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Postoperative Radiation Therapy for Prostate Cancer: Comparison of Conventional Versus Hypofractionated Radiation Regimens
Accepted Manuscript Post-operative radiation therapy for prostate cancer: Comparison of conventional versus hypofractionated radiation regimens Daniel J. Tandberg, Taofik Oyekunle, W.Robert Lee, Yuan Wu, Joseph K. Salama, Bridget F. Koontz PII:
S0360-3016(18)30248-7
DOI:
10.1016/j.ijrobp.2018.02.002
Reference:
ROB 24779
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 19 October 2017 Revised Date:
18 January 2018
Accepted Date: 1 February 2018
Please cite this article as: Tandberg DJ, Oyekunle T, Lee WR, Wu Y, Salama JK, Koontz BF, Postoperative radiation therapy for prostate cancer: Comparison of conventional versus hypofractionated radiation regimens, International Journal of Radiation Oncology • Biology • Physics (2018), doi: 10.1016/ j.ijrobp.2018.02.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Post-operative radiation therapy for prostate cancer: Comparison of conventional versus hypofractionated radiation regimens Daniel J. Tandberg1, Taofik Oyekunle2, W. Robert Lee1, Yuan Wu2, Joseph K. Salama1, Bridget F.
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Koontz1 1 Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 2 Department of Biostatistics and Bioinformatics, Duke Cancer Institute, Durham, NC
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Corresponding Author: Daniel J. Tandberg, M.D.
Duke University School of Medicine DUMC Box 3085, Durham, NC 27710 Ph: 919-668-7336 Fax: 919-668-7345 E-mail: [email protected]
Taofik Oyekunle, M.S. Ph: 919-613-4336
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Statistical Analysis:
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Department of Radiation Oncology
Yuan Wu, Ph.D. Ph: 919-681-5018
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Email: [email protected]
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Email: [email protected]
Manuscript Type: Original article Short Title: Conventional or Hypofractionated PORT Disclosures: DT, TO, WRL, YW, and JS have no disclosures. BK receives unrestricted research funding from Janssen Pharmaceuticals and is an advisory board member for Blue Earth Diagnostics and Bayer. Funding: There was no outside funding for this research
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Post-operative radiation therapy for prostate cancer: Comparison of conventional versus hypofractionated radiation regimens Abstract:
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Purpose/Objectives: Post-prostatectomy radiotherapy (PORT) for adverse pathologic factors results in improved overall and biochemical progression-free survival. Conventional PORT (coPORT) is delivered over 7-8 weeks. Hypofractionated PORT (hypoPORT) offers a more resource-efficient option if shown to have acceptable efficacy and toxicity compared to coPORT. We compared acute/late toxicity and
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biochemical control in contemporaneous patient cohorts treated with hypoPORT or coPORT.
Methods/Materials: Consecutive patients treated with intensity-modulated hypoPORT (2.5 Gy/fraction, median cumulative dose 65 Gy [range 57.5-70 Gy]) or coPORT (1.8-2.0 Gy/fraction, median cumulative
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dose 66 Gy [range 60-74 Gy]) between 2005-2016 at two institutions comprised the study cohort. Acute toxicity, cumulative late grade 2 and ≥3 GU and GI toxicity incidences (CI) were calculated for all patients using the Kaplan-Meier methods and compared between cohorts. Biochemical progression free survival (bPFS) was calculated in patients with ≥12 months follow-up (FU) Results: Median FU for all 461 patients was 38.6 months. 167 (36%) received hypoPORT; 294 (64%) patients received coPORT. The hypoPORT cohort had significantly worse baseline urinary incontinence.
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Acute grade ≥2 GU toxicity was more common after hypoPORT (22% vs 8%) (p=0.0001). Late grade ≥3 GU toxicity CI at 6 years was 11% (hypoPORT) and 4% (coPORT) (p=0.0081). However, hypoPORT was not associated with late grade ≥2 GU toxicity on MVA (HR 1.39, 95% CI 0.86-2.34) (p=0.18). There was no difference in acute or late GI toxicity. In the subset of patients with ≥12 month FU (n=364,
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median FU 52 months) 4-year bPFS was 78% (95% CI 69.4-85.0%) after hypoPORT (p=0.0038) and 65% (95% CI 57.6-71.1%) after coPORT. HypoPORT was not significant for bPFS on MVA (HR 0.64
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95% CI 0.41-1.02, p=0.059).
Conclusions: HypoPORT shows promising early biochemical control. After controlling for baseline urinary function, hypoPORT was not associated with greater GU toxicity than coPORT.
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Introduction: Prostate cancer is the most common malignancy among men in the United States, with an estimated 161,380 new cases in 2017.1 Following radical prostatectomy (RP), post-operative radiotherapy (PORT) is routinely offered for adverse pathologic features (i.e. seminal vesicle invasion, extraprostatic
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extension, positive surgical margins) as adjuvant RT was shown to improve overall survival in one randomized controlled trial and biochemical control in two others.2-4 For men with biochemical recurrence following RP, salvage PORT has been shown to improve prostate cancer specific survival compared to observation.5
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While typical PORT courses deliver 1.8-2 Gy daily to cumulative doses of 64 to 74 Gy completing in 7-8 weeks,6 moderately hypofractionated RT schedules, delivering fewer, higher doses per Pre-clinical and clinical data suggest
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treatment, may be advantageous for prostate cancer patients.
prostate cancer is preferentially sensitive to greater dose per fraction.7 Further, moderately hypofractionated RT schedules are more convenient often requiring half as many radiation treatments. In the intact prostate setting, multiple randomized studies have demonstrated hypofractionated RT has similar efficacy to conventional RT.8-13
In the post-operative setting, the role of hypofractionated RT is less clear. Several retrospective
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studies report promising biochemical control following hypofractionated PORT (hypoPORT).14-16 However, these studies are small and have not compared outcomes to patients treated with conventional PORT. Further, the impact of hypoPORT on late toxicity is conflicting, with one study reporting infrequent late urinary toxicity15 while two others reporting higher than expected late urinary toxicity.16, 17
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Given the potential advantages of hypoPORT weighted against the risk for increased toxicity, a randomized trial is underway (NRG-GU003, NCT03274687), but results are not expected for many years. Therefore, we compared the efficacy and toxicity outcomes of post-prostatectomy patients treated
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contemporaneously with either conventionally fractionated or hypofractionated PORT. Methods: Patients
Patients with a histopathologic diagnosis of prostate cancer and prior radical prostatectomy (RP)
treated with adjuvant or salvage intensity-modulated RT (IMRT) with or without concurrent androgen deprivation therapy (ADT) between 2005-2016 comprised the study cohort. Patients with pathologic nodal involvement at RP, those with metastatic disease and those receiving pelvic lymph node RT were
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excluded. The institutional review boards at *** and the *** Veterans Affairs Medical Center approved this retrospective analysis. Treatment
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Patients underwent radical prostatectomy at the discretion of the treating surgeon. Pathologic nodal sampling or dissection was not required for inclusion. Adjuvant or salvage RT was recommended based on adverse pathologic features or persistent/rising PSA. ADT was used at the discretion of the treating urologist/radiation oncologist.
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All patients underwent computed tomographic (CT) based simulation, typically with a full bladder and empty rectum. The prostate bed clinical target volume was most often contoured based on the Radiation Therapy Oncology Group (RTOG) consensus guidelines with final contours based on the
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discretion of the treating radiation oncologist.18 Patient treatment plans were developed using 6-15 MV photons and IMRT or volumetric modulated arc therapy (VMAT) techniques. Conventional PORT (coPORT) and hypoPORT cohorts were treated contemporaneously based on institutional protocol: 1.8 or 2 Gy daily fractions over 42-51days at *** (coPORT) versus 2.5 Gy daily fractions over 31-38 days at the *** VA (hypoPORT). Prior to treatment, daily image-guidance with either orthogonal kV radiographs or cone beam CT was performed in all cases.
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Patients were evaluated weekly during RT for acute sequelae. Acute toxicity was graded based on weekly provider notes using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Following RT completion, patients were seen at regular intervals for physical examination, PSA measurement, and prospective toxicity assessment including the Urological Association Symptom Score
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(AUA-SS) and International Index of Erectile Function (IIEF). Late toxicities (>30 days after RT completion) were scored using the RTOG/EORTC toxicity criteria. Urinary incontinence was graded
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using CTCAE. Statistical Analysis
The objectives of this analysis were to compare biochemical control and toxicity between two
contemporaneous cohorts of patients treated with coPORT or moderately hypoPORT.
Patient and
treatment characteristics were described and compared between cohorts using the Mann-Whitney U-test for continuous variables and chi-square tests for categorical variables. Acute and late toxicity were evaluated in all treated patients. Crude incidence of acute genitourinary (GU) and gastrointestinal (GI) toxicity was compared using chi-square test. Cumulative
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incidence for late GU and GI events were analyzed using the Kaplan-Meier (K-M) product-limit method. Cox multivariate analyses were performed to assess patient and treatment factors associated with an increased risk of late GU or GI toxicity. Variables were included in the multivariate model if they achieved a p≤0.05 on univariate analysis.
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Disease outcomes were evaluated only in patients with at least 12 months of follow-up. Biochemical progression was defined as a PSA increase of 0.2 ng/mL or greater from the post-RT nadir (confirmed with a second increase), a continued rise in PSA despite RT, or the initiation of salvage ADT. All time-based variables were defined from the completion of radiation therapy. Biochemical progression
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free survival (bPFS) was defined as the time from completion of radiation to biochemical progression or death, whichever came first. Time to distant metastases was defined as the time from completion of
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radiation to the development of distant metastases.
The K-M method was used to estimate bPFS in both RT groups with 95 % CI. The log-rank test was used to test for survival differences between groups. Cox multivariate analysis was performed to assess for clinical, pathologic, and treatment factors associated with an increased risk of biochemical progression. Variables were included in the multivariate model if they achieved a p≤0.05 on univariate analysis. Categorical PSA groups only were entered into the multivariate analysis. Distant metastasis free survival and overall survival were calculated using the K-M method. All statistical tests were two-sided
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and <0.05 was considered statistically significant. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC) and R version 3.3.3 (Vienna, Austria). Results:
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Between January 2005 and October 2016, 461 patients met the inclusion criteria and were included in the analysis. Of these, 294 (64%) received conventional post-operative RT of 1.8-2.0 Gy per
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fraction (coPORT) while 167 (36%) received hypofractionated PORT of 2.5 Gy per fraction (hypoPORT). The median cumulative RT dose in the coPORT cohort was 66 Gy (range 60-74 Gy). Eighty-seven percent of patients in the coPORT cohort received 66 Gy at 2 Gy/fraction. The median cumulative RT dose in the hypoPORT cohort was 65 Gy (range 57.5-70 Gy). Eighty-seven percent of patients in the hypoPORT cohort received 65 Gy at 2.5 Gy/fraction (EQD2 74.3 Gy)(Supplement, Table 1).
Baseline patient demographic, clinical and treatment characteristics for all patients are shown in Table 1. The coPORT patients had a higher rate of extracapsular extension (56% vs 43%) and higher preRT PSA (median 0.4 vs 0.2 ng/mL) compared to hypoPORT patients. An equal percentage of patients in
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both cohorts received ADT, but ADT duration was significantly longer in the hypoPORT cohort (median 24 versus 6 months in those receiving ADT). Patients treated with hypoPORT had significantly higher pre-RT AUA SS compared to patients who received coPORT (table 1). Prior to RT 49% of patients in the hypoPORT cohort had CTCAE grade 2-3 incontinence compared to 18% of coPORT patients (p<0.0001).
