| | A Double-Blind Randomized Crossover Study of Oral Thalidomide Versus Placebo for Androgen Dependent Prostate Cancer Treated With Intermittent Androgen AblationReceived 26 August 2008 published online 23 January 2009.
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Bo Sun, Jacob A. Moibi, Allan Mak, Zhengwen Xiao, Wilson Roa, Ronald B. Moore
The Journal of Urology
March 2009 (Vol. 181, Issue 3, Pages 1361-1371)
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MicroRNA-143 as a Tumor Suppressor for Bladder Cancer
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The Journal of Urology
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Preventing Bladder Tumor Implantation With Photodynamic Therapy in a Rat Model Mimicking Post-Fluorescence Guided Transurethral Resection
, 20 January 2009
Saoussen Berrahmoune, Lina Bezdetnaya, Agnès Leroux, François Guillemin, Marie Ange D'Hallewin
The Journal of Urology
March 2009 (Vol. 181, Issue 3, Pages 1381-1386)
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PurposeWe determined whether thalidomide can prolong progression-free survival in men with biochemically recurrent prostate cancer treated with limited androgen deprivation therapy. Materials and MethodsA total of 159 patients were enrolled in a double-blind randomized trial to determine if thalidomide can improve the efficacy of a gonadotropin-releasing hormone agonist in hormone responsive patients with an increasing prostate specific antigen after primary definitive therapy for prostate cancer. Patients were randomized to 6 months of gonadotropin-releasing hormone agonist followed by 200 mg per day oral thalidomide or placebo (oral phase A). At the time of prostate specific antigen progression gonadotropin-releasing hormone agonist was restarted for 6 additional months. Patients were then crossed over to the opposite drug and were treated until prostate specific antigen progression (oral phase B). Testosterone and dihydroxytestosterone were likewise monitored throughout the study. ResultsDuring oral phase A the median time to prostate specific antigen progression was 15 months for the thalidomide group compared to 9.6 months on placebo (p = 0.21). The median time to prostate specific antigen progression during oral phase B for the thalidomide group was 17.1 vs 6.6 months on placebo (p = 0.0002). No differences in time to serum testosterone normalization between the thalidomide and placebo arms were documented during oral phase A and oral phase B. Thalidomide was tolerable although dose reductions occurred in 47% (58 of 124) of patients. ConclusionsDespite thalidomide having no effect on testosterone normalization, there was a clear effect on prostate specific antigen progression during oral phase B. This is the first study to our knowledge to demonstrate the effects of thalidomide using intermittent hormonal therapy. Abbreviations and Acronyms: ADT, androgen deprivation therapy, CONSORT, Consolidated Standards of Reporting Trials, CRPC, castration resistant prostate cancer, CTEP, Cancer Therapy Evaluation Program, DHT, dihydroxytestosterone, ECOG, Eastern Cooperative Oncology Group, GnRH-A, gonadotropin-releasing hormone agonist, NCI, National Cancer Institute, OPA, oral phase A, OPB, oral phase B, PFS, progression-free survival, PSA, prostate specific antigen, T, testosterone Although definitive treatment with primary surgery or radiotherapy affords cure in a majority of patients with prostate cancer, a significant proportion who have an increasing PSA have this status in the absence of radiographic evidence of metastasis, so-called stage D0 prostate cancer or biochemical recurrence. Biochemical recurrence occurs in approximately 30% to 40% of patients undergoing definitive local therapy.1, 2, 3, 4 Several salvage options may be offered to these patients including salvage radiation, prostatectomy, observation or ADT. Unfortunately virtually all patients treated with ADT eventually have progression to overt metastatic disease. Definite recommendations on how to treat this subset of patients are currently lacking.5 Angiogenesis is important in the pathogenesis, aggressiveness and potential for metastasis in prostate cancer.6, 7 We have previously demonstrated the clinical activity of thalidomide in phase II clinical trials of heavily pretreated patients with metastatic CRPC alone8 and in combination with docetaxel.9 Although the exact mechanisms by which thalidomide controls prostate cancer is still unknown, the inhibition of angiogenesis has been widely postulated. In addition, antiangiogenic therapy has been hypothesized to achieve maximal benefit when the tumor burden is low. Intermittent ADT is increasingly being used in patients with biochemical recurrence of prostate cancer.10, 11 Patients who present with only biochemical recurrence have the least burden of disease and hormone responsive prostate cancer is associated with a better prognosis than castration resistant prostate cancer. As such, we conducted a randomized, double-blind, multi-institutional, placebo controlled, crossover trial design using thalidomide in patients with androgen dependent prostate