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Colon Cancer Treatment (PDQ®)

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Stage IV and Recurrent Colon Cancer Treatment

Treatment of Liver Metastasis
        Surgery
        Neoadjuvant chemotherapy
        Local ablation
        Adjuvant chemotherapy
        Intra-arterial chemotherapy
Treatment of Stage IV and Recurrent Colon Cancer
        Surgery
        Chemotherapy and targeted therapy
        Second-line chemotherapy
        Third-line chemotherapy
Treatment Options Under Clinical Evaluation
Current Clinical Trials

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 for Stage IV and Recurrent Colon Cancer

Treatment options for stage IV and recurrent colon cancer 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.[2-11]

  4. Resection of isolated pulmonary or ovarian metastases in selected patients.[12]

  5. Palliative radiation therapy.

  6. Palliative chemotherapy.

  7. Targeted therapy.

  8. Clinical trials evaluating new drugs and biological therapy.

  9. Clinical trials comparing various chemotherapy regimens or biological therapy, alone or in combination.

Treatment of 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. These include the following:

Surgery

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

  • 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 resulted in 5-year survival rates of 25% to 40% in mostly nonrandomized studies, such as the NCCTG-934653 trial.[5,7,13-16] Improved surgical techniques and advances in preoperative imaging have allowed for better 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]

Neoadjuvant chemotherapy

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]

Local ablation

Radiofrequency ablation has emerged as a safe technique (2% major morbidity and <1% mortality rate) that may provide for long-term tumor control.[18-24] Radiofrequency ablation and cryosurgical ablation [25-28] 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]

Adjuvant chemotherapy

The role of adjuvant chemotherapy after potentially curative resection of liver metastases is uncertain.

Evidence (adjuvant chemotherapy):

  1. A trial of hepatic arterial floxuridine and dexamethasone plus systemic fluorouracil (5-FU) and leucovorin compared with systemic 5-FU plus leucovorin alone showed improved 2-year progression-free survival (PFS) (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]

  2. 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.

Intra-arterial chemotherapy

Hepatic intra-arterial chemotherapy with floxuridine for liver metastases has produced higher overall response rates but no consistent improvement in survival when compared with systemic chemotherapy.[2,35-39] A meta-analysis of the randomized studies, which were all done in the era when only fluoropyrimidines were available for systemic therapy, did not demonstrate a survival advantage.[40]

Several studies show increased local toxic effects with hepatic infusional therapy, including liver function abnormalities and fatal biliary sclerosis.

Treatment of Stage IV and Recurrent Colon Cancer Surgery

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.

Chemotherapy and targeted therapy

Currently, there are eight active and approved drugs for patients with metastatic colorectal cancer that are used alone and in combination with other drugs:

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 (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:
    • 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:
    • 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.

  • 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 (1,000 mg/m2) twice a day for 14 days plus oxaliplatin (130 mg/m2) on day 1 every 3 weeks.

5-FU

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 [41,42] as well as improved survival and quality of life for patients receiving chemotherapy, compared with the best supportive care.[43-45] 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.[46]

Capecitabine

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.[47,48][Level of evidence: 1iiA]

Irinotecan

Three randomized studies demonstrated improved response rates, PFS, and OS when irinotecan or oxaliplatin was combined with 5-FU-leucovorin.[49-51]

Evidence (irinotecan):

  1. An intergroup study (NCCTG-N9741) 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]

  2. Subsequently, two studies compared FOLFOX with FOLFIRI, and patients were allowed to cross over upon progression on first-line therapy, respectively.[52,53][Level of evidence: 1iiDiii]
    • PFS and OS were identical between the treatment arms in both studies.

  3. 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, including FOLFIRI, mIFL, and Capecitabine/irinotecan (CAPIRI).[54][Level of evidence: 1iiA]
    • 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.

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.

When using an irinotecan-based regimen as first-line treatment of metastatic colorectal cancer, FOLFIRI is preferred.[54][Level of evidence: 1iiDiii]

Oxaliplatin

Randomized phase III trials have addressed the equivalence of substituting capecitabine for infusional 5-FU. Two phase III studies have evaluated FUOX versus CAPOX.[55,56]

Evidence (oxaliplatin):

  1. 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.

  2. The Spanish Cooperative Group randomly assigned 348 patients to CAPOX or FUOX.[55]

When using an oxaliplatin-based regimen as first-line treatment of metastatic colorectal cancer, a CAPOX regimen is not inferior to a FUOX regimen.

Bevacizumab

Bevacizumab is a partially humanized monoclonal antibody that binds to vascular endothelial growth factor. Bevacizumab can reasonably be added to either FOLFIRI or FOLFOX for patients undergoing first-line treatment of metastatic colorectal cancer.

Evidence (bevacizumab):

  1. 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).

