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© 2001 American Society for Clinical Oncology Flutamide Versus Prednisone in Patients With Prostate Cancer Symptomatically Progressing After Androgen-Ablative Therapy: A Phase III Study of the European Organization for Research and Treatment of Cancer Genitourinary GroupFrom the Department of Medical Oncology and Radiotherapy, Norwegian Radium Hospital, Oslo, Norway; St Antonius Hospital, Nieuwegein, and Netherlands Cancer Hospital, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands; San Raffaele, Milan, Italy; Freeman Hospital, Newcastle, and Princess Royal Hospital, Hull, United Kingdom; and European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium. Address reprint requests to Sophie D. Fosså, MD, Department of Oncology, Norwegian Radium Hospital, Ullernchausseen 70, 0310 Olso, Norway; email s.d.fossa{at}klinmed.uio.no
PURPOSE: Time to progression (TTP), overall survival, and quality of life (QL) were compared in patients with hormone-resistant prostate cancer (HRPC) treated with prednisone (5 mg orally, four times a day) or flutamide (250 mg orally, three times a day).
PATIENTS AND METHODS: Symptomatic patients were randomized to receive either prednisone (101 patients) or flutamide (100 patients). Subjective response was assessed based on performance status, the use of analgesics, and the need to apply alternative palliative treatment. Prostate-specific antigen (PSA)–based biochemical response ( RESULTS: There was no difference between the groups in median TTP (prednisone, 3.4 months; flutamide, 2.3 months) or overall survival (prednisone, 10.6 months; flutamide, 11.2 months). In the prednisone group, 56% of the patients experienced a subjective response, compared with 45% in the flutamide group (P = .18). The median response duration was 4.8 months for prednisone and 4.2 months for flutamide. A biochemical response was observed in 21% and 23% of the prednisone and flutamide groups, respectively. Gastrointestinal toxicity was the reason for trial discontinuation in seven patients receiving flutamide and two patients receiving prednisone. The QL assessment parameters favored the use of prednisone with statistically significant differences in pain, fatigue, role functioning, appetite loss, gastrointestinal distress, and overall QL. CONCLUSION: In symptomatic HRPC, treatment with prednisone or flutamide leads to similar rates of TTP and overall survival and no difference in subjective or biochemical response. The QL results favor the use of low-cost prednisone in patients with HRPC.
APPROXIMATELY 70% to 80% of patients with advanced prostate cancer respond initially or remain stable when treated by medical or surgical castration, but in 20% to 30% of the patients, the malignancy progresses despite primary androgen deprivation. In addition, disease will progress in 60% to 80% of the responding patients during the first 3 years after the start of treatment.1-3 In a recent meta-analysis, the addition of an antiandrogen to initial androgen suppression (total androgen blockade [TAB]) was shown to have a limited effect, if any at all.4 If the malignancy progresses despite androgen ablation after castration, three biologically different subgroups of hormone-resistant prostate cancer (HRPC) can be identified.
In the individual patient with HRPC, most often a mixture of these three cell populations is present in unknown proportions. Patients with prostate cancer who progress after primary androgen deprivation present with increasing somatic and psychologic distress, including pain due to bone metastases, anemia, and fatigue. Ten percent to 20% of the patients develop micturition problems caused by a growing primary tumor. Radiotherapy and analgesics can relieve local symptoms, but effective systemic therapies are needed to slow down or reverse the progressive development of the malignancy. Several end points can be considered during the treatment of HRPC: overall survival, time to progression (TTP), objective response, physician-assessed subjective response, and quality of life (QL). The evaluation of objective response according to the World Health Organization (WHO) criteria5 is problematic because only 10% to 20% of the patients have easily measurable metastatic lesions. Objective response based on assessment of bone scans is also difficult due to frequent interobserver and interexamination variation.6 Relief of metastatic bone pain and improvement of the patient’s general condition are the most important parameters of subjective response in patients with HRPC and should be recorded routinely. During recent years, patient-based monitoring of QL has been introduced into clinical oncology, and appropriate questionnaires have been developed.7 Biochemical response based on measurements of serum prostate-specific antigen (PSA) should be monitored as a separate entity. A recent consensus meeting has published guidelines for the evaluation of PSA-based response, thereby enabling more uniform reporting of observed changes.8 In addition to the above methodologic problems, trials of chemotherapy to treat HRPC have been hampered by relatively frequent toxicity problems in the elderly prostate cancer patients who often present with major comorbidity. In this situation, it seems reasonable to influence the disease with hormones as long as possible, because hormonal manipulation is easily applied and has limited toxicity. Surgical and medical adrenalectomy, the latter by hydrocortisone or prednisone, has been used in the treatment of HRPC for many years9,10 to suppress the adrenal production of androstenedione and dehydroepiandrosterone. Up to the early 1990s, however, only a few well-designed phase II or III studies were published that evaluated medical adrenalectomy in HRPC. Flutamide exhibits antiandrogenic effects by binding to the cellular androgen receptors and thus reducing the cell’s androgen uptake. This drug has been used extensively in previously untreated patients, as a part of TAB or as monotherapy.1,3,11 In limited series, flutamide has also been evaluated in the treatment of HRPC, with subjective response rates of 15% to 30%.12,13 In 1990, the European Organization for Research and Treatment of Cancer (EORTC) Genitourinary Group initiated a phase III study to compare the effectiveness of prednisone and flutamide as secondary hormone manipulation in patients with metastatic HRPC. At that time, the expectation was that flutamide would be more effective than prednisone because of its specific activity in the cancer cell. The present report represents the final analysis of this study.
