Prostatic Neoplasms: Scher HI

Loblaw DA, Virgo KS, Nam R, Somerfield MR, Ben-Josef E, Mendelson DS, Middleton R, Sharp SA, Smith TJ, Talcott J, Taplin M, Vogelzang NJ, Wade JL, Bennett CL, Scher HI, Anonymous00323. · American Society of Clinical Oncology, Alexandria, VA 22314, USA. · J Clin Oncol. · Pubmed #17404365 No free full text.

Abstract: PURPOSE: To update the 2004 American Society of Clinical Oncology (ASCO) guideline on initial hormonal management of androgen-sensitive, metastatic, recurrent, or progressive prostate cancer (PCa). METHODS: The writing committee based its recommendations on an updated systematic literature review. Recommendations were approved by the Expert Panel, the ASCO Health Services Committee, and the ASCO Board of Directors. RESULTS: Seven randomized controlled trials (four new), one systematic review, one meta-analysis (new), one Markov model, and one delta-method 95% CI procedure for active controlled trials (new) informed the guideline update. RECOMMENDATIONS: Bilateral orchiectomy or luteinizing hormone-releasing hormone agonists are recommended initial androgen-deprivation treatments (ADTs). Nonsteroidal antiandrogen monotherapy merits discussion as an alternative; steroidal antiandrogen monotherapy should not be offered. Combined androgen blockade should be considered. In metastatic or progressive PCa, immediate versus symptom-onset institution of ADT results in a moderate decrease (17%) in relative risk (RR) for PCa-specific mortality, a moderate increase (15%) in RR for non-PCa-specific mortality, and no overall survival advantage. Therefore, the Panel cannot make a strong recommendation for early ADT initiation. Prostate-specific antigen (PSA) kinetics and other metrics allow identification of populations at high risk for PCa-specific and overall mortality. Further studies must be completed to assess whether patients with adverse prognostic factors gain a survival advantage from immediate ADT. For patients electing to wait until symptoms for ADT, regular monitoring visits are indicated. For patients with recurrence, clinical trials should be considered if available. Currently, data are insufficient to support use of intermittent androgen blockade outside clinical trials

Loblaw DA, Mendelson DS, Talcott JA, Virgo KS, Somerfield MR, Ben-Josef E, Middleton R, Porterfield H, Sharp SA, Smith TJ, Taplin ME, Vogelzang NJ, Wade JL, Bennett CL, Scher HI, Anonymous00081. · Cancer Policy and Clinical Affairs, 1900 Duke St, Suite 200, Alexandria, VA 22314, USA. · J Clin Oncol. · Pubmed #15184404 No free full text.

Abstract: PURPOSE: To develop a clinical practice guideline for the management of men with metastatic, recurrent, or progressive carcinoma of the prostate. The focus of this document is on the use, combinations, and timing of various forms of androgen deprivation therapy (ADT) for the palliation of men with androgen-sensitive disease. METHODS: An expert panel and writing committee were formed. The questions to be addressed by the guideline were determined, and a systematic review of the literature was performed, which included a search of online databases, bibliographic review, and consultation with content experts. A priori criteria were used to select studies for analysis and study authors were contacted when necessary. RESULTS: There were 10 randomized controlled trials, six systematic reviews, and one Markov model available to inform the guidelines. CONCLUSION: A full discussion between practitioner and patient should occur to determine which therapy is best for the patient. Bilateral orchiectomy or luteinizing hormone releasing hormone agonists are the recommended initial treatments. Nonsteroidal antiandrogen therapy may be discussed as an alternative, but steroidal antiandrogens should not be offered as monotherapy. Patients willing to accept the increased toxicity of combined androgen blockage for a small benefit in survival should be offered nonsteroidal antiandrogen in addition to castrate therapy. Until data from studies using modern medical diagnostic/biochemical tests and standardized follow-up schedules become available, no specific recommendations can be issued regarding the question of early versus deferred ADT. A discussion about the pros and cons of early versus deferred ADT should occur.

