Abstract
Purpose
Emerging data indicate comparable disease control and toxicity of normal postoperative fractionation and moderate hypofractionation radiation therapy (RT) in prostate cancer. In RADICALS-RT, patients were planned for treatment with either 66 Gy in 33 fractions (f) over 6.5 weeks or 52.5 Gy in 20f over 4 weeks. This non-randomized, exploratory analysis explored the toxicity of these 2 schedules in patients who had adjuvant RT.
Methods and Materials
Information on RT dose was collected in all patients. The Radiation Therapy Oncology Group toxicity score was recorded every 4 months for 2 years, every 6 months until 5 years, then annually until 15 years. Patient-reported data were collected at baseline and at 1, 5, and 10 years using standard measures, including the Vaizey fecal incontinence score (bowel) and the International Continence Society Male Short-Form questionnaire (urinary incontinence). The highest event grade was recorded within the first 2 years and beyond 2 years and compared between treatment groups using the χ² test.
Results
Of 634 patients, 217 (34%) were planned for 52.5 Gy/20f and 417 (66%) for 66 Gy/33f. In the first 2 years, grade 1 to 2 cystitis was reported more frequently among the 66 Gy/33f group (52.5 Gy/20f: 20% vs 66 Gy/33f: 30%; P = .04). After 2 years, grade 1 to 2 cystitis was reported in 16% in the 66-Gy group and 9% in the 52.5-Gy group (P = .08). Other toxic effects were similar in the 2 groups, and very few patients had any grade 3 to 4 toxic effects. Patients reported slightly higher urinary and fecal incontinence scores at 1 year than at baseline, but no clinically meaningful differences were reported between the 52.5 Gy/20f and 66 Gy/33f groups. Patient-reported health was similar at baseline and at 1 year and similar between the 52.5 Gy/20f and 66 Gy/33f groups.
Conclusions
Severe toxic effects were rare after prostate bed radiation therapy with either 52.5 Gy/20f or 66 Gy/33f. Only modest differences were recorded in toxic effects or in patient-reported outcomes between these 2 schedules.
Introduction
The RADICALS-RT trial aimed to test, in men having surgery for prostate cancer, the efficacy and safety of adjuvant radiation therapy (RT) versus a policy of observation with early salvage RT for prostate-specific antigen progression. The early results did not support using adjuvant RT after radical prostatectomy.1
In primary RT for low- and intermediate-risk prostate cancer, moderately hypofractionated RT schedules have tumor control and toxicity comparable with normally fractionated RT.2, 3, 4 Phase 2 studies have shown acceptable toxic effects in patients treated with hypofractionated radiation after prostatectomy.5,6 Recent data in postprostatectomy RT have also indicated comparable short-term toxic effects in normal fractionation and moderate hypofractionation.7
In the RADICALS-RT trial, there was a choice of 1 of 2 dose-fractionation schedules for prostate bed RT: 66 Gy in 33 fractions (f) over 6.5 weeks (66 Gy/33f group) or 52.5 Gy in 20 fractions over 4 weeks (52.5 Gy/20f group). This choice was made on an individual patient basis nominated before randomization and was used as a stratification variable. This article explores the toxicity of 52.5 Gy/20f compared with 66 Gy/33f in patients who had adjuvant RT in the RADICALS-RT trial.
Methods
The RADICALS-RT trial is an international, phase 3, multicenter, open-label, randomized controlled trial for men with prostate cancer. Participants were randomly assigned shortly after radical prostatectomy, where there was uncertainty about RT use, to adjuvant or salvage postoperative RT (RADICALS-RT) and, in participants planned for postoperative RT, to add short-course (6 months), long-course (24 months), or no hormone therapy (RADICALS-HD). Details of the protocol have been published previously.1
Radiation therapy was planned according to the choice of the treating physician as either 52.5 Gy/20f or 66 Gy/33f. Hence, the choice of RT schedule was not randomized. Treatment with either 3-dimensional conformal therapy or with intensity-modulated RT was allowed. The treatment was targeted to the prostate bed or prostate bed and pelvic lymph nodes as decided by the treating physician. The protocol included a contouring and treatment planning guideline, and each participating center went through an accrediting process. As per protocol, the minimal dose to the planning target volume was 95% of the prescribed dose, and the maximum dose was 105% of the prescribed dose.
