Clinical outcomes of pediatric patients with autism spectrum disorder and other neurodevelopmental disorders and intracranial germ cell tumors.

INTRODUCTION: Intracranial germ cell tumors (IGCTs) are rare tumors of the central nervous system with peak incidence around puberty. Given the developmental origins of IGCTs, we investigated the prevalence of neurodevelopmental disorders (NDDs) in patients with IGCTs and characterized outcomes for patients with NDD and IGCTs. METHODS: A retrospective review of medical records was conducted for 111 patients diagnosed with IGCTs between 1998 and 2018 and evaluated at the Massachusetts General Hospital. Kaplan-Meier method and log-rank test was used for survival analyses. Cox regression analyses were performed for parameters associated with progression-free survival (PFS). RESULTS: Median age at IGCT diagnosis was 12.8 years (range: 4.3-21.7) and median follow-up was 6.5 years (range: 0.2-20.5). Eighteen patients were diagnosed with NDDs prior to IGCT diagnosis, including five patients with autism spectrum disorder (ASD). Of the 67 patients with pure germinomas, four (6.0 %) had prior ASD diagnoses. Patients with NDD had significantly inferior PFS in the nongerminomatous germ cell tumor (NGGCT) cohort. On univariate and multivariable analyses, craniospinal irradiation (CSI) was significantly associated with improved PFS in the NGGCT cohort. CONCLUSIONS: Our study found an ASD prevalence in the pure germinoma cohort more than threefold greater than the national prevalence, suggesting an association between ASD and pure germinomas. Furthermore, patients with NDD and NGGCT had worse PFS, possibly due to fewer patients with NDD receiving CSI. Future prospective studies with larger cohorts are needed to examine associations between NDDs and IGCTs, and further characterize outcomes for patients with NDDs and IGCTs.

Travel distance and stereotactic body radiotherapy for localized prostate cancer.

BACKGROUND: Definitive stereotactic body radiotherapy (SBRT) represents an emerging and debated treatment option for patients with prostate cancer, with potential economic savings and reports of short-term efficacy since 2006. The current study sought to define national trends in definitive prostate SBRT use and determine whether patterns vary by travel distance for treatment. METHODS: The National Cancer Data Base identified 181,544 men with localized prostate cancer who were treated with definitive external beam radiotherapy from 2004 through 2012. Joinpoint regression analyzed definitive prostate SBRT trends over time, whereas multivariable logistic regression defined the odds for its receipt by travel distance for treatment. RESULTS: Definitive prostate SBRT use increased from 1.8% in 2004 to 5.9% in 2012 (P for trend <.0001), with a joinpoint for increased use noted in 2006 (P<.0001). Higher SBRT use was found to be associated with longer travel distance for treatment, younger age, white race, more affluent zip code of residence, academic treatment center, favorable disease characteristics, and fewer comorbidities (all P<.0001). Compared with travel distances <25 miles for treatment, travel distances of 25 to 50 miles and >50 miles were associated with increasing adjusted odds of receipt of definitive prostate SBRT (1.63 [95% confidence interval, 1.51-1.76] and 2.35 [95% confidence interval, 2.14-2.57], respectively; both P < .0001). CONCLUSIONS: Definitive prostate SBRT use increased more than 3-fold since 2004, with a significant increase in use coinciding with early reports of short-term efficacy. Long-distance travel for treatment was associated with greater than twice the odds of receipt of definitive prostate SBRT compared with short-distance travel, suggesting that treatment decisions with unknown long-term clinical implications may be strongly driven by sociodemographic factors. Cancer 2018;124:1141-9. © 2017 American Cancer Society.

Analysis of patient outcomes following proton radiation therapy for retinoblastoma.

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.

Incidence of CNS Injury for a Cohort of 111 Patients Treated With Proton Therapy for Medulloblastoma: LET and RBE Associations for Areas of Injury.

