Prostatic Neoplasms: Dahut WL

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.

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.

Aragon-Ching JB, Dahut WL. · Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. · Cancer J. · Pubmed #18303479 No free full text.

Abstract: Prostate cancer is the leading noncutaneous malignancy in American men. Only the combination of docetaxel and prednisone has been shown to improve survival in patients with metastatic castrate-resistant prostate cancer. However, responses are short and a search for better agents either alone or synergistic with chemotherapy continues to be an urgent medical need. Angiogenesis has been shown to be a prerequisite event for tumor growth and metastasis in prostate cancer. Several strategies have been used to target angiogenesis in prostate cancer. These include blocking of pro-angiogenic factors via monoclonal antibodies or small molecule inhibitors targeting downstream signaling effector pathways, direct inhibition of endothelial cells, or targeting other receptors involved in cell adhesion, proliferation, and survival. Agents such as thalidomide and bevacizumab have shown encouraging results in phase II trials, and this review focuses on the clinical trials that have used these agents and other novel agents. The use of angiogenesis inhibitors is rapidly emerging as a promising treatment strategy in a variety of solid tumors, currently including prostate cancer.

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.

Arlen PM, Dahut WL, Gulley JL. · Clinical Research Group, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, MSC 1750, Bethesda, MD 20892-1750, USA. · Hematol Oncol Clin North Am. · Pubmed #16861126 No free full text.

Abstract: Prostate cancer is the most common noncutaneous cancer and second leading cause of cancer death among US men. A greater understanding of basic immunologic principles has led to a variety of new techniques,which has led to advancements in prostate cancer vaccines. This article discusses the rationale for the development of antibody-based therapy and vaccines therapy, including whole tumor cells, dendritic cells, and pox viral vectors. A summary of selected clinical studies incorporating these strategies and new approaches incorporating a combination of immunotherapy with traditional treatments for prostate cancer is presented.

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.

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.

Sharifi N, Gulley JL, Dahut WL. · Medical Oncology Clinical Research Unit, National Cancer Institute, Bethesda, MD 20892, USA. · JAMA. · Pubmed #16014598 links to  free full text

Abstract: CONTEXT: Prostate cancer is the most common nonskin cancer and second most common cause of cancer mortality in US men. Androgen deprivation therapy (ADT), specifically surgical or medical castration, is the first line of treatment against advanced prostate cancer and is also used as an adjuvant to local treatment of high-risk disease. OBJECTIVE: To review systematically the evidence on the risks and benefits of ADT for prostate cancer as well as clinical management of its adverse effects. EVIDENCE ACQUISITION: We performed MEDLINE searches of English-language literature (1966 to March 2005) using the terms androgen deprivation therapy, hormone treatment, and prostate cancer. We reviewed bibliographies of literature to extract other relevant articles. Studies were selected based on clinical pertinence, with an emphasis on controlled study design. EVIDENCE SYNTHESIS: Androgen deprivation therapy is effective for palliation in many patients with advanced prostate cancer and improves outcomes for high-risk patients treated with radiation therapy for localized disease. Although patients with increasing prostate-specific antigen levels after local treatment without metastatic disease frequently undergo ADT, the benefits of this strategy are not clear. Adverse effects of ADT include decreased libido, impotence, hot flashes, osteopenia with increased fracture risk, metabolic alterations, and changes in cognition and mood. CONCLUSIONS: Androgen deprivation therapy has clear roles in the management of advanced prostate cancer and high-risk localized disease. The benefits of ADT in other settings need to be weighed carefully against substantial risks and adverse effects on quality of life.

Gulley J, Dahut WL. · National Cancer Institute, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, 10 Center Drive, 8B07 MSC 1750, Bethesda, MD 20892, USA. · Expert Rev Anticancer Ther. · Pubmed #15877520 No free full text.

