Anatomy

Rectum

The rectum begins at the point where the large bowel loses its mesentery, which is at the level of the body of the third sacral vertebra. Peritoneum covers the upper portion of the rectum laterally and anteriorly near its junction with the sigmoid colon and only anteriorly near the peritoneal reflection. The peritoneum is reflected anteriorly onto the seminal vesicles and bladder in the male and onto the upper vagina and uterus in the female, leaving the lower half of the rectum without a peritoneal covering. The location of the peritoneal reflection is important in patients undergoing sphincter-preservation procedures. Electrocoagulation of anterior tumors above the peritoneal reflection is considered unsafe because of the risk of perforation. However, location above the peritoneal reflection does not contraindicate management of selected tumors by endocavitary radiation therapy.
The three transverse folds of the rectum, two on the left and one on the right, apportion it into thirds. The middle transverse fold lies approximately 11 cm from the anal verge and provides a landmark for the peritoneal reflection. The portion of the rectum below the middle valve is the rectal ampulla; if the ampulla is resected, stool frequency often is increased markedly. This morbidity is an important factor to consider in choosing between a "radical" sphincter-sparing procedure, such as coloanal anastomosis, and a "conservative" sphincter-sparing procedure, such as endocavitary irradiation.
The principal route of lymphatic drainage for carcinomas of the rectum follows the superior rectal vessels, which empty into the inferior mesenteric nodes. Lymphatic drainage of the middle and lower rectum also occurs along the middle rectal vessels, terminating in internal iliac nodes. The lowest part of the rectum and the upper part of the anal canal share a plexus that drains to lymphatics that accompany the inferior rectal and internal pudendal blood vessels and ultimately drain to internal iliac nodes. Carcinomas of the lower rectum and those that extend into the anal canal occasionally may metastasize to superficial inguinal nodes through connections to efferent lymphatics draining the lower anus (Fig. 54-1).

Colon

The ascending and descending colon and the splenic and hepatic flexures lack a mesentery and are immobile because of their retroperitoneal location. Cancers that extend through the bowel wall on the posterior aspect may have compromised surgical margins.
The cecum lacks a true mesentery but may have some mobility because of short folds of peritoneum that are variably present. Surgical margins may be narrow when lesions extend posteriorly.
The lymphatic drainage of the colon follows the inferior mesenteric vessels for the left colon and the superior mesenteric vessels for the right colon. Additional lymph node groups can be at risk if adjacent organs or structures are involved by cancer. If tumors involve adjacent organs in the true or false pelvis, the iliac nodes may be at risk. Periaortic lymph nodes may be at risk when cancer invades the retroperitoneum.

