Initial Quality of Life and Toxicity Analysis of a Randomized Phase 3 Study of Moderately Hypofractionated Radiation Therapy With or Without Androgen Suppression for Intermediate-Risk Adenocarcinoma of the Prostate: PCG GU003.

Purpose: Our objective was to report the quality of life (QoL) analysis and toxicity in patients with intermediate-risk prostate cancer treated with or without androgen deprivation therapy (ADT) in Proton Collaborative Group (PCG) GU003. Methods and Materials: Between 2012 and 2019, patients with intermediate-risk prostate cancer were enrolled. Patients were randomized to receive moderately hypofractionated proton beam therapy (PBT) to 70 Gy relative biologic effectiveness in 28 fractions to the prostate with or without 6 months of ADT. Expanded Prostate Cancer Index Composite, Short-Form 12, and the American Urological Association Symptom Index instruments were given at baseline and 3, 6, 12, 18, and 24 months after PBT. Toxicities were assessed according to Common Terminology Criteria for Adverse Events (version 4). Results: One hundred ten patients were randomized to PBT either with 6 months of ADT (n = 55) or without ADT (n = 55). The median follow-up was 32.4 months (range, 5.5-84.6). On average, 101 out of 110 (92%) patients filled out baseline QoL and patient-reported outcome surveys. The compliance was 84%, 82%, 64%, and 42% at 3, 6, 12, and 24 months, respectively. Baseline median American Urological Association Symptom Index was comparable between arms (6 [11%] ADT vs 5 [9%] no ADT, P = .359). Acute and late grade 2+ genitourinary and gastrointestinal toxicity were similar between arms. The ADT arm experienced a QoL decline of mean scores in the sexual (-16.1, P < .001) and hormonal (-6.3, P < .001) domains, with the largest time-specific hormonal differences at 3 (-13.8, P < .001) and 6 (-11.2, P < .001) months. The hormonal QoL domain returned to baseline 6 months after therapy. There was a trend to baseline in sexual function 6 months after completion of ADT. Conclusions: After 6 months of ADT, sexual and hormonal domains returned to baseline 6 months after completion of treatment for men with intermediate-risk prostate cancer.

Outcomes and toxicities after proton partial breast radiotherapy for early stage, hormone receptor positive breast cancer: 3-Year results of a phase II multi-center trial.

Purpose: Proton therapy (PT) for partial breast irradiation (PBI) in early-stage breast cancer can decrease morbidity versus photon PBI with superior organs-at-risk sparing. We report 3-year outcomes of the first prospective, multicenter, phase II trial of proton PBI. Methods and Materials: This Proton Collaborative Group phase II trial (PCG BRE007-12) recruited women ≥ 50 years with node-negative, estrogen receptor (ER)-positive, ≤3cm, invasive ductal carcinoma (IDC) or ductal carcinoma in situ undergoing breast conserving surgery followed by proton PBI (40 Gy(RBE), 10 daily fractions). Primary endpoint was freedom from ipsilateral breast cancer recurrence. Adverse events were prospectively graded using CTCAEv4.0. Breast Cancer Treatment Outcome Scale (BCTOS) assessed patient-reported quality of life (PRQOL). Results: Thirty-eight evaluable patients enrolled between 2/2013-11/2016. Median age was 67 years (range 50-79); 55 % had left-sided disease, and median tumor size was 0.9 cm. Treatment was delivered in ≥ 2 fields predominantly with uniform scanning PT (n = 37). At 35-month median follow-up (12-62), all patients were alive, and none had local, regional or distant disease progression. One patient developed an ER-negative contralateral IDC. Seven grade 2 adverse events occurred; no radiotherapy-related grade ≥ 3 toxicities occurred. Changes in BCTOS subdomain mean scores were maximum 0.36, indicating no meaningful change in PRQOL. Median heart volume receiving 5 Gy (V5Gy), lung V20Gy, and lung V10Gy were 0 %, 0 % and 0.19 %, respectively. Conclusion: At 3 years, proton PBI provided 100 % cancer control for early-stage, ER-positive breast cancer. Toxicities are minimal, and PRQOL remains acceptable with continued follow-up. These findings support PT as a safe and effective PBI delivery option.

