Abstract
Background
We sought to characterize and compare late patient-reported outcomes (PROs) after moderately hypofractionated intensity modulated radiation therapy (IMRT) and proton beam therapy (PBT) for localized prostate cancer (PC).
Methods
This multi-institutional analysis included low- or intermediate-risk group PC patients treated with moderately hypofractionated radiation to an intact prostate stratified by treatment modality: IMRT or PBT. The primary outcomes were prospectively collected patient-reported late gastrointestinal (GI) and genitourinary (GU) toxicity assessed by International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index Composite (EPIC). Multivariable regression analysis (MVA) controlling for age, race, and risk group tested the effect of time, treatment, and their interaction.
Results
287 IMRT and 485 PBT patients were included. Intermediate risk group (81.2 vs. 68.2%; P < 0.001) and median age at diagnosis (70 vs 67 years; P < 0.001) were higher in the IMRT group. On MVA, there was no significant difference between modalities. PBT IPSS did not differ from IMRT IPSS at 12 months (odds ratio [OR], 1.19; P = 0.08) or 24 months (OR, 0.99; P = 0.94). PBT EPIC overall GI function at 12 months (OR, 3.68; P = 0.085) and 24 months (OR 2.78; P = 0.26) did not differ from IMRT EPIC overall GI function. At 24 months, urinary frequency was no different between PBT and IMRT groups (OR 0.35; P = 0.096).
Conclusions
This multi-institutional analysis of low- or intermediate-risk PC treated with moderately hypofractionated PBT and IMRT demonstrated low rates of late patient-reported GI and GU toxicities. After covariate adjustment, late GI and GU PROs were not significantly different between PBT or IMRT cohorts.
Keywords: Prostate cancer, Hypofractionation, Proton therapy, Patient reported outcomes, Quality of life
Introduction
Hypofractionated radiation therapy is increasingly utilized for the management of localized prostate cancer and is now considered the standard of care.1 Multiple phase III randomized clinical trials have demonstrated the feasibility, safety, and acceptable outcomes of patients treated with moderately hypofractionated radiation therapy regimens for low- and intermediate-risk prostate cancer.2–4 Hypofractionated prostate radiation allows for the delivery of a higher biologically effective dose as compared to conventional fractionation because of prostate cancer’s low α/β ratio.5 Additionally, a shorter treatment duration is more convenient for patients. Prostate cancer hypofractionation studies have primarily recruited patients treated with photon-based radiation, with study findings extrapolated to proton beam therapy (PBT), another clinically available external beam modality treatment of prostate cancer.6–9
Previous reports have detailed the common and expected outcomes for moderately hypofractionated prostate radiation administered with photon-based intensity modulated radiation therapy (IMRT)10–12 and PBT.13 Additionally, our pooled toxicity analysis of patients treated with either IMRT or PBT demonstrated low rates of physician-graded toxicity without significant difference in late GI or GU toxicity.14 Recognizing that physicians may underreport the reduction in patient-reported quality of life (PRQOL)15–16 and patient reported outcomes (PROs) may differ from physician-rated toxicities, we set to characterize and compare late GI and GU PROs between PBT and IMRT cohorts. We hypothesize that a difference in late GI and GU PROs will be seen between cohorts, favoring the PBT cohort.
Methods and Materials
Patient population
This multi-institutional analysis included patients with biopsy-proven National Comprehensive Cancer Network (NCCN) low- or intermediate-risk group prostate cancer17 treated at four tertiary referral centers in the United States with moderately hypofractionated PBT or IMRT with prospective PRQOL collection. One center contributed to both cohorts, while the other three centers treated patients with either PBT or IMRT.
