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Expert Insights: Pediatric Proton Therapy

Trends in Proton and Carbon Ion Therapy to Assist Clinical Choices and Research Pursuits

Matthew Hall, MD

Neuroendocrine Function Following Radiation Therapy: A Review of Two Prospective Trials

Matthew Hall, MD

Miami Cancer Institute, Baptist Health South Florida

Proton therapy can significantly reduce normal tissue exposure and the resulting risk of toxicity compared to photon-based radiotherapy. The major critique remains the lack of prospective evidence that dosimetric sparing is associated with a clinical benefit. Two recent clinical investigations have helped to expand our knowledge regarding neuroendocrine function following radiation therapy. 

Vatner and colleagues modelled the risk of endocrine dysfunction following proton therapy in 189 pediatric and young adult patients treated on three prospective clinical trials at two institutions. The analysis cohort included 130 patients treated with proton craniospinal irradiation for medulloblastoma between 2003 and 2016 and 56 patients who received focal proton therapy between 2011 and 2015. Patients with baseline hormone deficits were excluded. With a median follow-up of 4.4 years, the 4-year incidence of any endocrinopathy was 48.8%. Growth hormone and thyroid hormone deficits were the most commonly observed deficits, reaching 37.4% and 20.5%, respectively, at 4 years. Patient age, time interval since treatment completion, and median dose to the hypothalamic pituitary axis (HPA) were associated with an increased incidence of hormone deficits. 

In a secondary analysis of a published trial where patients with benign and low-grade brain tumors were randomized to conventional versus limited-margin radiotherapy, Jalali and colleagues analyzed data from 51 patients (median age, 13 years; range, 5-25 years) with baseline and longitudinal neuroendocrine data collected for =2 years. In this study, worsening endocrine function was defined as either the new development or worsening of a preexisting endocrine deficit. The authors reported that 27 of 51 patients (41%) developed new or worsening endocrine function after treatment at a median follow-up of 5.92 years. Growth hormone levels were most commonly affected (70%), followed by cortisol (44%), gonadotropin (40%), and thyroxine (7%). Using logistic regression, the authors found that patients receiving =27 Gy to any portion of the HPA had a four-fold increase in endocrinopathy risk (odds ratio, 4.05; 95% confidence interval, 1.7-15.62; p=0.038). 

These important studies add to the growing body of literature on post-treatment neuroendocrine dysfunction following radiation therapy. Both provide data collected from prospective clinical trials and suggest that sparing of the HPA should be pursued whenever feasible in patients receiving cranial radiation therapy. Based on these data, we have incorporated HPA dose <27 Gy as a treatment planning objective to minimize the risk of neuroendocrine dysfunction at our institution.

1. Vatner RE, Niemierko A, Misra M, Weyman EA, Goebel CP, Ebb DH, et al. 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;36:2854-2862.

2. Jalali R, Maitre M, Gupta T, Goda JS, Shah N, Krishna U, et al. Dose-Constraint Model to Predict Neuroendocrine Dysfunction in Young Patients With Brain Tumors: Data From a Prospective Study. Pract Radiat Oncol. 2019;9:e362-e371.

Recent Investigations in the Treatment of Unresected Rhabdomyosarcoma Highlight the Importance of Local Control

Radiotherapy places a central role in the management of group 3 (unresected) rhabdomyosarcoma (RMS) patients, with local control serving as an important and necessary component of curative therapy.  This tenet is supported by two recent investigations by Bradley et al. [1] and Casey et al. [2] published in the Red Journal.  

Due to the potential risk of toxicity, local therapy guidelines were not mandated in children =2 years old in the COG ARST0331 and ARST0531 studies.  Bradley and colleagues examined adherence to protocol-specified local therapy guidelines with regard to outcomes in 124 patients =2 years of age who enrolled on these studies; in this group, 58% had group 3 disease.  The authors reported that 43% of patients received “individualized” local therapy that did not agree with protocol guidelines, which most commonly were characterized by omission of or delay in radiotherapy.  With a median follow-up of 5.6 years, local failures were significantly higher in patients who received individualized local therapy compared to those who received protocol-specified treatment (35% vs. 16%, p=0.02).  The first site of failure was local in 64% of patients, local and distant in 5%, and distant only in 23%.

Casey and colleagues evaluated 76 pediatric patients with head and neck RMS who were treated at a single institution between 2000 and 2018. The authors found that 2-year local failure was significantly associated with total cumulative cyclophosphamide dose, with a 15.3% rate of local failure at cyclophosphamide doses =20 g/m2 compared to 0% for >20 g/m2 (p=0.04).  Event-free survival in parameningeal RMS patients receiving reduced-dose intensity cyclophosphamide was 59.2% compared to 70.6% (p=0.11).  Of note, patients treated with proton therapy were significantly more likely to have received reduced-dose cyclophosphamide (p<0.001) and exhibited a trend toward inferior local failure compared to IMRT (14.6% vs. 7.9%, p=0.07).  