cancer. This report describes the results of the first randomized trial to our knowledge to evaluate the time to PSA progression using thalidomide in biochemically recurrent androgen dependent prostate cancer. Methods  Study Objectives The primary objective of this study was to determine if thalidomide could improve PFS or time to PSA progression after limited hormonal ablation in androgen sensitive prostate cancer in patients with biochemical recurrence. Secondary objectives included safety and toxicity evaluation, pharmacokinetic characterization, and analysis of T and DHT. Patient Eligibility All patients had PSA only (biochemical recurrence) androgen dependent adenocarcinoma of the prostate. Previous local definitive therapy with radical prostatectomy, radiation therapy or cryosurgery had failed. Prior neoadjuvant or adjuvant hormonal therapy was allowed only if administered more than 1 year before enrollment. To be eligible patients were required to meet the criteria of histopathological documentation of prostate cancer, no radiographic or scintigraphic evidence of disease, progressive prostate cancer based on 2 consecutively increasing PSAs above the post-definitive therapy PSA nadir with an absolute value greater than 1.0 ng/ml separated by at least 2 weeks, life expectancy greater than 12 months and ECOG performance status 0 to 2. Patients with abnormal hematological and biochemical parameters (as defined by a granulocyte count less than 1,000/mm3, platelet count less than 75,000/mm3, creatinine greater than 2.0 mg/dl or total bilirubin greater than 1 mg/dl), concurrent malignancies (except stage 0 chronic lymphocytic leukemia or nonmelanoma skin cancer), unstable angina, recent myocardial infarction, or other uncontrolled cardiac problems, were excluded from analysis. Study Design This was a randomized, 2-arm, double-blind, placebo controlled trial of thalidomide in patients with biochemical recurrence of androgen sensitive prostate cancer. Standard balanced randomization was used with variable block sizes. There was no stratification for any potential prognostic factors. This study was approved by the institutional review board of the National Cancer Institute and 7 other institutions including Louisiana State University, University of Washington, Columbia University, Wayne State University, University of Minnesota, University of Pittsburgh and Holy Cross Hospital, Fort Lauderdale, Florida. Patients were initially administered gonadotropin-releasing hormone agonists for 6 months, and subsequently received thalidomide or placebo depending on their randomization schedule (fig. 1). GnRH-A generally consisted of leuprolide (22.5 mg for 3 months) or goserelin (10.8 mg for 3 months). This constituted oral phase A. Once patients had PSA progression as defined by an increasing PSA greater than 5 ng/ml or reaching on-study value (minimum 1 ng/ml), whichever occurred first, they were re-treated with a GnRH-A for another 6 months and crossed over to the opposite treatment. This constituted oral phase B. While patients were crossed over to the other treatment the time until crossover was determined by individual patient time to progression. An initial sample size of 140 patients on each arm was planned for this study to provide 80% power to detect a difference between progression-free survival curves with a median of 10 and 14 months using a 0.05 one-tailed alpha level test. The assumption was that 18 months would be required to accrue patients with an additional 18 months of followup after the entry of the last patient. Treatment Plan All patients signed informed consent before randomization. The blinded study drugs were provided by the Pharmaceutical Management Branch of the Cancer Therapy Evaluation Program of the NCI. Thalidomide was given orally in a 200 mg dose every evening. This dose was based on our previous experience using thalidomide in patients with prostate cancer.8, 9 Treatment continued as long as patients tolerated the drug without significant toxicity or evidence of disease progression. PSA was monitored monthly and patients were evaluated in clinic monthly for the duration of the study. Radiographic studies (computerized tomography and bone scan) were obtained at the time of PSA progression. The treatment dose was reduced to 100 mg (50%) whenever drug related peripheral neuropathy of grade 2 or more, or any toxicity of grade 3 or more occurred. No further dose reductions beyond 50% were allowed. Patients who were unable to tolerate thalidomide despite a 50% dose reduction were crossed over to the opposite drug treatment if it occurred during OPA or taken off the treatment drug if it occurred in OPB. Toxicity Evaluation and Response Evaluation This study used the NCI/CTEP Common Terminology Criteria (version 2.0) for toxicity grading. Response was evaluated by measuring monthly PSA concentrations. Patients who did not achieve a PSA less than 5 ng/ml at the end of either GnRH-A treatment cycle were not allowed to proceed to drug treatment. Patients who commenced drug treatment and experienced progressively increasing PSA concentrations with an absolute value greater than 5.0 