Dosimetry and Acute Toxicity Profile of Patients With Esophageal Cancer Treated With Proton Beam Radiation Therapy: Outcomes From the Proton Collaborative Group REG001-09 Trial.

PURPOSE: Concurrent chemoradiation plays an integral role in the treatment of esophageal cancer. Proton beam radiation therapy has the potential to spare adjacent critical organs, improving toxicity profiles and potentially improving clinical outcomes. METHODS AND MATERIALS: We evaluated the REG001-09 registry for patients undergoing proton radiation therapy for esophageal cancer. Demographic, clinicopathologic, toxicity, and dosimetry information were compiled. RESULTS: We identified 155 patients treated at 10 institutions between 2010 and 2019. One hundred twenty (77%) had adenocarcinoma and 34 (22%) had squamous cell carcinoma. One hundred thirty-seven (88%) received concurrent chemotherapy. The median delivered dose was 50.51 Gy-equivalent (GyE; range, 41.4-70.1). Grade ≥3 toxicities occurred in 22 (14%) of patients and were most commonly dysphagia (6%), esophagitis (4%), anorexia (4%), and nausea (2%). There were no episodes of grade ≥4 lymphopenia and no grade 5 toxicities. The average mean heart, lung, and liver doses and average maximum spinal cord dose were 10.0 GyE, 4.8 GyE, 3.8 GyE, and 34.2 GyE, respectively. For gastroesophageal junction tumors, 8% of patients developed acute grade ≥3 toxicity and the mean heart, liver, right kidney, and left kidney doses were 10.5 GyE, 3.9 GyE, 0.4 GyE, and 4.9 GyE, respectively. Gastroesophageal junction location was protective against development of grade ≥3 toxicity on univariate (P = .0009) and multivariate (P = .004) analysis. CONCLUSIONS: Proton beam radiation therapy affords excellent dosimetric parameters and low toxicity in patients with esophageal cancer treated with curative intent. Prospective trials are underway investigating the comparative benefit of proton-based therapy.

Patient reported outcomes following proton pencil beam scanning vs. passive scatter/uniform scanning for localized prostate cancer: Secondary analysis of PCG 001-09.

BACKGROUND: Although pencil beam scanning (PBS) is the most conformal method for proton beam therapy (PBT) delivery, it is unknown if outcomes differ compared to treatment with passive scatter/uniform scanning (PS/US). This analysis compares patient reported outcomes (PRO) changes following PBS and PS/US for prostate cancer (PC) in a prospective multicenter registry study. METHODS: We evaluated PROs with the Expanded Prostate Cancer Index Composite (EPIC) instrument for men with localized PC enrolled in PCG 001-09 (NCT01255748). PROs were assessed at baseline and through 12 months of follow-up. We compared mean changes in EPIC scores, as well as the proportions of men experiencing a one- and two-fold minimally important difference (MID) in domain scores, between PBS and PS/US. Multivariate analyses (MVAs) were performed to further evaluate the association between proton modality and PRO changes. RESULTS: Three-hundred-and-four men completed EPIC at baseline; 72 received PBS and 232 received PS/US. The average quality-of-life (QOL) declines from baseline through 12 months did not significantly differ between the two groups. The proportion of men reporting a 1-MID decline at 12 months for PBS and PS/US was 34.3% and 27.4%, respectively, for urinary QOL (P = 0.27); 40. 1% and 40.9% for bowel QOL (P = 0.36); and 30. 1% and 36.6% for sexual QOL (P = 0.94). Corresponding 2-MID declines for PBS and PS/US were observed in 26.9% and 13.2% of men for urinary QOL (P = 0.01), 35.3% and 29.1% for bowel QOL (P = 0.33); and 16.4% and 18.1% for sexual QOL (P = 0.76). The association between proton modality and 2-MID changes in urinary QOL at 12-months remained significant on MVA (P = 0.007). CONCLUSIONS: The results of this analysis show differences between PBS and PS/US with regards to two-fold MID changes in urinary function at 12 months, but no differences for average score declines over time. Future studies evaluating PRO measures between the two PBT modalities are warranted.

