Rectal Cancer Treatment (Professional) (cont.)
Stage IV and Recurrent Rectal Cancer
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Treatment options for local control:
- Resection of locally recurrent rectal cancer may be curative in selected patients.
- Palliative surgical resection with either low-anterior resection (LAR) or abdominoperineal resection (APR).
- Palliative radiation therapy.[2,3]
- Palliative chemotherapy.[4,5,6,7,8,9,10]
- Palliative chemoradiation.[11,12]
- Chemotherapy alone for local control.
- Palliative, endoscopic-placed stents to relieve obstruction.
Treatment options for systemic control:
- Resection of liver metastases in selected patients (5-year cure rate with resection of solitary metastases exceeds 20%).[14,15,16,17,18,19,20,21,22,23]
- Resection of isolated pulmonary or ovarian metastases.
- Systemic chemotherapy (see below).
- Clinical trials evaluating new drugs.
Metastatic Rectal Cancer
Treatment of patients with recurrent or advanced colorectal cancer depends on the location of the disease. For patients with locally recurrent and/or liver-only and/or lung-only metastatic disease, surgical resection, if feasible, is the only potentially curative treatment.
Treatment of patients with recurrent or advanced colorectal cancer depends on the location of the disease. For patients with locally recurrent and/or liver-only and/or lung-only metastatic disease, surgical resection, if feasible, is the only potentially curative treatment. For patients with hepatic metastasis considered to be resectable (i.e., based on limited number of lesions, intrahepatic locations of lesions, lack of major vascular involvement, absent or limited extrahepatic disease, and sufficient functional hepatic reserve), a negative margin resection has been associated with 5-year survival rates of 25% to 40% in nonrandomized studies (such as the NCCTG-934653 trial).[24,25,26,27,28][Level of evidence: 3iiiDiv] Better surgical techniques and advances in preoperative imaging have improved patient selection for resection. In addition, multiple studies with multiagent chemotherapy have demonstrated that patients with metastatic disease isolated to the liver, which historically would be considered unresectable, can occasionally be made resectable after the administration of chemotherapy.
Currently, there are seven active and approved drugs for patients with metastatic colorectal cancer:
Currently, there are seven active and approved drugs for patients with metastatic colorectal cancer: 5-FU, capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab, and panitumumab. When 5-FU was the only active chemotherapy drug, trials in patients with locally advanced, unresectable, or metastatic disease demonstrated partial responses and prolongation of the time-to-progression (TTP) of disease,[5,30] as well as improved survival and quality of life for patients receiving chemotherapy compared with best supportive care.[31,32,33] Several trials have analyzed the activity and toxic effects of various 5-FU-leucovorin regimens, using different doses and administration schedules, and showed essentially equivalent results with a median survival time in the 12-month range. Prior to the advent of multiagent chemotherapy, two randomized studies demonstrated that capecitabine was associated with equivalent efficacy when compared with the Mayo Clinic regimen of 5-FU-leucovorin.[35,36][Level of evidence: 1iiA]
Drug combinations described in this section include the following:
- The Arbeitsgemeinschaft Internische Onkologie (AIO) or German AIO regimen (folic acid, 5-FU, and irinotecan):
- Irinotecan (100 mg/m2) administered as a 2-hour infusion on day 1; leucovorin (500 mg/m2) administered as a 2-hour infusion on day 1; followed by 5-FU (2,000 mg/m2) intravenous (IV) bolus via ambulatory pump administered for a period of 24 hours on a weekly basis four times a year (52 weeks).
- The CAPOX regimen (capecitabine and oxaliplatin):
- Capecitabine (1,000 mg/m2) twice a day on days 1 through 14 plus oxaliplatin (70 mg/m2) on days 1 and 8 every 3 weeks.
