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Colon and Rectal Cancer
Wim Ceelen, MD, PhD,FACS GI Surgery, UZ Gent
www.heelkunde.gent
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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
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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
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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%
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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
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Yamaguchi Surg Today 2014
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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)
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Stintzing Hematology/Oncology Clinics of North America 2015
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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
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Molecular pathology • PIK3CA
– Phosphatidylinositol kinase catalytic subunit A – Mutated in 10%-30% of mCRC – Predictive and prognostic value uncertain
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Phipps Gastroenterology 2015
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TNM 7
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Colon cancer: staging • Total colonoscopy + biopsies • Obstructing tumor: total colonoscopy
postop • CEA • CT scan chest and abdomen • PET-CT: no role in staging
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Surgery for Colon Cancer • Bowel prep • Anatomy • High tie versus low tie • Lymph nodes • Laparoscopic surgery
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Cao Int J Colorect Dis 2012
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High tie Low tie
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Cirocchi Surg Oncol 2012
High tie versus Low tie: 5 year overall survival
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Anastomotic leak
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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
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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
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Greenstein et al. Cancer 2008
SEER database; no neoadjuvant therapy
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LeVoyer J Clin Oncol 2003
LN count and survival in node pos CRC – INT0089 trial
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Govindarajan J Clin Oncol 2011
LN counts and survival after CRT in rectal cancer
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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
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The Lymph Node Ratio in Stage III CRC
LNR = # Positive Nodes / # Total Nodes Examined
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Hohenberger Colorectal Dis 2008
Total mesocolic excision
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Total Mesocolic Excision
West J Clin Oncol 2009
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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
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COLOR trial, DFS @ 3 years (Lancet Oncol 2009)
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COST trial: long term DFS
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CLASICC trial: late results (BJS 2012)
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Kuhry Cancer Treat Rev 2008
Laparoscopic surgery for CRC: meta-analysis
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Ann Surg 2011
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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
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Rectal Cancer
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Overview • Anatomy and Local Staging • Surgery • Neoadjuvant therapy selection • Adjuvant therapy selection • Organ preservation
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Carl Toldt (1840-1920)
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Levator Ani Nerve Wallner J Clin Oncol 2008
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PS: Emptying
S: closure of IUS
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Why stage?
Define pertinent anatomy
• Prognostic stage grouping • Identification of High Risk patients • Evaluate response to neoadj Tx
Tailored approach
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DRE: what to look for • EAS invaded? If free restorative surgery possible • Fixed/tethered? • Distance from anal verge • Circumference
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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
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Difference between MRI versus pathology measured extramural tumor depth: 0.046mm (Radiology 2007)
MRI is the standard of care
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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
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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
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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
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ProCare
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Effect of a surgical training programme on outcome of rectal cancer in the County of Stockholm. Martling et al. Lancet 2000
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Br J Surg 2002
16%
9%
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The problem with APR
Nagtegaal JCO 2005
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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
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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
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- 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
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Arezzo Surg Endosc 2012
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Lap versus open RC surgery: ongoing trials
• COREAN • COLOR II • Japanese JCOG 0404 • ACOSOG Z6051
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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%
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Jeong Lancet Oncol 2014
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COREAN trial (Lancet Oncol 2010)
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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%
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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%
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Other ongoing trials
• JCOG 0404 (Japan) – Planned sample size 818 – Primary endpoint: OS
• ACOSOG Z6051 – Noninferiority design – Primary endpoint: completeness/quality of
resection
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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
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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
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Preoperative CRT is superior to postoperative CRT: German rectal cancer trial (NEJM 2004)
-Overall survival not different -Lower treatment related toxicity in preop arm
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Preoperative RT lowers local recurrence rate and improves survival
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The efficacy of preop RT is influenced by the biologically equivalent dose (BED) and therapy duration
IJROBP 42, No. 5, pp. 943–951, 1998
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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
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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%
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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
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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
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P=0.21
Bujko BJS 2006
• pCR: 0,7% versus 15% • LR 9% versus 14,2% (CRT) • No differences in late toxicity
Polish study
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Ngan JCO 2012
• pCR: 15% versus 1% • in subgroup of distal cancers: LR 12,5% versus 3% • No differences in late toxicity
TROG 0104
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Latkauskas Colorectal Dis 2012
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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
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Preop CRT versus RT alone: conclusions
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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
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Ceelen WP. Progress in rectal cancer treatment. ISRN Gastroenterol. 2012;2012:648183
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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
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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
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LR
Kidane DCR 2014 (T1N0M0 rectal cancer)
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DSS
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T2 or small T3 Node negative CRT Restaging
cCR
cPR
TME LE/TEM
R
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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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