Abstract
Background:
The role of pelvic irradiation in men receiving external beam radiotherapy (EBRT) for prostate cancer is unclear, in part due to a lack of data on patient-reported outcomes. We sought to compare functional outcomes for men receiving prostate and pelvic versus prostate-only radiotherapy, longitudinally over 5 years.
Materials and methods:
We performed a population-based, prospective cohort study of men with clinically-localized prostate cancer undergoing EBRT. We examined the effect of prostate and pelvic (n=102) versus prostate-only (n=485) radiotherapy on patient-reported disease-specific (using the EPIC-26) and general health-related (using the SF-36) function, over 5 years. Regression models were adjusted for outcome-specific baseline function, clinicopathologic characteristics, and androgen deprivation therapy (ADT).
Results:
587 men (median [quartiles] age 69 [64–73] years) met inclusion criteria and completed ≥1 post-treatment survey. More men treated with prostate and pelvic radiotherapy had high-risk disease (58% vs. 18%, p<0.01) and received ADT (75% vs. 41%, p<0.01). These men reported worse sexual (6 months to 5 years), hormonal (at 6 months), and physical (6 months to 5 years) function. Accounting for baseline function, patient and tumor characteristics, and use of ADT, pelvic irradiation was not associated with statistically or clinically significant differences in bowel function, urinary incontinence, irritative voiding symptoms or sexual function through 5-years (all p>0.05). Marginally clinically important differences were noted in hormonal function at 3-years (adjusted mean difference 4.7, 95% confidence interval [1.2–8.3]; minimally clinically important difference (MCID) 4–6) and 5-years (4.2, [0.4–8.0]) following treatment. After adjustment, there was a transient statistically significant, but not clinically important, difference in emotional well being at 6 months (3.0, [0.19–5.8]; MCID 6) that resolved by 1 year and no differences in physical functioning or energy and fatigue.
Conclusions:
This prospective, population-based cohort study of men with localized prostate cancer treated with EBRT, showed no clinically important differences in disease-specific or general health-related quality of life with the addition of pelvic irradiation to prostate radiotherapy, supporting the use of pelvic radiotherapy when it may be of clinical benefit, such as men with increased risk of nodal involvement.
Keywords: Prostatic neoplasms, prospective studies, patient reported outcome measures, survey and questionnaires, cohort studies
INTRODUCTION
The role of pelvic radiotherapy in men undergoing external-beam radiotherapy for prostate cancer remains controversial1. Data on both oncologic and toxicity-related effects of this approach are conflicting1, despite a number of published randomized controlled trials. Concerning toxicity, available studies have examined use of 3D-conformal radiotherapy or comprised small cohorts with physician-adjudicated toxicity assessment2–6. Recently, the POP-RT study reported improvements in biochemical failure-free survival and disease-free survival but not overall survival7 for patients receiving pelvic radiotherapy with increased late genitourinary toxicity8.
There are two main issues applying the available data to patient counselling. First, there is poor correlation between patient- and physician-reported symptoms among patients with prostate cancer9. Thus, given importance of patient-centered care, most available toxicity data have limited value. Second, it is well accepted that treatment effects observed in randomized controlled trials may differ substantially from their effects in clinical practice, the so-called efficacy-effectiveness gap10,11. To address each of these issues, we utilized data from the prospectively accrued Comparative Effectiveness Analysis of Surgery and Radiation study (CEASAR) to assess the effect of adding pelvic, to prostate, radiotherapy on longitudinal measures of patient-reported outcomes (PROs).
METHODS
From 2011–2012, the prospective population-based CEASAR study recruited men aged ≤80 years with clinically-localized prostate cancer (cT1-cT2, PSA<50ng/dL) from 5 population-based Surveillance, Epidemiology, and End Results registries and the Cancer of the Prostate Strategic Urologic Research Endeavour (CaPSURE) within 6 months following diagnosis. Institutional review board approval was obtained from Vanderbilt University Medical Center (coordinating center) and from each participating sites.
The CEASAR study collected data on men treated with radiotherapy, surgery, ablation, and active surveillance utilizing baseline and follow-up surveys and medical chart abstraction at 1 year following enrollment. This analysis relies on patients treated with EBRT. Our exposure variable was radiotherapy approach (prostate plus pelvic versus prostate-only).