Proton beam therapy delivered using pencil beam scanning vs. passive scattering/uniform scanning for localized prostate cancer: Comparative toxicity analysis of PCG 001-09.

BACKGROUND AND PURPOSE: Patient-level benefits of proton beam therapy (PBT) relative to photon therapy for prostate cancer (PC) continue to be the focus of debate. Although trials comparing the two modalities are underway, most are being conducted using "conventional" PBT (passive scattering/uniform scanning [PS/US]) rather than pencil beam scanning (PBS). The dosimetric benefits of PBS are well-known, but comparative data are limited. This analysis compares PBS toxicity rates with those of PS/US in a prospective multicenter registry. METHODS: We evaluated acute/late gastrointestinal (GI) and genitourinary (GU) toxicity rates for men with low-to-intermediate risk PC enrolled in PCG 001-09. Acute toxicities with the two techniques were compared using χ2 tests, and the cumulative incidence methods for late toxicity. Multivariable analyses (MVAs) for acute toxicity were performed using logistic regression, and cox proportional hazards models for late toxicity. RESULTS: Patients were treated using PS/US (n = 1105) or PBS (n = 238). Acute grade ≥2 GI toxicity in PBS did not significantly differ from that with PS/US (2.9% and 2.1%, respectively; P = 0.47). Acute grade ≥2 GU toxicity was significantly higher with PBS (21.9% and 15.1%; P < 0.01). In MVA, PBS was significantly associated with increased acute grade ≥2 GU toxicity (RR = 1.57, p < 0.001). Late grade ≥2 GI and GU toxicities did not differ significantly between groups. CONCLUSIONS: This is the first multi-institutional comparative effectiveness evaluation of PBT techniques in PC. Differences in acute GU toxicity warrant further evaluation, and highlight the urgent need for prospective data using PBT.

Initial toxicity, quality-of-life outcomes, and dosimetric impact in a randomized phase 3 trial of hypofractionated versus standard fractionated proton therapy for low-risk prostate cancer.

PURPOSE: Randomized evidence for extreme hypofractionation in prostate cancer is lacking. We aimed to identify differences in toxicity and quality-of-life outcomes between standard fractionation and extreme hypofractionated radiation in a phase 3 randomized trial. METHODS AND MATERIALS: We analyzed the results of the first 75 patients in our phase 3 trial, comparing 38 Gy relative biologic effectiveness (RBE) in 5 fractions (n = 46) versus 79.2 Gy RBE in 44 fractions (n = 29). Patients received proton radiation using fiducials and daily image guidance. We evaluated American Urological Association Symptom Index (AUASI), adverse events (AEs), and Expanded Prostate Index Composite (EPIC) domains. The primary endpoint of this interim analysis was the cumulative incidence of grade 2 (G2) or higher AEs. The randomized patient allocation scheme was a 2:1 ratio favoring the 38 Gy RBE arm. RESULTS: The median follow-up was 36 months; 30% of patients reached 48-month follow-up. AUASI scores differed <5 points (4.4 vs 8.6; P = .002) at 1 year, favoring the 79.2 Gy arm. Differences in AUASI were not significant at ≥18 months. EPIC urinary symptoms favored the 79.2 Gy arm at 1 year (92.3 vs 84.5; P = .009) and 18 months (92.3 vs 85.3; P = .03); bother scores were not significant at other time points. Cumulative ≥G2 genitourinary toxicity was similar between the 79.2 Gy and 38 Gy arms (34.5% vs 30.4%; P = .80). We found no differences in the EPIC domains of bowel symptoms, sexual symptoms, or bowel ≥G2 toxicities. Bladder V80 (79.2 Gy arm; P = .04) and V39 (38 Gy arm; P = .05) were predictive for cumulative G2 genitourinary AEs. CONCLUSIONS: Low AE rates were seen in both study arms. Early temporary differences in genitourinary scores disappeared over time. Bladder constraints were associated with genitourinary AEs.