Introduction

Prostate cancer remains the most commonly diagnosed noncutaneous malignancy in the United States, with an estimated 241,700 new cases in 2012, resulting in an estimated 28,840 deaths in the same year. Localized prostate cancer is frequently characterized by a lengthy natural history and relatively indolent clinical course. This is in stark contrast to advanced disease, which commonly results in a considerable symptom burden to patients. Indeed, both disease burden and treatment may result in significant changes in patients’ health-related quality of life (HRQOL), a patient-reported outcome measure (PRO) that represents the patient’s overall perception of his disease and its treatment and captures evaluations of the patient’s physical, psychological, and social functioning. This article will discuss commonly used instruments in the evaluation of HRQOL among cancer patients, the HRQOL implications of advanced metastatic prostate cancer, and incremental changes in HRQOL associated with treatment.

HRQOL instruments

HRQOL is assessed using surveys, known as instruments, that query the patient regarding different areas, or domains, of his quality of life. Questions on the instruments are often referred to as items and are often grouped into scales, which generate summary scores for a particular domain. Individual instruments measure either general or disease-specific HRQOL. General HRQOL domains tend to be applicable to all patients, regardless of their underlying illnesses. General HRQOL focuses on general health perceptions, sense of overall well being, and function in the physical, emotional, and social domains. On the contrary, disease-specific HRQOL instruments such as the University of California Los Angeles (UCLA) Prostate Cancer Index (UCLA-PCI) evaluate domains germane to a particular disease. Examples would include measurement of erectile function and urinary control in prostate cancer patients.

There are a number of general and disease-specific instruments commonly used in the evaluation of HRQOL in men with advanced prostate cancer. Perhaps the most commonly used general HRQOL instrument is the RAND 36-Item Short Form Health Survey (SF-36), which assesses 8 health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, general mental health, social functioning, energy/fatigue, and general health perceptions. The SF-36 may be scored as 2 separate physical (PCS) and mental (MCS) composite scores to allow the physician or investigator to identify differences between physical and mental dysfunction. More recently the SF-12, an abbreviated version of the SF-36, has been introduced, which can be self-administered in 2 minutes or less. The SF-12 has been found to reproduce the vast majority of the variance found in the SF-36 PCS and MCS measures, and it is a useful alternative in studies in which the SF-36 is too cumbersome. Other commonly used general HRQOL instruments include the Quality of Well-Being scale (QWB), the Sickness Impact Profile (SIP), and Nottingham Health Profile (NHP).

In addition to the commonly used general HRQOL instruments, there are various cancer-specific instruments that measure changes in HRQOL related to malignancy. One such tool is the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). The EORTC QLQ-C30 is a 30-item scale that incorporates 5 functional scales (physical, role, cognitive, emotional, social), 3 symptom scales (pain, fatigue, nausea/vomiting), and a global health and quality-of-life scale. Additionally, there are a number of single-item questions related to common symptoms among cancer patients. While the EORTC instrument was initially tested in patients with unresectable lung cancer, it has undergone validation in patients with various tumor types, including prostate. There is a prostate cancer module, the EORTC QLQ–PR25, that specifically addresses urinary, sexual, and bowel symptoms and function as well as adverse effects of androgen deprivation therapy (ADT). The PR25 instrument has been evaluated in prostate cancer populations with both localized and metastatic disease.

The Functional Assessment of Cancer Therapy (FACT) is another commonly used cancer-specific HRQOL instrument. The FACT is a 2-part instrument that evaluates general HRQOL measures related to cancer and cancer therapy (FACT-G) and tumor-specific measures related to the disease of interest. The 28-item FACT-G includes a total score and subscale scores for physical, functional, social, and emotional well being, as well as satisfaction with the treatment relationship. There is a specific module for prostate cancer (FACT-P) that includes items related to sexual function, urinary function, and bowel function. Additionally, the Cancer Rehabilitation Evaluation System Short Form (CARES-SF) is an instrument dedicated to the evaluation of general HRQOL in cancer patients. The CARES-SF contains 59 items and has 5 multi-item subscales including physical, psychosocial, medical interaction, marital interaction, and sexual function.

