Proton Collaborative Group Research Articles

Proton Pencil Beam Scanning Facilitates the Safe Treatment of Extended Radiation Targets for Hodgkin Lymphoma: A Report from the Proton Collaborative Group Registry.

Because proton beam therapy (PBT) can lower the dose of radiation to the heart, lungs, and breast, it is an established radiation modality for patients with Hodgkin lymphoma (HL). Pencil beam scanning (PBS) PBT facilitates the treatment of more extensive targets. This may be especially of value for lymphoma patients who require RT to both mediastinal and axillary targets, defined here as extended target RT (ETRT), given the target distribution and need to minimize the lung, heart, and breast dose. Using the Proton Collaborative Group registry, we identified patients with HL treated with PBT to both their mediastinum and axilla, for which DICOM-RT was available. All patients were treated with PBS. To evaluate the dosimetric impact of PBS, we compared delivered PBS plans with VMAT butterfly photon plans optimized to have the same target volume coverage, when feasible. Between 2016 and 2021, twelve patients (median 26 years) received PBS ETRT (median 30.6 Gy (RBE)). Despite the large superior/inferior (SI, median 22.2 cm) and left/right (LR, median 22.8 cm) extent of the ETRT targets, all patients were treated with one isocenter except for two patients (both with SI and LR > 30 cm). Most commonly, anterior beams, with or without posterior beams, were used. Compared to photons, PBS had greater target coverage, better conformity, and lower dose heterogeneity while achieving lower doses to the lungs and heart, but not to the breast. No acute grade 3+ toxicities were reported, including pneumonitis. Proton ETRT in this small cohort was safely delivered with PBS and was associated with an improved sparing of the heart and lungs compared to VMAT.

P 06 - Multi-institutional experience of pre-operative proton therapy for retroperitoneal sarcoma in the prospective Proton Collaborative Group (PCG) Registry

P 06 - Multi-institutional experience of pre-operative proton therapy for retroperitoneal sarcoma in the prospective Proton Collaborative Group (PCG) Registry

Reirradiation With Proton Therapy for Recurrent Malignancies of the Esophagus and Gastroesophageal Junction: Results of the Proton Collaborative Group Multi-Institutional Prospective Registry Trial

Background and purposeTreatment options for recurrent esophageal cancer (EC) previously treated with radiation therapy are limited. Reirradiation (reRT) with proton beam therapy (PBT) can offer lower toxicities by limiting doses to surrounding tissues. In this study, we present the first multi-institutional series reporting on toxicities and outcomes after reRT for locoregionally recurrent EC with PBT. Materials and methodsAnalysis of the prospective, multicenter, Proton Collaborative Group registry of patients with recurrent EC who had previously received photon-based RT and underwent PBT reRT was performed. Patient/tumor characteristics, treatment details, outcomes, and toxicities were collected. Local control (LC), distant-metastasis free survival (DMFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Event time was determined from reRT start. ResultsBetween 2012 and 2020, 31 patients received reRT via uniform scanning/passive scattering (61.3%) or pencil beam scanning (38.7%) PBT at seven institutions. Median prior RT, PBT reRT, and cumulative doses were 50.4 Gy (range, 37.5 – 110.4), 48.6 Gy (RBE) (25.2-72.1), and 99.9 Gy (79.1-182.5), respectively. 12.9% of patients had two prior RT courses, and 67.7% received PBT with concurrent chemotherapy. Median follow-up was 7.2 months (0.9-64.7). Post PBT, there were 16.7% locoregional only, 11.1% distant only, and 16.7% locoregional and distant recurrences. Six-month LC, DMFS, and OS were 80.5%, 83.4%, and 69.1%, respectively. One-year LC, DMFS, and OS were 67.1%, 83.4%, and 27%, respectively. Acute grade ≥3 toxicities occurred in 23% of patients, with one acute grade 5 toxicity secondary to esophageal hemorrhage, unclear if related to reRT or disease progression. No grade ≥3 late toxicities were reported. ConclusionIn the largest report to date of PBT for reRT in patients with recurrent EC, we observed acceptable acute toxicities and encouraging rates of disease control. However, these findings are limited by the poor prognoses of these patients, who are at high risk of mortality. Further research is needed to better assess the long-term benefits and toxicities of PBT in this specific patient population.

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.

