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A Phase 1 Trial of Highly Conformal, Hypofractionated Postprostatectomy Radiation Therapy

Open AccessPublished:July 11, 2022DOI:https://doi.org/10.1016/j.adro.2022.101024

      Abstract

      Purpose

      This phase 1 trial aimed to identify the maximally tolerated hypofractionated dose schedule for postoperative radiation therapy (PORT) after radical prostatectomy. Secondary objectives included biochemical control and quality of life (QoL) measures.

      Methods and Materials

      Patients were treated on 1 of 3 dose levels (DLs): 56.4 Gy in 20 fractions (DL1), 51.2 Gy in 15 fractions (DL2), and 44.2 Gy in 10 fractions (DL3). Treatment was delivered to the prostate bed without pelvic nodal irradiation. Dose escalation followed a standard 3 + 3 design with an expansion for 6 additional patients at the maximally tolerated hypofractionated dose schedule. Acute dose-limiting toxicity (DLT) was defined as grade 3 toxicity lasting >4 days within 21 days of PORT completion; late DLT was defined as grade 4 gastrointestinal (GI) or genitourinary (GU) toxicity.

      Results

      Between January 2018 and August 2019, 15 patients underwent radiation treatment: 3 on DL1, 3 on DL2, and 9 on DL3. The median follow-up was 24 months. There were no DLTs, and the maximally tolerated hypofractionated dose schedule was identified as DL3. Two of the 15 patients (13.3%) experienced biochemical failure (prostate-specific antigen >0.1). Ten of 15 patients (67%) had grade 2+ acute toxicities, consisting of transient GI toxicities. Three patients experienced late grade 2+ GI toxicity, and 5 patients experienced late grade 2+ GU toxicity. Late grade 3 GU toxicity occurred in 2 patients. There were no grade 4+ acute or late toxicities. There were no significant differences in GI measures of QoL, however, there was an increase in GU symptoms and corresponding decrease in GU QoL between 12 and 24 months.

      Conclusions

      The maximum tolerated hypofractionated dose schedule for hypofractionated PORT to the prostate bed was determined to be 44.2 Gy in 10 daily fractions. The most frequent clinically significant toxicities were late grade 2+ GU toxicities, which corresponded to a worsening of late GU QoL.

      Introduction

      Recently, there has been an increase in the rate of diagnosis of localized prostate cancer with high-risk features.
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      Prostate cancer incidence across stage, NCCN risk groups, and age before and after USPSTF Grade D recommendations against prostate-specific antigen screening in 2012.
      Over this same period, there has been a trend toward an increase in the utilization of upfront surgical management of this risk stratum.
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      The co-occurrence of these 2 trends has created a growing population of men who will eventually require postoperative radiation therapy (PORT).
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      This population experiences several barriers to completing radiation therapy including the length of a treatment course
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      and financial toxicity of treatment,
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      providing a rationale for the development of novel hypofractionated dose schedules with the objectives of mitigating these barriers and maintaining oncologic efficacy without an undue decrement in long-term quality of life (QoL).
      After several randomized trials verified the safety and efficacy of moderately hypofractionated radiation therapy (MHRT) in the treatment of intact prostate cancer,
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      MHRT has been accepted as the new standard of care in this setting.
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      This change in the standard of care has improved convenience for patients and has decreased the financial burden of treatment.
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      The financial impact of hypofractionated radiation for localized prostate cancer in the United States.
      Although recently presented studies of MHRT have suggested this approach compares favorably to conventional fractionation in regard to post-therapy QoL,
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      Primary endpoint analysis of a randomized phase III trial of hypofractionated vs. conventional post-prostatectomy radiotherapy: NRG Oncology GU003.
      a similar shift in the standard of care toward more compressed dose schedules has not yet been widely adopted as the standard of care in the postoperative setting, due to the lack of robust data to establish comparative efficacy and toxicity of such regimens. Due to the low ⍺/β ratio of prostate cancer
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      Estimation of α/β for late rectal toxicity based on RTOG 94-06.
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      of the surrounding normal tissues,
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      Radical radiotherapy for invasive bladder cancer: What dose and fractionation schedule to choose?.
      hypofractionated PORT may allow for the compression of the standard postoperative dose schedule without significantly increasing rates of toxicity. Thus far, however, the optimal total dose and fractionation in this setting have yet to be established.
      This report describes the findings of a prospective phase 1 trial investigating the safety of 3 isoeffective and increasingly hypofractionated dose schedules to the prostate bed with the intention of defining the maximally hypofractionated dose schedule for future investigation.