Patients were seen every 4 months for 2 years, every 6 months until 5 years, then annually until 15 years. Radiation Therapy Oncology Group toxicity scores were collected at each follow-up visit regarding diarrhea, proctitis, cystitis, hematuria, and urethral stricture. Data classified as serious adverse events were also collected. Patient-reported data were collected at baseline and at 1, 5, and 10 years post-randomization using standard measures that included the Vaizey fecal incontinence score (bowel) and the International Continence Society Male Short-Form questionnaire (urinary incontinence).
Toxicity data were dichotomized into events reported within 2 years after randomization and after more than 2 years. The highest event grade was compared between groups using the χ² test within each period. For patient-reported outcomes, groups were compared at 1 and 5 years using analysis of covariance adjusted for the baseline score. Stata, version 16.1 (StataCorp, LLC), was used for statistical analysis. No adjustment was made for baseline characteristics such as hormone therapy or RT technique use. This analysis used the data set used for the early reporting of biochemical outcomes, which was frozen on March 21, 2019.1
Results
Patient characteristics
Of the 364 participants receiving adjuvant RT, 217 (34%) were planned for 52.5 Gy/20f and 417 (66%) for 66 Gy/33f (Table 1). Median follow-up was 4.9 years (IQR, 3.1-6.1 years) in these 634 patients. No difference was seen regarding age between the 2 groups. However, fewer patients with 52.5 Gy/20f planned had pT3b/pT4 disease than those planned for 66 Gy (28 of 217 [13%] vs 90 of 417 [21%]; P = .008), and fewer had a Gleason score of 8 to 10 (24 of 217 [11%] vs 79 of 417 [19%]; P = .001). Patients with 66 Gy/33f planned were significantly more likely to have RT targeted at the pelvic nodes and the prostate bed (7% vs 1%; P = .002) (Table 2). There was no difference between groups in the size of the prostate bed target volume of RT, and almost all patients received their planned schedule, starting treatment within the protocol-defined time windows. Most patients (95% in both groups) received their intended dose.
Table 1.
Patient characteristics
| Patients* |
|||
|---|---|---|---|
| Characteristic | 52.5 Gy (n = 217) | 66 Gy (n = 417) | P value |
| Age, median (IQR), years | 64 (60-68) | 65 (59-68) | .86 |
| PSA level at diagnosis, median (IQR), ng/mL | 7.5 (5.6-11) | 7.9 (6-12.1) | .047 |
| Gleason score | |||
| <7 | 18 (8) | 23 (6) | .001 |
| 3+4 | 129 (59) | 192 (46) | |
| 4+3 | 46 (21) | 123 (30) | |
| ≥8 | 24 (11) | 79 (19) | |
| Pathologic T stage | |||
| pT2 | 43 (20) | 99 (24) | .008 |
| pT3a | 146 (67) | 228 (55) | |
| pT3b | 28 (13) | 85 (20) | |
| pT4 | 0 (0) | 5 (1) | |
| Positive margins | |||
| Present | 142 (65) | 258 (62) | .38 |
| Absent | 75 (35) | 159 (38) | |
| Lymph node involvement | |||
| N1 | 5 (2) | 28 (7) | .039 |
| N0 | 115 (53) | 196 (47) | |
| Nx | 96 (44) | 192 (46) | |
| CAPRA-S score | |||
| Low, 0-2 | 21 (10) | 31 (7) | .010 |
| Intermediate, 3-5 | 133 (61) | 214 (51) | |
| High, 6+ | 63 (29) | 172 (41) | |
| Country | |||
| England | 217 (100) | 321 (77) | < .001 |
| Denmark | 0 (0) | 74 (18) | |
| Canada | 0 (0) | 19 (5) | |
| Republic of Ireland | 0 (0) | 3 (1) | |
Abbreviation: CAPRA-S = cancer of the prostate risk assessment post-surgical score; PSA = prostate-specific antigen.
