Colon, Rectal, and Anal Cancers

Adjuvant therapy for colon cancer

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 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.

Systemic adjuvant chemotherapy. 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. Recently, a multigene assay (Oncotype Dx colon cancer assay, Genomic Health, Inc) became 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).

• FOLFOX, FLOX—FOLFOX, FLOX, (5-FU, leucovorin, and oxaliplatin(Drug information on oxaliplatin)) has been approved by the FDA 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 those receiving FOLFOX. More recently, FOLFOX6 or a modified version of it (Table 8) 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 by the FDA for adjuvant therapy for patients with stage III colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. Capecitabine(Drug information on capecitabine) was not inferior to bolus 5-FU and low-dose leucovorin for 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 to mFOLFOX. NSABP C-08 randomized patients with resected stage II or III colon cancer to 12 cycles of mFOLFOX6 alone or with bevacizumab(Drug information on bevacizumab). Bevacizumab was given for 6 months beyond 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 randomized patients with resected stage III colon cancer to 12 cycles of mFOLFOX6 alone or with cetuximab(Drug information on cetuximab). The final design of this trial only randomized patients with wild-type KRAS to one of the two treatment arms. The clinical trial PETACC-8 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(Drug information on 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 (ACCORD-2). 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.

Adjuvant therapy for rectal cancer

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.

TABLE 7Adjuvant chemotherapy regimens for colorectal adenocarcinoma (nonmetastatic)

In the absence of nodal metastases, 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.

Preoperative or postoperative radiation therapy. Radiation therapy has been used to reduce the locoregional recurrence rate of rectal tumors. Preoperative radiation therapy has been demonstrated to reduce 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. Preoperative radiation therapy reduced local recurrence rates when combined with TME (13.3% vs 6.3%) in a Dutch phase III trial at a median follow-up of 6 years. 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%.

Chemoradiation therapy.

• 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 is a 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 9.

The most effective combination of drugs, optimal mode of administration, and sequence of irradiation and chemotherapy still need to be determined. Radiation doses of 45 to 55 Gy are recommended in combination with 5-FU–based chemotherapy. Postoperative bolus 5-FU administration with irradiation is inferior to protracted venous infusion, resulting in lower 3-year rates of both overall survival (68% vs 76%) and disease-free survival (56% vs 67%).

An adjuvant treatment combining chemotherapy and pelvic irradiation in patients with stage II or III rectal cancer used the following regimen: 5-FU, 500 mg/m²/d administered as a rapid IV infusion on days 1 to 5 and 450 mg/m²/d on days 134 to 138 and days 169 to 173. Patients received a protracted IV infusion of 5-FU, 225 mg/m²/d, by portable ambulatory infusion pump during the entire period of pelvic irradiation. Pelvic radiation therapy began on day 64 with a multiple-field technique to the tumor bed and nodal groups. A total of 4,500 cGy in 180-cGy fractions was administered over a 5-week period. Patients received a minimal boost dose of 540 cGy to the entire tumor bed, adjacent nodes, and 2 cm of adjacent tissue. A second boost dose of 360 cGy was allowed in select patients, with excellent displacement of the small bowel.

• 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, unresectable rectal cancer, because the disease in most of them 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 investigators have reported good results with transanal excision of T2 and T3 tumors following a complete response to neoadjuvant therapy. However, this approach cannot be considered the current standard of care.

A phase III randomized trial (Gérard 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.

• 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 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—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 pCC 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 number of retrospective and phase II studies have suggested that the combination of capecitabine and radiation provides 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.