Patients with histologically confirmed prostate cancer were eligible for the trial if they fulfilled the following criteria: (1) presence of symptomatic metastatic disease that had progressed after medical castration with luteinizing hormone-releasing hormone (LHRH) analogs (not estrogens) or bilateral orchiectomy. The pretrial serum testosterone level had to be within the range of the institution’s castration levels. In the present study, symptomatic disease implied cancer-induced deterioration of the patient’s general condition and/or painful, progressive metastatic disease with or without the use of analgesics, with or without complete pain relief; (2) WHO performance status of 0 to 3; (3) no previous use of prednisone, flutamide, or any other oral antiandrogen, but patients were eligible if they had received an antiandrogen transiently (for a maximum of 4 weeks) during their LHRH treatment in order to prevent a flare reaction; (4) no previous systemic anticancer treatment, except the above primary hormonal manipulation; and (5) certainty of clinical disease progression after prior surgery or previous radiotherapy. The patients were not allowed to receive radiotherapy at the time of trial entry. Patients with a second primary tumor (except basal cell skin cancer), serious cardiovascular problems, or insulin-dependent diabetes mellitus were ineligible for the trial, as were those who were unable to comply with regular follow-up. The trial was approved by the institutions’ local ethical committee, and patients provided written informed consent before randomization. The trial was open for patient entry from January 1992 to March 1998. In October 1995, an independent data-monitoring committee approved continuation of the trial without modification. At the time of the present analysis, the median follow-up was 330 days.
Trial Design All patients were examined for acute toxicity 3 weeks after trial entry. Response was evaluated at 6-week intervals from the start of treatment. Patients had to remain in the trial for at least 6 weeks to be assessable for response. They were otherwise included in the analysis as "non-assessable." Patients who progressed during the first 6 weeks were included in the progression category. Patients remained on the trial until subjective progression or unacceptable toxicity was recorded or until they wished to discontinue participation for any reason. Therapeutic interventions in patients who had gone off protocol treatment were chosen by the individual clinical investigator. All patients were followed until death.
At trial entry and at each follow-up visit, patients underwent a clinical examination, including assessment of pain using a five-point scale (level 0, analgesics not required; level 1, nonnarcotic analgesics occasionally required; level 2, nonnarcotic analgesics regularly required; level 3, oral or parenteral narcotic analgesics occasionally required; level 4, oral or parenteral narcotic analgesics regularly required). Types and doses of the prescribed analgesics were recorded. A chest x-ray and radioisotope bone scan were mandatory; other radiologic examinations were optional. "Superscan" was defined as Blood samples were taken for analysis of hemoglobin, WBC count, and thrombocytes, together with the determination of PSA, alkaline phosphatase, creatinine, liver enzyme, and testosterone levels. Clinical examinations and blood tests were repeated at each follow-up visit. Patients’ performance status, weight, and degree of vomiting and diarrhea were recorded using the WHO criteria for toxicity.5 The performance of other tests was left to the discretion of the clinical investigator.
