Irinotecan-Based Combinations for the Adjuvant Treatment of Stage III Colon Cancer
Irinotecan-Based Combinations for the Adjuvant Treatment of Stage III Colon Cancer
Localized or local-regional colon cancer is potentially curable by surgery alone. If all gross disease is resected, then the success or failure of the operation, and hence the ultimate cure and survival of the patient, will depend upon whether or not micrometastases were already present at the time of surgery, thereby rendering the procedure more palliative than curative. If it could be determined that no micrometastases were present after all gross disease is removed, then the patient could be considered cured and no further therapy of an adjuvant nature would be necessary.
Given the current limitations of technology for detecting micrometastases, treatment decisions are currently based on the probability of microscopic cancer being present, and on the relative effectiveness of available cytotoxic chemotherapy. Stage I and II colon cancer patients have a relatively low probability of harboring micrometastases, and thus have a relatively high probability of being cured by surgery alone. Adjuvant chemotherapy has not consistently been shown to improve survival in these patients, and is not, at this time, routinely recommended. However, lymph node-positive, or stage III, patients have a substantial risk of having microscopic metastatic disease at the time of resection. Looking back at historical controls from the era prior to chemotherapy, a roughly 40% to 50% cure rate for stage III colon cancer patients was seen with surgery alone, indicating that slightly more than half of patients did in fact have microscopic metastatic disease at the time of resection.
Initial attempts at adjuvant therapies following stage III colon cancer surgery were not successful,[2-4] and until the late 1980s expectant observation was the standard of care following resection for these patients. Studies carried out by the North Central Cancer Treatment Group (NCCTG), later confirmed by larger studies conducted by the National Cancer Institute (NCI) Intergroup, established a 12-month regimen of fluorouracil (5-FU) plus levamisole as the first effective adjuvant treatment of colorectal cancer.
A subsequent Intergroup study was done comparing this 52-week regimen of 5-FU plus levamisole to 5-FU plus leucovorin, either on a weekly schedule for 32 weeks, a daily x 5 schedule for 28 weeks, or a daily x 5 schedule for 28 weeks with concurrent levamisole. Results of this trial are summarized in Table 1. The 5-FU/leucovorin regimens were found to be at least as good as the longer 5-FU/levamisole treatment. The 5-FU/leucovorin/levamisole combination was found to be more toxic without increasing efficacy relative to the 5-FU/leucovorin regimens. These 5-FU/leucovorin regimens can therefore be regarded as the current standard of care. They represent a substantial improvement over surgery alone, with approximately two-thirds of stage III patients now being cured. One-third of stage III patients, however, can be expected to have recurrence of disease and ultimately die of their disease. The need for improved adjuvant therapies for these patients is clear.
Irinotecan (CPT-11, Camptosar) is a topoisomerase I inhibitor that has demonstrated substantial antitumor activity in both chemotherapy-naive and 5-FU-refractory colorectal cancer. In a phase II trial involving 41 colorectal cancer patients with no prior chemotherapy, Conti et al demonstrated a 32% major objective response rate, with an additional 44% of patients achieving stable disease. The median duration of response in this study was 8 months, and median survival was 12 months. Very similar results were obtained in a parallel study performed at the Mayo Clinic. These results suggested that while irinotecan had substantial antitumor activity, the overall response rates, durations of response, and survivals were similar to those seen with currently available 5-FU-based regimens. Another phase II trial, reported by Rothenberg et al, indicated that irinotecan also had substantial antitumor activity in patients with 5-FU-refractory colorectal cancer. These activity rates were subsequently confirmed in a series of multicenter trials.
The demonstration of activity of irinotecan in cancers that were refractory to 5-FU, along with the radically different mechanism of actions between irinotecan and 5-FU, suggested that a combination regimen permitting concurrent administration of these agents might have superior antitumor activity to either agent alone. Two concerns at the time when these combinations were first being developed were whether there would be negative pharmacokinetic interactions between these two agents and whether overlapping toxicities would make concurrent administration intolerable.
To address these issues, a phase I study was undertaken at Memorial Sloan-Kettering Cancer Center in which escalating doses of 5-FU were added to fixed weekly doses of irinotecan and leucovorin. The result of this phase I study is a regimen in which full-dose irinotecan at 125 mg/m2 by 90-minute infusion is followed by leucovorin at 20 mg/m2 by IV bolus and then by 5-FU at 500 mg/m2 by IV bolus. All drugs are given weekly for 4 consecutive weeks followed by a 2-week rest. Pharmacokinetic studies performed during this phase I study indicated that there was no substantial pharmacokinetic interaction between 5-FU and irinotecan. The dose-limiting toxicities were neutropenia and diarrhea, both of which appeared to be manageable.
