Colon And Rectal Cancer

Jose G. Guillem, M.D., M.P.H., F.A.C.S., F.A.S.C.R.S.
Associate Professor of Surgery
Memorial Sloan Kettering Cancer Center

Since the last Core Subject Update on colon and rectal cancer (CRC) in 1994, a significant number of advances have been made in: our understanding of the molecular biology of CRC, screening and early detection of CRC, functional and oncological results following radical surgery as well as local procedures for rectal cancer, minimally invasive CRC resection, adjuvant therapy for CRC as well as multi-modality management of locally advanced rectal cancer.

Statistics

In the United States, the incidence of CRC continues to decrease 1. According to the American Cancer Society estimates, in 1998 there will be 131,600 new CRC cases with 56,500 CRC related deaths 2. Although the incidence of colon (95,600) and rectal cancer cases (36,000) are lower than the 1994 estimates of 107,000 and 42,000, respectively, the estimated deaths due to colon cancer are only slightly lower than those for 1994 (47,700 versus 49,000). For rectal cancer-related deaths, the rates are actually higher from 7,000 in 1994 to 8,800 in 1998. The reasons for the continued decrease in the incidence of CRC remain multi-factorial and, in part, due to increase surveillance and aggressive endoscopic removal of adenomas as well as environmental, dietary and lifestyle factors. However, the estimated increase in rectal cancer-related death is of concern and further underscores the need for continued advancement in the wide-spread utilization of optimal surgical technique and multi-modality management of rectal cancer.

Genetics of Colorectal Cancer

Currently oncogenes, suppressor genes and mismatch repair (MMR) genes are considered to play an essential role in CRC carcinogenesis. Proto-oncogenes, which are part of the normal genome and involved in growth and regulation, may facilitate cell cycle turnover and cellular proliferation when abnormally activated. Mutation of a proto-oncogene leads to dominant transformation of a cell by diverse causes such as activation of receptors, change in signal transduction pathways or loss of regulating mechanisms. Tumor suppressor genes, however, act in a recessive manner and promote cancer only when both copies of the gene are inactive either by mutation or loss of both alleles. In familial cancer, one of these mutations is passed along the germ line and is present in all cells. The remaining normal copy of the gene is sufficient to suppress cancer, but when this copy is lost in a single cell, neoplasia may ensue. In sporadic cases, both copies of the gene (alleles) must be lost or mutated. The latest genes to be associated with CRC carcinogenesis include the MMR genes which are responsible for hereditary non-polpyposis colorectal cancer syndromes (HNPCC). MMR genes are responsible for identifying and repairing mismatched nucleotides in DNA.

Genes related to CRC carcinogenesis include the K-ras oncogene, the APC, p53, DCC, and MCC tumor suppressor genes and the DNA MMR genes including MSH2, MLH1, PMS1, PMS2 and MSH-6. Although the APC gene is responsible for FAP and MMR genes are responsible for HNPCC, the genetics of sporadic CRC, which account for the great majority of CRC are much more complicated. Currently, two genetic pathways exist: the loss of heterozygosity (LOH) pathway in which somatic mutations result in loss of APC, K-ras, p53, DCC etc. in parallel with histopathological changes of the adenoma-carcinoma sequence and (2) the MMR pathway which is initiated by an inherited or somatic mutation within one of the MMR genes. Activation of MMR genes lead to replication errors (RER) or microsatellite instability (MIN). This mutated phenotype leads to increased mutation rates and marked cellular dysfunctions including mutations of the TGF-beta receptor II (TGF-beta RII), leading to CRC cell escape from TGF-beta mediated growth control and mutations in the beta-2-microglobulin (beta-2 m) gene which allow these CRC cells to evade T-cell surveillance.

Clinical application of these advances have: led to pre-symptomatic diagnosis of FAP and HNPCC syndromes; helped guide surgical management of FAP based upon the location of the APC mutation; prognostic value, particularly LOH of chromosomes 18q, 17p and 1p as well as altered p53 protein expression. Future, prospective studies will define the actual clinical utility of these prognostic markers in identifying high-risk individuals, particularly lymph node negative CRC in need of adjuvant therapy. The identification of essential genetic alterations during CRC development may also identify potential novel sites for tumor-specific therapy (Reviews 3,4).

