A predictive model of the effect of therapeutic radiation on the human ovary.

Radiation to the female pelvis as part of treatment for cancer predisposes young women to develop Premature Ovarian Insufficiency (POI). As the human female is born with their full complement of non-growing follicles which decline in an exponential fashion until the menopause, the age at which POI occurs is dependent on the age of the patient at treatment and the dose received by the ovary. A model that predicts the age at which POI occurs for a known dose at a known age will aid counselling patients on their fertility risk. Patients deemed to be at high risk of POI may be considered to be good candidates for established fertility preservation techniques. An updated and externally validated model of the age-related decline in human ovarian reserve was combined with the best available estimate of the median lethal dose LD50 for the human ovary. Using known age at diagnosis and posited radiotherapy treatment plan to estimate the dose to the least-affected ovary, we use an age-related model of the decline in ovarian reserve to generate a personalized age prediction of premature ovarian insufficiency. Our algorithm is available as an online calculator which graphs model outputs to inform discussions around survivor fertility. We report four example cases across different ages and diagnoses, each with two carefully designed photon and proton treatment plans. The treatment options are compared in terms of remaining fertile lifespan for the survivor. International oncology guidelines now mandate the consideration of later fertility when reviewing treatment options for children diagnosed with cancer. Our calculator (https://sites.cs.st-andrews.ac.uk/radiosensitivity), and the underlying algorithm and models, allow detailed predictions of the impact of various radiotherapy plans on fertility. These patient-specific data enhance pre-treatment discussions around post-treatment fertility and fertility preservation.

Identified Enrollment Challenges of Adolescent and Young Adult Patients on the Nonchemotherapy Arm of Children's Oncology Group Study ARST1321.

ARST1321, a trial of patients with advanced soft tissue sarcoma, was the first National Clinical Trials Network study codeveloped by pediatric and adult consortia with two treatment cohorts. We report on the findings of a survey to identify barriers to enrolling adolescent and young adult patients (15-39 years) onto the nonchemotherapy arm. The survey response rate was 31% with a 70% completion rate. Common identified reasons for low accrual in order of decreasing frequency included insufficient funding, lack of study awareness or interest, competing trials, toxicity concerns, philosophical differences in the therapy backbone, and regulatory and infrastructure barriers. Clinical Trials.gov ID: NCT02180867.

Molecular grouping and outcomes of young children with newly diagnosed ependymoma treated on the multi-institutional SJYC07 trial.

BACKGROUND: This report documents the clinical characteristics, molecular grouping, and outcome of young children with ependymoma treated prospectively on a clinical trial. METHODS: Fifty-four children (aged ≤3 y) with newly diagnosed ependymoma were treated on the St Jude Young Children 07 (SJYC07) trial with maximal safe surgical resection, 4 cycles of systemic chemotherapy, consolidation therapy using focal conformal radiation therapy (RT) (5-mm clinical target volume), and 6 months of oral maintenance chemotherapy. Molecular groups were determined by tumor DNA methylation using Infinium Methylation EPIC BeadChip and profiled on the German Cancer Research Center/Molecular Neuropathology 2.0 classifier. RESULTS: One of the 54 study patients had metastases (cerebrospinal fluid positive) at diagnosis. Gross or near-total resection was achieved in 48 (89%) patients prior to RT. At a median follow-up of 4.4 years (range, 0.2-10.3 y), 4-year progression-free survival (PFS) was 75.1% ± 7.2%, and overall survival was 92.6% ± 4.4%. The molecular groups showed no significant difference in PFS (4-year estimates: posterior fossa ependymoma group A [PF-EPN-A; 42/54], 71.2% ± 8.3%; supratentorial ependymoma positive for v-rel avian reticuloendotheliosis viral oncogene homolog A [ST-EPN-RELA; 8/54], 83.3% ± 17.0%; and supratentorial ependymoma positive for Yes-associated protein [4/54], 100%, P = 0.22). Subtotal resection prior to RT was associated with an inferior PFS compared with gross or near-total resection (4-year PFS: 41.7% ± 22.5% vs 79.0% ± 7.1%, P = 0.024), as was PF-EPN-A group with 1q gain (P = 0.05). Histopathologic grading was not associated with outcomes (classic vs anaplastic; P = 0.89). CONCLUSIONS: In this prospectively treated cohort of young children with ependymoma, ST-EPN-RELA tumors had a more favorable outcome than reported from retrospective data. Histologic grade did not impact outcome. PF-EPN-A with 1q gain and subtotal resection were associated with inferior outcomes.

