Hypofractionated Proton Beam Therapy Research Articles

Prospective phase II trial of preoperative hypofractionated proton therapy for extremity and truncal soft tissue sarcoma: the PRONTO study rationale and design

BackgroundOncologic surgical resection is the standard of care for extremity and truncal soft tissue sarcoma (STS), often accompanied by the addition of pre- or postoperative radiation therapy (RT). Preoperative RT may decrease the risk of joint stiffness and fibrosis at the cost of higher rates of wound complications. Hypofractionated, preoperative RT has been shown to provide acceptable outcomes in prospective trials. Proton beam therapy (PBT) provides the means to decrease dose to surrounding organs at risk, such as the skin, bone, soft tissues, and adjacent joint(s), and has not yet been studied in patients with extremity and truncal sarcoma.MethodsOur study titled “PROspective phase II trial of preoperative hypofractionated protoN therapy for extremity and Truncal soft tissue sarcOma (PRONTO)” is a non-randomized, prospective phase II trial evaluating the safety and efficacy of preoperative, hypofractionated PBT for patients with STS of the extremity and trunk planned for surgical resection. Adult patients with Eastern Cooperative Group Performance Status ≤ 2 with resectable extremity and truncal STS will be included, with the aim to accrue 40 patients. Treatment will consist of 30 Gy radiobiological equivalent of PBT in 5 fractions delivered every other day, followed by surgical resection 2–12 weeks later. The primary outcome is rate of major wound complications as defined according to the National Cancer Institute of Canada Sarcoma2 (NCIC-SR2) Multicenter Trial. Secondary objectives include rate of late grade ≥ 2 toxicity, local recurrence-free survival and distant metastasis-free survival at 1- and 2-years, functional outcomes, quality of life, and pathologic response.DiscussionPRONTO represents the first trial evaluating the use of hypofractionated PBT for STS. We aim to prove the safety and efficacy of this approach and to compare our results to historical outcomes established by previous trials. Given the low number of proton centers and limited availability, the short course of PBT may provide the opportunity to treat patients who would otherwise be limited when treating with daily RT over several weeks. We hope that this trial will lead to increased referral patterns, offer benefits towards patient convenience and clinic workflow efficiency, and provide evidence supporting the use of PBT in this setting.Trial registration: NCT05917301 (registered 23/6/2023).

Moderately hypofractionated proton beam therapy for localized prostate cancer: 5-year outcomes of a phase II trial.

The usefulness of moderately hypofractionated radiotherapy for localized prostate cancer has been extensively reported, but there are limited studies on proton beam therapy (PBT) using similar hypofractionation schedules. The aim of this prospective phase II study is to confirm the safety of a shortened PBT course using 70Gy relative biological effectiveness (RBE) in 28 fractions. From May 2013 to June 2015, 102 men with localized prostate cancer were enrolled. Androgen deprivation therapy was administered according to risk classification. Toxicity was assessed using Common Terminology Criteria for Adverse Events version 4.0. Of the 100 patients ultimately evaluated, 15 were classified as low risk, 43 as intermediate risk, and 42 as high risk. The median follow-up time of the surviving patients was 96months (range: 60-119months). The 5-year cumulative incidences of grade 2 gastrointestinal/genitourinary adverse events were 1% (95% CI: 0.1-6.9) and 4% (95% CI: 1.5-10.3), respectively; no grade ≥ 3 gastrointestinal/genitourinary adverse events were observed. The current study revealed a low incidence of late adverse events in prostate cancer patients treated with moderately hypofractionated PBT of 70Gy (RBE) in 28 fractions, indicating the safety of this schedule.

Prospective study investigating hypofractionated proton beam therapy in patients with inoperable early stage non-small cell lung cancer.

To report the results of hypofractionated proton beam therapy (PBT) for the treatment of early stage lung cancer in patients not suitable for surgical resection. Data from 27 adult patients, who were diagnosed with inoperable cT1-3N0 non-small cell lung cancer (NSCLC) between March 2018 and August 2020, were analyzed. PBT was prescribed as 64 Cobalt Grey equivalents delivered in 8 fractions (Sumitomo, Japan). The primary endpoint was local control; secondary endpoints included overall survival, quality of life, and grade ≥3 toxicity. The median follow-up was 28.9 months (range, 1.1-62.1 months). During follow-up, 13 (48.1%) patients experienced disease progression, including local progression in 7. Two-year local control rates were 73.5%, 85.7% for T1, and 61.4% for T2-3. The worse local control rate was observed in those with large clinical target volumes (≥ 47.5 cc) and heavy smoking history (≥30 pack-years). The two-year overall survival rate was 76.5%. Grade 3 radiation-related toxicities were observed in 2 (7.4%) patients. In the European Organization for Research and Treatment of Cancer Quality of Life Core 30 results, the global score did not change significantly from baseline. However, dyspnea score increased from 19.8 before PBT to 33.3 at 4 months' post-PBT (p=0.047) and was maintained until 13 months (p=0.028). Hypofractionated PBT was a safe treatment option for inoperable early stage NSCLC and appeared to be appropriate for small tumor volumes. However, local control for larger tumors requires further improvement.

