Publications by authors named "Torunn I Yock"

117 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

Circulating Lymphocyte Counts Early During Radiotherapy are Associated with Recurrence in Pediatric Medulloblastoma.

Int J Radiat Oncol Biol Phys 2021 Feb 5. Epub 2021 Feb 5.

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

Background: Decreased peripheral lymphocyte counts are associated with outcome after RT in several solid tumors, though appear late during or after the radiation course and often correlate with other clinical factors. Here we investigate if absolute lymphocyte counts (ALC) are independently associated with recurrence in pediatric medulloblastoma early during RT.

Methods: We assessed 202 medulloblastoma patients treated between 2000 and 2016 and analyzed ALC throughout therapy, focusing on both early markers (ALC during week 1 - ALC; grade 3+ Lymphopenia during week 2 - Lymphopenia) and late markers (ALC nadir). Uni- and multivariable regressions were used to assess association of clinical and treatment variables with ALC and of ALC with recurrence.

Results: Thirty-six recurrences were observed, with a median time to recurrence of 1.6 years (Range 0.2-10.3) and 7.1 years median follow-up. ALC during RT was associated with induction chemotherapy (p<0.001), concurrent carboplatin (p=0.009), age (p=0.01) and high-risk status (p=0.05). On univariable analysis, high-risk disease (HR 2.0[1.06-3.9],p=0.03) and M stage≥1 (HR 2.2[1.1-4.4]) were associated with recurrence risk, as was lower ALC early during RT (ALC HR 0.28[0.12-0.65],p=0.003; Lymphopenia HR 2.27[1.1-4.6],p=0.02). Neither baseline ALC nor nadir correlated with outcome. These associations persisted when excluding carboplatin and pre-RT chemotherapy patients, and in the multivariable analysis accounting for confounders lymphocyte counts remain significant (ALC HR 0.23[0.09-0.57],p=0.002; Lymphopenia HR 2.3[1.1-4.8],p=0.03).

Conclusion: ALC during weeks 1 and 2 of RT was associated with recurrence and low ALC is an independent prognostic factor in medulloblastoma. Strategies to mitigate the risk of radiation-induced lymphopenia should be considered.
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http://dx.doi.org/10.1016/j.ijrobp.2021.01.035DOI Listing
February 2021

Local control for high-grade Non-Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS) assigned to radiation therapy on xxx: A report from the xxx.

Int J Radiat Oncol Biol Phys 2021 Feb 3. Epub 2021 Feb 3.

University of California Davis, Sacramento, CA.

Purpose: XXX trial for pediatric and young adults with NRSTS used risk-based treatment including primary resection with lower-than-standard radiation doses to optimize local control (LC) while minimizing long-term toxicity in those requiring radiation therapy (RT). RT for high-grade NRSTS was based extent of resection (R0: negative margins, R1: microscopic margins, R2/U: gross disease/unresectable); those with >5 cm tumors received chemotherapy (CT; ifosfamide/doxorubicin). This analysis evaluates LC for patients assigned to RT and prognostic factors associated with local recurrence (LR).

Patients And Methods: Patients <30 years with high-grade NRSTS received RT (55.8 Gy) for R1 ≤ 5cm tumor (Arm B), RT (55.8 Gy)/CT for R0/R1 >5 cm tumor (Arm C), or neoadjuvant RT (45 Gy)/CT plus delayed surgery, CT, and post-operative boost for 10.8 Gy R0 <5mm margins/R1,19.8 Gy R2/U (Arm D).

Results: 193 eligible patients had 24 LR: Arm B 1/15 (6.7%), Arm C 7/65 (10.8%), Arm D 16/113 (14.2%) at median time to LR 1.1 years (range 0.11-5.27). Of 95 eligible for delayed surgery after neoadjuvant therapy, 89 (93.7%) achieved R0/R1 margins. Overall LC after RT were: R0 106/109 (97%), R1 51/60 (85%), R2/unresectable 2/6 (33%). LR predictors include extent of delayed resection (p<0.001), imaging response before delayed surgery (p<0.001), histologic subtype (p<0.001), and no RT (p=0.046). The 5-year event-free survival (EFS) was significantly lower (p=0.0003) for patients unable to undergo R0/R1 resection.