Low contralateral failure rate with unilateral proton beam radiotherapy for oropharyngeal squamous cell carcinoma: A multi-institutional prospective study from the proton collaborative group

IntroductionUnilateral radiation therapy is appropriate for select patients with oropharyngeal squamous cell carcinoma (OPSCC). The use of proton beam therapy (PBT) in the unilateral setting decreases the dose to the contralateral neck and organs at risk. This study aims to evaluate contralateral recurrences in patients who received ipsilateral PBT. MethodsWe evaluated the Proton Collaborative Group database for patients treated with PBT for head and neck squamous cell carcinoma between the years 2015–2020 at 12 institutions. Dosimetric analysis was performed in five cases. ResultsOur analysis included 41 patients that received ipsilateral PBT with a mean follow-up of 14.7 months. 37% patients (n = 15) were treated for recurrent disease, and 63% (n = 26) were treated for de novo disease. Oropharyngeal sites included tonsillar fossa (n = 30) and base of tongue (n = 11). The median dose and BED delivered were 69.96 CGE and 84 Gy, respectively. Eight (20%) patients experienced at least one grade 3 dysphagia (n = 4) or esophagitis (n = 4) toxicity. No grade ≥ 4 toxicities were reported. There was one (2.4%) failure in the contralateral neck. The 1-year locoregional control was 88.9% and the freedom from distant metastasis was 95.5% (n = 2). The dosimetric analysis demonstrated similar ipsilateral level II cervical nodal region doses, whereas contralateral doses were higher with photon plans, mean: 15.5 Gy and 0.7CGE, D5%: 25.1 Gy and 6.6CGE. ConclusionsOur series is the first to report outcomes for patients with OPSCC receiving unilateral PBT. The contralateral neck failure rate was excellent and comparable to failure rates with photon irradiation.

Multi-Institutional Experience of Proton Therapy for Osteosarcoma in the Proton Collaborative Group (PCG) Prospective Registry

To report on the utilization of dose-escalated radiotherapy, acute toxicities, and survival following definitive proton therapy (PT) for osteosarcoma patients in a prospective multi-institutional study. Data on patients with osteosarcoma treated with definitive intent PT were queried from the Proton Collaborative Group (PCG) prospective registry. A similar query was performed on an institutional database with IRB approval. Overall survival rates were calculated by Kaplan-Meier. Toxicities were scored using CTCAE v4.0. Forty osteosarcoma patients across 9 institutions received definitive intent PT between 2011-2021 and met the eligibility criteria. Median age was 32 years (Range: 6-86 years). Median PT dose was 66.6 GyRBE (Range: 50.4-80.0 GyRBE); 38 patients received proton therapy alone, whereas 2 received combined proton/photon therapy. Seventeen (42.5%) patients received doses ≥70 GyRBE. Median follow-up was 3.1 years (Range: 0.9-10.5 years). One-year and three-year overall survival rates were 83.5% and 59.1%, respectively, with 14 deaths due to disease. Excluding skin desquamation and alopecia, 22 patients (55.0%) developed any acute grade 2+ toxicity, and 5 patients (12.5%) developed any grade 3 toxicities. No acute grade 4-5 toxicities were reported. The most frequent grade 2+ non-skin toxicities were fatigue (37.5%), anorexia/weight loss (17.5%), mucositis/esophagitis (22.5%), pain (20.0%), and nausea/vomiting (10.0%). The most frequent grade 3 toxicities were anorexia/weight loss (5.0%), mucositis/esophagitis (5.0%), and neurologic symptoms (5.0%). In this multi-institutional study, 42.5% of osteosarcoma patients treated with PT received doses between 70-80 Gy, with 12.5% experiencing any grade 3 toxicity. Long-term outcomes for disease control, late toxicity, and quality-of-life are needed to more fully assess the benefits and risks of dose-escalated radiotherapy in this radioresistant tumor. The authors plan to assess the outcomes of osteosarcoma patients treated with dose-escalated radiotherapy for unresectable or gross residual disease in future studies.

Multi-Institutional Experience of Proton Therapy for Rhabdomyosarcoma and Ewing Sarcoma in the Proton Collaborative Group (PCG) Prospective Registry

