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Halabi S.,Duke University | Lin C.-Y.,Duke University | Small E.J.,University of California at San Francisco | Armstrong A.J.,Duke Prostate Center and the Duke Cancer Institute | And 7 more authors.
Journal of the National Cancer Institute | Year: 2013

Background Several prognostic models for overall survival (OS) have been developed and validated in men with metastatic castration-resistant prostate cancer (mCRPC) who receive first-line chemotherapy. We sought to develop and validate a prognostic model to predict OS in men who had progressed after first-line chemotherapy and were selected to receive second-line chemotherapy. Methods Data from a phase III trial in men with mCRPC who had developed progressive disease after first-line chemotherapy (TROPIC trial) were used. The TROPIC was randomly split into training (n = 507) and testing (n = 248) sets. Another dataset consisting of 488 men previously treated with docetaxel (SPARC trial) was used for external validation. Adaptive least absolute shrinkage and selection operator selected nine prognostic factors of OS. A prognostic score was computed from the regression coefficients. The model was assessed on the testing and validation sets for its predictive accuracy using the time-dependent area under the curve (tAUC). Results The nine prognostic variables in the final model were Eastern Cooperative Oncology Group performance status, time since last docetaxel use, measurable disease, presence of visceral disease, pain, duration of hormonal use, hemoglobin, prostate specific antigen, and alkaline phosphatase. The tAUCs for this model were 0.73 (95% confidence interval [CI] = 0.72 to 0.74) and 0.70 (95% CI = 0.68 to 0.72) for the testing and validation sets, respectively. Conclusions A prognostic model of OS in the postdocetaxel, second-line chemotherapy, mCRPC setting was developed and externally validated. This model incorporates novel prognostic factors and can be used to provide predicted probabilities for individual patients and to select patients to participate in clinical trials on the basis of their prognosis. Prospective validation is needed. © The Author 2013.

Cerbone L.,San Camillo and Forlanini Hospital | Sternberg C.N.,San Camillo and Forlanini Hospital | Sengelov L.,Herlev Hospital | Agerbaek M.,Aarhus University Hospital | And 5 more authors.
Oncology (Switzerland) | Year: 2016

Background/Objective: Lapatinib is a potent HER1 and HER2 inhibitor. Gemcitabine-cisplatin (GC) is a standard chemotherapy regimen for advanced/metastatic bladder cancer. This phase I study examined the safety of lapatinib in combination with GC in patients with bladder cancer. The primary aim was to determine the maximum tolerated dose (MTD) of lapatinib in combination with GC. Methods: A 3 + 3 dose escalation protocol was used with lapatinib at 750, 1,000 and then 1,250 mg. It was dosed daily with gemcitabine (1,000 mg/m2 on days 1, 8 and 15) and cisplatin (70 mg/m2 on day 2) every 28 days. In all, 18 patients with a median age of 63 years (range 50-77) were included; 3/6, 3/5 and 6/7 patients received lapatinib at 750, 1,000 and 1,250 mg, combined with GC, in cohorts 1, 2 and 3, respectively. Results: No dose-limiting toxicities (DLTs) were observed in cohort 1 or 2 (3 patients each); in cohort 3 (2 × 3 patients), 1 of the 6 patients presented DLTs (grade 4, treatment-related febrile neutropenia and renal failure). Twelve patients received 6 cycles. Conclusions: Lapatinib at 750-1,250 mg combined with GC appears safe and tolerable. The MTD of lapatinib combined with GC in bladder cancer was 1,250 mg. © 2015 S. Karger AG, Basel.

Fitzpatrick J.M.,University College Dublin | Bellmunt J.,University of the Sea | Fizazi K.,University Paris - Sud | Heidenreich A.,RWTH Aachen | And 17 more authors.
European Journal of Cancer | Year: 2014

The exponential growth of novel therapies for the treatment of metastatic castration-resistant prostate cancer (mCRPC) over the last decade has created an acute need for education and guidance of clinicians regarding optimal strategies for patient management. A multidisciplinary panel of 21 European experts in mCRPC assembled for comprehensive discussion and consensus development, seeking to move the field forward and provide guidance and perspectives on optimal selection and sequencing of therapeutic agents and monitoring of response to treatment and disease progression. A total of 110 clinically-relevant questions were addressed and a modified Delphi method was utilised to obtain a consensus. The panel reached a consensus on several important issues, providing recommendations on appropriate phase III clinical trial end-points and optimal strategies for imaging and monitoring of bone metastases. Guidance regarding selection and sequencing of therapy in patients with newly diagnosed or progressive mCRPC is emphasised, including the use of novel bone-targeted agents, chemotherapy, androgen receptor pathway-targeted agents and immunotherapy. The impact of drug resistance and prostate-specific antigen flare on treatment decisions was also addressed. Ultimately, individualised therapy for patients with mCRPC is dependent on continued refinement of clinical decision-making based on patient and disease characteristics. This consensus statement offers clinicians expert guidance on the implementation of recent advances to improve patient outcome, focusing on the future of prostate cancer care. © 2014 Elsevier Ltd. All rights reserved.

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