Current Clinical Trials

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.)

Locally recurrent rectal cancer may be resectable, particularly if an inadequate prior operation was performed. For patients with local recurrence alone following 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.[1] 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.[2,3] Intraoperative radiation therapy in patients who received previous external beam radiation may improve local control in patients with locally recurrent disease with acceptable morbidity.[4] The presence of hydronephrosis associated with recurrence appears to be a contraindication to surgery with curative intent.[5] 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.[6-8]

In stage IV and recurrent rectal cancer, chemotherapy has been used for palliation with fluorouracil (5-FU)-based treatment and is considered to be standard therapy.[9,10] 5-FU has been shown to be more cytotoxic, with increased response rates but with variable effects on survival, when modulated by leucovorin,[11-17] methotrexate,[18] or other agents.[19-23] Interferon alfa appears to add toxic effects but no clinical benefit to 5-FU therapy.[24,25] Continuous-infusion 5-FU regimens have also resulted in increased response rates in some studies, with a modest benefit in median survival.[26] The benefits of continuous-infusion 5-FU compared to bolus regimens have been summarized in a meta-analysis.[27] Oral regimens using prodrugs of 5-FU or inhibitors of DPD pharmacologically simulate continuous infusion and are under clinical evaluation.[28] The choice of a 5-FU-based chemotherapy regimen for an individual patient should be based on known response rates and toxic effects profile of the chosen regimen, as well as cost and quality-of-life issues.[29,30] Innovative ways of altering toxic effects patterns, and potentially improving clinical benefit, include chronomodulated therapy, in which drug doses are varied throughout the day to allow for greater dose intensity without increased toxic effects.[31,32] In a meta-analysis of 1219 patients in randomized trials where patients were assigned to receive 5-FU with or without leucovorin via either continuous infusion or bolus, neutropenia was noted in 4% of patients who received continuous infusion versus 31% of patients who received bolus and hand-foot syndrome was found in 34% of patients who received continuous infusion versus 13% of patients who received bolus. All other toxic effects were noted with similar frequency and severity, regardless of continuous infusion or bolus administration.[33]

Irinotecan (CPT-11) is a topoisomerase-I inhibitor with a 10% to 20% partial response rate in patients with metastatic rectal cancer, in patients who have received no prior chemotherapy, and in patients progressing on 5-FU therapy.[34,35] Irinotecan is now considered standard therapy for patients with stage IV disease who do not respond to or progress on 5-FU.[36]

CPT-11 has been compared to either retreatment with 5-FU or best supportive care in a pair of randomized European trials of patients with colorectal cancer refractory to 5-FU.[37,38][Level of evidence: 1iiA,1iiC]

Two phase III prospective randomized, controlled trials were designed to evaluate the combination of 5-FU, leucovorin, and CPT-11 to 5-FU and leucovorin alone. The first of these trials compared the bolus 5-FU, leucovorin, and CPT-11 to bolus 5-FU and leucovorin alone and to CPT-11; the primary endpoint was progression-free survival.[39] The trial demonstrated significant benefit in terms of confirmed response rates, time-to-tumor progression, and overall survival.[39][Level of evidence: 1iiA] The combination treatment showed confirmed responses in 39% of patients, compared with 21% in patients treated with 5-FU and leucovorin alone and 18% in patients treated with CPT-11. This benefit was highly significant in favor of the combination. In addition, time-to-tumor progression was significantly prolonged with the combination (7.0 vs. 4.3 months, P = .004). Median survival was also improved with the combination; median survival was 14.8 months for patients on the combination arm and 12.6 months for patients on the 5-FU and leucovorin arm (P = .042).

The second pivotal trial of combination chemotherapy with CPT-11 compared 2 different regimens of infusional 5-FU and folinic acid (either the AIO [Arbeitsgemeinschaft Internische Onkologie] or the deGramont regimen).[40] Either weekly or biweekly CPT-11 was administered according to the schedule of the infusional 5-FU. This trial also demonstrated improvements in response rate, time-to-tumor progression, and median survival. For the most important endpoint, median survival, the combination arm was associated with a median survival of 17.4 months, compared with 14.1 months for the 5-FU and folinic acid arm (P = .032).[40][Level of evidence: 1iiA] A combined analysis of the survival advantages seen in these 2 trials was presented at the 2000 American Society of Clinical Oncology meeting.[41] The combined survival for the combination of CPT-11, 5-FU, and leucovorin was 15.9 months, compared to 13.3 months for the non-CPT-11 regimen (P = .003). This represents a survival hazard ratio of 0.79.

Another drug, raltitrexed (Tomudex), is a specific thymidylate synthase inhibitor which has demonstrated activity similar to that of bolus 5-FU and leucovorin.[42][Level of evidence: 1iiA];[43] A number of other drugs are undergoing evaluation for the treatment of rectal cancer.[44]

Oxaliplatin, alone or combined with 5-FU and leucovorin, has shown promising activity in previously treated and untreated patients with metastatic colorectal cancer and in patients with 5-FU refractory disease.[45-47] One multicenter trial reported a response rate of 21%, a median progression-free survival of 5 months, and a median survival of 11 months.[48] Overall survival from the start of first-line chemotherapy was 19 months. In this trial, oxaliplatin was given first, followed by 48-hour infusion of 5-FU, with short leucovorin infusion.

The data and safety monitoring committees of the cooperative groups conducting studies comparing the value of 5-FU/leucovorin/CPT-11 to 5-FU/leucovorin in the adjuvant setting, and comparing the value to 5-FU/leucovorin/oxaliplatin or oxaliplatin/CPT-11 in the advanced disease setting have suspended accrual to these trials because of an unexpectedly high death rate on the 5-FU/leucovorin/CPT-11 arms.[49] This 3 drug regimen appears to be more toxic than initially reported. The majority of deaths in both studies were observed in the first 60 days, usually during the first chemotherapy cycle. This may imply increased sensitivity in a minority of patients, possibly based on genetic differences in key steps in the metabolic activation/deactivation of irinotecan, 5-FU, or both agents. Additional analyses may provide guidance in dose adjustment for the initial cycle and/or in patient selection. For the present, the use of this regimen should be accompanied by careful attention to early signs of diarrhea, dehydration, neutropenia, or other toxic effects, especially during the first chemotherapy cycle.

Standard treatment options:

1. Resection of locally recurrent rectal cancer may be palliative or curative in selected patients.[50]
2. Resection of liver metastases in selected patients (5-year cure rate with resection of solitary metastases exceeds 20%).[37,51-56]
3. Resection of isolated pulmonary or ovarian metastases.
4. Palliative radiation therapy.[4,38]
5. Palliative chemotherapy.[11-15,19,57]
6. Palliative chemoradiation.
7. Palliative endoscopic-placed stents to relieve obstruction.[58]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with 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.

References

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