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Belal Abousaida,1,* Danushka Seneviratne,1,* Bradford S Hoppe,1 Stephen J Ko,1 Aroumougame Asaithamby,2 Francis A Cucinotta,3 Jessica M Kirwan,4 Kabir Mody,5 Beau Toskich,6 Jonathan B Ashman,7 Christopher L Hallemeier,8 Sunil Krishnan1 1Department of Radiation Oncology, Mayo Clinic Florida, Jacksonville, FL, USA; 2Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA; 3School of Integrated Health Sciences, University of Las Vegas, Las Vegas, NV, USA; 4Department of Radiation Oncology, University of Florida, Gainesville, FL, USA; 5Division of Hematology and Medical Oncology, Department of Internal Medicine, Mayo Clinic Florida, Jacksonville, FL, USA; 6Division of Interventional Radiology, Department of Radiology, Mayo Clinic Florida, Jacksonville, FL, USA; 7Department of Radiation Oncology, Mayo Clinic Arizona, Phoenix, AZ, USA; 8Department of Radiation Oncology, Mayo Clinic Rochester, Rochester, MN, USA*These authors contributed equally to this workCorrespondence: Sunil KrishnanDepartment of Radiation Oncology, Mayo Clinic Florida, Jacksonville, FL, 32224, USATel +1 713-202-8063Email krishnan.sunil@mayo.eduAbstract: Localized hepatocellular carcinoma (HCC) that is unresectable and non-transplantable can be treated by several liver-directed therapies. External beam radiation therapy (EBRT) is an increasingly accepted and widely utilized treatment modality in this setting. Accelerated charged particles such as proton beam therapy (PBT) and carbon ion radiation therapy (CIRT) offer technological advancements over conventional photon radiotherapy. In this review, we summarize the distinct advantages of CIRT use for HCC treatment, focusing on physical and biological attributes, and outline dosimetric and treatment planning caveats. Based on these considerations, we posit that HCC may be among the best indications for use of CIRT, as it allows for maximizing tumoricidal doses to the target volume while minimizing the dose to the organs at risk.Keywords: carbon ion therapy, hepatocellular carcinoma, hypofractionation

Abstract: Unirradiated patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) who undergo anti-CD19 chimeric antigen receptor T-cell therapy (CART) have a predominant localized pattern of relapse, the significance of which is heightened in individuals with limited/localized disease before CART. This study reports on the outcomes of patients with R/R NHL and limited (<5 involved sites) disease bridged with or without radiotherapy. A multicenter retrospective review of 150 patients with R/R NHL who received CART with <5 disease sites before leukapheresis was performed. Bridging treatment, if any, was administered between leukapheresis and CART infusion. Study end points included relapse-free survival (RFS), event-free survival (EFS), and overall survival. Before CART infusion, 48 patients (32%) received bridging radiotherapy (BRT), and 102 (68%) did not. The median follow-up was 21 months. After CART infusion, BRT patients had higher objective response (92% vs 78%; P = .046) and sustained complete response rates (54% vs 33%; P = .015). Local relapse in sites present before CART was lower in the BRT group (21% vs 46%; P = .003). BRT patients had improved 2-year RFS (53% vs 44%; P = .023) and 2-year EFS (37% vs 34%; P = .039) compared with patients who did not receive BRT. The impact of BRT was most prominent in patients who had ≤2 pre-CART involved disease sites, with 2-year RFS of 62% in patients who received BRT compared with 42% in those who did not (P = .002). BRT before CART for patients with limited (<5 involved disease sites) R/R NHL improves response rate, local control, RFS, and EFS without causing significant toxicities., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Abstract: Immune checkpoint inhibitors (ICIs) have demonstrated remarkable response rates in relapsed or refractory Hodgkin lymphoma (HL). Still, most patients eventually progress. Patterns of progression after ICIs are not well described and are essential to defining the role of local therapies in combination with ICIs. We identified patients who received ICIs for HL between 2013 and 2022. Fludeoxyglucose-18 positron emission tomography (FDG-PET) before initiating ICI and at progression on/after ICI were reviewed, and areas of active HL were recorded. An exploratory analysis of treatable progression included patients with ≤5 sites of disease on pre-ICI FDG-PET and progression only at pre-ICI sites. Ninety patients were identified; 69 had complete records, and of these, 32 (52%) had relapsed at ICI initiation, 17 (25%) were refractory, and 16 (23%) received ICI as first-line therapy. Forty-five of 69 patients had ≤5 sites of disease (limited) on pre-ICI FDG-PET. Patients with >5 sites of disease had a higher risk of progression, and every site of disease >5 sites conferred an additional 1.2x higher chance of progression. At a median follow-up of 4.0 years, 41 of 69 patients had progressed on/after ICIs (cumulative incidence 66.4%), and of these, 22 of 41 patients progressed only at pre-ICI sites (cumulative incidence 39.4%). In an exploratory analysis, the cumulative incidence of a treatable progression among 45 patients with limited disease was 34%. The cumulative incidence of any progression among this cohort was 58.9%. More than one-third of patients with limited disease before ICIs experienced progression only at pre-ICI sites of disease. These patients could be candidates for radiation during or after ICIs., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Anti-CD19 chimeric antigen receptor T-cell therapy (CART) has revolutionized the outcomes of relapsed and/or refractory B-cell non-Hodgkin lymphoma. However, CART is still limited by its availability, toxicity, and response durability. Not all patients make it to the CART infusion phase due to disease progression. Among those who receive CART, a significant number of patients experience life-threatening cytokine release syndrome toxicity, and less than half maintain a durable response with the majority relapsing in pre-existing sites of disease present pre-CART. Radiation therapy stands as a promising peri-CART and salvage treatment that can improve the outcomes of these patients. Evidence suggests that bridging radiotherapy prior to CART controls the disease during the manufacturing period, augments response rates and local control, cytoreduces/debulks the disease and decreases the severity of cytokine release syndrome, and may prolong disease-free intervals and survival especially in patients with bulky disease. Consolidative radiotherapy for residual post-CART disease alters the pattern of relapse and improves local recurrence-free and progression-free survivals. Salvage radiotherapy for relapsed post-CART disease has favorable survival outcomes when delivered comprehensively for patients with limited relapsed disease and palliates symptoms for patients with diffuse relapsed disease. The biology of the disease during the peri-CART period is poorly understood, and further studies investigating the optimal timing and dosing of radiation therapy (RT) are needed. In this review, we tackle the most significant challenges of CART, review and propose how RT can help mitigate these challenges, and provide The Mayo Clinic experts' approach on incorporating RT with CART., (© 2023 Wiley Periodicals LLC.)

Majority of non-Hodgkin lymphoma (NHL) patients who achieve partial response (PR) or stable disease (SD) to CAR T-cell therapy (CAR T) on day +30 progress and only 30% achieve spontaneous complete response (CR). This study is the first to evaluate the role of consolidative radiotherapy (cRT) for residual fluorodeoxyglucose (FDG) activity on day +30 post- CAR T in NHL. We retrospectively reviewed 61 patients with NHL who received CAR T and achieved PR or SD on day +30. Progression-free survival (PFS), overall survival (OS), and local relapse-free survival (LRFS) were assessed from CAR T infusion. cRT was defined as comprehensive - treated all FDG-avid sites - or focal. Following day +30 positron emission tomography scan, 45 patients were observed and 16 received cRT. Fifteen (33%) observed patients achieved spontaneous CR, and 27 (60%) progressed with all relapses involving initial sites of residual FDG activity. Ten (63%) cRT patients achieved CR, and four (25%) progressed with no relapses in the irradiated sites. The 2-year LRFS was 100% in the cRT sites and 31% in the observed sites (P<0.001). The 2-year PFS was 73% and 37% (P=0.025) and the 2-year OS was 78% and 43% (P=0.12) in the cRT and observation groups, respectively. Patients receiving comprehensive cRT (n=13) had superior 2- year PFS (83% vs. 37%; P=0.008) and 2-year OS (86% vs. 43%; P=0.047) compared to observed or focal cRT patients (n=48). NHL patients with residual FDG activity following CAR T are at high risk of local progression. cRT for residual FDG activity on day +30 post-CAR T appears to alter the pattern of relapse and improve LRFS and PFS.

