Editor(s): Thomas Anthony, M.D. Reviewers: Robert W. Beart, Jr., M.D., Jose Guillem, M.D., Fabrizio Michelassi, M.D.,Heidi Nelson, M.D., Nicholas J. Petrelli, M.D., David A. Rothenberger, M.D., Clifford L. Simmang, M.D, Glenn D. Steele,Jr. M.D.,PhD, Harold J. Wanebo, M.D.

General Review

Rothenberger DA ed. Colorectal Cancer. In Surg Oncol Clin NA, WB Saunders 2000;9(4):643-878.

This is an excellent review of many aspects of colorectal cancer including screening, prevention, treatment, and follow-up. The reader is encouraged to use this reference in addition to the references presented in the following update.

Screening

Lieberman D, Weiss D, Bond J, et al.: Use of colonoscopy to screen assymptomatic adults for colorectal cancer. N Engl J Med 2000;343:162-168.

Simmang CL, Senatore P, Lowry A, et al.: Practice parameters for detection of colorectal neoplasms. Dis Colon Rectum 1999;42:1123-1129.

These first two papers are the reports of large multidisciplinary expert panels that have reviewed the available literature concerning screening for colorectal cancer. The first paper resulted in a dramatic change in the recommendations for screening. Its recommendations are stratified based on average risk and increased risk. A concise review of these recommendations appears between pages 596 and 600. The remainder of the article is an comprehensive review of the background information that led to these recommendations. The second article offers the practice guidelines of The American Society of Colon and Rectal Surgeons. This group also stratifies its recommendations based on degree of risk (low, moderate, and high risk).

Mandel JS, Church TR, Bond JH, et al. The effect of fecal occult blood screening on the incidence of colorectal cancer. N Engl J Med 2000;343:1603-1607.

The first article describes the performance of colonoscopy at 13 Veterans Affairs Medical Centers to determine the prevalence and location of advanced colonic neoplasms and the risk of proximal neoplasia in assymptomatic patients with or without distal neoplasia. Colonoscopy detected lesions that would not have been detected by sigmoidoscopy. According to the authors it is therefore the preferred method of screening assymptomatic adults. The second article offers the practice guidelines of The American Society of Colon and Rectal Surgeons. This article also divides its recommendations based on degree of risk (low, moderate, and high risk). Mandel and colleagues update the results of the Minnesota Colon Cancer Control Study. This paper exams the role of fecal occult blood testing in the reduction of the incidence of colorectal cancer.

Overviews of Colon and Rectal Cancer

Ruo L, Guillem JG. Major 20th-century advancements in the management of rectal cancer. Dis Colon Rectum 1999:42:563-578.

Nelson H, Petrelli N, Carlin A, et al. Guidelines 2000 for colon and rectal cancer surgery. J Natl Cancer Inst 2001;93(8):583-96

Wexner SD, Rotholtz NA. Surgeon influenced variables in resectional rectal cancer surgery. Dis Colon Rectum 2000;43:1606-1627.

Ruo and Guillem provide an excellent overview of the history, recent advances, and a brief outline of contemporary management of rectal cancer. This article references many of the early seminal works in the diagnosis, treatment, and prognosis of rectal cancer. The second article by Nelson and colleagues is a report from an expert panel sponsored by the NCI, convened to review the available literature and draft guidelines designed to provide uniform definitions, principles and practices for the oncologic resection of colon and rectal cancers. Wexner and Rotholtz review many aspects of the treatment of rectal cancer that influence therapeutic outcome emphasizing the role of variables within surgical control.

Local Excision of Rectal Cancer

Steele GD Jr, Herndon JE, Bleday R, et al.: Sphincter-sparing treatment for distal rectal adenocarcinoma. Ann Surg Oncol 1999;433-441. (Also see accompanying editorial pp. 413-415).

Garcia-Aguilar J, Mellgren A, Sirivongs P, et al. Local excision of rectal cancer without adjuvant therapy: a word of caution. Ann Surg 2000;231(3):345-51.

