A Phase I Trial of Surgical Resection and Intraoperative Hyperthermic Cisplatin and Gemcitabine for Pleural Mesothelioma.

INTRODUCTION: The primary objective of this single-institution phase I clinical trial was to establish the maximum tolerated dose of gemcitabine added to cisplatin and delivered as heated intraoperative chemotherapy after resection of malignant pleural mesothelioma. METHODS: The extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) treatment arms were based on investigators' assessment of patient fitness and potential for macroscopic complete resection. Previously established intracavitary dosing of cisplatin (range 175-225 mg/m2) with systemic cytoprotection was used in combination with escalating doses of gemcitabine, following a 3-plus-3 design from 100 mg/m2 in 100-mg increments. RESULTS: From 2007 to 2011, 141 patients were enrolled and 104 completed treatment. The median age of those completing treatment was 65 years (range 43-85 years), and 22 (21%) were female. In the EPP arm (n = 59), 31 patients (53%) had the epithelioid histologic type and the median radiographic tumor volume was 236 cm3 (range 16-4285 cm3). In the P/D arm (n = 41), 29 patients (71%) had the epithelioid histologic type and the median tumor volume was 79 cm3 (range 6-1107 cm3). The operative mortality rate was 2%, and 35 and 22 serious adverse events were encountered among 27 patients (46%) and 16 patients (39%) in the EPP and P/D arms, respectively. Dose-limiting toxicity (grade 3 leukopenia) was observed in two patients who were receiving 1100 mg/m2 of gemcitabine, thus establishing the maximum tolerated dose at 1000 mg/m2, in combination with 175 mg/m2 of cisplatin. The median overall and recurrence-free survival times in treated patients were 20.3 and 10.7 months, respectively. CONCLUSIONS: Combination cisplatin and gemcitabine heated intraoperative chemotherapy can be administered safely and feasibly in the context of complete surgical resection of malignant pleural mesothelioma by EPP or P/D.

Predictors and outcomes of limited resection for early-stage non-small cell lung cancer.

BACKGROUND: Lobectomy is considered the standard treatment for early-stage non-small cell lung cancer (NSCLC); however, more limited resections are commonly performed. We examined patient and surgeon factors associated with limited resection and compared postoperative and long-term outcomes between sublobar and lobar resections. METHODS: A population- and health system-based sample of patients newly diagnosed with stage I or II NSCLC between 2003 and 2005 in five geographically defined regions, five integrated health-care delivery systems, and 15 Veterans Affairs hospitals was observed for a median of 55 months, through May 31, 2010. Predictors of limited resection and postoperative outcomes were compared using unadjusted and propensity score-weighted analyses. All P values are from two-sided tests. RESULTS: One hundred fifty-five (23%) patients underwent limited resection and 524 (77%) underwent lobectomy. In adjusted analyses of patient-specific factors, smaller tumor size (P = .004), coverage by Medicare or Medicaid, no insurance or unknown insurance (P = .02), more severe lung disease (P < .001), and a history of stroke (P = .049) were associated with receipt of limited resection. In adjusted analyses of surgeon characteristics, thoracic surgery specialty (P = .02), non-fee-for-service compensation (P = .008), and National Cancer Institute cancer center designation (P = .006) were associated with higher odds of limited resection. Unadjusted 30-day mortality was higher with limited resection than with lobectomy (7.1% vs 1.9%, difference = 5.2%, 95% confidence interval [CI] = 1.5% to 10.8%, P = .003), and the adjusted difference was not statistically significant (6.5% vs 2.9%, difference = 3.6%, 95% CI = -.1% to 9.2%, P = .09). Postoperative complications did not differ by type of surgery (all P > .05). Over the course of the study, a non-statistically significant trend toward improved long-term survival was evident for lobectomy, compared with limited resection, in adjusted analyses (hazard ratio of death = 1.35 for limited resection, 95% CI = 0.99 to 1.84, P = .05). CONCLUSIONS: Evidence is statistically inconclusive but suggestive that lobectomy, compared with limited resection, is associated with increased long-term survival for early-stage lung cancer. Clinical, socioeconomic, and surgeon factors appear to be associated with the choice of surgical resection.