ng/ml or return to baseline value were crossed over to the opposite drug treatment (during OPA) or taken off study if this occurred during OPB. Development of any bone or soft tissue lesions which were attributed to prostate cancer were considered progressive disease and patients were taken off study at that time. Thalidomide Pharmacokinetics Complete pharmacokinetics of thalidomide in patients with prostate cancer have previously been characterized.12 However, no clear pharmacodynamic associations have been made with regard to efficacy or toxicity. Therefore, limited pharmacokinetic analysis was performed on NCI patients to assess steady state concentrations. Blood was drawn at each monthly visit into a tube containing sodium heparin as an anticoagulant (time of collection varied based on clinic appointment). After centrifugation plasma was transferred to a cryovial and stored at −80C until analysis. A total of 39 samples from 15 patients (median 2 samples per patient) were analyzed using a validated high performance liquid chromatography-ultraviolet analytical assay for thalidomide. Androgen Assessment Initial results of T and DHT data have been published.13 T was measured using the Immulite® 2000 solid phase competitive chemiluminescent enzyme immunoassay while DHT was measured by radioimmunoassay after oxidation and extraction (Mayo Clinic, Rochester, Minnesota). Both assays were performed as previously described.13 The normal range for the T assay is 212 to 742 ng/dl while the normal range for DHT is 150 to 980 pg/ml. T and DHT were obtained every 3 months while on the GnRH-A therapy, and monthly on oral study drug. Data were mostly available for patients enrolled at the NCI. Statistical Analysis All patients who received any oral study medication were assessable for response and toxicity. PFS was calculated from the date at which the blinded study drug was administered until progression or time of last followup. Patients who did not meet the criteria for PSA progression or went off treatment due to toxicity were censored. Analyses were also performed beginning from the date at which the blinded study drug was first administered. The probability of PFS was determined using the Kaplan-Meier method and the statistical significance of the overall difference between a pair of Kaplan-Meier curves was determined by the log rank test. All p values are 2-tailed. In addition, the probability of normalization of T and DHT levels, where available, were statistically analyzed using Kaplan-Meier curves. All results were expressed from the last 3-month GnRH-A minus 12 weeks to account for the activity of the GnRH-A therapy. Patients were censored if serum T or DHT did not return to normal by the cutoff PSA progression. Results Patient Data A total of 159 patients were accrued beginning in March 2000 until January 2005 (Figure 2, Figure 3). Accrual rates were less than anticipated and the study was subsequently closed to further patient entry by the Independent Data Safety and Monitoring Board for the NCI Center for Cancer Research. Patient characteristics were similar in both groups and are presented in table 1. The median age of all patients was 68 years, with a range of 49 to 87. A total of 131 patients (82%) enrolled were white. The median Gleason score was 7 and on-study PSA concentration was 5.1 ng/ml (range 0.9 to 311.8). All patients had received prior local therapy which failed as shown in table 1. The ECOG performance status was 0 in most patients (142) and 1 in others (17). Exposure to Study Medication Of the 159 patients enrolled 11 received neither oral phase A nor oral phase B medications. Of the 148 patients who were randomized to thalidomide or placebo 34 (23%) received only thalidomide and did not cross over to the placebo arm, while 24 (16%) received only placebo and did not cross over to the thalidomide arm. For the 124 patients who received any thalidomide the median number of cycles received was 6 (range less than 0.5 to 56). Each cycle corresponded to 1 month. Of the 113 patients who received any placebo the median number of cycles received was 6 (range 1 to 60). However, dose reduction occurred in 58 of 124 patients (47%) in the thalidomide arm and in only 7 of 113 (6.2%) in the placebo arm. The median number of cycles received before the first dose reduction was 2 for the patients in the thalidomide arm and 3 for the placebo arm. Among the most prevalent conditions necessitating protocol required, principal investigator initiated or patient requested dose reductions that occurred in the thalidomide arm were peripheral neuropathy, dyspnea, dizziness, fatigue and alteration in consciousness, including depression or cognitive disturbances. Most of the symptoms improved after dose reduction without requiring any treatment. Progression-Free Survival Of the 159 patients 79 were randomized to thalidomide during OPA and 80 were randomized to placebo. Only patients who received any oral study medication were included in the analysis for OPA (147) and OPB (88) (Figure 2, Figure 3). The overall median progression-free time for all patients in OPA and OPB was 12 and 9.9 months, respectively. For