Abstract: Many solid tumors, including breast and prostate cancer, metastasize to bone, thereby putting patients at high risk for developing skeletal complications including pathologic fracture, spinal cord compression and debilitating bone pain. Patients often live for many years after developing bone metastasis, a fact that highlights the importance of therapies to reduce morbidity from skeletal complications. Bisphosphonates, including clodronate, have been shown to be useful in reducing skeletal complications in patients with cancer. This review will highlight the role of clodronate for skeletal metastasis.

Gulley J, Dahut WL. · Clinical Immunotherapy Group, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, 10 Center Drive, 8B07 MSC 1750, Bethesda, MD 20892, USA. · Am J Ther. · Pubmed #15266221 No free full text.

Abstract: Patients with metastatic prostate cancer can be treated with androgen deprivation strategies; however, most patients will eventually develop androgen-independent prostate cancer (AIPC). Until recently, chemotherapy has been shown to palliate symptoms of disease but not improve survival. Now 2 large phase 3 trials have demonstrated an overall survival advantage for docetaxel-based regimens compared with the best standard of care. This firmly cements docetaxel-based therapies as the standard of care for patients with metastatic androgen-independent disease. In addition, this foundation provides a platform for the translation of novel agents into new combination cancer therapies. In this paper, we not only review standard treatment options available for AIPC including the recently completed docetaxel trials, but also present some of the promising new drug combinations of currently available drugs.

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.

Gulley J, Dahut WL. · Laboratory of Tumor Immunology and Biology, and the Genitourinary Clinical Research Section, Medical Oncology Clinical Research Unit, National Cancer Institute, Bethesda, Maryland 20892, USA. · Urology. · Pubmed #14747053 No free full text.

Abstract: For >50 years, the standard treatment for advanced prostate cancer has been hormonal therapy. However, all such treated patients eventually develop disease refractory to androgen suppression as manifested by increasing prostate-specific antigen (PSA) levels, progressive disease on radiographic imaging, and ultimately, symptomatic deterioration. Historical perceptions that treatment of hormone-refractory prostate cancer was a largely futile venture have faded over the past decade with the advances in new therapeutic strategies. With the use of PSA values to follow the progress of patients after definitive therapy, physicians are seeing more patients who have failed hormonal therapy yet have no symptoms from their disease. There are standard therapies available for patients who require palliation for symptoms, but there is no consensus on treatment for asymptomatic patients. To date, there has been no definitive increase in survival with any therapy in this group of patients. In addition, several novel drugs have advanced through preclinical testing into early clinical trials. It is these drugs--alone or in combination--that are designed to target strategic tumor pathways in these patients. This article will review a selection of agents that may be potentially useful in this population.

Retter AS, Gulley JL, Dahut WL. · Genitourinary Branch, Medical Oncology Clinical Research Unit, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. · Cancer Biol Ther. · Pubmed #14726702 links to  free full text

Abstract: Prostate cancer is the most common noncutaneous cancer in American men and the second most common cause of death. It is estimated that in 2003, 220,900 new cases will be diagnosed and 28,900 men will die from the disease.1 Hormonal therapy via surgical or chemical castration is the mainstay of treatment for metastatic prostate cancer. While this is quite effective initially, with time patients become refractory to this treatment and may require additional therapy. There have been a substantial number of novel agents that have been developed in the last 10 years that show promise in the treatment of patients with prostate cancer, when used alone or when combined with current approaches (Table 1).

Posadas EM, Dahut WL, Gulley J. · Medical Oncology Clinical Research Unit, Laboratory of Tumor Immunology and Biology, Center for Cancer Research National Cancer Institute, National Institutes of Health, 10 Center Drive, MSC 1750, Building 10, Room 5B52, Bethesda, MD 20892, USA. · Am J Ther. · Pubmed #14704597 No free full text.

