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External beam radiation therapy (EBRT) with low-dose-rate (LDR) brachytherapy boost has been associated with improved biochemical progression–free survival and overall survival (OS) compared with dose-escalated EBRT (DE-EBRT) alone for unfavorable-risk prostate cancer. However, it is not known whether high-dose-rate (HDR) boost provides a similar benefit. We compare HDR boost against LDR boost and DE-EBRT with respect to OS.
Methods
Using the National Cancer Database, we identified 122,896 patients who were diagnosed with National Comprehensive Cancer Network intermediate- or high-risk prostate cancer between 2004 and 2014 and treated with DE-EBRT (75.6–86.4 Gy), LDR boost, or HDR boost. We compared the OS among the three groups using multivariable Cox proportional hazards regression. Inverse probability treatment weighting was used to adjust for covariate imbalance.
Results
On multivariable Cox proportional hazards regression, HDR boost was associated with a similar OS to LDR boost (adjusted hazard ratio [AHR] 1.03 [0.96, 1.11]; p = 0.38) but significantly better OS than DE-EBRT (AHR 1.36 [1.29, 1.44]; p < 0.001). Inverse probability treatment weighting analysis yielded similar results. There was no significant difference between LDR and HDR boosts for National Comprehensive Cancer Network intermediate-risk (AHR 1.05 [0.96, 1.15]; p = 0.32) and high-risk (AHR 1.00 [0.89, 1.12]; p = 0.98) subgroups (p-interaction = 0.55).
Conclusions
Our results suggest that HDR brachytherapy boost yields similar OS benefits compared with LDR brachytherapy boost for unfavorable-risk prostate cancer. HDR boost may be a suitable alternative to LDR boost.
Recently, the Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (ASCENDE-RT) randomized controlled trial demonstrated a significant improvement in biochemical progression–free survival (bPFS) with the addition of low-dose-rate (LDR) brachytherapy boost to EBRT compared with dose-escalated EBRT (DE-EBRT) alone (78 Gy) in men with intermediate- and high-risk prostate cancer (
Androgen suppression combined with elective nodal and dose escalated radiation therapy (the ASCENDE-RT trial): An analysis of survival endpoints for a randomized trial comparing a low-dose-rate brachytherapy boost to a dose-escalated external beam boost for high- and intermediate-risk prostate cancer.
). Although this trial was not powered to show a statistically significant difference in overall survival (OS), a recent retrospective analysis using data from the National Cancer Database did report a significant improvement in OS with LDR boost (
). Recent American Society of Clinical oncology/Cancer Care Ontario guidelines recommend that brachytherapy boost be offered to patients with intermediate- and high-risk patients receiving EBRT (
ASCENDE-RT: An analysis of treatment-related morbidity for a randomized trial comparing a low-dose-rate brachytherapy boost with a dose-escalated external beam boost for high- and intermediate-risk prostate cancer.
). High-dose-rate (HDR) brachytherapy is an alternative modality that may allow for faster recovery of acute urinary symptoms compared with LDR in the monotherapy setting (
). Although two randomized controlled trials have shown that HDR brachytherapy boost was associated with significantly improved bPFS compared with EBRT, none of these trials compared HDR brachytherapy boost against current dose-escalated EBRT regimens (
Randomized trial comparing iridium implant plus external-beam radiation therapy with external-beam radiation therapy alone in node-negative locally advanced cancer of the prostate.
). Furthermore, it is not known whether HDR boost provides a similar clinical benefit as LDR boost. As a result, we performed a comparative analysis of HDR boost against LDR boost and DE-EBRT with OS as the primary endpoint using a large national database.
), we identified 122,896 patients with National Comprehensive Cancer Network (NCCN) intermediate- (Gleason 7, prostate specific antigen (PSA) 10–20 ng/mL, or cT2b-T2c) or high-risk (Gleason 8–10 or PSA 20–40 ng/mL and ≤c3) prostate cancer who were diagnosed between 2004 and 2014 and treated with DE-EBRT (75.6–86.4 Gy), LDR boost, or HDR boost (Fig. 1). We compared the OS among these three groups using multivariable Cox proportional hazards regression, after adjusting for clinical and demographic factors. Clinical factors included age, PSA value, Gleason grade (6, 7, 8–10), clinical T-stage (T1, T2, T3), Charlson-Deyo score (0, 1, 2+), and androgen deprivation therapy use (yes, no). Demographic factors included race (non-Hispanic white, black, Hispanic, other), facility location (Northeast, Midwest, South, West, NA), facility type (nonacademic, academic), educational attainment, income, and insurance (Medicare, Medicaid, private, uninsured, other). Baseline characteristics were compared using t-tests for continuous variables and chi squared tests for categorical variables.
