Ronny L. Rotondo

Incidence and dosimetric parameters of pediatric brainstem toxicity following proton therapy

Abstract Background. Proton therapy offers superior low and intermediate radiation dose distribution compared with photon-based radiation for brain and skull base tumors; yet tissue within and adjacent to the target volume may receive a comparable radiation dose. We investigated the tolerance of the pediatric brainstem to proton therapy and identified prognostic variables. Material and methods. All patients < 18 years old with tumors of the brain or skull base treated from 2007 to 2013 were reviewed; 313 who received > 50.4 CGE to the brainstem were included in this study. Brainstem toxicity was graded according to the NCI Common Terminology Criteria for Adverse Events v4.0. Results. The three most common histologies were ependymoma, craniopharyngioma, and low-grade glioma. Median patient age was 5.9 years (range 0.5–17.9 years) and median prescribed dose was 54 CGE (range 48.6–75.6 CGE). The two-year cumulative incidence of toxicity was 3.8% ± 1.1%. The two-year cumulative incidence of grade 3 + toxicity was 2.1% ± 0.9%. Univariate analysis identified age < 5 years, posterior fossa tumor location and specific dosimetric parameters as factors associated with an increased risk of toxicity. Conclusion. Utilization of current national brainstem dose guidelines is associated with a low risk of brainstem toxicity in pediatric patients. For young patients with posterior fossa tumors, particularly those who undergo aggressive surgery, our data suggest more conservative dosimetric guidelines should be considered.

Late toxicity following craniospinal radiation for early-stage medulloblastoma

Abstract Background. The purpose of this study is to review late toxicity following craniospinal radiation for early-stage medulloblastoma. Material and methods. Between 1963 and 2008, 53 children with stage M0 (n = 50) or M1 (n = 3) medulloblastoma were treated at our institution. The median age at diagnosis was 7.1 years (range 1.2–18.5). The median craniospinal irradiation (CSI) dose was 28.8 Gy (range 21.8–38.4). The median total dose, including boost, was 54 Gy (range 42.4–64.8 Gy). Since 1963, the CSI dose has been incrementally lowered and the high-risk boost volume reduced. Twenty-one patients (40%) received chemotherapy in their initial management, including 12 who received concurrent chemotherapy. Late sequelae were evaluated by analyzing medical records and conducting phone interviews with surviving patients and/or care-takers. Complications were graded using the NCI Common Terminology Criteria for Adverse Events, version 4.0. Results. The median follow-up for all patients was 15.4 years (range 0.4–44.4) and for living patients it was 24 years (range 5.6–44.4). The overall survival, cause-specific survival, and progression-free survival rates at 10 years were 67%, 67%, and 71%, respectively. Sixteen patients (41% of patients who survived five years or more) developed grade 3 + toxicity; 15 of these 16 patients received a CSI dose > 23.4 Gy. The most common grade 3 + toxicities for long-term survivors are hearing impairment requiring intervention (20.5%) and cognitive impairment (18%) prohibiting independent living. Four patients developed secondary (non-skin) malignancies, including three meningiomas, one rhabdomyosarcoma, and one glioblastoma multiforme. Three patients (5.6%) died from treatment complications, including radionecrosis, severe cerebral edema, and fatal secondary malignancy. Conclusion. Ongoing institutional and cooperative group efforts to minimize radiation exposure are justified given the high rate of serious toxicity observed in our long-term survivors. Follow-up through long-term multidisciplinary clinics is important and warranted for all patients exposed to radiotherapy in childhood.

A Prospective Outcomes Study of Proton Therapy for Chordomas and Chondrosarcomas of the Spine.

