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Weekly administration of docetaxel for symptomatic metastatic hormone-refractory prostate carcinoma
Evaluation of clinical benefit, quality of life, and tolerance
Article first published online: 17 SEP 2003
Copyright © 2003 American Cancer Society
Volume 98, Issue 8, pages 1627–1634, 15 October 2003
How to Cite
Gravis, G., Bladou, F., Salem, N., Macquart-Moulin, G., Serment, G., Camerlo, J., Genre, D., Bardou, V.-J., Maraninchi, D. and Viens, P. (2003), Weekly administration of docetaxel for symptomatic metastatic hormone-refractory prostate carcinoma. Cancer, 98: 1627–1634. doi: 10.1002/cncr.11687
Fax: (011) 33 04 91 22 36 18
- Issue published online: 3 OCT 2003
- Article first published online: 17 SEP 2003
- Manuscript Accepted: 11 JUL 2003
- Manuscript Revised: 10 JUL 2003
- Manuscript Received: 17 APR 2003
- hormone-refractory prostate carcinoma
The current Phase II study investigated the clinical benefit, impact on quality of life (QOL), and tolerability of weekly docetaxel in symptomatic patients with metastatic hormone-refractory prostate carcinoma (HRPC).
Patients received weekly docetaxel 35 mg/m2 intravenously for 6 consecutive weeks followed by a 2-week rest repeatedly for a maximum of 24 weeks of treatment. Clinical benefit evaluations, based on Karnofsky performance status (KPS) and pain, were assessed weekly during therapy. A clinical benefit response was defined as a sustained (≥ 4-week) improvement in at least one of these parameters without worsening in the other. Patient-assessed QOL (using the European Organization for Research and Treatment of Cancer QLQ-C30), changes in prostate-specific antigen (PSA) levels, tumoral response, and toxicity also were evaluated.
Thirty men (median age, 67 years), 15 of whom had received previous chemotherapy, were treated. Overall, 46% of patients achieved a positive pain response and 48% achieved a 50%-or-greater reduction in PSA. KPS was high at baseline (80%), and no significant changes in this parameter were observed. Compared with baseline, all scores improved after the first cycle of therapy, particularly emotional (P = 0.015), pain (P = 0.001), constipation (P = 0.001), and global QOL (P = 0.011) scores. After the second cycle, dyspnea scores decreased (P = 0.010). At the last QOL assessment, there also was deterioration in terms of fatigue (P = 0.013), dyspnea (P = 0.010), and physical functioning (P = 0.017). Toxicity was mild and included neutropenia (Grade 3–4, n = 2).
Of these elderly symptomatic patients with HRPC, half had received previous chemotherapy. Weekly docetaxel was found to be associated with improvements in clinical benefit response and in QOL and was well tolerated. Cancer 2003. © 2003 American Cancer Society.
Prostate carcinoma is the most commonly diagnosed malignancy in American males and is the second leading cause of cancer-related death among men.1 Death occurs primarily due to metastatic disease in bone and pelvic lymph nodes. The standard initial treatment for metastatic disease is androgen ablation, which relieves symptoms. Although control of metastatic disease is obtained in most patients, nearly all will experience disease progression within 12–18 months. Secondary disease remission after additional hormonal therapy and/or antiandrogen withdrawal occurs less frequently, is usually of shorter duration, and does not significantly prolong survival.2
Treatment options for hormone-refractory prostate carcinoma (HRPC) are palliation and/or chemotherapy. The conventional approach of using palliative treatment alone has been driven primarily by the finding that patients with HRPC tend to be old and have comorbid conditions. Most have bone pain, profound asthenia, and anemia. Historically, responses obtained with chemotherapy in clinical trials of men with HRPC have been disappointing.3 This is most likely related to the small number of active agents available at the time and to the fact that most of these agents were evaluated in patients with end-stage disease. This finding, coupled with the toxicities of these older therapies, and the difficulties associated with assessing responses to chemotherapy have, in the past, made chemotherapy a less favorable option compared with palliative treatment alone. However, the development of new drugs with less toxic profiles; the use of prostate-specific antigen (PSA), a useful indicator of outcome in HRPC (posttherapy declines of 50% have been associated with prolonged survival); and the inclusion of new measures such as quality of life (QOL) assessments in clinical trials revealed the significant benefit associated with certain drugs previously considered to be ineffective in this setting. For example, the combination of mitoxantrone and prednisone, which produced a significant palliative response compared with corticosteroids alone in terms of pain score and analgesic consumption, is now widely approved for standard clinical use.4, 5 More recently, the taxoid docetaxel has been evaluated in men with HRPC and has demonstrated significant activity when administered alone or in combination with estramustine.6–8 Experience with the taxoids has shown that weekly administration of either paclitaxel or docetaxel at dosages lower than those used in standard every-3-week schedules can provide consistent antitumoral activity with a lower toxicity profile.9, 10
