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Japanese Journal of Clinical Oncology Advance Access originally published online on August 2, 2007
Japanese Journal of Clinical Oncology 2007 37(8):603-608; doi:10.1093/jjco/hym071
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© 2007 Foundation for Promotion of Cancer Research

Three-weekly Docetaxel with Prednisone is Feasible for Japanese Patients with Hormone-refractory Prostate Cancer: A Retrospective Comparative Study with Weekly Docetaxel Alone

Toru Shimazui, Koji Kawai, Naoto Miyanaga, Takahiro Kojima, Noritoshi Sekido, Shiro Hinotsu, Takehiro Oikawa, Akira Joraku and Hideyuki Akaza

Department of Urology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575 Japan

For reprints and all correspondence: Toru Shimazui, Department of Urology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575 Japan. E-mail: torushim{at}md.tsukuba.ac.jp

Received January 23, 2007; accepted March 8, 2007


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Conflict of interest
 References
 
Background: We previously reported that weekly treatment with docetaxel alone is useful for and well tolerated by patients with hormone-refractory prostate cancer (HRPC). Here, we compare it with the regimen of docetaxel once every 3 weeks (q3w) plus daily prednisone (PSL) based on a TAX 327 trial in order to clarify the efficacy and toxicity of docetaxel regimens in Japan.

Methods: Thirty-two patients with HRPC were treated with docetaxel weekly (regimen 1) or docetaxel q3w plus PSL daily (regimen 2) at Tsukuba University Hospital and the changes in serum prostate-specific antigen (PSA), tumor size and survival were evaluated. The dose of docetaxel in regimen 1 was based on our previous report and that of regimen 2 was modified from a TAX 327 trial.

Results: A >50% decrease in PSA was observed in 53% of the patients with a median time to progression of 3.5 months and 69% with 8.5 months with regimens 1 and 2, respectively. Patients who received regimen 2 had a significantly better survival rate than those who received regimen 1. Myelosuppression and neuropathy were statistically more frequent in regimen 2 than in regimen 1.

Conclusion: A regimen of docetaxel q3w with PSL daily was associated with a high rate of PSA reduction and prolongation of patient survival. Although docetaxel has not been approved in Japan yet, this treatment is considered feasible for Japanese patients with HRPC.

Key Words: chemotherapy • PSA failure • paclitaxel


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Conflict of interest
 References
 
Incidence of prostate cancer has been increasing in Japan as well as in Western countries and thus it is now a growing problem worldwide. The majority of patients with advanced prostate carcinoma respond to androgen depletion therapy by means of classical surgical castration or an LH-RH agonist as chemical castration, especially using maximum androgen blockade (MAB) therapy along with the anti-androgen. However, the median duration of the response to hormone therapy is less than two years (1,2). Docetaxel was approved by the US Food and Drug Administration and is currently a promising treatment for patients with hormone-refractory prostate cancer (HRPC). A regimen of docetaxel once every 3 weeks (q3w) with daily oral prednisone (PSL) based on a TAX 327 trial has shown a significant advantage for the survival of patients with HRPC as compared with mitoxantorone plus PSL (3).

We previously reported the efficacy of single-agent docetaxel for HRPC (4). Berry et al. (5) originally reported that weekly docetaxel alone was associated with a good response in terms of prostate-specific antigen (PSA) reduction, time to progression (TTP), survival and minimal myelosuppression in patients with HRPC. Our previous study (4) showed that docetaxel weekly was effective in 56% of HRPC patients with a low rate of adverse events, but with the relatively short TTP of 4.5 months. Based on the TAX 327 trial, we investigated a regimen of docetaxel q3w plus PSL daily and analyzed its usefulness and safety in comparison to weekly docetaxel alone for HRPC.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Conflict of interest
 References
 