We assessed patient-reported disease-specific and general health-related function using the validated 26-item Expanded Prostate Index Composite (EPIC)12 and Short Form Health Survey (SF-36)13, respectively. Each domain is scored from 0–100, with higher scores indicating better function. We interpreted results based on previously determined minimally clinical important differences for each functional domain: sexual, 12; urinary incontinence, 9; urinary irritative, 7; bowel, 6; and hormonal function, 6; physical functioning, 7; emotional well-being, 6; and energy and fatigue, 914,15. Surveys were completed at baseline, 6-months, 1-, 3-, and 5-years after enrollment.
Important demographic, clinicopathologic, and treatment-related covariates were captured from patient-reported surveys and chart abstraction, as appropriate.
Patients’ baseline demographic, tumor and treatment characteristics were summarized with median and interquartile range (continuous variables) or frequency and percentage (categorical variables) by receipt of Pelvic radiation treatment (Pelvic radiation versus No Pelvic radiation). Differences between treatments were assessed using Wilcoxon Rank-Sum or Pearson’s chi-squared tests. The study endpoints (PROs including five EPIC domain scores and three SF-36 scores) were compared between treatments at each study time point using Wilcoxon Rank-Sum test. To further evaluate the associations between treatments and PROs over time, using the longitudinal survey data, we fit multivariable longitudinal linear regression models adjusting Gleason grade, clinical tumor stage, PSA, baseline PRO scores (outcome specific), and propensity score of receipt Pelvic radiation. To allow for variable estimation of treatment at different time points, we included the interaction terms between treatment and time since treatment in the models. To mitigate the confounding from differences in patients’ baseline characteristics (including baseline PROs), we included the propensity scores in the multivariable models. By adjusting for the propensity scores, we further controlled patients’ age (continuous, restricted cubic splines), race, insurance status, household income, marital status, Gleason grade, clinical tumor stage, PSA, ADT, D’Amico risk group, TIBI-CaP, study site, CESD score (continuous, linear), social support (continuous, linear), participatory decision-making index (continuous, linear), baseline EPIC-26, and SF-36 scores (continuous, linear). In all models, to account for the correlation due to repeated measurements collected on the same subjects from multiple time points, the Huber-White method16,17 was implemented by robcov function in rms R package to estimate the variance-covariance matrices. Mean differences between treatments and associated 95% confidence intervals (CI) were reported as effect measurements. All missing covariate values were imputed 10 times using the MICE (multiple imputation using chained equations) implemented by aregImpute function in rms R package. Statistical significance was considered for all two-sided p values < 5%. All analyses were conducted using R version 4.0.2.
RESULTS
Among 587 men treated with EBRT who completed baseline and ≥1 post-baseline survey, 102 men received prostate and pelvic radiotherapy while 485 received prostate only radiotherapy (Figure). 99% of pelvic radiotherapy was delivered with IMRT. Patients who received pelvic radiotherapy were more likely to have high risk-disease (58% vs. 18%) driven by a higher proportion of patients with palpable disease (38% vs. 25%), and high-grade histology. Accordingly, these patients were more likely to receive androgen deprivation therapy (ADT). Further differences were observed with respect to age, marital status, income, and health insurance (Table 1).
Figure.
Diagram of the Assembly of the Analytic Cohort based on CEASAR Study Cohort.
Table 1.
Baseline characteristics of cohort, stratified by receipt of pelvic radiotherapy.
| N | Pelvic Radiation (n=102) | No Pelvic Radiation (n=485) | Combined (n=587) | P-value | |
|---|---|---|---|---|---|
| DEMOGRAPHICS | |||||
| Age at diagnosis, median (IQR), y | 587 | 70 (65–75) | 69 (64–73) | 69 (64–73) | 0.017 |
| Race | 585 | 0.137 | |||
| White | 69 (68%) | 341 (70%) | 410 (70%) | ||
| Black | 25 (25%) | 82 (17%) | 107 (18%) | ||