Skull-base chordoma and chondrosarcoma are rare radioresistant tumors treated with surgical resection and/or radiotherapy. Because of the established dosimetric and biological benefits of heavy particle therapy, we performed a systematic and evidence-based review of the clinical outcomes of patients with skull-base chordoma and chondrosarcoma treated with carbon ion radiotherapy (CIRT). A literature review was performed using a MEDLINE search of all articles to date. We identified 227 studies as appropriate for review, and 24 were ultimately included. The published data illustrate that CIRT provides benchmark disease control outcomes for skull-base chordoma and chondrosarcoma, respectively, with acceptable toxicity. CIRT is an advanced treatment technique that may provide not only dosimetric benefits over conventional photon therapy but also biologic intensification to overcome mechanisms of radioresistance. Ongoing research is needed to define the magnitude of benefit, patient selection, and cost-effectiveness of CIRT compared to other forms of radiotherapy.

Children, adolescents, and young adults (CAYA) with relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) without complete metabolic response (CMR) before autologous hematopoietic cell transplantation (auto-HCT) have poor survival outcomes. CheckMate 744, a phase 2 study for CAYA (aged 5-30 years) with R/R cHL, evaluated a risk-stratified, response-adapted approach with nivolumab plus brentuximab vedotin (BV) followed by BV plus bendamustine for patients with suboptimal response. Risk stratification was primarily based on time to relapse, prior treatment, and presence of B symptoms. We present the primary analysis of the standard-risk cohort. Data from the low-risk cohort are reported separately. Patients received 4 induction cycles with nivolumab plus BV; those without CMR (Deauville score >3, Lugano 2014) received BV plus bendamustine intensification. Patients with CMR after induction or intensification proceeded to consolidation (high-dose chemotherapy/auto-HCT per protocol). Primary end point was CMR any time before consolidation. Forty-four patients were treated. Median age was 16 years. At a minimum follow-up of 15.6 months, 43 patients received 4 induction cycles (1 discontinued), 11 of whom received intensification; 32 proceeded to consolidation. CMR rate was 59% after induction with nivolumab plus BV and 94% any time before consolidation (nivolumab plus BV ± BV plus bendamustine). One-year progression-free survival rate was 91%. During induction, 18% of patients experienced grade 3/4 treatment-related adverse events. This risk-stratified, response-adapted salvage strategy had high CMR rates with limited toxicities in CAYA with R/R cHL. Most patients did not require additional chemotherapy (bendamustine intensification). Additional follow-up is needed to confirm durability of disease control. This trial was registered at www.clinicaltrials.gov as #NCT02927769., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Surgical treatment of pelvic sarcoma involving the bone is the standard of care but is associated with several sequelae and reduced functional quality of life (QOL). Treatment with photon and proton radiotherapy is associated with relapse. Carbon ion radiotherapy (CIRT) may reduce both relapse rates and treatment sequelae. The PROSPER study is a tricontinental, nonrandomized, prospective, three-arm, pragmatic trial evaluating treatments of pelvic sarcoma involving the bone. Patients aged at least 15 years are eligible for inclusion. Participants must have an Eastern Cooperative Oncology Group Performance Status score of two or less, newly diagnosed disease, and histopathologic confirmation of pelvic chordoma, chondrosarcoma, osteosarcoma, Ewing sarcoma with bone involvement, rhabdomyosarcoma (RMS) with bone involvement, or non-RMS soft tissue sarcoma with bone involvement. Treatment arms include (1) CIRT ( n = 30) delivered in Europe and Asia, (2) surgical treatment with or without adjuvant radiotherapy ( n = 30), and (3) proton therapy ( n = 30). Arms two and three will be conducted at Mayo Clinic campuses in Arizona, Florida, and Minnesota. The primary end point is to compare the 1-year change in functional QOL between CIRT and surgical treatment. Additional comparisons among the three arms will be made between treatment sequelae, local control, and other QOL measures.

Primary adenoid cystic carcinoma of the trachea (ACC-T) is an extremely rare cancer of the central bronchial system. It is usually associated with an excellent prognosis. Surgery is the standard treatment for resectable tumors, while radiation therapy is used for unresectable tumors or medically inoperable patients. Radiation therapy can be delivered with photons, protons, or carbon ion therapy. In this report, we review a case of unresectable ACC-T in a middle-aged female patient who was treated with radiation therapy and review the potential benefits of the different types of radiation therapy., Competing Interests: Conflicts of Interest: Bradford S. Hoppe, MD, MPH, is an Associate Editor of the International Journal of Particle Therapy. The authors have no additional conflicts of interest to disclose., (©Copyright 2023 The Author(s).)

Purpose: When treating esophageal cancer with radiation therapy, it is critical to limit the dose to surrounding structures, such as the lung and/or heart, as much as possible. Proton radiation therapy allows a reduced radiation dose to both the heart and lungs, potentially reducing the risk of cardiopulmonary toxicity. Here, we report disease control, survival, and toxicity outcomes among patients with esophageal cancer treated with proton radiation therapy and concurrent chemotherapy (chemoradiation therapy; CRT) with or without surgery., Materials and Methods: We enrolled 17 patients with thoracic esophageal carcinoma on a prospective registry between 2010 and 2021. Patients received proton therapy to a median dose of 50.4-GyRBE (range, 50.4-64.8) in 1.8-Gy fractions.Acute and late toxicities were graded per the Common Terminology Criteria for Adverse Events, version 4.0 (US National Cancer Institute, Bethesda, Maryland). In addition, disease control, patterns of failure, and survival outcomes were collected., Results: Nine patients received preoperative CRT, and 8 received definitive CRT. Overall, 88% of patients had adenocarcinoma, and 12% had squamous cell carcinoma. With a median follow-up of 2.1 years (range, 0.5-9.4), the 3-year local progression-free, disease-free, and overall survival rates were 85%, 66%, and 55%, respectively. Two patients (1 with adenocarcinoma and 1 with squamous cell carcinoma) recurred at the primary site after refusing surgery after a complete clinical response to CRT. The most common acute nonhematologic and hematologic toxicities, respectively, were grades 1 to 3 esophagitis and grades 1 to 4 leukopenia, both affecting 82% of patients. No acute cardiopulmonary toxicities were observed in the absence of surgical resection. Reagarding surgical complications, 3 postoperative cardiopulmonary complications occurred as follows: 1 grade 1 pleural effusion, 1 grade 3 pleural effusion, and 1 grade 2 anastomotic leak. Two severe late CRT toxicities occurred: 1 grade 5 tracheoesophageal fistula and 1 grade 3 esophageal stenosis requiring a feeding tube., Conclusion: Proton radiation therapy is a safe, effective treatment for esophageal cancer with increasing evidence supporting its role in reducing cardiopulmonary toxicity., Competing Interests: Conflicts of Interest: Bradford Hoppe, MD, MPH, and Perry Johnson, PhD, are Associate Editors of the International Journal of Particle Therapy. All other authors have no relevant conflicts of interest to disclose., (©Copyright 2022 The Author(s).)

Purpose: Combined modality therapy with multiagent chemotherapy and radiation therapy is a standard treatment option for aggressive mediastinal non-Hodgkin lymphomas (AMNHLs); however, concerns regarding acute and late radiation toxicities have fueled an effort to use systemic therapy alone. The use of proton therapy (PT) is a promising treatment option, but there are still limited data regarding clinical outcomes with this treatment modality. In this Particle Therapy Cooperative Group lymphoma subcommittee collaboration, we report outcomes of patients with AMNHL treated with pencil-beam scanning PT or double-scatter PT after chemotherapy., Methods and Materials: This was a multi-institutional retrospective observational cohort study of patients with AMNHL treated with PT following chemotherapy between 2011 and 2021. Progression-free survival (PFS), local recurrence-free survival (LRFS), and overall survival (OS) rates were estimated with the Kaplan-Meier method. PT toxicity was graded by the Common Terminology Criteria for Adverse Events version 5.0. A 2-tailed paired t test was used for dosimetric comparisons., Results: Twenty-nine patients were identified. With a median follow-up time of 4.2 years (range, 0.2-8.9 years), the estimated 5-year PFS for all patients was 93%, 5-year LRFS was 96%, and estimated 5-year OS was 87%. Maximum acute grade 1 (G1) toxicities occurred in 18 patients, and 7 patients had maximum G2 toxicities. No G3+ radiation-related toxicities were observed. Average mean lung dose and lung V20 Gy were lower for patients treated with pencil-beam scanning PT compared with double-scatter PT ( P  = .016 and .006, respectively), while patients with lower mediastinal disease had higher doses for all evaluated dosimetric heart parameters., Conclusions: PT after chemotherapy for patients with AMNHL resulted in excellent outcomes with respect to 5-year PFS, LRFS, and OS without high-grade toxicities. Future work with larger sample sizes is warranted to further elucidate the role of PT in the treatment of AMNHL., (© 2022 Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.)