  2. Patients with previously untreated metastatic colorectal cancer were randomly assigned to either IFL or IFL and bevacizumab.[57]
    • 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).[57][Level of evidence: 1iiA]

  3. 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 the NCCTG-N9741 trial.[58] 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% CI, 0.72–0.95, P = .0023).[59][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.[59,60]

    • The effect of bevacizumab on OS is likely to be less than what was seen in the original Hurwitz study.[57]

  4. Investigators from the Eastern Cooperative Oncology Group 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).[61][Level of evidence: 1iiA]

Based on these studies, bevacizumab can reasonably be added to either FOLFIRI or FOLFOX for patients undergoing first-line treatment of metastatic colorectal cancer. A major question was whether the use of bevacizumab after first-line therapy was warranted when bevacizumab was used as a component of first-line therapy. At the 2012 American Society of Clinical Oncology Annual Meeting, data was presented from a randomized, controlled trial.[62] In the trial, 820 patients with metastatic colorectal cancer, after progressing on first-line chemotherapy that included bevacizumab, were randomly assigned to chemotherapy without bevacizumab or chemotherapy with bevacizumab. Patients who received bevacizumab experienced an improved OS compared with the patients who did not receive bevacizumab. Median OS was 11.2 months for patients who received bevacizumab plus chemotherapy and 9.8 months for patients who received chemotherapy without bevacizumab (HR, 0.81; 95% CI, 0.69–0.94; unstratified log-rank test, P = .0062). Median PFS was 5.7 months for patients who received bevacizumab plus chemotherapy and 4.1 months for those who received chemotherapy without bevacizumab (HR, 0.68; 95% CI, 0.59–0.78; unstratified log-rank test, P < .0001).[62]][Level of evidence: 1iiA]

Aflibercept

Aflibercept is a novel anti-VEGF molecule and has been evaluated as a component of second-line therapy in patients with metastatic colorectal cancer. In one trial, 1,226 patients were randomly assigned to receive aflibercept (4 mg/kg IV) or placebo every 2 weeks in combination with FOLFIRI.[63] Patients who received aflibercept plus FOLFIRI had a significantly improved OS relative to placebo plus FOLFIRI (HR, 0.817; 95.34% CI, 0.713–0.937; P = .0032) with median survival times of 13.50 months versus 12.06 months, respectively. Aflibercept also significantly improved PFS (HR, 0.758; 95% CI, 0.661–0.869; P < .0001), with median PFS times of 6.90 months versus 4.67 months, respectively. On the basis of these results, the use of FOLFIRI plus aflibercept is an acceptable second-line regimen for patients previously treated with FOLFOX-based chemotherapy.[63][Level of evidence: 1A] Whether to continue bevacizumab or initiate aflibercept in second-line therapy has not been addressed as yet in any clinical trial, and there are no data available.

Cetuximab

Cetuximab is a partially humanized monoclonal antibody against the epidermal growth factor receptor (EGFR). Because cetuximab affects tyrosine kinase signaling at the surface of the cell membrane, tumors with mutations causing activation of the pathway downstream of the EGFR, such as KRAS mutations, are not sensitive to its effects. The addition of cetuximab to multiagent chemotherapy improves survival in patients with colon cancers that lack a KRAS mutation (i.e., KRAS wild type). Importantly, patients with mutant KRAS tumors may experience worse outcome when cetuximab is added to multiagent chemotherapy regimens containing bevacizumab.

Evidence (cetuximab):

  1. 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.[64][Level of evidence: 1iiDiii]

    • On the basis of this study, cetuximab was approved for use in patients with metastatic colorectal cancer refractory to 5-FU and irinotecan.

  2. The Crystal Study (NCT00154102) randomly assigned 1,198 patients with stage IV colorectal cancer to FOLFIRI with or without cetuximab.[65]
    • 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.[65][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 codon 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).

  3. In a randomized trial, patients with metastatic colorectal cancer received capecitabine/oxaliplatin/bevacizumab with or without cetuximab.[66]
    • 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).[66][Level of evidence: 1iiDiii]

  4. The Medical Research Council (MRC) (COIN [NCT00182715] trial) sought to answer the question of whether adding cetuximab to combination chemotherapy with a fluoropyrimidine and oxaliplatin in first-line treatment for patients with first-line KRAS wild-type tumors was beneficial.[67,68]
    • In addition, the MRC sought to evaluate the effect of intermittent chemotherapy versus continuous chemotherapy. The 1,630 patients were randomly assigned to three treatment groups:
      • Arm A: fluoropyrimidine/oxaliplatin.
      • Arm B: fluoropyrimidine/oxaliplatin/cetuximab.
      • Arm C: intermittent fluoropyrimidine/oxaliplatin.

