colon and rectal cancer - bast · heald rj, husband em, ryall rdh. the mesorectum in rectal cancer...
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Colon and Rectal Cancer
Wim Ceelen, MD, PhD,FACS GI Surgery, UZ Gent
www.heelkunde.gent
Molecular Pathways • Chromosomal instability (CIN)
– 85% – Leads to mutations in APC, KRAS, PIK3CA, SMAD4, and TP53
• Microsatellite instability (MSI) – 15% – Based on deficient DNA mismatch repair (MMR) genes (MLH1, MSH2,
PMS2, MSH6) – Germ line mutation (Lynch) or sporadic
• CpG island methylator phenotype (CIMP) – Methylation and inactivation of promotor regions of TS genes – Typical profile: older age, proximal location, poor differentiation, wild type
P53, MSI, and B-type Raf (BRAF) mutations – Believed to arise via the serrated pathway
Lynch Syndrome (HNPCC) • 3%; AD germline mutation in MMR genes • Clinical features
– Mean 45yrs, right sided, high risk of metachronous CRC – Accelerated AC progression; often mucinous/signet ring cell
differentiation – Better outcome per stage; resistant to fluoropyrimidines – Risk of extracolonic cancers
• Endometrium (40-60% lifetime risk); ovary (15% • Other: stomach, SB, TCC ureter/renal pelvis, brain (Turcot syndrome) • Sebaceous adenomas, sebaceous carcinomas, and multiple
keratoacanthomas in Muir-Torre’s syndrome • Diagnosis: IHC, MS status (PCR), mutation analysis
FAP • 0,5%; germ-line mutation APC gene (5q21) • 100% lifetime risk (median age 36) • associated with:
– Upper GI polyps and carcinomas – hypertrophy of the retinal pigment epithelium – Desmoid tumours – Thyroid cancer and hepatoblastomas – Gardner syndrome (desmoids, osteomas, epidermal cysts, and
supernumerary teeth) • Attenuated FAP
– < 100 adenomas, right-sided predominance, flat morphology – later onset – lifetime risk 70%
MAP- MUTYH associated polyposis • Component of a base excision repair system by excising
adenine incorporated opposite 8-oxo-G • Germline mutation leads to mutation of APC and/or KRAS • Clinical features
– 10-100 polyps – Early onset CRC – AR inheritance – Better prognosis – Rislk reducing total colectomy recommended
Yamaguchi Surg Today 2014
Molecular Pathology • KRAS
– Kirsten rat sarcoma viral oncogene homolog – Activating mutations in approx 36% of mCRCs – Little prognostic consequences – Negative predictive marker for anti-EGFR
therapy (cetuximab, panitumumab)
Stintzing Hematology/Oncology Clinics of North America 2015
Molecular pathology • BRAF
– member of the RAF (RAS-associated factor) gene family
– Activating BRAF mutations (exon 15, V600E) in 10%-15% of mCRC (mutually exclusive with KRAS mutation)
– Associated with poor prognosis – Good response to FOLFOXIRI+bev
Molecular pathology • PIK3CA
– Phosphatidylinositol kinase catalytic subunit A – Mutated in 10%-30% of mCRC – Predictive and prognostic value uncertain
Phipps Gastroenterology 2015
TNM 7
Colon cancer: staging • Total colonoscopy + biopsies • Obstructing tumor: total colonoscopy
postop • CEA • CT scan chest and abdomen • PET-CT: no role in staging
Surgery for Colon Cancer • Bowel prep • Anatomy • High tie versus low tie • Lymph nodes • Laparoscopic surgery
Cao Int J Colorect Dis 2012
High tie Low tie
Cirocchi Surg Oncol 2012
High tie versus Low tie: 5 year overall survival
Anastomotic leak
Lymphadenectomy and CRC
• Guideline: 12 nodes should be examined • Consistent relation between LN count and
survival • LN count mainly determined by non surgical
factors • In stage III patients, the LNR is important
Cancer metastasis models
HELLMAN model
HALSTED model
FISHER model
Cancer starts as a locoregional disease
Cancer is a systemic disease from the onset
Head and neck SCC
Breast Cancer Pancreatic cancer
Colorectal
Therapeutic effect of lymphadenectomy
Greenstein et al. Cancer 2008
SEER database; no neoadjuvant therapy
LeVoyer J Clin Oncol 2003
LN count and survival in node pos CRC – INT0089 trial
Govindarajan J Clin Oncol 2011
LN counts and survival after CRT in rectal cancer
LN count and improved survival • Therapeutic effect? • Stage migration • Study Bias • Patient related factors
– Age – Ethnicity – BMI – Immune response
• Tumor related factors – Tumor size, LN size, MSI status, lymphocyte infiltration, location (right > left)
• Treatment related factors – Specialized surgeons – Specialized pathologists – Referral or high volume centers
The Lymph Node Ratio in Stage III CRC
LNR = # Positive Nodes / # Total Nodes Examined
Hohenberger Colorectal Dis 2008
Total mesocolic excision
Total Mesocolic Excision
West J Clin Oncol 2009
Laparoscopic resection for Colon Cancer
• Quicker recovery; shorter LOS • No difference in incisional hernia or
reoperation for adhesions • Equivalent cancer outcome • Cost-effectiveness not clear
COLOR trial, DFS @ 3 years (Lancet Oncol 2009)
COST trial: long term DFS
CLASICC trial: late results (BJS 2012)
Kuhry Cancer Treat Rev 2008
Laparoscopic surgery for CRC: meta-analysis
Ann Surg 2011
Adjuvant chemotherapy
• Stage III – 15-20% absolute decrease in risk of death – Standard: FP with oxaliplatin – Addition of bevacizumab without added value
• Stage II – 5% absolute decrease – Tailored approach: high risk patients
Rectal Cancer
Overview • Anatomy and Local Staging • Surgery • Neoadjuvant therapy selection • Adjuvant therapy selection • Organ preservation
Carl Toldt (1840-1920)
Levator Ani Nerve Wallner J Clin Oncol 2008
PS: Emptying
S: closure of IUS
Why stage?
