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Heavy ion radiotherapy is an emerging technology for treating radioresistant solid tumors. Unlike current low-linear energy transfer techniques, heavy ion radiotherapy, such as carbon ion radiotherapy, enhances the biologic effects related to cancer therapy. Prospective clinical evidence has demonstrated feasibility and efficacy in several disease sites, including head and neck, thoracic, central nervous system, gastrointestinal, pelvic tumors, and sarcomas. Although presently unavailable in the Americas, Mayo Clinic is constructing a heavy ion facility in the United States that is planned for clinical operation in 2028., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Proton beam therapy (PBT) plays an important role in the management of primary spine tumors. The purpose of this consensus statement was to summarize safe and optimal delivery of PBT for spinal tumors., Methods and Materials: The Particle Therapy Cooperative Group Skull Base/Central nervous system/Sarcoma Subcommittee consisting of radiation oncologists and medical physicists with specific expertise in spinal irradiation developed expert recommendations discussing treatment planning considerations and current approaches in the treatment of primary spinal tumors., Results: Computed tomography simulation: factors that require significant consideration include (1) patient comfort, (2) setup reproducibility and stability, and (3) accessibility of appropriate beam angles., Spine Stabilization Hardware: If present, hardware should be placed with cross-links well above/below the level of the primary tumor to reduce the metal burden at the level of the tumor bed. New materials that can reduce uncertainties include polyether-ether-ketone and composite polyether-ether-ketone-carbon fiber implants., Field Arrangement: Appropriate beam selection is required to ensure robust target coverage and organ at risk sparing. Commonly, 2 to 4 treatment fields, typically from posterior and/or posterior-oblique directions, are used., Treatment Planning Methodology: Robust optimization is recommended for all pencil beam scanning plans (the preferred treatment modality) and should consider setup uncertainty (between 3 and 7 mm) and range uncertainty (3%-3.5%). In the presence of metal hardware, use of an increased range uncertainty up to 5% is recommended., Conclusions: The Particle Therapy Cooperative Group Skull Base/Central nervous system/Sarcoma Subcommittee has developed recommendations to enable centers to deliver PBT safely and effectively for the management of primary spinal tumors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Treatment of squamous cell carcinoma of the tonsil involves primary radiation therapy (RT) or surgical resection. Historically, if RT was the primary or adjuvant treatment modality, most of the bilateral retropharyngeal lymph nodes (RPLNs) were treated electively with a therapeutic dose for subclinical disease, regardless of whether radiographically pathologic lymph nodes were seen on initial diagnostic imaging. De-escalation strategies include the incorporation of transoral surgery with the goal to either eliminate or reduce the dose of adjuvant RT or chemotherapy. Transoral surgery does not include elective removal of the RPLNs, and no guideline or outcome paper recommends adjuvant RT specifically to electively treat RPLNs. In this Topic Discussion, we discuss pertinent literature and suggest management decisions. The management decisions discussed in this Topic Discussion pertain to only tonsillar primaries and not those of the soft palate or base of the tongue., Competing Interests: Disclosures None., (Copyright © 2024 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Proton therapy has emerged as a crucial tool in the treatment of head and neck and skull-base cancers, offering advantages over photon therapy in terms of decreasing integral dose and reducing acute and late toxicities, such as dysgeusia, feeding tube dependence, xerostomia, secondary malignancies, and neurocognitive dysfunction. Despite its benefits in dose distribution and biological effectiveness, the application of proton therapy is challenged by uncertainties in its relative biological effectiveness (RBE). Overcoming the challenges related to RBE is key to fully realizing proton therapy's potential, which extends beyond its physical dosimetric properties when compared with photon-based therapies. In this paper, we discuss the clinical significance of RBE within treatment volumes and adjacent serial organs at risk in the management of head and neck and skull-base tumors. We review proton RBE uncertainties and its modeling and explore clinical outcomes. Additionally, we highlight technological advancements and innovations in plan optimization and treatment delivery, including linear energy transfer/RBE optimizations and the development of spot-scanning proton arc therapy. These advancements show promise in harnessing the full capabilities of proton therapy from an academic standpoint, further technological innovations and clinical outcome studies, however, are needed for their integration into routine clinical practice.

Purpose: Adenoid cystic carcinoma (ACC) is a rare malignancy accounting for 1% of all head and neck cancers. Treatment for ACC has its challenges and risks, yet few outcomes studies exist. We present long-term outcomes of patients with ACC of the head and neck treated with proton therapy (PT)., Materials and Methods: Under an institutional review board-approved, single-institutional prospective outcomes registry, we reviewed the records of 56 patients with de novo, nonmetastatic ACC of the head and neck treated with PT with definitive ( n  = 9) or adjuvant PT ( n  = 47) from June 2007 to December 2021. The median dose to the primary site was 72.6 gray relative biological equivalent (range, 64-74.4) delivered as either once ( n  = 19) or twice ( n  = 37) daily treatments. Thirty patients received concurrent chemotherapy. Thirty-one patients received nodal radiation, 30 electively and 1 for nodal involvement., Results: With a median follow-up of 6.2 years (range, 0.9-14.7), the 5-year local-regional control (LRC), disease-free survival, cause-specific survival, and overall survival rates were 88%, 85%, 89%, and 89%, respectively. Intracranial extension ( P  = .003) and gross residual tumor ( P  = .0388) were factors associated with LRC rates. While the LRC rate for those with a gross total resection was 96%, those with subtotal resection or biopsy alone were 81% and 76%, respectively. The 5-year cumulative incidence of clinically significant grade ≥3 toxicity was 15%, and the crude incidence at the most recent follow-up was 23% ( n  = 13)., Conclusion: This is the largest sample size with the longest median follow-up to date of patients with ACC treated with PT. PT can provide excellent disease control for ACC of the head and neck with acceptable toxicity. T4 disease, intracranial involvement, and gross residual disease at the time of PT following either biopsy or subtotal resection were significant prognostic features for worse outcomes.

Background: Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represent a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology-based topics spanning the field., Methods: In accordance with prior International Consensus Statement on Allergy and Rhinology documents, ICSNT assigned each topic as an Evidence-Based Review with Recommendations, Evidence-Based Review, and Literature Review based on the level of evidence. An international group of multidisciplinary author teams were assembled for the topic reviews using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses format, and completed sections underwent a thorough and iterative consensus-building process. The final document underwent rigorous synthesis and review prior to publication., Results: The ICSNT document consists of four major sections: general principles, benign neoplasms and lesions, malignant neoplasms, and quality of life and surveillance. It covers 48 conceptual and/or histopathology-based topics relevant to sinonasal neoplasms and masses. Topics with a high level of evidence provided specific recommendations, while other areas summarized the current state of evidence. A final section highlights research opportunities and future directions, contributing to advancing knowledge and community intervention., Conclusion: As an embodiment of the multidisciplinary and collaborative model of care in sinonasal neoplasms and masses, ICSNT was designed as a comprehensive, international, and multidisciplinary collaborative endeavor. Its primary objective is to summarize the existing evidence in the field of sinonasal neoplasms and masses., (© 2023 The Authors. International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Background: Pediatric esthesioneuroblastoma (EN) can infiltrate skull base anatomy, presenting challenges due to high radiation doses and pediatric tissue sensitivity. This study reports outcomes of pediatric EN treated with proton radiotherapy (PT)., Procedure: Using an IRB-approved prospective outcomes registry, we evaluated patient, tumor, and treatment-related variables impacting disease control and toxicity in pediatric nonmetastatic EN treated with modern multimodality therapy, including PT., Results: Fifteen consecutive patients (median age 16) comprising Kadish stage B (n = 2), C (n = 9), and D (n = 4) tumors were assessed, including six with intracranial involvement, four with cranial nerve deficits, and four with cervical lymphadenopathy. Before radiation, two had subtotal and 13 had gross total resections (endoscopic or craniofacial). Two underwent neck dissection. Eleven received chemotherapy before radiation (n = 5), concurrent with radiation (n = 4), or both (n = 2). Median total radiation dose (primary site) was 66 Gy/CGE for gross disease and 54 Gy/CGE (cobalt Gray equivalent) for microscopic disease. Median follow-up was 4.8 years. No patients were lost to follow-up. Five-year disease-free and overall survival rates were 86% (no local or regional recurrences). Two patients developed vertebral metastases and died. Two required a temporary feeding tube for oral mucositis/dysphagia. Late toxicities included symptomatic retinopathy, major reconstructive surgery, cataracts, chronic otitis media, chronic keratoconjunctivitis, hypothyroidism, and in-field basal cell skin cancer., Conclusions: A multimodality approach for pediatric EN results in excellent local control. Despite the moderate-dose PT, serious radiation toxicity was observed; further dose and target volume reductions may benefit select patients. Longer follow-up and comparative data from modern photon series are necessary to fully characterize any relative PT advantage., (© 2023 Wiley Periodicals LLC.)

Background: Prescription drug monitoring programs (PDMPs) have proliferated due to increasing opioid-related deaths. We evaluated acute opioid use changes for 64 patients treated with highly conformal radiotherapy (RT) following a state-mandated PDMP., Methods: Patients receiving proton therapy (PT) (n=40), intensity-modulated RT (IMRT) (n=14), or both (n=10) were divided into preintervention (n=26) and postintervention cohorts (n=38); records were reviewed retrospectively under an institutional review board (IRB)-approved tracking protocol. Dosages prescribed during acute therapy (during RT-3 months post-RT) and patient-reported pain (Defense and Veterans Pain Rating Scale) were endpoints. Dosages were treated as responses in Chi-square tests (three-level ordinal response)., Results: Overall, 72% (n=46) received opioids; of which 22% (n=10) of all patients and 10% (n=2) of opioid-naive patients continued analgesic management 3 months post-RT. Median total doses were 975 and 1,025 morphine milligram equivalents (MME) in pre- and postintervention groups, with no significant differences in MME prescribed (P=0.8) or uncontrolled pain (P=0.3). Statistically significant factors were tonsil primaries (P<0.01) and alcohol use (P=0.02). Uncontrolled pain episodes during and post-RT did not vary per cohort (P=0.19)., Conclusions: PDMP use was not associated with management changes in patient-reported acute pain during RT (IMRT or PT). Following highly conformal RT, few patients remained on narcotics 3 months post-RT.

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.

Proton therapy (PT) is a form of highly conformal external-beam radiotherapy used to mitigate acute and late effects following radiotherapy. Indications for treatment include both benign and malignant skull-base and central nervous system pathologies. Studies have demonstrated that PT shows promising results in minimizing neurocognitive decline and reducing second malignancies with low rates of central nervous system necrosis. Future directions and advances in biologic optimization may provide additional benefits beyond the physical properties of particle dosimetry., Competing Interests: Conflicts of Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: In 2008, the UK National Health Service started the Proton Overseas Programme (POP), to provide access for proton beam therapy (PBT) abroad for selected tumour diagnoses while two national centres were being planned. The clinical outcomes for the patient group treated for central nervous system (CNS), base of skull, spinal and paraspinal malignancies are reported here., Materials and Methods: Since the start of the POP, an agreement between the National Health Service and UK referring centres ensured outcomes data collection, including overall survival, local tumour control and late toxicity data. Clinical and treatment-related data were extracted from this national patient database. Grade ≥3 late toxicities were reported following Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 definition, occurring later than 90 days since the completion of treatment., Results: Between 2008 and September 2020, 830 patients were treated within the POP for the above listed malignancies. Overall survival data were available for 815 patients and local control data for 726 patients. Toxicity analysis was carried out on 702 patients, with patients excluded due to short follow-up (<90 days) and/or inadequate toxicity data available. After a median follow-up of 3.34 years (0.06-11.58), the overall survival was 91.2%. The local control rate was 85.9% after a median follow-up of 2.81 years (range 0.04-11.58). The overall grade ≥3 late toxicity incidence was 11.97%, after a median follow-up of 1.72 years (0.04-8.45). The median radiotherapy prescription dose was 54 GyRBE (34.8-79.2)., Conclusions: The results of this study indicate the safety of PBT for CNS tumours. Preliminary clinical outcomes following PBT for paediatric/teen and young adult and adult CNS tumours treated within the POP are encouraging, which reflects accurate patient selection and treatment quality. The rate of late effects compares favourably with published cohorts. Clinical outcomes from this patient cohort will be compared with those of UK-treated patients since the start of the national PBT service in 2018., (Copyright © 2023 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Purpose: Benign intracranial meningioma is one of the most common primary brain neoplasms. Proton therapy has been increasingly utilized for nonoperative management of this neoplasm, yet few long-term outcomes studies exist., Methods: The medical records of a total of 59 patients with 64 lesions were reviewed under a prospective outcomes tracking protocol for histologically proven or radiographically benign meningioma. The patients were treated with proton therapy at the University of Florida Proton Therapy Institute between 2007 and 2019 and given a median dose of 50.4 GyRBE at 1.8 GyRBE (relative biological effectiveness) (range 48.6-61.2 GyRBE) in once-daily treatments., Results: With a median clinical and imaging follow-up of 6.3 and 4.7 years, the rates of 5-year actuarial local progression and cumulative incidence of grade 3 or greater toxicity were 6% (95% confidence interval [CI] 1%-14%), and 2% (95% CI < 1%-15%), respectively. Two patients experienced local progression after 5 years. The 5-year actuarial overall survival rate was 87% (95% CI 74-94%)., Conclusion: Fractionated PBT up to 50.4 GyRBE is a safe and highly effective therapy for treating benign intracranial meningioma., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: We report outcomes among patients with T2 and select T3 glottic squamous cell carcinoma (SCC) treated with radiotherapy., Methods: We reviewed T2 and T3 (only paraglottic space invasion) N0 M0 glottic SCC patients treated with curative-intent hypofractionated larynx radiotherapy, with or without concurrent systemic therapy., Results: Of 71 patients, those who received concurrent chemotherapy (23/71; 32%) had worse prognostic factors, including impaired cord mobility (70% vs. 40%, p = 0.02) and larger median gross tumor volume (3.0 vs. 1.6 cm 3 , p = 0.003). Over a median follow-up of 3.8 years, 2-year local control among patients with impaired cord mobility appeared higher for those who received chemotherapy (88% vs. 61%, p = 0.12), but the difference was not statistically significant. Acute and late toxicity rates were not higher among patients who received chemotherapy., Conclusions: The addition of concurrent platinum-based chemotherapy to hypofractionated larynx radiotherapy among patients with early-stage glottic SCC with impaired cord mobility appears safe and worthy of additional investigation., (© 2022 Wiley Periodicals LLC.)

Background: Dose escalation for skull-based malignancies often presents risks to critical adjacent neural structures, including the brainstem. We report the incidence of brainstem toxicity following fractionated high-dose conformal proton therapy and associated dosimetric parameters., Material and Methods: We performed a single-institution review of patients with skull-base chordoma or chondrosarcoma who were treated with proton therapy between February 2007 and January 2020 on a prospective outcomes-tracking protocol. The primary endpoint was grade ≥2 brainstem toxicity. No patients received concurrent chemotherapy, and brainstem toxicity was censored for analysis if it coincided with local disease progression., Results: We analyzed 163 patients who received a minimum of 45 GyRBE to 0.03 cm 3 of the brainstem. Patients were treated to a median total dose of 73.8 (range 64.5-74.4) GyRBE at 1.8 GyRBE per fraction with 17 patients undergoing twice-daily treatment at 1.2 GyRBE per fraction. With a median follow-up of 4 years, the 5-year cumulative incidence of grade ≥2 brainstem injury was 1.3% (95% CI 0.25-4.3%). There was one grade 2, one grade 3, and no grade 4 or 5 events, with all patients recovering function with medical management., Conclusion: In delivering curative-intent radiotherapy for skull-base chordoma and chondrosarcoma in adults, small volumes of the brainstem can safely receive at least 64 GyRBE with minimal risk of serious brainstem injury.

Purpose: To report disease control and treatment-related side effects among adult patients with craniopharyngioma treated with radiotherapy., Methods: We performed a single-institution review of adult patients (> 21 years old) with craniopharyngioma treated with radiotherapy either definitively or postoperatively for gross residual disease. We report disease control, survival, and radiotherapy-related side effects., Results: A total of 49 adult patients with craniopharyngioma were included, 27 of whom were treated at initial presentation and 22 for recurrent disease following initial surgery and observation. Overall, 77% received radiotherapy postoperatively (either after primary surgery or surgery for recurrence). With a median clinical and radiographic follow-up of 4.2 (range, 0.4-21.6) years and 3.0 (range, 0-21.5) years, the 5- and 10-year local control rates were 100 and 94%, respectively. The 5- and 10-year overall survival rates were 80 and 66%, respectively. Eleven percent of patients experienced grade 2 vision deterioration and 18% suffered grade 2 endocrinopathies following radiotherapy., Conclusions: Radiotherapy provides excellent disease control with acceptable toxicity among adult patients with craniopharyngioma. These data support the use of fractionated radiotherapy in adult patients with recurrent or gross residual disease after surgery. For inoperable patients or those with moderate or high surgical risk to neurologic and/or vascular structures, we advocate for limited surgical resection and postoperative radiotherapy to balance optimal tumor control with tumor- and treatment-related morbidity., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: For curative treatment of Hodgkin lymphoma, radiation therapy benefit must be weighed against toxicity. Although more costly, proton radiation therapy reduces dose to healthy tissue, potentially improving the therapeutic ratio compared with photons. We sought to determine the cost-effectiveness of proton versus photon therapy for mediastinal Hodgkin lymphoma (MHL) based on reduced heart disease., Methods and Materials: Our model approach was 2-fold: (1) Use patient-level dosimetric information for a cost-effectiveness analysis using a Markov cohort model. (2) Use population-based data to develop guidelines for policymakers to determine thresholds of proton therapy favorability for a given photon dose. The HD14 trial informed relapse risk; coronary heart disease risk was informed by the Framingham risk calculator modified by the mean heart dose (MHD) from radiation. Sensitivity analyses assessed model robustness and identified the most influential model assumptions. A 30-year-old adult with MHL was the base case using 30.6-Gy proton therapy versus photon intensity modulated radiation therapy., Results: Proton therapy was not cost-effective in the base case for male ($129,000/ quality-adjusted life years [QALYs]) or female patients ($196,000/QALY). A 5-Gy MHD decrease was associated with proton therapy incremental cost-effectiveness ratio <$100,000/QALY in 40% of scenarios. The hazard ratio associating MHD and heart disease was the most influential clinical parameter., Conclusions: Proton therapy may be cost-effective a select minority of patients with MHL based on age, sex, and MHD reduction. We present guidance for clinicians using MHD to aid decision-making for radiation therapy modality., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: We report disease control, survival outcomes, and treatment-related toxicity among adult medulloblastoma patients who received proton craniospinal irradiation (CSI) as part of multimodality therapy., Methods: We reviewed 20 adults with medulloblastoma (≥ 22 years old) who received postoperative proton CSI ± chemotherapy between 2008 and 2020. Patient, disease, and treatment details and prospectively obtained patient-reported acute CSI toxicities were collected. Acute hematologic data were analyzed., Results: Median age at diagnosis was 27 years; 45% of patients had high-risk disease; 75% received chemotherapy, most (65%) after CSI. Eight (40%) patients received concurrent vincristine with radiotherapy. Median CSI dose was 36GyE with a median tumor bed boost of 54GyE. Median duration of radiotherapy was 44 days. No acute ≥ grade 3 gastrointestinal or hematologic toxicities attributable to CSI occurred. Grade 2 nausea and vomiting affected 25% and 5% of patients, respectively, while 36% developed acute grade 2 hematologic toxicity (36% grade 2 leukopenia and 7% grade 2 neutropenia). Those receiving concurrent chemotherapy with CSI had a 38% rate of grade 2 hematologic toxicity compared to 33% among those not receiving concurrent chemotherapy. Among patients receiving adjuvant chemotherapy (n = 13), 100% completed ≥ 4 cycles and 85% completed all planned cycles. With a median follow-up of 3.1 years, 4-year actuarial local control, disease-free survival, and overall survival rates were 90%, 90%, and 95%, respectively., Conclusions: Proton CSI in adult medulloblastoma patients is very well tolerated and shows promising disease control and survival outcomes. These data support the standard use of proton CSI for adult medulloblastoma., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To report long-term disease control, survival, and toxicity after proton therapy for sinonasal cancer., Patients and Methods: We reviewed 143 cases of adults with nonmetastatic sinonasal cancers treated with primary (18%; n = 26) or adjuvant (82%; n = 117) proton therapy. The most common histologies were squamous cell carcinoma (29%; n = 42), olfactory neuroblastoma (23%; n = 33), and adenoid cystic carcinoma (16%; n = 23). Patients had predominantly advanced-stage disease (T3, 24%, n = 35; T4, 66%, n = 94) and high-grade histology (52%; n = 74). Surgery included endoscopic resection alone (50%) with craniotomy (10%) or open resection (40%), and 31% had gross disease present at radiotherapy. Most (91%) received high-dose (median, 73.6 Gy radiobiological equivalent [GyRBE]; 84% >70 GyRBE) passive-scatter proton therapy using accelerated hyperfractionation (1.2 GyRBE twice daily) and concurrent chemotherapy (70%). Univariate and multivariate models assessed prognostic factors. Grade 3 + toxicities were recorded per Common Terminology Criteria, version 4. Median follow-up was 3.4 years (range, 0.1-12.5 years) overall and 4.9 years (range, 0.9-12.5 years) for living patients., Results: The 5-year outcomes were as follows: local control (LC), 80%; neck control, 96%; local-regional control, 78%; freedom from distant metastases, 71%; and disease-free survival, 62%; cause-specific survival, 64%; and overall survival, 59%. Surgery improved LC, but only with gross total resection (5-year LC 87% versus subtotal resection 62.9%, and biopsy alone 55% ( P < 0.001). Gross residual disease was the only significant prognostic factor for local-regional control on multivariate analysis. High-grade, T4, and local recurrence were associated with decreased overall survival. Late (G3 + ) toxicity occurred in 22% (32 of 143), including central nervous system necrosis and vision loss in 6% (9 of 143) and 3.5% (5 of 143), respectively., Conclusion: Proton therapy after gross-total resection provides excellent long-term LC in patients with locally advanced, high-grade sinonasal cancer. Moreover, LC remains strongly associated with long-term survival. With gross disease, about 60% of patients had long-term LC with proton therapy and induction or concurrent chemotherapy., Competing Interests: Conflicts of Interest: William M. Mendenhall, MD, is Operating Editor of the International Journal of Particle Therapy. The authors have no other relevant conflicts of interest to disclose., (©Copyright 2021 The Author(s).)

Purpose: To evaluate the effectiveness of external-beam proton therapy (PT) on local control and survival in patients with skull-base chordoma., Materials and Methods: We reviewed the medical records of patients with skull-base chordoma treated with definitive or adjuvant high-dose PT and updated their follow-up when feasible. We assessed overall survival, disease-specific survival, local control, and freedom from distant metastasis. Radiotherapy toxicities were scored using the Common Terminology Criteria for Adverse Events, version 4.0., Results: A total 112 patients were analyzed, of whom 105 (94%) received PT and 7 (6%) received combined proton-photon therapy between 2007 and 2019. Eighty-seven patients (78%) underwent a subtotal resection, 22 (20%) a gross total resection, and 3 (3%) a biopsy alone. The median radiotherapy dose was 73.8 Gy radiobiologic equivalent (GyRBE; range, 69.6-74.4). Ninety patients (80%) had gross disease at radiotherapy and 7 (6%) were treated for locally recurrent disease following surgery. Median follow-up was 4.4 years (range, 0.4-12.6); for living patients, it was 4.6 years (range, 0.4-12.6), and for deceased patients, 4.1 years (range, 1.2-11.2). At 5 years after radiotherapy, the actuarial overall survival, disease-specific survival, local control, and freedom from distant metastasis rates were 78% (n = 87), 83% (n = 93), 74% (n = 83), and 99% (n = 111), respectively. The median time to local progression was 2.4 years (range, 0.8-7). Local control and disease-specific survival by resection status was 95% versus 70% ( P  = 0.28) and 100% versus 80% ( P  = 0.06) for gross total, versus subtotal, resection or biopsy alone, respectively. There were no serious acute toxicities (grade ≥ 3) related to radiotherapy., Conclusion: High-dose PT alone or after surgical resection for skull-base chordoma reaffirms the favorable 5-year actuarial local control rate compared with conventional techniques with acceptable late-complication-free survival. Outcomes following gross total resection and adjuvant PT were excellent. Further follow-up of this cohort is necessary to better characterize long-term disease control and late toxicities., Competing Interests: Conflicts of Interest: Adam L. Holtzman, MD, has received a speaking honorarium from the American Academy of Insurance Medicine and the American Council of Life Insurers. William M. Mendenhall, MD, is Operating Editor of the International Journal of Particle Therapy., (©Copyright 2021 The Author(s).)

Purpose: To report our experience with the delivery of passively scattered proton therapy in the management of nonmelanoma skin cancers with clinical perineural invasion., Materials and Methods: We reviewed the medical records of patients who received definitive or postoperative proton therapy for nonmelanoma skin cancer with clinical perineural invasion at our institution and updated patient follow-up when possible. All patients were treated with curative intent with or without the delivery of concurrent systemic therapy. We report disease control rates and the rates of late toxicity among this cohort., Results: Twenty-six patients treated between 2008 and 2017 were included in the analysis. Following proton therapy, the 3-year overall, cause-specific, and disease-free survival rates were 59%, 73%, and 60%, respectively. The 3-year local control, local regional control, and distant metastasis-free survival rates were 80%, 65%, and 96%, respectively. On univariate analysis, surgical resection before radiation therapy significantly improved local regional control rates at 3 years (55% versus 86%; P  = .04). Grade 3+ late toxicities occurred in 13 patients (50%) and the most common toxicities included grade 3+ keratitis of the ipsilateral eye, which occurred in 4 patients (15%) and grade 3+ brain necrosis in 4 patients (15%)., Conclusion: Proton therapy is effective in the management of nonmelanoma skin cancer with clinical perineural invasion. Although disease control and complication rates compare favorably to those previously published for photon-based radiation therapy, the risk for late toxicity is significant and patients should be appropriately counseled., Competing Interests: Conflicts of Interest: William M. Mendenhall, MD, is Operating Editor of the International Journal of Particle Therapy. The authors have no additional conflicts of interest to disclose., (©Copyright 2021 The Author(s).)

Background & Purpose: Dose escalation for skull-based chordoma and chondrosarcoma can put critical adjacent structures at risk, specifically the anterior optic pathway. We report the incidence of vision loss following high-dose conformal proton-based radiotherapy., Materials and Methods: We reviewed patients with skull-base chordoma or chondrosarcoma treated with proton-based therapy between 2007 and 2018. We analyzed 148 patients and 283 individual eyes with functional vision at baseline who received a minimum 30GyRBE to 0.1 cm 3 of the anterior optic pathway. Eyes were classified as "functionally blind" if visual acuity was 20/200 or worse. Kaplan-Meier and normal tissue complication probability modeling were used to establish the relationship between radiation dose and risk of functional vision loss., Results: At last follow-up, 110 of 148 patients were alive with no evidence of disease progression. With a median follow-up of 4.1 years (range, 0.5-12.8), 5 eyes in 3 patients developed functional blindness, with 2 patients developing bilateral blindness. Median time to blindness was 15.2 months. The 5-year incidence of vision loss was 2.1% (95% CI: 0.9-4.9%). On univariate analysis, development of blindness was associated with presence of multiple medical comorbidities (p = 0.0040). While there were no events with a maximum dose < 60GyRBE delivered to the anterior optic pathway, the crude rate was 3.6% over 60GyRBE, with all events occurring between 60-65GyRBE., Conclusions: Despite the high radiotherapy dose delivered to patients with skull-base chordoma and chondrosarcoma, the rate of vision loss is low and no events occurred in those who received a maximum dose under 60GyRBE., Competing Interests: Declaration of Competing Interest ALH has received honorariums for educational events from the American Academy of Insurance Medicine and the American Council of Life Insurers unrelated to this research., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: Due to the location and high dose required for disease control, pediatric chordomas are theoretically well-suited for treatment with proton therapy, but their low incidence limits the clinical outcome data available in the literature. We sought to report the efficacy and toxicity of proton therapy among a single-institution cohort., Methods and Materials: Between 2008 and 2019, 29 patients with a median age of 14.8 years (range, 3.8-21.8) received passive-scattered proton therapy for nonmetastatic chordoma. No patient received prior irradiation. Twenty-four tumors arose in the clivus/cervical spine region and 5 in the lumbosacral spine. Twenty-six tumors demonstrated classic well-differentiated histology and 3 were dedifferentiated or not otherwise specified. Approximately half of the tumors underwent specialized testing: 14 were brachyury-positive and 10 retained INI-1. Three patients had locally recurrent tumors after surgery alone (n = 2) or surgery + chemotherapy (n = 1), and 17 patients had gross disease at the time of radiation. The median radiation dose was 73.8 Gy relative biological effectivness (range, 69-75.6)., Results: With a median follow-up of 4.3 years (range, 1.0-10.7), the 5-year estimates of local control, progression-free survival, and overall survival rates were 85%, 82%, and 86%, respectively. No disease progression was observed beyond 3 years. Excluding 3 patients with dedifferentiated/not-otherwise-specified chordoma, the 5-year local control, progression-free survival, and overall survival rates were 92%, 92%, and 91%, respectively. Serious toxicities included 3 patients with hardware failure or related infection requiring revision surgery, 2 patients with hormone deficiency, and 2 patients with Eustachian tube dysfunction causing chronic otitis media. No patient experienced brain stem injury, myelopathy, vision loss, or hearing loss after radiation., Conclusions: In pediatric patients with chordoma, proton therapy is associated with a low risk of serious toxicity and high efficacy, particularly in well-differentiated tumors. Complete resection may be unnecessary for local control, and destabilizing operations requiring instrumentation may result in additional complications after therapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction  In adults with skull base chordoma or chondrosarcoma, the impact of treatment center and access to care have not been well described in regard to perioperative mortality and survival. Methods  A query of the National Cancer Database (NCDB) and review of 1,102 adults-488 with chordomas and 614 with chondrosarcomas-was performed. The Kaplan-Meier's product limit method and chi-square analysis, respectively, assessed overall survival and 30-day (30D) and 90-day (90D) mortalities. Results  For 925 patients who had surgery and available mortality data, the 30D and 90D mortality rates were 0.9 and 1.5%. Lower education level ( p  = 0.0185) and treatment at a nonacademic facility ( p  = 0.016) were associated with increased risk of 90-day mortality. Median follow-up was 52 months and analysis was dichotomized by histology. For those with skull base chordoma, patients from a larger metro size ( p  = 0.002), age below the median 52 years ( p ≤ 0.001), and private insurance (<0.001) were associated with prolonged survival, whereas for skull base chondrosarcoma, the factors were treatment at an academic medical center ( p  = 0.001), high-volume center ( p  = 0.007), age below the median 52 years ( p ≤ 0.001), higher income ( p  = 0.043), higher education ( p  = 0.017), and private insurance ( p ≤ 0.001). Comparing high-, medium-, and low-volume centers, high-volume centers were most likely to be academic, deliver radiotherapy, escalate doses >70 Gy, and utilize proton radiotherapy consistent across both disease subsets. Conclusion  Higher educational attainment and treatment at an academic facility were associated with decreased 90D mortality for patients with skull base chordoma and chondrosarcoma. For those with skull base chordoma, larger metro size, younger age, and private insurance were associated with prolonged survival; for those with chondrosarcoma, it was treatment at a high-volume or academic medical center, younger age, higher income or education, and private insurance., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Study Design: Literature review., Objective: To review the current role of radiotherapy (RT) in the management of oral cavity squamous cell carcinoma (SCC)., Methods: Review of selected literature., Results: T1-T2N0 SCCs may be treated with either RT alone or surgery with a high likelihood of cure. The pendulum swung toward surgery with postoperative RT (PORT) added depending on the pathological findings in the mid 1980s. Patients with positive margins, extranodal extension (ENE), and/or 4 or more positive nodes receive concomitant chemotherapy (POCRT). Patients with T3-T4 and/or positive regional nodes are treated with surgery and PORT alone or POCRT. The likelihood of cure is moderate to low depending on extent of disease. The likelihood of major complications ranges from 10% to 30% depending on the method of reconstruction and the aggressiveness of postoperative PORT/POCRT. Patients with very advanced disease are treated with palliative RT, chemotherapy, or supportive care., Conclusions: The role of RT in the management of oral cavity SCC is primarily in the postoperative setting with palliative RT being reserved for those with very advanced disease where the likelihood of cure is remote., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RPF is an Editor in Chief of CMTR., (© The Author(s) 2020.)

Background: Craniopharyngioma is a benign tumor that commonly develops within the suprasellar region. The tumor and treatment can have debilitating consequences for pediatric and adult patients, including vision loss and pituitary/hypothalamic dysfunction. Most craniopharyngioma series focus on treatment of the pediatric population. We evaluated the outcomes of all adult craniopharyngioma patients treated at our institution using proton therapy to report outcomes for disease control, treatment-related toxicity, and tumor response., Methods: We analyzed 14 adult patients (≥ 22 years old). All patients had gross disease at the time of radiotherapy. Five were treated for de novo disease and 9 for recurrent disease. Patients received double-scattered conformal proton therapy to a mean dose of 54 GyRBE in 1.8 GyRBE/fraction (range 52.2-54 GyRBE). Weekly magnetic resonance imaging (MRI) helped to evaluate tumor changes during radiotherapy., Results: With median clinical and radiographic follow-up of 29 and 26 months, respectively, the 3-year local control and overall survival rates were both 100%. There were no grade 3 or greater acute or late radiotherapy-related side effects. There was no radiotherapy-related vision loss or optic neuropathy. No patients required intervention or treatment replanning due to tumor changes during radiotherapy. Two patients experienced transient cyst expansion at their first post-radiotherapy MRI. Both patients were followed closely clinically and radiographically and had subsequent dramatic tumor/cyst regression, requiring no interventions., Conclusions: Our data support the safety and efficacy of proton therapy in the treatment of adult craniopharyngioma as part of primary or salvage treatment. We recommend early consideration of radiotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03224767.

Non-melanomatous skin cancer (NMSC) is the most common malignancy worldwide. Perineural invasion (PNI) is an uncommon (<5%), high-risk feature observed with NMSC more commonly seen in those with squamous cell carcinoma. One-third of these patients will have clinical PNI, which refers to tumor cell invasion extensive enough to cause clinically detectable deficits of the involved nerve. Uncontrolled disease within the skull base can be debilitating and, if not eradicated, fatal. The primary management options including radiotherapy with or without surgery, with local control rates exceeding 50%. Given the overwhelming influence of local control on disease control and survival, dose escalation and complication mitigation through hyperfractionated and high-dose conformal skull-base proton therapy are strategies to improving the therapeutic window in patients with cutaneous head and neck cancer with clinical PNI., (Copyright © 2019 Elsevier Ltd. 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: We sought to evaluate the effectiveness of definitive or adjuvant external-beam proton therapy on local control and survival in patients with skull-base chondrosarcoma., Methods: We reviewed the medical records of 43 patients with a median age of 49 years (range, 23-80 years) treated with double-scattered 3D conformal proton therapy for skull-base chondrosarcomas between January 2007 and February 2016. Proton therapy-related toxicities were scored using CTCAE v4.0., Results: The median radiotherapy dose was 73.8 Gy(RBE) (range, 64.5-74.4 Gy[RBE]). Thirty-six (84%) and 7 (16%) patients underwent surgical resection or biopsy alone. Tumor grade distribution included: grade 1, 19 (44%) patients; grade 2, 22 (51%); and grade 3, 2 (5%). Forty patients had gross disease at the time of radiotherapy and 7 patients were treated for locally recurrent disease following surgery. The median follow-up was 3.7 years (range, 0.7-10.1 years). There were no acute grade 3 toxicities related to RT. At 4 years following RT, actuarial rates of overall survival, cause-specific survival, local control, and RT-related grade 3 toxicity-free survival were 95%, 100%, 89%, and 95%., Conclusion: High-dose, double-scattered 3D conformal proton therapy alone or following surgical resection for skull-base chondrosarcoma is an effective treatment with a high rate of local control with no acute grade 3 radiation-related toxicity. Further follow-up of this cohort is necessary to better characterize long-term disease control and late toxicities.

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.)

Background: Skull base chordomas and chondrosarcomas are rare tumors traditionally treated by surgical resection and adjuvant radiation therapy (RT). We will discuss data evaluating clinical outcomes of proton therapy in the treatment of skull base chordomas and chondrosarcomas., Methods: A literature review was performed using a MEDLINE search from January 1990 to January 2017., Results: The published data suggest that the dose intensification allowed by proton therapy has resulted in good clinical outcomes and a tolerable toxicity profile., Conclusion: Proton therapy is a modern RT technique that has demonstrated improved preliminary clinical outcomes in the treatment of skull base chordomas and chondrosarcomas compared to conventional radiotherapy, and comparable to other advanced photon-based RT techniques., (© 2018 Wiley Periodicals, Inc.)

Objectives: Pain management during radiotherapy helps assess quality of care. By establishing an intervention to address pain during on-treatment visits (OTVs), we aim to lower patient-reported pain scores., Methods: A total of 171 patients were included in the analysis: 58 were retrospectively reviewed to provide a control and 113 were prospectively enrolled and evaluated after the intervention. The intervention included (1) a pain management in-service performed with the resident physician and nurses, (2) distribution of pain management educational materials, and (3) nurse consultation for patients with a pain score ≥5 within 2 days of the in-service. Study aims were to reduce the number of pain scores ≥5 by 30% and increase the number of pain scores documented during every OTV to >90%., Results: Median patient age was 65 years. Before the intervention, the average DVPRS score at initial consultation was 2 (range, 0 to 9) and 98% of patients had scores documented during OTVs. Overall, 26% (44/171) of OTV scores measured ≥5. Following the intervention, average DVPRS score at initial consultation was 2 (range, 0 to 10) and 99% of scores were documented during OTVs. About 14% (49/341) of patient-reported scores were ≥5, representing an ~50% relative reduction (P=0.023). The number of patients with 2+ pain scores ≥5 was reduced from 21% (12/58) before the intervention to 11% (12/109) after the intervention (P=0.1068)., Conclusion: Involving nursing staff in the education and follow-up of patients with uncontrolled pain during radiotherapy led to an ~50% relative reduction in patient-reported DVPRS scores of 5+ during weekly OTVs.

Anxiety and depression are disabling, underdiagnosed issues that affect the management of oncology patients. Until recently, there has been no standard protocol for screening and treating these ailments at our cancer centre. The purpose of this institutional review board-approved study was to analyse the implementation of a screening tool in our clinical workflow with the aim of screening over 90% of patients and increasing referrals to mental health services by 50%., Competing Interests: Competing interests: None declared.

Purpose: Local recurrence of prostate cancer after cryosurgery (CS) and high-intensity focused ultrasound (HIFU) is an emerging problem for which optimal management is unknown. Proton therapy (PT) may offer advantages over other local therapeutic options. This article reviews a single institution's experience using PT for salvage of local recurrent disease after HIFU or CS., Methods and Materials: We reviewed the medical records of 21 consecutive patients treated with salvage PT following a local recurrence of prostate cancer after CS (n=12) or HIFU (n=9) between January 2007 and July 2014. Patients were treated to a median dose of 74 Gy(relative biological effectiveness [RBE]; range: 74-82 Gy[RBE]) and 8 patients received androgen deprivation therapy with radiation therapy. Patients were evaluated for quality of life (QOL) by using the Expanded Prostate Index Composite questionnaire and toxicity by using Common Terminology Criteria for Adverse Events, version 3.0, weekly during treatment, every 6 months for 2 years after treatment, and then annually., Results: Median follow-up was 37 months (range: 6-95 months). The 3-year biochemical progression-free survival (bPFS) rate was 77%. The 3-year grade 3 toxicity rate was 17%; however, 2 of these patients had pre-existing grade 3 GU toxicities from their HIFU/CRYO prior to PT. At 1 year, bowel summary, urinary incontinence, and urinary obstructive QOL scores declined, but only the bowel QOL score at 12 months met the minimally important difference threshold., Conclusions: PT achieved a high rate of bPFS with acceptable toxicity and minimal changes in QOL scores compared with baseline pre-PT functions. Although most patients have done fairly well, the study size is small, follow-up is short, and early results suggest that outcomes with PT for salvage after HIFU or CS failure are inferior to outcomes with PT given in the de novo setting with respect to disease control, toxicity, and QOL., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Hookah smoking is a popular form of tobacco use on university campuses. This study documented use, attitudes, and knowledge of hookah smoking among college students., Participants: The sample included 943 university students recruited between February 2009 and January 2010. Respondents (M age = 20.02) included 376 males, 533 females, and 34 who did not report sex., Methods: An anonymous online questionnaire was completed by respondents., Results: In this sample, 42.9% of college students had tried hookah, and 40% of those individuals had used it in the past 30 days. Students perceived fewer negative consequences of hookah smoking compared with cigarette smoking. Age, sex, racial background, marijuana/cigarette use, and perceptions of side effects were significantly associated with hookah use., Conclusions: University students are misinformed regarding the health consequences of hookah smoking. Programs aimed at education, prevention, and intervention for hookah use are needed to address this growing public health concern.