Steele et al report the only prospective multiinstitutinal study of local excision for rectal cancer (conducted by The Cancer and Leukemia Group B). Garcia-Aguilar et al report a large single institution experience with local excision of T1 and T2 rectal cancers meeting "ideal" selection criteria and point out a high rate of local recurrence, especially for T2 tumors.

Total Mesorectal Excision

Heald RJ, Moran BJ, Ryall RD, Sexton R, MacFarlane JK. Rectal Cancer: The Basingstoke Experience of total mesorectal excision, 1978-1997. Arch Surg. 1998;133:894-899.

Kapiteijn E, Kranenbarg EK, Steup WH, et al.: Total mesorectal excision (TME) with or without preoperative radiotherapy in the treatment of primary rectal cancer. Prospective randomised trial with standard operative and histopathological techniques. Eur J Surg 1999;165:410-420.

Lindsey I, Guy RJ, Warren BF, Mortensen NJMcC. Anatomy of Denonvilliers' fascia and pelvic nerves, impotence, and implications for the colorectal surgeon. Br J Surg 2000;87:1288-1299.

Bissett IP, Hill GL. Extrafascial excision of the rectum for cancer: a technique for the avoidance of the complications of rectal mobilization. Semin Surg Oncol 2000;18:207-215.

Heald et al review their extensive experience with total mesorectal excision (TME) specifically highlighting local recurrence and survival rates. Kapiteijn and colleagues provide a preliminary report of the Dutch Colorectal Cancer group randomized trial that is attempting to define the role of radiotherapy (5GY x 5; preop) given the low local recurrence rates reported with TME alone. Lindsey et al. review the often-misunderstood anatomic relationships of Denonvilliers' fascia and the pelvic sympathetic and parasympathetic nerves that come into play during total mesorectal excision and the significance of these structures in determining postoperative functional outcome. Bissett and Hill provide an excellent discussion of the surgical anatomy of the rectum and the implications of deviation from extrafascial excision in terms of potential functional complications.

Colorectal Cancer Therapy Morbidity and Mortality

Longo WE, Virgo KS, Johnson FE, et al.: Outcome after proctectomy for rectal cancer in Department of Veterans Affairs Hospitals: A report from the National Surgical Quality Improvement Program. Ann Surg 1998;228:64-70.

Longo WE, Virgo KS, Johnson FE, et al.: Risk factors for morbidity and mortality after colectomy for colon cancer. Dis Colon Rectum 2000;43:83-91.

Ooi B, Tjandra JJ, Green MD. Morbidities of adjuvant chemotherapy and radiotherapy for resectable rectal cancer: an overview. Dis Colon Rectum 1999;42:403-418.

Utilizing the National Surgical Quality Improvement Program data base Longo et al. review morbidity and mortality rates for colon and rectal cancer resections. These papers also explore the interrelation between preoperative risk factors and postoperative morbidity/mortality. Ooi et al give a contemporary review of the complications associated with both pre and postoperative chemoradiation in the treatment of rectal carcinoma.

The Influence of Surgeon Expertise/Environment on Outcomes

Harmon JW, Tang DG, Gordon TA, et al.: Hospital volume can serve as a surrogate for surgeon volume for achieving excellent outcomes in colorectal resection. Ann Surg 1999;230:404-413.

Porter GA, Soskolne CL, Yakimets WW, Newman SC. Surgeon-related factors and outcome in rectal cancer. Ann Surg 1998;227:157-167.

Schrag D, Cramer LD, Bach PB, et al. Influence of hospital procedure volume on outcomes following surgery for colon cancer. JAMA 2000;284;3028-35.

Using Maryland state discharged data Harmon et al. examine the role of both surgeon colorectal cancer case load and hospital environment on the end points of in-hospital deaths, length of stay, and cost. Porter et al. investigate the role of surgical subspecialty training and rectal cancer caseload on local recurrence and survival in 663 patients treated in 5 general hospitals in Edmonton, Alberta. (see also Wexner and Rotholtz article in Overview section). Schrag et al used linked SEER-Medicare data to show that hospital case volume directly correlated with 30 day and long term survival.