Abstract: Bisphosphonates are a class of therapeutic agents originally designed to treat loss of bone density. It has been shown that the primary mechanism of action is inhibition of osteoclastic activity. Accumulating data show that these drugs are useful in diseases with propensities toward osseous metastases. In particular, they are effective in diseases in which there is clear upregulation of osteoclastic or osteolytic activity such as breast cancer and multiple myeloma. Despite the fact that osseous metastases in prostate cancer manifest as osteosclerosis rather than osteolysis, studies now show that bisphosphonates are useful in the management of this disease. In particular, they have demonstrated an impact on osteoporosis associated with hormonal therapy, bone pain from metastases, and skeleton-related events from prostatic adenocarcinoma. This review briefly summarizes the available clinical data on the utilization of bisphosphonates in the disease of prostate cancer.

Aragon-Ching JB, Ning YM, Chen CC, Latham L, Guadagnini JP, Gulley JL, Arlen PM, Wright JJ, Parnes H, Figg WD, Dahut WL. · Medical Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA. · Cancer Invest. · Pubmed #19235596 links to  free full text

Abstract: ONJ is an important toxicity in cancer patients receiving bisphosphonate therapy. Here we report a higher than usual incidence of ONJ, 11 of 60 (18.3%, 95% Confidence Interval, CI: 9%-28%) patients enrolled in a phase II clinical trial combining bevacizumab, docetaxel, thalidomide, and prednisone (ATTP) in chemotherapy-naive men with metastatic castration resistant prostate cancer (mCRPC). The use of bisphosphonates was allowed at study entry. Our study suggests that anti-angiogenic and chemotherapy agents can predispose to the development of ONJ in men with mCRPC on zoledronic acid. Imaging modalities, such as bone scans, may be useful in following the clinical course of patients who develop ONJ.

Aragon-Ching JB, Jain L, Gulley JL, Arlen PM, Wright JJ, Steinberg SM, Draper D, Venitz J, Jones E, Chen CC, Figg WD, Dahut WL. · Medical Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA. · BJU Int. · Pubmed #19154507 No free full text.

Abstract: OBJECTIVE: To determine if sorafenib is associated with an improved 4-month probability of progression-free survival, using radiographic and clinical criteria alone, in patients with metastatic castration-resistant prostate cancer. Secondary endpoints included pharmacokinetics, toxicity analysis and overall survival. PATIENTS AND METHODS: The study was an open-label, phase II, two-stage design, focusing on the results from the second stage, as criteria for progression were modified after completing the first stage. Sorafenib was given at a dose of 400 mg orally twice daily in 28-day cycles. Clinical and laboratory assessments were done every 4 weeks, and radiographic scans were obtained every 8 weeks. RESULTS: Twenty-four patients were accrued in the second stage; the median (range) age was 66 (49-85) years, the on-study prostate-specific antigen level was 68.45 (5.8-995) ng/mL, the Gleason score 8 (6-9) and Eastern Cooperative Oncology Group status 1 (in 17 patients). Of the 24 patients, 21 had previous chemotherapy with docetaxel. All patients had bony metastases, either alone (in 11) or with soft-tissue disease (in 13). One patient had a partial response; 10 patients had stable disease (median duration 18 weeks, range 15-48). At a median potential follow-up of 27.2 months, the median progression-free survival was 3.7 months and the median overall survival was 18.0 months. For the whole trial of 46 patients the median survival was 18.3 months. Most frequent toxicities included hand-foot skin reaction (grade 2 in nine patients, grade 3 in three), rash, abnormalities in liver function tests, and fatigue. CONCLUSIONS: Sorafenib has moderate activity as a second-line treatment for metastatic castration-resistant prostate cancer.

Gulley JL, Aragon-Ching JB, Steinberg SM, Hussain MH, Sartor O, Higano CS, Petrylak DP, Chatta GS, Arlen PM, Figg WD, Dahut WL. · Center for Cancer Research, Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, Maryland 20892, USA. · J Urol. · Pubmed #18710748 No free full text.