Epidemiology

Adenocarcinoma of the large bowel occurred in an estimated 131,200 persons in the United States in 1997 and caused approximately 54,900 deaths. The incidences of large bowel cancer in males and females are approximately equal. Large bowel cancer risk and distribution may be affected by genetic factors, the presence of acquired conditions, screening, and environmental factors.
Acquired and genetic conditions that influence the risk of developing large bowel cancer include inflammatory bowel disease, polyposis syndromes, and hereditary nonpolyposis colorectal cancer. The risk of large bowel cancer is markedly increased in patients with inflammatory bowel disease, particularly ulcerative colitis. Genetic polyposis syndromes include familial adenomatous polyposis, Gardner syndrome, Peutz-Jeghers syndrome, and familial juvenile polyposis.
These conditions are inherited in an autosomal dominant pattern with almost complete penetrance. Patients with familial adenomatous polyposis and Gardner syndrome have thousands of polyps in the large bowel and inevitably develop cancer at an early age if the large bowel is not surgically removed. These polyposis syndromes result from APC gene mutations on chromosome 5q. Peutz-Jeghers syndrome and juvenile polyposis are also associated with an increased risk of gastrointestinal neoplasia, including colon cancer.
The other major genetic condition associated with large bowel cancer is hereditary nonpolyposis colon cancer, which is inherited in an autosomal dominant pattern and includes Lynch syndromes I and II. Lynch syndrome I is characterized by a familial tendency to early-age onset of predominantly proximal large bowel cancer. Lynch syndrome II is similar, except that an increased risk of endometrial cancer, ovarian cancer, and other malignancies has also been observed. The influence of genetic factors in "sporadic" large bowel cancer is demonstrated by the fact that the incidence of colon cancer is two to three times that expected by chance in first-degree relatives of patients with large bowel cancer. A family history should be obtained from every colorectal cancer patient so that relatives who may benefit from early screening can be identified.
In the last 30 to 50 years, the site of colon and rectal cancer has shifted toward the right colon. Increased early detection of distal precancerous lesions (for example, by proctoscopy) has been suggested as a possible contributing factor.
The influence of environment is suggested by studies assessing cancer risk and dietary factors and by studies of immigrant populations. Immigrant Japanese populations acquire the higher large bowel cancer mortality rates of the host country within one generation. Seventh Day Adventists and Mormons follow dietary practices that increase their fiber consumption and decrease their meat consumption. Among Seventh Day Adventists, mortality rates from colon cancer are approximately 60% to 70% of those of the general population, and the incidence of colon and rectal cancer in the Utah Mormon population is approximately 60% of that in the non-Mormon population.
Epidemiologic evidence suggests a preventive role for dietary fiber in large bowel cancer. Burkitt called attention to the low incidence of large bowel cancer in developing nations, in which high-fiber diets are common. Other studies have shown an inverse correlation between fiber intake and risk of large bowel cancer. Although not all reports confirm this relation, a National Cancer Institute review found an inverse relation between dietary fiber intake and colon cancer in most studies.
Fecal bile acids promote carcinogenesis in an animal model, and fecal excretion of bile acids has been shown to be high in colon cancer patients. Cholecystectomy, which results in an increase in the amount of secondary bile acids that reach the colon, could result in an increased incidence of colon cancer if secondary bile acids have a role in colon carcinogenesis in humans. Although some studies lend support to the hypothesis that cholecystectomy increases the risk of colon cancer, others do not. A study of fecal bile acid physiology in a low-risk, high-fiber-intake population in Finland suggested a possible link between promotion of colon cancer by secondary bile acids and prevention of colon cancer by high-fiber intake.
Several studies indicate a positive association between fat intake and colon carcinogenesis. Armstrong and Doll found a strong association between mortality rates for colon cancer and total fat consumption. A possible carcinogenic effect of dietary cholesterol was suggested by Liu and co-workers. Dietary cholesterol has been hypothesized to be the fat-related substance that has cocarcinogenic properties.
Selenium appears to inhibit carcinogenesis in laboratory animals. Areas of the United States with high bioavailability of selenium have lower death rates from cancer in general and from cancer of the intestines and rectum in particular.

Patterns of Spread and Natural History

Discontinuous spread of colon and rectal cancer can occur by four mechanisms: peritoneal seeding, lymphatic spread, hematogenous spread, and surgical implantation. Peritoneal spread is rare in patients with rectal cancer because most of the rectum is below the peritoneal reflection.
Extension within the bowel usually occurs only for short distances. Black and Waugh found that only 4 of 103 patients had microscopic intramural spread farther than 0.5 cm from the gross lesion. Further evidence of the limited tendency for intramural spread was found in a study by Pollett and Nicholls, in which anastomotic recurrence, local control, and survival were almost identical in patients with longitudinal margins less than or greater than 2 cm.
Because primary venous and lymphatic channels originate in submucosal layers of the bowel, cancers limited to the mucosa are at little risk for dissemination. Lymph node involvement is found in almost 50% of patients and usually is orderly and predictable. Skip metastasis or retrograde spread occurs in only 1% to 3% of node-positive patients and is generally thought to be caused by lymphatic blockage.

Clinical Presentation

The most common presenting feature in patients with rectal and lower sigmoid cancer is melena. Abdominal pain is the most common presenting feature in patients with colon cancer. In taking a history from a patient with cancer of the large bowel, particular attention should be given to these features. Other presenting features of large bowel cancer include change in bowel habit, nausea, vomiting, weakness, and abdominal mass. Patients found incidentally to have microcytic anemia should be considered to have large bowel cancer until proved otherwise.