Conclusion: Risk-based treatment for young patients with high-grade NRSTS treated on xxx produced very high LC, particularly after R0 resection (97%) despite lower-than-standard RT doses. Neoadjuvant CT/RT enabled delayed R0/R1 resection in most patients and is preferred over adjuvant therapy due to the lower RT dose delivered.
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http://dx.doi.org/10.1016/j.ijrobp.2021.01.051DOI Listing
February 2021

Case report: Intra-arterial chemotherapy for rhabdomyosarcoma.

Pediatr Hematol Oncol 2021 Jan 13:1-6. Epub 2021 Jan 13.

University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colorado, USA.

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http://dx.doi.org/10.1080/08880018.2020.1871138DOI Listing
January 2021

Metabolic response as assessed by F-fluorodeoxyglucose positron emission tomography-computed tomography does not predict outcome in patients with intermediate- or high-risk rhabdomyosarcoma: A report from the Children's Oncology Group Soft Tissue Sarcoma Committee.

Cancer Med 2021 Feb 19;10(3):857-866. Epub 2020 Dec 19.

Seattle Children's Hospital, Seattle, WA, USA.

Background: Strategies to optimize management in rhabdomyosarcoma (RMS) include risk stratification to assign therapy aiming to minimize treatment morbidity yet improve outcomes. This analysis evaluated the relationship between complete metabolic response (CMR) as assessed by F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET) imaging and event-free survival (EFS) in intermediate-risk (IR) and high-risk (HR) RMS patients.

Methods: FDG-PET imaging characteristics, including assessment of CMR and maximum standard uptake values (SUVmax) of the primary tumor, were evaluated by central review. Institutional reports of SUVmax were used when SUVmax values could not be determined by central review. One hundred and thirty IR and 105 HR patients had FDG-PET scans submitted for central review or had SUVmax data available from institutional report at any time point. A Cox proportional hazards regression model was used to evaluate the relationship between these parameters and EFS.

Results: SUVmax at study entry did not correlate with EFS for IR (p = 0.32) or HR (p = 0.86) patients. Compared to patients who did not achieve a CMR, EFS was not superior for IR patients who achieved a CMR at weeks 4 (p = 0.66) or 15 (p = 0.46), nor for HR patients who achieved CMR at week 6 (p = 0.75) or 19 (p = 0.28). Change in SUVmax at week 4 (p = 0.21) or 15 (p = 0.91) for IR patients or at week 6 (p = 0.75) or 19 (p = 0.61) for HR patients did not correlate with EFS.

Conclusion: Based on these data, FDG-PET does not appear to predict EFS in IR or HR-RMS. It remains to be determined whether FDG-PET has a role in predicting survival outcomes in other RMS subpopulations.
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http://dx.doi.org/10.1002/cam4.3667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897958PMC
February 2021

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

Risk of Pneumonitis and Outcomes After Mediastinal Proton Therapy for Relapsed/Refractory Lymphoma: A PTCOG and PCG Collaboration.

Int J Radiat Oncol Biol Phys 2021 Jan 28;109(1):220-230. Epub 2020 Aug 28.

Department of Radiation Oncology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania.

Purpose: Despite high response rates, there has been reluctance to use radiation therapy for patients with relapsed/refractory (r/r) Hodgkin (HL) or aggressive non-Hodgkin lymphoma (NHL) given concerns for subacute and late toxicities. Symptomatic pneumonitis, a subacute toxicity, has an incidence of 17% to 24% (≥grade 2) even with intensity modulated radiation therapy. Proton therapy (PT), which has no exit radiation dose, is associated with a lower dose to lung compared with other radiation techniques. As risk of radiation pneumonitis is associated with lung dose, we evaluated whether pneumonitis rates are lower with PT.

Methods And Materials: Within an international, multi-institutional cohort, we retrospectively evaluated the incidence and grade of radiation pneumonitis (National Cancer Institute Common Terminology Criteria for Adverse Events v4) among patients with r/r HL or NHL treated with PT.