      Methods and Materials

      Participants

      NCT03388619 is a single-institution, phase 1 trial of highly conformal, hypofractionated, image guided postprostatectomy radiation therapy designed to evaluate increasingly hypofractionated dose schedules for patients requiring radiation therapy after prostatectomy. The trial was conducted with approval from the institutional review board of the National Cancer Institute, and all study participants provided written informed consent before enrollment. The trial included 2 cohorts run in parallel. The first, pending full accrual, included participants with evidence of local recurrence within the prostate fossa on imaging. The second, reported here, included participants without evidence of local recurrence on imaging and has been closed due to completion of accrual and protocol mandated follow-up.
      Eligible patients were 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 in whom adjuvant or salvage prostate bed radiation therapy was recommended. Treatment indications included high-risk surgical pathology (≥ pT3, pN1, positive surgical margins), persistent postoperative prostate-specific antigen (PSA), or biochemical recurrence, defined as a detectable postoperative verified by repeat measurement. Receipt of prior ADT was not an exclusion criterion, and occurred only before surgery in this trial. Patients were staged with a bone scan or 18F-sodium fluoride positron emission tomography/computed tomography and a multiparametric MRI of the prostate bed. Individuals were considered ineligible if pretreatment staging discovered diseases outside of the prostate bed, including nodal or osseous metastases.

      Treatment protocol

      Patients were treated with 3 increasingly abbreviated courses of radiation therapy as specified in Table 1. Each dose level was selected as the isoeffective dose schedule to a standard, conventionally fractionated prescription (68.4 Gy in 38 fractions) at its respective treatment course length as determined by the linear-quadratic model with an ⍺/β of 3 Gy representing normal tissues. The initial course length of 20 fractions was selected as prior studies demonstrated the tolerability of a 26-fraction course of treatment.
      • Kruser TJ
      • Jarrard DF
      • Graf AK
      • et al.
      Early hypofractionated salvage radiotherapy for postprostatectomy biochemical recurrence.
      The clinical target volume (CTV) was defined by the RTOG consensus definition.
      • 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.
      A PTV margin of 7 mm was used concentrically with allowance for minimization to 5 mm posteriorly to meet dose constraints if necessary. The dose was prescribed to the 100% isodose line using intensity modulated radiation therapy (IMRT). The maximum heterogeneity allowed was a minimum of 95% and a maximum of 115% of the prescription dose within the PTV. Organs at risk (OARs) were contoured. Dose constraints were calculated as isoeffective to previously, widely established values for prostate cancer using the linear-quadratic model and an ⍺/β ratio of 3 as detailed in Table E1. Treatments were delivered with daily fractionation, 5 days per week, using daily cone beam computed tomography image guidance with physician approval of alignment before each fraction.
      Table 1Hypofractionated dose schedules used in NCT03388619, arm 2
      Dosing schemeFractions (n)Dose per fraction (Gy)Total dose (Gy)EQD2 (Gy3)BED (Gy3)EQD2 (Gy10)BED (Gy10)Patients (n)
      α/β = 3 Gyα/β = 10 Gy
      Dose level 1202.8256.465.6109.460.372.33
      Dose level 2153.4151.265.6109.457.280.33
      Dose level 3104.4244.265.6109.353.163.79
      Abbreviations: BED = biologically effective dose; EQD2 = equivalent dose in 2-Gy fractions.
      Androgen deprivation therapy (ADT) was allowed at the discretion of the treating physician. When clinically appropriate, 6 months of ADT was given with a depot GnRH antagonist with or without a run-in period of a nonsteroidal antiandrogen.

      Assessments

      Patients were followed for 24 months after completion of radiation therapy. Patients with biochemical progression during follow-up were removed from the study. Adverse events (AEs) were classified using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) and were scored weekly during treatment and at each follow-up visit. After the completion of treatment, patients were followed every 3 months and outcome measures were assessed including PSA, testosterone, and AEs. AEs were classified as acute if occurring from the start of treatment to 90 days after treatment and late if occurring > 90 days after treatment. Patient-reported QoL was assessed with the Expanded Prostate Cancer Index Composite Short Form (EPIC-26), Sexual Health Inventory for Men (SHIM), American Urologic Association-Symptom Index (AUA-SI), Patient-Reported Outcomes Measurement Information System (PROMIS) Psychosocial Illness Impact-Positive (PII), PROMIS Anxiety (PROMIS-A), PROMIS Depression (PROMIS-D), and Decision Regret Scale (DRS). All patient-reported QoL instruments were collected at baseline and at the 6-, 12-, 18-, and 24-month time points.

