Chemotherapy in patients with castration-resistant prostate cancer

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Introduction

Prostate cancer is, excluding non-melanoma skin cancer, the most common cancer among men, with approximately 301,500 new cases and 67,800 deaths annually in the European Union [1]. Prostate cancer is a major clinical problem, not only because of its high incidence and mortality, but also because of the severe morbidity associated with the advanced stages of this disease.

Treatment for clinically localised disease consists of early intervention with surgery, radiation therapy (external beam or brachytherapy), androgen suppression, or observation.

Treatment for metastatic prostate cancer is palliative. In patients with metastatic prostate cancer, androgen ablation therapy is almost universally accepted as the initial treatment of choice, with a response rate ranging from 80% to 90%. However, these tumours, at a median of 18 months, become androgenindependent and grow despite androgen ablation [2]. Because patients may respond to secondand thirdline hormonal therapies, the Prostate-Specific Antigen Working Group (PCWG 2) advised the classification of tumours that are progressing with castrate levels of testosterone (serum testosterone levels <50 ng/dL) as castration resistant [3]. Hormone-refractory prostate cancer (HRPC) arises when disease progression continues despite secondary hormonal manoeuvres that may include anti-androgen withdrawal [4]. The mechanisms of the development of hormone resistance are largely unknown, although the molecular changes of the androgen receptor, e.g. mutation or amplification, can explain some observations [5].

Historically, clinical management for advanced prostate cancer has been primarily focused on controlling symptoms. Over the last two decades, treatment options for patients with CRPC have changed notably.

Prostate cancer was considered resistant to chemotherapy until the mid-1990s, when randomised trials showed that mitoxantrone with prednisone resulted in prostate specific antigen (PSA) responses greater than 50%, pain relief and improved quality of life (QoL) more frequently than prednisone alone [6, 7]. In 2004, two landmark trials, TAX 327 [8] and Southwest Oncology Group (SWOG) 99-16 [2]0, showed for the first time a survival benefit in patients with advanced CRPC by docetaxel-based chemotherapy as compared to mitoxantrone plus prednisone.

Section snippets

Mitoxantrone

Cytotoxic chemotherapy has been studied in the treatment of CRPC for many years. Until 1996, when Tannock and colleagues [7] reported a randomised phase III trial defining a clear role for mitoxantrone based chemotherapy, there was no convincing evidence to suggest that chemotherapy was of benefit to a meaningful proportion of patients with CRPC [9]. In the trial by Tannock and colleagues, 161 men were randomised to receive mitoxantrone plus prednisone or prednisone alone. Palliative response,

TAX 327 [8]

The TAX 327 study was a large international randomised trial which compared the effectiveness of three schedules: 3-weekly mitoxantrone (12 mg/m2), 3-weekly docetaxel (75 mg/m2) and weekly docetaxel (30 mg/m2), all combined with prednisone (5 mg twice daily) in patients with CRPC [8]. The treatment duration was 30 weeks in all treatment schedules. A total of 1006 patients were randomised from March 2000 to June 2002. The median overall survival was 16.5 months in the mitoxantrone group, 17.4

Predicting outcomes in CRPC

CRPC is a heterogeneous disease with rather well characterised factors associated with outcome. Several prognostic models have been developed to estimate survival in patients with CRPC. The CALGB co-operative study group performed a pooled analysis combining data from six trials involving 1101 patients with metastatic CRPC treated between 1991 and 2001 and created a prognostic model for risk stratification of metastatic CRPC, by comparing the predicted probability with the actual survival

When to start cytotoxic therapy

The widespread use of PSA monitoring has resulted in earlier detection of CRPC, often in asymptomatic patients. An important question for the management of asymptomatic disease is whether to initiate chemotherapy or to wait until symptoms occur. Although chemotherapy may halt or reverse progression, associated toxicity of the chemotherapy might lead to deterioration of QoL. Comparative data evaluating the merits of delaying the initiation of chemotherapy are lacking. As previously mentioned,

Assessing response for therapy

Assessing the response to treatment in prostate cancer is difficult as measurable disease, by standard oncologic criteria, occurs infrequently. The majority of men have bone metastases which are difficult to quantify objectively and reproducibly. The identification of surrogate endpoints, replacing solid endpoints, is crucial to the rapid evaluation of new cancer drugs. Recently, the PCWG 2 updated eligibility and outcome measures in trials that evaluate systemic treatment for patients with

Future directions

Different combinations of chemotherapy and numerous agents with novel mechanisms of anti-tumour activity have been studied in patients with CRPC; due to the rapid progress of this field it is beyond the scope of this review to cover all compounds under investigation.

Second-line treatment

There are no approved agents for second-line therapy in patients with CRPC who progress after first-line docetaxel-based chemotherapy. Several options for these patients have been suggested e.g. clinical trials of novel agents, other cytotoxic agents, docetaxel retreatment, additional hormonal manipulations, and best supportive care [52]. However none of them have proven to improve QoL or overall survival. Being the previous standard of care, second-line mitoxantrone chemotherapy has been

Conclusions

Following the results of the two landmark phase III studies, TAX 327 and SWOG 99-16, the combination of 3-weekly docetaxel plus low-dose prednisone has become standard treatment for patients with CRPC. These two independent randomised studies have demonstrated that 3-weekly docetaxel significantly improves overall survival compared with mitoxantronebased chemotherapy, with acceptable toxicity. An updated survival analysis of data from TAX 327 showed that survival benefit was sustained at 3

Conflict of interest statement

Dr de Wit has received research grant support and consultancy fees from Sanofi-Aventis. Dr Meulenbeld and Dr Hamberg have no conflicts of interest to report.

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