To report on outcomes, acute toxicities, and the use of dose-escalation with proton therapy (PT) in patients with rhabdomyosarcoma and Ewing sarcoma in a prospective multi-institutional registry (PCG). Data on patients with primary rhabdomyosarcoma and Ewing sarcoma treated with definitive PT (defined as ≥45 Gy) were queried from the PCG registry. A similar query was performed of our institutional database with IRB approval. Overall survival rates were calculated by Kaplan-Meier. Toxicities were scored using CTCAE v4.0. A total of 354 patients across 10 institutions (203 rhabdomyosarcoma, 151 Ewing sarcoma) met the eligibility criteria. Median age was 9 years (Interquartile Range: 5-15). Median dose was 50.4 GyRBE for rhabdomyosarcoma patients (Range: 45-66 GyRBE) and 55.8 GyRBE for Ewing sarcoma patients (Range: 45-66 GyRBE). Median follow-up was 2.4 years (Range 0.3-12.3 years). Two-year overall survival rates were 81.1% (95% CI: 73.7%-88.5%) for rhabdomyosarcoma and 79.1% (95% CI: 71.7%-86.2%) for Ewing sarcoma. The Table lists the prescription doses delivered by tumor histology; 28.1% of rhabdomyosarcoma and 21.9% of Ewing sarcoma patients, respectively, received dose-escalated radiotherapy (defined as >50.4 Gy for rhabdomyosarcoma and >55.8 Gy for Ewing sarcoma). Excluding alopecia and skin desquamation, 153 patients (43.2%) developed any acute grade 2+ non-hematologic toxicity, while 49 patients (13.8%) developed one or more grade 3 toxicities. The most common grade 3 toxicities were anorexia/weight loss (7.3%), pain (7.3%) mucositis/esophagitis (4.8%), and nausea/vomiting (3.1%). One grade 4 toxicity (esophagitis) and no deaths were reported during treatment. In this multi-institutional prospective registry, 28.1% of rhabdomyosarcoma and 21.9% of Ewing sarcoma patients received dose-escalated PT, with 13.8% of patients developing grade 3 toxicities. Long-term outcomes for disease control and late toxicity and anticipated cooperative group trial results are needed to fully assess the benefits and risks of dose-escalated radiotherapy for these tumors.

Treatment of Thymoma and Thymic Carcinoma with Proton Beam Therapy: Outcomes from the Proton Collaborative Group Prospective Registry

Given the generally long natural history of thymic malignancies, proton beam therapy (PBT) is advocated to minimize the risk of long-term toxicities to mediastinal organs. Adverse events (AE) and long-term clinical outcomes for this population have not been well-characterized. The Proton Collaborative Group registry (NCT01255748), a multi-institutional prospective database of academic and community proton centers in the US, was queried for patients with thymomas and thymic carcinomas treated with PBT. Patients with recurrent/metastatic disease, non-thymic histology, received either prior or palliative radiotherapy (dose < 40 Gy RBE) were excluded. Overall survival (OS) and local control (LC) were estimated using Kaplan-Meier methods. A total of 97 patients were identified in the PCG registry. After applying relevant exclusion criteria, 70 patients from 12 proton centers treated from 2011-2021 were included for analysis. Median follow-up length was 16 months. Median age was 58.5 years (IQR 46-63), and 60% were female. 81.4% had a diagnosis of thymoma, and 18.6% thymic carcinoma. 59 patients underwent surgical resection. 11 were treated with definitive PBT, of which 5 received concurrent chemotherapy. Median dose was 54 Gy RBE (range 41.4 - 70 Gy RBE), median number of fractions was 30 (range 21 - 38). 73.4% received pencil beam scanning and 23% uniform scanning PBT. Treatment was overall well-tolerated: a single patient developed grade 4 pneumonitis. Grade 3 AEs were seen in 3 patients - dyspnea, anorexia, and heart failure. Highest grade toxicity experienced was grade 2 for 47.1% and grade 1 for 42.9% of patients. 3-year overall survival (OS) was 82.6% for the entire cohort. 3-year OS was 94% for resected/adjuvant cohort and 35.6% in the non-surgical/definitive cohort. 3-year local control (LC) was 91.7% for the entire cohort. By surgery/margin status, 3-year LC was 96.8% in patients with close or negative margins (a single failure in a patient with close margins), whereas 3-year LC was 55.1% for patients with positive margins/unresectable disease. Thymic malignancies treated with PBT appear to have favorable outcomes, especially in the adjuvant setting, in this cohort representing the largest series of such patients.

Relative thoracic changes from supine to upright patient position: A proton collaborative group study.

This study presents position changes of a few radiotherapy-relevant thoracic organs between upright and typical supine patient orientations. Using tools in a commercial treatment planning system (TPS), key anatomical distances were measured for four-dimensional CT data sets and analyzed for the two patient orientations. The uncertainty was calculated as the 95% confidence interval (CI) on the relative difference for each of the four analyzed changes for upright relative to supine, as follows: the distance of the bottom of the heart to the top of the sternum, it changed +2.6% or +4mm (95% CI [+0.30%,+4.9%]); the distance of the center of the C3 vertebra to the backrest, it changed +29% (95% CI [+22%,+36%]); the contoured left and right lungs increased their volumes respectively: +17% (95% CI [+12%,+21%]) for the left, and +9.9% (95% CI [+4.1%,+16%]); and lastly, the distance from the top of the sternum to the top of the liver, but its uncertainty far exceeded the average change by a factor of two. This last result is therefore inconclusive, the others show that with 95% confidence that a change in internal positions is observed for lung volumes and heart position that could be important for upright treatments.