Children's Oncology Group (COG) trial AHOD0431 reduced systemic therapy and used response-adapted involved-field radiotherapy (IFRT) in early-stage pediatric classic Hodgkin lymphoma. We investigated the impact of positron emission tomographic response after 1 cycle (PET1) and on IFRT outcomes and pattern of relapse. Patients in AHOD0431 underwent PET1 response assessment after AVPC (doxorubicin, vincristine, prednisone, and cyclophosphamide). "Rapid early responders" (RERs) had a negative PET1 (PET1-); "slow early responders" (SERs) had a positive PET1 (PET1+). Patients with a partial response by computed tomographic and functional imaging after 3 chemotherapy cycles received 21-Gy IFRT, whereas complete responders had no IFRT. Progression-free survival (PFS) was evaluated for RERs and SERs treated with or without IFRT. Recurrence sites were initial, new, or both. Relapses involving initial sites were characterized as "within the PET1+ site" or "initially involved but outside the PET1+ site." Median follow-up was 118 months. The 10-year PFS rate among RERs was 96.6% with IFRT and 84.1% without IFRT (P = .10), whereas SERs were 80.9% with IFRT and 64.0% without IFRT (P = .03). Among 90 RERs who did not receive IFRT, all 14 relapses included an initial site. Among 45 SERs receiving no IFRT, 14 of 16 relapses were in the initial site (9 PET1+ site only). Among 58 patients receiving IFRT, 5 of 10 relapses were in the PET1+ site. After 3 cycles of AVPC alone, RERs showed favorable results. Conversely, SERs had unfavorable outcomes with AVPC alone, although they improved with 21-Gy IFRT. RT remains an important component of treatment for SERs. This trial was registered at www.clinicaltrials.gov as #NCT00302003., (© 2022 by The American Society of Hematology.)

Multiple clinical trials have assessed de-escalation strategies from combined modality therapy (CMT) to chemotherapy-alone for the treatment of early-stage classical Hodgkin lymphoma (cHL), confirming similar outcomes. The application of these data to the real-world is limited, however. We conducted a retrospective, multicenter cohort study comparing CMT vs chemotherapy-alone in patients with early-stage cHL (stage IA-IIB) treated between January 2010 and December 2020. Positron emission tomography (PET) scans after chemotherapy cycle 2 (PET2) were independently reviewed by a nuclear radiologist (Deauville score ≥4, positive; ≤3, negative). Patient outcomes were compared by using an intention-to-treat analysis. Among 125 patients (CMT, n = 63; chemotherapy-alone, n = 62) with a median follow-up of 59.8 months (95% CI, 48.6-71.0), no differences in overall survival were observed (5-year overall survival, CMT 98.0% vs chemotherapy-alone 95.1%; log-rank test, P = .38). However, there was reduced progression-free survival (PFS) with chemotherapy-alone among all patients (2-year PFS, CMT 95.1% vs chemotherapy-alone 75.3%; log-rank test, P = .005) and in those with bulky (n = 43; log-rank test, P < .001), unfavorable (n = 81; log-rank test, P = .002), or PET2-positive (n = 15; log-rank test, P = .02) disease. No significant differences in PFS were seen for patients with non-bulky (log-rank test, P = .35), favorable (log-rank test, P = .62), or PET2-negative (log-rank test, P = .19) disease. Based on our real-world experience, CMT seems beneficial for patients with early-stage cHL, especially those with PET2-positive and unfavorable disease. Chemotherapy-alone regimens can lead to comparable outcomes for patients with favorable, non-bulky, or PET2-negative disease. We conclude that although results seen in clinical trials are replicated in certain patient subgroups, other subgroups not fitting trial criteria do poorly when radiotherapy is excluded., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objectives: Cost-effectiveness analyses (CEAs) may provide useful data to inform management decisions depending on the robustness of a model's input parameters. We sought to determine the level of heterogeneity in health state utility values, transition probabilities, and cost estimates across published CEAs assessing primarily radiotherapeutic management strategies in prostate cancer., Methods: We conducted a systematic review of prostate cancer CEAs indexed in MEDLINE between 2000 and 2018 comparing accepted treatment modalities across all cancer stages. Search terms included "cost effectiveness prostate," "prostate cancer cost model," "cost utility prostate," and "Markov AND prostate AND (cancer OR adenocarcinoma)." Included studies were agreed upon. A Markov model was designed using the parameter estimates from the systematic review to evaluate the effect of estimate heterogeneity on strategy cost acceptability., Results: Of 199 abstracts identified, 47 publications were reviewed and 37 were included; 508 model estimates were compared. Estimates varied widely across variables, including gastrointestinal toxicity risk (0%-49.5%), utility of metastatic disease (0.25-0.855), intensity-modulated radiotherapy cost ($21 193-$61 996), and recurrence after external-beam radiotherapy (1.5%-59%). Multiple studies assumed that different radiotherapy modalities delivering the same dose yielded varying cancer control rates. When using base estimates for similar parameters from included studies, the designed model resulted in 3 separate acceptability determinations., Conclusions: Significant heterogeneity exists across parameter estimates used to perform CEAs evaluating treatment for prostate cancer. Heterogeneity across model inputs yields variable conclusions with respect to the favorability and cost-effectiveness of treatment options. Decision makers are cautioned to review estimates in CEAs to ensure they are up to date and relevant to setting and population., (Copyright © 2021 ISPOR–The International Society for Pharmacoeconomics and Outcomes Research, Inc. Published by Elsevier Inc. All rights reserved.)

Data comparing outcomes in prostate cancer and factors affecting treatment choice are sparse. To inform the design of a comparative effectiveness clinical trial, we engaged patients in developing a 28-question survey about decision making on treatment and research participation and dispersed it among men greater than or equal to 50 years of age. The 1046 respondents ranked long-term clinical outcomes as most important in making treatment decisions, specific functional outcomes as slightly less important, and duration, location, and cost of treatment as least important. Treatment choice was strongly impacted by side effect profile. Responses to whether the subject would agree to participation in a randomized trial between two types of radiation with minimal differences in outcomes were "yes" in 15%, "no" in 39%, and "undecided" in 46%. Responses to whether the subject would agree to participation in a randomized trial between two treatment durations with similar outcomes were yes in 36%, no in 24%, and undecided in 40%. Findings suggest many potential patients have strong treatment preferences and are averse to randomization, particularly when outcomes of importance may be affected. Patient engagement in study design and novel nonrandomized trial designs may offer a path to increase clinical trial success., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Radiation therapy (RT) is an integral component of potentially curative management of esophageal cancer (EC). However, RT can cause significant acute and late morbidity due to excess radiation exposure to nearby critical organs, especially the heart and lungs. Sparing these organs from both low and high radiation dose has been demonstrated to achieve clinically meaningful reductions in toxicity and may improve long-term survival. Accruing dosimetry and clinical evidence support the consideration of proton beam therapy (PBT) for the management of EC. There are critical treatment planning and delivery uncertainties that should be considered when treating EC with PBT, especially as there may be substantial motion-related interplay effects. The Particle Therapy Co-operative Group Thoracic and Gastrointestinal Subcommittees jointly developed guidelines regarding patient selection, treatment planning, clinical trials, and future directions of PBT for EC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chuong, Hallemeier, Li, Zhu, Zhang, Tryggestad, Yu, Yang, Choi, Kang, Liu, Knopf, Meijers, Molitoris, Apisarnthanarax, Giap, Hoppe, Lee, Chang, Simone and Lin.)

