Yust-Katz S.,University of Houston |
Liu D.,University of Houston |
Yuan Y.,University of Houston |
Liu V.,University of Houston |
And 9 more authors.
BACKGROUND Lonafarnib is an oral selective farnesyltransferase inhibitor, a class of drugs which have shown activity in preclinical glioma models. Temozolomide (TMZ) is an alkylating agent that is the first-line chemotherapy for glioblastoma. METHODS The current study combined the cytotoxic agent TMZ with the cytostatic agent lonafarnib for patients with recurrent glioblastoma to establish a maximum tolerated dose (MTD) of the combination and its preliminary efficacy. Three dose cohorts of lonafarnib were studied in the phase 1 component of the trial (100 mg twice daily [bid], 150 mg bid, and 200 bid) with dose-dense schedule of TMZ (150 mg/m2 daily) administered in an alternating weekly schedule. After establishing the MTD of lonafarnib, a subsequent expansion phase 1b was undertaken to evaluate efficacy, primarily measured by 6-month progression-free survival (PFS-6). RESULTS Fifteen patients were enrolled into the phase 1 component and 20 patients into the phase 1b component. The MTD of lonafarnib in combination with TMZ was 200 mg bid. Among the patients enrolled into the study, 34 were eligible for 6-month progression evaluation and 35 patients were evaluable for time-to-progression analysis. The PFS-6 rate was 38% (95% confidence interval [CI] = 22%, 56%) and the median PFS was 3.9 months (95% CI = 2.5, 8.4). The median disease-specific survival was 13.7 months (95% CI = 8.9, 22.1). Hematologic toxicities, particularly lymphopenia, were the most common grade 3 and 4 adverse events. There were no treatment-related deaths. CONCLUSIONS These results demonstrate that TMZ can be safely combined with a farnesyltransferase inhibitor and that this regimen is active, although the current study cannot determine the relative contributions of the 2 agents or the contribution of the novel administration schedule. © 2013 American Cancer Society. Source
Yust-Katz S.,University of Houston |
Mathis S.,University of Houston |
Groves M.D.,University of Houston |
Groves M.D.,Austin Brain Tumor Center
Leptomeningeal metastasis (LM) most commonly arise from breast and lung cancers, and melanoma. Genitourinary cancer (including ovarian, prostate, uterine kidney and bladder) rarely cause LM, with only case reports published. The aims of the study were to describe cases of patients with Genitourinary cancer and Leptomeningeal metastasis, to estimate its prevalence and describe its behavior and outcome. We queried the MD Anderson database for patients with LM and genitourinary cancer between 1978 and 2011. The files of all patients with genitourinary cancer and leptomeningeal disease were retrospectively reviewed. Out of 93960 GU cancer patients treated in MD Anderson (cervix cancer 13,289, ovarian cancer 13,126, bladder cancer 11,834, prostate cancer 41,830, and kidney 13,881), 31 cases (0.03 %) of GU cancer with LM were identified in MD Anderson Cancer Center (MDACC) between 1978 and 2011. Eight patients had bladder cancer, 4 had cervical cancer, 4 had renal cancer, 8 had ovarian cancer and 7 had prostate cancer. Mean age of diagnosis of cancer was 55.9 ± 11.7 (range 20-74). Mean time from primary diagnosis to LM diagnosis was 141.46 ± 244 weeks (range 0.43-409.57). Median survival after LM diagnosis was 15.7 weeks (range 0.85-142.57). The patients presented with multiple signs and symptoms. Although rare - LM should be considered as a complication of GU cancer. Awareness of early neurological signs and symptoms may help the clinician to make an early diagnosis and possibly intervene to prevent neurological deficits. © 2013 Springer Science+Business Media New York. Source
Yust-Katz S.,University of Texas M. D. Anderson Cancer Center |
Garciarena P.,University of Texas M. D. Anderson Cancer Center |
Liu D.,University of Texas M. D. Anderson Cancer Center |
Yuan Y.,University of Texas M. D. Anderson Cancer Center |
And 5 more authors.