Proton therapy for high-risk prostate cancer: Results from the Proton Collaborative Group PCG 001-09 prospective registry trial.

Data for proton therapy in high-risk prostate cancer (HRPC) are limited. Using the Proton Collaborative Group prospective registry, we evaluated outcomes for HRPC patients treated with proton therapy. A totsl of 605 men with localized HRPC treated with proton therapy from 8/2009 to 3/2019 at nine institutions were selected. Outcomes examined included freedom from progression (FFP), metastasis free survival (MFS), overall survival (OS), and toxicity. Multivariable cox/binomial regression models were used to assess predictors of FFP and toxicity. Median age was 71 years. Gleason grade groups 4 (49.4%) and 5 (31.7%) were most common, as were clinical stage T1c (46.1%) and cT2 (41.3%). The median pretreatment prostate specific antigen (PSA) was 9.18 and median International Prostate Symptom Score (IPSS) was 6. Androgen deprivation therapy was given in 63.6%. Median dose was 79.2 GyE in 44 fractions. Pelvic lymph nodes were treated in 58.2% of cases. Pencil beam scanning was used in 54.5%, uniform scanning in 38.8%, and a rectal spacer in 14.2%. At a median followup of 22 months, the 3- and 5-year FFP were 90.7% and 81.4%, respectively. Five-year MFS and OS were 92.8% and 95.9%, respectively. Independent correlates of FFP included Gleason ≥8, PSA > 10, and cT2 (all p < 0.05). No grade 4 or 5 adverse events were reported. There were 23 (5%) grade 2 and 0 grade 3 gastrointestinal events. Prevalence of late grade 3, late grade 2, acute grade 3, and acute grade 2 genitourinary toxicity was 1.7%, 5.8%, 0%, and 21.8%, respectively. Prevalence of grade 2 and 3 erectile dysfunction at 2 years was 48.4% and 8.4%, respectively. In the largest series published to date, our results suggest early outcomes using proton therapy for HRPC are encouraging for both safety and efficacy. Further evaluation is needed to determine if an advantage exists to use protons over other radiation techniques in this population.

Clinical outcomes and toxicities of 100 patients treated with proton therapy for chordoma on the proton collaborative group prospective registry

BackgroundWe present efficacy and toxicity outcomes among patients with chordoma treated on the Proton Collaborative Group prospective registry. MethodsConsecutive chordoma patients treated between 2010–2018 were evaluated. One hundred fifty patients were identified, 100 had adequate follow-up information. Locations included base of skull (61%), spine (23%), and sacrum (16%). Patients had a performance status of ECOG 0–1 (82%) and median age of 58 years. Eighty-five percent of patients underwent surgical resection. The median proton RT dose was 74 Gy (RBE) (range 21–86 Gy (RBE)) using passive scatter proton RT (PS-PBT) (13%), uniform scanning proton RT (US-PBT) (54%) and pencil beam scanning proton RT (PBS-PBT) (33%). Rates of local control (LC), progression-free survival (PFS), overall survival (OS) and acute and late toxicities were assessed. Results2/3-year LC, PFS, and OS rates are 97%/94%, 89%/74%, and 89%/83%, respectively. LC did not differ based on surgical resection (p = 0.61), though this is likely limited by most patients having undergone a prior resection. Eight patients experienced acute grade 3 toxicities, most commonly pain (n = 3), radiation dermatitis (n = 2), fatigue (n = 1), insomnia (n = 1) and dizziness (n = 1). No grade ≥ 4 acute toxicities were reported. No grade ≥ 3 late toxicities were reported, and most common grade 2 toxicities were fatigue (n = 5), headache (n = 2), CNS necrosis (n = 1), and pain (n = 1). ConclusionsIn our series, PBT achieved excellent safety and efficacy outcomes with very low rates of treatment failure. CNS necrosis is exceedingly low (<1%) despite the high doses of PBT delivered. Further maturation of data and larger patient numbers are necessary to optimize therapy in chordoma.

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.

Reirradiation with Proton Therapy for Recurrent Malignancies of the Esophagus and Gastroesophageal Junction: Results of the Proton Collaborative Group Multi-Institutional Prospective Registry Trial