| Hispanic | 3 ( 3%) | 35 ( 7%) | 38 ( 6%) | ||
| Asian | 2 ( 2%) | 21 ( 4%) | 23 ( 4%) | ||
| Other | 2 ( 2%) | 5 ( 1%) | 7 ( 1%) | ||
| Education | 571 | 0.091 | |||
| Less than high school | 24 (24%) | 70 (15%) | 94 (16%) | ||
| High school graduate | 18 (18%) | 98 (21%) | 116 (20%) | ||
| Some college | 24 (24%) | 104 (22%) | 128 (22%) | ||
| College graduate | 20 (20%) | 96 (20%) | 116 (20%) | ||
| Graduate/professional school | 13 (13%) | 104 (22%) | 117 (20%) | ||
| Marital status | 569 | <0.001 | |||
| Not married | 39 (39%) | 109 (23%) | 148 (26%) | ||
| Married | 60 (61%) | 361 (77%) | 421 (74%) | ||
| Comorbidity score (TIBI) | 574 | 0.056 | |||
| 0–2 | 13 (13%) | 87 (18%) | 100 (17%) | ||
| 3–4 | 34 (34%) | 200 (42%) | 234 (41%) | ||
| 5 or more | 52 (53%) | 188 (40%) | 240 (42%) | ||
| Income | 527 | 0.001 | |||
| Less than $30,000 | 42 (48%) | 125 (28%) | 167 (32%) | ||
| $30,001 -- $50,000 | 19 (22%) | 99 (23%) | 118 (22%) | ||
| $50,001 -- $100,000 | 19 (22%) | 120 (27%) | 139 (26%) | ||
| More than $100,000 | 8 ( 9%) | 95 (22%) | 103 (20%) | ||
| Health insurance | 587 | 0.018 | |||
| Medicare | 78 (76%) | 323 (67%) | 401 (68%) | ||
| Private/HMO | 15 (15%) | 139 (29%) | 154 (26%) | ||
| VA/military | 1 ( 1%) | 3 ( 1%) | 4 ( 1%) | ||
| Medicaid | 5 ( 5%) | 6 ( 1%) | 11 ( 2%) | ||
| Other | 1 ( 1%) | 5 ( 1%) | 6 ( 1%) | ||
| None | 2 ( 2%) | 9 ( 2%) | 11 ( 2%) | ||
| Employment | 579 | 0.068 | |||
| Full time | 14 (14%) | 117 (24%) | 131 (23%) | ||
| Part time | 7 ( 7%) | 39 ( 8%) | 46 ( 8%) | ||
| Retired | 74 (74%) | 289 (60%) | 363 (63%) | ||
| Unemployed | 5 ( 5%) | 34 ( 7%) | 39 ( 7%) | ||
| Site | 587 | <0.001 | |||
| Utah | 3 ( 3%) | 11 ( 2%) | 14 ( 2%) | ||
| Atlanta | 5 ( 5%) | 42 ( 9%) | 47 ( 8%) | ||
| LA | 8 ( 8%) | 135 (28%) | 143 (24%) | ||
| Louisiana | 77 (75%) | 148 (31%) | 225 (38%) | ||
| NJ | 5 ( 5%) | 127 (26%) | 132 (22%) | ||
| CaPSURE | 4 ( 4%) | 22 ( 5%) | 26 ( 4%) | ||
| TUMOR AND TREATMENT CHARACTERISTICS | |||||
| PSA at diagnosis, corrected, median (IQR) | 587 | 7 (5–12) | 6 (5–9) | 6 (5–9) | 0.118 |
| Clinical tumor stage | 586 | 0.006 | |||
| T1 | 63 (62%) | 363 (75%) | 426 (73%) | ||
| T2 | 39 (38%) | 121 (25%) | 160 (27%) | ||
| Biopsy Gleason score | 585 | <0.001 | |||
| 6 or less | 9 ( 9%) | 195 (40%) | 204 (35%) | ||
| 3 + 4 | 29 (28%) | 171 (35%) | 200 (34%) | ||
| 4 + 3 | 22 (22%) | 63 (13%) | 85 (15%) | ||
| 8,9,10 | 42 (41%) | 54 (11%) | 96 (16%) | ||
| Damico risk group | 585 | <0.001 | |||
| Low Risk | 7 ( 7%) | 163 (34%) | 170 (29%) | ||
| Intermediate Risk | 36 (35%) | 234 (48%) | 270 (46%) | ||
| High Risk | 59 (58%) | 86 (18%) | 145 (25%) | ||
| Use of ADT within 1 year of diagnosis | 582 | <0.001 | |||
| No | 26 (25%) | 285 (59%) | 311 (53%) | ||
| Yes | 76 (75%) | 195 (41%) | 271 (47%) | ||
| Use of IMRT | 587 | <0.001 | |||
| Yes | 101 (99%) | 387 (80%) | 488 (83%) | ||
| No | 1 (1%) | 98 (20%) | 99 (17%) | ||
| Use of IGRT | 557 | 0.13 | |||
| Yes | 92 (90%) | 384 (84%) | 476 (85%) | ||
| No | 10 (10%) | 71 (16%) | 81 (15%) | ||
| Radiation dose, Gy, median (IQR) | 582 | 78 (77.4–79.2) | 78 (76–79.2) | 78 (76–79.2) | 0.56 |
| Radiation dose ≥75Gy | 582 | 0.42 | |||
| Yes | 92 (90%) | 419 (87%) | 511 (88%) | ||
| No | 10 (10%) | 61 (13%) | 71 (12%) | ||
Abbreviations: IQR, interquartile range; TIBI, Total Illness Burden Index for Prostate Cancer; HMO, Health maintenance organization; VA, Veterans Affairs; CaPSURE, Cancer of the Prostate Strategic Urologic Research Endeavor; ADT, androgen deprivation therapy
In unadjusted analysis, patient-reported disease-specific functional outcomes were similar between prostate and pelvic radiotherapy and prostate-only radiotherapy groups from baseline through 5 years (Table 2), with the notable exception of worse sexual (from 6 months to 5 years) and hormonal function (at 6 months) among those receiving pelvic radiotherapy. In adjusted analyses, no significant differences were found in bowel, urinary incontinence, irritative voiding symptoms, or sexual function through 5-years between treatment groups, while marginally clinically significant differences were noted in hormonal function at 3-years (adjusted mean difference 4.7, 95% confidence interval [1.2–8.3]; minimally clinically important difference (MCID) 4–6) and 5-years (4.2, [0.4–8.0]) following treatment (Table 2).