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Toxicity
Acute and late toxicities were evaluated in all patients (n=461) with a median follow-up of 38.6 months. The incidence of acute grade ≥2 GU toxicity was significantly higher among patients who received hypoPORT compared to coPORT, 22% vs 8% respectively (p=0.0001). There was 1 acute grade
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3 GU toxicity in the hypoPORT cohort and 3 in the coPORT cohort. All grade 3 toxicity events were acute urinary retention requiring urinary catheter placement, cystoscopy and dilation or incision of
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bladder neck contracture. There was no significant difference in the incidence of acute grade ≥2 GI toxicity, between the hypoPORT and coPORT cohorts, 5% vs 7% respectively (p=0.3655). There were no acute grade 3 or greater GI toxicities in either cohort.
The cumulative incidence of late grade 2 GU toxicity at 6 years was 39% (95% CI 30-49) in the hypoPORT cohort and 26% (95% CI 20-33%) in the coPORT cohort (p=0.0033)(Figure 1a). Cumulative incidence of late grade ≥ 3 GU toxicity at 6 years was 11% (6-21%) and 4% (2-8%) for the hypoPORT
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and coPORT cohorts, respectively (p=0.0081)(Figure 1b). Because of differences in baseline urinary function, we analyzed the cohorts stratified by baseline AUA SS and incontinence grade (Supplement, Figure 1). The 6 year cumulative incidence of late grade ≥2 GU toxicity was significantly higher in the hypoPORT cohort compared to the coPORT cohort in the subset of patients with AUA SS <8 (51% vs
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34%, p=0.0059) and pre-RT incontinence grade 0-1 (43% vs 25%, p=0.0066). Supplement table 2 describes the individual cases of grade 3 or 4 GU toxicity. There were 10
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cases of late grade 3 GU toxicity in the hypoPORT cohort, all being frequent hematuria requiring multiple cystoscopies, transfusions, hospital admission, and/or hyperbaric oxygen therapy. One patient in the hypoPORT cohort had a late grade 4 GU toxicity. This patient presented with dysuria and obstructive symptoms following RT. Cystoscopy and biopsies of the bladder revealed bladder necrosis. The patient was subsequently in a motor vehicle accident and suffered bladder rupture requiring operative repair. After the patient developed recurrent urinary tract infections and pelvic pain cystoscopy and MRI confirmed an urosymphyseal fistula and pubic bone osteomyelitis. The patient ultimately underwent cystectomy and pubic symphysiectomy. There were 6 cases of late grade 3 GU toxicity in the coPORT cohort, all consisting of frequent hematuria. At last follow-up 2 patients in the hypoPORT and 2 patients in the coPORT were experiencing late grade >3 GU toxicity. 5
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Review of the bladder dose-volume metrics was performed for all patients with grade 3 or 4 GU toxicity and compared to per protocol bladder dose constraints in the ongoing randomized NRG-GU003 trial comparing hypoPORT (62.5 Gy at 2.5 Gy per fraction) to coPORT (66.6 Gy at 1.8 Gy per fraction (Supplement, Table 2). Overall 9 of 11 of the cases of grade ≥ 3 GU toxicity in the hypoPORT cohort met
GU toxicity in the coPORT cohort met the per protocol constraints.
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the per protocol bladder dose constraints including the case of grade 4 GU toxicity. All 6 cases of grade 3
Univariate (UVA) and multivariate analyses (MVA) for late grade ≥2 GU toxicity is shown in Table 2. AUA SS ≥8, pre-RT incontinence grade 2-3, and hypoPORT were associated with higher risk of
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late grade ≥2 GU toxicity on UVA. On MVA patients with pre-RT grade 2-3 incontinence were at an increased risk of late grade ≥2 GU toxicity (HR 2.03, 95% CI 1.23-3.35) (p=0.006). The use of coPORT or hypoPORT was not significantly associated with risk of late grade ≥2 GU toxicity on MVA (HR 1.39,
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95% CI 0.86-2.34) (p=0.18). In the subset of patients with pre-RT grade 0-1 incontinence (n=320) hypoPORT was the only variable significantly associated with risk of late grade ≥2 GU toxicity on UVA (HR 1.59, 95% CI 1.21-3.56) (p=0.008) (Supplement, Table 3).
AUA-SS, AUA bother score, and IIEF were relatively unchanged compared to pretreatment values in both cohorts.
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The cumulative incidence of late grade 2 GI toxicity at 6 years was 10% (95% CI 6-17%) in the hypoPORT cohort and 6% (95% CI 3-10%) in the coPORT cohort (p=0.0542)(Figure 2). One patient with a history of a thrombosed hemorrhoid was found to have a fistula following hypoPORT that was
coPORT cohort. Clinical Outcomes
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surgically corrected and scored as a late grade 3 GI toxicity. There were no late ≥ grade 3 toxicities in the
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Patients with a 12-month minimum follow-up were analyzed for bPFS (n=364). With a median
follow-up of 52 months, 4-year estimated bPFS was 64.8% (95% CI 57.6-71.1%) for the coPORT cohort and 78.4% (95% CI 69.4-85.0%) for the hypoPORT cohort (p=0.0038) (Figure 3a). In the subset of ADT free patients (n=261) bPFS was 68.4% (95% CI 59.9-75.4%) after coPORT and 80.5% (95% CI 70.587.5%) following hypoPORT (p=0.0234) (Figure 3b). Overall 114 patients had a biochemical progression event, 87 in the coPORT cohort and 27 in the hypoPORT cohort. Among patients with biochemical progression, 22% of patients in the coPORT cohort and 23% of patients in the hypoPORT cohort had persistent PSA progression despite RT. The remaining patients with biochemical progression had an initial PSA response to RT. 6
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UVA and MVA for biochemical progression are listed in table 3. On MVA a higher Gleason score, negative surgical margins, and a higher pre-RT PSA level were significantly associated with increased risk of biochemical progression. There was a trend for decreased risk of biochemical progression in the hypoPORT cohort compared to the coPORT cohort (HR 0.64 95% CI 0.41-1.02) but
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this was not significant (p=0.059). Four year distant metastasis free survival was 92.2% (95% CI 87.0-95.4%) for the coPORT cohort and 95.4% (95% CI 89.2-98.1%) for the hypoPORT cohort (p=0.1746) (Supplement, Figure 2a). A total of 19 patients died during the study period, 13 in the coPORT cohort and 6 in the hypoPORT cohort.
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Four year overall survival was 97.6% (95% CI 93.8-99.1%) and 94.3% (95% CI 86.7-97.6%) for the coPORT and hypoPORT cohorts, respectively (p=0.7071) (Supplement, Figure 2b).
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Discussion:
Adjuvant and salvage post-prostatectomy radiation therapy are standard treatments for men with adverse pathologic risk factors or rising post-prostatectomy PSA following surgery.19 While moderately hypofractionated RT has been shown to be non-inferior to conventionally fractionated RT in the definitive intact prostate setting8-10, there are few reports of moderately hypofractionated RT in the postprostatectomy setting and no comparisons to the far more commonly used conventional fractionation15, 16, 20
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. If hypoPORT demonstrated similar efficacy and toxicity as conventionally fractionated RT,
hypoPORT could offer significant economic and practical benefits for patients. In this non-randomized contemporaneous cohort analysis of the two fractionation schedules we found a promising 4-year bPFS of 78% following hypoPORT with acceptable late toxicity. To the best of our knowledge the present
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analysis is the largest study to date comparing clinical outcomes and toxicity of cohorts of patients treated with hypofractionated or conventional RT using modern radiation techniques. With or without ADT,
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The biochemical control following hypoPORT was favorable.
biochemical control following hypoPORT was ~13% greater than patients treated with coPORT. However, differences in the two cohort’s disease characteristics might explain some of the observed differences in biochemical control. Overall the coPORT cohort appeared to have less favorable disease including a higher pre-RT PSA (0.4 vs 0.2 ng/mL) and higher rate of extracapsular extension (56% vs 43%). On multivariate analysis PORT fractionation was not significantly associated with biochemical control (p=0.059).
It is also possible that the favorable biochemical control with hypoPORT is a
reflection of the higher biologically effective dose (BED) compared to coPORT regimens. Using an α/β of 1.5 the most common hypofractionated RT regimen used in this study (65 Gy at 2.5 Gy per fraction) is equivalent to approximately 74 Gy in conventional 2 Gy fractions, representing significant dose 7
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escalation, compared to the commonly used conventionally fractionated dose schemes of 60-66 Gy. Several retrospective reports have shown that biochemical control is improved with larger cumulative doses of salvage RT, suggesting a dose-response effect.21, 22 Thus any benefit of the hypofractionated RT regimen on bPFS in this study may simply be the result of dose-escalation and not any intrinsic advantage
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of the larger dose per fraction. Further follow-up of our study cohort and randomized data are needed to confirm the potential impact of hypofractionated RT on biochemical control in the post-operative setting. The possibility of hypofractionated RT to increase the risk of late toxicity compared to conventional RT is a topic of great interest. We found late grade 2 and grade ≥3 GU toxicity was more
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common in the hypofractionated RT cohort compared to the conventional RT cohort. This difference was seen in both the subset of patients with low baseline AUA SS and the subset with minimal pre-RT incontinence. However, this subset was a smaller cohort due to the fact that patients in the
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hypofractionated cohort had significantly worse baseline urinary symptoms. On multivariate analysis with the full cohort, including both baseline AUA SS and pre-RT incontinence as variables, hypofractionated RT was not associated with increased risk of late grade ≥2 toxicity. In both the conventional and hypofractionated cohorts, all cases of late grade 3 GU toxicity resulted from frequent gross hematuria and most resolved by the time of last follow-up. The one late grade 4 GU toxicity in our study, a urosymphyseal fistula, is a very rare but debilitating late toxicity of radiation therapy, often occurring in
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patients who have undergone open or endoscopic repair of bladder neck contractures.23 While this occurred in the hypofractionated cohort there is no known correlation between hypofractionation and this rare adverse event. Late severe GI toxicity was rare in both cohorts and not significantly different. Independent of radiation dosing cohort, we identified that pre-RT incontinence was associated
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with late GU toxicity. There are a limited number of studies reporting predictors of late GU toxicity following PORT. A prior evaluation of factors associated with late GU toxicity in a population of patients treated with both conventional and hypofractionated post-operative RT reported 17 presence of acute grade
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≥2 GU toxicity and increasing dose per fraction independently associated with late grade ≥3 GU toxicity. However, they did not include baseline urinary function (AUA SS or incontinence). Other studies, including only patients treated with conventional RT, have shown pre-RT urinary incontinence to be predictive of late GU toxicity.24 Our data suggests that baseline urinary incontinence, regardless of RT fractionation increases the risk of late GU toxicity. In the intact prostate cancer setting, most8, 10, 12 but not all9, 25 randomized studies have shown that moderate hypofractionation has equivalent late toxicity to conventional fractionation. It is not clear if these studies can be extrapolated to the post-operative setting. The post-operative anatomy potentially
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increases radiation exposure of the bowel and bladder to radiation. Indeed in the RTOG consensus guidelines the post-operative clinical target volume encompasses a significant portion of the bladder inferiorly and the bladder wall posteriorly.18 Further, post-operative patients may have surgical toxicity that could potentially increase their risk of late GU toxicity, as our data seems to support.