Purpose: Early stage (stages I-II) classical Hodgkin lymphoma (cHL) is a highly curable disease typically diagnosed in adolescents and young adults (AYAs). Proton therapy can also reduce the late toxicity burden in this population, but data on its comparative efficacy with photon radiotherapy in this population are sparse. We assessed outcomes in AYAs with cHL in a multi-institution retrospective review., Materials and Methods: We identified 94 patients aged 15 to 40 years with stages I and II cHL treated with radiotherapy as part of their initial treatment between 2008 and 2017. We used Kaplan-Meier analyses and log-rank testing to evaluate survival differences between groups of patients., Results: A total of 91 patients were included in the analysis. The 2-year progression-free survival (PFS) rate was 89%. Of the 12 patients who experienced progression after radiotherapy, 4 occurred out-of-field, 2 occurred in-field, and 6 experienced both in- and out-of-field progression. There was no significant difference in 2-year PFS among AYA patients by radiotherapy dose received (≥ 30 Gy, 91%; < 30 Gy, 86%; P  = .82). Likewise, there was no difference in 2-year PFS among patients who received either proton or photon radiotherapy (proton, 94%; photon, 83%; P  = .07)., Conclusion: Our cohort of AYA patients had comparable outcomes regardless of radiotherapy dose or modality used. For patients with significant risk of radiation-induced late effects, proton therapy is a reasonable treatment modality., Competing Interests: Conflicts of Interest: Nancy P. Mendenhall, MD, and Bradford S. Hoppe, MD, MPH are Editor-in-Chief and Associate Editor of the International Journal of Particle Therapy, respectively. In the past 3 years, Raymond B. Mailhot Vega, MD, MPH, received an unrestricted educational grant from IBA. The other authors have no relevant conflicts of interest to disclose., (©Copyright 2021 The Author(s).)

Purpose: This study compares reduced (<27 Gy) to standard dose (≥30 Gy) radiation therapy (RT) in the treatment of gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (gMALT lymphoma)., Methods and Materials: Forty-two patients with stage I or II disease were retrospectively reviewed. Response to RT was assessed with endoscopy after RT. Complete response rate (CR), freedom from treatment failure, and overall survival (OS) were calculated., Results: All patients were stage I (n = 40) or II (n = 2). All patients had residual biopsy proven gMALT lymphoma before RT. Twenty-six patients (61.9%) were treated with standard dose RT, 30 to 36 Gy, and 16 (38.1%) with the reduced dose RT, 23.5 to 27 Gy. The median follow-up was 29.5 months (range, 6-85). Thirty-six patients (86%) achieved complete response (CR), and 6 patients (14%) achieved partial response (PR). The complete response rate (CR) at the first endoscopic assessment, median time of 3 months, was 81% (95% confidence interval, 0.61%-0.93%) for standard RT, and 94% (confidence interval, 0.69%-0.99%) for reduced RT. Among CR patients, one patient had locally relapsed disease at 50 months. The 1-year overall survival (OS) was 100% in both groups. The 1-year freedom from treatment failure (FFTF) was 100% in the reduced RT group and 92% in the standard RT group. The 2-year FFTF and OS of the whole cohort were 92% and 96%, respectively. There was no significant difference in the OS, FFTF, and CR between the 2 treatment groups ( P  = .38, P  = .18, and P  = .267, respectively). For toxicity, the mean liver dose and the mean V20 heart dose were significantly lower in the reduced RT group ( P <.001 and P  = .001, respectively). However, incidence and severity of reported toxicities were similar between the 2 groups., Conclusions: Reduced dose RT (23.5-27 Gy) achieved excellent complete response rates with minimal toxicity, comparable with standard dose RT (30-36 Gy), for gMALT., (© 2021 The Author(s).)

Proton therapy is a promising but controversial treatment in the management of prostate cancer. Despite its dosimetric advantages when compared with photon radiation therapy, its increased cost to patients and insurers has raised questions regarding its value. Multiple prospective and retrospective studies have been published documenting the efficacy and safety of proton therapy for patients with localized prostate cancer and for patients requiring adjuvant or salvage pelvic radiation after surgery. The Particle Therapy Co-Operative Group (PTCOG) Genitourinary Subcommittee intends to address current proton therapy indications, advantages, disadvantages, and cost effectiveness. We will also discuss the current landscape of clinical trials. This consensus report can be used to guide clinical practice and research directions., Competing Interests: Conflicts of Interest: Nancy P. Mendenhall, MD, and William M. Mendenhall, MD, are Editor-in-Chief and Operating Editor, respectively, of the International Journal of Particle Therapy (IJPT). Bradford S. Hoppe, MD, MPH, and Neha Vapiwala, MD, are IJPT Associate Editors. The authors have no additional conflicts of interest to disclose., (©Copyright 2021 The Author(s).)

Purpose: Postprostatectomy radiation improves disease control, but limited data exist regarding outcomes, toxicities, and patient-reported quality of life with proton therapy., Method and Materials: The first 102 patients who were enrolled on an outcome tracking protocol between 2006 and 2017 and treated with double-scattered proton therapy after prostatectomy were retrospectively reviewed. Eleven (11%) received adjuvant radiation, while 91 (89%) received salvage radiation. Seventy-four received double-scattered proton therapy to the prostate bed only. Twenty-eight received a double-scattered proton therapy prostate-bed boost after prostate-bed and pelvic-node treatment. Eleven adjuvant patients received a median dose of 66.6 GyRBE (range, 66.0-70.2). Ninety-one salvage patients received a median dose of 70.2 GyRBE (range, 66.0-78.0). Forty-five patients received androgen deprivation therapy for a median 9 months (range, 1-30). Toxicities were scored using Common Terminology Criteria for Adverse Events v4.0 criteria, and patient-reported quality-of-life data were reviewed., Results: The median follow-up was 5.5 years (range, 0.8-11.4 years). Five-year biochemical relapse-free and distant metastases-free survival rates were 72% and 91% for adjuvant patients, 57% and 97% for salvage patients, and 57% and 97% overall. Acute and late grade 3 or higher genitourinary toxicity rates were 1% and 7%. No patients had grade 3 or higher gastrointestinal toxicity. Acute and late grade 2 gastrointestinal toxicities were 5% and 2%. The mean values and SDs of the International Prostate Symptom Score, International Index of Erectile Function, and Expanded Prostate Cancer Index Composite bowel function and bother were 7.5 (SD = 5.9), 10.2 (SD = 8.3), 92.8 (SD = 11.1), and 91.2 (SD = 6.4), respectively, at baseline, and 12.1 (SD = 9.1), 10.1 (SD = 6.7), 87.3 (SD = 18), and 86.7 (SD = 13.8) at the 5-year follow-up., Conclusion: High-dose postprostatectomy proton therapy provides effective long-term biochemical control and freedom from metastasis, with low acute and long-term gastrointestinal and genitourinary toxicity., Competing Interests: Conflicts of Interest: Nancy P. Mendenhall, MD, and William M. Mendenhall, MD, are Editor-in-Chief and Operating Editor of the International Journal of Particle Therapy, respectively. Bradford S. Hoppe, MD, MPH, is an Associate Editor of the International Journal of Particle Therapy and a Scientific Consultant for Merck & Co., Inc., and Bristol-Myers Squibb, (©Copyright 2021 The Author(s).)

Purpose: Due to the excellent outcomes with image-guided stereotactic body radiotherapy for patients with early-stage non-small cell lung cancer (NSCLC) and the low treatment-related toxicities using proton therapy (PT), we investigated treatment outcomes and toxicities when delivering hypofractionated PT., Materials and Methods: Between 2009 and 2018, 22 patients with T1 to T2 N0M0 NSCLC (45% T1, 55% T2) received image-guided hypofractionated PT. The median age at diagnosis was 72 years (range, 58-90). Patients underwent 4-dimensional computed tomography simulation following fiducial marker placement, and daily image guidance was performed. Nine patients (41%) were treated with 48 GyRBE in 4 fractions for peripheral lesions, and 13 patients (59%) were treated with 60 GyRBE in 10 fractions for central lesions. Patients were assessed for CTCAEv4 toxicities with computed tomography imaging for tumor assessment. The primary endpoint was grade 3 to 5 toxicity at 1 year., Results: The median follow-up for all patients was 3.5 years (range, 0.2-8.8 years). The overall survival rates at 3 and 5 years were 81% and 49%, respectively. Cause-specific survival rates at 3 and 5 years were 100% and 75%, respectively. The 3-year local, regional, and distant control rates were 86%, 85%, and 95%, respectively. Four patients experienced in-field recurrences between 18 and 45 months after treatment. One patient (5%) developed a late grade 3 bronchial stricture requiring hospitalization and stent., Conclusion: Image-guided hypofractionated PT for early-stage NSCLC provides promising local control and long-term survival with a low likelihood of toxicity. Regional nodal and distant relapses remain a problem., Competing Interests: Conflicts of Interest: Bradford S. Hoppe, MD, MPH, is an associate editor of the International Journal of Particle Therapy and a scientific consultant for Merck & Co., Inc., and Bristol-Myers Squibb., (©Copyright 2020 The Author(s).)

