Data-Review Panel Calls for Close Monitoring with IFL Colon Cancer Regimen

Without identifying specific faults, a special task force has recommended close monitoring and aggressive intervention, including dose reduction, for colon cancer patients treated with a regimen of irinotecan and bolus fluorouracil(5-FU)/leucovorin (IFL). The recommendations followed a review of mortality data from two clinical trials that were interrupted when interim analyses showed an increased early mortality with IFL compared with just 5-FU and leucovorin. The task force's report, published in the September 15th issue of the Journal of Clinical Oncology (2001;18:3801–3807), attributed the early mortality risk to clustering of toxicities, particularly a vascular syndrome and a gastrointestinal syndrome. No Specific Factors Linked to Early Mortality The review failed to reveal any specific factors clearly associated with an increased early mortality risk, although patients who died tended to be older than the typical colon cancer patient enrolled in clinical trials. The task force recommended especially close monitoring of older patients in clinical trials of colorectal cancer, regardless of the therapeutic regimen employed. “These recommendations can be readily integrated into the clinical practice setting,” said Neal Meropol, MD, Director of the Gastrointestinal Cancer Program at Fox Chase Cancer Center in Philadelphia and a coauthor of the task force report. “Heightened awareness of the potential for severe toxicity and a commensurate degree of careful patient follow-up should substantially increase the safety of the IFL regimen.” The recommendations include “real-time monitoring of life-threatening or fatal adverse events or hospitalizations” for early identification of unexpected or severe toxicity and weekly patient assessment for at least the first cycle of therapy. The IFL regimen came to prominence after two published clinical trials demonstrated a statistically significant survival advantage compared with conventional treatment with 5-FU and leucovorin for patients with advanced colorectal cancer (N Engl J Med 2000;343:905–912 and Lancet 2000;355:1041–1047). The regimen subsequently was evaluated in two Phase III Intergroup trials. In a trial conducted by the North Central Cancer Treatment Group (NCCTG), IFL served as the control for two investigational regimens. A trial organized by Cancer and Leukemia Group B (CALGB) compared IFL against a weekly regimen of 5-FU and leucovorin. Interim data analysis of both trials showed an unexpectedly high 60-day mortality in patients treated with IFL. In the NCCTG trial, IFL patients had a 60-day mortality rate of 4.8 percent compared with 1.8 percent for the other two arms. Interim data from the CALGB trial revealed a mortality rate of 2.2 percent with IFL versus 0.8 percent with 5-FU and leucovorin. The findings ultimately led to early termination of patient accrual in both trials. 3 Definitions Representatives of NCCTG, CALGB, Pharmacia, and the National Cancer Institute agreed that an independent panel should be convened to review the records of patients who died early in both trials. As part of the review process, the panel developed and adopted three definitions for attribution of the cause of death: (1) treatment induced (clearly caused by the treatment); (2) treatment unrelated; and (3) treatment exacerbated (exacerbation of an underlying disorder by the treatment). In both trials, three times as many treatment-induced and treatment-exacerbated deaths occurred in the IFL arm as in the other treatment arms, the panel reported. In most instances, a clustering of toxicities was implicated in the deaths. Two particular toxicity clusters or syndromes were closely associated with early mortality—a gastrointestinal syndrome that included severe diarrhea, nausea, vomiting, anorexia, and abdominal cramping; and a vascular syndrome, defined as acute, fatal myocardial infarction, pulmonary embolus, or cerebrovascular accident that occurred shortly after the patient received the chemotherapy. Patients who died early tended to be older—median ages of 73 and 69.5 in the control and IFL groups, respectively, in the CALGB trial, and a median of 65 to 68 in the treatment arms of the NCCTG trial. Historically, patients enrolled in cooperative group trials of adjuvant chemotherapy have had median ages of 60 to 63 years, the panel noted. However, the reviewers did not have enough evidence to implicate age as a factor in the increased mortality risk. “We only reviewed the records of the people who died,” Dr. Meropol said. “We didn't have access to information about older people who didn't die, so we really couldn't draw any conclusions about age as factor.” Location of the primary tumor, baseline performance status, concomitant medication, and other variables reviewed by the panel provided no additional insights into early mortality. Overall, the panel came up with a dozen recommendations for monitoring patients on IFL and for early intervention at the first sign of trouble. The task force gave particular attention to management