
69
27
63
Gion et al e349
© 2016 Wichtig Publishing
24
Acro
nym
s of
CPG
s
Dom
ain
1 Sc
ope
and
purp
ose
Dom
ain
2 St
akeh
olde
r in
volv
emen
t
Dom
ain
3 Ri
gor o
f de
velo
pmen
t
Dom
ain
4 Cl
arity
of
pres
enta
tion
Dom
ain
5 Ap
plic
abili
ty
Dom
ain
6 Ed
itoria
l in
depe
nden
ce
ISG
PS 2
014-‐
A 81
44
58
67
27
42
IS
GPS
201
4-‐B
81
44
59
67
27
42
NIC
E 20
15
89
97
91
89
73
88
S3 2
014
58
44
60
69
27
63
26
DETAILED SUMMARY TABLES -‐ Users’ instructions
Definition and target audience Detailed Summary Tables are tables prepared for every tumor type which report recommendations and supplementary information from different guidance documents with enough details to be useful for health care providers, policy makers (for potential adaptation to specific settings) and staff developing educational material informed by available evidence. Structure
Total number of selected documents (number of CPGs, number of OGDs)
Clinical question
CPG
OGD
Summary of recommendations
Supplementary information
The different clinical questions are reported
Number of CPGs addressing the clinical question
Number of OGDs addressing the clinical question
Recommendations from CPGs and from OGDs that are consistent with those of CPGs Only those parts of the text explicitly defined as recommendations and clearly recognizable as such were considered Similar recommendations and supplementary information from different guidance documents are reported once, followed by the acronyms of the guidance documents by which they are provided Acronyms of CPGs are printed in bold blue type, those of OGDs are printed in regular type
Useful supplementary information for the clinical application of TMs from both CPGs and OGDs are summarized (e.g., suggested cutoff points, timing of serial sample monitoring, causes of false positive or false negative TM results) Recommendations from OGDs that are inconsistent with those of CPGs are reported Advice for clinical practice not declared or not recognizable as recommendation in the document is reported Acronyms of CPGs are printed in bold blue type, those of OGDs are printed in regular type
Detailed summary tables
Users' instructions
Definition and target audience
Take-Home Messages are presented in table format for every tumor type, summarizing essential information to support decision-making in clinical practice. They are intended for use by health care providers.
STRUCTURE
Total number of selected documents (number of CPGs, number of OGDs)
Circulating tumor markers: a guide to their appropriate clinical usee350
© 2016 Wichtig Publishing
27
Bilia
ry c
ance
r
Exam
ined
doc
umen
ts: 7
(2 C
PGs,
5 O
GD
s)
Clin
ical
que
stio
n CP
G
OG
D
Sum
mar
y of
reco
mm
enda
tions
(1)
Supp
lem
enta
ry in
form
atio
n (2
)
Scre
enin
g of
peo
ple
at
incr
ease
d ris
k
1 2
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed
(ACG
201
4)
The
curr
ent e
vide
nce
does
not
supp
ort r
outin
e sc
reen
ing
for c
hola
ngio
carc
inom
a in
as
ympt
omat
ic p
atie
nts w
ith u
nder
lyin
g pr
imar
y sc
lero
sing
chol
angi
tis (A
CG 2
014,
AAS
LD 2
010,
SI
GE
2010
)
Patie
nts w
ith p
rimar
y sc
lero
sing
chol
angi
tis sh
ould
und
ergo
car
eful
surv
eilla
nce
for
chol
angi
ocar
cino
ma
deve
lopm
ent m
ainl
y du
ring
the
first
2 y
ears
of f
ollo
w-‐u
p (S
IGE
2010
)
Surv
eilla
nce
with
CA1
9.9
and
one
imag
ing
tech
niqu
e (C
T or
MRI
) is a
t pre
sent
the
sugg
este
d ap
proa
ch (S
IGE
2010
)
No
stud
y ha
s dem
onst
rate
d an
y va
lue
for t
he se
rum
CA1
9.9
test
as a
scre
enin
g m
odal
ity in
as
ympt
omat
ic p
rimar
y sc
lero
sing
chol
angi
tis (A
ASLD
201
0, S
IGE
2010
)
Diff
eren
tial d
iagn
osis
2
5 Cl
inic
al q
uest
ion
cons
ider
ed, n
o ex
plic
it re
com
men
datio
ns o
n TM
s pro
vide
d (A
CG 2
014,
NIC
E 20
15,
AIRO
201
2, N
CCN
201
5, S
IGE
2010
)
CA19
.9 is
a se
rum
mar
ker t
hat c
an b
e m
easu
red
to id
entif
y ca
ses w
ith in
trah
epat
ic
chol
angi
ocar
cino
ma
in p
atie
nts w
ith fo
cal l
iver
lesio
ns, b
ut it
has
low
spec
ifici
ty a
nd
sens
itivi
ty (A
CG 2
014,
AAS
LD 2
010,
AIR
O 2
012,
SIG
E 20
10)
No
prim
ary
care
evi
denc
e w
as id
entif
ied
pert
aini
ng to
the
diag
nost
ic a
ccur
acy
of …
CA1
9.9
in
patie
nts w
ith su
spec
ted
gallb
ladd
er c
ance
r whe
re th
e cl
inic
al re
spon
sibili
ty w
as re
tain
ed b
y pr
imar
y ca
re (N
ICE
2015
)
CA19
.9 c
an b
e el
evat
ed in
pat
ient
s with
dise
ases
oth
er th
an b
iliar
y ca
ncer
(AAS
LD 2
010,
AI
RO 2
012,
NCC
N 2
015)
: -‐ o
ther
mal
igna
ncie
s (e.
g., g
astr
ic o
r pan
crea
tic c
ance
r)
-‐ ben
ign
cond
ition
s (ba
cter
ial c
hola
ngiti
s, c
hole
stat
ic ja
undi
ce, g
allb
ladd
er li
thia
sis)
Patie
nts n
egat
ive
for t
he L
ewis
antig
en w
ill n
ot h
ave
an e
leva
ted
seru
m C
A19.
9 le
vel d
espi
te
havi
ng c
hola
ngio
carc
inom
a (A
ASLD
201
0)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (E
SMO
201
1)
Preo
pera
tive
wor
kup
1 3
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed
(ACG
201
4)
CEA
and
CA19
.9 c
ould
be
cons
ider
ed a
s par
t of t
he in
itial
wor
kup
(in c
onju
nctio
n w
ith
imag
ing
stud
ies)
(AIR
O 2
012,
NCC
N 2
015)
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs p
rovi
ded
(SIG
E 20
10)
Reas
sess
men
t aft
er in
itial
cu
rativ
e tr
eatm
ent
0 1
Clin
ical
que
stio
n no
t add
ress
ed b
y CP
Gs
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (E
SMO
201
1)
Early
det
ectio
n of
re
curr
ence
or p
rogr
essi
on
0 3
Clin
ical
que
stio
n no
t add
ress
ed b
y CP
Gs
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs p
rovi
ded
(AIR
O 2
012,
N
CCN
201
5)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (E
SMO
201
1)
BIL
IAR
Y C
AN
CER
D
etai
led
sum
mar
y ta
bles
Exam
ined
doc
umen
ts: 7
(2 C
PGs,
5 O
GD
s)
to b
e co
ntinu
ed
Gion et al e351
© 2016 Wichtig Publishing
28
Clin
ical
que
stio
n CP
G
OG
D
Sum
mar
y of
reco
mm
enda
tions
(1)
Supp
lem
enta
ry in
form
atio
n (2
)
Mon
itorin
g of
trea
tmen
t re
spon
se in
adv
ance
d di
seas
e
0 3
Clin
ical
que
stio
n no
t add
ress
ed b
y CP
Gs
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (E
SMO
201
1)
In th
e ev
ent o
f dise
ase
rela
pse
or p
rogr
essio
n CE
A an
d CA
19.9
cou
ld b
e co
nsid
ered
as p
art o
f th
e in
itial
wor
kup
… in
con
junc
tion
with
imag
ing
stud
ies (
NCC
N 2
015)
CA19
.9 te
stin
g ca
n be
con
sider
ed a
fter
bili
ary
deco
mpr
essio
n (N
CCN
201
5)
Clin
ical
que
stio
n co
nsid
ered
, but
crit
eria
to m
onito
r tre
atm
ent r
espo
nse
(incl
udin
g TM
s) n
ot
addr
esse
d (S
IGE
2010
) (1
) Reco
mm
enda
tions
from
CPG
s and
from
OG
Ds,
if c
onsis
tent
with
thos
e of
CPG
s.
(2) Su
pple
men
tary
info
rmat
ion
from
bot
h CP
Gs
and
OG
Ds,
and
reco
mm
enda
tions
from
OG
Ds
that
are
inco
nsist
ent w
ith th
ose
of C
PGs.
BIL
IAR
Y C
AN
CER
D
etai
led
sum
mar
y ta
bles
Exam
ined
doc
umen
ts: 7
(2 C
PGs,
5 O
GD
s)
Circulating tumor markers: a guide to their appropriate clinical usee352
© 2016 Wichtig Publishing
29
Colo
rect
al c
ance
r
Exam
ined
doc
umen
ts: 1
9 (1
0 CP
Gs,
9 O
GD
s)
Clin
ical
que
stio
n CP
G
OG
D
Sum
mar
y of
reco
mm
enda
tions
(1)
Supp
lem
enta
ry in
form
atio
n (2
)
Scre
enin
g of
peo
ple
at
incr
ease
d ris
k
4 3
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (A
GA
2010
, N
ICE
2011
-‐SU
, SIG
N 2
011,
USM
STF
2012
, AIO
M 2
015,
ESM
O 2
013-‐
C,
NCC
N 2
015-‐
C)
Diff
eren
tial d
iagn
osis
5
4 Cl
inic
al q
uest
ion
cons
ider
ed, b
ut T
Ms n
ot a
ddre
ssed
(A
SCRS
201
2-‐C,
CCO
201
4-‐CR
C, N
ICE
2014
, NIC
E 20
15, S
IGN
201
1,
AIO
M 2
015,
ESM
O 2
012-‐
CRC,
ESM
O 2
013-‐
R)
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs p
rovi
ded
(ESM
O 2
012-‐
C)
CEA
has l
ow p
redi
ctiv
e va
lue
for d
iagn
osis
in a
sym
ptom
atic
pat
ient
s due
to it
s re
lativ
ely
low
sens
itivi
ty a
nd sp
ecifi
city
(ESM
O 2
013-‐
C)
Preo
pera
tive
wor
kup
6 7
CEA
shou
ld b
e as
sess
ed b
efor
e el
ectiv
e su
rger
y fo
r the
es
tabl
ishm
ent o
f bas
elin
e va
lues
(ASC
RS 2
012-‐
C, A
SCRS
201
3-‐R,
CC
O 2
014-‐
R, A
IOM
201
5, E
GTM
201
3, E
SMO
201
2-‐CR
C, E
SMO
201
3-‐C,
ESM
O 2
013-‐
R, N
CCN
201
5-‐C,
NCC
N 2
015-‐
R)
At p
rese
nt th
ere
is in
suffi
cien
t evi
denc
e to
supp
ort t
he ro
utin
e us
e of
oth
er T
Ms s
uch
as C
A19.
9 (A
SCRS
201
2-‐C,
ASC
RS 2
013-‐
R,
AIO
M 2
015)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed
(AG
A 20
10, N
ICE
2014
, SIG
N 2
011)
Incr
ease
d le
vels
of C
EA h
ave
been
cor
rela
ted
with
poo
rer p
rogn
osis
(ASC
RS 2
012-‐
C, A
SCRS
201
3-‐R,
AIO
M 2
015,
EG
TM 2
013,
ESM
O 2
013-‐
C)
Data
are
insu
ffici
ent t
o ju
stify
the
use
of a
hig
h pr
eope
rativ
e CE
A le
vel a
s an
indi
catio
n fo
r adj
uvan
t th e
rapy
(ASC
RS 2
012-‐
C, A
SCRS
201
3-‐R,
AIO
M 2
015,
EG
TM 2
013)
Reas
sess
men
t aft
er in
itial
cu
rativ
e tr
eatm
ent
1 3
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed
(SIG
N 2
011,
ESM
O 2
013-‐
R)
An in
crea
sed
preo
pera
tive
valu
e no
t nor
mal
ized
aft
er 1
mon
th fo
llow
ing
surg
ical
re
sect
ion
may
indi
cate
per
siste
nt d
iseas
e (A
IOM
201
5, E
SMO
201
3-‐C)
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs p
rovi
ded
(ESM
O 2
013-‐
C)
COLO
REC
TAL
CA
NC
ER
D
etai
led
sum
mar
y ta
bles
Exam
ined
doc
umen
ts: 1
9 (1
0 CP
Gs,
9 O
GD
s)
to b
e co
ntinu
ed
Gion et al e353
© 2016 Wichtig Publishing
30
Clin
ical
que
stio
n CP
G
OG
D
Sum
mar
y of
reco
mm
enda
tions
(1)
Supp
lem
enta
ry in
form
atio
n (2
)
Early
det
ectio
n of
re
curr
ence
or p
rogr
essi
on
4
8
CEA
shou
ld b
e re
gula
rly a
sses
sed
durin
g fo
llow
-‐up
to m
onito
r for
sig
ns o
f rec
urre
nce
(ASC
RS 2
012-‐
C, A
SCRS
201
3-‐R,
NIC
E 20
14,
SIG
N 2
011,
AIO
M 2
015,
ASC
O 2
013,
EG
TM 2
013,
ESM
O 2
012-‐
CRC,
ES
MO
201
3-‐C,
NCC
N 2
015-‐
C, N
CCN
201
5-‐R)
A co
nfirm
ed ri
se in
the
post
oper
ativ
e CE
A du
ring
surv
eilla
nce
shou
ld p
rom
pt fu
rthe
r inv
estig
atio
n fo
r rec
urre
nt d
iseas
e (A
SCRS
201
2-‐C,
ASC
RS 2
013-‐
R, A
IOM
201
5, E
GTM
201
3, E
SMO
201
3-‐C,
NCC
N 2
015-‐
C, N
CCN
201
5-‐R)
At p
rese
nt th
ere
is in
suffi
cien
t evi
denc
e to
supp
ort t
he ro
utin
e us
e of
oth
er T
Ms s
uch
as C
A19.
9 (A
SCRS
201
2-‐C,
ASC
RS 2
013-‐
R,
ESM
O 2
013-‐
C)
Repo
rted
sche
dule
(s) o
f CEA
det
erm
inat
ion:
-‐ at l
east
eve
ry 6
mon
ths i
n th
e fir
st 3
yea
rs (N
ICE
2014
) -‐ e
very
2-‐3
mon
ths i
n th
e fir
st 3
yea
rs, e
very
6 m
onth
s at y
ears
4 a
nd 5
(E
GTM
201
3)
-‐ eve
ry 3
mon
ths i
n th
e fir
st 3
yea
rs, e
very
6 m
onth
s at y
ears
4 a
nd 5
(E
SMO
201
2-‐CR
C)
-‐ eve
ry 3
-‐4 m
onth
s in
the
first
3 y
ears
, eve
ry 6
mon
ths a
t yea
rs 4
and
5
(AIO
M 2
015)
-‐ e
very
3-‐6
mon
ths f
or 5
yea
rs. P
atie
nts a
t hig
her r
isk o
f rec
urre
nce
shou
ld b
e co
nsid
ered
for t
estin
g in
the
mor
e fr
eque
nt e
nd o
f the
rang
e (A
SCO
201
3)
-‐ eve
ry 3
-‐6 m
onth
s in
the
first
2 y
ears
, eve
ry 6
mon
ths a
t yea
rs 4
and
5
(NCC
N 2
015-‐
C, N
CCN
201
5-‐R)
-‐ eve
ry 3
-‐6 m
onth
s in
the
first
3 y
ears
, eve
ry 6
-‐12
mon
ths a
t yea
rs 4
and
5
(ESM
O 2
013-‐
C)
-‐ evi
denc
e do
es n
ot c
onse
nt to
reco
mm
end
one
spec
ific
prot
ocol
, but
a
prag
mat
ic p
roto
col o
f fol
low
-‐up
is re
com
men
ded
(NIC
E 20
14, S
IGN
201
1)
Caut
ion
shou
ld b
e ex
erci
sed
in in
terp
retin
g CE
A le
vels,
as b
oth
false
-‐pos
itive
rate
s of
CEA
ele
vatio
n (7
%-‐1
6%) a
nd fa
lse-‐n
egat
ive
rate
s (up
to 4
0%) h
ave
been
re
port
ed (E
GTM
201
3, E
SMO
201
3-‐C)
In re
ctal
can
cer,
clin
ical
, lab
orat
ory
(incl
udin
g CE
A) a
nd ra
diol
ogic
al e
xam
inat
ions
ar
e of
unp
rove
n be
nefit
and
shou
ld b
e re
stric
ted
to p
atie
nts w
ith su
spic
ious
sy
mpt
oms (
ESM
O 2
013-‐
R)
COLO
REC
TAL
CA
NC
ER
D
etai
led
sum
mar
y ta
bles
Exam
ined
doc
umen
ts: 1
9 (1
0 CP
Gs,
9 O
GD
s)
to b
e co
ntinu
ed
Circulating tumor markers: a guide to their appropriate clinical usee354
© 2016 Wichtig Publishing
31
Clin
ical
que
stio
n CP
G
OG
D
Sum
mar
y of
reco
mm
enda
tions
(1)
Supp
lem
enta
ry in
form
atio
n (2
)
Mon
itorin
g of
trea
tmen
t re
spon
se in
adv
ance
d di
seas
e
3 7
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (N
ICE
2014
)
Clin
ical
que
stio
n co
nsid
ered
, but
crit
eria
to m
onito
r tre
atm
ent
resp
onse
(inc
ludi
ng T
Ms)
not
add
ress
ed (A
SCRS
201
2-‐C,
SI
GN
201
1, A
IOM
201
5, E
SMO
201
3-‐R)
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs p
rovi
ded
(ESM
O 2
012-‐
CRC)
CEA
>50
ng/m
L is
an e
stab
lishe
d po
or p
rogn
ostic
fact
ors i
n ad
vanc
ed C
RC
(ESM
O 2
012-‐
CRC)
CEA
flare
and
dro
p ar
e pr
edic
tive
fact
ors o
f res
pons
e to
trea
tmen
t in
adva
nced
CR
C (E
SMO
201
2-‐CR
C)
CEA
– if
initi
ally
ele
vate
d –
shou
ld b
e m
easu
red
befo
re a
nd p
erio
dica
lly d
urin
g ch
emot
hera
py fo
r met
asta
tic d
iseas
e (E
GTM
201
3, E
SMO
201
4-‐m
CRC)
CEA
shou
ld b
e in
clud
ed in
the
initi
al w
orku
p of
susp
ecte
d or
pro
ven
met
asta
tic
dise
ase
(NCC
N 2
015-‐
C, N
CCN
201
5-‐R)
Use
of C
EA is
as a
ccur
ate
as C
T im
agin
g fo
r ass
essin
g th
e re
spon
se o
f col
orec
tal
canc
er li
ver m
etas
tasis
to c
hem
othe
rapy
(EG
TM 2
013)
Repo
rted
sche
dule
of p
atie
nt re
-‐eva
luat
ion:
-‐ pat
ient
s sho
uld
be re
-‐eva
luat
ed e
very
2-‐3
mon
ths i
f che
mot
hera
py is
con
tinue
d (E
SMO
201
4-‐m
CRC)
(1
) Reco
mm
enda
tions
from
CPG
s and
from
OG
Ds,
if c
onsis
tent
with
thos
e of
CPG
s.
(2) Su
pple
men
tary
info
rmat
ion
from
bot
h CP
Gs a
nd O
GD
s, a
nd re
com
men
datio
ns fr
om O
GD
s th
at a
re in
cons
isten
t with
thos
e of
CPG
s.
COLO
REC
TAL
CA
NC
ER
D
etai
led
sum
mar
y ta
bles
Exam
ined
doc
umen
ts: 1
9 (1
0 CP
Gs,
9 O
GD
s)
Gion et al e355
© 2016 Wichtig Publishing
32
Esop
hage
al c
ance
r
Exam
ined
doc
umen
ts: 9
(5 C
PGs,
4 O
GD
s)
Clin
ical
que
stio
n CP
G
OG
D
Sum
mar
y of
reco
mm
enda
tions
(1)
Supp
lem
enta
ry in
form
atio
n (2
)
Scre
enin
g of
peo
ple
at
incr
ease
d ris
k
(Bar
rett
's e
soph
agus
)
3 0
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (A
HS
2014
, mep
201
2,
NH
MRC
201
4)
Diff
eren
tial d
iagn
osis
5
3 Cl
inic
al q
uest
ion
cons
ider
ed, b
ut T
Ms n
ot a
ddre
ssed
(AH
S 20
14, m
ep 2
012,
N
HM
RC 2
014,
NIC
E 20
15, S
TS 2
013,
AIO
M 2
015,
ESM
O 2
013,
NCC
N 2
015)
Preo
pera
tive
wor
kup
3 4
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (A
HS
2014
, N
HM
RC 2
014,
STS
201
3, A
IOM
201
5, A
IRO
201
2, E
SMO
201
3, N
CCN
201
5)
Reas
sess
men
t aft
er in
itial
cu
rativ
e tr
eatm
ent
0 4
Clin
ical
que
stio
n no
t add
ress
ed b
y CP
Gs
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (A
IOM
201
5, A
IRO
201
2,
ESM
O 2
013,
NCC
N 2
015)
Early
det
ectio
n of
re
curr
ence
or p
rogr
essi
on
1 4
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (A
HS
2014
, AIO
M 2
015,
AI
RO 2
012,
ESM
O 2
013,
NCC
N 2
015)
Mon
itorin
g of
trea
tmen
t re
spon
se in
adv
ance
d di
seas
e
1 4
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (S
TS 2
013,
AIO
M 2
015,
AI
RO 2
012,
ESM
O 2
013,
NCC
N 2
015)
(1) Re
com
men
datio
ns fr
om C
PGs a
nd fr
om O
GD
s, if
con
siste
nt w
ith th
ose
of C
PGs.
(2
) Supp
lem
enta
ry in
form
atio
n fr
om b
oth
CPG
s and
OG
Ds,
and
reco
mm
enda
tions
from
OG
Ds
that
are
inco
nsist
ent w
ith th
ose
of C
PGs.
ESO
PHA
GEA
L C
AN
CER
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 9 (5
CPG
s, 4
OG
Ds)
Circulating tumor markers: a guide to their appropriate clinical usee356
© 2016 Wichtig Publishing
33
Gas
tric
can
cer
Ex
amin
ed d
ocum
ents
: 8 (3
CPG
s, 5
OG
Ds)
Clin
ical
que
stio
n CP
G
OG
D
Sum
mar
y of
reco
mm
enda
tions
(1)
Supp
lem
enta
ry in
form
atio
n (2
)
Scre
enin
g of
peo
ple
at
incr
ease
d ris
k
1 1
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed
(ACC
C 20
09, N
CCN
201
5)
Diff
eren
tial d
iagn
osis
1
2 Cl
inic
al q
uest
ion
cons
ider
ed, b
ut T
Ms n
ot a
ddre
ssed
(N
ICE
2015
, AIO
M 2
015,
ESM
O 2
013)
Preo
pera
tive
wor
kup
1 5
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed
(ACC
C 20
09, A
IOM
201
5, E
SMO
201
3, N
CCN
201
5)
CEA
and
CA19
.9 m
ay b
e co
nsid
ered
(AIR
O 2
012)
Cl
inic
al q
uest
ion
cons
ider
ed, n
o ex
plic
it re
com
men
datio
ns o
n TM
s pro
vide
d (E
GTM
201
3)
Reas
sess
men
t aft
er in
itial
cu
rativ
e tr
eatm
ent
0 1
Clin
ical
que
stio
n no
t add
ress
ed b
y CP
Gs
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (N
CCN
201
5)
Early
det
ectio
n of
re
curr
ence
or p
rogr
essi
on
1 4
Dete
rmin
ing
TMs f
or th
e fo
llow
-‐up
of p
atie
nts o
pera
ted
on
for g
astr
ic c
arci
nom
a is
not w
orth
whi
le b
ecau
se it
doe
s not
le
ad to
clin
ical
ben
efit
(ACC
C 20
09)
CEA
and
CA19
.9 m
ay b
e co
nsid
ered
(AIO
M 2
015,
AIR
O 2
012)
TMs c
ontr
ibut
e to
the
earli
er d
etec
tion
of re
curr
ence
s aft
er su
rger
y w
ith c
urat
ive
inte
nt; h
owev
er, t
his i
s with
out t
hera
peut
ic c
onse
quen
ces (
ACCC
200
9, A
IOM
201
5)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (E
SMO
201
3, N
CCN
201
5)
Mon
itorin
g of
trea
tmen
t re
spon
se in
adv
ance
d di
seas
e
2 4
Clin
ical
que
stio
n co
nsid
ered
, but
crit
eria
to m
onito
r tr
eatm
ent r
espo
nse
(incl
udin
g TM
s) n
ot a
ddre
ssed
(A
CCC
2009
, CCO
201
4, A
IOM
201
5, A
IRO
201
2, E
SMO
201
3,
NCC
N 2
015)
(1) Re
com
men
datio
ns fr
om C
PGs a
nd fr
om O
GD
s, if
con
siste
nt w
ith th
ose
of C
PGs.
(2
) Supp
lem
enta
ry in
form
atio
n fr
om b
oth
CPG
s and
OG
Ds,
and
reco
mm
enda
tions
from
OG
Ds
that
are
inco
nsist
ent w
ith th
ose
of C
PGs.
G
AST
RIC
CA
NC
ER
D
etai
led
sum
mar
y ta
bles
Exam
ined
doc
umen
ts: 8
(3 C
PGs,
5 O
GD
s)
Gion et al e357
© 2016 Wichtig Publishing
34
Hep
atoc
ellu
lar c
arci
nom
a (H
CC)
Exam
ined
doc
umen
ts: 1
2 (6
CPG
s, 6
OG
Ds)
Clin
ical
que
stio
n CP
G
OG
D
Sum
mar
y of
reco
mm
enda
tions
(1)
Supp
lem
enta
ry in
form
atio
n (2
)
Scre
enin
g of
peo
ple
at
incr
ease
d ri
sk
3 6
Surv
eilla
nce
of p
atie
nts
in th
e hi
gh-‐r
isk
grou
p is
ba
sed
on p
erio
dic
ultr
ason
ogra
phy
com
bine
d w
ith
mea
sure
men
t of A
FP (J
SH 2
013,
NIC
E 20
13-‐H
BV,
NCC
N 2
015)
D
o no
t off
er s
urve
illan
ce fo
r HCC
in p
eopl
e w
ith
low
risk
(NIC
E 20
13-‐H
BV)
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs
prov
ided
(MCC
201
1,
ESM
O 2
012)
Risk
cat
egor
ies
for s
urve
illan
ce s
trat
egy:
cirr
hosi
s as
soci
ated
with
hep
atiti
s B
or a
lcoh
ol, g
enet
ic
hem
ochr
omat
osis
, aut
oim
mun
e he
patit
is, n
onal
coho
lic s
teat
ohep
atiti
s, p
rimar
y bi
liary
cirr
hosi
s, a
lpha
-‐1
antit
ryps
in d
efic
ienc
y; in
divi
dual
s w
ithou
t cirr
hosi
s w
ho a
re H
BV c
arrie
rs o
r hav
e ot
her r
isk
fact
ors
(e.g
., ac
tive
vira
l rep
licat
ion,
hig
h H
BV D
NA
conc
entr
atio
n, fa
mily
his
tory
of H
CC);
patie
nts
with
chr
onic
HCV
in
fect
ion
and
seve
re li
ver f
ibro
sis
(NIC
E 20
13-‐H
BV, A
IRO
201
2, N
CCN
201
5)
AFP
(and
oth
er T
Ms)
not
indi
cate
d fo
r sur
veill
ance
str
ateg
y be
caus
e of
low
sen
sitiv
ity (l
ower
than
ul
tras
onog
raph
y) a
nd lo
w s
peci
ficity
(MCC
201
1, A
IOM
201
5, A
IRO
201
2, A
ISF
2013
, EAS
L-‐EO
RTC
2012
, ES
MO
201
2)
Scre
enin
g fo
r HCC
sho
uld
use
ultr
ason
ogra
phy
alon
e (M
CC 2
011,
AIO
M 2
015,
AIS
F 20
13, E
ASL-‐
EORT
C 20
12,
ESM
O 2
012)
Co
mbi
natio
n of
AFP
and
oth
er m
arke
rs (A
FP-‐L
3, D
CP) i
s su
gges
ted
(JSH
201
3)
The
use
of o
ther
mar
kers
(DCP
, AFP
-‐L3)
in c
ombi
natio
n w
ith A
FP is
not
sug
gest
ed (M
CC 2
011,
AIR
O 2
012,
EAS
L-‐EO
RTC
2012
, NCC
N 2
015)
AFP
shou
ld b
e us
ed o
nly
in c
ombi
natio
n w
ith u
ltras
onog
raph
y (A
IRO
201
2)
AFP
can
be u
sed
auto
nom
ousl
y on
ly if
ultr
ason
ogra
phy
is n
ot fe
asib
le (A
IOM
201
5)
Repo
rted
sur
veill
ance
sch
edul
e(s)
of u
ltras
onog
raph
y an
d AF
P de
term
inat
ion:
-‐ e
very
3-‐4
mon
ths
in p
eopl
e at
ext
rem
ely
high
risk
; eve
ry 6
mon
ths
in th
ose
at h
igh
risk
(JSH
201
3)
-‐ eve
ry 6
mon
ths
in p
eopl
e at
hig
h an
d in
term
edia
te ri
sk (N
ICE
2013
-‐HBV
)
-‐ eve
ry 6
-‐12
mon
ths
(NCC
N 2
015)
El
evat
ed A
FP fo
und
durin
g su
rvei
llanc
e is
not
nec
essa
ry re
late
d to
can
cer (
MCC
201
1)
AFP
can
also
be
elev
ated
in in
trah
epat
ic c
hola
ngio
carc
inom
a an
d in
som
e ca
ses
of m
etas
tasi
s fr
om c
olon
ca
ncer
(NCC
N 2
015)
Diff
eren
tial d
iagn
osis
4
6 Cl
inic
al q
uest
ion
cons
ider
ed, n
o ex
plic
it re
com
men
datio
ns o
n TM
s pr
ovid
ed (A
CG 2
014-‐
FLL,
N
ICE
2015
, AIO
M 2
015,
EAS
L-‐EO
RTC
2012
)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s no
t ad
dres
sed
(JSH
201
3, M
CC 2
011,
AIR
O 2
012)
The
diag
nost
ic w
orku
p of
a p
atie
nt w
ith s
uspe
cted
HCC
incl
udes
ser
um A
FP m
easu
rem
ent (
ACG
201
4-‐FL
L,
AIO
M 2
015,
ESM
O 2
012)
AF
P m
easu
rem
ent s
houl
d no
t be
cons
ider
ed a
dia
gnos
tic te
st fo
r HCC
in th
e as
sess
men
t of f
ocal
live
r les
ions
(A
ISF
2013
)
No
prim
ary
care
evi
denc
e w
as id
entif
ied
pert
aini
ng to
the
diag
nost
ic a
ccur
acy
of u
ltras
ound
, CT,
MRI
or A
FP
in p
atie
nts
with
sus
pect
ed li
ver c
ance
r whe
re th
e cl
inic
al re
spon
sibi
lity
was
reta
ined
by
prim
ary
care
(N
ICE
2015
)
AFP
has
low
dia
gnos
tic s
ensi
tivity
and
spe
cific
ity (A
IOM
201
5, A
ISF
2013
, NCC
N 2
015)
AF
P m
ay a
lso
be e
leva
ted
in in
trah
epat
ic c
hola
ngio
carc
inom
a, s
ome
met
asta
ses
from
col
on c
ance
r, a
nd g
erm
ce
ll tu
mor
s (A
IOM
201
5, A
ISF
2013
, NCC
N 2
015)
HEP
ATO
CEL
LULA
R C
AR
CIN
OM
A (H
CC)
Det
aile
d su
mm
ary
tabl
es
Exam
ined
doc
umen
ts: 1
2 (6
CPG
s, 6
OG
Ds)
to b
e co
ntinu
ed
Circulating tumor markers: a guide to their appropriate clinical usee358
© 2016 Wichtig Publishing
35
Clin
ical
que
stio
n CP
G O
GD
Sum
mar
y of
reco
mm
enda
tions
(1)
Supp
lem
enta
ry in
form
atio
n (2
)
Preo
pera
tive
wor
kup
2 6
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs p
rovi
ded
(MCC
201
1,
EASL
-‐EO
RTC
2012
)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
ad
dres
sed
(JSH
2013
, AIR
O 2
012,
ESM
O 2
012)
Elev
ated
AFP
leve
ls, p
ossib
ly in
tegr
ated
into
pro
gnos
tic a
lgor
ithm
s, m
ay o
ffer p
rogn
ostic
info
rmat
ion
(e.g
., CL
IP sc
ore)
(MCC
201
1, A
IOM
201
5, A
ISF
2013
, EAS
L-‐EO
RTC
2012
, NCC
N 20
15)
AFP
cann
ot b
e us
ed to
gui
de th
erap
eutic
dec
ision
s bas
ed o
n th
e be
st sc
ient
ific
evid
ence
cur
rent
ly a
vaila
ble
(AIS
F 20
13)
Live
r tra
nspl
ant p
riorit
y an
d de
listin
g po
licie
s 3
4 Pe
riodi
c w
aitin
g-‐lis
t mon
itorin
g sh
ould
be
perf
orm
ed b
y im
agin
g an
d AF
P m
easu
rem
ent
(OLT
4HCG
201
2)
AFP
conc
entr
atio
ns a
dd p
rogn
ostic
info
rmat
ion
(OLT
4HCG
201
2)
Clin
ical
que
stio
n co
nsid
ered
, but
crit
eria
to a
sses
s dr
opou
t (in
clud
ing
TMs)
not
add
ress
ed (J
SH 2
013,
M
CC 2
011,
AIO
M 2
015,
NCC
N 20
15)
The
pres
ence
of h
igh
AFP
conc
entr
atio
ns se
em to
pre
dict
a h
ighe
r risk
of d
ropo
ut (O
LT4H
CG 2
012,
AIS
F 20
13,
EASL
-‐EO
RTC
2012
)
Incr
ease
d AF
P le
vels
(see
cut
off v
alue
s bel
ow) a
nd/o
r cha
nges
in se
rum
AFP
ove
r tim
e m
ay b
e us
eful
to
eval
uate
the
risk
of d
ropo
ut fr
om li
ver t
rans
plan
t wai
ting
list (
AISF
201
3, E
ASL-‐
EORT
C 20
12)
-‐ hig
her t
han
200
ng/m
L (EA
SL-‐E
ORT
C 20
12)
-‐ hig
her t
han
400
ng/m
L (O
LT4H
CG 2
012)
Biom
arke
rs o
ther
than
AFP
can
not y
et b
e us
ed fo
r clin
ical
dec
ision
-‐mak
ing
rega
rdin
g liv
er tr
ansp
lant
for H
CC
(OLT
4HCG
201
2)
Reas
sess
men
t aft
er in
itial
cu
rativ
e tr
eatm
ent
0
5 Cl
inic
al q
uest
ion
not a
ddre
ssed
by
CPGs
In
pat
ient
s with
mar
kedl
y el
evat
ed (>
200-‐
400
ng/m
L) o
r pro
gres
sivel
y in
crea
sing
leve
ls, A
FP m
ay p
rovi
de
usef
ul p
rogn
ostic
info
rmat
ion
to a
sses
s the
resp
onse
to lo
core
gion
al a
nd sy
stem
ic tr
eatm
ents
(AIS
F 20
13,
EASL
-‐EO
RTC
2012
, NCC
N 20
15)
AFP
leve
ls m
ay b
e he
lpfu
l, pa
rtic
ular
ly in
the
case
of n
ot e
asily
mea
sura
ble
dise
ase,
but
shou
ld n
ot b
e us
ed a
s th
e on
ly d
eter
min
ant f
or tr
eatm
ent d
ecisi
ons (
ESM
O 2
012)
Cl
inic
al q
uest
ion
cons
ider
ed, n
o ex
plic
it re
com
men
datio
ns o
n TM
s pro
vide
d (A
IRO
201
2, E
ASL-‐
EORT
C 20
12,
NCCN
201
5)
Early
det
ectio
n of
re
curr
ence
or p
rogr
essio
n 1
5 M
onito
ring
afte
r liv
er tr
ansp
lant
and
pal
liativ
e tr
eatm
ents
may
incl
ude
perio
dic
AFP
mea
sure
men
ts (O
LT4H
CG 2
012,
ESM
O 2
012,
NC
CN 2
015)
An in
crea
se in
AFP
dur
ing
follo
w-‐u
p m
ay su
gges
t HCC
recu
rren
ce. N
ever
thel
ess,
AFP
asse
ssm
ent c
anno
t re
plac
e ra
diol
ogic
al su
rvei
llanc
e fo
llow
-‐up
(AIS
F 20
13)
AFP
leve
ls m
ay b
e he
lpfu
l but
shou
ld n
ot b
e us
ed a
s the
onl
y de
term
inan
t for
trea
tmen
t dec
ision
s (E
SMO
201
2)
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs p
rovi
ded
(AIR
O 2
012,
AIS
F 20
13)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (A
IOM
201
5)
Mon
itorin
g of
trea
tmen
t re
spon
se in
adv
ance
d di
seas
e
2
6
Clin
ical
que
stio
n co
nsid
ered
, but
crit
eria
to
mon
itor t
reat
men
t res
pons
e (in
clud
ing
TMs)
not
ad
dres
sed
(JSH
2013
, MCC
201
1, A
IOM
201
5,
AIRO
201
2, A
ISF
2013
)
AFP
dete
rmin
atio
n m
ay b
e he
lpfu
l for
ass
essm
ent o
f res
pons
e, p
artic
ular
ly in
the
case
of n
ot e
asily
m
easu
rabl
e di
seas
e, b
ut sh
ould
not
be
used
as t
he o
nly
dete
rmin
ant f
or tr
eatm
ent d
ecisi
ons
(EAS
L-‐EO
RTC
2012
, ESM
O 2
012,
NCC
N 20
15)
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs p
rovi
ded
(EAS
L-‐EO
RTC
2012
, NCC
N 20
15)
(1) Re
com
men
datio
ns fr
om C
PGs a
nd fr
om O
GDs,
if co
nsist
ent w
ith th
ose
of C
PGs.
(2
) Supp
lem
enta
ry in
form
atio
n fr
om b
oth
CPGs
and
OGD
s, a
nd re
com
men
datio
ns fr
om O
GDs t
hat a
re in
cons
isten
t with
thos
e of
CPG
s.
HEP
ATO
CEL
LULA
R C
AR
CIN
OM
A (H
CC)
Det
aile
d su
mm
ary
tabl
es
Exam
ined
doc
umen
ts: 1
2 (6
CPG
s, 6
OG
Ds)
Gion et al e359
© 2016 Wichtig Publishing
37
Clin
ical
que
stio
n CP
G
OG
D
Sum
mar
y of
rec
omm
enda
tion
s (1
) Su
pple
men
tary
info
rmat
ion
(2)
Scre
enin
g
0 2
Clin
ical
que
stio
n no
t add
ress
ed b
y CP
Gs
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s no
t add
ress
ed (E
SMO
201
2)
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs
prov
ided
(N
CCN
201
5)
Diff
eren
tial
dia
gnos
is
2 3
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs
prov
ided
(ISG
PS 2
014-‐
A, N
ICE
2015
, AIO
M 2
015,
ESM
O 2
012,
N
CCN
201
5)
No
prim
ary
care
evi
denc
e w
as id
entif
ied
pert
aini
ng to
the
diag
nost
ic a
ccur
acy
of
TMs
(CA
19.9
and
CA
72-‐4
) in
patie
nts
with
sus
pect
ed p
ancr
eatic
can
cer w
here
the
clin
ical
resp
onsi
bilit
y w
as re
tain
ed b
y pr
imar
y ca
re (N
ICE
2015
) Se
rum
TM
s (C
A19
.9, C
EA) …
are
use
ful o
nly
whe
n th
ey a
re p
ositi
ve. W
hen
nega
tive,
they
do
not a
id in
det
erm
inin
g th
e na
ture
of t
he s
uspi
ciou
s le
sion
and
th
eref
ore
have
litt
le in
fluen
ce o
n th
e de
cisi
on to
pro
ceed
with
ex
plor
atio
n/re
sect
ion
or n
ot (I
SGPS
201
4-‐A
) CA
19.9
is o
f lim
ited
diag
nost
ic v
alue
sin
ce it
is n
ot s
peci
fic fo
r pa
ncre
atic
can
cer
(ESM
O 2
012)
CA19
.9 h
as g
ood
diag
nost
ic s
ensi
tivity
and
spe
cific
ity in
sym
ptom
atic
pat
ient
s (N
CCN
201
5) a
nd in
thos
e w
ith a
dvan
ced
dise
ase
(AIO
M 2
015)
CA
19.9
may
be
fals
ely
posi
tive
in c
ases
of b
iliar
y ob
stru
ctio
n (r
egar
dles
s of
et
iolo
gy) (
ISG
PS 2
014-‐
A, A
IOM
201
5, E
SMO
201
2, N
CCN
201
5) a
nd in
cas
es o
f bili
ary
infe
ctio
n (c
hola
ngiti
s) o
r inf
lam
mat
ion
(NCC
N 2
015)
CA
19.9
may
be
unde
tect
able
in L
ewis
ant
igen
-‐neg
ativ
e pa
tient
s w
ith p
ancr
eatic
ca
ncer
, who
are
una
ble
to s
ynth
esiz
e CA
19.9
(ESM
O 2
012,
NCC
N 2
015)
Preo
pera
tive
wor
kup
3 3
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs
prov
ided
(ISG
PS 2
014-‐
A, S
3 20
14, E
SMO
201
2)
CA19
.9 m
ay b
e in
clud
ed in
sta
ndar
d pr
eope
rativ
e di
agno
stic
s fo
r pa
tient
s w
ith borderline re
sectab
le pan
creatic can
cer
to a
sses
s po
tent
ial b
enef
its in
sur
viva
l with
sur
gery
but
not
for
pred
ictio
n of
re
sect
abili
ty (I
SGPS
201
4-‐B)
Seru
m C
A19
.9 le
vel a
lone
is n
ot a
dvoc
ated
for
dete
rmin
ing
oper
abili
ty in
pa
ncre
atic
can
cer
(ISG
PS 2
014-‐
A)
Elev
ated
pre
oper
ativ
e CA
19.9
has
neg
ativ
e pr
ogno
stic
val
ue (I
SGPS
201
4-‐B,
A
IOM
201
5, N
CCN
201
5) b
ut m
ust b
e ev
alua
ted
with
cau
tion
beca
use
the
evid
ence
is b
ased
on
retr
ospe
ctiv
e co
hort
ana
lyse
s (IS
GPS
201
4-‐B)
El
evat
ed p
reop
erat
ive
CA19
.9 le
vels
cor
rela
te w
ith a
dvan
ced
stag
e (E
SMO
201
2,
NCC
N 2
015)
incl
udin
g pe
rito
neal
car
cino
sis
(S3
2014
) CA
19.9
may
be
fals
ely
posi
tive
in c
ases
of b
iliar
y ob
stru
ctio
n (r
egar
dles
s of
et
iolo
gy) a
nd in
cas
es o
f bili
ary
infe
ctio
n (c
hola
ngiti
s) o
r in
flam
mat
ion
(NCC
N 2
015)
CA19
.9 m
ay b
e un
dete
ctab
le in
Lew
is a
ntig
en-‐n
egat
ive
patie
nts
with
pan
crea
tic
canc
er, w
ho a
re u
nabl
e to
syn
thes
ize
CA19
.9 (E
SMO
201
2, N
CCN
201
5)
Preo
pera
tive
mea
sure
men
t of C
A19
.9 is
ther
efor
e be
st p
erfo
rmed
whe
n bi
liary
de
com
pres
sion
is c
ompl
ete
and
bilir
ubin
is n
orm
al. I
f bili
ary
deco
mpr
essi
on is
no
t per
form
ed in
a ja
undi
ced
patie
nt, C
A19
.9 le
vels
can
be
asse
ssed
but
do
not
repr
esen
t an
accu
rate
bas
elin
e (N
CCN
201
5)
CA19
.9 s
houl
d be
mea
sure
d be
fore
sur
gery
(AIO
M 2
015,
NCC
N 2
015)
PAN
CR
EATI
C C
AN
CER
D
etai
led
sum
mar
y ta
bles
Exam
ined
doc
umen
ts: 7
(4 C
PGs,
3 O
GD
s)
to b
e co
ntinu
ed
Circulating tumor markers: a guide to their appropriate clinical usee360
© 2016 Wichtig Publishing
38
Clin
ical
que
stio
n CP
G
OG
D
Sum
mar
y of
rec
omm
enda
tion
s (1
) Su
pple
men
tary
info
rmat
ion
(2)
Reas
sess
men
t aft
er in
itia
l cu
rati
ve tr
eatm
ent
0 2
Clin
ical
que
stio
n no
t add
ress
ed b
y CP
Gs
CA19
.9 s
houl
d be
mea
sure
d fo
llow
ing
surg
ery
imm
edia
tely
pri
or to
ad
min
istr
atio
n of
adj
uvan
t the
rapy
(AIO
M 2
015,
NCC
N 2
015)
Low
pos
tope
rativ
e se
rum
CA
19.9
leve
ls o
r a
seri
al d
ecre
ase
in C
A19
.9 le
vels
fo
llow
ing
surg
ery
have
bee
n fo
und
to b
e pr
ogno
stic
for
surv
ival
(AIO
M 2
015,
N
CCN
201
5)
Earl
y de
tect
ion
of
recu
rren
ce o
r pr
ogre
ssio
n 0
3 Cl
inic
al q
uest
ion
not a
ddre
ssed
by
CPG
s A
sses
smen
t of C
A19
.9 c
ould
be
perf
orm
ed p
erio
dica
lly d
urin
g fo
llow
-‐up
(AIO
M 2
015,
ESM
O 2
012,
NCC
N 2
015)
Repo
rted
sch
edul
e(s)
of C
A19
.9 m
easu
rem
ent:
-‐ e
very
3 m
onth
s fo
r 2
year
s if
preo
pera
tive
leve
ls w
ere
elev
ated
(ESM
O 2
012)
-‐ eve
ry 3
-‐6 m
onth
s fo
r 2
year
s (N
CCN
201
5)
-‐ eve
ry 6
mon
ths
for
3 ye
ars
(AIO
M 2
015)
N
o da
ta a
re a
vaila
ble
to s
how
that
ear
lier
trea
tmen
t of r
ecur
renc
es fo
llow
ing
dete
ctio
n by
incr
ease
d TM
leve
ls o
r CT
sca
n le
ads
to b
ette
r pa
tient
out
com
es
(NCC
N 2
015)
Mon
itor
ing
of tr
eatm
ent
resp
onse
in a
dvan
ced
dise
ase
1 3
Clin
ical
que
stio
n co
nsid
ered
, but
cri
teri
a to
mon
itor
ther
apy
resp
onse
(inc
ludi
ng T
Ms)
not
add
ress
ed (S
3 20
14)
CA19
.9 c
an b
e pe
riod
ical
ly m
easu
red
duri
ng th
e tr
eatm
ent o
f adv
ance
d di
seas
e (A
IOM
201
5)
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs
prov
ided
(N
CCN
201
5)
Chan
ge in
CA
19.9
leve
ls d
urin
g ch
emot
hera
py in
pat
ient
s w
ith a
dvan
ced
dise
ase
has
been
sho
wn
to b
e us
eful
for
eval
uatin
g th
e be
nefit
of t
reat
men
t, a
lthou
gh
the
data
are
not
ent
irel
y co
nsis
tent
(NCC
N 2
015)
Cl
inic
al q
uest
ion
cons
ider
ed, b
ut T
Ms
not a
ddre
ssed
(ESM
O 2
012)
(1
) Reco
mm
enda
tions
from
CPG
s an
d fr
om O
GD
s, if
con
sist
ent w
ith th
ose
of C
PGs.