In treating HRPC, for which chemotherapy frequently is considered to be palliative, potentially less toxic taxoid regimens are attractive, provided that activity can be maintained. We therefore conducted a Phase II trial to evaluate the clinical benefit of weekly docetaxel and the impact of this regimen on HRPC-related symptoms, patient QOL, PSA response, tumor response, and toxicity profile. For this purpose, we adapted a clinical benefit scale that had been validated previously in the palliative setting of pancreatic carcinoma to make it specific for HRPC, and we associated this evaluation with sequential measurement of QOL.11, 12
MATERIALS AND METHODS
The current open-label study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the ethics committee of Marseille, France, and informed consent was obtained from all patients before enrollment.
Patients who had pathologically proven adenocarcinoma of the prostate with measurable or assessable tumors (radionuclide bone scan for bone metastases) that were refractory to primary hormonal therapy were eligible for inclusion. Patients also had to meet at least one of the following criteria: Karnofsky performance status (KPS) less than 80%, analgesic consumption of ≥ 10 mg/day of morphine equivalent; and a pain intensity score of 2 or higher assessed on a 10-point visual analog scale (VAS).11, 12 Patients also were required to have adequate major organ function.
Antiandrogen therapy was to be discontinued ≥ 4 weeks before enrollment. Continued evidence of disease progression was required after antiandrogen withdrawal. Before treatment, analgesic medication and pain were to be stabilized for 2–7 days. Patients with an elevated PSA level as the sole evidence of tumor progression were not eligible. Patients who had received radiotherapy, chemotherapy, or estramustine were required to have completed their last treatment ≥ 4 weeks before study entry.
Docetaxel (Aventis, Paris, France) was administered intravenously at 35 mg/m2 per day over 1 hour each week for 6 consecutive weeks with 2 weeks of rest, for a maximum of 4 cycles. Treatment was administered in the outpatient setting. Patients who did not have bilateral orchidectomy continued to receive testicular androgen suppression with a luteinizing hormone-releasing hormone agonist throughout the study. Premedication consisted of 8 mg oral dexamethasone 12 hours and 1 hour before, as well as 12 hours after, docetaxel infusion. If platelet or neutrophil counts decreased to less than 75,000 or 1000/μL, respectively, chemotherapy was discontinued until counts increased above these levels. If patients experienced febrile neutropenia, the subsequent dose of docetaxel was reduced by 25%. Granulocyte-colony-stimulating factor was not used. For other Grade 3–4 toxicities, treatment was stopped until resolution to Grade 2 or better, after which treatment was resumed, but with the dosage reduced by 25% for the rest of the therapy. Other reasons for discontinuation of treatment were hematologic or extrahematologic toxicity that persisted despite one omitted docetaxel dose, Grade 3–4 toxicity despite docetaxel dose reduction, patient request, and evidence of progressive disease.
Before treatment, patient's medical histories were recorded. Patients also underwent a physical examination and assessment of KPS, pain intensity (using a pain VAS),13 analgesic consumption, and QOL (Table 1).
|Week||Cycle 1||Cycle 2||Cycle 3||Cycle 4||End|
|Pain intensity (VAS)||xxxxxx||xxxxxx||xxxxxx||xxxxxx||x|
|Karnofsky performance status||******||******||******||******||*|
|Quality of life questionnaire (QLQ-C3014)||x||x||x||x||x|
|CT scans (measurable lesions)||x||x||x|
Clinical benefit was assessed using a combined measure of pain (pain intensity and analgesic consumption) and KPS (Fig. 1).11 Baseline was considered to be the first day of treatment. Pain intensity was assessed by the patient using a VAS. A positive response was defined as an improvement of ≥ 50% from baseline sustained for ≥ 4 weeks (assuming a minimum pain score ≥ 2). Analgesic consumption was measured in morphine-equivalent milligrams. A positive response was defined as a decrease of ≥ 50% from baseline sustained for ≥ 4 weeks (assuming a minimum analgesic consumption ≥ 10 mg/day). Improvement in KPS was defined as a ≥ 20% increase from baseline sustained for ≥ 4 weeks (for patients with a KPS of 50-60-70).
