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Introduction: Despite the advances in radiation techniques and chemotherapy, survival with current platinum-based chemotherapy and concomitant thoracic radiation remains dismal. Bortezomib, a proteasome inhibitor, modulates apoptosis and cell cycle through disruption of protein degradation. The combination of bortezomib and carboplatin/paclitaxel and concurrent radiation in unresectable stage III non-small-cell lung cancer was evaluated in this phase I/II study., Methods: Patients with histologic or cytologic confirmed stage III nonmetastatic non-small-cell lung cancer who were candidates for radiation therapy were eligible. In the phase I portion, patients received escalating doses of bortezomib, paclitaxel, and carboplatin concomitantly with thoracic radiation (60 Gy/30 daily fractions) using a modified 3 + 3 design. The primary endpoint for the phase II portion was the 12-month survival rate (12MS). A one-stage design with an interim analysis yielded 81% power to detect a true 12MS of 75%, with a 0.09 level of significance if the true 12MS was 60% using a sample size of 60 patients. Secondary endpoints consisted of adverse events (AEs), overall survival, progression-free survival, and the confirmed response rate., Results: Thirty-one patients enrolled during the phase I portion of the trial, of which four cancelled before receiving treatment, leaving 27 evaluable patients. Of these 27 patients, two dose-limiting toxicities were observed, one (grade 3 pneumonitis) at dose level 1 (bortezomib at 0.5 mg/m, paclitaxel at 150 mg/m, and carboplatin at area under the curve of 5) and one (grade 4 neutropenia lasting ≥8 days) at dose level 6 (bortezomib 1.2 mg/m, paclitaxel 175 mg/m, and carboplatin at area under the curve of 6). During the phase I portion, the most common grade 3 of 4 AEs were leukopenia (44%), neutropenia (37%), dyspnea (22%), and dysphagia (11%). Dose level 6 was declared to be the recommended phase II dose (RP2D) and the phase II portion of the study opened. After the first 26 evaluable patients were enrolled to the RP2D, a per protocol interim analysis occurred. Of these 26 patients, 23 (88%) survived at least 6 months (95% confidence interval [CI], 70-98%), which was enough to continue to full accrual per study design. However, due to slow accrual, the study was stopped after 27 evaluable patients were enrolled (6-phase I RP2D; 21-phase II). Of these 27 patients, the 12MS was 73% (95% CI, 58-92%), the median overall survival was 25.0 months (95% CI, 15.6-35.8), and the median progression-free survival was 8.4 months (95% CI, 4.1-10.5). The confirmed response rate was 26% (seven of 27; 95% CI, 11-46%), consisting of four partial responses and three complete responses. Grade 3+ and grade 4+ AEs occurred in 82% and 56% of patients, respectively. One patient experienced grade 5 pneumonitis that was possibly related to the treatment. Grade 3 and 4 hematological toxicities were observed in 82% and 56% patients, respectively., Conclusions: The addition of bortezomib to concurrent carboplatin/paclitaxel and radiation seemed to be feasible, although associated with increased hematological toxicities. A favorable median overall survival of 25 months suggests a potential benefit for this regimen.

Introduction: Hot flashes represent a significant problem in men undergoing androgen deprivation therapy., Materials and Methods: Via a prospective, double-blind, placebo-controlled clinical trial, men with hot flashes, on a stable androgen deprivation therapy program for prostate cancer, received a placebo or gabapentin at target doses of 300, 600, or 900 mg/day. Hot flash frequencies and severities were recorded daily during a baseline week and for 4 weeks while the patients took the study medication., Results: In the 214 eligible patients who began the study drug on this trial, comparing the fourth treatment week to the baseline week, mean hot flash scores decreased in the placebo group by 4.1 units and in the three increasing dose gabapentin groups by, 3.2, 4.6, and 7.0 units. Comparing the three combined gabapentin arms to the placebo arm did not result in significant hot flash differences. Wilcoxon rank-sum P values for change in hot flash scores and frequencies after 4 weeks of treatment were 0.10 and 0.02, comparing the highest dose gabapentin arm to the placebo arm, respectively. The gabapentin was well tolerated in this trial., Conclusion: These results support that gabapentin decreases hot flashes, to a moderate degree, in men with androgen ablation-related vasomotor dysfunction.