One unique instrument that is often used in assessments of HRQOL in cancer patients is the EQ5D/EuroQol instrument. The EQ5D/EuroQol instrument combines self-assessment with valuation of a standard set of health states. The EQ5D/EuroQol instrument is unique in that it evaluates patients’ specific utilities, and has the potential to provide some insight into the value assigned to specific domains among patients with specific disease states. The EQ5D/EuroQol instrument measures well being in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and responses are weighted to generate a summary index.

Evaluation of HRQOL in patients with advanced metastatic prostate cancer is generally performed using 1 of the instruments developed for the measurement of general HRQOL in cancer patients. Nonetheless, there exist multiple prostate cancer-specific HRQOL instruments that merit discussion. Certainly, the UCLA-PCI and the Expanded Prostate Cancer Index-50 (EPIC-50) are 2 such instruments that have been well studied. The UCLA-PCI is a 20-item instrument that is generally coadministered with the RAND SF-36 to men with early stage prostate cancer. The instrument contains 6 subscales, including urinary function, urinary bother, sexual function, sexual bother, bowel function, and bowel bother. The UCLA-PCI was broadened to develop the EPIC-50. The expanded instrument includes such as the assessment of hormonal symptoms, irritative urinary symptoms, and multi-item scores quantifying bother between the sexual, urinary, hormonal, and bowel domains. There is an abbreviated version of the EPIC-50, the EPIC-26, which has demonstrated internal consistency and reliability in patients with localized prostate cancer. The application of prostate cancer-specific instruments to advanced metastatic disease is certainly valuable for assessment of prostate cancer-specific domains; however, these instruments fail to provide the same degree of global assessment as the general cancer instruments such as the FACT-G/P, EORTC-C30, and the CARES-SF. It is for this reason that these instruments are not commonly encountered in the metastatic prostate cancer literature.

Metastatic prostate cancer frequently results in significant pain, and pain measurement is common in HRQOL evaluation, particularly among advanced prostate cancer patients. There are several pain scales that are commonly used to evaluate chronic pain. The McGill Pain Questionnaire evaluates sensory, affective, evaluative, and temporal aspects of the patient’s pain condition. Based upon the answers to various questions, sensory, affective, and total pain indices are calculated. The Present Pain Intensity (PPI) scale is part of the McGill Pain Questionnaire and uses verbal pain descriptors and scores pain from 0 to 5, with higher scores representing worse pain. The Brief Pain Inventory (BPI) was developed from the Wisconsin Brief Pain Questionnaire. The BPI evaluates pain severity, the degree of interference with function, and relief from current pain regimen. The BPI uses a numeric rating scale, with higher scores representing more severe pain.

HRQOL instruments

HRQOL is assessed using surveys, known as instruments, that query the patient regarding different areas, or domains, of his quality of life. Questions on the instruments are often referred to as items and are often grouped into scales, which generate summary scores for a particular domain. Individual instruments measure either general or disease-specific HRQOL. General HRQOL domains tend to be applicable to all patients, regardless of their underlying illnesses. General HRQOL focuses on general health perceptions, sense of overall well being, and function in the physical, emotional, and social domains. On the contrary, disease-specific HRQOL instruments such as the University of California Los Angeles (UCLA) Prostate Cancer Index (UCLA-PCI) evaluate domains germane to a particular disease. Examples would include measurement of erectile function and urinary control in prostate cancer patients.