Scher HI, Eisenberger M, D'Amico AV, Halabi S, Small EJ, Morris M, Kattan MW, Roach M, Kantoff P, Pienta KJ, Carducci MA, Agus D, Slovin SF, Heller G, Kelly WK, Lange PH, Petrylak D, Berg W, Higano C, Wilding G, Moul JW, Partin AN, Logothetis C, Soule HR. · Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. · J Clin Oncol. · Pubmed #14752077 No free full text.

Abstract: PURPOSE: To define methodology to show clinical benefit for patients in the state of a rising prostate-specific antigen (PSA). RESULTS: Hypothesis: A clinical states framework was used to address the hypothesis that definitive phase III trials could not be conducted in this patient population. Patient Population: The Group focused on men with systemic (nonlocalized) recurrence and a defined risk of developing clinically detectable metastases. Models to define systemic versus local recurrence, and risk of metastatic progression were discussed. Intervention: Therapies that have shown favorable effects in more advanced clinical states; meaningful biologic surrogates of activity linked with efficacy in other tumor types; and/or effects on a target or pathway known to contribute to prostate cancer progression in this state can be considered for evaluation. Outcomes: An intervention-specific posttherapy PSA-based outcome definition that would justify further testing should be described at the outset. Reporting: Trial reports should include a table showing the number of patients who achieve a specific PSA-based outcome, the number who remain enrolled onto the trial, and the number who came off study at different time points. The term PSA response should be abandoned. Trial Design: The phases of drug development for this state are optimizing dose and schedule, demonstration of a treatment effect, and clinical benefit. To move a drug forward should require a high bar that includes no rise in PSA in a defined proportion of patients for a specified period of time at a minimum. Agents that do not produce this effect can only be tested in combination. The preferred end point of clinical benefit is prostate cancer-specific survival; the time to development of metastatic disease is an alternative. CONCLUSION: Methodology to show that an intervention alters the natural history of prostate cancer is described. At each stage of development, only agents with sufficient activity should be moved forward.

Morris MJ, Scher HI. · No affiliation provided · Eur J Nucl Med Mol Imaging. · Pubmed #17238014 No free full text.

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Scher HI, Kelly WK. · No affiliation provided · J Urol. · Pubmed #12441937 No free full text.

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Scher HI. · No affiliation provided · J Natl Cancer Inst. · Pubmed #11106669 links to  free full text

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Scher HI. · No affiliation provided · JAMA. · Pubmed #10235160 No free full text.

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Chen Y, Sawyers CL, Scher HI. · Genitourinary Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Curr Opin Pharmacol. · Pubmed #18674639 links to  free full text

Abstract: When prostate cancers progress following androgen depletion therapy, there are currently few treatment options with only one, docetaxel, that has been shown to prolong life. Recent work has shown that castration-resistant prostate cancers (CRPCs) continue to depend on androgen receptor (AR) signaling which is reactivated despite low serum androgen levels. Currently available AR-targeted therapy, including GnRH agonists and antiandrogens, cannot completely shut down AR signaling. Several mechanisms that enhance AR signaling in an androgen-depleted environment have been elucidated. These include AR mutations that allow activation by low androgen levels or by other endogenous steroids, AR overexpression, increased local intracrine synthesis of androgens, and upregulation of tyrosine kinase pathways. This has led to the development of a number of novel agents targeting the AR signaling pathway, including more effective antiandrogens, inhibitors of CYP17, an enzyme required for androgen synthesis, inhibitors of 5alpha-reductase, inhibitors of HSP90 which protects AR from degradation, inhibitors of histone deacetylases which is required for optimal AR-mediated transcription, as well as inhibitors of tyrosine kinase inhibitors. Many of these strategies are currently being tested in clinical trials in CRPC.