Journal of Neuro-Oncology
Leptomeningeal disease (LMD) occurs in 5 % of breast cancer patients. The aim of this study was to identify risk factors related to survival and time to development of LMD in breast cancer patients. A retrospective analysis of breast cancer patients with LMD, evaluated in MDACC between 1995 and 2011. 103 patients with diagnosis of breast cancer and LMD were identified (one male). The median age at LMD diagnosis was 49.2 years. 78.2 % had invasive ductal carcinoma. Hormone receptors (HRs) were positive in 55.3 % of patients, 47.4 % were human epidermal growth factor receptor 2-positive and 22.8 % were triple negative. 52 % of the patients were treated with WBRT, 19 % with spinal radiation, 36 % with systemic chemotherapy and 55 % with intrathecal chemotherapy. Estimated median overall survival from time of breast cancer diagnosis was 3.66 years. Median survival from time of LMD diagnosis was 4.2 months. Time from breast cancer diagnosis to LMD was 2.48 years. In multivariate analysis, HR status and stage at diagnosis were significantly associated with time to LMD diagnosis (p < 0.05). In triple negative patients, time to LMD was shorter. In patients who were HR positive, time to LMD was longer. Survival from LMD diagnosis was significantly associated with both treatment, as well as positive HR status (multivariate analysis p < 0.05). In conclusion LMD has dismal prognosis in breast cancer patients. HR status contributes to time to LMD diagnosis and survival from LMD diagnosis. The impact of treatment aimed at LMD cannot be ascertained in our retrospective study due to the inherent bias associated with the decision to treat. © 2013 Springer Science+Business Media New York. Source
Chamberlain M.,Fred Hutchinson Cancer Research Center |
Soffietti R.,University of Turin |
Raizer J.,Northwestern University |
Ruda R.,University of Turin |
And 10 more authors.
Purpose. To date, response criteria and optimal methods for assessment of outcome have not been standardized in patients with leptomeningeal metastasis (LM). Methods. A Response Assessment in Neuro-Oncology working group of experts in LM critically reviewed published literature regarding randomized clinical trials (RCTs) and trial design in patients with LM. Results. A literature review determined that 6 RCTs regarding the treatment of LM have been published, all of which assessed the response to intra-CSF based chemotherapy. Amongst these RCTs, only a single trial attempted to determine whether intra-CSF chemotherapy was of benefit compared with systemic therapy. Otherwise, this pragmatic question has not been formally addressed in patients with solid cancers and LM. The methodology of the 6 RCTs varied widely with respect to pretreatment evaluation, type of treatment, and response to treatment. Additionally there was little uniformity in reporting of treatment-related toxicity. One RCT suggests no advantage of combined versus single-agent intra-CSF chemotherapy in patients with LM. No specific intra-CSF regimen has shown superior efficacy in the treatment of LM, with the exception of liposomal cytarabine in patients with lymphomatous meningitis. Problematic with all RCTs is the lack of standardization with respect to response criteria. There was considerable variation in definitions of response by clinical examination, neuroimaging, and CSF analysis. Conclusion. Based upon a review of published RCTs in LM, there exists a significant unmet need for guidelines for evaluating patients with LM in clinical practice as well as for response assessment in clinical trials. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. Source
Raizer J.J.,Northwestern University |
Giglio P.,Ohio State University |
Hu J.,Cedars Sinai Medical Center |
Groves M.,Austin Brain Tumor Center |
And 19 more authors.
Journal of Neuro-Oncology
Survival for glioblastoma (GBM) patients with an unmethyated MGMT promoter in their tumor is generally worse than methylated MGMT tumors, as temozolomide (TMZ) response is limited. How to better treat patients with unmethylated MGMT is unknown. We performed a trial combining erlotinib and bevacizumab in unmethylated GBM patients after completion of radiation (RT) and TMZ. GBM patients with an unmethylated MGMT promoter were trial eligible. Patient received standard RT (60 Gy) and TMZ (75 mg/m2 × 6 weeks) after surgical resection of their tumor. After completion of RT they started erlotinib 150 mg daily and bevacizumab 10 mg/kg every 2 weeks until progression. Imaging evaluations occurred every 8 weeks. The primary endpoint was overall survival. Of the 48 unmethylated patients enrolled, 46 were evaluable (29 men and 17 women); median age was 55.5 years (29–75) and median KPS was 90 (70–100). All patients completed RT with TMZ. The median number of cycles (1 cycle was 4 weeks) was 8 (2–47). Forty-one patients either progressed or died with a median progression free survival of 9.2 months. At a follow up of 33 months the median overall survival was 13.2 months. There were no unexpected toxicities and most observed toxicities were categorized as CTC grade 1 or 2. The combination of erlotinib and bevacizumab is tolerable but did not meet our primary endpoint of increasing survival. Importantly, more trials are needed to find better therapies for GBM patients with an unmethylated MGMT promoter. © 2015, Springer Science+Business Media New York. Source