Bipolar androgen therapy sensitizes castration-resistant prostate cancer to subsequent androgen receptor ablative therapy.

BACKGROUND: Cyclical, high-dose testosterone administration, termed bipolar androgen therapy (BAT), can induce clinical responses and restore sensitivity to androgen signalling inhibition in patients with previously treated castration-resistant prostate cancer (PCa) (CRPC). This trial evaluated whether BAT is a safe and effective first-line hormonal therapy for patients with CRPC. PATIENTS AND METHODS: In cohort C of this single-centre, open-label, phase II, multi-cohort trial (RE-sensitizing with Supraphysiologic Testosterone to Overcome REsistance study), 29 patients with CRPC received first-line hormonal therapy with 400 mg of testosterone cypionate intramuscularly every 28 days concurrent with a luteinising hormone-releasing hormone agonist/antagonist. The primary end-point of the study was the PSA50 response rate to BAT treatment. RESULTS: After treatment with BAT, four of 29 patients (14%; 95% confidence interval [CI]: 4-32%) experienced a PSA50 response. The median radiographic progression-free survival to BAT was 8.5 months (95% CI: 6.9-15.1) for patients with metastatic CRPC. After progression on BAT, 17 of 18 patients (94%; 95% CI: 73-100%) achieved a PSA50 response and 15 of 18 patients (83%; 95% CI: 59-96) achieved a PSA90 response on abiraterone or enzalutamide. Twelve of 15 patients (80%; 95% CI: 52-96) with metastatic CRPC remain on abiraterone or enzalutamide with a median duration of follow-up of 11.2 months. CONCLUSION: As first-line hormonal treatment for CRPC, BAT was well tolerated and resulted in prolonged disease stabilisation. After progression on BAT, patients had favourable responses to second-generation androgen receptor-targeted therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02090114.

Kidney Cancer: Toxicity Management, Symptom Control, and Palliative Care.

The challenges of managing the toxicities associated with the current armamentarium to combat kidney cancer continue to grow. It is therefore paramount for providers to not only have knowledge of the disease, but to also have an understanding of the potential adverse effects associated with the various treatments. In addition, it is important to incorporate palliative care strategies to help manage symptoms, improve quality of life, and support patients and their families throughout the continuum of the disease. This article will discuss the general toxicities and symptomatic issues encountered in patients with kidney cancer who are receiving targeted therapies and immunotherapies. It will also define the components of palliative care and its benefits. The recommendations in this article are from source documentation noted in various guidelines of the Oncology Nursing Society, ASCO, the National Comprehensive Cancer Network, and the Society for Immunotherapy of Cancer. We feel it is appropriate to modify and individualize management as deemed necessary to provide the best outcome for patients and their families.

Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study.

BACKGROUND: Prostate cancer that progresses after enzalutamide treatment is poorly responsive to further antiandrogen therapy, and paradoxically, rapid cycling between high and low serum testosterone concentrations (bipolar androgen therapy [BAT]) in this setting might induce tumour responses. We aimed to evaluate BAT in patients with metastatic castration-resistant prostate cancer that progressed after enzalutamide. METHODS: We did this single-centre, open-label, phase 2, multicohort study in the USA. We included patients aged 18 years or older who had histologically confirmed and radiographically documented metastatic castration-resistant prostate cancer, with no more than two previous second-line hormonal therapies, and a castrate concentration of testosterone. Patients were asymptomatic, with Eastern Cooperative Oncology Group performance status of 0-2, and did not have high-risk lesions for tumour flare (eg, >5 sites of visceral disease or bone lesions with impending fracture). For the cohort reported here, we required patients to have had progression on enzalutamide with a continued prostate-specific antigen (PSA) rise after enzalutamide treatment discontinuation. Patients received BAT, which consisted of intramuscular testosterone cipionate 400 mg every 28 days until progression and continued luteinising hormone-releasing hormone agonist therapy. Upon progression after BAT, men were rechallenged with oral enzalutamide 160 mg daily. The co-primary endpoints were investigator-assessed 50% decline in PSA concentration from baseline (PSA50) for BAT (for all patients who received at least one dose) and for enzalutamide rechallenge (based on intention-to-treat analysis). These data represent the final analysis for the post-enzalutamide cohort, while two additional cohorts (post-abiraterone and newly castration-resistant prostate cancer) are ongoing. The trial is registered with ClinicalTrials.gov, number NCT02090114. FINDINGS: Between Aug 28, 2014, and May 18, 2016, we accrued 30 eligible patients and treated them with BAT. Nine (30%; 95% CI 15-49; p<0·0001) of 30 patients achieved a PSA50 to BAT. 29 patients completed BAT and 21 proceeded to enzalutamide rechallenge, of whom 15 (52%; 95% CI 33-71; p<0·0001) achieved a PSA50 response. During BAT, the only grade 3-4 adverse event occurring in more than one patient was hypertension (three [10%] patients). Other grade 3 or worse adverse events occurring during BAT in one [3%] patient each were pulmonary embolism, myocardial infarction, urinary obstruction, gallstone, and sepsis. During enzalutamide retreatment, no grade 3-4 toxicities occurred in more than one patient. No treatment-related deaths were reported during either BAT or enzalutamide retreatment. INTERPRETATION: BAT is a safe therapy that resulted in responses in asymptomatic men with metastatic castration-resistant prostate cancer and also resensitisation to enzalutamide in most patients undergoing rechallenge. Further studies with BAT are needed to define the potential clinical role for BAT in the management of metastatic castration-resistant prostate cancer and the optimal strategy for sequencing between androgen and antiandrogen therapies in metastatic castration-resistant prostate cancer to maximise therapeutic benefit to patients. FUNDING: National Institutes of Health and National Cancer Institute.