Background: Decreased libido is one of several changes in sexual function that are often experienced by female cancer patients. Transdermal testosterone therapy has been associated with increased libido among estrogen-replete women who report low libido., Methods: In a phase III randomized, placebo-controlled crossover clinical trial, we evaluated whether transdermal testosterone would increase sexual desire in female cancer survivors. Postmenopausal women with a history of cancer and no current evidence of disease were eligible if they reported a decrease in sexual desire and had a sexual partner. Eligible women were randomly assigned to receive 2% testosterone in Vanicream for a testosterone dose of 10 mg daily or placebo Vanicream for 4 weeks and were then crossed over to the opposite treatment for an additional 4 weeks. The primary endpoint was sexual desire or libido, as measured using the desire subscales of the Changes in Sexual Functioning Questionnaire, as assessed at baseline and at the end of 4 and 8 weeks of treatment. Serum levels of bioavailable testosterone were measured at the same times. All statistical tests were two-sided., Results: We enrolled 150 women. Women who were on active testosterone cream had higher serum levels of bioavailable testosterone than women on placebo (mean change from baseline, testosterone versus placebo, week 4, 11.57% versus 0%, difference = 11.57%, 95% confidence interval [CI] = 8.49% to 14.65%; week 8, 10.21% versus 0.28%, difference = 9.92%, 95% CI = 5.42% to 14.42%; P<.001 for all). However, the average intrapatient libido change from baseline to weeks 4 and 8 was similar on both arms., Conclusion: Increased testosterone level did not translate into improved libido, possibly because women on this study were estrogen depleted.

Purpose: This phase II study (S9914) evaluated the efficacy and toxicity of the three-drug combination of paclitaxel, carboplatin, and topotecan with granulocyte colony-stimulating factor support in previously untreated patients with extensive stage small cell lung cancer., Patients and Methods: Patients with newly diagnosed extensive stage small cell lung cancer received topotecan 1.0 mg/m intravenously on days 1 through 4; paclitaxel 175 mg/m intravenously on day 4, and carboplatin AUC = 5 intravenously on day 4, treatments were repeated every 21 days for a maximum of six cycles. All patients also received granulocyte colony-stimulating factor 5 mug/kg/day beginning on day 5 of each cycle., Results: A total of 88 patients were enrolled on the study; 79 patients were assessable for survival and toxicity and 74 patients for response. Objective response was observed in 50 patients (68%; 95% confidence interval [CI]: 56%-78%) with nine patients (12%) achieving a complete response. Median progression-free survival was 7 months (95% CI: 6-8 months) and median overall survival was 12 months (95% CI: 11-14 months). The 1- and 2-year survival rates were 48% (95% CI: 37%-59%) and 20% (95% CI: 11%-29%), respectively. The most common toxicities were hematologic. Grade 3 and 4 neutropenia was noted in 17 (22%) and 27 (34%) patients, respectively. Febrile neutropenia developed in only four patients. Two patients (3%) died of treatment-related causes., Conclusion: The combination of paclitaxel, carboplatin, and topotecan combined with granulocyte colony-stimulating factor support is an active and reasonably well-tolerated regimen for the treatment of extensive stage small cell lung cancer.

Rituximab, a chimeric antibody that targets CD20(+) B cells, produces a 48% response rate in patients with refractory low-grade non-Hodgkin lymphoma. In this phase II trial, patients with low-grade non-Hodgkin lymphoma who had previously received no systemic therapy were treated with rituximab, 375 mg/m(2), administered by IV infusion for 4 consecutive weeks. Patients with objective response or stable disease received repeat 4-week courses of rituximab at 6-month intervals. At the time of initial reevaluation at 6 weeks, 21 of 39 patients (54%) had objective response to treatment, and an additional 14 patients (36%) had stable disease or minor response. Response rates were similar in patients with follicular and small lymphocytic (CLL-type) lymphoma (52% versus 57%, respectively). At present, follow-up is short and only 13 patients have undergone a second course of rituximab treatment. However, 4 additional responses were documented either prior to the second course of rituximab (2 patients) or following the second course (2 patients) and 4 patients improved from partial to complete response. The current response rate is 64%, with 6 complete responses (15%). Treatment with rituximab was well tolerated, with only 1 patient experiencing grade 3/4 infusion-related toxicity. Rituximab is well tolerated and highly active in patients with low-grade non-Hodgkin lymphoma previously untreated with systemic therapy. Although further follow-up is required, the demonstration of minimal toxicity and considerable activity of this new biologic agent represents an important beginning of more specific, less toxic treatment for this important group of cancer patients.

An apparent cluster of four aplastic anemia (AA) cases in teenagers residing in a small South Carolina town was further investigated. Incidence of AA in all age groups in a surrounding three county area (TCA) over a 12-year time interval was determined and compared with AA incidence rates in Baltimore, representing the only known population based United States incidence data. The same general age-specific incidence pattern (based on 27 cases in the TCA and 118 in Baltimore) was found in the two areas, both overall and for the four race-sex groups. Although based on small numbers, nonwhite average annual age-adjusted rates for males and females were higher in the TCA (6.8 and 13.7 per million) than in Baltimore (4.7 and 7.3). For whites, TCA rates were 11.7 and 5.4 (for males and females) and Baltimore rates were 7.1 and 5.4. The differences for non-whites in the two areas may indicate a greater prevalence of risk factors for AA in the TCA than in Baltimore, but the small numbers of cases and the lack of comparable data from other areas of the country, together with the possibility of misdiagnosis of the disease, make definitive conclusions impossible.