Abstract: PURPOSE: Groups have investigated time to testosterone recovery in patients who have undergone androgen deprivation therapy, usually by measuring androgen every 3 months, with varying results. To our knowledge this represents the largest study using monthly testosterone and dihydroxytestosterone measurement to evaluate the kinetics of androgen recovery following limited androgen deprivation therapy. MATERIALS AND METHODS: Monthly serum androgen levels were analyzed following 2, 6-month cycles of gonadotropin-releasing hormone agonist therapy as part of a randomized, placebo controlled study of the role of thalidomide in delaying time to prostate specific androgen progression. RESULTS: By the Kaplan-Meier method the median time to testosterone normalization in cycles 1 vs 2 was 15.4 vs 18.3 weeks with similar dihydroxytestosterone recovery times. Neither on-study prostate specific antigen, Gleason score nor thalidomide treatment had a significant impact on time to testosterone normalization. However, in cycle 1 men with low baseline dihydroxytestosterone and those who were more than 67 years old had significantly longer time to T normalization on Cox model analysis. Additionally, in cycle 2 patients with prior local radiation therapy had longer time to testosterone normalization, although this was no longer significant on Cox model analysis. Cox model analysis in cycle 2 showed that low baseline dihydroxytestosterone and testosterone, low testosterone nadir and white race were associated with longer time to testosterone normalization. CONCLUSIONS: Findings of delayed testosterone recovery may be useful for designing and analyzing clinical trials of limited androgen deprivation therapy and for estimating the duration of treatment associated side effects in patients undergoing limited androgen deprivation therapy.

Lechleider RJ, Arlen PM, Tsang KY, Steinberg SM, Yokokawa J, Cereda V, Camphausen K, Schlom J, Dahut WL, Gulley JL. · Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bethesda, Maryland, USA. · Clin Cancer Res. · Pubmed #18698048 No free full text.

Abstract: PURPOSE: We have previously reported on the safety and immunologic response of a poxvirus-based vaccine encoding prostate-specific antigen (PSA) used in combination with radiation therapy in patients with localized prostate cancer. We hypothesized that a "metronomic" dose of interleukin 2 (IL-2) as a biological adjuvant would cause less toxicity while maintaining immunologic response. EXPERIMENTAL DESIGN: Eighteen patients with localized prostate cancer were treated in a single-arm trial using previously established doses of vaccine and radiation therapy. The vaccine used was a recombinant vaccinia virus engineered to encode PSA admixed with a recombinant vaccinia encoding the costimulatory molecule B7.1, followed by booster vaccinations with a recombinant fowlpox vector expressing PSA. Patients received a total of eight planned vaccination cycles, once every 4 weeks, with granulocyte-macrophage colony-stimulating factor given on days 1 to 4 and interleukin 2 (IL-2) at a dose of 0.6 MIU/M2 given from days 8 to 21 after each vaccination. Definitive external beam radiation therapy was initiated after the third vaccination cycle. Patients were evaluated for safety and immunologic response. Toxicity and immunologic activity were compared with the previously reported regimen containing a higher dose of IL-2. RESULTS: Seventeen of 18 patients received all eight cycles of vaccine with IL-2. Five of eight HLA-A2+ patients evaluated had an increase in PSA-specific T cells of > or =3-fold. Toxicities were generally mild, with only seven vaccination cycles of 140 given resulting in grade 3 toxicities possibly attributable to IL-2. CONCLUSIONS: Metronomic-dose IL-2 in combination with vaccine and radiation therapy is safe, can induce prostate-specific immune responses, and has immunologic activity similar to low-dose IL-2, with markedly reduced toxicities.