Screening for Colorectal Cancer

It is estimated 6% of all Americans will develop CRC sometime in their lives and that approximately 70-80% of all CRC will occur in people at "average risk". The Agency for Healthcare Policy and Research recently funded a collaborative effort by numerous American Societies including the ASCRS in order to address screening for CRC .5 The American Cancer Society Guidelines from 1992 have been recently updated and call for everyone over age 50 who is at average risk to be screened with a fecal occult blood test plus flexible sigmoidoscopy or total colonic evaluation with either a colonoscopy or double contrast barium enema. The fecal occult blood test should be repeated every year with a flexible sigmoidoscopy every 5 years. Alternatively, a colonoscopy could be repeated every 10 years or a double contrast barium enema every 5-10 years. Individuals with even a single small (<1 cm) adenoma are required to have a total colonoscopic evaluation. The ACS guidelines have also been updated regarding other moderate risk individuals such as those with a personal history of CRC, a relative with CRC particularly those with a first-degree relative as well as those at high-risk for CRC: with FAP, HNPCC or IBD. Despite the establishment of screening guidelines by the ACS, ASCRS and other societies, it is estimated that screening for CRC is currently practiced by fewer than 20% of American adults.(6)

Local Excision For Early Stage Rectal Cancers

When strict selection criteria are adhered to, a local excision can provide acceptable oncological results. In series reporting local excisions for T1 or T2 lesions, failure rates ranged from 0-26%, with an overall rate of 20% and an overall survival rate of 73%. Of interest, approximately 50% of all local recurrences are amenable to salvage surgery usually by an APR. Overall, it appears that in carefully selected early stage lesions, local excision of T1 lesions along with post-operative radiation therapy for T2 or T3 lesions may give comparable results to an APR as long as there are no adverse features such as lymphatic, vascular, perineural invasion or positive margin.(7,8)

Laparoscopic Surgery for Colorectal Cancer

Although there is significant evidence to support the role of laparoscopy in the management of benign colorectal diseases, the current accepted roles of laparoscopy in the management of CRC are in staging, for example, of rectal cancer patients about to undergo pre-operative radiochemotherapy or for palliation such as creation of a diverting colostomy. The role of laparoscopy in the curative management of CRC remains to be defined by ongoing multi-center clinical trials.9 Currently, the ASCRS recommends that a curative CRC resection not be performed laparoscopically except as part of a prospective, controlled clinical trial.

Sharp Mesorectal Excision And Autonomic Nerve Preservation

Sharp mesorectal excision (SME) requires precise dissection in an areolar plane between the visceral fascia that envelops the rectum and mesorectum and the parietal fascia overlying pelvic wall structures. SME facilitates nerve preservation, makes complete total mesorectal excision (TME) possible and emphasizes gentle handling to avoid tearing the smooth surface of the mesorectum. TME involves removal of the entire rectal mesentery, including that distal to the tumor, as an intact unit. For mid and distal rectal cancers, TME is appropriate where as for upper rectal lesions (>10 cms from the anal verge) sharp mesorectal excision with transection of the mesorectum 5 cms distal to the lower most border of the tumor is optimal since a TME of an upper rectal cancer may be fraught with a high anastomotic leak rate probably due to devascularization of the distal rectal segment. Therefore, although oncological principles require only 2 cms of distal margin clearance, to ensure perfusion of the distal half of the anastomosis following a total mesorectal excision, the rectum should be transected at the inferior-most border of the mesorectum. This usually results in a 2 cm muscular tube adequate for an ultra-low colorectal or a coloanal anastomosis.(10)

TME has been shown to achieve a negative circumferential margin in 93% of resected specimens. 11 Most importantly, several surgical teams worldwide, using similar TME techniques, have reported local failure rates of less than 10% for transmural or node-positive rectal cancers corroborating Dr. Heald's 5% local failure rate without the use of radiotherapy. The importance of TME has been demonstrated by a prospective study in Sweden that revealed a local recurrence rate of 7% following the addition of TME compared to a historical control rate of 23%. An ongoing randomized study of TME with or without pre-operative radiotherapy for resectable rectal cancer in the Netherlands will assess the efficacy of TME and the relative benefit of surgery and radiation in the control of rectal cancer.(8)

Careful studies of pelvic autonomic nerve anatomy have lead to the development of techniques that reduce the risk of sexual and bladder dysfunction while ensuring optimal local control. The hypogastric sympathetic nerve trunks arise from the pre-aortic plexus. Injury to these nerves results in increased bladder tone with reduced bladder capacity, impaired ejaculation and loss of vaginal lubrication. The parasympathetic trunks (nervi erigentis) arise from the sacral nerve roots, Damage to these nerves leads to erectile dysfunction. A conventional rectal cancer resection in men is associated with post-operative impotence and retrograde ejaculation or both in 25-75% of cases, In contrast, impotence after nerve-sparing dissections has been reported in only 10-28% of all rectal cancer patients and in 10-15% of rectal cancer patients younger than 60 years of age. Sexual dysfunction is more common in patients treated by an APR.(12)

Coloanal Pouch Anastomosis

In an effort to increase function following a low anterior resection, the last 10 years have witnessed the development of the J pouch coloanal anastomosis in order to increase reservoir capacity. Randomized studies have demonstrated the superiority of a 6-8 cms coloanal J pouch anastomoses relative to a straight coloanal anastomosis particularly during the first year following surgery.(13) In addition, pouch patients were noted to have a lower incidence of anastomotic leakage which may be due, in part, to improved microcirculation at the apex of the pouch relative to that noted at the end of a straight colon anastomosis.(14) After the first year, it appears that the J pouch and straight coloanal anastomosis have comparable rates of urgency and incontinence but there is a significant reduction in the number of stools per day in patients with a J pouch versus those with a straight coloanal anastomosis. 10,15