Colonic J-pouches

Dennett ER, Parry BR. Misconceptions about the colonic j-pouch: what the accumulating data show. Dis Colon Rectum 1999;42:804-811.

Dennett and Parry review the available literature pertaining to colonic j-pouches, specifically emphasizing anastomotic leak rate, manometry, and functional outcome. There are a number of randomized trials examining the functional results after coloanal anastamosis with a J-pouch, all of which are referenced in this review

Adjuvant Therapy and Chemotherapy for Advanced Disease

Diaz-Canton EA, Pazdur R. Adjuvant medical therapy for colorectal cancer. Surg Clin NA 1997;77:211-228.

Minsky BD. Role of adjuvant therapy in adenocarcinoma of the rectum. Semin Surg Oncol 1999;17:189-198.

Mamounas E, Wieand S, Wolmark N, et al. Comparative efficacy of adjuvant chemotherapy in patients with Dukes' B versus Dukes' C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol 1999;17:1349-1355.

Diaz-Canton and Pazdur provide a comprehensive review of adjuvant chemotherapy for both colon and rectal cancer. The paper by Minsky is a concise review of clinical trial data for adjuvant chemotherapy and radiation for rectal cancer. This article also examines the influence of preoperative therapy on sphincter preservation, current controversies in adjuvant therapy, and investigational approaches to adjuvant therapy for rectal cancer. Mamounas and colleagues review the NSABP experience in colon cancer to address the controversial question of the efficacy of chemotherapy in Dukes' B patients.

Saltz LB Cox JV, Blanke C, et al. Irinotecan plus florouracil and leucovorin for metastatic colon cancer. N Engl J Med 2000;343:905-914.

Diaz-Canton and Pazdur provide a comprehensive review of adjuvant chemotherapy for both colon and rectal cancer. The paper by Minsky gives a concise review of available trials data for adjuvant chemotherapy and radiation for rectal cancer. This article additionally examines data concerning the influence of preoperative therapy on sphincter preservation, current controversies in adjuvant therapy, and investigational approaches to adjuvant therapy for rectal cancer. Mamounas and colleagues review the NSABP experience in colon cancer to try and answer the controversial question of the efficacy of chemotherapy in Dukes' B patients. Saltz et al. report the results of a large multicenter trial which demonstrated improved progression free and overall survival for patients with metastatic disease treated with irinotecan and 5-florouracil/leucovorin compared with those patients receiving either irinotecan or 5-florouracil/leucovorin alone.

Colorectal Cancer Genetics and Related Issues

Chung DC. The genetic basis of colorectal cancer: insights into critical pathways of tumorigenesis. Gastroenterology 2000;119:854-865.

Lynch HT, Lynch JF. Heriditary nonpolyposis colorectal cancer. Semin Surg Oncol 2000;18:305-313.

Wong N, Lasko D, Rabelo R, Pinsky L, Gordon PH, Foulkes W. Genetic counseling and interpretation of genetic tests in familial polyposis and hereditary nonpolyposis colorectal cancer. Dis Colon Rectum 2001;44:271-279.

Chung provides an update on our current understanding of the events involved in adenoma to carcinoma sequence focusing on APC/ ß-catenin, DNA mismatch repair, and TGF-ß/SMAD pathways. Lynch provides a review of HNPCC including information on history, genetics, screening, and management. Wong and colleagues provide an overview of the complex issues of genetic counseling and a guide to the interpretation of the results of genetic testing for FAP and HNPCC.

Prognosis/Staging/Survival

Merrill RM, Henson DE, Ries LA. Conditional survival estimates in 34,963 patients with invasive carcinoma of the colon. Dis Colon Rectum 1998;41:1097-1106.