Madan RA, Gulley JL, Schlom J, Steinberg SM, Liewehr DJ, Dahut WL, Arlen PM. · Laboratory of Tumor Immunology and Biology, Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA. · Clin Cancer Res. · Pubmed #18628467 links to  free full text

Abstract: PURPOSE: We reported previously the first randomized study of any kind in patients with nonmetastatic, castrate-resistant prostate cancer. The study employed vaccine, the hormone nilutamide, and the combined therapy (crossover for each arm) with an endpoint of time to progression. We now report survival analyses at 6.5 years from the initiation of therapy with a median potential follow-up of 4.4 years. EXPERIMENTAL DESIGN: Forty-two patients were randomized to receive either a poxvirus-based prostate-specific antigen (PSA) vaccine or nilutamide. Patients in either arm who developed increasing PSA without radiographic evidence of metastasis could cross over to receive the combined therapies. RESULTS: Median survival among all patients was 4.4 years from date of enrollment. Median survival exhibited a trend toward improvement for patients initially randomized to the vaccine arm (median, 5.1 versus 3.4 years; P = 0.13). Starting from the on-study date, the retrospectively determined subset of 12 patients who initially received vaccine and then later received nilutamide suggested improved survival compared with the 8 patients who began with nilutamide and subsequently were treated with vaccine (median, 6.2 versus 3.7 years; P = 0.045). A subgroup analysis of patients randomized to the vaccine arm versus the nilutamide arm showed substantial improvements in survival if at baseline patients had a Gleason score <7 (P = 0.033) and PSA <20 ng/dL (P = 0.013) or who had prior radiation therapy (P = 0.018). CONCLUSIONS: These data indicate that patients with nonmetastatic castration-resistant prostate cancer (D0.5) who receive vaccine before second-line hormone therapy may potentially result in improved survival compared with patients who received hormone therapy and then vaccine. These data also suggest that patients with more indolent disease may derive greater clinical benefit from vaccine alone or vaccine before second-line hormone therapy compared with hormone therapy alone or hormone therapy followed by vaccine. These findings have potential implications for both the design and endpoint analysis of larger vaccine combination therapy trials.

Dahut WL, Scripture C, Posadas E, Jain L, Gulley JL, Arlen PM, Wright JJ, Yu Y, Cao L, Steinberg SM, Aragon-Ching JB, Venitz J, Jones E, Chen CC, Figg WD. · Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA. · Clin Cancer Res. · Pubmed #18172272 links to  free full text

Abstract: PURPOSE: To determine if sorafenib is associated with a 4-month probability of progression-free survival, which is consistent with 50%, as determined by clinical, radiographic, and prostate-specific antigen (PSA) criteria in patients with metastatic androgen-independent prostate cancer (AIPC). EXPERIMENTAL DESIGN: Patients with progressive metastatic AIPC were enrolled in an open-label, single-arm phase II study. Sorafenib was given continuously at a dose of 400 mg orally twice daily in 28-day cycles. Clinical assessment and PSA measurement were done every cycle whereas radiographic measurements were carried out every two cycles. RESULTS: Twenty-two patients were enrolled in the study to date, completing a planned first stage of the trial. Baseline patient characteristics included a median age of 63.9 years (range, 50-77 years), Gleason score of 9 (range, 4-9.5), and PSA concentration of 53.3 ng/mL (range, 2-1,905 ng/mL). Fifty-nine percent of patients had received one prior chemotherapy regimen. Of the 21 patients with progressive disease, 13 progressed only by PSA criteria in the absence of evidence of clinical and radiographic progression. Two patients were found to have dramatic reduction of bone metastatic lesions as shown by bone scan, although they met PSA progression criteria at the time when scans were obtained. Toxicities likely related to treatment included one grade 3 hypertension; one grade 3 hand-foot syndrome; and grade 1/2 toxicities: fatigue, anorexia, hypertension, skin rash, nausea, and diarrhea. Results from in vitro studies suggested that PSA is not a good marker of sorafenib activity. The geometric mean exposure (AUC(0-12)) and maximum concentration (C(max)) were 9.76 h mg/L and 1.28 mg/L, respectively. The time to maximum concentration (t(max)) and accumulation ratio (after second dose) ranged from 2 to 12 h and 0.68 to 6.43, respectively. CONCLUSIONS: Sorafenib is relatively well tolerated in AIPC with two patients showing evidence of improved bony metastatic lesions. Interpretation of this study is complicated by discordant radiographic and PSA responses. PSA may not be an adequate biomarker for monitoring sorafenib activity. Based on these observations, further investigation using only clinical and radiographic end points as progression criteria is warranted. Accrual to the second stage of trial is ongoing.

