A Renewed Call for Equipoise
Authors: Neal J. Meropol
Journal: Journal of Clinical Oncology (2007)

In this issue of the Journal of Clinical Oncology, Saltz et al report the results of Cancer and Leukemia Group B (CALGB) 89803, a prospective randomized phase III trial of adjuvant therapy for patients with stage III colon cancer. In this study, patients with resected stage III adenocarcinoma of the colon were assigned to treatment with fluorouracil (FU) plus leucovorin (LV; weekly 6, every 8 weeks for four cycles) or FU plus LV plus irinotecan (CPT-11; weekly 4, every 6 weeks for five cycles). This welldesigned and well-conducted clinical trial by the publicly funded National Cancer Institute (Bethesda, MD) cooperative group system clearly demonstrated that CPT-11 plus FU plus LV failed to improve disease-free, recurrence-free, or overall survival compared with FU plus LV. These results were unexpected. After all, CPT-11 had previously shown clear activity in patients with metastatic cancer—the accepted proving ground for subsequent adjuvant therapies. In 1996, CPT-11 was granted accelerated US Food and Drug Administration approval based on phase II single-agent activity in patients with metastatic colorectal cancer refractory to FU. Full approval was granted approximately 2 years later based on randomized phase III trials that demonstrated a modest (2 to 3 months) survival benefit from CPT-11 compared with best supportive care, or to infusional FU in patients who had previously received bolus FU. Subsequent phase III studies showed that CPT-11 improved survival when added to FU plus LV compared with FU plus LV in the initial management of patients with metastatic colorectal cancer. One of these CPT-11 regimens, CPT-11 plus FU plus LV, was selected as the experimental arm of CALGB 89803. We may consider several potential explanations for the negative results of CALGB 89803. One might initially question whether the weekly bolus CPT-11 plus FU plus LV regimen was an optimal choice for the experimental arm. At the time that CALGB 89803 was designed, the CPT-11 plus FU plus LV regimen was the standard in North America FU plus LV plus CPT-11 regimen in North America. During the study, toxicity concerns surfaced, including an excess of toxic deaths on the experimental arm. It would be useful to know whether there was a substantial imbalance in scheduled therapy delivered between the study conditions that might help explain the outcomes. In fact, Saltz et al note that nearly twice as many patients withdrew consent or discontinued treatment on the CPT-11 plus FU plus LV arm than in the control group. Subsequent to this trial, data emerged to suggest that infusional FU delivery has a superior therapeutic index in combination with CPT-11. However, preliminary results of two additional adjuvant studies comparing infusional FU plus LV to infusional FU plus LV plus CPT-11 also failed to demonstrate superiority of the CPT-11– containing arms. Therefore, a demonstrable lack of activity for CPT-11 in the adjuvant setting has been consistently observed. These data must be interpreted in the context of other studies that demonstrated improved recurrence-free survival when oxaliplatin is added to a FU plus LV backbone as adjuvant therapy. The benefit of CPT-11 in patients with metastatic disease in terms of response rate and progression is similar to that observed with oxaliplatin. In addition, two studies comparing infusional FU plus oxaliplatin to infusional FU plus CPT-11 as initial therapy in patients with metastatic colorectal cancer showed equivalent response rates, time to progression, and overall survival between the study arms. Thus, one may have reasonably expected similar results in the adjuvant setting. However, these advanced disease studies comparing oxaliplatin and CPT-11 were of moderate size and were not powered to demonstrate equivalency. The trial reported by Tournigand et al included 220 patients and was designed to have 80% power to detect a 20% difference in the proportion of patients without progression at 15 months. Similarly, Colucci et al enrolled 336 patients with response rate as the primary objective, with statistical power to demonstrate a 15% difference between the arms. Thus, it is plausible that there are subtle differences in the clinical activity of CPT-11 and oxaliplatin that were not observed in underpowered trials in patients with metastatic disease, but became manifest in much larger trials in the adjuvant setting. Furthermore, patient preferences and tolerance of specific toxicities that differ between regimens (such as alopecia or hospitalization rate) might become more apparent in the adjuvant setting where premature treatment discontinuation could affect long-term outcomes. Underlying successful application of adjuvant therapy is the hypothesis that microscopic metastatic disease exists and can be eradicated with systemic treatment. Another possible explanation for the findings of CALGB 89803, and other adjuvant studies of CPT-11 in combination with FU plus LV, is that mechanisms of CPT-11 resistance might be expressed in micrometastases to a greater extent than in macrometastatic colon cancer. The primary mechanism of action for CPT-11 is interference with JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 23 AUGUST 1