PURPOSE To evaluate the effectiveness of definitive or adjuvant external beam proton therapy on survival in patients with chordomas and chondrosarcomas of the spine. METHODS AND MATERIALS Between March 2007 and May 2013, 51 patients with a median age of 58 years (range, 22-83 years) with chordoma (n=34) or chondrosarcomas (n=17) of the sacrum (n=21), the cervical spine (n=20), and the thoracolumbar spine (n=10) were treated with external beam proton therapy to a median dose of 70.2 Gy(RBE) [range, 64.2-75.6 Gy(RBE)] at our institution. Distant metastases, overall survival, cause-specific survival, local control, and disease-free survival were calculated. RESULTS The mean follow-up time was 3.7 years (range, 0.3-7.7 years). Across all time points, 25 patients experienced disease recurrence: 18 local recurrences, 6 local and distant recurrences, and 1 distant metastasis. The 4-year rates of overall survival and cause-specific survival were 72%; disease-free survival was 57%, local control was 58%, and freedom from distant metastases was 86%. The median time to local progression was 1.7 years (range, 0.2-6.0 years), and the median time to distant progression was 1.6 years (range, 0.2-6.0 years). The risk factors for local recurrence were age ≤58 years (62% vs 26%; P=.04) and recurrence after prior surgery (29% vs 81%; P=.01). Secondary cancers developed in 2 patients: B-cell lymphoma 5.5 years after treatment and bladder cancer 2 years after treatment. We observed the following toxicities: sacral soft tissue necrosis requiring surgery (n=2), T1 vertebral fracture requiring fusion surgery (n=1), chronic urinary tract infections (n=1), surgery for necrotic bone cyst (n=1), and grade 2 bilateral radiation nephritis (n=1). CONCLUSION High-dose proton therapy controls more than half of spinal chordomas and chondrosarcomas and compares favorably with historic photon data. Local progression is the dominant mode of treatment failure and may be reduced by treating patients at the time of initial diagnosis. The impact of age is a novel finding of this study.

A treatment planning comparison of highly conformal radiation therapy for pediatric low-grade brainstem gliomas

To the Editor, The brainstem encompasses the midbrain, pons, and medulla. Brainstem gliomas arise at any age, but most frequently occur during childhood. In children, brainstem gliomas constitute approximately 10–20% of the malignancies affecting the central nervous system (CNS) [1], and the average age at diagnosis is 7–9 years with no gender predilection [2,3]. There are approximately 150–300 new cases diagnosed in USA annually [2]. The diagnosis of brainstem glioma includes a histopathologically diverse number of tumor types, which makes it difficult to assign an overall prognosis [4]. Similar to tumors in other CNS sites, however, low-grade brainstem gliomas are curable with current treatment modalities, whereas high-grade gliomas are often fatal despite aggressive treatment [5]. Of those children diagnosed with brainstem gliomas, approximately 20% are low-grade gliomas [2,3]. There is variability with regard to the resectability of these tumors; however, in general, complete resection is often impossible [2,3,6–8]. External-beam radiation therapy is an accepted and effective treatment modality for patients with unresectable low-grade brainstem gliomas [1,5–8]. When determining the therapeutic ratio, the risks of radiation therapy must be considered along with the potential benefits [9]. As the best 10-year survival rates mandate a relatively high radiation dose deposited in radiosensitive tissue, children treated for brainstem gliomas with radiation therapy are subject to a number of late sequelae, including hearing loss, neuroendocrine deficits, chronic otitis media, neurocognitive dysfunction, and the development of secondary malignancies [9]. There are few contemporary studies in the literature directly addressing the treatment of low-grade pediatric brainstem gliomas. In general, to minimize the risk of late effects in pediatric patients treated with radiation, investigators have historically sought to attenuate the dose to non-target, healthy tissues. For treatment of low-grade brainstem gliomas, recent studies have sought to investigate the role of gamma knife surgery to reduce dose to non-target tissue [10] and therapies of increased conformality, such as photon-based intensity-modulated radiation therapy (IMRT) and proton therapy [11]. Technology facilitating the delivery of highly conformal radiation therapy, such as IMRT and proton therapy, may allow for better sparing of non-target tissues. In this study, we sought to investigate the relative dosimetric features of photon IMRT and proton therapy in the treatment of low-grade brainstem gliomas in order to assess their potential value in reducing late toxicity.

Local control in non-metastatic medulloblastoma.