Agreement among RTOG sarcoma radiation oncologists in contouring suspicious peritumoral edema for preoperative radiation therapy of soft tissue sarcoma of the extremity.

PURPOSE: Peritumoral edema may harbor sarcoma cells. The extent of suspicious edema (SE) included in the treatment volume is subject to clinical judgment, balancing the risk of missing tumor cells with excess toxicity. Our goal was to determine variability in SE delineation by sarcoma radiation oncologists (RO). METHODS AND MATERIALS: Twelve expert ROs were provided with T1 gadolinium and T2-weighted MR images of 10 patients with high-grade extremity soft-tissue sarcoma. Gross tumor volume, clinical target volume (CTV)3cm (3 cm longitudinal and 1.5 cm radial margin), and CTV2cm (2 cm longitudinal and 1 cm radial margin) were contoured by a single observer. Suspicious peritumoral edema, defined as abnormal signal on T2 images, was independently delineated by all 12 ROs. Contouring agreement was analyzed using the simultaneous truth and performance level estimation (STAPLE) algorithm and kappa statistics. RESULTS: The mean volumes of GTV, CTV2cm, and CTV3cm were, respectively, 130 cm(3) (7-413 cm(3)), 280 cm(3) and 360 cm(3). The mean consensus volume computed using the STAPLE algorithm at 95% confidence interval was 188 cm(3) (24-565 cm(3)) with a substantial overall agreement corrected for chance (mean kappa = 0.71; range: 0.32-0.87). The minimum, maximum, and mean volume of SE (excluding the GTV) were 4, 182, and 58 cm(3) (representing a median of 29% of the GTV volume). The median volume of SE not included in the CTV2cm and in the CTV3cm was 5 and 0.3 cm(3), respectively. There were 3 large tumors with >30 cm(3) of SE not included in the CTV3cm volume. CONCLUSION: Despite the fact that SE would empirically seem to be a more subjective volume, a substantial or near-perfect interobserver agreement was observed in SE delineation in most cases with high-grade soft-tissue sarcomas of the extremity. A median of 97% of the consensus SE is within the CTV2cm (99.8% within the CTV3cm). In a minority of cases, however, significant expansion of the CTVs is required to cover SE.

Children's Oncology Group's 2013 blueprint for research: radiation oncology.

Radiation therapy (RT) is used to treat children with CNS tumors, solid tumors or Hodgkin lymphoma. Pediatric radiation oncologists have provided critical input into the development and implementation of concepts for clinical trials to further define the modality's role and test newer methods to reduce side effects or intensify therapy. The quality of pediatric oncology clinical trials that include radiation therapy is linked to the quality of guidelines. Radiation oncology is an adult medical specialty; thus, pediatric radiation oncologists are uniquely positioned to work with adult cancer investigators in the reorganized US National Cancer Institute Clinic Trials Network.

Response to sunitinib in combination with proton beam radiation in a patient with chondrosarcoma: a case report.

INTRODUCTION: Chondrosarcoma is well-known to be primarily resistant to conventional radiation and chemotherapy. CASE PRESENTATION: We present the case of a 32-year-old Caucasian man with clear cell chondrosarcoma who presented with symptomatic recurrence in his pelvis and metastases to his skull and lungs. Our patient underwent systemic therapy with sunitinib and then consolidation with proton beam radiation to his symptomatic site. He achieved complete symptomatic relief with a significantly improved performance status and had an almost complete and durable metabolic response on fluorine-18-fluorodeoxyglucose positron emission tomography. CONCLUSIONS: Our findings have important clinical implications and suggest novel clinical trials for this difficult to treat disease.