(2
) Supp
lem
enta
ry in
form
atio
n fr
om b
oth
CPG
s an
d O
GD
s, a
nd re
com
men
datio
ns fr
om O
GD
s th
at a
re in
cons
iste
nt w
ith th
ose
of C
PGs.
PA
NC
REA
TIC
CA
NC
ER
Det
aile
d su
mm
ary
tabl
es
Exam
ined
doc
umen
ts: 7
(4 C
PGs,
3 O
GD
s)
Gion et al e361
© 2016 Wichtig Publishing
Selected guidelines (by cancer site)
Biliary cancer
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ESMO 2011. Eckel F, Brunner T, Jelic S; ESMO Guidelines Working Group. Biliary cancer: ESMO Clinical Practice Guide-lines for diagnosis, treatment and follow-up. Ann Oncol. 2011; 22(Suppl 6):vi40-4. doi: 10.1093/annonc/mdr375.
NCCN 2015. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Hepatobi-liary cancers, version 1.2016. Fort Washington, PA: National Comprehensive Cancer Network; 2015.
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Colorectal cancer
AGA 2010. Farraye FA, Odze RD, Eaden J, et al. AGA med-ical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gas-troenterology. 2010 ;138(2):738-45. doi: 10.1053/j.gastro. 2009.12.037.
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ASCRS 2013-R. Monson JR, Weiser MR, Buie WD, et al. Practice parameters for the management of rectal cancer (re-vised). Dis Colon Rectum. 2013; 56(5):535-50. doi: 10.1097/DCR.0b013e31828cb66c.
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NICE 2011-SU. National Institute for Health and Clinical Excellence (NICE). Colonoscopic surveillance for prevention of colorectal cancer in people with ulcerative colitis, Crohn’s dis-ease or adenomas. London, UK: National Institute for Health and Clinical Excellence (NICE); 2011. URL: https://www.nice.org.uk/guidance/CG118.
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USMSTF 2012. Lieberman DA, Rex DK, Winawer SJ, et al. Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2012; 143(3):844-57. doi: 10.1053/j.gastro.2012.06.001.
Esophageal cancer
AHS 2014. Alberta Provincial Gastrointestinal Tumour Team. Management of patients with early esophageal cancer, dysplastic and non-dysplastic Barrett’s esophagus. Edmon-ton, Alberta: CancerControl Alberta; 2014.
AIOM 2015. Associazione Italiana di Oncologia Medica. Tumori dell’esofago e della giunzione gastroesofagea. Milano, IT: Associazione Italiana di Oncologia Medica (AIOM); 2015.
AIRO 2012. Gruppo di studio AIRO per i tumori gastroin-testinali. La Radioterapia dei Tumori Gastrointestinali: Indi-cazioni e Criteri Guida. Roma, IT: Associazione Italiana di Ra-dioterapia Oncologica (AIRO); 2012.
ESMO 2013. Stahl M, Mariette C, Haustermans K, et al. Oesophageal cancer: ESMO Clinical Practice Guidelines for di-agnosis, treatment and follow-up. Ann Oncol. 2013; 24 (Suppl 6):vi51-6. doi: 10.1093/annonc/mdt342.
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STS 2013. Varghese TK Jr, Hofstetter WL, Rizk NP, et al. The society of thoracic surgeons guidelines on the diagnosis and staging of patients with esophageal cancer. Ann Thorac Surg. 2013; 96(1):346-56. doi: 10.1016/j.athoracsur.2013.02.069.
Gastric cancer
ACCC 2009. National Working Group on Gastrointestinal Cancers. Gastric carcinoma. Utrecht, The Netherlands: Asso-ciation of Comprehensive Cancer Centres; 2009.
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CONTRIBUTORS
Salvatore AlfieriSC Oncologia Medica 3 Tumori Testa e ColloFondazione IRCCS Istituto Nazionale dei Tumori Milano - Italy
Emiliano AroasioDipartimento di Scienze Cliniche e BiologicheAzienda Ospedaliero-Universitaria San Luigi GonzagaOrbassano (Torino) - Italy
Alessandro BertacciniClinica UrologicaAzienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-MalpighiBologna - Italy
Francesco BoccardoUOC Clinica di Oncologia MedicaIRCCS AOU San Martino IST - Istituto Nazionale per la Ricerca sul CancroUniversità degli StudiGenova - Italy
Mario BragaSistema Monitoraggio Nazionale (Area Monitoraggio Spesa Sanitaria e LEA)Agenzia Nazionale per i Servizi Sanitari Regionali (AGENAS)Roma - Italy
Roberto BuzzoniSC Day Hospital e Terapia Ambulatoriale OncologicaFondazione IRCCS Istituto Nazionale dei TumoriMilano - Italy
Maurizio CancianSocietà Italiana di Medicina Generale SIMGScuola Veneta di Medicina Generale SVeMGConegliano Veneto (Treviso) - Italy
Ettore D. CapoluongoUOS Diagnostica Molecolare Clinica e Personalizzata, Dipartimento di Medicina LaboratorioFondazione Policlinico Universitario “Agostino Gemelli”Roma - Italy
Elisabetta CarianiSSD Laboratorio Patologia Clinica - Tossicologia e Diagnostica AvanzataNuovo Ospedale Civile S. Agostino-Estense - Azienda USL ModenaModena - Italy
Vanna Chiarion SileniSSD Oncologia Melanoma ed EsofagoIstituto Oncologico Veneto IOV – IRCCSPadova - Italy
Michela CinquiniUnità di Metodologia delle Revisioni Sistematiche e Produzione di Linee GuidaLaboratorio di Metodologia per la Ricerca BiomedicaIRCCS Istituto di Ricerche Farmacologiche “Mario Negri” Milano - Italy
Giuseppe CivardiUOC Medicina InternaPOI della Val d’Arda - Azienda USL PiacenzaFiorenzuola d’Arda (Piacenza) - Italy
Renzo ColomboDivisione Oncologia/UrologiaUrological Research InstituteIRCCS Ospedale San Raffaele Milano - Italy
Mario CorrealeSOC Patologia ClinicaIRCCS “S. De Bellis”Castellana Grotte (Bari) - Italy
Gaetano D’AmbrosioMedico di Medica Generale ASL BTSocietà Italiana di Medicina Generale SIMGBisceglie (Barletta-Adria-Trani) - Italy
Bruno DanieleUOC Oncologia Medica, Dipartimento OncologiaAzienda Ospedaliera “G. Rummo”Benevento - Italy
Marco Danova Dipartimento di Area MedicaAzienda SST di PaviaPavia - Italy
Giovanna Del Vecchio Blanco UOC GastroenterologiaDipartimento di Medicina InternaFondazione Policlinico Tor VergataUniversità degli Studi di Roma “Tor Vergata”Roma - Italy
Francesca Di FabioUOC Oncologia MedicaAzienda Ospedaliero-Universitaria Policlinico S. Orsola-MalpighiBologna - Italy
Massimo Di MaioDipartimento di Oncologia, Università degli Studi di TorinoSCDU Oncologia Medica, AO Ordine MaurizianoTorino - Italy
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Ruggero DittadiUOC Laboratorio Analisi, Dipartimento di Patologia Clinica e Medicina TrasfusionaleOspedale dell’Angelo - Azienda ULSS 12 VenezianaVenezia-Mestre - Italy
Aline Sueli Coelho Fabricio Centro e Programma Regionale Biomarcatori Diagnostici, Prognostici e PredittiviAzienda ULSS 12 VenezianaVenezia - Italy
Massimo FalconiChirurgia del PancreasIRCCS Ospedale San Raffaele Università Vita-Salute San RaffaeleMilano - Italy
Andrea FandellaUnità Funzionale UrologiaCasa di Cura Giovanni XXIIIMonastier (Treviso) - Italy
Tommaso FasanoSC Laboratorio Analisi Chimico-Cliniche e di Endocrinologia, Dipartimento di Diagnostica per Immagini e Medicina di LaboratorioClinical Cancer CenterIRCCS-Arcispedale Santa Maria NuovaReggio Emilia - Italy
Simona FerraroUOC Patologia Clinica, Dipartimento di Medicina di LaboratorioOspedale Universitario “Luigi Sacco”ASST Fatebenefratelli-Sacco Milano - Italy
Antonio FortunatoUOC Laboratorio Analisi, Dipartimento di Urgenza ed EmergenzaAzienda ULSS 6Vicenza - Italy
Bruno Franco NovellettoSocietà Italiana di Medicina Generale SIMGScuola Veneta di Medicina Generale SVeMGPadova - Italy
Angiolo GadducciDipartimento di Medicina Clinica e SperimentaleDivisione di Ginecologia e OstetriciaUniversità degli Studi di PisaPisa - Italy
Luca GermagnoliSynlab Italia Servizi DiagnosticiCastenedolo (Brescia) - Italy
Maria Grazia GhiUOC Oncologia Medica, Dipartimento OncologicoAzienda ULSS 12 VenezianaVenezia - Italy
Davide GiavarinaUOC Laboratorio Analisi, Dipartimento di Urgenza ed EmergenzaAzienda ULSS 6Vicenza - Italy
Massimo GionCentro e Programma Regionale Biomarcatori Diagnostici, Prognostici e Predittivi Azienda ULSS 12 VenezianaVenezia - Italy
Marién González LorenzoUnità di Epidemiologia ClinicaIRCCS Istituto Ortopedico GaleazziDipartimento di Scienze Biomediche per la SaluteUniversità degli Studi di MilanoMilano - Italy
Stefania GoriDipartimento di OncologiaCancer Care Center “Sacro Cuore-Don Calabria”Negrar (Verona) - Italy
Fiorella GuadagniUniversità San Raffaele RomaBiomarker Discovery and Advanced Technologies (BioDAT)Biobanca Interistituzionale Multidisciplinare (BioBIM)SR Research Center- IRCCS San Raffaele PisanaRoma - Italy
Cinzia IottiSC Radioterapia OncologicaClinical Cancer CenterIRCCS Arcispedale Santa Maria NuovaReggio Emilia - Italy
Tiziana LatianoUOC Oncologia MedicaCasa Sollievo della Sofferenza – IRCCSSan Giovanni Rotondo (Foggia) - Italy
Lisa LicitraSC Oncologia Medica 3 Tumori Testa e ColloFondazione IRCCS Istituto Nazionale dei TumoriMilano - Italy
Tiziano MagginoUOC Ostetricia e Ginecologia, Dipartimento Materno-InfantileOspedale dell’Angelo - Azienda ULSS 12 VenezianaVenezia-Mestre - Italy
Circulating tumor markers: a guide to their appropriate clinical usee366
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Evaristo MaielloUOC Oncologia MedicaCasa Sollievo della Sofferenza – IRCCSSan Giovanni Rotondo (Foggia) - Italy
Gianluca MasiUOC Oncologia MedicaAzienda Ospedaliero-Universitaria PisanaPisa - Italy
Paolo MorandiUOC Oncologia Medica, Dipartimento OncologicoAzienda ULSS 12 VenezianaVenezia - Italy
Maria Teresa MuratoreUOC Diagnostica ClinicaPO Belcolle - Azienda Sanitaria Locale ViterboViterbo - Italy
Gianmauro NumicoSC Oncologia MedicaAzienda Ospedaliera SS. Antonio e Biagio e C. ArrigoAlessandria - Italy
Valentina PecoraroSSD Laboratorio Patologia Clinica - Tossicologia e Diagnostica AvanzataNuovo Ospedale Civile S. Agostino-Estense - Azienda USL ModenaModena - Italy
Paola Pezzati SOD Laboratorio Generale AOUC Azienda Ospedaliero-Universitaria CareggiFirenze - Italy
Carmine PintoUOC OncologiaClinical Cancer CenterIRCCS Arcispedale Santa Maria NuovaReggio Emilia - Italy
Silvia PregnoUO Governance ClinicaArea Direzione Strategica - Azienda USL ModenaModena - Italy
Giulia RainatoCentro e Programma Regionale Biomarcatori Diagnostici, Prognostici e Predittivi Azienda ULSS 12 Veneziana Istituto Oncologico Veneto IOV – IRCCSPadova - Italy
Stefano RapiSOD Laboratorio Generale AOUC Azienda Ospedaliero-Universitaria CareggiFirenze - Italy
Francesco RicciDépartement Oncologie MédicaleInstitut CurieParis - France
Lorena Fabiola Rojas LlimpeUOC Oncologia MedicaAzienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-MalpighiBologna - Italy
Laura RoliSSD Laboratorio Patologia Clinica EndocrinologiaNuovo Ospedale Civile S. Agostino-Estense - Azienda USL ModenaModena- Italy
Giovanni RostiSC Oncologia MedicaFondazione IRCCS Policlinico San MatteoPavia - Italy
Tiziana RubecaLaboratorio Regionale Prevenzione OncologicaISPO Istituto per lo Studio e la Prevenzione Oncologica Firenze - Italy
Giuseppina RuggeriUOC Laboratorio AnalisiASST Spedali CiviliBrescia - Italy
Anne W.S. RutjesDivision of Clinical Epidemiology & BiostatisticsInstitute of Social and Preventive MedicineUniversity of BernBern - Switzerland
Gian Luca SalvagnoUOC Laboratorio Analisi, DAI Patologia e DiagnosticaOspedale Borgo Roma - Azienda Ospedaliera Universitaria IntegrataVerona - Italy
Maria Teresa SandriDivisione Medicina LaboratorioIstituto Europeo di Oncologia IRCCSMilano - Italy
Giovanni ScambiaIstituto di Clinica ostetrico e ginecologica Università Cattolica del Sacro CuoreRoma - Italy
Mario ScartozziClinica di Oncologia MedicaPresidio Policlinico Universitario “Duilio Casula”Azienda Ospedaliera UniversitariaCagliari - Italy
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Ornella ScattolinCentro e Programma Regionale Biomarcatori Diagnostici, Prognostici e Predittivi Azienda ULSS 12 VenezianaAVAPO Venezia OnlusVenezia - Italy
Vincenzo ScattoniUO UrologiaIRCCS Ospedale San Raffaele Università Vita-Salute San RaffaeleMilano - Italy
Holger Schünemann Department of Clinical Epidemiology & BiostatisticsMcMaster University Health Sciences CentreHamilton - Canada
Giuseppe SicaUOC Chirurgia Generale A, Dipartimento di ChirurgiaFondazione PTV Policlinico Universitario Tor Vergata Università Roma-Tor VergataRoma - Italy
Alessandro TerreniSOD Laboratorio Generale AOUC Azienda Ospedaliero-Universitaria CareggiFirenze - Italy
Marcello TiseoSC Oncologia MedicaAzienda Ospedaliero-UniversitariaParma - Italy
Valter TorriLaboratorio Metodologia per la Ricerca Biomedica, Dipartimento OncologiaIRCCS Istituto di Ricerche Farmacologiche “Mario Negri” Milano - Italy
Quinto TozziRicerca e Studio Rischio ClinicoAgenzia Nazionale per i Servizi Sanitari Regionali (AGENAS)Roma - Italy
Tommaso TrentiDipartimento Integrato Interaziendale di Medicina di Laboratorio ed Anatomia PatologicaAzienda Ospedaliera Universitaria e Azienda USL di ModenaModena - Italy
Chiara TrevisiolCentro e Programma Regionale Biomarcatori Diagnostici, Prognostici e Predittivi Azienda ULSS 12 Veneziana Istituto Oncologico Veneto IOV – IRCCSPadova - Italy
Paolo ZolaDipartimento Scienze ChirurgicheAOU Città della Salute e della ScienzaUniversità degli StudiTorino - Italy
IJBMeISSN 1724-6008
Int J Biol Markers 2017; 32(1): e1-e52
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GUIDELINES
DOI: 10.5301/ijbm.5000259
Circulating tumor markers: a guide to their appropriate clinical use Comparative summary of recommendations from clinical practice guidelines (PART 2)
Massimo Gion1, Chiara Trevisiol2, Anne W.S. Rutjes3, Giulia Rainato2, Aline S.C. Fabricio1
1 Regional Center and Program for Biomarkers, Department of Clinical Pathology and Transfusion Medicine, Azienda ULSS 3 Serenissima, Venice - Italy
2 Istituto Oncologico Veneto IOV - IRCCS, Padova - Italy3 Institute of Social and Preventive Medicine, University of Bern, Bern - Switzerland
Endorsed byAGENAS National Agency for Regional Health Services, Rome, ItalyRegional Center for Biomarkers, Azienda ULSS 12 Veneziana, Venice, Italy
On behalf of and in collaboration withRegione del Veneto, IOV - Istituto Oncologico Veneto - I.R.C.C.S., AIOM (Associazione Italiana di Oncologia Medica), SIBioC - Medicina di Laboratorio (Società Italiana di Biochimica Clinica e Biologia Molecolare Clinica), AIRO (Associazione Italiana di Radioterapia Oncologica), ELAS-Italia (European Ligand Assay Society Italia), FADOI (Federazione delle Associazioni dei Dirigenti Ospedalieri Internisti), SICO (Società Italiana di Chirurgia Oncologica), SIGO (Società Italiana di Ginecologia e Ostetricia), SIMG (Società Italiana di Medicina Generale), SIUrO (Società Italiana di Urologia Oncologica), AVAPO Venezia Onlus (Associazione Volontari per l’Assistenza di Pazienti Oncologici)
Steering CommitteeMario Braga, Massimo Gion, Carmine Pinto, Bruno Rusticali, Holger Schünemann, Tommaso TrentiFor complete contributors' affiliations see end of article (pp. e49-e52)
Scientific CommitteeAline S.C. Fabricio, Evaristo Maiello, Anne W.S. Rutjes, Valter Torri, Quinto Tozzi, Chiara TrevisiolFor complete contributors' affiliations see end of article (pp. e49-e52)
Received: November 25, 2016Accepted: January 12, 2017Published online:
Corresponding author:Dr. Massimo GionCentro Regionale BiomarcatoriAzienda ULSS3 SerenissimaOspedale Civile30122 Venice, Italymassimo.gion@aulss3.veneto.it
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Contributions of panel members(1) Search and selection of guidelines (2) Appraisal of guidelines through the AGREE II tool (3) Assessment of the rate of utilization of a subset of guidance documents in clinical practice (4) Synthesis of recommendations and other information concerning tumor markers into summary tables (5) Assessment of correctness and completeness of the information summarized in the tables
External validationInterregional Biomarkers Working Group, instituted by the Health Commission of the Italian Permanent Conference for Relations between State, Regions and the Autonomous Provinces of Trento and Bolzano. Antonino Iaria (Calabria), Vincenzo Montesarchio (Campania), Tommaso Trenti (Emilia Romagna), Laura Conti (Lazio), Luigina Bonelli and Gabriella Paoli (Liguria), Mario Cassani (Lombardia), Lucia Di Furia (Marche), Emiliano C. Aroasio (Piemonte), Mario Brandi (Puglia), Marcello Ciaccio and Antonio Russo (Sicilia), Gianni Amunni (Toscana), Emanuela Toffalori (P.A. Trento), Basilio Ubaldo Passamonti (Umbria), Claudio Pilerci and Francesca Russo (Veneto), Annarosa Del Mistro (IOV IRCCS, Veneto)
Executive secretaryOrnella Scattolin
FundingAGENAS Agenzia Nazionale per i Servizi Sanitari Regionali Azienda ULSS 12 VenezianaIOV - Istituto Oncologico Veneto - I.R.C.C.S.AIOM (Associazione Italiana di Oncologia Medica)SIBioC - Medicina di Laboratorio (Società Italiana di Biochimica Clinica e Biologia Molecolare Clinica)ELAS-Italia (European Ligand Assay Society Italia)SIUrO (Società Italiana di Urologia Oncologica) AVAPO Venezia Onlus (Associazione Volontari per l’Assistenza di Pazienti Oncologici)
This study was helpful in the exploration of unmet needs in tumor marker application in the frame of an AIRC 5x1000 research project, from which it was partially supported (Italian Association for Research on Cancer - AIRC; Grant Special Program Molecu-lar Clinical Oncology, 5x1000, No. 12214).
The authors would like to thank the following cultural associations in Venice for their supportAssociazione “Un amico a Venezia”, “Chiostro Tintorettiano di Venezia”, “I ragazzi di don Bepi”, SKÅL International Venezia for their support.
AcknowledgmentsThe authors would like to thank the following researchers for their collaboration: Mauro Antimi (Roma), Alessandro Battaggia (Padova), Nicola L. Bragazzi (Genova), Massimo Brunetti (Modena), Michele Cannone (Canosa di Puglia), Antonette E. Leon (Venezia).
This guide is published in Italian as:Gion M, Trevisiol C, Rainato G, Fabricio ASC. Marcatori circolanti in oncologia: guida all'uso clinico appropriato. I Quaderni di Monitor. Roma, IT: AGENAS, Agenzia Nazionale per i Servizi Sanitari Regionali, 2016.
Multidisciplinary panel of experts Salvatore Alfieri(5), Emiliano Aroasio(3,5), Alessandro Bertaccini(3,5), Francesco Boccardo(3,5), Roberto Buzzoni(3,5), Maurizio Cancian(5), Ettore D. Capoluongo(5), Elisabetta Cariani(5), Vanna Chiarion Sileni(3,5), Michela Cinquini(1,3,5), Giuseppe Civardi(5), Renzo Colombo(3,5), Mario Correale(3,5), Gaetano D’Ambrosio(5), Bruno Daniele(3,5), Marco Danova(3,5), Giovanna Del Vecchio Blanco(3,5), Francesca Di Fabio(3,5), Massimo Di Maio(3,5), Ruggero Dittadi(3,5), Massimo Falconi(3,5), Andrea Fandella(3,5), Tommaso Fasano(5), Simona Ferraro(3,5), Antonio Fortunato(3,5), Bruno Franco Novelletto(5), Angiolo Gadducci(3,5), Luca Germagnoli(3,5), Maria Grazia Ghi(3,5), Davide Giavarina(3,5), Marién González Lorenzo(2,5), Stefania Gori(3,5), Fiorella Guadagni(3,5), Cinzia Iotti(3,5), Tiziana Latiano(1,3,5), Lisa Licitra(3,5), Tiziano Maggino(5), Gianluca Masi(5), Paolo Morandi(3,5), Maria Teresa Muratore(3,5), Gianmauro Numico(5), Valentina Pecoraro(2,5), Paola Pezzati(3,5), Silvia Pregno(5), Giulia Rainato(4), Stefano Rapi(3,5), Francesco Ricci(3,5), Lorena Fabiola Rojas Llimpe(3,5), Laura Roli(1,5), Giovanni Rosti(3,5), Tiziana Rubeca(3,5), Giuseppina Ruggeri(5), Gian Luca Salvagno(5), Maria Teresa Sandri(5), Giovanni Scambia(3,5), Mario Scartozzi(3,5), Vincenzo Scattoni(3,5), Giuseppe Sica(3,5), Alessandro Terreni(3,5), Marcello Tiseo(3,5), Paolo Zola(5)
For complete contributors' affiliations see end of article (pp. e49-e52)
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Contents Introduction e4Take-home messages
Users’ instructions e5Bladder cancer e6Breast cancer e8Cervical cancer e10Endometrial cancer e11Ovarian cancer e12Prostate cancer e15Renal cancer e20Testicular cancer e22
Detailed summary tables Users’ instructions e24Bladder cancer e25Breast cancer e27Cervical cancer e28Endometrial cancer e29Ovarian cancer e30Prostate cancer e34Renal cancer e39Testicular cancer e40
Selected guidelines (by cancer site) e44Contributors e49
Acronyms
Abbreviations of tumor markers cited in the present article
AFP Alpha- FetoProteinCA125 Cancer Antigen 125CA15.3 Cancer Antigen 15.3CA19.9 Cancer Antigen 19.9CA27.29 Cancer Antigen 27-29CEA CarcinoEmbryonic AntigenhCG human Chorionic GonadotropinHE4 Human Epididymis protein 4
LDH Lactate DeHydrogenaseMCM5 MiniChromosome Maintenance 5NMP22 Nuclear Matrix Protein number 22PCA3 Prostate Cancer Associated 3PHI Prostate Health IndexPSA Prostate-Specific AntigenPSADT Prostate-Specific Antigen Doubling TimeSCC Squamous Cell Carcinoma antigen
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Introduction
This is the second of 3 parts of a guide to the appropriate clinical use of circulating tumor markers (TMs). The full docu-ment was published in Italy in October 2016 by the Italian National Agency for Regional Health Services (AGENAS) on behalf of and in collaboration with 9 Italian scientific societies representative of a range of stakeholders (1). The publication of the document in English was planned in 3 parts; the first, concerning malignancies of the gastrointestinal tract, was published in December 2016 (2); the second, appearing in the present issue, refers to urogenital tract malignancies and breast cancer.
Rationale
The number of TMs requested is considerably higher than expected based on the cancer prevalence, and this shows the low compliance of clinicians to clinical practice guidelines (CPGs). Barriers preventing clinicians from adherence to CPG recommendations include discrepancies between the cau-tious position of CPGs and the encouraging results of primary studies. In fact, the evidence provided by primary studies tends to focus on the diagnostic accuracy of the tests rather than on patient outcomes, the latter being a prerequisite for good-level evidence in guideline development. While await-ing the distillation of higher quality evidence into compre-hensive guidelines, efforts should be made to improve the adherence to existing CPGs. A project was developed to sum-marize recommendations on circulating TMs offered by avail-able CPGs on solid tumors, in order to provide all possible evidence-based choices concerning TMs for anyone facing a clinical question in which the use of a TM could be consid-ered.
Methods
The structured and rigorous methodology adopted for the extraction and synthesis of relevant information from selected guidelines has been previously described in detail (2). In brief, a systematic search for CPGs was performed and a standardized set of selection criteria was used to identify potentially relevant publications. Only documents containing recommendations for clinical practice were included. A total of 1,181 potentially relevant documents were selected from 8,266 identified records. Full-text reports were obtained for 559 guidelines concerning 20 different malignancies. The se-lected documents were further appraised for adherence to the standards of the Institute of Medicine (IOM), which re-quire guidelines to be based on systematic review of existing evidence (3), and clustered into 2 groups: 127 documents in which recommendations were generated through systematic review (CPGs) and 432 guidance documents without evidence of systematic review (other guidance documents – OGDs). CPGs were further assessed with the Appraisal of Guidelines for Research & Evaluation (AGREE II) tool in order to facilitate comparison of the quality of the summarized CPGs. OGDs produced by authoritative institutions or medical societ-ies are currently used by clinicians in their daily practice. All
OGDs were therefore presented to the panel members with a request to indicate those actually used in clinical practice. When 25% or more of the panel members declared that a given guidance document was used in clinical practice, it was retained. In all, 111 of 432 OGDs qualified for inclusion. Circu-lating biomarkers measured in body fluids (serum or plasma/urine) were considered.
Results
The tabulation of the information was structured by indi-vidual malignancies; within each malignancy, the information was clustered according to a set of clinical questions estab-lished as being common to all malignancies. All information extracted from the guidance documents was synthesized in 4 rounds (levels) of increasing simplification. The last 2 levels of synthesis are the Take-Home Messages and Detailed Sum-mary Tables. The former are intended for use by health care providers in their clinical practice with the goal of improving the appropriateness of TM use; the Detailed Summary Tables are addressed to both policy makers for potential adaptation to their own context and educators to design teaching pro-grams consistent with the available evidence.
The implicit goal of the present guidance document is to “stimulate extensive discussion and promote commentaries and debate, with the ultimate ambition of improving the ap-propriate use of TMs but also optimizing the proposed model of comparative summary of the available evidence to facili-tate extensive dissemination and consultation of the guid-ance provided” (4).
References1. Gion M, Trevisiol C, Rainato G, Fabricio ASC. Marcatori circol-
anti in oncologia: guida all'uso clinico appropriato. I Quaderni di Monitor. Roma: AGENAS, Agenzia Nazionale per i Servizi Sanitari Regionali 2016.
2. Gion M, Trevisiol C, Rutjes AWS, Rainato G, Fabricio ASC. Circu-lating tumor markers: a guide to their appropriate clinical use. Comparative summary of recommendations from clinical prac-tice guidelines (Part 1). Int J Biol Markers. 2016;31:e332-e367.
3. IOM (Institute of Medicine). Clinical practice guidelines we can trust. Washington, DC: The National Academies Press 2011.
4. Gion M. Need for knowledge translation to improve tumor marker application. Int J Biol Markers. 2016;31:e331.
Gion et al e5
© 2017 Wichtig Publishing
AGREE evaluation
CPGs concerning every malignancy were also assessed with the Appraisal of Guidelines for Research & Evaluation (AGREE II) tool. A higher score equals a better quality of the domain. The results are reported after the Take-Home Message tables.
Additional notes
▪ Take-Home Messages are reported in alphabetical order.
▪ Information from OGDs on a specific clinical question were only reported in the Take-Home Messages if the clinical question was considered by CPGs. Descriptions regarding these OGDs can, however, be found in the Detailed Summary Tables.
▪ References concerning both CPGs and OGDs are reported after the Detailed Summary Tables, divided by type of malignancy and cited with the acronyms used in the Tables.
15
AGREE evaluation
CPGs concerning every malignancy were also assessed with the Appraisal of Guidelines for Research & Evaluation (AGREE II) tool. A higher score equals a better quality of the domain. The results are reported after the Take-‐Home Message tables.
Acronym Domain 1 Scope and purpose
Domain 2 Stakeholder involvement
Domain 3 Rigor of development
Domain 4 Clarity of
presentation
Domain 5 Applicability
Domain 6 Editorial
independence
Acronyms of CPGs
Scores concerning the overall aim of the guideline, the specific health questions, and the target population are reported for every CPG
Scores concerning the extent to which the guideline was developed by the appropriate stakeholders and represents the views of its intended users are reported for every CPG
Scores concerning the process used to gather and synthesize the evidence, and the methods to formulate the recommendations and update them are reported for every CPG
Scores concerning the language, structure, and format of the guideline are reported for every CPG
Scores concerning the likely barriers and facilitators to implementation, strategies to improve uptake, and resource implications of applying the guideline are reported for every CPG
Scores concerning the formulation of recommendations not being unduly biased with competing interests are reported for every CPG
The scores of the 6 domains were subdivided into quartiles and marked in different colors as shown in the following table:
0-‐25th percentile 26th-‐50th percentile 51st-‐75th percentile
76th-‐100th percentile Additional notes − Take-‐Home Message tables are reported in alphabetical order − Information from OGDs on a specific clinical question were only reported in the Take-‐Home Message table if the clinical question was considered by CPGs. Descriptions regarding these OGDs
can, however, be found in the Detailed Summary Tables. − References concerning both GPGs and OGD are reported after the Detailed Summary Tables, divided by type of malignancy and cited with the acronyms used in the Tables
Take-home messages
Users' instructions
Definition and target audience
Take-Home Messages are presented in table format for every tumor type, summarizing essential information to support decision-making in clinical practice. They are intended for use by health care providers.
14
TAKE-‐HOME MESSAGES -‐ Users’ instructions
Definition and target audience Take-‐Home Messages are presented in table format for every tumor type, summarizing essential information to support decision-‐making in clinical practice. They are intended for use by health care providers. Structure
Total number of selected documents (number of CPGs, number of OGDs)
Clinical question
Summary of recommendations
Recommended tumor marker(s)
CPG/total CPG (CPG acronyms)
OGD/total OGD
(OGD acronyms)
The different clinical questions are reported
The symbol denotes that CPGs formulated inconsistent recommendations on TMs in the clinical question
Recommendations and information from CPGs that consider the clinical question are summarized
The sentence “Recommendations on TMs not available” is reported when the clinical question was considered by CPGs, but either TMs were not addressed or no explicit recommendations on TMs were provided
The recommended TM(s) are reported
When CPGs explicitly recommend against TM(s), the word “None” is reported
The symbol ∅ is shown when the examined CPGs either do not address TMs or, if TMs are addressed, CPGs do not formulate explicit recommendations
Number of CPGs reporting the summarized information in proportion to the total number of CPGs that consider the clinical question (acronyms of the CPGs in parenthesis)
Number of ODGs reporting the summarized information in proportion to the total number of CPGs that consider the clinical question (acronyms of the OGDs in parenthesis)
STRUCTURETotal number of selected documents (number of CPGs, number of OGDs)
Circulating tumor markers: a guide to their appropriate clinical usee6
© 2017 Wichtig Publishing
2 ∅ The examined CPG
s that con
sider the clinical question either do no
t add
ress TMs o
r, if TM
s are add
ressed, CPG
s do no
t present explicit recommendatio
ns.
Acronyms of CPG
s
Dom
ain 1
Scop
e and pu
rpose
Dom
ain 2
Stakeholder
involvem
ent
Dom
ain 3
Rigor o
f developm
ent
Dom
ain 4
Clarity of
presentatio
n
Dom
ain 5
Applicability
Dom
ain 6
Edito
rial
independ
ence
AHS 2013-‐M
I 92
42
67
67
67
58
AHS 2013-‐NM
86
42
66
69
58
79
AHS 2013-‐UT
83
42
65
67
58
79
CUA 2013
44
28
58
56
23
58
NICE 2015-‐SC
89
98
92
89
72
78
NICE 2015-‐BC
97
89
90
94
85
83
USPSTF 2011
92
47
79
78
44
79
1 Bladder cancer
Exam
ined docum
ents: 15 (7 CPG
s, 8 OGDs)
Clinical question
Summary of re
commendatio
ns
Recommended
tumor marker(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2)
(OGD acron
yms)
Screening
Recommendatio
ns on TM
s not available
∅
1/1
(USPSTF 2011)
4/4
(AIOM 2015, EAU
2015-‐NM,
EAU 2015-‐UT, ESM
O 2014)
Differentia
l diagnosis
Urin
ary biom
arkers (e.g., NMP22) can be used as a
n adjunct to cystoscopy
to detect invisible tumor in se
cond
ary care
NMP22
∅
1/2
(NICE 2015-‐BC)
1/8
(EAU
2015-‐NM)
In prim
ary care do no
t sub
stitu
te urin
ary biom
arkers fo
r cystoscop
y to
investigate suspected bladder cancer
1/2
(NICE 2015-‐BC)
2/8
(AURO
2010, EAU
2015-‐NM)
Recommendatio
ns on TM
s not available
1/2
(NICE 2015-‐SC)
6/8
(AIOM 2015, EAU
2015-‐MI,
EAU 2015-‐UR, EAU
2015-‐UT,
ESMO 2014, NCC
N 2015)
Supp
lementary inform
ation: No primary care evidence was identified
pertaining to
the diagno
stic accuracy of urin
e markers (N
MP22 and
MCM
5) in patients w
ith su
spected bladder cancer w
here th
e clinical
respon
sibility was re
tained by primary care
1/2
(NICE 2015-‐SC)
0/8
Preoperativ
e workup
Recommendatio
ns on TM
s not available
∅
4/4
(AHS
2013-‐MI, AH
S 2013-‐NM,
AHS 2013-‐UT, NICE 2015-‐BC)
8/8
(AIOM 2015, AURO
2010,
EAU 2015-‐MI, EA
U 2015-‐NM,
EAU 2015-‐UR, EAU
2015-‐UT,
ESMO 2014, NCC
N 2015)
Reassessment a
fter initial
curativ
e treatm
ent
Clinical question no
t add
ressed by CP
Gs
-‐-‐-‐
-‐-‐-‐
-‐-‐-‐
Early
detectio
n of
recurrence or p
rogression
Do
not su
bstitute urinary biom
arkers fo
r cystoscop
y for follow-‐up after
treatm
ent for bladd
er cancer
Non
e ∅
1/5
(NICE 2015 BC)
3/8
(AIOM 2015, EAU
2015-‐NM,
ESMO 2014)
Recommendatio
ns on TM
s not available
4/5
(AHS
2013-‐MI, AH
S 2013-‐NM,
AHS 2013-‐UT, CUA 2013)
4/8
(AURO
2010, EAU
2015-‐MI,
EAU 2015-‐UR, EAU
2015-‐UT)
Mon
itorin
g of treatm
ent
respon
se in advanced
disease
Recommendatio
ns on TM
s not available
∅
3/3
(AHS
2013-‐MI, AH
S 2013-‐UT,
NICE 2015-‐BC)
4/5
(AIOM 2015, AURO
2010,
ESMO 2014, NCC
N 2015)
(1) CPG
/total CPG
: CPG
s reportin
g the summarize
d inform
ation/total num
ber o
f CPG
s that con
sider th
e clinical question.
(2) OGD/total OGD: O
GDs re
porting the summarize
d inform
ation/total num
ber o
f OGDs th
at con
sider th
e clinical question.
BLA
DD
ER C
AN
CER
Take
-hom
e m
essa
geEx
amin
ed d
ocum
ents
: 15
(7 C
PGs,
8 O
GDs
)
to b
e co
ntinu
ed
Gion et al e7
© 2017 Wichtig Publishing
2 ∅ The examined CPG
s that con
sider the clinical question either do no
t add
ress TMs o
r, if TM
s are add
ressed, CPG
s do no
t present explicit recommendatio
ns.
Acronyms of CPG
s
Dom
ain 1
Scop
e and pu
rpose
Dom
ain 2
Stakeholder
involvem
ent
Dom
ain 3
Rigor o
f developm
ent
Dom
ain 4
Clarity of
presentatio
n
Dom
ain 5
Applicability
Dom
ain 6
Edito
rial
independ
ence
AHS 2013-‐M
I 92
42
67
67
67
58
AHS 2013-‐NM
86
42
66
69
58
79
AHS 2013-‐UT
83
42
65
67
58
79
CUA 2013
44
28
58
56
23
58
NICE 2015-‐SC
89
98
92
89
72
78
NICE 2015-‐BC
97
89
90
94
85
83
USPSTF 2011
92
47
79
78
44
79
BLA
DD
ER C
AN
CER
Take
-hom
e m
essa
geEx
amin
ed d
ocum
ents
: 15
(7 C
PGs,
8 O
GDs
)
Circulating tumor markers: a guide to their appropriate clinical usee8
© 2017 Wichtig Publishing
3 Breast cancer
Exam
ined docum
ents: 15 (9 CPG
s, 6 OGDs)
Clinical question
Summary of re
commendatio
ns
Recommended
tumor marker(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2)
(OGD acron
yms)
Differentia
l diagnosis
Recommendatio
ns on TM
s not available
∅
2/2
(NICE 2012-‐EarlyBC
, NICE 2015-‐
SC)
5/5
(AIOM 2015, ESM
O 2013-‐
EarlyBC
, EUSO
MA 2014-‐You
ng,
NCC
N 2014-‐Diagn, NCC
N 2015)
Preoperativ
e workup
Recommendatio
ns on TM
s not available
∅
2/2
(AHS
2012-‐BB
, NICE 2012-‐
EarlyBC
)
3/4
(AIOM 2015, EUSO
MA 2014-‐
Youn
g, NCC
N 2015)
Reassessment a
fter initial
curativ
e treatm
ent
Clinical question no
t add
ressed by CP
Gs
-‐-‐-‐
-‐-‐-‐
-‐-‐-‐
Early
detectio
n of
recurrence or p
rogression
The use of CA1
5.3 or CA2
7.29 or C
EA is not re
commended for rou
tine
surveillance of breast cancer a
fter prim
ary therapy in an otherw
ise
asym
ptom
atic patient with
no specific fin
dings o
n clinical examination
Non
e CA
15.3, CEA
∅
3/4
(AHS
2013-‐FU
, ASCO 2012-‐FU
, NHM
RC 2010)
3/4
(AIOM 2015, ESM
O 2013-‐
EarlyBC
, EUSO
MA 2014-‐You
ng)
TMs a
re re
commended on
ly if clinically indicated
1/4
(NHM
RC 2010)
1/4
(ESM
O 2013-‐EarlyBC
)
Recommendatio
ns on TM
s not available
1/4
(NICE 2012-‐EarlyBC
) 1/4
(NCC
N 2015)
Mon
itorin
g of treatm
ent
respon
se in advanced
disease
TMs m
ay be used as a
djun
ctive assessment to contrib
ute to decision
s regarding therapy for m
etastatic breast cancer
CA15.3, CEA
∅
1/3
(ASCO 2015-‐M+)
2/4
(ESM
O 2014-‐AB
C,
EUSO
MA 2014-‐You
ng,
NCC
N 2015)
Data are insufficient to recommend use of TMs a
lone fo
r mon
itorin
g respon
se to
treatm
ent
1/3
(ASCO 2015-‐M+)
3/4
(ESM
O 2014-‐AB
C,
EUSO
MA 2014-‐You
ng,
NCC
N 2015)
Recommendatio
ns on TM
s not available
2/3
(CECOG 2009, NICE 2014-‐M
+)
1/4
(AIOM 2015)
(1) CPG
/total CPG
: CPG
s reportin
g the summarize
d inform
ation/total num
ber o
f CPG
s that con
sider th
e clinical question.
(2) OGD/total OGD: O
GDs re
porting the summarize
d inform
ation/total num
ber o
f OGDs th
at con
sider th
e clinical question.
∅ The examined CPG
s that con
sider th
e clinical question either do no
t add
ress TMs o
r, if TM
s are add
ressed, CPG
s do no
t present explicit recommendatio
ns.
BREA
ST C
AN
CER
Ta
ke-h
ome
mes
sage
Exam
ined
doc
umen
ts: 1
5 (9
CPG
s, 6
OG
Ds)
to b
e co
ntinu
ed
Gion et al e9
© 2017 Wichtig Publishing
4 Ac
ronyms of CPG
s
Dom
ain 1
Scop
e and pu
rpose
Dom
ain 2
Stakeholder
involvem
ent
Dom
ain 3
Rigor o
f developm
ent
Dom
ain 4
Clarity of
presentatio
n
Dom
ain 5
Applicability
Dom
ain 6
Edito
rial
independ
ence
AHS 2012-‐BB
83
38
65
81
67
92
AHS 2013-‐FU
41
55
62
78
65
86
ASCO
2012-‐FU
87
83
83
83
64
61
ASCO
2015-‐M+
94
70
80
85
61
94
CECO
G 2009
72
56
68
69
23
33
NHMRC
2010
81
78
78
78
57
69
NICE 2014-‐M
+ 96
91
90
94
92
89
NICE 2012-‐EarlyBC
94
89
88
94
89
83
NICE 2015-‐SC
94
96
90
87
94
89
BREA
ST C
AN
CER
Take
-hom
e m
essa
geEx
amin
ed d
ocum
ents
: 15
(9 C
PGs,
6 O
GDs
)
Circulating tumor markers: a guide to their appropriate clinical usee10
© 2017 Wichtig Publishing
5 Cervical cancer
Exam
ined docum
ents: 7 (3 CPG
s, 4 OGDs)
Clinical question
Summary of re
commendatio
ns
Recommended
tumor marker(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2)
(OGD acron
yms)
Differentia
l diagnosis
Recommendatio
ns on TM
s not available
∅
1/1
(NICE 2015)
3/4
(AIOM 2015, ESM
O 2012,
NCC
N 2015)
Preoperativ
e workup
Recommendatio
ns on TM
s not available
∅
1/1
(AHS
2013)
3/4
(AIOM 2015, ESM
O 2012,
NCC
N 2015)
Reassessment a
fter initial
curativ
e treatm
ent
Clinical question no
t add
ressed by CP
Gs
-‐-‐-‐
-‐-‐-‐
-‐-‐-‐
Early
detectio
n of
recurrence or p
rogression
The use of TMs (includ
ing SCC) in asymptom
atic patients c
anno
t be
recommended because the impact of asymptom
atic re
currence detectio
n on
survival ra
tes is n
ot kno
wn
Non
e ∅
1/2
(CCO
2015)
2/4
(AIOM 2015, NAC
B 2010)
Recommendatio
ns on TM
s not available
1/2
(AHS
2013)
2/4
(ESM
O 2012, NCC
N 2015)
Mon
itorin
g of treatm
ent
respon
se in advanced
disease
Recommendatio
ns on TM
s not available
∅
1/1
(AHS
2013)
3/3
(AIOM 2015, ESM
O 2012,
NCC
N 2015)
(1) CPG
/total CPG
: CPG
s reportin
g the summarize
d inform
ation/total num
ber o
f CPG
s that con
sider th
e clinical question.
(2) OGD/total OGD: O
GDs re
porting the summarize
d inform
ation/total num
ber o
f OGDs th
at con
sider th
e clinical question.
∅ The examined CPG
s that con
sider th
e clinical question either do no
t add
ress TMs o
r, if TM
s are add
ressed, CPG
s do no
t present explicit recommendatio
ns.
Acronyms of CPG
s
Dom
ain 1
S cop
e and pu
rpose
Dom
ain 2
Stakeholder
involvem
ent
Dom
ain 3
Rigor o
f developm
ent
Dom
ain 4
Clarity of
presentatio
n
Dom
ain 5
Applicability
Dom
ain 6
Edito
rial
independ
ence
AHS 2013
97
47
58
69
50
75
CCO 2015
72
50
58
75
40
71
NICE 2015
89
97
91
89
67
83
CERV
ICA
L CA
NCE
R
Take
-hom
e m
essa
geEx
amin
ed d
ocum
ents
: 7 (3
CPG
s, 4
OG
Ds)
Gion et al e11
© 2017 Wichtig Publishing
6 Endo
metria
l cancer
Exam
ined docum
ents: 7 (3 CPG
s, 4 OGDs)
Clinical question
Summary of re
commendatio
ns
Recommended
tumor marker(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2)
(OGD acron
yms)
Screening
Clinical question no
t add
ressed by CP
Gs
-‐-‐-‐
-‐-‐-‐
-‐-‐-‐
Differentia
l diagnosis
Recommendatio
ns on TM
s not available
∅
1/1
(NICE 2015)
4/4
(AIOM 2015, ESM
O 2013,
NCC
N 2015, SGO 2014)
Preoperativ
e workup
In case of increased serum CA1
25 levels preoperative imaging is advisable
to ru
le out metastatic sp
read
CA125
1/1
(ACN
2011)
1/3
(NCC
N 2015)
Reassessment a
fter initial
curativ
e treatm
ent
Clinical question no
t add
ressed by CP
Gs
-‐-‐-‐
-‐-‐-‐
-‐-‐-‐
Early
detectio
n of
recurrence or p
rogression
Re
commendatio
ns on TM
s not available
∅
1/1
(AHS
2013)
1/4
(ESM
O 2013)
Mon
itorin
g of treatm
ent
respon
se in advanced
disease
Recommendatio
ns on TM
s not available
∅
1/1
(AHS
2013)
4/4
(AIOM 2015, ESM
O 2013,
NCC
N 2015, SGO 2014)
(1) CPG
/total CPG
: CPG
s reportin
g the summarize
d inform
ation/total num
ber o
f CPG
s that con
sider th
e clinical question.
(2) OGD/total OGD: O
GDs re
porting the summarize
d inform
ation/total num
ber o
f OGDs th
at con
sider th
e clinical question.
∅ The examined CPG
s that con
sider th
e clinical question either do no
t add
ress TMs o
r, if TM
s are add
ressed, CPG
s do no
t present explicit recommendatio
ns.
