Prostatic Neoplasms: Figg WD

Arlen PM, Bianco F, Dahut WL, D'Amico A, Figg WD, Freedland SJ, Gulley JL, Kantoff PW, Kattan MW, Lee A, Regan MM, Sartor O, Anonymous00032. · Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA. · J Urol. · Pubmed #18423743 links to  free full text

Abstract: PURPOSE: Prostate specific antigen is a glycoprotein found almost exclusively in normal and neoplastic prostate cells. Prostate specific antigen doubling time, or the change in prostate specific antigen over time, has emerged as a useful predictive marker for assessing disease outcome in patients with prostate cancer. It is important to agree on definitions and values for the calculation of prostate specific antigen doubling time, and to develop a common approach to outcome analysis and reporting. MATERIALS AND METHODS: In September 2006 a conference was held at the National Cancer Institute in Bethesda, Maryland to define these parameters and develop guidelines for their use. RESULTS: The Prostate Specific Antigen Working Group defined criteria regarding prostate specific antigen doubling time including the calculation of prostate specific antigen doubling time, evidence to support prostate specific antigen doubling time as a predictive factor in the setting of biochemical recurrence and the use of prostate specific antigen doubling time as a stratification factor in clinical trials. CONCLUSIONS: We propose that investigators calculate prostate specific antigen doubling time before enrolling patients in clinical studies and calculate it as an additional measurement of therapeutic activity. We believe we have developed practical guidelines for the calculation of prostate specific antigen doubling time and its use as a measurement of prognosis and outcome. Furthermore, the use of common standards for prostate specific antigen doubling time in clinical trials is important as we determine which treatments should progress to randomized trials in which "hard" end points such as survival will be used.

Sartor O, Alchalabi T, Figg WD. · No affiliation provided · Clin Genitourin Cancer. · Pubmed #17026796 No free full text.

This publication has no abstract.

Sharifi N, Dahut WL, Figg WD. · Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. · Clin Cancer Res. · Pubmed #18676736 links to  free full text

Abstract: Androgen deprivation therapy (ADT) is the cornerstone treatment for advanced prostate cancer. Despite frequent responses, the majority of metastatic tumors will progress to castration-resistant prostate cancer. Numerous molecular and genetic perturbations have been described in castration-resistant prostate cancer, which are attributable for gain-of-function changes in the androgen receptor, allowing for cell survival and proliferation with castrate levels of testosterone. The utility of these somatic perturbations, which are selected for in the tumor after ADT, for prognostication of response and response duration in metastatic prostate cancer, is problematic. Here, we discuss recent studies that describe germline polymorphisms that determine the response to ADT. Coding and noncoding germline polymorphisms in genes involved in the androgen pathway affect the response to ADT. These polymorphisms require further study and validation. However, they have the potential to be useful for prognosticating the response to ADT, designing clinical trials for patients who have poor germline prognostic features and designing novel therapies targeted against genes that influence the response to ADT.

Sharifi N, Dahut WL, Figg WD. · National Cancer Institute, Medical Oncology Branch, Bethesda, Maryland 20892, USA. · BJU Int. · Pubmed #17922868 No free full text.

Abstract: Androgen deprivation therapy with medical or surgical castration is generally the first-line treatment against advanced prostate cancer. Almost invariably, metastatic prostate cancer overcomes testosterone depletion and grows, despite castrate levels of testosterone. Despite advances in cytotoxic chemotherapy, secondary hormonal therapies are often used after the development of castrate-resistant prostate cancer. Secondary hormonal therapies either lower the androgen levels further or directly antagonize the androgen receptor in prostate cancer cells. We discuss novel secondary hormonal agents that are under development, which work by either inhibiting androgen synthesis or directly targeting the androgen receptor.

Sharifi N, Figg WD. · Medical Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA. · Cancer Biol Ther. · Pubmed #17881894 No free full text.