Table 2.
Association between pelvic radiation and disease-specific-related patient-reported functional outcomes.
| Time | N | Pelvic Radiation, median (quartiles) | No Pelvic Radiation, median (quartiles) | Combined, median (quartiles) | Crude P-valuea | Multivariable adjusted modelb | |
|---|---|---|---|---|---|---|---|
| Pelvic Radiation vs. No Pelvic Radiation | |||||||
| Effect estimate (95% CI) | P-value | ||||||
| EPIC-26 urinary incontinence domain score | |||||||
| Baseline | 560 | 93 (73, 100) | 100 (79, 100) | 100 (79, 100) | 0.04 | n/a | |
| 6 month | 570 | 92 (67, 100) | 100 (77, 100) | 100 (73, 100) | 0.08 | 0.55 (−3.83 to 4.93) | 0.81 |
| 1 year | 522 | 92 (71, 100) | 100 (79, 100) | 100 (75, 100) | 0.28 | 1.78 (−1.85 to 5.42) | 0.34 |
| 3 year | 458 | 100 (75, 100) | 94 (75, 100) | 94 (75, 100) | 0.95 | 4.12 (−0.32 to 8.57) | 0.07 |
| 5 year | 402 | 100 (73, 100) | 100 (75, 100) | 100 (73, 100) | 0.99 | 3.78 (−1.80 to 9.36) | 0.18 |
| EPIC-26 urinary irritative domain score | |||||||
| Baseline | 560 | 88 (69, 94) | 88 (75, 94) | 88 (75, 94) | 0.83 | n/a | |
| 6 month | 564 | 88 (75, 94) | 88 (75, 94) | 88 (75, 94) | 0.32 | 0.59 (−2.70 to 3.87) | 0.73 |
| 1 year | 540 | 88 (81, 98) | 88 (77, 94) | 88 (80, 94) | 0.82 | 1.74 (−0.86 to 4.34) | 0.19 |
| 3 year | 458 | 88 (81, 100) | 88 (81, 100) | 88 (81, 100) | 0.26 | 3.20 (0.01 to 6.39) | 0.05 |
| 5 year | 403 | 94 (81, 100) | 88 (81, 100) | 88 (81, 100) | 0.99 | 1.41 (−2.50 to 5.32) | 0.48 |
| EPIC-26 bowel function score | |||||||
| Baseline | 572 | 100 (88, 100) | 100 (92, 100) | 100 (92, 100) | 0.24 | n/a | |
| 6 month | 570 | 100 (79, 100) | 96 (83, 100) | 96 (83, 100) | 0.68 | 0.94 (−2.60 to 4.49) | 0.60 |
| 1 year | 549 | 96 (83, 100) | 96 (83, 100) | 96 (83, 100) | 0.78 | 2.02 (−0.75 to 4.79) | 0.15 |
| 3 year | 469 | 96 (84, 100) | 96 (83, 100) | 96 (83, 100) | 0.54 | 3.07 (−0.38 to 6.52) | 0.081 |
| 5 year | 409 | 96 (83, 100) | 96 (88, 100) | 96 (88, 100) | 0.65 | 0.76 (−3.38 to 4.90) | 0.72 |
| EPIC-26 sexual function score | |||||||
| Baseline | 548 | 48 (12, 80) | 58 (22, 80) | 58 (18, 80) | 0.09 | n/a | |
| 6 month | 535 | 5 (0, 38) | 35 (0, 68) | 27 (0, 67) | <0.001 | −1.78 (−7.60 to 4.03) | 0.55 |
| 1 year | 529 | 7 (0, 58) | 38 (10, 65) | 33 (7, 65) | <0.001 | −1.71 (−7.59 to 4.16) | 0.57 |
| 3 year | 448 | 8 (0, 57) | 38 (10, 70) | 33 (7, 70) | <0.001 | −0.23 (−7.63 to 7.16) | 0.95 |
| 5 year | 384 | 16 (0, 52) | 32 (7, 66) | 28 (5, 65) | 0.01 | 2.50 (−5.84 to 10.83) | 0.56 |
| EPIC-26 hormonal domain score | |||||||
| Baseline | 553 | 90 (75, 100) | 90 (80, 100) | 90 (80, 100) | 0.06 | n/a | |
| 6 month | 555 | 80 (65, 90) | 90 (75, 100) | 85 (75, 100) | <0.001 | −0.36 (−4.03 to 3.32) | 0.85 |
| 1 year | 534 | 85 (70, 95) | 90 (75, 100) | 90 (75, 100) | 0.06 | 1.41 (−1.82 to 4.65) | 0.39 |