Compton CC, Fielding LP, Burgart LJ, et al. Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement 1999. Arch Path Lab Med 2000;124:979-994.

Gryfe R, Kim H, Hsieh ETK, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 2000;342:69-77.

Using Surveillance, Epidemiology and End Results Program, Merrill et al. provide conditional survival estimates by stage, gender and race. Compton and colleagues provide an extensive review of the literature pertaining to prognostic factors and staging for colorectal cancer and include the College of American Pathologists guidelines. Gryfe et al. used the Ontario Cancer Registry to identify patients with colorectal cancers younger than age 50 and identified a subset of patients with high-frequency microsatellite instability (MSI). High-frequency MSI conferred a survival advantage independent of standard prognostic factors including stage.

Laparoscopic Colorectal Surgery

Tomita H, Marcello PW, Milsom JW. Laparoscopic surgery of the colon and rectum. World J Surg 1999;23:397-405.

Maxwell-Armstrong CA, Robinson MH, Scholefield JH. Laparoscopic colorectal cancer surgery. Am J Surg 2000;179:500-507.

Tomita et al discuss important topics related to laparoscopic colorectal cancer surgery including the need to maintain oncologic standards, port-site recurrences, and future directions. Maxwell-Armstrong and colleagues have performed a literature review and discuss the present state of knowledge concerning many of the controversial issues surrounding laparoscopic surgery for colorectal malignancy.

Therapy for Hepatic Metastases

Fong Y, Salo J. Surgical therapy of hepatic colorectal metastasis. Semin Oncol 1999;26:514-523.

Kemeny NE, Ron IG. Hepatic arterial chemotherapy in metastatic colorectal patients. Semin Oncol 1999;26:524-535.

Fong and Salo provide an overview of the outcome of surgical resection of colorectal liver metastases, selection criteria for resection, imaging used in preoperative evaluation, post-resection adjuvant therapy and ablative techniques. Kemeny and Ron provide an in-depth review of hepatic arterial chemotherapy (HAI). They include information on rationale for HAI, results of randomized trials, toxicity, quality of life, and cost.

Post-treatment follow-up

Rosen M, Chan L, Beart RW, et al. Follow-up of colorectal carcinoma: a meta-analysis. Dis Colon Rectum 1998;41:1116-1126.

Benson III AB, Desch CE, Flynn P, et al. 2000 update of American Society of Clinical Oncology colorectal cancer surveillance guidelines. J Clin Oncol 2000;18:3586-3588.

Rosen and colleagues paper represents the most carefully performed meta-analysis on the controversial issue of postoperative surveillance for colorectal cancer. The paper by Benson is a report of the updated American Society of Clinical Oncology guidelines for follow-up of colorectal cancer including pertinent background.

Anal Cancer

Klas JV, Rothenberger DA, Wong WD, Madoff RD. Malignant tumors of the anal canal: the spectrum of disease, treatment, and outcomes. Cancer 1999;85:1686-1693.

Ryan DP, Compton CC, Mayer RJ. Carcinoma of the anal canal. N Engl J Med 2000;342(11) 792-800.

Klas et al is a report of a 10 year, large tertiary referral center experience with malignant tumors of the anal canal, offering insight into treatment and outcome for the various histologic variants that may be encountered. Ryan and colleagues present a current review of the anatomy, epidemiology, treatment, and outcomes for anal canal carcinoma..

SELECTED ABSTRACTS

Swanson R, Compton C, Stewart A, Bland K. The prognosis of T3N0 colon cancer is dependent upon the number of lymph nodes examined (Abstract #58).

This paper suggested a direct relationship between the number of nodes examined and survival. Although unable to differentiate between pathologist or surgeon related factors, this study has important quality control implications.

Libutti SK, Alexander HR, Choyke P, et al. Prospective study of FDG-PET, CEA scan, and blind second look laparotomy for detecting colon cancer recurrence in patients with rising CEA levels (Abstract #61).

