Preclinical, epidemiological and prior clinical trial data suggest that green tea catechins (GTCs) may reduce prostate cancer (PCa) risk. We conducted a placebo-controlled, randomized clinical trial of Polyphenon E® (PolyE), a proprietary mixture of GTCs, containing 400 mg (–)-epigallocatechin-3-gallate (EGCG) per day, in 97 men with high-grade prostatic intraepithelial neoplasia (HGPIN) and/or atypical small acinar proliferation (ASAP). The primary study endpoint was a comparison of the cumulative one-year PCa rates on the two study arms. No differences in the number of PCa cases were observed: 5/49 (PolyE) versus 9/48 (placebo), P=0.25. A secondary endpoint comparing the cumulative rate of PCa plus ASAP among men with HGPIN without ASAP at baseline, revealed a decrease in this composite endpoint: 3/26 (PolyE) versus 10/25 (placebo), P<0.024. This finding was driven by a decrease in ASAP diagnoses on the Poly E (0/26) compared to the placebo arm (5/25). A decrease in serum prostate specific antigen (PSA) was observed on the PolyE arm [−0.87 ng/ml (95%CI: −1.66, −0.09)]. Adverse events related to the study agent did not significantly differ between the two study groups. Daily intake of a standardized, decaffeinated catechin mixture containing 400 mg EGCG per day for 1 year accumulated in plasma and was well tolerated but did not reduce the likelihood of PCa in men with baseline HGPIN or ASAP.

Opinion statementThe complex syndrome of cancer cachexia (CC) that occurs in 50% to 80% cancer patients has been identified as an independent predictor of shorter survival and increased risk of treatment failure and toxicity, contributing to the mortality and morbidity in this population. CC is a pathological state including a symptom cluster of loss of muscle (skeletal and visceral) and fat, manifested in the cardinal feature of emaciation, weakness affecting functional status, impaired immune system, and metabolic dysfunction. The most prominent feature of CC is its non-responsiveness to traditional treatment approaches; randomized clinical trials with appetite stimulants, 5-HT3 antagonists, nutrient supplementation, and Cox-2 inhibitors all have failed to demonstrate success in reversing the metabolic abnormalities seen in CC. Interventions based on a clear understanding of the mechanism of CC, using validated markers relevant to the underlying metabolic abnormalities implicated in CC are much needed. Although the etiopathogenesis of CC is poorly understood, studies have proposed that NFkB is upregulated in CC, modulating immune and inflammatory responses induce the cellular breakdown of muscle, resulting in sarcopenia. Several recent laboratory studies have shown that n-3 fatty acid may attenuate protein degradation, potentially by preventing NFkB accumulation in the nucleus, preventing the degradation of muscle proteins. However, clinical trials to date have produced mixed results potentially attributed to timing of interventions (end stage) and utilizing outcome markers such as weight which is confounded by hydration, cytotoxic therapies, and serum cytokines. We propose that selective targeting of proteasome activity with a standardized dose of omega-3-acid ethyl esters, administered to cancer patients diagnosed with early stage CC, in addition to a standard intervention with nutritionally adequate diet and appetite stimulants, will alter metabolic abnormalities by downregulating NFkB, preventing the breakdown of myofibrillar proteins and resulting in increasing serum protein markers, lean body mass, and functional status.

Objective The goal of this report is to describe the on going strategies, successes, challenges and solutions for recruitment in this multi-center, phase II chemoprevention trial targeting men at high risk for prostate cancer. Methods We developed and implemented a multi-center clinical trial in institutions with supportive infrastructure, lead by a recruitment team of experienced and committed physicians and clinical trial staff, implementing multi-media and community outreach strategies to meet recruitment goals. Screening logs were reviewed to identify trends as well as patient, protocol and infrastructure -related barriers impacting accrual and revisions to protocol implemented. Results Between January 2008 and February 2011 a total of 3547 individuals were prescreened with 94% (n=3092) determined to be ineligible based on diagnosis of cancer or benign biopsy results. Of these, 216 were considered eligible for further screening with 52% (n=113) declining to participate due to patient related factors and 14% (n=29) eliminated due to protocol-related criteria for exclusion. Ninety four (94) subjects consented to participate with 34% of these subjects (n=74) meeting all eligibility criteria to be randomized to receive study agent or placebo. Across all sites, 99% of the recruitment of subjects in this clinical trial is via physician recruitment and referral with less than 1% responding to other recruitment strategies. Conclusion A contemporary approach to subject recruitment and frequent evaluation is needed to assure responsiveness to emerging challenges to accrual and the evolving scientific literature. A focus on investing on improving systems for physician recruitment may be key to meeting recruitment target in chemoprevention trials.