Results: A total of 85 patients with r/r lymphoma (66% HL, 34% NHL; 46% primary chemorefractory) received thoracic PT from 2009 to 2017 in the consolidation (45%) or salvage (54%) setting. Median dose was 36 Gy(RBE). Before PT, patients underwent a median of 1 salvage systemic therapy (range, 0-4); 40% received PT within 4 months of transplant. With a median follow-up of 26.3 months among living patients, 11 patients developed symptomatic (grade 2) pneumonitis (12.8%). No grade 3 or higher pneumonitis was observed. Dose to lung, including mean lung dose, lung V5, and V20, significantly predicted risk of symptomatic pneumonitis, but not receipt of brentuximab, history of bleomycin toxicity, sex, or peritransplant radiation.

Conclusions: PT for relapsed/refractory lymphoma was associated with favorable rates of pneumonitis compared with historical controls. We confirm that among patients treated with PT, pneumonitis risk is associated with mean lung and lung V20 dose. These findings highlight how advancements in radiation delivery may improve the therapeutic ratio for patients with relapsed/refractory lymphoma. PT may be considered as a treatment modality for patients with relapsed/refractory lymphoma in the consolidation or salvage setting.
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http://dx.doi.org/10.1016/j.ijrobp.2020.08.055DOI Listing
January 2021

Prolongation of radiotherapy duration is associated with inferior overall survival in patients with pediatric medulloblastoma and central nervous system primitive neuroectodermal tumors.

Pediatr Blood Cancer 2020 10 25;67(10):e28558. Epub 2020 Jul 25.

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

Background: The importance of radiotherapy (RT) duration in medulloblastoma in the modern era of chemotherapy has not been well elucidated. The aim of this study was to determine the impact of RT treatment duration on overall survival (OS) in pediatric medulloblastoma and cenral nervous system neuroectodermal tumors (PNETs).

Methods: The National Cancer Database (NCDB) was queried to identify patients with newly diagnosed medulloblastoma and CNS PNETs diagnosed between 2004 and 2014. Patients were excluded if they had extraneural metastasis, did not receive standard craniospinal irradiation dose, had a nonstandard total dose outside of 54 or 55.8 Gy, did not receive adjuvant chemotherapy, or if the RT duration was outside of the expected range of 37 to 80 days. The Kaplan-Meier estimator was used to estimate the association between RT duration (≤45 days or >45 days) and OS. Multivariate Cox regression was used to assess other confounders of OS.

Results: Six-hundred twenty-five patients met inclusion criteria, of which 181 were assigned to the "RT long" (>45 days) cohort (29.0%) and 444 (71.0%) to the "RT short" group (≤45 days). The five-year OS for the "RT short" compared with "RT long" cohort was 82.2% versus 70.9%, respectively (log-rank, P < 0.0037). For average risk patients, the five-year OS was 84.6% versus 86.4% for "RT short" and "RT long," respectively (log-rank, P = 0.40). However, for high-risk patients, five-year OS was 77.7% versus 51.0% (log-rank, P < 0.0001) in the "RT short" and "RT long" cohorts.

Conclusion: For patients with high-risk medulloblastoma and CNS PNETs, RT duration >45 days was associated with inferior OS.
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http://dx.doi.org/10.1002/pbc.28558DOI Listing
October 2020

Modern Radiotherapy for Pediatric Brain Tumors.

Cancers (Basel) 2020 Jun 11;12(6). Epub 2020 Jun 11.

Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, 55 Fruit St, Boston, MA 02114, USA.

Cancer is a leading cause of death in children with tumors of the central nervous system, the most commonly encountered solid malignancies in this population. Radiotherapy (RT) is an integral part of managing brain tumors, with excellent long-term survival overall. The tumor histology will dictate the volume of tissue requiring treatment and the dose. However, radiation in developing children can yield functional deficits and/or cosmetic defects and carries a risk of second tumors. In particular, children receiving RT are at risk for neurocognitive effects, neuroendocrine dysfunction, hearing loss, vascular anomalies and events, and psychosocial dysfunction. The risk of these late effects is directly correlated with the volume of tissue irradiated and dose delivered and is inversely correlated with age. To limit the risk of developing these late effects, improved conformity of radiation to the target volume has come from adopting a volumetric planning process. Radiation beam characteristics have also evolved to achieve this end, as exemplified through development of intensity modulated photons and the use of protons. Understanding dose limits of critical at-risk structures for different RT modalities is evolving. In this review, we discuss the physical basis of the most common RT modalities used to treat pediatric brain tumors (intensity modulated radiation therapy and proton therapy), the RT planning process, survival outcomes for several common pediatric malignant brain tumor histologies, RT-associated toxicities, and steps taken to mitigate the risk of acute and late effects from treatment.
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http://dx.doi.org/10.3390/cancers12061533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352417PMC
June 2020

Radiation for pediatric low-grade gliomas: who will benefit and how late is soon enough?