- The Douillard regimen (folic acid, 5-FU, and irinotecan):
- Irinotecan (180 mg/m2) administered as a 2-hour infusion on day 1; leucovorin (200 mg/m2) administered as a 2-hour infusion on day 1 and day 2; followed by a loading dose of 5-FU (400 mg/m2) IV bolus, then 5-FU (600 mg/m2) via ambulatory pump administered for a period of 22 hours on day 1 and day 2 every 2 weeks.
- The FOLFOX4 regimen (oxaliplatin, leucovorin, and 5-FU):
- Oxaliplatin (85 mg/m2) administered as a 2-hour infusion on day 1; leucovorin (200 mg/m2) administered as a 2-hour infusion on day 1 and day 2; followed by a loading dose of 5-FU (400 mg/m2) IV bolus, then 5-FU (600 mg/m2) administered via ambulatory pump for a period of 22 hours on day 1 and day 2 every 2 weeks.
- The FOLFOX6 regimen (oxaliplatin, leucovorin, and 5-FU):
- Oxaliplatin (85–100 mg/m2) administered as a 2-hour infusion on day 1; leucovorin (400 mg/m2) administered as a 2-hour infusion on day 1; followed by a loading dose of 5-FU (400 mg/m2) IV bolus on day 1, then 5-FU (2,400–3,000 mg/m2) administered via ambulatory pump for a period of 46 hours every 2 weeks.
- The FOLFIRI regimen (folic acid, 5-FU, and irinotecan):
- Irinotecan (180 mg/m2) administered as a 2-hour infusion on day 1; leucovorin (400 mg/m2) administered as a 2-hour infusion on day 1; followed by a loading dose of 5-FU (400 mg/m2) IV bolus administered on day 1, then 5-FU (2,400–3,000 mg/m2) administered via ambulatory pump for a period of 46 hours every 2 weeks.
- The FUFOX regimen (fluorouracil, leucovorin, and oxaliplatin):
- Oxaliplatin (50 mg/m2) plus leucovorin (500 mg/m2) plus 5-FU (2,000 mg/m2) as a 22-hour continuous infusion on days 1, 8, 22, and 29 every 36 days.
- The FUOX regimen (fluorouracil plus oxaliplatin):
- Continuous infusion 5-FU (2,250 mg/m2) during 48 hours on days 1, 8, 15, 22, 29 and 36 plus oxaliplatin (85 mg/m2) on days 1, 15, and 29 every 6 weeks.
- IFL (or Saltz) regimen (irinotecan, 5-FU, and leucovorin):
- Irinotecan (125 mg/m2), 5-FU (500 mg/m2) IV bolus, and leucovorin (20 mg/m2) IV bolus administered weekly for 4 out of 6 weeks.
- The XELOX regimen (capecitabine plus oxaliplatin):
- Oral capecitabine (1,000 mg/m2) twice a day for 14 days plus oxaliplatin (130 mg/m2) on day 1 every 3 weeks.
First-line multiagent chemotherapy
Three randomized studies in patients with metastatic colorectal cancer demonstrated improved response rates, progression-free survival (PFS), and OS when irinotecan or oxaliplatin was combined with 5-FU-leucovorin.[37,38,39] An intergroup study (E-N9741 ) then compared IFL with FOLFOX4 in first-line treatment for patients with metastatic colorectal cancer. Patients assigned to FOLFOX4 experienced improved PFS (median, 6.9 months vs. 8.7 months; P = .014; hazard ratio [HR] = 0.74; 95% confidence interval [CI], 0.61–0.89) and OS (15.0 months vs. 19.5 months, P = .001; HR = 0.66; 95% CI, 0.54–0.82) compared with patients randomly assigned to IFL.[Level of evidence: 1iiA] Subsequently, two studies compared FOLFOX with FOLFIRI, and patients were allowed to cross over after progression on first-line therapy, respectively.[40,41][Level of evidence: 1iiDiii] PFS and OS were identical between the treatment arms in both studies. Since the publication of these studies, the use of either FOLFOX or FOLFIRI is considered acceptable for first-line treatment of patients with metastatic colorectal cancer.