patients on OPA the median time to progression for those on thalidomide was 15 months vs 9.6 for those on placebo (p = 0.21) (fig. 4, A). The median time to PSA progression during OPB for the thalidomide arm was 17.1 months vs 6.6 for the placebo arm (p = 0.0002) (fig. 4, B). Toxicity All patients who received any treatment were evaluated for toxic effects. The observed grade 3 and 4 adverse events, as well as grade 2 events that occurred in more than 10% of patients after 1,346 cycles of thalidomide and 1,323 cycles of placebo are summarized in table 2. There were no grade 3 or 4 toxicities that occurred in more than 5% of patients. The most prevalent grade 2 complications in more than 10% of patients were constipation, fatigue, dizziness or lightheadedness, change in consciousness, dyspnea as well as sensory neuropathy. Hot flashes occurred frequently in both arms but were probably secondary to the previous GnRH-A therapy. The grade 3 hematological toxicities were mild in the thalidomide arm. Only 3 patients had grade 3 neutropenia and another patient had grade 3 leukopenia. Of the nonhematological toxicities the most common grade 3 toxicities occurring in the thalidomide arm included depressed level of consciousness, dyspnea, syncope and dizziness. Grade 3 cardiovascular events occurred mostly in the thalidomide arm and most of the grade 4 adverse events in the thalidomide arm were related to cardiac or thromboembolic events with an incidence of less than 2%. Pharmacokinetics of Thalidomide The mean steady state plasma concentration of thalidomide was 352.9 ± 219.5 ng/ml. There was no apparent correlation between plasma concentration of thalidomide and time to progression (r2 = 0.05). Androgen Concentrations Of the 159 patients on study 129 had evaluable T concentrations. Median baseline value before OPA was 311.5 ng/dl (range 10 to 1,000) and median baseline value before OPB was 326 ng/dl (range 20 to 1,400). There were 17 and 14 patients in OPA and OPB, respectively, who had low baseline T levels before starting GnRH-A (defined as T concentrations less than 212 ng/dl). During OPA the median time to T normalization was 15.4 weeks and to DHT normalization was 15.2 weeks. Time to T and DHT normalization was defined as time from the second 3-month depot of GnRH-A until normal values of T (212 ng/dl) or DHT (150 pg/ml) were reached minus 12 weeks. Analysis of the secondary T end points of this study has been previously reported.13, 14 There was no difference during OPA between the median time to serum T normalization in the thalidomide group (14.5 weeks) vs the placebo group (16.7 weeks, p = 0.20) while the median time to serum DHT normalization in the thalidomide group was 15.2 vs 14.8 weeks in the placebo group (p = 0.31). There were 85 patients who had evaluable T concentrations in OPB. During OPB the median time to serum T normalization was 18.3 weeks while time to DHT normalization was 18.7 weeks. Similar to OPA thalidomide did not affect time to serum normalization of T with a median of 18.0 weeks vs 19.2 for placebo (p = 0.70). Patients who had low baseline T concentrations had similar progression-free survival times compared to those with normal T concentrations in OPA (10 months for the low T group and 11.8 months for the normal T group, p = 0.57) and OPB (14.4 months for the low T group and 8.7 months for the normal T group, p = 0.37). Discussion In 1994 researchers in the laboratory of Dr. Judah Folkman found that thalidomide, an agent originally synthesized in 1954 and used as a sedative until it was linked to more than 10,000 infants with severe malformation, had antiangiogenic activity. Based on those preclinical observations we conducted several studies using monotherapy or combining thalidomide with chemotherapy in patients with metastatic CRPC. A phase II trial combined docetaxel with or without thalidomide (50 and 25, respectively) in patients with metastatic CRPC,9 and demonstrated that the addition of thalidomide to docetaxel resulted in an encouraging overall median survival rate for patients in the combination arm (docetaxel plus thalidomide 25.9 months vs docetaxel alone 14.7 months, p = 0.0407).15 This clinical trial indicated that thalidomide may have a role in treatment of prostate cancer beyond the well documented activity in multiple myeloma. Intermittent ADT is increasingly being used in patients with biochemical recurrence. Although the efficacy of applying immediate ADT in those with biochemical recurrence, compared to deferring therapy until the emergence of metastatic disease, is a subject of ongoing controversy, there may be a role for instituting early treatment.16 The increasing use of ADT is based on studies suggesting clinical benefit in patients with early stage prostate cancer treated earlier with ADT compared to those receiving it later in the disease course.17, 18 It is postulated that the efficacy of antiangiogenic agents such as thalidomide will be greatest in the setting of minimal disease burden. Patients found to have an increasing PSA after definitive therapy for prostate cancer as their only evidence of disease are believed