There are a number of general and disease-specific instruments commonly used in the evaluation of HRQOL in men with advanced prostate cancer. Perhaps the most commonly used general HRQOL instrument is the RAND 36-Item Short Form Health Survey (SF-36), which assesses 8 health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, general mental health, social functioning, energy/fatigue, and general health perceptions. The SF-36 may be scored as 2 separate physical (PCS) and mental (MCS) composite scores to allow the physician or investigator to identify differences between physical and mental dysfunction. More recently the SF-12, an abbreviated version of the SF-36, has been introduced, which can be self-administered in 2 minutes or less. The SF-12 has been found to reproduce the vast majority of the variance found in the SF-36 PCS and MCS measures, and it is a useful alternative in studies in which the SF-36 is too cumbersome. Other commonly used general HRQOL instruments include the Quality of Well-Being scale (QWB), the Sickness Impact Profile (SIP), and Nottingham Health Profile (NHP).

In addition to the commonly used general HRQOL instruments, there are various cancer-specific instruments that measure changes in HRQOL related to malignancy. One such tool is the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). The EORTC QLQ-C30 is a 30-item scale that incorporates 5 functional scales (physical, role, cognitive, emotional, social), 3 symptom scales (pain, fatigue, nausea/vomiting), and a global health and quality-of-life scale. Additionally, there are a number of single-item questions related to common symptoms among cancer patients. While the EORTC instrument was initially tested in patients with unresectable lung cancer, it has undergone validation in patients with various tumor types, including prostate. There is a prostate cancer module, the EORTC QLQ–PR25, that specifically addresses urinary, sexual, and bowel symptoms and function as well as adverse effects of androgen deprivation therapy (ADT). The PR25 instrument has been evaluated in prostate cancer populations with both localized and metastatic disease.

The Functional Assessment of Cancer Therapy (FACT) is another commonly used cancer-specific HRQOL instrument. The FACT is a 2-part instrument that evaluates general HRQOL measures related to cancer and cancer therapy (FACT-G) and tumor-specific measures related to the disease of interest. The 28-item FACT-G includes a total score and subscale scores for physical, functional, social, and emotional well being, as well as satisfaction with the treatment relationship. There is a specific module for prostate cancer (FACT-P) that includes items related to sexual function, urinary function, and bowel function. Additionally, the Cancer Rehabilitation Evaluation System Short Form (CARES-SF) is an instrument dedicated to the evaluation of general HRQOL in cancer patients. The CARES-SF contains 59 items and has 5 multi-item subscales including physical, psychosocial, medical interaction, marital interaction, and sexual function.

One unique instrument that is often used in assessments of HRQOL in cancer patients is the EQ5D/EuroQol instrument. The EQ5D/EuroQol instrument combines self-assessment with valuation of a standard set of health states. The EQ5D/EuroQol instrument is unique in that it evaluates patients’ specific utilities, and has the potential to provide some insight into the value assigned to specific domains among patients with specific disease states. The EQ5D/EuroQol instrument measures well being in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and responses are weighted to generate a summary index.

Evaluation of HRQOL in patients with advanced metastatic prostate cancer is generally performed using 1 of the instruments developed for the measurement of general HRQOL in cancer patients. Nonetheless, there exist multiple prostate cancer-specific HRQOL instruments that merit discussion. Certainly, the UCLA-PCI and the Expanded Prostate Cancer Index-50 (EPIC-50) are 2 such instruments that have been well studied. The UCLA-PCI is a 20-item instrument that is generally coadministered with the RAND SF-36 to men with early stage prostate cancer. The instrument contains 6 subscales, including urinary function, urinary bother, sexual function, sexual bother, bowel function, and bowel bother. The UCLA-PCI was broadened to develop the EPIC-50. The expanded instrument includes such as the assessment of hormonal symptoms, irritative urinary symptoms, and multi-item scores quantifying bother between the sexual, urinary, hormonal, and bowel domains. There is an abbreviated version of the EPIC-50, the EPIC-26, which has demonstrated internal consistency and reliability in patients with localized prostate cancer. The application of prostate cancer-specific instruments to advanced metastatic disease is certainly valuable for assessment of prostate cancer-specific domains; however, these instruments fail to provide the same degree of global assessment as the general cancer instruments such as the FACT-G/P, EORTC-C30, and the CARES-SF. It is for this reason that these instruments are not commonly encountered in the metastatic prostate cancer literature.

