Irinotecan (Camptosar) is a topoisomerase I inhibitor with demonstrated antitumor activity against a wide variety of malignancies. Phase II studies have shown that this agent has significant single-agent activity against both chemotherapy-naive and fluorouracil (5-FU)-refractory colorectal cancer. Phase III studies now indicate that irinotecan/5-FU/leucovorin combinations have antitumor activity superior to standard 5-FU/leucovorin regimens alone. These irinotecan-based combinations are now entering clinical trials for the adjuvant treatment of resected stage III colon cancer. It is hypothesized that the superior antitumor activity of these irinotecan-based combinations seen in the metastatic setting will translate into improved survival and increased cure rates in these earlier-stage patients. [ONCOLOGY 14(Suppl 14):47-50, 2000]
ABSTRACT: Irinotecan (Camptosar) is a topoisomerase I inhibitor with demonstrated antitumor activity against a wide variety of malignancies. Phase II studies have shown that this agent has significant single-agent activity against both chemotherapy-naive and fluorouracil (5-FU)-refractory colorectal cancer. Phase III studies now indicate that irinotecan/5-FU/leucovorin combinations have antitumor activity superior to standard 5-FU/leucovorin regimens alone. These irinotecan-based combinations are now entering clinical trials for the adjuvant treatment of resected stage III colon cancer. It is hypothesized that the superior antitumor activity of these irinotecan-based combinations seen in the metastatic setting will translate into improved survival and increased cure rates in these earlier-stage patients. [ONCOLOGY 14(Suppl 14):47-50, 2000]
Localized or local-regional colon canceris potentially curable by surgery alone. If all gross disease is resected, thenthe success or failure of the operation, and hence the ultimate cure andsurvival of the patient, will depend upon whether or not micrometastases werealready present at the time of surgery, thereby rendering the procedure morepalliative than curative. If it could be determined that no micrometastases werepresent after all gross disease is removed, then the patient could be consideredcured and no further therapy of an adjuvant nature would be necessary.
Given the current limitations of technology for detectingmicrometastases, treatment decisions are currently based on the probability ofmicroscopic cancer being present, and on the relative effectiveness of availablecytotoxic chemotherapy. Stage I and II colon cancer patients have a relativelylow probability of harboring micrometastases, and thus have a relatively highprobability of being cured by surgery alone. Adjuvant chemotherapy has notconsistently been shown to improve survival in these patients, and is not, atthis time, routinely recommended. However, lymph node-positive, or stage III,patients have a substantial risk of having microscopic metastatic disease at thetime of resection. Looking back at historical controls from the era prior tochemotherapy, a roughly 40% to 50% cure rate for stage III colon cancer patientswas seen with surgery alone, indicating that slightly more than half ofpatients did in fact have microscopic metastatic disease at the time ofresection.
Initial attempts at adjuvant therapies following stage III coloncancer surgery were not successful,[2-4] and until the late 1980s expectantobservation 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) pluslevamisole as the first effective adjuvant treatment of colorectal cancer.
A subsequent Intergroup study was done comparing this 52-weekregimen of 5-FU plus levamisole to 5-FU plus leucovorin, either on a weeklyschedule for 32 weeks, a daily x 5 schedule for 28 weeks, or a daily x 5schedule for 28 weeks with concurrent levamisole. Results of this trial aresummarized in Table 1. The5-FU/leucovorin regimens were found to be at least as good as the longer5-FU/levamisole treatment. The 5-FU/leucovorin/levamisole combination was foundto be more toxic without increasing efficacy relative to the 5-FU/leucovorinregimens. These 5-FU/leucovorin regimens can therefore be regarded as thecurrent standard of care. They represent a substantial improvement over surgeryalone, with approximately two-thirds of stage III patients now being cured.One-third of stage III patients, however, can be expected to have recurrence ofdisease and ultimately die of their disease. The need for improved adjuvanttherapies for these patients is clear.
Irinotecan (CPT-11, Camptosar) is a topoisomerase I inhibitorthat has demonstrated substantial antitumor activity in both chemotherapy-naiveand 5-FU-refractory colorectal cancer. In a phase II trial involving 41colorectal cancer patients with no prior chemotherapy, Conti et al demonstrateda 32% major objective response rate, with an additional 44% of patientsachieving stable disease. The median duration of response in this study was 8months, and median survival was 12 months. Very similar results were obtained ina parallel study performed at the Mayo Clinic. These results suggested thatwhile irinotecan had substantial antitumor activity, the overall response rates,durations of response, and survivals were similar to those seen with currentlyavailable 5-FU-based regimens. Another phase II trial, reported by Rothenberget al, indicated that irinotecan also had substantial antitumor activity inpatients with 5-FU-refractory colorectal cancer. These activity rates weresubsequently confirmed in a series of multicenter trials.
The demonstration of activity of irinotecan in cancers that wererefractory to 5-FU, along with the radically different mechanism of actionsbetween irinotecan and 5-FU, suggested that a combination regimen permittingconcurrent administration of these agents might have superior antitumor activityto either agent alone. Two concerns at the time when these combinations werefirst being developed were whether there would be negative pharmacokineticinteractions between these two agents and whether overlapping toxicities wouldmake concurrent administration intolerable.