Dosimetric Correlation of Acute Radiation Dermatitis in Patients With Breast Cancer Undergoing Hypofractionated Proton Beam Therapy Using Pencil Beam Scanning.

Pencil-beam scanning (PBS) is a modern delivery technique used in proton beam therapy (PBT) to reduce normal tissue reactions. No dosimetric correlation between dermatitis and PBS has been reported for breast cancer. The current study aimed to investigate the factors associated with grade 2 or higher dermatitis in patients with breast cancer undergoing PBT using PBS. The medical data of 42 patients with breast cancer who underwent adjuvant radiotherapy between December 2019 and September 2023 were reviewed. All patients received hypofractionated radiotherapy (HFRT), either 26 Gy (relative biological effectiveness [RBE])/five fractions or 40.05 or 43.5 Gy (RBE)/15 fractions, for the whole breast/chest wall with or without nodal irradiation. The duration of acute radiation dermatitis was defined as within 90 days from the start of radiotherapy. The Kaplan-Meier method and Cox proportional hazards model were used for univariate and multivariate analyses of the actuarial rates of grade 2-3 dermatitis. Twenty-two (52.4%) and 20 (47.6%) patients were diagnosed with grade 1 and 2 dermatitis, respectively. Multivariate analysis revealed a clinical target volume (CTV) ≥ of 320 cc (p = 0.035) and a skin dose of D10cc ≥ 38.3 Gy (RBE) (p = 0.009) as independent factors of grade 2 dermatitis. The 10-week cumulative grade 2 dermatitis rates were 88.2%, 39.4%, and 8.3% (p < 0.001) for patients with both high, either high, and neither high CTV and D10cc, respectively. To the best of our knowledge, this is the first study on dosimetric correlations for dermatitis in patients with breast cancer who underwent hypofractionated PBT using PBS. In the era of HFRT, skin dose modulation using PBS may reduce the incidence of dermatitis.

A pooled patient-reported outcomes analysis of moderately hypofractionated proton beam therapy and photon-based intensity modulated radiation therapy for low- or intermediate-risk prostate cancer.

We sought to characterize and compare late patient-reported outcomes (PROs) after moderately hypofractionated intensity modulated radiation therapy (IMRT) and proton beam therapy (PBT) for localized prostate cancer (PC). This multi-institutional analysis included low- or intermediate-risk group PC patients treated with moderately hypofractionated radiation to an intact prostate stratified by treatment modality: IMRT or PBT. The primary outcomes were prospectively collected patient-reported late gastrointestinal (GI) and genitourinary (GU) toxicity assessed by International Prostate Symptom Score (IPSS) and Expanded PC Index Composite (EPIC). Multivariable regression analysis (MVA) controlling for age, race, and risk group tested the effect of time, treatment, and their interaction. 287 IMRT and 485 PBT patients were included. Intermediate risk group (81.2 vs. 68.2%; p < 0.001) and median age at diagnosis (70 vs. 67 years; p < 0.001) were higher in the IMRT group. On MVA, there was no significant difference between modalities. PBT IPSS did not differ from IMRT IPSS at 12 months (odds ratio [OR], 1.19; p = 0.08) or 24 months (OR, 0.99; p = 0.94). PBT EPIC overall GI function at 12 months (OR, 3.68; p = 0.085) and 24 months (OR 2.78; p = 0.26) did not differ from IMRT EPIC overall GI function. At 24 months, urinary frequency was no different between PBT and IMRT groups (OR 0.35; p = 0.096). This multi-institutional analysis of low- or intermediate-risk PC treated with moderately hypofractionated PBT and IMRT demonstrated low rates of late patient-reported GI and GU toxicities. After covariate adjustment, late GI and GU PROs were not significantly different between PBT or IMRT cohorts.