    • The comparisons between arms A and B and arms A and C were analyzed and published separately.[67,68]

    • In patients with KRAS wild-type tumors (arm A, n = 367; arm B, n = 362), OS did not differ between treatment groups (median survival, 17.9 months [interquartile range (IQR) 10.3–29.2] in the control group vs. 17.0 months [IQR, 9.4–30.1] in the cetuximab group; HR, 1.04; 95% CI, 0.87–1.23, P = .67). Similarly, there was no effect on PFS (8.6 months [IQR, 5.0–12.5] in the control group versus 8.6 months [IQR, 5.1–13.8] in the cetuximab group; HR, 0.96; 0.82–1.12, P = .60).[67,68][Level of evidence: 1iiA]

    • The reasons for lack of benefit in adding cetuximab are unclear. Subset analyses suggest that the use of capecitabine was associated with an inferior outcome, and the use of second-line therapy was less frequent in patients treated with cetuximab.

    • There was no difference between the continuously treated patients (arm A) and the intermittently treated patients (arm C). Median survival in the intent-to-treat population (n = 815 in both groups) was 15.8 months (IQR, 9.4–26.1) in arm A and 14.4 months (IQR, 8.0–24.7) in arm C (HR, 1.084; 80% CI, 1.008–1.165). In the per-protocol population, which included only those patients who were free from progression at 12 weeks and randomly assigned to continue treatment or go on a chemotherapy holiday (arm A, n = 467; arm C, n = 511), median survival was 19.6 months (IQR, 13.0–28.1) in arm A and 18.0 months (IQR, 12.1–29.3) in arm C (HR, 1.087; 95% CI, 0.986–1.198). The upper limits of CIs for HRs in both analyses were greater than the predefined noninferiority boundary. While intermittent chemotherapy was not deemed noninferior, there appeared to be clinically insignificant differences in patient outcomes.

  5. The OPUS study sought to evaluate the effect of adding cetuximab to first-line treatment with a FOLFOX regimen in an open-labeled, randomized, multicenter, phase II study of patients with EGFR-expressing metastatic colorectal cancer.[69]
    • In the trial, 344 patients were randomly assigned to receive FOLFOX-4 alone or FOLFOX-4 plus cetuximab. There was no statistically significant difference in response rate or PFS.

    • On subset analysis, patients with KRAS wild-type tumors were analyzed separately. In the KRAS wild-type tumor population, there was a statistically significant improvement in response rate (61% vs. 37%, P = .011) and PFS (7.7 months vs. 7.2 months, P = .0163).

    • On subset analysis, patients with KRAS mutant tumors receiving FOLFOX4-cetuximab had a statistically significant worse PFS than patients with KRAS mutant tumors receiving FOLFOX4 (5.5 months vs. 8.6 months, P = .0192).[69][Level of evidence: 1iiD]

Panitumumab

Panitumumab is a fully humanized antibody against the EGFR. The U.S. Food and Drug Administration approved panitumumab for use in patients with metastatic colorectal cancer refractory to chemotherapy.[70] In clinical trials, panitumumab demonstrated efficacy as a single agent or in combination therapy, which was consistent with the effects on PFS and OS with cetuximab. There appears to be a consistent class effect.

Evidence (panitumumab):

  1. 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).[70][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.

  2. 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.[71] 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).[71][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.

  3. 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).[72][Level of evidence: 1iiDiii]

  4. 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.[73]
    • 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).[73][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.

Second-line chemotherapy

Second-line chemotherapy with irinotecan in patients treated with 5-FU-leucovorin as first-line therapy demonstrated improved OS when compared with either infusional 5-FU or supportive care.[74-77]

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).[78][Level of evidence: 1iiDiii]

Third-line chemotherapy

Regorafenib is an inhibitor of multiple tyroisine kinase pathways including vascular endothelial growth factor (VEGF). In September 2012, the FDA granted approval for the use of regorafenib in patients who had progressed on prior therapy. The safety and effectiveness of regorafenib were evaluated in a single, clinical study of 760 patients with previously treated metastatic colorectal cancer.[79] Patients were randomly assigned to receive regorafenib or placebo in addition to best supportive care. Patients treated with regorafenib had a statistically significant improvement in OS (6.4 months vs. 5 months, HR, 0.493; 95% CI, 0.418–0.581; 1-sided P < .000001).[79]

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation for stage IV and recurrent colon cancer include the following:

  1. Clinical trials evaluating new drugs and biological therapy.

  2. Clinical trials comparing various chemotherapy regimens or biological therapy, alone or in combination.

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.

References
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  2. Wagman LD, Kemeny MM, Leong L, et al.: A prospective, randomized evaluation of the treatment of colorectal cancer metastatic to the liver. J Clin Oncol 8 (11): 1885-93, 1990.  [PUBMED Abstract]

  3. Scheele J, Stangl R, Altendorf-Hofmann A: Hepatic metastases from colorectal carcinoma: impact of surgical resection on the natural history. Br J Surg 77 (11): 1241-6, 1990.  [PUBMED Abstract]

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