This management guide covers the risk factors, symptoms, diagnosis, staging, and treatment of colorectal and anal cancers.
Despite the existence of excellent screening and preventive strategies, colorectal carcinoma (CRC) remains a major public health problem in Western countries. The American Cancer Society (ACS) estimates that in 2016, CRC will be diagnosed in 134,490 people, and 49,190 will die of the disease. CRC is the third most common type of cancer in both sexes (after prostate and lung cancers in men and lung and breast cancers in women) and the third most common cause of cancer death in the United States.
About 72% of new CRCs arise in the colon, and the remaining 28% arise in the rectum. Rectal cancer is defined as cancer arising below the peritoneal reflection, up to approximately 12 to 15 cm from the anal verge.
The lifetime risk of CRC in the United States is estimated to be 5.9% for men and 5.5% for women.
Overall, the incidence of CRC and mortality rates are higher in men than in women; tumors of the colon are slightly more frequent in women than in men (1.2:1), whereas rectal carcinomas are more common in men than in women (1.7:1).
The vast majority, 90%, of all new CRC cases occur in individuals older than 50. In the United States, the median age at presentation is 72 years.
The incidence and mortality rates of CRC are higher among African Americans than among whites (15% higher and 40% higher, respectively). The incidence rates among Asian Americans, Hispanics/Latinos, and American Indians/Alaskan natives are lower than those among whites.
The incidence of CRC is higher in developed regions (the United States, Canada, the Scandinavian countries, northern and western Europe, New Zealand, Australia) and lower in Asia, Africa (among blacks), and South America (except Argentina and Uruguay).
TABLE 1: Five-year relative survival rates in colorectal cancer by stage at diagnosis (1995–2005)
Five-year survival rates (Table 1) for patients with CRC have improved in recent years. This fact may be due to wider surgical resections, modern anesthetic techniques, and improved supportive care. In addition, better preoperative staging and abdominal exploration reveal clinically occult disease and allow treatment to be delivered more accurately. Survival also has improved through the use of adjuvant chemotherapy for colon cancer and neoadjuvant chemoradiation therapy for rectal cancer. Mortality from CRC is decreasing, likely from earlier diagnosis and screening as well as improvements in treatment modalities.
TABLE 2: Summary of selected risk factors for colorectal cancer
The specific causes of CRC are unknown, but environmental, nutritional, genetic, and familial factors, as well as preexisting diseases, have been found to be associated with this cancer. A summary of selected risk factors for CRC is shown in Table 2.
Asians, Africans, and South Americans who emigrate from low-risk areas assume the colon cancer risk of their adopted country, suggesting the importance of environmental factors in CRC. Smoking and alcohol intake (four or more drinks per week) increase the risk of CRC.
Diets rich in fat and cholesterol have been linked to an increased risk of colorectal tumors. Dietary fat causes endogenous production of secondary bile acids and neutral steroids and increases bacterial degradation and excretion of these acids and steroids, thereby promoting colonic carcinogenesis. Historically, diets rich in cereal fiber or bran and yellow and green vegetables are said to have protective effects, although epidemiologic studies have failed to prove a risk reduction with increased dietary fiber intake. A protective role also has been ascribed to calcium salts and calcium-rich foods, because they decrease colon-cell turnover and reduce the cancer-promoting effects of bile acid and fatty acids.
Several studies have reported a lower risk of CRC in individuals who participate in regular physical activity. High levels of physical activity may decrease the risk by as much as 50%. Being overweight or obese has been consistently associated with a higher risk of CRC.
Patients with inflammatory bowel disease (ulcerative colitis, Crohn’s disease) have a higher incidence of CRC. The risk of CRC in patients with ulcerative colitis is associated with the duration of active disease, extent of colitis, development of mucosal dysplasia, and duration of symptoms.
The risk of CRC increases exponentially with the duration of colitis, from approximately 3% in the first decade to 20% in the second decade to more than 30% in the third decade. CRC risk also is increased in patients with Crohn’s disease, although to a lesser extent.
Colorectal tumors develop more often in patients with adenomatous polyps than in those without polyps. There is approximately a 5% probability that carcinoma will be present in an adenoma; the risk correlates with the histology and size of the polyp. The potential for malignant transformation is higher for villous and tubulovillous adenomas than for tubular adenomas. Adenomatous polyps smaller than 1 cm have a slightly greater than 1% chance of being malignant, in comparison with adenomas larger than 2 cm, which have up to a 40% likelihood of malignant transformation if left untreated.
Patients with a history of CRC are at increased risk for a second primary colon cancer or other malignancy. The risk of a second CRC is higher if the first diagnosis was made before age 60.
Following ureterosigmoidostomy, an increased incidence of colon cancer at or near the suture line has been reported. Cholecystectomy also has been associated with colon cancer in some studies but not in others.
Prior radiation to the prostate has been associated with a 1.7 relative risk of rectal cancer compared with nonirradiated tissues. In this study, the effect was limited to the irradiated tissues only, not to the rest of the bowel.
TABLE 3: Hereditary polyposis syndromes
Individuals with a first-degree relative with the disease have an increased risk of developing CRC. Those with two or more relatives with the disease make up about 20% of all people with CRC. The risk of developing CRC is significantly increased in several forms of inherited susceptibility (Table 3). About 5% to 10% of all patients with CRC have an inherited susceptibility to the disease. The risks of developing CRC in the subgroups of familial or hereditary CRC vary from 15% in relatives of patients with CRC diagnosed before 45 years of age, through 20% for family members with two first-degree relatives with CRC, to approximately 70% to 95% in patients with familial adenomatous polyposis (FAP) and hereditary nonpolyposis CRC (HNPCC).
FAP is inherited as an autosomal dominant trait with variable penetrance. Patients characteristically develop pancolonic and rectal adenomatous polyps. Approximately 50% of patients with FAP will develop adenomas by 16 years of age, and 95% by age 35. Left untreated, almost 100% of patients with FAP will develop CRC, with an average age at diagnosis ranging from 34 to 43 years. Prophylactic surgery, either total colectomy with ileorectal anastomosis or restorative proctocolectomy with an ileal anal pouch anastomosis, performed in the mid to late teens, is the procedure of choice in this group of patients. The familial adenomatous polyposis coli (APC) gene has been localized to chromosome 5q21. Currently, it is possible to detect mutations in the APC gene in up to 82% of families with FAP. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as sulindac (a nonspecific COX-1 [cyclooxygenase-1] and COX-2 inhibitor) and celecoxib (a COX-2 inhibitor), have been shown to decrease the size and number of adenomas in FAP patients. However, these agents should not be a substitute for surgery. In a small study in pediatric patients, sulindac did not prevent the development of adenomas in APC mutation carriers who had not yet developed polyps at the time of enrollment in the study.
HNPCC is transmitted as an autosomal dominant trait. It is associated with germline mutations in DNA mismatch repair genes (MSH2, MLH1, PMS2, MSH6, and deletions of the 3' region of EPCAM [TACSTD1]). The incidence of a mutated mismatch repair (MMR) gene is approximately 1 in 1,000 people. In 1990 and 1991, the Amsterdam criteria were proposed and published, respectively. These criteria were proposed to identify high-risk families with suspected Lynch syndrome, so that the syndrome could be further studied and delineated. In 1999, they were revised (Amsterdam II) to recognize extracolonic manifestations as part of the family history. The criteria include the following factors:
• Three or more relatives with a histologically verified HNPCC-associated cancer (colorectal, endometrial, small-bowel, ureter, or renal pelvis), one of whom is a first-degree relative of the other two (FAP should be excluded)
• CRC involving at least two generations
• One or more CRCs diagnosed before the age of 50
The majority of CRC tumors from HNPCC patients have high-frequency microsatellite instability (MSI-H). The Bethesda guidelines were developed to test tumors from high-risk individuals for MSI-H, to identify those who are at risk for HNPCC. These criteria are much less restrictive than the Amsterdam criteria and serve to help identify patients at risk for HNPCC who might benefit from further evaluation. They have been modified and include the following:
• CRC diagnosed in a patient who is younger than 50 years
• The presence of synchronous, metachronous CRC, or other HNPCC-associated tumors regardless of age
• CRC with MSI-H histology diagnosed in a patient who is younger than 60 years
• CRC diagnosed in one or more first-degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed in a person younger than 50 years
• CRC diagnosed in two or more first- or second-degree relatives with HNPCC-related tumors regardless of age
With newer molecular techniques, mutations in the DNA MMR genes, namely MLH-1, MSH-2, MSH-6, and PMS-2, have been found in up 50% of individuals meeting clinical criteria. Because MSI occurs in more than 90% of cases of CRC with Lynch syndrome compared with sporadic cases (in which it occurs in about 15% of colorectal tumors), MSI testing has been used to screen tumors before genetic testing. Immunohistochemistry (IHC) for DNA (MMR) has also been advocated for screening tumors before genetic testing. Both of these methods will not detect all tumors, but they are complementary. A selective approach toward testing tumors for mismatch repair deficiency in CRC patients diagnosed at age 70 or younger, and in older patients fulfilling the modified Bethesda guidelines, was reported to miss about 5% of all Lynch syndrome cases while decreasing by 35% the tumors that required testing and by about 29% the number of patients undergoing germline genetic testing compared with the universal approach of testing all colorectal cancers. In addition to having MSI-H, MSH-6 colorectal tumors may be designated MSI-L (low-frequency microsatellite instability) or MSS (microsatellite stable). Individuals with absence of protein expression of MSH-2 by IHC and MSI-H tumors in which a mutation in the coding region of MSH-2 has not been detected should be tested for germline mutations in the epithelial cell adhesion molecule (EPCAM). Deletions in the 3' region of EPCAM cause methylation of the promoter of MSH-2. Aspirin at a dose of 600 mg per day for a mean of 25 months decreased cancer incidence after 55.7 months in patients with HNPCC who were mutation carriers.