Data are presented as the number (percentage) of patients unless otherwise indicated.
Table 2.
Radiation therapy treatment
| Patients⁎ |
|||
|---|---|---|---|
| 52.5 Gy (n = 217) | 66 Gy (n = 417) | P value | |
| Planned RT target | |||
| Prostate bed | 214 (99) | 388 (93) | .002 |
| Prostate bed and pelvic lymph nodes | 3 (1) | 29 (7) | |
| Target volume (PTV_prostate bed), median (IQR), cm3 | 280 (228-332) | 277 (218-354) | .52 |
| Dose given, Gy | |||
| Median | 52.5 | 66 | |
| p25-p75 | 52.5-52.6 | 66-66 | |
| p10-p90 | 52.4-54.2 | 66-66 | |
| Range, p0-p100 | 2.6-66 | 20-68 | |
| Time from randomization to RT, days | |||
| Not starting HT, n | 174 | 328 | |
| Median (IQR) days | 34 (29-47) | 36 (28-56) | .17 |
| Starting HT, n | 43 | 89 | |
| Median (IQR) days | 74 (62-88) | 74 (68-90) | .10 |
Abbreviations: HT = hormone therapy; PTV = planning target volume; RT = radiation therapy.
Data are presented as the number (percentage) of patients unless otherwise indicated.
Toxicity
Toxicity data are shown in Table 3. In the first 2 years, grade 1 to 2 cystitis was reported more frequently for the 66 Gy/33f group (30%) than for the 52.5 Gy/20f group (20%; P = .02). Beyond 2 years, grade 1 to 2 cystitis was reported among 16% of the 66 Gy/33f group and 9% of the 52.5 Gy/20f group (P = .08). Other toxic effects were similar for both groups. Grade 3 to 4 toxic effects were reported in very few patients.
Table 3.
RTOG toxicity
| Patients, n(%) |
||||||
|---|---|---|---|---|---|---|
| Within 2 y |
After 2 y |
|||||
| 52.5 Gy (n = 217) | 66 Gy (n = 418) | P value | 52.5 Gy (n = 195) | 66 Gy (n = 371) | P value | |
| Diarrhea | ||||||
| Grade 1 | 64 (29) | 130 (31) | .10 | 24 (12) | 57 (15) | .48 |
| Grade 2 | 26 (12) | 36 (9) | 6 (3) | 16 (4) | ||
| Grade 3 | 6 (3) | 3 (1) | 2 (1) | 3 (1) | ||
| Grade 4 | 0 (0) | 0 (0) | 1 (1) | 0 (0) | ||
| Proctitis | ||||||
| Grade 1 | 35 (16) | 64 (15) | .77 | 21 (11) | 32 (9) | .46 |
| Grade 2 | 12 (6) | 32 (8) | 9 (5) | 11 (3) | ||
| Grade 3 | 2 (1) | 5 (1) | 1 (1) | 5 (1) | ||
| Grade 4 | 0 (0) | 0 (0) | 0 (0) | 0 (0) | ||
| Cystitis | ||||||
| Grade 1 | 30 (14) | 87 (21) | .04 | 10 (5) | 40 (11) | .08 |
| Grade 2 | 12 (6) | 36 (9) | 7 (4) | 20 (5) | ||
| Grade 3 | 2 (1) | 9 (2) | 1 (1) | 4 (1) | ||
| Grade 4 | 0 (0) | 1 (<1) | 0 (0) | 0 (0) | ||
| Hematuria | ||||||
| Grade 1 | 20 (9) | 28 (7) | .73 | 11 (6) | 23 (6) | .87 |
| Grade 2 | 7 (3) | 14 (3) | 13 (7) | 22 (6) | ||
| Grade 3 | 7 (3) | 13 (3) | 6 (3) | 16 (4) | ||
| Grade 4 | 0 (0) | 0 (0) | 0(0) | 1 (<1) | ||
| Urethral stricture | ||||||
| Grade 1 | 8 (4) | 14 (3) | .58 | 8 (4) | 16 (4) | .33 |
| Grade 2 | 7 (3) | 12 (3) | 3 (2) | 9 (2) | ||
| Grade 3 | 9 (4) | 28 (7) | 5 (3) | 21 (6) | ||
| Grade 4 | 0 (0) | 2 (<1) | 0 (0) | 0 (0) | ||
Abbreviation: RTOG = Radiation Therapy Oncology Group.