BACKGROUND: Central nervous system (CNS) injury is a rare complication of radiation therapy for pediatric brain tumors, but its incidence with proton radiation therapy (PRT) is less well defined. Increased linear energy transfer (LET) and relative biological effectiveness (RBE) at the distal end of proton beams may influence this risk. We report the incidence of CNS injury in medulloblastoma patients treated with PRT and investigate correlations with LET and RBE values. METHODS AND MATERIALS: We reviewed 111 consecutive patients treated with PRT for medulloblastoma between 2002 and 2011 and selected patients with clinical symptoms of CNS injury. Magnetic resonance imaging (MRI) findings for all patients were contoured on original planning scans (treatment change areas [TCA]). Dose and LET distributions were calculated for the treated plans using Monte Carlo system. RBE values were estimated based on LET-based published models. RESULTS: At a median follow-up of 4.2 years, the 5-year cumulative incidence of CNS injury was 3.6% for any grade and 2.7% for grade 3+. Three of 4 symptomatic patients were treated with a whole posterior fossa boost. Eight of 10 defined TCAs had higher LET values than the target but statistically nonsignificant differences in RBE values (P=.12). CONCLUSIONS: Central nervous system and brainstem injury incidence for PRT in this series is similar to that reported for photon radiation therapy. The risk of CNS injury was higher for whole posterior fossa boost than for involved field. Although no clear correlation with RBE values was found, numbers were small and additional investigation is warranted to better determine the relationship between injury and LET.

Early Cognitive Outcomes Following Proton Radiation in Pediatric Patients With Brain and Central Nervous System Tumors.

PURPOSE: To report, from a longitudinal study, cognitive outcome in pediatric patients treated with proton radiation therapy (PRT) for central nervous system (CNS) tumors. METHODS AND MATERIALS: Sixty patients receiving PRT for medulloblastoma (38.3%), gliomas (18.3%), craniopharyngioma (15.0%), ependymoma (11.7%), and other CNS tumors (16.7%) were administered age-appropriate measures of cognitive abilities at or near PRT initiation (baseline) and afterward (follow-up). Patients were aged ≥ 6 years at baseline to ensure consistency in neurocognitive measures. RESULTS: Mean age was 12.3 years at baseline; mean follow-up interval was 2.5 years. Treatment included prior surgical resection (76.7%) and chemotherapy (61.7%). Proton radiation therapy included craniospinal irradiation (46.7%) and partial brain radiation (53.3%). At baseline, mean Wechsler Full Scale IQ was 104.6; means of all 4 Index scores were also in the average range. At follow-up, no significant change was observed in mean Wechsler Full Scale IQ, Verbal Comprehension, Perceptual Reasoning/Organization, or Working Memory. However, Processing Speed scores declined significantly (mean 5.2 points), with a significantly greater decline for subjects aged <12 years at baseline and those with the highest baseline scores. Cognitive outcome was not significantly related to gender, extent of radiation, radiation dose, tumor location, histology, socioeconomic status, chemotherapy, or history of surgical resection. CONCLUSIONS: Early cognitive outcomes after PRT for pediatric CNS tumors are encouraging, compared with published outcomes from photon radiation therapy.

Proton radiation therapy for the treatment of retinoblastoma.

PURPOSE: To investigate long-term disease and toxicity outcomes for pediatric retinoblastoma patients treated with proton radiation therapy (PRT). METHODS AND MATERIALS: This is a retrospective analysis of 49 retinoblastoma patients (60 eyes) treated with PRT between 1986 and 2012. RESULTS: The majority (84%) of patients had bilateral disease, and nearly half (45%) had received prior chemotherapy. At a median follow-up of 8 years (range, 1-24 years), no patients died of retinoblastoma or developed metastatic disease. The post-PRT enucleation rate was low (18%), especially in patients with early-stage disease (11% for patients with International Classification for Intraocular Retinoblastoma [ICIR] stage A-B disease vs 23% for patients with ICIR stage C-D disease). Post-PRT ophthalmologic follow-up was available for 61% of the preserved eyes (30 of 49): 14 of 30 eyes (47%) had 20/40 visual acuity or better, 7 of 30 (23%) had moderate visual acuity (20/40-20/600), and 9 of 30 (30%) had little or no useful vision (worse than 20/600). Twelve of 60 treated eyes (20%) experienced a post-PRT event requiring intervention, with cataracts the most common (4 eyes). No patients developed an in-field second malignancy. CONCLUSIONS: Long-term follow-up of retinoblastoma patients treated with PRT demonstrates that PRT can achieve high local control rates, even in advanced cases, and many patients retain useful vision in the treated eye. Treatment-related ocular side effects were uncommon, and no radiation-associated malignancies were observed.

Patterns of failure after proton therapy in medulloblastoma; linear energy transfer distributions and relative biological effectiveness associations for relapses.

