Updated recommendations from the Spanish Oncology Genitourinary Group for the treatment of patients with metastatic castration-resistant prostate cancer
Introduction
Prostate cancer is the most prevalent male urogenital malignancy. In 2012, 416,732 new cases of prostate cancer were diagnosed in Europe, with 27,853 cases in Spain. Age-standardized incidence and mortality per 100,000 inhabitants per year were 96.0 and 19.3 in Europe and 96.8 and 15.2 in Spain, respectively [1]. Approximately 30% of patients with prostate cancer will develop advanced disease. Androgen deprivation therapy (ADT) achieves disease control in about 90% of these patients, for a median of 18–24 months, but the majority eventually will develop progressive disease, a status called castration-resistant prostate carcinoma (CRPC). In 2004, the combination of docetaxel and prednisone demonstrated an improvement in overall survival (OS) [2]. Since then, several new strategies such as immunotherapy, hormonal manipulations, chemotherapy agents and some bone-targeted therapies have also demonstrated an improvement in OS in controlled trials.
In 2012, the Spanish Oncology Genitourinary Group (SOGUG) published its recommendations for the treatment of patients with CRPC. Due to the recent appearance of important new data and the complexity of making decisions in this field, SOGUG has decided to update its recommendations based on the information available up to September 2014. Structure and content of the guideline, the working method and the deadlines were established by a committee. The members responsible for each section reviewed the status quo and recent advances in their section and prepared a draft of recommendations. Levels of Evidence and Grades of Recommendation modified from Sackett were included [3]. All authors agreed on the final content of the document.
Section snippets
Definition of castration-resistant prostate cancer
Although the majority of patients with advanced prostate cancer respond to initial suppression of gonadal androgens by medical or surgical castration, most eventually progress and reach castration-resistant status. CRPC is defined as disease progression (as demonstrated by increased prostate-specific antigen [PSA] levels in serum, new clinical metastases, or progression of existing metastases) despite the administration of ADT. The Prostate Cancer Clinical Trials Working Group 2 (PCWG2) [4]
Asymptomatic or minimally symptomatic patients with metastatic castration-resistant prostate cancer (mCRPC)
To date, 3 randomized phase III trials have demonstrated increased survival in patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). The 3 studies included patients with Eastern Cooperative Oncology Group (ECOG) performance status equal to 0–1, with a low level of pain as measured by the Brief Pain Inventory-Short Form scale (BPI-SF) equal to 0–1 (asymptomatic) or 2–3 (minimally symptomatic), respectively. In these trials, metastatic
First-line chemotherapy with docetaxel
Cytotoxic chemotherapy with docetaxel is generally advisable for patients with rapid progressive or symptomatic disease for whom less toxic approaches are not an appropriate option. Docetaxel given every 3 weeks in combination with daily prednisone significantly prolonged OS, improved quality of life, pain control, and objective tumor response compared with mitoxantrone plus prednisone in the TAX 327 phase III trial. Based on these results, docetaxel plus prednisone has become the standard
Chemotherapy with docetaxel in castration sensitive metastatic prostate cancer (mCSPC)
In the 2014 American Society of Clinical Oncology (ASCO) meeting, results of the CHAARTED study (E3805) were communicated [19]. This study was performed in 790 patients with androgen-sensitive metastatic prostate cancer who were randomized to receive ADT continuously, alone or associated with six cycles of docetaxel chemotherapy at standard doses. Around 65% of patients presented high volume of metastases (visceral involvement or more than four bone metastases, with at least one beyond the
Treatment with radium 223
Radium 223 (223Ra) is an alpha particle-emitting radiopharmaceutical that is indicated for the treatment of patients with CRPC, symptomatic bone metastases and no known visceral metastases. 223Ra has increased both OS and time to first symptomatic SRE in the ALSYMPCA trial. This trial was an international, randomized, double-blind, phase 3 study conducted in men with symptomatic mCRPC comparing 223Ra with placebo [21]. The trial enrolled patients failing on, not eligible for, or refusing prior
