Abstract
Purpose
To investigate the effect of androgen deprivation therapy (ADT) on health-related quality of life (HRQOL) in Asian men with all stages of prostate cancer.
Materials and Methods
READT (real-life evaluation of the effect of ADT in prostate cancer patients in Asia) was a multi-center, prospective observational study involving six sites across four Asian populations. We enrolled eligible prostate cancer patients, who opted for ADT alone or in combination without prior neoadjuvant or adjuvant ADT within 12 months. The EuroQoL-5 dimensions, 5 level scale (EQ-5D-5L) utility index scores and visual analog scale (VAS) were evaluated at baseline, month 6 and month 12.
Results
A total of 504 patients were recruited into READT between September 2016 and May 2020 with 52.9% diagnosed with metastatic prostate cancer. The EQ-5D-5L was evaluable in 442/504 (87.7%) of patients. Overall baseline EQ-5D-5L utility index score was 0.924 (interquartile range [IQR] 0.876–1.000). We observed a statistically significant difference in baseline EQ-5D-5L utility index score among different populations with a median EQ-5D-5L utility index score of 1 for Taiwan & Hong Kong, 0.897 for China and 0.838 for Malaysia. Similar trend was observed throughout multiple treatment time-points. Stage IV prostate cancer were significantly associated with a lower baseline EQ-5D-5L utility index score compared to stage I–III prostate cancer, producing a median disutility value of -0.080. Participants had a high median VAS (80, IQR 70–90), indicating good overall health on average during ADT initiation.
Conclusions
The study highlights the differences in health state utility index scores among various Asian prostate cancer patients receiving ADT at real-world setting. Our findings will be informative and useful in cost-effectiveness evaluation and policy decision making.
Keywords: Asia, Health status indicators, Health surveys, Quality of life, Visual analog scale
INTRODUCTION
Prostate cancer is ranked the fifth most common cancer in Asia [1] with a high mortality-to-incidence ratio particularly in developing nations, attributing to late stage at diagnosis, access to survival-prolonging treatment and community awareness program [2]. Androgen deprivation therapy (ADT) is the core treatment throughout the whole disease continuum including high-risk, locally-advanced non-metastatic and metastatic prostate cancer [3]. However, recent evidence suggested that ADT patients experienced various adverse effects including bone loss, metabolic changes, muscle loss, decreased libido and sexual function as well as potential increased risk of cardiovascular events [4]. There are ethnic differences in susceptibility to adverse effects of ADT. For instance, the cardiovascular mortality rate of Japanese patients receiving ADT was comparable to those reported in the general population [5]. Conversely, Chinese patients presented with similar cardiovascular events observed among Caucasian after ADT initiation [6,7].
With the social diversity and health disparities in Asian countries [8], it is important to broaden our treatment goals from solely prolonging survival to minimizing symptoms and enabling patients to live a fulfilling life. Establishing the value of patient-reported outcomes (PROs) has become increasingly crucial to maintain and improve health-related quality of life (HRQOL) during treatment regimen selection. Health state utility index score, a measure of preference-weighted HRQOL has been utilized in many countries to evaluate cost-effectiveness of a medical intervention [9], ensuring its economic value justifies the health benefit it delivers.
Therefore, the Real-life evaluation of the effect of ADT in prostate cancer patients in Asia (READT) study was initiated to evaluate the clinical and health-related outcomes in patients receiving ADT across Asia. Here, we described the effect of ADT on HRQOL in Asian men with prostate cancer by capturing their health state utility index scores in the period of ADT over 12 months. This study provides an opportunity to generate useful data including health utility index scores from validated HRQOL measurement for cost-effective modeling and better understanding about the treatment state.
MATERIALS AND METHODS
1. Ethics statement
This study was approved by the regional ethical review board at each center (e.g. Ref no. 2015.434 for The Chinese University of Hong Kong; Ref No. 20169224271 for University of Malaya). Informed consent was obtained from all participants prior to study enrollment.
2. Study design and participants
The READT study (ClinicalTrials.gov number, NCT03703778) is a multi-center, prospective observational study at six sites across Asia including Hong Kong, China, Malaysia, and Taiwan. Eligible patients had clinically- or histologically-diagnosed prostate cancer and opted for ADT alone or in combination without prior neoadjuvant or adjuvant ADT within 12 months.
Basic demographic and clinical parameters, tumor characteristics, primary treatment and follow up were retrieved prospectively from the hospital-based patients’ case notes or electronic medical records using a written form (proforma). Details from the proforma were then transferred into the Research Electronic Data Capture (REDCap) System for further analysis.
3. Variables
Basic demographic data included age at diagnosis (year) and history of major comorbidities such as hypertension, diabetes and hyperlipidaemia. Baseline Eastern Cooperative Oncology Group (ECOG) status and prostate specific antigen (PSA) level at ADT initiation were collected.
Tumor characteristic consisted of histological type, Gleason score grading, primary tumor site (T), lymph node involvement (N) and presence of distant metastasis (M) based on Union for International Cancer Control (UICC) TNM classification. Primary local treatment included radical prostatectomy or/and radiotherapy. Primary ADT included orchidectomy, luteinizing hormone-releasing hormone (LHRH) agonist monotherapy, LHRH antagonist, maximum androgen blockade (MAB), chemohormonal therapy and androgen receptor pathway inhibitors (APRIs).