Abstract: Androgen receptor (AR) is an important transcription factor in prostatic diseases, such as prostate cancer and benign prostatic hyperplasia (BPH). AR regulates the growth and survival of both benign and cancerous prostate epithelial cells. Therefore, modulation of AR function is an important means of treating prostatic diseases. Modern pharmacotherapy for these diseases includes, for example, medical castration and AR antagonists for prostate cancer and 5-alpha-reductase inhibitors for BPH. However, these treatments have limitations and are illustrated by AR reactivation after medical castration for prostate cancer, commonly termed castrate-resistant prostate cancer. A novel method of AR modulation has been demonstrated in spinal and bulbar muscular atrophy, a disease defined by a polyglutamine repeat expansion which leads to gain-of-function changes in AR and neuromuscular pathology. Here, we examine recent findings from the description of a compound that degrades AR and induces dissociation of AR from an AR coactivator. The biochemistry of this compound may have implications for prostate cancer.

Di Lorenzo G, Autorino R, Figg WD, De Placido S. · Department of Clinical and Molecular Oncology, Federico II University, Naples, Italy. · Drugs. · Pubmed #17521214 No free full text.

Abstract: This article addresses the current status of therapeutic options in the management of hormone-refractory prostate cancer (HRPC). Following the publication of two landmark randomised trials, docetaxel chemotherapy is now the standard of care for men with metastatic HRPC. However, the benefit of this treatment is limited. Trials are now focusing on improving the efficacy of docetaxel by combining it with novel biological agents. Several new docetaxel-based combinations are under evaluation and promising results have been found for the combination of docetaxel with angiogenesis inhibitors. Early phase III trial data for atrasentan appear interesting. New cytotoxic agents such as satraplatin and ixabepilone are being investigated in several ongoing studies in order to define their role as second-line treatments of HRPC. Vaccine therapy offers an active immunological approach for combating malignancy in a targeted manner.

Cox MC, Dahut WL, Figg WD. · Clinical Pharmacology Research Core, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. · Urol Oncol. · Pubmed #16678058 No free full text.

Abstract: More than 200,000 men will be diagnosed with prostate cancer during the year 2006. Approximately 20% to 30% of these cases may develop advanced disease, for which there currently is no cure. Although therapy for this disease has improved significantly over the past few years, with docetaxel treatment showing improved survival times in metastatic disease, there remains the need for improved treatment options. Dr. Folkman put forth the idea of angiogenesis in 1971, and, since that time, researchers have been trying to determine the best possible way to inhibit blood vessel formation. This review summarizes the use of thalidomide in androgen-independent prostate cancer and the results of trials conducted at the National Cancer Institute.

Singh AS, Chau CH, Price DK, Figg WD. · New Jersey School of Medicine, USA. · Nat Clin Pract Urol. · Pubmed #16474655 No free full text.

Abstract: Androgens are of primary importance in the etiology of prostate cancer, and binding of the androgen dihydrotestosterone to the androgen receptor is thought to stimulate prostate growth. It has been proposed that polymorphisms within key androgen regulatory genes may contribute to an individual's risk of developing prostate cancer. Attributing single polymorphisms to complex, late-onset, chronic diseases such as prostate cancer is probably not feasible, but identification of genes that increase risk will contribute to larger-scale multigenic risk assessment. Here, we review the current status of our knowledge of associations between important androgen regulatory gene polymorphisms and prostate cancer risk.

Longoria RL, Cox MC, Figg WD. · Clinical Pharmacology Research Core, Medical Oncology Clinical Research Unit, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. · Clin Genitourin Cancer. · Pubmed #16425989 No free full text.

Abstract: With a need for effective treatment modalities in prostate cancer, angiogenesis is a likely target for the interference of tumor progression. Angiogenesis promotes the vasculature of a tumor, allowing for tumor progression and for cancer cells to metastasize and spread throughout the circulatory system. To date, there are > 20 antiangiogenic drugs undergoing preclinical and clinical investigation alone and in conjunction with other treatment options to determine the validity of antiangiogenic agents in the treatment of prostate cancer. This article reviews several aspects of antiangiogenesis and its relationship to the treatment of prostate cancer.

Gulley J, Figg WD, Dahut WL. · Clinical Trials Group in the Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. · Clin Adv Hematol Oncol. · Pubmed #16227960 No free full text.