Adjuvant Therapy of Rectal Cancer

Based upon the National Institute of Health consensus statement in 1991, adjuvant radiation therapy and 5FU-based chemotherapy remain the standard of care for > T3 and/or N1 rectal cancers. A number of recent studies have examined variations in the timing, type and duration of chemoradiotherapy. The results of a recent intergroup trial did not show any benefit to adding leucovorin, levamisole or both to standard 5FU chemotherapy. However, toxicity was increased. The Rectal Cancer Project Group in Norway has demonstrated that a short course of continuous 5FU chemotherapy has significant benefit in local control and overall disease-free survival compared to surgery alone. These results suggest that a short-term course of 5FU chemotherapy may be as effective as prolonged courses.(Review 16)

Several studies have demonstrated the efficacy of pre-operative radiotherapy in enhancing sphincter salvage rates. Preliminary results from Memorial Sloan Kettering Cancer Center using pre-operative 5-FU, low-dose leucovorin and concurrent RT for clinically resectable rectal cancer have demonstrated a 22% complete response rate and an 85% sphincter-saving rate with no local recurrences at a median follow up of 22 months and a 60% actual 3-year survival.(17) Preliminary results from the National Surgical Adjuvant Breast and Bowel Project Protocol (NSABBP) R-03 trial using a similar pre-operative combined therapy approach also indicated an improved sphincter-saving rate.(18)

Although several randomized studies have shown a reduction in local recurrence rates following pre-operative RT compared to surgery alone, none had demonstrated any survival advantage until the recent randomized Swedish Rectal Cancer Trial which compared pre-operative radiation therapy (25 Gy over 1 week) versus surgery along. Pre-operative radiation therapy improved local recurrence rates (11% vs 27%), and overall 5-year survival rate (58% vs 48%). Furthermore, for patients treated with a curative intent, the 9-year cancer-specific survival was 74% vs 65% for patients receiving pre-operative radiotherapy versus surgery alone, respectively. 19 As the optimal roles of radiation and chemotherapy for rectal cancer are defined, it is important to emphasize that pre-operative RT enhances the likelihood of performing a sphincter-saving ultra-low anterior resection by tumor bulk reduction and not by increasing the distal margins of clearance. If distal surgical margins are thought to be inadequate prior to RT, sphincter preservation should be aborted regardless of enhanced distal margin after RT, as we are currently unable to distinguish reliably between post-RT residual cancer and RT fibrosis. This point is of particular importance with poorly differentiated lesions which are more likely to have distal mural spread.

Adjuvant Therapy for Colon Cancer

In patients with Stage III colon cancer, therapy with 5-FU based chemotherapy increases overall and disease-free survival. One year treatment with 5-FU and levamisole has been shown to reduce the cancer-related mortality by approximately 1/3. Recent trials suggest that a similar benefit can be obtained with a 6-month course of 5/FU and leucorvoin. For Stage II (node negative) colon cancer, data suggests a minimal benefit to adjuvant therapy. However high-risk patients with node negative colon cancer but with obstruction, perforation, high-grade, aneuploidy can be offered chemotherapy. Although new promising drugs including tomudex, irinotecan, (CPT-11) and oxaliplatin have shown significant activity against metastatic CRC, their role in the adjuvant setting needs to be defined.(Review 16)

Follow-up of Colorectal Cancer Patients

The guidelines on the type and frequency of follow up of patients following curative CRC surgery remain unclear. Several studies have analyzed the follow up care for patients with CRC and demonstrated significant differences in follow-up programs. A recent prospective, randomized study has conclusively demonstrated that the efficacy of standard follow up by history, physical exam, liver function test, CEA and colonoscopy at 5 years is as good as that with a more intense program including yearly colonoscopy, CT scan of the liver and chest -x-ray. At 5 years of follow up, there was no significant difference in survival between the two groups. (20) It has already been shown that colonoscopy for patients with polyps at 3 year intervals is as effective as an annual colonoscopy. Based on current data, it remains unclear whether every 5 or 3 years is optimal follow-up following CRC resection, but clearly annual colonoscopy following an initial one-year post-resection baseline negative colonoscopy may not be indicated. Although a well design randomized clinical trial will help definitively define practice guidelines, it appears that q 3 months careful history, physical examination, liver function test, CEA (rigid sigmoidoscopy for rectal cancer) along with a normal baseline colonoscopy at one year post-resection followed by colonoscopy every 3-5 years may not be an unreasonable follow up program. Chest x-ray and CT scans would be reserved for investigating symptoms or LFT changes. Clearly, the utilization of CT scan will be defined by future studies aimed at demonstrating the survival benefit following resection of liver metastases detected by CT scan relative to those detected through clinical and biochemical screening alone.

References

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