Although moderately hypofractionated radiotherapy (MHRT) is an accepted treatment for localized prostate cancer, its adaptation remains limited in the United States.1,2 MHRT theoretically exploits α/β ratio differences between the prostate (1.5 Gy), bladder (5-10 Gy), and rectum (3 Gy), thereby reducing late treatment-related adverse effects compared with those of conventional fractionation at biologically equivalent doses.3-8 Multiple randomized noninferiority trials have demonstrated equivalent outcomes between MHRT and conventional fraction with no appreciable increase in patient-reported toxicity.9-14 Although these studies have led to the acceptance of MHRT as a standard treatment, the majority of these trials involve individuals with low- and intermediate-risk disease.
There are less phase 3 data addressing MHRT for high-risk prostate cancer (HRPC).10,12,14-17 Only 2 studies examined predominately high-risk populations, accounting for 83 and 292 patients, respectively.15,16 Additional phase 3 trials with small proportions of high-risk patients (n = 126, 12%; n = 53, 35%) offer limited additional information regarding clinical outcomes and toxicity rates specific to high-risk disease.10-12 Numerous phase 1 and 2 studies report various field designs and fractionation plans for MHRT in the context of high-risk disease, although the applicability of these data to off-trial populations remains limited.18-20
Furthermore, African American individuals are underrepresented in the trials establishing the role of MHRT despite higher rates of prostate cancer incidence, more advanced disease stage at diagnosis, and higher rates of prostate cancer–specific survival (PCSS) when compared with White patients.21 Racial disparities across patients with prostate cancer and their management are multifactorial across health care literacy, education level, access to care (including transportation issues), and issues of adherence and distrust.22-25 Correlation of patient race to prostate cancer outcomes varies greatly across health care systems, with the US Department of Veterans Affairs (VA) equal access system providing robust mental health services and transportation services for some patients, while demonstrating similar rates of stage-adjusted PCSS between African American and White patients across a broad range of treatment modalities.26-28 Given the paucity of data exploring outcomes following MHRT for African American patients with HRPC, the present analysis provides long-term clinical outcomes and toxicity profiles for an off-trial majority African American population with HRPC treated with MHRT within the VA.
Methods
Records were retrospectively reviewed under an institutional review board–approved protocol for all patients with HRPC treated with definitive MHRT at the Durham Veterans Affairs Healthcare System in North Carolina between November 2008 and August 2018. Exclusion criteria included < 12 months of follow-up or elective nodal irradiation. Demographic variables obtained included age at diagnosis, race, clinical T stage, pre-MHRT prostate-specific antigen (PSA), Gleason grade group at diagnosis, favorable vs unfavorable high-risk disease, pre-MHRT international prostate symptom score (IPSS), and pre-MHRT urinary medication usage (yes/no).29
Concurrent androgen deprivation therapy (ADT) was initiated 6 to 8 weeks before MHRT unless medically contraindicated per the discretion of the treating radiation oncologist. Patients generally received 18 to 24 months of ADT, with those with favorable HRPC (ie, T1c disease with either Gleason 4+4 and PSA < 10 mg/mL or Gleason 3+3 and PSA > 20 ng/mL) receiving 6 months after 2015.29 Patients were simulated supine in either standard or custom immobilization with a full bladder and empty rectum. MHRT fractionation plans included 70 Gy at 2.5 Gy per fraction and 60 Gy at 3 Gy per fraction. Radiotherapy targets included the prostate and seminal vesicles without elective nodal coverage per institutional practice. Treatments were delivered following image guidance, either prostate matching with cone beam computed tomography or fiducial matching with kilo voltage imaging. All patients received intensity-modulated radiotherapy. For plans delivering 70 Gy at 2.5 Gy per fraction, constraints included bladder V (volume receiving) 70 < 10 cc, V65 ≤ 15%, V40 ≤ 35%, rectum V70 < 10 cc, V65 ≤ 10%, V40 ≤ 35%, femoral heads maximum point dose ≤ 40 Gy, penile bulb mean dose ≤ 50 Gy, and small bowel V40 ≤ 1%. For plans delivering 60 Gy at 3 Gy per fraction, constraints included rectum V57 ≤ 15%, V46 ≤ 30%, V37 ≤ 50%, bladder V60 ≤ 5%, V46 ≤ 30%, V37 ≤ 50%, and femoral heads V43 ≤ 5%.
Gastrointestinal (GI) and genitourinary (GU) toxicities were graded using Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, with acute toxicity defined as on-treatment < 3 months following completion of MHRT. Late toxicity was defined as ≥ 3 months following completion of MHRT. Individuals were seen in follow-up at 6 weeks and 3 months with PSA and testosterone after MHRT completion, then every 6 to 12 months for 5 years and annually thereafter. Each follow-up visit included history, physical examination, IPSS, and CTCAE grading for GI and GU toxicity.
The Wilcoxon rank sum test and χ2 test were used to compare differences in demographic data, dosimetric parameters, and frequency of toxicity events with respect to patient race. Clinical endpoints including biochemical recurrence-free survival (BRFS; defined by Phoenix criteria as 2.0 above PSA nadir), distant metastases-free survival (DMFS), PCSS, and overall survival (OS) were estimated from time of radiotherapy completion by the Kaplan-Meier method and compared between African American and White race by log-rank testing.30 Late GI and GU toxicity-free survival were estimated by Kaplan-Meier plots and compared between African American and White patients by the log-rank test. Statistical analysis was performed using SAS 9.4.