Chemoprevention aims to block the action of carcinogens on cells before the development of cancer.
Controlled trials of vitamins C and E and calcium have produced mixed results. Clinical trials have shown that calcium supplementation modestly decreases the risk of colorectal adenomas.
NSAIDs inhibit colorectal carcinogenesis, possibly by reducing endogenous prostaglandin production through COX inhibition. Sulindac has induced regression of large-bowel polyps in patients with FAP. Controlled studies have shown a reduction in the incidence of colorectal polyps with regular, long-term use of aspirin. Hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors may reduce the risk of CRC after extended treatment.
Women who use postmenopausal hormone replacement therapy appear to have a lower rate of CRC than those who do not. Postmenopausal hormones may increase the risk of other types of cancer, however.
During the early stages of CRC, patients may be asymptomatic or complain of vague abdominal pain and flatulence, which may be attributed to gallbladder or peptic ulcer disease. Minor changes in bowel movements, with or without rectal bleeding, are also seen; they are frequently ignored and/or attributed to hemorrhoids or other benign disorders.
Cancers occurring in the left side of the colon generally cause constipation alternating with diarrhea, abdominal pain, and obstructive symptoms, such as nausea and vomiting.
Right-sided colon lesions produce vague, abdominal aching, unlike the colicky pain seen with obstructive left-sided lesions. Anemia resulting from chronic blood loss, weakness, weight loss, and/or an abdominal mass may also accompany carcinoma of the right side of the colon.
Patients with cancer of the rectum may present with a change in bowel movements; rectal fullness, urgency, or bleeding; and tenesmus.
Fecal occult blood testing (FOBT) consists of guaiac-based testing (gFOBT), which can be performed in the doctor’s office, or a fecal immunohistochemical test (FIT), which is usually processed in clinical laboratories. The difference between these tests is based on the detected analyte. Blood in the stool detected by gFOBT depends on the reaction of a pseudoperoxidase with heme or hemoglobin, whereas FIT depends on the reaction with globin. For these tests, two samples should be collected from three consecutive bowel movements. The majority of the adenomas and CRCs go undetected because they usually are not bleeding at the time of the test. Newer gFOBT and FIT appear to have a better sensitivity than older tests without sacrificing specificity.
Three large, prospective, randomized, controlled clinical trials have demonstrated a 15% to 33% decrease in CRC mortality over an 8- to 13-year period of follow-up in those individuals randomized to undergo FOBT. A positive FOBT result should be followed by colonoscopy.
Stool DNA (sDNA) testing takes advantage of molecular changes or mutations that occur in the carcinogenesis of CRC. DNA shed in the stool is analyzed for molecular changes. Multiple targets, including mutations in KRAS, p53, APC, and BAT 26 (which can be a surrogate marker for MSI), are analyzed. There are no data on the performance of sDNA for screening; however, the test has been shown to be able to detect both significant adenomas and CRCs.
Digital rectal examination should be an integral part of the physical examination. It can detect lesions up to 7 cm from the anal verge.
Flexible proctosigmoidoscopy is safe and more comfortable than examination using a rigid proctoscope. Almost 50% of all colorectal neoplasms are within the reach of a 60-cm sigmoidoscope. Even though flexible sigmoidoscopy visualizes only the distal portion of the colorectum, the identification of adenomas can lead to colonoscopy. When we add the percentage of colorectal neoplasms in the distal 60 cm of the colorectum to the percentage of patients with distal polyps leading to complete colonoscopy, 80% of individuals with a significant neoplasm anywhere in the colorectum can be identified. Four prospective, randomized, controlled trials evaluating flexible sigmoidoscopy for screening have been conducted in the United States and Europe, but at this time not all the results are available. In the United Kingdom, in a prospective randomized study of more than 100,000 individuals aged 55 to 64 years, a single flexible sigmoidoscopy reduced CRC incidence by 33% and mortality by 43%. Similar results were reported in the Italian randomized study in which in the per-protocol analysis, CRC incidence was reduced by 31% and CRC-related mortality was reduced by 38% in individuals aged 55 to 64 years who underwent single flexible sigmoidoscopy, compared with controls. Based on the area examined by the sigmoidoscopy, the incidence of distal CRC (rectum and sigmoid colon) was reduced by 50% (hazard ratio [HR] = 0.50; 95% CI, 0.42–0.59; secondary outcome).
Optical. This form of colonoscopy provides information on the mucosa of the entire colon, and its sensitivity in detecting tumors is extremely high. Most physicians consider colonoscopy to be the best screening modality for CRC. Colonoscopy can be used to obtain biopsy specimens of adenomas and carcinomas and permits the excision of adenomatous polyps. For this reason, colonoscopy is the only screening modality ever shown to reduce the incidence of cancer in screened individuals. Colonoscopy is the best follow-up strategy for evaluating patients with a positive gFOBT and the best screening modality for high-risk patients.
Limitations of colonoscopy include its inability to detect some polyps and small lesions because of blind corners and mucosal folds and the fact that sometimes the cecum cannot be reached. A supplementary double-contrast barium enema may be needed if a colonoscopic examination fails to reach the cecum.
CT colonography (virtual colonoscopy). This form of colonoscopy utilizes CT images that are reconstructed to visualize the colon. It requires a bowel preparation and adequate distention of the colon for success. There is no prospective randomized study demonstrating that colonoscopic CT reduces CRC mortality. However, a trial comparing optical colonoscopy with colonoscopic CT resulted in similar detection rates for advanced neoplasia.
Barium enemas can accurately detect CRC; however, the false-negative rate associated with double-contrast barium enemas ranges from 2% to 61% because of misinterpretation, poor preparation, and difficulties in detecting smaller lesions. A supplementary colonoscopy may be needed if a double-contrast barium enema does not adequately visualize the entire colon, or to obtain histopathology or perform polypectomy in the event of abnormal findings. There is no role for single-contrast barium enema. If this modality is to be used, a well-conducted double-contrast barium enema needs to be performed.
TABLE 4: American Cancer Society guidelines on screening and surveillance for the early detection of colorectal adenomas and cancer-Average risk
TABLE 5: A joint guideline from the American Cancer Society, the US Multi-Society Task Force on CRC, and the American College of Radiology for screening and surveillance in high-risk individuals
Adults at average risk should begin CRC screening at age 50. The ACS guidelines on screening and surveillance for the early detection of colorectal adenomatous polyps and cancer provide several options for screening average-risk individuals (Table 4).
Recommendations for screening and surveillance of high-risk individuals are given in Table 5.
Adenomatous colon polyps should be completely removed endoscopically to prevent progression to malignancy. Colon polyps with severe dysplasia or carcinoma in situ can also be managed with colonoscopic polypectomy as long as the entire polyp is removed. A malignant polyp is defined as one with cancer invading through the muscularis mucosa and into the submucosa (pT1).
Management of malignant polyps removed by colonoscopy is somewhat controversial. In general, malignant polyps can be removed colonoscopically as long as they can be removed with a confirmed negative margin and do not invade the submucosa beneath the polyp stalk, do not have lymphovascular invasion, or are poorly differentiated. These characteristics increase the risk of nodal metastases.
Studies from Japan and the United States have correlated the incidence of lymph node metastases with the level of submucosal involvement. Individuals with cancer in polyps invading the upper third of the submucosa have a low risk of nodal metastases, whereas those invading the lower third have up to a 25% incidence of nodal metastases. Sessile polyps with submucosal invasion should probably be removed by colon resection. Each situation should be individualized according to the histology, prognostic factors, extent of submucosal invasion, and completeness of excision. The comorbidities and general health of the patient are also factors to consider.
An initial diagnostic workup for patients with suspected colorectal tumors should include a complete history, including a three-generation family history, and a physical examination. It should also include:
• Digital rectal examination and FOBT
• Biopsy of any detected lesions
Adequate staging prior to surgical intervention requires:
• CT scan of the chest, abdomen, and pelvis
• Endorectal ultrasonography or MRI to evaluate and appropriately stage a rectal cancer for potential neoadjuvant therapy
• Complete blood cell count with platelet count
• Liver and renal function tests
• Measurement of carcinoembryonic antigen (CEA) level; if CEA levels are elevated preoperatively, postoperative CEA levels should be monitored every 3 months for 3 years in patients with stage II or III CRC and every 6 to 12 months thereafter
In monitoring response to therapy for metastatic cancer, CEA levels should be measured every 1 to 8 months during active treatment.
18F-fluorodeoxyglucose (FDG)-positron emission tomographic (PET) scanning has emerged as a highly sensitive study for the evaluation of patients who have metastatic disease. Although not usually recommended in the evaluation of early-stage primary disease, this modality can aid in the staging of recurrence.
Adenocarcinomas constitute 90% to 95% of all large-bowel neoplasms. These tumors consist of cuboidal or columnar epithelia with multiple degrees of differentiation and variable amounts of mucin.