<h3>Purpose/Objective(s)</h3> Salvage treatment options for locoregional recurrences of esophageal/gastroesophageal junction (GEJ) cancers previously treated with radiation therapy are limited. Photon reirradiation, which has historically been employed as one such modality in these cases, is associated with high toxicity rates. Proton therapy provides superior normal tissue sparing and may permit safer dose escalation during reirradiation. However, there are limited current data on proton reirradiation. Thus, we sought to evaluate patient outcomes and toxicities after proton reirradiation for recurrent esophageal/GEJ cancers. <h3>Materials/Methods</h3> The Proton Collaborative Group prospective, multi-institutional registry was queried for patients with recurrent esophageal/GEJ cancers retreated with proton therapy. All patients included in this analysis received prior photon radiotherapy, either in the definitive or adjuvant setting. Baseline demographics, treatment details, outcomes, and acute toxicities (CTCAEv4.0) were evaluated. Local control (LC) and overall survival (OS) were estimated using the Kaplan-Meier method, with the time to event determined from the start of reirradiation for LC and the time from first recurrence for OS. <h3>Results</h3> Thirty-one patients retreated between May 2012 and October 2020 were analyzed. The median age was 68 years (range 40-87 years), and most were male (74%) and non-Hispanic Caucasian (81%) with adenocarcinoma (55%). The initial stages of their cancers were as follows: T1 6%, T2 10%, T3 77%, unknown 6%; N0 29%, N+ 67%, unknown 3%; stage I 0%, IIA 3%, IIB 23%, IIIA 29%, IV 10%, unknown 35%. During their first course of radiation therapy, they received a median of 49.5 Gy (10.8-66.0 Gy) in 6-33 fractions. Additionally, 71% received concurrent chemotherapy and 35% underwent resection. The median time to recurrence was 22.1 months (3.7–134.1 months). Proton reirradiation was primarily delivered using uniform scanning/passive scattering (n=18) or pencil beam scanning (n=12) to a median dose of 46.17 Gy relative biological effectiveness (RBE) (25.2 – 72.1 Gy(RBE)) in 12- fractions, given daily or twice daily, and 71% (n=22) received concurrent chemotherapy. Median follow-up from reirradiation completion was 9.2 months (0-63.3). OS at 6 and 12 months were 93.5% and 60.1%, respectively, and LC at 6 and 12 months were 80.5% and 69.0%, respectively. Grade 3 acute toxicities occurred in 13% (anorexia=1; dyspnea=1; dysphagia=1; cough=1; esophagitis=2) and grade 2 in 45% (most commonly, fatigue=7). No grade 4 or 5 acute events occurred. Additionally, zero patients developed an esophageal fistula or stricture, or experienced esophageal necrosis. <h3>Conclusion</h3> In this multi-institutional cohort, proton reirradiation for locoregionally recurrent esophageal/GEJ cancers resulted in high rates of early local control with acceptable acute toxicities. Longer follow-up to assess for late adverse events and additional prospective investigations are warranted.

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

PurposeProton 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 MaterialsThis 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). ResultsThirty-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. ConclusionAt 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.

Proton Therapy Outcomes for Head and Neck Cutaneous Melanoma: Proton Collaborative Group Analysis.

PurposeReports of proton beam therapy (PBT) utilization for cutaneous melanoma of the head and neck (HN) region is virtually non-existent. This study reports on the efficacy and acute toxicities of PBT for primary HN cutaneous melanoma.Materials and MethodsWe queried the prospectively collected, multi-institutional Proton Collaborative Group registry for all consecutive patients with HN cutaneous melanoma receiving PBT from May 2010 to December 2019. Kaplan-Meier methods were used to estimate overall survival (OS), progression free survival (PFS), and local regional recurrence free survival (LRFS). Toxicity was reported per CTCAE version 4.0.ResultsA total of 8 patients were identified with a median age of 69 (range, 37-88). All patients (100%) underwent surgery followed with postoperative PBT. There were 3 patients (37.5%) with T3 or T4 disease and 4 (50%) with N2 or N3 disease. The median radiation dose was 46 GyRBE (range, 27-70) and median dose per fraction was 2.4 GyRBE (range, 2.0-6.0) with the most common dose fractionation being 44 or 48 GyRBE in 20 fractions (n = 4). At a median follow-up of 40.1 months (range, 1.6-62.4) the 1 and 3 year OS rates were 85.7% and 35.7%, respectively. The median PFS was 25.40 months (95% CI, 2.53-58.70) while PFS at 1 year and 3 years was 85.7% and 35.7%, respectively. LRFS was 100% at 1 year and 85.7% at 3 years. Five of the 8 patients developed distant metastases, of which 3 received immunotherapy. Acute G2+ and G3+ toxicities occurred in 5 of 8 patients and 2 of 8 patients, respectively. G3 toxicities included radiation dermatitis (n = 1) and immunotherapy-related rash (n = 1). No G4+ toxicities were reported.ConclusionSingle modality PBT for HN melanomas in the definitive setting provides effective and durable local control rates with tolerable acute toxicity. Distant failure remains the primary pattern of failure.