To address these issues, a phase I study was undertaken atMemorial Sloan-Kettering Cancer Center in which escalating doses of 5-FU wereadded to fixed weekly doses of irinotecan and leucovorin. The result of thisphase I study is a regimen in which full-dose irinotecan at 125 mg/m2by 90-minute infusion is followed by leucovorin at 20 mg/m2by IV bolus and then by 5-FU at 500 mg/m2 by IVbolus. All drugs are given weekly for 4 consecutive weeks followed by a 2-weekrest. Pharmacokinetic studies performed during this phase I study indicated thatthere was no substantial pharmacokinetic interaction between 5-FU andirinotecan. The dose-limiting toxicities were neutropenia and diarrhea, both ofwhich appeared to be manageable.
To assess the appropriateness of concurrent use ofirinotecan/5-FU/leucovorin, a phase III trial was undertaken. The results ofthis multicenter trial have now been reported. This trial was conducted at71 sites throughout the United States, Canada, Australia, and New Zealand. Itwas a prospective, open-label, multicenter, randomized phase III study toevaluate the efficacy and safety of irinotecan/5-FU/leucovorin vs 5-FU andleucovorin as first-line therapy for patients with metastatic colorectal cancer.
Patients were stratified by performance status, age, time frominitial diagnosis, and whether or not they had received prior adjuvant therapy.Three treatment arms were employed. One arm was the aforementionedirinotecan/5-FU/leucovorin combination. One arm was a standard regimen of 5-FUand leucovorin, with 5-FU given at 425 mg/m2 byIV bolus and leucovorin at 20 mg/m2 by IVbolus, each given for 5 consecutive days repeated every 28 days. The thirdtreatment arm was irinotecan alone given at 125 mg/m2by 90-minute infusion weekly for 4 weeks followed by a 2-week break. This lastarm was included in order to evaluate the safety and efficacy of single-agentirinotecan in a multicenter setting.
It is noteworthy that this study began accrual at approximatelythe same time that irinotecan received accelerated approval from the US Food andDrug Administration for use in 5-FU-refractory colorectal cancer. Thiseffectively created a crossover design in the study, since patients receiving5-FU/leucovorin now had the option of obtaining irinotecan commercially assalvage therapy, and patients receiving irinotecan as first-line therapylogically received 5-FU-based therapy as a salvage treatment when clinicalconditions permitted.
The entry criteria for the study were standard phase IIIcriteria. Patients were required to have measurable metastatic colorectalcancer. They were required to have no prior chemotherapy for metastatic disease.Prior adjuvant chemotherapy was permitted if the patient had remaineddisease-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 marrowfunction.
Efficacy results are shown in Table2. The objective response rate, time to treatment failure, and overallsurvival were all statistically significantly superior in those patientsreceiving irinotecan/5-FU/leucovorin vs 5-FU and leucovorin alone. Of note,while the toxicity profiles varied between treatment arms, the overall incidenceof clinically significant toxicity was not substantially different between thetreatment arms (Table 3). While grade 3/4diarrhea was more common in the irinotecan/5-FU/leucovorin arm than in the5-FU/leucovorin arm, grade 4 neutropenia and neutropenic fevers were more commonwith 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 thisparticular trial, clinicians selected their preference from two different 5-FUand leucovorin schedules, and then patients were treated on that 5-FU/leucovorinschedule with or without irinotecan. Again, superior antitumor activity for theirinotecan/5-FU/leucovorin combination was seen. In this trial, the toxicity ofthe irinotecan-containing regimens was somewhat greater than the 5-FU/leucovorinregimens. However, the difference in survival was again statisticallysignificant in favor of the irinotecan/5-FU/leucovorin combination.
Irinotecan has been shown to be an effective second-line agentfor metastatic colorectal cancer, with a randomized trial now demonstrating asurvival advantage for treatment with irinotecan over best supportive care.Ultimately, however, all patients treated in this manner are likely to die oftheir disease. Likewise, while irinotecan/5-FU/leucovorin combinations representa step forward in the first-line treatment of metastatic disease, these regimensare not curative in the standard metastatic setting. Micrometastatic disease inthe adjuvant setting, however, is the one scenario in which systemicchemotherapy for colorectal cancer can be curative. Since the success oftreatment depends on the degree of antitumor activity, regimens with higherantitumor response rates could logically be expected to provide superior resultsin the adjuvant setting. Furthermore, it would seem that if 5-FU could eradicateone population of cells and irinotecan could eradicate yet another population ofcells, the chance of rendering the patient disease free would be increased.
The only way to test this hypothesis is in a randomized phaseIII trial. For this reason, such a study has now been activated through the NCIIntergroup mechanism. Intergroup study C89803 is now accruing patients withstage III resected colon cancer. Patients are randomized to receive eitherstandard weekly 5-FU and leucovorin or to receive irinotecan/5-FU/leucovorin inthe doses and schedule outlined in Figure 1.
It is hoped that the improved response rate and overall survivalseen with irinotecan/5-FU/leucovorin in the metastatic setting will betranslated to improved survival and an increased cure rate in the adjuvantsetting, thereby moving irinotecan from its current strictly palliative roleinto a realm in which it is actually saving lives.
It must be emphasized, however, that until this hypothesis isadequately tested in this phase III study, use of irinotecan-containing regimensin the adjuvant setting remains investigational. Patients eligible forenrollment in this trial should be strongly encouraged to participate. It isonly through the completion of randomized clinical trials such as this one thatnew treatment ideas can be properly tested, so as to determine whether or notthey truly constitute a step forward in the standard of care.
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