      Statistical design

      The primary objective of this study was to determine the maximally tolerated hypofractionated dose schedule in the postprostatectomy setting. Acute dose-limiting toxicity (DLT) was defined as a grade 3 or higher in-field, physician-assessed toxicity which did not resolve to grade 2 or less within 4 days and occurred during the treatment course or within 3 weeks after completion of treatment. As an additional safety measure, a late DLT constraint was also included in the trial. A late DLT was defined as a grade 4 or higher gastrointestinal (GI) or genitourinary (GU) toxicity occurring after the DLT assessment period (more than 3 weeks after completion of therapy). Both acute and late DLTs were considered in regard to escalating dose levels.
      Three patients were allocated sequentially to each dose level. If none of the 3 patients experienced a DLT during the assessment period, escalation to the next dose level was initiated. If one of 3 participants experienced a DLT at any dose level, 3 additional patients were enrolled at that dose level. If 2 participants experienced a DLT at any dose level, that dose level would be considered the maximally tolerated hypofractionated dose schedule. If no DLTs were observed at the most hypofractionated dose level, that dose level was considered the maximally tolerated hypofractionated dose schedule.
      Secondary objectives were an evaluation of the safety and tolerability of the investigational treatment, the rate of biochemical control (defined as a PSA <0.1) at 12- and 24-months posttreatment, and patient-reported outcomes (PROs) measured with the SHIM, AUA-SI, and EPIC-26 instruments. Exploratory objectives included additional psychometric testing with the PROMIS-PII, PROMIS-A, PROMIS-D, and DRS.
      Changes to PROs from baseline to each follow-up visit were tested by the Wilcoxon signed-rank test. Changes with respect to ADT use and castrate level of testosterone (< 50 ng/mL) for overall sexual function of EPIC and overall SHIM score were compared by Kruskal rank test. In evaluating these measures, the minimally important difference (MID), or threshold beyond which changes in PRO measurements are considered clinically relevant, was defined based on previously used values for the AUA-SI,
      • Blanker MH
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      Determining the minimal important differences in the International Prostate Symptom Score and Overactive Bladder Questionnaire: Results from an observational cohort study in Dutch primary care.
      EPIC,
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      • et al.
      Minimally important difference for the Expanded Prostate Cancer Index Composite Short Form.
      PROMIS-A,
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      Comparative responsiveness and minimally important difference of common anxiety measures.
      PROMIS-D,
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      • et al.
      Minimally important differences and severity thresholds are estimated for the PROMIS depression scales from three randomized clinical trials.
      and DRS.
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      • Tarr ME.
      Satisfaction and regret following uterosacral ligament suspension and sacrocolpopexy: A prospective multicenter analysis from the Fellows' Pelvic Research Network.
      As previous work has shown the MID to be dependent on the baseline SHIM score, the MID was variably defined as 2 for mild (score 0-10), as 5 for moderate (score 11-16), and 7 for severe erectile dysfunction (score 17-25).
      • Rosen RC
      • Allen KR
      • Ni X
      • Araujo AB.
      Minimal clinically important differences in the erectile function domain of the International Index of Erectile Function scale.
      P values <.05 were considered statistically significant. As these analyses were exploratory in nature, no adjustment for multiple comparisons was made.

      Results

      Patient characteristics

      From January 29, 2018 to August 9, 2019, a total of 15 patients were enrolled. All participants were followed until 24 months or until removal from protocol after biochemical failure. The median follow-up was 24 months. The median age was 69.9 years (range: 46.8-76.0 years). The majority patients were treated in the salvage setting for biochemical persistence or recurrence (n = 14/15). Twelve of the 15 patients (80%) had margin negative resections, and most patients (60%) had National Comprehensive Cancer Network high-risk disease defined by pathologic staging. The remainder of the key patient characteristics are summarized in Table 2.
      Table 2Patient characteristics
      CategorySubcategoryn (%)
      Age, median (range)69.9 (46.8-76.0)
      Ethnicity
      Hispanic0 (0.0)
      Non-Hispanic15 (100.0)
      Race
      Black/other3 (20.0)
      White12 (80.0)
      Pathologic ISUP grade group
      GG10 (0.0)
      GG26 (40.0)
      GG34 (26.7)
      GG43 (20.0)
      GG52 (13.3)
      Pathologic T stage
      T27 (46.7)
      T3a7 (46.7)
      T3b1 (6.7)
      Resection status
      R012 (80.0)
      R13 (20.0)
      Extraprostatic extension
      Yes8 (53.3)
      No7 (46.7)
      Seminal vesicle invasion
      Yes1 (6.7)
      No14 (93.3)
      NCCN risk group (preoperative)
      Lowrisk1 (6.7)
      Low-intermediate risk5 (33.3)
      High-intermediate risk4 (26.7)
      High risk5 (33.3)
      Very high risk0 (0.0)
      NCCN risk group (postoperative)
      Low risk0 (0.0)
      Low-intermediate risk3 (20.0)
      High-intermediate risk2 (13.3)
      High risk9 (60.0)
      Very high risk1 (6.7)
      CAPRA-S risk group
      Low risk3 (20.0)
      Intermediate risk10 (66.7)
      High risk2 (13.3)
      Indication
      Adjuvant1 (6.7)
      Salvage14 (93.3)
      Post-operative PSA nadir
      <0.0210 (66.7)
      ≥0.02-0.105 (33.3)
      PSA before salvage radiation therapy
      <0.021 (6.7)
      ≥0.02-0.105 (33.3)
      ≥0.10-0.205 (33.3)
      ≥0.20-0.503 (20.0)
      ≥0.501 (6.7)
      Concurrent ADT
      Yes9 (60.0)
      No6 (40.0)
      Abbreviations: ISUP = International Society of Urological Pathology; ADT = androgen deprivation therapy; CAPRA-S = Cancer of the Prostate Risk Assessment-Surgery; NCCN = National Comprehensive Cancer Network; PSA = prostate-specific antigen.
      Data are presented as n (%) unless otherwise indicated.