Dose-escalated proton therapy with elective nodal irradiation and concomitant chemotherapy for unresectable, borderline resectable, or medically inoperable pancreatic cancer: a phase II trial.

To report outcomes of a phase II single-institution trial of dose-escalated proton radiotherapy with elective nodal irradiation (ENI) and concomitant chemotherapy for patients with unresectable, borderline resectable, or medically inoperable pancreatic adenocarcinoma. Patients received 40.5 GyRBE in 18 fractions to the gross disease and elective nodal volumes followed by 22.5 GyRBE as a 10-fraction boost to the gross disease for a cumulative dose of 63 GyRBE over 28 fractions. Oral capecitabine (1,000 mg taken orally twice daily) was given on radiation treatment days. The primary objective of this study was to improve the proportion surviving to at least 1 year from the historical rate of 50% to 75%. Secondary objectives included assessing gastrointestinal (GI) toxicity and weight loss during treatment, and evaluating the safety of subsequent surgical resection. This single-institution study was closed to accrual early after the opening of the multicenter PAN009-18 trial by the Proton Collaborative Group (PCG), which follows a similar protocol. At enrollment, 10 (67%) patients had unresectable disease, 3 (20%) had borderline-resectable disease, and 2 (13%) refused surgery. All 15 patients successfully completed radiation therapy as prescribed. With regard to toxicity, a single patient experienced grade 3 nausea requiring cessation of capecitabine, which ultimately resolved by treatment completion. The median percentage weight loss during treatment was -3.0% (range, -9.6% to +12.0%). Two (13%) initially borderline patients ultimately underwent R0 resection: their total operating room times were 267 and 410 minutes, and blood loss was 700 and 400 mL, respectively. Neither patient experienced intraoperative or postoperative complications. Both were discharged on postoperative day 6. The median follow-up was 0.93 years (range, 0.21 to 2.14 years). The 1-year overall survival (OS) rate was 47%. Three enrolled patients are currently alive: 2 with no evidence of disease and 1 with stable disease. The primary objective of 1-year OS of 75% was not reached. Proton therapy was well-tolerated. Patients undergoing surgery did not experience operative or perioperative complications, suggesting that patients with borderline resectable or even resectable disease may benefit from neoadjuvant proton therapy. The PCG will test this premise as patients accrue to the multicenter PAN009-18 trial. NCT02598349.

Chemoradiation with Hypofractionated Proton Therapy in Stage II-III Non-Small Cell Lung Cancer: A Proton Collaborative Group Phase 2 Trial

Hypofractionated radiation therapy has been safely implemented in the treatment of early-stage non-small cell lung cancer (NSCLC) but not locally advanced NSCLC owing to prohibitive toxicities with photon therapy. Proton therapy, however, may allow for safe delivery of hypofractionated radiation therapy. We sought to determine whether hypofractionated proton therapy with concurrent chemotherapy improves overall survival. The Proton Collaborative Group conducted a phase 1/2 single-arm nonrandomized prospective multicenter trial from 2013 through 2018. We received consent from 32 patients, of whom 28 were eligible for on-study treatment. Patients had stage II or III unresectable NSCLC (based on the 7th edition of the American Joint Committee on Cancer's staging manual) and received hypofractionated proton therapy at 2.5 to 4 Gy per fraction to a total 60 Gy with concurrent platin-based doublet chemotherapy. The primary outcome was 1-year overall survival comparable to the 62% reported for the Radiation Therapy Oncology Group (RTOG) 9410 trial. The trial closed early owing to slow accrual, in part, from a competing trial, RTOG 1308. Median patient age was 70 years (range, 50-86 years). Patients were predominantly male (n=20), White (n=23), and prior smokers (n=27). Most had stage III NSCLC (n=22), 50% of whom had adenocarcinoma. After a median follow-up of 31 months, the 1- and 3-year overall survival rates were 89% and 49%, respectively, and progression-free survival rates were 58% and 32%, respectively. No acute grade ≥3 esophagitis occurred. Only 14% developed a grade ≥3 radiation-related pulmonary toxic effect. Hypofractionated proton therapy delivered at 2.5 to 3.53 Gy per fraction to a total 60 Gy with concurrent chemotherapy provides promising survival, and additional examination through larger studies may be warranted.

