Weekly Administration of Docetaxel in Patients with Hormonerefractory Prostate Cancer: a Pilot Study on Japanese Patients

Jpn J Clin Oncol 2004;34(3)137 141 Weekly Administration of Docetaxel in Patients with Hormonerefractory Prostate Cancer: a Pilot Study on Japanese Patients Takahiro Kojima, Toru Shimazui, Mizuki Onozawa, Sadamu Tsukamoto, Shiro Hinotsu, Naoto Miyanaga, Kazunori Hattori, Koji Kawai and Hideyuki Akaza Department of Urology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba City, Ibaraki, Japan Received November 1, 2003; accepted January 9, 2004 Objective: Although treatment of hormone-refractory prostate cancer (HRPC) is difficult, a single-agent weekly dose of docetaxel has been reported as a promising regimen for patients with HRPC. The purpose of this study was the investigation of the efficacy of docetaxel for Japanese patients with HRPC. Methods: Ten patients with HRPC were treated with weekly docetaxel at Tsukuba University Hospital and were evaluated for the responses with respect to serum prostate-specific antigen (PSA), tumor size and survival. Considering the ethnic balance, the dose of docetaxel was reduced to 30 mg/m 2 weekly compared with 36 mg/m 2 in the study reported previously. Results: A biochemical response (>50% decrease in PSA) was observed in five patients (56%; 5/9) with an average time to progression of 4.5 months. In two partial responders as determined by PSA, respective metastatic lesions in bone and soft tissue were also improved. The estimated median survival duration was 6 months. Most of these responses were accompanied by a significant reduction in the requirement for analgesic agents. No severe toxicity of this regimen was observed, except for gastric ulcer in one patient who was excluded from the evaluation. Conclusions: Weekly administration of docetaxel as a single agent was associated with a high rate of PSA reduction. This treatment is feasible for patients with HRPC, even those who have a poor performance status and extensive prior treatments. Key words: prostate cancer docetaxel weekly hormone refractory INTRODUCTION Mortality from prostate cancer is increasing both in Japan and in Western countries and is becoming a serious health problem worldwide. The majority of patients with advanced prostate carcinoma respond to hormonal ablation therapy by means of bilateral orchidectomy or a luteinizing-hormone releasinghormone (LH-RH) agonist. However, the median duration of the response to hormone therapy is less than 2 years (1,2). Once the disease becomes hormone-refractory, it is currently difficult to cure this disease by other treatment modalities. Most recently, several clinical investigators have reported that systemic chemotherapy using taxanes was effective in hormone-refractory prostate carcinoma (HRPC) (3,4). Taxanes were originally administered every 3 4 weeks, but myelosuppression was frequently observed (5). In a phase II study in patients with metastatic breast cancer, docetaxel given as a For reprints and all correspondence: Takahiro Kojima, Department of Urology, Tsukuba University Hospital, 2 1 1 Amakubo, Tsukuba City, Ibaraki 305-8576, Japan. E-mail: tkojima-jua@umin.ac.jp single agent weekly for 6 weeks followed by a 2-week interval produced minimal myelosuppression, but its efficacy was not compromised (5). Similarly promising results in patients with breast cancer have been reported by other investigators (6). Berry et al. (7) also reported that single-agent docetaxel at 36 mg/m 2 weekly was associated with a PSA response rate of 41%, increased time to progression and survival and minimal myelosuppression in patients with HRPC. In the present study, we investigated the efficacy and feasibility of weekly docetaxel treatment for Japanese patients with HRPC. PATIENTS AND METHODS PATIENTS AND INCLUSION CRITERIA Between November 2000 and September 2002, 10 patients with advanced prostate cancer were enrolled in this study at Tsukuba University Hospital. At the time of initial diagnosis, prostate cancers were pathologically diagnosed based on the General Rules for Clinical and Pathological Studies on Prostate Cancer (3rd edition) (8). To be eligible for this study, all 2004 Foundation for Promotion of Cancer Research

