(2012) 360–364

Clinical Imaging 36

Are RECIST criteria sufficient to assess response to therapy inneuroendocrine tumors?☆

Anna Sowa-Staszczak a,⁎, Robert Chrzan b, Dorota Pach a, Agnieszka Stefańska a,Monika Tomaszuk a, Monika Buziak-Bereza a, Maciej Kołodziej a, Elwira Przybylik-Mazurek a,

Alicja Hubalewska-Dydejczyk a,⁎

aNuclear Medicine Unit Endocrinology Department, Jagiellonian University, Medical College, Krakow, PolandbDepartment of Radiology, Jagiellonian University, Medical College, Krakow, Poland

Received 1 September 2011; accepted 3 November 2011

Abstract

Material and Methods: Within the group of 47 patients treated with peptide receptor radionuclide therapy (PRRT), four patients werechosen: three with inoperable tumors without liver metastases and one with two lesions in the pancreas and metastases. Results: In allpatients, after PRRT, the changes in the sum of the longest diameters of tumors were between −1% and −21%, resulting in stable diseasereported [strict Response Evaluation Criteria in Solid Tumors (RECIST)]. But the measurements of tumor volume and attenuation incomputed tomography and the tumor to nontumor ratio in somatostatin receptor scintigraphy resulted in different response assessments.Conclusions: The RECIST standard may be not sufficient to properly assess the therapy response in patients with neuroendocrine tumors.© 2012 Elsevier Inc. All rights reserved.

Keywords: Optimization of PRRT response; Neuroendocrine tumors; Peptide receptor radionuclide therapy; RECIST criteria

1. Background

Neuroendocrine tumors (NETs) are a usually slow-growing, mostly well-differentiated, heterogeneous groupof neoplasms, which consist of diffused neuroendocrine cells[1]. The first step of the treatment of these tumors is surgicaleradication of the tumor, which becomes impossible in thecase of large tumors or infiltration into other tissues and/orimportant blood vessels [2,3]. When surgical intervention isimpossible due to inoperable tumor or metastatic disease,peptide receptor radionuclide therapy (PRRT) is the besttherapeutic tool as it enables stabilization or regression of thetumor size. In cases of inoperable primary tumor, PRRT

☆ No potential conflicts of interest were disclosed.⁎ Corresponding author. Department of Endocrinology, ul. Kopernika

17, 31-501 Krakow, Poland. Tel.: +48 12 424 75 00; fax: +48 12 424 73 99.E-mail addresses: sowiana@gmail.com (A. Sowa-Staszczak),

alahub@cm-uj.krakow.pl (A. Hubalewska-Dydejczyk).

0899-7071/$ – see front matter © 2012 Elsevier Inc. All rights reserved.doi:10.1016/j.clinimag.2011.11.005

might be used as neoadjuvant treatment to diminish tumorsize and enable surgical intervention [3–6]. The response tothe therapy is assessed according to the Response EvaluationCriteria in Solid Tumors (RECIST), which include mea-surement of the longest diameter of every measurable lesionon axial computed tomographic (CT) slices and calculationof the sum of the longest diameters (SLD) for all selectedtarget lesions [7,8]. For partial response (PR), at least a 30%decrease in the SLD of target lesions should be found, takingthe baseline SLD as reference [7,8]. One very importantdiagnostic tool for NETs is somatostatin receptor scintigra-phy (SRS), which localizes the primary tumor better thanother diagnostic studies and also enables assessment of theadvancement of the disease. SRS is positive when there is anoverexpression of somatostatin receptors at the surface ofthe tumor cells. The results of the study depend on the typeof the somatostatin analogue and isotope used and grade ofthe receptors' internalization. With SRS, small primarytumors and their metastases, not visible in CT scans, mightbe revealed. This shows that, in some cases, CT is not

361A. Sowa-Staszczak et al. / Clinical Imaging 36 (2012) 360–364

efficient in the diagnostic process for NET [6,9–11].Moreover, NETs are usually well vascularized, and PRRTtreatment might cause changes not only in tumor size butalso in contrast enhancement and attenuation. Therefore,tumor size changes in CT scans taken into considerationwhile using RECIST criteria seem to be insufficient toassess response to the therapy in NET. Furthermore, CTscans should be compared with SRS results based on fusionof CT/SRS images [12]. Results of fusion images andassessment of tumor size, contrast enhancement, andattenuation changes in CT scan provide more preciseinformation about treatment results.

