Taxanes in the management of metastatic castration-resistant prostate cancer: Efficacy and management of toxicity

Abstract

Androgen deprivation is the therapy of choice in the majority of patients with metastatic prostate cancer. However, a state of castration resistance ultimately occurs after hormone therapy, thus defining metastatic castration-resistant prostate cancer (mCRPC). mCRPC has historically been considered a relatively chemoresistant tumor. However, due to its ability to improve survival and the quality of life in comparison with mitoxantrone, docetaxel has been established as the standard chemotherapeutic agent for first-line therapy since 2004. Moreover, recent results have shown that the novel taxane cabazitaxel is able to prolong the overall survival of patients with mCRPC previously treated with docetaxel. Even though these taxanes display a favorable toxicity profile, their routine use in clinical practice requires knowledge about the most frequent and distinct adverse events that may result from their administration.

Introduction

Prostate cancer is typically diagnosed at early stages, often through transrectal biopsy triggered by elevated levels of prostate specific antigen (PSA) [1], [2]. In part due to the PSA screening programs, it is now the most common cancer in the male population in the United States, with an estimated 241,740 new cases in 2012 [2]. Despite its indolent course in most cases and the curability of localized disease by prostatectomy and/or radiation therapy in most patients, nearly over 10,000 men in the US alone are newly diagnosed with metastatic disease each year, and many other recur after local therapy, and it was responsible for an estimated 28,170 deaths in 2012 [2], [3], [4]. For these patients, who typically have involvement of the axial skeleton, treatment is done with a palliative intent and often consists in androgen deprivation through surgical or pharmacological means [5]. Due to the reliance of prostate cancer cells on testosterone, androgen deprivation is initially active in 80–90% of patients and is associated with median progression-free survival (PFS) times that range from 12 to 30 months after treatment initiation [5], [6]. However, prostate tumor cells eventually acquire the ability to proliferate in a serum androgen-depleted environment [3], [7], and a median overall survival (OS) of only 8–16 months has been historically observed after the appearance of such androgen independency [5], [6]. Along the years, the terms ‘androgen-independent’, and ‘hormone-refractory’, were used interchangeably – but today given the demonstrated sensitivity of CRPC to various androgen-targeted therapies, castrate-resistant is the current preferred term [8] – to denote disease that progresses despite castrate levels of testosterone [9], [10]. Over the past 15 years, substantial progress has been achieved in the treatment of patients with of metastatic castration-resistant prostate cancer (mCRPC) with chemotherapy. In the following review, we will present historical developments and current perspectives on the treatment of these patients with taxanes, the most active class of chemotherapeutic agents in this setting.