Schaefer, Paul

Purpose In February 2000, the criteria for measuring tumor shrinkage as an indicator of antitumor activity were redefined by the Response Evaluation Criteria in Solid Tumors (RECIST). This resulted in simplifying bidimensional to unidimensional measurement of lesions. Under RECIST, all lesions, up to 10, must be measured. Scanning and measuring multiple lesions is costly, time-consuming, and a disincentive to participation in clinical trials. We investigated whether fewer than 10 lesions can be measured without compromising the accuracy of assessing a regimen's activity. Patients and Methods Thirty-two North Central Cancer Treatment Group trials including 2,374 patients were analyzed. Twelve studies were conducted before RECIST; 20 were conducted post-RECIST. Agreement between objective status by cycle, confirmed response, overall response rate, and time to progression (TTP) was evaluated based on all 10 versus the largest one through five lesions. Results The median number of lesions reported on RECIST trials did not differ from pre-RECIST trials (median = 2.0). One lesion at baseline was reported in 49% of patients, two lesions in 28% of patients, three lesions in 12% of patients, four lesions in 6% of patients, and five lesions in 5% of patients in post-RECIST trials. Utilizing the largest two lesions produced excellent concordance with that using all lesions for all end points. In no trial did the overall response rate differ by more than 3% when two versus all lesions were considered. Evaluating more than two lesions did not significantly improve agreement. Conclusion Based on these trials, the assessment of more than two lesions did not alter the conclusions regarding a treatment's efficacy as judged by response rate or TTP.

Purpose A phase II study was conducted to determine the efficacy and toxicity of radiotherapy with concomitant gemcitabine and cisplatin for patients with locally advanced pancreatic adenocarcinoma. Patients and Methods Forty-eight patients with locally advanced pancreatic adenocarcinoma received gemcitabine (30 mg/m2) and cisplatin (10 mg/m2) twice weekly during the first 3 weeks of radiotherapy. The radiation dose to the primary tumor and regional nodes was 45 Gy in 25 fractions, and the gross tumor volume received an additional 5.4 Gy in three fractions. Four weeks after radiotherapy, patients received gemcitabine (1,000 mg/m2) once weekly every 3 of 4 weeks for a 12-week period. The primary end point was survival at 12 months. Secondary end points were time to progression, toxicity, and quality of life. Results Survival at 1 year was 40% for 47 eligible patients. The median survival was 10.2 months. Confirmed responses were observed for 8.5% (two partial, two complete), and median time to progression was 7.3 months. Grade 4 or higher toxicity was observed for 31% and consisted primarily of hematologic and GI toxicity. There was a trend toward improved overall quality of life, measured by the Symptom Distress Scale (P = .06), with significant improvements in domains of insomnia, pain, and outlook. Conclusion The combination of radiotherapy, gemcitabine, and cisplatin was well tolerated. Survival results were similar to those achieved with other treatment regimens for patients with locally advanced pancreatic cancer but did not meet our predefined criteria for additional evaluation of this regimen.

Purpose There is growing recognition that the primary cause of cognitive deficits in adult patients with primary brain tumors is the tumor itself and more significantly, tumor progression. To assess the cognitive performance of high-grade glioma patients, prospectively collected cognitive performance data were analyzed. Patients and Methods We studied 1,244 high-grade brain tumor patients entered onto eight consecutive North Central Cancer Treatment Group treatment trials that used radiation and nitrosourea-based chemotherapy. Imaging studies and Folstein Mini-Mental State Examination (MMSE) scores recorded at baseline, 6, 12, 18, and 24 months were analyzed to assess tumor status and cognitive function over time. Results The proportion of patients without tumor progression who experienced clinically significant cognitive deterioration compared with baseline was stable at 6, 12, 18, and 24 months (18%, 16%, 14%, and 13%, respectively). In patients without radiographic evidence of progression, clinically significant deterioration in MMSE scores was a strong predictor of a more rapid time to tumor progression and death. At evaluations preceding interval radiographic evidence of progression, there was significant deterioration in MMSE scores for patients who were to experience progression, whereas the scores remained stable for the patients who did not have tumor progression. Conclusion The proportion of high-grade glioma patients with cognitive deterioration over time is stable, most consistent with the constant pressure of tumor progression over time. Although other factors may contribute to cognitive decline, the predominant cause of cognitive decline seems to be subclinical tumor progression that precedes radiographic changes.

