Roshan V. Sethi

Proton radiotherapy for pediatric central nervous system ependymoma: clinical outcomes for 70 patients

BACKGROUND Ependymoma is treated with maximal surgical resection and localized radiotherapy. Minimizing unnecessary exposure to radiation is of paramount importance for young children. Proton radiotherapy (PRT) spares healthy tissues outside the target region, but reports of clinical outcomes are scarce. We report outcomes for 70 patients treated with PRT for intracranial ependymoma. METHODS Seventy patients with localized ependymoma treated with involved-field PRT at the Massachusetts General Hospital between October 2000 and February 2011 were included. RESULTS Median age at diagnosis was 38 months (range, 3 mo-20 y). Nineteen (27%) patients had supratentorial ependymoma and 51(73%) had infratentorial ependymoma. Forty-six (66%) had gross total resection (GTR), and 24 (34%) had subtotal resection (STR). At a median follow-up of 46 months, 3-year local control, progression-free survival, and overall survival were 83%, 76%, and 95%, respectively. STR was significantly associated with worse progression-free survival (54% vs 88%, P = .001) and overall survival (90% vs 97% for GTR, P = .001). In a subset of patients (n = 14), mean intelligence was 108.5 at baseline and 111.3 after mean 2.05 years of follow-up. In a larger group of patients (n = 28), overall adaptive skills were 100.1 at baseline and 100.8 after 2.21 years of follow-up. Few patients developed evidence of growth hormone deficiency, hypothyroidism, or hearing loss. CONCLUSION Outcomes for children treated with PRT compare favorably with the literature. STR correlated with inferior outcome. The young age at diagnosis and the proximity of critical structures in patients with ependymoma make PRT an ideal radiation modality.

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

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.

Mammary analogue secretory carcinoma: Update on a new diagnosis of salivary gland malignancy

To review the known histopathologic findings and clinical behavior of mammary analogue secretory carcinoma (MASC).

Proton Radiation Therapy for Pediatric Medulloblastoma and Supratentorial Primitive Neuroectodermal Tumors: Outcomes for Very Young Children Treated With Upfront Chemotherapy

PURPOSE To report the early outcomes for very young children with medulloblastoma or supratentorial primitive neuroectodermal tumor (SPNET) treated with upfront chemotherapy followed by 3-dimensional proton radiation therapy (3D-CPT). METHODS AND MATERIALS All patients aged <60 months with medulloblastoma or SPNET treated with chemotherapy before 3D-CPT from 2002 to 2010 at our institution were included. All patients underwent maximal surgical resection, chemotherapy, and adjuvant 3D-CPT with either craniospinal irradiation followed by involved-field radiation therapy or involved-field radiation therapy alone. RESULTS Fifteen patients (median age at diagnosis, 35 months) were treated with high-dose chemotherapy and 3D-CPT. Twelve of 15 patients had medulloblastoma; 3 of 15 patients had SPNET. Median time from surgery to initiation of radiation was 219 days. Median craniospinal irradiation dose was 21.6 Gy (relative biologic effectiveness); median boost dose was 54.0 Gy (relative biologic effectiveness). At a median of 39 months from completion of radiation, 1 of 15 was deceased after a local failure, 1 of 15 had died from a non-disease-related cause, and the remaining 13 of 15 patients were alive without evidence of disease recurrence. Ototoxicity and endocrinopathies were the most common long-term toxicities, with 2 of 15 children requiring hearing aids and 3 of 15 requiring exogenous hormones. CONCLUSIONS Proton radiation after chemotherapy resulted in good disease outcomes for a small cohort of very young patients with medulloblastoma and SPNET. Longer follow-up and larger numbers of patients are needed to assess long-term outcomes and late toxicity.

Early Clinical Outcomes Using Proton Radiation for Children With Central Nervous System Atypical Teratoid Rhabdoid Tumors

PURPOSE Atypical teratoid/rhabdoid tumor (AT/RT) is an uncommon and aggressive tumor that often affects infants. Irradiation improves survival but has traditionally been avoided in patients under the age of 3 due to the increasing risk of neurocognitive side effects. We report the first cohort of AT/RT patients treated with proton therapy. METHODS AND MATERIALS All patients with AT/RT treated at Massachusetts General Hospital (MGH) Frances H. Burr Proton Beam Therapy Benter between July 2004 and November 2011 were included in this study. All patients were treated with 3-dimensional conformal proton therapy (3D-CPT). RESULTS Ten consecutive patients of a median 2.3 years of age and with a median follow-up of 27.3 months (range, 11.3-99.4 months) were identified. Two patients suffered distant relapse; 1 patient was successfully treated with involved field irradiation and chemotherapy, while the second patient died of disease. At last follow-up, 9 patients were alive without evidence of disease. Proton radiation demonstrated increasing sparing of the cerebrum, temporal lobe, cochlea, and hypothalamus. CONCLUSIONS Initial clinical outcomes with proton therapy are favorable. The advantages of proton therapy are particularly suited to the treatment of AT/RT, a tumor that often requires irradiation treatment at an age when avoiding irradiation to healthy tissues is most desirable.

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.

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.

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.

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.

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.