Data sharing agreements were reviewed and approved by each institution’s internal review board, allowing data contribution to the coordinating sites. For this pooled analysis, informed consent was waived by the institutions. De-identified data were shared in concordance with the Health Insurance Portability and Accountability Act and managed using a secure electronic data capture tool.18
Radiation therapy treatment
Patients were treated with definitive radiation to an intact prostate gland using moderate hypofractionation, defined as 250 to 300 cGy per daily fraction given for 4 to 6 weeks. The most common dose fractionation schemes were 7,000 cGy / 28 fx, 7,020 cGy / 26 fx, and 6,000 cGy / 20 fx. Static IMRT and rotational arc therapy/volumetric arc therapy were included within the IMRT group. Uniform scanning and pencil beam scanning were included within the PBT group. All patients underwent daily 3-dimensional image guidance. Use of androgen deprivation therapy was allowed. There was no use of hydrogel rectal spacer. No patients received pelvic lymph node irradiation. For specific treatment and planning details for each institution, refer to individual center published experiences. 2,9,12,19
Outcomes
Patients completed International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) symptom indices pre-treatment and at 3- to 6-month intervals following treatment. Late toxicity was evaluated starting three months after the completion of treatment. EPIC-CP is a validated questionnaire measuring urinary incontinence, urinary irritation, bowel, sexual, and hormonal health-related quality of life (HRQOL) .20 This analysis is limited to urinary irritation/obstructive and bowel symptom scores, questions 5 and 6 in EPIC-CP (see supplementary material). Questions are scored from 0 (No problem) to 4 (Big problem). An EPIC-CP score of three (Moderate problem) or four (Big problem) was considered a clinically meaningful QOL decrement. The IPSS is a screening tool that measures GU HRQOL and was first developed by the American Urological Association (AUA) as a validated tool to assess benign prostatic hyperplasia symptoms. The IPSS is a 7-question index that covers symptoms of frequency, nocturia, weak urinary stream, hesitancy, intermittence, incomplete emptying, and urgency. Each question is measured from a score of 0 to 5 with a maximum score of 35. The three categories of symptom intensity are interpreted as mild (score: 0 – 7), moderate (score: 8 – 19), and severe (score: 20+).21
Statistical analysis
Baseline characteristics and outcomes were compared by treatment modality using Chi-square tests and t-tests. Multivariable regression analysis (MVA) testing effects of time, treatment, and their interaction were fit via generalized linear regression models, controlling for age, race, and NCCN risk group. We used robust standard errors with Generalized Estimating Equations to account for within-center correlation. Models were limited to long-term data, at 12, 24 and 36 months with 30 months substituted when there was no available 36-month input (follow-up time was treated as a categorical covariate). No further imputation for missing data was performed, however, for each patient all observed datapoints were included in the model (i.e. patients with some missing data at follow-up contributed to the model estimates). For IPSS, a Poisson regression was used, while for the EPIC domains, a logistic regression model was used with outcomes separated by a score of < 3 vs. 3+. The interaction term between treatment and follow-up time was used to determine whether changes from baseline differed by treatment. All tests were two-sided and a p-value < 0.05 was considered statistically significant. Statistical analyses were done using R software (version 3.6).
Patients were treated between 2002 and 2018 (IMRT: 2002 – 2018, PBT: 2008 – 2018). IPSS data was collected for 62% (IMRT: 55.7%, PBT: 65.8%; completed by 479 patients total, IMRT: 160 patients, PBT: 319 patients) of patients at 12 months, 49% (IMRT: 40.4%, PBT:54.5%; completed by 381 patients total, IMRT: 116 patients, PBT: 265 patients) of patients at 24 months and 50% (IMRT: 44.2%, PBT: 53.2%; completed by 385 patients total, IMRT: 127, PBT: 258) of patients at 36 months. EPIC was recorded for 64% (IMRT: 58.2%, PBT: 68.0%; completed by 497 patients total, IMRT: 167 patients, PBT: 330 patients) of patients at 12 months, 37% (IMRT: 15.3%, PBT: 50.1%; completed by 287 patients total, IMRT: 44 patients, PBT: 243 patients) of patients at 24 months and 46% (IMRT: 34.4%, PBT: 52.3%; completed by 353 patients total, IMRT: 99 patients, PBT: 254 patients) of patients at 36 months. Within this report, the maximum follow-up reported is 36 months.