A clinical benefit response required a sustained (i.e., ≥ 4 weeks long) improvement in at least 1 parameter (pain, KPS) without worsening in any others. To be evaluable for clinical benefit, patients need to receive ≥ 4 consecutive weeks of treatment.
Quality of Life
Health-related QOL was assessed before the start of treatment, on the first day of each treatment cycle, and 15–30 days after study completion using a French-language validated translation of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 core questionnaire (Version 3).14, 15 This 30-item questionnaire is cancer-specific and has been validated for prostate carcinoma.16 Authorization for its use was obtained from the EORTC Quality-of-Life Study Group (Brussels, Belgium).
Tumor and PSA Response
PSA levels were measured before treatment, before each cycle, and at the end of treatment. A PSA response was defined as a reduction from baseline of ≥ 50% on 2 consecutive measurements taken at least 2 weeks apart. Progression was defined as 2 consecutive increases in serum PSA taken at least 2 weeks apart.17 The durations of 50% decreases in PSA and of PSA normalization were calculated from the time of PSA decrease to the date of the first PSA progression.
For patients with bidimensionally measurable disease, a complete response (CR) was defined as the resolution of bidimensionally measurable masses and a partial response (PR) was defined as a ≥ 50% reduction. Confirmation of a CR or a PR with a second computed tomography scan was required.
Toxicity was assessed every week during chemotherapy using the National Cancer Institute Common Toxicity Scale. Patients were considered evaluable for toxicity after one administered dose of chemotherapy.
The current Phase II study was designed to test the hypothesis that the clinical benefit response with docetaxel was ≥ 30% for 84% of the patients (beta = 0.16). Statistical design was based on a 3-step Fleming plan with a 0.03 global alpha value.18 Analyses were scheduled after 10, 20, and 30 patients (final analysis) were evaluable for clinical benefit response. A trial was closed early if a clinical benefit response was observed in ≤ 2 of 20 patients or in ≤ 6 of 30 patients; such results indicated that treatment was not effective.
Survival was calculated from the date of enrollment. Disease-related death was scored as an event. Patients still alive at the time of last follow-up were censored. Survival rates were derived from Kaplan-Meier estimates.
QOL data were analyzed using nonparametric tests based on ordinal measures (answers to items on the EORTC QLQ-C30 were obtained using Likert scales) and the nonnormality of distributions to limit assumptions and maintain consistency. No adjustment of P values for multiple testing was made.
Between October 1999 and September 2001, 30 patients with a median age 67 years (range, 52–83 years) and a median KPS of 80% entered the study. All were evaluable for toxicity, and 28 were fully evaluable for clinical benefit. Two patients were not evaluable for clinical benefit (one discontinued treatment at his own request after 2 weeks; the other discontinued treatment because of ischemic pain that was unrelated to metastatic prostate carcinoma). Baseline characteristics of the 30 patients enrolled in the study are described in Table 2.
|No. of patients||30|
|Age (yrs)||67 (52–83)|
|Karnofsky performance status||80 (70–90)|
|Pain intensity (10-point VAS)||4 (2–7)|
|Morphine consumption (mg/day)||360 (40–11,550)|
|Quality of life score (assessed by EORTC QLQ-C3014)||50 (33–83)|
|PSA (ng/mL)||73 (1–895)|
|Sites of metastases (no. [%] of patients)|
|Bone and lymph nodes||6 (20.0)|
|Bone and visceral||5 (16.7)|
|Previous radiotherapy (no. [%] of patients)||20 (66.7)|
|Previous chemotherapy (no. [%] of patients)|
|LDH (U/L)||285 (115–1937)|
|Hemoglobin (g/dL)||13 (8–18)|
|Alkaline phosphatase (U/L)||222 (63–2570)|
Thirteen patients completed all 24 weeks of treatment program. The median duration of treatment was 18 weeks (range, 2–24 weeks). The total dose of docetaxel administered was 840 mg/m2, and the median dose per patient was 595 mg/m2 (range, 70–840 mg/m2). Treatment was discontinued because of toxicity for 2 patients (Grade 4 mucositis [n = 1] and Grade 4 neutropenia [n = 1]), disease progression for 10 patients, and patient request for 5 patients.