The aim of the study was the optimization of the responseto the therapy prior to further treatment planning in patientswith NETs.

2. Material and methods

At the beginning, within the group of 47 patients treatedwith the PRRT at the Nuclear Medicine Unit of theEndocrinology Department in the University Hospital inCracow, a group of only four patients was chosen—threewith large, inoperable tumors localized in the head (two) andthe body (one) of the pancreas without liver metastases, andone with two lesions in the pancreas (in the tail and the head)and numerous liver metastases—to assess the usefulness ofadditional CT parameters such as volume, contrast enhance-ment, and attenuation changes in the assessment of responseto the therapy. The mean age was 58.8 years (±7.9 years, min48 years, max 67 years). There were three men and onewoman. All the patients were included in the PRRT with90Y-DOTA-TATE on the basis of the positive SRS scans, a

Fig. 1. Patient 1: a 59-year-old man with large inoperable gastrinoma localized in tfusion, and 99mTc-EDDA/HYNIC-TOC SRS image before (A1, A2, A3) and afte

good general condition (Karnofsky index N70%–100%), andrequired levels in morphotic and renal parameters.

Prior to radioisotope therapy, one of the patients under-went surgical intervention which enabled excision of theprimary tumor. PRRT was given due to local recurrence andinoperability of the tumor. A further surgical intervention isbeing considered.

Every patient received a dose of 7.4 GBq/m2 90Y-DOTA-TATE in four to five cycles every 6–9 weeks. The mean dosewas 14.3 GBq (min 12.6 GBq, max 14.8 GBq). Response tothe therapy was assessed according to RECIST criteria.

At baseline and each 6 months after the PRRT, SRS andCT were performed for staging all patients (Fig. 1).

The SRS examination was performed at the NuclearMedicine Unit of the Endocrinology Department in theUniversity Hospital in Cracow. A dual-head, large field ofview E.CAM gamma camera (Siemens) with parallel, low-energy, high-resolution collimators was used. 99mTc-EDDA/-HYNIC-TOC tracer with activity of 740MBq was injected ineach patient. All patients underwent whole-body scans after1, 4, and 24 h (256×1024 matrix, 12 cm/min, 8 cm/min, 6cm/min, respectively) and SPECT of the abdomen (180° orbitfor each head, step and shoot mode, 64 images, at 30 s perview, 128×128matrix). The data acquired were reconstructedusing iterative reconstruction OSEM Flash 3D with 8 subsetsand 10 iterations. Volumetric analysis was performed forassessing the tumor to nontumor (T/nT) ratio.

The CT examinations were performed in the I-st CT Unitof the Radiology Department in the University Hospital inCracow using a spiral multirow CT scanner (SiemensSomatom Sensation 16) and standard protocol for abdomenand pelvis (detector configuration 16×0.75 mm, slice

he head of the pancreas without liver metastases. The results of CT, SRS/CTr (B1, B2, B3) the therapy with PRRT are presented.

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thickness and reconstruction increment 2 mm, reconstructionkernel B31f, before and multiphase after intravenousnonionic contrast media administration in dose of 1 ml/kg,flow 2.5 ml/s, delay of arterial phase 30 s and venous phase60 s after the start of contrast administration). Linearmeasurements of focal lesions were performed on a SiemensWizard workstation using the tools of CT images browser.For volume measurements, we used the Siemens Wizardworkstation with the dedicated Volume application. Theborders of every lesion were manually marked on consec-utive slices of the CT examination. In order to eliminate theinfluence of fatty tissue and calcifications on the attenuation,the measurement included pixels with CT attenuation valuesfrom −30 to 200 HU. Based on the obtained results, theprogram automatically calculated the volume and meanattenuation of the lesion [12].

3. Results

According to the RECIST criteria, stable disease (SD)was reported in the all four patients.

In patient number 1 (Table 1), the longest tumor diameterincreased after PRRT from 6.5 to 6.8 cm (5% difference),corresponding to SD. Similar change was seen in the volumemeasurements (5% difference from 84.0 to 87.8 cm3).However, greater changes were observed in the attenuationvalues (30% increase from 60 to 78 HU) as a result of tumortissue proliferation. An analogous trend was observed forT/nT ratio (71% difference from 4.0 to 6.8). This patientshould therefore be considered as having progressive disease(PD) and not SD as reported. The patient was qualified forrepeated PRRT cycles.