Neuro Oncol 2020 08;22(8):1068-1069

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

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http://dx.doi.org/10.1093/neuonc/noaa144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594570PMC
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

Assessing second cancer risk after primary cancer treatment with photon or proton radiotherapy.

Cancer 2020 Aug 19;126(15):3397-3399. Epub 2020 May 19.

Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1002/cncr.32936DOI Listing
August 2020

Brain tumors: Medulloblastoma, ATRT, ependymoma.

Pediatr Blood Cancer 2020 May 9:e28395. Epub 2020 May 9.

Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts.

Children with medulloblastoma, atypical teratoid rhabdoid tumor (ATRT), and ependymoma are treated with a multidisciplinary approach including surgery, radiotherapy, and chemotherapy. Lower doses of craniospinal irradiation and tumor bed boost together with chemotherapy are the current standard of care for average-risk medulloblastoma in the Children's Oncology Group (COG). The International Society of Pediatric Oncology (SIOP) is examining the role of hyperfractionated craniospinal irradiation and chemotherapy in high-risk patients. The recent stratification of medulloblastoma into specific molecular risk groups has prompted both COG and SIOP to reexamine the role of these modalities in these different risk groups to maximize cure rates and minimize long-term complications. Proton therapy has shown lower rates of neurocognitive and endocrine complications compared with photons. Ependymomas are treated with maximal surgical resection and adjuvant radiation therapy. The role of chemotherapy in ependymoma is currently being studied in both COG and SIOP. Likewise, for ATRT the role of different high-dose chemotherapy regimens together with local radiation therapy in infants, or craniospinal radiation in older children, is the current focus of research.
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http://dx.doi.org/10.1002/pbc.28395DOI Listing
May 2020

The role of proton therapy in pediatric malignancies: Recent advances and future directions.

Semin Oncol 2020 02 21;47(1):8-22. Epub 2020 Feb 21.

Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Francis H. Burr Proton Therapy Center, Boston, MA. Electronic address:

Proton radiotherapy has promised an advantage in safely treating pediatric malignancies with an increased capability to spare normal tissues, reducing the risk of both acute and late toxicity. The past decade has seen the proliferation of more than 30 proton facilities in the United States, with increased capacity to provide access to approximately 3,000 children per year who will require radiotherapy for their disease. We provide a review of the initial efforts to describe outcomes after proton therapy across the common pediatric disease sites. We discuss the main attempts to assess comparative efficacy between proton and photon radiotherapy concerning toxicity. We also discuss recent efforts of multi-institutional registries aimed at accelerating research to better define the optimal treatment paradigm for children requiring radiotherapy for cure.
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http://dx.doi.org/10.1053/j.seminoncol.2020.02.002DOI Listing
February 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

Pediatric Cancer.

Hematol Oncol Clin North Am 2020 02 31;34(1):143-159. Epub 2019 Oct 31.

Francis H. Burr Proton Therapy Center, 30 Fruit Street, Boston, MA 02114, USA; Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA. Electronic address:

In pediatric brain tumors, the intensification of chemotherapy has allowed for a reduction in radiotherapy (RT) volume to an involved field approach, particularly in patients with medulloblastoma. For patients with low-grade gliomas, the trend has remained to delay RT with chemotherapy; however, when RT is used, typically smaller clinical target volume margins are used. For patients with extracranial tumors, intensive chemotherapy to address systemic disease with local control is considered standard. Proton beam therapy shows significant promise in addressing both short-term and long-term toxicities in both central nervous system (CNS) and non-CNS pediatric tumors.
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http://dx.doi.org/10.1016/j.hoc.2019.08.021DOI Listing
February 2020

An open invitation to join the Pediatric Proton/Photon Consortium Registry to standardize data collection in pediatric radiation oncology.