Quality of Life At trial entry and at each follow-up visit, patients were asked to complete the EORTC Quality of Life Questionnaire (QLQ) C-30 (version 1.0).7 The QLQ C-30 is a 30-item questionnaire that was developed to assess a range of physical, emotional, and social health issues relevant to a broad spectrum of cancer patients. It has been shown to be reliable and valid in a wide range of patient populations and treatment settings and is currently being used in a large number of oncology clinical trials. The questions are organized into a number of multi-item scales and single-item symptom measures (five functioning scales [physical, role, cognitive, emotional, and social], three symptom scales [fatigue, nausea and vomiting, and pain], and six single items [assessing dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact]). The last two questions ask patients to rate their overall health and QL. The QLQ C-30 was supplemented by three questions pertaining to analgesic use (Did you take any medication for pain? If so, how much did it help? Have you had pain despite the use of analgesics?). All scales and single-item measures were linearly transformed to a 0 to 100 scale.14 For the functioning scales and the global QL scale, a higher score represents a higher level of functioning/QL; for the symptom measures, a higher score corresponds to a greater degree of symptoms.
Response Criteria
Response.
At least one of the following three conditions had to be fulfilled: (1) reduction of the pain score (WHO criteria) by at least one level, with no deterioration of performance status; (2) unchanged pain level and reduction of the prescribed daily dose of analgesics by at least 25% as compared with the pretreatment situation, with no deterioration of performance status; and (3) improvement of the WHO performance status by at least one level without either an increase of the daily dose of analgesics by No change. "No change" was defined as an unchanged pain score, with less than a 25% reduction in the prescribed daily analgesic dose as compared with the pretreatment situation, and unchanged performance status. Progression. Progression was evaluated relative to the best condition, observed at start of treatment or obtained during treatment. Progression was determined to have occurred if patients met at least one of the following conditions: increase of the pain score by at least one level, increase of the daily analgesic dose by at least 25%, any need to give additional pain treatment, such as radiotherapy, and WHO performance status deterioration by at least one level.
Duration of subjective response was calculated from trial entry to the date of progression. Biochemical response was defined as a decrease of the serum PSA level by
Statistics Given an anticipated median survival time of 8 to 10 months (based on the published literature on HRPC) and the number of available observations at each subsequent assessment point, the QL analysis was restricted to the 6-month period following entry onto the study. Means and confidence intervals were calculated for the QL scores of both treatment groups at each assessment point, yielding a series of descriptive profiles that could be displayed in graphic form. In order to adjust for multiple comparisons over time, 99% confidence intervals were calculated to maintain an overall 95% confidence interval for each QL outcome. A linear mixed model analysis of variance was used that accounts for serial correlations between observations, as well as for intermittent missing forms. The main effects of treatment and time were tested on a reduced model (without an interaction term) whenever the interaction effect was found not to be statistically significant. The intention-to-treat principle was followed in all statistical analysis (ie, including ineligible and nonassessable patients in the analysis and considering patients in the treatment group they were allocated to by randomization).
Patients A total of 201 patients were randomized to receive prednisone (101 patients) or flutamide (100 patients, Table 1). Presumed prognostic factors and comorbidities were equally distributed between the two treatment groups (P > .05). Almost all patients used analgesics, with approximately 25% regularly using narcotics for pain level 4. The median number of hot spots on bone scans was 12 in both groups, and approximately 25% of the patients displayed superscans. The initial PSA level was elevated to more than 100 times the upper limit of the normal range in 29% of the P-group patients and 24% of the F-group patients.
Two patients in each group were finally deemed to be ineligible (prior treatment with prednisone, 1; no metastases at trial entry, 1; palliative radiotherapy at the time of randomization, 1; testosterone level above the castration range, 1).
Treatment Compliance and Side Effects
No grade 3 or grade 4 leukopenia or thrombocytopenia was observed, except in one patient in the F group. This patient developed grade 4 thrombocytopenia, which most probably was related to disease progression. There was no difference between the two groups in liver function during the trial period.
Response
A biochemical response was observed in 21% of the patients in the P group and 23% of patients in the F group. Responding patients from the P group had significantly higher baseline PSA values than those from the F group (Table 4). In nine of the patients in the P group and 10 in the F group, the  50% PSA reduction was confirmed after 4 weeks. Both subjective and biochemical responses were available in 180 patients.