Fig. 1Formulation of study cohort. EBRT = External beam radiation therapy; SBRT = stereotactic body radiation therapy.
To reduce imbalances in baseline characteristics among the three groups, we also performed weighted Cox regression using inverse probability of treatment weighting (IPTW). IPTW is a propensity scoring method, in which subjects are weighted according to the inverse of the probability of receiving the treatment that the subject actually received. This allows for the generation of a synthetic sample, in which the distribution of baseline covariates is independent of the treatment assignment (
The use of propensity score methods with survival or time-to-event outcomes: Reporting measures of effect similar to those used in randomized experiments.
). Unadjusted and IPTW-adjusted Kaplan-Meier curves were reported.
We also performed unweighted Cox regressions for patient subgroups defined by Gleason grade, clinical T-stage, NCCN risk category (intermediate, high), and androgen deprivation therapy use. For the NCCN risk category subgroup, Gleason grade, clinical T-stage, and PSA were not included in the models. For each subgroup, the significance of interaction terms between the subgroup and boost modality was estimated with the Wald test. An additional subgroup analysis was also run for patients with Gleason 9 or 10 disease (
Clinical outcomes for patients with Gleason score 9–10 prostate adenocarcinoma treated with radiotherapy or radical prostatectomy: A multi-institutional comparative analysis.
Radical prostatectomy, external beam radiotherapy, or external beam radiotherapy with brachytherapy boost and disease progression and mortality in patients with Gleason score 9-10 prostate cancer.
). Multivariate hazard ratios for boost modality are included in Forest plots for each subgroup. All statistical analysis was performed using R version 3.5.0 (The R Foundation for Statistical Computing). This work was performed with approval of our institutional review board.
Results
The median followup for the entire cohort was 5.0 years (interquartile range: 3.0, 7.4). Table 1 summarizes baseline clinical and demographic factors among the three groups. Small but statistically significant differences in baseline characteristics were observed for all factors. Fig. 2a shows respective Kaplan-Meier curves before IPTW adjustment. On multivariable Cox proportional hazards regression, HDR boost was associated with a similar OS to LDR boost (adjusted hazard ratio [AHR] 1.03 [0.96, 1.11]; p = 0.38) but significantly better OS than DE-EBRT (AHR 1.36 [1.29, 1.44]; p < 0.001). Detailed results are shown in Table 2. After IPTW adjustment, there were no statistically significant differences among the three treatment groups for any baseline factor. IPTW-weighted Cox proportional hazards model yielded no significant OS difference with LDR boost (AHR 1.01 [0.93, 1.10]; p = 0.77) but significantly better OS than DE-EBRT (AHR 1.31 [1.23, 1.39]; p < 0.001). IPTW-adjusted Kaplan-Meier curves are shown in Fig. 2b.