Patients
Between November 2000 and September 2006, a total of 32 patients with HRPC were enrolled in the phase II study with two regimens of docetaxel at the Tsukuba University Hospital. The prostate cancers of all patients were pathologically diagnosed based on the General Rules for Clinical and Pathological Studies on Prostate Cancer (3rd edn) (6). All patients with HRPC, which was confirmed by failure of previous hormone therapy and disease progression even after withdrawal of anti-androgen, were considered eligible for this study. Disease progression was documented by either elevation of serum PSA level on at least three separate measurements or enlarged lesions on radiology. As the treatment protocol, a regimen of docetaxel alone weekly was applied until August 2004, and then between September 2004 and September 2006, docetaxel q3w plus PSL daily was used, as described in the following section. In the case of previous radiologic treatment, patients were eligible at least 4 weeks after standard radiation, whereas other previous modalities were not considered criteria for eligibility.

For inclusion, patients were required to have a pre-treatment white blood cell (WBC) above 2000/µl, a platelet count above 100 x 103/µl, and a hemoglobin concentration above 8 g/dl. However, the levels of serum bilirubin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were required to be lower than the upper limits of normal. In all patients, use of docetaxel was reviewed and approved by the Committee of the University Hospital Investigative Fund, and informed consent was obtained by oral explanation and written documentation.

Treatment Protocols
Regimen 1 was a weekly intravenous infusion of docetaxel for 3 weeks (days 1, 8 and 15), with a second course started after a 2-week interval. The dose of docetaxel was 30 mg/m2 of body surface area in 5% glucose solution administered over 2 h. Patients were orally administered 4 mg dexamethasone and 10 mg famotidine 17 and 5 h before docetaxel administration, and at 7 h after docetaxel administration. After September 2004, regimen 2 was used. Seventy mg/m2 of docetaxel in 5% glucose solution was administered intravenously over 2 h once every 3 weeks and 10 mg/day of PSL was given orally. Pre-medication was not used in regimen 2 because of the daily steroid treatment.

Pre-treatment characteristics of the patients are summarized in Table 1. No difference in variables was apparent. Although the rate of bone metastasis was higher in patients who received regimen 2, the ratio was not statistically significant. Prior treatments included MAB in all patients of both groups. During docetaxel-based treatment, patients took the androgen-ablation therapy continuously.


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  		Table 1. Baseline characteristics of patients with HRPC

 
In general, patients underwent a physical examination and laboratory studies including complete blood cell count, blood chemistry and PSA at a minimum of every 4 weeks. Radiological evaluations to document measurable disease or bone lesions were repeated at a minimum of every 12 weeks. Response to treatment was evaluated using the guidelines supported by the General Rules for Clinical and Pathological Studies on Prostate Cancer (6). Response was determined by a reduction in the PSA level and by imaging studies in patients with measurable disease. In both regimens, treatment continued until disease progression or unacceptable adverse effects occurred.

Evaluation of Response and Toxicity and Statistical Analyses
The first endpoint of the evaluation was the percentage of patients who achieved more than 50% reduction of PSA and an objective tumor response. Progressive disease was defined as a 25% increase in the serum PSA level over the last pre-treatment measurement. The second endpoint was determined by TTP and survival. The best response rate compared with baseline PSA was analyzed by waterfall charts. Survival curves were constructed by the Kaplan–Meier method and statistically evaluated by a log-rank test. The severity of the adverse events was scored according to the National Cancer Institute Toxicity Criteria, Version 2.

In statistical analyses, pre-treatment characteristics between two regimens and the response was analyzed by Fisher's exact test and student's t-test. Survival curves were constructed by Kaplan–Meier method and evaluated by log-rank test. The rates of adverse events between two regimens were evaluated by means of Fisher's exact test according to grade of the event.