Metastatic prostate cancer frequently results in significant pain, and pain measurement is common in HRQOL evaluation, particularly among advanced prostate cancer patients. There are several pain scales that are commonly used to evaluate chronic pain. The McGill Pain Questionnaire evaluates sensory, affective, evaluative, and temporal aspects of the patient’s pain condition. Based upon the answers to various questions, sensory, affective, and total pain indices are calculated. The Present Pain Intensity (PPI) scale is part of the McGill Pain Questionnaire and uses verbal pain descriptors and scores pain from 0 to 5, with higher scores representing worse pain. The Brief Pain Inventory (BPI) was developed from the Wisconsin Brief Pain Questionnaire. The BPI evaluates pain severity, the degree of interference with function, and relief from current pain regimen. The BPI uses a numeric rating scale, with higher scores representing more severe pain.

HRQOL implications of metastatic prostate cancer

Both disease burden and treatment may contribute to changes in HRQOL. It is clear from numerous series that patients with metastatic prostate cancer suffer from significant decrements in numerous HRQOL domains. Curran and colleagues evaluated HRQOL using the EORTC-C30 instrument in men enrolled in 3 different EORTC phase 3 studies: locoregional disease (EORTC 30,891), poor prognosis metastatic disease (EORTC 30,893), or painful progressive hormone-resistant disease (30,903). Patients in the hormone-resistant study and the poor prognosis metastatic trials reported significantly worse pain scores, role functioning scores, physical functioning scores, and global health status than patients in the locoregional trial. These data suggest that disease burden is inversely related to HRQOL in patients with prostate cancer. These data are supported by data from Albertsen and colleagues, who studied HRQOL in 113 men with metastatic prostate cancer, 60 of whom were in remission and 53 of whom had progressive disease. Not surprisingly, patients in remission had more favorable overall quality of life as measured with the EORTC QLQ-C30. Patients in remission demonstrated a significantly higher level of physical function and had fatigue, pain, weight loss, and appetite loss. The investigators then stratified the cohort by disease burden into 3 categories: those with minimal disease in remission, those with extensive disease in remission, and those with extensive disease in progression. Patients with minimal disease in remission reported similar scores on the SF-36 to the general US population. When compared with patients with extensive disease in progression, those with extensive disease in remission had more favorable physical functioning, fatigue, pain, and appetite loss. Sullivan and colleagues administered multiple HRQOL questionnaires to an observational cohort with metastatic castrate-resistant prostate cancer (CRPC) over time. The study revealed significant declines in the FACT-P PCS, EQ5D/EuroQol, and in 10 of 14 domains of the EORTC QLQ-C30 from baseline to 3, 6, and 9 months ( Fig. 1 ). Patients reported increasing pain, fatigue, and appetite loss as a function of time. Taken together, these data suggest inverse dose-dependent changes in HRQOL with increasing disease burden.

Mean change in HRQOL scores from baseline to 3, 6, and 9 months for the EQ-5D, FACT-P PCS and EORTC QLQ-C30 domains. Higher scores in domains denoted with (+) represent less favorable HRQOL.

( Reproduced from Sullivan PW, Mulani PM, Fishman M, et al. Quality of life findings from a multicenter, multinational, observational study of patients with metastatic hormone-refractory prostate cancer. Qual Life Res 2007;16:574; with permission.)