Quality of life
Urinary and fecal incontinence scores were slightly higher 1 year after randomization than at baseline, but the change was not clinically meaningful. The differences between the 52.5 Gy/20f and 66 Gy/33f groups were not statistically significant (Table 4). Overall, patients reported similar physical and mental health scores at baseline and at 1 year, which were similar between the 52.5 Gy/20f and 66 Gy/33f groups.
Table 4.
Quality of life 1 year after randomization
| 52.5 Gy (n = 217) | 66 Gy (n = 417) | P value | |
|---|---|---|---|
| ICS male incontinence score | |||
| Data at baseline and 1 y | 135 (62) | 207 (50) | |
| Baseline score, mean (SD) | 4.39 (3.79) | 4.71 (3.72) | |
| 1-y score, mean (SD) | 4.42 (3.92) | 5.05 (3.99) | |
| Difference between arms at 1 y, mean (95% CI)* | 0.34 (–0.37 to 1.05) | .35 | |
| Vaizey fecal incontinence score | |||
| Data at baseline and 1 y | 119 (55) | 196 (47) | |
| Baseline score, mean (SD) | 2.45 (3.23) | 2.51 (3.32) | |
| 1-y score, mean (SD) | 3.27 (3.61) | 3.37 (4.02) | |
| Difference between arms at 1 y, mean (95% CI)* | 0.07 (–0.74 to 0.88) | .86 | |
| SF-12 physical health score† | |||
| Data at baseline and 1 y | 123 (57) | 193 (46) | |
| Baseline score, mean (SD) | 51.3 (7.8) | 50.3 (8.5) | |
| 1-y score, mean (SD) | 51.5 (7.6) | 49.9 (9.2) | |
| Difference between arms at 1 y, mean (95% CI)* | –1.42 (–3.15 to 0.32) | .11 | |
| SF-12 mental health score‡ | |||
| Data at baseline and 1 y | 123 (57) | 193 (46) | |
| Baseline score, mean (SD) | 51.6 (9.6) | 51.2 (9.5) | |
| 1-y score, mean (SD) | 52.9 (9.2) | 52.1 (8.6) | |
| Difference between arms at 1 y, mean (95% CI)* | –0.62 (–2.42 to 1.18) | .50 | |
Adjusted for baseline score, age, T stage, and Gleason score.
Possible score range, 13 to 69.
Possible score range, 10 to 70
Discussion
These exploratory, nonrandomized data from the adjuvant RT group of the RADICALS-RT trial indicate that prostate bed RT after radical prostatectomy was usually well tolerated regardless of the choice of dose-fractionation schedule. The shorter 20-fraction schedule offers an obvious advantage regarding patient convenience, environmental considerations, and hospital capacity.
This current analysis is not designed to test differences in disease outcomes between the 2 dose-fractionation groups. However, 64 Gy in 32 fractions seems to be sufficient for biochemical control in the absence of macroscopic local recurrence in the prostate bed,8 a dose biologically equivalent to the 52.5 Gy/20f schedule, so it is not expected that there will be a difference in efficacy by choice of fractionation schedule in RADICALS-RT.
