COLORECTAL CANCER: PART I
Educational Objectives
| The goal of this program is to improve the management of colorectal cancer. After hearing and assimilating this program,
the clinician will be better able to:
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 | 1. Discuss the advantages and disadvantages of resection of the primary colon tumor in patients with unresectable stage
IV colon cancer.
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| 2. Discuss the results of studies that looked at whether a subgroup of patients with unresectable hepatic metastases
from colorectal cancer could become resectable with newer chemotherapeutic agents.
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| 3. Utilize the current surveillance recommendations for patients with hereditary nonpolyposis colon cancer (HNPCC).
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| 4. Determine when prophylactic surgery is indicated for HNPCC.
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| 5. Recognize the characteristics of a malignant polyp that require further resection.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest.
Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a
proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose.
Acknowledgments
Dr. Petrelli was recorded at the 3rd Annual Surgical Symposium, held July 11-14, 2007, in Napa, CA, and sponsored by
Kaiser Permanente. Drs. Mahmoud and Gemlo were recorded at the 70th Annual Colon and Rectal Surgery Conference,
held October 24-27, 2007, in Minneapolis, MN, and sponsored by the Division of Colon and Rectal Surgery at the
University of Minnesota Medical School, Colon and Rectal Surgery Associates, Ltd, and the Minnesota Colon and
Rectal Foundation. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the
production of this program.
| CLINICAL TRIAL QUESTIONS IN COLORECTAL CANCER SURGERY: PRESENT STATUS —Nicholas J. Petrelli,
MD, Medical Director, Helen F. Graham Cancer Center, Newark, DE
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| Necessary to remove primary colon cancer in patient with distant unresectable metastasis? phase 2
trial by National Surgical Adjuvant Breast and Bowel Project (NSABP) looking at chemotherapy alone in patients with
stage IV unresectable disease with asymptomatic primary colon cancer; speaker against resection of primary colon cancer;
arguments for resection—patient more fit for resection when asymptomatic; present chemotherapeutic agents more
effective for microscopic disease and may cause bleeding and perforation of primary tumor; greater risk associated with
emergency surgery (20% operative mortality and higher rate for permanent colostomy); arguments against resection—
initiation of chemotherapy delayed by surgery recovery time and chemotherapy; primary tumor may never become
symptomatic; subsequent obstruction possibly managed with stent placement
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| Hepatic resection in presence of extrahepatic disease: resection of extrahepatic disease in presence of simultaneous
hepatic metastasis from colorectal cancer (CRC) based on manuscript by Elias et al; 75 patients underwent negative-margin
hepatic resection simultaneously with extrahepatic disease resection; 294 patients underwent R0 negative-
margin resection, of whom 25% had hepatic disease resected also; those individuals with single sites of extrahepatic disease
resected did better than those with multiple extrahepatic sites resected, along with hepatic resection; number of patients
between multiple and single sites very small; results not reproduced; conclusions—in CRC patients, extrahepatic
disease no longer contraindication to hepatic resection (speaker disagrees); necessary that resections be R0 (negative
margin), of single extrahepatic site, and have <4 metastases (speaker agrees, but only in clinical trial scenario); results
need to be reproduced in multicenter randomized prospective trial; agreed that hepatic resection only potentially curative
modality in patients with metastasis to liver from CRC; radiofrequency ablation (RFA)—study of 418 consecutive patients
who underwent hepatic resection or RFA; patients not randomized (physician bias and selection bias present); patients
who underwent hepatic resection did better than those who underwent RFA alone or combination; gold standard
still hepatic resection; RFA not replacement for hepatic resection
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| Possible for subgroup of patients with unresectable hepatic metastasis from CRC to be resectable
with newer agents? majority of patients referred for hepatic metastasis unresectable; 10% to 20% of patients resectable;
overall survival benefit, 30% to 50% at 5 yr (due to patient selection); series—looked at cause of initial nonresectability
in patients who presented with unresectable hepatic metastasis but became resectable after chemotherapy; number
one reason multiple lesions; second reason, 22% of patients had extrahepatic disease; concluded that current chemotherapy
allows conversion of ≈15% of patients to resectable disease
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| Effect of intra-arterial chemotherapy after resection and/or ablation of hepatic metastasis on cure