Acronyms of CPG
s
Dom
ain 1
S cop
e and pu
rpose
Dom
ain 2
Stakeholder
involvem
ent
Dom
ain 3
Rigor o
f developm
ent
Dom
ain 4
Clarity of
presentatio
n
Dom
ain 5
Applicability
Dom
ain 6
Edito
rial
independ
ence
ACN 2011
78
42
71
89
54
67
AHS 2013
86
44
65
72
58
100
NICE 2015
89
97
92
89
71
79
END
OM
ETRI
AL
CAN
CER
Take
-hom
e m
essa
geEx
amin
ed d
ocum
ents
: 7 (3
CPG
s, 4
OG
Ds)
Circulating tumor markers: a guide to their appropriate clinical usee12
© 2017 Wichtig Publishing
7 Ovaria
n cancer
Examined docum
ents: 22 (12 CP
Gs, 10 OGDs)
Clinical question
Summary of re
commendatio
ns
Recommended
tumor marker(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2)
(OGD acron
yms)
Screening general
polulatio
n Screening for o
varia
n cancer in th
e general pop
ulation is no
t recommended
Non
e 2/2
(SIGN 2013-‐EC, U
SPSTF 2012)
3/3
(ACO
G 2011-‐EC, A
IOM 2015,
NCC
N 2015)
Screening of people at
increased risk (positive
family history)
Screening for o
varia
n cancer in high-‐risk grou
ps sh
ould only be offe
red in
the context o
f a re
search stud
y
Non
e 3/3
(AHS
2011-‐HR
, NHM
RC 2011-‐HR
, SIGN 2013-‐EC )
2/5
(ACO
G 2011-‐EC, N
CCN 2015)
Differentia
l diagnosis
CA125 measurement in conjun
ction with
pelvic ultrasou
nd sh
ould be
carried ou
t in wom
en with
suspicious sy
mptom
s of o
varia
n cancer or a
n adnexal m
ass
CA125
5/6
(BSG
E 2011, CCO
2011-‐AM
, NICE 2011-‐EC, NICE 2015,
SIGN 2013-‐EC)
5/7
(ACO
G 2011-‐EC, A
COG 2013-‐
AM, A
IOM 2015, ESM
O 2013-‐
EC, N
CCN 2015)
An estimation of th
e risk of malignancy shou
ld be carried ou
t for th
e assessment o
f an ovarian mass
4/6
(BSG
E 2011, CCO
2011-‐AM
, NICE 2011-‐EC, SIGN 2013-‐EC)
1/7
(ESM
O 2013-‐EC)
Supp
lementary inform
ation: CA1
25 can be elevated fo
r reasons other
than ovaria
n cancer, such as other malignancies, physio
logical causes a
nd
benign con
ditio
ns
3/6
(BSG
E 2011, CCO
2011-‐AM
, SIGN 2013-‐EC)
3/7
(ACO
G 2011-‐EC, A
COG 2013-‐
AM, ESM
O 2013-‐EC)
LDH, A
FP and
βhC
G sh
ould be measured in all wom
en und
er age 40 with
a
complex ovaria
n mass b
ecause of the possib
ility of germ cell tum
ors
AFP, βhC
G, LDH
3/6
(AHS
2013-‐GCT, BSG
E 2011,
NICE 2011-‐EC)
3/7
(ACO
G 2013-‐AM
, ESM
O 2012-‐
GCT, N
CCN 2015)
Preoperativ
e workup
Recommendatio
ns on TM
s not available for e
pithelial ovaria
n cancer
∅
2/3
(AHS
2013-‐EC, SIGN 2013-‐EC)
3/4
(AIOM 2015, ESM
O 2013-‐EC,
ESMO 2012-‐GCT)
Tumor histology-‐specific TM
s sho
uld be used in associatio
n with
clinical
findings to determ
ine the progno
sis and
class risk of n
onepith
elial ovaria
n cancer
AFP, βhC
G, LDH
1/3
(AHS
2013-‐GCT)
1/4
(NCC
N 2015)
Reassessment a
fter initial
curativ
e treatm
ent
Recommendatio
ns on TM
s not available
∅
1/1
(AHS
2013-‐EC)
0/4
OVA
RIA
N C
AN
CER
Take
-hom
e m
essa
geEx
amin
ed d
ocum
ents
: 22
(12
CPG
s, 1
0 O
GDs
)
to b
e co
ntinu
ed
Gion et al e13
© 2017 Wichtig Publishing
8 Clinical question
Summary of re
commendatio
ns
Recommended
tumor marker(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2)
(OGD acron
yms)
Early
detectio
n of
recurrence or p
rogression
In th
e absence of sy
mptom
s, ro
utine measurement o
f CA1
25 during
follow-‐up is no
t mandatory
Non
e or
CA125
1/4
(SIGN 2013-‐EC)
0/6
CA125 is no
t recom
mended for rou
tine follow-‐up
1/4
(AHS
2013-‐EC)
0/6
Some wom
en may benefit from
routine measurement o
f CA1
25, including
those who
are eligible fo
r secon
dary cytoreductive surgery
1/4
(NHM
RC 2012)
5/6
(AIOM 2015, ESG
O 2011,
ESGO 2012-‐FU
, ESM
O 2013-‐EC,
NCC
N 2015)
Radiological im
aging shou
ld be performed if th
ere is CA
125 evidence of
recurrence
1/4
(NHM
RC 2012)
3/6
(AIOM 2015, ESG
O 2012-‐FU
, ESMO 2013-‐EC)
Wom
en sh
ould be fully inform
ed of the pros a
nd con
s of rou
tine
measurement o
f CA1
25 during follow-‐up
1/4
(NHM
RC 2012)
3/6
(AIOM 2015, ESG
O 2012-‐FU
, NCC
N 2015)
It is recommended to con
tinue histology-‐specific TM
measurement in the
routine follow-‐up of patients w
ith non
epith
elial ovaria
n cancer
AFP, βhC
G, LDH,
inhibin
1/4
(AHS
2013-‐GCT)
2/6
(ESG
O 2011, NCC
N 2015)
Mon
itorin
g of treatm
ent
respon
se in advanced
disease
Seria
l measurement o
f CA1
25 is useful to assess th
e respon
se to
chem
otherapy
CA125
∅
1/5
(CCO
2011)
2/4
(ESM
O 2013-‐EC, N
CCN 2015)
Recommendatio
ns on TM
s not available
4/5
(AHS
2013-‐EC, A
HS 2013-‐GCT,
NICE 2011-‐EC, SIGN 2013-‐EC)
1/4
(AIOM 2015)
(1) CPG
/total CPG
: CPG
s reportin
g the summarize
d inform
ation/total num
ber o
f CPG
s that con
sider th
e clinical question.
(2) OGD/total OGD: O
GDs re
porting the summarize
d inform
ation/total num
ber o
f OGDs th
at con
sider th
e clinical question.
∅ The examined CPG
s that con
sider th
e clinical question either do no
t add
ress TMs o
r, if TM
s are add
ressed, CPG
s do no
t present explicit recommendatio
ns.
Incon
sistent re
commendatio
ns on TM
s in the clinical question are repo
rted by diffe
rent CPG
s.
OVA
RIA
N C
AN
CER
Take
-hom
e m
essa
geEx
amin
ed d
ocum
ents
: 22
(12
CPG
s, 1
0 O
GDs
)
to b
e co
ntinu
ed
Circulating tumor markers: a guide to their appropriate clinical usee14
© 2017 Wichtig Publishing
9 Ac
ronyms of CPG
s
Dom
ain 1
Scop
e and pu
rpose
Dom
ain 2
Stakeholder
involvem
ent
Dom
ain 3
Rigor o
f developm
ent
Dom
ain 4
Clarity of
presentatio
n
Dom
ain 5
Applicability
Dom
ain 6
Edito
rial
independ
ence
AHS 2011-‐HR
92
44
67
75
58
87
AHS 2013-‐EC
80
39
70
69
58
83
AHS 2013-‐GCT
86
30
64
69
56
83
BSGE 2011
83
67
76
78
50
58
CCO 2011
86
44
74
69
31
58
CCO 2011-‐AM
92
56
78
75
35
58
NHMRC
2011-‐HR
78
69
70
69
25
58
NHMRC
2012
69
67
74
69
29
58
NICE 2011-‐EC
100
89
92
94
85
86
NICE 2015
94
89
91
89
81
83
SIGN 2013-‐EC
86
86
80
86
75
75
USPSTF 2012
83
39
65
86
27
75
OVA
RIA
N C
AN
CER
Take
-hom
e m
essa
geEx
amin
ed d
ocum
ents
: 22
(12
CPG
s, 1
0 O
GDs
)
Gion et al e15
© 2017 Wichtig Publishing
10
Prostate cancer
Exam
ined docum
ents: 33 (24 CP
Gs, 9 OGDs)
Clinical question
Summary of re
commendatio
ns
Recommended
tumor marker(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2)
(OGD acron
yms)
Organized screening
programs
PSA-‐based mass screening fo
r prostate cancer is not re
commended
Non
e 2/2
(EAU
2015, USPSTF 2012)
2/2
(AIOM 2015, ESM
O 2013)
Spon
taneou
s screening
Screening for p
rostate cancer of asymptom
atic men with
the PSA test is
not recom
mended
Non
e or
PSA
2/9
(CTFPH
C 2014, U
SPSTF 2012)
0/3
For m
en aged less th
an 55 years o
r older th
an 70-‐75, or w
ith a life
expectancy <10 years sc
reening for p
rostate cancer with
the PSA test is
not recom
mended
4/9
(ASCO 2012, AUA 2013-‐ED,
SIOG 2014, UMHS
2012)
1/3
(AIOM 2015)
An individu
alized, risk
-‐adapted strategy fo
r early detectio
n might be
offered to a well -‐informed man with
a goo
d performance status and
life
expectancy of at least 10-‐15 years
4/9
(AHS
2013, CUA 2011, EAU
2015,
UMHS
2012)
2/3
(AIOM 2015, NCC
N 2014)
If there is a higher risk of p
rostate cancer (e.g., po
sitive family history or
African-‐American descent), PSA-‐based screening shou
ld be offered at age
40 years
5/9
(AUA 2013-‐ED, CUA 2011,
EAU 2015, UMHS
2012,
USPSTF 2012)
1/3
(AIOM 2015)
If prostate cancer screening is con
sidered, m
en sh
ould be inform
ed of the
potential benefits and
risks o
f early detectio
n
4/9
(AHS
2013, ASCO 2012,
AUA 2013-‐ED, USPSTF 2012)
3/3
(AIOM 2015, ESM
O 2013,
NCC
N 2014)
No evidence has dem
onstrated that age-‐adjusted PSA cutoffs; free PSA;
and PSA density, velocity, slope, and
dou
bling-‐tim
e testing improve health
outcom
es when used fo
r screening purpo
ses
5/9
(ASCO 2012, CTFPH
C 2014,
EAU 2015, UMHS
2012,
USPSTF 2012)
0/3
PRO
STAT
E CA
NCE
R Ta
ke-h
ome
mes
sage
Exam
ined
doc
umen
ts: 3
3 (2
4 CP
Gs,
9 O
GDs
)
to b
e co
ntinu
ed
Circulating tumor markers: a guide to their appropriate clinical usee16
© 2017 Wichtig Publishing
to b
e co
ntinu
ed 11
Clinical question
Summary of re
commendatio
ns
Recommended
tumor marker(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2)
(OGD acron
yms)
Differentia
l diagnosis
Indicatio
ns fo
r biopsies includ
e a clinical su
spicion of prostate cancer
based on
PSA
and
DRE find
ing s, con
sidering also clinical history and risk
factors
PSA
3/8
(AHS
2013, EAU
2015, NICE 2015)
4/6
(AIOM 2015, GEC-‐ESTRO
2013,
ESMO 2013, NCC
N 2015)
Limite
d PSA elevation alon
e shou
ld not prompt im
mediate biopsy. PSA
level sho
uld be verified after a few weeks usin
g the same assay un
der
standardized con
ditio
ns
2/8
(EAU
2015, NICE 2014)
2/6
(AIOM 2015, NCC
N 2014)
Consider PSA
to assess for prostate cancer in men with
any lower urin
ary
tract sym
ptom
s or a
ny unexplained sy
mptom
s suggestive of metastatic
prostate cancer
2/8
(CCO
2015, NICE 2015)
0/6
Supp
lementary inform
ation n. 1: Elevated PSA and/or abn
ormal DRE are
not d
iagnostic of p
rostate cancer; they do
serve to risk stratify patie
nts
1/8
(AHS
2013)
0/6
Supp
lementary inform
ation n. 2: M
any cond
ition
s other th
an prostate
cancer may increase PSA
2/8
(CUA 2011, EAU
2015)
1/6
(NCC
N 2014)
Supp
lementary inform
ation n. 3: There is no level of P
SA below
which th
e risk of prostate cancer can be eliminated
1/8
(EAU
2015)
1/6
(NCC
N 2014)
Supp
lementary inform
ation n. 4: O
ther te
sts (PSA density, PSA
velocity,
PSA free-‐to-‐total ratio, PHI, PCA
3) may im
prove the PSA sensitivity and
specificity but have lim
ited clinical im
pact given th
e slight n
et benefit
provided fo
r clinical decision
-‐making
3/8
(CUA 2011, EGAP
P 2014,
EAU 2015)
3/6
(AIOM 2015, NCC
N 2014,
SIURO
2013)
Rebiop
sy
The indicatio
ns fo
r a re
peat biopsy are: risin
g and/or persistently elevated
PSA
only PSA
or
PSA, PCA
3
2/4
(EAU
2015, NICE 2014)
3/4
(AIOM 2015, ESM
O 2013,
SIURO
2013)
Currently, the main indicatio
n for P
CA3 is to determine whether re
peat
biop
sy is needed after a
n initially negative biop
sy
1/4
(EAU
2015)
1/4
(NCC
N 2014)
Evidence is insufficient to recommend PC
A3 or P
HI to
inform
decision
s as
to when to re
biop
sy previou
sly biopsy-‐negative patie
nts
2/4
(EGAP
P 2014, N
ICE 2015-‐PCA
3)
0/4
Supp
lementary inform
ation: Very low quality evidence is available for a
ge,
PSA free-‐to-‐total ratio, PSA
velocity, PCA
3 score, and
PSA
density in th
e indicatio
n for a
repeat biopsy.
4/4
(EGAP
P 2014, EAU
2015,
NICE 2014, N
ICE 2015-‐PCA
3)
0/4
PRO
STAT
E CA
NCE
R Ta
ke-h
ome
mes
sage
Exam
ined
doc
umen
ts: 3
3 (2
4 CP
Gs,
9 O
GDs
)
Gion et al e17
© 2017 Wichtig Publishing
12
Clinical question
Summary of re
commendatio
ns
Recommended
tumor marker(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2)
(OGD acron
yms)
Preoperativ
e workup
PSA, com
bined with
clinical stage and Gleason
score, is used as risk
stratifi
catio
n to disc
uss w
ith th
e patie
nt th
e choice of therapy options
PSA
7/8
(AHS
2013, AUA 2011, CCO
2010,
CCO 2012-‐BT, EAU
2015,
NICE 2014, SIOG 2014)
4/5
(AIOM 2015, AUA 2013,
ESMO 2013, NCC
N 2015)
Radiograph
ic staging (CT and bo
ne sc
an) is recom
mended for p
atients
with
a PSA
level >10 ng/mL prior to treatm
ent
2/8
(AUA 2011, EAU
2015)
3/5
(AIOM 2015, AUA 2013, G
EC-‐
ESTRO 2013)
Supp
lementary inform
ation: Evidence is insufficient to recommend PC
A3
to determine if the disease is indo
lent or a
ggressive in order to
develop
an
optim
al treatm
ent p
lan
1/8
(EGAP
P 2014)
1/5
(AIOM 2015)
Activ
e surveillance
PSA <10 ng/m
L is on
e of th
e crite
ria to
identify patie
nts e
ligible fo
r active
surveillance
PSA
3/10
(CCO
2014-‐AS, EAU
2015,
SIOG 2014)
1/2
(AIOM 2015)
Mon
itorin
g of patients o
n active surveillance shou
ld includ
e PSA testing
(every 3-‐6 mon
ths)
6/10
(ACS 2014, AHS
2013, ASCO 2015,
CCO 2014-‐AS, EAU
2015,
NICE 2014)
2/2
(AIOM 2015, NCC
N 2015)
Accelerated elevation of th
e PSA level (PSA do
ubling tim
e) is one of the
crite
ria con
sidered to
start a
ctive therapy
3/10
(CUA 2011, A
HS 2013, EAU
2015)
1/2
(AIOM 2015)
Supp
lementary inform
ation: Evidence is no
t sufficient to
recommend
PCA3
testing to determine if the disease is indo
lent or a
ggressive
2/10
(CCO
2014-‐AS, EGAP
P 2014)
1/2
(AIOM 2015)
Reassessment a
fter initial
curativ
e treatm
ent
(RP and RT)
First p
ostoperative PSA measurement sho
uld be don
e 4-‐12 weeks after
surgery and PSA shou
ld be un
detectable
PSA
4/4
(ACS 2014, AHS
2013, EAU
2015,
NICE 2014)
3/3
(AIOM 2015, AUA 2013,
NCC
N 2015)
PSA level sho
uld progressively decrease after RT, re
aching th
e nadir a
fter
6-‐12 mon
ths (interval before PSA nadir is reached can be up
to 3 years)
2/2
(EAU
2015, NICE 2014)
2/2
(AIOM 2015, AUA 2013)
PRO
STAT
E CA
NCE
R
Take
-hom
e m
essa
ge
Exam
ined
doc
umen
ts: 3
3 (2
4 CP
Gs,
9 O
GDs
)
to b
e co
ntinu
ed
Circulating tumor markers: a guide to their appropriate clinical usee18
© 2017 Wichtig Publishing
14
Incon
sistent re
commendatio
ns on TM
s in the clinical question are repo
rted by diffe
rent CPG
s.
CT = com
puted tomograph
y; DRE = digita
l rectal examination; RP = radical prostatectomy; RT = radiotherapy.
Acronyms of CPG
s
Dom
ain 1
Scop
e and pu
rpose
Dom
ain 2
Stakeholder
involvem
ent
Dom
ain 3
Rigor o
f developm
ent
Dom
ain 4
Clarity of
presentatio
n
Dom
ain 5
Applicability
Dom
ain 6
Edito
rial
independ
ence
ACS 2014
58
39
66
69
33
67
AHS 2013
43
24
38
43
36
47
ASCO
2012
92
47
58
81
33
63
ASCO
2014
89
69
74
81
33
63
ASCO
2015
83
78
65
86
33
63
ASCO
-‐CCO
2014
86
83
81
78
63
75
AUA 2011
61
42
73
86
42
75
AUA 2013-‐ED
58
44
72
89
42
83
AUA 2015
64
42
75
92
42
88
CCO 2010
89
50
75
83
42
63
CCO 2012-‐BT
89
56
82
78
42
71
CCO 2014-‐AS
94
56
76
83
42
67
CCO 2015
97
56
77
81
42
58
CTFPHC 2014
89
58
80
81
73
67
CUA 2011
61
44
68
81
31
42
EAU 2015
64
78
68
83
33
88
EGAP
P 2014
86
47
76
75
42
42
NICE 2014
92
94
93
92
83
83
NICE 2015
89
97
91
86
73
83
NICE 2015-‐PCA
3 92
89
88
97
85
92
SIOG 2014
67
72
61
81
46
67
SOGUG 2012
67
42
68
83
27
67
UMHS 2012
58
42
50
75
31
50
USPSTF 2012
83
44
83
89
33
83
13
Clinical question
Summary of re
commendatio
ns
Recommended
tumor marker(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2)
(OGD acron
yms)
Early
detectio
n of
recurrence or p
rogression
(RP)
Perio
dic PSA measurement sho
uld be offe
red to detect d
isease
recurrence
PSA
6/6
(ACS 2014, AHS
2013, ASCO 2014,
ASCO
2015, EAU
2015,
NICE 2014)
4/5
(AIOM 2015, AUA 2013,
ESMO 2013, NCC
N 2015)
After R
P biochemical re
currence is defined by 2 consecutive PSA values
>0.2 ng/mL
3/6
(AHS
2013, ASCO 2014,
EAU 2015)
3/5
(AIOM 2015, AUA-‐ASTRO 2013,
NCC
N 2015)
It is recommended that th
e fin
ding of a single elevated serum PSA
level be
reconfirm
ed before startin
g therapy
2/6
(EAU
2015, NICE 2014)
0/5
Accelerated PSA do
ubling tim
e is a negative progno
stic factor after a
biochemical re
lapse
2/6
(AHS
2013, EAU
2015)
1/5
(NCC
N 2015)
Bone sc
an and
CT shou
ld only be con
sidered in asymptom
atic patients
with
biochem
ical failure after RP who
have high baseline PSA (>10 ng/mL)
or high PSA kinetics (PSA do
ubling tim
e <6 mon
ths o
r PSA
velocity >0.5
ng/m
L/mon
th)
1/6
(EAU
2015)
0/5
Early
detectio
n of
recurrence or p
rogression
(RT)
Perio
dic PSA measurement sho
uld be offe
red to detect d
isease
recurrence
PSA
3/3
(AHS
2013, EAU
2015, NICE 2014)
1/1
(AIOM 2015 )
Biochemical re
currence after RT is defin
ed as a
rise ≥2 ng/m
L above the
nadir (defin
ed as the lowest P
SA level reached)
3/3
(AHS
2013, EAU
2015, NICE 2014)
1/1
(AIOM 2015)
Accelerated PSA do
ubling tim
e is a negative progno
stic factor after
biochemical re
lapse
2/6
(AHS
2013, EAU
2015)
1/5
(NCC
N 2015)
Mon
itorin
g of treatm
ent
respon
se in advanced
disease
Patie
nts w
ith stage M1 disease show
ing a good
treatm
ent respo
nse
shou
ld be evaluated at 3 and
6 mon
ths w
ith PSA
and
testosterone
measurement d
uring ho
rmon
al treatm
ent
PSA
4/6
(AHS
2013, ASCO-‐CCO
2014,
AUA 2015, EAU
2015)
3/3
(AIOM 2015, APC
2015,
NCC
N 2015)
Castratio
n-‐resis
tant prostate cancer (C
RPC) is defined as serum
testosterone <50 ng/dL plus 3
con
secutive rises in PSA
, 1 week apart,
resulting in tw
o 50% increases o
ver the nadir, with
PSA
>2 ng/m
L
3/6
(AUA 2015, EAU
2015,
SOGUG 2012)
1/3
(APC
2015)
In patients u
ndergoing interm
ittent a
ndrogen deprivation, PSA
and
testosterone sh
ould be mon
itored at se
t intervals du
ring the treatm
ent
pause (1 or 3
mon
ths) and
interm
ittent h
ormon
e therapy shou
ld be
stop
ped when PSA is >10 ng/m
L
2/6
(EAU
2015, NICE 2014)
0/3
(1) CPG
/total CPG
: CPG
s reportin
g the summarize
d inform
ation/total num
ber o
f CPG
s that con
sider th
e clinical question.
(2) OGD/total OGD: O
GDs re
porting the summarize
d inform
ation/total num
ber o
f OGDs th
at con
sider th
e clinical question.
∅ The examined CPG
s that con
sider th
e clinical question either do no
t add
ress TMs o
r, if TM
s are add
ressed, CPG
s do no
t present explicit recommendatio
ns.
PRO
STAT
E CA
NCE
R
Ta
ke-h
ome
mes
sage
Exam
ined
doc
umen
ts: 3
3 (2
4 CP
Gs,
9 O
GDs
)
Gion et al e19
© 2017 Wichtig Publishing
14
Incon
sistent re
commendatio
ns on TM
s in the clinical question are repo
rted by diffe
rent CPG
s.
CT = com
puted tomograph
y; DRE = digita
l rectal examination; RP = radical prostatectomy; RT = radiotherapy.
Acronyms of CPG
s
Dom
ain 1
Scop
e and pu
rpose
Dom
ain 2
Stakeholder
involvem
ent
Dom
ain 3
Rigor o
f developm
ent
Dom
ain 4
Clarity of
presentatio
n
Dom
ain 5
Applicability
Dom
ain 6
Edito
rial
independ
ence
ACS 2014
58
39
66
69
33
67
AHS 2013
43
24
38
43
36
47
ASCO
2012
92
47
58
81
33
63
ASCO
2014
89
69
74
81
33
63
ASCO
2015
83
78
65
86
33
63
ASCO
-‐CCO
2014
86
83
81
78
63
75
AUA 2011
61
42
73
86
42
75
AUA 2013-‐ED
58
44
72
89
42
83
AUA 2015
64
42
75
92
42
88
CCO 2010
89
50
75
83
42
63
CCO 2012-‐BT
89
56
82
78
42
71
CCO 2014-‐AS
94
56
76
83
42
67
CCO 2015
97
56
77
81
42
58
CTFPHC 2014
89
58
80
81
73
67
CUA 2011
61
44
68
81
31
42
EAU 2015
64
78
68
83
33
88
EGAP
P 2014
86
47
76
75
42
42
NICE 2014
92
94
93
92
83
83
NICE 2015
89
97
91
86
73
83
NICE 2015-‐PCA
3 92
89
88
97
85
92
SIOG 2014
67
72
61
81
46
67
SOGUG 2012
67
42
68
83
27
67
UMHS 2012
58
42
50
75
31
50
USPSTF 2012
83
44
83
89
33
83
PRO
STAT
E CA
NCE
R
Take
-hom
e m
essa
geEx
amin
ed d
ocum
ents
: 33
(24
CPG
s, 9
OG
Ds)
Circulating tumor markers: a guide to their appropriate clinical usee20
© 2017 Wichtig Publishing
15
Renal cancer
Exam
ined docum
ents: 10 (7 CPG
s, 3 OGDs)
Clinical question
Summary of re
commendatio
ns
Recommended
tumor marker(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2)
(OGD acron
yms)
Screening
Recommendatio
ns on TM
s not available
∅
2/2
(ACC
C 2012, ICU
D-‐EA
U 2011)
0/0
Differentia
l diagnosis
LDH may also
be determ
ined at the mom
ent o
f presentation for a
ll no
nmetastatic patients, given th
at it is not always immediately clear if a
patie
nt has metastatic dise
ase
LDH
∅
1/5
(ACC
C 2012)
1/3
(ESM
O 2014)
Recommendatio
ns on TM
s not available
4/5
(AHS
2012, EAU
2015, ICUD-‐
EAU 2011, NICE 2015)
2/3
(AIOM 2015, NCC
N 2015)
Preoperativ
e workup
Recommendatio
ns on TM
s not available
∅
4/4
(ACC
C 2012, A
HS 2012,
EAU 2015, ICUD-‐EA
U 2011)
3/3
(AIOM 2015, ESM
O 2014,
NCC
N 2015)
Reassessment a
fter initial
curativ
e treatm
ent
Recommendatio
ns on TM
s not available
∅
1/1
(AUA 2013)
0/0
Early
detectio
n of
recurrence or p
rogression
LDH determ
ination may be used at the disc
retio
n of th
e clinician
LDH
∅
1/5
(AUA 2013)
0/3
Recommendatio
ns on TM
s not available
4/5
(ACC
C 2012, A
HS 2012,
EAU 2015, ICUD-‐EA
U 2011)
2/3
(ESM
O 2014, NCC
N 2015)
Mon
itorin
g of treatm
ent
respon
se in advanced
disease
LDH may be used as a
prognostic factor (incorpo
rated in th
e Mem
orial
Sloan-‐Kettering Cancer Center [MSKCC
] or M
otzer score) in patie
nts w
ith
advanced/m
etastatic dise
ase treated with
some types o
f systemic th
erapy
LDH
∅
3/5
(ACC
C 2012, EAU
2015, ICUD-‐
EAU 2011)
3/3
(AIOM 2015, ESM
O 2014,
NCC
N 2015)
Recommendatio
ns on TM
s not available
2/5
(AHS
2012, SOGUG 2014)
0/3
(1) CPG
/total CPG
: CPG
s reportin
g the summarize
d inform
ation/total num
ber o
f CPG
s that con
sider th
e clinical question.
(2) OGD/total OGD: O
GDs re
porting the summarize
d inform
ation/total num
ber o
f OGDs th
at con
sider th
e clinical question.
∅ The examined CPG
s that con
sider th
e clinical question either do no
t add
ress TMs o
r, if TM
s are add
ressed, CPG
s do no
t present explicit recommendatio
ns.
REN
AL
CAN
CER
Take
-hom
e m
essa
geEx
amin
ed d
ocum
ents
: 10
(7 C
PGs,
3 O
GDs
)
to b
e co
ntinu
ed
Gion et al e21
© 2017 Wichtig Publishing
16
Acronyms of CPG
s
Dom
ain 1
Scop
e and pu
rpose
Dom
ain 2
Stakeholder
involvem
ent
Dom
ain 3
Rigor o
f developm
ent
Dom
ain 4
Clarity of
presentatio
n
Dom
ain 5
Applicability
Dom
ain 6
Edito
rial
independ
ence
ACCC 2012
75
78
64
67
29
50
AHS 2012
80
44
66
67
58
75
AUA 2013
72
44
78
80
33
75
EAU 2015
64
72
64
72
33
83
ICUD-‐EAU
2011
72
44
66
69
33
50
NICE 2015
89
97
91
89
73
88
SOGUG 2014
56
36
61
81
21
42
REN
AL
CAN
CER
Ta
ke-h
ome
mes
sage
Exam
ined
doc
umen
ts: 1
0 (7
CPG
s, 3
OG
Ds)
Circulating tumor markers: a guide to their appropriate clinical usee22
© 2017 Wichtig Publishing
17
Testicular cancer
Exam
ined docum
ents: 12 (7 CPG
s, 5 OGDs)
Clinical question
Summary of re
commendatio
ns
Recommended
tumor marker(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2)
(OGD acron
yms)
Screening
Serum TMs o
r any other blood
tests a
re not re
commended to sc
reen fo
r germ
cell tum
ors in asym
ptom
atic men
Non
e ∅
1/2
(ASCO 2010)
0/1
Recommendatio
ns on TM
s not available
1/2
(USPSTF 2011)
1/1
(EAU
2015)
Differentia
l diagnosis
Serum TMs a
re re
commended before orchiectomy for a
ll patie
nts suspected
of having a testicular germ cell tum
or to
help establish
the diagno
sis and
interpret p
ost-‐orchiectom
y levels
AFP, βhC
G, LDH
∅
2/3
(ASCO 2010, SIGN 2011)
5/5
(AIOM 2015, EAU
2015,
EGCC
CG 2013, ESM
O 2013,
NCC
N 2015)
The use of se
rum TM re
sults is not re
commended to guide decision
-‐making
on th
e need fo
r orchiectomy because concentrations in th
e no
rmal ra
nge do
no
t rule ou
t testicular cancer o
r the need for d
iagnostic orchiectomy
1/3
(ASCO 2010)
0/5
Supp
lementary inform
ation n. 1: W
hen using TM
results fo
r clinical
decisio
ns one sh
ould con
sider th
e po
ssible occurrence of false
positive
results (o
ther malignancies, benign cond
ition
s, physio
logical causes)
1/3
(ASCO 2010)
0/5
Supp
lementary inform
ation n. 2: For hCG
determination the use of assay
metho
ds th
at measure to
tal hCG
(intact α
/β dimer plus free β mon
omer) is
recommended
1/3
(ASCO 2010)
0/5
Recommendatio
ns on TM
s not available
1/3
(NICE 2015)
0/5
Preoperativ
e workup
(before and after
orchiectom
y, and
before
chem
otherapy and
/or
additio
nal surgery)
Serum AFP, βhC
G and
LDH
are re
commended pre-‐orchiectom
y, sh
ortly after
orchiectom
y, and
weekly thereafter until no
rmalization or plateau
AFP, βhC
G, LDH
4/4
(AHS
2013, ASCO 2010,
SIGN 2011, SIU-‐IC
UD-‐UICC 2011 )
5/5
(AIOM 2015, EAU
2015,
EGCC
CG 2013, ESM
O 2013,
NCC
N 2015)
Marker con
centratio
ns sh
ould be used along with
imaging techniqu
es to
allocate patients to progno
stic group
s (UICC, 2009, 7th ed.)
3/4
(AHS
2013, ASCO 2010,
SIGN 2011)
4/5
(AIOM 2015, EAU
2015,
EGCC
CG 2013, ESM
O 2013)
Supp
lementary inform
ation: The persistence of elevated serum TMs a
fter
orchiectom
y might indicate th
e presence of m
etastatic dise
ase (m
acro-‐ o
r microscop
ic) and
classify patients into the substage S1
3/4
(AHS
2013, ASCO 2010,
SIU-‐IC
UD-‐UICC 2011)
4/5
(AIOM 2015, EAU
2015,
EGCC
CG 2013, ESM
O 2013)
TEST
ICU
LAR
CAN
CER
Take
-hom
e m
essa
ge
Exam
ined
doc
umen
ts: 1
2 (7
CPG
s, 5
OG
Ds)
to b
e co
ntinu
ed
Gion et al e23
© 2017 Wichtig Publishing
18
Clinical question
Summary of re
commendatio
ns
Recommended
tumor marker(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2)
(OGD acron
yms)
Early
detectio
n of
recurrence or
progression
Perio
dic determ
ination of TMs is recom
mended. Duration of fo
llow-‐up after
therapy is completed sh
ould be at least 1
0 years in NSG
CTs a
nd at least 5
years in seminom
as; evaluation shou
ld be more frequent in th
e first 2 years
and in patients u
nder active surveillance
AFP, βhC
G, LDH
∅
4/5
(AHS
2013, ASCO 2010,
SIGN 2011, SIU-‐IC
UD-‐UICC 2011)
5/5
(AIOM 2015, EAU
2015,
EGCC
CG 2013, ESM
O 2013,
NCC
N 2015)
Supp
lementary inform
ation n. 1: Frequ
ency of TM determination du
ring
follow-‐up shou
ld be schedu
led with
reference to initial stage, histological
type and
post-‐orchiectom
y treatm
ents
2/5
(AHS
2013, ASCO 2010)
2/5
(EAU
2015, NCC
N 2015)
Supp
lementary inform
ation n. 2: LDH
has not been show
n to be helpful in
the follow-‐up of patients w
ith germ cell tum
ors
1/5
(SIGN 2011)
0/5
Recommendatio
ns on TM
s not available
1/5
(CCO
2014)
0/5
Mon
itorin
g of treatm
ent
respon
se in advanced
disease
In NSG
CT determination of TMs is recom
mended at th
e start o
f each
chem
otherapy cycle and
again when chem
otherapy is com
pleted
AFP, βhC
G, LDH
2/2
(AHS
2013, ASCO 2010)
5/5
(AIOM 2015, EAU
2015,
EGCC
CG 2013, ESM
O 2013,
NCC
N 2015)
In metastatic patients, TM levels before th
e start o
f chemotherapy sh
ould
be used for the correct allocatio
n to th
e IGCC
C progno
stic category into
good
-‐, interm
ediate-‐ o
r poo
r-‐risk grou
ps
2/2
(AHS
2013, ASCO 2010)
5/5
(AIOM 2015, EAU
2015,
EGCC
CG 2013, ESM
O 2013,
NCC
N 2015)
(1) CPG
/total CPG
: CPG
s reportin
g the summarize
d inform
ation/total num
ber o
f CPG
s that con
sider th
e clinical question.
(2) OGD/total OGD: O
GDs re
porting the summarize
d inform
ation/total num
ber o
f OGDs th
at con
sider th
e clinical question.
∅ The examined CPG
s that con
sider th
e clinical question either do no
t add
ress TMs o
r, if TM
s are add
ressed, CPG
s do no
t present explicit recommendatio
ns.
IGCC
C = International G
erm Cell Con
sensus Classificatio
n; NSG
CT = non
-‐sem
inom
atou
s germ cell tum
or.
Acronyms of CPG
s
Dom
ain 1
S cop
e and pu
rpose
Dom
ain 2
Stakeholder
involvem
ent
Dom
ain 3
Rigor o
f developm
ent
Dom
ain 4
Clarity of
presentatio
n
Dom
ain 5
Applicability
Dom
ain 6
Edito
rial
independ
ence
AHS 2013
75
44
66
72
60
79
ASCO
2010
92
81
83
86
33
67
CCO 2014
94
72
83
75
54
71
NICE 2015
89
97
91
86
73
83
SIGN 2011
92
89
80
94
73
58
SIU-‐IC
UD-‐UICC 2011
72
44
69
81
33
33
USPSTF 2011
81
33
73
81
29
67
TEST
ICU
LAR
CAN
CER
Take
-hom
e m
essa
geEx
amin
ed d
ocum
ents
: 12
(7 C
PGs,
5 O
GDs
)
Circulating tumor markers: a guide to their appropriate clinical usee24
© 2017 Wichtig Publishing
26
DETAILED SUMMARY TABLES -‐ Users’ instructions
Definition and target audience Detailed Summary Tables are tables prepared for every tumor type which report recommendations and supplementary information from different guidance documents with enough details to be useful for health care providers, policy makers (for potential adaptation to specific settings) and staff developing educational material informed by available evidence. Structure
Total number of selected documents (number of CPGs, number of OGDs)
Clinical question
CPG
OGD
Summary of recommendations
Supplementary information
The different clinical questions are reported
Number of CPGs addressing the clinical question
Number of OGDs addressing the clinical question
Recommendations from CPGs and from OGDs that are consistent with those of CPGs Only those parts of the text explicitly defined as recommendations and clearly recognizable as such were considered Similar recommendations and supplementary information from different guidance documents are reported once, followed by the acronyms of the guidance documents by which they are provided Acronyms of CPGs are printed in bold blue type, those of OGDs are printed in regular type
Useful supplementary information for the clinical application of TMs from both CPGs and OGDs are summarized (e.g., suggested cutoff points, timing of serial sample monitoring, causes of false positive or false negative TM results) Recommendations from OGDs that are inconsistent with those of CPGs are reported Advice for clinical practice not declared or not recognizable as recommendation in the document is reported Acronyms of CPGs are printed in bold blue type, those of OGDs are printed in regular type
Detailed summary tables
Users' instructions
Definition and target audience
Take-Home Messages are presented in table format for every tumor type, summarizing essential information to support decision-making in clinical practice. They are intended for use by health care providers.
STRUCTURETotal number of selected documents (number of CPGs, number of OGDs)
Gion et al e25
© 2017 Wichtig Publishing
1 Bladder cancer
Exam
ined docum
ents: 15 (7 CPG
s, 8 OGDs)
Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Screening
1 4
Clinical que
stion co
nsidered
, no ex
plicit reco
mmen
datio
ns on TM
s prov
ided
(USPSTF 2011
, EAU
201
5-‐NM)
Curren
t evide
nce is insufficien
t to assess th
e ba
lanc
e of ben
efits
and
harms
of sc
reen
ing for b
ladd
er can
cer in asym
ptom
atic adu
lts (U
SPSTF 2011
, EA
U 201
5-‐NM)
Routine ap
plication of sc
reen
ing is no
t recom
men
ded (EAU
201
5-‐NM,
ESMO 201
4)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(AIOM 201
5, EAU
201
5-‐UT, ESM
O 201
4)
Differentia
l diagnosis
2 8
In prim
ary care do no
t sub
stitu
te urin
ary biom
arke
rs fo
r cystoscop
y to
inve
stigate suspected blad
der c
ancer, ex
cept in
the co
ntex
t of a
clin
ical
research
stud
y (NICE 2015-‐BC, AURO
201
0, EAU
201
5-‐NM)
Urin
ary biom
arke
rs (e
.g., NMP2
2) can
be used
as a
n ad
junc
t to cystosco
py
to detect inv
isible tumor in
seco
ndary care (N
ICE 2015-‐BC, EAU
201
5-‐NM)
Clinical que
stion co
nsidered
, no ex
plicit reco
mmen
datio
ns on TM
s prov
ided
(NICE 2015-‐SC, AIOM 201
5, EAU
201
5-‐MI, ES
MO 201
4)
No prim
ary care evide
nce was id
entified pe
rtaining
to th
e diag
nostic
accu
racy of u
rine marke
rs (N
MP2
2 an
d MCM
5) in
patients w
ith su
spected
blad
der c
ancer w
here th
e clinical re
spon
sibility w
as re
tained
by prim
ary
care (N
ICE 2015-‐SC)
No blad
der T
M te
st has yet bee
n show
n to be supe
rior to urine cytology
and cystosco
py (A
IOM 201
5, AURO
201
0, EAU
201
5-‐MI, EA
U 201
5-‐NM,
ESMO 201
4)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(EAU
201
5-‐UR,
EAU 201
5-‐UT, NCC
N 201
5)
Preoperativ
e workup
4 8
Clinical que
stion co
nsidered
, no ex
plicit reco
mmen
datio
ns on TM
s prov
ided
(NICE 2015-‐BC)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(AHS 2013-‐M
I, AH
S 2013-‐NM, A
HS 2013-‐UT, AIOM 201
5, AURO
201
0, EAU
201
5-‐MI,
EAU 201
5-‐NM, E
AU 201
5-‐UR, EAU
-‐201
5 UT, ESM
O 201
4, NCC
N 201
5)
Reassessment a
fter initial
curativ
e treatm
ent
0 0
Clinical que
stion no
t add
ressed
by CP
Gs
Early
detectio
n of
recurrence or p
rogression
5
8 Do
not su
bstitute urinary biom
arke
rs fo
r cystoscop
y for follow-‐up after
trea
tmen
t for bladd
er can
cer (NICE 2015-‐BC, AIOM 201
5, EAU
201
5-‐NM,
ESMO 201
4)
Do not use urin
ary biom
arke
rs or c
ytolog
y in add
ition
to cystoscop
y for
follo
w-‐up after treatmen
t for lo
w-‐risk
bladd
er can
cer (NICE 2015-‐BC,
AIOM 201
5)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(AHS 2013-‐M
I, AH
S 2013-‐NM, A
HS 2013-‐UT, CUA 2013
, EAU
201
5-‐MI, EA
U 201
5-‐UR,
EAU 201
5-‐UT)
No blad
der T
M te
st has yet bee
n show
n to be supe
rior to urine cytology
and cystosco
py (A
IOM 201
5, AURO
201
0, ESM
O 201
4, NCC
N 201
5)
Urin
ary urothe
lial T
M m
easuremen
t is c
onsid
ered
an op
tiona
l inv
estig
ation
(NCC
N 201
5)
Clinical que
stion co
nsidered
, no ex
plicit reco
mmen
datio
ns on TM
s prov
ided
(AURO
201
0)
BLA
DD
ER C
AN
CER
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 15
(7 C
PGs,
8 O
GDs
)
to b
e co
ntinu
ed
Circulating tumor markers: a guide to their appropriate clinical usee26
© 2017 Wichtig Publishing
2 Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Mon
itorin
g of treatm
ent
respon
se in advanced
disease
3 5
Clinical que
stion co
nsidered
, but criteria to
mon
itor treatmen
t respo
nse
(includ
ing TM
s) not add
ressed
(AHS 2013-‐M
I, AH
S 2013-‐UT, NICE 2015-‐BC,
AURO
201
0, ESM
O 201
4, NCC
N 201
5)
Curren
tly, n
o biom
arke
rs can
be reco
mmen
ded in daily clin
ical practice
because they
hav
e no
impa
ct on ou
tcom
e pred
ictio
n, trea
tmen
t decision
s,
or th
erap
y mon
itorin
g in m
uscle-‐inva
sive blad
der c
ancer (EA
U 201
5-‐MI)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(AIOM 201
5)
(1) Recom
men
datio
ns from
CPG
s an
d from
OGDs, if con
sistent w
ith th
ose of CPG
s.
(2) Sup
plem
entary in
form
ation from
both CP
Gs an
d OGDs, and
reco
mmen
datio
ns from
OGDs that are in
consist
ent w
ith th
ose of CPG
s.
BLA
DD
ER C
AN
CER
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 15
(7 C
PGs,
8 O
GDs
)
Gion et al e27
© 2017 Wichtig Publishing
3 Breast cancer
Exam
ined docum
ents: 15 (9 CPG
s, 6 OGDs)
Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Differentia
l diagnosis
2 5
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(NICE 2012-‐EarlyBC
, NICE 2015-‐SC, AIOM 201
5, ESM
O 201
3-‐Ea
rlyBC
, EUSO
MA 20
14-‐You
ng,
NCC
N 201
4-‐Diag
n, NCC
N 201
5)
Preoperativ
e workup
2 4
Clinical que
stion co
nsidered
, but no ex
plicit reco
mmen
datio
ns on TM
s prov
ided
(AHS 2012-‐BB)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(NICE 2012-‐EarlyBC
, AIOM 201
5, EUSO
MA 20
14-‐You
ng, N
CCN 201
5)
Patie
nts d
o no
t ben
efit from TM st
aging (ESM
O 201
3-‐Ea
rlyBC
)
Reassessment a
fter initial
curativ
e treatm
ent
0 0
Clinical que
stion no
t add
ressed
by CP
Gs
Early
detectio
n of
recurrence or p
rogression
4
4 Th
e use of CA1
5.3, CA2
7.29
or C
EA is not re
commen
ded for rou
tine
surveilla
nce of breast c
ancer a
fter prim
ary therap
y in an othe
rwise
asym
ptom
atic patient w
ith no specific fin
ding
s on clinical examination
(AHS 2013-‐FU, A
SCO 2012-‐FU
, NHMRC
2010, AIOM 201
5, ESM
O 201
3-‐Ea
rlyBC
, EU
SOMA 20
14-‐You
ng)
TMs a
re re
commen
ded on
ly if clin
ically in
dicated (NHMRC
2010,
ESMO 201
3-‐Ea
rlyBC
)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(NICE 2012-‐EarlyBC
)
In asymptom
atic patients, th
ere are no
data to in
dicate th
at any
TMs (such
as CA1
5 .3 or CEA
) produ
ce a su
rvival ben
efit (NHMRC
2010, ESM
O 201
3-‐Ea
rlyBC
, NCC
N 201
5)
Clinical que
stion co
nsidered
, but no ex
plicit reco
mmen
datio
ns on TM
s prov
ided
(NCC
N 201
5)
Mon
itorin
g of treatm
ent
respon
se in advanced
disease
3 4
CEA, CA1
5.3 an
d CA
27.29 may
be used
as a
djun
ctive assessmen
ts to
co
ntrib
ute to decision
s reg
arding
therap
y for m
etastatic
breast c
ancer
(ASCO 2015-‐M+, ESM
O 201
4-‐AB
C, EUSO
MA 20
14-‐You
ng, N
CCN 201
5)
Data are in
sufficien
t to reco
mmen
d use of CEA
, CA1
5.3 an
d CA
27.29 alon
e for m
onito
ring respon
se to
trea
tmen
t (AS
CO 2015-‐M+, ESM
O 201
4-‐AB
C,
EUSO
MA 20
14-‐You
ng, N
CCN 201
5)
Clinical que
stion co
nsidered
, but criteria to
mon
itor treatmen
t respo
nse
(includ
ing TM
s) not add
ressed
(CECOG 2009, AIOM 201
5)
Clinical que
stion co
nsidered
, but no ex
plicit reco
mmen
datio
ns on TM
s prov
ided
(NICE 2014-‐M
+)
Caution shou
ld be used
whe
n interpretin
g increa
sing CE
A, CA1
5.3 or
CA27
.29 leve
l s du
ring the first 4 to
6 w
eeks of a
dminist
ratio
n of a new
therap
y, given
that sp
urious early in
crea
ses m
ay occur ( A
SCO 2015-‐M+)
In th
e ab
senc
e of re
adily m
easurable disease, a 20%
to 30%
increa
se in
CE
A, CA1
5.3 or CA2
7.29
may
be used
to in
dicate trea
tmen
t failure, a
long
with
supp
ortin
g clinical evide
nce, before co
nsidering discon
tinua
tion of
therap
y (ASCO 2015-‐M+)
Serum TM le
vels in assoc
iatio
n with
patient sy
mptom
s may
be indicativ
e of
disease prog
ression in patients w
ith bon
e-‐do
minan
t metastatic
dise
ase
( NCC
N 201
5)
(1) Recom
men
datio
ns from
CPG
s an
d from
OGDs, if con
sistent w
ith th
ose of CPG
s.
(2) Sup
plem
entary in
form
ation from
both CP
Gs an
d OGDs, and
reco
mmen
datio
ns from
OGDs that are in
consist
ent w
ith th
ose of CPG
s.
