Colon, Rectal, and Anal Cancers

Advanced colon cancer

Local recurrences from colon cancers usually occur at the site of anastomosis, in the resection bed, or in the contiguous and retroperitoneal (para-aortic, paracaval) 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.

Chemotherapy. The development of chemotherapy for advanced CRC has become an active field (Table 8). After decades of 5-FU–based treatment, and of little 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(Drug information on irinotecan) and oxaliplatin(Drug information on 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.

• 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 8). 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.

TABLE 8Chemotherapy for advanced disease

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.

TABLE 9Five-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

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 (Chibaudel B et al: J Clin Oncol 2009). Control of disease 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(Drug information on 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. A bolus combination of irinotecan, 5-FU, and leucovorin (IFL) 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(Drug information on 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 those 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.

Molecular targeted agents. A variety of monoclonal antibodies and small molecules are being evaluated in clinical trials and preclinical studies. Three of these agents (bevacizumab [Avastin], cetuximab(Drug information on 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 (Erbitux) and panitumumab (Vectibix). 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(Drug information on 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.

• 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. SWOG C80405 compared either FOLFOX or FOLFIRI, with a direct randomized comparison of chemotherapy plus either bevacizumab or cetuximab; results are pending.

• 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.

• 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.

Chemotherapy and surgery for stage IV CRC. 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. 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 with the development of 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.

Metastasectomy. 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 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. Resectable extrapulmonary metastases, particularly liver metastases, do not preclude resection.

Advanced rectal cancer

Radiation therapy. 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 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.

• Chemoradiation therapy—Chemoradiation therapy may be useful to convert fixed unresectable lesions into resectable lesions. These regimens have generally used protracted infusions of 5-FU (200 to 250 mg/m²/d) delivered via a portable infusion pump during pelvic radiation therapy (450 cGy over 5 weeks).

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. 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 10NCCN recommendations for post-treatment surveillance/monitoring

Endoscopic stent placement. 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.

Follow-up of long-term survivors

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 10.