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon histologic variant, and the optimal treatment of stage I-II NLPHL is undefined. We conducted a multicenter retrospective study including patients ≥16 years of age with stage I-II NLPHL diagnosed from 1995 through 2018 who underwent all forms of management, including radiotherapy (RT), combined modality therapy (CMT; RT+chemotherapy [CT]), CT, observation after excision, rituximab and RT, and single-agent rituximab. End points were progression-free survival (PFS), freedom from transformation, and overall survival (OS) without statistical comparison between management groups. We identified 559 patients with median age of 39 years: 72.3% were men, and 54.9% had stage I disease. Median follow-up was 5.5 years (interquartile range, 3.1-10.1). Five-year PFS and OS in the entire cohort were 87.1% and 98.3%, respectively. Primary management was RT alone (n = 257; 46.0%), CMT (n = 184; 32.9%), CT alone (n = 47; 8.4%), observation (n = 37; 6.6%), rituximab and RT (n = 19; 3.4%), and rituximab alone (n = 15; 2.7%). The 5-year PFS rates were 91.1% after RT, 90.5% after CMT, 77.8% after CT, 73.5% after observation, 80.8% after rituximab and RT, and 38.5% after rituximab alone. In the RT cohort, but not the CMT cohort, variant immunoarchitectural pattern and number of sites >2 were associated with worse PFS (P < .05). Overall, 21 patients (3.8%) developed large-cell transformation, with a significantly higher transformation rate in those with variant immunoarchitectural pattern (P = .049) and number of involved sites >2 (P = .0006). OS for patients with stage I-II NLPHL was excellent after all treatments., (© 2020 by The American Society of Hematology.)

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Since the relapse rate of DLBCL to frontline chemoimmunotherapy and salvage autologous hematopoietic cell transplant is high, CD19-directed chimeric antigen receptor (CAR) T-cell therapy was adopted. Given the time interval needed for CAR T cells to be manufactured (3-5 weeks) and the aggressiveness of these relapsed/refractory lymphomas, some patients do not make it to the CAR T-cell infusion phase. This calls for a bridging therapy to control, debulk, and sensitize the disease during this period. Radiation therapy can serve this purpose and has shown promising results in some studies. Proton therapy, compared to standard radiation therapy, in some locations, can reduce the radiation dose to the organs at risk, which may lead to fewer side effects for patients with lymphomas. Thus, we hypothesize that proton therapy may serve as a promising bridging strategy to CAR T-cell therapy for some patients., Competing Interests: Conflicts of Interest: The authors have no relevant conflicts of interest to disclose., (©Copyright 2020 The Author(s).)

Background: Local relapse is a predominant form of recurrence among pediatric patients with Hodgkin lymphoma (PHL). Although PHL radiotherapy doses have been approximately 20 Gy, adults with Hodgkin lymphoma receiving 30 to 36 Gy experience fewer in-field relapses. We investigated the dosimetric effect of such a dose escalation to the organs at risk (OARs)., Materials and Methods: Ten patients with PHL treated with proton therapy to 21 Gy involved-site radiation therapy (ISRT 21Gy ) were replanned to deliver 30 Gy by treating the ISRT to 30 Gy (ISRT 30Gy ), delivering 21 Gy to the ISRT plus a 9-Gy boost to postchemotherapy residual volume (rISRT boost ), and delivering 30 Gy to the residual ISRT target only (rISRT 30Gy ). Radiation doses to the OARs were compared., Results: The ISRT 30Gy escalated the dose to the target by 42% but also to the OARs. The rISRT boost escalated the residual target dose by 42%, and the OAR dose by only 17% to 26%. The rISRT 30Gy escalated the residual target dose by 42% but reduced the OAR dose by 25% to 46%., Conclusion: Boosting the postchemotherapy residual target dose to 30Gy can allow for dose escalation with a slight OAR dose increase. Treating the residual disease for the full 30Gy, however, would reduce the OAR dose significantly compared with ISRT 21Gy . Studies should evaluate these strategies to improve outcomes and minimize the late effects., Competing Interests: Conflicts of Interest: Bradford S. Hoppe, MD, MPH, and Nancy P. Mendenhall, MD, are Associate Editor and Editor-in-Chief of the International Journal of Particle Therapy, respectively. In addition, Dr Hoppe is a scientific consultant for Merck & Co, Inc, and Bristol-Myers Squibb. Raymond B. Mailhot Vega, MD, MPH, has received a travel grant from IBA., (©Copyright 2020 The Author(s).)

Purpose: Acute and late toxicity from chemotherapy, targeted therapy, and radiation therapy can cause significant morbidity among survivors of Hodgkin lymphoma (HL), including pulmonary dysfunction. Improved dosimetry may influence pulmonary function tests (PFTs), an objective and clinically significant measure of pulmonary toxicity. The present study investigates the impact of proton therapy on PFTs among HL survivors., Patients and Methods: We monitored 15 patients with mediastinal HL who were enrolled in an institutional HL trial. All patients were treated with combination chemotherapy plus involved-node proton therapy. All patients were to undergo PFTs before starting treatment and at approximately 6 and 12 months after completing proton therapy., Results: Twelve patients were included in the analysis and 3 excluded. The mean forced vital capacity (FVC) was 96.2% ± 16.5% (mean ± SD) predicted at baseline and 98.2% ± 19.4% predicted at 12 months. The mean forced expiratory volume in 1 second (FEV 1 ) was 96.7% ± 17.2% predicted at baseline and 97% ± 15.1% predicted at 12 months. The mean FEV 1 /FVC ratio was 99.5 ± 8.29 at baseline and 97.8 ± 8.02 at 12 months. The mean diffusing capacity of the lung for carbon monoxide was 81.4% ± 18.4% predicted at baseline and 95.7% ± 23.5% predicted at 12 months., Conclusion: No unexpected changes were observed to the lungs as illustrated through follow-up PFTs. Long-term follow-up and validation in a larger cohort are needed., Competing Interests: Conflicts of Interest: Bradford S. Hoppe, MD, MPH, is an Associate Editor of The International Journal of Particle Therapy. The authors have no other conflicts of interest to disclose., (© Copyright 2019 International Journal of Particle Therapy.)

Purpose: Treatment success in lung cancer is no longer restricted to objective measures of disease-specific outcomes and overall survival alone but now incorporates treatment morbidity and subjective quality of life (QoL). This study reports how lung cancer patients, survivors, and caregivers define treatment success and prioritize treatment decisions., Materials and Methods: An online survey with both ranking and free-response questions was administered among lung cancer survivors and caregivers. Responses were used to evaluate treatment priorities, perceptions of treatment success based on Eastern Cooperative Oncology Group (ECOG) Performance Status, and troublesomeness of treatment-related toxicities., Results: Among 61 respondents (29 lung cancer survivors, 28 caregivers of survivors, and 4 who were both survivors and caregivers), cancer cure was the highest priority when making treatment decisions for 74.5% of respondents, with QoL during and after treatment ranking second and third. Seventy percent of respondents felt that treatment morbidity resulting in complete dependence on others and spending the entire day confined to bed or chair would represent unsuccessful treatment. Requiring oxygen use was ranked as a very or extremely troublesome treatment toxicity by 64%, followed by shortness of breath (62%), fatigue (49%), chronic cough (34%), and appetite loss (30%). Even with remission, a 3- to 7-day hospital admission for pneumonia during treatment was deemed an unsuccessful outcome by 30%., Conclusion: This study highlights the importance of physicians discussing in detail with their lung cancer patients their desires and goals. Accounting for factors like expected performance status following treatment, troublesomeness of treatment toxicities, and hospitalization rates may help guide treatment decisions., Competing Interests: Conflicts of Interest: In the past 24 months, Jennifer C. King, PhD, has served on advisory boards for AbbVie, GRAIL, Foundation Medicine, and Tesaro, and has accepted speaking honoraria from AstraZeneca and Genentech. Bradford S. Hoppe, MD, MPH, is on the scientific council for Merck & Co, Inc, and Bristol Myers Squibb. Bradford S. Hoppe, MD, MPH, is an Associate Editor of the International Journal of Particle Therapy. Nancy P. Mendenhall, MD, serves as Editor-in-Chief of the International Journal of Particle Therapy., (© Copyright 2019 The Author(s).)