When both groups were combined, there was a significant association between PSA response at any time and subjective response at any time (Table 5) (P < .001). However, 33% of the patients had a subjective response without a biochemical response, and 5% of the patients had 50% decrease from baseline PSA without a subjective response. Most often, subjective responses preceded biochemical responses or were recorded simultaneously with biochemical responses. In only 18% of the available cases was a subjective response observed after a biochemical response had been reported.
QL At baseline, QLQ C-30 data were available for 90% of patients in both treatment arms. Patients without baseline QL data were excluded from further serial analyses. During the subsequent 24-week period, compliance with QL assessment decreased to approximately 70%, equally in both arms (Table 6). Progression of the disease and/or death was the main reason for noncompliance in both arms.
Overall, scores on the functioning scales tended to decline just before dropout, whereas scores on the symptom scales tended to increase, indicating a nonrandom pattern of missing data. This held for both treatment arms of the trial. The pattern of QL scores over time for the P group and F group are presented graphically in Figures 1 and 2. Statistically significant treatment effects favoring the P group were noted for pain (P < .005), nausea and vomiting (P < .001), and diarrhea (P < .001). Patients receiving prednisone reported significantly less constipation (data not shown), probably as a result of having used less narcotic analgesics. In addition, as compared with the F group, the P group reported significantly less fatigue at 6 weeks (P < .05) and significantly better role functioning (P < .01) and less appetite loss (P < .01) at 3 months. Because there was a trend for a significant group difference in overall QL at baseline, change scores were used to evaluate group differences in overall QL over time. The results indicated a statistically signi-ficant treatment effect over time that favored the P group (P < .01). This difference in overall QL was observed primarily from week 3 to week 12.
Survival At the time of the analysis, four patients from the P group and five patients from the F group were still alive. There was no difference in TTP or overall survival between the two groups, with the respective median duration times of 3.4 and 10.6 months in the P group and 2.3 and 11.2 months in the F group (Table 3 and Fig 3).
When both groups were combined, a biochemical response was associated with a hazards ratio of 0.42 for the risk of death (95% confidence interval, 0.29 to 0.60; P = .0001) ie, the risk of death for patients with a biochemical response was 0.42 that of patients without. The comparable figure for the association between subjective response and risk of death was 0.55 (95% confidence interval, 0.41 to 0.75; P = .0001).
In the late 1980s, the blockade of adrenal hormone production was a valid option in the treatment of HRPC by the application of corticosteroids (hydrocortisone or prednisone) with or without aminoglutethimide.9,10,16-20 Monotherapy with prednisone or hydrocortisone leads to the reduction of adrenal androgens, at least in a subgroup of patients.9 Responses are more likely to occur in patients with reduced amounts of adrenal androgens. The present study was planned with the knowledge of this adrenosuppressive effect of prednisone. In addition, low doses of corticosteroids have an unspecific, beneficial, anabolic, and fatigue-reducing effect.21 Due to its specific activity in the prostate cancer cell, flutamide was, in 1990, expected to be more effective than prednisone; investigators hoped that flutamide treatment would result in higher response rates and improved survival. Recent research, however, has shed some doubt on whether the application of oral antiandrogens is beneficial in all cases. Mutations of the androgen receptor(s) occur in the castrated patient.22 As a result, a prostate cancer cell may become sensitive to a stimulating effect of the oral antiandrogens. The "antiandrogen withdrawal effect"23 is observed in 20% to 30% of patients whose disease progresses during TAB. In HRPC, subjective relief is an important goal of treatment,24 and patients need to be assessed systematically. In this study, physician-evaluated subjective response was based on performance status and pain level (WHO criteria) combined with prescribed analgesic dosage. Progression also included the clinical parameter "need to start another major palliative treatment, as for example, radiotherapy." The use of analgesics was, however, not systematically monitored on a daily basis, which would be preferable with today’s standard. Furthermore, today one would rely more on a patient’s self-assessment of pain for the overall evaluation of subjective response. In the present study, patient-based QL assessment, including the patient’s evaluation of pain, was analyzed separately from physician-based subjective response. A further limitation of our response criteria is the lack of a defined minimum duration of pain relief, as used in other investigations. However, the post hoc inclusion of a minimum duration of subjective response of at least 6 weeks did not significantly alter the differences in response rates between the two trial arms. The validity of our criteria of subjective response is also supported by the statistical association between subjective and biochemical response. Biochemical response was defined retrospectively using the currently accepted cutoff point of 50% reduction from the baseline value.8,9 Such PSA reduction has previously15 and in the current study been shown to be associated with increased survival and (weakly) with subjective response. In general, however, one has to be reluctant to claim a life-prolonging treatment effect if responding patients survive longer than nonresponding patients. More research is needed to understand the biologic significance of PSA reduction.