The Bolus, Infusional, or Capecitabine with Camptosar-Celecoxib (BICC-C) trial evaluated several different irinotecan-based regimen in patients with previously untreated metastatic colorectal cancer: FOLFIRI, mIFL, and capecitabine/irinotecan (CAPIRI). The study randomly assigned 430 patients and was closed early due to poor accrual. The patients who received FOLFIRI had a better PFS than the patients who received either mIFL (7.6 months vs. 5.9 months, P = .004) or CAPIRI (7.6 months vs. 5.8 months, P = .015). Patients who received CAPIRI had the highest (grade 3 or higher) rates of nausea, vomiting, diarrhea, dehydration, and hand-foot syndrome. After bevacizumab was approved, the BICC-C trial was amended and an additional 117 patients were randomly assigned to receive FOLFIRI/bevacizumab or mIFL/bevacizumab. Although the primary endpoint of PFS was not significantly different, patients receiving FOLFIRI/bevacizumab had a significantly better OS (28.0 months vs. 19.2 months, P = .037; HR for death = 1.79, 95% CI 1.12 to 2.88). When using an irinotecan-based regimen as first-line treatment of metastatic colorectal cancer, FOLFIRI is preferred.[Level of evidence: 1iiDiii]
Randomized phase III trials have addressed the equivalence of oral FUOX substituting for infusional 5-FU. Two phase III studies have evaluated FUOX versus CAPOX.[43,44] The AIO Colorectal Study Group randomly assigned 474 patients to either FUFOX or CAPOX. The median PFS was 7.1 months for the CAPOX arm and 8.0 months for the FUFOX arm (HR = 1.17; 95% CI, 0.96–1.43: P = .117), and the HR was in the prespecified equivalence range. The Spanish Cooperative Group randomly assigned 348 patients to CAPOX or FUOX. The TTP was 8.9 months versus 9.5 months (P = .153) and met the prespecified range for noninferiority.[Level of evidence: 1iiDiii] When using an oxaliplatin-based regimen as first-line treatment of metastatic colorectal cancer, a CAPOX regimen is not inferior to a FUOX regimen.
The Addition of Targeted Therapy to Multiagent Chemotherapy
Patients with previously untreated metastatic colorectal cancer were randomly assigned to either IFL or IFL plus bevacizumab. The patients randomly assigned to IFL plus bevacizumab experienced a significantly better PFS (10.6 months with IFL and bevacizumab compared to 6.2 months with IFL plus placebo; HR for disease progression = 0.54; P <.001) and OS (20.3 months with IFL plus bevacizumab compared to 15.6 months with IFL plus placebo; HR for death = 0.66; P <.001). Investigators from the Eastern Cooperative Oncology Group (ECOG) randomly assigned patients who had progressed on 5-FU-leucovorin and irinotecan to either FOLFOX or FOLFOX plus bevacizumab. The results demonstrated that patients randomly assigned to FOLFOX plus bevacizumab experienced a statistically significant improvement in PFS (7.3 months vs. 4.7 months: HR for progression = 0.61; P <.0001) and OS (12.9 months vs. 10.8 months; HR for death = 0.75; P = .001).[Level of evidence: 1iiA] Based on these two studies, bevacizumab can reasonably be added to either FOLFIRI or FOLFOX for patients undergoing first-line treatment of metastatic colorectal cancer.