Mucinous adenocarcinoma is a histologic variant characterized by huge amounts of extracellular mucus in the tumor and the tendency to spread within the peritoneum. Approximately 10% of colorectal adenocarcinomas are mucinous. It is more commonly seen in younger patients.
Signet-ring cell carcinoma is an uncommon variant, accounting for 1% of colorectal adenocarcinomas. These tumors contain large quantities of intracellular mucinous elements (causing the cytoplasm to displace the nucleus) and tend to involve the submucosa, making their detection difficult with conventional imaging techniques.
A histology consisting of an adenocarcinoma with poor differentiation with an intense lymphocytic infiltrate and Crohn’s like reaction should alert the clinician that the tumor may be mismatch repair–deficient or MSI-H.
Squamous cell carcinomas, small-cell carcinomas, carcinoid tumors, and adenosquamous and undifferentiated carcinomas also have been found in the colon and rectum. Nonepithelial tumors, such as sarcomas and lymphomas, are exceedingly rare.
CRC has a tendency toward local invasion by circumferential growth and for lymphatic, hematogenous, transperitoneal, and perineural spread. Longitudinal spread is usually not extensive, with microscopic spread averaging only 1 to 2 cm from gross disease, but radial spread is common and depends on anatomic location.
The most common site of extralymphatic involvement is the liver, with the lungs the most frequently affected extra-abdominal organ (more common site than liver in rectal cancer). Other sites of hematogenous spread include the bones, kidneys, adrenal glands, and brain, although metastases can spread to any organ.
The TNM staging classification, which is based on the depth of tumor invasion in the intestinal wall, the number of regional lymph nodes involved, and the presence or absence of distant metastases, has largely replaced the older Dukes’ classification scheme (Table 6).
TABLE 6: AJCC staging for cancer of the colon and rectum
Pathologic stage is the single most important prognostic factor following surgical resection of colorectal tumors. The prognosis for early stages (I and II) is favorable overall, in contrast to the prognosis for advanced stages (III and IV). However, there appears to be superior survival for patients with stage III disease whose disease is confined to the bowel wall (ie, ≤ T2, N+).
Histologic grade may be correlated with survival. Five-year survival rates of 56% to 100%, 33% to 80%, and 11% to 58% have been reported for grades 1, 2, and 3 colorectal tumors, respectively.
Other prognostic factors (such as age at diagnosis, presurgical CEA level, sex, presence and duration of symptoms, site of disease, histologic features, obstruction or perforation, perineural invasion, venous or lymphatic invasion, ploidy status, and S-phase fraction) have not consistently been correlated with overall disease recurrence and survival. Furthermore, the size of the primary lesion has had no influence on survival. Elevated expression of thymidylate synthase (TS) and allelic loss of chromosome 18 have been correlated with a poor prognosis. MSI or mismatch repair deficient status has been correlated as an independent prognostic factor for survival, favoring patients with unstable tumors (MSI-H).
Management of CRC relies primarily on resection of the bowel with the adjacent draining lymph nodes. The need for neoadjuvant or adjuvant chemotherapy, with or without concurrent irradiation, depends on tumor location (colon vs rectum) and stage of disease. In surgery for both colon and rectal cancers, if the tumor is attached to other organs, an en bloc resection of the primary tumor and adjacent organ(s) is indicated. If the adhesions are violated, there is an increase in local recurrence and a decrease in survival; thus, the potential cure for that patient will be compromised. Occasionally, neoadjuvant chemoradiation therapy will be indicated in colon tumors before surgical resection. In rectal cancer, preoperative (preferred) or postoperative chemoradiation is indicated for stages II and III disease.
Colon. The primary therapy for adenocarcinoma of the colon is surgical extirpation of the bowel segment containing the tumor, the adjacent mesentery, and draining lymph nodes. On the basis of studies that correlated the number of lymph nodes removed and survival, it is recommended that at least 12 lymph nodes be available for examination by a pathologist to confirm. Surgical resection can be performed by open or laparoscopic approaches.
The type of resection depends on the anatomic location of the tumor. Right, left, or transverse colectomy is the surgical treatment of choice in patients with right, left, or transverse colonic tumors, respectively. For transverse colon tumors, depending on the location of the tumor, an extended right hemicolectomy or in some cases a left hemicolectomy is preferred to a transverse colectomy. Tumors in the sigmoid colon may be treated with wide sigmoid resection. The length of colon resected depends largely on the requirement for wide mesenteric nodal clearance.
FIGURE 1: Mesorectal excision
Rectum. For rectal carcinoma, the distal surgical margin should be at least 2 cm, although some investigators have suggested that a smaller but still negative margin (after neoadjuvant chemoradiation) may be adequate. The resection should include the node-bearing mesorectum surrounding the rectum. This procedure, which is termed “total mesorectal excision” (TME), is accomplished using a sharp dissection technique (Figure 1). The mesorectal dissection is carried out sharply in the plane between the fascia propria of the mesorectum and the parietal fascia (presacral fascia). Anteriorly, the dissection follows the posterior vaginal wall in females or Denonvilliers’ fascia in males, either of which may be resected in the presence of an anterior wall rectal cancer. The use of TME has been associated with a significant reduction in local recurrence rates for patients with rectal cancer.
Reported rates of local recurrence following TME for rectal cancer have generally been less than 10%, compared with rates of recurrence up to 30% before the advent of TME. Selective use of radiation therapy can improve on the results of TME alone.
Circumferential resection margin is an important predictor of local failure in patients with rectal cancer. A population-based review of 3,196 patients with rectal cancer found that local recurrence at 5 years was 23.7% with margins of 0 to 2 mm vs 8.9% with margins greater than 2 mm. The 5-year rate of distant metastases was higher and 5-year survival was lower for the group with smaller margins. Because only 10% of patients in this study received neoadjuvant therapy and patients who received postoperative radiation therapy were excluded, it is not clear whether these data can be extrapolated to patients treated with radiation therapy.
Sphincter-sparing approaches. Technologies (eg, circular stapling devices) and the application of surgical techniques, such as coloanal anastomosis and creation of intestinal pouches, are employed to maintain anal sphincter function for tumors in the lower one-third of the rectum. If the tumor is located proximally between 6 and 15 cm from the anal verge, a low anterior resection with end-to-end anastomosis may be performed.
Abdominoperineal resection. Abdominoperineal resection, removing the anus and sphincter muscle with permanent colostomy, may be necessary if the tumor is located in the distal rectum and if other characteristics of the tumor (eg, bulky size, proximity to the sphincter musculature) preclude an oncologically adequate sphincter-sparing approach. An alternative procedure for distant rectal tumors is to resect the entire rectum, sparing the anoderm and anal sphincter musculature, and to perform a coloanal anastomosis. Either procedure, sphincter-sparing resection or abdominoperineal resection, can be performed with autonomic nerve preservation, minimizing bladder and sexual function morbidity.
Local excision alone. Local excision alone may be indicated for select patients who have small (< 3 to 4 cm), T1, well to moderately differentiated rectal cancers without histologic evidence of lymphovascular involvement, provided that a full-thickness negative margin can be achieved. In some series, transanal excision for these T1 lesions with good histology results in excellent long-term control. However, some large studies with long-term follow-up demonstrated significant local recurrence rates, even with T1 lesions. For T2 or T3 tumors, the standard therapy remains a transabdominal resection because of the risk of mesorectal nodal spread. Preoperative transrectal ultrasonography is useful in defining lesions that can be resected by local excision alone. A trial sponsored by the Cancer and Leukemia Group B (CALGB) demonstrated reasonable results for patients with T2 rectal cancer who underwent negative margin local excision followed by fluorouracil (5-FU) and external beam radiation therapy (EBRT). The locoregional recurrence rate at 6 years was only 14%. A similar study conducted by the American College of Surgeons Oncology Group (ACOSOG) but with neoadjuvant chemoradiation followed by local excision has been completed. In this study, 44% of the patients had a pathologic complete response and 6% had pT3 tumors following neoadjuvant chemoradiation.
Laparoscopic colonic resection. Multiple large randomized trials have established laparoscopic colonic resection as an oncologically acceptable method of treating cancer of the colon. Resection of rectal cancer using laparoscopic approaches also has been and is being evaluated in a number of randomized trials. Minimally invasive surgical techniques (laparoscopy, robotic) for rectal resection still require confirmation as procedures that are oncologically equivalent to open surgery. The potential advantages include a shorter hospital stay, reduced postoperative ileus, decreased time away from work, fewer adhesive complications, and a lower risk of hernia formation. The potential disadvantages compared with open transabdominal resection include longer operative time, higher operative costs, and technical considerations related to operator skill. Large randomized trials with long-term follow-up are still needed. In the United States, ACOSOG Z-6051, a randomized prospective study evaluating minimally invasive (laparoscopic, robotic) vs open surgery for rectal cancer, has completed accrual. COREAN (Comparison of Open vs Laparoscopic Surgery for Mid and Low Rectal Cancer After Neoadjuvant Chemoradiotherapy), a noninferiority trial of a laparoscopic vs open-resection approach toward management of 340 patients with T3N0–2M0 rectal cancer following neoadjuvant chemoradiotherapy at three Korean centers, showed that these two surgical approaches yielded similar 3-year disease free survival outcomes.
The natural history and patterns of failure following “curative” resection are different for colon and rectal carcinomas. Locoregional failure as the only or major site of recurrence is common in rectal cancer, whereas colon cancer tends to recur in the peritoneum, liver, lung, and other distant sites, with a lower rate of local failure. As a result, local therapy, such as irradiation, may play a significant role in the treatment of rectal tumors but is not used routinely for colon cancers.