138 Docetaxel for HRPC in Japan Table 1. Patients characteristics Case Age (years) PS Initial diagnosis PSA (ng/ml) Metastasis Prior therapy* Duration (months) Stage Pathology Bone Soft tissue A B 1 58 3 D2 Poor 2342 + LN MAB, RTx, EE, DEX, FOS 10 7 2 69 1 D2 Poor 1414 + Adrenal MAB, EE, FOS, CAP, DEX, NK, RTx 17 46 3 68 0 D2 Moderate 0.1 + LN MAB, RTx 8 2 4 52 1 D2 Poor 433 + MAB, RTx, EE, NK 12 6 5 72 0 D2 Poor 16 + MAB 22 2 6 66 1 D2 Moderate 720 LN MAB 7 11 7 69 3 D2 Poor 700 + LN MAB 4 1 8 75 1 D1 Moderate 22 LN MAB 20 2 9 76 2 D2 Moderate 1002 + RTx, MAB, Str 12 45 10 78 1 D2 Moderate 600 + LN MAB, UFT, RTx 40 20 Mean 68.3 724.9 *LN, lymph node; MAB, maximum androgen blockade; RTx, radiation; EE, combination chemotherapy with estramustine phosphate and etoposide; DEX, dexamethasone; CAP, cyclophosphamide, doxorubicin, cisplatin; NK, natural killer; FOS, fosfestrol; Str, strontium. A, duration between the initial diagnosis and the judgment of the hormone refractory status; B, duration between the judgment of the hormone refractory and the start of docetaxel. Disease progression was observed without PSA elevation. Prostate re-biopsy revealed neuroendocrine carcinoma. patients were classified as HRPC, which was confirmed by failure of previous hormone therapy and disease progression even after anti-androgen withdrawal. Disease progression was documented by either three consecutive elevations of the serum PSA level or radiological measurements of enlarged lesions. In cases of prior radiotherapy, patients were eligible at least 4 weeks after standard irradiation or 6 weeks after strontium therapy, whereas patients who had undergone other previous modalities were not considered eligible. Pretreatment laboratory findings used as inclusion criteria for patients were a white blood cell count >2000/mm 3, a platelet count >100 10 3 /mm 3 and a hemoglobin concentration >8 g/dl. On the other hand, biochemical values were required to be within the normal range. Because docetaxel has not yet been approved by the Ministry of Health, Labor and Welfare, it was purchased by the investigation fund of the University. Informed consent was taken from the patients and their families after an oral explanation and documentation. Characteristics of the patients are summarized in Table 1. The age distribution ranged from 52 to 78 years with an average of 68.3 years. The performance status of patients ranged between 0 and 3 with an average of 1.3 (ECOG performance Status Scale). The mean pretreatment baseline PSA was 724.9 ng/ml and was distributed from 0.1 to 2342 ng/ml. In case 3, disease progression was observed without PSA elevation during maximum androgen blockade (MAB) therapy. In this case, serum neuro-specific enolase (NSE, 12.1 ng/ml) was used as the tumor marker instead of PSA because prostate biopsy revealed neuroendocrine carcinoma. Metastasis to bone and lymph nodes was observed in eight and six patients, respectively. Prior treatments included MAB (all patients), estramustine and etoposide (three patients), fosfestrol (two patients), dexamethasone (two patients) and cytotherapy with natural killer cells (two patients). Six patients had received palliative radiotherapy to the bone, prostate and lymph nodes. Docetaxel was intravenously infused weekly for 3 weeks (days 1, 8 and 15) and after a 2-week interval a second course was started. Considering the ethnic difference, the dose of docetaxel in our study was modified to 30 mg/m 2 weekly, because no toxicity has been observed in Japanese patients with breast cancer who were treated with weekly docetaxel at 25 mg/m 2 (9). A 30 mg dose of docetaxel per m 2 of body surface area in 5% glucose solution was administered over a period of 2 h. Premedication with 4 mg of dexamethasone and 10 mg of famotidine was performed orally at 17 and 5 h before docetaxel administration and post-medication was given 7 h after the administration. During the docetaxel regimen, patients continuously took androgen ablation therapy with LH- RH agonist. EVALUATION OF RESPONSE AND TOXICITIES Response was evaluated by a reduction in PSA level and imaging studies in patients with measurable disease and determined using the guidelines supported by the General Rules for Clinical and Pathological Studies on Prostate Cancer (3rd edition) (8). The first endpoint of the evaluation was the percentage of patients who achieved >50% reduction in PSA and an objective tumor response. The second endpoints were determined by the time to progression (TTP), survival and symptom palliation. The severity of the toxicity was scored according to the National Cancer Institute Toxicity Criteria (version 2, 1999).