4. EQ-5D-5L questionnaire and outcomes
PRO assessment was carried out during ADT initiation (baseline), month 6 and month 6 at treatment visit with the EuroQoL-5 dimensions, 5 level scale (EQ-5D-5L) questionnaire. This is the standard tool to measure quality of life in prostate cancer patients undergoing ADT. The EQ-5D-5L describes five health dimensions including mobility (MO), self-care (SC), usual activities (UA), pain-discomfort (PD), and anxiety depression (AD). Each domain was scored based on a 1–5 Likert-type scale (1=no problem, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems) [10]. The EQ-5D-5L also includes a visual analog scale (VAS) to rate one’s current health state with a scale 0–100 (0=worst imaginable health state and 100=best imaginable health state). The EQ-5D health state can be described in a unique five-digit code (e.g. 11111=no problem in any dimension) or summarized into a single EQ-5D utility index score on a 0 (death) to 1 (full health) scale with negative values reflecting health states worse than death.
In this study, the EQ-5D utility index score was derived from a value set for each participating country/region [11,12,13,14] as appropriate. The PRO questionnaire was done by means of paper and pencil versions and patients were not given assistance and specific order whilst completing the forms.
5. Statistical analysis
All categorical variables were described by proportions whilst continuous variables were presented in median and interquartile range (IQR). Descriptive statistics of baseline individual EQ-5D-5L dimensions were provided across all countries/regions. The PROs were analyzed between countries/regions with baseline and post-baseline (month 6 and month 12) of EQ-5D-5L utility index scores and EQ-VAS using Kruskal–Wallis H test. To assess the change in utility index score across different regions over time, the linear quantile mixed model was used. This allowed us to handle the correlation of repeated measurements within patients and the skewed distribution of the utility index scores. Region and follow-up time were included as fixed effects. The model was performed with the lqmm package in R. All statistical analysis was performed using SPSS for Windows version 21.0 (SPSS Inc.) and R software version 4.2.0 (R Foundation for Statistical Computing). Two-tailed p value <0.05 was termed as statistically significant.
RESULTS
A total of 504 patients were recruited into the READT study between September 2016 and May 2020. Summary of baseline demographic and clinical characteristics of this cohort were presented in Table 1. The median age at diagnosis was 71 years (IQR 66–77 years) and presence of metastasis (M1) was observed in 52.9% of patients. Compared to Taiwanese (36.1%), majority of patients from Hong Kong (64.1%), China (80.0%), and Malaysia (68.5%) were diagnosed with stage IV prostate cancer. A high burden of comorbidity was observed in the READT patients with 44.8% had history of three or more major comorbidities. Primary ADT was the most common form of treatment in the READT cohort, achieved by LHRH agonists (49.9%), LHRH antagonists (14.9%) or orchidectomy (5.3%). The proportion of patients receiving combination therapies were low in the present cohorts; of which, chemohormonal therapy only accounted for 10.8% of patients whilst 3.3% were administered with APRIs including abiraterone acetate or apalutamide.
Table 1. Baseline characteristics of 504 prostate cancer patients.
| Characteristic | Frequency distribution | ||||||
|---|---|---|---|---|---|---|---|
| Overall (n=504) | Hong Kong (n=261) | China (n=112) | Taiwan (n=75) | Malaysia (n=56) | |||
| At diagnosis | |||||||
| Age (y) | 71 (66–77) | 73 (68–78) | 67 (63–73.75) | 72 (68–80) | 71 (67–78) | ||
| Unknown | 2 | 2 | 0 | 0 | 0 | ||
| ECOG status | |||||||
| 0 | 325 (66.5) | 188 (72.6) | 36 (35.0) | 67 (89.3) | 34 (65.4) | ||
| 1 | 143 (29.2) | 61 (23.6) | 65 (63.1) | 5 (6.7) | 12 (23.1) | ||
| 2 | 17 (3.5) | 8 (3.1) | 2 (1.9) | 2 (2.7) | 5 (9.6) | ||