BREA
ST C
AN
CER
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 15
(9 C
PGs,
6 O
GDs
)
Circulating tumor markers: a guide to their appropriate clinical usee28
© 2017 Wichtig Publishing
4 Cervical cancer
Exam
ined docum
ents: 7 (3 CPG
s, 4 OGDs)
Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Differentia
l diagnosis
1 4
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(NICE 2015
, AIOM 201
5,
ESMO 201
2, NCC
N 201
5)
Curren
tly ava
ilable serum TMs, in
clud
ing SC
C, are not re
commen
ded for
use in sc
reen
ing or diagn
osis of cervical can
cer (NAC
B 20
10)
Preoperativ
e workup
1 4
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(AHS 2013
, ESM
O 201
2,
NCC
N 201
5)
Pretreatmen
t SCC
con
centratio
ns are not re
commen
ded for rou
tine use.
In fa
ct, a
n elev
ated
pretrea
tmen
t SCC
con
centratio
n ha
s bee
n foun
d to
be an inde
pend
ent risk
factor fo
r poo
r progn
osis in se
veral studies, b
ut
the clinical usefulness in trea
tmen
t plann
ing is un
certain (N
ACB 20
10)
Elev
ated
con
centratio
ns hav
e be
en fo
und in con
ditio
ns other th
an
cervical can
cer (NAC
B 20
10):
-‐ other m
aligna
ncies (squa
mou
s cell carcino
mas of the
vulva
, vag
ina,
head
and
neck, esoph
agus, a
nd lu
ng)
-‐ ben
ign co
ndition
s of the
skin (e
.g., psoriasis
, eczem
a), lun
g (e.g.,
sarcoido
sis), liver, a
nd kidne
y. Very high
value
s hav
e be
en fo
und in
patie
nts w
ith re
nal failure or lun
g disease
Clinical que
stion co
nsidered
, but no ex
plicit reco
mmen
datio
ns on TM
s prov
ided
(AIOM 201
5)
Reassessment a
fter initial
curativ
e treatm
ent
0 1
Clinical que
stion no
t add
ressed
by CP
Gs
Clinical que
stion co
nsidered
, but no ex
plicit reco
mmen
datio
ns on TM
s prov
ided
(NAC
B 20
10)
Persist
ently
eleva
ted serum SCC
con
centratio
ns after trea
tmen
t sug
gest
tumor persis
tenc
e (N
ACB 20
10)
Early
detectio
n of
recurrence or p
rogression
2
4 Th
e use of TMs (includ
ing SC
C) in
asymptom
atic patients c
anno
t be
reco
mmen
ded be
cause the im
pact of a
symptom
atic re
curren
ce detectio
n on
on
survival ra
tes is n
ot kno
wn (CCO
2015, AIOM 201
5, NAC
B 20
10)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(AHS 2013
, ESM
O 201
2,
NCC
N 201
5)
SCC mon
itorin
g after p
rimary trea
tmen
t stron
gly co
rrelates w
ith clin
ical
course of d
isease in patients w
ith sq
uamou
s cell cervical can
cer b
ut th
ere
is as yet no clea
r evide
nce that earlie
r detectio
n im
prov
es outco
me
(CCO
2015, NAC
B 20
10)
TMs m
ay be co
nsidered
in high-‐ris
k pa
tients w
ith lo
cally adv
anced
disease in w
hom clin
ical eva
luation is im
paire
d as a con
sequ
ence of
trea
tmen
t (AIOM 201
5)
Mon
itorin
g of treatm
ent
respon
se in advanced
disease
1 3
Clinical que
stion co
nsidered
, but criteria to
mon
itor treatmen
t respo
nse
(includ
ing TM
s) not add
ressed
(AHS 2013
, AIOM 201
5, NCC
N 201
5)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(ESM
O 201
2)
(1) Recom
men
datio
ns from
CPG
s an
d from
OGDs, if con
sistent w
ith th
ose of CPG
s.
(2) Sup
plem
entary in
form
ation from
both CP
Gs an
d OGDs, and
reco
mmen
datio
ns from
OGDs that are in
consist
ent w
ith th
ose of CPG
s.
CERV
ICA
L CA
NCE
R
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 7 (3
CPG
s, 4
OG
Ds)
Gion et al e29
© 2017 Wichtig Publishing
5 Endo
metria
l cancer
Exam
ined docum
ents: 7 (3 CPG
s, 4 OGDs)
Clinical question
CPG
OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Screening
0 1
Clinical que
stion no
t add
ressed
by CP
Gs
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(NCC
N 201
5)
Differentia
l diagnosis
1 4
Clinical que
stion co
nsidered
, no ex
plicit reco
mmen
datio
ns on TM
s prov
ided
(NICE 2015
) No ev
iden
ce w
as id
entified pe
rtaining
to th
e diag
nostic accuracy of CA1
25
in patients w
ith su
spected en
dometria
l can
cer w
here th
e clinical
respon
sibility w
as re
tained
by prim
ary care (N
ICE 2015
)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(AIOM 201
5,
ESMO 201
3, NCC
N 201
5, SGO 201
4)
Preoperativ
e workup
1 3
Preo
perativ
e ab
dominop
elvic CT
scan
may
be useful in
cases w
ith
increa
sed serum CA1
25 le
vels (ACN
2011)
CA12
5 is no
t recom
men
ded for rou
tine preo
perativ
e worku
p, th
ough
it
may
be useful in
selected
cases (N
CCN 201
5)
CA12
5 may
be indicated as an op
tiona
l test in pa
tients in who
m m
etastatic
disease is suspected (N
CCN 201
5)
Clinical que
stion co
nsidered
, but TMs no
t add
ressed
(AIOM 201
5,
ESMO 201
3)
Reassessment a
fter initial
curativ
e treatm
ent
0 0
Clinical que
stion no
t add
ressed
by CP
Gs
Early
detectio
n of
recurrence or p
rogression
1
4 Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(AHS 2013
, ES
MO 201
3)
Do not m
easure TMs (CE
A, CA1
25, C
A19.9, AFP
, etc.) if there are no
suspicious sy
mptom
s of recurrenc
e (AIOM 201
5)
The utility of serum
CA1
25 assessm
ent rem
ains con
trov
ersia
l (SG
O 201
4)
CA12
5 is op
tiona
l (NCC
N 201
5)
Mon
itorin
g of treatm
ent
respon
se in advanced
disease
1 4
Clinical que
stion co
nsidered
, but criteria to
mon
itor treatmen
t respon
se (inc
luding
TMs) not add
ressed
(AHS 2013
, AIOM 201
5,
ESMO 201
3, NCC
N 201
5, SGO 201
4)
(1) Recom
men
datio
ns from
CPG
s an
d from
OGDs, if con
sistent w
ith th
ose of CPG
s.
(2) Sup
plem
entary in
form
ation from
both CP
Gs an
d OGDs, and
reco
mmen
datio
ns from
OGDs that are in
consist
ent w
ith th
ose of CPG
s.
END
OM
ETRI
AL
CAN
CER
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 7 (3
CPG
s, 4
OG
Ds)
Circulating tumor markers: a guide to their appropriate clinical usee30
© 2017 Wichtig Publishing
6 Ovaria
n cancer
Examined docum
ents: 22 (12 CP
Gs, 10 OGDs)
Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Screening general
polulatio
n 2
3 In asymptom
atic w
omen
with
out k
nown ge
netic
mutations th
at
increa
se th
e ris
k of ova
rian canc
er, d
o no
t scree
n for o
varia
n canc
er
(USPSTF 2012
, ACO
G 201
1-‐EC
, NCC
N 201
5)
Screen
ing for o
varia
n canc
er in
the ge
neral p
opulation shou
ld not be
performed
outsid
e the research
setting (SIGN 2013-‐EC
)
No clea
r ben
efit of sc
reen
ing (serum
CA1
25 le
vel com
bine
d with
tran
svag
inal
ultrasou
nd or transva
gina
l ultrasou
nd alone
) has bee
n de
mon
strated (SIGN 2013-‐
EC, U
SPSTF 2012
, ACO
G 201
1-‐EC
, AIOM 201
5)
Clinical que
stion co
nsidered
, no ex
plicit reco
mmen
datio
ns on TM
s provide
d (AIOM 201
5)
Screening of people at
increased risk (positive
family history)
3 5
Ova
rian canc
er su
rveilla
nce shou
ld not be reco
mmen
ded for w
omen
at high or poten
tially high ris
k (AHS 2011-‐HR, NHMRC
2011-‐HR,
ACOG 201
1-‐EC
)
Screen
ing for o
varia
n canc
er in
high-‐ris
k grou
ps sh
ould only be
offered in th
e co
ntex
t of a
research
stud
y (SIGN 2013-‐EC
)
Individu
als s
hould be
cou
nseled
on the lim
itatio
ns of the
currently ava
ilable
surveilla
nce metho
ds and
the symptom
s/sig
ns of o
varia
n canc
er (A
HS 2011-‐HR)
No clea
r evide
nce was id
entified as to
whe
ther sc
reen
ing in high-‐ris
k grou
ps has
an im
pact on mortality from
ova
rian canc
er (SIGN 2013-‐EC
, ACO
G 201
1-‐EC
, NCC
N 201
5)
For tho
se patients w
ho hav
e no
t elected
risk-‐red
ucing salpingo
-‐oop
horectom
y,
there may
be circum
stan
ces w
here clin
icians find
screen
ing he
lpful (NCC
N 201
5-‐HR
)
The low preva
lenc
e of ova
rian canc
er and
the high
like
lihoo
d of a positive
screen
ing test re
sult ne
cessita
ting furthe
r inv
asive surgical eva
luation are
obstacles in ov
arian canc
er sc
reen
ing prog
rams a
mon
g wom
en at inh
erite
d ris
k (ACO
G 200
9-‐HR
)
Clinical que
stion co
nsidered
, no ex
plicit reco
mmen
datio
ns on TM
s provide
d (ACO
G 200
9-‐HR
, AIOM 201
5)
OVA
RIA
N C
AN
CER
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 22
(12
CPG
s, 1
0 O
GDs
)
to b
e co
ntinu
ed
Gion et al e31
© 2017 Wichtig Publishing
7 Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Differentia
l diagnosis
6 7
CA12
5 in con
junc
tion with
tran
svag
inal pelvic ultrasou
nd sh
ould be
carried ou
t in wom
en w
ith su
spicious sy
mptom
s of o
varia
n canc
er or
an adn
exal m
ass (NICE 2011-‐EC, NICE 2015, SIGN 2013-‐EC, A
COG 201
1-‐EC
, ACO
G 201
3-‐AM
, AIOM 201
5, ESM
O 201
3-‐EC
, NCC
N 201
5)
An estim
ation of th
e ris
k of m
aligna
ncy shou
ld be carried ou
t for th
e assessmen
t of a
n ov
arian mass (BSGE 2011, CCO
2011-‐AM
, NICE 2011-‐
EC, SIGN 2013-‐EC
, ESM
O 201
3-‐EC
)
As a st
anda
lone
mod
ality
, serum
CA1
25 is not re
commen
ded for
distingu
ishing be
twee
n be
nign
and
maligna
nt adn
exal m
asses
(CCO
2011-‐AM
)
CA12
5 assay do
es not nee
d to be un
dertak
en in
premen
opau
sal
wom
en w
hen an
ultrason
ograph
ic diagn
osis of a simple ov
arian cyst
has b
een mad
e (BSG
E 2011
)
LDH, AFP
and
hCG
shou
ld be mea
sured in all wom
en und
er age
40
with
a com
plex
ova
rian mass b
ecau
se of the
possib
ility of g
erm cell
tumors:
-‐ CA1
25 (A
HS 2013-‐GCT, N
ICE 2011-‐EC, NCC
N 201
5)
-‐ AFP
(AHS 2013-‐GCT, BSG
E 2011, N
ICE 2011-‐EC, ACO
G 201
3-‐AM
, ES
MO 201
2-‐GCT
, NCC
N 201
5)
-‐ βhC
G (A
HS 2013-‐GCT, BSG
E 2011, N
ICE 2011-‐EC, ACO
G 201
3-‐AM
, ES
MO 201
2-‐GCT
, NCC
N 201
5)
-‐ LDH
(AHS 2013-‐GCT, BSG
E 2011
, ACO
G 201
3-‐AM
, ESM
O 201
2-‐GCT
) -‐ inh
ibin (E
SMO 201
2-‐GCT
, NCC
N 201
5)
RMI I (R
isk of M
aligna
ncy Index I) is the most a
ccurate scoring system
for w
omen
with
suspected ov
arian canc
er (B
SGE 2011, N
ICE 2011-‐EC, SIGN 2013-‐EC
)
The ch
oice of sco
ring system
may
be mad
e ba
sed on
clin
ician preferen
ce
(CCO
2011-‐AM
)
Serum CA1
25 is eleva
ted in only 50
% of e
arly-‐stage
ova
rian canc
ers (BSGE 2011,
CCO 2011-‐AM
, ACO
G 201
1-‐EC
, ESM
O 201
3-‐EC
)
Mea
surin
g the CA
125 leve
l may
predict can
cer m
ore accu
rately in
po
stmen
opau
sal tha
n prem
enop
ausal w
omen
(CCO
2011-‐AM
, ACO
G 201
1-‐EC
, AC
OG 201
3-‐AM
)
CA12
5 can be
eleva
ted for rea
sons other th
an ova
rian canc
er (B
SGE 2011,
CCO 2011-‐AM
, SIGN 2013-‐EC
, ACO
G 201
1-‐EC
, ACO
G 201
3-‐AM
, ESM
O 201
3-‐EC
): -‐ o
ther m
aligna
ncies (tumors o
f the
pan
crea
s, breast, lung
, colon
) -‐ b
enign co
ndition
s (en
dometrio
sis, p
elvic infla
mmatory disease an
d liver
disease, uterin
e leiomyo
mata, sy
stem
ic lu
pus e
rythem
atosus, inflammatory
bowel dise
ase, ascite
s of a
ny etio
logy, p
leural or p
ericardial effu
sions, a
recent
lapa
rotomy)
-‐ phy
siological cau
ses (men
struation, pregn
ancy)
CA12
5 is likely to be raise
d to se
veral h
undred
s or tho
usan
ds of u
nits/m
L in st
age
III-‐IV
end
ometrio
sis (B
SGE 2011
, ACO
G 201
3-‐AM
)
Other TMs h
ave no
t bee
n prov
ed to
improv
e ea
rly detectio
n an
d survival ra
tes
(NICE 2011-‐EC, ACO
G 201
1-‐EC
, NCC
N 201
5)
Prelim
inary da
ta on HE
4 show
ed it to
hav
e relativ
ely high
sensitivity and
specificity, b
ut data on
HE4
are not yet su
bstantial e
noug
h to ena
ble it to be
reco
mmen
ded instea
d of se
rum CA1
25 (N
ICE 2011-‐EC)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(ESG
O 201
1)
Preoperativ
e workup
3 4
AFP, βhC
G and
LDH
in assoc
iatio
n with
clin
ical find
ings are used to
determ
ine prog
nosis
for d
ysge
rminom
as and
non
-‐dysge
rminom
as
(AHS 2013-‐GCT
)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(AHS 2013-‐EC,
SIGN 2013-‐EC
, ESM
O 201
2-‐GCT
, ESM
O 201
3-‐EC
)
Risk class definition
(in association with
clin
ical find
ings) (AH
S 2013-‐GCT
): Dy
sgerminom
a -‐ G
ood: any
LDH
, βhC
G, n
ormal AFP
. Intermed
iate: a
ny LDH
, βh
CG, n
ormal AFP
Non
-‐dysge
rminom
a -‐ G
ood: LDH
<1.5 tim
es N, A
ND
βhCG
<5,00
0, AND AF
P <1
,000
. Intermed
iate: LDH
1.5-‐10 tim
es N, O
R βh
CG 5,000
-‐50,00
0, OR AF
P 1,00
0-‐10
,000
. Poo
r: LD
H >1
0 tim
es N, O
R βh
CG >50
,000
, OR AF
P >1
0,00
0
(N: u
pper limit of th
e referenc
e interval)
TMs (includ
ing CA
125, in
hibin an
d βh
CG) c
an be mea
sured if clinically in
dicated
(NCC
N 201
5)
Clinical que
stion co
nsidered
, no ex
plicit reco
mmen
datio
ns on TM
s provide
d (AIOM 201
5)
OVA
RIA
N C
AN
CER
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 22
(12
CPG
s, 1
0 O
GDs
)
to b
e co
ntinu
ed
Circulating tumor markers: a guide to their appropriate clinical usee32
© 2017 Wichtig Publishing
8 Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Reassessment a
fter initial
curativ
e treatm
ent
1 4
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(AHS 2013-‐EC)
Seria
l mea
suremen
t of C
A125
is a useful m
arke
r to assess th
e respon
se to
ch
emothe
rapy
in epithelial o
varia
n canc
er (A
IOM 201
5, ESM
O 201
3-‐EC
, NCC
N 201
5)
If the CA
125 leve
l doe
s not re
ach the no
rmal ra
nge be
fore th
e en
d of
chem
othe
rapy
, the
dise
ase status w
ould be rega
rded
as a
partia
l respo
nse to
fron
tline
trea
tmen
t (ES
MO 201
3-‐EC
)
If the CA
125 leve
l doe
s not re
ach the no
rmal ra
nge ap
prox
imately 20
day
s after
radical surge
ry, it s
hould be
con
sidered
as a
neg
ative prog
nostic fa
ctor
(AIOM 201
5)
Serum TMs (CA
125 an
d inhibin, AFP
, βhC
G, LDH
) can
correlate w
ith tu
mor
respon
se during ch
emothe
rapy
(ESM
O 201
2-‐GCT
, NCC
N 201
5)
Early
detectio
n of
recurrence or p
rogression
4
6 CA
125 bloo
d test has not bee
n prov
en to
be be
nefic
ial a
nd is
therefore no
t recom
men
ded for rou
tine follo
w-‐up (AHS 2013-‐EC)
In th
e ab
senc
e of sy
mptom
s, ro
utine mea
suremen
t of C
A125
during
follo
w-‐up is no
t man
datory (SIGN 2013-‐EC
)
It is reco
mmen
ded to con
tinue
hist
olog
y-‐specific TM
mea
suremen
t in
the routine follo
w-‐up of patients w
ith non
epith
elial o
varia
n canc
er
(AHS 2013-‐EC, ESG
O 201
1, NCC
N 201
5)
A ris
ing CA
125 leve
l sho
uld trigge
r further im
aging (NHMRC
2012
, AIOM 201
5, ESG
O 201
2-‐FU
, NCC
N 201
5)
Wom
en sh
ould be fully in
form
ed of the
pros a
nd con
s of rou
tine
mea
suremen
t of C
A125
during follo
w-‐up (NHMRC
2012
, AIOM 201
5,
ESGO 201
2-‐FU
, NCC
N 201
5)
Some wom
en m
ay ben
efit from
routine mea
suremen
t of C
A125
, includ
ing those who
are elig
ible fo
r secon
dary cytored
uctiv
e surgery
(NHMRC
2012
)
Follo
w-‐up may
includ
e CA
125 (ESG
O 201
1, ESG
O 201
2-‐FU
, NCC
N 201
5)
A ris
ing CA
125 leve
l doe
s not dire
ctly le
ad to
a cha
nge in trea
tmen
t (AIOM 201
5,
ESMO 201
3-‐EC
, NCC
N 201
5)
Elev
ated
value
s must b
e co
nfirm
ed by 2 sepa
rate m
easuremen
ts obtaine
d at
least 1
wee
k ap
art (ES
MO 201
3-‐EC
)
There is no
evide
nce of a su
rvival ben
efit for w
omen
who
com
men
ced ea
rly
chem
othe
rapy
for firs
t relap
se based
on raise
d CA
125 leve
l alone
(NHMRC
2012
, NCC
N 201
5)
There is no
reco
mmen
ded freq
uenc
y of fo
llow-‐up co
nsultatio
ns. D
ifferen
t gu
idelines re
port partia
lly differen
t sch
emes, w
hich
are su
mmarized
as follows:
-‐ the
re is no reco
mmen
ded freq
uenc
y of fo
llow-‐up co
nsultatio
ns (N
HMRC
2012
) -‐ o
bserve
TMs e
very 3 m
onths if lev
els a
re in
itially eleva
ted; observe
for 2
yea
rs.
After 2
yea
rs from
com
pleting trea
tmen
t, visit
s eve
ry 6 m
onths (AH
S 2013-‐EC)
-‐ mea
suremen
t of C
A125
is often
carrie
d ou
t eve
ry 3 m
onths for 2 yea
rs, the
n ev
ery 6 mon
ths d
uring ye
ars 4
and
5 or u
ntil prog
ression (ESM
O 201
2-‐GCT
, ES
MO 201
3-‐EC
) -‐ e
very 3 m
onths for th
e first 2 yea
rs, the
n ev
ery 6 mon
ths d
uring the third
, fourth and
fifth ye
ars (
AIOM 201
5)
-‐ at lea
st eve
ry 3/4 m
onths d
uring the first 3 yea
rs after in
itial trea
tmen
t and
ev
ery ye
ar th
erea
fter (E
SGO 201
1)
Prolon
ged follo
w-‐up is requ
ired in w
omen
with
borde
rline
ova
rian tumors
because late re
curren
ces h
ave be
en re
ported
(after 20 ye
ars) (E
SGO 201
1)
OVA
RIA
N C
AN
CER
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 22
(12
CPG
s, 1
0 O
GDs
)
to b
e co
ntinu
ed
Gion et al e33
© 2017 Wichtig Publishing
9 Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Mon
itorin
g of treatm
ent
respon
se in advanced
disease
5 4
Seria
l mea
suremen
t of C
A125
is useful to assess th
e respon
se to
ch
emothe
rapy
(CCO
2011, ESM
O 201
3-‐EC
, NCC
N 201
5)
Clinical que
stion co
nsidered
, but criteria to
mon
itor treatmen
t respon
se (inc
luding
TMs) not add
ressed
(AHS 2013-‐EC, AHS 2013-‐GCT,
SIGN 2013 EC, N
ICE 2011 EC, AIOM 201
5)
Prog
ression or re
curren
ce based
on serum CA1
25 le
vel is d
efined
according
to
Gyn
ecolog
ic Can
cer InterGroup
(GCIG) c
riteria (E
SMO 201
3-‐EC
) GCIG re
spon
se criteria: C
A125
respon
se is defined
as a
t lea
st a 50%
redu
ction in
CA12
5 leve
ls from
a pretrea
tmen
t sam
ple. The
respon
se m
ust b
e co
nfirm
ed and
maintaine
d for a
t lea
st 28 da
ys. P
atients c
an be ev
alua
ted acco
rding to CA1
25
only if th
ey hav
e a pretreatmen
t sam
ple that is at lea
st tw
ice the up
per lim
it of
the referenc
e rang
e an
d with
in 2 w
eeks before startin
g the trea
tmen
t
Serum TMs (
βhCG
, AFP
, LDH
, CA1
25 and
inhibin) can
be mea
sured du
ring
chem
othe
rapy
in non
epith
elial o
varia
n canc
er (E
SMO 201
2-‐GCT
) (1) Recom
men
datio
ns from
CPG
s an
d from
OGDs, if con
sistent w
ith th
ose of CPG
s.
(2) Sup
plem
entary in
form
ation from
both CP
Gs an
d OGDs, and
reco
mmen
datio
ns from
OGDs that are in
consist
ent w
ith th
ose of CPG
s.
OVA
RIA
N C
AN
CER
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 22
(12
CPG
s, 1
0 O
GDs
)
Circulating tumor markers: a guide to their appropriate clinical usee34
© 2017 Wichtig Publishing
10
Prostate cancer
Exam
ined docum
ents: 33 (24 CP
Gs, 9 OGDs)
Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Organized screening
programs
2 2
Do not use PSA
-‐based
mass s
cree
ning
for p
rostate canc
er (EAU
2015,
USPSTF 2012
, AIOM 201
5, ESM
O 201
3)
The be
nefits o
f PSA
-‐based
screen
ing for p
rostate canc
er do no
t outweigh
the ha
rms (mainly du
e to high ov
erdiag
nosis
and
ove
rtreatmen
t rates)
( USPSTF 2012, E
SMO 201
3)
Spon
taneou
s screening
9 3
Screen
ing for p
rostate canc
er w
ith th
e PS
A test is not re
commen
ded
( CTFPH
C 2014
)
PSA screen
ing for a
verage
-‐risk
men
of a
ll ag
es is not re
commen
ded
( USPSTF 2012
)
Eviden
ce is su
fficien
t to reco
mmen
d ag
ainst P
SA sc
reen
ing in m
en older
that 75 or w
ith a life exp
ectanc
y <1
0 ye
ars (AS
CO 2012)
For m
en age
d less th
an 55 ye
ars o
r older th
at 70 screen
ing for p
rostate
canc
er w
ith PSA
is not re
commen
ded (AUA 2013-‐ED, SIOG 2014, AIOM 201
5)
Prostate can
cer s
cree
ning
shou
ld be offered to all men
50 ye
ars o
f age
with
at le
ast a
10-‐ye
ar life exp
ectanc
y (AHS 2013, CUA 2011, U
MHS 2012
)
An in
dividu
alized
risk-‐ada
pted
strategy fo
r early detectio
n might be offered
to a w
ell -‐informed
man
with
a goo
d pe
rforman
ce st
atus and
at lea
st 10-‐15
ye
ars o
f life
exp
ectanc
y (EAU
2015, AIOM 201
5, NCC
N 201
4)
If there is a high
er risk of p
rostate canc
er (e
.g., po
sitive family hist
ory or
Afric
an-‐American
descent), PS
A-‐ba
sed screen
ing shou
ld be offered at age
40
yea
rs ( A
UA 2013-‐ED, CUA 2011, EAU
2015, UMHS 2012, U
SPSTF 2012
, AIOM 201
5)
If prostate can
cer s
cree
ning
is con
sidered
, men
shou
ld be inform
ed of the
po
tential b
enefits
and
risks o
f early detectio
n (AHS 2013
, ASCO 2012,
AUA 2013-‐ED, U
SPSTF 2012
, AIOM 201
5, ESM
O 201
3, NCC
N 201
4)
Men
at e
leva
ted ris
k of prostate canc
er: m
en ove
r 50 ye
ars o
f age
, men
ov
er 45 ye
ars o
f age
and
a fa
mily hist
ory of prostate canc
er, A
frican
-‐Am
erican
s, m
en w
ith a PSA
leve
l >1 ng
/mL at 40 ye
ars o
f age
, men
with
a
PSA leve
l >2 ng
/mL at 60 ye
ars o
f age
(EAU
2015)
No ev
iden
ce has dem
onstrated that age
-‐adjusted PS
A cu
toffs
; free PS
A;
and PS
A de
nsity
, veloc
ity, slope
, and
dou
bling-‐tim
e testing im
prov
e he
alth
outcom
es w
hen used
for s
cree
ning
purpo
ses (AS
CO 2012, CTFPH
C 2014,
EAU 2015, UMHS 2012, U
SPSTF 2012)
Whe
n used
for s
cree
ning
, ann
ual P
SA determination ha
s bee
n the
stan
dard; h
owev
er, 2
screen
ing stud
ies fou
nd th
at sc
reen
ing is be
nefic
ial
every 2 to 4 yea
rs (C
UA 2011
, USPSTF 2012
)
Whe
n a ris
k-‐ad
apted screen
ing strategy is con
sidered
, PSA
may
be
repe
ated
eve
ry 2 yea
rs fo
r men
initially at risk
(EAU
2015, NCC
N 201
4)
PRO
STAT
E CA
NCE
R
D
etai
led
sum
mar
y ta
bles
Exam
ined
doc
umen
ts: 3
3 (2
4 CP
Gs,
9 O
GDs
)
to b
e co
ntinu
ed
Gion et al e35
© 2017 Wichtig Publishing
11
Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Differentia
l diagnosis
8 6
Indicatio
ns fo
r biopsies inc
lude
a clin
ical su
spicion of prostate canc
er based
on
PSA
and
DRE
find
ing s, con
sidering also clin
ical hist
ory an
d ris
k factors.
Do not autom
atically offe
r a prostate biop
sy on the ba
sis of serum
PSA
leve
l alone
(AHS 2013
, EAU
2015, NICE 2015
, AIOM 201
5, ESM
O 201
3, GEC
-‐ES
TRO 201
3, NCC
N 201
5)
Consider PSA
to assess for prostate canc
er in
men
with
any
lower urin
ary
tract s
ymptom
s or a
ny une
xplained
symptom
s sug
gestive of m
etastatic
prostate can
cer (CCO 2015, NICE 2015
)
Limite
d PS
A elev
ation alon
e shou
ld not prompt im
med
iate biopsy. PSA
leve
l sho
uld be
verified
after a fe
w w
eeks usin
g the same assay un
der
stan
dardi zed
con
ditio
ns (EAU
2015, NICE 2014
, AIOM 201
5, NCC
N 201
4)
Eviden
ce is not su
fficien
t to reco
mmen
d PC
A3 to
inform
decision
s to
cond
uct initia
l biopsies for prostate canc
er in
at-‐ris
k men
(inc
reased
PSA
or
suspicious DRE
) (EG
APP 2014, EAU
2015, AIOM 201
5)
Elev
ated
PSA
and
/or a
bnormal DRE
are not diagn
ostic
of p
rostate canc
er;
they
do serve to risk st
ratify pa
tients (AH
S 2013)
Man
y co
ndition
s may
increa
se PSA
(inc
luding
BPH
, prostatitis, urethral
instrumen
tatio
n, prostate biop
sy, a
vigorou
s DRE
and
recent ejacu
latio
n)
(CUA 2011
, EAU
2015, NCC
N 201
4)
There is no
leve
l of P
SA below
which
the ris
k of prostate canc
er can
be
elim
inated
(EAU
2015, NCC
N 201
4)
5-‐alph
a redu
ctase inhibitors (5
αRIs) red
uce the PS
A leve
l by ab
out 5
0% at 6
mon
ths a
nd are non
-‐dose-‐de
pend
ent (CU
A 2011
, NCC
N 201
4)
Empiric
use of a
ntibiotic
s in an
asymptom
atic patient in
order to
lower th
e PS
A shou
ld not be un
dertak
en (EAU
2015, NCC
N 201
4)
PSA ve
locity, P
SA den
sity an
d PS
A free
-‐to-‐total ratio m
ay im
prov
e PS
A sensitivity and
specificity (C
UA 2011
, NCC
N 201
4, SIURO
201
3)
PSA ve
locity and
PSA
den
sity ha
ve limite
d diag
nostic use and
do no
t prov
ide ad
ditio
nal information co
mpa
red with
PSA
alone
(EAU
2015)
The use of age
-‐adjusted PS
A rang
es m
ay im
prov
e PS
A specificity (C
CO 2015,
SIURO
201
3)
The role of a
ge-‐adjusted PS
A rang
es is st
ill und
er deb
ate (USPSTF 2012
)
The PH
I test h
as as y
et und
etermined
clin
ical im
pact given
the sligh
t net
bene
fit provide
d for c
linical decision
-‐mak
ing (EAU
2015)
Rebiop
sy
4 4
The indicatio
ns fo
r a re
peat biopsy are: risin
g an
d/or persis
tently eleva
ted
PSA ( EAU
2015, AIOM 201
5, ESM
O 201
3, SIURO
201
3)
Eviden
ce is in
sufficien
t to reco
mmen
d PC
A3 to
inform
decision
s for w
hen
to re
biop
sy previou
sly biopsy -‐ne
gativ
e pa
tients (EG
APP 2014
, NICE 2015-‐
PCA3
)
PHI is n
ot re
commen
ded for u
se in
peo
ple who
hav
e ha
d a ne
gativ
e or
inco
nclusiv
e prostate biopsy (NICE 2015-‐PCA
3)
A man
with
risk fa
ctors w
hose m
ultip
aram
etric
MRI w
as neg
ative shou
ld
not n
ecessarily ha
ve re
biop
sy but sh
ould be mon
itored in se
cond
ary care
and rebiop
sied an
d reim
aged
based
on PS
A kine
tics o
r patient cho
ice
( NICE 2014
)
Curren
tly, the
main indicatio
n for P
CA3 is to determine whe
ther re
peat
biop
sy is nee
ded after a
n initially neg
ative biop
sy (EAU
2015, NCC
N 201
4)
Very lo
w qua
lity ev
iden
ce is ava
ilable for a
ge, P
SA free
-‐to-‐total ratio, P
SA
velocity, P
CA3 score, and
PSA
den
sity in th
e indicatio
n for a
repe
at biopsy
( NICE 2014
)
PRO
STAT
E CA
NCE
R
D
etai
led
sum
mar
y ta
bles
Exam
ined
doc
umen
ts: 3
3 (2
4 CP
Gs,
9 O
GDs
)
to b
e co
ntinu
ed
Circulating tumor markers: a guide to their appropriate clinical usee36
© 2017 Wichtig Publishing
12
Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Preoperativ
e workup
8 5
PSA, com
bine
d with
clin
ical st
age an
d Gleason
score, is used as risk
stratifi
catio
n to disc
uss t
herapy
options w
ith th
e pa
tient (A
HS 2013
, AU
A 2011, CCO
2010, CCO
2012-‐BT, EAU
2015, NICE 2014
, SIOG 2014,
AIOM 201
5, AUA 20
13, E
SMO 201
3, NCC
N 201
5)
Radiog
raph
ic st
aging (CT an
d bo
ne sc
an) is r
ecom
men
ded for p
atients w
ith
a PS
A leve
l >20
ng/mL (AUA 2011, A
UA 20
13, G
EC-‐EST
RO 201
3) or >
10 ng/mL
prior to trea
tmen
t (EA
U 2015, AIOM 201
5)
Eviden
ce is in
sufficien
t to reco
mmen
d PC
A3 te
sting to determine if the
disease is indo
lent or a
ggressive in order to
dev
elop
an op
timal trea
tmen
t plan
( EGAP
P 2014, A
IOM 201
5)
Risk group
s (en
dorsed
by: AHS 2013
, AUA 2011, CCO
2010, CCO
2012-‐BT,
EAU 2015, NICE 2014
, SIOG 2014, AIOM 201
5, ESM
O 201
3, NCC
N 201
5):
-‐ Low
risk: P
SA <10
and
Gleason
≤6 an
d clinical st
age
≤T2a
-‐ Intermed
iate risk: P
SA 10-‐20
or G
leason
7
-‐ High ris
k: PSA
>20
or G
leason
≥8 or clin
ical st
age ≥T
3
Mea
suremen
t of P
SA le
vel a
lone
has limite
d ab
ility to
predict fina
l pa
tholog
ical st
age accu
rately (EAU
2015, AIOM 201
5)
Activ
e surveillance
10
2 PS
A <1
0 ng
/mL is on
e of th
e crite
ria to
iden
tify pa
tients e
ligible fo
r active
surveilla
nce (CCO
2014-‐AS
, EAU
2015, SIOG 2014, AIOM 201
5)
Mon
itorin
g of patients o
n activ
e surveilla
nce shou
ld in
clud
e PS
A testing
(eve
ry 3-‐6 m
onths) (A
HS 2013, A
CS 2014, ASCO 2015, CCO
2014-‐AS
, EA
U 2015, NICE 2014, A
IOM 201
5, NCC
N 201
5)
Accelerated elev
ation of PSA
leve
l (i.e
., a PS
ADT <3
yea
rs according
to
AHS 2013, EAU
2015) is one
of the
criteria to
start a
ctive therap
y (CUA 2011,
AIOM 201
5)
Eviden
ce is not su
fficien
t to reco
mmen
d PC
A3 te
sting in m
en w
ith can
cer-‐
posit
ive biop
sies t
o de
term
ine if the disease is indo
lent or a
ggressive in
orde
r to de
velop an
optim
al trea
tmen
t plan (CCO
2014-‐AS
, EGAP
P 2014,
AIOM 201
5)
The op
timal timing for follow-‐up is still unc
lear (A
CS 2014, AUA 2011,
EAU 2015, NICE 2014
, AIOM 201
5)
Reassessment a
fter initial
curativ
e treatm
ent (RP
) 4
3 First p
ostope
rativ
e PS
A mea
suremen
t sho
uld be
don
e 4-‐12
wee
ks after
surgery (RP) (A
CS 2014, AHS 2013, EAU
2015, NICE 2014
)
PSA shou
ld decrease an
d remain at und
etectable leve
ls 4-‐12
wee
ks after
RP (EAU
2015, NICE 2014
, AIOM 201
5, AUA 20
13, N
CCN 201
5)
To date, th
ere ha
s bee
n no
con
sensus definition
of a
threshold leve
l of P
SA
below w
hich
PSA
is truly “u
ndetectable” (N
CCN 201
5)
PSA shou
ld be mea
sured with
stan
dard assay
metho
ds (u
ltrasen
sitive
assays are not in
dicated) ( A
IOM 201
5)
Reassessment a
fter initial
curativ
e treatm
ent (RT)
2 2
The PS
A leve
l falls slo
wly after externa
l-‐bea
m RT or brach
ythe
rapy
and
do
es not normally re
ach zero (N
ICE 2014, EAU
2015, AIOM 201
5, AUA 20
13)
The interval before the PS
A na
dir is r
each
ed m
ay be ve
ry lo
ng, som
etim
es
up to
3 yea
rs or m
ore (EAU
2015, AIOM 201
5, AUA 20
13)
A PS
A na
dir <
1.0 ng
/mL after e
xterna
l-‐bea
m RT or brach
ythe
rapy
is
associated
with
a fa
vorable prog
nosis
(EAU
2015, AIOM 201
5)
PSA may
rise te
mpo
rarily after initia
l externa
l-‐bea
m RT or brach
ythe
rapy
( PSA
bou
nce) (N
ICE 2014
)
PRO
STAT
E CA
NCE
R
D
etai
led
sum
mar
y ta
bles
Exam
ined
doc
umen
ts: 3
3 (2
4 CP
Gs,
9 O
GDs
)
to b
e co
ntinu
ed
Gion et al e37
© 2017 Wichtig Publishing
13
Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Early
detectio
n of
recurrence or p
rogression
(RP)
6 5
Perio
dic PS
A de
term
ination shou
ld be offered to detect d
isease recu
rren
ce
(ACS 2014, AHS 2013
, ASCO 2014, ASCO 2015, EAU
2015, NICE 2014
, AIOM 201
5, AUA 20
13, E
SMO 201
3, NCC
N 201
5)
After R
P, bioch
emical re
curren
ce is defined
by 2 co
nsecutive PS
A va
lues of
>0.2 ng/mL (AHS 2013
, ASCO 2014, EAU
2015, AIOM 201
5, AUA-‐AS
TRO 201
3,
NCC
N 201
5)
It is reco
mmen
ded that th
e fin
ding
of a
sing
le eleva
ted serum PSA
leve
l shou
ld be reco
nfirm
ed before startin
g therap
y (EAU
2015, NICE 2014
)
Analyze seria
l PSA
leve
ls after rad
ical trea
tmen
t usin
g the same assay
tech
niqu
e (NICE 2014
)
Bone
scan
and
abd
ominop
elvic CT
shou
ld only be
con
sidered
in
asym
ptom
atic patients w
ith bioch
emical fa
ilure after RP who
hav
e a high
ba
selin
e PS
A ( >10
ng/mL) or h
igh PS
A kine
tics (PS
ADT <6
mon
ths o
r PSA
ve
locity >0.5 ng
/mL/mon
th (EAU
2015)
PET/CT
can
not b
e reco
mmen
ded in patients w
ith bioch
emical re
curren
ce
and PS
A leve
ls <2
ng/mL (EAU
2015)
Distress/dep
ression/PS
A an
xiety shou
ld be pe
riodically m
onito
red (at lea
st
annu
ally) u
sing sim
ple screen
ing tools (AC
S 2014
, ASCO 2015)
Sugg
ested pe
riodicity of P
SA m
onito
ring:
-‐ low
or intermed
iate risk: P
SA m
easuremen
t eve
ry 6 to
12 mon
ths for th
e first 5 yea
rs, the
n an
nually th
erea
fter. H
igh ris
k ev
ery 6 mon
ths (AH
S 2013
) -‐ e
very 6 to
12 mon
ths for th
e first 5 yea
rs, the
n an
nually th
erea
fter
( ACS 2014, ASCO 2015)
-‐ 3, 6
and
12 mon
ths a
fter trea
tmen
t, then
eve
ry 6 m
onths u
ntil 3 ye
ars,
and then
ann
ually (EAU
2015)
-‐ eve
ry 6 m
onths for th
e first 2 yea
rs and
then
at lea
st onc
e a ye
ar
( NICE 2014
)
PSAD
T <3
mon
ths is a
neg
ative prog
nostic fa
ctor after bioch
emical re
lapse
(AHS 2013
, EAU
2015, NCC
N 201
5)
Ultrasen
sitive PS
A (U
S PS
A) assay
remains con
trov
ersia
l for ro
utine follo
w-‐
up (EAU
2015)
Early
detectio
n of
recurrence or p
rogression
(RT)
3 1
Perio
dic PS
A de
term
ination shou
ld be offered to detect d
isease recu
rren
ce
(AHS 2013
, EAU
2015, NICE 2014
, AIOM 201
5)
Follo
wing RT
, bioch
emical re
curren
ce is defined
as a
rise by 2 ng
/mL or
more ab
ove the PS
A na
dir (de
fined
as t
he lo
west P
SA le
vel rea
ched
) ( AHS 2013
, EAU
2015, NICE 2014
, AIOM 201
5)
After R
T, PSA
DT <3 mon
ths is a
ssoc
iated with
high ris
k of clin
ical
recu
rren
ce and
PSA
DT >15
mon
ths w
ith lo
w risk (EAU
2015)
PRO
STAT
E CA
NCE
R
D
etai
led
sum
mar
y ta
bles
Exam
ined
doc
umen
ts: 3
3 (2
4 CP
Gs,
9 O
GDs
)
to b
e co
ntinu
ed
Circulating tumor markers: a guide to their appropriate clinical usee38
© 2017 Wichtig Publishing
14
Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Mon
itorin
g of treatm
ent
respon
se in advanced
disease
6 3
Patie
nts w
ith st
age M1 disease with
a goo
d trea
tmen
t respo
nse shou
ld be
evalua
ted at 3 and
6 m
onths w
ith PSA
and
testosterone
mea
suremen
t du
ring ho
rmon
al trea
tmen
t (AH
S 2013
, ASCO-‐CCO
2014, AUA 2015
, EA
U 2015, AIOM 201
5, APC
201
5, NCC
N 201
5)
PSA shou
ld not be mea
sured routinely, but only whe
n it will affe
ct
man
agem
ent (AH
S 2013
)
Castratio
n-‐resis
tant prostate cancer (C
RPC) is defined
as s
erum
testosterone
<50
ng/dL
(1.7 nmol/L) p
lus 3
con
secu
tive ris
es in
PSA
, 1 w
eek
apart, resulting
in tw
o 50
% in
crea
ses o
ver the
nad
ir, w
ith PSA
>2 ng
/mL
(AUA 2015, EAU
2015, SOGUG 2012, APC
201
5)
In patients u
ndergo
ing interm
itten
t and
roge
n de
privation, PSA
and
testosterone
shou
ld be mon
itored at se
t interva
ls du
ring the trea
tmen
t pa
use (1 or 3
mon
ths) (EAU
2015, NICE 2014
)
Interm
itten
t hormon
e therap
y shou
ld be stop
ped if PS
A is >1
0 ng
/mL
(EAU
2015, NICE 2014)
Patie
nts s
hould no
t be started on
seco
nd-‐line
therap
y un
less th
eir s
erum
PS
A leve
l is >
2 ng
/mL an
d testosterone
is <50
ng/dL
(EAU
2015)
As lo
ng as P
SA re
mains at the
nad
ir va
lues obtaine
d with
therap
y, bon
e scan
, CT or PET
/CT are no
t necessary becau
se th
e prob
ability of c
linical
prog
ression is ve
ry lo
w (A
IOM 201
5)
Respon
se to
therap
y is de
fined
as a
con
firmed
decrease in PSA
leve
l >50
%
( AIOM 201
5)
Visceral m
etastases m
ay dev
elop
in m
en w
ithou
t rising
PSA
(APC
201
5)
In th
e first 2-‐3 m
onths a
fter st
artin
g ch
emothe
rapy
or n
ewer hormon
al
therap
ies, 20%
of m
en exp
erienc
e a PS
A fla
re, w
ith a sign
ificant drop in PSA
after the
initial rise (P
SA su
rge synd
rome). Imag
ing is no
t req
uired in th
is circum
stan
ce (A
IOM 201
5, APC
201
5)
(1) Recom
men
datio
ns from
CPG
s an
d from
OGDs, if con
sistent w
ith th
ose of CPG
s.
(2) Sup
plem
entary in
form
ation from
both CP
Gs an
d OGDs, and
reco
mmen
datio
ns from
OGDs that are in
consist
ent w
ith th
ose of CPG
s.
BPH = be
nign
prostatic hyp
erplasia; C
T = co
mpu
ted tomog
raph
y; DRE
= digita
l rectal e
xamination; M
RI = m
agne
tic re
sona
nce im
aging; PET
= positron
emiss
ion tomog
raph
y; PSA
DT = PSA
dou
bling tim
e; RP =
radical p
rostatectomy; RT = radiothe
rapy
.
PRO
STAT
E CA
NCE
R
D
etai
led
sum
mar
y ta
bles
Exam
ined
doc
umen
ts: 3
3 (2
4 CP
Gs,
9 O
GDs
)
Gion et al e39
© 2017 Wichtig Publishing
15
Renal cancer
Exam
ined docum
ents: 10 (7 CPG
s, 3 OGDs)
Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Screening
2 0
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(ACCC 2012
)
Clinical que
stion co
nsidered
, no ex
plicit reco
mmen
datio
ns on TM
s prov
ided
(ICU
D-‐EAU
2011)
Differentia
l diagnosis
5 3
LDH de
term
ination may
also
be pe
rformed
at the
mom
ent o
f presentation
for a
ll no
nmetastatic
patients, given
that it is not alw
ays immed
iately clear
if a pa
tient has m
etastatic
dise
ase (ACCC 2012
)
Clinical que
stion co
nsidered
, no ex
plicit reco
mmen
datio
ns on TM
s prov
ided
(EAU
2015, ICUD-‐EAU
2011, AIOM 201
5)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(AHS 2012, N
ICE 2015
, NCC
N 201
5)
Suspicion of re
nal cell carcino
ma shou
ld prompt la
boratory examinations
of LDH
(ESM
O 201
4)
Preoperativ
e workup
4 3
Clinical que
stion co
nsidered
, no ex
plicit reco
mmen
datio
ns on TM
s prov
ided
(EAU
2015, ICUD-‐EAU
2011, ESM
O 201
4)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
for n
onmetastatic
disease (ACCC 2012, A
HS 2012
, AIOM 201
5, NCC
N 201
5)
Reassessment a
fter initial
curativ
e treatm
ent
1 0
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(AUA 2013
)
Early
detectio
n of
recurrence or p
rogression
5
3 LD
H de
term
ination may
be used
at the
disc
retio
n of th
e clinician
(AUA 2013
)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(ACCC 2012, A
HS 2012,
EAU 2015, ICUD-‐EAU
2011)
There are no
data de
mon
stratin
g that re
gular L
DH m
easuremen
ts in
the
nonm
etastatic
setting im
prov
e de
tection of m
etastatic
dise
ase (AUA 2013
)
TM determinations are disc
ourage
d in th
e ab
senc
e of sy
mptom
s or c
linical
finding
s (AIOM 201
5)
Mon
itorin
g of treatm
ent
respon
se in advanced
disease
5 3
LDH may
be used
as a
progn
ostic
factor (inc
orpo
rated in th
e Mem
orial
Sloa
n-‐Ke
ttering Ca
ncer Cen
ter [MSK
CC] o
r Motzer s
core) in pa
tients w
ith
adva
nced
/metastatic
dise
ase trea
ted with
some type
s of systemic th
erap
y (ACCC 2012, EAU
2015, ICUD-‐EAU
2011, AIOM 201
5, ESM
O 201
4, NCC
N 201
5)
Clinical que
stion co
nsidered
, but criteria to
mon
itor treatmen
t respo
nse
(includ
ing TM
s) not add
ressed
(AHS 2012, SOGUG 2014)
LDH >1
.5 times th
e up
per lim
it of th
e labo
ratory ra
nge (if in
corporated
in
the MSK
CC sc
ore) has neg
ative prog
nostic value
(EAU
2015)
(1) Recom
men
datio
ns from
CPG
s an
d from
OGDs, if con
sistent w
ith th
ose of CPG
s.