Definitive Reirradiation of Intracranial Neoplasms With Intensity-Modulated Proton Therapy: Early Outcomes and Toxicities

Management of recurrent or new primary intracranial tumors in a previously irradiated area presents a significant challenge. For inoperable patients, reirradiation (re-RT) may provide the best chance for prolonged disease control. However, given concerns for excessive morbidity, re-RT with definitive doses (≥ 45 Gy) is not commonly prescribed. Given its dosimetric advantages over photon-based techniques, we hypothesize that intensity-modulated proton therapy (IMPT) may permit safer dose escalation in the re-RT setting. This study examined feasibility of definitive brain re-RT in a cohort of patients treated with IMPT.The electronic medical record of a pencil beam scanning-only proton center was queried for adult patients who developed in-field recurrence or new primary tumor for which they subsequently received definitive-dose (≥ 45 Gy) re-RT. Dosimetric and clinical characteristics were collected. Survival was examined using the Kaplan-Meier method. Toxicities were assessed using the Common Terminology Criteria for Adverse Events v.5.0.Between August 2019 and February 2021, 62 consecutive patients received intracranial re-RT with IMPT. Twelve (18%) were treated to ≥ 45 Gy and were included for analysis. Median age at the time of re-RT was 51.5 years, and 83% of patients had an Eastern Cooperative Oncology Group score of 0. The most common histologies were oligodendroglioma (n = 4), astrocytoma (n = 3), and meningioma (n = 3). Median time from prior radiation course to IMPT was 9.4 years (range, 3.6 - 42.0 years). IMPT was delivered with conventional fractionation in 92% and hypofractionation in 8% of cases. Median equivalent dose in 2 Gy fractions (EQD2) for initial course was 53.1 Gy. Median EQD2 for the re-RT course was 54.0 Gy. The entire re-RT course was completed as planned by 83% of patients. Patients received concurrent temozolomide (66%) or temozolomide plus bevacizumab plus nivolumab (8%). Dosimetric data from the initial course were available for 58% of patients. The median cumulative (initial radiation and re-RT combined) maximum EQD2 doses were 116.8 Gy to brain, 66.2 Gy to brainstem, 67.7 Gy to chiasm, 72.0 Gy to ipsilateral optic nerve, and 54.5 Gy to contralateral optic nerve. At a median follow-up of 5.4 months, 58.3% (n = 7) of patients developed grade 2 toxicities including fatigue (n = 6) and alopecia (n = 5). No grade ≥3 neurotoxicities were documented. Median progression free survival was 7 months; median overall survival was not reached.Early results of our single-institution experience suggest a potential for safe intracranial re-RT with definitive-dose IMPT for select patients. Based on these findings, we are activating a prospective study to identify subsets of patients who are best fit for IMPT re-RT and formulate optimal dose regimens and normal tissue composite dose constraints.L. Maillie: None. S. Sharma: None. J.T. Yang: None. N. Ohri: Consultant; Merck, AstraZeneca. I.J. Choi: Employee; New York Proton Center. Travel Expenses; Varian; National Association of Proton Therapy, Proton Collaborative Group. Oversee and provide guidance for new and existing research protocols, ensure best practices for organization research endeavors.; Proton Collaborative Group. B.K. Yeh: None. R.H. Press: None. A. Chhabra: None. M.K. Garg: None. Y. Yamada: Consultant; University of Wollongong. Speaker's Bureau; Varian Medical Systems, BrainLab. Medical advisor; Chordoma Foundation. C.B. Simone: Employee; New York Proton Center. Honoraria; Varian Medical System, Novocure. Travel Expenses; Varian Medical System; Proton Collaborative Group (PCG), Annals of Palliative Medicine, American Society for Radiation Oncology. S. Lazarev: None.

Impact of Time Interval Between Diagnostic and Planning MRI on Tumor Volume and Anatomic Displacement for Brain Metastases Undergoing Stereotactic Radiosurgery