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Conflict of interest
 References
 
Two patients (#10 and #13) received only one treatment cycle owing to gastric ulcer and withdrawal of informed consent, respectively. One patient (#13) was excluded from the evaluation because of withdrawal of informed consent. Accordingly, 15 and 16 patients were eventually evaluated in regimens 1 and 2, respectively. A representative case, #27, of regimen 2, who was evaluated as complete response (CR) in PSA response, is shown in Fig. 1. During two cycles of docetaxel q3w, PSA was decreased from 650 ng/ml to the normal range (Fig. 1), and local tumor invasion and metastatic sites were evaluated as partial response (PR) (Fig. 2A and B). The median number of treatment cycles, PSA response, response of measurable metastatic sites, overall response, TTP and survival are summarized in Table 2. Although the PSA response rate, TTP and survival seemed to be superior in regimen 2 (68.8%, 8.5+ months, and 12.5+ months, respectively) than in regimen 1 (53.3%, 3.5 months, and 8.0+ months, respectively), the difference in response rate between the two regimens was not statistically significant whereas TTP and survival period were different between the two regimens (P = 0.007 and 0.002, respectively). Time-dependent changes in PSA of each patient after completion of the two regimens are shown in Fig. 3 and the best responses in terms of PSA reduction are shown in the waterfall chart (Fig. 4). Apparently, PSA reductions were better in regimen 2 than in regimen 1 (Figs 3 and 4). Although there is no difference in median duration of TTP and survival between the two regimens, as mentioned above, the progression-free survival curves and overall survival curves of the two regimens were statistically different (P < 0.0001 for both survival curves) (Fig. 5).


Figure 1
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  		Figure 1. In a representative case of regimen 2 (#27), PSA decreased from 650 ng/ml to the normal range during two cycles of docetaxel every 3 weeks plus prednisone daily. Maximum androgen blockade therapy with bicartamide followed by fultamide was performed prior to docetaxel therapy. PSA, prostate-specific antigen; q3w, every 3 weeks.

 

Figure 2
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  		Figure 2. In a representative case (#27), local invasion of bladder and lymph node metastases (A) were reduced after two cycles of regimen 2. Local invasion and lymph node metastases were both evaluated as PR (B). Arrows, lymph node metastases.

 

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  		Table 2. Comparison of responses to docetaxel alone and docetaxel q3w + PSL

 

Figure 3
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  		Figure 3. Time-dependent PSA changes during docetaxel-based chemotherapy show that the response to docetaxel every 3 weeks plus prednisone daily (B) is apparently better than weekly docetaxel alone (A).

 

Figure 4
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  		Figure 4. Waterfall plots of best PSA response rates shows that higher rate of PR and 50% > reduction rate are observed in docetaxel as compared with weekly docetaxel. Partial response rate and 50% > reduction rate are 53 and 17% in weekly docetaxel, and 69 and 25% in docetaxel every 3 weeks, respectively.

 

Figure 5
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  		Figure 5. Progression-free survival curves (A) and overall survival curves (B) show that the survival rates of patients receiving docetaxel plus prednisone daily are statistically better than those receiving weekly docetaxel alone.

 
In terms of adverse events, no grade 3/4 event was observed in regimen 1, whereas neutropenia and neuropathy were observed in regimen 2 and the frequency was statistically significant (P = 0.0001, Table 3). In patients undergoing regimen 2, more than 75% of patients, including two patients with febrile neutropenia, received granulocyte colony-stimulating factor (G-CSF) by subcutaneous injection when the WBC count was lower than 2000/µl until it was higher than 10 000/µl. In three patients with severe neutropenia, dose of docetaxel was reduced from 70 to 50 mg/m2. Two patients discontinued treatment in cycles 10 and 12 because of peripheral neuropathy.