to have a minimal disease state. The presence of hormone responsive disease also implies a better prognosis than for those who do not respond to androgen ablation. Therefore, it is in this setting that we proposed to evaluate the clinical efficacy of thalidomide. The results of this trial support this hypothesis. Although time to PSA based progression was not significantly different during OPA, time to PSA progression was substantially longer during OPB at 17.1 months vs only 6.6 for patients on the placebo arm (p = 0.0002). This finding is independent of the effects on T normalization brought about by intermittent androgen deprivation therapy since thalidomide had no apparent effects on T normalization by itself. In addition, there were no apparent differences between PFS times in patients with low T compared to those with normal T concentrations in OPA or OPB, suggesting that the observed effects were not due to any baseline variation or recovery of T concentrations. The results seen during the first course of GnRH-A could be postulated to occur secondary to the natural history of hormone sensitive disease, when the majority of patients would respond well to ADT regardless of any additional further therapy. Therefore, the benefit of thalidomide may not be readily apparent in this setting. However, in OPB the possible emergence of castration resistance, coupled with a therapy such as thalidomide that is perhaps most effective when disease burden is low, provides the rationale for the observed prolongation of PSA based progression in men with biochemically recurrent prostate cancer. Although we did not reach the intended accrual goal, the trial was adequately powered to detect a reasonably large difference in PSA progression between thalidomide vs placebo in OPB. However, the possibility that these results were observed because of a limited sample size cannot be excluded. Biochemical recurrence is a challenging disease state in which true or surrogate end points are difficult to characterize. PSA based progression may be a surrogate end point in this population of patients and may translate to overall clinical benefit.19 These results have implications not only for this disease state in general but also for clinical trial design, where agents that would have modest activity as monotherapy such as thalidomide may have a more pronounced effect in early disease states such as that which we observed here after intermittent hormonal therapy. Intermittent ADT is increasingly used and provides certain advantages compared to continuous ADT. Administering hormonal therapy intermittently may obviate the potential long-term effects of ADT and improve cost benefits. However, given the deleterious effects of ADT and possible long natural history of biochemical recurrence before evidence of metastatic disease, it is essential to weigh the risks and benefits of commencing ADT as well as the potential additive side effects of thalidomide.20 Conclusions Thalidomide is associated with an increase in PSA progression-free survival in men with biochemically recurrent prostate cancer after intermittent GnRH-A. These effects were independent of any effects on testosterone. Larger studies with longer followup are warranted to determine the clinical usefulness of this approach. Acknowledgments Drs. Mike Hamilton, Leonard Siegel, Hikaru Nakajima, Jon L. Hopkins, Howard Streicher, David Kohler, Jim Pluda, Ulka Vaishampayan, Joseph Fontana and Eddie Reed; and nurses David Draper, Mary Lewis, Alisa Trout, Debbie Lifsey, Jane Carter, Kathy Fedenko, Cathy Parker and Lea Latham contributed to the trial. 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a Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland b Molecular Pharmacology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland c Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland d Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland e Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland f Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland g Departments of Internal Medicine and Urology, University of Michigan Medical Center, Ann Arbor, and Department of Medical Oncology, Wayne State University/Barbara Ann Karmanos Cancer Institute, Detroit, Michigan h Department of Medicine, New York-Presbyterian Hospital/Columbia University Medical Center, New York, New York i Departments of Medicine and Urology, University of Washington, Seattle, Washington j Department of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania k Tulane Medical School, New Orleans, Louisiana  Correspondence: Medical Oncology Branch, National Cancer Institute, Bldg 10/Room 5A01, 9000 Rockville Pike, Bethesda, Maryland 20892 (telephone: 301-402-3623; FAX: 301-402-8606)
Supported by the Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research. Study received institutional review board approval. For other articles on related topics see pages 1361, 1372 and 1381. PII: S0022-5347(08)03053-X doi:10.1016/j.juro.2008.11.026 © 2009 American Urological Association. Published by Elsevier Inc. All rights reserved. | |
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