Table 1Baseline characteristics based on treatment (HDR boost, LDR boost, and DE-EBRT)
Factor
Total
Unadjusted
IPTW-adjusted
HDR boost
LDR boost
DE-EBRT
p (min)
p (min)
n
(n = 8526)
(n = 9877)
(n = 104486)
Age—Mean (SD)
-
67.1 (7.6)
66.7 (7.6)
69.9 (7.6)
<0.001
0.12
Prostate specific antigen—Mean (SD)
-
9.1 (6.7)
9.0 (6.6)
10.0 (7.2)
<0.001
0.19
Gleason grade
6
13902 (11.3%)
8.7%
9.7%
11.7%
<0.001
0.07
7
73337 (59.7%)
63.3%
65.5%
58.8%
8–10
35657 (29.0%)
28.0%
24.7%
29.5%
Clinical T-stage
T1
71149 (57.9%)
53.5%
58.6%
58.2%
<0.001
0.09
T2
45121 (36.7%)
39.5%
37.8%
36.4%
T3
6626 (5.4%)
7.0%
3.6%
5.4%
Race
Non-Hispanic white
93599 (76.2%)
76.1%
75.5%
76.2%
<0.001
0.34
Black
19894 (16.2%)
14.5%
18.5%
16.1%
Hispanic
4682 (3.8%)
3.3%
3.0%
3.9%
Other
4721 (3.8%)
6.1%
2.9%
3.7%
Charlson-Deyo score
0
105047 (85.5%)
86.3%
85.4%
85.4%
<0.001
0.57
1
14663 (11.9%)
11.8%
12.5%
11.9%
2+
3186 (2.6%)
2.0%
2.1%
2.7%
Facility location
Northeast
31896 (25.9%)
21.5%
22.0%
26.6%
<0.001
0.47
Midwest
30962 (25.2%)
21.9%
18.8%
26.1%
South
39911 (32.5%)
29.0%
48.3%
31.3%
West
20182 (16.4%)
27.6%
10.8%
16.0%
NA
5 (0.0%)
0.0%
0.0%
0.0%
Facility type
Nonacademic
85273 (69.4%)
66.4%
77.4%
68.9%
<0.001
0.62
Academic
37623 (30.6%)
33.6%
22.6%
31.1%
Educational attainment
Quartile 1–lowest
20074 (16.3%)
12.9%
18.2%
16.4%
<0.001
0.09
Quartile 2
31053 (25.3%)
22.6%
25.5%
25.5%
Quartile 3
40756 (33.2%)
32.0%
32.6%
33.3%
Quartile 4–highest
30151 (24.5%)
32.0%
22.4%
24.1%
NA
862 (0.7%)
0.4%
1.3%
0.7%
Income
Quartile 1–lowest
21607 (17.6%)
13.5%
18.6%
17.8%
<0.001
0.13
Quartile 2
28043 (22.8%)
20.5%
24.1%
22.9%
Quartile 3
32506 (26.5%)
24.1%
23.3%
26.9%
Quartile 4–highest
39790 (32.4%)
41.5%
32.6%
31.6%
NA
950 (0.8%)
0.5%
1.4%
0.7%
Insurance
Medicare
77352 (62.9%)
55.2%
55.5%
64.3%
<0.001
0.20
Medicaid
3322 (2.7%)
1.6%
2.6%
2.8%
Other
5382 (4.4%)
2.7%
2.7%
4.7%
Private
35067 (28.5%)
39.7%
38.3%
26.7%
Uninsured
1773 (1.4%)
0.7%
0.9%
1.5%
Androgen deprivation therapy
No
64041 (52.1%)
59.6%
56.9%
51.0%
<0.001
0.43
Yes
58855 (47.9%)
40.4%
43.1%
49.0%
DE-EBRT = dose-escalated external beam radiation therapy; HDR = high-dose-rate; IPTW = inverse probability of treatment weighting; LDR = low-dose-rate.
Unadjusted p-values (min) and IPTW-adjusted p-values (min) are reported.
p (min) represents the minimum p-value among the 3-group comparisons (HDR vs. LDR, HDR vs. DE-EBRT, LDR vs. DE-EBRT).
As shown in Fig. 3, there was no significant difference between LDR and HDR boosts for patient subgroups divided by Gleason grade, clinical T-stage, NCCN risk category, or androgen deprivation therapy. All interaction terms between analyzed subgroups and boost modality were not significant. For the Gleason 9–10 subgroup, AHRs for LDR boost and DE-EBRT were 1.03 ([0.84, 1.25]; p = 0.81) and 1.25 ([1.09, 1.44]; p = 0.001), respectively.
Fig. 3Forest plots of multivariable hazard ratios with 95% confidence intervals for LDR boost (left) and DE-EBRT (right) against HDR boost as baseline for specific subgroups. p (int) represents p-values for the interaction terms. DE-EBRT = dose-escalated external beam radiation therapy; HDR = high-dose-rate; HR = hazard ratio; LDR = low-dose-rate; NCCN = National Comprehensive Cancer Network.
Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group.
). A large multiinstitutional retrospective propensity-adjusted analysis also showed no difference in distant metastasis or prostate cancer specific mortality between LDR vs. HDR brachytherapy boost (
Radical prostatectomy, external beam radiotherapy, or external beam radiotherapy with brachytherapy boost and disease progression and mortality in patients with Gleason score 9-10 prostate cancer.