Abstract: Patients with recurrent prostate cancer may be treated with androgen deprivation strategies, but most patients will develop androgen-independent prostate cancer (AIPC). Current strategies for treatment of patients who develop AIPC have shown significant palliation, but no definitive increase in survival to date. The results of large chemotherapy trials with survival endpoints are expected soon. In addition, several novel drugs have proceeded through preclinical testing into early clinical trials. These drugs-either alone or in combination-are designed to target strategic pathways to improve survival and quality of life in patients. This article summarizes standard treatment options and promising new drugs and combination therapies under investigation for AIPC.

Cox MC, Scripture CD, Figg WD. · Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bldg 10, Rm 5A01, MSC 1910, Bethesda, MD 20892, USA. · Expert Rev Anticancer Ther. · Pubmed #16111462 No free full text.

Abstract: Androgen deprivation therapy is a mainstay for the treatment of advanced prostate cancer. Hormonal therapy commonly consists of injection of gonadotropin hormone-releasing hormone agonists. Based on the need for improved convenience of administration, a novel formulation of leuprolide acetate (Eligard; Atrix Laboratories Inc. & Sanofi Aventis) which incorporates a mixture of selected polymers and solvents to achieve sustained drug delivery after subcutaneous injection, was developed. The US Food and Drug Administration has approved 1-, 3-, 4- and 6-month formulations of leuprolide acetate. In clinical trials, leuprolide acetate achieves sustained suppression of serum testosterone to castration levels (< or =50 ng/dl). The adverse-event profile is consistent with the effects of testosterone suppression. This novel delivery system in addition to the availability of a 6-month formulation of leuprolide acetate, offers patients the option of a convenient twice-yearly injection schedule.

Singh AS, Figg WD. · Molecular Pharmacology Section, Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA. · J Urol. · Pubmed #16093963 No free full text.

Abstract: PURPOSE: The metastasis of prostate cancer to bone is the most significant cause of morbidity and mortality in this disease. An estimated 28,900 men die annually secondary to prostate cancer bone metastasis. Current treatments increase survival for 2 months and only bisphosphonates offer any palliative benefit. This shortcoming is due in part to inadequate models in which to study the molecular biology of the disease and evaluate therapeutic regimens. We examined the breadth of models available that recapitulate the process of prostate cancer metastasis to bone. MATERIALS AND METHODS: A PubMed search was done for publications concerning prostate cancer metastasis to bone and the imaging of bone metastases. Only studies focusing on model systems of disease progression and imaging of the process were included. Additional studies were found by cross-reference searching. RESULTS: Prostate cancer metastasis to bone is a lengthy, complex process characterized by multiple stages. This has made it difficult to find adequate laboratory models in which to recreate the disease process. Each available model has characteristics of particular phases of disease progression to bone. The most widely used models are transgenic mice, variations of SCID mice, and the traditional orthotopic and xenotransplantation models. Furthermore, investigators have started to adapt their models to incorporate imaging modalities for following the progression of prostate cancer to bone. CONCLUSIONS: The development of models of prostate cancer metastasis to bone is an evolving discipline. A deeper understanding of the metastatic process has served to improve current models and it will continue to do so in the future.

Cox MC, Permenter M, Figg WD. · National Cancer Institute, 10 Center Drive, Building 10, Room 5A-01, Bethesda, MD 20892, USA. · Curr Oncol Rep. · Pubmed #15847713 No free full text.

Abstract: Prostate cancer is the leading cause of cancer diagnosis in men and the second leading cause of cancer-related death. Androgen ablation is effective initially, and progression of disease often occurs in many patients. Although recent reports have noted a survival benefit when patients with androgen-independent prostate cancer are treated with docetaxel, patients still have disease progression. Angiogenesis plays a pivotal role for the growth, invasion, and metastasis of prostate cancer. Therefore, antiangiogenesis is a promising new therapeutic modality. More than 20 antiangiogenic agents are now in various stages of clinical trials. We discuss current knowledge on controlling tumor angiogenesis and advances in the development of antiangiogenic agents with promising antitumor activity in prostate cancer.