Theoret MR, Arlen PM, Pazdur M, Dahut WL, Schlom J, Gulley JL. · Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. · Clin Genitourin Cancer. · Pubmed #17645835 No free full text.

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Lakhani NJ, Sparreboom A, Xu X, Veenstra TD, Venitz J, Dahut WL, Figg WD. · Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA. · J Pharm Sci. · Pubmed #17252610 No free full text.

Abstract: The aim of this study was to characterize the metabolic pathways of 2-methoxyestradiol (2ME2), an investigational anticancer drug. In vitro metabolism studies were performed by incubation of 2ME2 with human liver microsomes under various conditions and metabolite identification was performed using liquid chromatography-tandem mass spectrometry. In microsomal mixtures, four major oxidative metabolites and two glucuronic acid conjugates were observed originating from 2ME2. Human liver S9 protein fraction was used to screen for in vitro sulfation but no prominent conjugates were observed. The total hepatic clearance as estimated using the well-stirred model was approximately 712 mL/min. In vivo metabolism, assessed using 24-h collections of urine from cancer patients treated with 2ME2 revealed that <0.01% of the total administered dose of 2ME2 is excreted unchanged in urine and about 1% excreted as glucuronides. Collectively, this suggests that glucuronidation and subsequent urinary excretion are elimination pathways for 2ME2.

Wu SL, Jones E, Gulley JL, Arlen PM, Chen CC, Figg WD, Dahut WL. · Medical Oncology Branch, Center for Cancer Research, National Cancer Institute/NIH, 10 Center Drive, Bethesda, MD 20892, USA. · BJU Int. · Pubmed #17155971 No free full text.

Abstract: OBJECTIVE: To identify patients with androgen-independent prostate cancer (AIPC) with bone metastasis and no soft-tissue metastases at the time of protocol enrollment, and analyse their disease progression by computed tomography (CT), bone scan, and prostate-specific antigen (PSA) level to determine the utility of routine interval CT in such patients. PATIENTS AND METHODS: Bone is the most common metastatic site in patients with AIPC and the only site of metastatic disease for many; because some with initial bone metastasis eventually develop soft-tissue disease, many clinical trials use routine CT to monitor for the latter as a sign of disease progression, but the actual incidence of new soft-tissue metastases is unknown and the role of routine interval CT in monitoring for disease progression, especially for asymptomatic patients, is unclear. Thus we reviewed 175 cases of metastatic AIPC from three randomized phase II clinical trials (docetaxel/thalidomide, docetaxel/vaccine, and ketoconazole/alendronate) at the National Cancer Institute between 1995 and 2004. The patients' PSA levels were assessed every 4 weeks, and CT and bone scans were done every 2-3 months. We retrospectively identified patients with bone metastasis only and examined subsequent CT for the occurrence of soft-tissue disease. For patients with progressive disease, we also examined bone scan and PSA progression. RESULTS: Of 175 patients with metastatic prostate cancer, 105 (60%) had bone metastasis only, 12 (6.9%) had soft-tissue metastases only, and 58 (33.1%) had both bone and soft-tissue metastases. The median (range) follow-up was 8 (1-44) months for the 105 patients with bone metastasis only. During that time, two patients (1.9%) developed new soft-tissue disease; one developed right iliac fossa lymphadenopathy after 8 months and the other developed a perirectal mass after 12 months. The patient with new lymphadenopathy also had multiple new bone lesions identified by bone scan and PSA progression. The patient with the perirectal mass had PSA progression and a palpable abnormality. CONCLUSION: This review of patients with AIPC and bone metastasis only, followed for a median of 8 months on clinical trials, shows that the incidence of asymptomatic new soft-tissue disease as the only sign of disease progression is quite low. Therefore, routine CT to exclude new soft-tissue disease in this population appears to be unwarranted. We recommend that for these patients CT is done only at the time of disease progression, as shown by bone scan, PSA level, or clinical presentation. We do not exclude the possibility that patients who remain on trial for significantly longer periods might benefit from routine interval CT.

