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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