Br J Radiol 2020 Mar 1;93(1107):20190673. Epub 2019 Nov 1.

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

Objective: The Pediatric Proton/Photon Consortium Registry (PPCR) is a comprehensive data registry composed of pediatric patients treated with radiation. It was established to expedite outcomes-based research. The attributes which allow the PPCR to be a successful collaboration are reviewed.

Methods And Materials: Current eligibility criteria are radiotherapy patients < 22 years treated at one of the 15 US participating institutions. Detailed health and treatment data are collected about the disease presentation and treatment exposures, and annually thereafter, in REDCap (Research Electronic Data Capture). DICOM (Digital Imaging and Communications in Medicine) imaging and radiation plans are collected through MIM/MIMcloud. An optional patient-reported quality-of-life (PedsQL) study is administered at 10 sites.

Results: Accrual started October 2012 with 2,775 participants enrolled as of 25 July 2019. Most patients, 62.0%, were treated for central nervous system (CNS) tumors, the most common of which are medulloblastoma ( = 349), ependymoma ( = 309), and glial/astrocytoma tumors ( = 279). The most common non-CNS diagnoses are rhabdomyosarcoma ( = 284), Ewing's sarcoma ( = 153), and neuroblastoma ( = 130). While the majority of participants are US residents, 18.7% come from 36 other countries. Over 685 patients participate in the PedsQL study.

Conclusions: The PPCR is a valuable research platform capable of answering countless research questions that will ultimately improve patient care. Centers outside of the USA are invited to participate directly or may engage with the PPCR to align data collection strategies to facilitate large-scale international research.

Advances In Knowledge: For investigators looking to carry out research in a large pediatric oncology cohort or interested in registry work, this paper provides an updated overview of the PPCR.
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http://dx.doi.org/10.1259/bjr.20190673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066966PMC
March 2020

Pediatric postoperative cerebellar cognitive affective syndrome follows outflow pathway lesions.

Neurology 2019 10 16;93(16):e1561-e1571. Epub 2019 Sep 16.

From the Neuroimaging and Noninvasive Brain Stimulation Laboratory (F.M.A., J.B., A.D.B.), Departments of Pediatrics, Neurology, and Psychiatry, University of Iowa Hospitals and Clinics, Iowa City; Department of Pediatric Neurology (R.M.J.), Department of Radiation Oncology (T.I.Y.), Department of Psychiatry (M.B.P.), and Department of Child and Adolescent Psychiatry and Pediatric Hematology Oncology (A.N.A.), Massachusetts General Hospital; Department of Neurology (A.L.C.), Boston Children's Hospital, MA; Department of Psychiatry (P.C.N.), University of Iowa Hospitals and Clinics, Iowa City; and Department of Pediatric Hematology Oncology (M.S.), Stead Family Children's Hospital, Iowa City, IA.

Objective: To evaluate lesion location after pediatric cerebellar tumor resection in relation to the development of severe cognitive and affective disturbances, or cerebellar cognitive affective syndrome (CCAS).

Methods: The postsurgical lesion location of 195 pediatric patients with cerebellar tumors was mapped onto a template brain. Individuals with CCAS were matched to 2 participants without CCAS by sex, age, and lesion volume. Lesion analyses included both a hypothesis-driven evaluation of the cerebellar outflow pathway (deep nuclei and superior cerebellar peduncles) and data-driven multivariate lesion symptom mapping. Lesion-associated networks were evaluated by comparing connectivity patterns between the lesion location of cases with and those without CCAS with resting-state functional connectivity MRI data from large normative adult and pediatric cohorts.

Results: CCAS was present in 48 of 195 participants (24.6%) and was strongly associated with cerebellar outflow tract lesions ( < 0.0001). Lesion symptom mapping also highlighted the cerebellar outflow pathway, with peak findings in the fastigial nuclei extending into the inferior vermis. Lesion network mapping revealed that the cerebellar region most associated with CCAS was functionally connected to the thalamic mediodorsal nucleus, among other sites, and that higher connectivity between lesion location and the mediodorsal nucleus predicts CCAS occurrence ( < 0.01). A secondary analysis of 27 participants with mutism revealed similar localization of lesions and lesion-associated networks.