Second-line chemotherapy with irinotecan in patients treated with 5-FU-leucovorin as first-line therapy demonstrated improved OS when compared to either infusional 5-FU or supportive care.[2,23,47,48] Similarly, a phase III trial randomly assigned patients who progressed on irinotecan and 5-FU-leucovorin to bolus and infusional 5-FU-leucovorin (LV5FU2), single-agent oxaliplatin, or FOLFOX4. Median TTP for FOLFOX4 versus LV5FU2 was 4.6 months versus 2.7 months (stratified log-rank test, 2-sided P < .001).[Level of evidence: 1iiDiii]
Erbitux is a partially humanized monoclonal antibody against the epidermal growth factor receptor (EGFR). For patients who have progressed on irinotecan-containing regimens, a randomized phase II study was performed of erbitux or irinotecan plus erbitux. Median TTP for patients receiving erbitux was 1.5 months compared to median TTP of 4.2 months for patients receiving irinotecan and erbitux.[Level of evidence: 3iiiDiv] On the basis of this study, erbitux was approved for use in patients with metastatic colorectal cancer refractory to 5-FU and irinotecan.
The Crystal Study (NCT00154102) randomly assigned 1,198 patients with stage IV colorectal cancer to FOLFIRI with or without cetuximab. The addition of cetuximab was associated with an improved PFS (HR = 0.85; 95% CI, 0.72–0.99, P = .048 by a stratified log rank test), but not OS.[Level of Evidence: 1iiDii] Retrospective studies of patients with metastatic colorectal cancer have suggested that responses to anti-epidermal growth factor receptor (EGFR) antibody therapy are confined to patients with tumors that harbor wild types of KRAS (i.e., lack activating mutations at code on 12 or 13 of the KRAS gene). A subset analysis evaluating efficacy vis a vis KRAS status was done in patients enrolled on the Crystal Study. There was a significant interaction for KRAS mutation status and treatment for tumor response (P = .03) but not for PFS (P = .07). Among KRAS wild-type patients, the HR favored the FOLFIRI/cetuximab group (HR = 0.68; 95% CI, 0.50–0.94).
Importantly, patients with mutant KRAS tumors may experience worse outcome when cetuximab is added to multiagent chemotherapy regimens containing bevacizumab. In a randomized trial, patients with metastatic colorectal cancer received capecitabine/oxaliplatin/bevacizumab with or without cetuximab. The median PFS was 9.4 months in the group receiving cetuximab and 10.7 months in the group not receiving cetuximab (P = .01). In a subset analysis, cetuximab-treated patients with tumors bearing a mutated KRAS gene had significantly decreased PFS compared with cetuximab-treated patients with wild type KRAS tumors (8.1 mo. vs. 10.5 mo.; P = .04). Cetuximab-treated patients with mutated KRAS tumors had a significantly shorter PFS compared with patients with mutated KRAS tumors not receiving cetuximab (8.1 mo. vs. 12.5 mo.; P = .003) as well as OS (17.2 mo. vs. 24.9 mo.; P = .03).[Level of evidence: 1iiDiii]
Panitumumab is a fully humanized antibody against the EGFR. In a phase III trial that has not yet been reported, patients with chemotherapy refractory colorectal cancer were randomly assigned to panitumumab or best supportive care. Patients receiving panitumumab experienced improved OS. Despite the preliminary nature of this study, the FDA approved panitumumab for use in patients with metastatic colorectal cancer refractory to chemotherapy.
Similarly, the addition of panitumumab to a regimen of FOLFOX/bevacizumab resulted in a worse PFS and worse toxicity compared to FOLFOX/bevacizumab alone in patients not selected for KRAS mutation in metastatic colon cancer (11.4 months vs. 10.0 months, HR = 1.27; 95% CI, 1.06–1.52).[Level of evidence: 1iiDiii]
Second-line and third-line chemotherapy
Approximately 15% to 25% of colorectal cancer patients will present with liver metastases at diagnosis, and another 25% to 50% will develop metaschronous hepatic metastasis following resection of the primary tumor.[55,56,57] Although only a small proportion of patients with liver metastasis are candidates for surgical resection, advances in tumor ablation techniques and in both regional and systemic chemotherapy provide a number of treatment options.