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Retrospective reports of hypofractionated post-operative RT have shown conflicting findings regarding late toxicity.15-17 While one study reported no late grade 3 GI or GU toxicities among 108 patients treated with hypofractionated salvage RT to 65 Gy in 2.5 Gy fractions,15 another reported high rates of late grade 3 GU toxicity (4 year rate of late grade 3 GU: 28%) among 56 patients treated with
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adjuvant or salvage hypoPORT to a median of 65 Gy in 2.5 Gy fractions.16 However, the latter study authors noted using a conservative grading of late GU toxicity such that even transient hematuria was considered late grade 3 GU toxicity. Most of the late grade 3 GU toxicity in this study resolved by last
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follow-up. The only other comparison of conventional to hypoPORT found increased rates of late grade ≥3 GU toxicity in the hypofractionated RT cohort (5 year late grade ≥3 GU toxicity 18% vs 7%, respectively) however there were differences in RT technique between the conventional and hypofractionated RT cohorts and heterogeneous RT doses in the hypofractionated arm (2.35-2.9 Gy).17 While supportive of hypoPORT, our analysis is ultimately limited by its non-randomized design and further understanding of risk with post-operative hypofractionation must await randomized results.
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Hypofractionated radiotherapy will be compared to conventionally fractionated radiotherapy in the post-prostatectomy setting in NRG-GU003, a randomized phase III trial (NCT # NCT03274687). The hypoPORT regimen used will be 62.5 Gy in 2.5 Gy fractions. Using an α/β of 1.5, this regimen is equivalent to approximately 71 Gy in 2 Gy fractions.
Although the cumulative dose in the
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hypofractionated arm of NRG-GU003 is one fraction less than what was most commonly delivered in the present study (65 Gy in 2.5 Gy fractions), it still offers dose escalation compared to the conventionally fractionated arm (66.6 Gy in 1.8 Gy fractions). As we demonstrate favorable biochemical control but
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increased late GU toxicity with hypoPORT in patients with favorable baseline urinary function it is possible that the slightly lower cumulative dose in the hypofractionated arm of NRG-GU003 may maintain efficacy while lowering toxicity. Further research will hopefully provide more insight into the optimal hypofractionated RT dose regimen. The strengths of this study include the large number of patients analyzed and the consistent modern intensity-modulated and image-guided radiation techniques used in both cohorts. Furthermore, we performed a robust analysis controlling for baseline treatment and pathologic details as well as baseline urinary function. However, the study has several limitations most prominently being the
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retrospective assessment. Additionally, although the hypofractionated and conventional RT patients were treated from the same geographic region and outcomes of VA patients mimic those treated elsewhere,26 unaccounted for differences in the patient populations, surgical technique/experience, and robustness of the electronic medical record and follow-up between institutions could impact comparisons of efficacy
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and toxicity. A comparison of patients with cancer in the VA health system and Medicare fee-for service demonstrated that the prevalence of severe comorbidity was higher in the VA population.26 We did not account for differences in comorbidity and this could impact the toxicity comparison. Further, longer follow-up may be needed to accurately assess for differences in late toxicity as our data suggests that severe late GU toxicity can first present greater than 5 years after treatment. Longer follow-up may also
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be needed to assess for differences in bPFS, especially as there were differences in the length of ADT between cohorts. Finally, although we did not perform a comprehensive dosimetric analysis, as prior data
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did not find associations with toxicity16 it is possible that specific RT dose-volume metrics could impact toxicity results.
In conclusion, hypofractionated post-operative RT demonstrated favorable early biochemical control outcomes to conventional RT. Acute and late urinary toxicity was more common in the hypofractionated RT cohort but was possibly related to worse baseline urinary function. Randomized data is needed to clarify the efficacy and toxicity of post-operative hypofractionated RT compared to
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conventional RT.
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References: 1. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67: 7-30. 2. Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a
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randomized clinical trial. J Urol. 2009;181: 956-962.
3. Bolla M, van Poppel H, Tombal B, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet. 2012;380: 2018-2027.
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4. Wiegel T, Bartkowiak D, Bottke D, et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol. 2014;66: 243-250. 5. Trock BJ, Han M, Freedland SJ, et al. Prostate cancer-specific survival following salvage radiotherapy
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vs observation in men with biochemical recurrence after radical prostatectomy. JAMA. 2008;299: 27602769.
6. Mohler JL, Armstrong AJ, Bahnson RR, et al. Prostate Cancer, Version 1.2016. J Natl Compr Canc Netw. 2016;14: 19-30.
7. Fowler JF, Toma-Dasu I, Dasu A. Is the α/β ratio for prostate tumours really low and does it vary with the level of risk at diagnosis? Anticancer Res. 2013;33: 1009-1011.
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8. Catton CN, Lukka H, Gu CS, et al. Randomized Trial of a Hypofractionated Radiation Regimen for the Treatment of Localized Prostate Cancer. J Clin Oncol. 2017;35: 1884-1890. 9. Lee WR, Dignam JJ, Amin MB, et al. Randomized Phase III Noninferiority Study Comparing Two Radiotherapy Fractionation Schedules in Patients With Low-Risk Prostate Cancer. J Clin Oncol. 2016;34:
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2325-2332.
10. Dearnaley D, Syndikus I, Mossop H, et al. Conventional versus hypofractionated high-dose intensitymodulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3
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CHHiP trial. Lancet Oncol. 2016.
11. Incrocci L, Wortel RC, Alemayehu WG, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016;17: 1061-1069. 12. Pollack A, Walker G, Horwitz EM, et al. Randomized trial of hypofractionated external-beam radiotherapy for prostate cancer. J Clin Oncol. 2013;31: 3860-3868. 13. Arcangeli S, Strigari L, Gomellini S, et al. Updated results and patterns of failure in a randomized hypofractionation trial for high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2012;84: 1172-1178.
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14. Wong GW, Palazzi-Churas KL, Jarrard DF, et al. Salvage hypofractionated radiotherapy for biochemically recurrent prostate cancer after radical prostatectomy. Int J Radiat Oncol Biol Phys. 2008;70: 449-455. 15. Kruser TJ, Jarrard DF, Graf AK, et al. Early hypofractionated salvage radiotherapy for
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postprostatectomy biochemical recurrence. Cancer. 2011;117: 2629-2636. 16. ***
17. Cozzarini C, Fiorino C, Deantoni C, et al. Higher-than-expected severe (Grade 3-4) late urinary toxicity after postprostatectomy hiypofractionated radiotherapy: a single-institution analysis of 1176 patients. Eur Urol. 2014;66: 1024-1030.
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18. Michalski JM, Lawton C, El Naqa I, et al. Development of RTOG consensus guidelines for the definition of the clinical target volume for postoperative conformal radiation therapy for prostate cancer.
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Int J Radiat Oncol Biol Phys. 2010;76: 361-368.
19. Thompson IM, Valicenti RK, Albertsen P, et al. Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO Guideline. J Urol. 2013;190: 441-449.
20. Fersino S, Tebano U, Mazzola R, et al. Moderate Hypofractionated Postprostatectomy Volumetric Modulated Arc Therapy With Daily Image Guidance (VMAT-IGRT): A Mono-institutional Report on Feasibility and Acute Toxicity. Clin Genitourin Cancer. 2017.
21. Pisansky TM, Agrawal S, Hamstra DA, et al. Salvage Radiation Therapy Dose Response for
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Biochemical Failure of Prostate Cancer After Prostatectomy-A Multi-Institutional Observational Study. Int J Radiat Oncol Biol Phys. 2016;96: 1046-1053.
22. Bernard JR, Buskirk SJ, Heckman MG, et al. Salvage radiotherapy for rising prostate-specific antigen levels after radical prostatectomy for prostate cancer: dose-response analysis. Int J Radiat Oncol Biol
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Phys. 2010;76: 735-740.
23. Bugeja S, Andrich DE, Mundy AR. Fistulation into the pubic symphysis after treatment of prostate cancer: An important and surgically correctable complication. J Urol 2016;195:391-8.
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24. Iyengar P, Levy LB, Choi S, Lee AK, Kuban DA. Toxicity associated with postoperative radiation therapy for prostate cancer. Am J Clin Oncol. 2011;34: 611-618. 25. Aluwini S, Pos F, Schimmel E, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): late toxicity results from a randomised, noninferiority, phase 3 trial. Lancet Oncol. 2016;17: 464-474. 26. Landrum MB, Keating NL, Lamont EB, et al. Survival of older patients with cancer in the Veterans Health Administration versus fee-for-service Medicare. J Clin Oncol. 2012;30: 1072-1079.
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Figure Legends Figure 1: Cumulative incidence of late (a) grade 2 GU and (b) grade ≥3 GU toxicity stratified by radiation therapy type.
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Figure 2: Cumulative incidence of late GI 2 toxicity stratified by radiation therapy type. Figure 3: Biochemical recurrence free survival for (a) patients with at least 12 months of follow-up
stratified by radiation therapy type (b) Patients with at least 12 months of follow-up and no concurrent
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ADT stratified by radiation therapy type.
Supplement Figure 1: Cumulative incidence of late ≥2 GU toxicity stratified by radiation therapy type and
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(a) AUA SS (a) and (b) pre-RT incontinence grade.
Supplement Figure 2: Distant metastasis free survival (a) and overall survival (b) for patients with at least
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12 months of follow-up stratified by radiation therapy type.
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Table 1: Clinical and Pathologic Characteristics
461(100)
294(64)
64.3(59.8-68.5)
64.4(59.1-69.6)
P-value
167(36) 64.3(60.9-67.1)
0.2684
38.6(15.4-70.3)
39.4(15.3-77.3)
185(40) 266(58) 10(2)
93(32) 197(67) 4(1)
49(11) 312(68) 95(21) 5(1)
35(12) 191(65) 66(22) 2(1)
37.5(16.2-61.8)
<.0001
358(78) 98(21) 5(1)
92(55) 69(41) 6(4)
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220(48) 235 (51) 6(1)
127(43) 164 (56) 3(1)
0.0074 93(56) 71(43) 3(2) 0.2587 124(74) 40(24) 3(2)
112(38) 181(62) 1(1)
63(38) 101(61) 3(2)
326 (71) 119 (26) 16 (3)
218 (74) 71 (24) 5 (2)
108 (65) 48 (29) 11 (6)
0.3(0.1-0.7)
0.4(0.2-0.7)
0.2(0.1-0.6)
149(32) 158(34) 84(18) 38(8) 32(7)
77(26) 115(39) 55(19) 25(9) 22(8)
72(43) 43(26) 29(17) 13(8) 10(6)
175(38) 282(61) 4(1)
0.1774
14(8) 121(72) 29(17) 3(2)
234(80) 58 (20) 2(1)
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Hypofractionated RT
0.3589
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Study sample n(%) Age at RT (year) Median(IQR) Follow-up Duration (month) Median(IQR) Race n (%) African-American White Other RP Gleason Score Sum n(%) 5-6 7 8-10 missing Extracapsular Extension n(%) Absent Present Missing Seminal Vesicle Invasion n(%) Absent Present Missing Positive Margins n(%) Absent Present Missing Pathological Nodal Assessment n(%) Yes No Missing Pre RT PSA Median(IQR) Pre RT PSA Group n(%) ≤ 0.2 0.21-0.50 0.51-1.0 1.01-2.0 > 2.0 Reason for RT n(%) Adjuvant Salvage Concurrent ADT, yes n(%) Duration of ADT (month)
Conventional RT
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All patients
0.9681
0.1584
0.0440 0.0038
0.3786 71(15) 390(85) 157(34)
42(14) 252(86) 98(33)
29(17) 138(83) 59(35)
0.6638 <.0001
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All patients
Conventional RT
Hypofractionated RT
P-value
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Median(IQR) 7.0(6.0-24.0) 6.0(6.0-8.0) 24.0(6.0-24.0) 0.2391 Time Surgery to RT (month) Median(IQR) 17.7(6.8-51.5) 17.5(6.5-48.9) 17.8(7.6-56.6) 193(42) 134(46) 59(35) 0.0320 Anticoagulation at Consultation, yes n(%) <.0001 Pre RT AUA Symptom Score Median(IQR) 7(3-13) 5(3-10) 11(6-18) <.0001 Pre RT Number of Urinary Pads Median(IQR) 0(0-1) 0(0-1) 1(0-3) Pre RT CTCAE Incontinence Group <.0001 n(%) Grade 0-1 320(69) 236(80) 84(50) Grade 2-3 136(30) 54(18) 82(49) Missing 5(1) 4 (2) 1(1) ADT, androgen deprivation therapy; AUA SS, American Urological Association Symptom Score; CTCAE, common terminology criteria for adverse events; IQR, interquartile range; PSA, prostate specific antigen; RP, radical prostatectomy; RT, radiation therapy
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Table 2: Univariate and multivariate analysis for late grade ≥2 GU toxicity in all patients Univariate 95% CI
HR
Multivariate (n=340) HR 95% CI p
p
RL 1.88
(1.23, 2.87)
0.004
RL 1.39
(0.86, 2.34)
0.18
-
0.99
(0.97, 1.03)
0.97
-
-
-
266 185 10
RL 1.32 1.76
(0.86, 2.01) (0.42, 7.30)
0.21 0.43
-
-
-
304 157
RL 1.29
(0.81, 2.05)
-
-
-
320 136
1.27 RL 1.99
(1.09, 1.46) (1.30, 3.05)
0.002
RL 2.03
(1.23, 3.35)
0.006
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294 167
0.29
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0.001
0.998
(0.993, 1.00)
0.53
-
-
-
71 390
RL 1.30
(0.72, 2.35)
0.38
-
-
-
182 158
1.03 RL 1.55
(1.00, 1.06)
0.02
(1.02, 2.36)
0.04
RL 1.12
(0.72,1.76)
0.61
RL 1.13
(0.74, 1.72)
0.57
-
-
-
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Variable RT Type* Conventional Hypofractionated Age Continuous Race White African-American Others Concurrent ADT No Yes Pre-RT Incontinence* Continuous Grade 0-1 Grade 2-3 Time, surgery to RT Continuous Reason for RT Adjuvant Salvage Pre-RT AUA Score* Continuous AUA < 8
N=461 n
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AUA ≥ 8 Anticoagulation at Consultation No 268 Yes 193 *significant in univariate analysis
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ADT, androgen deprivation therapy; AUA SS, American Urological Association Symptom Score; CTCAE, common terminology criteria for adverse events; RL, reference level; RT, radiation therapy
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Table 3: Univariate and multivariate analysis of bPFS for patients with at least 12 months follow-up.