Results
Patient and treatment characteristics
Of 772 patients included in this study, 287 were in the IMRT cohort and 485 were in the PBT cohort. The median follow-up was 24 months in the IMRT cohort and 36 months in the PBT cohort, based on last observed EPIC survey. For both cohorts, the median ECOG performance status was 0 (range 0 – 1). Treatment cohorts were not completely balanced. NCCN intermediate risk group prostate cancer (81.2 vs 68.2%; P < 0.001) and median age at diagnosis (70 vs 67 years; P < 0.001) were higher in the IMRT cohort. The IMRT group less frequently had Gleason score 6 disease (32.1 vs 38.8%, P < 0.001). Twelve percent of PBT patients had rectal balloon deployed for prostate immobilization. ADT utilization was balanced between cohorts, with 9% of patients receiving ADT. Of the four participating institutions, one contributed to IMRT patient cohort alone, two contributed to the PBT patient cohort alone, and one contributed to both cohorts. All patients were treated in 250 to 300 cGy per daily fraction to a total dose of 6,000 to 7,250 cGy with fractionation patterns listed in Table 1.
Table 1.
Patient and treatment characteristics
| Characteristic | IMRT (N=287) | PBT (N=485) | Total (N=772) | P Value | |
|---|---|---|---|---|---|
| Age at diagnosis | Mean (SD) | 69 (7) | 66 (7) | 67 (7) | <0.001 |
| BMI | Mean (SD) | 29.0 (4.4) | 28.0 (4.7) | 28.3 (4.6) | 0.053 |
| NCCN group | Low | 54 (18.8%) | 154 (31.8%) | 208 (26.9%) | <0.001 |
| Intermediate | 233 (81.2%) | 331 (68.2%) | 564 (73.1%) | ||
| Tumor stage | T1c | 154 (53.7%) | 339 (69.9%) | 493 (63.9%) | <0.001 |
| T2a | 73 (25.4%) | 95 (19.6%) | 168 (21.8%) | ||
| T2b | 36 (12.5%) | 38 (7.8%) | 74 (9.6%) | ||
| T2c | 23 (8.0%) | 12 (2.5%) | 35 (4.5%) | ||
| Unknown | 1 (0.3%) | 1 (0.2%) | 2 (0.3%) | ||
| Baseline PSA | Median | 5.2 | 5.4 | 5.4 | 0.943 |
| Mean (SD) | 5.9 (4.5) | 5.9 (3.3) | 5.9 (3.8) | ||
| Gleason score | 6 | 92 (32.1%) | 188 (38.8%) | 280 (36.3%) | <0.001 |
| 7 (3+4) | 50 (17.4%) | 165 (34.0%) | 215 (27.8%) | ||
| 7 (4+3) | 25 (8.7%) | 72 (14.8%) | 97 (12.8%) | ||
| 7 (NOS) | 117 (40.8%) | 59 (12.2%) | 176 (22.8%) | ||
| Lower than 6 | 3 (1.0%) | 1 (0.2%) | 4 (0.5%) | ||
| Race | AA | 20 (7.0%) | 35 (7.2%) | 55 (7.1%) | 0.008 |
| Asian | 0 (0.0%) | 2 (0.4%) | 2 (0.3%) | ||
| Caucasian | 256 (89.2%) | 428 (88.2%) | 684 (86.6%) | ||
| Hispanic | 2 (0.7%) | 3 (0.6%) | 5 (0.6%) | ||
| Other | 6 (2.1%) | 0 (0.0%) | 6 (0.8%) | ||
| Unknown | 3 (1.0%) | 17 (3.5%) | 20 (2.6%) | ||
| Rectal balloon | Yes | 0 (0.0%) | 60 (12.4%) | 60 (7.8%) | |
| No | 287 (100.0%) | 425 (87.6%) | 712 (92.2%) | ||
| ADT | Yes | 27 (9.4%) | 47 (9.7%) | 74 (9.6%) | |
| No | 112 (39.0%) | 342 (70.5%) | 454 (58.8%) | ||
| Unknown | 148 (51.6%) | 96 (19.8%) | 244 (31.6%) | ||
| RT dose (cGy) | Median | 7,020 | 7,000 | 7,000 | |
| Range | 6,000 – 7,020 | 6,000 – 7,250 | 6,000 – 7,250 | ||
| # Fractions | Median | 26 | 28 | 26 | |
| Mean (SD) | 24.3 (2.8) | 26.6 (3.2) | 25.3 (3.2) | ||
| Institutions | 1 | 139 (48.4%) | 0 (0.0%) | 139 (18.0%) | |