Predicting the Effect of Proton Beam Therapy Technology on Pulmonary Toxicities for Patients With Locally Advanced Lung Cancer Enrolled in the Proton Collaborative Group Prospective Clinical Trial

This study aimed to predict the probability of grade ≥2 pneumonitis or dyspnea within 12 months of receiving conventionally fractionated or mildly hypofractionated proton beam therapy for locally advanced lung cancer using machine learning. Demographic and treatment characteristics were analyzed for 965 consecutive patients treated for lung cancer with conventionally fractionated or mildly hypofractionated (2.2-3 Gy/fraction) proton beam therapy across 12 institutions. Three machine learning models (gradient boosting, additive tree, and logistic regression with lasso regularization) were implemented to predict Common Terminology Criteria for Adverse Events version 4 grade ≥2 pulmonary toxicities using double 10-fold cross-validation for parameter hyper-tuning without leak of information. Balanced accuracy and area under the curve were calculated, and 95% confidence intervals were obtained using bootstrap sampling. The median age of the patients was 70 years (range, 20-97), and they had predominantly stage IIIA or IIIB disease. They received a median dose of 60 Gy in 2 Gy/fraction, and 46.4% received concurrent chemotherapy. In total, 250 (25.9%) had grade ≥2 pulmonary toxicity. The probability of pulmonary toxicity was 0.08 for patients treated with pencil beam scanning and 0.34 for those treated with other techniques (P = 8.97e-13). Use of abdominal compression and breath hold were highly significant predictors of less toxicity (P = 2.88e-08). Higher total radiation delivered dose (P = .0182) and higher average dose to the ipsilateral lung (P = .0035) increased the likelihood of pulmonary toxicities. The gradient boosting model performed the best of the models tested, and when demographic and dosimetric features were combined, the area under the curve and balanced accuracy were 0.75 ± 0.02 and 0.67 ± 0.02, respectively. After analyzing performance versus the number of data points used for training, we observed that accuracy was limited by the number of observations. In the largest analysis of prospectively enrolled patients with lung cancer assessing pulmonary toxicities from proton therapy to date, advanced machine learning methods revealed that pencil beam scanning, abdominal compression, and lower normal lung doses can lead to significantly lower probability of developing grade ≥2 pneumonitis or dyspnea.

Phase II study of short course hypofractionated proton beam therapy incorporating 18F-DOPA-PET/MRI for elderly patients with newly diagnosed glioblastoma.

2002 Background: Elderly patients with glioblastoma have a poor prognosis with phase III trials reporting median overall survival (OS) and global time to deterioration of 6–9 and 1.2 months respectively. 18F-DOPA (3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine) positron emission tomography (PET) is sensitive and specific for identifying regions of high density and biologically aggressive glioblastoma. Proton beam therapy (PBT) can spare more healthy tissue that may improve quality of life for this patient population. With improved targeting of disease along with dosimetric advantages of PBT, this phase II trial tested whether hypofractionated PBT can offer both improved survival and quality of life. Methods: Patients with newly diagnosed glioblastoma aged ≥65 years without contraindications to 18F-DOPA were eligible. Target volumes were defined by PET (tumor/normal brain SUV ≥2.0) and MRI areas of contrast enhancement including surgical cavity. Patients received dose escalated hypofractionated PBT of 35-40 GyE to PET/MRI over 5-10 treatments with 10 mm margin. Patients received concurrent/adjuvant temozolomide. With an alpha of 0.1, 18 of 39 patients would be required to be alive at 12 months for the study to be considered a success. Kaplan-Meier/Cox regression analysis was performed for progression free survival (PFS) and OS. Toxicities were evaluated with CTCAE v4.0. Patients completed EORTC BN20, QLQ-C30, and MMSE questionnaires. Time to deterioration, defined as a 10-point decrease in the score of the function domain or 10-point increase in score of symptom domain, was evaluated. Results: Between 5/2019-6/2021, 43 patients were enrolled, with 4 patients withdrawing due to progression/insurance denial prior to beginning protocol therapy. The median age was 70.2 yrs. and median follow-up was 12.5 months. MGMT methylation was present in 13 (33%). Tumors were multifocal in 10 (26%) and unifocal in 29 (74%). The primary endpoint was met with median PFS/OS was 6.5/12.9 months for all patients and for MGMT methylated patients 11.9/29.8 months respectively. Grade 3 baseline adjusted treatment related adverse events included 1 (3%) confusion, 2 (5%) fatigue, and 1 (3%) seizure. There were no grade 4/5 events. Multivariate analysis revealed MGMT unmethylated, ECOG 2 and biopsy only patients had worse survival. PET volume was more predictive than MRI volume for OS with PET volume&gt;26 cc having a hazard ratio of 3.7. The median time to global deterioration per QLC-C30 was 6.3 months. Conclusions: This phase II trial incorporating 18F-DOPA PET-guided dose escalated hypofractionated proton beam treatment for elderly patients with glioblastoma met its primary endpoint for improved OS and patient reported quality of life compared to historical controls. Further investigation is warranted. Clinical trial information: NCT03778294 .

Long-term Outcomes After Moderate Hypofractionated Proton Therapy for Centrally Located Non-small Cell Lung Cancer.

