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Sonpavde G.,Baylor College of Medicine | Sternberg C.N.,San Camillo and Forlanini Hospitals
International Journal of Urology | Year: 2010

Docetaxel based chemotherapy has been shown to modestly extend life, relieve pain and improve the quality of life in patients with metastatic castration-resistant prostate cancer. Current trials are attempting to build on the backbone of docetaxel by combining it with novel biological agents. Trials are also investigating the role of docetaxel for earlier stages of prostate cancer. No standard second-line systemic therapy exists and such patients are candidates for clinical trials. The increased understanding of the mechanisms of progressive castration-resistant prostate cancer is being translated into an increasing pipeline of novel therapies. © 2010 The Japanese Urological Association.

Tran H.T.,University of Houston | Liu Y.,Glaxosmithkline | Zurita A.J.,University of Houston | Lin Y.,Glaxosmithkline | And 8 more authors.
The Lancet Oncology | Year: 2012

Background: Several targeted drugs are approved for treatment of patients with metastatic renal-cell cancer, but no validated biomarkers are available for prediction of clinical outcome. We aimed to assess the prognostic and predictive associations of pretreatment plasma concentrations of cytokine and angiogenic factors (CAFs) with data from a phase 2 and a phase 3 trial of pazopanib treatment. Methods: We used a three-step approach for screening, confirmation, and validation of prospective CAF biomarkers. We screened 17 CAFs in 129 patients who had the greatest or least tumour shrinkage in a phase 2 trial of 215 patients treated with pazopanib. We confirmed associations of candidate CAFs (those identified in the screening and from previous studies) with tumour response and progression-free survival (PFS) in 215 patients from this phase 2 trial with an independent analytical platform. We validated confirmed markers in 344 patients from a randomised, placebo-controlled, phase 3 clinical study of pazopanib. Findings: Five candidate markers emerged from initial screening-interleukin 6, interleukin 8, hepatocyte growth factor (HGF), tissue inhibitor of metalloproteinases (TIMP)-1, and E-selectin. Confirmatory analyses identified associations of interleukin 6, interleukin 8, VEGF, osteopontin, E-selectin, and HGF with continuous tumour shrinkage or PFS in patients treated with pazopanib. In the validation set of samples from the phase 3 trial, patients treated with pazopanib who had high concentrations (relative to median) of interleukin 8 (p=0·006), osteopontin (p=0·0004), HGF (p=0·010), and TIMP-1 (p=0·006) had shorter PFS than did those with low concentrations. In the placebo group, high concentrations of interleukin 6 (p<0·0001), interleukin 8 (p=0·002), and osteopontin (p<0·0001) were all prognostically associated with shorter PFS. These factors were stronger prognostic markers than were standard clinical classifications (Eastern Cooperative Oncology Group, Memorial Sloan-Kettering Cancer Center, and Heng criteria). High concentrations of interleukin 6 were predictive of improved relative PFS benefit from pazopanib compared with placebo (p interaction=0·009); standard clinical classifications were not predictive of PFS benefit. Interpretation: CAF profiles could provide prognostic information beyond that of standard clinical classification and identify markers predictive of pazopanib benefit in patients with metastatic renal-cell carcinoma. Further studies of the predictive effects of these markers in different populations and with different drugs (eg, mTOR inhibitors) are warranted. Funding: GlaxoSmithKline. © 2012 Elsevier Ltd.

Eisen T.,Cambridge Cancer Trials Center | Sternberg C.N.,San Camillo and Forlanini Hospitals | Robert C.,Institute Gustave Roussy | Mulders P.,Radboud University Nijmegen | And 4 more authors.
Journal of the National Cancer Institute | Year: 2012