| 3–4 | 4 (0.8) | 2 (0.8) | 0 (0) | 1 (1.3) | 1 (1.9) | ||
| Unknown | 15 | 2 | 9 | 0 | 4 | ||
| Comorbidity count | |||||||
| 0 | 114 (22.6) | 16 (6.1) | 72 (64.3) | 16 (21.3) | 10 (17.9) | ||
| 1 | 86 (17.1) | 21 (8.0) | 24 (21.4) | 24 (32.0) | 17 (30.4) | ||
| 2 | 78 (15.5) | 36 (13.8) | 14 (12.5) | 16 (21.3) | 12 (21.4) | ||
| ≥3 | 226 (44.8) | 188 (72.0) | 2 (1.8) | 19 (25.3) | 17 (30.4) | ||
| Gleason score | |||||||
| ≤6 | 37 (7.9) | 20 (8.1) | 8 (8.3) | 5 (6.7) | 4 (8.2) | ||
| 7 | 78 (16.7) | 34 (13.8) | 9 (9.4) | 24 (32.0) | 11 (22.4) | ||
| ≥8 | 352 (75.4) | 193 (78.1) | 79 (82.3) | 46 (61.3) | 34 (69.4) | ||
| Unknown | 37 | 14 | 16 | 0 | 7 | ||
| Presence of metastases (M1) | |||||||
| No | 221 (47.1) | 113 (45.2) | 42 (42.4) | 44 (67.7) | 22 (40.0) | ||
| Yes | 248 (52.9) | 137 (54.8) | 57 (57.6) | 21 (32.3) | 33 (60.0) | ||
| Unknown | 35 | 11 | 13 | 10 | 1 | ||
| UICC staging system | |||||||
| Stage I | 40 (8.4) | 25 (9.7) | 3 (3.3) | 9 (12.5) | 3 (5.6) | ||
| Stage II | 56 (11.8) | 31 (12.0) | 5 (5.6) | 16 (22.2) | 4 (7.4) | ||
| Stage III | 78 (16.4) | 37 (14.3) | 10 (11.1) | 21 (29.2) | 10 (18.5) | ||
| Stage IV | 301 (63.4) | 166 (64.1) | 72 (80.0) | 26 (36.1) | 37 (68.5) | ||
| Unknown | 29 | 2 | 22 | 3 | 2 | ||
| At ADT initiation | |||||||
| PSA (ng/mL) | 58.6 (18.9–188.0) | 96.9 (28.5–293.0) | 36.5 (16.5–83.7) | 26.8 (8.3–60.3) | 97.7 (15.9–526.7) | ||
| Unknown | 3 | 0 | 3 | 0 | 0 | ||
| Primary local treatment | |||||||
| Radical prostatectomy (RP) | 35 (6.9) | 4 (1.5) | 24 (21.4) | 7 (9.3) | 0 (0.0) | ||
| Radiotherapy (RT) | 9 (1.8) | 2 (0.8) | 0 (0.0) | 5 (6.7) | 2 (3.6) | ||
| RP+RT | 5 (1.0) | 2 (0.8) | 0 (0.0) | 3 (4.0) | 0 (0.0) | ||
| None | 455 (90.3) | 253 (96.9) | 88 (78.6) | 60 (80.0) | 54 (96.4) | ||
| Primary ADT | 455 | 253 | 88 | 60 | 54 | ||
| LHRH agonist | 227 (49.9) | 145 (57.3) | 4 (4.5) | 44 (73.3) | 34 (63.0) | ||
| LHRH antagonist | 68 (14.9) | 56 (22.1) | 0 (0.0) | 1 (1.7) | 11 (20.4) | ||
| Orchidectomy | 24 (5.3) | 20 (7.9) | 0 (0.0) | 0 (0.0) | 4 (7.4) | ||
| LHRH agonist+AA (MAB) | 63 (13.8) | 5 (2.0) | 50 (56.8) | 7 (11.7) | 1 (1.9) | ||
| Orchidectomy+AA (MAB) | 2 (0.4) | 1 (0.4) | 1 (1.1) | 0 (0.0) | 0 (0.0) | ||
| Chemohormonal therapy | 49 (10.8) | 17 (6.7) | 24 (27.3) | 4 (6.7) | 4 (7.4) | ||
| ARPI+ADT | 15 (3.3) | 9 (3.6) | 2 (2.3) | 4 (6.7) | 0 (0.0) | ||
| AA monotherapy | 5 (1.1) | 0 (0.0) | 5 (2.7) | 0 (0.0) | 0 (0.0) | ||
| Others | 2 (0.4) | 0 (0.0) | 2 (2.3) | 0 (0.0) | 0 (0.0) | ||
Values are presented as median (interquartile range) or number (%).
AA: anti-androgen, ADT: androgen deprivation therapy, ARPI: androgen receptor pathway inhibitor, ECOG: Eastern Cooperative Oncology Group, LHRH: luteinizing hormone-releasing hormone, MAB: maximum androgen blockade, PSA: prostate specific antigen, UICC: Union for International Cancer Control.
The EQ-5D-5L was evaluable in 442 (87.7%) of 504 patients receiving ADT alone or in combination with the exclusion of 62 (12.3%) patients due to missing EQ-5D-5L questionnaires. Summary of individual EQ-5D-5L dimensions at baseline was described in Table 2. Overall, most patients reported no problems with MO (76.7%), SC (87.3%), or performing their UA (83.0%), no PD (68.3%) and were not anxious or depressed (72.6%) during ADT initiation. We observed a relatively higher proportion of Malaysian patients having slight problems in MO (30.4%) and UA (25.0%) as well as slight PD (48.2%) and moderate AD (10.7%) compared to those from Hong Kong (MO: 12.6%, UA: 3.3%, PD: 18.0%, and AD: 1.3%) and Taiwan (MO: 6.7%, UA: 5.3%, PD: 18.7%, and AD: 5.3%). Similar trend was observed in the patients from China across all EQ-5D-5L dimensions except AD component. Participants had an overall high baseline EQ-5D-5L health status (VAS) (median: 80, IQR: 70–90), indicating good overall health during ADT initiation (Table 3). The change of response rate by level of severity for EQ-5D-5L dimensions across different Asian populations at baseline, month 6 and month 12 was evaluable in 235 patients (46.6%) as illustrated in Fig. 1.