Basch EM, Somerfield MR, Beer TM, Carducci MA, Higano CS, Hussain MH, Scher HI, Anonymous00303. · Memorial Sloan-Kettering Cancer Center, New York, NY, USA. · J Clin Oncol. · Pubmed #17925542 No free full text.

Abstract: PURPOSE In 2006, the American Society of Clinical Oncology (ASCO) Board of Directors (BOD) approved a policy and a set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS The Cancer Care Ontario (CCO) Guideline on Non-Hormonal Therapy for Men With Metastatic Hormone-Refractory Prostate Cancer (HRPC) was reviewed for developmental rigor by methodologists. An ad hoc prostate cancer guideline review panel consisting of prostate cancer experts reviewed the content. Results The ASCO ad hoc prostate cancer guideline review panel concurred that the recommendations are clear, thorough, based on the most relevant scientific evidence in this content area, and present options that will be acceptable to patients. The CCO guideline was subsequently endorsed by the ASCO BOD. The guideline recommends the use of docetaxel, prednisone/hydrocortisone, and/or mitoxantrone in specific settings. Docetaxel-based chemotherapy is the only treatment that has demonstrated an overall survival benefit in men with HRPC. The use of estramustine in combination with other cytotoxic agents is not recommended. Continued gonadal androgen suppression and discontinuance of antiandrogens is recommended for men receiving chemotherapy. CONCLUSION The review panel agreed with the recommendations as stated in the CCO guideline, with the following qualifications: two of the ASCO content reviewers noted the importance of considering other, nonhormonal therapies in this context that are beyond the scope of this guideline. The review panel notes that CCO has published separate guidelines on radiopharmaceuticals and bisphosphonates in men with castration-resistant (ie, hormone-refractory) metastatic prostate cancer.

Fleming MT, Morris MJ, Heller G, Scher HI. · Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancer, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. · Nat Clin Pract Oncol. · Pubmed #17139317 No free full text.

Abstract: To the investigator and clinician, prostate-specific antigen (PSA) level is a seemingly perfect outcome measure because it is easily assessable, quantitative, reproducible, and inexpensive. Whether post-therapy decline in PSA reflects true clinical benefit, and whether post-therapy declines can be used as an intermediate endpoint for accelerated drug approval is still open to question. At present, no drug has been approved strictly on the basis of a post-treatment decline in PSA, as it is unproven that such PSA changes are surrogates for true clinical benefits. Post-therapy PSA changes have been associated with improved survival in patients with castrate metastatic disease. The role of PSA changes as potential surrogates of clinical benefit have only been explored to a limited degree because to date, only two prospective randomized trials showing a survival benefit have been reported. Such trials are necessary, but not a sufficient pre-requisite to explore the potential role of any outcome measure as an intermediate endpoint. The clear demonstration that a post-therapy PSA change can account for all of the treatment effects seen is not yet available. A cytotoxic drug that does not produce any PSA decline is unlikely to be effective, but the converse is not always true because not all PSA rises represent a treatment failure. It is important to recognize that there are a range of clinical benefits to patients that can improve the quality and possibly the duration of survival, independent of PSA.

Scher HI, Sawyers CL. · 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 10021, USA. · J Clin Oncol. · Pubmed #16278481 No free full text.

Abstract: Prostate cancers that are progressing on medical and surgical therapies designed to ablate the action of androgens continue to express androgen receptor (AR) and to depend on signaling through the receptor for growth. A more clinically relevant classification of castration-resistant disease focuses on the mechanisms of receptor activation, which include (1) changes in the level of ligand(s) in tumor tissue; (2) increased levels of the protein due to gene amplification or altered mRNA expression; (3) activating mutations in the receptor that affect structure and function; (4) changes in coregulatory molecules including coactivators and corepressors; and (5) factors that lead to activation of the receptor independent of the level of ligand or receptor allowing kinase cross talk. From an AR perspective, the term "hormone refractory" is inappropriate. On the basis of this schema, we discuss strategies that are focused on the AR either directly or indirectly, as single agents or in combination, that are in clinical development.

Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. · Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. · Clin Cancer Res. · Pubmed #16033840 links to  free full text

Abstract: PURPOSE: To relate clinical issues to the clinical manifestations of prostate cancers across disease states using the eligibility and outcome criteria defined by Response Evaluation Criteria in Solid Tumors (RECIST). EXPERIMENTAL DESIGN: The manifestations of prostate cancer that characterize localized, recurrent, and metastatic disease were considered using the eligibility criteria for trials defined by RECIST. To do so, we analyzed the sites, size, and distribution of lesions in patients enrolled on contemporary Institutional Review Board-approved trials for progressive castrate and noncastrate metastatic disease. Prostate-specific antigen (PSA) levels were also assessed. RECIST-defined outcome measures for tumor regression were then applied to the metastatic patient cohorts, and separately to the states of a rising PSA (noncastrate and castrate) and localized disease. RESULTS: Only 43.5% of men with castrate metastatic and 16% of noncastrate metastatic disease had measurable target lesions > 2 cm in size. Overall, 84.4% of the target lesions were lymph nodes, of which 67.7% were > or = 2 cm in the long axis. There are no target lesions in patients in the states of a rising PSA and localized disease, making them ineligible for trials under these criteria. PSA-based eligibility and outcomes under RECIST conflict with established reporting standards for the states of a rising PSA and castrate metastatic disease. The clinical manifestations of prostate cancer across multiple disease states are not addressed adequately using the eligibility criteria and outcomes measures defined by RECIST. Important treatment effects are not described. CONCLUSIONS: Trial eligibility and end points based solely on tumor regression are not applicable to the majority of the clinical manifestations of prostate cancers representing all clinical states. Treatment effects can be described more precisely if eligibility criteria are adapted to the clinical question being addressed and clinical state under study, focusing on the duration of benefit defined biochemically, radiographically, and/or clinically.

Morris MJ, Pandit-Taskar N, Divgi C, Larson S, Scher HI. · Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 444, New York, NY 10021, USA. · Curr Urol Rep. · Pubmed #15869719 No free full text.

Abstract: For patients with metastatic prostate cancer, bone is the primary site of tumor localization and the major cause of disease-related morbidity and mortality. Hormonal therapy and chemotherapy alone cannot eradicate disease harbored in bone. The delivery of radiotherapy to the reservoir of disease is an approach previously only achievable using bone-seeking radiopharmaceuticals. Now, however, with the identification of tumor-specific targets, antibodies are being used to deliver radiotherapy to these sites. In this article, we review the rationale behind this approach, the targets being explored, the radiation sources available, and the antibodies currently under clinical development.

Scher HI, Buchanan G, Gerald W, Butler LM, Tilley WD. · Genitourinary Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center, Department of Medicine, Joan and Sanford I Weill College of Medicine, New York, New York 10021, USA. · Endocr Relat Cancer. · Pubmed #15369448 links to  free full text

Abstract: The categorization of prostate cancers that are progressing after castration as 'hormone-refractory' evolved from the clinical observation that surgical or medical castration (i.e. androgen ablation therapy; AAT) is not curative and, despite an initial response, virtually all tumors eventually regrow. Successful AAT is contingent on the dependence of prostate cancer cells for androgen signaling through an intracellular mediator, the androgen receptor (AR) for survival. Current preclinical and clinical data imply that the AR is expressed and continues to mediate androgen signaling after failure of AAT. As AAT does not completely eliminate circulating androgens, sufficient concentrations of dihydrotestosterone may accumulate in tumor cells to maintain AR signaling, especially in the context of upregulated receptor levels or increased sensitivity of the AR for activation. In addition, ligands of non-testicular origin or ligand-independent activation can contribute to continued AR signaling. In many cases, therefore, from the perspective of the AR, a 'hormone-refractory' classification after failure of AAT is inappropriate. Classifying prostate tumors that progress after AAT as 'castration-resistant' may be more relevant. Clinical responses to second- and third-line hormonal therapies suggest that the mechanisms of AR activation are in part a function of previously administered AAT. Accordingly, the increasing trend to utilize AAT earlier in the course of the clinical disease may have a greater influence on the genotype and phenotype of the resistant tumor. In this article, we detail strategies to inhibit the growth of prostate cancer cells that specifically target the AR in addition to those practiced traditionally that indirectly target the receptor by reducing the amount of circulating ligand. We propose that treatment regimes combining AAT with direct AR targeting strategies may provide a more complete blockade of androgen signaling, thereby preventing or significantly delaying the emergence of treatment-resistant disease.