rates when added to modern chemotherapy: NSABP-CO9 trial; found statistically significant advantage in patients
who received combination of systemic chemotherapy with intra-arterial fluorodeoxyuridine (FUDR); included patients
with 6 metastases to liver from CRC, and no extrahepatic disease; before surgery, patients randomized to either
systemic chemotherapy with capecitabine or oxaliplatin postoperatively or to same systemic chemotherapy with intra-arterial
FUDR; study—trial by European Organization for Research and Treatment of Cancer (EORTC); 364 participants
with 1 to 4 liver metastases (patients presented with resectable disease); patients randomized to surgery alone or to 2 cycles
of folinic acid/fluorouracil (5-FU)/oxaliplatin (FOLFOX) before hepatic resection, then resected, and given 2 cycles
of FOLFOX after resection; 9% survival advantage seen in participants who received chemotherapy, compared to those
who had surgery alone; however, difference between giving and not giving chemotherapy not significant in survival;
when all patients taken together, no difference in disease-free survival; difference in 3-yr disease-free survival found only
on subset analysis
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| Chemotherapeutic agents: issues include specific chemotherapy-associated hepatic toxicity; irinotecan causes steatohepatitis;
oxaliplatin causes sinusoidal and vascular injury; affect normal parenchyma of liver; if patient on bevacizumab
before hepatic resection, must wait 6 to 8 wk before performing resection because of effect on liver regeneration and
hemorrhage; hepatic morbidity increased with prolonged course of chemotherapy with these agents; postoperative complications
in EORTC trial—statistically significant number of complications in those who received preoperative chemotherapy,
compared to those who had surgery alone; complications serious and include biliary fistula, hepatic failure,
intra-abdominal infections, and need for reoperation; conclusions—performing hepatic resection first, still good option
for resectable disease (afterwards, can decide whether patient needs adjuvant therapy); consider patient selection, drug
type, and duration of chemotherapy; treatment of liver metastasis requires multidisciplinary approach; however, as soon
as patient resectable, surgery should be performed; constant communication between surgeon and oncologist necessary
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| SURGERY IN FAMILIAL NONPOLYPOSIS COLON CANCER —Najjia Mahmoud, MD, Assistant Professor of Surgery,
Division of Colon and Rectal Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA
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| Hereditary nonpolyposis colon cancer (HNPCC): most common hereditary colon cancer syndrome; controversy
about nature of surgery and operation; Lynch I and Lynch II syndromes; autosomal dominant disorder caused by germline
mutations in DNA mismatch repair (MMR) genes; ≈70% of patients have MMR gene defect in MLH1 or MSH2; responsible
for 2% to 4% of colon cancer cases; occurs in 1 to 2 in 1000 people; substantially increases progression of adenoma-carcinoma
sequence; presents at slightly later age than familial adenomatous polyposis (FAP), but progression of disease occurs
within 1 to 2 yr (compared to adenomatous polyposis coli [Apc]-initiated FAP syndrome or sporadic cancer in which initiation
increased and patients present at younger age); difficult to diagnose due to many phenotypes; has unique phenotypic
identifier (microsatellite instability [MSI]); lifetime risk for neoplasia—80% for CRC (mean age 46 yr); endometrial, gastric,
upper urinary tract, renal pelvis and ureters, and ovarian cancer (10%-12%); Amsterdam criteria—3 first-degree relatives;
2 generations; 1 case <50 yr of age; 0 cases of FAP; revised Bethesda guidelines more inclusive and used by most
clinicians; common tumors include colon, endometrium, ovary, and stomach; rare tumors include small intestine, upper urinary
tract, skin, brain, and biliary tract
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| Surveillance: current recommendations—due to rapid progression of cancers, colonoscopy should be performed every 1
to 2 yr, beginning at 20 to 25 yr of age, then annually after 40 yr of age; esophagogastroduodenoscopy (EGD) annually
for kindred with gastric cancer; however, difficult to determine, so most recommend performing EGD at time of screening
colonoscopy; in women, endometrial aspiration and ultrasonography (US) annually beginning at age 30 to 35 yr;
urine cytology and US of renal pelvis every 1 to 2 yr in kindred with genitourinary tract tumors; only colon and rectal surveillance
colonoscopy proven effective in reducing HBPCC-related cancer; surveillance at 3-yr intervals leads to detection
of premalignant lesions and early cancers in asymptomatic family members; surveillance at 1- to 2-yr intervals leads
to detection of cancers at earlier stages than 3-yr intervals; can detect adenomas in HNPCC that can be endoscopically resected
when 1- to 2-yr intervals maintained; reduces cancer incidence from 16% to 6%, and reduces mortality by 65%
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| Surgical decision-making in HNPCC: is segmental colectomy acceptable in surgery for colon cancer?—overall life
