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Rectal Cancer Treatment (PDQ®)

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Stage IV and Recurrent Rectal Cancer

Treatment of patients with advanced or recurrent rectal cancer depends on the location of the disease.

Metastatic and Recurrent Rectal Cancer

Standard treatment options for stage IV and recurrent rectal cancer include the following:

Surgery with or without chemotherapy or radiation therapy

For patients with locally recurrent, liver-only, or lung-only metastatic disease, surgical resection, if feasible, is the only potentially curative treatment.[1] 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.[2-5] The presence of hydronephrosis associated with recurrence appears to be a contraindication to surgery with curative intent.[6]

Locally recurrent rectal cancer may be resectable, particularly if an inadequate prior operation was performed. For patients with local recurrence alone after an initial, attempted curative resection, aggressive local therapy with repeat low anterior resection and coloanal anastomosis, abdominoperineal resection, or posterior or total pelvic exenteration can lead to long-term disease-free survival (DFS).[7,8]

The use of induction chemoradiation therapy for previously nonirradiated patients with locally advanced pelvic recurrence (pelvic side-wall, sacral, and/or adjacent organ involvement) may increase resectability and allow for sphincter preservation.[9,10] Intraoperative radiation therapy in patients who underwent previous external-beam radiation therapy may improve local control in patients with locally recurrent disease, with acceptable morbidity.[11]

First-line chemotherapy and targeted therapy

Currently, there are eight active U.S. Food and Drug Administration (FDA)-approved drugs for patients with metastatic colorectal cancer that are used alone and in combination with other drugs:

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,[12,13] and improved survival and quality of life in patients who received chemotherapy versus best supportive care.[14-16] Several trials have analyzed the activity and toxic effects of various 5-FU/leucovorin (LV) regimens, using different doses and administration schedules, and showed essentially equivalent results with a median survival time of approximately 12 months.[17]

Irinotecan and oxaliplatin

Three randomized studies in patients with metastatic colorectal cancer demonstrated improved response rates, progression-free survival (PFS), and overall survival (OS) when irinotecan or oxaliplatin was combined with 5-FU/LV.[18-20]

Evidence (irinotecan versus oxaliplatin):

  1. An intergroup study (NCCTG-N9741) compared irinotecan/5-FU/LV (IFL) with oxaliplatin/LV/5-FU (FOLFOX4) in first-line treatment for patients with metastatic colorectal cancer. [21]; [Level of evidence: 1iiA]
    • Patients assigned to FOLFOX4 experienced improved PFS compared with patients randomly assigned to IFL (median, 8.7 months vs. 6.9 months; P = .014; hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.61–0.89) and OS (19.5 months vs. 15.0 months; P = .001; HR, 0.66; 95% CI, 0.54–0.82).
  2. Two studies compared FOLFOX with LV/5-FU/irinotecan (FOLFIRI), and patients were allowed to cross over after progression on first-line therapy.[22,23][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: FOLFIRI; irinotecan plus bolus 5-FU/LV (mIFL); and capecitabine/irinotecan (CAPIRI).[24] 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. However, when using an irinotecan-based regimen as first-line treatment of metastatic colorectal cancer, FOLFIRI is preferred.[24][Level of evidence: 1iiDiii]

Capecitabine

Before 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/LV.[25,26][Level of evidence: 1iiA]

Randomized phase III trials have addressed the equivalence of substituting capecitabine for infusional 5-FU. Two phase III studies have evaluated capcetabine/oxaliplatin (CAPOX) versus 5-FU/oxaliplatin regimens (FUOX or FUFOX).[27,28]

Evidence (oxaliplatin versus capecitabine):

  1. The Arbeitsgemeinschaft Internische Onkologie (AIO) Colorectal Study Group randomly assigned 474 patients to either CAPOX or FUFOX.
    • 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.[28]
  2. The Spanish Cooperative Group randomly assigned 348 patients to CAPOX or FUOX.[27]Level of evidence: 1iiDiii
    • The TTP was 8.9 months for CAPOX versus 9.5 months for FUOX (P = .153) and met the prespecified range for noninferiority.

When using an oxaliplatin-based regimen as first-line treatment of metastatic colorectal cancer, a CAPOX regimen is not inferior to a 5-FU/oxaliplatin regimen.

Bevacizumab

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 second-line or third-line treatment after progressing on a first-line bevacizumab regimen extends survival.

