Stage IV and Recurrent Colon 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.)

Stage IV colon cancer denotes distant metastatic disease. Treatment of recurrent colon cancer depends on the sites of recurrent disease demonstrable by physical examination and/or radiographic studies. In addition to standard radiographic procedures, radioimmunoscintography may add clinical information that may affect management.[1] Such approaches have not led to improvements in long-term outcome measures such as survival.

Treatment options include the following:

1. Surgical resection of locally recurrent cancer.
2. Surgical resection and anastomosis or bypass of obstructing or bleeding primary lesions in selected metastatic cases.
3. Resection of liver metastases in selected metastatic patients (5-year cure rate for resection of solitary or combination metastases exceeds 20%) or ablation in selected patients.[2,3,4,5,6,7,8,9,10,11]
4. Resection of isolated pulmonary or ovarian metastases in selected patients.[12]
5. Palliative radiation therapy.
6. Palliative chemotherapy.
7. Clinical trials evaluating new drugs and biological therapy.
8. Clinical trials comparing various chemotherapy regimens or biological therapy, alone or in combination.

Liver Metastasis

Approximately 50% of colon cancer patients will be diagnosed with hepatic metastases, either at the time of initial presentation or as a result of disease recurrence. Although only a small proportion of patients with hepatic metastases are candidates for surgical resection, advances in tumor ablation techniques and in both regional and systemic chemotherapy administration provide for a number of treatment options.

Hepatic metastasis may be considered to be resectable based on the following:[5,7,13,14,15,16]

• Limited number of lesions.
• Intrahepatic locations of lesions.
• Lack of major vascular involvement.
• Absent or limited extrahepatic disease.
• Sufficient functional hepatic reserve.

For patients with hepatic metastasis considered to be resectable, a negative margin resection has resulted in 5-year survival rates of 25% to 40% in mostly nonrandomized studies, such as the NCCTG-934653 trial.[5,7,13,14,15,16] 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.[17] Radiofrequency ablation has emerged as a safe technique (2% major morbidity and <1% mortality rate) that may provide for long-term tumor control.[18,19,20,21,22,23,24] Radiofrequency ablation and cryosurgical ablation [25,26,27,28] remain options for patients with tumors that cannot be resected and for patients who are not candidates for liver resection.

Other local ablative techniques that have been used to manage liver metastases include embolization and interstitial radiation therapy.[29,30] 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.[12,31,32]

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 progression-free survival (57% vs. 42%, P = .07) and overall survival (OS) (86% vs. 72%, P = .03) but did not show a significant statistical difference in median survival, compared with systemic 5-FU therapy alone. Median survival in the combined therapy arm was 72.2 months versus 59.3 months in the monotherapy arm (P = .21).[33][Level of evidence: 1iiA]

A second trial preoperatively randomly assigned 109 patients who had one to three potentially resectable colorectal hepatic metastases to either no further therapy or postoperative hepatic arterial floxuridine plus systemic 5-FU.[34] Of those randomly assigned patients, 27% were deemed ineligible at the time of surgery, which left only 75 patients evaluable for recurrence and survival. While liver recurrence was decreased, median or 4-year survival was not significantly different. Further studies are required to evaluate this treatment approach and to determine if more effective systemic combination chemotherapy alone may provide similar results compared with hepatic intra-arterial therapy plus systemic treatment.

Hepatic intra-arterial chemotherapy with floxuridine for liver metastases has produced higher overall response rates but no consistent improvement in survival when compared to systemic chemotherapy.[2,35,36,37,38,39] Controversy regarding the efficacy of regional chemotherapy led to initiation of a large multicenter phase III trial (CALGB-9481, now completed) of hepatic arterial infusion versus systemic chemotherapy. The use of the combination of intra-arterial chemotherapy with hepatic radiation therapy, especially employing focal radiation of metastatic lesions, is under evaluation.[40] Several studies show increased local toxic effects with hepatic infusional therapy, including liver function abnormalities and fatal biliary sclerosis.

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 (1000 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:
  • Oxaliplatin (50 mg/m²) plus leucovorin (500 mg/m²) plus 5-FU (2000 mg/m²) as a 22-hour continuous infusion on days 1, 8, 22, and 29 every 36 days.
• The FUOX regimen:
  • Continuous infusion 5-FU (2250 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.
• The 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:
  • Oral capecitabine (1000 mg/m²) twice a day for 14 days plus oxaliplatin (130 mg/m²) on day 1 every 3 weeks.