In patient number 2 (Table 1), five lesions were taken intoconsideration as target lesions. A reduction of the SLD oflesions on axial CT slices after PRRT from 22.1 to 17.7 cmwas calculated (−20% difference), corresponding to SD.However, the sum of the lesions' volumes declinedsignificantly (−39% difference from 203.2 to 124.2 cm3),similarly to the mean T/nT ratio (−72% difference from 58.5to 16.5). The mean attenuation values decreased insignifi-cantly from 36 to 35 HU (−4% difference). And so, in this

Table 1The quantitative evaluation of tumor before and 6 months after PRRT in CT and

Patient Dbas.(cm)

Vbas.(cm3)

Abas.(HU)

T/nTbas.

Dcon.(cm)

Vcon.(cm3)

Acon.(HU)

T/co

1 6.5 84.0 60 4.0 6.8 87.8 78 62 22.1 203.2 36 58.5 17.7 124.2 35 163 9.6 301.5 71 15.5 9.5 336.2 53 74 7.2 208.3 45 26.4 5.7 82.4 41 16

D bas., D con., D change: the longest tumor diameter at baseline and at 6-monthV bas., V con., V change: the tumor volume at baseline and at 6-month control tiA bas., A con., A change: the tumor CT attenuation at baseline and at 6-month coT/nT bas., T/nT con., T/nT change: the tumor to nontumor ratio in SRS at baselin

case, the patient should properly be reported as having PRand not SD.

In patient number 3 (Table 1), the longest tumor diameterdecreased after PRRT from 9.6 to 9.5 cm (−1% difference).The lesion volume increased from 301.5 to 336.2 cm3 (12%difference). However, the attenuation values declinedsignificantly from 71 to 53 HU (−25% difference) as aresult of tumor tissue necrosis. Similar change was observedin the T/nT ratio (−50% difference from 15.5 to 7.7). Inconsequence, this patient, too, should be considered ashaving PR rather than the SD reported.

In patient number 4 (Table 1), the longest tumor diameterdecreased after PRRT from 7.2 to 5.7 cm (−21% difference).The lesion volume declined very significantly from 208.3 to82.4 cm3 (−60% difference), with the same trend observedfor T/nT ratio (−39% difference from 26.4 to 16.1). Theattenuation values decreased slightly from 45 to 41 HU(−10% difference). And so, this patient, too, should beconsidered as having PR and not SD.

4. Discussion

Proper assessment of the antitumoral effect of therapyapplied is the most important factor determining furtherdecisions on the current treatment continuation/discontinua-tion. Correct identification of the disease recurrence orprogression enables earlier commencement of the appropriatetherapy. Inappropriate evaluation of the response to the therapymay lead to delayed commencement of proper treatment,whichmay result in further progression of the disease and evenpatient death. Therefore, precise response criteria are crucialfor choosing further suitable therapeutic steps.

NETs are usually slow-growing lesions, and therefore,even if we observe progression in the disease, there are stillboth opportunity and time to choose the proper therapy—thekey is adequate evaluation of the disease's advancement[1,2]. NETs are usually well-vascularized tumors, and in thecourse of treatment, different changes might be observed inthe whole mass of the tumor, not limited to tumor size butalso including its morphology, resulting in significant CTattenuation differences [13]. In all our patients, after the

SRS

nTn.

Dchange(%)

Vchange(%)

Achange(%)

T/nTchange(%)

Therapyresponseacc. toRECIST

Therapyresponserevised

.8 5% 5% 30% 71% SD PD

.5 −20% −39% −4% −72% SD PR

.7 −1% 12% −25% −50% SD PR

.1 −21% −60% −10% −39% SD PR

control time point, and the percentage change.me point, and the percentage change.ntrol time point, and the percentage change.e and at 6-month control time point, and the percentage change.

363A. Sowa-Staszczak et al. / Clinical Imaging 36 (2012) 360–364

radioisotope therapy, the changes in the sum of the longestdiameters of tumors were between 5 to −21%, resulting inSD reported according to strict RECIST criteria. But themeasurements of tumor volume and attenuation in CT andthe T/nT ratio in SRS resulted in quite different therapyresponse assessments.