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.[24]
    • Although the primary endpoint of PFS was not significantly different, patients who received FOLFIRI/bevacizumab had a significantly better OS (28.0 months vs. 19.2 months; P = .037; HR for death, 1.79; 95% CI, 1.12–2.88).
  2. In the Hurwitz study, patients with previously untreated metastatic colorectal cancer were randomly assigned to either IFL or IFL/bevacizumab.[29]
    • The patients randomly assigned to IFL/bevacizumab experienced a significantly better PFS (10.6 months with IFL/bevacizumab compared with 6.2 months with IFL/placebo; HR for disease progression, 0.54; P <.001) and OS (20.3 m with IFL/bevacizumab compared with 15.6 months with IFL/placebo; HR for death, 0.66; P <.001).[29]
  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 NCCTG-N9741.[21] Subsequently, in a randomized phase III study, 1,401 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. [30][Level of evidence: 1iiDiii]
    • The median PFS was 9.4 months for patients who received bevacizumab and 8.0 months for the patients who received placebo (HR, 0.83; 97.5% CI, 0.72–0.95; P = .0023).
    • Median OS was 21.3 months for patients who received bevacizumab and 19.9 months for patients who received 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.[30,31]
    • The effect of bevacizumab on OS is likely to be less than what was seen in the original Hurwitz study.
  4. Investigators from the Eastern Cooperative Oncology Group randomly assigned patients who had progressed on 5-FU/LV and irinotecan to either FOLFOX or FOLFOX and bevacizumab.
    • Patients randomly assigned to FOLFOX/bevacizumab experienced a statistically significant improvement in PFS compared with patients assigned to FOLFOX alone (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).[32][Level of evidence: 1iiA]
FOLFOXIRI

Evidence (FOLFOXIRI):

  1. The combination of FOLFOXIRI with bevacizumab was compared with FOLFIRI with bevacizumab in a randomized, phase III study of 508 patients with untreated metastatic colorectal cancer.[33]
    • The median PFS was 12.1 months in the FOLFOXIRI group, compared with 9.7 months in the FOLFIRI group (HR for progression, 0.75; 95% CI, 0.62–0.90; P = .003). OS was not significantly different between the groups (31.0 vs. 25.8 months; HR for death, 0.79; 95% CI, 0.63–1.00; P = .054).[33][Level of evidence: 1iiDiii]
    • Patients who received FOLFOXIRI had significantly more grade 3 and 4 toxicities, including neutropenia, stomatitis, and peripheral neuropathy.
Cetuximab

Cetuximab is a partially humanized monoclonal antibody against the epidermal growth factor receptor (EGFR). 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 that used either cetuximab or irinotecan/cetuximab.[34][Level of evidence: 3iiiDiv]
    • The median TTP for patients who received cetuximab was 1.5 months, compared with median TTP of 4.2 months for patients who received irinotecan and cetuximab. 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 (EMR 62202-013 [NCT00154102]) randomly assigned 1,198 patients with stage IV colorectal cancer to FOLFIRI with or without cetuximab.[35][Level of Evidence: 1iiDii]
    • 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.
    • 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 KRAS wild-type patients, 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.[36][Level of evidence: 1iiDiii]
    • The median PFS was 9.4 months in the group who received cetuximab and 10.7 months in the group who did not receive 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 than patients with mutated KRAS tumors who did not receive cetuximab (8.1 months vs. 12.5 months; P = .003) and a significantly shorter OS (17.2 months vs. 24.9 months; P = .03).
  4. The Medical Research Council (MRC) (UKM-MRC-COIN-CR10 [NCT00182715] or COIN 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 KRAS wild-type tumors was beneficial.[37,38] 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.[37,38]

    1. 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, 10.3–29.2] in the control group vs. 17.0 m [interquartile range, 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 [interquartile range, 5.0–12.5] in the control group vs. 8.6 months [interquartile range, 5.1–13.8] in the cetuximab group; HR, 0.96; 0.82–1.12, P = .60).[37,38][Level of evidence: 1iiA]
    2. 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 in patients treated with cetuximab.
    3. 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 (interquartile range, 9.4–26.1) in arm A and 14.4 months (interquartile range, 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 (interquartile range, 13.0–28.1) in arm A and 18.0 months (interquartile range, 12.1–29.3) in arm C (HR, 1.087, 95% CI, 0.986–1.198).
    4. 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.
Panitumumab

Panitumumab is a fully humanized antibody against the EGFR. The FDA approved panitumumab for use in patients with metastatic colorectal cancer refractory to chemotherapy.