To assess the appropriateness of concurrent use of irinotecan/5-FU/leucovorin, a phase III trial was undertaken. The results of this multicenter trial have now been reported. This trial was conducted at 71 sites throughout the United States, Canada, Australia, and New Zealand. It was a prospective, open-label, multicenter, randomized phase III study to evaluate the efficacy and safety of irinotecan/5-FU/leucovorin vs 5-FU and leucovorin as first-line therapy for patients with metastatic colorectal cancer.
Patients were stratified by performance status, age, time from initial diagnosis, and whether or not they had received prior adjuvant therapy. Three treatment arms were employed. One arm was the aforementioned irinotecan/5-FU/leucovorin combination. One arm was a standard regimen of 5-FU and leucovorin, with 5-FU given at 425 mg/m2 by IV bolus and leucovorin at 20 mg/m2 by IV bolus, each given for 5 consecutive days repeated every 28 days. The third treatment arm was irinotecan alone given at 125 mg/m2 by 90-minute infusion weekly for 4 weeks followed by a 2-week break. This last arm was included in order to evaluate the safety and efficacy of single-agent irinotecan in a multicenter setting.
It is noteworthy that this study began accrual at approximately the same time that irinotecan received accelerated approval from the US Food and Drug Administration for use in 5-FU-refractory colorectal cancer. This effectively created a crossover design in the study, since patients receiving 5-FU/leucovorin now had the option of obtaining irinotecan commercially as salvage therapy, and patients receiving irinotecan as first-line therapy logically received 5-FU-based therapy as a salvage treatment when clinical conditions permitted.
The entry criteria for the study were standard phase III criteria. Patients were required to have measurable metastatic colorectal cancer. They were required to have no prior chemotherapy for metastatic disease. Prior adjuvant chemotherapy was permitted if the patient had remained disease-free for 1 year or more following the completion of adjuvant therapy. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and adequate hepatic, renal, and bone marrow function.
Efficacy results are shown in Table 2. The objective response rate, time to treatment failure, and overall survival were all statistically significantly superior in those patients receiving irinotecan/5-FU/leucovorin vs 5-FU and leucovorin alone. Of note, while the toxicity profiles varied between treatment arms, the overall incidence of clinically significant toxicity was not substantially different between the treatment arms (Table 3). While grade 3/4 diarrhea was more common in the irinotecan/5-FU/leucovorin arm than in the 5-FU/leucovorin arm, grade 4 neutropenia and neutropenic fevers were more common with standard 5-FU/leucovorin than with the irinotecan-containing combination. Overall, the incidence of treatment-related deaths was 1% in each arm.
A similar study has been conducted in Europe. In this particular trial, clinicians selected their preference from two different 5-FU and leucovorin schedules, and then patients were treated on that 5-FU/leucovorin schedule with or without irinotecan. Again, superior antitumor activity for the irinotecan/5-FU/leucovorin combination was seen. In this trial, the toxicity of the irinotecan-containing regimens was somewhat greater than the 5-FU/leucovorin regimens. However, the difference in survival was again statistically significant in favor of the irinotecan/5-FU/leucovorin combination.
Irinotecan has been shown to be an effective second-line agent for metastatic colorectal cancer, with a randomized trial now demonstrating a survival advantage for treatment with irinotecan over best supportive care. Ultimately, however, all patients treated in this manner are likely to die of their disease. Likewise, while irinotecan/5-FU/leucovorin combinations represent a step forward in the first-line treatment of metastatic disease, these regimens are not curative in the standard metastatic setting. Micrometastatic disease in the adjuvant setting, however, is the one scenario in which systemic chemotherapy for colorectal cancer can be curative. Since the success of treatment depends on the degree of antitumor activity, regimens with higher antitumor response rates could logically be expected to provide superior results in the adjuvant setting. Furthermore, it would seem that if 5-FU could eradicate one population of cells and irinotecan could eradicate yet another population of cells, the chance of rendering the patient disease free would be increased.
The only way to test this hypothesis is in a randomized phase III trial. For this reason, such a study has now been activated through the NCI Intergroup mechanism. Intergroup study C89803 is now accruing patients with stage III resected colon cancer. Patients are randomized to receive either standard weekly 5-FU and leucovorin or to receive irinotecan/5-FU/leucovorin in the doses and schedule outlined in Figure 1.
It is hoped that the improved response rate and overall survival seen with irinotecan/5-FU/leucovorin in the metastatic setting will be translated to improved survival and an increased cure rate in the adjuvant setting, thereby moving irinotecan from its current strictly palliative role into a realm in which it is actually saving lives.
It must be emphasized, however, that until this hypothesis is adequately tested in this phase III study, use of irinotecan-containing regimens in the adjuvant setting remains investigational. Patients eligible for enrollment in this trial should be strongly encouraged to participate. It is only through the completion of randomized clinical trials such as this one that new treatment ideas can be properly tested, so as to determine whether or not they truly constitute a step forward in the standard of care.
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