| 3 year | 455 | 90 (75, 95) | 95 (80, 100) | 94 (80, 100) | 0.12 | 4.74 (1.22 to 8.27) | 0.01 |
| 5 year | 398 | 90 (80, 95) | 95 (80, 100) | 95 (80, 100) | 0.16 | 4.18 (0.40 to 7.97) | 0.03 |
Crude P-values are calculated by Wilcoxon test.
All regression models are adjusted for baseline domain score, time since treatment, biopsy Gleason score, PSA at diagnosis (corrected) and propensity scores.
Crude estimates of general health-related function using the SF-36 identified baseline differences in physical functioning, which persisted over time but not in emotional well being or energy and fatigue (Table 3). In adjusted analyses, we found a transient statistically significant, but not clinically important, difference in emotional well being at 6 months that resolved by 1 year and no differences in physical functioning or energy and fatigue (Table 3).
Table 3.
Association between pelvic radiation and general health-related patient-reported functional outcomes.
| Time | N | Pelvic Radiation, median (quartiles) | No Pelvic Radiation, median (quartiles) | Combined, median (quartiles) | Crude P-valuea | Multivariable adjusted modelb | |
|---|---|---|---|---|---|---|---|
| Pelvic Radiation vs. No Pelvic Radiation | |||||||
| Effect estimate (95% CI) | P-value | ||||||
| SF36 physical functioning score | |||||||
| Baseline | 564 | 85 (50, 95) | 90 (70, 100) | 90 (65, 100) | 0.04 | n/a | |
| 6 month | 572 | 75 (45, 94) | 85 (65, 95) | 85 (60, 95) | 0.003 | 2.44 (−2.31 to 7.18) | 0.31 |
| 1 year | 550 | 85 (50, 95) | 90 (67, 100) | 87 (65, 100) | 0.003 | 2.03 (−2.49 to 6.54) | 0.38 |
| 3 year | 470 | 75 (45, 90) | 85 (60, 95) | 85 (55, 95) | 0.003 | −0.43 (−6.15 to 5.29) | 0.88 |
| 5 year | 415 | 70 (32, 95) | 85 (60, 95) | 85 (55, 95) | 0.006 | −3.74 (−10.92 to 3.43) | 0.31 |
| SF36 emotional well being score | |||||||
| Baseline | 574 | 84 (68, 92) | 88 (72, 92) | 84 (72, 92) | 0.76 | n/a | |
| 6 month | 571 | 84 (75, 92) | 84 (71, 92) | 84 (72, 92) | 0.61 | 3.01 (0.19 to 5.83) | 0.04 |
| 1 year | 548 | 84 (68, 92) | 84 (72, 92) | 84 (72, 92) | 0.90 | 2.30 (−0.31 to 4.91) | 0.08 |
| 3 year | 467 | 84 (76, 92) | 88 (72, 92) | 88 (72, 92) | 0.71 | 1.40 (−2.19 to 4.99) | 0.44 |
| 5 year | 414 | 88 (72, 92) | 88 (72, 92) | 88 (72, 92) | 0.90 | 2.48 (−1.40 to 6.36) | 0.21 |
| SF36 energy and fatigue score | |||||||
| Baseline | 574 | 70 (55, 85) | 75 (55, 85) | 75 (55, 85) | 0.50 | n/a | |
| 6 month | 571 | 65 (50, 80) | 70 (50, 80) | 70 (50, 80) | 0.25 | 2.23 (−1.71 to 6.17) | 0.27 |
| 1 year | 548 | 65 (53, 75) | 70 (50, 80) | 70 (50, 80) | 0.31 | 1.85 (−1.42 to 5.11) | 0.27 |
| 3 year | 467 | 70 (55, 80) | 70 (55, 80) | 70 (55, 80) | 0.28 | 1.80 (−2.11 to 5.70) | 0.37 |
| 5 year | 414 | 65 (52, 80) | 70 (50, 80) | 70 (50, 80) | 0.48 | 3.28 (−1.40 to 7.96) | 0.17 |
Crude P-values are calculated by Wilcoxon test.