      Primary objective and toxicity

      The maximal tolerated hypofractionated dose schedule was found to be 44.2 Gy in 10 daily fractions over 2 weeks (DL3) on which 9 of the 15 patients were treated. No acute or late DLTs were encountered at any dose level. Adverse events possibly, probably, or definitely related to radiation are summarized in Table 3. Overall, the most common acute adverse events were grade 1 GU toxicity and grade 2 GI toxicity each occurring in 60% of the patient population. The most common acute grade 2 GI toxicity was proctitis, occurring in 7 patients. A single patient encountered acute grade 3 proctitis that resolved to grade 2 within 3 days with medical management and did not meet the prespecified criterion for a DLT due to its duration. No other acute grade 3 toxicity was observed. Two late grade 3 toxicities occurred. These consisted of one episode of noninfective cystitis that resolved after 11 weeks in one patient on DL2 and an increase of baseline postoperative incontinence from grade 2 to grade 3 which developed 6 months after treatment and was ongoing at 24 months of follow-up in one patient on DL3. No grade 4 or 5 adverse events were observed.
      Table 3Maximum physician-reported adverse events during protocol follow-up
      Adverse eventGrade 1 (n)Grade 2 (n)Grade 3 (n)Grade ≥2 (%)
      Acute GI39167
      Acute GU9000
      Acute other5000
      Late GI33020
      Late GU33233
      Late other2107
      Abbreviations: GI = gastrointestinal; GU = genitourinary.
      One notable toxicity occurred in a patient treated on DL3 after removal from the protocol for biochemical progression, which occurred 14 months after the completion of treatment. This patient experienced intermittent, gross hematuria adjudicated to likely be treatment-related. After infectious causes were excluded, imaging revealed left ureteral and renal pelvis dilation. Cystoscopy with biopsies of the prostatic urethra and bladder trigone revealed necroinflammatory debris from the former and reactive appearing urothelium from the latter. There was no evidence of prostate or bladder cancer. Unilateral ureteral stenosis was addressed with a combination of balloon dilation and temporary stent placement. As this event occurred after removal from the protocol, it is not reported in Table 3.

      Oncologic outcomes

      Of the 15 patients in this study, a single patient met the prespecified definition for biochemical failure (PSA >0.1, confirmed on subsequent measurement) by 12 months and a second patient met these criteria for biochemical failure by 24 months. This corresponded to a 12-month rate of biochemical control of 93% and a 24-month rate of 86%. Of the 2 biochemical failure events, the first exhibited no PSA response to treatment with a PSA trajectory which continued to rise on all post-treatment measurements. The second biochemical failure occurred after an initial PSA response at 22 months post-treatment in a patient who also received ADT. While initial restaging at the time of biochemical failure did not detect any recurrent disease in either case, PSMA PET/CT scans obtained at PSA values of >1.0 ng/mL did eventually document an out-of-field pattern of failure and provide radiographic verification of in-field disease control.

      Genitourinary patient-reported outcomes

      AUA-SI

      The baseline AUA-SI was evenly distributed between no/mild burden of urinary symptoms (score: 0-7; 47%) and a moderate burden of urinary symptoms (score: 8-19; 53%). The mean baseline AUA-SI score was 7.6 (median: 8; range: 0-17). There was a trend toward continued deterioration of urinary function from baseline over the follow-up period with statistically significant changes at the 12-,18-, and 24-month time point (Fig. 1A). The increase in the mean AUA-SI score at 24-month follow-up was below the MID at 4.9 points higher than baseline. Throughout the follow-up period, 6 patients had elevations of their AUA-SI score above the MID threshold, however, only 4 of these patients had an elevation above the MID threshold by final follow-up. As expected, the resultant AUA-SI QoL score showed a trend toward an increase over time, corresponding to a worse rating of QoL, as seen in Fig. 1B. The average difference was significant only at 24 months (P = .049), with an absolute difference of 0.9 points on a 7-point scale.
      Fig 1
      Fig. 1Box plots of quality-of-life scores for the (A) American Urologic Association-Symptom Index (AUA-SI), (B) AUA-SI quality of life subdomain, (C) Expanded Prostate Cancer Index Composite Short Form (EPIC-26) overall genitourinary (GU) subdomain, and (D) EPIC-26 Overall gastrointestinal (GI) subdomain at 0 (baseline), 6, 12, 18, and 24 months.

      EPIC-26 GU

      While there was no significant difference in the distribution of EPIC-26 Overall GU score at 6 and 12 months (P > .05) from baseline (mean: 66.7), there was a significant worsening from baseline at the 18 month (mean: 46.2; P = .02) and 24-month time points (mean: 41.1, P = .013) which exceeded the MID in magnitude. These results are shown in Fig. 1C.

      Gastrointestinal patient-reported outcomes

      EPIC-26 GI

      The baseline average EPIC-26 GI score was high with a mean of 93.3 (median: 100), indicating favorable QoL among this cohort. At each subsequent time point, the mean was lower than baseline; however, these differences did not reach statistical significance at 6, 12, 18, or 24 months (P > .05) as shown in Fig. 1D.