Treatment of Patients With Stage IV Disease

Treatment of patients with recurrent or advanced colon 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.

Hepatic metastasis may be considered to be resectable based on the following:[5,7,13,14,15,16]

• Limited number of lesions.
• Intrahepatic locations of lesions.
• Lack of major vascular involvement.
• Absent or limited extrahepatic disease.
• Sufficient functional hepatic reserve.

For patients with hepatic metastasis considered to be resectable, a negative margin resection has been associated with 5-year survival rates of 25% to 40% in mostly nonrandomized studies.[41,42,43,44,45][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.[17]

Currently, there are seven active and approved drugs for patients with metastatic colorectal cancer:

• 5-FU.
• Capecitabine.
• Irinotecan.
• Oxaliplatin.
• Bevacizumab.
• Cetuximab.
• 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 [46,47] as well as improved survival and quality of life for patients receiving chemotherapy, compared with the best supportive care.[48,49,50] 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.[51] 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.[52,53][Level of evidence: 1iiA]

First-line Multiagent Chemotherapy

Three randomized studies demonstrated improved response rates, progression-free survival (PFS), and OS when irinotecan or oxaliplatin was combined with 5-FU-leucovorin.[54,55,56] An intergroup study (NCCTG-N9741) then compared IFL with FOLFOX4 in first-line treatment for patients with metastatic colorectal cancer. Patients assigned to FOLFOX4 experienced an 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 upon progression on first-line therapy, respectively.[57,58][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 regimens in patients with previously untreated metastatic colorectal cancer: FOLFIRI, mIFL, and capecitabine/irinotecan (CAPIRI).[59] 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, PFS, was not significantly different, patients receiving FOLFIRI/bevacizumab had a significantly better OS (not yet reached with a median follow-up of 22.6 months vs. 19.2 months, P = .007). When using an irinotecan-based regimen as first-line treatment of metastatic colorectal cancer, FOLFIRI is preferred.[59][Level of evidence: 1iiDiii] (Refer to the PDQ summary on Nausea and Vomiting, and for information on diarrhea and dehydration refer to the Gastrointestinal Complications summary.)

Randomized phase III trials have addressed the equivalence of substituting capecitabine for infusional 5-FU. Two phase III studies have evaluated FUOX versus CAPOX.[60,61] The AIO Colorectal Study Group randomly assigned 474 patients to either FUFOX or CAPOX. The median PFS was 7.1 m for the CAPOX arm and 8.0 m 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.[60] The TTP was 8.9 months versus 9.5 months (P = .153) and met the prespecified range for noninferiority.[60][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

Bevacizumab

Patients with previously untreated metastatic colorectal cancer were randomly assigned to either IFL or IFL and bevacizumab.[62] The patients randomly assigned to IFL and bevacizumab experienced a significantly better PFS (10.6 months in the group given IFL and bevacizumab, as compared with 6.2 months in the group given IFL and placebo; HR for disease progression = 0.54; P < .001) and OS (20.3 months in the group given IFL and bevacizumab, as compared with 15.6 months in the group given IFL and placebo corresponding to an HR for death = 0.66; P < .001).[62]

Despite the lack of direct data, in standard practice, bevacizumab was added to FOLFOX as a standard first-line regimen based on the results of NCCTG-N9741.[63] Subsequently, in a randomized phase III study, patients with untreated, stage IV colorectal cancer were randomly assigned in a 2 × 2 factorial design to CAPOX versus FOLFOX4, then to bevacizumab versus placebo. PFS was the primary endpoint. In this trial, 1,401 patients were randomly assigned, and the median PFS was 9.4 months for patients receiving bevacizumab and 8.0 months for the patients receiving placebo (HR = 0.83; 97.5% confidence interval [CI] 0.72–0.95, P = .0023).[64][Level of evidence: 1iiDiii] Median OS was 21.3 months for patients receiving bevacizumab and 19.9 months for patients receiving placebo (HR = 0.89; 97.5% CI, 0.76–1.03, P = .077). The median PFS (intention-to-treat analysis) was 8.0 months in the pooled CAPOX-containing arms versus 8.5 months in the FOLFOX4-containing arms (HR = 1.04; 97.5% CI, 0.93–1.16), with the upper limit of the 97.5% CI being below the predefined noninferiority margin of 1.23.[64,65] The effect of bevacizumab on OS is likely to be less than what was seen in the original Hurwitz study.