For patients with hepatic metastasis considered to be resectable (based on a limited number of lesions, intrahepatic locations of lesions, lack of major vascular involvement, absent or limited extrahepatic disease, and sufficient functional hepatic reserve), a negative-margin resection has resulted in 5-year survival rates of 25% to 40% in mostly nonrandomized studies.[17,21,58,59,60,61] Improved surgical techniques and advances in preoperative imaging have allowed for better patient selection for resection.
Patients with hepatic metastases that are deemed unresectable will occasionally become candidates for resection if they have a good response to chemotherapy. These patients have 5-year survival rates similar to patients who initially had resectable disease. Radiofrequency ablation has emerged as a safe technique (2% major morbidity and <1% mortality rate) that may provide long-term tumor control.[62,63,64,65,66,67,68] Radiofrequency ablation and cryosurgical ablation remain options for patients with tumors that cannot be resected and for patients who are not candidates for liver resection.[69,70,71]
Other local ablative techniques that have been used to manage liver metastases include embolization and interstitial radiation therapy.[72,73,74] Patients with limited pulmonary metastasis, and patients with both pulmonary and hepatic metastasis, may also be considered for surgical resection, with 5-year survival possible in highly selected patients.[75,76,77,78]
The role of adjuvant chemotherapy after potentially curative resection of liver metastases is uncertain. A trial of hepatic arterial floxuridine and dexamethasone plus systemic fluorouracil (5-FU) and leucovorin compared to systemic 5-FU plus leucovorin alone showed improved 2-year PFS (57% vs. 42%, P =.07) and overall survival (OS) (86% vs. 72%, P = .03) for patients in the combined therapy arm; median survival in the combined therapy arm was 72.2 months versus 59.3 months in the monotherapy arm (P =.21).[Level of evidence: 1iiA]
A second trial preoperatively randomly assigned patients with one to three potentially resectable colorectal hepatic metastases to either no further therapy or postoperative hepatic arterial floxuridine plus systemic 5-FU. Among those randomized, 27% were deemed ineligible at the time of surgery, leaving only 75 patients evaluable for recurrence and survival. Although liver recurrence was decreased, median or 4-year survival was not significantly different between the patient groups. Additional studies are required to evaluate this treatment approach and to determine whether more effective systemic combination chemotherapy alone would provide similar results compared to hepatic intra-arterial therapy plus systemic treatment.
Hepatic intra-arterial chemotherapy with floxuridine for liver metastasis has produced higher overall response rates but no consistent improvement in survival when compared to systemic chemotherapy.[16,81,82,83,84,85] Controversy regarding the efficacy of regional chemotherapy has led to initiation of a large multicenter phase III trial (CLB-9481) of hepatic arterial infusion versus systemic chemotherapy. The use of combination intra-arterial chemotherapy with hepatic radiation therapy, especially employing focal radiation of metastatic lesions, is under evaluation. Several studies show increased local toxic effects with hepatic infusional therapy, including liver function abnormalities and fatal biliary sclerosis.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV rectal cancer and recurrent rectal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Locally Recurrent Rectal Cancer
Locally recurrent rectal cancer may be resectable, particularly if an inadequate prior operation was performed. For patients with local recurrence alone following an initial, attempted curative resection, aggressive local therapy with repeat LAR and coloanal anastomosis, APR, or posterior or total pelvic exenteration can lead to long-term disease-free survival (DFS).[87,88] The use of induction chemoradiation for previously nonirradiated patients with locally advanced (pelvic side-wall, sacral, and/or adjacent organ involvement) pelvic recurrence may increase resectability and allow for sphincter preservation.[89,90] Intraoperative radiation therapy in patients who received previous external-beam radiation may improve local control in patients with locally recurrent disease, with acceptable morbidity.
The presence of hydronephrosis associated with recurrence appears to be a contraindication to surgery with curative intent. Patients with limited pulmonary metastases and patients with both pulmonary and hepatic metastases may also be considered for surgical resection, with 5-year survival possible in highly selected patients.[75,76,77]
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV rectal cancer and recurrent rectal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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