(2) Sup
plem
entary in
form
ation from
both CP
Gs an
d OGDs, and
reco
mmen
datio
ns from
OGDs that are in
consist
ent w
ith th
ose of CPG
s.
REN
AL
CAN
CER
D
etai
led
sum
mar
y ta
bles
Exam
ined
doc
umen
ts: 1
0 (7
CPG
s, 3
OG
Ds)
Circulating tumor markers: a guide to their appropriate clinical usee40
© 2017 Wichtig Publishing
16
Testicular cancer
Exam
ined docum
ents: 12 (7 CPG
s, 5 OGDs)
Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Screening
2 1
Serum TMs o
r any
other blood
tests a
re not re
commen
ded to
screen
for g
erm cell tum
ors in asymptom
atic m
en (A
SCO 2010)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(USPSTF 2011
, EA
U 201
5)
Differentia
l diagnosis
3 5
Serum TM m
easuremen
ts are re
commen
ded be
fore orchiectomy
for a
ll pa
tients s
uspe
cted
of h
aving a testicular germ cell tum
or to
he
lp estab
lish the diag
nosis
and
interpret p
ostorchiectomy leve
ls (ASCO 2010, SIGN 2011, AIOM 201
5, EAU
201
5, EGCC
CG 201
3,
ESMO 201
3, NCC
N 201
5)
Reco
mmen
ded TM
s:
AFP, βhC
G and
LDH
(SIGN 2011, EAU
201
5, EGCC
CG 201
3, NCC
N 201
5)
AFP an
d βh
CG (A
SCO 2010, ESM
O 201
3)
The use of se
rum TM re
sults
is not re
commen
ded to guide
decision
-‐mak
ing on
the ne
ed fo
r an orch
iectom
y, becau
se con
centratio
ns in
the no
rmal ra
nge do
not ru
le out te
sticular can
cer o
r the
nee
d for
diag
nostic orchiectomy (ASCO 2010)
A sig
nific
antly
eleva
ted serum AFP
leve
l can
estab
lish the diag
nosis
of a m
ixed
germ cell tum
or in
a patient w
hose hist
opatho
logical
diag
nosis
is pure seminom
a, becau
se se
minom
as do no
t produ
ce
AFP. How
ever, b
orde
rline
eleva
ted va
lues sh
ould be interpreted
cautiously ( A
SCO 2010)
Serum TMs a
re not re
commen
ded to guide
trea
tmen
t of p
atients
with
can
cers of u
nkno
wn prim
ary an
d inde
term
inate histolog
y,
because ev
iden
ce is la
cking to su
pport this u
se (A
SCO 2010)
In ra
re m
ale pa
tients p
resenting with
a te
sticular, retrope
riton
eal o
r an
terio
r med
iastinal prim
ary tumor and
who
se dise
ase bu
rden
has
resulte
d in an urge
nt nee
d to st
art treatmen
t, substantially eleva
ted
serum AFP
and
/or h
CG m
ay be co
nsidered
sufficien
t for a diagn
osis
of germ cell tum
or. F
or su
ch ra
re, m
edically unstable pa
tients,
trea
tmen
t nee
d no
t be de
laye
d un
til after tissue
diagn
osis
( ASCO 2010, EAU
201
5)
For h
CG determination the use of assay
metho
ds th
at m
easure to
tal
hCG (intact α
/β dim
er plus free β mon
omer) is r
ecom
men
ded
( ASCO 2010)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(NICE 2015
)
Factors o
ther th
an germ cell tum
or th
at m
ay eleva
te se
rum m
arke
rs (A
SCO 2010)
AFP
-‐ other m
aligna
ncies: hep
atoc
ellular c
arcino
ma, gastric, lun
g, colon
and
pa
ncreatic can
cer a
nd other poo
rly differen
tiated canc
ers
-‐ ben
ign liver dise
ase: hep
atitis, cirrho
sis, h
epatic to
xicity from
che
mothe
rapy
, alco
hol a
buse, b
iliary tract o
bstruc
tion
-‐ con
stitu
tively elev
ated
AFP
: som
e individu
als h
ave serum AFP
leve
ls that are
chronically m
ildly eleva
ted in th
e rang
e of 15 -‐30
ng/mL
βhCG
-‐ o
ther m
aligna
ncies: neu
roen
docrine tumors, carcino
mas of b
ladd
er, k
idne
y,
lung
, hea
d, neck, gastrointestin
al tract, cervix, u
terus a
nd vulva
, lym
phom
a an
d leuk
emia
-‐ unilateral o
rchiectomy an
d ch
emothe
rapy
can
cau
se lo
w te
stosterone
leve
ls,
which
in tu
rn can
lead
to in
crea
sed prod
uctio
n of LH an
d hC
G by the pituita
ry
glan
d. LH can cross-‐react w
ith so
me assays fo
r hCG
-‐ h
eterop
hilic antibod
ies h
ave be
en re
ported
to re
sult in fa
lse-‐positive
hCG
results
in w
omen
LDH
-‐ other m
aligna
ncies: lymph
oma, sm
all cell lun
g canc
er, E
wing’s s
arco
ma,
osteog
enic sa
rcom
a, m
elan
oma
-‐ alm
ost a
nything that re
sults
in cell lysis or in
jury: stren
uous exe
rcise
, liver
disease, m
yocardial infarction, kidne
y disease, hem
olysis, pne
umon
ia, a
nd
coun
tless other th
ings
Serum AFP
, βhC
G and
LDH
leve
ls may
rise during the first w
eek of che
mothe
rapy
be
cause of tu
mor lysis
. If T
M le
vels ris
e be
twee
n da
y 1 of cycle 1 and
day
1 of
cycle 2, TM le
vel a
ssay
s sho
uld be
repe
ated
midway
throug
h cycle 2 to
determ
ine whe
ther le
vels ha
ve beg
un to
decl in
e (ASCO 2010)
The on
ly prove
n utility of L
DH is fo
r progn
osis of che
mothe
rapy
-‐naïve
patients
with
hist
opatho
logically diagn
osed
metastatic
germ cell tum
ors (AS
CO 2010)
TEST
ICU
LAR
CAN
CER
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 12
(7 C
PGs,
5 O
GDs
)
to b
e co
ntinu
ed
Gion et al e41
© 2017 Wichtig Publishing
17
Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Preoperativ
e workup
(before and after
orchiectom
y, and
before
chem
otherapy and
/or
additio
nal surgery)
4 5
Serum AFP
, βhC
G and
LDH
are re
commen
ded for a
ll pa
tients w
ith
testicular NSG
CT pre-‐orchiectomy, sh
ortly
after orchiectomy, and
wee
kly therea
fter until no
rmalization or plateau
dev
elop
men
t ( AHS 2013
, ASCO 2010, SIGN 2011, SIU-‐IC
UD-‐UICC 2011
, AIOM 201
5,
EAU 201
5, EGCC
CG 201
3, ESM
O 201
3, NCC
N 201
5)
Serum TMs a
fter orchiectomy shou
ld be de
term
ined
before
chem
othe
rapy
or rad
iotherap
y (AHS 2013
, ASCO 2010, SIGN 2011,
AIOM 201
5, EAU
201
5, EGCC
CG 201
3, ESM
O 201
3, NCC
N 201
5)
Marke
r con
centratio
ns sh
ould be used
along
with
imag
ing
tech
niqu
es to
allo
cate patients t
o prog
nostic group
s (SIGN 2011)
The pe
rsist
ence of e
leva
ted serum TM le
vels after o
rchiectomy
might in
dicate th
e presen
ce of m
etastatic
dise
ase (m
acro-‐ o
r microscop
ic) a
nd classify
patients into the substage
S1 (AHS 2013,
ASCO
2012, SIU-‐IC
UD-‐UICC 2011
, AIOM 201
5, EAU
201
5, ESM
O 201
3)
TMs a
re not re
commen
ded to guide
trea
tmen
t decision
s for
seminom
a be
cause ev
iden
ce is la
cking that se
lecting therap
y ba
sed
on TM le
vels yields better o
utco
mes (A
SCO 2010)
AFP, βhC
G and
LDH
shou
ld be de
term
ined
before ch
emothe
rapy
be
gins fo
r tho
se patients w
ith m
ediastinal or retrope
riton
eal
NSG
CTs t
o stratify ris
k an
d select trea
tmen
t (AS
CO 2010,
EGCC
CG 201
3)
Sugg
ested sche
dules o
f TM determination
-‐ Pre-‐ orchiectomy, 24 ho
urs a
fter orchiectomy, and
wee
kly therea
fter until
norm
alization or plateau
dev
elop
men
t (SIGN 2011)
-‐ Pre-‐ orchiectomy an
d 5-‐7 da
ys after orchiectomy (EAU
201
5)
Slightly eleva
ted an
d stab
le AFP
and
βhC
G le
vels after o
rchiectomy shou
ld be
interpreted with
cau
tion, becau
se th
ese might not necessarily stem
from
dissem
inated
NSG
CT (SIU-‐IC
UD-‐UICC 2011)
The mea
n serum half-‐life
of A
FP and
βhC
G is 5-‐7 day
s and
2-‐3 day
s, re
spectiv
ely.
The pe
rsist
ence of e
leva
ted serum TM le
vels after o
rchiectomy might in
dicate
the presen
ce of m
etastatic
dise
ase (m
acro-‐ o
r microscop
ic), while th
e no
rmalization of m
arke
r lev
els a
fter orchiectomy do
es not ru
le out th
e presen
ce
of tu
mor m
etastases (AS
CO 2010, EAU
201
5, EGCC
CG 201
3)
TNM classificatio
n for testic
ular can
cer (UICC, 200
9, 7th ed.) (EA
U 201
5)
Serum TMs:
SX Serum
marke
r studies not ava
ilable or not perform
ed
S0 Serum
marke
r study
leve
ls with
in normal limits
S1
LDH
(U/L) <
1.5 × N and
hCG
(mIU/m
L) <5,00
0 an
d AF
P (ng/mL) <1,00
0 S2
LDH
(U/L) 1
.5-‐10 × N or h
CG (m
IU/m
L) 5,000
-‐50,00
0 or AFP
(ng/mL) 1,000
-‐10
,000
S3
LDH
(U/L) >
10 × N or h
CG (m
IU/m
L) >50
,000
or A
FP (n
g/mL) >10
,000
(N
: upp
er limit of th
e referenc
e interval)
TEST
ICU
LAR
CAN
CER
D
etai
led
sum
mar
y ta
bles
Exam
ined
doc
umen
ts: 1
2 (7
CPG
s, 5
OG
Ds)
to b
e co
ntinu
ed
Circulating tumor markers: a guide to their appropriate clinical usee42
© 2017 Wichtig Publishing
18
Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Early
detectio
n of
recurrence or p
rogression
5
5 Pe
riodic de
term
ination of TMs is r
ecom
men
ded. Duration of fo
llow-‐
up after th
erap
y is co
mpleted
shou
ld be at le
ast 1
0 ye
ars in NSG
CTs
and at le
ast 5
yea
rs in
seminom
as; e
valuations sh
ould be more
freq
uent in
the first 2 yea
rs and
in patients u
nder active surveilla
nce
( AHS 2013
, ASCO 2010, SIGN 2011, SIU-‐IC
UD-‐UICC 2011
, AIOM 201
5,
EAU 201
5, EGCC
CG 201
3, ESM
O 201
3, NCC
N 201
5)
TMs a
re not re
ccom
ende
d for s
urve
illan
ce of stage
I seminom
a ( ASCO 2010)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(CCO
2014)
LDH ha
s not bee
n show
n to be he
lpful in the follo
w-‐up in patients w
ith germ cell
tumors (SIGN 2011)
The freq
uenc
y of TM determination du
ring follo
w-‐up shou
ld be sche
duled with
referenc
e to in
itial st
age, hist
olog
ical ty
pe and
post-‐orch
iectom
y trea
tmen
ts.
Diffe
rent guide
lines re
port partia
lly differen
t sch
emes, w
hich
are su
mmarized
in
the follo
wing table ( AHS 2013
, ASCO 2010, EAU
201
5, NCC
N 201
5)
Seminom
a Clinical
stag
e Ye
ars a
fter th
erap
y is
completed
Su
ggested tim
ing of TM
determ
ination (m
in-‐m
ax)
Stag
e I
1
every 2-‐6 mon
ths
2
every 3-‐6 mon
ths
3
every 4-‐12
mon
ths
4
every 4-‐12
mon
ths
5
every 6-‐12
mon
ths
Th
erea
fter
every 12
mon
ths
Stag
es IIA, IIB, IIC, IID, III
1
every 2-‐4 mon
ths
2
every 3-‐4 mon
ths
3
every 4-‐6 mon
ths
4
every 4-‐12
mon
ths
5
every 6-‐12
mon
ths
Th
erea
fter
every 12
mon
ths
NSG
CT
Clinical
stag
e Ye
ars a
fter th
erap
y is
completed
Su
ggested tim
ing of TM
determ
ination (m
in-‐m
ax)
Stag
e I S
0
1
every 1-‐3 mon
ths
2
every 2-‐6 mon
ths
3
every 3-‐6 mon
ths
4
every 3-‐12
mon
ths
5
every 6-‐12
mon
ths
Th
erea
fter
every 12
mon
ths
Stag
es I S+
, II, III
1
every 1-‐3 mon
ths
2
every 2-‐6 mon
ths
3
every 3-‐6 mon
ths
4
every 3-‐12
mon
ths
5
every 6-‐12
mon
ths
Th
erea
fter
every 12
mon
ths
18
Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Early
detectio
n of
recurrence or p
rogression
5
5 Pe
riodic de
term
ination of TMs is r
ecom
men
ded. Duration of fo
llow-‐
up after th
erap
y is co
mpleted
shou
ld be at le
ast 1
0 ye
ars in NSG
CTs
and at le
ast 5
yea
rs in
seminom
as; e
valuations sh
ould be more
freq
uent in
the first 2 yea
rs and
in patients u
nder active surveilla
nce
( AHS 2013
, ASCO 2010, SIGN 2011, SIU-‐IC
UD-‐UICC 2011
, AIOM 201
5,
EAU 201
5, EGCC
CG 201
3, ESM
O 201
3, NCC
N 201
5)
TMs a
re not re
ccom
ende
d for s
urve
illan
ce of stage
I seminom
a (ASCO 2010)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(CCO
2014)
LDH ha
s not bee
n show
n to be he
lpful in the follo
w-‐up in patients w
ith germ cell
tumors (SIGN 2011)
The freq
uenc
y of TM determination du
ring follo
w-‐up shou
ld be sche
duled with
referenc
e to in
itial st
age, hist
olog
ical ty
pe and
post-‐orch
iectom
y trea
tmen
ts.
Diffe
rent guide
lines re
port partia
lly differen
t sch
emes, w
hich
are su
mmarized
in
the follo
wing table ( AHS 2013
, ASCO 2010, EAU
201
5, NCC
N 201
5)
Seminom
a Clinical
stag
e Ye
ars a
fter th
erap
y is
completed
Su
ggested tim
ing of TM
determ
ination (m
in-‐m
ax)
Stag
e I
1
every 2-‐6 mon
ths
2
every 3-‐6 mon
ths
3
every 4-‐12
mon
ths
4
every 4-‐12
mon
ths
5
every 6-‐12
mon
ths
Th
erea
fter
every 12
mon
ths
Stag
es IIA, IIB, IIC, IID, III
1
every 2-‐4 mon
ths
2
every 3-‐4 mon
ths
3
every 4-‐6 mon
ths
4
every 4-‐12
mon
ths
5
every 6-‐12
mon
ths
Th
erea
fter
every 12
mon
ths
NSG
CT
Clinical
stag
e Ye
ars a
fter th
erap
y is
completed
Su
ggested tim
ing of TM
determ
ination (m
in-‐m
ax)
Stag
e I S
0
1
every 1-‐3 mon
ths
2
every 2-‐6 mon
ths
3
every 3-‐6 mon
ths
4
every 3-‐12
mon
ths
5
every 6-‐12
mon
ths
Th
erea
fter
every 12
mon
ths
Stag
es I S+
, II, III
1
every 1-‐3 mon
ths
2
every 2-‐6 mon
ths
3
every 3-‐6 mon
ths
4
every 3-‐12
mon
ths
5
every 6-‐12
mon
ths
Th
erea
fter
every 12
mon
ths
18
Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Early
detectio
n of
recurrence or p
rogression
5
5 Pe
riodic de
term
ination of TMs is r
ecom
men
ded. Duration of fo
llow-‐
up after th
erap
y is co
mpleted
shou
ld be at le
ast 1
0 ye
ars in NSG
CTs
and at le
ast 5
yea
rs in
seminom
as; e
valuations sh
ould be more
freq
uent in
the first 2 yea
rs and
in patients u
nder active surveilla
nce
( AHS 2013
, ASCO 2010, SIGN 2011, SIU-‐IC
UD-‐UICC 2011
, AIOM 201
5,
EAU 201
5, EGCC
CG 201
3, ESM
O 201
3, NCC
N 201
5)
TMs a
re not re
ccom
ende
d for s
urve
illan
ce of stage
I seminom
a (ASCO 2010)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(CCO
2014)
LDH ha
s not bee
n show
n to be he
lpful in the follo
w-‐up in patients w
ith germ cell
tumors (SIGN 2011)
The freq
uenc
y of TM determination du
ring follo
w-‐up shou
ld be sche
duled with
referenc
e to in
itial st
age, hist
olog
ical ty
pe and
post-‐orch
iectom
y trea
tmen
ts.
Diffe
rent guide
lines re
port partia
lly differen
t sch
emes, w
hich
are su
mmarized
in
the follo
wing table ( AHS 2013
, ASCO 2010, EAU
201
5, NCC
N 201
5)
Seminom
a Clinical
stag
e Ye
ars a
fter th
erap
y is
completed
Su
ggested tim
ing of TM
determ
ination (m
in-‐m
ax)
Stag
e I
1
every 2-‐6 mon
ths
2
every 3-‐6 mon
ths
3
every 4-‐12
mon
ths
4
every 4-‐12
mon
ths
5
every 6-‐12
mon
ths
Th
erea
fter
every 12
mon
ths
Stag
es IIA, IIB, IIC, IID, III
1
every 2-‐4 mon
ths
2
every 3-‐4 mon
ths
3
every 4-‐6 mon
ths
4
every 4-‐12
mon
ths
5
every 6-‐12
mon
ths
Th
erea
fter
every 12
mon
ths
NSG
CT
Clinical
stag
e Ye
ars a
fter th
erap
y is
completed
Su
ggested tim
ing of TM
determ
ination (m
in-‐m
ax)
Stag
e I S
0
1
every 1-‐3 mon
ths
2
every 2-‐6 mon
ths
3
every 3-‐6 mon
ths
4
every 3-‐12
mon
ths
5
every 6-‐12
mon
ths
Th
erea
fter
every 12
mon
ths
Stag
es I S+
, II, III
1
every 1-‐3 mon
ths
2
every 2-‐6 mon
ths
3
every 3-‐6 mon
ths
4
every 3-‐12
mon
ths
5
every 6-‐12
mon
ths
Th
erea
fter
every 12
mon
ths
18
Clinical question
CPG OGD Summary of re
commendatio
ns (1
) Supp
lementary inform
ation
(2)
Early
detectio
n of
recurrence or p
rogression
5
5 Pe
riodic de
term
ination of TMs is r
ecom
men
ded. Duration of fo
llow-‐
up after th
erap
y is co
mpleted
shou
ld be at le
ast 1
0 ye
ars in NSG
CTs
and at le
ast 5
yea
rs in
seminom
as; e
valuations sh
ould be more
freq
uent in
the first 2 yea
rs and
in patients u
nder active surveilla
nce
( AHS 2013
, ASCO 2010, SIGN 2011, SIU-‐IC
UD-‐UICC 2011
, AIOM 201
5,
EAU 201
5, EGCC
CG 201
3, ESM
O 201
3, NCC
N 201
5)
TMs a
re not re
ccom
ende
d for s
urve
illan
ce of stage
I seminom
a (ASCO 2010)
Clinical que
stion co
nsidered
, but TMs n
ot add
ressed
(CCO
2014)
LDH ha
s not bee
n show
n to be he
lpful in the follo
w-‐up in patients w
ith germ cell
tumors (SIGN 2011)
The freq
uenc
y of TM determination du
ring follo
w-‐up shou
ld be sche
duled with
referenc
e to in
itial st
age, hist
olog
ical ty
pe and
post-‐orch
iectom
y trea
tmen
ts.
Diffe
rent guide
lines re
port partia
lly differen
t sch
emes, w
hich
are su
mmarized
in
the follo
wing table ( AHS 2013
, ASCO 2010, EAU
201
5, NCC
N 201
5)
Seminom
a Clinical
stag
e Ye
ars a
fter th
erap
y is
completed
Su
ggested tim
ing of TM
determ
ination (m
in-‐m
ax)
Stag
e I
1
every 2-‐6 mon
ths
2
every 3-‐6 mon
ths
3
every 4-‐12
mon
ths
4
every 4-‐12
mon
ths
5
every 6-‐12
mon
ths
Th
erea
fter
every 12
mon
ths
Stag
es IIA, IIB, IIC, IID, III
1
every 2-‐4 mon
ths
2
every 3-‐4 mon
ths
3
every 4-‐6 mon
ths
4
every 4-‐12
mon
ths
5
every 6-‐12
mon
ths
Th
erea
fter
every 12
mon
ths
NSG
CT
Clinical
stag
e Ye
ars a
fter th
erap
y is
completed
Su
ggested tim
ing of TM
determ
ination (m
in-‐m
ax)
Stag
e I S
0
1
every 1-‐3 mon
ths
2
every 2-‐6 mon
ths
3
every 3-‐6 mon
ths
4
every 3-‐12
mon
ths
5
every 6-‐12
mon
ths
Th
erea
fter
every 12
mon
ths
Stag
es I S+
, II, III
1
every 1-‐3 mon
ths
2
every 2-‐6 mon
ths
3
every 3-‐6 mon
ths
4
every 3-‐12
mon
ths
5
every 6-‐12
mon
ths
Th
erea
fter
every 12
mon
ths
TEST
ICU
LAR
CAN
CER
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 12
(7 C
PGs,
5 O
GDs
)
to b
e co
ntinu
ed
Gion et al e43
© 2017 Wichtig Publishing
TEST
ICU
LAR
CAN
CER
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 12
(7 C
PGs,
5 O
GDs
)
Circulating tumor markers: a guide to their appropriate clinical usee44
© 2017 Wichtig Publishing
Selected guidelines (by cancer site)
Bladder cancer
AHS 2013-MI. Alberta Provincial Genitourinary Tumour Team. Muscle invasive and locally advanced/metastatic blad-der cancer. Edmonton, Alberta: CancerControl Alberta; 2013.
AHS 2013-NM. Alberta Provincial Genitourinary Tumour Team. Nonmuscle invasive bladder cancer. Edmonton, Alber-ta: CancerControl Alberta; 2013. http://www.albertahealth-services.ca/assets/info/hp/cancer/if-hp-cancer-guide-gu009-noninvasive-bladder.pdf.
AHS 2013-UT. Alberta Provincial Genitourinary Tumour Team. Upper tract urothelial tumours. Edmonton, Alberta: CancerControl Alberta; 2013. http://www.albertahealthser-vices.ca/assets/info/hp/cancer/if-hp-cancer-guide-gu008-upper-tract.pdf.
AIOM 2015. Associazione Italiana di Oncologia Medica (AIOM). Carcinoma della vescica. Milan: AIOM; 2015.
AURO 2010. Puppo P, Conti G, Francesca F, Mandressi A, Naselli A; AURO.it guideline committee. New Italian guide-lines on bladder cancer, based on the World Health Organi-zation 2004 classification. BJU Int. 2010; 106(2):168-79. doi: 10.1111/j.1464-410X.2010.09324.x.
CUA 2013. Kapoor A, Allard CB, Black P, Kassouf W, Mo-rash C, Rendon R. Canadian guidelines for postoperative surveillance of upper urinary tract urothelial carcinoma. Can Urol Assoc J. 2013;7(9-10):306-11. doi: 10.5489/cuaj.1578.
EAU 2015-MI. Witjes LA, Compérat E, Cowan NC, et al. Guidelines on muscle-invasive and metastatic bladder cancer. Arnhem, Netherlands: European Association of Urology; 2015.
EAU 2015-NM. Babjuk M, Böhle A, Burger M, et al. Guide-lines on non-muscle-invasive bladder Cancer (Ta, T1 and CIS). Arnhem, Netherlands: European Association of Urology; 2015.
EAU 2015-UR. Gakis G, Witjes JA, Compérat E, et al. Guidelines on primary urethral carcinoma. Arnhem, Nether-lands: European Association of Urology; 2015.
EAU 2015-UT. Rouprêt M, Babjuk M, Böhle A, et al. Guide-lines on urothelial carcinomas of the upper urinary tract. Arn-hem, Netherlands: European Association of Urology; 2015.
ESMO 2014. Bellmunt J, Orsola A, Leow JJ, et al. Bladder cancer: ESMO practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014; 25 (Suppl 3):iii40-8. doi: 10.1093/annonc/mdu223.
NCCN 2015. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology. Bladder can-cer, version 1.2015. Fort Washington, PA: National Compre-hensive Cancer Network; 2015.
NICE 2015-SC. National Collaborating Centre for Cancer. Suspected cancer: recognition and referral. London, UK: Na-tional Institute for Health and Care Excellence; 2015. https://www.nice.org.uk/guidance/ng12.
NICE 2015-BC. National Collaborating Centre for Cancer. Bladder cancer: diagnosis and management. NICE guideline NG2. London, UK: National Institute for Health and Care Ex-
cellence; 2015. https://www.nice.org.uk/guidance/ng2.USPSTF 2011. Moyer VA; U.S. Preventive Services Task
Force. Screening for bladder cancer: U.S. Preventive Ser-vices Task Force recommendation statement. Ann Intern Med. 2011;155(4):246-51. doi: 10.7326/0003-4819-155-4-201108160-00008.
Breast cancer
AHS 2012-BB. Alberta Provincial Breast Tumour Team. Staging investigations for asymptomatic and newly diagnosed breast cancer. Edmonton, Alberta: Alberta Health Services, Cancer Care; 2012.
AHS 2013-FU. Alberta Provincial Breast Tumour Team. Follow-up care for early-stage breast cancer. Edmonton, Al-berta: CancerControl Alberta; 2013.
AIOM 2015. Associazione Italiana di Oncologia Medica (AIOM). Neoplasie della mammella. Milan, Italy: Associazione Italiana di Oncologia Medica (AIOM); 2015.
ASCO 2012-FU. Khatcheressian JL, Hurley P, Bantug E, et al. Breast cancer follow-up and management after prima-ry treatment: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013; 31(7):961-5. doi: 10.1200/JCO.2012.45.9859.
ASCO 2015-M+. Van Poznak C, Somerfield MR, Bast RC, et al. Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2015; 33(24):2695-704. doi: 10.1200/JCO.2015.61.1459.
CECOG 2009. Beslija S, Bonneterre J, Burstein HJ, et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol. 2009; 20(11):1771-85. doi: 10.1093/an-nonc/mdp261.
ESMO 2013-EarlyBC. Senkus E, Kyriakides S, Penault-Llor-ca F, et al. Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013; 24 (Suppl 6):vi7-23. doi: 10.1093/annonc/mdt284.
ESMO 2014-ABC. Cardoso F, Costa A, Norton L, et al. ESO-ESMO 2nd international consensus guidelines for ad-vanced breast cancer (ABC2). Ann Oncol. 2014;25(10):1871-88. doi: 10.1093/annonc/mdu385.
EUSOMA 2014-Young. Partridge AH, Pagani O, Abulkhair O, et al. First international consensus guidelines for breast cancer in young women (BCY1). Breast. 2014;23(3):209-20. doi: 10.1016/j.breast.2014.03.011.
NCCN 2014-Diagn. National Comprehensive Cancer Net-work (NCCN). Clinical Practice Guidelines in Oncology. Breast cancer screening and diagnosis, version 1.2015. Fort Wash-ington, PA: National Comprehensive Cancer Network; 2015.
NCCN 2015. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Breast can-cer, version 1.2016. Fort Washington, PA: National Compre-hensive Cancer Network; 2015.
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NHMRC 2010. National Breast and Ovarian Cancer Cen-tre. Recommendations for follow-up of women with early breast cancer. Surry Hills, NSW: National Breast and Ovarian Cancer Centre; 2010. https://guidelines.canceraustralia.gov.au/guidelines/early_breast_cancer.
NICE 2012-EarlyBC. National Collaborating Centre for Cancer. Early and locally advanced breast cancer. Diagnosis and treatment. London, UK: National Institute for Health and Clinical Excellence (NICE); 2009. https://www.nice.org.uk/guidance/cg80. Validity verification: 2012.
NICE 2014-M+. National Collaborating Centre for Can-cer. Advanced breast cancer: diagnosis and treatment. Lon-don, UK: National Institute for Health and Clinical Excellence (NICE); 2009. https://www.nice.org.uk/guidance/cg81. Valid-ity verification: 2014.
NICE 2015-SC. National Collaborating Centre for Cancer. Suspected cancer: recognition and referral. London, UK: Na-tional Institute for Health and Care Excellence; 2015. https://www.nice.org.uk/guidance/ng12.
Cervical cancer
AHS 2013. Alberta Provincial Gynecologic Oncology Team. Cancer of the uterine cervix. Edmonton, Alberta: CancerCon-trol Alberta; 2013.
AIOM 2015. Associazione Italiana di Oncologia Medica (AIOM). Neoplasie dell’utero: endometrio e cervice. Milan, It-aly: Associazione Italiana di Oncologia Medica (AIOM); 2015.
CCO 2015. Elit L, Fyles A, Fung-Kee-Fung M, Oliver T; Gy-necology Cancer Disease Site Group. Follow-up for women after treatment for cervical cancer. Toronto, ON: Cancer Care Ontario; 2009. Validity verification: 2015.
ESMO 2012. Colombo N, Carinelli S, Colombo A, Marini C, Rollo D, Sessa C; ESMO Guidelines Working Group. Cervical cancer: ESMO clinical practice guidelines for diagnosis, treat-ment and follow-up. Ann Oncol. 2012; 23 (Suppl 7):vii27-32.
NACB 2010. Sturgeon CM, Duffy MJ, Hofmann BR, et al. National Academy of Clinical Biochemistry laboratory med-icine practice guidelines for use of tumor markers in liv-er, bladder, cervical, and gastric cancers. Clin Chem. 2010; 56(6):e1-48. doi: 10.1373/clinchem.2009.133124.
NCCN 2015. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Cervical can-cer, version 2.2015. Fort Washington, PA: National Compre-hensive Cancer Network; 2015.
NICE 2015. National Collaborating Centre for Cancer. Sus-pected cancer: recognition and referral. London, UK: National Institute for Health and Care Excellence; 2015. https://www.nice.org.uk/guidance/ng12.
Endometrial cancer
ACN 2011. Cancer Council Australia Endometrial Cancer Guidelines Working Party. Clinical practice guidelines for the treatment and management of endometrial cancer. Sydney: Cancer Council Australia; 2011. http://wiki.cancer.org.au/aus-tralia/Guidelines:Endometrial_cancer/Treatment/Early_stage.
AHS 2013. Alberta Provincial Gynecologic Oncology Tumour Team. Endometrial cancer. Edmonton, Alberta:
Cancer Control Alberta; 2013.AIOM 2015. Associazione Italiana di Oncologia Medica
(AIOM). Neoplasie dell’utero: endometrio e cervice. Milan, It-aly: Associazione Italiana di Oncologia Medica (AIOM); 2015.
ESMO 2013. Colombo N, Preti E, Landoni F, et al. Endome-trial cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013; 24 (Suppl 6):vi33-8. doi: 10.1093/annonc/mdt353.
NCCN 2015. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Uterine neo-plasms, version 2.2015. Fort Washington, PA: National Com-prehensive Cancer Network; 2015.
NICE 2015. National Collaborating Centre for Cancer. Sus-pected cancer: recognition and referral. London, UK: National Institute for Health and Care Excellence; 2015. https://www.nice.org.uk/guidance/ng12.
SGO 2014 (a). SGO Clinical Practice Endometrial Cancer Working Group, Burke WM, Orr J, Leitao M, et al. Endome-trial cancer: a review and current management strategies: part I. Gynecol Oncol. 2014; 134(2):385-92. doi: 10.1016/j.ygyno.2014.05.018.
SGO 2014 (b). SGO Clinical Practice Endometrial Cancer Working Group, Burke WM, Orr J, Leitao M, et al. Endometri-al cancer: a review and current management strategies: part II. Gynecol Oncol. 2014; 134(2):393-402. doi: 10.1016/j.ygy-no.2014.06.003.
Ovarian cancer
ACOG 2009-HR. American College of Obstetricians and Gynecologists; ACOG Committee on Practice Bulletins--Gy-necology; ACOG Committee on Genetics; Society of Gyneco-logic Oncologists. ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. Obstet Gynecol. 2009; 113(4):957-66. doi: 10.1097/AOG.0b013e3181a106d4.
ACOG 2011-EC. American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. Com-mittee Opinion No. 477: the role of the obstetrician-gy-necologist in the early detection of epithelial ovarian can-cer. Obstet Gynecol. 2011; 117(3):742-6. doi: 10.1097/AOG.0b013e31821477db.
ACOG 2013-AM. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin. Management of ad-nexal masses. Obstet Gynecol. 2007; 110(1):201-14. Validity verification: 2013.
AHS 2011-HR. Alberta Provincial Breast Tumour Team. Risk reduction and surveillance strategies for individuals at high genetic risk for breast and ovarian cancer. Edmonton, Al-berta: Alberta Health Services, Cancer Care; 2011.
AHS 2013-EC. Alberta Provincial Gynecologic Oncology Tumour Team. Epithelial ovarian, fallopian tube, and primary peritoneal cancer. Edmonton, Alberta: CancerControl Alber-ta; 2013.
AHS 2013-GCT. Alberta Provincial Gynecologic Oncology Tumour Team. Ovarian germ cell tumours. Edmonton, Alber-ta: CancerControl Alberta; 2013.
AIOM 2015. Associazione Italiana di Oncologia Medica (AIOM). Tumori dell’ovaio. Milan, Italy: Associazione Italiana di Oncologia Medica (AIOM); 2015.
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BSGE 2011. Royal College of Obstetricians and Gynaecol-ogists (RCOG), British Society of Gynaecological Endoscopy (BSGE). Management of suspected ovarian masses in pre-menopausal women. London, UK: Royal College of Obstetri-cians and Gynaecologists; 2011. https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg62/.
CCO 2011. Fung Kee Fung M, Kennedy E, Francis J, Mack-ay H; Gynecologic Cancer Disease Site Group. Optimal che-motherapy for recurrent ovarian cancer. Toronto, ON: Cancer Care Ontario; 2011.
CCO 2011-AM. Dodge J, Covens A, Lacchetti C, et al. Man-agement of a suspicious adnexal mass. Toronto, ON: Cancer Care Ontario; 2011.
ESGO 2011. Morice P, Denschlag D, Rodolakis A, et al. Rec-ommendations of the Fertility Task Force of the European So-ciety of Gynecologic Oncology about the conservative man-agement of ovarian malignant tumors. Int J Gynecol Cancer. 2011; 21(5):951-63. doi: 10.1097/IGC.0b013e31821bec6b.
ESGO 2012-FU. Verheijen RH, Cibula D, Zola P, Reed N; Council of the European Society of Gynaecologic Oncolo-gy. Cancer antigen 125: lost to follow-up?: a European So-ciety of Gynaecological Oncology consensus statement. Int J Gynecol Cancer. 2012; 22(1):170-4. doi: 10.1097/IGC.0b013e318226c636.
ESMO 2012-GCT. Colombo N, Peiretti M, Garbi A, et al. Non-epithelial ovarian cancer: ESMO clinical practice guide-lines for diagnosis, treatment and follow-up. Ann Oncol. 2012; 23 (Suppl 7):vii20-6.
ESMO 2013-EC. Ledermann JA, Raja FA, Fotopoulou C, et al. Newly diagnosed and relapsed epithelial ovarian carci-noma: ESMO clinical practice guidelines for diagnosis, treat-ment and follow-up. Ann Oncol. 2013; 24 (Suppl 6):vi24-32. doi: 10.1093/annonc/mdt333.
NCCN 2015. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Ovarian can-cer. Version 1.2015. Fort Washington, PA: National Compre-hensive Cancer Network (NCCN); 2015.
NCCN 2015-HR. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Genetic/familial high-risk assessment: breast and ovarian, version 1.2015. Fort Washington, PA: National Comprehensive Can-cer Network; 2015.
NHMRC 2011-HR. Cancer Australia. Recommendations for management of women at high risk of ovarian cancer. Surry Hills, NSW: Cancer Australia; 2011. https://cancer-australia.gov.au/publications-and-resources/clinical-prac-tice-guidelines/recommendations-management-wom-en-high-risk-ovarian-cancer.
NHMRC 2012. Cancer Australia. Follow-up of women with epithelial ovarian cancer. Surry Hills, NSW: Cancer Australia; 2012. https://www.clinicalguidelines.gov.au/portal/2172/fol-low-women-epithelial-ovarian-cancer.
NICE 2011-EC. National Collaborating Centre for Cancer. Ovarian cancer. The recognition and initial management of ovarian cancer. London, UK: National Institute for Health and Clinical Excellence (NICE); 2011. http://www.nice.org.uk/guidance/cg122.
NICE 2015. National Collaborating Centre for Cancer. Sus-pected cancer: recognition and referral. London, UK: National
Institute for Health and Care Excellence; 2015. https://www.nice.org.uk/guidance/ng12.
SIGN 2013-EC. Scottish Intercollegiate Guidelines Net-work (SIGN). Management of epithelial ovarian cancer. A na-tional clinical guideline. Edinburgh, Scotland: Scottish Inter-collegiate Guidelines Network (SIGN); 2013.
USPSTF 2012. Moyer VA; U.S. Preventive Services Task Force. Screening for ovarian cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann In-tern Med. 2012; 157(12):900-4. doi:10.7326/0003-4819-157-11-201212040-00539.
Prostate cancer
ACS 2014. Skolarus TA, Wolf AM, Erb NL, et al. Ameri-can Cancer Society prostate cancer survivorship care guide-lines. CA Cancer J Clin. 2014; 64(4):225-49. doi: 10.3322/caac.21234.
AHS 2013. Alberta Provincial Genitourinary Tumour Team. Prostate cancer. Edmonton, Alberta: CancerControl Alberta; 2013.
AIOM 2015. Associazione Italiana di Oncologia Medica (AIOM). Linee guida carcinoma della prostata. Milan: AIOM; 2015.
APC 2015. Gillessen S, Omlin A, Attard G, et al. Manage-ment of patients with advanced prostate cancer: recommen-dations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015. Ann Oncol. 2015; 26(8):1589-604. doi: 10.1093/annonc/mdv257.
ASCO 2012. Basch E, Oliver TK, Vickers A, et al. Screen-ing for prostate cancer with prostate-specific antigen test-ing: American Society of Clinical Oncology provisional clini-cal opinion. J Clin Oncol. 2012; 30(24):3020-5. doi: 10.1200/JCO.2012.43.3441.
ASCO 2014. Freedland SJ, Rumble RB, Finelli A, et al. Ad-juvant and salvage radiotherapy after prostatectomy: Ameri-can Society of Clinical Oncology clinical practice guideline en-dorsement. J Clin Oncol. 2014; 32(34):3892-8. doi: 10.1200/JCO.2014.58.8525.
ASCO 2015. Resnick MJ, Lacchetti C, Bergman J, et al. Prostate cancer survivorship care guideline: American Soci-ety of Clinical Oncology clinical practice guideline endorse-ment. J Clin Oncol. 2015; 33(9):1078-85. doi: 10.1200/JCO.2014.60.2557.
ASCO-CCO 2014. Basch E, Loblaw DA, Oliver TK, et al. Systemic therapy in men with metastatic castration-resistant prostate cancer: American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline. J Clin Oncol. 2014; 32(30):3436-48. doi: 10.1200/JCO.2013.54.8404.
AUA 2011. Thompson I, Thrasher JB, Aus G, et al. Guide-line for the management of clinically localized prostate can-cer: 2007 update. Linthicum, MD: American Urological As-sociation Education and Research, Inc.; 2007. http://www.auanet.org/education/guidelines/prostate-cancer.cfm. Valid-ity verification: 2011.
AUA 2013. Carroll P, Albertsen PC, Greene K, et al. PSA testing for the pretreatment staging and posttreatment man-agement of prostate cancer: 2013 revision of 2009 best prac-tice statement. Linthicum, MD: American Urological Associa-
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tion Education and Research, Inc.; 2013.AUA 2013-ED. Carter HB, Albertsen PC, Barry MJ, et al.
Early detection of prostate cancer: AUA guideline. Linthicum, MD: American Urological Association Education and Re-search, Inc.; 2013. http://www.auanet.org/education/guide-lines/prostate-cancer-detection.cfm.
AUA 2015. Cookson MS, Roth BJ, Dahm P, et al. Castra-tion-resistant prostate cancer: AUA guideline. Linthicum, MD: American Urological Association Education and Research, Inc.; 2015. http://www.auanet.org/education/guidelines/castration-resistant-prostate-cancer.cfm.
AUA-ASTRO 2013. Thompson IM, Valicenti RK, Albertsen P, et al. Adjuvant and salvage radiotherapy after prostatec-tomy: AUA/ASTRO Guideline. J Urol. 2013; 190(2):441-9. doi: 10.1016/j.juro.2013.05.032.
CCO 2010. Chin J, Srigley J, Mayhew LA, et al. Guideline for optimization of surgical and pathological quality performance for radical prostatectomy in prostate cancer management. Toronto, ON: Cancer Care Ontario; 2008. https://www.can-cercare.on.ca/common/pages/UserFile.aspx?fileId=13952. Validity verification: 2010.
CCO 2012-BT. Rodrigues G, Yao X, Loblaw A, Brundage M, Chin J, Genitourinary Cancer Disease Site Group. Low-dose rate brachytherapy for patients with low- or intermediate-risk prostate cancer. Toronto, ON: Cancer Care Ontario; 2012.
CCO 2014-AS. Morash C, Tey R, Agbassi C, et al. Active surveillance for the management of localized prostate cancer. Toronto, ON: Cancer Care Ontario; 2014.
CCO 2015. Young S, Bansal P, Vella E, et al. Referral of suspected prostate cancer by family physicians and other primary care providers. Program in Evidence-Based Care Ev-idence-Based Guideline No. 24-3. Toronto, ON: Cancer Care Ontario; 2012. Validity verification: 2015.
CTFPHC 2014. Canadian Task Force on Preventive Health Care, Bell N, Connor Gorber S, Shane A, et al. Recommenda-tions on screening for prostate cancer with the prostate-spe-cific antigen test. CMAJ. 2014; 186(16):1225-34. doi: 10.1503/cmaj.140703.
CUA 2011. Izawa JI, Klotz L, Siemens DR, et al. Prostate cancer screening: Canadian guidelines 2011. Can Urol Assoc J. 2011; 5(4):235-40. doi: 10.5489/cuaj.11134.
EAU 2015. Mottet N, Bellmunt J, Briers E, et al. Guidelines on prostate cancer. Arnhem, Netherlands: European Associa-tion of Urology; 2015.
EGAPP 2014. Evaluation of Genomic Applications in Prac-tice and Prevention (EGAPP) Working Group. Recommenda-tions from the EGAPP Working Group: does PCA3 testing for the diagnosis and management of prostate cancer improve patient health outcomes? Genet Med. 2014; 16(4):338-46. doi: 10.1038/gim.2013.141.
ESMO 2013. Horwich A, Parker C, de Reijke T, Kataja V; ESMO Guidelines Working Group. Prostate cancer: ESMO clinical practice guidelines for diagnosis, treatment and fol-low-up. Ann Oncol. 2013; 24 (Suppl 6):vi106-14. doi: 10.1093/annonc/mdt208.
GEC-ESTRO 2013. Hoskin PJ, Colombo A, Henry A, et al. GEC/ESTRO recommendations on high dose rate af-terloading brachytherapy for localised prostate cancer: an update. Radiother Oncol. 2013; 107(3):325-32. doi:
10.1016/j.radonc.2013.05.002.NCCN 2014. National Comprehensive Cancer Network
(NCCN). Clinical Practice Guidelines in Oncology. Prostate cancer early detection, version 1.2014. Fort Washington, PA: National Comprehensive Cancer Network; 2014.
NCCN 2015. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Prostate Cancer. Fort Washington, PA: National Comprehensive Can-cer Network; 2015.
NICE 2014. National Collaborating Centre for Cancer. Pros-tate cancer: diagnosis and treatment. London, UK: National Institute for Health and Care Excellence (NICE); 2014. http://www.nice.org.uk/guidance/cg175.
NICE 2015. National Collaborating Centre for Cancer. Sus-pected cancer: recognition and referral. NICE guideline NG12. London, UK: National Institute for Health and Care Excellence; 2015. https://www.nice.org.uk/guidance/ng12.
NICE 2015-PCA3. National Institute for Health and Care Excellence (NICE). Diagnosing prostate cancer: PROGENSA PCA3 assay and Prostate Health Index. London, UK: National Institute for Health and Care Excellence (NICE); 2015. https://www.nice.org.uk/guidance/dg17.
SIOG 2014. Droz JP, Aapro M, Balducci L, et al. Manage-ment of prostate cancer in older patients: updated recom-mendations of a working group of the International Society of Geriatric Oncology. Lancet Oncol. 2014; 15(9):e404-14. doi: 10.1016/S1470-2045(14)70018-X.
SIUrO 2013. Bertaccini A, Fandella A, Pappagallo GL, et al. Italian Prostate Biopsies Group: update guidelines’ com-pendium. Bologna, Italy: Società Italiana Urologia Oncologica; 2013. http://www.siuro.it/it/eventi/italian-prostate-biopsies-group-update-guidelines-compendium.
SOGUG 2012. Climent MA, Piulats JM, Sánchez-Hernández A, et al. Recommendations from the Spanish Oncology Geni-tourinary Group for the treatment of patients with metastatic castration-resistant prostate cancer. Crit Rev Oncol Hematol. 2012; 83(3):341-52. doi: 10.1016/j.critrevonc.2012.01.002.
UMHS 2012. University of Michigan Health System. Can-cer screening. Ann Arbor, MI: University of Michigan Health System; 2012. http://www.med.umich.edu/1info/FHP/prac-ticeguides/adult_cancer.html.
USPSTF 2012. Moyer VA; U.S. Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Ser-vices Task Force recommendation statement. Ann Intern Med. 2012; 157(2):120-34. doi: 10.7326/0003-4819-157-2-201207170-00459.
Renal cancer
ACCC 2012. Urological Tumours National Working Group. Renal cell carcinoma - Version: 2.0. Utrecht, Netherlands: Association of Comprehensive Cancer Centres; 2010. http://www.oncoline.nl/renal-cell-carcinoma. Validity verification: 2012.
AHS 2012. Alberta Provincial Genitourinary Tumour Team. Renal cell carcinoma. Edmonton, Alberta: Alberta Health Ser-vices, Cancer Care; 2012.
AIOM 2015. Associazione Italiana di Oncologia Medica (AIOM). Tumori del rene. Milan, Italy: Associazione Italiana di
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Oncologia Medica (AIOM); 2015.AUA 2013. Donat SM, Diaz M, Bishoff JT, et al. Follow-up
for clinically localized renal neoplasms: AUA guideline. Lin-thicum, MD: American Urological Association Education and Research, Inc.; 2013.
EAU 2015. Ljungberg B, Bensalah K, Bex A, et al. Guide-lines on renal cell carcinoma. Arnhem, Netherlands: Europe-an Association of Urology; 2015.
ESMO 2014. Escudier B, Porta C, Schmidinger M, et al. Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014 Sep;25 (Suppl 3):iii49-56. doi: 10.1093/annonc/mdu259.