These reports are thought-provoking in the setting of the continued trends toward reducing treatment intensity, specifically the dose intensity of cyclophosphamide in ARST1431.  Of note, this protocol was amended to add maintenance low-dose chemotherapy (vinorelbine and cyclophosphamide) based on the results of the European RMS2005 study presented by Bisogno et al. at ASCO in 2018 [3].  From these studies, we are reminded that local failure was more common in very young patients receiving individualized local therapy and also was increased in patients receiving lower-dose-intensity cyclophosphamide.  Special attention is warranted to monitor and reverse these trends of increased local failure in RMS patients

1. Bradley JA, Kayton ML, Chi YY, Hawkins DS, Tian J, Breneman J, et al. Treatment Approach and Outcomes in Infants With Localized Rhabdomyosarcoma: A Report From the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Int J Radiat Oncol Biol Phys. 2019;103(1):19-27.

2. Casey DL, Wexler LH, Wolden SL. Worse Outcomes for Head and Neck Rhabdomyosarcoma Secondary to Reduced-Dose Cyclophosphamide. Int J Radiat Oncol Biol Phys. 2019;103(5):1151-1157.

3. Bisogno G, De Salvo GL, Bergeron C, Jenney M, Merks JHM, Minard-Colin V, et al. Maintenance low-dose chemotherapy in patients with high-risk (HR) rhabdomyosarcoma (RMS): A report from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG). Journal of Clinical Oncology 2018;36(18_suppl):LBA2-LBA2.

Pediatric Proton Therapy

Commentary on: Pulsifer MB, Duncanson H, Grieco J, Evans C, Tseretopoulos ID, MacDonald S, Tarbell NJ, Yock TI. Cognitive and Adaptive Outcomes After Proton Radiation for Pediatric Patients With Brain Tumors. Int J Radiat Oncol Biol Phys. 2018 Oct 1;102(2):391-398. doi: 10.1016/j.ijrobp.2018.05.069. Epub 2018 Jun 6. PubMed PMID: 30108004.

The primary benefit of proton therapy (PT) derives from reducing both the dose delivered to normal tissues and the resulting collateral radiation damage. The major critique of PT is the lack of prospective evidence that dosimetric sparing is associated with improved patient outcomes, despite the fact that to report late effects can require years of concerted follow-up and the development of such “rigorous” follow-up needs improvement with regard to other highly conformal radiation modalities. 

This gap in prospective evidence continues to be filled by ongoing clinical investigations, highlighted by a recent publication by Pulsifer and colleagues in the Red Journal ( The authors prospectively measured cognitive and adaptive functioning at baseline and during follow-up for 155 pediatric brain tumor patients treated with PT between 2002 and 2017. The mean patient age was 8.9 years; 61% of patients were treated with focal PT and 39% received craniospinal irradiation (CSI). With a mean follow-up of 3.6 years, mean Full Scale IQ scores demonstrated a small but statistically significant decline in the total sample from 105.4 to 102.5 (p<0.01). Of note, this decline was only observed in patients <6 years of age receiving CSI, whereas no significant change was observed in older patients receiving CSI or patients of all ages treated with focal fields. Processing speed and working memory scores were significantly lower for patients treated with CSI, regardless of age, but were no different in patients receiving focal PT. Adaptive functioning scores for performance reasoning and verbal comprehension were stable across all ages and treatment field groups. While longer follow-up will help better characterize ongoing neurocognitive effects following PT, this study represents an important contribution to our understanding of this important endpoint. 

Pulsifer et al’s report is timely and thought-provoking in the setting of the recent presentation of preliminary results of NRG CC001 at SNO 2018 by Gondi and colleagues. In their study, 518 patients with brain metastases were randomized to whole-brain radiotherapy (WBRT) plus memantine with or without hippocampal avoidance. Patients treated with hippocampal-sparing WBRT had a significantly longer time to decline in neurocognitive function, the primary endpoint of the study. This finding provides level I evidence that hippocampal-sparing is protective for neurocognition and provides a framework to consider Pulsifer’s findings. Taken together, these reports suggest that hippocampal sparing should be considered whenever feasible in not only those patients with brain metastases but all brain tumor patients who can achieve significant dosimetric sparing from intensity-modulated radiotherapy and PT. 

1. Pulsifer MB, Duncanson H, Grieco J, Evans C, Tseretopoulos ID, MacDonald S, Tarbell NJ, Yock TI. Cognitive and Adaptive Outcomes After Proton Radiation for Pediatric Patients With Brain Tumors. Int J Radiat Oncol Biol Phys. 2018;102(2):391-398. 

2. Gondi V, Pugh S, Brown PD, Wefel J, Gilbert M, Bovi CR, Benzinger T, Tome W, Armstrong T, Bruner D, Khuntia D, Grosshans D, Konski A, Robidoux A, Kundapur V, Kevisetty K, Shah S, Usuki K, Anderson B, Stea B, Yoon H, Li J, Laack N, Kruser T, Chmura S, Shi W, Mehta MP, Kachnic L. NCOG-01: Preservation of Neurocognitive Function (NCF) With Hippocampal Avoidance During Whole-Brain Radiotherapy (WBRT) for Brain Metastases: Preliminary Results of Phase III Trial NRG Oncology CC001. Neuro Oncol. 2018;20(Suppl 6):vi172.

3. Gondi V, Deshmukh S, Brown PD, Wefel JS, Tome WA, Bruner DW, Bovi JA, Robinson CG, Khuntia D, Grosshans DR, Konski AA, Roberge D, Kundapur V, Devisetty K, Shah SA. Preservation of neurocognitive function with conformal avoidance of the hippocampus during whole-brain radiotherapy for brain metastases: Preliminary results of phase III trial NRG Oncology CC001. Int J Radiat Oncol Biol Phys. 2018;102(5):1607.

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