Morris MJ, Pandit-Taskar N, Divgi C, Larson S, Scher HI. · Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 444, New York, NY 10021, USA. · Curr Oncol Rep. · Pubmed #15066234 No free full text.

Abstract: For patients with metastatic prostate cancer, bone is the primary site of tumor localization and the major cause of disease-related morbidity and mortality. Hormonal therapy and chemotherapy alone cannot eradicate disease harbored in bone. The delivery of radiotherapy to the reservoir of disease is an approach previously only achievable using bone-seeking radiopharmaceuticals. Now, however, with the identification of tumor-specific targets, antibodies are being used to deliver radiotherapy to these sites. In this article, we review the rationale behind this approach, the targets being explored, the radiation sources available, and the antibodies currently under clinical development.

Solit DB, Scher HI, Rosen N. · Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. · Semin Oncol. · Pubmed #14571418 No free full text.

Abstract: Prostate cancers are hormone-dependent malignancies that respond to drugs that reduce circulating testosterone levels or prevent binding of this ligand to the androgen receptor (AR). While effective, these approaches are not curative and, in almost all cases, progression to a castration-resistant state is eventually observed. The mechanisms underlying the development of hormone resistance are poorly defined but several molecular changes are commonly associated with this process. Since a common element of these resistance mechanisms is restoration of AR signaling, agents that target AR expression represent an attractive treatment option for prostate cancer patients with disease progression following castration. Prior to ligand binding, AR exists in a complex with heat shock protein 90 (Hsp90) and other co-chaperones. The AR-Hsp90 interaction maintains AR in a high-affinity ligand-binding conformation, which is necessary for efficient response to hormone. 17-Allyamino-17-demethoxygeldanamycin (17-AAG) is an inhibitor of the Hsp90 chaperone protein. Inhibition of Hsp90 function causes the proteasomal degradation of proteins that require this chaperone for maturation or stability. Hsp90 clients include several proteins of potential importance in mediating prostate cancer progression, including wild-type and mutated AR, HER2, and Akt. In murine models of prostate cancer, 17-AAG causes the degradation of these client proteins at nontoxic doses and inhibits the growth of hormone-naive and castration-resistant tumors. These data suggest that inhibitors of Hsp90 may represent a novel strategy for the treatment of patients with prostate cancer and clinical trials to test this hypothesis are currently ongoing.

Wolchok JD, Gregor PD, Nordquist LT, Slovin SF, Scher HI. · Clinical Immunology Services, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. · Semin Oncol. · Pubmed #14571413 No free full text.

Abstract: Immunotherapy is currently being investigated as a treatment for patients with asymptomatic, recurrent prostate cancer manifested only by a rising prostate-specific antigen (PSA) level. Several different approaches to active immunization against antigens found on cancer cells have been explored. Immunization with DNA overcomes many of the obstacles noted in previous studies. Injection of plasmid DNA encoding a xenogeneic differentiation antigen (prostate-specific membrane antigen [PSMA]) is a potent means to induce antibody and T-cell responses to these otherwise poorly immunogenic self proteins. Use of the xenogeneic DNA (ie, human PSMA DNA injected into mouse) has been shown to be an absolute requirement to overcome immunologic tolerance. We are currently conducting a phase I trial of human and mouse PSMA DNA vaccines in patients with recurrent prostate cancer, based on preclinical experiments described below.