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 and bevacizumab. Patients randomly assigned to FOLFOX and bevacizumab experienced a statistically significant improvement in PFS (7.43 months vs. 4.7 months, HR = 0.61; P < .0001) and OS (12.9 months vs. 10.8 months, HR = 0.75; P = .0011).[66][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.

There are currently no completed randomized controlled studies evaluating whether continued use of bevacizumab in the second line or third line after progressing on a first-line bevacizumab regimen is worthwhile.

Cetuximab/panitumumab and second-line chemotherapy

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.[67,68,69,70] 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. The median TTP for FOLFOX4 versus LV5FU2 was 4.6 months versus 2.7 months (stratified log-rank test, 2-sided P < .001).[71][Level of evidence: 1iiDiii]

Cetuximab 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 either cetuximab or irinotecan and cetuximab. The median TTP for patients receiving cetuximab was 1.5 months, and the median TTP for patients receiving irinotecan and cetuximab was 4.2 months.[72][Level of evidence: 3iiiDiv] On the basis of this study, cetuximab 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.[73] 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.[73][Level of Evidence: 1iiDii] Retrospective studies of patients with metastatic colorectal cancer have suggested that responses to anti-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 patients with KRAS wild-type tumors, 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 months vs. 10.5 months; 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 months vs. 12.5 months; P = .003) as well as OS (17.2 months vs. 24.9 months; P = .03).[74][Level of evidence: 1iiDiii]

Panitumumab is a fully humanized antibody against the EGFR. In a phase III trial, patients with chemotherapy refractory colorectal cancer were randomly assigned to panitumumab or best supportive care. Patients receiving panitumumab experienced an improved PFS (8 weeks vs. 7.3 weeks, HR = 0.54; 95% CI, 0.44–0.66; P <.0001).[75][Level of evidence: 1iiDiii] There was no difference in OS, which was thought to be the result of 76% of patients on best supportive care crossing over to panitumumab. The FDA-approved panitumumab for use in patients with metastatic colorectal cancer refractory to chemotherapy.[75]

In the PRIME (NCT00364013) study, 1,183 patients were randomly assigned to FOLFOX4 with or without panitumumab as first-line therapy for metastatic colorectal cancer.[76] The study was amended to enlarge the sample size to address patients with the KRAS wild-type tumors and patients with mutant KRAS tumors separately. For patients with KRAS wild-type tumors, a statistically significant improvement in PFS was observed in those who received panitumumab-FOLFOX4 compared with those who received only FOLFOX4 (HR = 0.80; 95% CI, 0.66–0.97; P = .02, stratified log-rank test).[76][Level of evidence: 1iiDiii] Median PFS was 9.6 months (95% CI, 9.2 months–11.1 months) for patients who received panitumumab-FOLFOX4 and 8.0 months (95% CI, 7.5 months–9.3 months) for patients who received FOLFOX4. OS was not significantly different between the groups (HR = 0.83; 95% CI, 0.67–1.02; P = .072). For patients with mutant KRAS tumors, there was worse PFS with the addition of panitumumab (HR = 1.29; 95% CI, 1.04–1.62; P = .02, stratified log-rank test). Median PFS was 7.3 months (95% CI, 6.3 months–8.0 months) for panitumumab-FOLFOX4 and 8.8 months (95% CI, 7.7 months–9.4 months) for FOLFOX4 alone.

Similarly, the addition of panitumumab to a regimen of FOLFOX/bevacizumab resulted in a worse PFS and worse toxicity compared to a regimen of 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).[77][Level of evidence: 1iiDiii]

In another study (NCT00339183), patients with metastatic colorectal cancer who had already received a fluoropyrimidine regimen were randomly assigned to either FOLFIRI or FOLFIRI plus panitumumab.[78] In a post hoc analysis, patients with KRAS wild-type tumors experienced a statistically significant PFS advantage (HR = 0.73; 95% CI, 0.59–0.90; P = .004, stratified log-rank).[78] [Level of evidence: 1iiDiii] Median PFS was 5.9 months (95% CI, 5.5 months–6.7 months) for panitumumab-FOLFIRI and 3.9 months (95% CI, 3.7 months–5.3 months) for FOLFIRI alone. OS was not significantly different. Patients with mutant KRAS tumors experienced no benefit from the addition of panitumumab.

It is unproven whether these EGFR agents should be combined or used in a sequential approach.

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 colon cancer and recurrent colon 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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