expectancy gain from subtotal vs segmental colectomy for all stages of cancer only 2.3 yr for individual 27 yr of age (gain
even less at age 47 yr); quality of life (QOL) significantly improved in sporadic cancers with segmental resections, compared
to subtotal colectomy; French ad hoc committee cites insufficient evidence for routine subtotal colectomy for
HNPCC-associated CRC, and considers frequent colonoscopic surveillance mandatory and efficacious; patient must be
compliant; annual postoperative colonoscopic screening mandatory; lifetime risk for metachronous lesions, 45% to 54%;
segmental colectomy—better option in older patients (incremental risk higher for subtotal colectomy; risk for poor follow-up
and metachronous lesions reduced); better option in compliant patients with poor preoperative sphincter function;
subtotal colectomy better option for younger compliant patient
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| Prophylactic surgery: pros—80% risk for colon cancer in patients with HNPCC; no need for colon surveillance; results
in increased life expectancy; cons—20% undergo unnecessary operation; functional issues severe and limiting, especially
in patients with poor sphincter function; serious-complication rates associated with surgery; does not reduce or change need
for extracolonic surveillance; associated with decreased QOL; study—much greater incremental benefits gained from performing
subtotal colectomy vs proctocolectomy; in patient 25 yr of age, 2.1-yr increase in life expectancy when proctocolectomy
compared to surveillance alone and to no intervention; benefits of proctocolectomy vs surveillance alone
decrease with increasing age; benefits of proctocolectomy minimal if performed at time of diagnosis; in all patients undergoing
prophylactic surgery (vs proctolectomy), ileorectal anastomosis led to substantial increases in QOL; prophylactic surgery
clearly indicated only in those patients for whom colonoscopic surveillance not technically possible or for those who
refuse to undergo regular surveillance; decision for surgery among known gene carriers based on disease penetration in
family, age at onset among family members, specific mutation, functional QOL, personal preference or anxiety over diagnosis,
and ability to comply with surveillance; recommended that gene carriers have ongoing surveillance; those anxious
over diagnosis, who have endometrial cancer, or having surgery for another reason should be offered subtotal colectomy
only if known gene carriers
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| Rectal cancer and risk in HNPCC: risk for rectal cancer 12% at 10 to 12 yr; annual surveillance (proctoscopy or
flexible sigmoidoscopy) required; functional preservation likely worth risk, but requires compliant patient; treatment
stage-dependent; advanced rectal cancer requires neoadjuvant chemotherapy and irradiation before resection; early-stage
cancers should be radically resected with proctectomy and ileal pouch-anal anastomosis (IPAA) as possibility, so that
maintenance of gastrointestinal (GI) continuity not compromised; anterior or low anterior resection done with primary
anastomosis, but yearly surveillance of remaining large bowel required
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| Gynecologic cancer and prophylactic surgery: 40% to 60% lifetime risk for endometrial cancer, and 10% to 12%
lifetime risk for ovarian cancer; advantages include 100% prophylaxis against cancer, few risks, and no significant QOL issues;
no studies comparing efficacy of surveillance to surgery; study—315 participants; no cases of endometrial or ovarian
cancer found among women who underwent prophylactic total abdominal hysterectomy with bilateral salpingo-oophorectomy
(TAHBSO) at time of surgery; among nonsurgical patients, incidence of endometrial cancer 33%, and of ovarian cancer
5%; risk reduction significant for endometrial cancer (not for ovarian cancer); summary—preoperative genetic testing and
counseling mandatory; surveillance colonoscopy effectively reduces mortality; segmental colectomy for CRC acceptable if
surveillance employed; prophylactic surgery may be delayed with close surveillance but may be done under certain circumstances
and recommended; TAHBSO best done at time of colectomy or after childbearing completed, and reduces risk for gynecologic
cancers to 0%
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| MANAGEMENT OF THE MALIGNANT POLYP —Brett T. Gemlo, MD, Adjunct Assistant Professor, Department of
Surgery, Division of Colon and Rectal Surgery, University of Minnesota Medical School, Minneapolis
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| Characteristics: clear-cut invasion into submucosa; not carcinoma in situ; not high-grade dysplasia; actually tumor (T1)
cancer, but lymph node and metastasis status unknown
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| Treatment options: if polyp already removed, polypectomy alone may be necessary; local or regional resection; quandary
over who requires radical resection or polypectomy alone and who requires transanal excision; in cases of polyp
with long stalk and minimal focus of invasive carcinoma in tip, polypectomy alone adequate; in case of flat sessile lesion
with focus of invasive carcinoma in middle, decision more difficult; after polypectomy, purpose of further resection to