Hricak H, Schöder H, Pucar D, Lis E, Eberhardt SC, Onyebuchi CN, Scher HI. · Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. · Semin Oncol. · Pubmed #14571410 No free full text.

Abstract: Imaging prostate cancer continues to represent a clinical challenge for both primary and recurrent disease. In the evaluation of the persistent/recurrent/metastatic prostate cancer, knowledge of cancer location (local v distant), size, and extent are essential in order to design a treatment, tailored to each patient's needs. There are evidence-based guidelines for the use of imaging in assessing the presence of distant spread of prostate cancer. Radionuclide bone scans and computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography (PET) supplement clinical and biochemical evaluations (prostate-specific antigen [PSA]) for suspected metastatic disease to bones and lymph nodes. There is no consensus about the use of imaging in the evaluation of local tumor recurrence. The use of ultrasound has been limited to biopsy guidance of the prostatic bed, or percutaneous biopsy of enlarged lymph nodes detected on CT or MRI. The use of MRI is evolving. Recent studies indicate that the use of MRI provides valuable information in the evaluation of local tumor recurrence, and nodal and bony metastases. In a patient post-radiation therapy, the method of combining MRI anatomic information with MR spectroscopic metabolic information is evolving. Another modality offering information about anatomy and metabolism of the local disease is PET/CT. The value of PET/CT at present is controversial, but new studies exploring the role of PET/CT in aggressive prostate cancer are promising.

Morris MJ, Scher HI. · Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 444, 10021, New York, NY, USA. · Crit Rev Oncol Hematol. · Pubmed #12850524 No free full text.

Abstract: Hormonal therapy and chemotherapy, though active treatments for prostate cancer, are not curative for patients with metastatic disease. Targeted therapy has the potential to control, if not eradicate, cells resistant to castration and chemotherapy. Despite several years of development, however, a biologic approach with clear clinical benefits has yet to emerge from a crowded field. This review outlines the approaches being studied at Memorial Sloan-Kettering Cancer Center to optimize biologic therapy. Trials of targeted therapy are designed on the basis of a clinical states model that describes both patient clinical risks and tumor biology. Drugs that act on multiple pathways are being developed, and targets that are expressed across all phases of the disease are selected. New molecular imaging techniques permit assessments of the target before, during, and after treatment. High-throughput preclinical assays of gene expression are being developed to enhance selection of drug sequences and combinations for clinical testing.

Shaffer DR, Scher HI. · Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. · Lancet Oncol. · Pubmed #12850191 No free full text.

Abstract: Despite high response rates and palliative clinical benefits, androgen ablation does not cure advanced prostate cancer because of the inevitable emergence of resistant cells. Many new therapies under development for prostate cancer target pathways and molecules that contribute to the growth and survival of these cells. The rational and effective use of targeted therapies to eradicate resistant populations of tumour cells should be grounded on the premise that prostate cancer is a dynamic disease that evolves as it progresses, and that specific molecular determinants mediating sensitivity and resistance may be relevant only during specific states of the disease. Directed approaches must account for this changing dynamic so that clinical outcomes may be improved.

Morris MJ, Scher HI. · Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. · Oncologist. · Pubmed #12697941 links to  free full text

Abstract: BACKGROUND: Prostate cancer is unique among solid tumors in its proclivity to metastasize primarily to bone. Osseous metastases pose a formidable health threat to patients with metastatic disease, putting them at risk for pain, marrow crowding, fracture, and other sequelae. Treatments directed against bone disease have the potential both to palliate pain and to increase survival. CONCLUSIONS: A number of agents exist that have the potential to palliate the effects of osseous metastases and should be routinely applied in the clinical care of the patient with advanced prostate cancer. These include hormones, bone-seeking radiopharmaceuticals, chemotherapy, and bisphosphonates. Strategies under investigation aim to eradicate bone disease, and not merely palliate symptoms. These approaches combine those listed above with tumor-directed targeting of osseous disease and manipulation of the biology that underlies the cancer's relationship to bone.