ICUD-EAU 2011. Kirkali Z, Mulders P. Kidney Cancer Edi-tion 2011: 1st EAU-ICUD International Consultation on Kid-ney Cancer Barcelona--2010. Paris, France: Edition 21; 2011. http://www.icud.info/kidneycancer.html.
NCCN 2015. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Kidney can-cer, version 3.2015. Fort Washington, PA: National Compre-hensive Cancer Network; 2015.
NICE 2015. National Collaborating Centre for Cancer. Sus-pected cancer: recognition and referral. London, UK: National Institute for Health and Care Excellence; 2015. https://www.nice.org.uk/guidance/ng12.
SOGUG 2014. García Del Muro X, Gallardo E, García Car-bonero I, et al. Recommendations from the Spanish Oncol-ogy Genitourinary Group for the treatment of patients with renal cell carcinoma. Cancer Chemother Pharmacol. 2014; 73(6):1095-107. doi: 10.1007/s00280-014-2413-0.
Testicular cancer
AHS 2013. Alberta Provincial Genitourinary Tumour Team. Testicular germ cell tumours. Edmonton, Alberta: CancerCon-trol Alberta; 2013.
AIOM 2015. Associazione Italiana di Oncologia Medica (AIOM). Tumore del testicolo. Milan, Italy: Associazione Itali-ana di Oncologia Medica (AIOM); 2015.
ASCO 2010. Gilligan TD, Seidenfeld J, Basch EM, et al. American Society of Clinical Oncology clinical practice guide-line on uses of serum tumor markers in adult males with germ cell tumors. J Clin Oncol. 2010; 28(20):3388-404. doi:
10.1200/JCO.2009.26.4481. CCO 2014. Chung P, Mayhew LA, Warde P, Winquist E,
Lukka H; members of the Genitourinary Cancer Disease Site Group. Management of stage I seminoma. Lock M and Brown J, reviewers. Toronto, ON: Cancer Care Ontario; 2008. Validity verification: 2014.
EAU 2015. Albers P, Albrecht W, Algaba F, et al. Guidelines on testicular cancer. Arnhem, Netherlands: European Associ-ation of Urology; 2015.
EGCCCG 2013. Beyer J, Albers P, Altena R, et al. Maintain-ing success, reducing treatment burden, focusing on survivor-ship: highlights from the third European Consensus Confer-ence on Diagnosis and Treatment of Germ-Cell Cancer. Ann Oncol. 2013; 24(4):878-88. doi: 10.1093/annonc/mds579.
ESMO 2013. Oldenburg J, Fosså SD, Nuver J, et al. Tes-ticular seminoma and non-seminoma: ESMO clinical prac-tice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013; 24 (Suppl 6):vi125-32. doi: 10.1093/annonc/mdt304.
NCCN 2015. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Testicular cancer, version 1.2015. Fort Washington, PA: National Com-prehensive Cancer Network; 2015.
NICE 2015. National Collaborating Centre for Cancer. Sus-pected cancer: recognition and referral. London, UK: National Institute for Health and Care Excellence; 2015. https://www.nice.org.uk/guidance/ng12.
SIGN 2011. Scottish Intercollegiate Guidelines Network. Management of adult testicular germ cell tumours. A na-tional clinical guideline. Edinburgh, Scotland: Scottish Inter-collegiate Guidelines Network; 2011. http://www.sign.ac.uk/guidelines/fulltext/124/index.html.
SIU-ICUD-UICC 2011. Stephenson AJ, Aprikian AG, Gilligan TD, et al. Management of low-stage nonseminomatous germ cell tumors of testis: SIU/ICUD Consensus Meeting on Germ Cell Tumors (GCT), Shanghai 2009. Urology. 2011;78(4 Sup-pl):S444-55. doi: 10.1016/j.urology.2011.02.030.
USPSTF 2011. U.S. Preventive Services Task Force. Screen-ing for testicular cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med. 2011; 154(7):483-6. doi: 10.7326/0003-4819-154-7-201104050-00006.
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CONTRIBUTORS
Salvatore AlfieriSC Oncologia Medica 3 Tumori Testa e ColloFondazione IRCCS Istituto Nazionale dei Tumori Milano - Italy
Emiliano AroasioDipartimento di Scienze Cliniche e BiologicheAzienda Ospedaliero-Universitaria San Luigi GonzagaOrbassano (Torino) - Italy
Alessandro BertacciniClinica UrologicaAzienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-MalpighiBologna - Italy
Francesco BoccardoUOC Clinica di Oncologia MedicaIRCCS AOU San Martino IST - Istituto Nazionale per la Ricerca sul CancroUniversità degli StudiGenova - Italy
Mario BragaSistema Monitoraggio Nazionale (Area Monitoraggio Spesa Sanitaria e LEA)Agenzia Nazionale per i Servizi Sanitari Regionali (AGENAS)Roma - Italy
Roberto BuzzoniSC Day Hospital e Terapia Ambulatoriale OncologicaFondazione IRCCS Istituto Nazionale dei TumoriMilano - Italy
Maurizio CancianSocietà Italiana di Medicina Generale SIMGScuola Veneta di Medicina Generale SVeMGConegliano Veneto (Treviso) - Italy
Ettore D. CapoluongoUOS Diagnostica Molecolare Clinica e Personalizzata, Dipartimento di Medicina LaboratorioFondazione Policlinico Universitario “Agostino Gemelli”Roma - Italy
Elisabetta CarianiSSD Laboratorio Patologia Clinica - Tossicologia e Diagnostica AvanzataNuovo Ospedale Civile S. Agostino-Estense - Azienda USL ModenaModena - Italy
Vanna Chiarion SileniSSD Oncologia Melanoma ed EsofagoIstituto Oncologico Veneto IOV – IRCCSPadova - Italy
Michela CinquiniUnità di Metodologia delle Revisioni Sistematiche e Produzione di Linee GuidaLaboratorio di Metodologia per la Ricerca BiomedicaIRCCS Istituto di Ricerche Farmacologiche “Mario Negri” Milano - Italy
Giuseppe CivardiUOC Medicina InternaPOI della Val d’Arda - Azienda USL PiacenzaFiorenzuola d’Arda (Piacenza) - Italy
Renzo ColomboDivisione Oncologia/UrologiaUrological Research InstituteIRCCS Ospedale San Raffaele Milano - Italy
Mario CorrealeSOC Patologia ClinicaIRCCS “S. De Bellis”Castellana Grotte (Bari) - Italy
Gaetano D’AmbrosioMedico di Medica Generale ASL BTSocietà Italiana di Medicina Generale SIMGBisceglie (Barletta-Adria-Trani) - Italy
Bruno DanieleUOC Oncologia Medica, Dipartimento OncologiaAzienda Ospedaliera “G. Rummo”Benevento - Italy
Marco Danova Dipartimento di Area MedicaAzienda SST di PaviaPavia - Italy
Giovanna Del Vecchio Blanco UOC GastroenterologiaDipartimento di Medicina InternaFondazione Policlinico Tor VergataUniversità degli Studi di Roma “Tor Vergata”Roma - Italy
Francesca Di FabioUOC Oncologia MedicaAzienda Ospedaliero-Universitaria Policlinico S. Orsola-MalpighiBologna - Italy
Massimo Di MaioDipartimento di Oncologia, Università degli Studi di TorinoSCDU Oncologia Medica, AO Ordine MaurizianoTorino - Italy
Circulating tumor markers: a guide to their appropriate clinical usee50
© 2017 Wichtig Publishing
Ruggero DittadiUOC Laboratorio Analisi, Dipartimento di Patologia Clinica e Medicina TrasfusionaleOspedale dell’Angelo - Azienda ULSS 12 VenezianaVenezia-Mestre - Italy
Aline Sueli Coelho Fabricio Centro e Programma Regionale Biomarcatori Diagnostici, Prognostici e PredittiviAzienda ULSS 12 VenezianaVenezia - Italy
Massimo FalconiChirurgia del PancreasIRCCS Ospedale San Raffaele Università Vita-Salute San RaffaeleMilano - Italy
Andrea FandellaUnità Funzionale UrologiaCasa di Cura Giovanni XXIIIMonastier (Treviso) - Italy
Tommaso FasanoSC Laboratorio Analisi Chimico-Cliniche e di Endocrinologia, Dipartimento di Diagnostica per Immagini e Medicina di LaboratorioClinical Cancer CenterIRCCS-Arcispedale Santa Maria NuovaReggio Emilia - Italy
Simona FerraroUOC Patologia Clinica, Dipartimento di Medicina di LaboratorioOspedale Universitario “Luigi Sacco”ASST Fatebenefratelli-Sacco Milano - Italy
Antonio FortunatoUOC Laboratorio Analisi, Dipartimento di Urgenza ed EmergenzaAzienda ULSS 6Vicenza - Italy
Bruno Franco NovellettoSocietà Italiana di Medicina Generale SIMGScuola Veneta di Medicina Generale SVeMGPadova - Italy
Angiolo GadducciDipartimento di Medicina Clinica e SperimentaleDivisione di Ginecologia e OstetriciaUniversità degli Studi di PisaPisa - Italy
Luca GermagnoliSynlab Italia Servizi DiagnosticiCastenedolo (Brescia) - Italy
Maria Grazia GhiUOC Oncologia Medica, Dipartimento OncologicoAzienda ULSS 12 VenezianaVenezia - Italy
Davide GiavarinaUOC Laboratorio Analisi, Dipartimento di Urgenza ed EmergenzaAzienda ULSS 6Vicenza - Italy
Massimo GionCentro e Programma Regionale Biomarcatori Diagnostici, Prognostici e Predittivi Azienda ULSS 12 VenezianaVenezia - Italy
Marién González LorenzoUnità di Epidemiologia ClinicaIRCCS Istituto Ortopedico GaleazziDipartimento di Scienze Biomediche per la SaluteUniversità degli Studi di MilanoMilano - Italy
Stefania GoriDipartimento di OncologiaCancer Care Center “Sacro Cuore-Don Calabria”Negrar (Verona) - Italy
Fiorella GuadagniUniversità San Raffaele RomaBiomarker Discovery and Advanced Technologies (BioDAT)Biobanca Interistituzionale Multidisciplinare (BioBIM)SR Research Center- IRCCS San Raffaele PisanaRoma - Italy
Cinzia IottiSC Radioterapia OncologicaClinical Cancer CenterIRCCS Arcispedale Santa Maria NuovaReggio Emilia - Italy
Tiziana LatianoUOC Oncologia MedicaCasa Sollievo della Sofferenza – IRCCSSan Giovanni Rotondo (Foggia) - Italy
Lisa LicitraSC Oncologia Medica 3 Tumori Testa e ColloFondazione IRCCS Istituto Nazionale dei TumoriMilano - Italy
Tiziano MagginoUOC Ostetricia e Ginecologia, Dipartimento Materno-InfantileOspedale dell’Angelo - Azienda ULSS 12 VenezianaVenezia-Mestre - Italy
Gion et al e51
© 2017 Wichtig Publishing
Evaristo MaielloUOC Oncologia MedicaCasa Sollievo della Sofferenza – IRCCSSan Giovanni Rotondo (Foggia) - Italy
Gianluca MasiUOC Oncologia MedicaAzienda Ospedaliero-Universitaria PisanaPisa - Italy
Paolo MorandiUOC Oncologia Medica, Dipartimento OncologicoAzienda ULSS 12 VenezianaVenezia - Italy
Maria Teresa MuratoreUOC Diagnostica ClinicaPO Belcolle - Azienda Sanitaria Locale ViterboViterbo - Italy
Gianmauro NumicoSC Oncologia MedicaAzienda Ospedaliera SS. Antonio e Biagio e C. ArrigoAlessandria - Italy
Valentina PecoraroSSD Laboratorio Patologia Clinica - Tossicologia e Diagnostica AvanzataNuovo Ospedale Civile S. Agostino-Estense - Azienda USL ModenaModena - Italy
Paola Pezzati SOD Laboratorio Generale AOUC Azienda Ospedaliero-Universitaria CareggiFirenze - Italy
Carmine PintoUOC OncologiaClinical Cancer CenterIRCCS Arcispedale Santa Maria NuovaReggio Emilia - Italy
Silvia PregnoUO Governance ClinicaArea Direzione Strategica - Azienda USL ModenaModena - Italy
Giulia RainatoCentro e Programma Regionale Biomarcatori Diagnostici, Prognostici e Predittivi Azienda ULSS 12 Veneziana Istituto Oncologico Veneto IOV – IRCCSPadova - Italy
Stefano RapiSOD Laboratorio Generale AOUC Azienda Ospedaliero-Universitaria CareggiFirenze - Italy
Francesco RicciDépartement Oncologie MédicaleInstitut CurieParis - France
Lorena Fabiola Rojas LlimpeUOC Oncologia MedicaAzienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-MalpighiBologna - Italy
Laura RoliSSD Laboratorio Patologia Clinica EndocrinologiaNuovo Ospedale Civile S. Agostino-Estense - Azienda USL ModenaModena- Italy
Giovanni RostiSC Oncologia MedicaFondazione IRCCS Policlinico San MatteoPavia - Italy
Tiziana RubecaLaboratorio Regionale Prevenzione OncologicaISPO Istituto per lo Studio e la Prevenzione Oncologica Firenze - Italy
Giuseppina RuggeriUOC Laboratorio AnalisiASST Spedali CiviliBrescia - Italy
Anne W.S. RutjesDivision of Clinical Epidemiology & BiostatisticsInstitute of Social and Preventive MedicineUniversity of BernBern - Switzerland
Gian Luca SalvagnoUOC Laboratorio Analisi, DAI Patologia e DiagnosticaOspedale Borgo Roma - Azienda Ospedaliera Universitaria IntegrataVerona - Italy
Maria Teresa SandriDivisione Medicina LaboratorioIstituto Europeo di Oncologia IRCCSMilano - Italy
Giovanni ScambiaIstituto di Clinica ostetrico e ginecologica Università Cattolica del Sacro CuoreRoma - Italy
Mario ScartozziClinica di Oncologia MedicaPresidio Policlinico Universitario “Duilio Casula”Azienda Ospedaliera UniversitariaCagliari - Italy
Circulating tumor markers: a guide to their appropriate clinical usee52
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Ornella ScattolinCentro e Programma Regionale Biomarcatori Diagnostici, Prognostici e Predittivi Azienda ULSS 12 VenezianaAVAPO Venezia OnlusVenezia - Italy
Vincenzo ScattoniUO UrologiaIRCCS Ospedale San Raffaele Università Vita-Salute San RaffaeleMilano - Italy
Holger Schünemann Department of Clinical Epidemiology & BiostatisticsMcMaster University Health Sciences CentreHamilton - Canada
Giuseppe SicaUOC Chirurgia Generale A, Dipartimento di ChirurgiaFondazione PTV Policlinico Universitario Tor Vergata Università Roma-Tor VergataRoma - Italy
Alessandro TerreniSOD Laboratorio Generale AOUC Azienda Ospedaliero-Universitaria CareggiFirenze - Italy
Marcello TiseoSC Oncologia MedicaAzienda Ospedaliero-UniversitariaParma - Italy
Valter TorriLaboratorio Metodologia per la Ricerca Biomedica, Dipartimento OncologiaIRCCS Istituto di Ricerche Farmacologiche “Mario Negri” Milano - Italy
Quinto TozziRicerca e Studio Rischio ClinicoAgenzia Nazionale per i Servizi Sanitari Regionali (AGENAS)Roma - Italy
Tommaso TrentiDipartimento Integrato Interaziendale di Medicina di Laboratorio ed Anatomia PatologicaAzienda Ospedaliera Universitaria e Azienda USL di ModenaModena - Italy
Chiara TrevisiolCentro e Programma Regionale Biomarcatori Diagnostici, Prognostici e Predittivi Azienda ULSS 12 Veneziana Istituto Oncologico Veneto IOV – IRCCSPadova - Italy
Paolo ZolaDipartimento Scienze ChirurgicheAOU Città della Salute e della ScienzaUniversità degli StudiTorino - Italy
IJBMeISSN 1724-6008
Int J Biol Markers 2017; 32(2): e147-e181
© 2017 Wichtig Publishing
GUIDELINES
DOI: 10.5301/ijbm.5000272
Circulating tumor markers: a guide to their appropriate clinical use Comparative summary of recommendations from clinical practice guidelines (PART 3)
Massimo Gion1, Chiara Trevisiol2, Anne W.S. Rutjes3, Giulia Rainato2, Aline S.C. Fabricio1
1 Regional Center and Program for Biomarkers, Department of Clinical Pathology and Transfusion Medicine, Azienda ULSS 3 Serenissima, Venice - Italy
2 Istituto Oncologico Veneto IOV - IRCCS, Padova - Italy3 Institute of Social and Preventive Medicine, University of Bern, Bern - Switzerland
Endorsed byAGENAS National Agency for Regional Health Services, Rome, ItalyRegional Center for Biomarkers, Azienda ULSS 3 Serenissima - formerly Azienda ULSS 12 Veneziana, Venice, Italy
On behalf of and in collaboration withRegione del Veneto, IOV - Istituto Oncologico Veneto - I.R.C.C.S., AIOM (Associazione Italiana di Oncologia Medica), SIBioC - Medicina di Laboratorio (Società Italiana di Biochimica Clinica e Biologia Molecolare Clinica), AIRO (Associazione Italiana di Radioterapia Oncologica), ELAS-Italia (European Ligand Assay Society Italia), FADOI (Federazione delle Associazioni dei Dirigenti Ospedalieri Internisti), SICO (Società Italiana di Chirurgia Oncologica), SIGO (Società Italiana di Ginecologia e Ostetricia), SIMG (Società Italiana di Medicina Generale), SIUrO (Società Italiana di Urologia Oncologica), AVAPO Venezia Onlus (Associazione Volontari per l’Assistenza di Pazienti Oncologici)
Steering CommitteeMario Braga, Massimo Gion, Carmine Pinto, Bruno Rusticali, Holger Schünemann, Tommaso TrentiFor complete contributors' affiliations see end of article (pp. e178-e181)
Scientific CommitteeAline S.C. Fabricio, Evaristo Maiello, Anne W.S. Rutjes, Valter Torri, Quinto Tozzi, Chiara TrevisiolFor complete contributors' affiliations see end of article (pp. e178-e181)
Received: February 1, 2017Accepted: March 16, 2017Published online: May 3, 2017
Corresponding author:Dr. Massimo GionCentro Regionale BiomarcatoriAzienda ULSS3 SerenissimaOspedale Civile30122 Venice, Italymassimo.gion@aulss3.veneto.it
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Contributions of panel members(1) Search and selection of guidelines (2) Appraisal of guidelines through the AGREE II tool (3) Assessment of the rate of utilization of a subset of guidance documents in clinical practice (4) Synthesis of recommendations and other information concerning tumor markers into summary tables (5) Assessment of correctness and completeness of the information summarized in the tables
External validationInterregional Biomarkers Working Group, instituted by the Health Commission of the Italian Permanent Conference for Relations between State, Regions and the Autonomous Provinces of Trento and Bolzano. Antonino Iaria (Calabria), Vincenzo Montesarchio (Campania), Tommaso Trenti (Emilia Romagna), Laura Conti (Lazio), Luigina Bonelli and Gabriella Paoli (Liguria), Mario Cassani (Lombardia), Lucia Di Furia (Marche), Emiliano C. Aroasio (Piemonte), Mario Brandi (Puglia), Marcello Ciaccio and Antonio Russo (Sicilia), Gianni Amunni (Toscana), Emanuela Toffalori (P.A. Trento), Basilio Ubaldo Passamonti (Umbria), Claudio Pilerci and Francesca Russo (Veneto), Annarosa Del Mistro (IOV IRCCS, Veneto)
Executive secretaryOrnella Scattolin
FundingAGENAS Agenzia Nazionale per i Servizi Sanitari Regionali Azienda ULSS 12 VenezianaIOV - Istituto Oncologico Veneto - I.R.C.C.S.AIOM (Associazione Italiana di Oncologia Medica)SIBioC - Medicina di Laboratorio (Società Italiana di Biochimica Clinica e Biologia Molecolare Clinica)ELAS-Italia (European Ligand Assay Society Italia)SIUrO (Società Italiana di Urologia Oncologica) AVAPO Venezia Onlus (Associazione Volontari per l’Assistenza di Pazienti Oncologici)
This study was helpful in the exploration of unmet needs in tumor marker application in the frame of an AIRC 5x1000 research project, from which it was partially supported (Italian Association for Research on Cancer - AIRC; Grant Special Program Molecu-lar Clinical Oncology, 5x1000, No. 12214).
The authors would like to thank the following cultural associations in Venice for their supportAssociazione “Un amico a Venezia”, “Chiostro Tintorettiano di Venezia”, “I ragazzi di don Bepi”, SKÅL International Venezia for their support.
AcknowledgmentsThe authors would like to thank the following researchers for their collaboration: Mauro Antimi (Roma), Alessandro Battaggia (Padova), Nicola L. Bragazzi (Genova), Massimo Brunetti (Modena), Michele Cannone (Canosa di Puglia), Antonette E. Leon (Venezia).
This guide is published in Italian as:Gion M, Trevisiol C, Rainato G, Fabricio ASC. Marcatori circolanti in oncologia: guida all'uso clinico appropriato. I Quaderni di Monitor. Roma, IT: AGENAS, Agenzia Nazionale per i Servizi Sanitari Regionali, 2016.
Multidisciplinary panel of experts Salvatore Alfieri(5), Emiliano Aroasio(3,5), Alessandro Bertaccini(3,5), Francesco Boccardo(3,5), Roberto Buzzoni(3,5), Maurizio Cancian(5), Ettore D. Capoluongo(5), Elisabetta Cariani(5), Vanna Chiarion Sileni(3,5), Michela Cinquini(1,3,5), Giuseppe Civardi(5), Renzo Colombo(3,5), Mario Correale(3,5), Gaetano D’Ambrosio(5), Bruno Daniele(3,5), Marco Danova(3,5), Giovanna Del Vecchio Blanco(3,5), Francesca Di Fabio(3,5), Massimo Di Maio(3,5), Ruggero Dittadi(3,5), Massimo Falconi(3,5), Andrea Fandella(3,5), Tommaso Fasano(5), Simona Ferraro(3,5), Antonio Fortunato(3,5), Bruno Franco Novelletto(5), Angiolo Gadducci(3,5), Luca Germagnoli(3,5), Maria Grazia Ghi(3,5), Davide Giavarina(3,5), Marién González Lorenzo(2,5), Stefania Gori(3,5), Fiorella Guadagni(3,5), Cinzia Iotti(3,5), Tiziana Latiano(1,3,5), Lisa Licitra(3,5), Tiziano Maggino(5), Gianluca Masi(5), Paolo Morandi(3,5), Maria Teresa Muratore(3,5), Gianmauro Numico(5), Valentina Pecoraro(2,5), Paola Pezzati(3,5), Silvia Pregno(5), Giulia Rainato(4), Stefano Rapi(3,5), Francesco Ricci(3,5), Lorena Fabiola Rojas Llimpe(3,5), Laura Roli(1,5), Giovanni Rosti(3,5), Tiziana Rubeca(3,5), Giuseppina Ruggeri(5), Gian Luca Salvagno(5), Maria Teresa Sandri(5), Giovanni Scambia(3,5), Mario Scartozzi(3,5), Vincenzo Scattoni(3,5), Giuseppe Sica(3,5), Alessandro Terreni(3,5), Marcello Tiseo(3,5), Paolo Zola(5)
For complete contributors' affiliations see end of article (pp. e178-e181)
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Acronyms
Abbreviations of tumor markers cited in the present article
CA125 Cancer Antigen 125CA19.9 Cancer Antigen 19.9CEA CarcinoEmbryonic AntigenCt CalcitoninCyfra 21-1 Cytokeratin 19 fragmentLDH Lactate DeHydrogenaseNSE Neuron-Specific Enolase
pro-GRP pro-Gastrin-Releasing PeptidePTH Parathyroid HormoneSMRP Soluble Mesothelin-Related PeptidesTg ThyroglobulinTgAb Tg AntibodiesTSH Thyroid-Stimulating Hormone
Contents Introduction e150 Take-home messages
Users’ instructions e151Head and neck cancer e152Lung cancer e153Melanoma e155Mesothelioma e157Thyroid cancer, differentiated e159Thyroid cancer, medullary (MTC) e161
Detailed summary tables Users’ instructions e163Head and neck cancer e164Lung cancer e165Melanoma e166Mesothelioma e167Thyroid cancer, differentiated e169Thyroid cancer, medullary (MTC) e172
Selected guidelines (by cancer site) e175Contributors e178
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Introduction
This is the last part of a guide to the appropriate clinical use of circulating tumor markers (TMs). The full document was published in Italy in October 2016 by the Italian National Agency for Regional Health Services (AGENAS) on behalf of and in collaboration with 9 Italian scientific societies repre-sentative of a range of stakeholders (1). The publication of the document in English was planned in 3 parts: the first, concerning malignancies of the gastrointestinal tract, was published in December 2016 (2); the second, published in February 2017 (3), addressed urogenital tract malignancies and breast cancer; the third, appearing in the present issue, refers to head-and-neck, thyroid and thoracic malignancies and melanoma.
Rationale
The number of TM tests requested is considerably high-er than expected based on the cancer prevalence, and this shows the low compliance of physicians to clinical practice guidelines (CPGs). Barriers preventing clinicians from adher-ence to CPG recommendations include discrepancies be-tween the cautious position of CPGs and the encouraging results of primary studies. In fact, the evidence provided by primary studies tends to focus on the diagnostic accuracy of the tests rather than on patient outcomes, the latter being a prerequisite for good-level evidence in guideline develop-ment. While awaiting the incorporation of higher-quality evidence into comprehensive guidelines, efforts should be made to improve the adherence to existing CPGs. A project was developed to summarize recommendations on circulat-ing TMs offered by available CPGs on solid tumors, in order to provide all possible evidence-based choices concerning TMs to anyone facing a clinical question in which the use of a TM could be considered.
The implicit goal of the present guidance document is to “stimulate discussion and promote commentaries and de-bate, with the ultimate ambition of improving the appropri-ate use of TMs but also optimizing the proposed model of comparative summary of the available evidence to facilitate extensive dissemination and consultation of the guidance provided” (4).
Methods
The structured and rigorous methodology adopted for the extraction and synthesis of relevant information from selected guidelines has been previously described in detail (2). In brief, a systematic search for CPGs was performed and a standardized set of selection criteria was used to identify potentially relevant publications. Only documents containing recommendations for clinical practice were included. A total of 1,181 potentially relevant documents were selected from 8,266 identified records. Full-text reports were obtained for 559 guidance documents concerning 20 different malignan-cies. The selected documents were further appraised for ad-herence to the standards of the Institute of Medicine (IOM), which require CPGs to be based on systematic review of exist-
ing evidence (5), and clustered into 2 groups: 127 documents in which recommendations were generated through system-atic review (CPGs) and 432 guidance documents without evidence of systematic review (Other Guidance Documents – OGDs). CPGs were further assessed with the Appraisal of Guidelines for Research & Evaluation (AGREE II) tool in order to facilitate comparison of the quality of the summarized CPGs. OGDs produced by authoritative institutions or medical societies are currently used by clinicians in their daily prac-tice. All OGDs were therefore presented to the panel mem-bers with a request to indicate those actually used in clinical practice. When 25% or more of the panel members declared that a given guidance document was used in clinical practice, it was retained. In all, 111 of 432 OGDs qualified for inclu-sion. Circulating biomarkers measured in body fluids (serum or plasma/urine) were considered.
Results
The tabulation of the information was structured by indi-vidual malignancies; within each malignancy, the information was clustered according to a set of clinical questions estab-lished as being common to all malignancies. All information extracted from the guidance documents was synthesized in 4 rounds (levels) of increasing simplification. The last 2 levels of synthesis are the Take-Home Messages and Detailed Sum-mary Tables. The former are intended for use by health care providers in their clinical practice with the goal of improving the appropriateness of TM use; the latter are addressed to policy makers for potential adaptation to their own context, and to educators, allowing them to design teaching programs consistent with the available evidence.
References1. Gion M, Trevisiol C, Rainato G, Fabricio ASC. Marcatori circolan-
ti in oncologia: guida all’uso clinico appropriato. I Quaderni di Monitor. Roma: AGENAS, Agenzia Nazionale per i Servizi Sani-tari Regionali 2016.
2. Gion M, Trevisiol C, Rutjes AWS, Rainato G, Fabricio ASC. Circu-lating tumor markers: a guide to their appropriate clinical use. Comparative summary of recommendations from clinical prac-tice guidelines (Part 1). Int J Biol Markers. 2016;31:e332-e367.
3. Gion M, Trevisiol C, Rutjes AWS, Rainato G, Fabricio ASC. Cir-culating tumor markers: a guide to their appropriate clinical use. Comparative summary of recommendations from clinical practice guidelines (Part 2). Int J Biol Markers. 2017;32:e1-e52.
4. Gion M. Need for knowledge translation to improve tumor marker application. Int J Biol Markers. 2016;31:e331.
5. IOM (Institute of Medicine). Clinical practice guidelines we can trust. Washington, DC: The National Academies Press 2011.
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AGREE evaluation
CPGs concerning every malignancy were also assessed with the Appraisal of Guidelines for Research & Evaluation (AGREE II) tool. A higher score equals a better quality of the domain. The results are reported after the Take-Home Message tables.
Additional notes▪ Take-Home Messages are reported in alphabetical order. ▪ Information from OGDs on a specific clinical question were only reported in the Take-Home Messages if the clinical question was considered by CPGs.
Descriptions regarding these OGDs can, however, be found in the Detailed Summary Tables.▪ References concerning both CPGs and OGDs are reported after the Detailed Summary Tables, divided by type of malignancy and cited with the acronyms used
in the Tables.
15
AGREE evaluation
CPGs concerning every malignancy were also assessed with the Appraisal of Guidelines for Research & Evaluation (AGREE II) tool. A higher score equals a better quality of the domain. The results are reported after the Take-‐Home Message tables.
Acronym Domain 1 Scope and purpose
Domain 2 Stakeholder involvement
Domain 3 Rigor of development
Domain 4 Clarity of
presentation
Domain 5 Applicability
Domain 6 Editorial
independence
Acronyms of CPGs
Scores concerning the overall aim of the guideline, the specific health questions, and the target population are reported for every CPG
Scores concerning the extent to which the guideline was developed by the appropriate stakeholders and represents the views of its intended users are reported for every CPG
Scores concerning the process used to gather and synthesize the evidence, and the methods to formulate the recommendations and update them are reported for every CPG
Scores concerning the language, structure, and format of the guideline are reported for every CPG
Scores concerning the likely barriers and facilitators to implementation, strategies to improve uptake, and resource implications of applying the guideline are reported for every CPG
Scores concerning the formulation of recommendations not being unduly biased with competing interests are reported for every CPG
The scores of the 6 domains were subdivided into quartiles and marked in different colors as shown in the following table:
0-‐25th percentile 26th-‐50th percentile 51st-‐75th percentile
76th-‐100th percentile Additional notes − Take-‐Home Message tables are reported in alphabetical order − Information from OGDs on a specific clinical question were only reported in the Take-‐Home Message table if the clinical question was considered by CPGs. Descriptions regarding these OGDs
can, however, be found in the Detailed Summary Tables. − References concerning both GPGs and OGD are reported after the Detailed Summary Tables, divided by type of malignancy and cited with the acronyms used in the Tables
Take-home messages
Users' instructions
Definition and target audience
Take-Home Messages are presented in table format for every tumor type, summarizing essential information to support decision-making in clinical practice. They are intended for use by health care providers.
14
TAKE-‐HOME MESSAGES -‐ Users’ instructions
Definition and target audience Take-‐Home Messages are presented in table format for every tumor type, summarizing essential information to support decision-‐making in clinical practice. They are intended for use by health care providers. Structure
Total number of selected documents (number of CPGs, number of OGDs)
Clinical question
Summary of recommendations
Recommended tumor marker(s)
CPG/total CPG (CPG acronyms)
OGD/total OGD
(OGD acronyms)
The different clinical questions are reported
The symbol denotes that CPGs formulated inconsistent recommendations on TMs in the clinical question
Recommendations and information from CPGs that consider the clinical question are summarized
The sentence “Recommendations on TMs not available” is reported when the clinical question was considered by CPGs, but either TMs were not addressed or no explicit recommendations on TMs were provided
The recommended TM(s) are reported
When CPGs explicitly recommend against TM(s), the word “None” is reported
The symbol ∅ is shown when the examined CPGs either do not address TMs or, if TMs are addressed, CPGs do not formulate explicit recommendations
Number of CPGs reporting the summarized information in proportion to the total number of CPGs that consider the clinical question (acronyms of the CPGs in parenthesis)
Number of ODGs reporting the summarized information in proportion to the total number of CPGs that consider the clinical question (acronyms of the OGDs in parenthesis)
STRUCTURETotal number of selected documents (number of CPGs, number of OGDs)
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1 He
ad and
neck cancer
Exam
ined
doc
umen
ts: 1
0 (5 CPG
s, 5 OGDs)
Clinical que
stion
Summary of re
commen
datio
ns
Reco
mmen
ded
tumor m
arke
r(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2
)
(OGD acron
yms)
Screen
ing
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
2/2
(ADA
201
0, U
SPST
F 20
13)
0/4
Differen
tial d
iagn
osis
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
3/3
(AHS
201
3, C
CO 2
009,
N
ICE
2015
)
4/4
(AIO
M 2
015,
ES
MO
-‐EHN
S-‐ES
TRO
201
0-‐SC
C,
ESM
O-‐E
HNS-‐
ESTR
O 2
012-‐
NPC
, N
CCN
201
5)
Preo
perativ
e worku
p Re
com
men
datio
ns o
n TM
s not
ava
ilabl
e ∅
2/2
(AHS
201
3, C
CO 2
009)
1/5
(ESM
O-‐E
HNS-‐
ESTR
O 2
010-‐
SCC)
Reassessmen
t after in
itial
curativ
e trea
tmen
t Re
com
men
datio
ns o
n TM
s not
ava
ilabl
e ∅
1/1
(CCO
200
9)
2/4
(ESM
O-‐E
HNS-‐
ESTR
O 2
010-‐
SCC,
N
CCN
201
5)
Early
detectio
n of
recu
rren
ce or p
rogression
Re
com
men
datio
ns o
n TM
s not
ava
ilabl
e ∅
1/1
(AHS
201
3)
1/5
(ESM
O-‐E
HNS-‐
ESTR
O 2
010-‐
SCC)
Mon
itorin
g of trea
tmen
t respon
se in
adv
anced
disease
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
2/2
(AHS
201
3, C
CO 2
009)
5/5
(AIO
CC-‐A
IRO
-‐AIO
M 2
012,
AI
OM
201
5,
ESM
O-‐E
HNS-‐
ESTR
O 2
010-‐
SCC,
ES
MO
-‐EHN
S-‐ES
TRO
201
2-‐N
PC,
NCC
N 2
015)
(1) C
PG/total CPG
: CPG
s rep
ortin
g th
e su
mm
arize
d in
form
atio
n/to
tal n
umbe
r of C
PGs t
hat c
onsid
er th
e cl
inic
al q
uest
ion.
(2) O
GD/total OGD
: OG
Ds re
port
ing
the
sum
mar
ized
info
rmat
ion/
tota
l num
ber o
f OG
Ds th
at c
onsid
er th
e cl
inic
al q
uest
ion.
∅ T
he e
xam
ined
CPG
s tha
t con
sider
the
clin
ical
que
stio
n ei
ther
do
not a
ddre
ss T
Ms o
r, if
TMs a
re a
ddre
ssed
, CPG
s do
not p
rese
nt e
xplic
it re
com
men
datio
ns.
Acrony
ms o
f CPG
s Dom
ain 1
Scop
e an
d pu
rpos
e Dom
ain 2
Stak
ehol
der
invo
lvem
ent
Dom
ain 3
Rigo
r of
deve
lopm
ent
Dom
ain 4
Clar
ity o
f pr
esen
tatio
n
Dom
ain 5
Appl
icab
ility
Dom
ain 6
Edito
rial
inde
pend
ence
ADA 20
10
83
56
86
89
58
79
AHS 20
13
81
44
65
75
58
79
CCO 200
9
92
56
76
69
38
63
NICE 20
15
89
97
91
89
71
79
USP
STF 20
13
78
44
75
81
42
79
HEA
D A
ND
NEC
K CA
NCE
R Ta
ke-h
ome
mes
sage
Exam
ined
doc
umen
ts: 1
0 (5
CPG
s, 5
OG
Ds)
Gion et al e153
© 2017 Wichtig Publishing
2 Lu
ng can
cer
Ex
amined
doc
umen
ts: 2
9 (18 CP
Gs, 11 OGDs)
Clinical que
stion
Summary of re
commen
datio
ns
Reco
mmen
ded
tumor m
arke
r(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2
)
(OGD acron
yms)
Screen
ing
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
2/2
(ACC
P 20
13, U
SPST
F 20
14-‐s
cr)
3/5
(AIO
M 2
015,
NCC
N 2
015-‐
scr,
NCC
N 2
015-‐
SCLC
)
Differen
tial d
iagn
osis
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
9/9
(ACC
P 20
13, A
HS 2
014-‐
NSC
LC.s
1,
AHS
2014
-‐NSC
LC.s
2, A
SCO
201
5-‐SC
LC,
BTS-‐
SCTS
201
0, C
CO 2
014-‐
dia,
N
ICE
2011
, NIC
E 20
15-‐d
ia, S
IGN
201
4)
9/9
(AIO
M 2
015,
ESM
O 2
013-‐
NSC
LC,
ESM
O 2
014,
ESM
O 2
014-‐
NSC
LC.m
+, E
SMO
-‐JSM
O 2
013-‐
SCLC
, FS
2013
, NCC
N 2
015-‐
NSC
LC, N
CCN
201
5-‐sc
r, N
CCN
201
5-‐SC
LC)
Preo
perativ
e worku
p
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
8/8
(ACC
P 20
13, A
HS 2
013-‐
NSC
LC.s
4,
AHS
2014
-‐NSC
LC.s
1, A
HS 2
014-‐
NSC
LC.s
2, A
SCO
201
5-‐SC
LC, B
TS-‐
SCTS
201
0, N
ICE
2011
, SIG
N 2
014)
4/7
(AIO
M 2
015,
ESM
O 2
013-‐
NSC
LC,
ESM
O 2
014,
NCC
N 2
015-‐
NSC
LC)
Reassessmen
t after in
itial
curativ
e trea
tmen
t Po
st-‐t
hera
py C
EA n
orm
aliz
atio
n or
sign
ifica
nt d
ecre
ase
seem
s to
be
rela
ted
to b
ette
r sur
viva
l in
early
-‐sta
ge N
SCLC
trea
ted
by su
rger
y
CEA
1/1
(ELC
WP
2012
) 0/2
Early
detectio
n of
recu
rren
ce or p
rogression
Fo
r lun
g ca
ncer
pat
ient
s tre
ated
with
cur
ativ
e in
tent
, it i
s sug
gest
ed th
at
surv
eilla
nce
biom
arke
r tes
ting
not b
e do
ne o
utsid
e of
clin
ical
tria
ls
Non
e ∅
1/7
(ACC
P 20
13)
1/7
(AIO
M 2
015)
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
6/7
(AHS
201
2-‐N
SCLC
.s3,
AHS
201
4-‐N
SCLC
.s1,
AHS
201
4-‐N
SCLC
.s2,
CC
O 2
014-‐
fu, N
ICE
2011
, SIG
N 2
014)
6/7
(ESM
O 2
013-‐
NSC
LC, E
SMO
201
4,
ESM
O 2
014-‐
NSC
LC.m
+, E
SMO
-‐JS
MO
201
3-‐SC
LC, N
CCN
201
5-‐N
SCLC
, NCC
N 2
015-‐
SCLC
)
Mon
itorin
g of trea
tmen
t respon
se in
adv
anced
disease
Som
e ci
rcul
atin
g m
arke
rs c
ould
cou
ld p
rovi
de p
rogn
ostic
info
rmat
ion
for
surv
ival
CE
A, Cyfra 21-‐1,
pro-‐GRP
∅
1/10
(E
LCW
P 20
12)
0/8
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
9/10
(A
CCP
2013
, AHS
201
2-‐SC
LC.e
s,
AHS
2012
-‐SCL
C.ls,
AHS
201
2-‐N
SCLC
.s3,
AH
S 20
13-‐N
SCLC
.s4,
ASC
O 2
015-‐
NSC
LC.s
4, A
SCO
201
5-‐SC
LC, C
CO 2
014-‐
NSC
LC.m
+, S
IGN
201
4)
8/8
(AIO
M 2
015,
AIO
T 20
12-‐N
SCLC
, CE
COG
201
2-‐N
SCLC
, ESM
O 2
014,
ES
MO
201
4-‐N
SCLC
.m+,
ESM
O-‐
JSM
O 2
013-‐
SCLC
, NCC
N 2
015-‐
NSC
LC, N
CCN
201
5-‐SC
LC)
(1) C
PG/total CPG
: CPG
s rep
ortin
g th
e su
mm
arize
d in
form
atio
n/to
tal n
umbe
r of C
PGs t
hat c
onsid
er th
e cl
inic
al q
uest
ion.
(2) O
GD/total OGD
: OG
Ds re
port
ing
the
sum
mar
ized
info
rmat
ion/
tota
l num
ber o
f OG
Ds th
at c
onsid
er th
e cl
inic
al q
uest
ion.
∅ T
he e
xam
ined
CPG
s th
at c
onsid
er th
e cl
inic
al q
uest
ion
eith
er d
o no
t add
ress
TM
s or,
if TM
s are
add
ress
ed, C
PGs d
o no
t pre
sent
exp
licit
reco
mm
enda
tions
. N
SCLC
= n
on-‐s
mal
l cel
l lun
g ca
ncer
.
2 Lu
ng can
cer
Ex
amined
doc
umen
ts: 2
9 (18 CP
Gs, 11 OGDs)
Clinical que
stion
Summary of re
commen
datio
ns
Reco
mmen
ded
tumor m
arke
r(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2
)
(OGD acron
yms)
Screen
ing
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
2/2
(ACC
P 20
13, U
SPST
F 20
14-‐s
cr)
3/5
(AIO
M 2
015,
NCC
N 2
015-‐
scr,
NCC
N 2
015-‐
SCLC
)
Differen
tial d
iagn
osis
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
9/9
(ACC
P 20
13, A
HS 2
014-‐
NSC
LC.s
1,
AHS
2014
-‐NSC
LC.s
2, A
SCO
201
5-‐SC
LC,
BTS-‐
SCTS
201
0, C
CO 2
014-‐
dia,
N
ICE
2011
, NIC
E 20
15-‐d
ia, S
IGN
201
4)
9/9
(AIO
M 2
015,
ESM
O 2
013-‐
NSC
LC,
ESM
O 2
014,
ESM
O 2
014-‐
NSC
LC.m
+, E
SMO
-‐JSM
O 2
013-‐
SCLC
, FS
2013
, NCC
N 2
015-‐
NSC
LC, N
CCN
201
5-‐sc
r, N
CCN
201
5-‐SC
LC)
Preo
perativ
e worku
p
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
8/8
(ACC
P 20
13, A
HS 2
013-‐
NSC
LC.s
4,
AHS
2014
-‐NSC
LC.s
1, A
HS 2
014-‐
NSC
LC.s
2, A
SCO
201
5-‐SC
LC, B
TS-‐
SCTS
201
0, N
ICE
2011
, SIG
N 2
014)
4/7
(AIO
M 2
015,
ESM
O 2
013-‐
NSC
LC,
ESM
O 2
014,
NCC
N 2
015-‐
NSC
LC)
Reassessmen
t after in
itial
curativ
e trea
tmen
t Po
st-‐t
hera
py C
EA n
orm
aliz
atio
n or
sign
ifica
nt d
ecre
ase
seem
s to
be
rela
ted
to b
ette
r sur
viva
l in
early
-‐sta
ge N
SCLC
trea
ted
by su
rger
y
CEA
1/1
(ELC
WP
2012
) 0/2
Early
detectio
n of
recu
rren
ce or p
rogression
Fo
r lun
g ca
ncer
pat
ient
s tre
ated
with
cur
ativ
e in
tent
, it i
s sug
gest
ed th
at
surv
eilla
nce
biom
arke
r tes
ting
not b
e do
ne o
utsid
e of
clin
ical
tria
ls Non
e ∅
1/7
(ACC
P 20
13)
1/7
(AIO
M 2
015)
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
6/7
(AHS
201
2-‐N
SCLC
.s3,
AHS
201
4-‐N
SCLC
.s1,
AHS
201
4-‐N
SCLC
.s2,
CC
O 2
014-‐
fu, N
ICE
2011
, SIG
N 2
014)
6/7
(ESM
O 2
013-‐
NSC
LC, E
SMO
201
4,
ESM
O 2
014-‐
NSC
LC.m
+, E
SMO
-‐JS
MO
201
3-‐SC
LC, N
CCN
201
5-‐N
SCLC
, NCC
N 2
015-‐
SCLC
)
Mon
itorin
g of trea
tmen
t respon
se in
adv
anced
disease
Som
e ci
rcul
atin
g m
arke
rs c
ould
cou
ld p
rovi
de p
rogn
ostic
info
rmat
ion
for
surv
ival
CE
A, Cyfra 21-‐1,
pro-‐GRP
∅
1/10
(E
LCW
P 20
12)
0/8
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
9/10
(A
CCP
2013
, AHS
201
2-‐SC
LC.e
s,
AHS
2012
-‐SCL
C.ls,
AHS
201
2-‐N
SCLC
.s3,
AH
S 20
13-‐N
SCLC
.s4,
ASC
O 2
015-‐
NSC
LC.s
4, A
SCO
201
5-‐SC
LC, C
CO 2
014-‐
NSC
LC.m
+, S
IGN
201
4)
8/8
(AIO
M 2
015,
AIO
T 20
12-‐N
SCLC
, CE
COG
201
2-‐N
SCLC
, ESM
O 2
014,
ES
MO
201
4-‐N
SCLC
.m+,
ESM
O-‐
JSM
O 2
013-‐
SCLC
, NCC
N 2
015-‐
NSC
LC, N
CCN
201
5-‐SC
LC)
(1) C
PG/total CPG
: CPG
s rep
ortin
g th
e su
mm
arize
d in
form
atio
n/to
tal n
umbe
r of C
PGs t
hat c
onsid
er th
e cl
inic
al q
uest
ion.
(2) O
GD/total OGD
: OG
Ds re
port
ing
the
sum
mar
ized
info
rmat
ion/
tota
l num
ber o
f OG
Ds th
at c
onsid
er th
e cl
inic
al q
uest
ion.
∅ T
he e
xam
ined
CPG
s th
at c
onsid
er th
e cl
inic
al q
uest
ion
eith
er d
o no
t add
ress
TM
s or,
if TM
s are
add
ress
ed, C
PGs d
o no
t pre
sent
exp
licit
reco
mm
enda
tions
. N
SCLC
= n
on-‐s
mal
l cel
l lun
g ca
ncer
.