      Sexual health patient-reported outcomes

      SHIM

      The majority of patients had low SHIM scores at baseline (mean: 5.9; median: 2) with most patients being classified as having severe erectile dysfunction (n = 12). At 24 months, there was a decrease in average SHIM score (mean: 2; median: 1) with an increase in the number of patients classified as having severe erectile dysfunction (n = 14) from baseline. The change in mean score from baseline was not significantly different at the 6-, 12-, and 18-month time point. This change, however, did reach significance at the 24-month time point (P = .029) as shown in Fig. 2A. The change in SHIM score from baseline was not found to correlate with the receipt of ADT or castrate testosterone level. Of the 14 evaluable patients at 24-month follow-up, 2 patients (14.2%), who initially had mild ED, experienced a clinically significant decline with change from baseline above the MID.
      Fig 2
      Fig. 2Box plots of quality-of-life scores for the (A) Sexual Health Inventory for Men (SHIM) and (B) Expanded Prostate Cancer Index Composite Short Form (EPIC-26) Overall Sexual Function subdomain at 0 (baseline), 6, 12, 18, and 24 months.

      EPIC-26 sexual health

      Similarly, the mean EPIC-26 Overall Sexual Function score was low, with a value of 31.7 at baseline. There were nominal improvements in the change in mean sexual function from baseline reported at 6, 12, and 18 months (range: +7.7 to +11.7) and a nominal decrement at 24 months (–5.4 points); changes from baseline at all time points did not exceed the MID and were not statistically significant (P > .05) as shown in Fig. 2B. Further, differences from baseline did not correlate with the receipt of ADT or castrate levels of testosterone in those who had received ADT at any time point (P > .05), potentially due to low baseline sexual function.

      Psychometric

      Psychological health

      The average change from baseline in psychological health on the PROMIS-D (Fig. 3A), and PROMIS-A (Fig. 3B) at 6, 12, 18, and 24 months ranged from 0.9 to 3.4 and 0.4 to 3.8, respectively; none of these changes were statistically significant (P > .05) nor did they exceed the MID. Likewise, the average change in PROMIS-PII ranged from –2.6 to –1.3. These changes were not statistically significant (P > .05) and are summarized in Fig. 3C.
      Fig 3
      Fig. 3Box plots of quality-of-life scores for the (A) Patient-Reported Outcomes Measurement Information System (PROMIS) Depression, (B) PROMIS Anxiety, and (C) PROMIS Psychosocial Illness Impact Inventory at 0 (baseline), 6, 12, 18, and 24 months.

      Decision regret

      At baseline, patients reported a low level of regret regarding their prior prostate cancer treatment (score: 8/25). At final follow-up, 2 patients had reduced regret from baseline, 4 patients had no change form baseline, and 9 patients had increased amounts of decision regret. Decision regret was not correlated with PSA failure.

      Discussion

      In this prospective, phase 1 trial evaluating 3 increasingly hypofractionated, isoeffective dose schedules in patients without gross locally recurrent disease, we found that the maximally tolerated hypofractionated dose schedule was 44.2 Gy in 10 daily fractions. No DLTs were observed, however, the crude rate of grade 3 toxicities was significant. In the entire cohort, there was a single acute grade 3 toxicity (6.7%), a GI toxicity in dose level 3, and 2 late grade 3 toxicities (13.3%), both of which were GU toxicities that occurred in patients treated on dose level 2 and dose level 3. As a secondary measure, the efficacy of this regimen appeared to compare favorably to conventionally fractionated PORT in contemporary trials.
      • Ghadjar P
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      • Bernhard J
      • et al.
      Dose-intensified versus conventional-dose salvage radiotherapy for biochemically recurrent prostate cancer after prostatectomy: The SAKK 09/10 randomized phase 3 trial.
      ,
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      • et al.
      Toxicity and biochemical outcomes of dose-intensified postoperative radiation therapy for prostate cancer: Results of a randomized phase III trial.