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p
HR
(0.99, 1.04)
0.31
-
RL 0.89
(0.61, 1.32)
0.057
-
RL 2.09 3.19
(0.95, 4.56) (1.40, 7.25)
0.07 0.006
RL 1.46
(0.99, 2.14)
0.05
RL 0.36
(0.24, 0.53)
p
-
-
-
-
RL 2.15 2.98
(0.97, 4.73) (1.29, 6.90)
0.05 0.003
RL 1.38
(0.93, 2.06)
0.114
RL 0.41
(0.27, 0.61)
<.0001
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1.02
Multivariate (n=356) 95% CI
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HR
<.0001
RL 1.33
(0.84, 2.10)
0.23
-
RL 1.13
(0.72, 1.78)
0.61
-
-
1.14 RL 2.22 2.29 2.80 6.73
(1.09, 1.20) (1.29, 3.83) (1.25, 4.12) (1.37, 5.74) (3.47, 13.03)
<0.001
<.0001 0.017 0.028 0.017 <.0001
RL 0.54
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Variable Age Continuous Race White 210 African-American 149 Others 5 Gleason Sum* 5 to 6 44 7 238 8 to 10 78 Extracapsular Extension* No 180 Yes 179 Positive Margin* No 141 Yes 219 Pathological Nodal Assessment No 95 Yes 255 Seminal Vesicle Invasion No 285 Yes 74 Pre-RT PSA* Continuous <0.2 119 120 0.21-0.50 0.51-1.0 71 1.01-2.0 30 >2.0 24 RT Type* Conventional 232 Hypofractionated 132 Concurrent ADT No 261 Yes 103 Time, surgery to RT Continuous Time, RT to last f/u Continuous *significant in univariate analysis
Univariate 95% CI
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N=364 n (%)
0.004 0.008 0.005 <0.001
RL 1.98 2.03 2.44 5.83
(1.13, 3.35) (1.08, 3.82) (1.17, 5.09) (2.97, 11.46)
(0.35, 0.85)
0.007
RL 0.64
(0.41, 1.02)
0.059
RL 1.36
(0.91, 2.03)
0.14
-
-
1.00
(0.99, 1.01)
0.21
-
-
-
1.00
(0.99, 1.01)
0.91
-
-
-
IQR, interquartile range; PSA, prostate specific antigen; RL, referent level; RP, radical prostatectomy; RT, radiation therapy
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Supplement Table 1. Cumulative RT doses and RT fraction sizes. Hypofractionation (2.5 Gy/fraction), n=167 Cumulative RT dose (Gy)
RT fraction dose (Gy)
EQD2 (Gy)
5 (3%)
57.5
2.5
65.7
2 (1%)
60
2.5
68.6
2 (1%)
62.5
2.5
71.4
145 (87%)
65
2.5
74.3
13 (8%)
70
2.5
80
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n (%)
RT fraction dose (Gy)
EQD2 (Gy)
16 (5%)
64.8
1.8
61.1
8 (3%)
60
2
60
3 (1%)
62
2
62
8 (3%)
64
2
64
255 (87%)
66
2
66
2 (1%)
70
2
70
2 (1%)
74
2
74
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Cumulative RT dose (Gy)
n (%)
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Supplement Table 2. Description of grade 3 or 4 GU toxicities with bladder dose-volume metrics.
Bladder Dose-Volume Metrics Hypofractionated NRG GU 003 constraints RT fraction size (Gy)
Late GU toxicity grade
Time to GU toxicity (mo)
Duration of GU toxicity (mo)
Last GU toxicity grade
V35 Gy (%): Per protocol <70%
V57 Gy (%): Per protocol <50%
6
2
24.9
21.3
66.8
17.7
662.4
24, ongoing
3
83.8
71.8
66.9
55.5
82.56
6
0
75.2
62.4
67.1
51
141.82
36
0
40.9
29.7
66.4
30.1
266.7
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Cumulative RT dose (Gy)
Conventional NRG GU 003 constraints V40 Gy (%): Per protocol <70%
V65 Gy (%): Per protocol <50%
Pathologic stage
Pre-RT AUA SS
Pre-RT incontinence grade
60
pT2cNx R1
28
1
65
2.5
3
62
Frequent gross hematuria, clot retention, cystoscopy with fulguration, HBO, medications
2
62
pT3aNx R0
9
0
65
2.5
3
75
Frequent gross hematuria, admission (multiple), CBI, cystoscopy (multiple) wth fulguaration, HBO
3
60
pT3bN0 R1
na
2
65
2.5
3
20
Frequent gross hematuria, admission, transfusion, cystoscopy with RT cystitis
4
66
pT2bN0 R1
2
2
65
2.5
3
29
Frequent gross hematuria, cystoscopy (multiple) with RT cystitis, medications
5
70
pT2bN0 R1
9
2
65
2.5
3
20
Gross hematuria, clot retention, CBI, cytoscopy with RT cystitis
<1
0
32
15.2
66.4
24.4
368.29
6
61
pT2cN0 R1
na
0
57.5
2.5
3
29
Gross hematuria, clot retention, admission, cystoscopy with RT cystitis
<1
2
13.5
3.5
58.9
10.6
538.27
7
64
pT3bN0 R1
21
2
65
2.5
3
28
Frequent gross hematuria, clot retention, admission, CBI, cystoscopy (multiple) with fulguration RT cystitis
24
2
50
32.9
67.7
37.3
362.7
8
64
pT3bN0 R1
7
2
62.5
2.5
3
15
Gross hematuria, clot retention, admission, transfusion, CBI, cystoscopy with RT cystitis
2
0
41.2
28.5
66.8
31.3
322.5
9
63
pT3aN0 R1
na
2
65
2.5
3
29
Gross hematuria, clot retention, admission, CBI, transfusions, cystoscopy with RT cystitis
<1
2
58.6
35.7
68
39.9
289
10
67
pT2cN0 R1
10
2
65
2.5
3
41
Gross hematuria, clot retention, admission, CBI, transfusions, cystoscopy with RT cystitis
<1
2
59.1
39.1
68.1
41.5
116.2
Bladder necrosis, tramuatic bladder injury, urosymphyseal fistula ultimately requiring cystectomy
24, ongoing
4
62.9
41.4
69.6
46.1
247.9
19
Frequent gross hematuria, cystoscopy with RT cystitis, transfusions, HBO, medications
6
2
54.5
0.4
66.4
44.1
136.9
40
Frequent gross hematuria, cystoscopy (multiple) with RT cystitis
6, ongoing
3
49.3
36.7
70.6
38.5
68.1
65
pT3aNx R1
5
2
65
2.5
4
12
59
pT3aNx R1
na
2
60
2
3
13
52
pT2cN0 R0
8
1
66
2
3
14
61
pT2cNx R1
3
0
66
15
70
pT3bN0 R0
5
0
66
16
55
pT2cN0 R1
na
na
66
17
74
pT2cN0 R1
8
2
66
16
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Description of GU toxicity
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Age
1
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Patient no
Max (Gy)
Mean (Gy)
Bladder Volume (cc)
2
3
22
Gross hematuria, clot retention, CBI, cystoscopy with RT cystitis, medications
2
2
23.2
12.6
71.1
21.5
216.7
2
3
52
Frequent gross hematuria, cystoscopy, transfusions
6, ongoing
3
43.4
21.3
69.4
34.6
148.8
2
3
51
Frequent gross hematuria, clot retention, cystoscopy (multiple) with RT cystitis, HBO
18
0
56.9
26.9
70.8
47.4
122.8
2
3
12
Gross hematuria, admission, CBI, cystoscopy with RT cystitis, fulgurationn
<1
0
59.7
39.7
68.4
43.8
171.9
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Supplement Table 3: Univariate analysis for late grade ≥2 GU toxicity among patients with none or minimal pre-RT incontinence (CTCAE grade 0-1) N=320 Variable
Univariate
n
HR
95% CI
p
Conventional
236
RL
-
-
Hypofractionated
84
1.59
(1.21, 3.56)
0.008
-
0.97
(0.94, 1.01)
0.16
White
202
RL
-
African-American
113
1.01
(0.57, 1.81)
0.96
3
1.87
(0.25, 13.85)
0.54
No
218
RL
-
-
Yes
102
1.34
(0.72, 2.50)
0.29
Continuous
Others
Time, surgery to RT Continuous
0.99
(0.99, 1.01)
0.07
RL
-
-
(0.39, 1.78)
0.65
(0.99, 1.07)
0.14
Salvage
279
Pre-RT AUA Score
0.84
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Reason for RT Adjuvant
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RT Type
Continuous
-
AUA < 8
150
RL
AUA ≥ 8
91
1.46
(0.84, 2.55)
0.18
No
184
RL
-
-
Yes
136
1.15
(0.64, 1.93)
0.7
Anticoagulation at Consultation
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Summary: We compared biochemical control and toxicity of contemporaneous cohorts of patients with prostate cancer treated with either hypofractionated or conventionally fractionated post-operative radiation therapy. After controlling for ADT use, surgical pathologic variables and baseline urinary function, we
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observed no significant difference in biochemical control or late toxicity between the radiation cohorts.