| 2 | 148 (51.6%) | 87 (17.9%) | 235 (30.4%) | ||
| 3 | 0 (0.0%) | 215 (44.3%) | 215 (27.8%) | ||
| 4 | 0 (0.0%) | 183 (37.7%) | 183 (23.7%) | ||
Abbreviations: AA = African American; ADT = Androgen deprivation therapy; BMI = Body mass index; IMRT = Intensity modulated radiation therapy; NCCN = National Comprehensive Cancer Network; PBT = Proton beam therapy; PSA = Prostate specific antigen
Late GU toxicity
Mean IPSS at pre-treatment baseline was 7.0 and 7.2 for the IMRT and PBT cohorts, respectively. Welch’s unequal variances t-test showed these groups to be similar at baseline (t = −0.33; 95% CI, −1.54 – 1.10; P = 0.74). Twelve, 24- and 36-month mean IMRT IPSS were 6.6, 6.5 and 7.1. Twelve, 24- and 36-month mean PBT IPSS values were 8.1, 6.7 and 7.0. IPSS quartiles are presented in Figure 1. On MVA, the changes in IMRT IPSS and PBT IPSS were not different at 12 months, 24 months or 36 months as demonstrated in Figure 2 and Table 2.
Fig 1.
IPSS five-number summaries from pre-treatment baseline through 36 months post-treatment. Follow-up time described in months. Abbreviations: IPSS = International Prostate Symptom Score.
Fig 2.
MVA of EPIC GU, EPIC GI, and IPSS comparing the change from baseline to every time point for IMRT and PBT cohorts. Controlled for race, age, and NCCN risk group. Abbreviations: MVA = Multivariable regression analysis; IPSS = International Prostate Symptom Score; EPIC = Expanded Prostate Cancer Index Composite; GI = Gastrointestinal; GU = Genitourinary; NCCN = National Comprehensive Cancer Network; IMRT = Intensity modulated radiation therapy; PBT = Proton beam therapy; OR = Odds ratio; CI = Confidence interval.
Table 2.
Multivariable regression analysis of late GU and GI toxicity
| Late PBT vs IMRT (reference group) PRO | |||
|---|---|---|---|
| 12 months OR (CI; P) | 24 months OR (CI; P) | 36 months OR (CI; P) | |
| EPIC GU frequency | 1.07 (0.49 – 2.36; 0.86) | 0.35 (0.10 – 1.20; 0.096) | 1.11 (0.45 – 2.72; 0.83) |
| EPIC urinary pain | 6.88 (1.12 – 42.2; 0.037) | 0.80 (0.075 – 8.31; 0.86) | Too few events |
| EPIC problematic GU stream | 1.08 (0.42 – 2.80; 0.87) | 0.79 (0.15 – 4.23; 0.78) | 1.51 (0.44 – 5.26; 0.51) |
| EPIC overall GI | 3.68 (0.84 – 16.24; 0.085) | 2.78 (0.47 – 16.38; 0.26) | 2.45 (0.49 – 12.27; 0.27) |
| EPIC bowel pain/urgency | 2.93 (0.84 – 10.22; 0.091) | 2.88 (0.61 – 13.49; 0.18) | 3.49 (0.79 – 15.39; 0.098) |
| EPIC bowel frequency | 3.48 (0.69 – 17.60; 0.13) | 1.20 (0.17 – 8.65; 0.86) | Too few events |
| IPSS | 1.19 (0.98 – 1.44; 0.08) | 0.99 (0.78 – 1.26; 0.94) | 1.01 (0.81 – 1.26; 0.94) |
Abbreviations: CI = Confidence interval; EPIC = Expanded Prostate Cancer Index Composite; GI = Gastrointestinal; GU = Genitourinary; IMRT = Intensity modulated radiation therapy; IPSS = International Prostate Symptom Score; PBT = Proton beam therapy; PRO = patient-reported outcomes
Turning to EPIC GU PROs, moderate or severe GU concerns were unlikely at 1-year post-treatment (3+ GU frequency: IMRT 17.6%, PBT 9.6%; 3+ GU pain: IMRT 3.6%, PBT 3.4%; 3+ stream problem: IMRT 11.4%, PBT 8.1%).