Of the 28 evaluable patients, 46% had a positive response in the pain category (Table 3). Therefore, clinical benefit was achieved in 46% of evaluable patients. The median time to achieve a clinical benefit was 4 weeks, and the median duration of clinical benefit was 14 weeks (range, 5–229 weeks). No difference in clinical benefit response was observed between patients who did and did not receive prior chemotherapy. There was a trend toward an association between PSA response and clinical benefit (chi-square P = 0.050): 69% of PSA responders had a clinical benefit.
|Karnofsky performance status (%)||80 (70–90)||80 (70–90)||80 (70–90)||80 (70–90)||80 (50–80)|
|Pain intensity (VAS points)||3.5 (2–7)||2 (0–4)||2.5 (0–4)||2 (0–5)||3 (0–8)|
|Morphine consumption (mg/day)||360 (40–11,550)||135 (0–2696)||300 (0–2016)||600 (0–1736)||128 (0–12,700)|
|Quality of life according to EORTC QLQ-C3014 (100-point scale)||50 (33–83)||58 (17–75)||50 (8–83)||58 (33–83)||50 (17–83)|
|Prostate-specific antigen (ng/mL)||73 (1–895)||27 (2–875)||30 (2–609)||60 (3–433)||45 (2–421)|
Quality of Life
Patient compliance with QOL questionnaires was high (94%). Patient QOL was somewhat deteriorated at baseline. Mean scores for role, social functioning, and global QOL were less than 60 (on a 100-point scale). At baseline, 31.0% of men had difficulty performing their occupational activity or daily tasks, 28.6% reported difficulties in their family lives, and 35.8% had difficulties in their social lives. Overall, 65.5% of patients reported pain. The other most troublesome symptoms were fatigue (mean score, 48) and constipation (mean score, 40). Patients treated with analgesics exhibited higher role functioning (P = 0.046) and global QOL (P = 0.022) scores at baseline than did patients who did not receive these agents. No other relations were found between baseline QLQ-C30 scores and any of the other patient characteristics assessed at baseline.
Compared with baseline, all EORTC QLQ-C30 scores improved by the end of Cycle 1, particularly emotional (P = 0.015), pain (P = 0.001), constipation (P = 0.001), and QOL (P = 0.011) scores. In parallel, the proportion of men who reported pain (21.7%) or had difficulties in their family life (19%) significantly decreased. During subsequent cycles, diarrhea (P = 0.021) and dyspnea (P = 0.010) results deteriorated and constipation results improved (P = 0.046) after Cycle 2. Fatigue (P = 0.013), dyspnea (P = 0.010), and physical functioning (P = 0.017) results deteriorated relative to baseline at the last QOL evaluation, performed 15–30 days after completion of treatment.
QOL analyses showed that patients who experienced a clinical benefit response due to therapy had significantly higher cognitive functioning scores than did other patients at the end of Cycle 1 (96 ± 7 vs. 80 ± 15; P = 0.018) and at the end of Cycle 3 (93 ± 9 vs. 58 ± 29; P = 0.007). Clinical benefit responders also had significantly higher emotional functioning scores at the end of Cycle 3 (87 ± 11 vs. 40 ± 30; P = 0.004) and a tendency toward better global QOL (63 ± 17 vs. 44 ± 16; P = 0.085) and insomnia (20 ± 28 vs. 58 ± 32; P = 0.052) scores compared with others.
When the longitudinal analysis was restricted to PSA responders (n = 13), results showed a significant improvement in pain (P = 0.026) and constipation (P = 0.005) scores after Cycle 1, a significant deterioration in dyspnea (P = 0.024) and diarrhea results (P = 0.034) after Cycle 2, and a deterioration in dyspnea (P = 0.006) and fatigue results (P = 0.032) 15–30 days after completion of Cycle 4.