S0360-3016(18)30248-7
DOI:
10.1016/j.ijrobp.2018.02.002
Reference:
ROB 24779
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 19 October 2017 Revised Date:
18 January 2018
Accepted Date: 1 February 2018
Please cite this article as: Tandberg DJ, Oyekunle T, Lee WR, Wu Y, Salama JK, Koontz BF, Postoperative radiation therapy for prostate cancer: Comparison of conventional versus hypofractionated radiation regimens, International Journal of Radiation Oncology • Biology • Physics (2018), doi: 10.1016/ j.ijrobp.2018.02.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Post-operative radiation therapy for prostate cancer: Comparison of conventional versus hypofractionated radiation regimens Daniel J. Tandberg1, Taofik Oyekunle2, W. Robert Lee1, Yuan Wu2, Joseph K. Salama1, Bridget F.
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Koontz1 1 Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 2 Department of Biostatistics and Bioinformatics, Duke Cancer Institute, Durham, NC
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Corresponding Author: Daniel J. Tandberg, M.D.
Duke University School of Medicine DUMC Box 3085, Durham, NC 27710 Ph: 919-668-7336 Fax: 919-668-7345 E-mail: [email protected]
Taofik Oyekunle, M.S. Ph: 919-613-4336
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Statistical Analysis:
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Department of Radiation Oncology
Yuan Wu, Ph.D. Ph: 919-681-5018
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Email: [email protected]
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Email: [email protected]
Manuscript Type: Original article Short Title: Conventional or Hypofractionated PORT Disclosures: DT, TO, WRL, YW, and JS have no disclosures. BK receives unrestricted research funding from Janssen Pharmaceuticals and is an advisory board member for Blue Earth Diagnostics and Bayer. Funding: There was no outside funding for this research
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Post-operative radiation therapy for prostate cancer: Comparison of conventional versus hypofractionated radiation regimens Abstract:
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Purpose/Objectives: Post-prostatectomy radiotherapy (PORT) for adverse pathologic factors results in improved overall and biochemical progression-free survival. Conventional PORT (coPORT) is delivered over 7-8 weeks. Hypofractionated PORT (hypoPORT) offers a more resource-efficient option if shown to have acceptable efficacy and toxicity compared to coPORT. We compared acute/late toxicity and
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biochemical control in contemporaneous patient cohorts treated with hypoPORT or coPORT.
Methods/Materials: Consecutive patients treated with intensity-modulated hypoPORT (2.5 Gy/fraction, median cumulative dose 65 Gy [range 57.5-70 Gy]) or coPORT (1.8-2.0 Gy/fraction, median cumulative
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dose 66 Gy [range 60-74 Gy]) between 2005-2016 at two institutions comprised the study cohort. Acute toxicity, cumulative late grade 2 and ≥3 GU and GI toxicity incidences (CI) were calculated for all patients using the Kaplan-Meier methods and compared between cohorts. Biochemical progression free survival (bPFS) was calculated in patients with ≥12 months follow-up (FU) Results: Median FU for all 461 patients was 38.6 months. 167 (36%) received hypoPORT; 294 (64%) patients received coPORT. The hypoPORT cohort had significantly worse baseline urinary incontinence.
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Acute grade ≥2 GU toxicity was more common after hypoPORT (22% vs 8%) (p=0.0001). Late grade ≥3 GU toxicity CI at 6 years was 11% (hypoPORT) and 4% (coPORT) (p=0.0081). However, hypoPORT was not associated with late grade ≥2 GU toxicity on MVA (HR 1.39, 95% CI 0.86-2.34) (p=0.18). There was no difference in acute or late GI toxicity. In the subset of patients with ≥12 month FU (n=364,
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median FU 52 months) 4-year bPFS was 78% (95% CI 69.4-85.0%) after hypoPORT (p=0.0038) and 65% (95% CI 57.6-71.1%) after coPORT. HypoPORT was not significant for bPFS on MVA (HR 0.64
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95% CI 0.41-1.02, p=0.059).
Conclusions: HypoPORT shows promising early biochemical control. After controlling for baseline urinary function, hypoPORT was not associated with greater GU toxicity than coPORT.
1
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Introduction: Prostate cancer is the most common malignancy among men in the United States, with an estimated 161,380 new cases in 2017.1 Following radical prostatectomy (RP), post-operative radiotherapy (PORT) is routinely offered for adverse pathologic features (i.e. seminal vesicle invasion, extraprostatic
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extension, positive surgical margins) as adjuvant RT was shown to improve overall survival in one randomized controlled trial and biochemical control in two others.2-4 For men with biochemical recurrence following RP, salvage PORT has been shown to improve prostate cancer specific survival compared to observation.5
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While typical PORT courses deliver 1.8-2 Gy daily to cumulative doses of 64 to 74 Gy completing in 7-8 weeks,6 moderately hypofractionated RT schedules, delivering fewer, higher doses per Pre-clinical and clinical data suggest
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treatment, may be advantageous for prostate cancer patients.
prostate cancer is preferentially sensitive to greater dose per fraction.7 Further, moderately hypofractionated RT schedules are more convenient often requiring half as many radiation treatments. In the intact prostate setting, multiple randomized studies have demonstrated hypofractionated RT has similar efficacy to conventional RT.8-13
In the post-operative setting, the role of hypofractionated RT is less clear. Several retrospective
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studies report promising biochemical control following hypofractionated PORT (hypoPORT).14-16 However, these studies are small and have not compared outcomes to patients treated with conventional PORT. Further, the impact of hypoPORT on late toxicity is conflicting, with one study reporting infrequent late urinary toxicity15 while two others reporting higher than expected late urinary toxicity.16, 17
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Given the potential advantages of hypoPORT weighted against the risk for increased toxicity, a randomized trial is underway (NRG-GU003, NCT03274687), but results are not expected for many years. Therefore, we compared the efficacy and toxicity outcomes of post-prostatectomy patients treated
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contemporaneously with either conventionally fractionated or hypofractionated PORT. Methods: Patients
Patients with a histopathologic diagnosis of prostate cancer and prior radical prostatectomy (RP)
treated with adjuvant or salvage intensity-modulated RT (IMRT) with or without concurrent androgen deprivation therapy (ADT) between 2005-2016 comprised the study cohort. Patients with pathologic nodal involvement at RP, those with metastatic disease and those receiving pelvic lymph node RT were
2
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excluded. The institutional review boards at *** and the *** Veterans Affairs Medical Center approved this retrospective analysis. Treatment
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Patients underwent radical prostatectomy at the discretion of the treating surgeon. Pathologic nodal sampling or dissection was not required for inclusion. Adjuvant or salvage RT was recommended based on adverse pathologic features or persistent/rising PSA. ADT was used at the discretion of the treating urologist/radiation oncologist.
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All patients underwent computed tomographic (CT) based simulation, typically with a full bladder and empty rectum. The prostate bed clinical target volume was most often contoured based on the Radiation Therapy Oncology Group (RTOG) consensus guidelines with final contours based on the
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discretion of the treating radiation oncologist.18 Patient treatment plans were developed using 6-15 MV photons and IMRT or volumetric modulated arc therapy (VMAT) techniques. Conventional PORT (coPORT) and hypoPORT cohorts were treated contemporaneously based on institutional protocol: 1.8 or 2 Gy daily fractions over 42-51days at *** (coPORT) versus 2.5 Gy daily fractions over 31-38 days at the *** VA (hypoPORT). Prior to treatment, daily image-guidance with either orthogonal kV radiographs or cone beam CT was performed in all cases.
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Patients were evaluated weekly during RT for acute sequelae. Acute toxicity was graded based on weekly provider notes using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Following RT completion, patients were seen at regular intervals for physical examination, PSA measurement, and prospective toxicity assessment including the Urological Association Symptom Score
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(AUA-SS) and International Index of Erectile Function (IIEF). Late toxicities (>30 days after RT completion) were scored using the RTOG/EORTC toxicity criteria. Urinary incontinence was graded
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using CTCAE. Statistical Analysis
The objectives of this analysis were to compare biochemical control and toxicity between two
contemporaneous cohorts of patients treated with coPORT or moderately hypoPORT.
Patient and
treatment characteristics were described and compared between cohorts using the Mann-Whitney U-test for continuous variables and chi-square tests for categorical variables. Acute and late toxicity were evaluated in all treated patients. Crude incidence of acute genitourinary (GU) and gastrointestinal (GI) toxicity was compared using chi-square test. Cumulative
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incidence for late GU and GI events were analyzed using the Kaplan-Meier (K-M) product-limit method. Cox multivariate analyses were performed to assess patient and treatment factors associated with an increased risk of late GU or GI toxicity. Variables were included in the multivariate model if they achieved a p≤0.05 on univariate analysis.
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Disease outcomes were evaluated only in patients with at least 12 months of follow-up. Biochemical progression was defined as a PSA increase of 0.2 ng/mL or greater from the post-RT nadir (confirmed with a second increase), a continued rise in PSA despite RT, or the initiation of salvage ADT. All time-based variables were defined from the completion of radiation therapy. Biochemical progression
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free survival (bPFS) was defined as the time from completion of radiation to biochemical progression or death, whichever came first. Time to distant metastases was defined as the time from completion of
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radiation to the development of distant metastases.
The K-M method was used to estimate bPFS in both RT groups with 95 % CI. The log-rank test was used to test for survival differences between groups. Cox multivariate analysis was performed to assess for clinical, pathologic, and treatment factors associated with an increased risk of biochemical progression. Variables were included in the multivariate model if they achieved a p≤0.05 on univariate analysis. Categorical PSA groups only were entered into the multivariate analysis. Distant metastasis free survival and overall survival were calculated using the K-M method. All statistical tests were two-sided
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and <0.05 was considered statistically significant. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC) and R version 3.3.3 (Vienna, Austria). Results:
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Between January 2005 and October 2016, 461 patients met the inclusion criteria and were included in the analysis. Of these, 294 (64%) received conventional post-operative RT of 1.8-2.0 Gy per
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fraction (coPORT) while 167 (36%) received hypofractionated PORT of 2.5 Gy per fraction (hypoPORT). The median cumulative RT dose in the coPORT cohort was 66 Gy (range 60-74 Gy). Eighty-seven percent of patients in the coPORT cohort received 66 Gy at 2 Gy/fraction. The median cumulative RT dose in the hypoPORT cohort was 65 Gy (range 57.5-70 Gy). Eighty-seven percent of patients in the hypoPORT cohort received 65 Gy at 2.5 Gy/fraction (EQD2 74.3 Gy)(Supplement, Table 1).
Baseline patient demographic, clinical and treatment characteristics for all patients are shown in Table 1. The coPORT patients had a higher rate of extracapsular extension (56% vs 43%) and higher preRT PSA (median 0.4 vs 0.2 ng/mL) compared to hypoPORT patients. An equal percentage of patients in
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both cohorts received ADT, but ADT duration was significantly longer in the hypoPORT cohort (median 24 versus 6 months in those receiving ADT). Patients treated with hypoPORT had significantly higher pre-RT AUA SS compared to patients who received coPORT (table 1). Prior to RT 49% of patients in the hypoPORT cohort had CTCAE grade 2-3 incontinence compared to 18% of coPORT patients (p<0.0001).
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Toxicity
Acute and late toxicities were evaluated in all patients (n=461) with a median follow-up of 38.6 months. The incidence of acute grade ≥2 GU toxicity was significantly higher among patients who received hypoPORT compared to coPORT, 22% vs 8% respectively (p=0.0001). There was 1 acute grade
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3 GU toxicity in the hypoPORT cohort and 3 in the coPORT cohort. All grade 3 toxicity events were acute urinary retention requiring urinary catheter placement, cystoscopy and dilation or incision of
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bladder neck contracture. There was no significant difference in the incidence of acute grade ≥2 GI toxicity, between the hypoPORT and coPORT cohorts, 5% vs 7% respectively (p=0.3655). There were no acute grade 3 or greater GI toxicities in either cohort.