Table 2. Analysis of individual EQ-5D-5L dimensions at baseline (EQ-5D-5L) based on countries (n=442).
| Dimension | Frequency distribution | |||||
|---|---|---|---|---|---|---|
| Overall (n=442) | Hong Kong (n=239) | China (n=72) | Taiwan (n=75) | Malaysia (n=56) | ||
| Mobility | ||||||
| No problems | 339 (76.7) | 195 (81.6) | 45 (62.5) | 65 (86.7) | 34 (60.7) | |
| Slight problems | 79 (17.9) | 30 (12.6) | 27 (37.5) | 5 (6.7) | 17 (30.4) | |
| Moderate problems | 15 (3.4) | 10 (4.2) | 0 (0) | 4 (5.3) | 1 (1.8) | |
| Severe problems | 9 (2.0) | 4 (1.7) | 0 (0) | 1 (1.3) | 4 (7.1) | |
| Unable to walk about | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |
| Self-care | ||||||
| No problems | 386 (87.3) | 228 (95.4) | 42 (58.3) | 70 (93.3) | 46 (82.1) | |
| Slight problems | 46 (10.4) | 7 (2.9) | 30 (41.7) | 3 (4.0) | 6 (10.7) | |
| Moderate problems | 6 (1.4) | 2 (0.8) | 0 (0) | 2 (2.7) | 2 (3.6) | |
| Severe problems | 2 (0.5) | 1 (0.4) | 0 (0) | 0 (0) | 1 (1.8) | |
| Unable to wash or dress | 2 (0.5) | 1 (0.4) | 0 (0) | 0 (0) | 1 (1.8) | |
| Usual activities | ||||||
| No problems | 367 (83.0) | 223 (93.3) | 41 (56.9) | 67 (89.3) | 36 (64.3) | |
| Slight problems | 57 (12.9) | 8 (3.3) | 31 (43.1) | 4 (5.3) | 14 (25.0) | |
| Moderate problems | 11 (2.5) | 4 (1.7) | 0 (0) | 4 (5.3) | 3 (5.4) | |
| Severe problems | 4 (0.9) | 4 (1.7) | 0 (0) | 0 (0) | 0 (0) | |
| Unable to do usual activities | 3 (0.7) | 0 (0) | 0 (0) | 0 (0) | 3 (5.4) | |
| Pain/discomfort | ||||||
| No pain/discomfort | 302 (68.3) | 178 (74.5) | 49 (68.1) | 53 (70.7) | 22 (39.3) | |
| Slight pain/discomfort | 107 (24.2) | 43 (18.0) | 23 (31.9) | 14 (18.7) | 27 (48.2) | |
| Moderate pain/discomfort | 21 (4.8) | 11 (4.6) | 0 (0) | 5 (6.7) | 5 (8.9) | |
| Severe pain/discomfort | 9 (2.0) | 7 (2.9) | 0 (0) | 1 (1.3) | 1 (1.8) | |
| Extreme pain/discomfort | 3 (0.7) | 0 (0) | 0 (0) | 2 (2.7) | 1 (1.8) | |
| Anxiety/depression | ||||||
| No anxious/depressed | 321 (72.6) | 179 (74.9) | 59 (81.9) | 51 (68.0) | 32 (57.1) | |
| Slightly anxious/depressed | 98 (22.2) | 54 (22.6) | 13 (18.1) | 17 (22.7) | 14 (25.0) | |
| Moderately anxious/depressed | 13 (2.9) | 3 (1.3) | 0 (0) | 4 (5.3) | 6 (10.7) | |
| Severely anxious/depressed | 7 (1.6) | 3 (1.3) | 0 (0) | 1 (1.3) | 3 (5.4) | |
| Extremely anxious/depressed | 3 (0.7) | 0 (0) | 0 (0) | 2 (2.7) | 1 (1.8) | |
Values are presented as number (%).
EQ-5D-5L: EuroQoL-5 dimensions, 5 level scale.
Table 3. Distribution of health-related quality of life profile in Asian prostate cancer patients receiving androgen deprivation therapy.
| Measure | EQ-5D-5L utility index score | EQ-VAS score | |||||
|---|---|---|---|---|---|---|---|
| Median | IQR | p-value | Median | IQR | p-value | ||
| Baseline | <0.001 | <0.001 | |||||
| Overall (n=442) | 0.924 | 0.876–1.000 | 80.0 | 70.0–90.0 | |||
| Hong Kong (n=239) | 1.000 | 0.891–1.000 | 80.0 | 70.0–90.0 | |||
| China (n=72) | 0.897 | 0.886–0.951 | 91.5 | 90.0–93.0 | |||
| Taiwan (n=75) | 1.000 | 0.881–1.000 | 80.0 | 70.0–90.0 | |||
| Malaysia (n=56) | 0.843 | 0.767–0.928 | 70.0 | 50.0–72.5 | |||
| Month 6 | <0.001 | <0.001 | |||||
| Overall (n=338) | 0.936 | 0.886–1.000 | 80.0 | 75.0–90.0 | |||
| Hong Kong (n=204) | 1.000 | 0.891–1.000 | 80.0 | 75.0–90.0 | |||
| China (n=44) | 0.892 | 0.886–0.934 | 90.0 | 89.0–92.5 | |||
| Taiwan (n=47) | 1.000 | 0.936–1.000 | 80.0 | 75.0–90.0 | |||
| Malaysia (n=43) | 0.838 | 0.703–0.928 | 70.0 | 62.5–82.5 | |||
| Month 12 | 0.001 | 0.001 | |||||
| Overall (n=242) | 0.933 | 0.849–1.000 | 80.0 | 70.0–90.0 | |||
| Hong Kong (n=178) | 1.000 | 0.891–1.000 | 80.0 | 70.0–90.0 | |||
| China (n=17) | 0.885 | 0.876–0.906 | 91.0 | 88.0–92.5 | |||
| Taiwan (n=33) | 1.000 | 0.881–1.000 | 80.0 | 70.0–90.0 | |||
| Malaysia (n=14) | 0.838 | 0.633–0.919 | 75.0 | 60.0–75.0 | |||
IQR: interquartile range, VAS: visual analog scale.
Fig. 1. Proportion of responses by level of severity (n=235) for each the EuroQoL-5 dimensions, 5 level scale dimension including (A) mobility, (B) self-care, (C) usual activities, (D) pain/discomfort, and (E) anxiety/depression across different Asian populations at baseline, month 6, and month 12.
The median EQ-5D-5L utility index scores were shown in Table 3. Overall, baseline EQ-5D-5L utility index score was 0.924 (IQR 0.876–1.000). We observed a statistically significant difference in baseline EQ-5D-5L utility index score between different countries/regions, χ2(3)=43.473, p<0.001, with a median EQ-5D-5L utility index score of 1 for Taiwan & Hong Kong, 0.897 for China and 0.838 for Malaysia. In addition, stage IV prostate cancer were significantly associated with a lower baseline EQ-5D-5L utility index score compared to stage I–III prostate cancer, χ2(3)=11.886, p=0.008, producing a median disutility value of -0.080. There was no statistical significance changes in median EQ-5D-5L utility index score from baseline to month 6 and month 12 based on disease stage (Fig. 2A).
Fig. 2. Distribution of median EQ-5D-5L utility index scores at baseline, month 6 and month 12 based on baseline. (A) Union for International Cancer Control (UICC) cancer stage (n=235) and (B) Eastern Cooperative Oncology Group (ECOG) status (n=234). EQ-5D-5L: EuroQoL-5 dimensions, 5 level scale.
Furthermore, ECOG status was associated with HRQOL inversely (χ2(3)=81.691, p<0.01), in which patients with ECOG 3 had a lower median baseline EQ-5D-5L utility index score of 0.219 compared to those of ECOG 0 (median baseline EQ-5D-5L utility index score: 1). Fig. 2B showed that median EQ-5D-5L utility index score were constant from baseline to month 6 and month 12 for those of ECOG 0–1. Although changes of EQ-5D-5L utility index score was observed in patients with ECOG 2–4 from baseline to month 6 and month 12, the number of patients was too small (7/235; 3.0%) to enable a meaningful analysis.
The number of patients available for EQ-5D-5L assessment declined over time, in which 76.5% (338/442) and 54.8% (242/442) completed the questionnaire at month 6 and month 12 respectively. There was a significant difference in EQ-5D-5L utility index score at month 6 and month 12 between different countries/regions (p<0.05). A full health state (median utility index score=1) was recorded consistently in patients from Hong Kong and Taiwan during both treatment visits compared to those of China (median utility index score=0.892 for month 6 and 0.885 for month 12) and Malaysia (median utility index score=0.838 for month 6 and month 12). The estimated coefficients and the 95% confidence intervals for the quantile mixed model were summarized in Table 4. The median utility index scores for Hong Kong and Taiwan were significantly higher than the scores for China and Malaysia at baseline. The change in score over time was not significant.
Table 4. Quantile mixed model results for median EQ-5D-5L utility index score (95% confidence interval).
| Measure | Median EQ-5D-5L utility index score | p-value | |
|---|---|---|---|
| Intercept | 0.961 (0.926 to 0.995) | <0.001 | |
| Region | |||
| Hong Kong | Reference | ||
| China | -0.059 (-0.093 to -0.025) | 0.001 | |
| Taiwan | 0.020 (-0.019 to 0.060) | 0.305 | |
| Malaysia | -0.107 (-0.152 to -0.063) | <0.001 | |
| Time | |||
| Baseline | Reference | ||
| Month 6 | 0.019 (-0.002 to 0.039) | 0.071 | |
| Month 12 | -0.0003 (-0.029 to 0.028) | 0.982 | |
EQ-5D-5L: EuroQoL-5 dimensions, 5 level scale.
Further analysis revealed that treatment affected the AD dimension particularly in Malaysian patients with an increase of 19.1% experiencing slight-to-moderate AD from baseline to month 6. There was no treatment effect in the overall EQ-5D-5L health status (VAS) from baseline to month 12 (Table 3) across all four Asian populations. In addition, 19 patients developed disease progression over 12 months of follow up with the median utility index score of 0.838. All of their initial ADT treatments were revised with either addition of APRI into ADT (47.4%), change of LHRH agonist and antagonist (42.1%) or chemohormonal therapy (10.5%).
DISCUSSION
Findings from this READT study provide an insight into the effect of ADT in the quality of life of prostate cancer patients at the real-world setting. We demonstrated that there were significant health utility index score variations across different Asian populations whilst overall EQ-5D-5L health status (VAS) remained unaffected during ADT. Of note, Hong Kong and Taiwan are high-income economies compared to China and Malaysia which are upper middle income countries based on the World Bank classification [15]. Higher health expenditure was recorded in high income economies (14.02% of gross domestic product [GDP]) than middle income countries (6.21% of GDP), leading to variations in healthcare system & infrastructure, resources and medical services [15]. Together, these socioeconomic disparities may also affect patients’ accessibility and affordability to comprehensive care and psychosocial support [8], resulting in lower health utility index score observed in China and Malaysia cohorts than those from Hong Kong and Taiwan. To our knowledge, this prospective, observational study is the first to evaluate and compare preference-weighted HRQOL data of Asian prostate cancer patients receiving ADT.
Whilst survival is undoubtedly a primary outcome, systemic treatment can be a double-edged sword. Response to treatment improves one’s clinical symptoms; however, his HRQOL may be negatively impacted due to side effects. In localized prostate cancer, initiation of ADT causes declines in HRQOL including general physical and emotional well-being as well as sexual and bowel dysfunction [16,17]. Similar treatment effects were experienced among patients with recurrent or metastatic prostate cancer, in addition to bone pain and fractures that result in HRQOL deterioration and increased mortality [18,19,20]. Long-term ADT is associated with cardiovascular, metabolic and cognitive complications [4]. Previous study revealed that 76.5% of men living 18–42 months after diagnosis of stage IV prostate cancer reported one or more problems on any EQ-5D dimensions with the highest proportion in PD (54.6%) [21]. This trend was consistently observed in the present study in which number of stage IV patients suffered from PD increased from 41.5% at baseline to 49.8% at month 6 of ADT.
With the exacerbating high-priced healthcare cost, health state utility index scores are used for cost-effectiveness analysis in quality-adjusted life years estimation [9,22]. Real-world data on utility index scores for prostate cancer patients remains scarce. It has been reported twice only using mapping preferences onto a value set via EQ-5D questionnaire [23,24]. Färkkilä et al [23] estimated the EQ-5D utility index score as 0.551 and 0.694 for end-stage Finnish prostate cancer patients, based on the EQ-5D-3L and 15D respectively. Interestingly, findings from Japanese patients revealed a higher (0.845) in distant metastatic prostate cancer patients [24], in line with the EQ-5D-5L utility index score (0.882) among stage IV patients in the present study. The discrepancy of HRQOL between Asian and Caucasian population may attribute to cultural perspective in defining health and HRQOL as well as stronger Asian family networks and emotional & practical support to patients [25].
Psychological distress are prevalent in prostate cancer patients particularly in advanced disease, leading to poor HRQOL, prolonged hospitalization and increased mortality rates [26,27,28]. Approximately 30% of prostate cancer patients suffered from de novo psychiatric illness including depression, dementia and anxiety [29]. In this study, there were ~25% of prostate cancer patients presented with slight-to-moderate AD pretreatment with an increase of 19.1% particularly in Malaysian patients whilst on-treatment, suggesting ADT affects the psychological well-being at various stages of one’s cancer journey. We cannot establish whether history of depression and anxiety were independently associated with their current psychological conditions as such data was unavailable at this stage. It is interesting to note that there was little to no difference in HRQOL over 12 months of follow up although high proportion of patients were of advanced prostate cancer. This may attribute to several factors including (i) good baseline ECOG performance status (ECOG 0–1) presented in 95.7% of patients, (ii) favorable treatment outcome and high tolerability of primary ADT with only 8% developed disease progression within 12 months as well as (iii) support and care from family members [24], which improve patients’ functional capacity and enhance their quality of life.
There are limitations in this multi-center study. First, comparative analyses were not conducted between baseline and on-treatment visits within the same country/region, owing to the limited sample size. Second, READT enrolled <15% patients with combination systemic therapy, which may limit the generalizability of these findings in the era of triplet therapy. Third, there is a risk of selection bias and case ascertainment bias, which was minimized by consecutive patient enrollment using standardized recruitment criteria. Fourth, there are inherent multiplicity issues with PROs throughout multiple treatment time point particularly lower number of patients towards the end of the study. This might introduce dropout bias as reasons of missing data were not well-documented and there was an imbalanced completion rate of ED-5D-5L between countries specifically at month 12 as observed in the China and Malaysia cohorts, increasing the probability of type I errors.
One of the strengths of this READT cohort is the substantial sample size (>400 subjects) to understand the change of HRQOL over a disease trajectory. The use of validated and reliable PRO questionnaire (EQ-5D-5L) further strengthened the analysis with high adherence rate at baseline and during month 6 treatment. We provide the first documented evidence of health state utility index scores during ADT initiation across various Asian populations at real-world setting, impacting both clinical practice and policy making. Health utility index scores serve as valuable information in patient-centered treatment recommendation consisting of both clinical and HRQOL outcomes [30]. This is crucial for clinicians to integrate patients’ perspectives and experiences in formulating an optimal treatment strategy during the shared decision-making process. Furthermore, findings from this study unlock the potential of real-world PROs evidence in aiding policy makers to define core outcomes of Asian prostate cancer patients undergoing ADT and generate evidence-based recommendations of prostate cancer management. Policy makers may utilize health utility index scores to make informed decisions in allocating resources and funding treatments that benefit the survival and HRQOL of prostate cancer patients.