      Quality of life

      There were 2 key findings from our QoL analysis. First, there was no significant change in GI QoL from baseline at any time point during the study period. This finding is in contrast to the results from a previous phase 1/2 trial from Wages et al,
      • Wages NA
      • Sanders JC
      • Smith A
      • et al.
      Hypofractionated postprostatectomy radiation therapy for prostate cancer to reduce toxicity and improve patient convenience: A phase 1/2 trial.
      which investigated 3 similar hypofractionated PORT regimens delivered in 20, 15, and 10 fractions and found a statistically significant decrease at the 1-year time point (92.08 vs 85.80, P = .026) in EPIC GI QoL. While the mean difference from baseline to 1-year was very similar between our trial and this previous trial (–5.36 vs. –6.28 points), a difference in the mean change from baseline did emerge at 2 years between the 2 studies (–16.07 vs. –4.49 points). As the treatment volume in the prior study was the same as that employed in the present study, and our rectal planning constraints were slightly more permissive than those in the prior study, the differences in these findings are likely explained by patient-related or technical factors, such as subtle differences in treatment planning or delivery. Future larger follow-up studies are needed to further profile the effect of hypofractionated PORT on GI QoL.
      The second key finding was that there is a substantial increase in patient-reported GU symptom burden as indicated by higher scores on the AUA-SI and corresponding worse GU QoL as measured by changes in the AUA-SI QoL score and EPIC-26 Overall GU score. In a previous, detailed, prospective study of PORT delivered via standard fractionation, similar decrements in GU QoL as measured by the EPIC-26 inventory were not seen in long term follow-up.
      • Akthar AS
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      • Liauw SL.
      Patient-reported outcomes and late toxicity after postprostatectomy intensity-modulated radiation therapy.
      Further, of note, this finding also differs from that of the previous trial examining a hypofractionated dose schedule.
      • Wages NA
      • Sanders JC
      • Smith A
      • et al.
      Hypofractionated postprostatectomy radiation therapy for prostate cancer to reduce toxicity and improve patient convenience: A phase 1/2 trial.
      In the prior study,
      • Wages NA
      • Sanders JC
      • Smith A
      • et al.
      Hypofractionated postprostatectomy radiation therapy for prostate cancer to reduce toxicity and improve patient convenience: A phase 1/2 trial.
      the phase 2 endpoint was the change in the EPIC-26 QoL subdomain scores at 1 year from baseline. In that study, no significant change in this measure of GU QoL was seen at this time point. Our trial corroborated this finding up to 1 year follow-up, showing no significant differences in GU QoL at 6 or 12 months. However, a noticeable decrement on GU QoL became apparent with later follow-up. At the 18- and 24-month time points, a statistically significant and clinically meaningful decrement in GU QoL emerged emphasizing the necessity of long-term follow-up to uncover the full QoL burden of hypofractionated PORT schedules on patient-reported QoL.

      Toxicity

      Hypofractionated PORT may also increase the objective rates of GU toxicity. Overall, 2 of the 15 patients (13.3%) enrolled on our trial experienced a late grade 3 GU toxicity. These consisted of one patient with self-resolving cystitis and a second with an exacerbation of baseline grade 2 incontinence. This rate of late toxicity is higher than that expected for conventional fractionation; contemporary phase 3 trials such as SAKK 09/1025 and RTOG 053429 report rates of late grade 3+ GU toxicity within the range of 5.3% to 7.9% in patients undergoing postoperative, prostate bed-directed, salvage radiation therapy. The preliminary results of a recent phase 3 noninferiority trial, NRG GU003, designed to compare the 2-year EPIC-26 QoL scores of a more protracted hypofractionated regimen than in our trial (62.5 Gy in 25 fractions) and a conventionally fractionated regimen (66.6 Gy in 37 fractions) also showed a possible signal of grade 3 adverse events in the hypofractionated arm with a 4.7% rate of grade 3 cystitis compared with 0% in the conventionally fractionated arm.
      • Buyyounouski MK
      • Pugh S
      • Chen RC
      • et al.
      Primary endpoint analysis of a randomized phase III trial of hypofractionated vs. conventional post-prostatectomy radiotherapy: NRG Oncology GU003.
      The aforementioned trial by Wages et al. reported a rate of late grade 3 GU toxicity of 9.4% at 24 months, but were unable to find any statistically significant dosimetric predictors of grade 2+ or grade 3+ GU toxicity on exploratory analysis.
      • Wages NA
      • Sanders JC
      • Smith A
      • et al.
      Hypofractionated postprostatectomy radiation therapy for prostate cancer to reduce toxicity and improve patient convenience: A phase 1/2 trial.
      Additionally, 4 of the 26 patients (15.4%) in a separate phase 1 5-fraction dose escalation trial encountered late grade 3 GU toxicity
      • Sampath S
      • Frankel P
      • Vecchio BD
      • et al.
      Stereotactic body radiation therapy to the prostate bed: Results of a phase 1 dose-escalation trial.
      with exploratory analysis revealing a candidate pool of dosimetric predictors of late GU toxicity.
      • Shinde A
      • Li R
      • Han C
      • Frankel P
      • Sampath S.
      Dosimetric predictors of genitourinary toxicity from a phase I trial of prostate bed stereotactic body radiation therapy.
      These findings from our study and the prior available reports underscore the need for further study of predictors of late GU toxicity in patients who receive PORT. Given that serious GI toxicity appears to be rare, a modification in the dosimetric objectives for treatment planning to prioritize sparing of bladder dose at the expense of higher integral doses to GI structures may produce a superior therapeutic index.