PURPOSE: The pattern of failure in medulloblastoma patients treated with proton radiation therapy is unknown. For this increasingly used modality, it is important to ensure that outcomes are comparable to those in modern photon series. It has been suggested this pattern may differ from photons because of variations in linear energy transfer (LET) and relative biological effectiveness (RBE). In addition, the use of matching fields for delivery of craniospinal irradiation (CSI) may influence patterns of relapse. Here we report the patterns of failure after the use of protons, compare it to that in the available photon literature, and determine the LET and RBE values in areas of recurrence. METHODS AND MATERIALS: Retrospective review of patients with medulloblastoma treated with proton radiation therapy at Massachusetts General Hospital (MGH) between 2002 and 2011. We documented the locations of first relapse. Discrete failures were contoured on the original planning computed tomography scan. Monte Carlo calculation methods were used to estimate the proton LET distribution. Models were used to estimate RBE values based on the LET distributions. RESULTS: A total of 109 patients were followed for a median of 38.8 months (range, 1.4-119.2 months). Of the patients, 16 experienced relapse. Relapse involved the supratentorial compartment (n=8), spinal compartment (n=11), and posterior fossa (n=5). Eleven failures were isolated to a single compartment; 6 failures in the spine, 4 failures in the supratentorium, and 1 failure in the posterior fossa. The remaining patients had multiple sites of disease. One isolated spinal failure occurred at the spinal junction of 2 fields. None of the 70 patients treated with an involved-field-only boost failed in the posterior fossa outside of the tumor bed. We found no correlation between Monte Carlo-calculated LET distribution and regions of recurrence. CONCLUSIONS: The most common site of failure in patients treated with protons for medulloblastoma was outside of the posterior fossa. The most common site for isolated local failure was the spine. We recommend consideration of spinal imaging in follow-up and careful attention to dose distribution in the spinal junction regions. Development of techniques that do not require field matching may be of benefit. We did not identify a direct correlation between lower LET values and recurrence in medulloblastoma patients treated with proton therapy. Patterns of failure do not appear to differ from those in patients treated with photon therapy.

Second nonocular tumors among survivors of retinoblastoma treated with contemporary photon and proton radiotherapy.

BACKGROUND: The leading cause of death among patients with hereditary retinoblastoma is second malignancy. Despite its high rate of efficacy, radiotherapy (RT) is often avoided due to fear of inducing a secondary tumor. Proton RT allows for significant sparing of nontarget tissue. The current study compared the risk of second malignancy in patients with retinoblastoma who were treated with photon and proton RT. METHODS: A retrospective review was performed of patients with retinoblastoma who were treated with proton RT at the Massachusetts General Hospital or photon RT at Boston Children's Hospital between 1986 and 2011. RESULTS: A total of 86 patients were identified, 55 of whom received proton RT and 31 of whom received photon RT. Patients were followed for a median of 6.9 years (range, 1.0 years-24.4 years) in the proton cohort and 13.1 years (range, 1.4 years-23.9 years) in the photon cohort. The 10-year cumulative incidence of RT-induced or in-field second malignancies was significantly different between radiation modalities (proton vs photon: 0% vs 14%; P = .015). The 10-year cumulative incidence of all second malignancies was also different, although with borderline significance (5% vs 14%; P = .120). CONCLUSIONS: Retinoblastoma is highly responsive to radiation. The central objection to the use of RT, the risk of second malignancy, is based on studies of patients treated with antiquated, relatively nonconformal techniques. The current study is, to the authors' knowledge, the first to present a series of patients treated with the most conformal of the currently available external-beam RT modalities. Although longer follow-up is necessary, the preliminary data from the current study suggest that proton RT significantly lowers the risk of RT-induced malignancy.

Radiation therapy: retinal tumors.

The major retinal tumor that requires radiotherapy (RT) is retinoblastoma (RB); to a lesser degree, RT is used for some cases of retinal capillary hemangioma and lymphoma of the retina. Although there are concerns about the risk of RT-induced second malignancy in patients who carry a germline mutation in the RB1 gene, RT remains a very important part of our approach to intra-ocular and extra-ocular RB. Technical innovations in RT allow more precise targeting of retinal tumors and decreased exposure of adjacent normal tissue, an advance that is particularly significant for patients with hereditary RB who are at risk of additional malignancies.

Delayed diagnosis in children with intracranial germ cell tumors.

