James D. Cox

BACKGROUND: The combination of chemotherapy with thoracic radiotherapy (TRT) compared with TRT alone has been shown to confer a survival advantage for good performance status patients with stage III non-small cell lung cancer. However, it is not known whether sequential or concurrent delivery of these therapies is the optimal combination strategy. METHODS: A total of 610 patients were randomly assigned to two concurrent regimens and one sequential chemotherapy and TRT regimen in a three-arm phase III trial. The sequential arm included cisplatin at 100 mg/m2 on days 1 and 29 and vinblastine at 5 mg/m2 per week for 5 weeks with 63 Gy TRT delivered as once-daily fractions beginning on day 50. Arm 2 used the same chemotherapy regimen as arm 1 with 63 Gy TRT delivered as once-daily fractions beginning on day 1 [corrected]. Arm 3 used cisplatin at 50 mg/m2 on days 1, 8, 29, and 36 with oral etoposide at 50 mg twice daily for 10 weeks on days 1, 2, 5, and 6 with 69.6 Gy delivered as 1.2 Gy twice-daily fractions beginning on day 1. The primary endpoint was overall survival, and secondary endpoints included tumor response and time to tumor progression. Kaplan-Meier analyses were used to assess survival, and toxic effects were examined using the Wilcoxon rank sum test. All statistical tests were two-sided. RESULTS: Median survival times were 14.6, 17.0, and 15.6 months for arms 1-3, respectively. Five-year survival was statistically significantly higher for patients treated with the concurrent regimen with once-daily TRT compared with the sequential treatment (5-year survival: sequential, arm 1, 10% [20 patients], 95% confidence interval [CI] = 7% to 15%; concurrent, arm 2, 16% [31 patients], 95% CI = 11% to 22%, P = .046; concurrent, arm 3, 13% [22 patients], 95% CI = 9% to 18%). With a median follow-up time of 11 years, the rates of acute grade 3-5 nonhematologic toxic effects were higher with concurrent than sequential therapy, but late toxic effects were similar. CONCLUSION: Concurrent delivery of cisplatin-based chemotherapy with TRT confers a long-term survival benefit compared with the sequential delivery of these therapies.

The mouse is an increasingly prominent model for the analysis of mammalian neuronal circuits. Neural circuits ultimately have to be probed during behaviors that engage the circuits. Linking circuit dynamics to behavior requires precise control of sensory stimuli and measurement of body movements. Head-fixation has been used for behavioral research, particularly in non-human primates, to facilitate precise stimulus control, behavioral monitoring and neural recording. However, choice-based, perceptual decision tasks by head-fixed mice have only recently been introduced. Training mice relies on motivating mice using water restriction. Here we describe procedures for head-fixation, water restriction and behavioral training for head-fixed mice, with a focus on active, whisker-based tactile behaviors. In these experiments mice had restricted access to water (typically 1 ml/day). After ten days of water restriction, body weight stabilized at approximately 80% of initial weight. At that point mice were trained to discriminate sensory stimuli using operant conditioning. Head-fixed mice reported stimuli by licking in go/no-go tasks and also using a forced choice paradigm using a dual lickport. In some cases mice learned to discriminate sensory stimuli in a few trials within the first behavioral session. Delay epochs lasting a second or more were used to separate sensation (e.g. tactile exploration) and action (i.e. licking). Mice performed a variety of perceptual decision tasks with high performance for hundreds of trials per behavioral session. Up to four months of continuous water restriction showed no adverse health effects. Behavioral performance correlated with the degree of water restriction, supporting the importance of controlling access to water. These behavioral paradigms can be combined with cellular resolution imaging, random access photostimulation, and whole cell recordings.

A phase Ilate/II trial of hyperfractionated (HFX) radiation therapy for non-small-cell carcinoma of the lung (NSCCL) was conducted by the Radiation Therapy Oncology Group (RTOG) between 1983 and 1987. Fractions of 1.2 Gy were administered twice daily with greater than or equal to 4 hours between fractions. Patients were randomized to receive minimum total doses of 60.0, 64.8, and 69.6 Gy. After acceptable risks of acute and late effects were found, 74.4 Gy and 79.2 Gy arms were added, and the lowest total dose arms were closed. No significant differences in the risks of acute or late effects in normal tissues were found among the 848 patients analyzed in the five arms; risks of severe or life-threatening pneumonitis were 2.6% for 60.0 to 64.8 Gy, 5.7% for 69.6 to 74.4 Gy, and 8.1% for 79.2 Gy. Among 350 patients who had the same criteria as Cancer and Leukemia Group B (CALGB) protocol 84-33 (American Joint Committee on Cancer Staging [AJCCS], 1984, stage III; Karnofsky performance status [KPS] 70 to 100; less than 6% weight loss), there was a dose response for survival: survival with 69.6 Gy (median, 13.0 months; 2 years, 29%) was significantly (P = .02) better than the lower total doses. There were no differences in survival among the three highest total-dose arms. Comparisons with results in similar patients treated with 60 Gy in 30 fractions of 2.0 Gy 5 days per week for 6 weeks suggest benefit from HFX radiation therapy with 69.6 Gy. Improvement in survival with HFX radiation therapy at 69.6 Gy total dose without increase in normal tissue effects, justifies phase III comparison with standard fractionation alone and combined with systemic chemotherapy in this common presentation of NSCCL.