Chau CH, Figg WD. · Molecular Pharmacology Section, Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA. · Cancer Biol Ther. · Pubmed #15738648 links to  free full text

Abstract: Metastatic prostate cancer remains a prevalent disease in the United States that requires detailed characterization of its pathobiology. In the December 2004 issue of Cancer Research, a comprehensive study by Shah et al. demonstrated that metastatic androgen-independent prostate cancer is a collective group of diseases even within the same patient. Understanding the molecular and phenotypic determinants of this heterogeneity is essential in assessing therapeutic outcomes in the management of prostate cancer progression.

Retter AS, Figg WD, Dahut WL. · Center for Cancer Research, National Cancer Institute/NIH, 10 Center Drive, 12N226, Bethesda, MD 20892, USA. · Clin Prostate Cancer. · Pubmed #15040858 No free full text.

Abstract: Metastatic prostate cancer is one of the leading causes of cancer death in men. Although initially responsive to hormone therapy, it eventually progresses in almost all patients. For this reason, there has been a search for novel agents to use in the fight against androgen-independent prostate cancer. Antiangiogenesis is a relatively new antitumor strategy that has been employed in the treatments of many malignancies. As prostate cancer is likely dependent on angiogenesis for its growth and progression, it would logically serve as a good target for this modality. Initially met with great enthusiasm, antiangiogenic drugs have seen only limited success when used as single agents. This has been attributed to many possible etiologies including lack of cytotoxicity and use in situations of large tumor burden. In order to overcome these problems, many investigators are combining antiangiogenic agents with more traditional cytotoxic chemotherapy regimens in hope of augmenting the effects of either drug alone. This article will review the background of angiogenesis inhibition and the use of such combinations in metastatic prostate cancer.

Price DK, Franks ME, Figg WD. · Molecular Pharmacology Section, Cancer Therapeutics Branch, National Cancer Institute, National Institute of Health, Bethesda, Maryland 20892, USA. · J Urol. · Pubmed #14713753 No free full text.

Abstract: PURPOSE: We review the current literature on genetic variations in the vitamin D receptor (VDR), androgen receptor (AR) and enzymes regulating androgen development. MATERIALS AND METHODS: A MEDLINE search was conducted to identify research investigating associations between polymorphisms in important regulatory genes that may indirectly affect cancer risk, with special regard to prostate cancer. RESULTS: Genes involved in androgen regulation, metabolism and their related pathways, and the vitamin D receptor are prime candidates for study of prostate cancer risk. Expression and nuclear activation of the VDR are necessary for the antiproliferative effects of 1alpha,25-dihydroxyvitamin D3 (calcitriol), which is involved in calcium and bone homeostasis. Several genetic variations have been identified in the VDR, and at least 1 VDR polymorphism appears to confer some predictability of prostate cancer risk in various ethnic cohorts. Interactions between the androgen receptor and circulating androgens have a major role in the development of normal and malignant prostate cells. CONCLUSIONS: Due to the relationship between the AR and prostatic growth, it has been proposed that polymorphisms within the AR may have a role in susceptibility to prostate cancer.

Macpherson GR, Franks M, Tomoaia-Cotisel A, Ando Y, Price DK, Figg WD. · Molecular Pharmacology Section, Division of Clinical Sciences, Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 5A01, 9000 Rockville Pike, 20892, Bethesda, MD, USA. · Crit Rev Oncol Hematol. · Pubmed #12850527 No free full text.

Abstract: Following the discovery of its anti-angiogenic properties and despite its tragic history, thalidomide has re-surfaced in the field of oncology. Concurrent with its evaluation in various clinical trials for cancer, thalidomide's mechanism of action is sought and new analogues with improved efficacy and pharmacological profile are emerging. This review is a critical evaluation of thalidomide metabolism, molecular targets, anti-angiogenic activity and clinical efficacy with an emphasis on metastatic prostate cancer.

Lakhani NJ, Sarkar MA, Venitz J, Figg WD. · Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA. · Pharmacotherapy. · Pubmed #12587805 No free full text.