Purpose: Metastatic non-small cell lung cancer (NSCLC) is associated with an exceedingly poor prognosis. Recent advances in immunotherapy offer promise in enhancing overall survival (OS) in these patients. Preclinical evidence suggests that radiotherapy (RT), especially when offered in a high-dose per fraction hypofractionated RT (HRT) as in stereotactic ablative body radiotherapy (SABR), may augment the efficacy of immunotherapy. We aimed to assess the role of RT in patients with metastatic NSCLC receiving immunotherapy in a national hospital-based database., Methods: Using the National Cancer Database (NCDB), we identified 6,383 patients treated with immunotherapy for metastatic NSCLC and 170,479 patients treated with RT but without immunotherapy. Patients receiving fractional doses of at least 5 Gy were designated as having received HRT, doses <5 Gy/fraction, were deemed standard fractionation (SFRT). The Kaplan-Meier analysis and proportional hazards modeling were performed, and propensity scores were generated via an inverse weighting method to evaluate the impact of RT on OS in this cohort., Results: The median follow-up of the cohort is 12 months. Patients receiving HRT had numerically improved 1-year OS (59.0%) compared to those not receiving RT (55.7%), however this was not statistically significant (hazard ratio = 0.9, p = 0.22). Patients receiving non-HRT RT did substantially worse than those receiving no RT. Immunotherapy improved OS in patients receiving RT regardless of fraction size., Conclusions: This hypothesis-generating retrospective analysis suggests that patients treated with immunotherapy with or without HRT in the upfront treatment of metastatic NSCLC experience similar survival. Further prospective evaluation of this combination should be undertaken in an attempt to maximize survival in this challenging disease., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Conventional radiation therapy (RT) has produced unprecedented cure rates in patients with Hodgkin's lymphoma (HL) but exposed large volumes of nontargeted tissue to radiation (integral dose)., Objective: Our goal was to report the effects of integral radiation dose on health outcomes in patients with at least 20 years of potential follow-up time., Methods and Materials: We reviewed the medical records of 365 patients who were treated with RT for HL between 1965 and 1995. All patients were confirmed to have received primary RT with curative intent at our institution for de novo HL. Serious adverse events were classified as HL progression or death, grade ≥3 treatment- or staging-related acute or late effects, second malignancies, or cardiovascular events., Results: The minimum potential follow-up time was 20 years, and the actual median follow-up time 22 years (range, <1-49 years) for all patients and 27 years (range, 5-49 years) for surviving patients. The overall survival rates at 5, 10, 20, 30, and 40 years were 86%, 76%, 64%, 44%, and 27%, respectively. The observed-to-expected ratio for second malignancy was 3.6 (95% confidence interval, 2.9-4.4). Grade ≥3 cardiovascular events occurred in 31% of all patients (n = 112). At the time of the most recent follow up, serious adverse events occurred in 70% of the entire cohort (n = 256) and 58% (n = 103), 77% (n = 103), and 93% (n = 50) among those with a potential 20, 30, and 40 years of follow up, respectively., Conclusions: With increased survivorship, the long-term impact of the integral radiation dose may result in clinically significant adverse events, which suggests the importance of surveillance and affirms advances in both chemotherapy and RT that minimize the integral dose in future patients with HL., (© 2019 The Authors.)

Background: Radiation-induced tumor immunity (RITI) influences primary tumor growth and development of metastases in preclinical cancer models with conventional radiotherapy. Antigen-specific immune responses have also been shown for prostate cancer treated with radiotherapy. We examined whether RITI can be induced in patients with non-small cell lung cancer (NSCLC) following proton radiotherapy., Methods: Pre- and post-radiotherapy plasma samples from 26 patients with nonmetastatic NSCLC who received radiotherapy between 2010 and 2012 were evaluated by western blotting for IgG and IgM bands to assess RITI response to tumor antigens from lung cancer cell lines. Statistical analysis was used to evaluate any correlation among IgG or IgM and clinical outcomes., Results: Twenty-one patients received proton therapy at 2 GyRBE/fraction (n = 17) or 6-12 Gy/fraction (n = 4); five received photon therapy at 2-2.5 GyRBE/fraction. Compared with the pretreatment baseline, new IgG or IgM binding was detected in 27% and 50% of patients, respectively. New IgG bands were detected in the 25-37 kD, 50-75 kD, and 75-100 kD ranges. New IgM bands were detected in the 20-25 kD, 25-37 kD, 37-50 kD, 50-75 kD, and 75-100 kD ranges. There was no difference in IgG and/or IgM RITI response in patients treated with photons versus protons, or in patients who received SBRT compared to standard fractionation (P > 0.05). There was no difference in overall survival, metastasis-free survival, or local control based on IgG and/or IgM RITI response (P > 0.05)., Conclusion: RITI can be induced in patients with NSCLC through upregulated IgG and/or IgM. RITI response was not associated with proton versus photon therapy or with clinical outcomes in this small cohort and should be examined in a larger cohort in future studies., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Objective: To help guide individualized treatment, we sought to identify baseline predictive factors that impact long-term erectile function following high-dose image-guided radiotherapy (HD-IGRT)., Methods: Potent men with localized prostate cancer treated with radiotherapy alone were enrolled in an institutional review board-approved prospective cohort study. Men received HD-IGRT as primary treatment of prostate cancer. Patient-reported inventories were used to assess erectile function at baseline, 6 months, 2 years, and 5 years after treatment. Long-term potency rates were compared to validated models, and baseline factors were used to create a novel, internally validated nomogram for predicting long-term function., Results: 1,159 men were treated with HD-IGRT. Among 676 men who were potent at baseline and did not receive hormone therapy, the potency rates at 6 months, 2 years, and 5 years were 81%, 68%, and 61%. Recursive partitioning categorized patients into 3 groups based on two factors: baseline response to EPIC Q57 (ability to have an erection) and pre-existing heart disease. At 5 years, the most favorable group reported "very good" on Q57 and had an 80% potency rate (n = 137; p = 0.83); the intermediate group reported "good" on Q57 and had no baseline cardiac disease with a 62% potency rate (n = 145; p = 0.86); and the remaining poor risk group had a 37% potency rate (n = 117; p = 0.19)., Conclusions: Patient-reported pretreatment sexual function and comorbidities enables stratification and prediction of erectile function. EPIC subset questions with baseline comorbidities may potentially serve as a quick and practical clinical tool for predicting sexual survivorship., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: The radiation dose to specific substructures of the heart may be more critical than the dose to the whole heart. Yet, these substructures are sensitive to intrafractional motion from breathing and cardiac motion, which can affect their dose-volume histograms. We sought to investigate intrafractional motion of the heart and its substructures among free-breathing patients undergoing radiation for mediastinal lymphoma or lung cancer., Methods and Materials: After institutional review board approval, the medical records of 20 patients (12 with mediastinal lymphoma; 8 with lung cancer) were retrospectively reviewed. Patients underwent 4-dimensional computed tomography simulation and a contrasted scan for treatment planning. Using MIMVista software, the heart, coronary arteries, chambers, and valves were contoured on the 50% phase, and these contours were propagated to the other phases and edited. Each substructure was graded on the basis of its ease of contouring across all phases (1 = no difficulty; 2 = minor difficulty; 3 = moderate difficulty; and 4 = very difficult). The centroid position and volume of each substructure for all phases were exported to Excel to calculate basic statistics and the independent t test., Results: The heart, 4 chambers, and atrioventricular valves were easily identified with a mean score of 1 to 1.2, and the pulmonic valve, left anterior descending artery, aortic valve, circumflex, and right coronary artery were minor-to-moderately difficult with a mean score of 2.1 to 3.2. The smallest centroid displacement was seen in the 4 chambers and mitral and pulmonic valves (0.7-1.1 cm). Greater displacement was seen in the coronary vessels and tricuspid and aortic valves (1.2-1.5 cm). The greatest displacement was in the Z direction (craniocaudal) for all substructures; however, the displacement was significantly greater among patients with lymphoma for the right ventricle, aortic valve, and left anterior descending artery ( P  < .05). However, patients with lung cancer had more displacement in the X and Y directions, which was statistically significant for the right atrium, tricuspid valve, right ventricle, and heart. When calculating overall displacement, no statistically significant difference was observed between patients with lymphoma and patients with lung cancer., Conclusions: Intrafractional motion of the cardiac substructures ranged from 0.7 to 1.5 cm, mostly in the Z direction. Further investigation of the respiratory motion effect on the dose-volume histogram of the substructures is needed for patients treated with contemporary radiation techniques.

