Dichloroacetate should be considered with platinum-based chemotherapy in hypoxic tumors rather than as a single agent in advanced non-small cell lung cancer.

OBJECTIVES: Dichloroacetate (DCA) is a highly bioavailable small molecule that inhibits pyruvate dehydrogenase kinase, promoting glucose oxidation and reversing the glycolytic phenotype in preclinical cancer studies. We designed this open-label phase II trial to determine the response rate, safety, and tolerability of oral DCA in patients with metastatic breast cancer and advanced stage non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This trial was conducted with DCA 6.25 mg/kg orally twice daily in previously treated stage IIIB/IV NSCLC or stage IV breast cancer. Growth inhibition by DCA was also evaluated in a panel of 54 NSCLC cell lines with and without cytotoxic chemotherapeutics (cisplatin and docetaxel) in normoxic and hypoxic conditions. RESULTS AND CONCLUSIONS: Under normoxic conditions in vitro, single-agent IC50 was >2 mM for all evaluated cell lines. Synergy with cisplatin was seen in some cell lines under hypoxic conditions. In the clinical trial, after seven patients were enrolled, the study was closed based on safety concerns. The only breast cancer patient had stable disease after 8 weeks, quickly followed by progression in the brain. Two patients withdrew consent within a week of enrollment. Two patients had disease progression prior to the first scheduled scans. Within 1 week of initiating DCA, one patient died suddenly of unknown cause and one experienced a fatal pulmonary embolism. We conclude that patients with previously treated advanced NSCLC did not benefit from oral DCA. In the absence of a larger controlled trial, firm conclusions regarding the association between these adverse events and DCA are unclear. Further development of DCA should be in patients with longer life expectancy, in whom sustained therapeutic levels can be achieved, and potentially in combination with cisplatin.

Risk factors for recurrence amongst high intermediate risk patients with endometrioid adenocarcinoma.

OBJECTIVE: To determine risk factors associated with recurrence in patients with high intermediate risk (HIR) endometrioid adenocarcinoma. METHODS: A retrospective analysis of patients with HIR endometrioid adenocarcinoma who underwent hysterectomy, bilateral salpingo-oophorectomy, with or without pelvic/para-aortic lymphadenectomy at the University of Pennsylvania between 1990 and 2009 was performed. RESULTS: A total of 103 women with HIR endometrial cancer were identified. Multivariable analysis revealed that ≥2/3 myometrial invasion (HR, 4.79; p=0.010) and grade 3 disease (HR, 3.04; p=0.045) were independently predictive of distant metastases. The 5-year distant metastases free survival (DMFS) for patients with neither or one of these risk factors was 89%, and the 5-year DMFS for patients with both risk factors was 48% (p<0.001). CONCLUSION: Patients with both grade 3 disease and deep third myometrial invasion have a high risk of distant metastases. Identifying these patients may be important in rationally selecting patients for systemic therapy.

Determination of prognostic factors for vaginal mucosal toxicity associated with intravaginal high-dose rate brachytherapy in patients with endometrial cancer.

PURPOSE: The objective of this study was to determine the patient- and treatment-related prognostic factors associated with vaginal toxicity in patients who received intravaginal high dose rate (HDR) brachytherapy alone as adjuvant treatment for endometrial cancer. Secondary goals of this study included a quantitative assessment of optimal dilator use frequency and a crude assessment of clinical predictors for compliant dilator use. METHODS AND MATERIALS: We retrospectively reviewed the charts of 100 patients with histologically confirmed endometrial cancer who underwent total hysterectomy and bilateral salpingo-oophorectomy with or without lymph node dissection and adjuvant intravaginal brachytherapy between 1995 and 2009 at the Hospital of the University of Pennsylvania. The most common treatment regimen used was 21 Gy in three fractions (71 patients). Symptoms of vaginal mucosal toxicity were taken from the history and physical exams noted in the patients' charts and were graded according to the Common Toxicity Criteria for Adverse Events v. 4.02. RESULTS: The incidence of Grade 1 or asymptomatic vaginal toxicity was 33% and Grade 2-3 or symptomatic vaginal toxicity was 14%. Multivariate analysis of age, active length, and dilator use two to three times a week revealed odds ratios of 0.93 (p = 0.013), 3.96 (p = 0.008), and 0.17 (p = 0.032) respectively. CONCLUSION: Increasing age, vaginal dilator use of at least two to three times a week, and shorter active length were found to be significantly associated with a decreased risk of vaginal stenosis. Future prospective studies are necessary to validate our findings.