Endpoints in phase II trials for advanced non-small cell lung cancer.

INTRODUCTION: We investigated the relationships between progression-free survival (PFS), response, confirmed response, and failure-free survival (FFS) with overall survival (OS) to assess their suitability as primary endpoints in phase II trials for advanced non-small cell lung cancer. METHODS: Individual data of 284 patients from four phase II trials were pooled. Progression status and response were modeled as time dependent variables in a multivariable (adjusted for baseline age, gender, stage, and performance status) Cox proportional hazards model for OS, stratified by trial. Subsequently, Cox proportional hazards models were used to assess the impact of PFS, response, confirmed response, and FFS on subsequent survival, using landmark analysis at 8, 12, 16, 20, and 24 weeks. Model discrimination was evaluated using the concordance index (c-index). RESULTS: The overall median OS, PFS, and FFS were 9.6, 3.7, and 2.8 months, and the response and confirmed response rates were 21 and 15%, respectively. Both progression status and response as time dependent covariates were significantly associated with OS (p < 0.0001; p = 0.009). PFS and FFS at 12 weeks significantly predicted for subsequent survival with the strongest c-index and hazard ratio combination in landmark analyses (hazard ratio, c-index: PFS: 0.39, 0.67; FFS: 0.37, 0.67). The c-indices for response and confirmed response were low (0.59-0.60), indicating their inability to sufficiently discriminate subsequent patient survival outcomes. CONCLUSIONS: FFS or PFS at 12 weeks is a stronger predictor of subsequent patient survival compared with tumor response and should be routinely used as endpoints in phase II trials for advanced non-small cell lung cancer.

Phase I/II trial of pyrazoloacridine and carboplatin in patients with recurrent glioma: a North Central Cancer Treatment Group trial.

PURPOSE: Novel therapeutic agents in the treatment of recurrent gliomas are urgently needed. Pyrazoloacridine (PZA), a rationally synthesized acridine derivative, has shown promising antitumor activity against glioma lines in combination with platinum compounds. This phase I/II trial of the PZA/carboplatin combination in recurrent glioma patients consisted of two phase I studies (studies 1 and 2) and a phase II trial (study 3). The objectives of studies 1 and 2 were to (a) assess the safety and toxicity and to establish the phase II dose of the pyrazoloacridine/carboplatin combination for recurrent glioma patients on P450 inducing anticonvulsants, and (b) to confirm the phase II dose for patients not on P450 inducing anticonvulsants. The primary objectives of study 3 were to determine the efficacy of the pyrazoloacridine/carboplatin combination in patients with recurrent gliomas, to further assess the toxicity of the combination, and to evaluate the impact of enzyme-inducing anticonvulsants on the pyrazoloacridine metabolism. EXPERIMENTAL DESIGN: Both carboplatin and pyrazoloacridine were administered intravenously every 28 days. Treatment was continued until unacceptable toxicity, tumor progression or patient withdrawal. RESULTS: 14 patients were treated in the two phase I studies and 32 patients in the phase II trial. The phase II dose of the combination was PZA 400 mg/m(2) and carboplatin AUC of 5 every 28 days. Neutropenia (4 patients) and dyspnea (1 patient) was the dose limiting toxicity in the phase I studies. In the phase II trial, the most frequent toxicity was myelosuppression with grade 3 and 4 hematologic adverse events being observed in 22 and 19% of the patients, respectively. The antitumor activity of this regimen was limited; the response rate in the phase II trial was 0%, (95% CI:0-11%) while 12 of the 32 patients (38%) had stable disease with a median duration of 2 months. The percentage of phase II patients who were progression free at three months was 22% and at six months was 16%. Median survival from study entry was 5.0 months for phase I patients and 5.8 months for phase II patients. Pharmacokinetic analysis performed in 8 phase I patients demonstrated no significant impact of the enzyme-inducing anticonvulsants on the pharmacokinetics of pyrazoloacridine. CONCLUSIONS: The phase II dose of the pyrazoloacridine/carboplatin combination is pyrazoloacridine 400 mg/m(2) in combination with carboplatin AUC of 5. Antitumor activity in patients with recurrent gliomas was limited. Initial disease stabilization occurred in approximately 38% of the patients, with median duration of 2 months. Enzyme-inducing anticonvulsants did not affect the pyrazoloacridine metabolism.

Ethical wills and suffering in patients with cancer: a pilot study.

INTRODUCTION: Suffering at the end of life may be caused by many factors, including pain and other symptoms, concern about family and friends, and loss of control of one's life. Several authors have suggested that loss of meaning is pivotal in suffering. An ethical will (EW) is a statement, usually written, capturing one's values, wisdom, hopes, and advice. EWs have been suggested as a vehicle for finding meaning as the end of life approaches. This pilot study of EWs examined methods for exploring the role of EWs in reducing suffering at the end of life. METHODS: Oncology clinic patients 65+ years of age in active therapy for cancer were randomly assigned to one of two arms: EW or control. Subjects in both arms had writing assignments, three home visits, and exit interviews. Suffering was measured at baseline and at the time of the exit interview, using a series of Likert-like scales. RESULTS: Twenty-four subjects (10 EW and 14 control) completed the study. Among EW subjects, trends toward reduced suffering were noted in "concern for loved ones," "unfinished business," and "fear of the future." Several methodological issues were identified by this pilot study, including selection of population for studying suffering, placebo effect, and randomization. CONCLUSIONS: EW may be valuable in alleviating suffering; a larger study will be needed to examine efficacy. The study of interventions designed to reduce suffering at the end of life requires careful attention to the definition and measurement of suffering, study design, and subject selection.

Phase III trial comparing chemotherapy plus once-daily or twice-daily radiotherapy in Stage III non-small-cell lung cancer.

PURPOSE: This Phase III study was performed to determine whether chemotherapy plus b.i.d. or q.d. radiotherapy (RT) resulted in superior survival for patients with Stage III non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Patients with Stage III NSCLC and an Eastern Cooperative Oncology Group performance status of