Posadas EM, Gulley J, Arlen PM, Trout A, Parnes HL, Wright J, Lee MJ, Chung EJ, Trepel JB, Sparreboom A, Chen C, Jones E, Steinberg SM, Daniels A, Figg WD, Dahut WL. · Medical Oncology Clinical Research Unit, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA. · Cancer Biol Ther. · Pubmed #16138006 links to  free full text

Abstract: OBJECTIVES: Perifosine is an alkylphospholipid that has exhibited broad antineoplastic activity in preclinical studies. The primary objective of this study was to determine the clinical efficacy of this agent in the treatment of androgen-independent prostate cancer (AIPC) using PSA and clinical criteria. PATIENTS AND METHODS: Nineteen patients with progressive, metastatic AIPC were treated with oral perifosine. Cycles were 28 days in length. A loading dose of 900 mg was given on day 1 of cycle 1 followed by a maintenance dose of 150 mg daily for the next 20 days. A loading dose of 600 mg was administered on the first day of subsequent cycles by the maintenance dose of 150 mg daily for the next 20 days. Pharmacokinetic measurements were made throughout the course of the study. Circulating epithelial cells were collected via leukapheresis on day 0, 3, and 28. RESULTS: Median patient age was 67 years and median PSA was 180 ng/mL (range: 19-904 ng/ml). Grade 1-2 fatigue and gastrointestinal toxicities were common. Pharmacokinetic studies showed an average minimum concentration at steady-state of approximately 4059 ng/ml which correlated well with previous studies. Median time to progression was four weeks. There were no radiographic responses or PSA declines of 50% or greater related to perifosine. CONCLUSIONS: Treatment with perifosine was complicated by fatigue and gastrointestinal toxicity. No significant clinical activity against prostate cancer was observed. This agent does not merit further study in the setting of monotherapy in this population.

Gulley JL, Figg WD, Steinberg SM, Carter J, Sartor O, Higano CS, Petrylak DP, Chatta G, Hussain MH, Dahut WL. · Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. · J Urol. · Pubmed #15821487 No free full text.

Abstract: PURPOSE: Patients with prostate cancer are treated with neoadjuvant, adjuvant and intermittent therapy with gonadotropin-releasing hormone agonists (GnRH-A). While these are largely successful in decreasing testosterone (T) and dihydroxytestosterone (DHT) to castrate levels, discontinuation of such therapy often results in continued suppression of androgens for variable periods of time. We present the largest published series of patients evaluating the timing of T and DHT increase after cessation of GnRH therapy. MATERIALS AND METHODS: Serial T and DHT measurements were prospectively obtained every 3 months while on GnRH-A then monthly upon discontinuation of GnRH-A. Analysis of time from the second 3-month GnRH-A administration to T and DHT increase was undertaken. RESULTS: A total of 80 evaluable patients had a median time to T 50 ng/dl or greater of 12.9 weeks and a median time to T normalization (212 ng/dl or greater) of 16.6 weeks. Low baseline T was associated with a prolonged time to T 212 ng/dl or greater (p = 0.0086) and a similar trend was seen in patients older than 66 years (p = 0.08). There were 62 evaluable patients with a median of 14.9 weeks to DHT 150 pg/ml or greater. There was no association with Gleason score at diagnosis, on study prostate specific antigen, type of prior definitive therapy, or any prior hormonal therapy and time to increase in circulating androgens. CONCLUSIONS: After 6 months of GnRH-A therapy in these patients, DHT and T levels did not return to normal for a median of 14.9 and 16.6 weeks, respectively.