Diagnostic Workup

Diagnostic procedures for the evaluation of colon and rectal cancer include a detailed history, physical examination, and endoscopic, radiographic, and laboratory studies (Table 54-1). The history should include a review of symptoms commonly associated with large bowel cancer. In addition, a family history should be obtained. Particular attention should be given to familial tendencies toward large bowel cancer, endometrial cancer, ovarian cancer, and other malignancies that may indicate the presence of one of the genetic syndromes associated with large bowel cancer. Physical examination should result in a detailed description of the primary tumor and a screen for potential sites of metastatic disease. In patients with rectal cancer, a digital rectal examination and endoscopy should provide information regarding the location of the lesion (i.e., distance above the anal verge and which rectal walls are involved), whether it is exophytic or ulcerative, its size and mobility, and whether any palpable perirectal nodes are present. For colon and rectal tumors, attention should be given to palpation of any anterior extrarectal mass that may suggest peritoneal spread. In women, a complete pelvic examination, including rectovaginal examination, is important. Particular attention should be given to potential areas of metastatic spread, including inguinal lymph nodes (particularly with rectal lesions near the dentate line) and supraclavicular lymph nodes. Abdominal examination should screen for evidence of liver metastasis, abdominal mass, or ascites.
When a large bowel cancer is found or suspected, the rectum and colon should be examined with barium enema and proctosigmoidoscopy or with colonoscopy to rule out second primary large bowel cancers. Biopsy of any suspicious lesions should be performed at the time of endoscopy. For patients with rectal cancer, barium enema performed before resection, including a cross-table lateral view, can also assist greatly in planning radiation therapy. Intrarectal ultrasonography is useful in determining whether lesions are limited to the bowel wall and therefore amenable to sphincter preservation by techniques such as local excision or endocavitary radiation therapy.
Additional laboratory evaluation should include liver and renal function studies. If the results are abnormal, computed tomography (CT) or ultrasonography is indicated. The preoperative carcinoembryonic antigen (CEA) value is an independent prognostic factor in large bowel cancer, and its serial measurement postoperatively has been used in some medical centers to identify disease progression in asymptomatic patients. A National Institutes of Health Consensus Development Panel determined that serial CEA measurement is the most sensitive laboratory indicator of recurrent disease. However, most patients with recurrence have symptoms before the CEA value increases. In one study, CEA increased in only 25% of patients with recurrent disease. Moreover, patients found with this test to have recurrent disease are unlikely to be cured. A retrospective analysis by Moertel and colleagues of patients from a large clinical trial of adjuvant treatment for colon cancer reported that 1017 (84%) of 1216 patients had CEA monitoring. Among the 345 CEA-monitored patients with recurrence, only 2.9% were alive more than 1 year after recurrence, compared with 2.0% of patients with recurrence who were not monitored with CEA. The estimated cost of CEA monitoring for the 1017 patients was almost $1.5 million. This study must be interpreted carefully because it was retrospective and because CEA monitoring was not standardized. Nevertheless, the results were similar to those of studies employing more systematic monitoring of CEA.


A preliminary report of a prospective randomized trial designed specifically to assess the value of CEA monitoring also suggests that this test is not beneficial when used as part of a broad-based screening program for recurrent disease. It seems unlikely that CEA monitoring is of benefit to broad groups of patients with large bowel cancer, given the extreme nature of the poor results observed in these studies. The very modest theoretic potential for benefit of postoperative CEA monitoring must be weighed against the potential for harm when, for example, asymptomatic patients are subjected prematurely to the distressing news that the disease has recurred and that there is no effective curative treatment.
Future studies may help to define whether CEA monitoring is of value in subgroups of patients, such as those most likely to develop potentially curable liver metastases.