      Implications

      Similarly, our findings may argue for a modification of treatment volumes. Current recommendations for the definition of a postoperative clinical target volume (CTV) are based primarily on the principle of encompassing the entirety of the surgical field and the inclusion of the most frequent sites of local failure.
      • 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.
      ,
      • Poortmans P
      • Bossi A
      • Vandeputte K
      • et al.
      Guidelines for target volume definition in post-operative radiotherapy for prostate cancer, on behalf of the EORTC Radiation Oncology Group.
      • Sidhom MA
      • Kneebone AB
      • Lehman M
      • et al.
      Post-prostatectomy radiation therapy: Consensus guidelines of the Australian and New Zealand Radiation Oncology Genito-Urinary Group.
      • Wiltshire KL
      • Brock KK
      • Haider MA
      • et al.
      Anatomic boundaries of the clinical target volume (prostate bed) after radical prostatectomy.
      • Robin S
      • Jolicoeur M
      • Palumbo S
      • et al.
      Prostate bed delineation guidelines for postoperative radiation therapy: On behalf of the Francophone Group of Urological Radiation Therapy.
      Another implicit criterion used in the definition of the planning target volume (PTV) is the feasibility of delivering a therapeutic dose to a certain treatment volume without undue toxicity. While this is common in routine clinical practice, formal evidence of this directive is provided by the specification of anisotropic PTV margins used in several clinical trials which recommend more conservative posterior margins
      • Ghadjar P
      • Hayoz S
      • Bernhard J
      • et al.
      Dose-intensified versus conventional-dose salvage radiotherapy for biochemically recurrent prostate cancer after prostatectomy: The SAKK 09/10 randomized phase 3 trial.
      ,
      • Avkshtol V
      • Ruth KJ
      • Ross EA
      • et al.
      Ten-year update of a randomized, prospective trial of conventional fractionated versus moderate hypofractionated radiation therapy for localized prostate cancer [published correction appears in J Clin Oncol. 2021;39:258].
      despite the lack of evidence that setup uncertainty or internal organ motion is lower in magnitude posteriorly at the rectal interface.
      • Bell LJ
      • Eade T
      • Hruby G
      • Bromley R
      • Kneebone A.
      Intra-fraction displacement of the prostate bed during post-prostatectomy radiotherapy.
      ,
      • de Muinck Keizer DM
      • Kerkmeijer LGW
      • Willigenburg T
      • et al.
      Prostate intrafraction motion during the preparation and delivery of MR-guided radiotherapy sessions on a 1.5T MR-Linac.
      Furthermore, in other reports of hypofractionated PORT there has been some heterogeneity in PTV margin definitions from as low as 2 mm
      • Sampath S
      • Frankel P
      • Vecchio BD
      • et al.
      Stereotactic body radiation therapy to the prostate bed: Results of a phase 1 dose-escalation trial.
      or 3 mm
      • Ballas LK
      • Luo C
      • Chung E
      • et al.
      Phase 1 trial of SBRT to the prostate fossa after prostatectomy.
      to as high as 7 mm
      • Wages NA
      • Sanders JC
      • Smith A
      • et al.
      Hypofractionated postprostatectomy radiation therapy for prostate cancer to reduce toxicity and improve patient convenience: A phase 1/2 trial.
      despite the use of daily image guidance in all cases.
      Based on the observation that hypofractionated PORT appears to have a more substantial effect on late grade 3+ GU toxicity compared with GI toxicity as well as higher rates of GU toxicity compared with prior conventionally fractionated treatments,
      • Buyyounouski MK
      • Pugh S
      • Chen RC
      • et al.
      Primary endpoint analysis of a randomized phase III trial of hypofractionated vs. conventional post-prostatectomy radiotherapy: NRG Oncology GU003.
      ,
      • Ghadjar P
      • Hayoz S
      • Bernhard J
      • et al.
      Dose-intensified versus conventional-dose salvage radiotherapy for biochemically recurrent prostate cancer after prostatectomy: The SAKK 09/10 randomized phase 3 trial.
      the risk-benefit ratio of the inclusion of various postprostatectomy anatomic zones in the treatment volume is likely different than in conventionally fractionated radiation therapy. Current CTV recommendations have been reported to inadequately provide coverage of the area posterior to the vesicourethral anastomosis (VUA)
      • El Kabbaj O
      • Robin P
      • Bourhis D
      • et al.
      Target definition in salvage postoperative radiotherapy for prostate cancer: 18F-fluorocholine PET/CT assessment of local recurrence.
      and in the posterolateral aspect of the treatment field at the anorectal interface.
      • Harmon G
      • Chan D
      • Lee B
      • et al.
      Validating modern NRG Oncology pelvic nodal and Groupe Francophone de Radiothérapie Urologique prostate bed contouring guidelines for post-prostatectomy salvage radiation: A secondary analysis of the LOCATE trial.
      Based on the possibility that serious late GI toxicity appears less frequent than corresponding rates of serious late GU toxicity when delivering treatment with a hypofractionated compared with a standard dose schedule, expansion of the posterior aspect of the treatment volume to ensure adequate coverage of the VUA and posterolateral anorectal recess may improve oncologic control without substantial cost in terms of GI toxicity.
      A final implication of these findings is that hypofractionated PORT may be most appropriate in a select patient population in whom rational field reduction strategies may be employed. One such group of these patients may be those in whom recurrent or residual disease can be radiographically detected within the prostate bed. In such a population, treatment volume reduction to the area of visible recurrence may be a viable strategy to control disease while limiting the volume of normal tissue exposure and consequent toxicity of treatment. A recent multi-institutional report of patients undergoing 5-fraction PORT to a limited CTV defined as gross disease with a 2-mm margin supports this conclusion.
      • Francolini G
      • Jereczek-Fossa BA
      • Di Cataldo V
      • et al.
      Stereotactic radiotherapy for prostate bed recurrence after prostatectomy: A multicentric series.
      This study reported a favorable rate of biochemical remission in patients who did not receive ADT despite otherwise unfavorable baseline characteristics such as a mean presalvage PSA of 2.3 ng/mL. These results are somewhat more favorable than older, small, retrospective series reporting on the efficacy of focal brachytherapy in the salvage setting
      • Buchser D
      • Gomez-Iturriaga A
      • Melcon JI
      • et al.
      Salvage high-dose-rate brachytherapy for histologically confirmed macroscopic local relapsed prostate cancer after radical prostatectomy.
      ,
      • Kumar AM
      • Smith KL
      • Reddy CA
      • Stephans KL
      • Klein EA
      • Ciezki JP.
      Safety and efficacy of salvage low-dose-rate brachytherapy for prostate bed recurrences following radical prostatectomy.
      likely owing to the sensitivity of positron emission tomography to detect local recurrences earlier in their natural history in the contemporary reports.