Abstract: Estrogens occurring naturally in the body are metabolized to catecholestrogens (2- and 4-hydroxyestradiol) by the cytochrome P450 enzymes. 2-Hydroxy catecholestrogens are further metabolized by catechol-O-methyltransferase to 2-methoxyestradiol, which is known to be protective against tumor formation. 2-Methoxyestradiol exhibits potent apoptotic activity against rapidly growing tumor cells. It also possesses antiangiogenic activity through a direct apoptotic effect on endothelial cells. Other molecular mechanisms, including microtubule stabilization by inhibition of the colchicine-binding site, have been reported. The exact mechanism of action of 2-methoxyestradiol is still unclear, but it has been shown to be effective in preventing tumor growth in a variety of cell lines. 2-Methoxyestradiol also possesses cardioprotective activity by inhibiting vascular smooth muscle cell growth in arteries. It has a lower binding affinity for estrogen receptor alpha compared with that of estradiol, and its affinity for estrogen receptor beta is even lower than that of estrogen receptor alpha, thus it has minimal estrogenic activity. 2-Methoxyestradiol is distinct because of its inability to engage estrogen receptors as an agonist, and its unique antiproliferative and apoptotic activities are mediated independently of estrogen receptors alpha and beta. A phase I clinical trial of 2-methoxyestradiol 200, 400, 600, 800, and 1,000 mg/day in 15 patients with breast cancer showed significant reduction in bone pain and analgesic intake in some patients, with no significant adverse effects. Another phase I study of 2-methoxyestradiol 200-1,000 mg/day in combination with docetaxel 35 mg/m2/week for 4-6 weeks performed in 15 patients with advanced refractory metastatic breast cancer showed no serious drug-related adverse effects. A phase II randomized, double-blind trial of 2-methoxyestradiol 400 and 1,200 mg/day in 33 patients with hormone-refractory prostate cancer showed that it was well tolerated and showed prostate specific antigen stabilizations and declines. We have started a phase I clinical trial to explore dosages greater than 1,000 mg/day.

Macpherson GR, Ng SS, Lakhani NJ, Price DK, Venitz J, Figg WD. · Molecular Pharmacology Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. · Cancer Metastasis Rev. · Pubmed #12400998 No free full text.

Abstract: It is now well documented that tumor progression from its early stages to an advanced metastatic state requires the recruitment of new vasculature. The reliance on angiogenesis by tumors renders them susceptible to agents that can interfere with the angiogenic process. Recent interest in the therapeutic potential of using angiogenesis as a target mechanism for anticancer therapy has led to the identification of various antiangiogenic agents that interfere at various stages of the process. This review is a summary of recent progress in the identification and characterization of antiangiogenesis agents with a focus on their utility with respect to prostate cancer. Though we focus on prostate cancer, this knowledge is relevant to any cancer that involves angiogenesis.

Kaur M, Reed E, Sartor O, Dahut W, Figg WD. · Molecular Pharmacology Section, Cancer Therapeutic Branch, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA. · Invest New Drugs. · Pubmed #12099581 No free full text.

Abstract: Suramin, a polysulphonated napthylurea, has been extensively evaluated over the past 10 years as an anticancer agent, with the most interest in the treatment of prostate cancer. Early clinical results were promising with response rates of up to 70% being reported. However, a recent double-blind study showed only modest palliative effect in patients with androgen independent prostate cancer. In retrospect, it appears those initial reports failed to control for confounding variables such as antiandrogen withdrawal and hydrocortisone. Suramin causes numerous reversible toxicities (lethargy, rash, fatigue, anemia, hyperglycemia, hypocalcemia, coagulopathies, neutropenia, renal and hepatic complications). Neurotoxicity has been the most significant complication and appears to be related to the intensity of the dosing regimen. An optimal therapeutic dose has not been determined, but it is clear that adaptive controls add little benefit. Aside from moderate toxicities and the low therapeutic index in patients with prostate cancer, suramin's development has taught us some valuable lessons (i.e., anti-androgen withdrawal was noted during suramin's development, the use of PSA as an indicator of tumor burden was initiated during the evaluation of suramin). These lessons can be applied to all clinical trials in hormone refractory prostate cancer. Suramin has significantly enhanced the evolution of our knowledge in several areas of prostate cancer biology and treatment.