All regression models are adjusted for baseline domain score, time since treatment, biopsy Gleason score, PSA at diagnosis (corrected) and propensity scores.
DISCUSSION
In this large, prospective cohort of men with localized prostate cancer, the use of pelvic IMRT, in addition to prostate, radiotherapy was not independently associated with clinically important differences in patient-reported functional and quality-of-life outcomes through five years. Observed crude differences in both hormonal and sexual function are likely attributable to the concomitant use of ADT, given its higher utilization in men receiving prostate and pelvic radiotherapy owing to higher rates of high-risk disease in this group.
Prior randomized controlled trials (GETUG-01, RTOG 9413, and POP-RT) have demonstrated conflicting results with respect to the oncologic benefit of whole pelvic radiotherapy18,19. As a result of these conflicting data on oncologic benefit, as well as toxicity-related concerns, the role of pelvic radiotherapy remains controversial. To date, most studies assessing this question have been small2,3 or utilized outdated radiotherapy approaches (including GETUG-01 and RTOG 9413)4–6. Recently, the POP-RT trial demonstrated no differences in quality of life for patients receiving image-guided intensity modulated radiotherapy (IMRT) among 224 patients randomized to prostate only or whole pelvis radiotherapy8. Differences between outcomes in randomized controlled trials and routine clinical practice are not uncommon, the so-called efficacy-effectiveness gap10,11. Further, the EORTC PR-25 tool utilized in this study has limited sensitivity for bowel dysfunction. The data from this study of patients in the CEASAR cohort demonstrates the generalizable observation that whole pelvic radiotherapy does not confer an added burden of patient-reported toxicity. Further corroboration can be found in the recent work of Parry and colleagues who examined the association between pelvic lymph node irradiation using IMRT and patient-reported outcomes in a cross-sectional analysis of men in the United Kingdom at least 18 months after diagnosis. These authors found a clinically insignificant difference in sexual function and no difference in other EPIC domains or health-related quality of life20. These results are similar to our analysis; however, in contrast, the authors of the UK study did not control for patient-reported baseline function (instead utilizing gastrointestinal and genitourinary procedures in the year prior to radiotherapy as a proxy) and did not account for the longitudinal nature of the symptoms due to the cross-sectional methodology.
Notably, in our study, fewer than one in five men undergoing EBRT received pelvic radiotherapy. This is somewhat less than previous analyses of the National Cancer Database21. While the observed utilization reflects practice patterns in the community at the time of study accrual, the CEASAR cohort, through the chosen inclusion criteria, excludes men with PSA ≥50 ng/mL and those with cT3 disease in whom the use of pelvic radiotherapy may be more common. Further, as has been previously noted21, we observed significant geographic variation in the use of pelvic radiotherapy. Additionally, there were many differences in unadjusted demographic characteristics of patients receiving pelvic radiotherapy and not, again in keeping with prior work showing that demographic characteristics including ethnicity, geographic location, facility type, insurance status, and distance to treatment facility are independently associated with receipt of pelvic radiotherapy21.
As with all observational research, this study is subject to confounding by indication. However, given the similarity in patient-reported outcomes at baseline and use of propensity scores in modeling, it is not clear that this would affect study conclusions. Second, patient surveys were collected at 6-, 12-, 36-, and 60-months following treatment. While this period is expected to capture the greatest treatment-related effects, there may be important differences at times not represented, including acute effects during treatment or important late effects, including secondary cancers22. Third, the relatively small study cohort raises the potential for type II error, however none of the statistically insignificant differences estimated from multivariable models are greater than the clinically important differences. Fourth, we are unable to capture the whole pelvic radiotherapy dose. Finally, while we can capture whether ADT was used concomitantly with radiotherapy, this was operationalized in a binary manner. This was done as chart abstraction was performed at one year following study enrollment and, thus, we could not accurately ascertain the duration of therapy. This may contribute to residual confounding due to within-group heterogeneity among those receiving ADT given higher rates of utilization among those receiving whole pelvic radiotherapy (and postulated longer durations). This is most likely to affect longer term (3- and 5-year) measures of hormonal function.