CONCLUSIONS
In summary, this study presents the health state utility index score estimates and HRQOL in Asian prostate cancer patients treated with ADT using EQ-5D-5L at real-world setting. We found a significant difference of health state utility index score among different Asian populations with considerable decline in HROQL from early stage to late stage disease. Whilst the landscape of prostate cancer treatments is evolving rapidly, our findings will be informative and aid in model-based economic evaluations and policy decision making.
Acknowledgements
The authors thank all associates for their assistance in the data collection at all participating hospitals.
Footnotes
Conflict of Interest: The authors have nothing to disclose.
Funding: None.
- Conceptualization: CFN, YW, TAO, PSKC, WKWC, CYH, KKF, JYCT, NX, PKFC, CHY.
- Data curation: JL, CFN, YW, TAO, PSKC, WKWC, CYH, KKF, JYCT, NX, JWL, WSY, PKFC, CHY, SCHL.
- Formal analysis: JL, CFN, JWL, TAO, SCHL.
- Writing – orginal draft: JL.
- Writing – review & editing: JL, CFN, TAO.
Data Sharing Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
- 1.GLOBOCAN 2020. Cancer today [Internet] Lyon: International Agency for Research on Cancer; c2020. [cited 2023 Feb 1]. Available from: https://gco.iarc.fr/today/home . [Google Scholar]
- 2.Lim J, Onozawa M, Saad M, Ong TA, Malek R, Akaza H. Recent trend of androgen deprivation therapy in newly diagnosed prostate cancer patients: comparing between high- and middle-income Asian countries. Cancer Sci. 2021;112:2071–2080. doi: 10.1111/cas.14889. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293–297. doi: 10.3322/canjclin.22.4.232. [DOI] [PubMed] [Google Scholar]
- 4.Nguyen PL, Alibhai SM, Basaria S, D'Amico AV, Kantoff PW, Keating NL, et al. Adverse effects of androgen deprivation therapy and strategies to mitigate them. Eur Urol. 2015;67:825–836. doi: 10.1016/j.eururo.2014.07.010. [DOI] [PubMed] [Google Scholar]
- 5.Akaza H. Future prospects for luteinizing hormone-releasing hormone analogues in prostate cancer treatment. Pharmacology. 2010;85:110–120. doi: 10.1159/000274486. [DOI] [PubMed] [Google Scholar]
- 6.Ng CF, Chiu PKF, Yee CH, Lau BSY, Leung SCH, Teoh JYC. Effect of androgen deprivation therapy on cardiovascular function in Chinese patients with advanced prostate cancer: a prospective cohort study. Sci Rep. 2020;10:18060. doi: 10.1038/s41598-020-75139-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Huang G, Yeung CY, Lee KK, Liu J, Ho KL, Yiu MK, et al. Androgen deprivation therapy and cardiovascular risk in Chinese patients with nonmetastatic carcinoma of prostate. J Oncol. 2014;2014:529468. doi: 10.1155/2014/529468. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Dee EC, Paguio JA, Yao JS, Lim J, Lasco G. Asian minorities in Asian countries: intersecting disparities affecting minoritised groups. Lancet Oncol. 2021;22:e381. doi: 10.1016/S1470-2045(21)00350-8. [DOI] [PubMed] [Google Scholar]
- 9.Drummond MF, Sculpher MJ, Claxton K, Stoddart GL, Torrance GW. Methods for the economic evaluation of health care programmes. 4th ed. Oxford University Press; 2015. [Google Scholar]
- 10.Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L) Qual Life Res. 2011;20:1727–1736. doi: 10.1007/s11136-011-9903-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Shafie AA, Vasan Thakumar A, Lim CJ, Luo N, Rand-Hendriksen K, Md Yusof FA. EQ-5D-5L valuation for the Malaysian population. Pharmacoeconomics. 2019;37:715–725. doi: 10.1007/s40273-018-0758-7. [DOI] [PubMed] [Google Scholar]
- 12.Luo N, Liu G, Li M, Guan H, Jin X, Rand-Hendriksen K. Estimating an EQ-5D-5L value set for China. Value Health. 2017;20:662–669. doi: 10.1016/j.jval.2016.11.016. [DOI] [PubMed] [Google Scholar]
- 13.Lin HW, Li CI, Lin FJ, Chang JY, Gau CS, Luo N, et al. Valuation of the EQ-5D-5L in Taiwan. PLoS One. 2018;13:e0209344. doi: 10.1371/journal.pone.0209344. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Wong ELY, Ramos-Goñi JM, Cheung AWL, Wong AYK, Rivero-Arias O. Assessing the use of a feedback module to model EQ-5D-5L health states values in Hong Kong. Patient. 2018;11:235–247. doi: 10.1007/s40271-017-0278-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.The World Bank [Internet] Washington, D.C.: World Bank Group; c2021. [cited 2023 Feb ]. Available from: https://www.worldbank.org/en/home . [Google Scholar]
