Recommendations from the Spanish Oncology Genitourinary Group for the treatment of patients with metastatic castration-resistant prostate cancer

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Abstract

Prostate cancer is the most prevalent urogenital malignancy. However, despite initial disease control using androgen deprivation, most of patients eventually develop progressive disease that is resistant to further hormone manipulation. For these patients with castration-resistant prostate cancer (CRPC), and particularly patients with metastatic disease, options have been limited, and prognosis is grim. However, as newer regimens and agents become available, higher rates of objective and biochemical response are being achieved, providing renewed hope for the management of these patients. With the aim of facilitating the treatment of these patients, the Spanish Oncology Genitourinary Group (SOGUG) has issued a series of the recommendations which have been collected in this review. Each recommendation is accompanied by the appropriate level of evidence and grade of recommendation on the basis of the characteristics of the data available.

Introduction

Prostate cancer is the most prevalent male urogenital malignancy. For men with metastatic prostate cancer, hormonal therapy usually provides disease control for a substantial period of time, within a median of 18–24 months. However, the vast majority of patients eventually develop progressive disease that is resistant to further hormone manipulation. Until recently, cytotoxic chemotherapy was considered to be relatively ineffective in men with castration-resistant prostate cancer (CRPC). In early trials, objective response rates were 10–20%, and median survival generally did not exceed 12 months. However, newer regimens, particularly those that include docetaxel, are associated with higher rates of objective and biochemical (prostate-specific antigen [PSA]) response, as well as longer survival durations. Lastly, some new agents have shown significant results in well-performed, controlled medical trials.

In contrast, metastatic CRPC has become a more complicated disease to be properly treated; thus, the availability of updated clinical guidelines might be useful for physicians when it comes to decision-making. It is a concern of the Spanish Oncology Genitourinary Group (SOGUG) to issue recommendations for the optimal management of patients with CRPC patients. To address this issue, the Spanish Oncology Genitourinary Group (SOGUG) selected several of their members to issue recommendations for the treatment of patients with metastatic CRPC. First, a bibliographic search of articles published from 1980 to February 2011 was performed in the Medline database (PubMed) and the Cochrane Library using MeSH terms whenever possible. Search terms considered were “prostate cancer” OR “prostate neoplasms” AND “metastatic” OR “advanced” AND “castration resistant” OR “hormone refractory” AND “treatment” OR “management”. Then, in a face-to-face working meeting held in March 15, 2011, the content and sections of the guideline were established, the group coordinators and members were selected, the working method to be followed was defined, and the deadlines were set. Before drafting of the manuscript, non-relevant or incomplete papers were discarded, and selected ones were evaluated using the Levels of Evidence and Grades of Recommendation modified from Sackett [1] (see Table 1, Table 2).

Finally, it is important to bear in mind that many patients with CRPC are older than 70 years. In older patients, CRPC should be managed according to their individual health status, which is conditioned mainly by the severity of associated comorbid conditions, level of independence and nutritional status, and not according to chronological age. Ideally, treatment options should be shaped by a thorough geriatric evaluation, as proposed by the International Society of Geriatric Oncology (SIOG) [2], [3].

Section snippets

Definition of CRPC

Although most patients respond to initial suppression of gonadal androgens by medical or surgical castration, most of them eventually progress and develop a castration-resistant status. Various different terms have been used to describe prostate cancers that relapse after initial hormonal ablation therapy, including CRPC, androgen-independent cancers and hormone-independent cancers. This clinical situation includes patient cohorts with significantly different median survival times and different

Continuing treatment with luteinizing hormone-releasing hormone analogs in patients with CRPC

Continuation of treatment with luteinizing hormone-releasing hormone (LHRH) analogs in patients with castration-resistant disease remains controversial, as exogenous testosterone has been demonstrated to exacerbate disease in the metastatic setting. Reports of clinical experiences in men who have progressed on endocrine therapy, and have been treated with chemotherapy, have shown an increase in PSA levels, with a subsequent decrease when androgen deprivation was reinstituted, suggesting that a

Secondary hormonal therapy

After failure of complete androgen blockade in metastatic prostate cancer, there are several treatment options that can be offered to patients before moving on to chemotherapy. However, their impact has not been established in randomized clinical trials, and the reported responses have not shown to be long lasting. Therefore, these therapies should be reserved for asymptomatic or oligosymptomatic patients, or for those with major contraindications for chemotherapy.