Conclusion: Lesions of the cerebellar outflow pathway and inferior vermis are associated with major cognitive and affective disturbances after pediatric cerebellar tumor resection, and disrupted communication between the cerebellum and the thalamic mediodorsal nucleus may be important.
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http://dx.doi.org/10.1212/WNL.0000000000008326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815203PMC
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

A comparison study assessing neuropsychological outcome of patients with post-operative pediatric cerebellar mutism syndrome and matched controls after proton radiation therapy.

Childs Nerv Syst 2020 02 19;36(2):305-313. Epub 2019 Jul 19.

Department of Psychiatry, Massachusetts General Hospital, One Bowdoin Square, 7th Floor, Boston, MA, 02114, USA.

Purpose: Post-operative pediatric cerebellar mutism syndrome (CMS), characterized by mutism, ataxia/hypotonia, and emotional lability, can result in long-term deficits following resection of posterior fossa (PF) tumors. This longitudinal study compared neuropsychological outcomes of pediatric patients with post-operative CMS to a matched control patient group without CMS.

Methods: Fifty-eight PF tumor patients received post-surgical proton radiation therapy (PRT) and testing at baseline and at ≥ 1-year post-PRT over a 10-year period. Of these, 18 (31%) had post-operative CMS with baseline and follow-up neuropsychological test data. Those participants were matched to 18 controls by tumor location, age, gender, and handedness; no significant group differences were found at baseline for clinical/demographic variables. Total mean age at baseline was 7.26 years (SD = 4.42); mean follow-up interval was 3.26 years (SD = 2.24). Areas assessed: overall intelligence, expressive and receptive vocabulary, visuomotor integration, fine motor speed, inhibition, emotional control, depression, and anxiety.

Results: Patients were 52% male; 86% medulloblastoma/14% ependymoma; 86% craniospinal irradiation/14% focal radiation; and 86% chemotherapy. No group differences were found between most mean baseline scores; expressive vocabulary and fine motor speed were significantly lower in the post-operative CMS group (p < 0.05). Mean change scores revealed no significant differences for the sample; scores were within the normal range except fine motor skills were impaired for both groups.

Conclusions: Longitudinal neuropsychological outcomes for post-operative pediatric CMS patients did not differ significantly from matched controls without this condition. Patients were in the normal range in all areas except fine motor speed, which was impaired for both groups independent of CMS diagnosis.
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http://dx.doi.org/10.1007/s00381-019-04299-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067447PMC
February 2020

Increased local failure for patients with intermediate-risk rhabdomyosarcoma on ARST0531: A report from the Children's Oncology Group.

Cancer 2019 09 7;125(18):3242-3248. Epub 2019 Jun 7.

Memorial Sloan Kettering Cancer Center, New York, New York.

Background: The objective of this study was to evaluate local control for patients with intermediate-risk rhabdomyosarcoma (RMS) treated on Children's Oncology Group (COG) protocol ARST0531.

Methods: This study analyzed 424 patients with intermediate-risk RMS. Patients were randomized to chemotherapy with either vincristine, dactinomycin, and cyclophosphamide (VAC) or VAC alternating with vincristine and irinotecan. With the goal of improving local control, radiation therapy (RT) was delivered early at week 4 and was concurrent with irinotecan in the experimental arm. Individualized local control plans for children 24 months old or younger were allowed. Local failure on ARST0531 was compared with local failure on the preceding COG intermediate-risk study, D9803.

Results: For patients with group I/II alveolar RMS (n = 55), the 5-year cumulative incidence of local failure was 13.4%; for group III alveolar RMS (n = 141), it was 20.2%; and for group III embryonal RMS (n = 228), it was 27.9% (P = .03). Among patients with group III disease, local failure did not differ by histology, site, nodal status, RT modality, or treatment arm. Local failure was worse for a tumor size >5 cm (32.3% vs 16.7%; P = .001). Among patients with group III embryonal RMS, local failure was higher on ARST0531 than D9803 (27.9% vs 19.4%; P = .03). After the exclusion of patients 24 months old or younger or patients who did not receive radiation, local failure remained significantly increased on ARST0531 (P = .02). After adjustments for clinical prognostic factors, event-free survival and overall survival were worse on ARST0531 (P = .004 and P = .05, respectively).