Approximately 75% of all patients with CRC will present at a stage when all gross carcinoma can be surgically resected. Nevertheless, despite the high resectability rate, almost half of all patients with stage III colorectal adenocarcinoma die of metastatic disease, primarily because of residual disease that is not apparent at the time of surgery. These individuals are candidates for adjuvant local or systemic therapies.
With the advent of more effective chemotherapeutic agents, induction chemotherapy is being evaluated in colon cancer (the FOxTROT [Fluoropyrimidine, Oxaliplatin and Targeted-Receptor pre-Operative Therapy] trial in the UK) and in rectal cancer (the PROSPECT [Preoperative Radiation or Selective Preoperative Evaluation of Chemotherapy and Total mesorectal excision] trial in the US; see below). Potential advantages of this approach are delivery of higher total doses of chemotherapy and the downsizing and downstaging of the tumor.
The use of chemotherapy for resected stage II colon cancer patients is of uncertain survival benefit. When determining the benefit of adjuvant therapy for this group, several factors should be taken into consideration, including the number of lymph nodes analyzed after surgery, the prognostic features (T4 lesion, perforation, peritumoral lymphovascular invasion, poorly differentiated histology, MSI status), life expectancy, and comorbid conditions. A multigene assay (Oncotype DX colon cancer assay, Genomic Health, Inc) is available to help define the risk of recurrence for patients with stage II colon cancer.
5-FU plus leucovorin. Studies have demonstrated the benefits of 5-FU plus leucovorin in the adjuvant treatment of colon carcinomas. Acceptable adjuvant regimens of 5-FU plus leucovorin for colon cancer include both low-dose leucovorin and high-dose leucovorin regimens (Table 7). The use of 5-FU plus leucovorin or capecitabine alone (see below) is generally reserved for patients likely to be intolerant of oxaliplatin (eg, those with preexisting neuropathy) or patients over 70 years of age.
FOLFOX, FLOX. FOLFOX, FLOX, (5-FU, leucovorin, and oxaliplatin) is approved for adjuvant therapy for resected stage III CRC. In a phase III trial for resected stages II and III colon cancer from Europe (MOSAIC), the use of FOLFOX4 compared with the same infusional regimen without oxaliplatin led to a higher 3-year disease-free survival rate (78% vs 73%) in patients receiving FOLFOX. More recently, FOLFOX6 or a modified version of it (Table 7) has been used in clinical trials as well as in clinical practice. In a subgroup analysis, a significant disease-free survival benefit was seen for patients with stage III colon cancer and for patients with high-risk stage II colon cancer. A significant overall survival advantage was also seen for patients with stage III disease.
In a separate randomized phase III trial conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) for patients with resected stage II or III colon cancer, FLOX was compared with a weekly bolus of 5-FU and leucovorin. The 3-year disease-free survival benefit from FLOX was similar to that seen with FOLFOX4. Stages II and III disease were not evaluated separately.
Capecitabine. Capecitabine is an oral fluorinated pyrimidine approved for adjuvant therapy in patients with stage III colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. Capecitabine was not inferior to bolus 5-FU and low-dose leucovorin in terms of disease-free survival, with an HR in the capecitabine group of 0.87 (95% CI, 0.75–1). Capecitabine is an alternative for patients who are unlikely to tolerate 5-FU, leucovorin, and oxaliplatin. Capecitabine may also be used in combination with oxaliplatin (XELOX) as an alternative to FOLFOX or FLOX. In a randomized phase III trial comparing XELOX with bolus 5-FU and leucovorin, the 3-year disease-free survival with XELOX was 70.9%.
Addition of targeted therapy to adjuvant chemotherapy. Four phase III trials of adjuvant therapy for resected colon cancer assessed the potential added benefit of a targeted therapy in conjunction with mFOLFOX. NSABP C-08 randomized patients with resected stage II or III colon cancer to 12 cycles of mFOLFOX6 alone or with bevacizumab. Bevacizumab was given for 6 months beyond treatment with mFOLFOX6. AVANT randomized patients with resected stage III and high-risk stage II colon cancer to FOLFOX4 alone, FOLFOX4 with bevacizumab, or XELOX with bevacizumab. The North Central Cancer Treatment Group (NCCTG) N0147 trial randomized patients with resected stage III colon cancer to 12 cycles of mFOLFOX6 alone or with cetuximab. The final design of this trial only randomized patients with wild-type KRAS to one of the two treatment arms. PETACC-8 (one of the Pan-European Trials in Adjuvant Colon Cancer) used a design similar to that of N0147, but with FOLFOX4. All of these trials failed to show benefit to the addition of a targeted therapy to mFOLFOX.
Irinotecan. Two phase III trials of FOLFIRI (5-FU, irinotecan, leucovorin) compared the same infusional regimen without irinotecan in either patients with resected stages II and III colon cancer (PETACC3) or high-risk stage III disease (the French ACCORD-2 trial). They did not show a benefit to the use of irinotecan in the adjuvant setting. Given the results of these two studies, the use of irinotecan currently is not considered a primary option for patients with resected stage II or III colon cancer.
FIGURE 7: Adjuvant chemotherapy regimens for colorectal adenocarcinoma (nonmetastatic)
Local recurrence alone or in combination with distant metastases occurs in up to 50% of patients with rectal carcinoma. Nodal metastases and deep bowel wall penetration are significant risk factors for locoregional failure.
In the absence of nodal metastases, with surgery alone, the rate of local recurrence may be as low as 5% to 10% for stage I rectal cancer and 15% to 30% for stage II tumors. In stage III disease, the incidence of pelvic failure increases to 50% or more. The use of TME significantly reduces this risk of local recurrence; however, local recurrence remains a concern in patients with stages II and III disease.
Local recurrence in the pelvis is complicated by involvement of contiguous organs, soft and bony tissues, and deep nodal disease. Presenting symptoms vary from vague pelvic fullness to sciatica related to mass effect in the fixed space of the bony pelvis and invasion of the sciatic nerve.
Because local recurrence in the absence of metastatic disease is more common in rectal cancer than in colon cancer, aggressive resections, such as pelvic exenteration (anterior and posterior), sacral resection, and wide soft tissue and pelvic floor resection, have been employed to treat these recurrences. Modern techniques of pelvic floor reconstruction, creation of continent urinary diversion, and vaginal reconstruction may be required for functional recovery.
The findings of the NSABP R-02 trial indicated postoperative adjuvant chemotherapy resulted in survival rates similar to those of postoperative chemoradiation therapy but was associated with a significantly higher rate of locoregional failure.
Radiation therapy has been part of recommended care for locally advanced (T3–T4, N+) rectal cancer for more than 25 years. Preoperative radiation therapy reduces local tumor recurrence, even in patients undergoing TME surgery. However, with the exception of one study, preoperative therapy has not affected overall survival in patients with stage II or III rectal cancer. Postoperative irradiation to the tumor bed can be considered in patients with T4 (B3 or C3) tumors located in retroperitoneal portions of the colon, because more than 30% of these patients develop local recurrence. A prospective study, terminated because of slow accrual, did not show improvement in overall survival or disease-free survival in patients treated with chemoradiation vs those treated with chemotherapy alone. However, the results must be interpreted with caution because of the problems with the study. Retrospective studies suggest improved local tumor control with irradiation, particularly in patients with positive resection margins. If available, intraoperative radiotherapy may be considered for patients with T4 or recurrent cancers as an additional boost. An improvement in local tumor control also has been observed with postoperative irradiation, but again with no benefit with regard to disease-free or overall survival. After a median follow-up of 12 years, preoperative radiation therapy reduced the 10-year cumulative incidence of local recurrence rates when combined with TME (11% vs 5%) in a Dutch phase III trial comparing short course radiation and TME vs TME alone. In a French study of 762 patients, preoperative chemoradiation therapy compared with preoperative radiotherapy reduced local failure rates in patients with T3-T4 rectal cancers from 17% to 8%. The primary indication to perform preoperative vs postoperative radiotherapy is to reduce the radiation toxicity to the “neorectum” or pouch by not radiating the part of the bowel used for reconstruction. There is better patient quality of life with this approach, including reduced pain and frequency of bowel movements, and improved nighttime continence.
Postoperative chemoradiation therapy. Clinical trials of surgical adjuvant treatment indicate that postoperative radiation therapy with concurrent chemotherapy (chemoradiation therapy) is superior to postoperative radiation therapy alone or surgery alone. Postoperative chemoradiation therapy was the standard of care for patients with stage II or III rectal cancer, based largely on the findings of the NCCTG and Gastrointestinal Tumor Study Group (GITSG) trials. A summary of the 5-year survival results of the Patterns of Care Study (PCS) of the American College of Radiology and the results of the National Cancer Data Base (NCDB), both of which are representative of American national averages, is shown in Table 8.
