Taxanes in the management of metastatic castration-resistant prostate cancer: Efficacy and management of toxicity
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.
Section snippets
Historical development of chemotherapy for mCRPC
Historically, prostate cancer has been considered a relatively chemoresistant tumor. Until the early 90s, several authors pointed out that the response rates to the agents that were then available were typically low and varied widely [11], [12], [13]. Moreover, authors postulated that the documentation of responses in metastatic prostate cancer was complicated by the lack of established criteria, as nearly 80% of patients with this disease have no measurable soft tissue lesions [14]. Thus,
Docetaxel in the first line
Docetaxel is a semisynthetic taxane that is able to inhibit the depolymerization of microtubules approximately twice as effectively as paclitaxel in pre-clinical models [33]. After the demonstration of its promising single-agent activity in phase II trials in mCRPC [34], [35], docetaxel was assessed in two phase III trials with slightly different designs [28], [36]. In the first trial, named TAX 327, 1006 patients with mCRPC were randomized to receive mitoxantrone (12 mg/m2 every 3 weeks),
Cabazitaxel in the second line
Cabazitaxel, a novel taxane identified in a systematic screening for novel compounds in this class, is active in preclinical models that are resistant to paclitaxel and docetaxel [44], [45]. Cabazitaxel inhibits the depolymerization of microtubules as effectively as docetaxel [46]. Furthermore, pre clinical models show that cabazitaxel is able to cross the blood–brain barrier, a potential advantage in the treatment of some malignancies [44]. Based on the results of phase I and II trials,
Incidence and management of taxane-associated toxicity
Despite their activity, all taxanes are associated with adverse events that may compromise patient quality of life and that may lead to dose reduction or discontinuation of treatment, potentially compromising its efficacy. In some circumstances, inadequately managed toxicity may outweigh the potential benefits of treatment with these agents. Thus, knowledge about the most frequent and the most distinct adverse events that may result from their administration is one of the keys to the successful
Conclusions
The introduction of docetaxel started a new era for patients with mCRPC, whose median OS was extended for the first time in randomized trials [28], [36]. Over the past 5 years, additional progress has resulted from the introduction of novel agents, including cabazitaxel, abiraterone, ezalutamide and radium-223, with activity in docetaxel-refractory disease and with the potential to improve OS also in the second line [49], [52], [53], [70]. As a result, a median OS approaching 30 months can now
Conflict of interest
FAS: None to declare.
ACB: Member of the advisory board of Sanofi-Aventis.
OS: Investigator and consultant, Sanofi.
Role of the funding source
Editorial support was provided by Dr. Everardo D. Saad from Dendrix Ltd. and supported by Sanofi. Neither Dendrix Ltd. nor Sanofi had any role in the final content of this manuscript. The authors had the final responsibility for the decision to submit the manuscript for publication.
Reviewers
Joaquim Bellmunt, MD, PhD, Section Chief, Solid Tumor Oncology (GU & GI), Hospital del Mar, Medical Oncology Service, Passeig Marítimo 25-29, E-08003 Barcelona, Spain.
Prof. Cora Sternberg, San Camillo and Forlanini Hospitals, Department of Medical Oncology, Nuovi Padiglioni, Circonvallazione Gianicolense 87, I-00152 Rome, Italy.
Dr. Dominik R. Berthold, Medical Oncology, Rue Bugnon 46, CH-1011 Lausanne, Switzerland.
Acknowledgement
We would like to thank Dr. Everardo D. Saad for the editorial support in this manuscript.
Dr. Fabio A.B. Schutz is a former Research Associate at Dana Farber Cancer Institute/Harvard Medical School, Lank Center for Genitourinary Oncology department. Currently, Dr. Schutz is a staff medical oncologist of Hospital Sao Jose and the clinical coordinator of Medical Oncology of the Hospital Sao Joaquim from the Beneficencia Portuguesa de Sao Paulo. Dr. Schutz authored and co-authored several manuscripts in genitourinary oncology.
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Dr. Fabio A.B. Schutz is a former Research Associate at Dana Farber Cancer Institute/Harvard Medical School, Lank Center for Genitourinary Oncology department. Currently, Dr. Schutz is a staff medical oncologist of Hospital Sao Jose and the clinical coordinator of Medical Oncology of the Hospital Sao Joaquim from the Beneficencia Portuguesa de Sao Paulo. Dr. Schutz authored and co-authored several manuscripts in genitourinary oncology.