Scher HI. · Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. · Cancer. · Pubmed #12548573 links to  free full text

Abstract: The development and progression of a prostate carcinoma from prediagnosis to death can be characterized as a series of clinical states. The states are milestones that can be used to assess prognosis, define therapeutic objectives, and assess outcomes. The antitumor effects of hormone therapies and cytotoxic agents in patients with prostate carcinoma are placed in context along with the bidrectional tumor-host interactions that contribute to the growth and resistance of osseous lesions. Identifying the factors that contribute to the growth of the disease at different points in the illness has lead to novel, systemic approaches. Proving the benefit of these approaches requires a series of unique trials with unique endpoints relevant to the clinical state of the patients and the specific therapy under evaluation.

Partin AW, Hanks GE, Klein EA, Moul JW, Nelson WG, Scher HI. · Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Oncology (Williston Park). · Pubmed #12380948 No free full text.

Abstract: Despite the impact of prostate-specific antigen (PSA) testing on the detection and management of prostate cancer, controversy about its usefulness as a marker of disease activity continues. This review, based on a recent roundtable discussion, examines whether PSA measurements can be used rationally in several clinical settings. Following radical prostatectomy and radiation therapy, prediction of survival by PSA level is most reliable in high-risk patients. PSA doubling time after radiation therapy is the strongest predictor of biochemical failure. PSA measurements have been associated with inconsistent results following hormonal treatment; reduced PSA levels may result from antiandrogen treatment, which decreases expression of the PSA gene, and therefore, the level of PSA production. In the setting of primary and secondary cancer prevention, PSA is important in risk stratification when selecting patients for studies. Part 2 of this two-part article, which began in the August issue, discusses the role of PSA in hormonal and drug therapies and in primary and secondary chemoprevention.

Partin AW, Hanks GE, Klein EA, Moul JW, Nelson WG, Scher HI. · Johns Hopkins University, School of Medicine, Baltimore, Maryland 21287, USA. · Oncology (Williston Park). · Pubmed #12201643 No free full text.

Abstract: Despite the impact of prostate-specific antigen (PSA) testing on the detection and management of prostate cancer, controversy about its usefulness as a marker of disease activity continues. This review, based on a recent roundtable discussion, examines whether PSA measurements can be used rationally in several clinical settings. Following radical prostatectomy and radiation therapy, prediction of survival by PSA level is most reliable in high-risk patients. PSA doubling time after radiation therapy is the strongest predictor of biochemical failure. PSA measurements have been associated with inconsistent results following hormonal treatment; reduced PSA levels may result from antiandrogen treatment, which decreases expression of the PSA gene, and therefore, the level of PSA production. In the setting of primary and secondary cancer prevention, PSA is important in risk stratification when selecting patients for studies. Part 1 of this two-part article, which concludes in the September issue, focuses on the physiology of PSA, its measurement and use in clinical practice, and its predictive value following radical prostatectomy and radiation therapy.

Morris MJ, Scher HI. · Department of Genitourinary Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 444, New York, NY 10021, USA. · Surg Oncol. · Pubmed #12031864 No free full text.

Abstract: The number of treatment options for patients with prostate cancer is expanding, as mechanism-based therapies enter clinical testing. Such strategies are based on manipulating tumoral genetics, cell signaling, apoptosis, angiogenesis, the immune system, and others. To properly develop these agents, traditional trial designs and outcome measures require reconsideration. This review describes these novel drugs and their targets using a clinical states model. Investigators use a clinical states model as a framework for matching specific agents with the needs of the treatment population and the biology of the tumor at any given point in the natural history of the disease.