To investigate the outcomes of patients with centrally located non-small-cell lung cancer (NSCLC) treated with proton beam therapy (PBT) using moderate hypofractionation. Between 2006 and 2019, 34 patients with centrally located T1-T4N0M0 NSCLC who received moderate hypofractionated PBT were retrospectively reviewed. The median follow-up was 50.8 months (range=5.8-100.4 months). The 3-year overall survival, progression-free survival (PFS), and local control rates were 70.4%, 55.5% and 80.5%, respectively. Grade 2 or 3 lung adverse events (AEs) after PBT were observed in five (14.7%) patients; however, grade 3 radiation pneumonitis was observed in one (2.9%) patient. Notably, no grade 4 or higher AEs were observed. Regarding the correlation between the lung dose and proximal bronchial tree maximum dose and grade 2 or higher lung AEs, a weak correlation was observed between the mean lung dose and AEs (p=0.035). Although the clinical target volume (CTV) was a risk factor for poor PFS, no significant correlation was found between the CTV and lung AEs after PBT. Moderate hypofractionated PBT may be a useful radiotherapy method for centrally located cT1-T4N0M0 NSCLC.

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

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. 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). 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. 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.

Clinical Efficacy of Hypofractionated Proton Beam Therapy for Intrahepatic Cholangiocarcinoma.

Forty-seven patients with intrahepatic cholangiocarcinoma (IHCC) who received proton beam therapy (PBT) were analyzed to evaluate the clinical efficacy and safety of hypofractionated PBT in patients with inoperable or recurrent IHCC. The median prescribed dose of PBT was 63.3 GyE (range: 45-80 GyE) in 10 fractions, and the median duration of follow-up in all the patients was 18.3 months (range: 2.4-89.9 months). Disease progression occurred in 35 of the 47 (74.5%) patients; local, intrahepatic, and extrahepatic progression occurred in 5 (10.6%), 20 (42.6%), and 29 (61.7%) patients, respectively. The 2-year freedom from local progression (FFLP), progression-free survival (PFS), overall survival (OS) rates, and median time of OS were 86.9% (95% confidence interval [CI], 74.4-99.4%), 16.8% (95% CI, 4.3-29.3%), 42.7% (95% CI, 28.0-57.4%), and 21.9 months (95% CI, 16.2-28.3 months), respectively; grade ≥ 3 adverse events were observed in four (8.5%) patients. In selected patients with localized disease (no viable tumors outside of the PBT sites), the median time of OS was 33.8 months (95% CI, 5.4-62.3). These findings suggest that hypofractionated PBT is safe and could offer a high rate of FFLP and promising OS in patients with inoperable or recurrent IHCC.

Long-Term Results of a Multi-Institutional Phase II Study of Hypofractionated Proton Beam Irradiation of Unresectable Primary Liver Tumors

<h3>Purpose/Objective(s)</h3> To report the long-term outcomes of a prospective, multi-institutional phase II trial of hypofractionated proton beam therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). <h3>Materials/Methods</h3> This single-arm, phase II, multi-institutional study enrolled 92 patients with localized, unresectable, biopsy-confirmed HCC or ICC with a Child-Turcotte-Pugh score (CTP) of A or B, and ECOG performance status of 0 to 2, to receive proton radiotherapy to a maximum dose of 67.5 GyRBE in 15 fractions. Overall survival (OS) and progression-free survival (PFS) rates were estimated using the Kaplan-Meier method. <h3>Results</h3> The patient characteristics, treatment techniques, and two-year outcomes have been previously reported on the 83 evaluable patients in this trial, including 44 with HCC and 39 with ICC who at that time had a median follow-up of 19.5 months. This updated analysis includes a median follow-up of 60.8 months (range 10.3–121.5) and 45.9 months (range 31.1–49.5) among the survivors with HCC and ICC, respectively. For those with HCC, the 5-year OS rate was 25.9% (95% CI 0.13-0.40), with a median OS of 29.2 months. For those with ICC, the 5-year OS rate was 12.3% (95% CI 0.03–0.27), with a median OS of 20.8 months. The 5-year PFS rate was 23.4% (95% CI 0.092-0.41) in HCC and 11.0% (95% CI 0.030-0.25) in ICC. As previously reported, two patients (6.8%) with HCC recurred locally, both within 2 years of treatment, and there were no further local failures. Among the patients with ICC, only one additional local failure occurred, for a total of 7/39 patients (17.9%), with a median time to recurrence of 26.1 months (range 5.5–42.3 months). All patients with local failure had CTP A scores, with a median tumor size of 5.8 cm (range 3.5–7.6 cm). The median radiation dose received by those who had a local recurrence was 58.0 GyRBE (range 45.0–67.5). Local failures occurred in 12.3% (7/57) of patients who received a BED less than 80.5 Gy and in 7.7% (2/26) of those who received a BED greater than 80.5 Gy. Distant failures, including intrahepatic non-local failures, occurred in 56.8% (25/44) of patients with HCC with a median time to progression of 10.2 months (range 2.7–63.6). In those with ICC, distant failures occurred in 61.5% of patients (24/39), with a median time to progression of 5.8 months (range 0.4–68.4). There were no grade 3 or greater late toxicities, including no late biliary toxicity. <h3>Conclusion</h3> Hypofractionated proton beam therapy is associated with durable, high rates of local control for both HCC and ICC, however, distant failures are common and remain a challenge. There were no significant late adverse effects, including no late biliary obstruction. Future strategies to incorporate radiation and systemic therapies, including immunotherapy, should be explored to further improve the long-term outcomes of HCC and ICC.