This paper suggests in the context of a patient with an elevated CEA, that FDG-PET can predict unresectable disease accurately enough (90% of patients surgically proven to have unresectable disease) to be useful in selecting patients for second look laparotomy versus systemic chemotherapy.

Allegra CJ, Paik S, Parr A, et al. Prognostic value of thymidylate synthetase (TS), Ki -67 and p53 in patients (Pts) with Dukes' B and C colon cancer. ASCO Proc. Abstract 491,124a.

Elsaleh H, Grieu F, Joesph D, Iacopetta B. Thymidylate synthase genotype and survival benefit from chemotherapy in patients with colorectal cancer. ASCO Proc. Abstract 493, 124a.

These two papers highlight the interest in identification of prognostic factors apart from stage of disease. Allegra et al. presented a paper in which a large cohort of Dukes' B and C colon cancers from NSABP trials (C01-04) were rexamined. Standard immunohistochemical techniques were use to identify TS, Ki-67 and p53 tumor staining. Although the relative risks were small (all <2.0), increased TS, increased p53, and decreased Ki-67 were associated with poorer relapse free and overall survival. The paper by Elsaleh and colleagues discussed the influence of TS genotype on outcome. Patients with the triple repeat homozygous condition have previously been shown to have higher tumor TS levels than double tandem repeat or the heterozygous patients. This study correlated the triple tandem repeat polymorphism with a lack of benefit of chemotherapy compared with the other conditions.

Roh MS, Petrelli N, Wieand S, et al. Phase III randomized trial of preoperative versus postoperative multimodality therapy in patients with carcinoma of the rectum (NSABP R-03). ASCO Proc. Abstract 490, 123a.

This paper by Roh and colleagues gave a preliminary report of the results from NSABP R-03, which was closed early due to lack of accrual. Preoperative therapy resulted in complete clinical response in 23%, Fourty-four percent of these patients were pathologic complete responders. Also, 28% of patients thought to have needed an APR at diagnosis were converted to sphincter preserving surgery in the preoperative arm. Survival data are not mature at this point

Renehan AG, Saunders MP, Egger M, O'Dwyer ST. The impact on survival of intensive follow-up after curative resection for colorectal cancer: a meta analysis.

These authors described a meta analysis concentrating on randomized controlled trials comparing intense versus less intense colorectal cancer follow-up. They found that more intensive surveillance was associated with a 6% decrease in colorectal cancer related mortality.

Clinical Trials

Phase III Randomized Study of Fluorouracil and Mitomycin with Concurrent Radiotherapy Versus Fluorouracil and Cisplatin with Concurrent Radiotherapy in Patients with Anal Canal Carcinoma (RTOG, ECOG, CALGB, SWOG).

The purpose of this study is to determine whether the relative value of mitomycin and cisplatin in the multimodal treatment of anal canal carcinoma. Patients are randomized to receive fluorouracil (5-FU) plus mitomycin (arm I) or 5-FU plus cisplatin (arm II) with concurrent radiotherapy. Chemotherapy in both arms starts within 24 hours of beginning radiotherapy. Patients are stratified by gender (male vs female), nodal status (positive vs negative), and primary tumor size (greater than 2 cm to 5 cm vs greater than 5 cm). Arm I: patients receive 5-FU by continuous 96-hour IV beginning on day's 1 and 29 and mitomycin bolus IV on days 1 and 29 with concurrent radiotherapy. Arm II: patients receive induction chemotherapy consisting of 5-FU by continuous 96-hour IV beginning on days 1, 29, 57, and 85 and cisplatin IV over 60 minutes on days 1, 29, 57 and 85. Beginning on day 57, patients receive concurrent radiotherapy. Arm I and II radiotherapy is administered daily, 5 days a week for 5-6.5 weeks (including no greater than a 10-day break if needed). Patients with T3, T4, or N+ lesions or T2 lesions with residual disease receive additional radiotherapy to a reduced field.

Phase III Randomized Study of Laparoscopic-Assisted Colectomy vs Open Colectomy for Colon Cancer (NCCTG, SWOG, RTOG, CALGB, NSABP, NCIC-CTG).