Sipuleucel-T

Sipuleucel-T is an active cellular immunotherapy consisting of autologous peripheral-blood mononuclear cells, including antigen-presenting cells, which have been activated ex vivo with a recombinant fusion protein known as PA2024. This fusion protein in turn consists of human prostatic acid phosphatase fused to granulocyte-macrophage colony-stimulating factor.

A small, randomized study of sipuleucel-T compared to placebo demonstrated a significant reduction of 41% in the relative risk of death

First-line chemotherapy with docetaxel

Docetaxel was approved in 2004 for the treatment of men with metastatic CRPC based on two large multicenter randomized clinical trials [19], [20], [21]. The TAX327 study randomized 1006 patients to receive either docetaxel in a three-weekly schedule, docetaxel in a weekly schedule or mitoxantrone, the three of them given with low-dose prednisone. The SWOG 9916 study randomized 770 patients to either docetaxel in combination with estramustine phosphate, or mitoxantrone plus prednisone. In both

Abiraterone

Abiraterone acetate is an inhibitor of the enzyme CYP17 that blocks androgen synthesis in the testes, adrenals and in the tumor itself [24]. As a result, plasma testosterone levels are significantly lower than those achieved with conventional hormone therapies; in addition, a reduction in intratumoral levels of androgens is obtained.

The safety and activity of abiraterone was tested in a dose-escalation trial of 21 patients with progressive prostate cancer [25]. Maximal endocrine effects were

Docetaxel rechallenge and other chemotherapy treatments

Patients with CRPC treated with docetaxel plus prednisone usually progress after 6–8 months. Until recently, there was no standard option for salvage chemotherapy, and patients were usually retreated with the same docetaxel schedule (‘rechallenge’), or received mitoxantrone, vinorelbine, metronomic schedules or palliative care. Docetaxel rechallenge may be an option for patients who have progressed after having previously responded, and who did not experience any severe toxicity. In

Bone targeted treatments

Osteoclast-mediated bone resorption is inhibited by bisphosphonates. In patients with bone metastases from CRPC, zoledronic acid treatment is recommended to diminish skeletal-related events, which included pathological fractures, spinal cord compression, and severe bone pain requiring palliative radiation therapy or bone surgery. To date, no data is available about if other bisphosphonates exert a similar activity.

In a phase III trial, 643 patients with CRPC and a history of bone metastases

Radionuclides and palliative treatments

Bone-targeted systemic radionuclides have become viable treatment options for patients with CRPC and multiple, painful bone metastases. They are particularly useful in patients who have relapsed following an initial course of hormonal or cytotoxic chemotherapy, and also in patients with progressive or recurrent symptoms at the treated sites after treatment with external beam radiation.

Three radionuclides are currently approved for the treatment of bone pain: first-generation phosphorus-32,

Conclusions

With the purpose of helping clinicians in the treatment of CRPC, the SOGUG has issued a series of recommendations based on the available evidence. In summary, the first-line treatment options for patients with metastatic CRPC are: a secondary hormonal treatment, treatment with sipuleucel-T (if available), docetaxel plus prednisone, and zoledronic acid or denosumab (if available) if bone metastases are present. Either palliative care or inclusion in a clinical trial must always be considered.

Funding

The development of this consensus was supported by a Grant from Novartis Pharmaceuticals, who did not participate in the discussions nor the decisions taken by the experts prior to publication.

Conflict of interest statement

The authors declare that they do not have any conflicts of interest that could inappropriately influence their work.

Reviewers

Mark Ware, M.D., Assistant Professor in Family Medicine & Anesthesia, McGill University, Centre for Medical Education, Lady House, 1110 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada.Donald I. Abrams, M.D., Professor, Clinical Medicine, UCSF, University of California, San Francisco, Divisions of Hematology & Oncology, Box 0874, UCSF, San Fransisco, CA 94143-0874, United States.

Acknowledgments

Editorial assistance in the preparation of this manuscript was provided by Dr. Ximena Alvira of HealthCo (Madrid, Spain).

Miguel A. Climent graduated in Medicine and Surgery at the Universidad Literaria de Valencia. Doctor in Medicine by the Universidad Autónoma de Barcelona. He is a practicing Medical Oncologist since 1992 at the Instituto Valenciano de Oncología. He is Chief of the Area of Genitourinary Tumors, and member of the SEOM and SOGUG.

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    Miguel A. Climent graduated in Medicine and Surgery at the Universidad Literaria de Valencia. Doctor in Medicine by the Universidad Autónoma de Barcelona. He is a practicing Medical Oncologist since 1992 at the Instituto Valenciano de Oncología. He is Chief of the Area of Genitourinary Tumors, and member of the SEOM and SOGUG.

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