Conclusions: Despite interventions designed to enhance local control, local control was inferior on ARST0531 in comparison with D9803. The reason for this is unclear, but it could be the reduced cyclophosphamide dose on ARST0531.
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http://dx.doi.org/10.1002/cncr.32204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717036PMC
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

Biopsy First, CSI Much Much Later.

Int J Radiat Oncol Biol Phys 2019 03;103(3):546

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

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http://dx.doi.org/10.1016/j.ijrobp.2018.10.029DOI Listing
March 2019

Proton beam therapy in pediatric oncology.

Curr Opin Pediatr 2019 02;31(1):28-34

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

Purpose Of Review: The advent of proton beam therapy (PBT) has initiated a paradigm shift in the field of pediatric radiation oncology, with increasing promise to alleviate both short-term and long-term toxicities. Given the dramatic rise in proton therapy centers in the United States, a discussion of the quality of evidence supporting its use in pediatric cancers is warranted.

Recent Findings: Proton radiotherapy appears to decrease the incidence and severity of late effects with the strongest evidence in pediatric brain tumor cohorts that shows benefits in neurocognitive, hearing, and endocrine outcomes. However, emerging data has shown that more conservative brainstem dose limits with protons compared with photons are required to limit brainstem toxicity; these modified recommendations have been incorporated into national cooperative group studies. Decreased toxicity in tumors outside of the CNS for PBT have also been reported in sarcomas, Hodgkin disease and neuroblastoma. Similarly, QoL outcomes are improved in brain tumor and other cohorts of patients treated with PBT.

Summary: The collective findings demonstrate improved understanding and refinement of PBT in pediatric cancers. Data on QOL, toxicity and disease outcomes with PBT should continue to be collected and reported in order to understand the full extent of the risks and benefits associated with PBT.
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http://dx.doi.org/10.1097/MOP.0000000000000724DOI Listing
February 2019

Patterns of proton therapy use in pediatric cancer management in 2016: An international survey.

Radiother Oncol 2019 03 7;132:155-161. Epub 2018 Nov 7.

Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, United States.

Purpose: To facilitate the initiation of observational studies on late effects of proton therapy in pediatric patients, we report on current patterns of proton therapy use worldwide in patients aged less than 22 years.

Materials & Methods: Fifty-four proton centers treating pediatric patients in 2016 in 11 countries were invited to respond to a survey about the number of patients treated during that year by age group, intent of treatment, delivery technique and tumor types.

Results: Among the 40 participating centers (participation rate: 74%), a total of 1,860 patients were treated in 2016 (North America: 1205, Europe: 432, Asia: 223). The numbers of patients per center ranged from 1 to 206 (median: 29). Twenty-four percent of the patients were <5 years of age, and 50% <10 years. More than 30 pediatric tumor types were identified, mainly treated with curative intent: 48% were CNS, 25% extra-cranial sarcomas, 7% neuroblastoma, and 5% hematopoietic tumors. About half of the patients were treated with pencil beam scanning. Treatment patterns were broadly similar across the three continents.

Conclusion: To our knowledge, this survey provides the first worldwide assessment of proton therapy use for pediatric cancer management. Since previous estimates in the United States and Europe, CNS tumors remain the cancer types most commonly treated with protons in 2016. However, the proportion of extra-cranial tumors is growing worldwide. The typically low numbers of patients treated in each center indicate the need for international research collaborations to assess long-term outcomes of proton therapy in pediatric patients.
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http://dx.doi.org/10.1016/j.radonc.2018.10.022DOI Listing
March 2019

The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy is feasible but does not improve outcome for patients with metastatic rhabdomyosarcoma: A report from the Children's Oncology Group.

Cancer 2019 01 23;125(2):290-297. Epub 2018 Oct 23.

Pediatric Hematology/Oncology, Seattle Children's Hospital, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: The outcome for patients with metastatic rhabdomyosarcoma (RMS) remains poor. A previous Children's Oncology Group (COG) study (ARST0431) for patients with metastatic RMS produced no improvement in outcome using multiple cytotoxic agents in a dose-intensive manner. The authors report results from the subsequent COG study (ARST08P1), which evaluated the feasibility and efficacy of adding cixutumumab (insulin-like growth factor-1 monoclonal antibody) or temozolomide to the ARST0431 intensive chemotherapy backbone.

