Abstract and Introduction
Background: Contemporary therapies for metastatic castration-resistant prostate cancer (mCRPC) have shown survival improvements, which do not account for patient experience and health-related quality of life (HRQoL).
Methods: This literature review included a search of MEDLINE for randomized clinical trials enrolling ≥50 patients with mCRPC and reporting on patient-reported outcomes (PROs) since 2010.
Results: Nineteen of 25 publications describing seven treatment regimens (10 clinical trials and nine associated secondary analyses) met the inclusion criteria and were critically appraised. The most commonly used measures were the Functional Assessment of Cancer Therapy-Prostate (n=5 trials) and Brief Pain Inventory Short Form (n=4 trials) questionnaires. The published data indicated that HRQoL and pain status augmented the clinical efficacy data by providing a better understanding of treatment impact in mCRPC. Abiraterone acetate and prednisone, enzalutamide, radium-223 dichloride and sipuleucel-T offered varying levels of HRQoL benefit and/or pain mitigation versus their respective comparators, whereas three treatments (mitoxantrone, estramustine phosphate and docetaxel, and cabazitaxel) had no meaningful impact on HRQoL or pain. The main limitation of the data were that the PROs utilized were not developed for use in mCRPC patients and hence may not have comprehensively captured symptoms important to this population.
Conclusions: Recently published randomized clinical trials of new agents for mCRPC have captured elements of the patient experience while on treatment. Further research is required to standardize methods for measuring, quantifying and reporting on HRQoL and pain in patients with mCRPC in the clinical practice setting.
Prostate cancer is the third most commonly diagnosed malignancy in the United States (after breast and lung), with an estimated 220 800 new cases and 27 540 deaths in 2015. Most patients present with localized disease and undergo initial surgical and/or radiological therapy, with concomitant or subsequent use of androgen deprivation therapy (ADT). Generally, PSA level should be <0.5 ng ml−1 after radiation therapy and <0.2 ng ml−1 after a radical prostatectomy, and occurrence of two consecutive PSA level elevations is often considered biochemical recurrence or progression to stage D1.5 disease. Biochemical recurrence develops in ≈10% of low-risk and up to 60% of high-risk prostate cancer patients after external beam radiation therapy[3–6] and in 20–30% of patients after radical prostatectomy[7–9] despite use of ADT.
Once prostate cancer has become metastatic, ADT is deployed and is highly effective, eliciting a response in most cases; however, resistance inevitably develops, resulting in transition to a lethal castration-resistant phenotype, affecting 10–20% of prostate cancer patients within 5 years, and the death of >50% of patients within 3 years with historical standard therapies.[11–15] This end of the disease continuum is termed metastatic castration-resistant prostate cancer (mCRPC), defined by cancer progression despite a testosterone level of <50 ng dl−1 (<1.7 nmoll−1).
The natural history of mCRPC can involve worsening symptomatology represented by a progressive decline in health-related quality of life (HRQoL) and worsening pain, where HRQoL is considered a multidomain phenomenon capturing an individual's perceived mental, emotional, physical and social well-being over time.[17,18] The first treatments approved by the US Food and Drug Administration for mCRPC management focused on the palliative benefits of pain control achieved by mitoxantrone, strontium and samarium.[19–21] In 2004, docetaxel became standard of care after two phase III trials demonstrated a survival benefit over mitoxantrone.[12,13] Data from one of these trials showed that global HRQoL improved from baseline to 6 months in patients receiving docetaxel despite similar rates of pain relief in both groups, suggesting that pain relief is only a component of HRQoL in mCRPC, as fatigue and physical function (upon which pain can have an impact) are also major contributors. Certainly, asymptomatic patients are more likely to have worsening HRQoL after cytotoxic chemotherapy treatment, and this risk must be weighed against potential benefits.
Since 2010, a fundamental shift has occurred in the mCRPC treatment landscape with the arrival of immunotherapy (sipuleucel-T (sip-T)), agents targeting androgen signaling (abiraterone acetate and enzalutamide), and a bone-targeting radiopharmaceutical (radium-223 dichloride), which extend survival when utilized before or after docetaxel chemotherapy.[24–31] Median overall survival (OS) among patients with nonvisceral mCRPC who received immunotherapy with sip-T was 25.8 versus 21.7 months in the placebo group. In patients with mCRPC before and after chemotherapy, respectively, targeted therapy with abiraterone acetate plus prednisone (OS, 34.7 vs 30.3 months and 15.8 vs 11.2 months),[25,31] enzalutamide (OS, 32.4 vs 30.2 months and 18.4 vs 13.6 months),[24,30] and radium-223 dichloride (OS, 16.1 vs 11.5 months and 14.4 vs 11.3 months) all increased OS relative to control. Additional cytotoxic therapy with cabazitaxel was found to extend OS (15.1 vs 12.7 months) in men whose mCRPC had progressed after docetaxel therapy, when compared with the prior palliative standard of mitoxantrone. The life-extending noncytotoxic therapies in particular have potential to have a favorable impact on patients' HRQoL and pain and may strike a better balance between cancer control and toxicity.
In response to the Prostate Cancer Clinical Trials Working Group 2 proposed principles of conduct for phase II and III mCRPC trials, the clinical trials of these new therapies evaluated patient-reported outcomes (PROs) to ensure that the overall efficacy and safety profiles of new therapies reflect patient experience and perceptions.[16,34] The US Food and Drug Administration defines a PRO as 'any report of the status of a patient's health condition that comes directly from the patient, without interpretation of the patient's response by a clinician or anyone else.' PRO instruments typically include information about HRQoL, symptoms, function, satisfaction with care or symptoms, adherence to prescribed medications or other therapy, and perceived value of treatment. In the prostate cancer setting, multiple instruments have included specific symptoms relevant to the disease (for example, urinary control and hot flashes), the most widely used being the multidimensional Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, which indicates a worsening or improving HRQoL when the total score changes by at least 6–10 points on a 0–156 scale.
Here we review PRO data from clinical trials of patients with mCRPC reported since 2010 in order to contextualize the overall impact of new treatment modalities from the patient's perspective, and in so doing, guide patient-centered care, clinical decision-making, and health policy decisions.
Prostate Cancer Prostatic Dis. 2016;19(2):111-121. © 2016 Nature Publishing Group