With the advent of targeted agents for the treatment of renal cell carcinoma (RCC), overall survival has improved, and patients are being treated continuously for increasingly long periods of time. This has raised challenges in the management of adverse events (AEs) associated with the six targeted agents approved in RCC-sorafenib, sunitinib, pazopanib, bevacizumab (in combination with interferon alpha), temsirolimus, and everolimus. Suggestions for monitoring and managing AEs have been published, but there are few consensus recommendations. In addition, there is a risk that patients will be subjected to multiple unnecessary investigations. In this review, we aimed to identify the level of supporting evidence for suggested AE management strategies to provide practical guidance on essential monitoring and management that should be undertaken when using targeted agents. Five databases were systematically searched for relevant English language articles (including American Society of Clinical Oncology abstracts) published between January 2007 and March 2011; European Society of Medical Oncology congress abstracts were hand searched. Strategies for AE management were summarized and categorized according to the level of recommendation. A total of 107 articles were identified that describe a large number of different investigations for monitoring AEs and interventions for AE management. We identify and summarize clear recommendations for the management of dermatologic, gastrointestinal, thyroid, cardiovascular, and other AEs, based predominantly on expert opinion. However, because the evidence for the suggested management strategies is largely anecdotal, there is a need for further systematic investigation of management strategies for AEs related to targeted therapies for RCC. © 2012 The Author.

Gartrell B.A.,Yeshiva University | Coleman R.E.,Academic Unit of Clinical Oncology | Fizazi K.,University Paris - Sud | Miller K.,University Hospital Charite | And 3 more authors.
European Urology | Year: 2014

Context Advanced prostate cancer (PCa) is associated with skeletal complications, both as a result of bone metastases and because of fractures associated with fragility due to androgen-deprivation therapy (ADT). Osteoclast inhibitors are commonly used to reduce skeletal complications but are associated with a number of potential adverse events. Objective To review clinical trials of osteoclast inhibitors in advanced PCa, to discuss the adverse event profile of these agents, and to discuss strategies to address specific adverse events. Evidence acquisition PubMed was searched for reports of clinical trials of osteoclast inhibitors in advanced PCa. As zoledronic acid and denosumab are used most commonly in this disease, these trials were the focus. The literature was reviewed to identify key publications addressing the prevention and management of adverse events associated with these drugs. Evidence synthesis The major findings of the trials and the adverse events are discussed. Prevention and management of common adverse events are addressed. Conclusions Zoledronic acid prevents loss of bone mineral density associated with ADT and delays skeletal-related events in metastatic castration-resistant PCa (mCRPC). Denosumab reduces the incidence of fragility fractures associated with ADT, delays the onset of bone metastases in nonmetastatic castration-resistant disease, and is superior to zoledronic acid in the prevention of skeletal complications in mCRPC. Adverse events associated with both agents include osteonecrosis of the jaw and hypocalcemia. Hypocalcemia is more common with denosumab. Zoledronic acid requires dose modifications for renal insufficiency, is contraindicated in severe renal insufficiency, and has been associated with deterioration of renal function. Appropriate patient selection with close attention to dental health, supplementation with calcium and vitamin D, and monitoring of laboratory values are effective strategies to minimize the impact of adverse events associated with osteoclast inhibitors in advanced PCa. © 2013 European Association of Urology.

Sonpavde G.,Baylor College of Medicine | Sternberg C.N.,San Camillo and Forlanini Hospitals
Current Urology Reports | Year: 2012

Neoadjuvant cisplatin-based combination chemotherapy is an established standard for resectable muscleinvasive bladder cancer, a disease with a pattern of predominantly distant and early recurrences. Pathologic complete remission appears to be an intermediate surrogate for survival when employing combination chemotherapy. Moreover, baseline host and tumor tissue studies may enable the discovery of biomarkers predictive of activity. The neoadjuvant setting also provides a window of opportunity to evaluate novel biologic agents or rational combinations of biologic agents to obtain a signal of biologic activity. The residual tumor after neoadjuvant therapy may be exploited to study the mechanism of action and resistance. Cisplatinineligible patients warrant the evaluation of tolerable neoadjuvant regimens. Given that bladder cancer is characterized by initial localized presentation in the vast majority of cases, the paradigm of neoadjuvant therapy may expedite the development of novel systemic agents. © Springer Science+Business Media, LLC 2012.

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