Patient Reported Quality of Life after Moderately Hypofractionated Proton Beam Therapy or Intensity Modulated Radiation Therapy for Prostate Cancer

<h3>Purpose/Objective(s)</h3> We aim to quantify and compare changes in patient reported quality of life (PRQOL) after moderately hypofractionated (MHF) Proton Beam Therapy (PBT) or Intensity Modulated Radiation Therapy (IMRT) for prostate cancer (PC). <h3>Materials/Methods</h3> This multi-institutional analysis included patients with NCCN low or intermediate risk PC treated at 4 tertiary cancer centers with MHF PBT or IMRT with prospective PRQOL collection. Patients completed International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC) pre-treatment and at 3-to-6-month intervals starting at the end of treatment. EPIC is a questionnaire measuring health related quality of life (HRQOL) domains of genitourinary (GU), gastrointestinal (GI), sexual, and hormonal function. Questions are scored from 0 (no problem) to 4 (big problem). EPIC score of 3 or more was considered a meaningful QOL decrement. IPSS measures GU HRQOL; each question is measured from a score of 0 to 5 with a maximum score of 35. Baseline characteristics were compared with Chi squared and t test for IPSS. Models were limited to long term data, at 12 and 36 months. Generalized linear regression models testing effects of time, treatment, and their interaction were fit via Generalized Estimating Equations, controlling for age, race, and NCCN risk group. <h3>Results</h3> 287 IMRT and 485 PBT patients were included. Intermediate NCCN risk group (81.2 vs. 68.2%; p < 0.001), median age at diagnosis (70 vs 66.9 years; p < 0.001) were higher in the IMRT group. Mean IPSS was slightly worse at baseline in the PBT arm (+0.22; CI, -1.54 – 1.10; p=0.74) and slightly better at 3 years (-0.09; CI, -1.48 – 1.65; p=0.91). On Poisson regression controlling for age, race, and NCCN risk group, PBT IPSS trended worse at 12 months (OR, 1.19; CI, 0.98 - 1.44; p=0.077) without any difference at 36 months (OR, 1.08; CI, 0.80 - 1.26; p=0.94). Similarly, EPIC questionnaire for overall GI function trended worse with PBT at 12 months (CI, 0.83 - 16.27; p=0.085) without difference at 36 months (CI, 0.49 - 12.27, p=0.27). 4.9% and 4.8% patients in the PBT and IMRT arms, respectively, rated their overall GI function at 12 months as a severe problem. Among PBT and IMRT patients combined, severe GU concerns were unlikely at 12 months (GU frequency: 17.5; GU pain: 3.6; stream problem: 11.2%). <h3>Conclusion</h3> PRQOL showed a non-significant trend toward worse 1-year overall GI function and IPSS for PBT; this effect was not present at 3 years. In this multi-institutional, prospective study of PC, long-term GU and GI function was not significantly different between PBT or IMRT arms.

Initial Provider and Patient-Reported Outcomes of a Phase II Study of Short Course Hypofractionated Proton Beam Therapy Incorporating 18F-DOPA-PET/MRI for Elderly Patients with Newly Diagnosed Glioblastoma