Define pertinent anatomy
• Prognostic stage grouping • Identification of High Risk patients • Evaluate response to neoadj Tx
Tailored approach
DRE: what to look for • EAS invaded? If free restorative surgery possible • Fixed/tethered? • Distance from anal verge • Circumference
EUS
• Advantages – Available, inexpensive – Accurate staging of early tumours
• T1/T2: SE >90%, SP >85% • Nodal status: Acc* 70-80%
• Disadvantages – Invasive – CRM assessment not possible – Cannot be used in stenosing tumours
* Accuracy = TP+TN/TP+FP+TN+FN
Difference between MRI versus pathology measured extramural tumor depth: 0.046mm (Radiology 2007)
MRI is the standard of care
PET-CT
• At present, no role in initial staging – Poor spatial resolution – Low SE for nodal involvement (29%)
• Indicated in: – Staging for recurrence and/or distant metastasis – Location of recurrence in patients with
unexplained CEA raise • PET-MR may redefine indications
Total Mesorectal Excision
• Based on: – pathological-clinical studies from the 1980s (Heald and
Quirke) showing distal spread in the mesorectum AND a significant relation between CRM involvement and local recurrence
• Encompasses: – Excision of (nearly) complete mesorectum in mid and
lower third cancers – down to the pelvic floor – Preservation of CRM by sharp dissection
Heald RJ, Husband EM, Ryall RDH. The mesorectum in rectal cancer surgery: the clue to pelvic recurrence? Br J Surg. 1982;69:613-616.
Miles E. A method of performing abdominoperineal excision for carcinoma of the rectum and of the terminal portion of the pelvic colon. Lancet, 1908
A distal margin of < 10 mm is safe
ProCare
Effect of a surgical training programme on outcome of rectal cancer in the County of Stockholm. Martling et al. Lancet 2000
Br J Surg 2002
16%
9%
The problem with APR
Nagtegaal JCO 2005
Evidence of the Oncologic Superiority of Cylindrical Abdominoperineal Excision for Low Rectal Cancer. West et al. J Clin Oncol 2008
‘Cylindrical or extralevator resection’ In APR
Laparoscopic RC Resection
• Assumed benefits – Recovery, function, LOS – Magnified view improved nerve preservation – Less tissue trauma less systemic recurrence?
• Drawbacks – Learning curve – Confined space – Low stapling, lack of tactile feedback
- Conversion rate for rectal cancer: 34% - CRM positivity: 12% vs 6% (p=0·19). - Conclusion: ‘impaired short-term outcomes after laparoscopic assisted anterior resection for cancer of the rectum do not yet justify its routine use’
CLASICC trial: rectal cancer patients
Arezzo Surg Endosc 2012
Lap versus open RC surgery: ongoing trials
• COREAN • COLOR II • Japanese JCOG 0404 • ACOSOG Z6051
COREAN trial
• Primary endpoint: DFS @ 3 years • 340 patients randomized 1:1 • All patients underwent neoadjuvant CRT • Only high volume centers • Conversion rate: 1.2%; anastomotic leak
rate 0%
Jeong Lancet Oncol 2014
COREAN trial (Lancet Oncol 2010)
COLOR II trial
• Non inferiority trial • Randomization ratio of 2:1 • Primary endpoint: local recurrence rate; hypothesis: LRR
10% in open surgery • Noninferiority when 95% CI in 3-yrs loco-regional
recurrence excludes a difference greater than 5% • 850 laparoscopic and 425 open patients power of 80% • Inclusion expected to be complete: end of 2009 • Conversion rate: 17%
COLOR II: prelim results
• No differences CRM or distal margin, anastomotic leakage rate, or nodal count
• Lap approach less blood loss, less analgesic use, quicker return of GI function, and shorter hospital stay
• Conversion rate 16%
Other ongoing trials
• JCOG 0404 (Japan) – Planned sample size 818 – Primary endpoint: OS
• ACOSOG Z6051 – Noninferiority design – Primary endpoint: completeness/quality of
resection
Conclusions: laparoscopy for rectal cancer
• Shortens hospital stay (2 days on average) and reduces analgesic consumption
• Allows equivalent ‘surgical’ quality in selected patients
• Does not alter LR, DFS or OS – But may adversely affect outcome in converted
cases
Neoadjuvant therapy: for whom?