Staging Systems

Dukes described a staging system based on the extent of disease penetration through the bowel wall and the presence or absence of nodal metastasis (Table 54-2). Dukes' staging has the disadvantage of not specifying the degree of tumor penetration through the wall of the bowel in node-positive patients. The Astler-Coller staging system allows specification of both tumor penetration and nodal involvement, and its subsequent modification also permits the specification of tumor adherence to surrounding organ structures. The Dukes, Astler-Coller, and modified Astler-Coller systems are postoperative pathologic staging systems and cannot be used preoperatively. The TNM system of the American Joint Committee can be used as a clinical (preoperative) or postoperative pathologic staging system.

Pathology

Most malignant tumors of the large bowel are adenocarcinomas, and most are moderately well differentiated histologically. Among patients who undergo operation for cure, approximately one third have lymph node metastasis. Retrograde lymph node involvement and skip metastasis are unusual, and both are associated with poor prognosis.

Molecular Biology

Several types of genetic alterations at the molecular level contribute to malignant transformation. One of the earliest changes is the loss of methyl groups in DNA.
Mutations in oncogenes are another common finding in colorectal neoplasia. For example, mutational activation of the ras gene is found in about 50% of colorectal carcinomas and advanced adenomas but in only 12% of early adenomas. Loss of genetic information is common in patients with colorectal cancer. Tumorigenesis associated with allelic loss is caused by the loss of function of tumor suppressor genes. Allelic deletions occurring in association with colorectal neoplasia are not distributed randomly but instead appear to occur most commonly at specific chromosomal locations. Allelic loss is particularly common on chromosomes 5, 17, and 18. Allelic loss at chromosome 18q contributes to colorectal neoplasia because of loss of DCC (deleted in colorectal carcinoma), one of several tumor suppressor genes. Another tumor suppressor gene, APC, has been identified on chromosome 5q.
The most commonly altered tumor suppressor gene in colon cancer is p53, which is located on chromosome 17q.
The p53 protein affects cellular proliferation and therapeutic response. Normal or wild-type p53 (wtp53) appears to limit tumor proliferation by at least two mechanisms. In some situations, p53 is involved in a reversible arrest in the G(1) phase of the cell cycle.
Expression of p53 can also lead to apoptosis, a physiologic irreversible process leading to cell death. Although p53 and other tumor suppressor genes are recessive, it appears that a point mutation in one allele is often followed by loss of the remaining wild-type allele. This is believed to be a late event in colorectal tumorigenesis.
P53-dependent apoptosis has significant implications for cancer therapy. Cells that express wtp53 typically undergo cell death by apoptosis in response to exposure to cytotoxic agents such as radiation, 5-fluorouracil (5-FU), etoposide, and doxorubicin. Cells that do not express wtp53 are resistant to these agents.
Colon cancer patients with mutations in the p53 gene appear to have a worse prognosis than those with wtp53. After exposure of cells to radiation, p53 interacts in a complex way with the products of other genes affecting cellular proliferation. An example is the relation between p53 and the MDM2 gene. The protein encoded by the p53 gene is induced by radiation. This, in turn, leads to a p53-dependent increase in the expression of the MDM2 gene. The MDM2 protein is able to bind to p53. If the MDM2 protein is present in sufficient quantities, this binding results in abrogation of p53-mediated arrest of the cell cycle at G(1).
Recently, a novel type of genetic alteration at DNA microsatellites (called microsatellite instability) has been described. Microsatellites are repeated sequences of DNA that occur abundantly and randomly throughout the human genome. Microsatellite instability has been identified in tumors from a subset of patients with sporadic colon cancer and in most patients with hereditary nonpolyposis colon cancer. At least in the latter group, microsatellite instability appears to be caused by a defect in one of several genes involved in DNA mismatch repair, including hMSH2, hMLH1, hPMS1, and hPMS2. [ref: 77] These same genes are now known to be the genetic susceptibility loci for hereditary nonpolyposis colon cancer.
The cause of the microsatellite instability in patients with sporadic colorectal cancer has not been clearly defined.