The cumulative incidence of late grade 2 GU toxicity at 6 years was 39% (95% CI 30-49) in the hypoPORT cohort and 26% (95% CI 20-33%) in the coPORT cohort (p=0.0033)(Figure 1a). Cumulative incidence of late grade ≥ 3 GU toxicity at 6 years was 11% (6-21%) and 4% (2-8%) for the hypoPORT
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and coPORT cohorts, respectively (p=0.0081)(Figure 1b). Because of differences in baseline urinary function, we analyzed the cohorts stratified by baseline AUA SS and incontinence grade (Supplement, Figure 1). The 6 year cumulative incidence of late grade ≥2 GU toxicity was significantly higher in the hypoPORT cohort compared to the coPORT cohort in the subset of patients with AUA SS <8 (51% vs
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34%, p=0.0059) and pre-RT incontinence grade 0-1 (43% vs 25%, p=0.0066). Supplement table 2 describes the individual cases of grade 3 or 4 GU toxicity. There were 10
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cases of late grade 3 GU toxicity in the hypoPORT cohort, all being frequent hematuria requiring multiple cystoscopies, transfusions, hospital admission, and/or hyperbaric oxygen therapy. One patient in the hypoPORT cohort had a late grade 4 GU toxicity. This patient presented with dysuria and obstructive symptoms following RT. Cystoscopy and biopsies of the bladder revealed bladder necrosis. The patient was subsequently in a motor vehicle accident and suffered bladder rupture requiring operative repair. After the patient developed recurrent urinary tract infections and pelvic pain cystoscopy and MRI confirmed an urosymphyseal fistula and pubic bone osteomyelitis. The patient ultimately underwent cystectomy and pubic symphysiectomy. There were 6 cases of late grade 3 GU toxicity in the coPORT cohort, all consisting of frequent hematuria. At last follow-up 2 patients in the hypoPORT and 2 patients in the coPORT were experiencing late grade >3 GU toxicity. 5
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Review of the bladder dose-volume metrics was performed for all patients with grade 3 or 4 GU toxicity and compared to per protocol bladder dose constraints in the ongoing randomized NRG-GU003 trial comparing hypoPORT (62.5 Gy at 2.5 Gy per fraction) to coPORT (66.6 Gy at 1.8 Gy per fraction (Supplement, Table 2). Overall 9 of 11 of the cases of grade ≥ 3 GU toxicity in the hypoPORT cohort met
GU toxicity in the coPORT cohort met the per protocol constraints.
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the per protocol bladder dose constraints including the case of grade 4 GU toxicity. All 6 cases of grade 3
Univariate (UVA) and multivariate analyses (MVA) for late grade ≥2 GU toxicity is shown in Table 2. AUA SS ≥8, pre-RT incontinence grade 2-3, and hypoPORT were associated with higher risk of
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late grade ≥2 GU toxicity on UVA. On MVA patients with pre-RT grade 2-3 incontinence were at an increased risk of late grade ≥2 GU toxicity (HR 2.03, 95% CI 1.23-3.35) (p=0.006). The use of coPORT or hypoPORT was not significantly associated with risk of late grade ≥2 GU toxicity on MVA (HR 1.39,
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95% CI 0.86-2.34) (p=0.18). In the subset of patients with pre-RT grade 0-1 incontinence (n=320) hypoPORT was the only variable significantly associated with risk of late grade ≥2 GU toxicity on UVA (HR 1.59, 95% CI 1.21-3.56) (p=0.008) (Supplement, Table 3).
AUA-SS, AUA bother score, and IIEF were relatively unchanged compared to pretreatment values in both cohorts.
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The cumulative incidence of late grade 2 GI toxicity at 6 years was 10% (95% CI 6-17%) in the hypoPORT cohort and 6% (95% CI 3-10%) in the coPORT cohort (p=0.0542)(Figure 2). One patient with a history of a thrombosed hemorrhoid was found to have a fistula following hypoPORT that was
coPORT cohort. Clinical Outcomes
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surgically corrected and scored as a late grade 3 GI toxicity. There were no late ≥ grade 3 toxicities in the
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Patients with a 12-month minimum follow-up were analyzed for bPFS (n=364). With a median
follow-up of 52 months, 4-year estimated bPFS was 64.8% (95% CI 57.6-71.1%) for the coPORT cohort and 78.4% (95% CI 69.4-85.0%) for the hypoPORT cohort (p=0.0038) (Figure 3a). In the subset of ADT free patients (n=261) bPFS was 68.4% (95% CI 59.9-75.4%) after coPORT and 80.5% (95% CI 70.587.5%) following hypoPORT (p=0.0234) (Figure 3b). Overall 114 patients had a biochemical progression event, 87 in the coPORT cohort and 27 in the hypoPORT cohort. Among patients with biochemical progression, 22% of patients in the coPORT cohort and 23% of patients in the hypoPORT cohort had persistent PSA progression despite RT. The remaining patients with biochemical progression had an initial PSA response to RT. 6
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UVA and MVA for biochemical progression are listed in table 3. On MVA a higher Gleason score, negative surgical margins, and a higher pre-RT PSA level were significantly associated with increased risk of biochemical progression. There was a trend for decreased risk of biochemical progression in the hypoPORT cohort compared to the coPORT cohort (HR 0.64 95% CI 0.41-1.02) but
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this was not significant (p=0.059). Four year distant metastasis free survival was 92.2% (95% CI 87.0-95.4%) for the coPORT cohort and 95.4% (95% CI 89.2-98.1%) for the hypoPORT cohort (p=0.1746) (Supplement, Figure 2a). A total of 19 patients died during the study period, 13 in the coPORT cohort and 6 in the hypoPORT cohort.
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Four year overall survival was 97.6% (95% CI 93.8-99.1%) and 94.3% (95% CI 86.7-97.6%) for the coPORT and hypoPORT cohorts, respectively (p=0.7071) (Supplement, Figure 2b).
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Discussion:
Adjuvant and salvage post-prostatectomy radiation therapy are standard treatments for men with adverse pathologic risk factors or rising post-prostatectomy PSA following surgery.19 While moderately hypofractionated RT has been shown to be non-inferior to conventionally fractionated RT in the definitive intact prostate setting8-10, there are few reports of moderately hypofractionated RT in the postprostatectomy setting and no comparisons to the far more commonly used conventional fractionation15, 16, 20
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. If hypoPORT demonstrated similar efficacy and toxicity as conventionally fractionated RT,
hypoPORT could offer significant economic and practical benefits for patients. In this non-randomized contemporaneous cohort analysis of the two fractionation schedules we found a promising 4-year bPFS of 78% following hypoPORT with acceptable late toxicity. To the best of our knowledge the present
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analysis is the largest study to date comparing clinical outcomes and toxicity of cohorts of patients treated with hypofractionated or conventional RT using modern radiation techniques. With or without ADT,
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The biochemical control following hypoPORT was favorable.
biochemical control following hypoPORT was ~13% greater than patients treated with coPORT. However, differences in the two cohort’s disease characteristics might explain some of the observed differences in biochemical control. Overall the coPORT cohort appeared to have less favorable disease including a higher pre-RT PSA (0.4 vs 0.2 ng/mL) and higher rate of extracapsular extension (56% vs 43%). On multivariate analysis PORT fractionation was not significantly associated with biochemical control (p=0.059).
It is also possible that the favorable biochemical control with hypoPORT is a
reflection of the higher biologically effective dose (BED) compared to coPORT regimens. Using an α/β of 1.5 the most common hypofractionated RT regimen used in this study (65 Gy at 2.5 Gy per fraction) is equivalent to approximately 74 Gy in conventional 2 Gy fractions, representing significant dose 7
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escalation, compared to the commonly used conventionally fractionated dose schemes of 60-66 Gy. Several retrospective reports have shown that biochemical control is improved with larger cumulative doses of salvage RT, suggesting a dose-response effect.21, 22 Thus any benefit of the hypofractionated RT regimen on bPFS in this study may simply be the result of dose-escalation and not any intrinsic advantage
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of the larger dose per fraction. Further follow-up of our study cohort and randomized data are needed to confirm the potential impact of hypofractionated RT on biochemical control in the post-operative setting. The possibility of hypofractionated RT to increase the risk of late toxicity compared to conventional RT is a topic of great interest. We found late grade 2 and grade ≥3 GU toxicity was more
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common in the hypofractionated RT cohort compared to the conventional RT cohort. This difference was seen in both the subset of patients with low baseline AUA SS and the subset with minimal pre-RT incontinence. However, this subset was a smaller cohort due to the fact that patients in the
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hypofractionated cohort had significantly worse baseline urinary symptoms. On multivariate analysis with the full cohort, including both baseline AUA SS and pre-RT incontinence as variables, hypofractionated RT was not associated with increased risk of late grade ≥2 toxicity. In both the conventional and hypofractionated cohorts, all cases of late grade 3 GU toxicity resulted from frequent gross hematuria and most resolved by the time of last follow-up. The one late grade 4 GU toxicity in our study, a urosymphyseal fistula, is a very rare but debilitating late toxicity of radiation therapy, often occurring in
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patients who have undergone open or endoscopic repair of bladder neck contractures.23 While this occurred in the hypofractionated cohort there is no known correlation between hypofractionation and this rare adverse event. Late severe GI toxicity was rare in both cohorts and not significantly different. Independent of radiation dosing cohort, we identified that pre-RT incontinence was associated
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with late GU toxicity. There are a limited number of studies reporting predictors of late GU toxicity following PORT. A prior evaluation of factors associated with late GU toxicity in a population of patients treated with both conventional and hypofractionated post-operative RT reported 17 presence of acute grade
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≥2 GU toxicity and increasing dose per fraction independently associated with late grade ≥3 GU toxicity. However, they did not include baseline urinary function (AUA SS or incontinence). Other studies, including only patients treated with conventional RT, have shown pre-RT urinary incontinence to be predictive of late GU toxicity.24 Our data suggests that baseline urinary incontinence, regardless of RT fractionation increases the risk of late GU toxicity. In the intact prostate cancer setting, most8, 10, 12 but not all9, 25 randomized studies have shown that moderate hypofractionation has equivalent late toxicity to conventional fractionation. It is not clear if these studies can be extrapolated to the post-operative setting. The post-operative anatomy potentially
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increases radiation exposure of the bowel and bladder to radiation. Indeed in the RTOG consensus guidelines the post-operative clinical target volume encompasses a significant portion of the bladder inferiorly and the bladder wall posteriorly.18 Further, post-operative patients may have surgical toxicity that could potentially increase their risk of late GU toxicity, as our data seems to support.
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Retrospective reports of hypofractionated post-operative RT have shown conflicting findings regarding late toxicity.15-17 While one study reported no late grade 3 GI or GU toxicities among 108 patients treated with hypofractionated salvage RT to 65 Gy in 2.5 Gy fractions,15 another reported high rates of late grade 3 GU toxicity (4 year rate of late grade 3 GU: 28%) among 56 patients treated with
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adjuvant or salvage hypoPORT to a median of 65 Gy in 2.5 Gy fractions.16 However, the latter study authors noted using a conservative grading of late GU toxicity such that even transient hematuria was considered late grade 3 GU toxicity. Most of the late grade 3 GU toxicity in this study resolved by last
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follow-up. The only other comparison of conventional to hypoPORT found increased rates of late grade ≥3 GU toxicity in the hypofractionated RT cohort (5 year late grade ≥3 GU toxicity 18% vs 7%, respectively) however there were differences in RT technique between the conventional and hypofractionated RT cohorts and heterogeneous RT doses in the hypofractionated arm (2.35-2.9 Gy).17 While supportive of hypoPORT, our analysis is ultimately limited by its non-randomized design and further understanding of risk with post-operative hypofractionation must await randomized results.