Our biochemical response rates of 22% and 23% for the P and F groups, respectively, are below those to be expected if hormone treatment is combined with chemotherapy (see Oh and Kantoff25 for review) but are consistent with the observations of Kantoff et al19 and Tannock et al.20 In general, hormonal manipulation alone in patients whose disease progresses despite androgen ablation leads to PSA reduction of Approximately half of our patients experienced a subjective response. This was observed more often in the P group than in the F group. Our subjective response rate was higher than that reported by Tannock et al20 for prednisone monotherapy. This is most probably due to the different definitions of subjective response. Our higher response rate in the P group may, however, also be related to the higher dose of prednisone in the current trial (20 mg/d v 10 mg/d in the study by Tannock et al). The duration of subjective response in patients receiving prednisone was about 4 months, which is in agreement with the Canadian experience. As for the duration of response, the combination of prednisone and mitoxantrone seems to be superior (the median response duration for the combined arm was 10 months in the study from Tannock et al). The study from Kantoff et al19 also favored the use of the hydrocortisone–chemotherapy combination, due to a prolonged time to progression. As the dropout from QL assessment was related to deterioration of the patients’ health, the observed QL results are probably too optimistic. However, this bias seemed to be present to the same degree in both treatment arms, justifying treatment comparisons. Overall, during the trial period, patients in the F group were more symptomatic and had inferior QL compared with patients from the P group. In particular, prednisone was superior to flutamide in terms of pain and fatigue recorded at 3 months and also when evaluated during the total trial period. Pain, fatigue, and reduced physical function have previously been shown to be the most frequent complaints in patients with HRPC,24 and thus improvement in these dimensions should represent an important treatment goal. In addition, gastrointestinal (GI) distress was more frequent in the F group than in the P group, in agreement with the physician-recorded side effects. Although both treatments were generally well tolerated by the majority of patients, clinical side effects alone led to the discontinuation of the trial drug in 5% of the patients, distributed equally in both arms. As expected, GI toxicity dominated in the F arm, especially, as has been described in a recent trial, when flutamide treatment was a part of the initial TAB.26 These adverse GI effects probably contributed to impaired QL. Not surprisingly, prednisone (20 mg/d) increased the risk of peptic ulcer and cardiovascular disorders. Patients receiving prednisone or flutamide should thus be kept on a regular clinical follow-up schedule for early intervention in case of clinical toxicity. The present trial included average, ambulatory patients with symptomatic HRPC treated at urologic and oncologic units in Europe during the last decade. The series is comparable to that of Tannock et al20 and many other phase III series.13,19,27,28 Therefore, it is not surprising that the median overall survival time of 8 to 10 months is similar in all of these series. Indeed, Iversen et al obtained comparable survival times in 68 patients receiving placebo. Despite subjective and biochemical responses induced by secondary hormonal or cytotoxic treatment, the efficacy of current therapeutic options is too low to increase the survival rates of HRPC patients. This is probably related to the considerable inter- and intrapatient heterogeneity of the cell population. Furthermore, the prostate cancer cells that are responsible for biochemical or subjective responses might not be those which determine the patient’s death. To improve the treatment results, two approaches can be combined: (1) development of more effective systemic treatment and (2) beginning treatment as early as possible. Tumor biologic considerations favor treatment of micrometastasis rather than macroscopically established tumors. However, it is outside the scope of the present trial to decide whether hormone manipulation, chemotherapy, or both would represent the optimal management in earlier phases of HRPC.
In conclusion, in patients with symptomatic, metastatic HRPC, prednisone 5 mg orally four times a day is superior to flutamide 250 mg orally three times a day with regard to important patient-assessed QL parameters (pain, fatigue, and global QL). Prednisone increases the risk of cardiovascular disorders and peptic ulcer, whereas intolerable GI toxicity may develop in patients receiving flutamide. No difference was seen between the two drugs when physician-assessed subjective response was used (observed in 56% and 45% of the patients in the P and F groups, respectively). During the trial period, PSA levels decreased by
Supported by grants no. 5U10 CA11488-11 through 5U10 CA11488-29 from the National Cancer Institute, Bethesda, MD.