Treatment with abiraterone, enzalutamide and cabazitaxel after docetaxel
Two molecules have been demonstrated to control the up-regulation of androgen biosynthesis enzymes in two ways. Abiraterone acetate is an inhibitor of the enzyme CYP17 that blocks androgen synthesis in the testis, adrenals and in the tumor itself [23]. On the other hand, enzalutamide inhibits the nuclear translocation of the AR because of its high affinity for AR, its binding to deoxyribonucleic acid (DNA) and its coactivator recruitment [24]. The large phase III trial COU-AA-301 included
Patients with bone metastases: Bone targeted therapies
Bone metastases occur in more than 80% of patients with advanced prostate cancer. Osteoclast-mediated bone resorption is inhibited by bisphosponates. Zoledronic acid is an intravenous bisphosphonate, which was evaluated in a phase III trial compared with placebo [31], [32]. All patients also received supplemental calcium and vitamin D. Results showed that significantly more patients receiving placebo displayed SREs compared with those receiving zoledronic acid 4 mg (44% vs. 33%; difference:−11%;
Sequential treatment or third-line therapy
As a consequence of the almost simultaneous clinical development of new hormonal agents, the role of these treatments after progression with respect to each other is not yet established. The best therapeutic sequence has not yet been defined and there are no molecular or clinical markers to help clinicians to select the best therapy for each patient.
Recently published data suggest that the presence of the variant 7 isoform of AR (ARV-7) in CTCs predicts resistance to abiraterone and
Utility of circulating tumor cells as a biomarker in current practice
To date, many platforms have been developed to isolate circulating tumor cells (CTCs), but the CellSearch® system is the only assay approved by the United States Food and Drug Administration (FDA). CTCs in prostate cancer have been shown to be an independent prognostic factor in CRPC in a series of 219 patients with mCRPC, starting a new line of chemotherapy [45]. Baseline CTC counts ≥5/7.5 mL predicted significantly worse results in terms of OS compared with patients with <5/7.5 mL CTCs (11.5
Assessment of elderly patients or patients presenting comorbidities
Prostate cancer is mainly a disease of older men [53]. With the rapid aging of the population, the burden of prostate cancer and the age of patients is likely to increase in the future.
Recently, the International Society of Geriatric Oncology (SIOG) developed recommendations for the assessment and treatment of older men with prostate cancer [54]. After reviewing the literature, the SIOG Prostate Working Group established that G8 screening should be used to determine which patients would get a
Final considerations
Medical oncologists should be aware that management of CRPC has evolved during the last few years from a mainly palliative approach to one based on the availability of modern treatments that may improve OS. These new developments have highlighted the problems that clinicians face when making therapeutic decisions. First of all, scientific advances occur much faster than regulatory approvals. Many new drugs share the same approved indication, but in most cases, there are neither conclusive data
Conflict of interest statement
The authors declare that they do not have any conflicts of interest that could inappropriately influence their work.
Acknowledgments
Editorial assistance in the preparation of this manuscript was provided by Ana Martín of HealthCo (Madrid, Spain).
The development of this consensus was supported by a grant from Astellas, Sanofi, Janssen Amgen and Bayer, who did not participate in the discussions nor the decisions taken by the experts prior to publication.
Dr. Miguel A. Climent graduated in Medicine and Surgery from the Universidad Literaria de Valencia. He became a Doctor of Medicine, specializing in Medical Oncology, at the Universidad Autónoma de Barcelona in 1992. He is currently working in the Instituto Valenciano de Oncología, where he is the Head of Genitourinary Cancer. He is a member of SEOM and SOGUG.
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Dr. Miguel A. Climent graduated in Medicine and Surgery from the Universidad Literaria de Valencia. He became a Doctor of Medicine, specializing in Medical Oncology, at the Universidad Autónoma de Barcelona in 1992. He is currently working in the Instituto Valenciano de Oncología, where he is the Head of Genitourinary Cancer. He is a member of SEOM and SOGUG.