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Hypofractionated radiotherapy will be compared to conventionally fractionated radiotherapy in the post-prostatectomy setting in NRG-GU003, a randomized phase III trial (NCT # NCT03274687). The hypoPORT regimen used will be 62.5 Gy in 2.5 Gy fractions. Using an α/β of 1.5, this regimen is equivalent to approximately 71 Gy in 2 Gy fractions.
Although the cumulative dose in the
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hypofractionated arm of NRG-GU003 is one fraction less than what was most commonly delivered in the present study (65 Gy in 2.5 Gy fractions), it still offers dose escalation compared to the conventionally fractionated arm (66.6 Gy in 1.8 Gy fractions). As we demonstrate favorable biochemical control but
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increased late GU toxicity with hypoPORT in patients with favorable baseline urinary function it is possible that the slightly lower cumulative dose in the hypofractionated arm of NRG-GU003 may maintain efficacy while lowering toxicity. Further research will hopefully provide more insight into the optimal hypofractionated RT dose regimen. The strengths of this study include the large number of patients analyzed and the consistent modern intensity-modulated and image-guided radiation techniques used in both cohorts. Furthermore, we performed a robust analysis controlling for baseline treatment and pathologic details as well as baseline urinary function. However, the study has several limitations most prominently being the
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retrospective assessment. Additionally, although the hypofractionated and conventional RT patients were treated from the same geographic region and outcomes of VA patients mimic those treated elsewhere,26 unaccounted for differences in the patient populations, surgical technique/experience, and robustness of the electronic medical record and follow-up between institutions could impact comparisons of efficacy
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and toxicity. A comparison of patients with cancer in the VA health system and Medicare fee-for service demonstrated that the prevalence of severe comorbidity was higher in the VA population.26 We did not account for differences in comorbidity and this could impact the toxicity comparison. Further, longer follow-up may be needed to accurately assess for differences in late toxicity as our data suggests that severe late GU toxicity can first present greater than 5 years after treatment. Longer follow-up may also
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be needed to assess for differences in bPFS, especially as there were differences in the length of ADT between cohorts. Finally, although we did not perform a comprehensive dosimetric analysis, as prior data
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did not find associations with toxicity16 it is possible that specific RT dose-volume metrics could impact toxicity results.
In conclusion, hypofractionated post-operative RT demonstrated favorable early biochemical control outcomes to conventional RT. Acute and late urinary toxicity was more common in the hypofractionated RT cohort but was possibly related to worse baseline urinary function. Randomized data is needed to clarify the efficacy and toxicity of post-operative hypofractionated RT compared to
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conventional RT.
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References: 1. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67: 7-30. 2. Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a
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randomized clinical trial. J Urol. 2009;181: 956-962.
3. Bolla M, van Poppel H, Tombal B, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet. 2012;380: 2018-2027.
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4. Wiegel T, Bartkowiak D, Bottke D, et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol. 2014;66: 243-250. 5. Trock BJ, Han M, Freedland SJ, et al. Prostate cancer-specific survival following salvage radiotherapy
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vs observation in men with biochemical recurrence after radical prostatectomy. JAMA. 2008;299: 27602769.
6. Mohler JL, Armstrong AJ, Bahnson RR, et al. Prostate Cancer, Version 1.2016. J Natl Compr Canc Netw. 2016;14: 19-30.
7. Fowler JF, Toma-Dasu I, Dasu A. Is the α/β ratio for prostate tumours really low and does it vary with the level of risk at diagnosis? Anticancer Res. 2013;33: 1009-1011.
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8. Catton CN, Lukka H, Gu CS, et al. Randomized Trial of a Hypofractionated Radiation Regimen for the Treatment of Localized Prostate Cancer. J Clin Oncol. 2017;35: 1884-1890. 9. Lee WR, Dignam JJ, Amin MB, et al. Randomized Phase III Noninferiority Study Comparing Two Radiotherapy Fractionation Schedules in Patients With Low-Risk Prostate Cancer. J Clin Oncol. 2016;34:
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2325-2332.
10. Dearnaley D, Syndikus I, Mossop H, et al. Conventional versus hypofractionated high-dose intensitymodulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3
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CHHiP trial. Lancet Oncol. 2016.
11. Incrocci L, Wortel RC, Alemayehu WG, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016;17: 1061-1069. 12. Pollack A, Walker G, Horwitz EM, et al. Randomized trial of hypofractionated external-beam radiotherapy for prostate cancer. J Clin Oncol. 2013;31: 3860-3868. 13. Arcangeli S, Strigari L, Gomellini S, et al. Updated results and patterns of failure in a randomized hypofractionation trial for high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2012;84: 1172-1178.
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14. Wong GW, Palazzi-Churas KL, Jarrard DF, et al. Salvage hypofractionated radiotherapy for biochemically recurrent prostate cancer after radical prostatectomy. Int J Radiat Oncol Biol Phys. 2008;70: 449-455. 15. Kruser TJ, Jarrard DF, Graf AK, et al. Early hypofractionated salvage radiotherapy for
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postprostatectomy biochemical recurrence. Cancer. 2011;117: 2629-2636. 16. ***
17. Cozzarini C, Fiorino C, Deantoni C, et al. Higher-than-expected severe (Grade 3-4) late urinary toxicity after postprostatectomy hiypofractionated radiotherapy: a single-institution analysis of 1176 patients. Eur Urol. 2014;66: 1024-1030.
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18. Michalski JM, Lawton C, El Naqa I, et al. Development of RTOG consensus guidelines for the definition of the clinical target volume for postoperative conformal radiation therapy for prostate cancer.
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Int J Radiat Oncol Biol Phys. 2010;76: 361-368.
19. Thompson IM, Valicenti RK, Albertsen P, et al. Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO Guideline. J Urol. 2013;190: 441-449.
20. Fersino S, Tebano U, Mazzola R, et al. Moderate Hypofractionated Postprostatectomy Volumetric Modulated Arc Therapy With Daily Image Guidance (VMAT-IGRT): A Mono-institutional Report on Feasibility and Acute Toxicity. Clin Genitourin Cancer. 2017.
21. Pisansky TM, Agrawal S, Hamstra DA, et al. Salvage Radiation Therapy Dose Response for
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Biochemical Failure of Prostate Cancer After Prostatectomy-A Multi-Institutional Observational Study. Int J Radiat Oncol Biol Phys. 2016;96: 1046-1053.
22. Bernard JR, Buskirk SJ, Heckman MG, et al. Salvage radiotherapy for rising prostate-specific antigen levels after radical prostatectomy for prostate cancer: dose-response analysis. Int J Radiat Oncol Biol
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Phys. 2010;76: 735-740.
23. Bugeja S, Andrich DE, Mundy AR. Fistulation into the pubic symphysis after treatment of prostate cancer: An important and surgically correctable complication. J Urol 2016;195:391-8.
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24. Iyengar P, Levy LB, Choi S, Lee AK, Kuban DA. Toxicity associated with postoperative radiation therapy for prostate cancer. Am J Clin Oncol. 2011;34: 611-618. 25. Aluwini S, Pos F, Schimmel E, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): late toxicity results from a randomised, noninferiority, phase 3 trial. Lancet Oncol. 2016;17: 464-474. 26. Landrum MB, Keating NL, Lamont EB, et al. Survival of older patients with cancer in the Veterans Health Administration versus fee-for-service Medicare. J Clin Oncol. 2012;30: 1072-1079.
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Figure Legends Figure 1: Cumulative incidence of late (a) grade 2 GU and (b) grade ≥3 GU toxicity stratified by radiation therapy type.
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Figure 2: Cumulative incidence of late GI 2 toxicity stratified by radiation therapy type. Figure 3: Biochemical recurrence free survival for (a) patients with at least 12 months of follow-up
stratified by radiation therapy type (b) Patients with at least 12 months of follow-up and no concurrent
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ADT stratified by radiation therapy type.
Supplement Figure 1: Cumulative incidence of late ≥2 GU toxicity stratified by radiation therapy type and
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(a) AUA SS (a) and (b) pre-RT incontinence grade.
Supplement Figure 2: Distant metastasis free survival (a) and overall survival (b) for patients with at least
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12 months of follow-up stratified by radiation therapy type.
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Table 1: Clinical and Pathologic Characteristics
461(100)
294(64)
64.3(59.8-68.5)
64.4(59.1-69.6)
P-value
167(36) 64.3(60.9-67.1)
0.2684
38.6(15.4-70.3)
39.4(15.3-77.3)
185(40) 266(58) 10(2)
93(32) 197(67) 4(1)
49(11) 312(68) 95(21) 5(1)
35(12) 191(65) 66(22) 2(1)
37.5(16.2-61.8)
<.0001
358(78) 98(21) 5(1)
92(55) 69(41) 6(4)
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220(48) 235 (51) 6(1)
127(43) 164 (56) 3(1)
0.0074 93(56) 71(43) 3(2) 0.2587 124(74) 40(24) 3(2)
112(38) 181(62) 1(1)
63(38) 101(61) 3(2)
326 (71) 119 (26) 16 (3)
218 (74) 71 (24) 5 (2)
108 (65) 48 (29) 11 (6)
0.3(0.1-0.7)
0.4(0.2-0.7)
0.2(0.1-0.6)
149(32) 158(34) 84(18) 38(8) 32(7)
77(26) 115(39) 55(19) 25(9) 22(8)
72(43) 43(26) 29(17) 13(8) 10(6)
175(38) 282(61) 4(1)
0.1774
14(8) 121(72) 29(17) 3(2)
234(80) 58 (20) 2(1)
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Hypofractionated RT
0.3589
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Study sample n(%) Age at RT (year) Median(IQR) Follow-up Duration (month) Median(IQR) Race n (%) African-American White Other RP Gleason Score Sum n(%) 5-6 7 8-10 missing Extracapsular Extension n(%) Absent Present Missing Seminal Vesicle Invasion n(%) Absent Present Missing Positive Margins n(%) Absent Present Missing Pathological Nodal Assessment n(%) Yes No Missing Pre RT PSA Median(IQR) Pre RT PSA Group n(%) ≤ 0.2 0.21-0.50 0.51-1.0 1.01-2.0 > 2.0 Reason for RT n(%) Adjuvant Salvage Concurrent ADT, yes n(%) Duration of ADT (month)
Conventional RT
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All patients
0.9681
0.1584
0.0440 0.0038
0.3786 71(15) 390(85) 157(34)
42(14) 252(86) 98(33)
29(17) 138(83) 59(35)
0.6638 <.0001
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All patients
Conventional RT
Hypofractionated RT
P-value
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Median(IQR) 7.0(6.0-24.0) 6.0(6.0-8.0) 24.0(6.0-24.0) 0.2391 Time Surgery to RT (month) Median(IQR) 17.7(6.8-51.5) 17.5(6.5-48.9) 17.8(7.6-56.6) 193(42) 134(46) 59(35) 0.0320 Anticoagulation at Consultation, yes n(%) <.0001 Pre RT AUA Symptom Score Median(IQR) 7(3-13) 5(3-10) 11(6-18) <.0001 Pre RT Number of Urinary Pads Median(IQR) 0(0-1) 0(0-1) 1(0-3) Pre RT CTCAE Incontinence Group <.0001 n(%) Grade 0-1 320(69) 236(80) 84(50) Grade 2-3 136(30) 54(18) 82(49) Missing 5(1) 4 (2) 1(1) ADT, androgen deprivation therapy; AUA SS, American Urological Association Symptom Score; CTCAE, common terminology criteria for adverse events; IQR, interquartile range; PSA, prostate specific antigen; RP, radical prostatectomy; RT, radiation therapy
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Table 2: Univariate and multivariate analysis for late grade ≥2 GU toxicity in all patients Univariate 95% CI
HR
Multivariate (n=340) HR 95% CI p
p
RL 1.88
(1.23, 2.87)
0.004
RL 1.39
(0.86, 2.34)
0.18
-
0.99
(0.97, 1.03)
0.97
-
-
-
266 185 10
RL 1.32 1.76
(0.86, 2.01) (0.42, 7.30)
0.21 0.43
-
-
-
304 157
RL 1.29
(0.81, 2.05)
-
-
-
320 136
1.27 RL 1.99
(1.09, 1.46) (1.30, 3.05)
0.002
RL 2.03
(1.23, 3.35)
0.006
SC
RI PT
294 167
0.29
M AN U
0.001
0.998
(0.993, 1.00)
0.53
-
-
-
71 390
RL 1.30
(0.72, 2.35)
0.38
-
-
-
182 158
1.03 RL 1.55
(1.00, 1.06)
0.02
(1.02, 2.36)
0.04
RL 1.12
(0.72,1.76)
0.61
RL 1.13
(0.74, 1.72)
0.57
-
-
-
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Variable RT Type* Conventional Hypofractionated Age Continuous Race White African-American Others Concurrent ADT No Yes Pre-RT Incontinence* Continuous Grade 0-1 Grade 2-3 Time, surgery to RT Continuous Reason for RT Adjuvant Salvage Pre-RT AUA Score* Continuous AUA < 8
N=461 n
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AUA ≥ 8 Anticoagulation at Consultation No 268 Yes 193 *significant in univariate analysis
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ADT, androgen deprivation therapy; AUA SS, American Urological Association Symptom Score; CTCAE, common terminology criteria for adverse events; RL, reference level; RT, radiation therapy
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Table 3: Univariate and multivariate analysis of bPFS for patients with at least 12 months follow-up.