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
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Bubley GJ, Carducci M, Dahut W, et al: Eligibility and response guidelines for phase ii clinical trials in androgen-independent prostate cancer: Recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 17: 3461-3467, 1999 9. Tannock I, Gospodarowicz M, Meakin W, et al: Treatment of metastatic prostatic cancer with low-dose prednisone: Evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol 7: 590-597, 1989[Abstract] 10. Plowman PN, Perry LA, Chard T: Androgen suppression by hydrocortisone without aminoglutethimide in orchiectomised men with prostatic cancer. Br J Urol 59: 255-257, 1987[Medline] 11. Boccon GL: Nonsteroidal antiandrogen monotherapy of metastatic cancer of the prostate. Eur Urol 24: 77-80, 1993 (suppl 2) 12. Labrie F, Dupont A, Giguere M, et al: Benefits of combination therapy with flutamide in patients relapsing after castration. Br J Urol 61: 341-346, 1988[Medline] 13. de-Kernion JN, Murphy GP, Priore R: Comparison of flutamide and Emcyt in hormone-refractory metastatic prostatic cancer. Urology 31: 312-317, 1988[Medline] 14. EORTC Study Group on Quality of Life: EORTC QLQ-C30 Scoring Manual. Brussels, Belgium, European Organization for Research and Treatment of Cancer, 1995 15. Kelly WK, Scher HI, Mazumdar M, et al: Prostate-specific antigen as a measure of disease outcome in metastatic hormone-refractory prostate cancer. J Clin Oncol 11: 607-615, 1993[Abstract] 16. Samojlik E, Lippman AJ, Kirschner MA, et al: Medical adrenalectomy for advanced prostatic cancer: Clinical and hormonal effects. Am J Clin Oncol 11: 579-585, 1988[Medline] 17. Harnett PR, Raghavan D, Caterson I, et al: Aminoglutethimide in advanced prostatic carcinoma. Br J Urol 59: 323-327, 1987[Medline] 18. Dawson NA, Cooper MR, Figg WD, et al: Antitumor activity of suramin in hormone-refractory prostate cancer controlling for hydrocortisone treatment and flutamide withdrawal as potentially confounding variables. Cancer 76: 453-462, 1995[Medline]
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Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: A Canadian randomized trial with palliative end points. J Clin Oncol 14: 1756-1764, 1996 21. Cleare AJ, Heap E, Malhi GS, et al: Low-dose hydrocortisone in chronic fatigue syndrome: A randomised crossover trial. Lancet 353: 455-458, 1999[Medline]
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Taplin ME, Bubley GJ, Shuster TD, et al: Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med 332: 1393-1398, 1995 23. Kelly WK, Scher HI: Prostate specific antigen decline after antiandrogen withdrawal: The flutamide withdrawal syndrome. J Urol 149: 607-609, 1993[Medline] 24. Fossa SD, Aaronson N, Calais-da SF, et al: Quality of life in patients with muscle-infiltrating bladder cancer and hormone-resistant prostatic cancer. Eur Urol 16: 335-339, 1989[Medline] 25. Oh WK, Kantoff PW: Management of hormone refractory prostate cancer: Current standards and future prospects. J Urol 160: 1220-1229, 1998[Medline] 26. Schellhammer PF, Sharifi R, Block NL, et al: Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: Final report of a double-blind, randomized, multicenter trial—Casodex Combination Study Group. Urology 50: 330-336, 1997[Medline] 27. Iversen P, Rasmussen F, Asmussen C, et al: Estramustine phosphate versus placebo as second line treatment after orchiectomy in patients with metastatic prostate cancer: DAPROCA study 9002—Danish Prostatic Cancer Group. J Urol 157: 929-934, 1997[Medline] 28. Newling DW, Fossa S, Tunn U, et al: Comparison of the effects of high dose estramustine phosphate and mitomycin C on the time to progression and length of survival of patients with progressive, advanced endocrine-independent prostatic cancer: An interim analysis of EORTC-GU Group study no. 30865. J Steroid Biochem Mol Biol 37: 971-975, 1990[Medline] Submitted March 24, 2000; accepted July 17, 2000. This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