Purpose To compare maintenance epoetin alfa administered once every 3 weeks with continued weekly epoetin alfa for patients with cancer-associated anemia. Patients and Methods Eligible patients were randomly assigned at enrollment to receive three weekly doses of epoetin alfa 40,000 U subcutaneously (SC), followed by either standard weekly epoetin alfa (40K arm) or 120,000 U of epoetin alfa (120K arm) SC every 3 weeks for 18 additional weeks. Results Three hundred sixty-five patients were enrolled. One hundred eighty-three patients were assigned to the 40K arm, and 182 were assigned to the 120K arm. There was no difference in the proportion of patients requiring transfusions during the study (23% in 40K arm and 18% in 120K arm, P = .22) or specifically during the maintenance phase (13% in 40K arm v 15% in 120K arm, P = .58). Patients randomly assigned to the 40K arm were more likely to have a ≥ 2 or ≥ 3 g/dL hemoglobin (Hb) increment, were more likely to have a drug dose held because of high Hb, and had higher mean end-of-study Hb levels. Toxicities, including thromboembolism, and overall survival were similar. Patients in the 40K arm had a higher global quality of life (QOL) at baseline for unclear reasons, whereas patients in the 120K arm had a greater global QOL improvement during the study, so end-of-study QOL was equivalent. Conclusion After three weekly doses of epoetin alfa 40,000 U, a dose of 120,000 U can be administered safely once every 3 weeks without increasing transfusion needs or sacrificing QOL. The Hb increment is somewhat greater with continued weekly epoetin alfa. Lack of blinding as a result of different treatment schedules may have confounded results.

Purpose Adverse events (AEs) are monitored in clinical trials for patient safety, to satisfy reporting requirements, and develop safety profiles. Recently, much attention has been placed on the reporting of serious AEs (SAEs) that are either life threatening or lethal in clinical trials. However, SAEs comprise a small subset of all AE data collected for trials; the majority of AE data collected are routine AEs (RAEs) regarding non–life-threatening events. We assessed the utility of the RAE data collected, relative to the volume. Patients and Methods We surveyed the RAE data from 26 North Central Cancer Treatment Group coordinated trials. Results A total of 8,318 (11%) of 75,598 of RAEs required queries. Of these, 86% were protocol-required RAEs, 83% of RAEs required per protocol were within normal limits (eg, platelets) or not present, and 61% of extra AEs were mild. One fifth of RAEs were considered unlikely to be related or unrelated to treatment. Overall, 3% of events were severe, life threatening, or caused death. Only 1% of RAE data reported required expedited reporting (eg, via Adverse Event Expedited Reporting System). Results indicate that 72% of RAEs would be eliminated if only the maximum severity per patient and type were required. These results were validated in a large phase III trial. Conclusion The majority of RAEs identified, transcribed, and entered are not clinically important. Our data suggest that reducing the number of AEs monitored will affect substantially neither overall patient safety nor compromise evaluation of regimens undergoing testing. We present several considerations for such a reduction in data collection, as well as a policy that we have used to address the deluge of RAE data.

Purpose: To determine whether (1) tailored nicotine patch therapy that is based on smoking rate can be carried out in a multisite oncology investigative group practice setting, (2) long-term use of bupropion reduces the rate of relapse to smoking in smokers who stop smoking with nicotine patch therapy, and (3) bupropion can initiate smoking abstinence among smokers who have failed to stop smoking after nicotine patch therapy. Participants and Methods: Fourteen North Central Cancer Treatment Group sites recruited generally healthy adult smokers from the general population for nicotine patch therapy and based the patch dosage on smoking rates. At completion of nicotine patch therapy, nonsmoking participants were eligible to be assigned to bupropion or placebo for 6 months (for relapse prevention). and smoking participants were eligible to be assigned to bupropion or placebo for 8 weeks of treatment. Results: Of 578 subjects, 31% were abstinent from smoking at the end of nicotine patch therapy. Of those subjects not smoking at the end of nicotine patch therapy who entered the relapse prevention phase, 28% and 25% were not smoking at 6 months (the end of the medication phase) for bupropion and placebo, respectively (P = .73). For those still smoking at the end of nicotine patch therapy, 3.1% and 0.0% stopped smoking with bupropion or placebo, respectively (P = .12). Conclusion: Tailored nicotine patch therapy for the general population of smokers can be provided in a multisite oncology investigative group setting. Bupropion did not reduce relapse to smoking in smokers who stopped smoking with nicotine patch therapy. Bupropion did not initiate abstinence among smokers who failed to stop smoking with nicotine patch therapy.