Maturing trials that randomize men to ADT and prostate radiotherapy with or without pelvic radiotherapy will provide additional information about patient-reported outcomes after pelvic radiotherapy. In the meantime, these data support the use of pelvic radiotherapy when it may be of clinical benefit, such as for men with increased risk of nodal involvement.
Supplementary Material
ACKNOWLEDGEMENTS:
We thank the men who participated in CEASAR and shared their experience. We thank all the study managers, staff, and chart abstractors for their efforts in data collection and help with this study.
FUNDING/SUPPORT: This study was supported by the Agency for Healthcare Research and Quality (1R01HS019356, 1R01HS022640), the Patient-Centered Outcomes Research Institute (CE-12-11-4667), and the National Cancer Institute (NIH/NCI grant R01CA230352). Data management was facilitated by Vanderbilt University’s Research Electronic Data Capture (REDCap) system, which is supported by the Vanderbilt Institute for Clinical and Translational Research grant (UL1TR000011 from NCATS/NIH).
ROLE OF THE FUNDER/SPONSOR: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Footnotes
DISCLAIMER: The statements in this article are solely the responsibility of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute, its board of governors, or its methodology committee. Each funding organization provided financial support through grants, but none was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the article; or decision to submit the article for publication.
DATA AVAILABILITY STATEMENT: Research data are not available at this time.
CONFLICT OF INTEREST: None
Contributor Information
Christopher J.D. Wallis, Department of Urology, Vanderbilt University Medical Center.
Li-Ching Huang, Department of Biostatistics, Vanderbilt University Medical Center.
Zhiguo Zhao, Department of Biostatistics, Vanderbilt University Medical Center.
David F. Penson, Department of Urology, Vanderbilt University Medical Center.
Tatsuki Koyama, Department of Biostatistics, Vanderbilt University Medical Center.
Ralph Conwill, Office of Patient and Community Education, Patient Advocacy Program, Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center.
Jacob E. Tallman, Department of Urology, Vanderbilt University Medical Center.
Michael Goodman, Department of Epidemiology, Emory University Rollins School of Public Health.
Ann S. Hamilton, Department of Preventative Medicine, Keck School of Medicine at the University of Southern California.
Xiao-Cheng Wu, Department of Epidemiology, Louisiana State University New Orleans School of Public Health.
Lisa E. Paddock, Department of Epidemiology, Cancer Institute of New Jersey, Rutgers Health.
Antoinette Stroup, Department of Epidemiology, Cancer Institute of New Jersey, Rutgers Health.
Matthew R. Cooperberg, Department of Urology, University of California, San Francisco.
Mia Hashibe, Department of Family and Preventative Medicine, University of Utah School of Medicine.
Brock B. O’Neil, Department of Urology, University of Utah Health.
Sherrie H. Kaplan, Department of Medicine, University of California Irvine.
Sheldon Greenfield, Department of Medicine, University of California Irvine.
Daniel A. Barocas, Department of Urology, Vanderbilt University Medical Center.
Karen E. Hoffman, Department of Radiation Oncology, The University of Texas MD Anderson Center.