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Inspite of the large number of promising nutrient-derived agents demonstrating promise as potential chemopreventive agents, most have failed to prove effectiveness in clinical trials. Critical requirements for moving nutrient-derived agents to recommendation for clinical use include adopting a systematic, molecular-mechanism based approach and utilizing the same ethical and rigorous methods such as are used to evaluate other pharmacological agents. Preliminary data on a mechanistic rationale for chemoprevention activity as observed from epidemiological, in vitro and preclinical studies, phase I data of safety in high-risk cohorts are required to inform design of phase II clinical trials. Additionally, a valid panel of biomarkers representing the hypothesized carcinogenesis pathway for measuring efficacy must be utilized to evaluate effectiveness in these trials. The goal of this paper is to provide a model, using a systematic approach for evaluating the safety, effectiveness and mechanism of action of a well characterized nutrient-derived agent-isoflavones - in a phase II clinical trial for prostate cancer (CaP) chemoprevention, targeting a population of African American (AA) and Caucasian men. Based on our previous observations, we hypothesize that the effects of isoflavones on prostate carcinogenesis are mainly mediated through the down regulation of androgen receptor (AR) and AR activity in AA men is higher due to its shorter length of Glutamine repeats in its N-terminus. We thus believe that isoflavones will exert a stronger protective effect for CaP in AA men and cause a higher activation of FOXO factors and their target genes. The aim of the study is to evaluate the comparative effectiveness of the study agent and placebo, in addition to a comparison of the effectiveness and safety in African American men compared to Caucasian men treated with this agent.

In spite of the large number of nutrient-derived agents demonstrating promise as potential chemopreventive agents, most have failed to prove effectiveness in clinical trials. Critical requirements for moving nutrient-derived agents to recommendation for clinical use include adopting a systematic, molecular-mechanism based approach and utilizing the same ethical and rigorous methods such as are used to evaluate other pharmacological agents. Preliminary data on a mechanistic rationale for chemoprevention activity as observed from epidemiological, in vitro and preclinical studies, phase I data of safety in suitable cohorts, duration of intervention based on time to progression of preneoplastic disease to cancer and the use of a valid panel of biomarkers Copyright: © 2012 Kumar N, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Conflict of Interest:To date, the results of this study in part or as a whole has not been reported nor presented elsewhere. Disclaimers:The authors disclose no conflict of interest. NIH Public Access Prostate Cancer ChemopreventionChemoprevention refers to the inhibition of preinvasive and invasive cancer and its progression or treatments of identifiable precancers [8,15]. Chemoprevention efforts require a thorough understanding of the mechanism of carcinogenesis including signaling and metabolic pathways and genetic progression pathways. Agent Selection and DescriptionEGCG is the major and most active catechin in green tea and is the most commonly studied GTC in vitro, because of its relative abundance in green tea extracts and strong cancer preventative properties [20][21][22]. However, EGCG has low rates of absorption and bioavailability when administered orally [23][24][25] and studies indicate that whole mixtures of GTCs may more accurately reflect the human consumption of green tea. This is possibly due to the fact that tea constituents other than catechins may also have anti-carcinogenetic activity and the combined interaction of tea components and catechins may contribute to the effectiveness of the anticarcinogenic activities of GTC mixtures [25][26][27][28][29]. The lack of assurance of infusion contents, differences in tea origin and brewing techniques, all which affect the tea catechin content, have made it necessary to use more standardized GTC mixtures for clinical purposes [30].Based on the safety profile established in phase I clinical trials [24,31,32], we selected a standardized decaffeinated botanical formulation of green tea catechins, Polyphenon E (Mitsui Norin Co., Ltd., Shizuoka, Japan; Mitsui Norin) for use in this clinical trial. Polyphenon E, is a botanical drug substance containing a mixture of catechins originating from the leaves of green tea (Camellia sinensis). The final product contains 85-95% total catechins; the main component is EGCG, which comprises 5...

Under the auspices of a partnership grant to reduce cancer health disparities, Moffitt Cancer Center (MCC) partnered with the Ponce School of Medicine to identify the perceived cultural communication needs of MCC healthcare providers regarding Hispanic patients with limited or no English skills. Oncologists (N=72) at MCC were surveyed to identify the specific areas of cultural communication techniques for which they desired to receive additional training. The majority of participants (66%) endorsed an interest in obtaining training to communicate difficult issues (terminal illness, controversial diagnosis) in a manner respectful to Hispanic culture. A workshop was conducted with providers (N=55) to improve cultural communication between Hispanic patients and families focusing on culture, terminal illness, and communication strategies. Findings from a pre–post test indicate an overall positive response to the workshop. Results from this study can help inform future efforts to enhance cultural competency among health providers.

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