Methods: Two nonrandomized pilot studies were conducted in patients with metastatic RMS, initially to determine feasibility, and both pilots were expanded to assess efficacy. All patients received 54 weeks of chemotherapy, including vincristine/irinotecan, interval-compressed vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, and vincristine/dactinomycin/cyclophosphamide. In pilot 1, patients received intravenous cixutumumab (3, 6, or 9 mg/kg) once weekly throughout therapy. In pilot 2, patients received oral temozolomide (100 mg/m ) daily for 5 days with irinotecan. All patients received radiation to the primary tumor and to metastatic sites.

Results: One hundred sixty-eight eligible patients were enrolled (97 on pilot 1 and 71 on pilot 2). Most patients were aged ≥10 years (73%), with alveolar histology (70%), and had bone and/or bone marrow metastases (59%). Toxicities observed in each pilot were similar to those reported on ARST0431. With a median follow-up of 2.9 years, the 3-year event-free survival rate was 16% (95% confidence interval, 7%-25%) with cixutumumab and 18% (95% confidence interval, 2%-35%) with temozolomide.

Conclusions: The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy for metastatic RMS was safe and feasible. Neither agent improved outcome compared with the same chemotherapy that was used on ARST0431.
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http://dx.doi.org/10.1002/cncr.31770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329653PMC
January 2019

Performance/outcomes data and physician process challenges for practical big data efforts in radiation oncology.

Med Phys 2018 Oct 19;45(10):e811-e819. Epub 2018 Sep 19.

University of California at San Francisco, San Francisco, CA, USA.

It is an exciting time for big data efforts in radiation oncology. The use of big data to help aid both outcomes and decision-making research is becoming a reality. However, there are true challenges that exist in the space of gathering and utilizing performance and outcomes data. Here, we summarize the current state of big data in radiation oncology with respect to outcomes and discuss some of the efforts and challenges in radiation oncology big data.
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http://dx.doi.org/10.1002/mp.13136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679351PMC
October 2018

Characteristics and Predictors for Secondary Leukemia and Myelodysplastic Syndrome in Ewing and Osteosarcoma Survivors.

Int J Radiat Oncol Biol Phys 2019 01 28;103(1):52-61. Epub 2018 Aug 28.

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

Purpose: Long-term survivors of Ewing sarcoma (ES) and osteosarcoma may be at risk for therapy-related acute leukemia or myelodysplastic syndrome (t-AL/MDS).

Methods And Materials: We retrospectively reviewed the clinicopathologic characteristics of 1071 patients with osteosarcoma (n = 757) and ES (n = 314) who were treated between 1985 and 2014. Multivariable competing risk analysis was used to analyze predictors of t-AL/MDS, including a radiation dose (≥55.8 Gy vs <55.8 Gy) × disease site (pelvis/spine vs other) interaction term. A supplemental nested case-control study was conducted to assess the association between cumulative chemotherapy dose and t-AL/MDS.

Results: The median follow-up for surviving patients was 97 months (range, 0.03-380). Twenty patients developed t-AL/MDS, all of whom received chemotherapy and 15 of whom were treated with radiation therapy. Radiation therapy to ≥55.8 Gy was associated with development of t-AL/MDS (adjusted hazard ratio, 2.89; 95% confidence interval [CI], 1.23-6.80; P = .015), and there was a significant radiation dose × disease site interaction term (adjusted hazard ratio, 6.70; 95% CI, 2.71-16.53; P < .001). The 5-year cumulative incidence of t-AL/MDS in patients receiving ≥55.8 Gy radiation therapy to the pelvis or spine was 5.0% (95% CI, 0.9-14.9) for osteosarcoma and 10.7% for ES (95% CI, 3.3-23.2). In our nested case-control study, cumulative doses of ifosfamide and etoposide were associated with development of t-AL/MDS.

Conclusions: Patients with osteosarcoma and ES receiving ≥55.8 Gy of radiation therapy to the pelvis or spine appear to be at increased risk for t-AL/MDS. Treatment with high cumulative doses of chemotherapy may further augment this risk.
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http://dx.doi.org/10.1016/j.ijrobp.2018.08.037DOI Listing
January 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