TABLE 8: Five-year overall survival in Patterns of Care Study (PCS) vs the National Cancer Data Base (NCDB), Gastrointestinal Tumor Study Group (GITSG), and Mayo/North Central Cancer Treatment Group (Mayo/NCCTG) studies
TABLE 9: Chemotherapy choices during radiation therapy
Neoadjuvant therapy. For rectal cancers approaching the anal sphincter, preoperative (neoadjuvant) irradiation or the combination of chemotherapy and irradiation will significantly reduce the size of the majority of tumors. This approach allows for sphincter-preserving surgery in many patients. In addition, the long-term morbidity of radiation therapy for rectal cancer may be reduced if it is administered before surgery. The use of preoperative chemotherapy and radiation therapy is particularly important for patients who present with locally advanced and unresectable rectal cancer, because in most of them the disease will be rendered resectable following neoadjuvant therapy. One additional role of neoadjuvant therapy may be in facilitating transanal excision of T2 and T3 rectal cancers in poor-surgical-risk patients. A number of groups have reported encouraging results with either observation or transanal excision of T1–T3 tumors following a complete response to neoadjuvant therapy.
In 2004, Habr-Gama published a series involving 265 patients with T2 or higher distal rectal cancers, 71 of whom had had a complete clinical response to chemoradiotherapy and undergone close observation. In this first series, at a mean 57.3 months follow-up, two patients (2.8%) developed endoluminal recurrence and three patients (4.2%) developed distant recurrence. Subsequently, at a mean follow-up of 59 months, the same group reported a 5% endorectal recurrence, 7% distant recurrence, and 1% combined local and distant recurrence. In their most recent report from 2014, at a median follow-up of 60 months (range 12–233 months), 31% of patients (28 of 90 who had experienced a clinical complete response at initial assessment after chemoradiation therapy) developed local recurrence and 14% developed distant recurrence. Among 28 patients in whom this approach failed, 26 patients (93%) were successfully salvaged.
In a smaller retrospective series from Memorial Sloan Kettering Cancer Center, Smith et al reported a 21% local recurrence and 8% distant recurrence at a median of 28 months (range 9–70). All patients with local recurrence were salvaged by surgery. Currently there are two watch-and-wait prospective trials accruing patients, one in the Netherlands by Maas et al that reported one local failure in 21 patients at a median follow-up of 22 months, and another led by the Royal Marsden NHS Foundation Trust in the United Kingdom (ClinicalTrials.gov identifier: NCT01047969). Based on the fact that there is a 15% to 18% complete pathologic response after chemoradiotherapy, there is a group of patients that could potentially be observed. The issue is identifying those patients.
A separate report of registry-derived data by Bhangu et al suggests that organ-preserving transanal excision of responsive stage T1–T2 tumors might be a viable approach. However, it is important to emphasize that patient inclusion criteria and clinical outcomes have varied considerably across available published reports; therefore, this approach remains experimental.
A phase III randomized trial (GÃ©rard JP et al: J Clin Oncol 2010) of neoadjuvant radiation for T3-4, M0 rectal cancer compared outcomes when either capecitabine (Xeloda) or capecitabine and oxaliplatin (Eloxatin) was added to radiation therapy. With 598 patients randomized, this trial showed no significant benefit to the addition of oxaliplatin. The investigators concluded that oxaliplatin does not add meaningful benefit when added to capecitabine and radiation therapy.
Selective use of radiotherapy with neoadjuvant chemotherapy is being evaluated by the PROSPECT phase III trial. Patients with 20% or greater decrease in tumor size in response to upfront 5-FU/leucovorin/oxaliplatin are randomized to immediate TME without radiation or to standard chemoradiation followed by TME. Poor responders receive standard chemoradiation prior to TME, and all enrolled patients receive adjuvant chemotherapy.
Preoperative vs postoperative chemoradiation therapy. Preoperative chemoradiation therapy is now preferred in most cases to postoperative adjuvant treatment, particularly in patients with T3 or T4 lesions. Such treatment may enhance resectability and may be associated with a lower frequency of complications compared with postoperative treatment. In a report of a randomized trial conducted by the German Rectal Cancer Study Group, Sauer et al reported that at 10-year follow-up, compared with postoperative chemoradiotherapy, preoperative chemoradiotherapy significantly decreased the rate of local failure (7.1% vs 10.1%; P = .048) with no difference in overall survival (59.6% vs 59.9%; P = .85). Sphincter preservation in low-lying tumors (39% vs 19%; P < .004) and the incidence of chronic anastomotic stricture were also lowest in the preoperative chemoradiotherapy group (4% vs 12%; P = .003). These findings are consistent with those from another large multi-institutional phase III trial, which found that short-course preoperative radiation therapy improved local tumor control and disease-free survival compared with postoperative chemoradiation therapy. In the NSABP R-03 study that compared preoperative and postoperative chemoradiotherapy, patients treated with preoperative chemoradiotherapy had an improved 5-year disease-free survival (64.7% vs 53.4%). No patient with a pathologic complete response had a recurrence. Collectively, these trials suggest that for patients with indications for chemoradiotherapy, preoperative therapy is preferred.
Choice of chemotherapy during radiation therapy. Commonly used chemotherapy regimens are shown in Table 9. The optimal chemotherapy to use in combination with radiation remains an area of active research. Although most large randomized trials have used bolus or infusional 5-FU in combination with radiation, the availability of oral agents, such as capecitabine, has raised interest in combining capecitabine and radiation alone and with other chemotherapeutic agents. The NSABP R-04 compared capecitabine-containing regimens combined with radiation with infusional 5-FU regimens. In the NSABP R-04 study, the sphincter-saving procedures, surgical downstaging, and pathologic complete responses were similar whether infusional 5-FU or capecitabine was used during preoperative radiation. Furthermore, the addition of oxaliplatin did not improve preliminary outcomes, but it did add toxicity. Two other studies did not confirm earlier phase I and II trials, failing to show improved pathologic complete response rate; disease-free and overall survival data are pending. A separate phase III trial of capecitabine alone or with oxaliplatin, when added to radiation, suggested no benefit to the addition of oxaliplatin. A preliminary report of the German AIO-4 trial testing the addition of oxaliplatin to 5-FU/leucovorin alone preoperatively with radiation and postoperatively as adjuvant therapy was presented at the 2014 meeting of the American Society of Clinical Oncology (ASCO). The results demonstrated a trend toward improved recurrence patterns with oxaliplatin (primary endpoint, disease-free survival); survival data are immature. A number of retrospective and phase II studies have suggested that the combination of capecitabine and radiation yields pathologic response rates similar to those observed with 5-FU and radiation. The initial results of a randomized phase III trial of neoadjuvant chemoradiotherapy, comparing capecitabine with 5-FU, found that capecitabine was more tolerable and provided a significantly better 3-year disease-free survival. Additional follow-up of these studies will be required to determine the optimal chemotherapy regimen during radiotherapy.
Alternative radiotherapy approaches. Localized radiation dose escalation, via either endocavitary contact treatment or endoluminal brachytherapy, has been attempted, with modest improvement in tumor response rates. A Danish trial reported by Jakobsen et al randomized patients with resectable T3-4 tumors to standard delivery of 50.4 Gy with 5-FU–based chemotherapy or identical treatment with an endorectal brachytherapy boost of 10 Gy in two treatments. Although T3 tumors in the brachytherapy-boost study arm demonstrated an improved major response rate (44% vs 29%), the pathologic complete response rate remained identical in both treatment arms. Alternatively, as Engels et al have reported, early work has demonstrated the potential feasibility of comprehensive radiation-dose escalation in patients with both primary and nodal disease, with IMRT delivered at a dose of at least 55 Gy. Further work will be required to demonstrate significant clinical benefit to this approach.
Local recurrences of colon cancer are rare. They usually occur at the site of anastomosis, in the resection bed, or in the contiguous lymph nodes. Anastomotic recurrences diagnosed during surveillance in asymptomatic patients are the most curable, followed by local soft tissue recurrences. Regional and retroperitoneal lymph node recurrences portend a poor prognosis and systemic disease.
The development of chemotherapy for advanced CRC has become an active field (Table 11). After decades of 5-FU–based treatment and few clinical gains, the arrival of new, effective agents has significantly changed the way this cancer is treated. Although 5-FU remains the backbone of most regimens, the new agents irinotecan and oxaliplatin have become an important part of front-line treatment of this disease in the United States and abroad. The recent development of molecular targeted agents has provided additional improvements in both response and survival for patients with CRC.
TABLE 10: Chemotherapy for advanced disease
5-FU. 5-FU remains an important agent in the treatment of advanced CRC. Mainly in the past, 5-FU was administered as a bolus injection either weekly or daily for 5 days, every 4 to 5 weeks (Table 7). With these regimens, response rates have been approximately 10% to 15%. The development of permanent venous access devices and portable infusion pumps has permitted the prolonged infusion of 5-FU on an outpatient basis.
The pattern of 5-FU toxicity differs depending on whether it is administered as a bolus or a prolonged infusion or by other methods. Bolus administration has pronounced myelotoxic effects, whereas the dose-limiting toxic effects of prolonged-infusion 5-FU are mucositis and diarrhea. Palmar-plantar erythrodysesthesia (hand-foot syndrome) has been reported with prolonged infusions. Infusional 5-FU is now an important component of therapy when combined with either irinotecan or oxaliplatin.
Biochemical modulation of 5-FU. Interest in the biochemical modulation of 5-FU by leucovorin is based on preclinical studies demonstrating that leucovorin raises the level of N5,N10-methylenetetrahydrofolate and, thus, forms a stable tertiary complex of TS, the folate coenzyme, and 5-FU (in the form of 5-fluorodeoxyuridine). The use of 5-FU with leucovorin results in higher response rates than 5-FU alone and may prolong survival.
Although there is no agreement as to the optimal dose of leucovorin, historically two dosing schedules (as shown in Table 7) have been used with either low-dose or high-dose leucovorin.