<h3>Purpose/Objective(s)</h3> Due to poorer prognosis, hypofractionated radiation therapy is considered for elderly patients with newly diagnosed glioblastoma. Targeted radiation delivery with proton beam therapy (PBT) utilizing 18F-DOPA PET to identify biologically aggressive disease may be desirable. We report both provider and patient reported outcomes of a phase II trial evaluating hypofractionated PBT incorporating 18F-DOPA in treatment planning. <h3>Materials/Methods</h3> Patients ≥ 65 with histologically confirmed glioblastoma without contraindications to 18-FDOPA were enrolled. Target volumes were defined by PET (tumor/normal brain SUV ≥2.0) and MRI areas of contrast enhancement (MRI-CE) including surgical cavity. A combined volume of 65 cc or less was treated with 25 (1 cm margin), 30 (MRI-CE), and 35 (PET) GyE over 5 fractions with a simultaneous integrated boost. A combined volume of more than 65 cc was treated with 30 (1 cm margin), 35 (MRI-CE), and 40 (PET) GyE over 10 fractions. Patients received concurrent/adjuvant temozolomide. Provider-reported toxicity was assessed according to CTCAE V4. Patients completed EORTC BN20, QLQ-C30, and MMSE. QOL outcomes were compared with prior published phase III trials (NCT00482677 and NCT00430911). Time to deterioration, defined as a 10-point decrease in the score of the function domain or 10-point increase in score of symptom domain, was evaluated. <h3>Results</h3> Between 5/19 and 10/21, 39 patients were enrolled. 36 (92.3%) patients were IDH1 wt and 3 were IDH1 (7.7%) mt. MGMT promotor methylation was present in 13 (33%). The median clinical follow-up was 5.2 months. Tumors were multifocal in 10 (25.6%) and unifocal in 29 (74.4%). The median tumor diameter was 5.2 cm. Twenty-one patients (53.8%) received 40 GyE in 10 fractions and 18 (46.2%) received 35 GyE in 5 fractions. Baseline adjusted treatment related grade 2+ adverse events were: 8 (20.5%) CNS necrosis, 3 (7.7%) confusion, 1 (2.5%) dysphasia, 9 (23.1%) fatigue, 2 (5.1%) headache, 5 (12.8%) seizure, and 4 (10.2%) alopecia. Grade 3 baseline adjusted treatment related adverse events included 1 (2.6%) confusion, 2 (5.1%) fatigue, and 1 (2.6%) seizure. There were no grade 4/5 events. The median time to deterioration per QLQ-C30 was 6.3 months which was greater compared to the treatment arms (1.2 months, p<0.05) of NCT00482677 trial. At 90 days, there was improved (p<0.05) functioning in global, physical, role, emotional, social domains of QLQ-C30 and visual domain of BN20 for patients receiving PBT versus the supportive care arm of the NCT00430911. <h3>Conclusion</h3> Hypofractionated PBT incorporating 18F-DOPA in elderly patients was feasible with reasonable provider reported toxicity. Patient-reported outcomes compared favorably to prior phase III studies with similar patient populations.

Normofractionated and moderately hypofractionated proton therapy: comparison of acute toxicity and early quality of life outcomes

AimData on the safety of moderately hypofractionated proton beam therapy (PBT) are limited. The aim of this study is to compare the acute toxicity and early quality of life (QoL) outcomes of normofractionated (nPBT) and hypofractionated PBT (hPBT).Material and methodsWe prospectively compared acute toxicity and QoL between patients treated with nPBT (dose per fraction 1.8–2.3 Gy, n = 90) and hPBT (dose per fraction 2.5–3.1 Gy, n = 49) in following locations: head and neck (H&N, n = 85), abdomen and pelvis (A&P, n = 43), and other soft tissue (ST, n = 11). The toxicities were grouped into categories—mucosal, skin, and other sites—and evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 at baseline, treatment completion, and 3 months after PBT completion. QoL was evaluated with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 scale for all locations and additionally with EORTC QLQ-HN35 for H&N patients.ResultsOverall, the highest toxicity grades of G0, G1, G2, and G3 were observed in 7 (5%), 40 (28.8%), 78 (56.1%), and 15 (10.8%) patients, respectively. According to organ and site, no statistically significant differences were detected in the majority of toxicity comparisons (66.7%). For A&P, hPBT showed a more favorable toxicity profile as compared to nPBT with a higher frequency of G0 and G1 and a lower frequency of G2 and G3 events (p = 0.04), more patients with improvement (95.7% vs 70%, p = 0.023), and full resolution of toxicities (87% vs 50%, p = 0.008). Skin toxicity was unanimously milder for hPBT compared to nPBT in A&P and ST locations (p = 0.018 and p = 0.025, respectively). No significant differences in QoL were observed in 97% of comparisons for QLQ-C30 scale except for loss of appetite in H&N patients (+33.3 for nPBT and 0 for hPBT, p = 0.02) and role functioning for A&P patients (0 for nPBT vs +16.7 hPBT, p = 0.003). For QLQ-HN35, 97.9% of comparisons did not reveal significant differences, with pain as the only scale varying between the groups (−8.33 vs −25, p = 0.016).ConclusionHypofractionated proton therapy offers non-inferior early safety and QoL as compared to normofractionated irradiation and warrants further clinical investigation.

Proton Beam Therapy in Elderly Patients With cT1-3N0M0 Non-small Cell Lung Cancer.