EP
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p
HR
(0.99, 1.04)
0.31
-
RL 0.89
(0.61, 1.32)
0.057
-
RL 2.09 3.19
(0.95, 4.56) (1.40, 7.25)
0.07 0.006
RL 1.46
(0.99, 2.14)
0.05
RL 0.36
(0.24, 0.53)
p
-
-
-
-
RL 2.15 2.98
(0.97, 4.73) (1.29, 6.90)
0.05 0.003
RL 1.38
(0.93, 2.06)
0.114
RL 0.41
(0.27, 0.61)
<.0001
-
SC
1.02
Multivariate (n=356) 95% CI
RI PT
HR
<.0001
RL 1.33
(0.84, 2.10)
0.23
-
RL 1.13
(0.72, 1.78)
0.61
-
-
1.14 RL 2.22 2.29 2.80 6.73
(1.09, 1.20) (1.29, 3.83) (1.25, 4.12) (1.37, 5.74) (3.47, 13.03)
<0.001
<.0001 0.017 0.028 0.017 <.0001
RL 0.54
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Variable Age Continuous Race White 210 African-American 149 Others 5 Gleason Sum* 5 to 6 44 7 238 8 to 10 78 Extracapsular Extension* No 180 Yes 179 Positive Margin* No 141 Yes 219 Pathological Nodal Assessment No 95 Yes 255 Seminal Vesicle Invasion No 285 Yes 74 Pre-RT PSA* Continuous <0.2 119 120 0.21-0.50 0.51-1.0 71 1.01-2.0 30 >2.0 24 RT Type* Conventional 232 Hypofractionated 132 Concurrent ADT No 261 Yes 103 Time, surgery to RT Continuous Time, RT to last f/u Continuous *significant in univariate analysis
Univariate 95% CI
M AN U
N=364 n (%)
0.004 0.008 0.005 <0.001
RL 1.98 2.03 2.44 5.83
(1.13, 3.35) (1.08, 3.82) (1.17, 5.09) (2.97, 11.46)
(0.35, 0.85)
0.007
RL 0.64
(0.41, 1.02)
0.059
RL 1.36
(0.91, 2.03)
0.14
-
-
1.00
(0.99, 1.01)
0.21
-
-
-
1.00
(0.99, 1.01)
0.91
-
-
-
IQR, interquartile range; PSA, prostate specific antigen; RL, referent level; RP, radical prostatectomy; RT, radiation therapy
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Supplement Table 1. Cumulative RT doses and RT fraction sizes. Hypofractionation (2.5 Gy/fraction), n=167 Cumulative RT dose (Gy)
RT fraction dose (Gy)
EQD2 (Gy)
5 (3%)
57.5
2.5
65.7
2 (1%)
60
2.5
68.6
2 (1%)
62.5
2.5
71.4
145 (87%)
65
2.5
74.3
13 (8%)
70
2.5
80
SC
RI PT
n (%)
RT fraction dose (Gy)
EQD2 (Gy)
16 (5%)
64.8
1.8
61.1
8 (3%)
60
2
60
3 (1%)
62
2
62
8 (3%)
64
2
64
255 (87%)
66
2
66
2 (1%)
70
2
70
2 (1%)
74
2
74
EP AC C
EQD2, equivalent dose in 2 Gy fractions
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Cumulative RT dose (Gy)
n (%)
M AN U
Conventional Fractionation (1.8-2.0 Gy/fraction), n=295
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Supplement Table 2. Description of grade 3 or 4 GU toxicities with bladder dose-volume metrics.
Bladder Dose-Volume Metrics Hypofractionated NRG GU 003 constraints RT fraction size (Gy)
Late GU toxicity grade
Time to GU toxicity (mo)
Duration of GU toxicity (mo)
Last GU toxicity grade
V35 Gy (%): Per protocol <70%
V57 Gy (%): Per protocol <50%
6
2
24.9
21.3
66.8
17.7
662.4
24, ongoing
3
83.8
71.8
66.9
55.5
82.56
6
0
75.2
62.4
67.1
51
141.82
36
0
40.9
29.7
66.4
30.1
266.7
RI PT
Cumulative RT dose (Gy)
Conventional NRG GU 003 constraints V40 Gy (%): Per protocol <70%
V65 Gy (%): Per protocol <50%
Pathologic stage
Pre-RT AUA SS
Pre-RT incontinence grade
60
pT2cNx R1
28
1
65
2.5
3
62
Frequent gross hematuria, clot retention, cystoscopy with fulguration, HBO, medications
2
62
pT3aNx R0
9
0
65
2.5
3
75
Frequent gross hematuria, admission (multiple), CBI, cystoscopy (multiple) wth fulguaration, HBO
3
60
pT3bN0 R1
na
2
65
2.5
3
20
Frequent gross hematuria, admission, transfusion, cystoscopy with RT cystitis
4
66
pT2bN0 R1
2
2
65
2.5
3
29
Frequent gross hematuria, cystoscopy (multiple) with RT cystitis, medications
5
70
pT2bN0 R1
9
2
65
2.5
3
20
Gross hematuria, clot retention, CBI, cytoscopy with RT cystitis
<1
0
32
15.2
66.4
24.4
368.29
6
61
pT2cN0 R1
na
0
57.5
2.5
3
29
Gross hematuria, clot retention, admission, cystoscopy with RT cystitis
<1
2
13.5
3.5
58.9
10.6
538.27
7
64
pT3bN0 R1
21
2
65
2.5
3
28
Frequent gross hematuria, clot retention, admission, CBI, cystoscopy (multiple) with fulguration RT cystitis
24
2
50
32.9
67.7
37.3
362.7
8
64
pT3bN0 R1
7
2
62.5
2.5
3
15
Gross hematuria, clot retention, admission, transfusion, CBI, cystoscopy with RT cystitis
2
0
41.2
28.5
66.8
31.3
322.5
9
63
pT3aN0 R1
na
2
65
2.5
3
29
Gross hematuria, clot retention, admission, CBI, transfusions, cystoscopy with RT cystitis
<1
2
58.6
35.7
68
39.9
289
10
67
pT2cN0 R1
10
2
65
2.5
3
41
Gross hematuria, clot retention, admission, CBI, transfusions, cystoscopy with RT cystitis
<1
2
59.1
39.1
68.1
41.5
116.2
Bladder necrosis, tramuatic bladder injury, urosymphyseal fistula ultimately requiring cystectomy
24, ongoing
4
62.9
41.4
69.6
46.1
247.9
19
Frequent gross hematuria, cystoscopy with RT cystitis, transfusions, HBO, medications
6
2
54.5
0.4
66.4
44.1
136.9
40
Frequent gross hematuria, cystoscopy (multiple) with RT cystitis
6, ongoing
3
49.3
36.7
70.6
38.5
68.1
65
pT3aNx R1
5
2
65
2.5
4
12
59
pT3aNx R1
na
2
60
2
3
13
52
pT2cN0 R0
8
1
66
2
3
14
61
pT2cNx R1
3
0
66
15
70
pT3bN0 R0
5
0
66
16
55
pT2cN0 R1
na
na
66
17
74
pT2cN0 R1
8
2
66
16
SC
M AN U
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Description of GU toxicity
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Age
1
EP
Patient no
Max (Gy)
Mean (Gy)
Bladder Volume (cc)
2
3
22
Gross hematuria, clot retention, CBI, cystoscopy with RT cystitis, medications
2
2
23.2
12.6
71.1
21.5
216.7
2
3
52
Frequent gross hematuria, cystoscopy, transfusions
6, ongoing
3
43.4
21.3
69.4
34.6
148.8
2
3
51
Frequent gross hematuria, clot retention, cystoscopy (multiple) with RT cystitis, HBO
18
0
56.9
26.9
70.8
47.4
122.8
2
3
12
Gross hematuria, admission, CBI, cystoscopy with RT cystitis, fulgurationn
<1
0
59.7
39.7
68.4
43.8
171.9
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Supplement Table 3: Univariate analysis for late grade ≥2 GU toxicity among patients with none or minimal pre-RT incontinence (CTCAE grade 0-1) N=320 Variable
Univariate
n
HR
95% CI
p
Conventional
236
RL
-
-
Hypofractionated
84
1.59
(1.21, 3.56)
0.008
-
0.97
(0.94, 1.01)
0.16
White
202
RL
-
African-American
113
1.01
(0.57, 1.81)
0.96
3
1.87
(0.25, 13.85)
0.54
No
218
RL
-
-
Yes
102
1.34
(0.72, 2.50)
0.29
Continuous
Others
Time, surgery to RT Continuous
0.99
(0.99, 1.01)
0.07
RL
-
-
(0.39, 1.78)
0.65
(0.99, 1.07)
0.14
Salvage
279
Pre-RT AUA Score
0.84
AC C
41
EP
Reason for RT Adjuvant
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Concurrent ADT
-
M AN U
Race
SC
Age
1.03
RI PT
RT Type
Continuous
-
AUA < 8
150
RL
AUA ≥ 8
91
1.46
(0.84, 2.55)
0.18
No
184
RL
-
-
Yes
136
1.15
(0.64, 1.93)
0.7
Anticoagulation at Consultation
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Summary: We compared biochemical control and toxicity of contemporaneous cohorts of patients with prostate cancer treated with either hypofractionated or conventionally fractionated post-operative radiation therapy. After controlling for ADT use, surgical pathologic variables and baseline urinary function, we
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observed no significant difference in biochemical control or late toxicity between the radiation cohorts.