FOLFOX. FOLFOX was approved by the FDA in 2004 as first-line therapy. Initial evidence of activity (a 45% response rate) was demonstrated in patients with pretreated, 5-FU–resistant CRC. In subsequent trials, patients with untreated metastatic CRC receiving FOLFOX had response rates of over 50%. In addition, patients receiving oxaliplatin, infusional 5-FU, and leucovorin have achieved overall survival rates of more than 20 months in several reported trials. However, many of these patients have received second- and even third-line therapies at the time of disease progression, reducing the validity of survival evaluation. Currently, there are several accepted FOLFOX regimens in use, including FOLFOX4, FOLFOX6, modified FOLFOX6, and FOLFOX7.
Oxaliplatin’s toxicity profile includes nausea/vomiting and cumulative, reversible peripheral neuropathy. Patients may also develop a reversible, cold-induced, acute pharyngolaryngeal neuropathy. The OPTIMOX trials demonstrated that patients with either stable or responding metastatic CRC may benefit from an oxaliplatin-free interval with either no therapy or maintenance 5-FU and leucovorin followed by reintroduction of FOLFOX at the time of disease progression. The use of maintenance therapy compared with continued FOLFOX provided a comparable overall period of disease control. Maintenance therapy lessened the amount of oxaliplatin-induced neuropathy.
In patients with metastatic colorectal cancer responding to FOLFOX, a break from chemotherapy was compared with maintenance chemotherapy (5-FU, leucovorin) in the randomized trial OPTIMOX2. As Chibaudel et al reported, disease control was significantly longer with maintenance chemotherapy than with a break from chemotherapy (13.1 vs 9.2 months).
Irinotecan. Irinotecan has significant clinical activity in patients with metastatic CRC whose disease has recurred or spread after standard chemotherapy. Its FDA approval was based on two phase III trials showing that irinotecan (350 mg/m2 once every 3 weeks) significantly increased survival, compared with best supportive care and infusional 5-FU, respectively, in patients with recurrent or progressive cancer following first-line 5-FU therapy. Irinotecan increased the median survival by 27% and 41%, respectively, in the two trials. Irinotecan is active in patients whose disease progressed while receiving 5-FU. Reproducible 15% to 20% response rates in this patient population led to the approval of irinotecan for use in patients with 5-FU–refractory disease. The dosage schedules most commonly used are 125 mg/m2 weekly for 4 weeks, followed by a 2-week rest period (United States) and 350 mg/m2 every 3 weeks (Europe). The primary toxicities of irinotecan are diarrhea and neutropenia. Intensive loperamide is important in the management of the former complication. An initial 4-mg loading dose is given at the first sign of diarrhea, followed by 2-mg doses every 2 hours until diarrhea abates for at least a 12-hour period.
Studies have shown that variation in the metabolism of irinotecan is associated with the pattern of allelic inheritance with the gene UGT 1A1. Although it is recommended that UGT 1A1 testing be performed prior to the use of irinotecan, dose-modification recommendations, based on the pattern of alleles inherited, are not currently available. However, it is recommended that patients with the UGT 1A1*28 pattern of inheritance should receive a reduced dose of irinotecan.
FOLFIRI. Several randomized trials have shown improved response rates and overall survival when irinotecan is added to an infusional regimen of 5-FU and leucovorin compared with 5-FU and leucovorin alone. IFL, a bolus combination of irinotecan, 5-FU, and leucovorin, had also shown better response rates and overall survival but proved to be much more toxic. The use of IFL is no longer recommended.
In a phase III trial comparing the sequence of FOLFIRI followed by FOLFOX or the reverse sequence for patients with metastatic CRC, no difference in median survival was seen. Grade 3 or 4 mucositis, nausea, and vomiting occurred more frequently with FOLFIRI, whereas grade 3 or 4 neutropenia and neurosensory toxicity were more frequent with FOLFOX. Response rates were similar between the two groups. The results of this clinical trial and others stress the importance of using all available agents in the treatment of metastatic CRC, and the sequence of their use appears to be less important.
Capecitabine. Capecitabine, an oral prodrug of 5-FU, in a phase III trial of previously untreated patients with metastatic colon cancer, produced higher response rates than did 5-FU and leucovorin. Overall survival and time to disease progression were similar (noninferior) to outcomes with 5-FU and leucovorin. As established in European trials, the recommended dose of capecitabine is 2,500 mg/m2 each day, given as a twice-daily dose, for 14 days followed by a 1-week rest period. However, most North American patients will not tolerate this dose of capecitabine and should instead receive 2,000 mg/m2 each day, given as a twice-daily dose, for 14 days followed by a 1-week rest period. The adverse effects of capecitabine tend to be similar to those seen with prolonged infusion of 5-FU, with hand-foot syndrome being the most common.
Capecitabine and oxaliplatin. Capecitabine and oxaliplatin may also provide significant benefit. Results of completed clinical trials with capecitabine and oxaliplatin are similar to those obtained with FOLFOX. This combination avoids the need for a central venous catheter.
Capecitabine and irinotecan. Capecitabine and irinotecan may also be of benefit. This combination should be used with caution because of diarrheal toxicity from both agents. Although some clinical trials have shown this combination to be tolerable and active, other trials of capecitabine and irinotecan have shown significant toxicity. overall response rate
FOLFOXIRI. Triple combinations of 5-FU (LV), irinotecan, and oxaliplatin (FOLFOXIRI) have been tested against FOLFIRI alone, showing improvements in response rate, progression-free survival, and overall survival. Such treatment could be considered for bulky disease, highly symptomatic patients, and poor-prognosis patients (eg, those with BRAF mutations, peritoneal disease). In the TRIBE study, Falcone et al reported that the addition of bevacizumab increased overall response rate and progression-free survival but not overall survival.
TAS-102. TAS-102, an oral agent that combines trifluridine and tipiracil hydrochloride, is effective in the treatment of refractory colorectal cancer. In a large phase III trial of TAS-102 in refractory metastatic CRC reported by Mayer et al, the median overall survival improved from 5.3 months with placebo to 7.1 months with TAS-102, and the HR for death in the TAS-102 group vs the placebo group was 0.68 (95% CI, 0.58–0.81; P < .001). These results are comparable to those seen with regorafenib (see below). This agent was approved by the FDA in September 2015.
A variety of monoclonal antibodies and small molecules are being evaluated in clinical trials and preclinical studies. Three of these agents (bevacizumab [Avastin], cetuximab [Erbitux], and panitumumab [Vectibix]) have been approved by the FDA for use in CRC.
Mutations in the gene KRAS have been associated with a lack of response to the epidermal growth factor receptor (EGFR) inhibitors cetuximab and panitumumab. However, an analysis of specific KRAS mutations indicates that the Gly13Asp mutation may still retain sensitivity to EGFR inhibitors (De Roock W et al: JAMA 2010). There is increasing retrospective evidence to show that mutations in BRAF may be associated with significantly shortened overall survival (Van Cutsem E et al: J Clin Oncol 2011). However, BRAF mutations do not preclude a potential benefit from chemotherapy (Laurent-Puig P et al: J Clin Oncol 2009; Richman SD et al: J Clin Oncol 2009).
Bevacizumab. Bevacizumab is a humanized monoclonal antibody that binds circulating vascular endothelial growth factor. When given with a 5-FU–containing regimen in several different trials as first-line therapy in patients with metastatic CRC, bevacizumab led to an improved outcome. The addition of bevacizumab to 5-FU and leucovorin resulted in significant improvement in progression-free survival. Even better results were seen with IFL, when the addition of bevacizumab to IFL resulted in significant improvement in overall survival and response rates. These studies led to approval of bevacizumab by the FDA. It is indicated for use in first-line therapy for metastatic CRC when combined with 5-FU–based chemotherapy, such as FOLFOX, and continued in second-line as well (TML study).
Aflibercept. Aflibercept is a recombinant fusion protein containing the VEGF receptor 1 and 2 binding domains fused to the Fc portion of human IgG1. When evaluated as second-line therapy, in combination with FOLFIRI, a significant survival benefit was seen compared with FOLFIRI and placebo.
Ramucirumab. Ramucirumab is a VEGFR2-directed antiangiogenic antibody. The RAISE trial compared second-line FOLFIRI alone vs FOLFIRI with ramucirumab. RAISE met its primary endpoint, demonstrating a statistically significant improvement in overall survival of 1.6 months for RAM and FOLFIRI vs placebo and FOLFIRI in second-line therapy for patients with mCRC. These overall survival results are similar to those achieved by aflibercept or second-line bevacizumab.
Cetuximab. Cetuximab is a human/mouse chimeric antibody directed against EGFR. In a randomized trial of patients with CRC refractory to irinotecan, patients were randomized to receive either cetuximab and irinotecan or cetuximab alone. The addition of cetuximab to irinotecan led to a significantly higher response rate compared with cetuximab alone. The median survival for those receiving cetuximab and irinotecan was also longer, although not significantly. On the basis of the results of this study, cetuximab was approved by the FDA for use in patients whose disease is refractory to irinotecan with tumors expressing EGFR. Data from a phase III trial in which cetuximab added to FOLFIRI was compared with FOLFIRI alone suggest that patients with tumors harboring mutant KRAS derived no benefit from the addition of cetuximab. A benefit in progression-free survival and response rates was seen with the addition of cetuximab in patients with wild-type KRAS. First-line treatment with cetuximab was approved by the FDA in July 2012 for patients with wild-type KRAS. Recent data suggest that KRAS and NRAS mutations beyond those currently tested, representing an additional 15% to 20% of patients, may also confer resistance to EGFR agents, thereby enriching the outcomes for wild-type tumors.