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  		Table 3. Treatment-related adverse events

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Conflict of interest
 References
 
Our comparative analyses showed that the PSA response rate and TTP were superior in the regimen of docetaxel every 3 weeks plus PSL daily to the regimen of weekly docetaxel alone, although treatment-related adverse events were more severe in the former. Docetaxel was originally administered every 3 or 4 weeks with frequent myelosuppression (7). In a phase I study of patients with metastatic breast cancer, a regimen in which docetaxel was dividedly given as a single agent weekly for 6 weeks, followed by 2 weeks off, produced minimal myelosuppression and its efficacy was not compromised (7). Berry et al. has also reported that a regimen of docetaxel alone at 36 mg/m2 weekly was associated with a PSA response of 41%, increased time to progression and survival, and minimal myelosuppression in patients with HRPC (5). However, a TAX 327 trial showed that docetaxel q3w at 70 mg/m2 plus PSL daily provided significantly better survival than mitoxantorone plus PSL, which was previously shown as a more effective regimen in improvement of quality of life (QoL), i.e. pain relief, of the patient than PSL alone (8).

It should be noted that the difference between the TAX 327 trial and the present study is the combination of daily PSL with the higher dose of docetaxel every 3 weeks. Although we could not confirm that the anti-tumor effect is associated with daily PSL or not by comparing the two regimens, several patients who responded to regimen 2 were already being treated with a steroid, e.g. PSL or dexamethasone. Randomized clinical trials, such as comparative studies of docetaxel with and without PSL, should be undertaken to reveal the significance of the combination with PSL. However, our present study shows that PR was observed in three of five patients (#19, #20, #22, #28 and #32) who were continuously treated with a steroid. The other two cases showed 37 and 49% decreases in PSA, suggesting that the combination with PSL is not a major concern for the efficacy of this treatment.

Docetaxel plus estramustine phosphate (EMP), another combination regimen, has produced evidence of in vitro synergy (9). Higher PSA response rates (63–82%) were obtained in two phase I studies (10,11) of docetaxel with EMP in patients with HRPC. In addition, a SWOG9916 trial (12) revealed that the median survival with docetaxel plus EMP was nearly 2 months longer than that with mitoxantrone plus PSL. The PSA response rate was 50% in docetaxel plus EMP, whereas grade 3 and 4 neutropenic fevers, nausea and vomiting, and cardiovascular events were more common among patients receiving docetaxel and EMP than among those receiving mitoxantrone and PSL. In other previous phase I and II studies of docetaxel with EMP, the incidence of vascular events (arterial thrombus, deep venous thrombus, superficial venous thrombus) ranged from 6 to 16% (10,11,13). In contrast, it is reported that no adverse vascular event was observed in single-agent docetaxel treatment (5). A recent report has shown that thromboembolism, including pulmonary thromboembolism, is observed in Japan at rates similar to those of Western countries (14). Although it may be possible to achieve even higher responses with combination regimens of docetaxel plus EMP, these benefits would have to be balanced against any increased toxicity (15).

In comparison with the efficacy of weekly docetaxel, even TAX 327 trials have not revealed the difference yet by means of direct comparative analyses (3). It is reported that the PSA responses were significantly greater in docetaxel groups including the single-agent weekly docetaxel regimen than in the mitoxantrone group, but the difference in median survival between the weekly docetaxel (17.4 months) and mitoxantrone regimens (16.4 months) was not statistically significant (P = 0.36) (3). Therefore, it can be currently considered that docetaxel q3w plus PSL daily would provide a better survival rate in Japanese patients with HRPC. According to the present study, grade 3 and 4 neuropathy was frequently observed as an adverse event in addition to laboratory abnormalities. In a TAX 327 trial (3), neuropathy was more frequent in the two docetaxel regimens than in the mitoxantrone regimen, but was not different between the two docetaxel regimens. In our study, neuropathy was more often observed in later phases of the treatment course and led to the discontinuation of treatment by two patients. Lin et al. (16) reported that long-term adverse effects associated with continuous docetaxel treatment include asthenia, edema, peripheral neuropathy and cytopenia. Although ten cycles of docetaxel therapy was selected in TAX 327, whether continuous therapy offers an advantage over intermittent therapy, in terms of balancing disease control and overall survival with treatment-related toxicity and QoL, is unanswered yet in HRPC (16). Intermittent docetaxel may avoid or delay the development of progressive toxicity for patients who experience an initial response to docetaxel.