This study is attempting to answer whether the laparoscopic approach to colon cancer offers any advantages to the patient. This trial will not only measure traditional outcomes of morbidity, mortality, recurrence and survival but will also answer important questions concerning cost and quality of life. Patients are randomized to one of two treatment arms. The extent of colon resection is identical for both arms. Arm I: Patients undergo open laparotomy and colectomy. Arm II: Patients undergo a laparoscopic assisted colectomy. Patients are stratified according to participating institution, primary surgeon, site of primary tumor (right vs left vs sigmoid), American Society of Anesthesiologists disease classification (I and II vs III), location of tumor (cecum vs hepatic flexure vs splenic flexure vs ascending vs descending vs sigmoid), prior abdominal surgery (none vs left upper quadrant vs right upper quadrant vs left lower quadrant vs right lower quadrant vs midline vs multiple vs unknown vs other), and subsequent adjuvant chemotherapy (yes vs no). Patients may be entered on adjuvant chemotherapy trials following surgery provided the subsequent trial does not include radiotherapy and allows entry of patients from both arms.

Phase III Study of Fluorouracil and Leucovorin Calcium With or Without Oxaliplatin in Patients With Stage II or III carcinoma of the Colon (NSABP).

This trial attempts to define the utility of adding oxaliplatin to standard 5-FU/leucovorin regimen. Patients are randomized to one of two treatment arms. In Arm I patients receive leucovorin calcium IV over 2 hours followed by fluorouracil IV over 1 hour weekly for 6 weeks. In Arm II patients receive oxaliplatin IV on days 1, 15, and 29 in addition to the regimen given in Arm I. Treatment continues every 8 weeks for three courses in the absence of the identification of metastatic/recurrent disease or unacceptable toxicity.

Phase III Randomized Study of Hepatic Artery FUDR/CF/DM vs Systemic 5-FU/CF for Hepatic Metastases From Colorectal Cancer (CALGB, ECOG).

This trial is attempting to compare the efficacy of chemotherapy given as a hepatic arterial infusion versus a similar chemotherapy given systemically in patients with unresectable hepatic metastases. Patients are randomized to one of two treatment arms: Arm I: 2-Drug Combination Chemotherapy with Drug Modulation. FUDR; DM; with CF. Intrahepatic infusion. Arm II: Single-Agent Chemotherapy with Drug Modulation. 5-FU; with CF. Intravenous infusion.

Phase III Randomized Study of Preoperative Radiotherapy Versus Selective Postoperative Chemoradiotherapy in Patients with Operable Rectal Cancer (MRC, EU (European Trial Groups).

This trial is another attempt to help settle the controversy surrounding the question of pre or postoperative adjuvant therapy for operable rectal cancer. Patients are randomized to receive preoperative radiotherapy (arm I) or postoperative chemoradiotherapy (arm II). Arm I: patients receive radiotherapy in 5 fractions over 1 week prior to surgery. Patients undergo surgery within 7 days of the last fraction of radiotherapy. Arm II: patients receive chemoradiotherapy 4-12 weeks after surgery. Radiotherapy is administered in 25 fractions over 5 weeks (5 days per week). During radiotherapy, patients either receive fluorouracil (5-FU) continuous infusion, 5-FU bolus IV and leucovorin calcium IV weekly, or a 5-day bolus schedule of 5-FU and leucovorin calcium. Patients may then receive adjuvant chemotherapy as per local policy.

A Randomized Phase III Trial of Irinotecan plus 5-Florouracil/Leucovorin versus 5-Florouracil/Leucovorin Alone After Curative Resection for Patients with Stage III Colon Adenocarcinoma (CALGB, NCCTG).

This study is attempting to answer whether the addition of Irinotecan to 5-Florouracil and Lecovorin will impact disease-free and overall survival in patients who have undergone potentially curative resection of stage III (lymph node positive) colon adenocarcinoma