The treatment time was shorter in the 52.5 Gy/20f group. The effect of the shorter treatment time on toxicity is uncertain but might be expected, if anything, to increase acute toxicity9,10; this phenomenon was not seen in this study. In the RADICALS trial, only a minority of patients had pelvic node radiation, with more of these in the 66 Gy/33f than the 52.5 Gy/20f group (7% vs 1%). This fact could bias our results to an extent because pelvic RT could increase gastrointestinal toxic effects. However, other studies did not show increased late bowel toxic effects with pelvic node RT.11,12
One retrospective study has suggested increased late urinary toxic effects with moderate hypofractionation compared with normal fractionation.13 The late urinary toxic effects in the RADICALS trial were comparable with those in the patients receiving normal fractionation in the previous study. This difference could be explained by the relatively high dose level corresponding to 2-Gy dose schedules (biologically effective dose calculated using an α/β ratio of 5 for urohtel) in the previous study.13
Interaction between hormone treatment and gastrointestinal toxicity has been suggested previously.10,11 Because we did not see any difference in the use of androgen deprivation therapy between the 2 groups, this potential interaction did not bias the results of the present analysis.
This exploratory analysis has limitations. First, the comparison between the 2 dose-fractionation schedules was nonrandomized. Second, RT techniques have continued to evolve because of RADICALS-RT recruitment between 2008 and 2016. Subsequent RT techniques would be expected to further reduce the dose to normal tissues such as the rectum and bladder, thus reducing the risk of radiation toxicity. Third, postoperative RT to the prostate bed is now more commonly delivered in the salvage setting rather than the adjuvant setting after the publication of the results of the RADICALS-RT, GETUG-17, and RAVES trials and the ARTISTIC meta-analysis.1,14, 15, 16 However, it is reasonable to assume that the toxicity of postoperative RT would be similar in the adjuvant and the salvage settings. Fourth, the choice of treatment schedule was closely associated with the center. We cannot completely rule out that this association affected the toxicity outcomes. The strengths of our analysis include the prospective collection of clinician-reported and patient-reported data in a predefined population in the context of a clinical trial.
Conclusion
Severe toxicity is rare after postprostatectomy prostate bed RT with either 52.5 Gy/20f or 66 Gy/33f. Only modest differences were seen in toxicity or in patient-reported quality of life between these 2 schedules. In the interests of patient convenience, hospital capacity, and environmental considerations, these exploratory results support using hypofractionated RT in the prostate bed.
Footnotes
Cancer Research UK: C7829/A6381, UKRI: MC_UU_12023/28, the Canadian Cancer Society: 704970, and the UK sites were part of the Health Research Clinical Research Network. This article represents independent research partly funded by the National Institute for Health Research Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research.
Disclosures: P.M.P. reported receiving advisory board fees from MSD and AAA Nordic and travel support from MSD. M.R.S. reported receiving grants from Astellas, Clovis Oncology, Janssen, Pfizer, Novartis, and Sanofi-Aventis; consulting fees from Eli Lilly; and payment or honoraria for lectures from Lilly Oncology and Janssen. W.C. reported receiving grants from Myriad Genetics; payment or honoraria for lectures from Janssen, Bayer, Astellas, and Myriad Genetics; and travel support from Janssen and Bayer. H.P. reported receiving grants from Astellas; consulting fees from Janssen, Astellas, Accord, and Amgen; payment or honoraria for lectures from Janssen, Astellas, and Bayer; and participation on a data safety monitoring board or advisory board for Accord, Amgen, and the IDMC POPS Study. F.S. reported receiving grants from Janssen, Bayer, Merck, Pfizer, Astellas, BMS, Novartis, Sanofi, and AstraZeneca; consulting fees from Janssen, Bayer-Astellas, BMS, Novartis, Sanofi, AstraZeneca, Merck, and Pfizer; and payment or honoraria for lectures from Janssen, Bayer, Myovant, Astellas, BMS, Novartis, Sanofi, AstraZeneca, Merck, and Pfizer. C.C.P. reported receiving consulting fees from ITM Radiopharma and AAA and payment or honoraria for lectures or presentations from Bayer. C.C. reported receiving honoraria for lectures or presentations from Bayer, Abbvie, and TerSera Therapeutics. All other authors have no disclosures to share.
The data set may be available upon request as per the moderated access approach of the MRC Clinical Trials Unit at UCL. Please contact the corresponding author for more information.
Supplementary material associated with this article can be found in the online version at doi:10.1016/j.ijrobp.2023.04.032.
Appendix. Supplementary materials
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