Sidebar: Two large trials, FIRE-3 and C80405, addressed the use of bevacizumab vs cetuximab in first-line KRAS wild-type patients. FIRE-3 combined FOLFIRI with either agent, and C80405 allowed either FOLFOX or FOLFIRI to be administered with the biologic. There are many differences between the two studies, making direct comparisons difficult. FIRE-3 showed a nonsignifcant trend for cetuximab in response rate, no difference in progression-free survival, but a 7.5-month improvement in overall survival. C80405 showed no significant improvement in any measure, with 10% of patients undergoing potentially curative surgery. Clinicians in Europe have embraced the FIRE-3 data, whereas in the US cetuximab is used less in first-line therapy (Venook AP et al: J Clin Oncol 32[suppl 5s], 2014: abstract LBA3; Heinemann V et al: Lancet Oncol 15:1065–1075, 2014).
Panitumumab. Panitumumab is a monoclonal antibody that targets EGFR. In a pivotal phase III trial, 463 patients with metastatic CRC who had failed to respond to previous standard therapy were randomized to panitumumab (6 mg/kg every 2 weeks) plus best supportive care or to best supportive care alone. Patients in the panitumumab arm achieved a significantly improved time to disease progression (96 days vs 60 days) and objective response rate (8% vs 0%). On the basis of the results of this trial, the FDA approved panitumumab for the treatment of patients with CRC that has metastasized following standard chemotherapy.
Regorafenib. Regorafenib is an oral multikinase inhibitor. In a randomized, placebo-controlled, phase III trial in last-line therapy, regorafenib significantly improved overall survival from 5 months with a placebo to 6.4 months with regorafenib.
Combination of targeted agents. The successes observed with cetuximab and bevacizumab in combination with 5-FU–based chemotherapy have led to studies combining these agents with 5-FU–based chemotherapy in patients with metastatic CRC. Combined antibody therapy with bevacizumab and cetuximab, when added to chemotherapy, surprisingly has shown no benefit and in some cases resulted in significantly shorter progression-free survival and an inferior quality of life. Similarly, the addition of panitumumab and bevacizumab to chemotherapy results in increased toxicity and decreased progression-free survival when compared with chemotherapy and bevacizumab alone. Therefore, the combination of chemotherapy and bevacizumab with either cetuximab or panitumumab should not be used outside a clinical trial.
The need for surgery, radiation, or intraluminal stenting of the primary tumor in patients presenting with synchronous metastatic CRC was assessed in patients from a prospective institutional database. All of the patients had received standard chemotherapy with or without bevacizumab. Of 233 patients identified in the database by Poultsides et al, 217 (93%) never required any intervention for their primary tumor. Similar results were reported when similar patients with asymptomatic colon cancers were identified prior to treatment and accrued in the NSABP C-10 trial. The combination of consistent retrospective and prospective data supports the nonoperative approach to surgically incurable scenarios. The Dutch CAIRO-4 trial is prospectively addressing this question.
For previously untreated patients with stage IV disease and limited organ involvement, such as liver-only metastases, in whom surgery is thought possible, consideration should be given to neoadjuvant chemotherapy followed by synchronous or staged partial colectomy and metastasectomy. The appropriate chemotherapy in this setting is uncertain. However, the use of FOLFOX or FOLFIRI is reasonable. The addition of bevacizumab may enhance the response. However, because of the potential risk for bleeding or other surgical complications, bevacizumab should be discontinued 6 to 8 weeks before surgery. Planned perioperative trials of FOLFOX, with or without cetuximab (the EPOC [Eloxatin Perioperative Chemotherapy] trial), have shown some prolongation of disease-free survival with hepatic surgery, but no impact on overall survival; the addition of cetuximab adversely affected outcomes for uncertain reasons (as seen in the New EPOC trial). In addition, because of liver-associated changes with oxaliplatin or irinotecan after approximately 2 to 3 months of chemotherapy, it is preferable to proceed with surgery after about 3 months of chemotherapy. Additional chemotherapy can be given after recovery from surgery. Patients who develop limited metastatic disease after surgery and adjuvant therapy for stages II to III disease may also obtain long-term benefit from further chemotherapy and surgery.
Metastases to the liver and lungs account for most cases of non-nodal systemic disease in CRC. Resection of metastases, or metastasectomy, has gained recognition as a viable treatment. Resection of liver metastases results in cure rates of 5% to 60%, depending on the number of metastases and the stage of disease. Resection of solitary metastases in patients with stage I or II disease results in a 5-year survival rate of approximately 40% to 60%.
Metastasectomy for liver metastases should only be considered when complete resection is feasible on the basis of anatomic grounds and when adequate hepatic function can be maintained. Debulking resections are generally not recommended. Patients who are initially unresectable can be considered for resection after neoadjuvant chemotherapy as long as all disease, including the primary tumor, can be resected. Hepatic resection is the treatment of choice for resectable liver metastases from CRC. Ablative techniques, such as radiofrequency ablation, can be considered in amenable lesions when surgical resection is not feasible.
Metastasectomy for lung metastases can be considered for highly select patients in whom complete resection is feasible with maintenance of adequate pulmonary function. Extrapulmonary metastases, particularly liver metastases, do not preclude resection.
Radiation therapy is moderately effective in palliating the symptoms of advanced rectal cancer. Pain is decreased in 80% of irradiated patients, although only 20% report complete relief. Bleeding can be controlled in more than 70% of patients. Obstruction cannot be reliably relieved by irradiation, and a diverting colostomy is recommended. Only 15% of patients with recurrent rectal cancers achieve local disease control with irradiation, and median survival is less than 2 years. Radiation therapy may be used for retreatment of recurrent rectal cancer, however, the best chances of local control and long-term survival are achieved when complete surgical extirpation can be accomplished.
Chemoradiation therapy. Chemoradiation therapy may be useful to convert fixed unresectable lesions into resectable lesions. These regimens have generally incorporated protracted infusions of 5-FU (200 to 250 mg/m2/d) delivered via a portable infusion pump during pelvic radiation therapy (4,500 cGy over 5 weeks) or treatment with capecitabine.
Intraoperative radiotherapy (localized irradiation given to the tumor or tumor bed at the time of resection) is under active investigation in advanced and locoregionally recurrent rectal cancers.
Laser photoablation is occasionally employed for temporary relief of obstructive rectal cancer in patients who are not surgical candidates because of the presence of distant metastases, surgical comorbidity, or extensive intra-abdominal disease.
TABLE 11: NCCN recommendations for post-treatment surveillance/monitoring
Endoscopic stents may have a place in patients with obstructing neoplasms. In this situation, the stent can serve as a bridge to relieve the obstruction before surgery and/or to allow for the administration of systemic therapy. However, the stent can migrate; thus, if there is response to therapy, the stent may dislodge and cause acute problems, such as perforation or pain. In some instances, the stent can also erode into adjacent structures, such as when radiation is used. Stents should not be used in mid or distal rectal cancers because if they migrate, they may cause pain.
Patients who have completed therapy for CRC require monitoring for potential treatment-related complications, recurrent disease, and new metachronous cancers. Specific follow-up recommendations for these patients are controversial. Guidelines for post-treatment surveillance/monitoring adopted by the National Comprehensive Cancer Network (NCCN) are shown in Table 11.
In the United States, an estimated 7,270 new cases of anal canal carcinoma (combined with anorectal cancers) were diagnosed in 2015, with over 100 deaths. Overall, it is slightly more common in women than in men. More than 80% of anal canal tumors occur in individuals older than 60 years. Epidemiologic studies suggest that receptive anal intercourse and human papillomavirus (HPV) infections are strongly related to anal cancer.
The incidence rate of anal cancer for single men is reported to be six times that for married men. In persons younger than 35 years, anal carcinoma is more common in men than in women. A history of genital warts has been observed, further suggesting that HPV infection may be an etiologic factor.
Given the availability of commercially available prophylatic HPV vaccines, anal canal cancer is a potentially preventable cancer. The quadravalent HPV vaccine (Gardasil) received supplemental approval from the FDA for prevention of anogential cancers in 2010. The more recent FDA approval of the nonavalent HPV vaccine (Gardasil 9) in late 2014 included an explicit indication for prevention of anal cancers.
The diagnosis of anal canal carcinoma is usually delayed because the symptoms (bleeding, pain, and sensation of mass) are often attributed to benign anorectal disorders, such as hemorrhoids or anal fissures.
Evaluation should include a careful rectal examination, endoscopic examination with description of lesion size, and assessment of whether there is invasion of disease into adjacent organs (vagina, urethra, or bladder). Reexamination with the patient under general anesthesia may be necessary. A diagnostic incisional biopsy is required. Although distant metastases are not common, chest, abdomen and pelvic CT or pelvic MRI should be performed upon initial evaluation. Suspicious inguinal nodes discovered on physical examination must be assessed pathologically. The incidence of inguinal nodal metastases at diagnosis varies from 13% to 25%. The presence of perirectal, inguinal, and pelvic lymph node involvement correlates with tumor size and is unusual for tumors less than 2 cm in diameter. Formal groin dissection is not advised; needle aspiration should be performed, with limited surgical biopsy if results of aspiration are inconclusive. As part of the workup, HPV (human papillomavirus) serotyping should be considered, as well as HIV (human immunodeficiency virus) testing if indicated.