LUN
G C
AN
CER
Tak
e-ho
me
mes
sage
Exam
ined
doc
umen
ts: 2
9 (1
8 CP
Gs,
11
OG
Ds)
Circulating tumor markers: a guide to their appropriate clinical usee154
© 2017 Wichtig Publishing
3 Ac
rony
ms of CPG
s Dom
ain 1
Scop
e an
d pu
rpos
e Dom
ain 2
Stak
ehol
der
invo
lvem
ent
Dom
ain 3
Rigo
r of
deve
lopm
ent
Dom
ain 4
Clar
ity o
f pr
esen
tatio
n
Dom
ain 5
Appl
icab
ility
Dom
ain 6
Edito
rial
inde
pend
ence
ACCP
201
3 81
67
86
83
73
75
AHS 20
12-‐N
SCLC
.s3
72
44
75
72
58
79
AHS 20
12-‐SCL
C.es
69
44
64
75
58
79
AHS 20
12-‐SCL
C.ls
69
44
64
72
58
79
AHS 20
13-‐N
SCLC
.s4
72
44
65
75
58
79
AHS 20
14-‐N
SCLC
.s1
78
44
66
69
54
79
AHS 20
14-‐N
SCLC
.s2
72
44
65
75
58
79
ASCO
201
5-‐NSC
LC.s4
86
86
76
72
58
58
ASCO
201
5-‐SC
LC
89
75
70
83
38
63
BTS-‐SC
TS 201
0 58
44
77
78
31
58
CCO 201
4-‐dia
92
56
76
78
40
67
CCO 201
4-‐fu
89
53
77
81
38
71
CCO 201
4-‐NSC
LC.m
+ 86
50
79
86
40
67
ELCW
P 20
12
83
44
68
78
29
50
NICE 20
11
92
94
96
94
85
92
NICE 20
15-‐dia
89
97
92
89
71
83
SIGN 201
4 89
89
81
92
83
71
USP
STF 20
14-‐scr
81
44
79
78
33
71
LUN
G C
AN
CER
Tak
e-ho
me
mes
sage
Exam
ined
doc
umen
ts: 2
9 (1
8 CP
Gs,
11
OG
Ds)
Gion et al e155
© 2017 Wichtig Publishing
4 Melan
oma
Exam
ined
doc
umen
ts: 1
4 (9 CPG
s, 5 OGDs)
Clinical que
stion
Summary of re
commen
datio
ns
Reco
mmen
ded
tumor m
arke
r(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2
)
(OGD acron
yms)
Screen
ing
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
3/3
(ACC
C 20
12, B
AD 2
010,
U
SPST
F 20
09)
2/2
(AIO
M 2
015,
SID
eMaS
T 20
11)
Differen
tial d
iagn
osis
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
5/5
(ACC
C 20
12, B
AD 2
010,
N
ICE
2015
-‐ME,
NIC
E 20
15-‐S
C,
USP
STF
2009
)
5/5
(AIO
M 2
015,
ED
F-‐EA
DO-‐E
ORT
C 20
12,
ESM
O 2
012,
NCC
N 2
015,
SI
DeM
aST
2011
)
Preo
perativ
e worku
p
LDH
is re
com
men
ded
in st
age
IV m
etas
tatic
dise
ase
to d
eter
min
e th
e su
bsta
ge a
nd is
opt
iona
l in
stag
e III
LD
H
∅
3/4
(ACC
C 20
12, A
HS 2
013-‐
PRO
P,
BAD
2010
)
5/5
(AIO
M 2
015,
ED
F-‐EA
DO-‐E
ORT
C 20
12,
ESM
O 2
012,
NCC
N 2
015,
SI
DeM
aST
2011
)
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
1/4
(NIC
E 20
15-‐M
E)
0/5
Reassessmen
t after in
itial
curativ
e trea
tmen
t Cl
inic
al q
uest
ion
not a
ddre
ssed
by CP
Gs
-‐-‐-‐
-‐-‐-‐
-‐-‐-‐
Early
detectio
n of
recu
rren
ce or p
rogression
It
is re
com
men
ded
not t
o pe
rfor
m la
bora
tory
test
ing
(or i
mag
ing)
for
recu
rren
ces a
nd m
etas
tase
s whe
n no
susp
icio
us fi
ndin
gs a
re m
ade
durin
g ph
ysic
al e
xam
inat
ion
Non
e ∅
2/4
(ACC
C 20
12, A
HS 2
013-‐
FU)
1/5
(NCC
N 2
015)
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
2/4
(BAD
201
0, N
ICE
2015
-‐ME)
4/5
(AIO
M 2
015,
ED
F-‐EA
DO-‐E
ORT
C 20
12,
ESM
O 2
012,
SID
eMaS
T 20
11)
Mon
itorin
g of trea
tmen
t respon
se in
adv
anced
disease
Initi
al la
bora
tory
ana
lysis
is p
erfo
rmed
with
at l
east
a se
rum
LDH
de
term
inat
ion
LDH
∅
1/5
(ACC
C 20
12)
1/5
(NCC
N 2
015)
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
4/5
(AHS
201
3-‐IV
, AHS
201
5-‐U
RM,
BAD
2010
, NIC
E 20
15-‐M
E)
4/5
(AIO
M 2
015,
ED
F-‐EA
DO-‐E
ORT
C 20
12,
ESM
O 2
012,
SID
eMaS
T 20
11)
(1) C
PG/total CPG
: CPG
s rep
ortin
g th
e su
mm
arize
d in
form
atio
n/to
tal n
umbe
r of C
PGs t
hat c
onsid
er th
e cl
inic
al q
uest
ion.
(2) O
GD/total OGD
: OG
Ds re
port
ing
the
sum
mar
ized
info
rmat
ion/
tota
l num
ber o
f OG
Ds th
at c
onsid
er th
e cl
inic
al q
uest
ion.
∅ T
he e
xam
ined
CPG
s tha
t con
sider
the
clin
ical
que
stio
n ei
ther
do
not a
ddre
ss T
Ms o
r, if
TMs a
re a
ddre
ssed
, CPG
s do
not p
rese
nt e
xplic
it re
com
men
datio
ns.
MEL
AN
OM
A Ta
ke-h
ome
mes
sage
Exam
ined
doc
umen
ts: 1
4 (9
CPG
s, 5
OG
Ds)
Circulating tumor markers: a guide to their appropriate clinical usee156
© 2017 Wichtig Publishing
6 Ac
rony
ms o
f CPG
s Do
main 1
Scop
e an
d pu
rpos
e Do
main 2
Stak
ehol
der
invo
lvem
ent
Domain 3
Rigo
r of
deve
lopm
ent
Domain 4
Clar
ity o
f pr
esen
tatio
n
Domain 5
Appl
icabi
lity
Domain 6
Edito
rial
inde
pend
ence
ACCC
201
2 81
56
68
81
67
42
AHS 20
13-‐FU
100
44
67
67
60
79
AHS 20
13-‐IV
80
44
64
69
60
79
AHS 20
13-‐PRO
P 86
44
64
69
58
79
AHS 20
15-‐U
RM
89
44
66
72
60
79
BAD 20
10
67
56
65
69
46
42
NICE 20
15-‐SC
89
97
93
86
71
88
NICE 20
15-‐M
E 94
94
92
97
92
96
USPS
TF 200
9 75
44
69
75
27
67
M
ELA
NO
MA
Take
-hom
e m
essa
geEx
amin
ed d
ocum
ents
: 14
(9 C
PGs,
5 O
GDs
)
Gion et al e157
© 2017 Wichtig Publishing
7 Mesothe
lioma
Exam
ined
doc
umen
ts: 9
(6 CPG
s, 3 OGDs)
Clinical que
stion
Summary of re
commen
datio
ns
Reco
mmen
ded
tumor m
arke
r(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2
)
(OGD acron
yms)
Screen
ing of peo
ple at
increa
sed ris
k
(asbestos-‐ex
posed
subjects)
Scre
enin
g of
all
asbe
stos
-‐exp
osed
subj
ects
with
thor
acic
imag
ing
and/
or
biol
ogic
al m
arke
rs c
anno
t be
pres
ently
reco
mm
ende
d Non
e
2/2
(ERS
-‐EST
S 20
10, N
HMRC
201
3)
2/2
(imp
2013
, NCC
N 2
015)
Differen
tial d
iagn
osis
Mea
sure
men
t of t
he b
lood
SM
RP le
vel i
s not
reco
mm
ende
d fo
r rou
tine
clin
ical
dia
gnos
is Non
e ∅
2/6
(BTS
201
0-‐M
PE, N
HMRC
201
3)
1/3
(ESM
O 2
010)
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
4/6
(AHS
201
2, A
HS 2
014-‐
MPE
, ER
S-‐ES
TS 2
010,
NIC
E 20
15)
2/3
(ESM
O 2
010,
imp
2013
)
Preo
perativ
e worku
p Ba
selin
e pr
ogno
stic
ass
essm
ent s
houl
d in
clud
e al
so m
arke
rs o
f in
flam
mat
ion
such
as C
-‐rea
ctiv
e pr
otei
n, w
hich
con
fer a
n un
favo
rabl
e pr
ogno
sis
C-‐reactiv
e protein
∅
1/3
(NHM
RC 2
013)
0/3
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
2/3
(AHS
201
2, E
RS-‐E
STS
2010
) 2/3
(ESM
O 2
010,
imp
2013
)
Supp
lem
enta
ry in
form
atio
n: In
crea
sed
LDH
leve
ls ha
ve b
een
asso
ciat
ed
with
poo
r pro
gnos
is
3/3
(AHS
201
2, E
RS-‐E
STS
2010
, N
HMRC
201
3)
0/3
Reassessmen
t after in
itial
curativ
e trea
tmen
t Cl
inic
al q
uest
ion
not a
ddre
ssed
by CP
Gs
-‐-‐-‐
-‐-‐-‐
-‐-‐-‐
Early
detectio
n of
recu
rren
ce or p
rogression
Re
com
men
datio
ns o
n TM
s not
ava
ilabl
e ∅
3/3
(AHS
201
2, E
RS-‐E
STS
2010
, N
HMRC
201
3)
2/2
(ESM
O 2
010,
imp
2013
)
Mon
itorin
g of trea
tmen
t respon
se in
adv
anced
disease
Incr
easin
g se
rum
SM
RP le
vels
durin
g tr
eatm
ent i
ndic
ate
prog
ress
ive
dise
ase
and
are
an u
nfav
orab
le p
rogn
ostic
mar
ker
SMRP
∅
1/4
(NHM
RC 2
013)
0/3
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
3/4
(AHS
201
2, A
HS 2
014-‐
MPE
, ER
S-‐ES
TS 2
010)
3/3
(ESM
O 2
010,
imp
2013
, N
CCN
201
5)
(1) C
PG/total CPG
: CPG
s rep
ortin
g th
e su
mm
arize
d in
form
atio
n/to
tal n
umbe
r of C
PGs t
hat c
onsid
er th
e cl
inic
al q
uest
ion.
(2) O
GD/total OGD
: OG
Ds re
port
ing
the
sum
mar
ized
info
rmat
ion/
tota
l num
ber o
f OG
Ds th
at c
onsid
er th
e cl
inic
al q
uest
ion.
∅ T
he e
xam
ined
CPG
s th
at c
onsid
er th
e cl
inic
al q
uest
ion
eith
er d
o no
t add
ress
TM
s or,
if TM
s are
add
ress
ed, C
PGs d
o no
t pre
sent
exp
licit
reco
mm
enda
tions
.
MES
OTH
ELIO
MA
Take
-hom
e m
essa
geEx
amin
ed d
ocum
ents
: 9 (6
CPG
s, 3
OG
Ds)
Circulating tumor markers: a guide to their appropriate clinical usee158
© 2017 Wichtig Publishing
8 Ac
rony
ms o
f CPG
s Dom
ain 1
Scop
e an
d pu
rpos
e Dom
ain 2
Stak
ehol
der
invo
lvem
ent
Dom
ain 3
Rigo
r of
deve
lopm
ent
Dom
ain 4
Clar
ity o
f pr
esen
tatio
n
Dom
ain 5
Appl
icab
ility
Dom
ain 6
Edito
rial
inde
pend
ence
AHS 20
12
83
44
63
78
62
79
AHS 20
14-‐M
PE
92
44
63
75
62
79
BTS 20
10-‐M
PE
78
69
72
78
33
50
ERS-‐ES
TS 201
0 69
44
69
81
33
58
NHMRC
201
3 75
78
76
83
42
63
NICE 20
15
89
97
92
89
73
92
MES
OTH
ELIO
MA
Take
-hom
e m
essa
geEx
amin
ed d
ocum
ents
: 9 (6
CPG
s, 3
OG
Ds)
Gion et al e159
© 2017 Wichtig Publishing
9 Th
yroid cancer, d
ifferen
tiated
Exam
ined
doc
umen
ts: 7
(4 CPG
s, 3 OGDs)
Clinical que
stion
Summary of re
commen
datio
ns
Reco
mmen
ded
tumor m
arke
r(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2
)
(OGD acron
yms)
Screen
ing of peo
ple at
increa
sed ris
k ( positive
family
history)
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
∅
3/3
(AAC
E-‐AM
E-‐ET
AM 2
010,
AT
A 20
09, B
TA 2
014)
2/2
(AIO
CC-‐A
IRO
-‐AIO
M 2
012,
N
CCN
201
5)
Differen
tial d
iagn
osis
Rout
ine
mea
sure
men
t of s
erum
Tg
for i
nitia
l eva
luat
ion
of th
yroi
d no
dule
s is
not r
ecom
men
ded
Non
e ∅
3/4
(AAC
E-‐AM
E-‐ET
AM 2
010,
AT
A 20
09, B
TA 2
014
1/3
(NCC
N 2
015)
Supp
lem
enta
ry in
form
atio
n: S
erum
Tg
leve
ls ca
n be
ele
vate
d in
mos
t th
yroi
d di
seas
es a
nd a
re a
n in
sens
itive
and
non
spec
ific
test
for t
hyro
id
canc
er
1/4
(ATA
200
9)
0/3
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
1/4
(NIC
E 20
15)
1/3
(ESM
O 2
012)
Preo
perativ
e worku
p
Ro
utin
e pr
eope
rativ
e m
easu
rem
ent o
f ser
um T
g is
not r
ecom
men
ded
Non
e or
Tg, T
gAb
2/3
(ATA
200
9, B
TA 2
014)
0/3
Seru
m T
g m
easu
rem
ent m
ay b
e us
eful
to d
etec
t pot
entia
l fal
se-‐n
egat
ive
valu
es d
ue to
dec
reas
ed th
yrog
lobu
lin im
mun
orea
ctiv
ity o
r het
erop
hilic
an
tibod
ies
1/3
(AAC
E-‐AM
E-‐ET
AM 2
010)
1/3
(AIO
CC-‐A
IRO
-‐AIO
M 2
012)
Reassessmen
t after in
itial
curativ
e trea
tmen
t Ba
selin
e po
stop
erat
ive
seru
m T
g sh
ould
be
chec
ked,
pre
fera
bly
no e
arlie
r th
an 6
wee
ks a
fter
surg
ery
or R
RA (d
etec
tabl
e se
rum
Tg
is hi
ghly
sugg
estiv
e of
thyr
oid
rem
nant
, res
idua
l or r
ecur
rent
tum
or)
Tg, T
gAb, TSH
1/2
(BTA
2014
) 3/3
(AIO
CC-‐A
IRO
-‐AIO
M 2
012,
ES
MO
201
2, N
CCN
201
5)
To v
erify
the
abse
nce
of re
sidua
l dise
ase,
seru
m T
g sh
ould
be
mea
sure
d af
ter t
hyro
xine
with
draw
al o
r rhT
SH st
imul
atio
n ap
prox
imat
ely
12 m
onth
s af
ter a
blat
ion
2/2
(ATA
200
9, B
TA 2
014)
0/3
TgAb
shou
ld b
e m
easu
red
by a
qua
ntita
tive
met
hod
simul
tane
ously
with
m
easu
rem
ent o
f ser
um T
g 2/2
(ATA
200
9, B
TA 2
014)
0/3
For p
atie
nts w
ho h
ave
unde
rgon
e to
tal t
hyro
idec
tom
y an
d RR
A, 9
-‐12
mon
ths p
ost-‐
RRA,
allo
catio
n to
1 o
f 3 re
spon
se g
roup
s aft
er d
ynam
ic ri
sk
stra
tific
atio
n (b
ased
on
stim
ulat
ed T
g, U
S an
d [o
ptio
nally
] nuc
lear
med
icin
e im
agin
g) is
reco
mm
ende
d
1/2
(BTA
201
4)
1/3
(NCC
N 2
015)
To e
nsur
e co
ntin
uity
in m
onito
ring
Tg a
nd T
gAb
assa
ys o
n a
long
-‐ter
m b
asis,
cl
inic
ians
shou
ld u
se th
e sa
me
labo
rato
ry a
nd la
bora
torie
s sho
uld
not
chan
ge m
etho
ds w
ithou
t prio
r con
sulta
tion
with
clin
ical
use
rs o
f the
serv
ice
2/2
(ATA
200
9, B
TA 2
014)
0/3
The
degr
ee o
f TSH
supp
ress
ion
to b
e m
aint
aine
d sh
ould
be
esta
blish
ed o
n th
e ba
sis o
f risk
cat
egor
ies d
efin
ed b
y dy
nam
ic ri
sk st
ratif
icat
ion
2/2
(ATA
200
9, B
TA 2
014)
1/3
(NCC
N 2
015)
THYR
OID
CA
NCE
R, D
IFFE
REN
TIAT
ED
Ta
ke-h
ome
mes
sage
Exam
ined
doc
umen
ts: 7
(4 C
PGs,
3 O
GDs
)
to b
e co
ntinu
ed
Circulating tumor markers: a guide to their appropriate clinical usee160
© 2017 Wichtig Publishing
10
Clinical que
stion
Summary of re
commen
datio
ns
Reco
mmen
ded
tumor m
arke
r(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2
)
(OGD acron
yms)
Early
detectio
n of
recu
rren
ce or p
rogression
At
eac
h vi
sit m
easu
re T
g, T
gAb
and
TSH
seru
m le
vels
and
perf
orm
nec
k U
S (e
very
6-‐1
2 m
onth
s dep
endi
ng o
n th
e ris
k le
vel o
f the
pat
ient
)
Tg, T
gAb, TSH
2/2
(ATA
200
9, B
TA 2
014)
3/3
(AIO
CC-‐A
IRO
-‐AIO
M 2
012,
ES
MO
201
2, N
CCN
201
5)
A sin
gle
elev
ated
seru
m T
g sh
ould
be
conf
irmed
by
repe
atin
g th
e te
st
befo
re p
roce
edin
g to
add
ition
al in
vest
igat
ion
or th
erap
y
1/2
(BTA
201
4)
0/3
Patie
nts i
n w
hom
the
basa
l Tg
rem
ains
per
siste
ntly
det
ecta
ble
whi
le o
n su
ppre
ssiv
e th
erap
y or
rise
s with
subs
eque
nt a
sses
smen
ts re
quire
furt
her
eval
uatio
n
1/2
(BTA
201
4)
0/3
Afte
r the
firs
t WBS
per
form
ed fo
llow
ing
RRA,
low
-‐risk
pat
ient
s with
un
dete
ctab
le T
g du
ring
supp
ress
ive
ther
apy
with
neg
ativ
e Tg
Ab a
nd
nega
tive
US
do n
ot re
quire
rout
ine
WBS
dur
ing
follo
w-‐u
p
1/2
(ATA
200
9)
0/3
Mon
itorin
g of trea
tmen
t respon
se in
adv
anced
disease
In th
e pr
esen
ce o
f per
siste
nt o
r met
asta
tic d
iseas
e, a
n un
dete
ctab
le se
rum
TS
H le
vel (
<0.1
mU
/L) s
houl
d be
mai
ntai
ned
durin
g fo
llow
-‐up
TSH
1/2
(ATA
200
9)
1/1
(ESM
O 2
012)
(1) C
PG/total CPG
: CPG
s rep
ortin
g th
e su
mm
arize
d in
form
atio
n/to
tal n
umbe
r of C
PGs t
hat c
onsid
er th
e cl
inic
al q
uest
ion.
(2) O
GD/total OGD
: OG
Ds re
port
ing
the
sum
mar
ized
info
rmat
ion/
tota
l num
ber o
f OG
Ds th
at c
onsid
er th
e cl
inic
al q
uest
ion.
∅ T
he e
xam
ined
CPG
s tha
t con
sider
the
clin
ical
que
stio
n ei
ther
do
not a
ddre
ss T
Ms o
r, if
TMs a
re a
ddre
ssed
, CPG
s do
not p
rese
nt e
xplic
it re
com
men
datio
ns.
: Inc
onsis
tent
reco
mm
enda
tions
on
TMs i
n th
e cl
inic
al q
uest
ion
are
repo
rted
by
diffe
rent
CPG
s.
rhTS
H =
reco
mbi
nant
hum
an T
SH; R
RA =
131 I r
adio
iodi
ne re
mna
nt a
blat
ion;
US
= ul
tras
ound
; WBS
= 13
1 I who
le b
ody
scan
. Ac
rony
ms of CPG
s Dom
ain 1
S cop
e an
d pu
rpos
e Dom
ain 2
Stak
ehol
der
invo
lvem
ent
Dom
ain 3
Rigo
r of
deve
lopm
ent
Dom
ain 4
Clar
ity o
f pr
esen
tatio
n
Dom
ain 5
Appl
icab
ility
Dom
ain 6
Edito
rial
inde
pend
ence
AACE
-‐AME-‐ET
AM 201
0 58
44
70
92
33
75
ATA 20
09
86
44
74
92
42
79
BTA 20
14
81
72
80
92
50
71
NICE 20
15
89
97
91
86
75
83
THYR
OID
CA
NCE
R, D
IFFE
REN
TIAT
ED
Ta
ke-h
ome
mes
sage
Exam
ined
doc
umen
ts: 7
(4 C
PGs,
3 O
GDs
)
Gion et al e161
© 2017 Wichtig Publishing
THYR
OID
CA
NCE
R, M
EDU
LLA
RY (M
TC)
Ta
ke-h
ome
mes
sage
Exam
ined
doc
umen
ts: 7
(4 C
PGs,
3 O
GDs
)
to b
e co
ntinu
ed
Circulating tumor markers: a guide to their appropriate clinical usee162
© 2017 Wichtig Publishing
12
Clinical que
stion
Summary of re
commen
datio
ns
Reco
mmen
ded
tumor m
arke
r(s)
CPG/total CPG
(1)
(CPG
acron
yms)
OGD/total OGD (2
)
(OGD acron
yms)
Patie
nts w
ith p
osto
pera
tive
Ct le
vels
<150
pg/
mL
shou
ld h
ave
a ph
ysic
al
exam
inat
ion
and
US
of th
e ne
ck. I
f the
se a
re n
egat
ive,
pat
ient
s sho
uld
be
follo
wed
with
mea
sure
men
t of s
erum
leve
ls of
Ct a
nd C
EA, a
nd U
S ev
ery
6 m
onth
s. P
atie
nts w
ith p
osto
pera
tive
Ct >
150
pg/m
L sh
ould
be
eval
uate
d by
im
agin
g pr
oced
ures
(nec
k, sk
elet
on, l
iver
)
1/2
(ATA
201
5)
1/3
(ESM
O 2
012)
Early
detectio
n of
recu
rren
ce or p
rogression
Se
rum
leve
ls of
Ct a
nd C
EA sh
ould
be
regu
larly
ass
esse
d du
ring
follo
w-‐u
p (a
t le
ast e
very
6 m
onth
s in
patie
nts w
ith d
etec
tabl
e se
rum
leve
ls of
Ct a
nd/o
r CEA
to
dete
rmin
e th
eir d
oubl
ing
times
)
Ct, C
EA
2/2
(ATA
201
5, B
TA 2
014)
3/3
(AIO
CC-‐A
IRO
-‐AIO
M 2
012,
ES
MO
201
2, N
CCN
201
5)
The
pres
ence
of a
n el
evat
ed b
ut st
able
Ct l
evel
pos
tope
rativ
ely
may
be
man
aged
co
nser
vativ
ely
(act
ive
surv
eilla
nce)
, pro
vide
d tr
eata
ble
dise
ase
has b
een
excl
uded
radi
olog
ical
ly. P
rogr
essiv
ely
risin
g Ct
con
cent
ratio
ns sh
ould
trig
ger
imag
ing
for f
urth
er st
agin
g
1/2
(BTA
201
4)
1/3
(NCC
N 2
015)
Supp
lem
enta
ry in
form
atio
n: C
t and
CEA
dou
blin
g tim
es c
orre
late
with
tum
or
prog
ress
ion
and
are
usef
ul p
rogn
ostic
indi
cato
rs fo
r MTC
recu
rren
ce a
nd su
rviv
al
1/2
(BTA
201
4)
2/3
(ESM
O 2
012,
NCC
N 2
015)
Mon
itorin
g of trea
tmen
t respon
se in
adv
anced
disease
Basa
l lev
els o
f ser
um C
t and
CEA
shou
ld b
e m
easu
red
conc
urre
ntly
in p
atie
nts
with
adv
ance
d M
TC
Ct, C
EA
∅
1/2
(ATA
201
5)
0/3
Syst
emic
ther
apy
shou
ld n
ot b
e ad
min
ister
ed to
pat
ient
s who
hav
e in
crea
sing
seru
m C
t and
CEA
leve
ls bu
t no
docu
men
ted
met
asta
tic d
iseas
e no
r to
patie
nts
with
stab
le lo
w-‐v
olum
e m
etas
tatic
dise
ase
and
Ct a
nd C
EA d
oubl
ing
times
gr
eate
r tha
n 2
year
s
1/2
(ATA
201
5)
0/3
Reco
mm
enda
tions
on
TMs n
ot a
vaila
ble
1/2
(BTA
201
4)
3/3
(AIO
CC-‐A
IRO
-‐AIO
M 2
012,
ES
MO
201
2, N
CCN
201
5)
(1) C
PG/total CPG
: CPG
s rep
ortin
g th
e su
mm
arize
d in
form
atio
n/to
tal n
umbe
r of C
PGs t
hat c
onsid
er th
e cl
inic
al q
uest
ion.
(2) O
GD/total OGD
: OG
Ds re
port
ing
the
sum
mar
ized
info
rmat
ion/
tota
l num
ber o
f OG
Ds th
at c
onsid
er th
e cl
inic
al q
uest
ion.
∅ T
he e
xam
ined
CPG
s th
at c
onsid
er th
e cl
inic
al q
uest
ion
eith
er d
o no
t add
ress
TM
s or,
if TM
s are
add
ress
ed, C
PGs d
o no
t pre
sent
exp
licit
reco
mm
enda
tions
. M
EN2
= m
ultip
le e
ndoc
rine
neop
lasia
type
2; R
ET g
ene
= RE
arra
nged
dur
ing
Tran
sfec
tion
gene
; US
= ul
tras
ound
. Ac
rony
ms of CPG
s Dom
ain 1
S cop
e an
d pu
rpos
e Dom
ain 2
Stak
ehol
der
invo
lvem
ent
Dom
ain 3
Rigo
r of
deve
lopm
ent
Dom
ain 4
Clar
ity o
f pr
esen
tatio
n
Dom
ain 5
Appl
icab
ility
Dom
ain 6
Edito
rial
inde
pend
ence
AACE
-‐AME-‐ET
AM 201
0 58
44
70
92
33
75
ATA 20
15
75
44
72
92
42
79
BTA 20
14
81
72
80
92
50
71
NICE 20
15
89
97
91
86
75
83
THYR
OID
CA
NCE
R, M
EDU
LLA
RY (M
TC)
Ta
ke-h
ome
mes
sage
Exam
ined
doc
umen
ts: 7
(4 C
PGs,
3 O
GDs
)
Gion et al e163
© 2017 Wichtig Publishing
26
DETAILED SUMMARY TABLES -‐ Users’ instructions
Definition and target audience Detailed Summary Tables are tables prepared for every tumor type which report recommendations and supplementary information from different guidance documents with enough details to be useful for health care providers, policy makers (for potential adaptation to specific settings) and staff developing educational material informed by available evidence. Structure
Total number of selected documents (number of CPGs, number of OGDs)
Clinical question
CPG
OGD
Summary of recommendations
Supplementary information
The different clinical questions are reported
Number of CPGs addressing the clinical question
Number of OGDs addressing the clinical question
Recommendations from CPGs and from OGDs that are consistent with those of CPGs Only those parts of the text explicitly defined as recommendations and clearly recognizable as such were considered Similar recommendations and supplementary information from different guidance documents are reported once, followed by the acronyms of the guidance documents by which they are provided Acronyms of CPGs are printed in bold blue type, those of OGDs are printed in regular type
Useful supplementary information for the clinical application of TMs from both CPGs and OGDs are summarized (e.g., suggested cutoff points, timing of serial sample monitoring, causes of false positive or false negative TM results) Recommendations from OGDs that are inconsistent with those of CPGs are reported Advice for clinical practice not declared or not recognizable as recommendation in the document is reported Acronyms of CPGs are printed in bold blue type, those of OGDs are printed in regular type
STRUCTURETotal number of selected documents (number of CPGs, number of OGDs)
Detailed summary tables
Users' instructions
Definition and target audience
Take-Home Messages are presented in table format for every tumor type, summarizing essential information to support decision-making in clinical practice. They are intended for use by health care providers.
Circulating tumor markers: a guide to their appropriate clinical usee164
© 2017 Wichtig Publishing
1 He
ad and
neck cancer
Ex
amined
doc
umen
ts: 1
0 (5 CPG
s, 5 OGDs)
Clinical que
stion
CPG OGD Su
mmary of re
commen
datio
ns (1
) Su
pplemen
tary in
form
ation
(2)
Screen
ing
2 0
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs p
rovi
ded
(ADA 20
10)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (U
SPST
F 20
13)
Differen
tial d
iagn
osis
3 4
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (A
HS 20
13, C
CO 200
9,
NICE 20
15, A
IOM
201
5, E
SMO
-‐EHN
S-‐ES
TRO
201
2-‐N
PC, E
SMO
-‐EHN
S-‐ES
TRO
201
0-‐SC
C,
NCC
N 2
015)
Preo
perativ
e worku
p 2
5 Cl
inic
al q
uest
ion
cons
ider
ed, b
ut T
Ms n
ot a
ddre
ssed
(AHS 20
13, C
CO 200
9,
ESM
O-‐E
HNS-‐
ESTR
O 2
010-‐
SCC)
Th
e pr
e-‐tr
eatm
ent p
lasm
a/se
rum
load
of E
pste
in-‐B
arr v
iral D
NA
has b
een
show
n to
be
of p
rogn
ostic
val
ue in
nas
opha
ryng
eal c
ance
r (AI
OCC
-‐AIR
O-‐
AIO
M 2
012,
AIO
M 2
015,
ESM
O-‐E
HNS-‐
ESTR
O 2
012-‐
NPC
, NCC
N 2
015)
Reassessmen
t after
initial curative trea
tmen
t 1
4 Cl
inic
al q
uest
ion
cons
ider
ed, b
ut T
Ms n
ot a
ddre
ssed
(CCO
200
9, E
SMO
-‐EHN
S-‐ES
TRO
201
0-‐SC
C, N
CCN
201
5)
The
dete
rmin
atio
n of
pla
sma/
seru
m E
pste
in-‐B
arr v
iral D
NA
2 m
onth
s aft
er
the
initi
al tr
eatm
ent c
an b
e co
nsid
ered
in n
asop
hary
ngea
l can
cer (
AIO
CC-‐
AIRO
-‐AIO
M 2
012,
AIO
M 2
015)
Early
detectio
n of
recu
rren
ce or
prog
ression
1 5
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (A
HS 20
13, E
SMO
-‐EHN
S-‐ES
TRO
201
0-‐SC
C)
Regu
lar p
ost-‐
trea
tmen
t det
erm
inat
ion
of p
lasm
a/se
rum
Eps
tein
-‐Bar
r vira
l DN
A ca
n be
con
sider
ed a
s it h
as b
een
show
n to
be
of p
rogn
ostic
val
ue in
na
soph
aryn
geal
can
cer (
AIO
CC-‐A
IRO
-‐AIO
M 2
012,
AIO
M 2
015,
ESM
O-‐E
HNS-‐
ESTR
O 2
012-‐
NPC
, NCC
N 2
015)
TMs a
re n
ot re
com
men
ded
in th
e ab
senc
e of
clin
ical
indi
catio
ns (A
IOM
201
5)
Mon
itorin
g of trea
tmen
t respon
se in
adv
anced
disease
2 5
Clin
ical
que
stio
n co
nsid
ered
, but
crit
eria
to m
onito
r tre
atm
ent r
espo
nse
(incl
udin
g TM
s) n
ot a
ddre
ssed
(AHS 20
13, C
CO 200
9, A
IOCC
-‐AIR
O-‐A
IOM
201
2,
AIO
M 2
015,
ESM
O-‐E
HNS-‐
ESTR
O 2
012-‐
NPC
, ESM
O-‐E
HNS-‐
ESTR
O 2
010-‐
SCC,
NCC
N 2
015)
(1) Re
com
men
datio
ns fr
om CPG
s an
d fr
om OGDs,
if c
onsis
tent
with
thos
e of
CPG
s.
(2) Su
pple
men
tary
info
rmat
ion
from
bot
h CP
Gs
and OGDs,
and
reco
mm
enda
tions
from
OGDs
that
are
inco
nsist
ent w
ith th
ose
of CPG
s.
HEA
D A
ND
NEC
K CA
NCE
R
D
etai
led
sum
mar
y ta
bles
Exam
ined
doc
umen
ts: 1
0 (5
CPG
s, 5
OG
Ds)
Gion et al e165
© 2017 Wichtig Publishing
2 Lu
ng can
cer
Exa
mined
doc
umen
ts: 2
9 (18 CP
Gs, 11 OGDs)
Clinical que
stion
CPG OGD Su
mmary of re
commen
datio
ns (1
) Su
pplemen
tary in
form
ation
(2)
Screen
ing
2 5
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (A
CCP 20
13, U
SPST
F 20
14-‐
scr,
AIO
M 2
015,
NCC
N 2
015-‐
SCLC
, NCC
N 2
015-‐
scr)
Th
e ro
le o
f bio
mar
kers
nee
ds to
be
dete
rmin
ed (A
CCP 20
13, U
SPST
F 20
14-‐scr
)
Oth
er sc
reen
ing
met
hods
, suc
h as
bio
mar
kers
, are
not
reco
mm
ende
d fo
r cl
inic
al u
se (E
SMO
201
3-‐N
SCLC
, ESM
O 2
014)
Differen
tial d
iagn
osis
9 9
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs p
rovi
ded
(ACC
P 20
13, S
IGN 201
4)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (A
HS 20
14-‐N
SCLC
.s1,
AH
S 20
14-‐N
SCLC
.s2,
ASC
O 201
5-‐SC
LC, B
TS-‐SCT
S 20
10, C
CO 201
4-‐dia,
NICE 20
11,
NICE 20
15-‐dia
, AIO
M 2
015,
ESM
O 2
013-‐
NSC
LC, E
SMO
201
4, E
SMO
201
4-‐N
SCLC
.m+,
ES
MO
-‐JSM
O 2
013-‐
SCLC
, FS
2013
, NCC
N 2
015-‐
NSC
LC, N
CCN
201
5-‐sc
r, N
CCN
201
5-‐SC
LC)
No
evid
ence
was
iden
tifie
d su
ppor
ting
the
use
of T
Ms i
n th
e di
agno
sis o
f lu
ng c
ance
r (AC
CP 201
3, SIGN 201
4)
Preo
perativ
e worku
p 8
7 Cl
inic
al q
uest
ion
cons
ider
ed, b
ut T
Ms n
ot a
ddre
ssed
(ACC
P 20
13, A
HS 20
13-‐
NSC
LC.s4,
AHS 20
14-‐N
SCLC
.s1,
AHS 20
14-‐N
SCLC
.s2,
ASC
O 201
5-‐SC
LC, B
TS-‐SCT
S 20
10,
NICE 20
11, SIGN 201
4, A
IOM
201
5, E
SMO
201
3-‐N
SCLC
, ESM
O 2
014,
NCC
N 2
015-‐
NSC
LC)
In N
SCLC
rout
ine
use
of se
rum
mar
kers
(suc
h as
CEA
) is n
ot re
com
men
ded
(ESM
O 2
014-‐
NSC
LC.M
+)
In S
CLC
initi
al a
sses
smen
t sho
uld
incl
ude
LDH
since
it is
ass
ocia
ted
with
ex
cess
ive
bulk
of d
iseas
e (E
SMO
-‐JSM
O 2
013-‐
SCLC
, NCC
N 2
015-‐
SCLC
)
Reassessmen
t after
initial curative trea
tmen
t 1
2 Po
stop
erat
ive
CEA
dete
rmin
atio
n co
uld
prov
ide
addi
tiona
l pro
gnos
tic
info
rmat
ion
(ELC
WP 20
12)
Post
-‐the
rapy
CEA
nor
mal
izat
ion
or si
gnifi
cant
dec
reas
e se
ems t
o be
rela
ted
to b
ette
r sur
viva
l in
early
-‐sta
ge N
SCLC
trea
ted
with
surg
ery
(ELC
WP 20
12)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (E
SMO
201
4-‐N
SCLC
.M+,
N
CCN
201
5-‐SC
LC)
Early
detectio
n of
recu
rren
ce or
prog
ression
7 7
For l
ung
canc
er p
atie
nts t
reat
ed w
ith c
urat
ive
inte
nt, i
t is s
ugge
sted
that
su
rvei
llanc
e bi
omar
ker t
estin
g no
t be
done
out
side
of c
linic
al tr
ials
(ACC
P 20
13, A
IOM
201
5)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (A
HS 20
12-‐N
SCLC
.s3,
AH
S 20
14-‐N
SCLC
.s1,
AHS 20
14-‐N
SCLC
.s2,
CCO
201
4-‐fu
, NICE 20
11, SIGN 201
4,
ESM
O 2
013-‐
NSC
LC, E
SMO
201
4, E
SMO
201
4-‐N
SCLC
.m+,
ESM
O-‐JS
MO
201
3-‐SC
LC,
NCC
N 2
015-‐
NSC
LC, N
CCN
201
5-‐SC
LC)
Mon
itorin
g of trea
tmen
t respon
se in
adv
anced
disease
10
8 So
me
circ
ulat
ing
mar
kers
(CEA
, Cyf
ra 2
1-‐1
and
pro-‐
GRP
, and
to a
less
er
exte
nt N
SE, C
A125
and
CA1
9.9)
cou
ld p
rovi
de p
rogn
ostic
info
rmat
ion
for
surv
ival
(ELC
WP 20
12)
Clin
ical
que
stio
n co
nsid
ered
, but
crit
eria
to m
onito
r tre
atm
ent r
espo
nse
(incl
udin
g TM
s) n
ot a
ddre
ssed
(ACC
P 20
13, A
HS 20
12-‐N
SCLC
.s3, AHS 20
12-‐SCL
C.es,
AHS 20
12-‐SCL
C.ls
, AHS 20
13-‐N
SCLC
.s4,
ASC
O 201
5-‐NSC
LC.s4,
ASC
O 201
5-‐SC
LC,
CCO 201
4-‐NSC
LC.m
+, SIGN 201
4, A
IOM
201
5, A
IOT
2012
-‐NSC
LC, C
ECO
G 2
012-‐
NSC
LC,
ESM
O 2
014,
ESM
O 2
014-‐
NSC
LC.m
+, E
SMO
-‐JSM
O 2
013-‐
SCLC
, NCC
N 2
015-‐
NSC
LC,
NCC
N 2
015-‐
SCLC
)
Post
-‐the
rapy
CEA
nor
mal
izat
ion
or si
gnifi
cant
dec
reas
e se
ems t
o be
rela
ted
to b
ette
r sur
viva
l in
adva
nced
NSC
LC tr
eate
d w
ith c
hem
othe
rapy
and
aft
er
salv
age
gefit
inib
in re
laps
ing
NSC
LC (E
LCWP 20
12)
(1) Re
com
men
datio
ns fr
om CPG
s an
d fr
om OGDs,
if c
onsis
tent
with
thos
e of
CPG
s.
(2) Su
pple
men
tary
info
rmat
ion
from
bot
h CP
Gs
and OGDs,
and
reco
mm
enda
tions
from
OGDs
that
are
inco
nsist
ent w
ith th
ose
of CPG
s.
NSC
LC =
non
-‐sm
all c
ell l
ung
canc
er; S
CLC
= sm
all c
ell l
ung
canc
er.
LUN
G C
AN
CER
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 29
(18
CPG
s, 1
1 O
GDs
)
Circulating tumor markers: a guide to their appropriate clinical usee166
© 2017 Wichtig Publishing
3 Melan
oma
Exam
ined
doc
umen
ts: 1
4 (9 CPG
s, 5 OGDs)
Clinical que
stion
CPG OGD Su
mmary of re
commen
datio
ns (1
) Su
pplemen
tary in
form
ation
(2)
Screen
ing
3 2
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (A
CCC 20
12, B
AD 201
0,
USP
STF 20
09, A
IOM
201
5, S
IDeM
aST
2011
)
Differen
tial d
iagn
osis
5 5
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (A
CCC 20
12, B
AD 201
0,
NICE 20
15-‐M
E, NICE 20
15-‐SC,
USP
STF 20
09, A
IOM
201
5, E
DF-‐E
ADO
-‐EO
RTC
2012
, ES
MO
201
2, N
CCN
201
5, S
IDeM
aST
2011
)
Preo
perativ
e worku
p 4
5 LD
H is
reco
mm
ende
d to
det
erm
ine
subs
tage
in st
age
IV m
etas
tatic
dise
ase
(ACC
C 20
12, A
HS 20
13-‐PRO
P, BAD
201
0, A
IOM
201
5, E
DF-‐E
ADO
-‐EO
RTC
2012
, ES
MO
201
2, N
CCN
201
5, S
IDeM
aST
2011
)
LDH
dete
rmin
atio
n is
optio
nal i
n st
age
III (A
HS 20
13-‐PRO
P)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (N
ICE 20
15-‐M
E)
Reassessmen
t after
initial curative trea
tmen
t 0
0 Cl
inic
al q
uest
ion
not a
ddre
ssed
by CP
Gs
Early
detectio
n of
recu
rren
ce or
prog
ression
4 5
It is
reco
mm
ende
d no
t to
perf
orm
labo
rato
ry te
stin
g (o
r im
agin
g) fo
r re
curr
ence
s and
met
asta
ses w
hen
no su
spic
ious
find
ings
are
mad
e du
ring
phys
ical
exa
min
atio
n (ACC
C 20
12, A
HS 20
13-‐FU
, NCC
N 2
015)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (B
AD 201
0, NICE 20
15-‐M
E,
AIO
M 2
015,
SID
eMaS
T 20
11)
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs p
rovi
ded
(EDF
-‐EAD
O-‐E
ORT
C 20
12, E
SMO
201
2)
Mon
itorin
g of trea
tmen
t respon
se in
adv
anced
disease
5 5
Initi
al la
bora
tory
ana
lysis
is p
erfo
rmed
with
at l
east
a se
rum
LDH
de
term
inat
ion
(ACC
C 20
12, N
CCN
201
5)
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs p
rovi
ded
(BAD
201
0)
Clin
ical
que
stio
n co
nsid
ered
, but
crit
eria
to m
onito
r tre
atm
ent r
espo
nse
(incl
udin
g TM
s) n
ot a
ddre
ssed
(AHS 20
13-‐IV
, AHS 20
15-‐U
RM, N
ICE 20
15-‐M
E,
AIO
M 2
015,
EDF
-‐EAD
O-‐E
ORT
C 20
12, E
SMO
201
2, S
IDeM
aST
2011
)
Patie
nts w
ith e
leva
ted
LDH
have
a re
duce
d lik
elih
ood
of b
enef
iting
from
cu
rren
tly a
vaila
ble
syst
emic
trea
tmen
t (BA
D 201
0)
(1) Re
com
men
datio
ns fr
om CPG
s an
d fr
om OGDs,
if c
onsis
tent
with
thos
e of
CPG
s.
(2) Su
pple
men
tary
info
rmat
ion
from
bot
h CP
Gs
and OGDs,
and
reco
mm
enda
tions
from
OGDs
that
are
inco
nsist
ent w
ith th
ose
of CPG
s.
MEL
AN
OM
A
D
etai
led
sum
mar
y ta
bles
Exam
ined
doc
umen
ts: 1
4 (9
CPG
s, 5
OG
Ds)
Gion et al e167
© 2017 Wichtig Publishing
4 Mesothe
lioma
Ex
amined
doc
umen
ts: 9
(6 CPG
s, 3 OGDs)
Clinical que
stion
CPG OGD Su
mmary of re
commen
datio
ns (1
) Su
pplemen
tary in
form
ation
(2)
Screen
ing of peo
ple at
increa
sed ris
k
(asbestos-‐ex
posed
subjects)
2 2
Scre
enin
g of
all
asbe
stos
-‐exp
osed
subj
ects
with
thor
acic
imag
ing
and/
or
biol
ogic
al m
arke
rs c
anno
t be
pres
ently
reco
mm
ende
d (ERS
-‐EST
S 20
10,
NHMRC
201
3, N
CCN
201
5)
Giv
en th
e pr
eval
ence
of t
he d
iseas
e, th
e se
nsiti
vity
and
spec
ifici
ty o
f the
av
aila
ble
biol
ogic
al m
arke
rs (s
uch
as S
MRP
and
ost
eopo
ntin
) are
not
ad
equa
te fo
r scr
eeni
ng p
urpo
ses (
ERS-‐ES
TS 201
0, NHMRC
201
3, im
p 20
13)
Ther
e is
no e
vide
nce
that
scre
enin
g pr
oced
ures
for m
alig
nant
mes
othe
liom
a af
fect
clin
ical
out
com
es (e
.g.,
decr
ease
mor
talit
y) (N
HMRC
201
3, im
p 20
13,
NCC
N 2
015)
Differen
tial d
iagn
osis
6 3
Mea
sure
men
t of t
he b
lood
SM
RP le
vel i
s not
reco
mm
ende
d fo
r rou
tine
clin
ical
dia
gnos
is (BTS
201
0-‐MPE
, NHMRC
201
3)
Pleu
ral f
luid
and
seru
m T
Ms d
o no
t cur
rent
ly h
ave
a ro
le in
the
rout
ine
inve
stig
atio
n of
ple
ural
effu
sions
(BTS
201
0-‐MPE
)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (A
HS 20
12, A
HS 20
14-‐
MPE
, ERS
-‐EST
S 20
10, N
ICE 20
15)
To d
ate,
no
seru
m b
iom
arke
r has
show
n su
ffici
ent p
ositi
ve p
redi
ctiv
e va
lue
for a
dia
gnos
is of
mal
igna
nt m
esot
helio
ma
that
wou
ld a
llow
it to
repl
ace
exist
ing
imag
ing-‐
cyto
logy
-‐bio
psy
requ
irem
ents
(NHMRC
201
3)
A po
sitiv
e se
rum
or p
leur
al fl
uid
mes
othe
lin le
vel i
s hig
hly
sugg
estiv
e of
pl
eura
l mal
igna
ncy
and
mig
ht b
e us
ed to
exp
edite
a ti
ssue
dia
gnos
is, b
ut a
ne
gativ
e re
sult
cann
ot b
e co
nsid
ered
reas
surin
g (BTS
201
0-‐MPE
)
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs p
rovi
ded
(ESM
O 2
010,
imp
2013
)
The
prec
ise ro
le o
f SM
RP a
nd o
steo
pont
in is
yet
to b
e de
fined
(ESM
O 2
010)
SMRP
and
ost
eopo
ntin
requ
ire fu
rthe
r val
idat
ion
befo
re c
linic
al a
pplic
atio
n (im
p 20
13)
SMRP
det
erm
inat
ion
is op
tiona
l; os
teop
ontin
doe
s not
app
ear t
o be
use
ful
for d
iagn
osis
(NCC
N 2
015)
Preo
perativ
e worku
p 3
3 Ba
selin
e pr
ogno
stic
ass
essm
ent s
houl
d in
clud
e al
so m
arke
rs o
f in
flam
mat
ion
such
as C
-‐rea
ctiv
e pr
otei
n (N
HMRC
201
3)
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs p
rovi
ded
(AHS 20
12, E
RS-‐EST
S 20
10, i
mp
2013
)
SMRP
seru
m le
vels
appe
ar to
be
pred
ictiv
e of
redu
ced
mea
n su
rviv
al in
the
epith
elio
id su
btyp
e. T
heir
pred
ictiv
e po
wer
is re
mov
ed in
mul
tivar
iate
m
odel
s whi
ch in
clud
e FD
G-‐P
ET. S
erum
ost
eopo
ntin
leve
ls ad
d no
mor
e pr
ogno
stic
info
rmat
ion
than
SM
RP (N
HMRC
201
3)
Incr
ease
d LD
H le
vels
have
bee
n as
soci
ated
with
a p
oor p
rogn
osis
(AHS 20
12,
ERS-‐ES
TS 201
0, NHMRC
201
3)
New
seru
m b
iom
arke
rs w
ith p
oten
tial p
rogn
ostic
sign
ifica
nce
(e.g
., SM
RP
and
oste
opon
tin) a
re c
urre
ntly
und
er in
vest
igat
ion
(ERS
-‐EST
S 20
10, i
mp
2013
)
SMRP
leve
ls m
ay a
lso b
e as
sess
ed a
nd m
ay c
orre
late
with
dise
ase
stat
us
(NCC
N 2
015)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (E
SMO
201
0)
Reassessmen
t after
initial curative trea
tmen
t 0
0 Cl
inic
al q
uest
ion
not a
ddre
ssed
by CP
Gs
MES
OTH
ELIO
MA
D
etai
led
sum
mar
y ta
bles
Exam
ined
doc
umen
ts: 9
(6 C
PGs,
3 O
GDs
)
to b
e co
ntinu
ed
Circulating tumor markers: a guide to their appropriate clinical usee168
© 2017 Wichtig Publishing
5 Cl
inical que
stion
CPG OGD Su
mmary of re
commen
datio
ns (1
) Su
pplemen
tary in
form
ation
(2)
Early
detectio
n of
recu
rren
ce or
prog
ression
3 2
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (A
HS 20
12, E
RS-‐
ESTS
201
0, NHMRC
201
3, E
SMO
201
0, im
p 20
13)
Mon
itorin
g of trea
tmen
t respon
se in
adv
anced
disease
4 3
Incr
easin
g se
rum
SM
RP le
vels
durin
g tr
eatm
ent a
re a
n un
favo
rabl
e pr
ogno
stic
mar
ker (
NHMRC
201
3)
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs p
rovi
ded
(ERS
-‐EST
S 20
10, i
mp
2013
)
Clin
ical
que
stio
n co
nsid
ered
, but
crit
eria
to m
onito
r tre
atm
ent r
espo
nse
(incl
udin
g TM
s) n
ot a
ddre
ssed
(AHS 20
12, A
HS 20
14-‐M
PE, E
SMO
201
0,
NCC
N 2
015)
Risin
g SM
RP is
indi
cativ
e of
pro
gres
sive
dise
ase.
