Prognostic and Predictive Factors in Patients with Androgen-Independent Prostate Cancer Treated with Docetaxel and Estramustine: A Single Institution Experience

Abstract

Objectives

To investigate potential prognostic and predictive factors in patients with androgen-independent prostate cancer (AIPC) treated with docetaxel chemotherapy.

Methods

This analysis included 94 consecutive AIPC patients who were treated between March 2001 and May 2006 with biweekly docetaxel 45 mg/m² (day 2) and estramustine 140 mg three dimes daily (days 1–3).

Results

Prostate-specific antigen (PSA) responses were observed in 45 of 84 evaluable patients (53%), whereas objective responses were observed in 16 of 40 patients with measurable disease (40%). Median survival (OS) was 16.2 mo (95% confidence interval [CI], 12.9–19.4) and median time to PSA progression (TTP) 5.0 mo (95%CI, 3.6–7.1). OS was independently associated with pain score baseline PSA and weight loss. Patients with only extraosseous disease had higher PSA response rate (87% vs. 49%, p = 0.014) and superior TTP compared with patients with bone metastases with or without extraosseous disease (7.3 vs. 4.3 vs. 4 mo, p = 0.002). Concurrent bone and extraosseous metastases were associated with worse prognosis compared with each site alone (median OS: 12.3 vs.19 vs.18.3 mo, p = 0.007).

Conclusions

Among patients with AIPC treated with biweekly docetaxel and estramustine, baseline PSA >100, existence of pain, weight loss, and simultaneous extraosseous and bone disease were associated with worse prognosis. Extraosseous metastases seem to be more sensitive than bone disease to this chemotherapy.

Introduction

Prostate cancer is a rising public health issue in the context of “aging” Western societies, accounting for 30% of new male cancer diagnoses in the United States [1]. While early-stage prostate cancer can be cured with surgery or radiation therapy, this is not the case for metastatic disease. Androgen-deprivation therapy is effective in the majority of patients with advanced prostate cancer; however, disease control is achieved for only an average period of 12–24 mo [2], and all patients ultimately develop “androgen-independent” cancers (AIPC), unresponsive to hormonal manipulations [2], [3].

AIPC is an invariably lethal condition associated with significant deterioration of the quality of life. Analgesics, external beam radiation, bone-seeking isotopes such as strontium-89, biphosphonates, and glucocorticoids are widely employed for palliation, with variable success [4]. Cytotoxic chemotherapy has been, until recently, considered largely ineffective in AIPC [5]. Mitoxantrone with prednisone or hydrocortisone proved to confer symptomatic relief and quality of life improvement for a large proportion of patients, but it failed to prolong survival [6], [7]. Recently, docetaxel has replaced mitoxantrone as the standard of care for patients with metastatic AIPC. Two recent phase 3 trials showed that docetaxel with estramustine or prednisone improved overall survival compared with mitoxantrone and prednisone [8], [9]. Since 2001, we have been treating patients with AIPC with a 2-weekly docetaxel and estramustine combination. The results in the first 54 patients were encouraging with 45% PSA response rate, 38% objective response rate, and a median survival of 13.3 mo [10]. This regime was well tolerated with grade 3 or 4 toxicities reported in only five cases. In addition, pain was improved in 54% and analgesic consumption was reduced in 40% of the patients.

In spite of the recent advances, the prognosis of AIPC remains poor and a significant proportion of patients do not benefit from docetaxel-based chemotherapy. Therefore, selection of patients likely to benefit from chemotherapy is essential, since patients with AIPC are often in poor general condition or have other comorbidities, which increase the likelihood of chemotherapy-related complications. In a relatively limited number of reports various factors, such as age, hemoglobin, time to AIPC, extent of metastatic disease PSA levels, and doubling time have been associated with survival [11], [12], [13], [14]. Nevertheless, these analyses were confounded by inhomogenous treatment and did not include patients treated with docetaxel, which represents the current standard of care. We, therefore, investigated the association of response and outcome of AIPC patients treated with biweekly docetaxel and estramustine, with baseline clinical characteristics attempting to identify potential prognostic and predictive factors in this population.