Most anal canal malignancies are squamous cell carcinomas. They have been classified as cloacogenic carcinomas, basaloid carcinomas, transitional cell carcinomas, or mucoepidermoid carcinomas. However, there is little difference in the natural history of these various types.
Unusual tumors arising in the anal canal include small-cell carcinomas, anal melanomas, and adenocarcinomas.
Small-cell carcinomas of the anal canal are aggressive neoplasms similar in natural history to bronchogenic small-cell carcinomas. If such a histology is identified, the clinician should be alerted to the possibility of early distant metastases, and treatment should include chemotherapeutic regimens used in bronchogenic small-cell carcinomas.
TABLE 12: TNM classification of anal canal tumors
Although advanced anal melanomas generally are associated with a dismal survival, prognosis may be related to the depth of disease penetration. Early anal melanomas less than 2 mm in depth can be cured with wide excision. More advanced disease can be treated with local excision and EBRT, with excellent local tumor control. Abdominoperineal resection is indicated only rarely in the management of anal melanoma, because lesions large enough to require radical surgery are almost always associated with distant spread of disease.
Adenocarcinomas are uncommon cancers associated with a poor prognosis. Treatment should be aggressive and based on a multimodality approach. The rarity of this tumor precludes the development of specific clinical trials.
The size of the primary tumor is the most important clinical predictor of survival for patients with anal carcinomas. Both the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) have agreed on a unified staging system (Table 12). The TNM classification distinguishes between anal canal carcinoma and anal margin tumors, because the latter exhibit biologic behavior similar to that of other skin cancers and are staged as skin cancers.
In select individuals with small superficial T1 tumors, local excision has achieved adequate local tumor control and survival. However, most studies of local excision have been retrospective, with small numbers of patients. Before the advent of primary radiotherapy and combined-modality treatment, abdominoperineal resection was considered to be the conventional treatment for patients with invasive anal canal cancer. Unfortunately, even with radical surgical procedures, local recurrences are frequent. Currently, radical extirpative surgery is indicated only after the failure of combined-modality treatment. Salvage abdominoperineal resection for persistent or recurrent disease has resulted in a 5-year survival of up to 60%. In one series, patients presenting with lymphadenopathy at primary diagnosis and those who received less than 55 Gy at initial chemoradiation treatment had a poorer prognosis.
Trials of primary EBRT in patients with anal canal carcinomas have used doses varying between 4,500 and 7,550 cGy. Local tumor control rates of 60% to 90%, with 5-year survival rates of 32% to 90%, are similar to the results of surgical series when the trials are controlled for tumor size.
Interstitial radiation therapy alone has been used primarily in Europe for early-stage lesions. A relatively high radiation dose is delivered to a small volume. This modality carries a high potential for radiation necrosis and fails to incorporate the treatment of the inguinal nodes.
Chemotherapy given concurrently with irradiation is the preferred therapy for most patients with anal canal cancer (Table 13). Investigators from Wayne State University pioneered the use of simultaneous pelvic irradiation and chemotherapy in the treatment of patients with anal canal carcinomas. They demonstrated that the majority of such patients could be treated with this combination, obviating the need for an abdominoperineal resection. The original study design used 3,000 cGy over a period of 3 weeks with 5-FU (1,000 mg/m2/d) as a continuous infusion on days 1 to 4 and then repeated on days 29 to 32. Mitomycin, at 15 mg/m2, was administered as an IV bolus on day 1. At 4 to 6 weeks after the completion of therapy, patients had a deep muscle biopsy of the anal canal scar.
TABLE 13: Chemotherapy regimen for anal canal cancer
An updated analysis of this experience demonstrated that 38 of 45 patients (84%) were rendered disease-free after chemotherapy and irradiation. Individuals who had positive results on biopsy underwent an abdominoperineal resection.
Because of the success of this experience, other investigators have attempted to implement infusional 5-FU and mitomycin with irradiation as definitive therapy. Most studies have used similar schedules of 5-FU and mitomycin but have used higher doses of pelvic irradiation (4,500 to 5,700 cGy). Five-year survival rates greater than 70% have been reported.
A randomized trial from the Radiation Therapy Oncology Group (RTOG) showed that the use of mitomycin with irradiation and 5-FU increased complete tumor regression and improved colostomy-free survival over irradiation and 5-FU alone. At 4 years, the colostomy-free survival rate was higher in the mitomycin arm than in the 5-FU–alone arm (71% vs 59%), as was the disease-free survival rate (73% vs 51%). Several investigators have compared the results of irradiation alone with those of irradiation plus chemotherapy. The current standard chemotherapy regimen for concurrent radiation is concurrent 5-FU and mitomycin. Intergroup RTOG 98-11 compared 5-FU plus mitomycin concurrently with radiotherapy, with 5-FU plus cisplatin induction followed by 5-FU plus cisplatin concurrently with radiotherapy. The mitomycin-containing regimen resulted in a lower colostomy rate but greater hematologic toxicity. In the ACT II trial, a prospective randomized factorial 2 × 2 study conducted in the UK, patients were randomized to 5-FU with mitomycin C or cisplatin concurrently with irradiation with or without two courses of maintenance chemotherapy consisting of 5-FU and cisplatin. In this study there was no superiority of cisplatin over mitomycin C in terms of complete response, 3-year colostomy-free survival, or 3-year progression-free survival. There was no benefit from maintenance chemotherapy. The authors concluded that 5-FU and mitomycin should remain the standard of therapy in the UK. Cummings et al found that with identical irradiation doses and techniques, the local tumor control rate for cancers larger than 2 cm rose from 49% with radiation therapy alone to 85% when 5-FU and mitomycin were combined with irradiation. Papillon and Montbarbon found an increase in the rate of local tumor control with a combined-modality approach compared with pelvic irradiation alone (81% vs 66%). Two randomized studies have shown improved local tumor control with chemoradiation therapy over irradiation.
A complete response to combined chemotherapy and radiation therapy is expected in 80% to 90% of patients with anal cancer. It is important to evaluate the response to therapy with a careful examination of the anal canal after treatment. Anal canal cancers can continue to regress for up to 3 or more months after completion of treatment. For this reason, it is recommended that a biopsy be performed no sooner than 3 months after the completion of treatment, unless there is evidence of disease progression or other evidence to suggest early recurrence. If pathologic evidence of recurrence is diagnosed, abdominoperineal resection is expected to yield long-term disease control and survival in 40% to 60% of patients.
Toxicity from combined radiotherapy and chemotherapy for anal carcinoma is significant, with high rates of dermatitis (often requiring treatment breaks) and gastrointestinal toxicity. Treatment breaks may decrease the efficacy of radiation. Intensity-modulated radiotherapy (IMRT) can help reduce the radiation dose to normal structures, such as the bowel, skin, genitalia, and femurs. Several phase II trials, including the RTOG 0529 trial, have evaluated the use of IMRT with concurrent chemotherapy to reduce these toxicities. Growing institutional experience, such as a retrospective series of 223 cases from Memorial Sloan Kettering reported by Dasgupta et al in 2013, suggests that conformal IMRT approaches provide at least equivalent tumor control outcomes with improved toxicity profiles. RTOG maintains an online IMRT contouring atlas for radiation oncology providers (available at https://www.rtog.org/CoreLab/ContouringAtlases/Anorectal.aspx).
Similar to rectal cancer, attempts have been made to escalate the local primary tumor dose with brachytherapy, to improve treatment response. For example, a prospective 2 × 2 randomized trial from France, reported by Peiffert et al, randomized patients with T2–T3N0 or T1–T2N+ anal canal disease to (1) induction 5-FU/cisplatin alone or (2) standard induction chemoradiation with 15 Gy external beam boosting, or to identical induction arms substituting the external beam boost with a high-dose 20–25 Gy interstitial brachytherapy boost. Unfortunately, both pathologic complete response and colostomy-free survival outcomes failed to improve significantly for patients in either high-dose–boost arm.
Reports of other chemotherapeutic agents in anal cancer have been relatively anecdotal, with limited phase II studies. Because of the activity of cisplatin in other squamous cell carcinomas, this agent has been employed as a single agent or combined with infusional 5-FU in advanced disease.
Novel chemoradiation regimens have been evaluated in the hope of providing improved tumor control rates in patients receiving combined chemotherapy and radiation. Recent studies have evaluated chemotherapy combinations including cetuximab with radiation. These early studies are promising in regard to tolerability and response rates. The combination of cetuximab, cisplatin, and 5-FU with radiation therapy is being tested in HIV-positive patients by the AIDS-Associated Malignancies Clinical Trials Consortium (AAMCTC) and the Eastern Cooperative Oncology Group (ECOG).
Immunocompromised patients are at higher risk for developing anal carcinoma. Because these patients may also have increased toxicity with combined chemotherapy and radiation, careful delivery of combined therapy should include a consideration of chemotherapy dose modification. Several series have evaluated the ability of immunocompromised patients to tolerate definitive chemoradiotherapy for anal cancer. Some series suggest that a CD4+ cell count lower than 200/Î¼L in HIV-positive patients is associated with higher rates of toxicity. Recent studies have shown that the vast majority of immunocompromised patients can tolerate concurrent chemoradiotherapy, although dose adjustments may be required. The use of IMRT may benefit this patient subset.
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