SM
RP re
spon
se c
orre
late
s w
ith ra
diol
ogic
al re
spon
se a
nd T
GV
on F
DG-‐P
ET (N
HMRC
201
3)
PET
scan
and
bio
logi
cal m
arke
rs a
re st
ill u
nder
inve
stig
atio
n fo
r the
ev
alua
tion
of re
spon
se to
trea
tmen
t (ER
S-‐ES
TS 201
0)
SMRP
and
ost
eopo
ntin
requ
ire fu
rthe
r val
idat
ion
befo
re c
linic
al a
pplic
atio
n (im
p 20
13)
(1) Re
com
men
datio
ns fr
om CPG
s an
d fr
om OGDs,
if c
onsis
tent
with
thos
e of
CPG
s.
(2) Su
pple
men
tary
info
rmat
ion
from
bot
h CP
Gs
and OGDs,
and
reco
mm
enda
tions
from
OGDs
that
are
inco
nsist
ent w
ith th
ose
of CPG
s.
FDG
-‐PET
= p
ositr
on e
miss
ion
tom
ogra
phy
with
2-‐d
eoxy
-‐2-‐[f
luor
ine-‐
18]fl
uoro
-‐D-‐g
luco
se; T
GV
= to
tal g
lyco
lytic
vol
ume.
MES
OTH
ELIO
MA
D
etai
led
sum
mar
y ta
bles
Exam
ined
doc
umen
ts: 9
(6 C
PGs,
3 O
GDs
)
Gion et al e169
© 2017 Wichtig Publishing
6 Th
yroid cancer, d
ifferen
tiated
Exam
ined
doc
umen
ts: 7
(4 CPG
s, 3 OGDs)
Clinical que
stion
CPG OGD Su
mmary of re
commen
datio
ns (1
) Su
pplemen
tary in
form
ation
(2)
Screen
ing of peo
ple at
increa
sed ris
k (positive
family
history)
3 2
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (A
ACE-‐AM
E-‐ET
AM 201
0,
ATA 20
09, B
TA 201
4, A
IOCC
-‐AIR
O-‐A
IOM
201
2)
Maj
or ri
sk fa
ctor
s for
diff
eren
tiate
d th
yroi
d ca
ncer
are
: nec
k irr
adia
tion
in
child
hood
; end
emic
goi
ter;
fam
ily o
r per
sona
l hist
ory
of th
yroi
d ad
enom
a;
fam
ilial
thyr
oid
canc
er (B
TA 201
4)
Clin
ical
que
stio
n co
nsid
ered
, no
expl
icit
reco
mm
enda
tions
on
TMs p
rovi
ded
(NCC
N 2
015)
Differen
tial d
iagn
osis
4 3
Rout
ine
mea
sure
men
t of s
erum
Tg
for i
nitia
l eva
luat
ion
of th
yroi
d no
dule
s is
not r
ecom
men
ded
(AAC
E-‐AM
E-‐ET
AM 201
0, ATA
200
9, BTA
201
4, N
CCN
201
5)
Dete
rmin
aton
of s
erum
cal
cium
or/
and
PTH
are
reco
mm
ende
nd if
a n
odul
ar
lesio
n is
sugg
estiv
e of
intr
athy
roid
al p
arat
hyro
id a
deno
ma
on U
S ex
amin
atio
n (AAC
E-‐AM
E-‐ET
AM 201
0, A
IOCC
-‐AIR
O-‐A
IOM
201
2)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (N
ICE 20
15, E
SMO
201
2)
Seru
m T
g le
vels
can
be e
leva
ted
in m
ost t
hyro
id d
iseas
es a
nd a
re a
n in
sens
itive
and
non
spec
ific
test
for t
hyro
id c
ance
r (AT
A 20
09)
Preo
perativ
e worku
p 3
3 Ro
utin
e pr
eope
rativ
e m
easu
rem
ent o
f ser
um T
g is
not r
ecom
men
ded
(ATA
200
9, BTA
201
4)
Seru
m T
g m
easu
rem
ent m
ay b
e us
eful
to d
etec
t pot
entia
l fal
se-‐n
egat
ive
valu
es d
ue to
dec
reas
ed T
g im
mun
orea
ctiv
ity o
r het
erop
hilic
ant
ibod
ies
(AAC
E-‐AM
E-‐ET
AM 201
0)
In c
ase
of su
spic
ious
US
feat
ures
of a
lym
ph n
ode,
the
met
asta
tic n
atur
e of
th
e no
de m
ay b
e co
nfirm
ed w
ith m
easu
rem
ent o
f Tg
in th
e w
asho
ut o
f the
ne
edle
use
d fo
r UG
FNA
biop
sy (A
ACE-‐AM
E-‐ET
AM 201
0)
Ther
e is
limite
d ev
iden
ce th
at h
igh
preo
pera
tive
conc
entr
atio
ns o
f ser
um T
g m
ay p
redi
ct a
hig
her s
ensit
ivity
for p
osto
pera
tive
surv
eilla
nce
with
seru
m T
g (ATA
200
9)
Mar
kers
indi
cate
d fo
r diff
eren
tiate
d th
yroi
d ca
rcin
oma:
Tg,
TgA
b (A
IOCC
-‐AI
RO-‐A
IOM
201
2)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (E
SMO
201
2, N
CCN
201
5)
THYR
OID
CA
NCE
R, D
IFFE
REN
TIAT
ED
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 7 (4
CPG
s, 3
OG
Ds)
to b
e co
ntinu
ed
Circulating tumor markers: a guide to their appropriate clinical usee170
© 2017 Wichtig Publishing
7 Clinical que
stion
CPG OGD Su
mmary of re
commen
datio
ns (1
) Su
pplemen
tary in
form
ation
(2)
Reassessmen
t after
initial curative trea
tmen
t 2
3 Ba
selin
e po
stop
erat
ive
seru
m T
g sh
ould
be
chec
ked,
pre
fera
bly
no e
arlie
r th
an 6
wee
ks a
fter
surg
ery
or R
RA (B
TA 201
4, A
IOCC
-‐AIR
O-‐A
IOM
201
2,
ESM
O 2
012,
NCC
N 2
015)
To v
erify
the
abse
nce
of re
sidua
l dise
ase,
seru
m T
g sh
ould
be
mea
sure
d af
ter t
hyro
xine
with
draw
al o
r rhT
SH st
imul
atio
n ap
prox
imat
ely
12 m
onth
s af
ter a
blat
ion
(ATA
200
9, BTA
201
4)
Follo
win
g to
tal t
hyro
idec
tom
y an
d RR
A, a
nd b
efor
e ev
alua
tion
of th
e pa
tient
’s re
spon
se to
trea
tmen
t aft
er 9
-‐12
mon
ths,
TSH
shou
ld b
e su
ppre
ssed
to b
elow
0.1
mU
/L (B
TA 201
4)
In p
atie
nts w
ho h
ave
not u
nder
gone
RRA
who
are
clin
ical
ly fr
ee o
f dise
ase
and
have
und
etec
tabl
e su
ppre
ssed
seru
m T
g an
d no
rmal
nec
k U
S, th
e se
rum
TS
H m
ay b
e al
low
ed to
rise
to th
e lo
w n
orm
al ra
nge
(0.3
-‐2 m
U/L
) (BT
A 20
14)
TgAb
shou
ld b
e m
easu
red
by a
qua
ntita
tive
met
hod
simul
tane
ously
with
m
easu
rem
ent o
f ser
um T
g. If
TgA
b ar
e de
tect
able
, mea
sure
men
t sho
uld
be
repe
ated
at r
egul
ar (~
6-‐m
onth
ly) i
nter
vals
(BTA
201
4)
TgAb
, eve
n if
nega
tive,
shou
ld b
e m
easu
red
at fo
llow
-‐up
whe
n Tg
is
mea
sure
d (ATA
200
9, BTA
201
4)
For p
atie
nts w
ho h
ave
unde
rgon
e to
tal t
hyro
idec
tom
y an
d RR
A, 9
-‐12
mon
ths p
ost-‐
RRA,
allo
catio
n to
1 o
f 3 re
spon
se g
roup
s aft
er d
ynam
ic ri
sk
stra
tific
atio
n (b
ased
on
stim
ulat
ed T
g, U
S an
d [o
ptio
nally
] nuc
lear
med
icin
e im
agin
g) is
reco
mm
ende
d (BTA
201
4, N
CCN
201
5)
The
degr
ee o
f TSH
supp
ress
ion
to b
e m
aint
aine
d sh
ould
be
esta
blish
ed o
n th
e ba
sis o
f risk
cat
egor
ies d
efin
ed b
y dy
nam
ic ri
sk st
ratif
icat
ion
(ATA
200
9,
BTA 20
14, N
CCN
201
5)
-‐ Lo
w ri
sk: T
SH m
ay b
e al
low
ed to
rise
to th
e lo
w-‐n
orm
al ra
nge
(0.3
-‐2
mU
/L)
-‐ In
term
edia
te ri
sk: T
SH sh
ould
be
mai
ntai
ned
betw
een
0.1
and
0.5
mU
/L
for 5
-‐10
year
s (th
en re
exam
ine)
-‐
High
risk
: TSH
shou
ld b
e m
aint
aine
d be
low
0.1
mU
/L in
defin
itely
in th
e ab
senc
e of
spec
ific
cont
rain
dica
tions
Dete
ctab
le se
rum
Tg
is hi
ghly
sugg
estiv
e of
thyr
oid
rem
nant
, res
idua
l or
recu
rren
t tum
or (B
TA 201
4)
Stim
ulat
ed T
g sh
ould
be
mea
sure
d on
day
5 fo
llow
ing
the
first
inje
ctio
n of
rh
TSH
(BTA
201
4)
A se
rum
TSH
con
cent
ratio
n >3
0 m
U/L
shou
ld b
e ac
hiev
ed to
ass
ess
stim
ulat
ed T
g (BTA
201
4)
To e
nsur
e co
ntin
uity
in m
onito
ring
Tg a
nd T
gAb
assa
ys o
n a
long
-‐ter
m b
asis,
cl
inic
ians
shou
ld u
se th
e sa
me
labo
rato
ry a
nd la
bora
torie
s sho
uld
not
chan
ge m
etho
ds w
ithou
t prio
r con
sulta
tion
with
clin
ical
use
rs o
f the
serv
ice
(ATA
200
9, BTA
201
4)
Tg sh
ould
be
mea
sure
d by
an
imm
unom
etric
ass
ay th
at is
cal
ibra
ted
agai
nst
the
CRM
-‐457
stan
dard
(ATA
200
9)
Dyna
mic Risk
Stratificatio
n -‐
Exce
llent
resp
onse
(low
risk
): al
l the
follo
win
g: (i
) sup
pres
sed
and
stim
ulat
ed T
g <1
μg/
L*, (
ii) n
eck
US
with
out e
vide
nce
of d
iseas
e, (i
ii)
cros
s-‐se
ctio
nal a
nd/o
r nuc
lear
med
icin
e im
agin
g ne
gativ
e (if
per
form
ed)
-‐ In
term
edia
te re
spon
se (i
nter
med
iate
risk
): an
y of
the
follo
win
g: (i
) su
ppre
ssed
Tg
1 μ
g/L*
and
stim
ulat
ed T
g ≥1
and
<10
μg/
L*, (
ii) n
eck
US
with
non
spec
ific
chan
ges o
r sta
ble
sub-‐
cent
imet
er ly
mph
nod
es, (
iii)
cros
s-‐se
ctio
nal a
nd/o
r nuc
lear
med
icin
e im
agin
g w
ith n
onsp
ecifi
c ch
ange
s, a
lthou
gh n
ot c
ompl
etel
y no
rmal
-‐
Inco
mpl
ete
resp
onse
(hig
h ris
k): a
ny o
f the
follo
win
g: (i
) sup
pres
sed
Tg ≥
1 μg
/L*
or st
imul
ated
Tg
≥10
μg/L
*, (i
i) ris
ing
Tg v
alue
s, (i
ii) p
ersis
tent
or
new
ly id
entif
ied
dise
ase
on c
ross
-‐sec
tiona
l and
/or n
ucle
ar m
edic
ine
imag
ing
(NB.
*As
sum
es a
bsen
ce o
f int
erfe
renc
e in
the
Tg a
ssay
) (BT
A 20
14)
THYR
OID
CA
NCE
R, D
IFFE
REN
TIAT
ED
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 7 (4
CPG
s, 3
OG
Ds)
to b
e co
ntinu
ed
Gion et al e171
© 2017 Wichtig Publishing
8 Clinical que
stion
CPG OGD Su
mmary of re
commen
datio
ns (1
) Su
pplemen
tary in
form
ation
(2)
Early
detectio
n of
recu
rren
ce or
prog
ression
2 3
At e
ach
visit
the
follo
win
g ta
sks s
houl
d be
com
plet
ed: d
eter
min
atio
n of
Tg
and
TgAb
seru
m le
vels;
ade
quac
y of
TSH
supp
ress
ion;
nec
k U
S (ATA
200
9,
BTA 20
14, A
IOCC
-‐AIR
O-‐A
IOM
201
2, E
SMO
201
2, N
CCN
201
5)
For l
ow-‐r
isk p
atie
nts w
ith n
o ev
iden
ce o
f bio
chem
ical
or s
truc
tura
l dise
ase,
an
nual
mea
sure
men
t of s
erum
Tg
whi
le o
n su
ppre
ssiv
e tr
eatm
ent i
s ad
equa
te (A
TA 200
9, BTA
201
4, A
IOCC
-‐AIR
O-‐A
IOM
201
2)
Ther
e is
norm
ally
no
need
to m
easu
re se
rum
Tg
mor
e fr
eque
ntly
than
3-‐
mon
thly
dur
ing
rout
ine
follo
w-‐u
p (BTA
201
4)
Patie
nts i
n w
hom
bas
al T
g re
mai
ns p
ersis
tent
ly d
etec
tabl
e w
hile
on
supp
ress
ive
ther
apy
or ri
ses w
ith su
bseq
uent
ass
essm
ents
requ
ire fu
rthe
r ev
alua
tion
(BTA
201
4)
Afte
r the
firs
t WBS
per
form
ed fo
llow
ing
RRA,
low
-‐risk
pat
ient
s with
un
dete
ctab
le T
g du
ring
supp
ress
ive
ther
apy
with
neg
ativ
e Tg
Ab a
nd
nega
tive
US
do n
ot re
quire
rout
ine
WBS
dur
ing
follo
w-‐u
p (ATA
200
9)
A sin
gle
elev
ated
seru
m T
g re
sult
shou
ld b
e co
nfirm
ed b
y re
peat
ing
the
test
be
fore
pro
ceed
ing
to a
dditi
onal
inve
stig
atio
n or
ther
apy
(BTA
201
4)
An e
leva
ted
seru
m T
g le
vel s
houl
d le
ad to
a d
etai
led
neck
US
(BTA
201
4)
Seru
m T
g sh
ould
be
mea
sure
d ev
ery
6-‐12
mon
ths d
epen
ding
on
the
risk
leve
l of t
he p
atie
nt (A
TA 200
9, BTA
201
4, A
IOCC
-‐AIR
O-‐A
IOM
201
2, E
SMO
201
2,
NCC
N 2
015)
TgAb
shou
ld b
e m
easu
red
by a
qua
ntita
tive
met
hod
simul
tane
ously
with
m
easu
rem
ent o
f ser
um T
g. If
TgA
b ar
e de
tect
able
, mea
sure
men
t sho
uld
be
repe
ated
at r
egul
ar (~
6-‐m
onth
ly) i
nter
vals
(BTA
201
4)
TgAb
, eve
n if
nega
tive,
shou
ld b
e m
easu
red
at fo
llow
-‐up
whe
n Tg
is
mea
sure
d (ATA
200
9, BTA
201
4)
Seru
m T
SH c
once
ntra
tion
shou
ld b
e de
term
ined
con
curr
ently
to a
id
inte
rpre
tatio
n (BTA
201
4)
To e
nsur
e co
ntin
uity
in m
onito
ring,
clin
icia
ns sh
ould
use
the
sam
e la
bora
tory
, Tg
and
TgAb
ass
ays o
n a
long
-‐ter
m b
asis.
Lab
orat
orie
s sho
uld
not c
hang
e m
etho
ds w
ithou
t prio
r con
sulta
tion
with
clin
ical
use
rs o
f the
se
rvic
e (ATA
200
9, BTA
201
4)
Tg sh
ould
be
mea
sure
d by
an
imm
unom
etric
ass
ay th
at is
cal
ibra
ted
agai
nst
the
CRM
-‐457
stan
dard
(ATA
200
9)
Mon
itorin
g of trea
tmen
t respon
se in
adv
anced
disease
2 1
In th
e pr
esen
ce o
f per
siste
nt o
r met
asta
tic d
iseas
e, a
n un
dete
ctab
le se
rum
TS
H le
vel (
<0.1
mU
/L) s
houl
d be
mai
ntai
ned
durin
g fo
llow
-‐up
(ATA
200
9,
ESM
O 2
012)
It is
unce
rtai
n w
heth
er e
mpi
rical
131 I t
reat
men
t is b
enef
icia
l in
patie
nts w
ith
raise
d se
rum
Tg,
com
pare
d to
act
ive
surv
eilla
nce
(BTA
201
4)
(1) Re
com
men
datio
ns fr
om CPG
s an
d fr
om OGDs,
if c
onsis
tent
with
thos
e of
CPG
s.
(2) Su
pple
men
tary
info
rmat
ion
from
bot
h CP
Gs
and OGDs,
and
reco
mm
enda
tions
from
OGDs
that
are
inco
nsist
ent w
ith th
ose
of CPG
s.
rhTS
H =
reco
mbi
nant
hum
an T
SH; R
RA =
131 I r
adio
iodi
ne re
mna
nt a
blat
ion;
UG
FNA
= ul
tras
ound
-‐gui
ded
fine-‐
need
le a
spira
tion;
US
= ul
tras
ound
; WBS
= 13
1 I who
le b
ody
scan
.
THYR
OID
CA
NCE
R, D
IFFE
REN
TIAT
ED
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 7 (4
CPG
s, 3
OG
Ds)
Circulating tumor markers: a guide to their appropriate clinical usee172
© 2017 Wichtig Publishing
9 Th
yroid cancer, m
edullary (M
TC)
Exa
mined
doc
umen
ts: 7
(4 CPG
s, 3 OGDs)
Clinical que
stion
CPG OGD Su
mmary of re
commen
datio
ns (1
) Su
pplemen
tary in
form
ation
(2)
Screen
ing of peo
ple at
increa
sed ris
k
(positive
family
history)
3 2
If th
ere
is st
rong
pre
sum
ptiv
e ev
iden
ce fr
om th
e in
divi
dual
or f
amily
hist
ory
of in
herit
ed d
iseas
e, c
onsid
er b
ioch
emic
al sc
reen
ing
of fa
mily
mem
bers
at
risk
usin
g st
imul
ated
(int
rave
nous
cal
cium
/pen
taga
strin
) Ct t
estin
g fr
om a
ge
5 ye
ars (
BTA 20
14)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (A
TA 201
5, A
IOCC
-‐AIR
O-‐
AIO
M 2
012)
Gen
etic
cou
nsel
ing
and
gene
tic te
stin
g fo
r spe
cific
ger
mlin
e m
utat
ions
sh
ould
be
offe
red
to fi
rst-‐
degr
ee re
lativ
es o
f pat
ient
s with
pro
ven
here
dita
ry M
TC (A
ACE-‐AM
E-‐ET
AM 201
0, ATA
201
5, BTA
201
4, A
IOCC
-‐AIR
O-‐
AIO
M 2
012,
NCC
N 2
015)
The
trad
ition
al a
ppro
ach
of st
imul
atin
g se
cret
ion
of C
t by
eith
er
pent
agas
trin
or c
alci
um in
fusio
n to
iden
tify
patie
nts w
ith M
TC is
no
long
er
reco
mm
ende
d, b
ecau
se e
leva
ted
Ct is
not
a sp
ecifi
c or
ade
quat
ely
sens
itive
m
arke
r for
MTC
(NCC
N 2
015)
Differen
tial d
iagn
osis
4 3
Mea
sure
men
t of b
asal
seru
m C
t lev
el m
ay b
e us
eful
in th
e in
itial
eva
luat
ion
of th
yroi
d no
dule
s (AA
CE-‐AME-‐ET
AM 201
0, E
SMO
201
2)
Mea
sure
men
t of b
asal
pla
sma
Ct a
nd C
EA m
ay b
e us
eful
if M
TC is
susp
ecte
d bu
t is n
ot re
com
men
ded
rout
inel
y fo
r all
thyr
oid
nodu
les (
BTA 20
14,
NCC
N 2
015)
Mea
sure
men
t is m
anda
tory
in p
atie
nts w
ith a
fam
ily h
istor
y or
clin
ical
su
spic
ion
of M
TC o
r MEN
2 (AAC
E-‐AM
E-‐ET
AM 201
0)
Phys
icia
ns sh
ould
dec
ide
whe
ther
mea
surin
g se
rum
Ct l
evel
s in
patie
nts
with
nod
ular
goi
ters
may
be
usef
ul in
the
man
agem
ent o
f pat
ient
s in
thei
r cl
inic
(ATA
201
5)
If th
e Ct
leve
l is i
ncre
ased
, the
test
shou
ld b
e re
peat
ed in
bas
al c
ondi
tions
an
d, if
con
firm
ed in
the
abse
nce
of m
odifi
ers,
a p
enta
gast
rin-‐ o
r cal
cium
-‐st
imul
atio
n te
st w
ill in
crea
se th
e di
agno
stic
acc
urac
y (AAC
E-‐AM
E-‐ET
AM 201
0,
BTA 20
14)
FNA
findi
ngs t
hat a
re in
conc
lusiv
e or
sugg
estiv
e of
MTC
shou
ld h
ave
Ct
mea
sure
d in
the
FNA
was
hout
flui
d to
det
ect t
he p
rese
nce
of m
arke
rs su
ch
as C
t, ch
rom
ogra
nin
and
CEA
and
the
abse
nce
of T
g (ATA
201
5)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (N
ICE 20
15, A
IOCC
-‐AIR
O-‐
AIO
M 2
012)
Ct c
an b
e in
crea
sed
for c
ause
s diff
eren
t fro
m M
TC (A
ACE-‐AM
E-‐ET
AM 201
0,
ATA 20
15)
-‐ ot
her m
alig
nanc
ies:
pul
mon
ary
or p
ancr
eatic
end
ocrin
e tu
mor
s,
pros
tate
can
cer,
smal
l cel
l and
larg
e ce
ll lu
ng c
ance
r -‐
beni
gn c
ondi
tions
: kid
ney
failu
re, a
utoi
mm
une
thyr
oid
dise
ase,
seps
is,
hype
rgas
trin
emia
(res
ultin
g fr
om p
roto
n-‐pu
mp
inhi
bito
r the
rapy
), hy
perp
arat
hyro
idism
-‐
misc
ella
nea:
sex,
age
, wei
ght,
incr
ease
d ca
lciu
m le
vels,
alc
ohol
co
nsum
ptio
n, sm
okin
g, h
eter
ophi
lic a
ntic
alci
toni
n an
tibod
ies
Seru
m C
t lev
els i
n pa
tient
s with
var
ious
non
thyr
oid
mal
igna
ncie
s do
not
incr
ease
in re
spon
se to
cal
cium
or p
enta
gast
rin st
imul
atio
n (ATA
201
5)
THYR
OID
CA
NCE
R, M
EDU
LLA
RY (M
TC)
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 7 (4
CPG
s, 3
OG
Ds)
to b
e co
ntinu
ed
Gion et al e173
© 2017 Wichtig Publishing
10
Clinical que
stion
CPG OGD Su
mmary of re
commen
datio
ns (1
) Su
pplemen
tary in
form
ation
(2)
Preo
perativ
e worku
p 3
3 Pa
tient
s pre
sent
ing
with
a th
yroi
d no
dule
and
a c
ytol
ogic
al o
r hist
olog
ical
di
agno
sis o
f MTC
shou
ld h
ave
dete
rmin
atio
n of
seru
m le
vels
of C
t and
CEA
, an
d ge
netic
test
ing
for a
RET
ger
mlin
e m
utat
ion
(ATA
201
5, A
IOCC
-‐AIR
O-‐A
IOM
201
2, E
SMO
201
2, N
CCN
201
5)
Befo
re su
rger
y, a
ll pa
tient
s with
susp
ecte
d M
TC sh
ould
und
ergo
a st
agin
g w
orku
p in
clud
ing
basa
l ser
um c
alci
um a
nd p
lasm
a or
24-‐
h ur
ine
met
anep
hrin
es a
nd n
orm
etan
ephr
ines
to e
xclu
de p
heoc
hrom
ocyt
oma
and
hype
rpar
athy
roid
ism (A
TA 201
5, BTA
201
4, A
IOCC
-‐AIR
O-‐A
IOM
201
2, E
SMO
201
2,
NCC
N 2
015)
eve
n in
the
abse
nce
of a
pos
itive
fam
ily h
istor
y or
sym
ptom
s (BTA
201
4)
Clin
icia
ns sh
ould
con
sider
false
ly h
igh
or lo
w se
rum
Ct l
evel
s whe
n se
rum
Ct
leve
ls ar
e di
spro
port
iona
te to
the
expe
cted
clin
ical
find
ings
(ATA
201
5)
Preo
pera
tive
syst
emic
stag
ing
is in
dica
ted
in n
ode-‐
posit
ive
patie
nts w
ith C
t le
vels
>400
pg/
mL
(BTA
201
4)
In p
atie
nts w
ith a
dvan
ced
MTC
, mar
ked
elev
atio
n of
the
seru
m C
EA le
vel
disp
ropo
rtio
nate
to a
low
er se
rum
Ct l
evel
or n
orm
al o
r low
leve
ls of
bot
h se
rum
Ct a
nd C
EA in
dica
te p
oorly
diff
eren
tiate
d M
TC (A
TA 201
5)
In c
ase
of su
spic
ious
US
feat
ures
, the
met
asta
tic n
atur
e of
a ly
mph
nod
e m
ay b
e co
nfirm
ed w
ith m
easu
rem
ent o
f Ct (
and/
or T
g) in
the
was
hout
of
the
need
le u
sed
for U
GFN
A bi
opsy
(AAC
E-‐AM
E-‐ET
AM 201
0)
Reassessmen
t after
initial curative trea
tmen
t 2
3 Cl
inic
ians
shou
ld c
onsid
er …
pos
tope
rativ
e se
rum
Ct l
evel
s in
pred
ictin
g ou
tcom
e an
d pl
anni
ng lo
ng-‐t
erm
follo
w-‐u
p of
pat
ient
s tre
ated
by
thyr
oide
ctom
y (ATA
201
5, BTA
201
4, E
SMO
201
2, N
CCN
201
5)
Post
oper
ativ
ely,
Ct a
nd C
EA sh
ould
be
mea
sure
d at
3 m
onth
s (no
ear
lier
than
15
days
aft
er th
yroi
dect
omy)
and
at 6
mon
ths (
ATA 20
15, B
TA 201
4,
NCC
N 2
015)
Patie
nts w
ith e
leva
ted
post
oper
ativ
e se
rum
Ct l
evel
s les
s tha
n 15
0 pg
/mL
shou
ld h
ave
a ph
ysic
al e
xam
inat
ion
and
US
of th
e ne
ck. I
f the
se a
re
nega
tive,
pat
ient
s sho
uld
be fo
llow
ed w
ith m
easu
rem
ent o
f ser
um le
vels
of
Ct a
nd C
EA, a
nd U
S ev
ery
6 m
onth
s (AT
A 20
15, E
SMO
201
2)
If th
e po
stop
erat
ive
seru
m C
t is >
150
pg/m
L, p
atie
nts s
houl
d be
eva
luat
ed
by im
agin
g pr
oced
ures
(nec
k, sk
elet
on, l
iver
) (AT
A 20
15, E
SMO
201
2)
Follo
win
g un
ilate
ral t
hyro
idec
tom
y, c
ompl
etio
n th
yroi
dect
omy
is re
com
men
ded
in p
atie
nts w
ith a
RET
ger
mlin
e m
utat
ion,
an
elev
ated
po
stop
erat
ive
seru
m C
t lev
el, o
r im
agin
g st
udie
s ind
icat
ing
resid
ual M
TC
(ATA
201
5)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (A
IOCC
-‐AIR
O-‐A
IOM
201
2)
THYR
OID
CA
NCE
R, M
EDU
LLA
RY (M
TC)
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 7 (4
CPG
s, 3
OG
Ds)
to b
e co
ntinu
ed
Circulating tumor markers: a guide to their appropriate clinical usee174
© 2017 Wichtig Publishing
11
Clinical que
stion
CPG OGD Su
mmary of re
commen
datio
ns (1
) Su
pplemen
tary in
form
ation
(2)
Early
detectio
n of
recu
rren
ce or
prog
ression
2 3
Seru
m le
vels
of C
t and
CEA
shou
ld b
e sh
ould
be
regu
larly
ass
esse
d (ATA
201
5, BTA
201
4, A
IOCC
-‐AIR
O-‐A
IOM
201
2, E
SMO
201
2, N
CCN
201
5)
Ct a
nd C
EA d
oubl
ing
times
cor
rela
te w
ith tu
mor
pro
gres
sion
and
are
usef
ul
prog
nost
ic in
dica
tors
for M
TC re
curr
ence
and
surv
ival
(BTA
201
4, E
SMO
201
2,
NCC
N 2
015)
Repo
rted
sche
dule
(s) o
f CEA
and
Ct d
eter
min
atio
n:
-‐ ev
ery
6 m
onth
s for
1 y
ear a
nd y
early
ther
eaft
er in
pat
ient
s with
un
dete
ctab
le b
asal
Ct a
nd C
EA w
ithin
refe
renc
e ra
nge
(ATA
201
5,
NCC
N 2
015)
-‐
at le
ast e
very
6 m
onth
s in
patie
nts w
ith d
etec
tabl
e se
rum
leve
ls of
Ct
and/
or C
EA to
det
erm
ine
thei
r dou
blin
g tim
es (A
TA 201
5, BTA
201
4,
NCC
N 2
015)
Incr
easin
g se
rum
CEA
leve
ls as
soci
ated
with
stab
le o
r dec
linin
g se
rum
Ct
leve
ls ar
e co
nsid
ered
an
indi
catio
n of
poo
rly d
iffer
entia
ted
MTC
(ATA
201
5)
At le
ast 4
Ct/
CEA
valu
es a
re re
quire
d to
cal
cula
te th
e do
ublin
g tim
e. A
n on
line
calc
ulat
or is
ava
ilabl
e (BTA
201
4)
Doub
ling
time
<6 m
onth
s is a
poo
r pro
gnos
tic fa
ctor
(BTA
201
4)
Dist
ant m
etas
tase
s exc
eede
d 50
% a
t Ct l
evel
s of 5
,000
pg/
mL
and
wer
e vi
rtua
lly a
lway
s pre
sent
whe
n Ct
leve
ls ex
ceed
ed 2
0,00
0 pg
/mL
(ATA
201
5)
The
pres
ence
of a
n el
evat
ed b
ut st
able
Ct l
evel
pos
tope
rativ
ely
may
be
man
aged
con
serv
ativ
ely
(act
ive
surv
eilla
nce)
, pro
vide
d tr
eata
ble
dise
ase
has b
een
excl
uded
radi
olog
ical
ly. P
rogr
essiv
ely
risin
g Ct
con
cent
ratio
ns
shou
ld tr
igge
r im
agin
g fo
r fur
ther
stag
ing
(BTA
201
4, N
CCN
201
5)
Mon
itorin
g of trea
tmen
t respon
se in
adv
anced
disease
2 3
Basa
l lev
els o
f ser
um C
t and
CEA
shou
ld b
e m
easu
red
conc
urre
ntly
in
patie
nts w
ith a
dvan
ced
MTC
(ATA
201
5)
Syst
emic
ther
apy
shou
ld n
ot b
e ad
min
ister
ed to
pat
ient
s who
hav
e in
crea
sing
seru
m C
t and
CEA
leve
ls bu
t no
docu
men
ted
met
asta
tic d
iseas
e no
r to
patie
nts w
ith st
able
low
-‐vol
ume
met
asta
tic d
iseas
e an
d Ct
and
CEA
do
ublin
g tim
es g
reat
er th
an 2
yea
rs (A
TA 201
5)
Clin
ical
que
stio
n co
nsid
ered
, but
crit
eria
to m
onito
r tre
atm
ent r
espo
nse
(incl
udin
g TM
s) n
ot a
ddre
ssed
(BTA
201
4, A
IOCC
-‐AIR
O-‐A
IOM
201
2, E
SMO
201
2)
Clin
ical
que
stio
n co
nsid
ered
, but
TM
s not
add
ress
ed (N
CCN
201
5)
(1) Re
com
men
datio
ns fr
om CPG
s an
d fr
om OGDs,
if c
onsis
tent
with
thos
e of
CPG
s.
(2) Su
pple
men
tary
info
rmat
ion
from
bot
h CP
Gs
and OGDs,
and
reco
mm
enda
tions
from
OGDs
that
are
inco
nsist
ent w
ith th
ose
of CPG
s.
FNA
= fin
e-‐ne
edle
asp
iratio
n; M
EN2
= m
ultip
le e
ndoc
rine
neop
lasia
type
2; R
ET g
ene
= RE
arra
nged
dur
ing
Tran
sfec
tion
gene
; UG
FNA
= ul
tras
ound
-‐gui
ded
fine-‐
need
le a
spira
tion;
US
= ul
tras
ound
.
THYR
OID
CA
NCE
R, M
EDU
LLA
RY (M
TC)
Det
aile
d su
mm
ary
tabl
esEx
amin
ed d
ocum
ents
: 7 (4
CPG
s, 3
OG
Ds)
Gion et al e175
© 2017 Wichtig Publishing
Selected guidelines (by cancer site)
Head and neck cancer
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Lung cancer
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Mesothelioma
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Thyroid cancer, differentiated
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CONTRIBUTORS
Salvatore AlfieriSC Oncologia Medica 3 Tumori Testa e ColloFondazione IRCCS Istituto Nazionale dei Tumori Milano - Italy
Emiliano AroasioDipartimento di Scienze Cliniche e BiologicheAzienda Ospedaliero-Universitaria San Luigi GonzagaOrbassano (Torino) - Italy
Alessandro BertacciniClinica UrologicaAzienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-MalpighiBologna - Italy
Francesco BoccardoUOC Clinica di Oncologia MedicaIRCCS AOU San Martino IST - Istituto Nazionale per la Ricerca sul CancroUniversità degli StudiGenova - Italy
Mario BragaSistema Monitoraggio Nazionale (Area Monitoraggio Spesa Sanitaria e LEA)Agenzia Nazionale per i Servizi Sanitari Regionali (AGENAS)Roma - Italy
Roberto BuzzoniSC Day Hospital e Terapia Ambulatoriale OncologicaFondazione IRCCS Istituto Nazionale dei TumoriMilano - Italy
Maurizio CancianSocietà Italiana di Medicina Generale SIMGScuola Veneta di Medicina Generale SVeMGConegliano Veneto (Treviso) - Italy
Ettore D. CapoluongoUOS Diagnostica Molecolare Clinica e Personalizzata, Dipartimento di Medicina LaboratorioFondazione Policlinico Universitario “Agostino Gemelli”Roma - Italy
Elisabetta CarianiSSD Laboratorio Patologia Clinica - Tossicologia e Diagnostica AvanzataNuovo Ospedale Civile S. Agostino-Estense - Azienda USL ModenaModena - Italy
Vanna Chiarion SileniSSD Oncologia Melanoma ed EsofagoIstituto Oncologico Veneto IOV – IRCCSPadova - Italy
Michela CinquiniUnità di Metodologia delle Revisioni Sistematiche e Produzione di Linee GuidaLaboratorio di Metodologia per la Ricerca BiomedicaIRCCS Istituto di Ricerche Farmacologiche “Mario Negri” Milano - Italy
Giuseppe CivardiUOC Medicina InternaPOI della Val d’Arda - Azienda USL PiacenzaFiorenzuola d’Arda (Piacenza) - Italy
Renzo ColomboDivisione Oncologia/UrologiaUrological Research InstituteIRCCS Ospedale San Raffaele Milano - Italy
Mario CorrealeSOC Patologia ClinicaIRCCS “S. De Bellis”Castellana Grotte (Bari) - Italy
Gaetano D’AmbrosioMedico di Medica Generale ASL BTSocietà Italiana di Medicina Generale SIMGBisceglie (Barletta-Adria-Trani) - Italy
Bruno DanieleUOC Oncologia Medica, Dipartimento OncologiaAzienda Ospedaliera “G. Rummo”Benevento - Italy
Marco Danova Dipartimento di Area MedicaAzienda SST di PaviaPavia - Italy
Giovanna Del Vecchio Blanco UOC GastroenterologiaDipartimento di Medicina InternaFondazione Policlinico Tor VergataUniversità degli Studi di Roma “Tor Vergata”Roma - Italy
Francesca Di FabioUOC Oncologia MedicaAzienda Ospedaliero-Universitaria Policlinico S. Orsola-MalpighiBologna - Italy
Massimo Di MaioDipartimento di Oncologia, Università degli Studi di TorinoSCDU Oncologia Medica, AO Ordine MaurizianoTorino - Italy
Gion et al e179
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Ruggero DittadiUOC Laboratorio Analisi, Dipartimento di Patologia Clinica e Medicina TrasfusionaleOspedale dell’Angelo - Azienda ULSS 12 VenezianaVenezia-Mestre - Italy
Aline Sueli Coelho Fabricio Centro e Programma Regionale Biomarcatori Diagnostici, Prognostici e PredittiviAzienda ULSS 12 VenezianaVenezia - Italy
Massimo FalconiChirurgia del PancreasIRCCS Ospedale San Raffaele Università Vita-Salute San RaffaeleMilano - Italy
Andrea FandellaUnità Funzionale UrologiaCasa di Cura Giovanni XXIIIMonastier (Treviso) - Italy
Tommaso FasanoSC Laboratorio Analisi Chimico-Cliniche e di Endocrinologia, Dipartimento di Diagnostica per Immagini e Medicina di LaboratorioClinical Cancer CenterIRCCS-Arcispedale Santa Maria NuovaReggio Emilia - Italy
Simona FerraroUOC Patologia Clinica, Dipartimento di Medicina di LaboratorioOspedale Universitario “Luigi Sacco”ASST Fatebenefratelli-Sacco Milano - Italy
Antonio FortunatoUOC Laboratorio Analisi, Dipartimento di Urgenza ed EmergenzaAzienda ULSS 6Vicenza - Italy
Bruno Franco NovellettoSocietà Italiana di Medicina Generale SIMGScuola Veneta di Medicina Generale SVeMGPadova - Italy
Angiolo GadducciDipartimento di Medicina Clinica e SperimentaleDivisione di Ginecologia e OstetriciaUniversità degli Studi di PisaPisa - Italy
Luca GermagnoliSynlab Italia Servizi DiagnosticiCastenedolo (Brescia) - Italy
Maria Grazia GhiUOC Oncologia Medica, Dipartimento OncologicoAzienda ULSS 12 VenezianaVenezia - Italy
Davide GiavarinaUOC Laboratorio Analisi, Dipartimento di Urgenza ed EmergenzaAzienda ULSS 6Vicenza - Italy
Massimo GionCentro e Programma Regionale Biomarcatori Diagnostici, Prognostici e Predittivi Azienda ULSS 12 VenezianaVenezia - Italy
Marién González LorenzoUnità di Epidemiologia ClinicaIRCCS Istituto Ortopedico GaleazziDipartimento di Scienze Biomediche per la SaluteUniversità degli Studi di MilanoMilano - Italy
Stefania GoriDipartimento di OncologiaCancer Care Center “Sacro Cuore-Don Calabria”Negrar (Verona) - Italy
Fiorella GuadagniUniversità San Raffaele RomaBiomarker Discovery and Advanced Technologies (BioDAT)Biobanca Interistituzionale Multidisciplinare (BioBIM)SR Research Center- IRCCS San Raffaele PisanaRoma - Italy
Cinzia IottiSC Radioterapia OncologicaClinical Cancer CenterIRCCS Arcispedale Santa Maria NuovaReggio Emilia - Italy
Tiziana LatianoUOC Oncologia MedicaCasa Sollievo della Sofferenza – IRCCSSan Giovanni Rotondo (Foggia) - Italy
Lisa LicitraSC Oncologia Medica 3 Tumori Testa e ColloFondazione IRCCS Istituto Nazionale dei TumoriMilano - Italy
Tiziano MagginoUOC Ostetricia e Ginecologia, Dipartimento Materno-InfantileOspedale dell’Angelo - Azienda ULSS 12 VenezianaVenezia-Mestre - Italy
Circulating tumor markers: a guide to their appropriate clinical usee180
© 2017 Wichtig Publishing
Evaristo MaielloUOC Oncologia MedicaCasa Sollievo della Sofferenza – IRCCSSan Giovanni Rotondo (Foggia) - Italy
Gianluca MasiUOC Oncologia MedicaAzienda Ospedaliero-Universitaria PisanaPisa - Italy
Paolo MorandiUOC Oncologia Medica, Dipartimento OncologicoAzienda ULSS 12 VenezianaVenezia - Italy
Maria Teresa MuratoreUOC Diagnostica ClinicaPO Belcolle - Azienda Sanitaria Locale ViterboViterbo - Italy
Gianmauro NumicoSC Oncologia MedicaAzienda Ospedaliera SS. Antonio e Biagio e C. ArrigoAlessandria - Italy
Valentina PecoraroSSD Laboratorio Patologia Clinica - Tossicologia e Diagnostica AvanzataNuovo Ospedale Civile S. Agostino-Estense - Azienda USL ModenaModena - Italy
Paola Pezzati SOD Laboratorio Generale AOUC Azienda Ospedaliero-Universitaria CareggiFirenze - Italy
Carmine PintoUOC OncologiaClinical Cancer CenterIRCCS Arcispedale Santa Maria NuovaReggio Emilia - Italy
Silvia PregnoUO Governance ClinicaArea Direzione Strategica - Azienda USL ModenaModena - Italy
Giulia RainatoCentro e Programma Regionale Biomarcatori Diagnostici, Prognostici e Predittivi Azienda ULSS 12 Veneziana Istituto Oncologico Veneto IOV – IRCCSPadova - Italy
Stefano RapiSOD Laboratorio Generale AOUC Azienda Ospedaliero-Universitaria CareggiFirenze - Italy
Francesco RicciDépartement Oncologie MédicaleInstitut CurieParis - France
Lorena Fabiola Rojas LlimpeUOC Oncologia MedicaAzienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-MalpighiBologna - Italy
Laura RoliSSD Laboratorio Patologia Clinica EndocrinologiaNuovo Ospedale Civile S. Agostino-Estense - Azienda USL ModenaModena- Italy
Giovanni RostiSC Oncologia MedicaFondazione IRCCS Policlinico San MatteoPavia - Italy
Tiziana RubecaLaboratorio Regionale Prevenzione OncologicaISPO Istituto per lo Studio e la Prevenzione Oncologica Firenze - Italy
Giuseppina RuggeriUOC Laboratorio AnalisiASST Spedali CiviliBrescia - Italy
Anne W.S. RutjesDivision of Clinical Epidemiology & BiostatisticsInstitute of Social and Preventive MedicineUniversity of BernBern - Switzerland
Gian Luca SalvagnoUOC Laboratorio Analisi, DAI Patologia e DiagnosticaOspedale Borgo Roma - Azienda Ospedaliera Universitaria IntegrataVerona - Italy
Maria Teresa SandriDivisione Medicina LaboratorioIstituto Europeo di Oncologia IRCCSMilano - Italy
Giovanni ScambiaIstituto di Clinica ostetrico e ginecologica Università Cattolica del Sacro CuoreRoma - Italy
Mario ScartozziClinica di Oncologia MedicaPresidio Policlinico Universitario “Duilio Casula”Azienda Ospedaliera UniversitariaCagliari - Italy
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Ornella ScattolinCentro e Programma Regionale Biomarcatori Diagnostici, Prognostici e Predittivi Azienda ULSS 12 VenezianaAVAPO Venezia OnlusVenezia - Italy
Vincenzo ScattoniUO UrologiaIRCCS Ospedale San Raffaele Università Vita-Salute San RaffaeleMilano - Italy
Holger Schünemann Department of Clinical Epidemiology & BiostatisticsMcMaster University Health Sciences CentreHamilton - Canada
Giuseppe SicaUOC Chirurgia Generale A, Dipartimento di ChirurgiaFondazione PTV Policlinico Universitario Tor Vergata Università Roma-Tor VergataRoma - Italy
Alessandro TerreniSOD Laboratorio Generale AOUC Azienda Ospedaliero-Universitaria CareggiFirenze - Italy
Marcello TiseoSC Oncologia MedicaAzienda Ospedaliero-UniversitariaParma - Italy
Valter TorriLaboratorio Metodologia per la Ricerca Biomedica, Dipartimento OncologiaIRCCS Istituto di Ricerche Farmacologiche “Mario Negri” Milano - Italy
Quinto TozziRicerca e Studio Rischio ClinicoAgenzia Nazionale per i Servizi Sanitari Regionali (AGENAS)Roma - Italy
Tommaso TrentiDipartimento Integrato Interaziendale di Medicina di Laboratorio ed Anatomia PatologicaAzienda Ospedaliera Universitaria e Azienda USL di ModenaModena - Italy
Chiara TrevisiolCentro e Programma Regionale Biomarcatori Diagnostici, Prognostici e Predittivi Azienda ULSS 12 Veneziana Istituto Oncologico Veneto IOV – IRCCSPadova - Italy
Paolo ZolaDipartimento Scienze ChirurgicheAOU Città della Salute e della ScienzaUniversità degli StudiTorino - Italy
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