Toxicity generally was mild and did not necessitate dose reduction. All toxicities resolved, and there were no treatment-related deaths. Five patients were hospitalized for toxicity, for a median length of 8 days (range, 5–31 days). Grade 3–4 toxicities are summarized in Table 4.
|Toxicity||No. of patients||% of patients|
|Grade 3||Grade 4||Grade 3–4|
PSA Response, Tumoral Response, and Survival
PSA responses are summarized in Table 3. Of the 27 patients evaluable for PSA, 48% had a ≥ 50% decrease in PSA and 19% had a ≥ 75% PSA decrease that was maintained for at least 2 successive measurements. Among PSA responders, 30% had previously received chemotherapy. Thirty-three percent of patients had responses for both PSA and clinical benefit, and 15% had a positive clinical benefit despite an increase in PSA level. Of nine patients with measurable metastases, only seven were evaluable (five had progressive disease and two remained stable).
The median follow-up period was 28 months (range, 18–41 months), and the median survival period was 20 months (range, 4–41 months). The median survival period was 23 months (range, 11–40 months) for patients with clinical benefit, compared with 20 months (range, 4–36 months) for patients who did not achieve a clinical benefit. In patients who achieved a ≥ 50% or ≥ 75% reduction in PSA levels, the median survival periods were 23 months (range, 10–40 months) and 20 months (range, 14–36 months), respectively. To date, overall patients had progressive disease and 23 had died.
Previous chemotherapy, metastatic disease at diagnosis, clinical benefit response, and a ≥ 50% decrease in serum PSA levels were not significant for prediction of survival duration. Median survival from the first diagnosis of metastasis were 55 months (range, 18–168 months), and median survival from the hormone-refractory period was 34 months (range, 5–80 months).
Metastatic prostate carcinoma has a fatal evolution at approximately 12–18 months after hormonal resistance. Until recently, chemotherapy was considered largely ineffective in patients with metastatic prostate carcinoma for reasons including the following: response rates generally were low, and responses were documented in few evaluable patients; elderly patients with frequent comorbidity experienced excessive toxicity; and there was no survival benefit compared with palliative care alone. However, over the last decade, several studies have shown the clear beneficial effect of chemotherapy in the palliative setting for patients with a number of advanced malignancies, such as pancreatic carcinoma and HRPC.11, 12 These studies have highlighted the importance of the palliative benefits of chemotherapy and, in addition to classic parameters of tumoral response, have included patient assessment of symptoms and QOL as important efficacy parameters. One of the major issues in managing these difficult-to-treat patients is ensuring that the benefits of chemotherapy with respect to tumoral response are not impaired by excessive toxicities. To achieve this objective, self-assessment of symptoms and QOL by the patient probably is one of the most important parameters to consider.
Docetaxel is an effective anticancer drug with broad-spectrum activity. Several studies have evaluated this drug in men with HRPC and have shown acceptable response rates.6, 8 Given that patients with HRPC have a relatively short life expectancy, we decided to use weekly regimens of this drug to ensure antitumoral activity with a low toxicity. Hainsworth et al.10 found that a similar regimen of docetaxel (36 mg/m2 per week) was very well tolerated. They reported rare Grade 3–4 toxicity in patients with advanced refractory cancer. We evaluated the effect of this weekly docetaxel regimen in older symptomatic men with metastatic HRPC who had pain and few or no measurable tumors. Our assessment of clinical benefit was based on pain intensity, analgesic consumption (in morphine-equivalent milligrams), and KPS.11 These parameters appeared to be the most appropriate for evaluating the impact of therapy on tumor-related symptoms. We did not include body weight, as previously used by Burris et al.11 in their study of pancreatic carcinoma, because this parameter is less affected in HRPC. Several studies have demonstrated that physicians underestimate patients' pain.19 Therefore, in the current study, we asked patients to assess their own pain intensity on a VAS.
In the current study, KPS was high at study entry (median, 80%) and significant improvements in this parameter therefore were not expected. Improvement in pain results was observed in 46% of 28 evaluable patients, and the median duration of pain response was 14 weeks. The pain score decreased rapidly and was maintained below baseline until the end of treatment for the majority of patients. Analgesic consumption also was reduced for the majority of evaluable patients for most of the time during treatment. The pain response rate in the current study (46%) is higher than that observed in the Canadian trial of mitoxantrone and prednisone (38%) compared with prednisone alone (21%, P = 0.025), although it is difficult to assess the contribution of prophylactic corticosteroids (dexamethasone 8 mg 3 times each week) on clinical benefit, QOL, and PSA response in the current study.