Changes in HRQOL among men with metastatic prostate cancer continue through the end of life. Certainly, death from prostate cancer is often characterized by significant pain and functional limitations. Sandblom and colleagues found that men dying from prostate cancer reported significantly more severe pain than those dying of other causes. Additionally, patients in the last year of life reported declines in multiple general HRQOL measures including the EQ5D/EuroQol; however, measures of general HRQOL were similar between those dying from prostate cancer and those dying of other causes. Melmed and colleagues evaluated changes in general HRQOL at the end of life in men with metastatic prostate cancer. Nearly all domains revealed declines in HRQOL toward the end of life. Interestingly, however, the investigators found differential decrements in various HRQOL domains by marital status and socioeconomic status. Specifically, those who were married or in a relationship experienced significant declines in emotional well being at the end of life, whereas single men experienced more rapid declines in physical function. Furthermore, men of lower socioeconomic status were more likely to experience rapid deterioration in the physical domains but slower deterioration in the emotional domains. Conversely, men of higher socioeconomic status were more likely to experience rapid declines in the emotional well being, social function, and general health perception domains. Improving the understanding of those factors associated with HRQOL changes may allow practitioners to provide intervention to at-risk populations and improve the overall quality of care administered to prostate cancer patients throughout their disease course.

HRQOL changes with ADT

While this article focuses on men with advanced metastatic CRPC, a complete assessment of HRQOL in this cohort requires some attention to changes imposed with the administration of ADT. The introduction of ADT, either in the form of medical or surgical castration, has considerable downstream HRQOL implications in men with prostate cancer. Certainly, initiating ADT in asymptomatic men results in unfavorable changes in a number of HRQOL domains. Alibhai and colleagues evaluated both physical function and HRQOL using the SF-36 in men with prostate cancer on ADT, men with prostate cancer not on ADT, and a healthy control group. The study revealed numerous declines in objective measures of physical function as well as in the physical function, role-physical, bodily pain, and vitality domains. These findings have been supported by Sadetsky and colleagues who, using CaPSURE, found worse physical well being in patients receiving ADT. Furthermore, patients receiving primary ADT suffered more severe HRQOL declines than those receiving combination ADT and local therapy. Indeed, numerous series in diverse populations have revealed declines in both general HRQOL and prostate cancer-specific HRQOL with the introduction of ADT.

There appears to be little difference in HRQOL outcomes between patients who undergo medical versus surgical castration. Litwin and colleagues evaluated HRQOL outcomes in 63 men with metastatic prostate cancer who underwent either surgical castration or combined medical castration using both the SF-36 and the UCLA-PCI. The study found no differences in either general or prostate cancer-specific HRQOL between treatment groups. Interestingly, Potosky and colleagues evaluated outcomes among men in the Prostate Cancer Outcomes Study who underwent either medical or surgical castration and found that those men on luteinizing hormone-releasing hormone (LHRH) therapy experienced breast swelling, physical discomfort, and worry because of cancer more frequently than did those men who underwent orchiectomy. Nonetheless, there were no differences in general HRQOL, as measured by the SF-36, between treatment groups. Similarly, Nygard and colleagues found no difference in HRQOL between those undergoing medical or surgical castration.

It follows that, if ADT use is associated with worse HRQOL, then increasing time off of ADT may have beneficial effects on HRQOL. Other possible advantages of intermittent ADT include reducing the morbidity of ADT associated with long-term therapy, monitoring the course of prostate cancer with prostate-specific antigen (PSA) testing, and the possibility of delaying hormone resistance. Additionally, considering the multitude of HRQOL impairments associated with ADT, it is possible that intermittent therapy ameliorates many of these adverse effects. In their phase 3 study of continuous versus intermittent ADT, Calais da Salva and colleagues measured the EORTC QLQ-C30 and found few differences in general HRQOL between patients receiving continuous and intermittent ADT. Interestingly, patients in both the intermittent and continuous arms experienced declines in sexual function; however, decline was more severe in the continuous group. Furthermore, upon withdrawal of ADT in the intermittent cohort, sexual function returned to near baseline. Multiple phase 2 studies have documented recovery in the sexual function domain while off therapy, leading many to advocate for intermittent therapy, particularly among men who assign high utility to sexual function. Certainly, the decision to pursue intermittent ADT depends on numerous factors including patient preference, extent of disease, and burden of comorbidity.