Navigating Treatment of Metastatic Castration- Resistant Prostate Cancer: Nursing Perspectives.

BACKGROUND: Treatment of metastatic castration-resistant prostate cancer (mCRPC) has evolved rapidly. In particular, five new treatments that extend survival in mCRPC have been approved since 2010, including the chemotherapy cabazitaxel (Jevtana®), hormonal agents abiraterone (Zytiga®) and enzalutamide (Xtandi®), vaccine sipuleucel-T (Provenge®), and radiopharmaceutical radium-223 (Xofigo®); all have different indications and toxicity profiles. OBJECTIVES: This review discusses treatment advances in mCRPC, including considerations for side-effect management and treatment sequencing. Studies relating to quality of care in prostate cancer are also discussed. METHODS: Nonsystematic searches were performed on published manuscripts and abstracts from major oncology or urology congresses, focusing on practical characteristics of the previously mentioned new treatments that extend survival in mCRPC, as well as studies relating to quality of care and the role of nurses in prostate cancer management. FINDINGS: To ensure that patients derive optimal clinical benefit, assessing overall health and proactively managing expected side effects are essential. Treatment sequencing in mCRPC is an important consideration, but clinical data in this area are limited. Despite medical advances in mCRPC, studies have identified other aspects of care in which improvement is needed. Nurses can make major contributions to addressing supportive care needs, which has been shown to improve patient care and outcomes in prostate cancer. Although patient navigation programs have improved coordination of care, inconsistent implementation among centers has been identified for prostate cancer. Greater use of outcome measures can help to identify unmet patient needs.

The effect of therapeutic anticoagulation on overall survival in men receiving first-line docetaxel chemotherapy for metastatic castration-resistant prostate cancer.

BACKGROUND: Anticoagulants have been postulated to possess antitumor activity, although clinical data supporting this claim are conflicting. No definitive data exist on the clinical impact of anticoagulation therapy in patients with prostate cancer. The aim of this study was to investigate the association between therapeutic anticoagulant use and survival in men with metastatic castration-resistant prostate cancer (mCRPC) receiving docetaxel chemotherapy. PATIENTS AND METHODS: We retrospectively reviewed the records of 247 consecutive patients with mCRPC who received first-line docetaxel chemotherapy between 1998 and 2010 at a single institution. Among them, 29 patients (11.7 %) received therapeutic anticoagulation (low-molecular-weight heparin [LMWH] or warfarin) for the treatment of venous thromboembolism. Univariate and multivariable Cox proportional hazards regression models were used to investigate the effect of anticoagulant use on overall survival. RESULTS: In univariate analysis, anticoagulant use was associated with improved survival (hazard ratio [HR], 0.61; P = .024). Median survival was 20.9 months in the anticoagulation group versus 17.1 months in the control group (P = .024). In multivariable analysis, anticoagulant use remained a significant predictor of survival after adjusting for other baseline prognostic factors (HR, 0.49; P = .023). When each anticoagulant was considered separately in the multivariable model, LMWH remained significantly prognostic for survival (HR, 0.48; P = .035), whereas warfarin use did not. CONCLUSIONS: Anticoagulant use (LMWH in particular) is an independent predictor of improved survival in men with mCRPC receiving docetaxel. These data provide the impetus to further explore the antitumor properties of anticoagulants in patients with prostate cancer and warrant validation in prospective studies.