Jpn J Clin Oncol 2004;34(3) 139 Figure 1. Changes in serum tumor markers during treatment period (PSA and NSE). In five patients (56%), a 50% decline in PSA was observed (cases 2, 5, 7, 8, 9). In case 3, changes in NSE are indicated because PSA in case 3 was within the normal range at the time of recurrence. PSA, prostate-specific antigen; NSE, neuro-specific enolase. Blue crosses: deceased. RESULTS RESPONSE TO TREATMENT One patient (case 10) received only one cycle of the treatment before he was excluded from the study for evaluation of a gastric ulcer. Accordingly, nine patients were eventually evaluated. The mean number of cycles per patient was 3.3 cycles (range: 2 8 cycles). Time-dependent changes in PSA after the docetaxel regimen are shown in Fig. 1. A biochemical response (>50% decrease in serum PSA) occurred in five patients (56%), of whom four (44%) had a decrease of >75%. The average TTP for patients with >50% PSA reduction from the beginning of the treatment was 4.5 months. One of those five patients (case 9) has been free from progression for 4 months after the study was started. Patients 1 and 3 discontinued the therapy because of the progression of the disease after two cycles of therapy. Patients 4 and 6 discontinued the therapy because the disease was stabilized after two cycles. The serum NSE level was not reduced in the patient with neuroendocrine carcinoma (case 3) during the treatment period. In two partial responders with 86% (case 2) and 91% (case 7), reductions of PSA level, respective metastatic lesions in bone and soft tissue were also improved to partial response (PR). Of the nine patients enrolled in the study, five (56%) died within 7 months. The estimated median survival time was 6 months (Table 2). Six patients had symptomatic bone pain and required narcotic analgesics at the time of study entry. Three of these responses were accompanied by a significant reduction in the requirement for analgesic agents and included one patient who was able to stop narcotic agents completely. TOXICITIES The toxicities of this regimen are summarized in Table 3. The most common toxicity was grade 1 neutropenia, but no grade 4 toxicity was observed. Only one patient (case 9) who had multiple bone metastases and had been in predisseminated intravascular coagulation (DIC) status on admission developed Table 2. Response status for PSA and metastasis Case Cycles Response of PSA* Response metastasis* Prognosis Bone Soft tissue 1 2 PD Unknown Unknown Dead (3 M) 2 5 PR (85%) PR NC Dead (7 M) 3 2 PD PD PD Dead (6 M) 4 2 NC Unknown Dead (7 M) 5 8 CR (78%) NC Alive (11 M+) 6 2 NC NC Alive (6 M+) 7 3 PR (91%) NC PR Dead (4 M) 8 2 PR (67%) NC Alive (4 M+) 9 4 PR (95%) NC Alive (4 M+) *CR, complete response; PR, partial response; NC, no change; PD, progression of disease. M, months.

140 Docetaxel for HRPC in Japan Table 3. Toxicity during chemotherapy Grade 1 2 3 4 Hematological Neutropenia 3 0 1 0 Anemia 0 0 1 0 Thrombocytopenia 1 0 0 0 Non-hematological Anorexia 2 0 0 0 Alopecia 2 0 0 0 Urticaria 1 0 0 0 Gastric ulcer 0 1 0 0 a grade 3 neutropenia with granulocyte colony-stimulating factor rescue. The regimen was discontinued in one patient because of gastric ulcer (grade 2). DISCUSSION Docetaxel has been demonstrated to have significant cytotoxity and combining docetaxel with estramustine or other antimicrotubular agents has produced evidence of in vitro synergy (10). Recently, the efficacy of docetaxel-based chemotherapy in hormone-refractory prostate cancer has been reported in Western countries (Table 4). Higher PSA response rates (63 82%) were obtained in two phase I studies (3,4) of docetaxel in patients with HRPC, both of which used a combination regimen with estramustine. In a phase II study, Copur et al. (11) reported that weekly administration of docetaxel (35 mg/m 2 ) with estramustine was associated with 76% PSA response. On the other hand, recent reports described PSA response rates ranging from 41 to 46% using a single-agent docetaxel protocol in patients with HRPC (7,12). In terms of the response of metastatic lesions, Picus and Schultz (12) reported that a complete response (CR) of all soft tissues including liver metastasis was observed in one patient and a partial response was seen in six patients. Copur et al. (11) also reported that three patients with CR and four patients with PR were documented among 12 patients with measurable soft tissue disease. Petrylak et al. (4) demonstrated that of 18 patients with measurable soft tissue lesions, four PRs were observed in metastasis of lymph nodes and one had a 90% reduction in pulmonary nodes. In phase I and II studies of estramustine with docetaxel, the incidence of vascular events, e.g. deep venous thrombosis and superficial venous thrombosis, ranged from 6 to 16%. On the other hand, no vascular events were observed in recent reports of single-agent docetaxel. Additionally, gastrointestinal