Patient number 3, with insignificant (1%) change in thetumor diameter, had substantial CT attenuation decrease(−25%) and T/nT ratio decrease (−50%) which might resultfrom tumor decay after therapy. In patient number 4, thetumor size decrease was −21%, corresponding to RECISTSD, but the tumor volume decrease was −60% and T/nT ratiodecrease was −39%. In patient number 2, with livermetastases, SLD decreased after PRRT (−20%) as inRECIST SD. However, the sum of tumor volumes decreasedby −39% and T/nT ratio substantially decreased by −72%.

Taking these additional parameters into consideration ledto a change in the assessment of the response to therapy andconsiderations on how to proceed with the patients.

In patient number 1, we observed a slight increase in thetumor size (5%), which also corresponds to RECIST SD, butthere was an important increase in tumor attenuation (30%)and a high increase in T/nT ratio (70%), which might resultfrom tumor proliferation. The patient was therefore assessedas having disease progression and was qualified for repeatedPRRT cycles.

In the other three cases assessed, disease regressioncorresponded with the clinical status of the patients.

As mentioned above, in order to assess lesions according toRECIST [7,8,12], the measurement of the longest diameter ofevery measurable lesion on axial CT slices and calculation ofthe sum of the longest diameters (SLD) for all selected targetlesions were performed. A decrease of at least 30% in the SLDof target lesions is required to define Partial Response (PR),where the reference should be the baseline SLD. Importantly,it should be taken into consideration that the volume changesproportionally to the cube of the linear measurement.Therefore, the sole assessment of the linear diameter changemay be insufficient to estimate the volume difference duringthe duration of the treatment. Additionally, a single linearmeasurement may not properly reflect volume changes in athree-dimensional structure—an example is an oval tumorexpanding only along the short axis, with a stable long axis,resulting in false RECIST SD. The same problem exists inmeasurements of irregular tumors or conglomerates of lesions.

Another inconvenience of the RECIST standard is that itonly takes into consideration the size of lesions, with noassessment of morphology in the course of treatment,manifesting in CT as changes of X-ray attenuation values(reduction of attenuation and weaker contrast enhancementas the effect of neoplastic tissue necrosis or attenuationincrease and better contrast enhancement in neoplastic tissueproliferation) [12].

Even the new version 1.1 of RECIST [8] does not takeinto consideration attenuation measurements, limiting its usein many types of tumors.

For CT reporting of well vascularized neoplasms, moreand more commonly modified standards of therapy responseare applied taking into consideration attenuation changes forexample, the Choi criteria for Gastrointestinal stromal tumor[13] or modified Response Evaluation Criteria in SolidTumors for hepatocellular carcinoma [14]. Because NETlesions are mostly well-vascularized neoplasms, a rationalsolution would be to draw up CT assessment criteria for suchlesions, taking into consideration attenuation and contrastenhancement changes in the course of treatment [12].

Also, the SRS T/nT ratio changes observed suggest thecreation of combined CT/SRS assessment criteria.

As presented above, in three cases (the two patients forwhom PRRT was used as neoadjuvant therapy and the onecase with liver metastases) with stabilization of the diseaseaccording to RECIST, the addition of attenuation andvolume changes to our considerations modified ourassessment of the therapy response to PR instead of SD.

The opposite example is the patient with stabilization ofthe disease according to RECIST, but significantlyincreased CT attenuation and increased SRS T/nT ratio asthe result of tumor tissue proliferation. Additional positronemission tomography (PET)–CT revealed two more livermetastases, not visible in CT and SRS. So, careful analysisof CT, SRS, and PET–CT images led to the conclusion thatthe patient should be reported as having PD and not SDaccording to RECIST.

As presented above, only combined analysis of volumeand attenuation changes in CT and T/nT ratio changes inSRS enables proper evaluation of the therapy response anddecision-making on further therapeutic steps.

Moreover, in the assessment of the clinical response to thetherapy, improvement in the patient's clinical condition andtreatment of NET symptoms should be also taken intoconsideration. At present, we are planning further observa-tion of these parameters in other patients after PRRT.

5. Conclusions

1. The RECIST standard may be not sufficient toproperly assess the therapy response in NET patients.

2. The evaluation of the therapy response in this tumorshould take into consideration additional parameters,such as tumor volume and attenuation changes in CTand T/nT ratio changes in SRS.

3. Dedicated NET therapy response criteria should bedefined based on study of large groups of patients.

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