      Limitations

      Our trial cohort was comprised mostly of patients with high-risk disease with 60% of our patient cohort being comprised of patients with high-grade surgical pathology (International Society of Urological Pathology grade group 3-5). Unsurprisingly, both treatment failures occurred in this subset of the patient population with evidence of at least one patient having out-of-field relapse at time of treatment as judged retrospectively by PSA trend. While our study was not designed to establish a high precision estimate of biochemical control, the 2-year rates for this population compare favorably to recent phase 3 data
      • Ghadjar P
      • Hayoz S
      • Bernhard J
      • et al.
      Dose-intensified versus conventional-dose salvage radiotherapy for biochemically recurrent prostate cancer after prostatectomy: The SAKK 09/10 randomized phase 3 trial.
      ,
      • Qi X
      • Li HZ
      • Gao XS
      • et al.
      Toxicity and biochemical outcomes of dose-intensified postoperative radiation therapy for prostate cancer: Results of a randomized phase III trial.
      with all patients except one recovering testosterone to noncastrate levels by protocol completion. While the rate of biochemical control is encouraging, the patient population is small, owing to the phase 1 design of the trial. Additional investigation is required to provide high precision estimates of the toxicity and oncologic efficacy of a ten-fraction dose schedule.
      Second, our treatment protocol included daily cone beam computed tomography image guidance with pretreatment approval by a GU-specialized radiation oncologist. This level of image guidance may not be practical in routine clinical practice. Further work is needed to determine whether the same toxicity and quality of life profile can be maintained in more routine practice settings.
      Finally, emerging data appears to suggest a benefit for pelvic nodal irradiation in some patients with prostate cancer. The preliminary results of RTOG 0534 (SPPORT) reported an increased freedom from progression at a median follow-up of 8.2 years with the inclusion of pelvic lymph node irradiation and short-term ADT to PORT.
      • Pollack A
      • Karrison TG
      • Balogh AG
      • et al.
      The addition of androgen deprivation therapy and pelvic lymph node treatment to prostate bed salvage radiotherapy (NRG Oncology/RTOG 0534 SPPORT): An international, multicentre, randomised phase 3 trial.
      In the current trial, no patients underwent pelvic nodal irradiation. The incorporation of pelvic nodal radiation therapy to hypofractionated treatment is an ongoing area of investigation, and several small prospective trials have been reported in the setting of intact prostate.
      • Glicksman RM
      • Liu SK
      • Cheung P
      • et al.
      Elective nodal ultra hypofractionated radiation for prostate cancer: Safety and efficacy from four prospective clinical trials.
      ,
      • Bauman G
      • Ferguson M
      • Lock M
      • et al.
      A phase 1/2 trial of Brief Androgen Suppression and Stereotactic Radiation Therapy (FASTR) for high-risk prostate cancer.
      Other reports, however, have identified concerning safety signals with unacceptable rates of severe GI toxicity,
      • Bauman G
      • Ferguson M
      • Lock M
      • et al.
      A phase 1/2 trial of Brief Androgen Suppression and Stereotactic Radiation Therapy (FASTR) for high-risk prostate cancer.
      and thus these hypofractionated dose schedules should be cautiously applied to patients in whom nodal irradiation is planned.

      Conclusion

      Our study identified the maximally hypofractionated tolerated dose schedule of the dose schedules investigated for postprostatectomy radiation therapy to be 44.2 Gy in 10 daily fractions with daily image guidance. This regimen was found to be safe by our prespecified criteria with acceptable rates of physician-reported toxicity. The most frequent clinically significant toxicities were late grade 2+ GU toxicities which translated into a worsening of GU QoL demonstrated only after the 12-month time point. While our early oncologic outcomes are promising, further prospective validations via randomized trials are required to demonstrate equivalent efficacy of this treatment regimen compared with standard dose schedules before widespread adoption for routine clinical use.

      Appendix. Supplementary materials

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