• All locally advanced rectal cancers (T3,T4) • All node positive cancers • Cancers close to the anal verge, when
aiming at SSS • Cancers with a CRM margin < 5 mm
Preoperative CRT is superior to postoperative CRT: German rectal cancer trial (NEJM 2004)
-Overall survival not different -Lower treatment related toxicity in preop arm
Preoperative RT lowers local recurrence rate and improves survival
The efficacy of preop RT is influenced by the biologically equivalent dose (BED) and therapy duration
IJROBP 42, No. 5, pp. 943–951, 1998
Preop RT: how?
Short course (5x5 Gy)
Long term CRT (25 fractions)
Interval with surgery 3-5 days At least 6 weeks Allows downsizing no yes Enhances pathol response no yes May be combined with chemotherapy/biologicals
no yes
Preop short term RT and % incontinence
Preop RT Surgery
SRCT 14% Solid 3% Solid
Stockholm I and II 57% 26%
Dutch TME 62% 38%
Preop RT Preop CRT
Polish trial 42% 50%
Late toxicity from 5x5 Gy: SRCT
• increased risk of admissions < 6 months (RR 1.64; 95% CI, 1.21 to 2.22)
• Main symptoms: bowel obstruction, abdominal pain, nausea
Birgisson JCO 2005
Short term RT versus long course CRT
• Completed trials – Polish trial – Trans-Tasman Radiation Oncology Group Trial 01.04
• Ongoing trials – Karolinska: 5x5 (immediate surgery), 5x5 (delayed
surgery), and versus 25x2 Gy (delayed surgery) – Lithuanian: SCRT versus CRT
P=0.21
Bujko BJS 2006
• pCR: 0,7% versus 15% • LR 9% versus 14,2% (CRT) • No differences in late toxicity
Polish study
Ngan JCO 2012
• pCR: 15% versus 1% • in subgroup of distal cancers: LR 12,5% versus 3% • No differences in late toxicity
TROG 0104
Latkauskas Colorectal Dis 2012
Preoperative chemoradiation
• Sound rationale (radiosensitization; systemic effect)
• Promising results in irresectable disease (downstaging; enhance resectability)
• Resectable disease: numerous phase II trials – pCR rate:18.5% (95% CI:15.6–21.4) – sphincter preservation rate: 58.7% (95% CI: 51.7–65.7) – Acceptable treatment related toxicity (grade 3 or 4 toxicity: 2.8–
28%) – post-operative morbidity (including anastomotic leaks) not
different from surgery alone series
Preop CRT versus RT alone: conclusions
Ongoing trials
• Observation: none of the trials comparing neoadjuvant RT with surgery alone or with CRT impact on survival
• CRT with more active chemo/biol Tx: oxaliplatin, EGFR inhibitors, angiogenesis inhibitors
• NACT followed by CRT • Chemotherapy during the waiting period
Ceelen WP. Progress in rectal cancer treatment. ISRN Gastroenterol. 2012;2012:648183
Condiderations for adjuvant therapy • Stage III
– No trial data in rectal cancer only – Reasonable to treat as stage III colon cancer
• Stage II or less – EORTC 22921 showed benefit of adj 5FU in ypT1-2, but not in yp T3-4
• Not shown in other trials • Methodological flaws
– ypCR: significantly better survival (pooled analysis: HR 0.44, 95%CI 0.34-0.57; p<0.0001)
– Confounding yp stage versus c stage – Reasonable to omit adj therapy in ypCR, and treat according to
pretherapy N stage
Considerations for organ preservation
• Current CRT regimens: ypCR 15-20% max • Smaller tumours higher response rate • cCR difficult to ascertain • Risk of LR prohibitive after local excision,
unless neoadjuvant CRT
LR
Kidane DCR 2014 (T1N0M0 rectal cancer)
DSS
T2 or small T3 Node negative CRT Restaging
cCR
cPR
TME LE/TEM
R
Ongoing prospective trials
Study Location Interventions GRECCAR2 France
Belgium CRT+Local excision
CRT+TME
NCT00738790 Poland (Bujko) 29 Gy + LE CRT+LE
CARTS NL CRT+LE in responders
NCT01308190 Barcelona CRT+LE TME
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