of diarrhea and other aspects of the GI syndrome. The members of the review group also advised withholding IFL from patients who have “significant treatment-related diarrhea.” Comments from Dr. Saltz An investigator closely associated with the IFL regimen said the panel's report affirms recommendations that emerged from discussions held in May, shortly after the NCCTG and CALGB trials halted patient accrual. “I was pleased to see the recommendations, because I believe they are consistent with what we had already done, and they are potentially useful in optimizing patient care,” said Leonard Saltz, MD, Associate Attending Physician in Gastrointestinal Oncology at Memorial Sloan-Kettering Cancer Center in New York City. The recommendations for closer monitoring are “completely practical within a clinical practice setting,” said Dr. Saltz, who was lead author of one of the two major studies demonstrating the survival advantage with IFL. “I think the monitoring is practical for any type of oncology practice setting.” Not Onerous Houston oncologist Edward Lin, MD, agreed that the monitoring recommendations should not prove onerous to community oncologists. “Oncologists have had experience with the IFL regimen,” said Dr. Lin, Assistant Professor of Medical Oncology at the University of Texas MD Anderson Cancer Center. “We have sent patients home with IFL as part of our treatment recommendations.” Even so, he said he considers the JCO report “a big alarm for all oncologists who treat patients with colon cancer. In particular, we ought to be very careful in dosing our patients in terms of seeking dose modifications.” Dr. Lin said he does not hesitate to start a patient on a lower dose of irinotecan if he thinks the patient won't be able to tolerate the recommended dose of 125 mg/m2. The report does not discourage the use of IFL but rather encourages more vigilance in monitoring patients. Better education of patients and physicians alike can go a long way toward preventing treatment-related deaths, particularly those arising from what Dr. Lin characterized as “cholera-like” diarrhea that can occur in some patients. Dr. Saltz noted that two IFL regimens are currently in use—one European and one North American. The European regimen involves two consecutive 24-hour infusions of 5-FU, repeated every other week, and irinotecan is given on alternating weeks. The American regimen employs a 5-FU bolus infusion, and irinotecan is given weekly for four weeks, followed by a two-week break. The two regimens have not yet been compared head to head to determine whether one dosing schedule might be safer or more effective than the other, he noted. Pharmacia sent out two “Dear Doctor” letters related to the developments involving irinotecan. The first letter informed oncologists about the safety concerns raised about the IFL regimen and the discontinuation of the NCCTG and CALGB trials, and the other reviewed the task force findings. In response to a request, a Pharmacia spokesperson said the company had no further comments regarding the matter. Outpatient Treatment for Liver Cancer Patients diagnosed with inoperable primary liver cancer face grim treatment options—external-beam radiation or chemotherapy—neither of which dramatically prolongs life. Now, physicians at the University of Pittsburgh Medical Center are testing a new treatment that they hope will produce a threefold reduction in the size of the tumor, as well as both lengthen and improve the quality of life for many such patients. The treatment, known as TheraSphere, can be given on an outpatient basis, with apparently few, if any, side effects. It delivers millions of microscopic glass beads embedded with the radioactive element yttrium-90 directly into the artery that feeds hepatocellular carcinoma (HCC) tumors. “TheraSphere allows us to focus radiation directly on a tumor without damaging nearby noncancerous tissues,” said Brian Carr, MD, PhD, Director of the Liver Tumor Service. “The result is that patients are more comfortable and can tolerate the treatments better.” Healthy tissue is spared despite the high concentration of radiation contained in the beads, because the beta radiation travels only an average of 2.5 mm, Dr. Carr explained. This ability to localize the treatment contributes to the lack of side effects, which means that it can be used safely in patients with hepatitis and cirrhosis. Another advantage of TheraSphere is that it makes it possible to deliver a much higher dose of radiation—up to five times the maximum possible dose for external-beam radiation. Additionally, patients have fewer hospital stays compared with those receiving chemotherapy. So far, Dr. Carr and his team have treated 24 patients with primary liver cancer. A second center, the University of Maryland, is using the method to treat patients with metastases to the liver. TheraSphere has been authorized by the FDA for use as a humanitarian device for the treatment of inoperable liver tumors. It is produced by MDS Nordion, a subsidiary of MDS, Inc. of Canada.

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