stage patient and determine who needs further treatment
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| Characteristics of removed polyp indicating need for further resection: classified into pedunculated and
sessile adenomas and by degree of invasion (head, neck, and stem [stalk]); with sessile polyp, any invasion into submucosa
level 4; in levels 1, 2, and 3 or invasion into head, neck, or stalk of polyp, <1% chance of regional lymph node metastasis;
for level 4 sessile and pedunculated polyps, incidence of metastasis ≈10%; invasion into submucosa stratified into superficial,
intermediate, or deep (Sm1, Sm2, or Sm3) and almost exclusively rectal lesions; percentage of lymph node metastasis
correlates with level of invasion; independent risk factors for local lymph node metastasis include being Sm3-positive,
lymphovascular invasion, and being in lower one-third of rectum; with superficial lesion in distal rectum, chance of lymph
node metastasis and consideration of radical resection higher (if local excision performed, salvage compromised if wrong
choice made); immediate radical resection associated with 94% incidence of 10-yr cancer-free survival; for malignant colon
polyps (pedunculated level 1, 2, and 3 polyps)—review pathology; ensure no evidence of disease at margin, and adequate
margin of normal tissue in stalk; reassure patient that chance of local disease <1%; observe patient and rescope
aggressively; level 4 sessile lesion—talk with patient; consider regional resection or positron emission tomography (PET)
in patient with questionable lesion in sigmoid colon and in those with medical comorbidities that make elective sigmoid resection
challenging; if regional disease seen on PET, patient needs radical resection; if PET negative, careful follow-up
and radical resection not necessary; in this setting, if patient young, healthy, and has no contraindication to surgery, radical
resection preferable; malignant rectal polyps—for pedunculated malignant polyp in rectum with no evidence of invasion,
review pathology, observe patient, and rescope; for sessile level 4 polyp (Sm1 or Sm2; superficial T1 lesion), reasonable to
re-excise polypectomy site, observe, and possibly perform PET; advise patient that chance of having regional lymph node
metastasis 1% to 8% and discuss whether radical resection should be performed; for sessile level 4 lesion (Sm3-positive),
treat like overt and extensive T1 rectal cancer; in young and fit patient, since risk for lymph node metastasis 15% to 20%,
radical resection recommended; if patient not fit for surgery or wants to avoid low operation, transanal excision with
chemoradiation reasonable option; successful management of malignant polyps requires careful melding of objective
pathologic factors, surgical judgment, and patient’s tolerance for risk
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Suggested Reading
André T et al: Oxaliplatin, fluorouracil, and leucovorin a.adjuvant treatment for colon cancer. N Engl J Med 350:2343,
2004; Balmaña J et al: Prediction of MLH1 and MSH2 mutations in Lynch syndrome. JAMA 296:1469, 2006; Bouzourene
H et al: A cost-effective algorithm for hereditary nonpolyposis colorectal cancer detection. Am J Clin Pathol
125:823, 2006; de Vos tot Nederveen Cappel WH et al: Decision analysis in the surgical treatment of colorectal
cancer due to a mismatch repair gene defect. Gut 52:1752, 2003; Ewald J et al: Immunohistochemical staining for mismatch
repair proteins, and its relevance in the diagnosis of hereditary non-polyposis colorectal cancer. Br J Surg 94:1020,
2007; Ford JM et al: Predicting and preventing hereditary colorectal cancer. JAMA 296:1521, 2006; Hoskins WJ:
How should women with a genetic predisposition for cancer be managed? Obstet Gynecol 110:5, 2007; Imperiale TF et
al: Guidelines for surveillance intervals after polypectomy: coping with the evidence. Ann Intern Med 148:477, 2008; Jenkins
MA et al: Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-
based study. Gastroenterology 133:48, 2007; Kuebler JP et al: Severe enteropathy among patients with stage II/III colon
cancer treated on a randomized trial of bolus 5-fluorouracil/leucovorin plus or minus oxaliplatin: a prospective analysis. Cancer
110:1945, 2007; Lynch HT et al: Immunology and the Lynch syndrome. Gastroenterology 134:1246, 2008; Nordlinger
B et al: Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver
metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 371:1007, 2008;
Nuzzo G et al: Influence of surgical margin on type of recurrence after liver resection for colorectal metastases: a single-
center experience. Surgery 143:384, 2008; Rex DK et al: Guidelines for colonoscopy surveillance after cancer resection: a
consensus update by the American Cancer Society and the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology
130:1865, 2006; Schmeler KM et al: Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch
syndrome. N Engl J Med 354:261, 2006; Tan D et al: Colorectal polyps: clinical significance of endoscopic and pathologic
correlation. Am J Clin Pathol 129:659, 2008; Xu J et al: Preoperative hepatic and regional arterial chemotherapy in the
prevention of liver metastasis after colorectal cancer surgery. Ann Surg 245:583, 2007.
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