Among adult lymphoma survivors, radiation treatment techniques that increase the excess radiation dose to organs at risk (OARs) put patients at risk for increased side effects, especially late toxicities. Minimizing radiation to OARs in adults patients with Hodgkin and non-Hodgkin lymphomas involving the mediastinum is the deciding factor for the choice of treatment modality. Proton therapy may help to reduce the radiation dose to the OARs and reduce toxicities, especially the risks for cardiac morbidity and second cancers. Because proton therapy may have some disadvantages, identifying the patients and the circumstances that may benefit the most from proton therapy is important. We present modern guidelines to identify adult lymphoma patients who may derive the greatest benefit from proton therapy, along with an analysis of the advantages and disadvantages of proton treatment., (© 2018 by The American Society of Hematology.)

The Radiation Therapy Committee of SWOG periodically evaluates its strategic plan in an effort to maintain a current and relevant scientific focus, and to provide a standard platform for future development of protocol concepts. Participants in the 2017 Strategic Planning Workshop included leaders in cancer basic sciences, molecular theragnostics, pharmaceutical and technology industries, clinical trial design, oncology practice, and statistical analysis. The committee discussed high-priority research areas, such as optimization of combined modality therapy, radiation oncology-specific drug design, identification of molecular profiles predictive of radiation-induced local or distant tumor responses, and methods for normal tissue-specific mitigation of radiation toxicity. The following concepts emerged as dominant questions ready for national testing: (i) what is the role of radiotherapy in the treatment of oligometastatic, oligorecurrent, and oligoprogressive disease? (ii) How can combined modality therapy be used to enhance systemic and local response? (iii) Can we validate and optimize liquid biopsy and other biomarkers (such as novel imaging) to supplement current response criteria to guide therapy and clinical trial design endpoints? (iv) How can we overcome deficiencies of randomized survival endpoint trials in an era of increasing molecular stratification factors? And (v) how can we mitigate treatment-related side effects and maximize quality of life in cancer survivors? The committee concluded that many aspects of these questions are ready for clinical evaluation and example protocol concepts are provided that could improve rates of cancer cure and quality of survival. Clin Cancer Res; 24(15); 3500-9. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Radiotherapy plays an important role in the management of childhood cancer, with the primary aim of achieving the highest likelihood of cure with the lowest risk of radiation-induced morbidity. Proton therapy (PT) provides an undisputable advantage by reducing the radiation 'bath' dose delivered to non-target structures/volume while optimally covering the tumor with tumoricidal dose. This treatment modality comes, however, with an additional costs compared to conventional radiotherapy that could put substantial financial pressure to the health care systems with societal implications. In this review we assess the data available to the oncology community of PT delivered to children with cancer, discuss on the urgency to develop high-quality data. Additionally, we look at the advantage of combining systemic agents with protons and look at the cost-effectiveness data published so far., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Radiotherapy for thymic malignancies is technically challenging due to their close proximity to the heart, lungs, esophagus, and breasts, raising concerns about significant acute and late toxicities from conventional photon radiotherapy. Proton therapy (PT) may reduce the radiation dose to these vital organs, leading to less toxicity. We reviewed the dosimetry and outcomes among patients treated with PT for thymic malignancies at our institution., Methods: From January 2008 to March 2017, six patients with de novo Masaoka stages II-III thymic malignancies were treated with PT on an IRB-approved outcomes tracking protocol. Patients were evaluated weekly during treatment, then every 3 months for 2 years, then every 6 months for 3 more years, and then annually for CTCAE vs. four toxicities and disease recurrence. Comparison intensity-modulated radiotherapy (IMRT) plans were developed for each patient. Mean doses to the heart, esophagus, bilateral breasts, lungs, and V20 of bilateral lungs were evaluated for the two treatment plans., Results: At last follow-up (median follow-up, 2.6 years), there were two patients with recurrences, including metastatic disease in the patient treated definitively with chemotherapy and PT without surgery and a local-regional recurrence in the lung outside the proton field in one of the post-operative cases. No patients with de novo disease experienced grade ≥3 toxicities after PT. The mean dose to the heart, lung, and esophagus was reduced on average by 36.5%, 33.5%, and 60%, respectively, using PT compared with IMRT (P<0.05 for each dose parameter)., Conclusions: PT achieved superior dose sparing to the heart, lung, and esophagus compared to IMRT for thymic malignancies. Patients treated with PT had few radiation-induced toxicities and similar survival compared to historic proton data., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Most extensive-stage small cell lung cancers have disseminated disease at diagnosis, and solitary adrenal metastasis from small cell lung cancer is rare. We report the case of a 51-year-old man with extensive-stage small cell lung cancer with solitary right adrenal metastasis (T2N0M1), who was cured with resection of primary tumor, chemotherapy (cisplatin, etoposide), adrenalectomy, consolidative thoracic radiotherapy, and prophylactic cranial irradiation. He remained cancer free, 7.5 years since diagnosis. For small cell lung cancer with solitary adrenal gland metastasis, metastasectomy combined with chemotherapy and radiotherapy can be curative and enable long-term survival. This treatment approach should be further studied, and similar cases should be reported., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Late cardiac complications from thoracic radiation of patients with Hodgkin lymphoma are of great concern. The authors investigated whether cardiac biomarkers could identify patients with early cardiac damage from thoracic radiation., Materials and Methods: Following completion of anthracycline-based chemotherapy, 14 patients with stage I-IIIA mediastinal Hodgkin lymphoma were enrolled on an IRB-approved prospective trial and agreed to serum evaluation of troponin, CK-MB, and BNP before beginning radiation, after completing radiation, and every 3 to 6 months for 5 years, during follow-up or until relapse., Results: Among the 14 patients, median follow-up for the entire cohort was 5 years. No evidence in abnormal values in troponin or CK-MB was observed among the patient cohort. BNP levels demonstrated statistically significant higher values at various follow-up time points. Higher levels of BNP were observed among patients receiving higher anthracycline doses (>250 mg), but not among patients with higher mean heart radiation doses., Conclusions: In the first 5 years after treatment, no rise in CK-MB or troponin was identified. BNP levels significantly increased following treatment, with larger increases among patients who received higher doses of anthracyclines. Further investigation is warranted., Competing Interests: Conflicts of Interest Statement: Drs. Nancy P. Mendenhall and Bradford S. Hoppe are part of the International Journal of Particle Therapy's editorial board., (© Copyright 2017 International Journal of Particle Therapy.)