- 16.Punnen S, Cowan JE, Chan JM, Carroll PR, Cooperberg MR. Long-term health-related quality of life after primary treatment for localized prostate cancer: results from the CaPSURE registry. Eur Urol. 2015;68:600–608. doi: 10.1016/j.eururo.2014.08.074. [DOI] [PubMed] [Google Scholar]
- 17.Potosky AL, Reeve BB, Clegg LX, Hoffman RM, Stephenson RA, Albertsen PC, et al. Quality of life following localized prostate cancer treated initially with androgen deprivation therapy or no therapy. J Natl Cancer Inst. 2002;94:430–437. doi: 10.1093/jnci/94.6.430. [DOI] [PubMed] [Google Scholar]
- 18.Lubeck DP, Grossfeld GD, Carroll PR. The effect of androgen deprivation therapy on health-related quality of life in men with prostate cancer. Urology. 2001;58(2 Suppl 1):94–100. doi: 10.1016/s0090-4295(01)01250-x. [DOI] [PubMed] [Google Scholar]
- 19.Sartor O, Flood E, Beusterien K, Park J, Webb I, MacLean D, et al. Health-related quality of life in advanced prostate cancer and its treatments: biochemical failure and metastatic disease populations. Clin Genitourin Cancer. 2015;13:101–112. doi: 10.1016/j.clgc.2014.08.001. [DOI] [PubMed] [Google Scholar]
- 20.McKay R, Haider B, Duh MS, Valderrama A, Nakabayashi M, Fiorillo M, et al. Impact of symptomatic skeletal events on health-care resource utilization and quality of life among patients with castration-resistant prostate cancer and bone metastases. Prostate Cancer Prostatic Dis. 2017;20:276–282. doi: 10.1038/pcan.2017.4. [DOI] [PubMed] [Google Scholar]
- 21.Downing A, Wright P, Hounsome L, Selby P, Wilding S, Watson E, et al. Quality of life in men living with advanced and localised prostate cancer in the UK: a population-based study. Lancet Oncol. 2019;20:436–447. doi: 10.1016/S1470-2045(18)30780-0. [DOI] [PubMed] [Google Scholar]
- 22.Berger ML. Health care cost, quality, and outcomes: ISPOR book of terms. ISPOR; 2003. [Google Scholar]
- 23.Färkkilä N, Torvinen S, Roine RP, Sintonen H, Hänninen J, Taari K, et al. Health-related quality of life among breast, prostate, and colorectal cancer patients with end-stage disease. Qual Life Res. 2014;23:1387–1394. doi: 10.1007/s11136-013-0562-y. [DOI] [PubMed] [Google Scholar]
- 24.Murasawa H, Sugiyama T, Matsuoka Y, Okabe T, Hino A, Tanaka N, et al. Health utility and health-related quality of life of Japanese prostate cancer patients according to progression status measured using EQ-5D-5L and FACT-P. Qual Life Res. 2019;28:2383–2391. doi: 10.1007/s11136-019-02184-y. [DOI] [PubMed] [Google Scholar]
- 25.Mao Z, Ahmed S, Graham C, Kind P, Sun YN, Yu CH. Similarities and differences in health-related quality-of-life concepts between the east and the west: a qualitative analysis of the content of health-related quality-of-life measures. Value Health Reg Issues. 2021;24:96–106. doi: 10.1016/j.vhri.2020.11.007. [DOI] [PubMed] [Google Scholar]
- 26.Watts S, Leydon G, Birch B, Prescott P, Lai L, Eardley S, et al. Depression and anxiety in prostate cancer: a systematic review and meta-analysis of prevalence rates. BMJ Open. 2014;4:e003901. doi: 10.1136/bmjopen-2013-003901. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Pirl WF, Siegel GI, Goode MJ, Smith MR. Depression in men receiving androgen deprivation therapy for prostate cancer: a pilot study. Psychooncology. 2002;11:518–523. doi: 10.1002/pon.592. [DOI] [PubMed] [Google Scholar]
- 28.Watson M, Haviland JS, Greer S, Davidson J, Bliss JM. Influence of psychological response on survival in breast cancer: a population-based cohort study. Lancet. 1999;354:1331–1336. doi: 10.1016/s0140-6736(98)11392-2. [DOI] [PubMed] [Google Scholar]
- 29.DiBlasio CJ, Hammett J, Malcolm JB, Judge BA, Womack JH, Kincade MC, et al. Prevalence and predictive factors for the development of de novo psychiatric illness in patients receiving androgen deprivation therapy for prostate cancer. Can J Urol. 2008;15:4249–4256. discussion 4256. [PubMed] [Google Scholar]
- 30.Van Hemelrijck M, Sparano F, Moris L, Beyer K, Cottone F, Sprangers M, et al. Harnessing the patient voice in prostate cancer research: systematic review on the use of patient-reported outcomes in randomized controlled trials to support clinical decision-making. Cancer Med. 2020;9:4039–4058. doi: 10.1002/cam4.3018. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.