To investigate the outcomes of elderly patients with cT1-3N0M0 non-small cell lung cancer (NSCLC) undergoing proton beam therapy (PBT). Between 2009 and 2019, 110 patients receiving hypofractionated PBT for cT1-3N0M0 NSCLC were retrospectively reviewed. The median follow-up was 36.5 months (range=4.9-131.0 months). In the elderly group (80 years or older), the 3-year overall survival and progression-free survival rates were 79.8% and 73.9%, respectively, and the corresponding rates in the younger group were 80.5% and 61.2%, respectively. Grade 3 radiation pneumonitis (RP) was observed in 4.4% patients in the young group, whereas no grade 3 RP was observed in the elderly group. Age was not a risk factor for symptomatic RP. There were no significant differences in the survival and adverse events between the elderly and younger groups. PBT may be a reasonable approach for treating lung cancer in elderly patients with T1-3N0M0 NSCLC.

The Role of Hypofractionation in Proton Therapy.

Simple SummaryHypofractionation is a radiation oncology concept in which larger doses per fraction are administered and therefore less fractions are prescribed in a given treatment course. This concept has been increasingly utilized in recent years in external beam radiotherapy (EBRT). Hypofractionation has the potential benefits of reducing the length of treatment and also treatment costs. In the case of proton beam therapy (PBT), which is a limited resource with only 99 facilities currently in operation worldwide in 2021, hypofractionation also has the benefit of potentially increasing the number of patients able to access PBT. This review article will discuss the reported clinical data and radiobiology of hypofractionated PBT. The aim is to report on the current knowledge of hypofractionation in PBT and the issues which still require investigation. Over 50 published manuscripts reporting clinical results involving hypofractionation and PBT were included in this review, where the most common treatment regions were prostate, lung and liver. Future clinical trials are still needed to determine the optimal fractionation regime.Hypofractionated radiotherapy is an attractive approach for minimizing patient burden and treatment cost. Technological advancements in external beam radiotherapy (EBRT) delivery and image guidance have resulted in improved targeting and conformality of the absorbed dose to the disease and a reduction in dose to healthy tissue. These advances in EBRT have led to an increasing adoption and interest in hypofractionation. Furthermore, for many treatment sites, proton beam therapy (PBT) provides an improved absorbed dose distribution compared to X-ray (photon) EBRT. In the past 10 years there has been a notable increase in reported clinical data involving hypofractionation with PBT, reflecting the interest in this treatment approach. This review will discuss the reported clinical data and radiobiology of hypofractionated PBT. Over 50 published manuscripts reporting clinical results involving hypofractionation and PBT were included in this review, ~90% of which were published since 2010. The most common treatment regions reported were prostate, lung and liver, making over 70% of the reported results. Many of the reported clinical data indicate that hypofractionated PBT can be well tolerated, however future clinical trials are still needed to determine the optimal fractionation regime.

Clinical Effectiveness of Hypofractionated Proton Beam Therapy for Liver Metastasis From Breast Cancer.

BackgroundFew studies of proton beam therapy (PBT) for patients with liver metastasis from breast cancer (LMBC) are available to date. The aim of the present study was to evaluate the clinical effectiveness of PBT for patients with LMBC.Material and MethodsSeventeen patients with LMBC treated with PBT were included in this study. The median prescribed dose of PBT was 66 GyE (range, 60–80) in 10 fractions, 5 times a week. In patients with LMBC receiving PBT, freedom from local progression (FFLP), progression-free survival (PFS), and overall survival (OS) rates were assessed.ResultsThe median follow-up time was 34.2 months (range, 11.5–56.1). The median FFLP time was not yet reached, and the 3-year FFLP rates were 94.1% (95% confidence interval [CI], 82.9–105.3). The median times of PFS and OS were 7.9 months (95% CI, 5.3–10.5) and 39.3 months (95% CI, 33.2–51.9), respectively, and the 3-year PFS and OS rates were 19.6% (95% CI, -1.8–41.0) and 71.7% (95% CI, 46.8–96.6), respectively. Grade 3 or higher adverse events were not observed.ConclusionPBT for patients with LMBC showed promising FFLP and OS with safe toxicity profiles. These findings suggest that PBT can be considered a local treatment option in patients with LMBC.

Hypofractionated Proton Beam Therapy for cT1-2N0M0 Non-small Cell Lung Cancer Patients With Interstitial Lung Disease.