Background: We investigated early outcomes for patients receiving chemotherapy followed by consolidative proton therapy (PT) for the treatment of Hodgkin lymphoma (HL)., Patients and Methods: From June 2008 through August 2015, 138 patients with HL enrolled on either IRB-approved outcomes tracking protocols or registry studies received consolidative PT. Patients were excluded due to relapsed or refractory disease. Involved-site radiotherapy field designs were used for all patients. Pediatric patients received a median dose of 21 Gy(RBE) [range 15-36 Gy(RBE)]; adult patients received a median dose of 30.6 Gy(RBE) [range, 20-45 Gy(RBE)]. Patients receiving PT were young (median age, 20 years; range 6-57). Overall, 42% were pediatric (≤18 years) and 93% were under the age of 40 years. Thirty-eight percent of patients were male and 62% female. Stage distribution included 73% with I/II and 27% with III/IV disease. Patients predominantly had mediastinal involvement (96%) and bulky disease (57%), whereas 37% had B symptoms. The median follow-up was 32 months (range, 5-92 months)., Results: The 3-year relapse-free survival rate was 92% for all patients; it was 96% for adults and 87% for pediatric patients (P = 0.18). When evaluated by positron emission tomography/computed tomography scan response at the end of chemotherapy, patients with a partial response had worse 3-year progression-free survival compared with other patients (78% versus 94%; P = 0.0034). No grade 3 radiation-related toxicities have occurred to date., Conclusion: Consolidative PT following standard chemotherapy in HL is primarily used in young patients with mediastinal and bulky disease. Early relapse-free survival rates are similar to those reported with photon radiation treatment, and no early grade 3 toxicities have been observed. Continued follow-up to assess late effects is critical., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Purpose: To compare 5-year biochemical control, toxicity, and patient-reported quality of life (QOL) outcomes for African American and White patients treated with proton therapy (PT) for prostate cancer., Materials and Methods: We reviewed the medical records of 1,066 men with clinically localized prostate cancer. Patients were treated with definitive PT between 2006 and 2010. Patients received a median radiation dose of 78 Gy (RBE) with conventional fractionation (1.8- 2 Gy [RBE] per fraction). Sixty-eight (6.4%) men self-identified as African American and 998 (93.6%) self-identified as White. Five-year rates of biochemical control, grade 3 genitourinary and gastrointestinal toxicity, and patient-reported QOL are reported and compared between African American and White patients., Results: Median biochemical follow-up was 5.0 years for both African American and White patients. Median follow-up for toxicity was 5.0 and 5.2 years, respectively. On multivariate analysis, race was not a significant predictor for 5-year freedom from biochemical failure (HR 0.8, p=0.55). No significant association was found between race and grade 3 genitourinary toxicity on multivariate analysis at 5 years (HR 2.5, p=0.10). Patient-reported QOL using median EPIC bowel, urinary incontinence, and irritative summaries scores were not significantly different between the groups. African Americans had higher median sexual summary scores at 2 years than White patients (75 vs. 54, p=0.01) but by 5+ years, the sexual summary scores were no longer significantly different (63 vs. 53, p=0.35)., Conclusion: With a median follow-up of 5 years, there were no racial disparities in biochemical control, grade 3 toxicity, or patient-reported QOL after PT for prostate cancer., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to disclose., (© Copyright 2017 International Journal of Particle Therapy.)

Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to disclose.

Purpose: This study analyzed the impact of pretreatment positron emission tomography/computed tomography (PET/CT) scans on involved site radiation therapy (ISRT) field design and pattern of relapse among patients with Hodgkin lymphoma (HL)., Methods and Materials: Thirty-seven patients with stage I or II HL who received first-line chemotherapy followed by consolidative ISRT to all initial sites of disease were enrolled in an institutional review board-approved outcomes-tracking protocol between January 2009 and December 2014. Patients underwent standard-of-care follow-up. Relapse-free survival (RFS) was evaluated using a Kaplan-Meier analysis and cohort comparisons using a χ 2 test., Results: Thirty-one patients underwent (PET/CT) scans before chemotherapy and 6 did not because of a lack of insurance (n = 2), inpatient chemotherapy administration (n = 2), scheduling conflicts (n = 1), and unknown reasons (n = 1). The median follow-up was 46 months, and the 4-year RFS rate was 92%. Patients without pretreatment PET imaging were more likely to experience disease relapse (4-year RFS, 97% vs. 67%; P = .001). Among the 6 patients who did not receive a baseline PET/CT scan, all 3 recurrences occurred in lymph node regions outside of, but immediately adjacent to, the radiation field., Conclusions: Patients with stage I/II HL who receive ISRT without pretreatment PET/CT scans appear to have an increased risk for relapse in adjacent nodal stations just outside the radiation field. A larger cohort with a longer follow-up is needed to confirm these findings.

Purpose: To determine the incidence of a bacterial urinary tract infection (UTI) necessitating hospitalization after transrectal placement of fiducial markers prior to proton radiotherapy (RT) for prostate cancer., Materials and Methods: Six hundred sixty six patients returning for follow up after proton RT consented to participate in this institutional review board (IRB) approved study. Patients were queried whether they required hospitalization within 1 month of transrectal placement of fiducial markers. Patients were treated with proton RT between August 2006 and December 2014. Median International Prostate Symptom Score (IPSS) was 7. Sixty four patients (9.6%) had diabetes, 9 patients (1.4%) had chronic obstructive pulmonary disease, 6 patients (0.9%) had prior bladder surgery, 7 patients (1.1%) had a transurethral prostatectomy within 3 months, and 549 patients (82.4%) had a course of antibiotics within 6 months. Fifty five patients (8.3%) were taking tamsulosin, 16 patients (2.4%) were taking finasteride, and 62 patients (9.3%) were taking saw palmetto. The interval between the most recent prostate biopsy prior to fiducial placement and fiducial marker placement was less than 6 months in 609 patients (91.4%). No patient had a prior recent rectal culture., Results: Ten patients (1.5%) developed a bacterial UTI necessitating hospitalization after transrectal placement of fiducial markers. A bacterial UTI occurred in 3 (0.7%) of 440 patients treated from 2006 to 2012 and in 7 (3.1%) of 226 patients treated from 2013 to 2014. Univariate analysis of potential association of a bacterial UTI with the following parameters revealed: IPSS less than or greater than the median (p=0.3400), diabetes (p=0.6099), tamsulosin (p=0.9999), saw palmetto (p=0.0093), interval between prostate biopsy and placement of fiducials (p=0.9999), year of treatment (p=0.0363), and antibiotics within 6 months (p=0.2233). A bacterial UTI was observed in 4 (6.5%) of 62 patients who were taking saw palmetto versus 6 (1.0%) of 604 patients who were not taking this medication. The incidence of a bacterial UTI between 2006 and 2012 was 3 (0.7%) of 440 patients and from 2013 to 2014 was 7 (3.1%) of 226 patients. Multivariate analysis revealed that the likelihood of a bacterial UTI was increased in patients taking saw palmetto (p=0.0044) and those treated in 2013-2014 (p=0.0303)., Conclusion: The incidence of a bacterial UTI requiring hospitalization after transrectal placement of fiducial markers prior to proton RT was 1.5% and was impacted by taking saw palmetto and year of treatment. Patients treated during 2013 and 2014 had a significantly higher risk of a bacterial UTI requiring hospitalization., Competing Interests: Conflicts of interest: The authors have no conflicts of interest to disclose., (© Copyright 2016 International Journal of Particle Therapy.)

Purpose: We report on quality of life (QOL) and early toxicity among men with prostate cancer who underwent transurethral resection of the prostate (TURP) before proton therapy., Materials and Methods: Between 2006 and 2010, 1,289 patients were treated definitively with proton therapy for prostate cancer at our institution and enrolled on a prospective outcomes-tracking protocol. Ninety-six of the men had received a TURP before proton therapy, while 1,193 men had not. Baseline comorbidities, medications, expanded prostate index composite (EPIC) score, international prostate symptom score (IPSS), and CTCAE vs.3 toxicity assessment were collected prospectively. The Kaplan-Meier product limit method was used to estimate freedom from toxicity., Results: Men who had TURP before proton therapy had lower baseline EPIC scores for urinary incontinence, bowel summary, and sexual summary compared with the non-TURP group, but no significant difference in urinary obstructive score was observed. After controlling for baseline scores, there was no significant difference in bowel summary or sexual summary scores between the two groups over time. There were, however, differences for urinary irritation/obstruction scores and urinary incontinence scores favoring those patients who did not have a TURP-like procedure. Toxicity assessment showed that the 2-year and 5-year rates of grade 3 genitourinary toxicity in the pretreatment TURP group were 12.3% and 17.2%, respectively., Conclusions: Pretreatment TURP was associated with both a high incidence of physician-assessed toxicity and inferior patient-reported QOL scores both before and after proton therapy treatment. Studies investigating QOL and toxicity after specific prostate cancer therapies should stratify patients by pretreatment TURP. Longer follow-up is needed to confirm if these differences ever resolve., Competing Interests: Conflict of interest: The authors have no conflicts to disclose.