The validity of the clinical benefit scale used in the current study is supported by the strong correlation between this parameter and PSA response and by the results of the concomitant evaluation of QOL. The QOL results from the current study should be analyzed with care because of the small sample, the absence of a control arm, and the need for multiple testing. Nevertheless, QLQ-C30 assessments confirmed the palliative benefits of docetaxel therapy.
Patient compliance in completing these assessments was high (94%), despite the fact that a copy of the questionnaire was to be completed before each physician visit. Some QOL item scores became worse after 2 cycles (12 weeks) of therapy. This finding may be due to the possible cumulative toxic effects of docetaxel at doses more than 420 mg/m2. Further evaluation with regard to the duration of treatment is warranted.
A previous Phase I study of weekly docetaxel found that doses as high as 36 mg/m2 per week were extremely well tolerated.10 That study reported a 2% incidence of Grade 2 leukopenia and no Grade 4 leukopenia or Grade 3–4 thrombocytopenia.10 In our heavily pretreated elderly population, the hematologic toxicity profile of this weekly docetaxel regimen compared favorably with the profile observed in studies of standard every-3-week docetaxel schedules in men with metastatic HRPC (50% Grade 3–4 neutropenia).6, 8 In the current study, the most frequent side effects were nail toxicity (observed in 50% of patients; 4 patients had Grade 3 toxicity), alopecia (13% Grade 3 toxicity), and asthenia (10% Grade 3 toxicity).
A ≥ 50% reduction in PSA level generally is accepted as a reasonable indicator of treatment efficacy and has been found to be correlated with increased survival.17, 20 The 48% PSA response rate (PSA reduction ≥ 50%) in the current study is comparable to the results observed in other Phase II studies of weekly or every-3-week schedules of docetaxel in patients with metastatic HRPC.6, 8, 21 In the current study, we found the median survival period to be 23 months (range, 11–40 months) for clinical responders and 23 months (range, 10–40 months) for PSA responders. The median survival duration was 20 months (range, 4–41 months). Fifty percent of patients had received non-taxane-based chemotherapy before study entry. A recent randomized Phase II trial demonstrated the survival benefit of docetaxel/estramustine/prednisone compared with mitoxantrone/prednisone (18.6 vs. 11.6 months; P = 0.002).22 Mitoxantrone-treated patients who were switched to docetaxel had a significantly longer survival period than did patients treated with mitoxantrone alone (P = 0.001). Docetaxel efficacy seems to be present in frontline chemotherapy or after previous chemotherapy. Other explanations for this long median survival duration are the median age of 67 years (range, 52–83 years), the rarity of visceral metastatic sites (16.7%), the baseline PSA level of 73 ng/mL (range, 1–895 ng/mL), and the hemoglobin level of 13 g/dL (range, 8–18 g/dL).
We await the results of a Phase III trial comparing docetaxel plus estramustine with mitoxantrone plus prednisone.
Despite this advance in therapy, novel therapeutic strategies still are needed to improve tumoral response, clinical benefit, QOL, and survival in patients with metastatic HRPC. In summary, the results of the current study confirm that weekly docetaxel is an effective regimen for elderly and symptomatic patients with metastatic HRPC in terms of clinical benefit, QOL, and PSA response. These findings support further studies comparing weekly docetaxel regimens with other standard treatments and regimens in this setting.
- 1American Cancer Society. Selected cancers: prostate. In: Cancer facts and figures 2001. Atlanta: American Cancer Society, 2001: 16–17.
- 8A Phase II trial of docetaxel in patients with hormone refractory prostate cancer (HRPC): long term results [abstract]. Proc Am Soc Clin Oncol. 1999; 18: 1206., .
- 15The EORTC QLQ-C30 scoring manual. Brussels: European Organization for Research and Treatment of Cancer, 1999., , , , .
- 22Results of a Phase II randomized trial of docetaxel, estramustine and prednisone—two schedules—versus mitoxantrone and prednisone in patients with hormone refractory prostate cancer (HRPC) [abstract]. Ann Oncol. 2002; 13: 90., , , et al.