toxicity was more frequently observed in patients who took docetaxel with estramustine. Thus, while it may be possible to achieve even higher responses with combination regimens of docetaxel and estramustine, these benefits would have to be balanced against any increase in toxicity. Conventionally, taxanes have been administered every 3 4 weeks, but a highly frequent incidence of myelosuppression was observed (5). In phase I and II studies using docetaxel every 3 weeks in patients with HRPC, in fact, the incidence of myelosuppression ranged from 35 to 62% (3,4,12,13). On the other hand, Copur et al. (11) reported that a combination regimen of weekly docetaxel and estramustine was related to lower neutropenia (6% for grades 1 3). Berry et al. (7) also reported that weekly docetaxel administration (36 mg/m 2 ) for six consecutive weeks followed by 2 weeks without treatment was associated with minimal myelosuppression (3% for grades 3 4). In the present study, >50 and >75% declines in PSA were observed in 56 and 44%, respectively, of HRPC patients without any vascular events and minimal myelosuppression. Of the six patients without previous chemotherapy, PSA response was observed in four patients (67%), compared with one (33%) of three patients with previous chemotherapy. We consider that the number of patients is too small to predict that patients without any chemotherapy will have a better PSA response. In spite of the fact that our study population was composed of elderly patients with heavily pretreated metastatic HRPC and a poor performance status, our response rates seemed to be comparable to those for docetaxel-based therapy previously reported in the literature. Table 4. Docetaxel-based chemotherapy trials in HRPC Ref. Regimen* Dose of docetaxel (mg/m 2 ) Case 50% PSA response Measurable disease response Neutropenia (grade 3/4) Thrombosis 4 E + D 40 80/3 weeks 34 63 28 62 9 3 E + D 40 80/3 weeks 17 82 35 16 13 E + D + DEX 70/3 weeks 47 69 50 56 9 12 D 75/3 weeks 35 46 28 43 0 11 E + D 35/weekly 30 76 58 6 (G 1 3) 6 (G 1 3) 7 D 36/weekly 60 41 33 3 0 This study D 30/weekly 10 56 22 11 0 *E, estramustine; D, docetaxel; DEX, dexamethasone.

Jpn J Clin Oncol 2004;34(3) 141 In conclusion, weekly administration of docetaxel, 30 mg/m 2, as a single agent was associated with high PSA response rate in Japanese patients with HRPC. This treatment is well tolerated even in patients who had poor performance status and extensive prior treatments. However, a larger study is needed to clarify the role of weekly single-agent docetaxel administration in a therapeutic strategy for HRPC. References 1. Crawford ED, Eisenberger MA, McLeod DG, Saulding JT, Benson R, Dorr FA, et al. A controlled trial of leuprolide with and without flutamide in prostate carcinoma. N Engl J Med 1989;321:419 24. 2. Eisenberger MA, Blumenstein BA, Crawford ED, Miller G, McLeod DG, Loehrer PJ, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 1998;339:1036 42. 3. Kreis W, Budman D. Daily oral estramustine and intermittent intervenous docetaxel (Taxotere) as chemotherapeutic treatment for metastatic, hormone-refractory prostate cancer. Semin Oncol 1999;26:S34 8. 4. Petrylak DP, Macarthur RB, O Connor J, Shelton G, Judge T, Balog J, et al. Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol 1999;17:958 67. 5. Hainsworth JD, Burris HA III, Greco FA. Weekly administration of docetaxel (Taxotere): summary of clinical data. Semin Oncol 1999;26: S19 24. 6. Hortobagyi GN. Recent progress in the clinical development of docetaxel (Taxotere). Semin Oncol 1999;26:32 6. 7. Berry W, Dakhil S, Gregurich M, Asmar L. Phase II trial of single-agent weekly docetaxel in hormone-refractory, symptomatic, metastatic carcinoma of the prostate. Semin Oncol 2001;28:8 15. 8. General Rules for Clinical and Pathological Studies on Prostate Cancer, 3rd ed. Japanese Urological Association, Japanese Society of Pathology 2001. 9. Kuroi K, Bando H, Nagai S, Tanaka C, Hayashi K, Toi M. Efficacy of weekly docetaxel therapy for advanced or recurrent breast cancer. Jpn J Cancer Chemother 2001;28:797 802. 10. Kreis W, Budman D, Calabro A. Unique synergism or antagonism of combinations of chemotherapeutic and hormonal agents in human prostate cancer cell lines. Br J Urol 1997;79:196 202. 11. Copur MS, Ledakis P, Lynch J, Hauke R, Tarantolo S, Bolton M, et al. Weekly docetaxel and estramustine in patients with hormone-refractory prostate cancer. Semin Oncol 2001;28:16 21. 12. Picus J, Schultz M. Docetaxel (Taxotere) as monotherapy in the treatment of hormone-refractory prostate cancer: preliminary results. Semin Oncol 1999;26:14 8. 13. Savarse D, Taplin ME, Halabi S, Hars V, Kreis W, Vogelzang N. A phase II study of docetaxel, estramustine and low-dose hydrocortisone in men with hormone-refractory prostate cancer. Preliminary results of Cancer and Leukemia Group B 9780. Semin Oncol 1999;26:39 44.