To evaluate the outcomes of proton beam therapy (PBT) for early-stage non-small cell lung cancer (NSCLC) in patients with interstitial lung disease (ILD). Between 2002 and 2017, 110 patients receiving hypofractionated PBT for cT1-2N0M0 NSCLC were reviewed. Of the 110 patients, 17 were diagnosed with ILD. The median follow-up period was 37.8 months. No significant difference in the 1-year cumulative rate of grade ≥2 pneumonitis was observed between patients with and those without ILD (17.6% vs. 14.1%, p=0.708). The lung doses were significantly lower in patients with than in those without ILD among patients without grade ≥2 pneumonitis. There were no significant differences in overall survival or local recurrence-free rates according to the presence of ILD. PBT appears to be a feasible and effective treatment for cT1-2N0M0 NSCLC in patients with ILD, but the lung dose should be strictly reduced.

Randomized Phase III Study of Moderately Hypofractionated Radiation Therapy With or Without Androgen Suppression for Intermediate Risk Adenocarcinoma of the Prostate: Analysis of Quality of Life and Toxicity, PCG GU 003

<h3>Purpose/Objective(s)</h3> To report the analysis on the quality of life (QOL) and toxicity in intermediate-risk prostate cancer patients treated with or without androgen deprivation therapy (ADT) on PCG GU 003. <h3>Materials/Methods</h3> Between 2012 and 2019, intermediate-risk prostate cancer patients were enrolled. Patients were randomized to receive moderately hypofractionated proton beam therapy (PBT) to 70 Gy relative biologic effectiveness (RBE) in 28 fractions to the prostate with or without 6 months of ADT. ADT was started 2 months prior to radiation and consisted of luteinizing hormone-releasing hormone (LHRH) agonists. Expanded Prostate Cancer Index Composite (EPIC), Short-Form 12, and the American Urological Association Symptom Index (AUASI) instruments were given at baseline, 3, 6, 12, 18, and 24 months after PBT. Toxicities were assessed according to Common Terminology Criteria for Adverse Events (Version 4). Clinically significant differences for EPIC domains were 6-9 points for urinary incontinence, 5-7 points for urinary irritative, 4-6 points for bowel, 10-12 points for sexual, and 4-6 points for hormonal. <h3>Results</h3> One hundred ten patients were randomized to PBT either with 6 months of ADT (n = 55) or without ADT (n = 55). Median follow-up was 32.4 months (range, 5.5-84.6). Patient and tumor characteristics were similar between arms with most patients being T1c (59.1%), Gleason 3+4 (62.7%) and PSA < 10 (79.1%). Baseline median AUASI was also similar (6 ADT vs 5 no ADT, <i>P</i> = 0.359). Acute and late grade 2+ genitourinary (GU) toxicity was similar between arms (acute 7.3% ADT vs 1.8% no ADT, <i>P</i> = 0.363; late 30.9% ADT vs 16.4% no ADT, <i>P</i> = 0.115). Acute and late grade 2+ gastrointestinal (GI) toxicity was similar between arms (acute 1.8% ADT vs 0% no ADT, <i>P</i> = 1; late 10.9% ADT vs 10.9% no ADT, <i>P</i> = 1). The only grade 3+ toxicities were in the ADT arm and consisted of 1 patient (1.8%) with an acute grade 3 GI and 1 patient (1.8%) with a late grade 3 GU toxicity. The ADT arm experienced worse overall QOL in the sexual (-16.1, <i>P</i> < 0.001) and hormonal (-6.3, <i>P</i> < 0.001) domains, with the largest time-specific hormonal differences at 3 (-13.8, <i>P</i> < 0.001) and 6 (-11.2, <i>P</i> < 0.001) months. However, there were no clinically significant differences 6 months after PBT. There were no clinically significant differences in AUASI, urinary incontinence, urinary irritative, or bowel domains. <h3>Conclusion</h3> Low acute and late toxicity rates were seen in both arms of the trial. Omitting ADT resulted in clinically significant improvement in hormonal and sexual QOL, typically resolving within 12 months after PBT.

Acute toxicity and patient-reported symptom score after conventional versus moderately hypofractionated proton therapy for prostate cancer.

IntroductionTo confirm the feasibility of hypofractionated proton beam therapy (PBT), we compared the acute adverse event rates and International Prostate Symptom Score (IPSS) in prostate cancer patients treated with hypofractionated versus conventionally fractionated (2.0 Gy relative biological effectiveness (RBE)/fraction) PBT.MethodsWe reviewed 289 patients with prostate cancer, of whom 73, 100, and 116 patients were treated with 2.0, 2.5, and 3.0 Gy (RBE)/fraction, respectively. The endpoints were acute genitourinary and gastrointestinal toxicities and the IPSS, evaluated up to 6 months after PBT initiation.ResultsNo significant differences were found in acute toxicity rates or the IPSS among the fractionation schedules. Diabetes mellitus, age, and androgen deprivation therapy were not identified as factors associated with the IPSS.ConclusionThere were no significant differences in adverse events or quality of life among the three fractionation schedules early after PBT.