Evidence (panitumumab):

  1. In a phase III trial, patients with chemotherapy-refractory colorectal cancer were randomly assigned to panitumumab or best supportive care.[39]
    • Patients who received panitumumab experienced an improved PFS (8 weeks vs. 7.3 weeks; HR, 0.54; 95% CI, 0.44–0.66; P < .0001).[39][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 Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME [20050203 or NCT00364013]) study, 1,183 patients were randomly assigned to FOLFOX4 with or without panitumumab as first-line therapy for metastatic colorectal cancer.[40][Level of evidence: 1iiDiii] The study was amended to enlarge the sample size to address patients with KRAS wild-type tumors and patients with mutant KRAS tumors separately.
    1. 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).
    2. Median PFS was 9.6 m (95% CI, 9.2–11.1 months) for patients who received panitumumab-FOLFOX4 and 8.0 months (95% CI, 7.5–9.3 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).
    3. For patients with mutant KRAS tumors, PFS was worse 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, 6.3–8.0 months) for panitumumab-FOLFOX4 and 8.8 months (95% CI, 7.7–9.4 months) for FOLFOX4 alone.
  3. Similarly, the addition of panitumumab to a regimen of FOLFOX/bevacizumab resulted in a worse PFS and worse toxicity than a regimen of FOLFOX/bevacizumab alone in patients not selected for KRAS mutation in metastatic rectal cancer (11.4 months vs. 10.0 months; HR, 1.27; 95% CI, 1.06–1.52).[41][Level of evidence: 1iiDiii]
  4. In another study (NCT00339183 [20050181]), patients with metastatic colorectal cancer who had already received a fluoropyrimidine regimen were randomly assigned to either FOLFIRI or FOLFIRI/panitumumab.[42][Level of evidence: 1iiDiii]
    1. 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).[42]
      • Median PFS was 5.9 months (95% CI, 5.5–6.7 months) for FOLFIRI/panitumumab and 3.9 months (95% CI, 3.7–5.3 months) for FOLFIRI alone.
    2. OS was not significantly different. Median OS was 14.5 months for the FOLFIRI/panitumumab group versus 12.5 months for the FOLFIRI alone group.
    3. 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/LV as first-line therapy demonstrated improved OS when compared with either infusional 5-FU or supportive care.[43-46]

Similarly, a phase III trial randomly assigned patients who progressed on irinotecan and 5-FU/LV to bolus and infusional 5-FU/LV, single-agent oxaliplatin, or FOLFOX4. The median TTP for FOLFOX4 versus 5-FU/LV was 4.6 months versus 2.7 months (stratified log-rank test, 2-sided P < .001).[47][Level of evidence: 1iiDiii]

Palliative therapy

Palliative radiation therapy[11,46], chemotherapy,[13,48-53] and chemoradiation therapy [54,55] may be indicated. Palliative, endoscopically-placed stents may be used to relieve obstruction.[56]

Treatment of Liver Metastasis

Approximately 15% to 25% of colorectal cancer patients will present with liver metastases at diagnosis, and another 25% to 50% will develop metachronous hepatic metastasis after resection of the primary tumor.[57-59] 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. These include the following:

Surgery

Hepatic metastasis may be considered to be resectable based on the following factors:[45,60-72]

  • 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 (e.g., the North Central Cancer Treatment Group trial, NCCTG-934653).[73-77][Level of evidence: 3iiiDiv] Improved 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 neoadjuvant chemotherapy.[78]

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. [78]

Local ablation

Radiofrequency ablation has emerged as a safe technique (2% major morbidity and <1% mortality rate) that may provide long-term tumor control.[79-85] Radiofrequency ablation and cryosurgical ablation remain options for patients with tumors that are not resectable and for patients who are not candidates for liver resection.[86-88] Other local ablative techniques that have been used to manage liver metastases include embolization and interstitial radiation therapy.[89-91]

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 5-FU/LV compared with systemic 5-FU/LV alone showed improved 2-year PFS (57% vs. 42%; P =.07) and OS (86% vs. 72%; P = .03) for patients in the combined therapy arm but did not show a significant statistical difference in median survival when compared with systemic 5-FU therapy alone.[92][Level of evidence: 1iiA]
    • Median survival in the combined therapy arm was 72.2 months versus 59.3 months in the monotherapy arm (P = .21).
  2. 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.[93] Among those randomly assigned patients, 27% were deemed ineligible at the time of surgery, leaving only 75 patients evaluable for recurrence and survival.
    • While 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 results similar to hepatic intra-arterial therapy plus systemic treatment.

Intra-arterial chemotherapy

Hepatic intra-arterial chemotherapy with floxuridine for liver metastasis has produced higher overall response rates but no consistent improvement in survival when compared with systemic chemotherapy.[68,94-98] Controversy regarding the efficacy of regional chemotherapy was the basis of a large multicenter phase III trial (Leuk-9481) (NCT00002716) 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.[99]

Increased local toxic effects after hepatic infusional therapy are seen, 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.

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  • Updated: December 16, 2014