Stereotactic radiosurgery (SRS) is increasingly used in brain metastasis patients. However, the impact of the timing on tumor volume change and tumor anatomical displacement between the diagnostic and treatment planning imaging is not well studied.Consecutive patients diagnosed with brain metastases and treated with SRS between July, 2017 and June, 2020 were evaluated. Only patients who underwent an institutionally standardized diagnostic MRI (MRI-1) and a treatment planning MRI (MRI-2) with identical imaging parameters were included. The impact of histology, inter-scan interval, lesion location, volume and size were evaluated on final lesion size, volume and anatomic displacement. Correlations were assessed using Kendall's rank correlation. The Kruskal Wallis rank sum test was used for all other comparisons.We included 101 eligible patients (531 lesions) with median inter-scan interval of 8 days (range: 1-42); 50% were NSCLC and 25% breast cancer. The three most common locations of lesions were the frontal (181 lesions, 34%), temporal (96, 18%), cerebellar (91, 17%) lobes. Median MRI-1 diameter and volume were 0.50 cm (Range: 0.23-0.89 cm) and 0.06 cm3 (Range: 0.01-4.62 cm3), respectively. Median percentage change in lesion diameter and volume were +9.5% (Range: -8.4% to +61.2%) and +20% (Range: -20% to +200%), respectively. Overall, there was a statistically significant change in percent tumor volume change between MRI-1 to MRI-2 (P = 0.01). Directional displacements exceeded 1 mm in 18 (3%) lesions in right to left (RL), 28 (5%) superior to inferior (SI), and 25 (4.7%) anterior to posterior (AP) directions. Overall, 355 (67%) lesions had any displacement in at least 1 direction between MRI-1 and MRI-2 and 205 (38%) in all 3 directions. Median lesion centroid displacement was 0.48 mm (0.10-3.09 mm) and was larger than 1 mm in 66 (12%) lesions. Differences were also observed across tumor histologies (P = 0.01); melanoma brain metastases had the largest magnitude changes. Tumor displacement also differed across various histologies with largest displacement in renal cell carcinoma metastases (P < 0.001). Magnitude of displacement was also significantly associated with tumor location (P = 0.03) with the largest displacement in parietal lobe lesions. Across all lesions, there was a difference in tumor size change in patients treated on corticosteroids (P = 0.01).Volumetric and positional changes can occur during the planning process for SRS and are histology and location specific. Additional analyses are key to understanding the impact of each of these variables, corticosteroids, and systemic therapy to better understand and model tumor dynamics.T. Kutuk: None. R.P. Tolakanahalli: None. A. Williams: None. M.C. Tom: Research Grant; Blue Earth Diagnostics. J.D. Vadhan: None. H. Appel: None. M.D. Hall: Research Grant; Florida Department of Health; Proton Collaborative Group (PCG) Executive Council. D. Wieczorek: None. S.D. Davis: None. M.W. McDermott: Consultant; Stryker, Diende. V. Siomin: None. M.D. Chuong: Research Grant; ViewRay, AstraZeneca. Honoraria; ViewRay, Sirtex, Accuray. Speaker's Bureau; ViewRay, Sirtex, Accuray. Advisory Board; ViewRay, Advanced Accelerator Applications. Travel Expenses; ViewRay, AstraZeneca, Accuray; Particle Therapy Cooperative Group. Manages the operations and activities within the proton center; Miami Cancer. M.P. Mehta: None. A. Gutierrez: Honoraria; ViewRay, Elekta. R. Kotecha: None.

A Phase II Trial of Escalated Dose Proton Radiotherapy With Elective Nodal Irradiation and Concomitant Chemotherapy for Patients with Unresectable, Borderline Resectable or Medically Inoperable Pancreatic Adenocarcinoma

To report outcomes of a phase II single-institution trial of escalated dose proton therapy with elective nodal irradiation and concomitant chemotherapy for patients with unresectable, borderline resectable, or medically inoperable pancreatic adenocarcinoma.Patients were treated to 40.5 GyE in 18 fractions to gross disease and elective nodal volumes with a 22.5 GyE in a 10-fraction boost to gross disease, for a total of 63 GyE. Oral capecitabine (1000mg orally twice a day) was given on radiation treatment days. The primary objective of this study was to achieve a 1-year overall survival rate of 75%. Secondary objectives included assessing gastrointestinal toxicity and patient quality of life during treatment, as well as evaluating the safety of subsequent surgical resection. The single-institution study was closed to accrual once opened as the multicenter PAN009-18 trial by the Proton Collaborative Group.At enrollment, 10 (67%) of patients were unresectable, 3 (20%) were borderline, and 2 (13%) refused surgery. Thirteen patients (87%) had previously received chemotherapy. All 15 patients successfully completed radiation therapy as prescribed. With regard to toxicity, a single patient experienced grade 3 nausea requiring cessation of capecitabine, which ultimately resolved at treatment completion. All other patients received concurrent capecitabine for the duration of their radiotherapy treatment. Radiation did not result in any other significant gastrointestinal toxicity during or after treatment. Median percentage weight loss during treatment was -3.0% (-9.6% - +12.0%). Two (13%) initially borderline patients ultimately underwent resection. Their total operating room times were 267 and 410 minutes; blood loss was 700mL and 400mL. Neither patient experienced intraoperative or postoperative complications. Both patients were discharged on postoperative day six. Median follow-up was 0.93 years (0.21-2.14). The 1-year overall survival rate was 47%. Three enrolled patients are currently alive: 2 with no evidence of disease and 1 with stable disease. One patient died of intercurrent disease. Of the remaining 11 patients who died following tumor recurrence, only 3 failed locally, with the remaining 8 failing distantly.Protocol therapy was well-tolerated. Patients undergoing surgery did not experience operative or perioperative complications - suggesting that patients with borderline resectable or even resectable disease may benefit from this regimen as neoadjuvant therapy. The Proton Collaborative Group will test this premise as patients accrue to the multicenter PAN009-18 trial.