OBJECTIVE: To review symptoms and provider history in a large cohort of patients with germ cell tumors (GCTs) to highlight the variety of manifestations and assess the effect of delayed diagnosis on outcomes. STUDY DESIGN: Patients treated for intracranial pure germinoma and nongerminomatous GCTs at Massachusetts General Hospital between 1998 and 2012 were included (n = 70). The primary outcome was time from onset of symptoms to diagnostic imaging. Delay was defined as an interval of ≥ 6 months. RESULTS: The median duration of symptoms before diagnostic magnetic resonance imaging was 6 months (range, 2 days to 72 months). Thirty-eight of the 70 patients (54%) had a delayed diagnosis. Patients with suprasellar tumors presented with symptoms related to endocrinopathies, and patients with pineal region tumors presented with symptoms related to hydrocephalus. Most of the patients were evaluated by a general pediatrician (49%) and/or pediatric subspecialists (66%) before diagnosis. Patients with delayed diagnosis saw a greater number of physicians before diagnosis (P = .006). The majority of patients (63%) with delayed diagnosis were seen by 2 or more physicians, and many (40%) were seen by 2 or more subspecialists. Progression-free survival was similar in the patients with delayed diagnosis and those without delayed diagnosis (P = .90), but the former were more likely to present with disseminated disease at diagnosis (34% vs 6%; P = .007). CONCLUSION: A significant proportion of patients with GCT experience a delay in time to diagnosis, in some cases despite evaluation by general pediatricians and specialists. This delay increases the risk of disseminated disease.

Bifocal intracranial tumors of nongerminomatous germ cell etiology: diagnostic and therapeutic implications.

BACKGROUND: Patients presenting with synchronous bifocal intracranial tumors (masses in the pineal and neurohypophyseal region), detectable human chorionic gonadotropin (hCG) levels (5-100 mIU/mL), and normal alpha feto-protein (AFP) levels (≤10 ng/mL) are often diagnosed empirically with pure germinoma. In such scenarios, pathologic confirmation is often deferred, given that bifocal nongerminomatous germ cell tumors (NGGCTs) are considered rare and because available literature and research protocols support such an approach. We sought to characterize the association between bifocal intracranial tumors and NGGCT histology. METHODS: Seventy-one patients treated for intracranial germ cell tumors at Massachusetts General Hospital in 1998-2012 were identified. Patients presenting with synchronous bifocal disease were selected for further review. RESULTS: Of the 71 patients presenting with intracranial germ cell tumors, 14 (19.7%) had synchronous bifocal disease. Of these 14 patients, 7 (50.0%) had germinoma, 3 (21.4%) had NGGCT, and 4 (28.6%) had hCG levels <200 mIU/mL and normal AFP levels and were treated without pathologic confirmation. Of the 3 patients with confirmed bifocal NGGCT, 2 had detectable hCG levels with AFP <10 ng/mL and 1 patient had a detectable hCG level with a modest elevation in AFP. CONCLUSIONS: NGGCTs should be considered in the differential diagnosis for patients presenting with bifocal intracranial tumors. Given differences in the management of germinomas and NGGCTs, clinicians should strongly consider a biopsy in patients presenting with bifocal masses and normal or modestly elevated biomarkers. Misclassification of such cases as germinomas could result in undertreatment and a possible increased risk for recurrence.

Malignant head and neck paragangliomas: treatment efficacy and prognostic indicators.

PURPOSE: Malignant head and neck paragangliomas (MHNPs) are rare and occur in 6%-19% of all HNPs. We sought to identify predictors of survival and compare efficacy of treatment modalities to inform management of this rare disease. MATERIALS AND METHODS: We performed a retrospective cohort study of MHNP cases in the National Cancer Institute Surveillance Epidemiology and End Results database (SEER) from 1973 to 2009. We identified 86 patients with MHNP who had documented regional or distant tumor spread with a median follow-up of 74 months. We used Cox proportional hazard models to assess the significance of demographic factors and treatment on five-year overall survival. RESULTS: The most common treatment was surgery alone (36.0 %), followed by surgery with adjuvant radiation (33.7%). Five-year overall survival was 88.1% for surgery alone and 66.5% for adjuvant radiation (p = 0.2251). In univariate analysis, regional (vs. distant) spread (HR 0.23, p < 0.0001), surgery alone (HR 0.29, p < 0.0001) and primary site in the carotid body (HR 0.32, p = 0.006) conferred significant survival advantage whereas age > 50 (HR 4.04, p < 0.0001) worsened survival. Regional (vs. distant) spread (HR 0.42, p = 0.046) and age > 50 (HR 2.98, p = 0.005) remained significant in multivariate analysis. In patients with regional-only disease, five-year overall survival was 95.4% for surgery alone compared to 75.6% for surgery with radiation (p = 0.1055). CONCLUSIONS: This is the largest and most contemporary series of MHNP patients. Age and tumor stage are significant factors in predicting survival. Surgical resection significantly improves survival outcomes. From this analysis, the value of adjuvant radiation is not clear.