A phase I study of extrapleural pneumonectomy and intracavitary intraoperative hyperthermic cisplatin with amifostine cytoprotection for malignant pleural mesothelioma.

OBJECTIVE: This study was undertaken to determine maximum tolerated dose and toxicity of intraoperative intracavitary hyperthermic cisplatin perfusion with amifostine after extrapleural pneumonectomy for malignant pleural mesothelioma. METHODS: Patients with mesothelioma were prospectively enrolled. Those with resectable disease received amifostine and 1-hour hyperthermic cisplatin perfusion of ipsilateral hemithorax and abdomen. Morbidity, recurrence, and survival were recorded. RESULTS: Forty-two patients were enrolled; 29 underwent resection (operative mortality 7%, 2/29). Median age was 57 years. Eighteen were in pathologic stage I or II; 11 were in stage III. Median hospitalization was 15 days. Common complications were atrial fibrillation (66%, 19 patients), deep venous thrombosis (31%, 9 patients), and grade 3+ renal toxicity (31%, 9 patients). Feasibility was determined. Renal toxicity was unrelated to cisplatin dose, with no maximum tolerated dose determined. Overall median survival was 17 months (resected 20 months, unresected 10 months). Median survivals were 26 months for patients receiving higher cisplatin doses and 16 months for those receiving lower doses (P = .35). Survival was significantly longer with negative extrapleural nodes (31 vs 14 months, P = .0115) and early stage (all resected 35 months for stage I-II vs 14 months for stage III, P = .0022, epithelial 39 months for stage I-II vs 15 months for stage III, P = .0072). CONCLUSION: Early stage and negative extrapleural lymph nodes were associated with prolonged survival. Single-dose amifostine did not protect adequately against cisplatin-induced renal toxicity. Additional cytoprotective strategies are needed to allow determination of cisplatin maximum tolerated dose.

Phase I to II study of pleurectomy/decortication and intraoperative intracavitary hyperthermic cisplatin lavage for mesothelioma.

PURPOSE: To evaluate morbidity, mortality, maximum-tolerated dose (MTD), and outcome of intraoperative intracavitary hyperthermic cisplatin lavage in patients undergoing pleurectomy for malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Sixty-one patients were prospectively registered. Forty-four resectable patients with MPM underwent pleurectomy, followed by a 1-hour lavage of the resection cavity with dose-escalated cisplatin (50, 100, 150, 175, 200, 225, and 250 mg/m2) at 42 degrees C and then intravenous sodium thiosulfate (16 g/m2 over 6 hours). Survival estimates were compared using the log-rank test and proportional hazards regression. RESULTS: Median age was 71 years (range, 50 to 82 years). Twenty-four patients had epithelial tumors, and 20 had sarcomatous or mixed histology. Postoperative mortality was 11% (five of 44 patients). Dose-limiting renal toxicity occurred at 250 mg/m2, establishing the MTD at 225 mg/m2. Other morbidity included atrial fibrillation (14 of 44 patients, 32%) and deep venous thrombosis (four of 44 patients, 9%). Median survival time of all registered patients was 9 months, and the median survival time of resected patients was 13 months. Survival estimates differed significantly for resectable patients exposed to low doses (50 to 150 mg/m2; n = 9; median, 6 months) versus high doses (175 to 250 mg/m2; n = 35; median, 18 months) of hyperthermic cisplatin (P = .0019); recurrence-free interval also differed significantly (4 v 9 months, respectively; P < .0001). Low dose level (relative risk = 3.418) and nonepithelial histology (relative risk = 2.336) were independent risk factors for poor survival. Twenty patients with epithelial tumors who underwent high-dose cisplatin lavage had a 26-month median survival time. CONCLUSION: Pleurectomy and high-dose intraoperative intracavitary hyperthermic cisplatin lavage is feasible in this patient population with restricted surgical options. An apparent dose-related survival benefit warrants further study.