Moderate or severe urinary frequency concerns at baseline were 18.5% in the IMRT group and 9.4% in the PBT group. Urinary frequency was the most common moderate or severe late GU concern at 12, 24 and 36 months (IMRT: 17.6%, 23.8%, 12.4%; PBT: 9.6%, 4.6%, 7.2%). On MVA, there were no significant differences in the change of EPIC urinary frequency scores from baseline to 12 months, 24 months, or 36 months between IMRT and PBT groups as demonstrated in Figure 2.
Moderate or severe urinary pain at baseline was 5.6% in the IMRT group and 0.8% in the PBT group. Moderate or severe late urinary pain was uncommon at these time points (PBT: 3.4%, 0.8%, 0.2%; IMRT: 3.6%, 6.8%, 0.0%). There was a significant difference in change in urinary pain at 12 months on MVA (OR 6.88; CI, 1.12 – 42.2; P = 0.037). There was no significant difference in change in urinary pain at 24 months on MVA (OR 0.80; CI, 0.075 – 8.31; P = 0.86). With only 4 3+ GU urinary pain events at 36 months (IMRT: 0, PBT: 4), there were too few events to produce a reliable comparative statistic.
Moderate or severe problems with urinary stream at baseline were 9.2% in the IMRT group and 5.8% in the PBT group. Moderate or severe late problems with urinary stream were uncommon at 12, 24 and 36 months (IMRT: 11.4%, 11.6%, 6.3%; PBT: 8.1%, 5.5%, 6.0%). There were no significant differences in changes between groups for problems related to GU stream, as demonstrated in Figure 2 and Table 2.
Late GI toxicity
The incidence of moderate or severe overall bowel problems was low at all follow-up time points. At baseline, clinically significant (a score of 3 or more) bowel problems were 4.9% in the IMRT group and 1.4% in the PBT group. In the IMRT group, clinically significant bowel problems at 12, 24 and 36 months were 4.8%, 6.8% and 6.1%. In the PBT group, clinically significant bowel problems at 12, 24 and 36 months were 4.9%, 5.0% and 4.0%. On MVA, the change in overall GI score did not significantly differ between IMRT and PBT cohorts at 12, 24 or 36 months after treatment. EPIC for overall GI function was not significantly different at 12 months, 24 months, or 36 months, as demonstrated in Figure 2 and Table 2.
The incidence of moderate or severe bowel pain/urgency was low at all follow-up time points. At baseline, clinically significant bowel pain/urgency was 7.6% in the IMRT group and 1.7% in the PBT group. In the IMRT group, clinically significant bowel pain/urgency at 12, 24 and 36 months were 7.8%, 9.5% and 6.3%. In the PBT group, clinically significant bowel pain/urgency at 12, 24 and 36 months were 4.9%, 5.8% and 4.3%. On MVA, the change in EPIC bowel pain/urgency between IMRT and PBT groups did not significantly differ at 12 months, 24 months (or 36 months, as demonstrated in Figure 2 and Table 2.
The incidence of moderate or severe bowel frequency was low at all follow-up time points. At baseline, clinically significant bowel frequency was 5.6% in the IMRT group and 0.8% in the PBT group. In the IMRT group, significant bowel frequency at 12, 24 and 36 months was 6.0%, 9.3% and 1.0%. In the PBT group, significant bowel frequency at 12, 24 and 36 months was 3.1%, 1.7% and 2.8%. While too few events were present at 36 months for comparative analysis, there was no statistically significant difference between groups in the change at 12 months or 24 months on MVA, as demonstrated in Figure 2 and Table 2.