). Our analysis using a large National Cancer Database also suggests that both LDR and HDR brachytherapy boost provide equivalent OS outcomes for unfavorable-risk prostate cancer. It is reassuring that similar results were obtained after propensity score adjustment with IPTW, which allowed for partial mitigation of treatment imbalances among the three treatment groups. Furthermore, consistent results were obtained for each of the evaluated patient subgroups. As a result, either LDR or HDR brachytherapy boost could be reasonably offered to patients across the clinical spectrum of NCCN intermediate- and high-risk disease. This is especially relevant because many centers only offer either LDR or HDR brachytherapy.
It is important that the results of this study are interpreted in light of the limitations of this retrospective analysis. These include selection bias and lack of data on androgen deprivation therapy duration, brachytherapy dosing regimens, and other clinically relevant endpoints (bPFS, metastasis-free survival, prostate cancer–specific mortality). As such, only an adequately powered randomized controlled trial could definitively demonstrate equivalent efficacy between LDR and HDR brachytherapy boosts.
It is unclear whether HDR boost is associated with less acute and late toxicities than LDR boost. With respect to short-term toxicity, a preliminary analysis of a randomized controlled trial of HDR vs. LDR in the monotherapy setting reported lower acute urinary toxicity, improved quality of life, and shorter time to urinary symptom resolution with HDR (
) or cesium-131, may also be associated with a shorter time to urinary symptom resolution. With respect to long-term toxicity, a recent analysis using the Surveillance, Epidemiology, and End Results Medicare database was unable to show a statistically significant difference in grade three urinary adverse events between LDR and HDR (
Time course and accumulated risk of severe urinary adverse events after high- versus low-dose-rate prostate brachytherapy with or without external beam radiation therapy.
). Results from the currently accruing BrachyQOL randomized controlled trial (NCT01936883) may provide a more definitive comparison of short- and long-term toxicity profiles between these two modalities in the boost setting (
ASCENDE-RT: An analysis of treatment-related morbidity for a randomized trial comparing a low-dose-rate brachytherapy boost with a dose-escalated external beam boost for high- and intermediate-risk prostate cancer.
An analysis of health-related quality of life for a randomized trial comparing low-dose-rate brachytherapy boost with dose-escalated external beam boost for high- and intermediate-risk prostate cancer.
), further research is urgently needed to mitigate toxicities for both LDR and HDR boost techniques, so that patients who receive these treatments can better preserve their quality of life.
Acknowledgements
This work was supported by the Prostate Cancer Foundation, the Wood Family Foundation, the Baker Family, the Freedman Family, Fitz’s Cancer Warriors, David and Cynthia Chapin, the Frashure Family, Hugh Simons in honor of Frank and Anne Simons, the Campbell Family in honor of Joan Campbell, the Scott Forbes and Gina Ventre Fund, and a grant from an anonymous family foundation.
References
Morris W.J.
Tyldesley S.
Rodda S.
et al.
Androgen suppression combined with elective nodal and dose escalated radiation therapy (the ASCENDE-RT trial): An analysis of survival endpoints for a randomized trial comparing a low-dose-rate brachytherapy boost to a dose-escalated external beam boost for high- and intermediate-risk prostate cancer.
ASCENDE-RT: An analysis of treatment-related morbidity for a randomized trial comparing a low-dose-rate brachytherapy boost with a dose-escalated external beam boost for high- and intermediate-risk prostate cancer.
Randomized trial comparing iridium implant plus external-beam radiation therapy with external-beam radiation therapy alone in node-negative locally advanced cancer of the prostate.
The use of propensity score methods with survival or time-to-event outcomes: Reporting measures of effect similar to those used in randomized experiments.
Clinical outcomes for patients with Gleason score 9–10 prostate adenocarcinoma treated with radiotherapy or radical prostatectomy: A multi-institutional comparative analysis.
Radical prostatectomy, external beam radiotherapy, or external beam radiotherapy with brachytherapy boost and disease progression and mortality in patients with Gleason score 9-10 prostate cancer.
Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group.
Time course and accumulated risk of severe urinary adverse events after high- versus low-dose-rate prostate brachytherapy with or without external beam radiation therapy.
An analysis of health-related quality of life for a randomized trial comparing low-dose-rate brachytherapy boost with dose-escalated external beam boost for high- and intermediate-risk prostate cancer.
Financial disclosure: P.L.N. reports personal fees from Medivation, GenomeDx, Ferring, Nanobiotix, Dendreon, Augmenix, and Blue Earth and has received grants from Astellas and Janssen, outside the submitted work. P.F.O. reports consulting with Augmenix, outside the submitted work.
Conflict of interest: The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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