Abstract Background. A single-institution review of long-term outcomes and factors affecting local control (LC) following radiotherapy for non-metastatic medulloblastoma. Material and methods. From 1963 to 2008, 50 children (median age, 7.3 years; range 1.2–18.5) with stage M0 medulloblastoma were treated with radiotherapy; half underwent a gross total resection (no visible residual tumor) or near-total resection (< 1.5 cm3 of gross disease remaining after resection). Median craniospinal dose was 28.8 Gy (range 21.8–38.4 Gy). Median total dose to the posterior fossa was 54.3 Gy (range 42.4–64.8 Gy). Eighteen patients (36%) received chemotherapy as part of multimodality management, including 11 who received concurrent chemotherapy. Results. Median follow-up was 15.7 years (range 0.3–44.4 years) for all patients and 26.6 years (range 7.3–44.4 years) for living patients. The 10-year overall survival, cancer-specific survival, and progression-free survival rates were 65%, 65%, and 69%. The 10-year LC rate was 84% and did not significantly change across eras. Four percent of patients experienced local progression five years after treatment. On univariate analysis, chemotherapy and overall duration of radiotherapy ≤ 45 days were associated with improved LC. Patients receiving chemotherapy had a 10-year 100% LC rate versus 76% in patients not receiving chemotherapy (p = 0.0454). When overall radiotherapy treatment lasted ≤ 45 days, patients experienced a superior 95% 10-year LC rate (vs. 73% in patients treated > 45 days; p = 0.0419). Three patients (6%) died from treatment complications, including radionecrosis/cerebellar degeneration, severe cerebral edema leading to herniation, and secondary malignancy. Conclusions. While we cannot draw definitive conclusions given the retrospective nature of our study, our long-term data suggest that reductions in craniospinal dose and boost target volume to reduce toxicity have not compromised disease control in the modern era. Our data also support analyses that implicate duration of radiotherapy, rather than interval between surgery and radiotherapy, as a factor in LC. Chemotherapy in multimodality management of medulloblastoma may have an underappreciated role in improving LC rates.

Clinical outcomes following proton therapy for children with central nervous system tumors referred overseas

International, multidisciplinary care of children with central nervous system (CNS) tumors presents unique challenges. The aim of this study is to report patient outcomes of U.K. children referred for proton therapy to a North American facility.

Fertility in childhood cancer survivors following cranial irradiation for primary central nervous system and skull base tumors

Recent advances in pediatric cancer treatment have improved disease control and survival outcomes for childhood cancers survivors, including those treated for primary central nervous system and skull base malignancies. Future research in this population will focus on identifying risk factors for infertility, novel screening techniques and recommendations, and quality-of-life outcomes improvement. The purpose of this review is to define the infertility complications observed in pediatric cancer survivors who receive cranial irradiation for central nervous system and skull base malignancies.

Late Effects After Radiotherapy for Childhood Low-grade Glioma.

Objectives: This single-institution report describes long-term disease control and late effects in pediatric patients with low-grade glioma (LGG) following radiotherapy (RT). Materials and Methods: Twenty-nine pediatric patients with LGG were treated with photon-based RT from 1970 to 2004 (mean age at time of RT, 9.8 y; range, 0.6 to 19 y). One patient underwent gross total resection, 25 underwent subtotal resection or biopsy, and 3 were treated based on radiographic characteristics alone. Three patients underwent chemotherapy before RT. The median RT dose was 54 Gy (range, 40 to 55 Gy). Results: The median follow-up was 17.8 years (range, 1.6 to 36.8 y) for all patients and 19.9 years (range, 1.6 to 36.8 y) for all living patients. The 5-, 10-, and 20-year local control and progression-free survival rates were equivalent at 82%, 74%, and 63%, respectively. The 5-, 10-, and 20-year cause-specific survival and overall survival rates were equivalent at 89%, 85%, and 58%, respectively. On univariate analysis, age below 4 years during treatment was associated with significantly inferior local control (P=0.0067), cause-specific survival (P=0.0021), and overall survival (P=0.0021). Of the 23 survivors analyzed for late toxicity, 15 (65%) developed grade 3+ toxicity. The most common Common Terminology Criteria for Adverse Events grade 3 toxicity (30% of survivors) was serious cognitive disability. Four patients (14%) died secondary to treatment complications, all occurring over a decade after completing RT. Conclusions: Over half of children diagnosed with LGG survive >20 years after RT; this report reveals the chronicity of toxicity beyond the typically reported follow-up. Our findings inform the therapeutic ratio of RT in this disease and may help guide late-effect screening recommendations.

Esophagitis associated with multimodality management of pediatric Ewing sarcoma of thorax

Ewing sarcoma of the thoracic spine and chest wall is frequently treated with concurrent chemotherapy and radiation therapy (RT). Treatment‐related acute esophagitis can lead to hospitalization and treatment delays. The aim of this study was to analyze the incidence, risk factors, and management of esophagitis in pediatric patients with Ewing sarcoma of the thoracic region.

Early outcomes and patterns of failure following proton therapy for nonmetastatic intracranial nongerminomatous germ cell tumors

Although dosimetric comparisons demonstrate the advantage of proton therapy (PT) over conventional radiotherapy for nongerminomatous germ cell tumors (NGGCT), clinical outcome data for this rare tumor are lacking. We sought to evaluate outcomes for children with NGGCT treated with PT.