Prognostic Factors

Important prognostic factors for radiation oncologists include tumor penetration of the bowel wall and lymph node involvement. Both factors are associated with an increased risk of local recurrence and, accordingly, are helpful in selecting candidates for adjuvant radiation therapy. The absolute number and the proportion of lymph nodes involved are important predictors of outcome. The presence of both lymph node involvement and extension of disease beyond the bowel wall is more ominous than the presence of either alone. In patients with low rectal cancer who are being considered for sphincter-sparing treatment, the clinical mobility, size, and morphology of the lesion are predictors of outcome.
Techniques for analyzing pathologic genetic modifications at the molecular level, enzymatic activity influencing metabolism of chemotherapeutic agents, DNA ploidy, and cell kinetics have led to the identification of additional prognostic factors. In one study, for example, deletions on chromosome 18q (the site of the DCC gene) were associated with a trend toward lower rates of disease-free survival in patients with colorectal cancer (P = 0.08). Other studies have also suggested a worse prognosis for patients with deletions from 18q or 17q. The presence of microsatellite instability has been correlated with improved patient survival in sporadic colon cancer. The overexpression of p53 is associated with worse survival in patients with node-positive colorectal cancer. Thymidylate synthase, an important target of the chemotherapeutic drug 5-FU, was found in one study to have significantly higher activity in patients with advanced colorectal cancer whose tumors did not respond to 5-FU than in those with responsive tumors. Aneuploidy and high proliferative index (measured by adding the percentage of cells in S phase to those of cells in G(2) and M phase) are associated with worse survival in patients with colorectal cancers. Information from studies of this type may be useful in the selection of patients for adjuvant therapy.

General Management

Operative Considerations

Surgical resection is the initial treatment of choice for most patients. The objective is to remove the tumor and adjacent lymph nodes. Anterior resections are technically feasible in patients with tumors at least 6 to 8 cm above the anal verge and result in survival rates similar to those for abdominoperineal resection.
Surgical and pathology reports commonly refer to the longitudinal bowel margin. However, nodal and circumferential (radial) margins may be more important. If a tumor spreads beyond the bowel wall in anatomically immobile segments of the large bowel, the narrowest margin of resection typically is situated laterally, anteriorly, or posteriorly rather than along the length of the bowel. A study of whole-mount sections found that 40% of patients who underwent resection of a rectal carcinoma had a radial margin of 3 mm or less. In patients in whom postoperative irradiation may be part of the treatment, several surgical procedures assist in planning treatment and minimizing toxicity. Pelvic floor reconstruction and reperitonealization help to minimize the volume of small bowel in the pelvis. For patients in whom high-dose treatment to the pelvis is anticipated, complete exclusion of all small bowel from the pelvis can be achieved by use of an absorbable mesh sling. Primary closure of the perineal wound after abdominoperineal resection generally results in more rapid healing and prevents delays in instituting postoperative radiation therapy. A full description of the extent of the tumor and placement of clips demarcating the tumor bed and residual disease can assist in the design of radiation therapy fields.

Patterns of Failure After Curative Resection

Detailed information regarding anatomic sites of failure after operation for rectal cancer is available from the University of Minnesota reoperation series (Fig. 54-2). Seventy-four patients thought to be at high risk for local recurrence underwent elective or symptomatic second-look operations. Of these, 52 (70%) had metastatic or locally recurrent cancer. Locoregional recurrence in the pelvis or paraaortic nodes was the sole failure in 24 (46%) of these 52 patients and occurred as a component of failure in 48 (92%). Table 54-3 provides information about failure patterns in an unselected patient population. Patients with disease extension beyond the bowel wall, nodal involvement, or both have local recurrence rates of 20% to 70%. Distant metastasis occurs in approximately 30% of patients who undergo curative resection of rectal cancer, and the most common sites of involvement are liver, lung, and peritoneum.
Patterns of failure in colon cancer have been analyzed in autopsy, clinical, and reoperation series. Data from these series suggest that local failure is a significant problem after resection of colon cancer in selected patients. Local failure is highest among patients with tumors adhering to surrounding structures and those who have both tumor extension beyond the bowel wall and metastatically involved lymph nodes. In one retrospective study, the local recurrence rate among patients with these pathologic characteristics was 30% to 49%.
Approximately 20% of patients who undergo curative resection of colon cancer develop distant metastasis. The most common sites of distant metastasis are liver, lung, and peritoneum.

Radiation Therapy Techniques