In relation to the pre-treatment PSA to response rate, patients with a baseline PSA less than 100 ng/ml had more favorable outcomes in both regimens. Precisely, CR, PR, no change (NC) and progressive disease (PD) were observed in 1, 2, 2 and 0 patients who received docetaxel weekly, and in 3, 2, 0 and 1 patients who received docetaxel q3w plus PSL daily, respectively. Accordingly, docetaxel-based regimens might provide more benefit in earlier stages of HRPC. Unfortunately, the optimal timing of docetaxel-based chemotherapy is still unknown (17). Whereas previous chemotherapy studies supported only a palliative role for cytotoxic chemotherapy, taxane-based chemotherapy has recently demonstrated a clear survival advantage that justifies its use in asymptomatic patients. Therefore, the treatment of asymptomatic, minimally metastatic HRPC patients with docetaxel-based chemotherapy should be further investigated.

In conclusion, our study showed that administration of docetaxel every 3 weeks plus PSL daily had a favorable outcome with high rate of PSA reduction and an acceptable number of adverse events in Japanese patients with HRPC. Although docetaxel is not yet approved in Japan, the phase II study has been finished and it is desirable for early approval for clinical use in treatment of prostate cancer.


   Conflict of interest
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Conflict of interest
References
 
None declared.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Conflict of interest
 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.[Abstract]

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.[Abstract/Free Full Text]

3 Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med (2004) 351:1502–12.[Abstract/Free Full Text]

4 Kojima T, Shimazui T, Onozawa M, Tsukamoto S, Hinotsu S, Miyanaga N, et al. Weekly administration of docetaxel in patients with hormone-refractory prostate cancer: a pilot study on Japanese patients. Jpn J Clin Oncol (2004) 34:137–41.[Abstract/Free Full Text]

5 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.[Web of Science][Medline]

6 General Rules for Clinical and Pathological Studies on Prostate Cancer. Japanese Urological Association. (2001) 3rd edn. Japanese Society of Pathology.

7 Hainsworth JD, Burris HA III, Greco FA. Weekly administration of docetaxel (Taxotere): summary of clinical data. Semin Oncol (1999) 26:S19–24.

8 Tannock IF, Osoba D, Stockler MR, Emst DS, Neville AJ, Moore MJ, 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 (1996) 14:1756–64.[Abstract/Free Full Text]

9 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.[Web of Science][Medline]

10 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.

11 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.[Abstract/Free Full Text]

12 Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med (2004) 351:1513–20.[Abstract/Free Full Text]

13 Sinibaldi VJ, Carducci MA, Moore-Cooper S, Laufer M, Zahurak M, Eisenberger MA. Phase II evaluation of docetaxel plus one-day oral estramustine phosphate in the treatment of patients with androgen independent prostate carcinoma. Cancer (2002) 94:1457–65.[CrossRef][Web of Science][Medline]

14 Sakon M, Maehara Y, Ysohikawa H, Akaza H. Incidence of venous thromboembolism following major abdominal surgery: a multi-center, prospective epidemiological study in Japan. J Thromb Haemost (2006) 4:581–6.[CrossRef][Web of Science][Medline]

15 Amstrong AJ, Carducci MA. Chemotherapy for advanced prostate cancer: results of new clinical trials and future studies. Curr Oncol Rep (2005) 7:220–7.[CrossRef][Medline]

16 Lin AM, Ryan CJ, Small EJ. Intermittent chemotherapy for metastatic hormone refractory prostate cancer. Crit Rev Oncol Hematol (2007) 61:243–54. Review.[CrossRef][Web of Science][Medline]

17 Calabro F, Sternberg CN. Current indications for chemotherapy in prostate cancer patients. Eur Urol (2007) 51:17–26.[CrossRef][Web of Science][Medline]


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