Figg WD, Kruger EA, Price DK, Kim S, Dahut WD. · Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. · Invest New Drugs. · Pubmed #12099578 No free full text.

Abstract: Prostate cancer is the most frequently diagnosed malignancy and the second most common cause of cancer-related death in men in the United States. Unfortunately, at the current time, no curative treatments are available for metastatic prostate cancer. As is the case for most solid tumors, the recruitment of blood vessels (angiogenesis) is key for the progression and metastasis of prostate cancer. Inhibition of this process is an attractive approach to treatment. Many antiangiogenic agents are currently in clinical development. The following discussion will outline the importance of angiogenesis in the metastasis and progression of prostate cancer, summarize the current surrogate markers of angiogenesis available for the drug development of antiangiogenic agents, and review examples of investigational agents that target tumor angiogenesis (e.g., TNP-470, Thalidomide, CC5013, Carboxyamido-triazole (CAI), Endostatin. SU5416, SU6668, Bevacizumab (Anti-VEGFrhuMAb), and 2-Methoxyestradiol).

Montgomery JS, Price DK, Figg WD. · Cancer Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA. · J Pathol. · Pubmed #11592091 No free full text.

Abstract: Prostate adenocarcinoma has the highest incidence of any malignancy and is the second leading cause of cancer-related deaths in men in industrialized countries. The development and progression of prostate cancer are dependent on testosterone and dihydrotestosterone; the androgen receptor is the vehicle through which these androgens exert their regulation on prostate cellular proliferation and differentiation. As a result, much effort has been devoted to elucidating the role of the androgen receptor in prostate cancer. The CAG and GGN trinucleotide repeats in exon 1 of the androgen receptor gene have been linked to prostate cancer risk and progression in some studies. Also, androgen receptor gene amplification may be a mechanism of prostate cancer cell adaptation to hormonal therapy. In addition, androgen receptor somatic mutations can result in receptors that have altered binding specificity when compared with wild-type receptors and heightened affinity for hormones other than testosterone and dihydrotestosterone. Gene amplification and somatic mutations, coupled with the fact that various growth factors have been shown to stimulate androgen receptor activity independently of androgens, may enable prostate cancer cells to grow despite testicular-androgen ablation. Unfortunately, current medical therapy for metastatic prostate cancer is deficient, hormone-refractory prostate cancer is a major obstacle in treatment, and, as a result, prostate cancer mortality is still significant. Further study of the function of the androgen receptor will offer a better understanding of prostate cancer pathogenesis and progression, aiding the development of more effective treatments for this disease.

Kang MH, Figg WD, Dahut W. · Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. · Cancer Pract. · Pubmed #10687598 No free full text.

This publication has no abstract.

Cude KJ, Dixon SC, Guo Y, Lisella J, Figg WD. · Medicine Branch, National Cancer Institute, Bethesda, MD 20892, USA. · J Mol Med. · Pubmed #10426191 No free full text.

Abstract: The action of androgens in the development and growth of prostate carcinomas is well documented. The androgen receptor (AR) facilitates androgen-induced regulation of genes involved in cellular proliferation and differentiation. Since the early 1940s androgen ablation has been the cornerstone of treatment for metastatic prostate cancer. Although initially highly effective, hormonal therapy is not curative, and resistant disease will ultimately prevail. Mutations that alter AR conformation, function, and regulation may provide a selective growth advantage for subpopulations of cells within the tumor that are then able to proliferate in an androgen-deprived environment. Clinically, these mutations are important because they may lead to the growth of androgen-independent tumors and progression to a refractory state. Further characterization of AR mutations will lead to a more thorough understanding of their role in the development of prostate carcinomas. This information, in addition to discovering which genes are regulated by the AR, can aid in the future development of more effective pharmacotherapy for prostate cancer.

Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, Hussain M, Anonymous00048. · Genitourinary Oncology Service, Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA. · J Clin Oncol. · Pubmed #18309951 No free full text.

Abstract: PURPOSE: To update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone. METHODS: A committee of investigators experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data. RESULTS: The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as "new lesions" or "no new lesions," changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group. CONCLUSION: PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit.