Publications by authors named "Shannon M MacDonald"

98 Publications

Proton Radiation Therapy for Pediatric Craniopharyngioma Protons for Craniopharyngioma.

Int J Radiat Oncol Biol Phys 2021 Mar 1. Epub 2021 Mar 1.

Massachusetts General Hospital, Department of Radiation Oncology, Boston, MA.

Background: Radiation therapy (RT) is used for pediatric craniopharyngioma in the definitive, adjuvant or salvage settings. Proton RT may be useful due to tumor proximity to eloquent anatomy. We report clinical outcomes for a large cohort treated with proton therapy.

Methods: We conducted a retrospective review of pediatric patients (< 21 years) treated with surgery and proton therapy for craniopharyngioma between August 2002-October 2018. Clinical characteristics, treatment course, and outcomes were recorded. Acute toxicity was graded using CTCAE, version 5.0. Late toxicity was assessed using neuroendocrine, neuro-ophthalmologic, and neuropsychological testing.

Results: Among 77 patients, median age at diagnosis was 8.6 years (range 1.3-20); median age at radiation was 9.6 years (range 2.3-20.5). Most common presenting symptoms were headache (58%), visual impairment (55%) and endocrinopathy (40%). Patients underwent a median of 2 surgical interventions (range 1-7) prior to protons. At initial surgery, 18% had gross total resection, 60% had subtotal resection, and 22% had biopsy/cyst decompression. Median RT dose was 52.2Gy (RBE). Common acute toxicities were headache (29%), fatigue (35%), and nausea/vomiting (12%). Only 4% developed any acute grade 3 toxicity. Nine patients experienced cyst growth requiring re-planning or surgical decompression. At a median of 4.8 years from RT (range 0.8-15.6), there were six local failures and three deaths, two related to disease progression. Effect of tumor and treatment contributed to late toxicity including Moyamoya syndrome (13%), visual impairment (40%), and endocrine deficiency requiring hormone replacement (94%). Subclinical decline in functional independence and adaptive skills in everyday life was detected at follow-up.

Conclusions: Surgery and proton therapy results in excellent disease control for pediatric craniopharyngioma. Severe acute toxicity is rare. Late toxicities from tumor, surgery, and radiation remain prevalent. Endocrine and ophthalmology follow-up is necessary, and neuropsychological testing may identify patients at risk for treatment-related cognitive and adaptive functioning changes.
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http://dx.doi.org/10.1016/j.ijrobp.2021.02.045DOI Listing
March 2021

Proton Therapy for Pediatric Ependymoma: Mature Results From a Bicentric Study.

Int J Radiat Oncol Biol Phys 2021 Jan 27. Epub 2021 Jan 27.

Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts.

Purpose: To report the long-term efficacy and toxicity of proton therapy for pediatric ependymoma.

Methods And Materials: Between 2000 and 2019, 386 children with nonmetastatic grade 2/3 intracranial ependymoma received proton therapy at 1 of 2 academic institutions. Median age at treatment was 3.8 years (range, 0.7-21.3); 56% were male. Most (72%) tumors were in the posterior fossa and classified as World Health Organization grade 3 (65%). Eighty-five percent had a gross total or near total tumor resection before radiation therapy; 30% received chemotherapy. Median radiation dose was 55.8 Gy relative biologic effectiveness (RBE) (range, 50.4-59.4).

Results: Median follow-up was 5.0 years (range, 0.4-16.7). The 7-year local control, progression-free survival, and overall survival rates were 77.0% (95% confidence interval [CI], 71.9%-81.5%), 63.8% (95% CI, 58.0%-68.8%), and 82.2% (95% CI, 77.2%-86.3%), respectively. Subtotal resection was associated with inferior local control (59% vs 80%; P < .005), progression-free survival (48% vs 66%; P < .001), and overall survival (70% vs 84%; P < .05). Male sex was associated with inferior progression-free (60% vs 69%; P < .05) and overall survival (76% vs 89%; P < .05). Posterior fossa tumor site was also associated with inferior progression-free (59% vs 74%; P < .05) and overall survival (79% vs 89%; P < .01). Twenty-one patients (5.4%) required hearing aids; of these, 13 received cisplatin, including the 3 with bilateral hearing loss. Forty-five patients (11.7%) required hormone replacement, typically growth hormone (38/45). The cumulative incidence of grade 2+ brain stem toxicity was 4% and occurred more often in patients who received >54 GyRBE. Two patients (0.5%) died of brain stem necrosis. The second-malignancy rate was 0.8%.

Conclusion: Proton therapy offers disease control commensurate with modern photon therapy without unexpected toxicity. The high rate of long-term survival justifies efforts to reduce radiation exposure in this young population. Independent of radiation modality, this large series confirms extent of resection as the most important modifiable factor for survival.
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http://dx.doi.org/10.1016/j.ijrobp.2021.01.027DOI Listing
January 2021

Arms positioning in post-mastectomy proton radiation: Feasibility and development of a new arms down contouring atlas.

Phys Imaging Radiat Oncol 2020 Apr 26;14:6-11. Epub 2020 May 26.

Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.

Background And Purpose: Breast cancer patients receiving radiation are traditionally positioned with both arms up, but this may not be feasible or comfortable for all patients. We evaluated the treatment planning and positioning reproducibility differences between the arms up and arms down positions for patients receiving post-mastectomy radiation therapy (PMRT) using proton pencil beam scanning (PBS).

Materials And Methods: Ten PMRT patients who were scheduled to receive PBS underwent CT-based treatment planning in both an arms down and a standard arms up position. An arms down contouring atlas was developed for consistency in treatment planning. Treatment plans were performed on both scans. A Wilcoxon test was applied to compare arms up and arms down metrics across patients. Five patients received treatment in the arms-down position at our institution while others were treated with the arms up. Residual set-up errors were recorded for each patient's treatment fractions and compared between positions.

Results: Target structure coverage remained consistent between the arms up and arms down positions. In regard to the OAR, the heart mean and maximum doses were statistically significantly lower in the arms up position versus the arms down position, however, the absolute differences were modest. Patients demonstrated similar setup errors, less than 0.5 mm differences, in all directions.

Conclusions: PBS for PMRT in the arms down position appeared stable and reproducible compared to the traditional arms up positioning. The degree of OAR sparing in the arms down group was minimally less robust but still far superior to conventional photon therapy.
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http://dx.doi.org/10.1016/j.phro.2020.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807669PMC
April 2020

A Multi-institutional Comparative Analysis of Proton and Photon Therapy-Induced Hematologic Toxicity in Patients With Medulloblastoma.

Int J Radiat Oncol Biol Phys 2021 Mar 23;109(3):726-735. Epub 2020 Nov 23.

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

Purpose: This multi-institutional retrospective study sought to examine the hematologic effects of craniospinal irradiation (CSI) in pediatric patients with medulloblastoma using proton or photon therapy.

Methods And Materials: Clinical and treatment characteristics were recorded for 97 pediatric patients with medulloblastoma who received CSI without concurrent chemotherapy or with concurrent single-agent vincristine from 2000 to 2017. Groups of 60 and 37 patients underwent treatment with proton-based and photon-based therapy, respectively. Overall survival was determined by Kaplan-Meier curves with log-rank test. Comparisons of blood counts at each timepoint were conducted using multiple t tests with Bonferroni corrections. Univariate and multivariate analyses of time to grade ≥3 hematologic toxicity were performed with Cox regression analyses.

Results: Median age of patients receiving proton and photon CSI was 7.5 years (range, 3.5-22.7 years) and 9.9 years (range, 3.6-19.5 years), respectively. Most patients had a diagnosis of standard risk medulloblastoma, with 86.7% and 89.2% for the proton and photon cohorts, respectively. Median total dose to involved field or whole posterior fossa was 54.0 Gy/Gy relative biological effectiveness (RBE) and median CSI dose was 23.4 Gy/Gy(RBE) (range, 18-36 Gy/Gy[RBE]) for both cohorts. Counts were significantly higher in the proton cohort compared with the photon cohort in weeks 3 to 6 of radiation therapy (RT). Although white blood cell counts did not differ between the 2 cohorts, patients receiving proton RT had significantly higher lymphocyte counts throughout the RT course. Similar results were observed when excluding patients who received vertebral body sparing proton RT or limiting to those receiving 23.4 Gy. Only photon therapy was associated with decreased time to grade ≥3 hematologic toxicity on univariate and multivariable analyses. No difference in overall survival was observed, and lymphopenia did not predict survival.

Conclusions: Patients who receive CSI using proton therapy experience significantly decreased hematologic toxicity compared with those receiving photon therapy.
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http://dx.doi.org/10.1016/j.ijrobp.2020.09.049DOI Listing
March 2021

Evolution of Care of Orbital Tumors with Radiation Therapy.

J Neurol Surg B Skull Base 2020 Aug 24;81(4):480-496. Epub 2020 Aug 24.

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States.

Orbital tumors are rare lesions comprising 0.1% of all tumors and less than 20% of all ocular diseases. These lesions in children and adults differ significantly in their incidence, tumor type, and treatment management. Although surgery and systemic therapies are commonly used in the management of these diseases, radiation therapy has become a widely used treatment for both benign and malignant tumors of the orbit. Radiotherapy is used as a definitive treatment to provide local control while avoiding morbidity associated with surgery for some tumors while it is used as an adjuvant treatment following surgical resection for others. For many tumors, radiation provides excellent tumor control with preservation of visual function. This article is dedicated for presenting the most common applications of orbital radiotherapy. A brief overview of the commonly available radiation therapy modalities is given. Dose constraint goals are reviewed and acute and long-term side effects are discussed. Orbital tumors covered in this article include optic glioma, ocular melanoma, retinoblastoma, orbital rhabdomyosarcoma, orbital lymphoma, and lacrimal gland tumors. Background information, indications for radiotherapy, and goals of treatment for each case example are described.
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http://dx.doi.org/10.1055/s-0040-1713894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561458PMC
August 2020

Clinical outcomes in a large pediatric cohort of patients with ependymoma treated with proton radiotherapy.

Neuro Oncol 2021 01;23(1):156-166

Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts.

Background: Treatment for pediatric ependymoma includes surgical resection followed by local radiotherapy (RT). Proton RT (PRT) enables superior sparing of critical structures compared with photons, with potential to reduce late effects. We report mature outcomes, patterns of failure, and predictors of outcomes in patients treated with PRT.

Methods: One hundred fifty patients (<22 y) with World Health Organization grades II/III ependymoma were treated with PRT between January 2001 and January 2019 at Massachusetts General Hospital. Demographic, tumor, and treatment-related characteristics were analyzed. Event-free survival (EFS), overall survival (OS), and local control (LC) were assessed.

Results: Median follow-up was 6.5 years. EFS, OS, and LC for the intracranial cohort (n = 145) at 7 years were 63.4%, 82.6%, and 76.1%. Fifty-one patients recurred: 26 (51.0%) local failures, 19 (37.3%) distant failures, and 6 (11.8%) synchronous failures. One hundred sixteen patients (77.3%) underwent gross total resection (GTR), 5 (3.3%) underwent near total resection (NTR), and 29 (19.3%) underwent subtotal resection (STR). EFS for the intracranial cohort at 7 years for GTR/NTR and STR was 70.3% and 35.2%. With multivariate analysis, the effect of tumor excision persisted after controlling for tumor location. There was no adverse effect on disease control if surgery to RT interval was within 9 weeks of GTR/NTR.

Conclusion: PRT is effective and safe in pediatric ependymoma. Similar to previous studies, GTR/NTR was the most important prognostic factor. Intervals up to 9 weeks from surgery to PRT did not compromise disease outcomes. There was no LC benefit between patients treated with >54 Gray relative biological effectiveness (GyRBE) versus ≤54 GyRBE.
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http://dx.doi.org/10.1093/neuonc/noaa139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849993PMC
January 2021

Low-Dose Image-Guided Pediatric CNS Radiation Therapy: Final Analysis From a Prospective Low-Dose Cone-Beam CT Protocol From a Multinational Pediatrics Consortium.

Technol Cancer Res Treat 2020 Jan-Dec;19:1533033820920650

Department of Radiation Oncology and Molecular Radiation Sciences, University of Minnesota, Minneapolis, MN, USA.

Background: Lower-dose cone-beam computed tomography protocols for image-guided radiotherapy may permit target localization while minimizing radiation exposure. We prospectively evaluated a lower-dose cone-beam protocol for central nervous system image-guided radiotherapy across a multinational pediatrics consortium.

Methods: Seven institutions prospectively employed a lower-dose cone-beam computed tomography central nervous system protocol (weighted average dose 0.7 mGy) for patients ≤21 years. Treatment table shifts between setup with surface lasers versus cone-beam computed tomography were used to approximate setup accuracy, and vector magnitudes for these shifts were calculated. Setup group mean, interpatient, interinstitution, and random error were estimated, and clinical factors were compared by mixed linear modeling.

Results: Among 96 patients, with 2179 pretreatment cone-beam computed tomography acquisitions, median age was 9 years (1-20). Setup parameters were 3.13, 3.02, 1.64, and 1.48 mm for vector magnitude group mean, interpatient, interinstitution, and random error, respectively. On multivariable analysis, there were no significant differences in mean vector magnitude by age, gender, performance status, target location, extent of resection, chemotherapy, or steroid or anesthesia use. Providers rated >99% of images as adequate or better for target localization.

Conclusions: A lower-dose cone-beam computed tomography protocol demonstrated table shift vector magnitude that approximate clinical target volume/planning target volume expansions used in central nervous system radiotherapy. There were no significant clinical predictors of setup accuracy identified, supporting use of this lower-dose cone-beam computed tomography protocol across a diverse pediatric population with brain tumors.
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http://dx.doi.org/10.1177/1533033820920650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225835PMC
November 2020

End-of-Range Radiobiological Effect on Rib Fractures in Patients Receiving Proton Therapy for Breast Cancer.

Int J Radiat Oncol Biol Phys 2020 07 30;107(3):449-454. Epub 2020 Mar 30.

Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

Purpose: A prospective trial of proton therapy for breast cancer revealed an increased rib fracture rate of 7%, which is higher than the expected rate based on the literature on photon therapies. We aim to evaluate the hypothesis that the increased relative biological effectiveness (RBE) at the distal edge of proton beams is the cause.

Methods And Materials: We combined the cohort from the prospective clinical trial and a retrospective cohort from a database. Monte Carlo simulations were performed to recalculate the physical dose and dose-averaged linear energy transfer (LETd). The first 10 ribs and fracture areas in patients with fractures were contoured and deformably registered. The LETd-weighted dose was used as a surrogate for biological effectiveness and compared with the conventional fixed RBE of 1.1. Dose to 0.5 cm of the ribs (D0.5) was selected to analyze the dose-response relationship using logistic regression. We chose an alpha/beta ratio of 3 to calculate the biological effective dose in Gy(RBE).

Results: Thirteen of 203 patients in the cohorts exhibited a total of 25 fractures. The LETd in fractured areas is increased (6.1 ± 2.0 keV/μm, mean ± standard deviation), suggesting possible end-of-range radiobiological effects with increased RBE. The D0.5 of the fractured ribs is 80.3 ± 9.4 Gy(RBE) with a generic factor of 1.1 and is relatively low compared with historical photon results. On the other hand, the D0.5 of the fractured ribs is 100.0 ± 12.5 Gy(RBE) using the LETd-based model with a dose-response curve that is more consistent with historical photon data.

Conclusions: The increased rib fracture rate seen in our trial is probably associated with the increased LETd and RBE at the distal edge of proton beams. This phenomenon warrants further investigation and possible integration of LETd into treatment planning and optimization in proton therapy.
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http://dx.doi.org/10.1016/j.ijrobp.2020.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293563PMC
July 2020

Long-term health-related quality of life in pediatric brain tumor survivors receiving proton radiotherapy at <4 years of age.

Neuro Oncol 2020 09;22(9):1379-1387

Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts.

Background: The purpose of this analysis is to report long-term health-related quality of life (HRQoL) among brain tumor survivors treated with proton therapy (PRT) at a very young age.

Methods: Fifty-nine children <4 years old received PRT between 2000 and 2011. Forty families participated. HRQoL was assessed by child self-report (CSR; age ≥5) and parent proxy report (PPR; age 2+) using the PedsQL Core.

Results: The median age was 2.5 years (range, 0.3-3.8) at PRT and 9.1 years (5.5-18) at last follow-up. The most common diagnoses were ependymoma (n = 22) and medulloblastoma (n = 7). Median follow-up is 6.7 years (3-15.4). Follow-up mean CSR and PPR scores were: total core (78.4 and 72.9), physical (82.9 and 75.2), psychosocial (76.0 and 71.6), emotional (74.4 and 70.7), social (81.2 and 75.1), and school (72.4 and 69.9). Parent-reported HRQoL fell within a previously defined range for healthy children in 37.5% of patients, and for children with severe health conditions in 45% of patients. PPR HRQoL was stable from baseline to last follow-up among all domains except for social functioning. History of gastrostomy tube was significantly associated with poorer CSR and PPR HRQoL on multivariable analysis. Ninety percent of children functioned in a regular classroom, 14 (36%) used a classroom aid, 9 (23%) used an outside tutor, and 18 (46%) had an individualized education plan.

Conclusion: Long-term HRQoL among brain tumor survivors treated with PRT at a very young age is variable, with over a third achieving HRQoL levels commensurate with healthy children.

Key Points: 1. One third of survivors reported long-term HRQoL scores comparable to those of healthy children.2. Treatment for hydrocephalus or a feeding tube was associated with significantly lower HRQoL.3. Total core HRQoL scores remained stable from baseline to last follow-up.
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http://dx.doi.org/10.1093/neuonc/noaa042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523456PMC
September 2020

Pragmatic randomised clinical trial of proton versus photon therapy for patients with non-metastatic breast cancer: the Radiotherapy Comparative Effectiveness (RadComp) Consortium trial protocol.

BMJ Open 2019 10 15;9(10):e025556. Epub 2019 Oct 15.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York city, New York, USA.

Introduction: A broad range of stakeholders have called for randomised evidence on the potential clinical benefits and harms of proton therapy, a type of radiation therapy, for patients with breast cancer. Radiation therapy is an important component of curative treatment, reducing cancer recurrence and extending survival. Compared with photon therapy, the international treatment standard, proton therapy reduces incidental radiation to the heart. Our overall objective is to evaluate whether the differences between proton and photon therapy cardiac radiation dose distributions lead to meaningful reductions in cardiac morbidity and mortality after treatment for breast cancer.

Methods: We are conducting a large scale, multicentre pragmatic randomised clinical trial for patients with breast cancer who will be followed longitudinally for cardiovascular morbidity and mortality, health-related quality of life and cancer control outcomes. A total of 1278 patients with non-metastatic breast cancer will be randomly allocated to receive either photon or proton therapy. The primary outcomes are major cardiovascular events, defined as myocardial infarction, coronary revascularisation, cardiovascular death or hospitalisation for unstable angina, heart failure, valvular disease, arrhythmia or pericardial disease. Secondary endpoints are urgent or unanticipated outpatient or emergency room visits for heart failure, arrhythmia, valvular disease or pericardial disease. The Radiotherapy Comparative Effectiveness (RadComp) Clinical Events Centre will conduct centralised, blinded adjudication of primary outcome events.

Ethics And Dissemination: The RadComp trial has been approved by the institutional review boards of all participating sites. Recruitment began in February 2016. Current version of the protocol is A3, dated 08 November 2018. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement efforts and presentation to the public via lay media outlets.

Trial Registration Number: NCT02603341.
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http://dx.doi.org/10.1136/bmjopen-2018-025556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797426PMC
October 2019

Revisiting the Role of Radiation Therapy for Pediatric Low-Grade Glioma.

J Clin Oncol 2019 12 9;37(35):3335-3339. Epub 2019 Sep 9.

Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA.

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http://dx.doi.org/10.1200/JCO.19.01270DOI Listing
December 2019

Phase II Study of Proton Beam Radiation Therapy for Patients With Breast Cancer Requiring Regional Nodal Irradiation.

J Clin Oncol 2019 10 26;37(30):2778-2785. Epub 2019 Aug 26.

Massachusetts General Hospital, Boston, MA.

Purpose: To evaluate the safety and efficacy of proton beam radiation therapy (RT) for patients with breast cancer who require regional nodal irradiation.

Methods: Patients with nonmetastatic breast cancer who required postoperative RT to the breast/chest wall and regional lymphatics and who were considered suboptimal candidates for conventional RT were eligible. The primary end point was the incidence of grade 3 or higher radiation pneumonitis (RP) or any grade 4 toxicity within 3 months of RT. Secondary end points were 5-year locoregional failure, overall survival, and acute and late toxicities per Common Terminology Criteria for Adverse Events (version 4.0). Strain echocardiography and cardiac biomarkers were obtained before and after RT to assess early cardiac changes.

Results: Seventy patients completed RT between 2011 and 2016. Median follow-up was 55 months (range, 17 to 82 months). Of 69 evaluable patients, median age was 45 years (range, 24 to 70 years). Sixty-three patients (91%) had left-sided breast cancer, two had bilateral breast cancer, and five had right-sided breast cancer. Sixty-five (94%) had stage II to III breast cancer. Sixty-eight (99%) received systemic chemotherapy. Fifty (72%) underwent immediate reconstruction. Median dose to the chest wall/breast was 49.7 Gy (relative biological effectiveness) and to the internal mammary nodes, 48.8 Gy (relative biological effectiveness), which indicates comprehensive coverage. Among 62 surviving patients, the 5-year rates for locoregional failure and overall survival were 1.5% and 91%, respectively. One patient developed grade 2 RP, and none developed grade 3 RP. No grade 4 toxicities occurred. The unplanned surgical re-intervention rate at 5 years was 33%. No significant changes in echocardiography or cardiac biomarkers after RT were found.

Conclusion: Proton beam RT for breast cancer has low toxicity rates and similar rates of disease control compared with historical data of conventional RT. No early cardiac changes were observed, which paves the way for randomized studies to compare proton beam RT with standard RT.
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http://dx.doi.org/10.1200/JCO.18.02366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351324PMC
October 2019

Multifocal Angiosarcoma Secondary to Partial Breast Irradiation: Reirradiate?

Int J Radiat Oncol Biol Phys 2019 09 22;105(1):17-18. Epub 2019 Jul 22.

Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.ijrobp.2018.07.006DOI Listing
September 2019

Increased distance from a treating proton center is associated with diminished ability to follow patients enrolled on a multicenter radiation oncology registry.

Radiother Oncol 2019 05 31;134:25-29. Epub 2019 Jan 31.

Departments of Radiation Oncology, Massachusetts General Hospital, Boston, USA. Electronic address:

Purpose: Consistent follow-up and data collection are necessary to identify long-term benefits/detriments of proton radiotherapy. Obtaining comprehensive clinical follow-up can be difficult and time-intensive for proton centers. Here we evaluate what factors affect maximum follow-up time among MGH Pediatric Proton Consortium Registry (PPCR) participants.

Patients And Methods: Enrollment in the PPCR was offered to any patient <22 years receiving protons. Patients were excluded from analysis if they were taken off study due to death or withdrawal. Distance from MGH was calculated by the great-circle formula. We utilized both univariate and multivariate analyses to determine risk factors associated with follow-up time.

Results: 333 PPCR patients enrolled between 10/2012 and 03/2017 were included. Median follow-up was 2.4 years (<1-5.5), and median distance away from the proton center was 256.4 km (<1.6-16,949.6). Distance from MGH significantly predicted follow-up time: patients living outside the Boston Metropolitan Statistical Area, >121 km from the proton center, had average follow-up that was 0.53 years less compared to those living within 121 km (p = 0.0002). Loss in average follow-up was also associated with Medicaid insurance, treatment delay due to insurance, and non-White race. Those co-enrolled on a proton trial or seen at a facility had significantly increased follow-up by almost one year (p < 0.0001).

Conclusion: Patients living further from treating proton center have shorter follow-up durations. Increased distance from treating centers may adversely affect clinical outcomes research. Enhanced sharing of medical information among care providers and improved collection methods are needed to effectively evaluate the benefits of proton therapy.
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http://dx.doi.org/10.1016/j.radonc.2019.01.007DOI Listing
May 2019

Tattoo free setup for partial breast irradiation: A feasibility study.

J Appl Clin Med Phys 2019 Apr;20(4):45-50

Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.

Purpose: Patients undergoing external beam accelerated partial breast irradiation (APBI) receive permanent tattoos to aid with daily setup alignment and verification. With the advent of three-dimensional (3D) body surface imaging and two-dimensional (2D) x-ray imaging-based matching to surgical clips, tattoos may not be necessary to ensure setup accuracy. We compared the accuracy of conventional tattoo-based setups to a patient setup without tattoos.

Materials/methods: Twenty consecutive patients receiving APBI at our institution from July 10, 2017 to February 13, 2018 were identified. All patients received tattoos per standard of care. Ten patients underwent setup using tattoos for initial positioning followed by surface imaging and 2D matching of surgical clips. The other ten patients underwent positioning using surface imaging followed by 2D matching without reference to tattoos. Overall setup time and orthogonal x-ray-based shifts after surface imaging per fraction were recorded. Shift data were used to calculate systematic and random error.

Results: Among ten patients in the "no tattoo" group, the average setup time per fraction was 6.83 min vs 8.03 min in the tattoo cohort (P < 0.01). Mean 3D vector shifts for patients in the "no tattoo" group were 4.6 vs 5.9 mm in the "tattoo" cohort (P = NS). Mean systematic errors in the "no tattoo" group were: 1.2 mm (1.5 mm SD) superior/inferior, 0.5 mm (1.6 mm SD) right/left, and 2.3 mm (1.9 mm SD) anterior/posterior directions. Mean systematic errors in the "tattoo" group were: 0.8 mm (2.2 mm SD) superior/inferior, 0.3 mm (2.5 mm SD) right/left, and 1.4 mm (4.4 mm SD) anterior/posterior directions. The random errors in the "no tattoo" group ranged from 0.6 to 0.7 mm vs 1.2 to 1.7 mm in the "tattoo" group.

Conclusions: Using both surface imaging and 2D matching to surgical clips provides excellent accuracy in APBI patient alignment and setup verification with reduced setup time relative to the tattoo cohort. Skin-based tattoos may no longer be warranted for patients receiving external beam APBI.
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http://dx.doi.org/10.1002/acm2.12557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448163PMC
April 2019

In Regard to Stecklein et al.

Int J Radiat Oncol Biol Phys 2019 04 13;103(5):1280-1281. Epub 2019 Mar 13.

Department of Radiation Oncology, University of Florida, Gainesville and Jacksonville, Florida.

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http://dx.doi.org/10.1016/j.ijrobp.2018.11.061DOI Listing
April 2019

Endocrine Deficiency As a Function of Radiation Dose to the Hypothalamus and Pituitary in Pediatric and Young Adult Patients With Brain Tumors.

J Clin Oncol 2018 10 17;36(28):2854-2862. Epub 2018 Aug 17.

Ralph E. Vatner, Andrzej Niemierko, Madhusmita Misra, Elizabeth A. Weyman, Claire P. Goebel, David H. Ebb, Robin M. Jones, Mary S. Huang, Takara Stanley, Shannon M. MacDonald, Nancy J. Tarbell, and Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Ralph E. Vatner, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Anita Mahajan, Mayo Clinic, Rochester, MN; and David R. Grosshans and Arnold C. Paulino, MD Anderson Cancer Center, Houston, TX.

Purpose: There are sparse data defining the dose response of radiation therapy (RT) to the hypothalamus and pituitary in pediatric and young adult patients with brain tumors. We examined the correlation between RT dose to these structures and development of endocrine dysfunction in this population.

Materials And Methods: Dosimetric and clinical data were collected from children and young adults (< 26 years of age) with brain tumors treated with proton RT on three prospective studies (2003 to 2016). Deficiencies of growth hormone (GH), thyroid hormone, adrenocorticotropic hormone, and gonadotropins were determined clinically and serologically. Incidence of deficiency was estimated using the Kaplan-Meier method. Multivariate models were constructed accounting for radiation dose and age.

Results: Of 222 patients in the study, 189 were evaluable by actuarial analysis, with a median follow-up of 4.4 years (range, 0.1 to 13.3 years), with 31 patients (14%) excluded from actuarial analysis for having baseline hormone deficiency and two patients (0.9%) because of lack of follow-up. One hundred thirty patients (68.8%) with medulloblastoma were treated with craniospinal irradiation (CSI) and boost; most of the remaining patients (n = 56) received involved field RT, most commonly for ependymoma (13.8%; n = 26) and low-grade glioma (7.4%; n = 14). The 4-year actuarial rate of any hormone deficiency, growth hormone, thyroid hormone, adrenocorticotropic hormone, and gonadotropin deficiencies were 48.8%, 37.4%, 20.5%, 6.9%, and 4.1%, respectively. Age at start of RT, time interval since treatment, and median dose to the combined hypothalamus and pituitary were correlated with increased incidence of deficiency.

Conclusion: Median hypothalamic and pituitary radiation dose, younger age, and longer follow-up time were associated with increased rates of endocrinopathy in children and young adults treated with radiotherapy for brain tumors.
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http://dx.doi.org/10.1200/JCO.2018.78.1492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161835PMC
October 2018

Asymptomatic Late-phase Radiographic Changes Among Chest-Wall Patients Are Associated With a Proton RBE Exceeding 1.1.

Int J Radiat Oncol Biol Phys 2018 07 17;101(4):809-819. Epub 2018 Apr 17.

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Purpose: Clinical practice assumes a fixed proton relative biological effectiveness (RBE) of 1.1, but in vitro experiments demonstrate higher RBEs at the distal edge of the proton spread-out Bragg peak, that is, in a region that falls within the lung for chest-wall patients. We performed retrospective qualitative and quantitative analyses of lung-density changes-indicative of asymptomatic fibrosis-for chest-wall patients treated with protons or photons. Our null hypothesis was that, assuming a fixed RBE of 1.1, these changes would be the same for the 2 cohorts, supporting current RBE practice. Our alternative hypothesis was that radiographic abnormalities would be greater for the proton cohort, suggesting an RBE > 1.1.

Methods And Materials: We analyzed follow-up computed tomography (CT) scans for 20 proton and photon patients. All were prescribed 50.4 Gy (RBE) in 28 fractions, assuming a fixed RBE of 1.1 for protons and 1 for photons. Deformable registrations enabled us to calculate density changes in the normal lung, specifically (1) median Hounsfield unit (HU) values among posttreatment CT scans and (2) changes in median HU values between pretreatment and posttreatment CT scans, both as a function of grays (RBE). In addition, qualitative abnormality grading was performed by a radiologist.

Results: Proton patients exhibited higher values of HU/Gy (RBE) (endpoint 1) and ΔHU/Gy (RBE) (endpoint 2): P = .049 and P = .00019, respectively, were obtained (likelihood ratio tests of full linear mixed-effects models against models without "modality"). Furthermore, qualitative radiologic scoring indicated a significant difference between the cohorts (Wilcoxon P = .018; median score, 3 of 9 for protons and 1.5 of 9 for photons).

Conclusions: Our data support the hypothesis that the proton RBE for lung-density changes exceeds 1.1. This RBE elevation could be attributable to (1) the late, normal tissue endpoint that we consider or (2) end-of-range proton linear energy transfer elevation-or a combination of the two. Regardless, our results suggest that variations in proton RBE prove important in vivo as well as in vitro.
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http://dx.doi.org/10.1016/j.ijrobp.2018.03.037DOI Listing
July 2018

Proton therapy for pediatric malignancies: Fact, figures and costs. A joint consensus statement from the pediatric subcommittee of PTCOG, PROS and EPTN.

Radiother Oncol 2018 07 21;128(1):44-55. Epub 2018 Jun 21.

Department of Radiation Oncology, Mayo Clinic, Rochester, USA.

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.
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http://dx.doi.org/10.1016/j.radonc.2018.05.020DOI Listing
July 2018

Quality of life in patients with proton-treated pediatric medulloblastoma: Results of a prospective assessment with 5-year follow-up.

Cancer 2018 08 15;124(16):3390-3400. Epub 2018 Jun 15.

Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts.

Background: To the authors' knowledge, health-related quality of life (HRQOL) outcomes are not well described in patients with medulloblastoma. The use of proton radiotherapy (RT) may translate into an improved HRQOL. In the current study, the authors report long-term HRQOL in patients with proton-treated pediatric medulloblastoma.

Methods: The current study was a prospective cohort HRQOL study of patients with medulloblastoma who were treated with proton RT and enrolled between August 5, 2002, and October 8, 2015. Both child report and parent-proxy report Pediatric Quality of Life Inventory (PedsQL) surveys were collected at baseline during RT and annually thereafter (score range on surveys of 0-100, with higher scores indicating better HRQOL). Patients were dichotomized by clinical/treatment variables and subgroups were compared. Mixed-model analysis was performed to determine the longitudinal trajectory of PedsQL scores. The Student t test was used to compare long-term HRQOL measures with published means from a healthy child population.

Results: Survey data were evaluable for 116 patients with a median follow-up of 5 years (range, 1-10.6 years); the median age at the time of diagnosis was 7.6 years (range, 2.1-18.1 years). At baseline, children reported a total core score (TCS) of 65.9, which increased by 1.8 points annually (P<.001); parents reported a TCS of 59.1, which increased by 2.0 points annually. Posterior fossa syndrome adversely affected baseline scores, but these scores significantly improved with time. At the time of last follow-up, children reported a TCS of 76.3, which was 3.3 points lower than that of healthy children (P = .09); parents reported a TCS of 69, which was 11.9 points lower than that of parents of healthy children (P<.001). Increased follow-up time from diagnosis correlated with improved HRQOL scores.

Conclusions: HRQOL scores appear to increase over time after treatment in children treated with proton RT for medulloblastoma but remain lower compared with those of parent-proxy reports as well as published means from a healthy normative sample of children. Additional follow-up may translate into continued improvements in HRQOL. Cancer 2018. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31575DOI Listing
August 2018

Estimated IQ Systematically Underestimates Neurocognitive Sequelae in Irradiated Pediatric Brain Tumor Survivors.

Int J Radiat Oncol Biol Phys 2018 07 21;101(3):541-549. Epub 2018 Mar 21.

Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Purpose: While cranial irradiation is often essential to attain a cure for pediatric brain tumors, it is associated with adverse neurocognitive outcomes, primarily manifested as declines in full-scale IQ (FSIQ). This decline results primarily from a decline in processing speed, a component of FSIQ. However, estimated IQ (EIQ) is frequently used in research and clinical settings but does not incorporate processing speed. We hypothesized that EIQ systematically underestimates neurocognitive sequelae in irradiated pediatric brain tumor survivors.

Methods And Materials: We treated 185 pediatric brain tumor patients with proton radiation therapy. All patients had at least 1 neuropsychological evaluation at baseline and/or 1 or more follow-up evaluations with sufficient data to calculate both FSIQ and EIQ. The Wechsler Intelligence Scales were used to calculate FSIQ and EIQ for each patient, and mixed linear models were used to assess disparities between FSIQ and EIQ.

Results: At baseline, EIQ was 2.2 points (95% confidence interval 1.2-3.2 points) higher on average than FSIQ (P < .001). The median follow-up period was 26 months. The disparity between EIQ and FSIQ persisted and worsened over time (P = .012), with FSIQ losing on average 0.4 points/year (95% confidence interval 0.01-0.8 points/year) relative to EIQ. The disparity at baseline varied with sex and age.

Conclusions: EIQ systematically underestimates the neurocognitive sequelae of children treated with cranial radiation therapy. FSIQ is much more likely than EIQ to identify neurocognitive deficits, allowing for appropriate interventions, as well as academic services and accommodations. Thus, EIQ should have a very limited role in both clinical and research settings for this population.
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http://dx.doi.org/10.1016/j.ijrobp.2018.03.012DOI Listing
July 2018

Proton therapy for central nervous system tumors in children.

Pediatr Blood Cancer 2018 07 6;65(7):e27046. Epub 2018 Apr 6.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland.

Proton therapy is a form of particle therapy with physical properties that provide a superior dose distribution compared to photons. The ability to spare healthy, developing tissues from low dose radiation with proton therapy is well known. The capability to decrease radiation exposure for children has been lauded as an important advance in pediatric cancer care, particularly for central nervous system (CNS) tumors. Favorable clinical outcomes have been reported and justify the increased cost and burden of this therapy. In this review, we summarize the current literature for proton therapy for pediatric CNS malignancies, with a focus on clinical outcomes to date.
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http://dx.doi.org/10.1002/pbc.27046DOI Listing
July 2018

Left hippocampal dosimetry correlates with visual and verbal memory outcomes in survivors of pediatric brain tumors.

Cancer 2018 05 2;124(10):2238-2245. Epub 2018 Mar 2.

Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts.

Background: Radiotherapy (RT) in the pediatric brain tumor population causes late neurocognitive effects. In the current study, the authors investigated associations between clinical and dosimetric risk factors and memory outcomes in a cohort of patients treated with proton radiotherapy (PRT).

Methods: A total of 70 patients (median age at PRT, 12.1 years [range, 5.0-22.5 years]) who were treated with PRT were identified with baseline and follow-up evaluations of visual and verbal memory (Children's Memory Scale and the third edition of the Wechsler Memory Scale). Whole-brain as well as bilateral hippocampal and temporal lobe contours were delineated for the calculation of dosimetric indices. Multivariate analyses were performed to assess associations of score changes over time with clinical factors and dosimetric indices.

Results: The median neurocognitive follow-up was 3.0 years (range, 1.1-11.4 years). For the entire cohort, delayed and immediate verbal memory scaled scores demonstrated small declines. The mean decline for delayed verbal memory scores was 0.6 (P = .01), and that for immediate verbal memory scores was 0.5 (P = .06). Immediate and delayed visual memory scores were not found to change significantly (+0.1 and -0.3, respectively; P>.30). A higher left hippocampal V (percentage of the volume of a particular anatomical region receiving at least a 20 gray equivalent) was correlated with a score decline in all 4 measures. Female sex was found to be predictive of lower delayed verbal memory follow-up scores (P = .035).

Conclusions: Only delayed verbal memory scores were found to have declined statistically significantly at follow-up after PRT, reflecting some weakness in verbal memory retrieval. Given a correlation of left hippocampal dosimetry and memory outcomes after PRT, left hippocampal-sparing PRT plans may assist patients with pediatric brain tumors in preserving memory-retrieval abilities. Cancer 2018;124:2238-45. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31143DOI Listing
May 2018

Brainstem Injury in Pediatric Patients With Posterior Fossa Tumors Treated With Proton Beam Therapy and Associated Dosimetric Factors.

Int J Radiat Oncol Biol Phys 2018 03 23;100(3):719-729. Epub 2017 Nov 23.

Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Purpose: Proton radiation therapy is commonly used in young children with brain tumors for its potential to reduce late effects. However, some proton series report higher rates of brainstem injury (0%-16%) than most photon series (2.2%-8.6%). We report the incidence of brainstem injury and a risk factor analysis in pediatric patients with posterior fossa primary tumors treated with proton radiation therapy at our institution.

Methods And Materials: The study included 216 consecutive patients treated between 2000 and 2015. Dosimetry was available for all but 4 patients. Grade 2 to 5 late brainstem toxicity was assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

Results: The histologies include medulloblastoma (n=154, 71.3%), ependymoma (n=56, 25.9%), and atypical teratoid rhabdoid tumor (n=6, 2.8%). The median age at irradiation was 6.6 years (range, 0.5-23.1 years); median dose, 54 gray relative biological effectiveness (Gy RBE) (range, 46.8-59.4 Gy RBE); and median follow-up period, 4.2 years (range, 0.1-15.3 years) among 198 survivors. Of the patients, 83.3% received chemotherapy; 70.4% achieved gross total resection. The crude rate of injury was 2.3% in all patients, 1.9% in those with medulloblastoma, 3.6% in those with ependymoma, and 0% in those with atypical teratoid rhabdoid tumor. The 5-year cumulative incidence of injury was 2.0% (95% confidence interval, 0.7%-4.8%). The median brainstem dose (minimum dose received by 50% of brainstem) in the whole cohort was 53.6 Gy RBE (range, 16.5-56.8 Gy RBE); maximum point dose within the brainstem (D), 55.2 Gy RBE (range, 48.4-60.5 Gy RBE); and mean dose, 50.4 Gy RBE (range, 21.1-56.7 Gy RBE). In the 5 patients with injury, the median minimum dose received by 50% of the brainstem was 54.6 Gy RBE (range, 50.2-55.1 Gy RBE); D, 56.2 Gy RBE (range, 55.0-57.1 Gy RBE); mean dose, 51.3 Gy RBE (range, 45.4-54.4 Gy RBE); and median volume of the brainstem receiving ≥55 Gy RBE (V), 27.4% (range, 0%-59.4%). Of the 5 patients with injury, 4 had a brainstem D in the highest quartile (≥55.8 Gy RBE, P = .016) and a V in the highest tertile (>6.0%) of the cohort distribution (P = .047). Of the 5 patients with injury, 3 were aged >6 years (age range, 4.1-22.8 years), and 4 of 5 patients received chemotherapy and achieved gross total resection.

Conclusions: The incidence of injury in pediatric patients with posterior fossa tumors is consistent with previous reports in the photon setting. Our data suggest that when D and V are kept <55.8 Gy RBE and ≤6.0%, respectively, the 5-year rate of radiation brainstem injury would be <2%.
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http://dx.doi.org/10.1016/j.ijrobp.2017.11.026DOI Listing
March 2018

Reirradiation for Recurrent Pediatric Central Nervous System Malignancies: A Multi-institutional Review.

Int J Radiat Oncol Biol Phys 2017 11 29;99(3):634-641. Epub 2017 Jul 29.

Department of Radiation and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center Johns Hopkins School of Medicine, Baltimore, Maryland. Electronic address:

Purpose: Reirradiation has been proposed as an effective modality for recurrent central nervous system (CNS) malignancies in adults. We evaluated the toxicity and outcomes of CNS reirradiation in pediatric patients.

Methods And Materials: The data from pediatric patients <21 years of age at the initial diagnosis who developed a recurrent CNS malignancy that received repeat radiation therapy (RT) across 5 facilities in an international pediatric research consortium were retrospectively reviewed.

Results: Sixty-seven pediatric patients underwent CNS reirradiation. The primary diagnoses included medulloblastoma/primitive neuroectodermal tumor (n=20; 30%), ependymoma (n=19; 28%), germ cell tumor (n=8; 12%), high-grade glioma (n=9; 13%), low-grade glioma (n=5; 7%), and other (n=6; 9%). The median age at the first course of RT was 8.5 years (range 0.5-19.5) and was 12.3 years (range 3.3-30.2) at reirradiation. The median interval between RT courses was 2.0 years (range 0.3-16.5). The median radiation dose and fractionation in equivalent 2-Gy fractions was 63.7 Gy (range 27.6-74.8) for initial RT and 53.1 Gy (range 18.6-70.1) for repeat RT. The relapse location was infield in 52 patients (78%) and surrounding the initial RT field in 15 patients (22%). Thirty-seven patients (58%) underwent gross or subtotal resection at recurrence. The techniques used for reirradiation were intensity modulated RT (n=46), 3-dimensional conformal RT (n=9), stereotactic radiosurgery (n=4; 12-13 Gy × 1 or 5 Gy × 5), protons (n=4), combined modality (n=3), 2-dimensional RT (n=1), and brachytherapy (n=1). Radiation necrosis was detected in 2 patients after the first RT course and 1 additional patient after reirradiation. Six patients (9%) developed secondary neoplasms after initial RT (1 hematologic, 5 intracranial). One patient developed a secondary neoplasm identified shortly after repeat RT. The median overall survival after completion of repeat RT was 12.8 months for the entire cohort and 20.5 and 8.4 months for patients with recurrent ependymoma and medulloblastoma after reirradiation, respectively.

Conclusions: CNS reirradiation in pediatric patients could be a reasonable treatment option, with moderate survival noted after repeat RT. However, prospective data characterizing the rates of local control and toxicity are needed.
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http://dx.doi.org/10.1016/j.ijrobp.2017.07.026DOI Listing
November 2017

Executive functioning, academic skills, and quality of life in pediatric patients with brain tumors post-proton radiation therapy.

J Neurooncol 2018 Mar 6;137(1):119-126. Epub 2017 Dec 6.

Department of Psychiatry, Massachusetts General Hospital, Boston, MA, 02114, USA.

Radiation therapy (RT) is integral in the treatment of pediatric brain tumors; however, photon RT (XRT) often results in intellectual decline, executive functioning (EF) deficits, academic underachievement/failure, and lower health-related quality of life (HRQoL). Proton RT (PRT) provides more targeted therapy, minimizing damage to the developing brain, yet few studies have examined its neuropsychological effects. This study investigated the role of EF in academic skills and HRQoL in a sample of children treated with PRT. A mediation model was proposed in which academic skills mediated relations between aspects of EF and school-based HRQoL (sHRQoL). Sixty-five children (x̅ = 12.4; 43.9% male) treated with PRT completed follow-up neuropsychological testing as part of routine care. Measures included assessment of intellectual functioning, EF, attention, and academic skills (reading, math, spelling). Parents reported on children's EF and attention problems. sHRQoL was assessed via child self-report. Children who underwent PRT demonstrated relatively intact intelligence, academics, attention, EF, and sHRQoL, but were at risk for reduced processing speed. Poorer working memory and processing speed were related to lower sHRQoL. Better EF and faster processing speed were associated with better academic skills, which were linked to higher sHRQoL. Better working memory was associated with better math performance, which was linked to higher sHRQoL; this relationship did not hold for reading or spelling. Results highlight the importance of EF skills in academic performance and sHRQoL, and the need for routine screening of EF deficits and proactive supports. Supports may include cognitive rehabilitation and in-class accommodations. Overall, results compare favorably to XRT outcomes reported in the literature.
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http://dx.doi.org/10.1007/s11060-017-2703-6DOI Listing
March 2018

Postmastectomy radiation therapy technique and cardiopulmonary sparing: A dosimetric comparative analysis between photons and protons with free breathing versus deep inspiration breath hold.

Pract Radiat Oncol 2017 Nov - Dec;7(6):e377-e384. Epub 2017 Jun 21.

Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts.

Purpose: Dosimetric studies have suggested greater cardiopulmonary sparing with protons over photons for left-sided postmastectomy radiation therapy (PMRT). Modern techniques such as deep inspiration breath hold (DIBH) can help spare the heart. This analysis compares photon and proton delivery with and without DIBH.

Methods And Materials: Ten women with left breast cancer referred for PMRT on a prospective clinical trial with unfavorable cardiac anatomy underwent free breathing (FB) and DIBH computed tomography simulation. A partially wide tangent photon (PWTF) during DIBH, passively scattered proton during FB, pencil-beam scanning (PBS) proton during FB, and PBS proton during DIBH plan was completed for each patient. Plans were designed to achieve 95% prescription dose coverage to 95% of chest wall and regional lymphatics while maximally sparing heart and lungs.

Results: All techniques resulted in similar target coverage, although protons improved homogeneity indices and cardiopulmonary sparing (omnibus P < .0001 for each metric). Heart/lung metrics for PWTF with DIBH, scattered protons with FB, PBS protons with FB, and PBS protons with DIBH, respectively, were as follows: mean heart dose (2.09, 0.39, 0.98, 0.71 Gy relative biological effectiveness [RBE]), mean left ventricle dose (3.72, 0.08, 0.19, 0.21 GyRBE), V20 left ventricle (2.73, 0.03, 0, 0%), maximum left anterior descending artery dose (46.14, 8.28, 4.58, 4.63 GyRBE), mean lung dose (13.30, 5.74, 7.63, 7.49 GyRBE), and V20 lung (26.04, 12.04, 15.18, 14.43 %). Pairwise testing confirmed an improvement in each metric with all proton plans compared with PWTF with DIBH; there were no differences in homogeneity indices or cardiopulmonary sparing between passively scattered and PBS protons, regardless of addition of DIBH.

Conclusions: For left-sided PMRT, passively scattered or PBS protons with or without DIBH improves homogeneity and cardiopulmonary sparing without compromise in target coverage compared with PWTF photons with DIBH. Furthermore, the addition of DIBH to proton therapy did not provide a significant dosimetric benefit.
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http://dx.doi.org/10.1016/j.prro.2017.06.006DOI Listing
July 2018

Practice patterns of palliative radiation therapy in pediatric oncology patients in an international pediatric research consortium.

Pediatr Blood Cancer 2017 Nov 11;64(11). Epub 2017 Jul 11.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD.

Background/objectives: The practice of palliative radiation therapy (RT) is based on extrapolation from adult literature. We evaluated patterns of pediatric palliative RT to describe regimens used to identify opportunity for future pediatric-specific clinical trials.

Design/methods: Six international institutions with pediatric expertise completed a 122-item survey evaluating patterns of palliative RT for patients ≤21 years old from 2010 to 2015. Two institutions use proton RT. Palliative RT was defined as treatment with the goal of symptom control or prevention of immediate life-threatening progression.

Results: Of 3,225 pediatric patients, 365 (11%) were treated with palliative intent to a total of 427 disease sites. Anesthesia was required in 10% of patients. Treatment was delivered to metastatic disease in 54% of patients. Histologies included neuroblastoma (30%), osteosarcoma (18%), leukemia/lymphoma (12%), rhabdomyosarcoma (12%), medulloblastoma/ependymoma (12%), Ewing sarcoma (8%), and other (8%). Indications included pain (43%), intracranial symptoms (23%), respiratory compromise (14%), cord compression (8%), and abdominal distention (6%). Sites included nonspine bone (35%), brain (16% primary tumors, 6% metastases), abdomen/pelvis (15%), spine (12%), head/neck (9%), and lung/mediastinum (5%). Re-irradiation comprised 16% of cases. Techniques employed three-dimensional conformal RT (41%), intensity-modulated RT (23%), conventional RT (26%), stereotactic body RT (6%), protons (1%), electrons (1%), and other (2%). The most common physician-reported barrier to consideration of palliative RT was the concern about treatment toxicity (83%).

Conclusion: There is significant diversity of practice in pediatric palliative RT. Combined with ongoing research characterizing treatment response and toxicity, these data will inform the design of forthcoming clinical trials to establish effective regimens and minimize treatment toxicity for this patient population.
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http://dx.doi.org/10.1002/pbc.26589DOI Listing
November 2017

Analysis of patient outcomes following proton radiation therapy for retinoblastoma.

Adv Radiat Oncol 2017 Jan-Mar;2(1):44-52

Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA.

Purpose: Proton radiotherapy (PRT) is used in the treatment of retinoblastoma (RB) and has the potential to minimize exposure of normal tissue to radiation and thus decrease risk of toxicity and second malignancies. However, comprehensive analyses of long-term patient outcomes are not available.

Methods: RB patients treated with PRT at our institution between 1986 and 2012 were invited to return for participation in a study designed to assess long-term outcomes. Enrolled patients underwent comprehensive analysis including oncologic, ophthalmic, endocrine, cephalometric, and quality of life (QOL) assessments.

Results: A total of 12 patients were enrolled in this study, and the average length of follow-up among enrolled patients was 12.9 years (range 4.8-22.2 years). All enrolled patients had bilateral disease, and the disease and visual outcomes for enrolled patients were similar to outcomes for all RB patients treated with PRT over the same time period at our institution. Endocrine evaluation revealed no growth abnormalities or hormonal deficiencies across the cohort. Based on MRI and external cephalometry, PRT was associated with less facial hypoplasia than enucleation. Patient and parent-proxy QOL assessments revealed that RB treatment did not appear to severely impact long-term QOL.

Conclusions: In addition to providing an opportunity for long-term disease control and functional eye preservation, PRT does not appear to be associated with unexpected late visual, endocrine, or QOL effects in this cohort.
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http://dx.doi.org/10.1016/j.adro.2016.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465815PMC
June 2017

Evaluating Intensity Modulated Proton Therapy Relative to Passive Scattering Proton Therapy for Increased Vertebral Column Sparing in Craniospinal Irradiation in Growing Pediatric Patients.

Int J Radiat Oncol Biol Phys 2017 05 1;98(1):37-46. Epub 2017 Feb 1.

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Purpose: At present, proton craniospinal irradiation (CSI) for growing children is delivered to the whole vertebral body (WVB) to avoid asymmetric growth. We aimed to demonstrate the feasibility and potential clinical benefit of delivering vertebral body sparing (VBS) versus WVB CSI with passively scattered (PS) and intensity modulated proton therapy (IMPT) in growing children treated for medulloblastoma.

Methods And Materials: Five plans were generated for medulloblastoma patients, who had been previously treated with CSI PS proton radiation therapy: (1) single posteroanterior (PA) PS field covering the WVB (PS-PA-WVB); (2) single PA PS field that included only the thecal sac in the target volume (PS-PA-VBS); (3) single PA IMPT field covering the WVB (IMPT-PA-WVB); (4) single PA IMPT field, target volume including thecal sac only (IMPT-PA-VBS); and (5) 2 posterior-oblique (-35°, +35°) IMPT fields, with the target volume including the thecal sac only (IMPT2F-VBS). For all cases, 23.4 Gy (relative biologic effectiveness [RBE]) was prescribed to 95% of the spinal canal. The dose, linear energy transfer, and variable-RBE-weighted dose distributions were calculated for all plans using the tool for particle simulation, version 2, Monte Carlo system.

Results: IMPT VBS techniques efficiently spared the anterior vertebral bodies (AVBs), even when accounting for potential higher variable RBE predicted by linear energy transfer distributions. Assuming an RBE of 1.1, the V10 Gy(RBE) decreased from 100% for the WVB techniques to 59.5% to 76.8% for the cervical, 29.9% to 34.6% for the thoracic, and 20.6% to 25.1% for the lumbar AVBs, and the V20 Gy(RBE) decreased from 99.0% to 17.8% to 20.0% for the cervical, 7.2% to 7.6% for the thoracic, and 4.0% to 4.6% for the lumbar AVBs when IMPT VBS techniques were applied. The corresponding percentages for the PS VBS technique were higher.

Conclusions: Advanced proton techniques can sufficiently reduce the dose to the vertebral body and allow for vertebral column growth for children with central nervous system tumors requiring CSI. This was true even when considering variable RBE values. A clinical trial is planned for VBS to the thoracic and lumbosacral spine in growing children.
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http://dx.doi.org/10.1016/j.ijrobp.2017.01.226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466873PMC
May 2017