REFERENCES
- 1.Nguyen PL, D’Amico AV. Targeting pelvic lymph nodes in men with intermediate- and high-risk prostate cancer despite two negative randomized trials. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;26(12):2055–2056; author reply 2056–2057. [DOI] [PubMed] [Google Scholar]
- 2.Habl G, Katayama S, Uhl M, et al. Helical intensity-modulated radiotherapy of the pelvic lymph nodes with a simultaneous integrated boost to the prostate--first results of the PLATIN 1 trial. BMC cancer. 2015;15:868. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Joo JH, Kim YJ, Kim YS, et al. Whole pelvic intensity-modulated radiotherapy for high-risk prostate cancer: a preliminary report. Radiat Oncol J. 2013;31(4):199–205. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Lawton CA, DeSilvio M, Roach M 3rd, et al. An update of the phase III trial comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen suppression: updated analysis of RTOG 94–13, with emphasis on unexpected hormone/radiation interactions. International journal of radiation oncology, biology, physics. 2007;69(3):646–655. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Aizer AA, Yu JB, McKeon AM, Decker RH, Colberg JW, Peschel RE. Whole pelvic radiotherapy versus prostate only radiotherapy in the management of locally advanced or aggressive prostate adenocarcinoma. International journal of radiation oncology, biology, physics. 2009;75(5):1344–1349. [DOI] [PubMed] [Google Scholar]
- 6.Pinkawa M, Piroth MD, Holy R, et al. Quality of life after whole pelvic versus prostate-only external beam radiotherapy for prostate cancer: a matched-pair comparison. International journal of radiation oncology, biology, physics. 2011;81(1):23–28. [DOI] [PubMed] [Google Scholar]
- 7.Murthy V, Maitre P, Kannan S, et al. Prostate-Only Versus Whole-Pelvic Radiation Therapy in High-Risk and Very High-Risk Prostate Cancer (POP-RT): Outcomes From Phase III Randomized Controlled Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2021:JCO2003282. [DOI] [PubMed] [Google Scholar]
- 8.Murthy V, Maitre P, Bhatia J, et al. Late toxicity and quality of life with prostate only or whole pelvic radiation therapy in high risk prostate cancer (POP-RT): A randomised trial. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2020;145:71–80. [DOI] [PubMed] [Google Scholar]
- 9.Rammant E, Ost P, Swimberghe M, et al. Patient- versus physician-reported outcomes in prostate cancer patients receiving hypofractionated radiotherapy within a randomized controlled trial. Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft [et al]. 2019;195(5):393–401. [DOI] [PubMed] [Google Scholar]
- 10.Eichler HG, Abadie E, Breckenridge A, et al. Bridging the efficacy-effectiveness gap: a regulator’s perspective on addressing variability of drug response. Nat Rev Drug Discov. 2011;10(7):495–506. [DOI] [PubMed] [Google Scholar]
- 11.Nordon C, Karcher H, Groenwold RH, et al. The “Efficacy-Effectiveness Gap”: Historical Background and Current Conceptualization. Value Health. 2016;19(1):75–81. [DOI] [PubMed] [Google Scholar]
- 12.Szymanski KM, Wei JT, Dunn RL, Sanda MG. Development and validation of an abbreviated version of the expanded prostate cancer index composite instrument for measuring health-related quality of life among prostate cancer survivors. Urology. 2010;76(5):1245–1250. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.McHorney CA, Ware JE Jr., Raczek AE The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Medical care. 1993;31(3):247–263. [DOI] [PubMed] [Google Scholar]
- 14.Skolarus TA, Dunn RL, Sanda MG, et al. Minimally important difference for the Expanded Prostate Cancer Index Composite Short Form. Urology. 2015;85(1):101–105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Jayadevappa R, Malkowicz SB, Wittink M, Wein AJ, Chhatre S. Comparison of distribution- and anchor-based approaches to infer changes in health-related quality of life of prostate cancer survivors. Health services research. 2012;47(5):1902–1925. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.White H. A Heteroskedasticity-Consistent Covariance Matrix Estimator and a Direct Test for Heteroskedasticity. Econometrica. 1980;48:817–838. [Google Scholar]
- 17.Huber PJ. The behavior of maximum likelihood estimates under nonstandard conditions. Proceedings of the fifth Berkeley symposium on mathematical statistics and probability. University of California. 1967:221–233. [Google Scholar]
- 18.Pommier P, Chabaud S, Lagrange JL, et al. Is there a role for pelvic irradiation in localized prostate adenocarcinoma? Preliminary results of GETUG-01. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25(34):5366–5373. [DOI] [PubMed] [Google Scholar]
- 19.Roach M, Moughan J, Lawton CAF, et al. Sequence of hormonal therapy and radiotherapy field size in unfavourable, localised prostate cancer (NRG/RTOG 9413): long-term results of a randomised, phase 3 trial. The lancet oncology. 2018;19(11):1504–1515. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Parry MG, Nossiter J, Cowling TE, et al. Toxicity of Pelvic Lymph Node Irradiation With Intensity Modulated Radiation Therapy for High-Risk and Locally Advanced Prostate Cancer: A National Population-Based Study Using Patient-Reported Outcomes. International journal of radiation oncology, biology, physics. 2020. [DOI] [PubMed] [Google Scholar]
- 21.Weiner AB, Ko OS, Zhu A, Spratt DE, Hu JC, Schaeffer EM. National practice patterns for lymph node irradiation in 197,000 men receiving external beam radiotherapy for localized prostate cancer. Urologic oncology. 2019;37(6):353 e351–353 e358. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Wallis CJ, Mahar AL, Choo R, et al. Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis. Bmj. 2016;352:i851. [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.