Between October 2003 and April 2008, 98 patients with HRPC were treated with docetaxel-based chemotherapy at the Asan Medical Center. All patients who fulfilled the following eligibility criteria were enrolled into the study: (1) histologic diagnosis of adenocarcinoma of the prostate with clinical or radiological evidence of metastatic disease; (2) documented disease progression during hormonal therapy defined by Prostate Cancer Clinical Trials Working Group (PCWG) criteria (Table 1) (8); (3) a minimum of 4 weeks or 6 weeks lapse between the withdrawal of flutamide or bicalutamide, respectively, to avoid the possibility of antiandrogen withdrawal phenomenon; (4) Eastern Cooperative Oncology Group performance status of 2 or better; (5) no prior treatment with mitoxantrone or radioisotope; (6) no history of another cancer within the preceding fiver years; (7) no evidence of central nervous system metastasis; (8) no serious or uncontrolled concomitant medical illnesses; and (9) adequate bone marrow and organ function. Patients were ineligible if they had received weekly docetaxel treatment or docetaxel-estramustine combination chemotherapy. The institutional review board of the Asan Medical Center granted permission for this retrospective study.

This was a retrospective cohort study that examined the medical records of patients with HRPC, who had been treated with docetaxel-based chemotherapy. Patients received docetaxel 75 mg/m² administered as 1-hour intravenous infusion on day 1, followed by one dose every 3 weeks with 5 mg oral prednisolone twice daily starting on day 1 and continuing throughout treatment (7). Premedication with dexamethasone for the prevention of fluid retention was administered. Prophylactic administration of G-CSF was not performed as this is not reimbursed by the Korean National Health Insurance policy. There was no preset maximal number of chemotherapy cycles and the treatment course was repeated until we observed disease progression, unacceptable toxicities, clinically significant concomitant illnesses, or patient refusal to continue treatment.

Prior to treatment, all patients had a detailed medical history, physical examinations, and baseline laboratory measurements performed. Pretreatment tumor status was evaluated using computed tomography or magnetic resonance imaging, and bone scans when necessary. Patients were seen on day 1 of every treatment cycle for a brief history, physical examination, and assessment of adverse events, complete blood count, renal and liver function testing, and PSA levels. Toxicities were re-evaluated according to the National Cancer Institute-Common Terminology Criteria of Adverse Events (NCI-CTCAE), version 3.0. There was no preset interval for tumor response imaging evaluation, but reevaluations occurred after the 6^th cycle or after clinical signs of disease progression.

The primary endpoint was PSA response and the secondary endpoints were overall survival (OS), safety, and time to PSA progression. Data collected included pretreatment disease characteristics, baseline biochemical parameters, prior therapies, first date of treatment. The 12-week and maximal PSA declines to treatment, date of PSA progression, date of symptomatic deterioration or tumor progression, and date of death or last follow-up. Kaplan-Meier estimates and the log-rank test were used to analyze time-event variables. Patients were considered assessable if they received at least 2 cycles of chemotherapy and at least 2 follow-up PSA assessments. Patients were considered assessable if they received fewer than the predefined number of chemotherapy cycles because of rapid tumor progression. All tests were 2 sided and a p-value<0.05 was considered statistically significant. SPSS for Windows version 13.0 (SPSS Inc., Chicago, IL) was used for statistical analyses.

Seventy-two of 98 HRPC patients who received docetaxel chemotherapy fulfilled the eligibility criteria for enrollment into the study. The patient demographics and disease characteristics are summarized in Table 2. Twenty-six patients were excluded for the following reasons: concomitant advanced gastric cancer (n=1); no evidence of distant metastasis (n=3); PSA value less than 2 ng/mL (n=2); serum creatinine level more than 2 mg/dL (n=1); prior exposure to radioisotope (n=1); Poor performance status (n=1); prior mitoxantrone plus prednisolone treatment (n=11); and concomitant administration of estramustine with weekly docetaxel (n=10). Three patients had multiple reasons for exclusion from the study.

At the time of analysis, 70 patients were taken off the treatment and 2 patients remain on chemotherapy. A total of 405 cycles of treatment were administered to 72 patients (median 6 cycles; range, 1~20 per patients). The frequencies of treatment-related hematological and nonhematological adverse events are shown in Table 3. Events of hematologic grade 3~4 toxicity included neutropenia (17%), leucopenia (15%), febrile neutropenia (13%), and anemia (6%). Asthenia (6%) was the most common non-hematologic grade 3 or worse event. There were no treatment-related deaths directly attributable to docetaxel chemotherapy. Docetaxel dose reduction was required in 2 of the 64 patients (3%) who received at least two cycles of treatment. The median docetaxel dose-intensity was 24.4 mg/m²/week (range, 17.5~25.6) with a relative dose intensity of 98%. When grade 3 or worse toxicities developed, in particular febrile neutropenia, the majority of the patients were withdrawn from the treatment. Considering this fact, the proportion of patients who required dose reduction may have been underestimated. Disease progression was the most common reason for discontinuation of chemotherapy (38 out of 70, 54%), followed by treatment-related adverse events (13%), and patient refusal of treatment (9%). Forty-four patients (63%) received subsequent cytotoxic chemotherapy with mitoxantrone plus prednisolone (31 patients, 44%), estramustine (23 patients, 33%), or cyclophosphamide-based combination chemotherapy (7 patients, 10%). Salvage hormonal therapy was also given to 40% of patients after treatment failure.

Post-chemotherapy 12-week and maximal PSA decline in response to treatment is shown in Fig. 1. A PSA response (confirmed PSA decline ≥50%) was seen in 32 of 63 evaluable patients (51%) at 12 weeks and a maximal PSA decline of 50% or more was seen in 42 of 70 evaluable patients (59%). Among 42 patients with measurable disease, tumor response was reevaluated in 13 patients. Four patients achieved a partial response and 5 patients maintained stable disease. With a median follow-up duration of 23.1 months using reverse Kaplan-Meier methods (95% CI, 16.7~29.5), the median time to PSA progression was 5.1 months (95% CI, 4.48~5.75) and median OS was 22.8 months (95% CI, 16.6~29.1) (Fig. 2).