Discussion
These results demonstrate that moderately hypofractionated PBT and IMRT yield low rates of late patient-reported GU and GI toxicity through three years post-treatment. No clinically significant differences were found in late moderate or severe PRO GI and GU toxicity rates between PBT and IMRT cohorts when adjusting for covariates. While the pragmatic, prospective COMPPARE (NCT03561220)22 and the randomized PARTIQoL (NCT01617161)23 clinical trials will evaluate late radiation toxicities among these cohorts, there is currently no published level I evidence comparing toxicity profiles between PBT and IMRT. To our knowledge, this multi-institutional patient-centric analysis represents the largest late toxicity pooled analysis from tertiary referral centers treating prostate cancer with moderately hypofractionated PBT and IMRT.
Prostate cancer PROs do not always show concordance between patients and medical providers; toxicity is often assigned greater severity by patients.24–25 We can corroborate that compared to physicians, patients generally ascribe greater severity to their symptoms. Our pooled collaborative physician-graded toxicity analysis14 showed no late GI or GU toxicity in 74.4% and 56.6% of patients, respectively. In this PRO analysis, at time points between 1- and 3-years post-treatment, between 65.6% - 69.0% of patients had no GI concerns. At these time points, between 38.1% - 39.4% of patients had no urinary frequency concerns.
Our moderately hypofractionated rates of 12-month post-treatment overall bowel dysfunction and urinary frequency problems were comparable (PBT: 4.9%, 9.6%; IMRT: 4.8%, 17.6%) to previously reported studies. 26–28 Among a multi-institutional group of patients treated with conventional fractionation (enrolled between 2003 and 2006), the rate of 12-month post-treatment overall bowel dysfunction and urinary frequency were 9% and 13%, respectively.26 Additionally, the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer trial 60 Gy schedule patient-reported moderate to severe bowel bother at 2 years of 6–7% was similar with our cohorts (PBT: 5.0%, IMRT: 6.8%).27–28
There are specific strengths of this study related to the number of patients and detailed reporting of toxicity information. The duration of follow-up is also appropriate for this analysis, as most adverse events occur in the first few years after treatment, with relatively limited change anticipated beyond three years post-treatment.29 However, we must account for study limitations. While the information was gathered in a prospective manner, study subjects were not randomized and thus, participants were subject to selection bias. Such bias may explain the consistent numerically worse baseline EPIC bowel and bladder function in the IMRT cohort. The broad survey collection range is attributed to the mode of data collection: paper forms completed at follow-up appointments. In other words, there were no paper forms delivered to home addresses, web-based data collection, telephone interviews, or audio-computer-assisted interviews. Data collection was better in the PBT group, thus increasing the likelihood of selection bias. Patients in the IMRT group were older and more often had intermediate risk prostate cancer. Additionally, we acknowledge treatment variability between institutions in treatment planning techniques. Further, the baseline rate of PROs was small, which sometimes led to large effect estimates with wide confidence intervals when estimating the differences in the change from baseline. Given the heterogeneity in moderate hypofractionation radiation fractionation schemes, we were not able to perform a dosimetry comparison between the cohorts. Finally, longer-term PROs will be necessary to determine whether late emerging toxicities exist and differ between cohorts. While further follow-up is needed, these results demonstrate that hypofractionated prostate radiation yields low rates of toxicity without significant differences between PBT and IMRT.
Conclusion
This multi-institutional cohort analysis of prostate cancer PRQOL outcomes demonstrated that moderately hypofractionated PBT and IMRT were well tolerated with low rates of late GU and GI toxicity. No clinically meaningful differences in late moderate or severe PROs were identified after adjusting for covariates. Moderately hypofractionated PBT and IMRT appear safe, with acceptable late GU and GI PRQOL when delivered as definitive treatment for NCCN low- and intermediate-risk group prostate cancer.
Footnotes
Conflict of Interest: None
Data Availability Statement:
Research data are stored in an institutional repository and will be shared upon request to the corresponding author.
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Associated Data
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Data Availability Statement
Research data are stored in an institutional repository and will be shared upon request to the corresponding author.