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Purpose: To describe the preliminary results after intraoperative radiotherapy (IORT) with the photon radiosurgery system in children with recurrent brain tumors treated at the first dose level (10 Gy) of a Phase I protocol. Methods and Materials: A Phase I IORT dose escalation protocol was initiated at Children’s Memorial Hospital to determine the maximal tolerated IORT dose in children with recurrent brain tumors. Results: Fourteen children have received IORT thus far. Eight had been previously irradiated. Thirteen children had ependymoma. The median follow-up was 16 months. Three patients (21%) developed radiation necrosis on follow-up MRI scans 6 to 12 months after IORT. They had not been previously irradiated and had received 10 Gy to a depth of 5 mm. One required surgery and the other two had resolution of their lesions without treatment. All 3 patients were asymptomatic at the last follow-up. No other late toxicity was observed at the last follow-up visit. Eight patients (57%) had tumor control within the surgical bed after IORT. Conclusion: Our findings have demonstrated the safety and feasibility of IORT to a dose of 10 Gy to 2 mm in children with previously irradiated brain tumors. IORT to a dose of 10 Gy at 5 mm was associated with a greater complication rate.

Purpose: To assess the role of consolidative radiation therapy (CRT) in conjunction with myeloablative therapy with or without total body irradiation (TBI) in children and young adults with metastatic or recurrent sarcoma. Methods and Materials: Twenty-one pediatric sarcoma patients with metastatic (10) or recurrent (11) disease were entered on a prospective feasibility study of intensive myeloablative therapy with or without TBI. Median patient age was 17.8 years (range, 9.4–24.7 years). Primary histologies included Ewing’s (12) , PNET (3) , and other soft tissue sarcomas (6) . Twenty patients received induction chemotherapy. Myeloablative therapy consisted of TBI in 11 patients with either high dose melphalan/etoposide (9) or high dose cytoxan/thiotepa (2) . TBI consisted of 12 Gy in 2 Gy fractions delivered twice daily over 3 days. Ten patients received high dose chemotherapy alone, either with thiotepa/carboplatinum/etoposide (8) or cytoxan/carboplatinum (2) . Myeloablative therapy was followed by autologous stem cell rescue (ASCR) 24 to 48 hours after completing chemotherapy. Fourteen patients (67%) received CRT either prior to (5) or following (9) myeloablative therapy. Median CRT dose was 37.2 Gy (range, 20–60). Fifty-one disease sites were present prior to myeloablative therapy. Twelve (24%) were bulky (> 8 cm) and 18 (35%) underwent surgical debulking. The median follow-up of surviving patients was 15 months (range, 8–20) with 25% of patients having been followed for more than 20 months. Results: The 3-year actuarial disease-free (DFS) and overall survival (OS) rates for the entire group were 36% and 27%, respectively. Following myeloablative treatment, responses were: 11 complete, 6 partial, 1 stable, and 3 progressive disease. Sixteen patients (71%) have relapsed. The most common site of relapse was the lung (13) . Of the 51 disease sites present prior to myeloablative therapy, 36 sites (71%) were amenable to CRT. Non-amenable sites were: multiple lung metastases (13) and bone marrow (2) . Twenty-six amenable sites (51%) received CRT either prior to (14) or following (12) ASCR. Amenable sites treated with CRT had a better 3-year actuarial local control (80 vs 37%) ( p = 0.0065) than amenable sites not treated with CRT. Factors associated with improved disease-free survival (DFS) in univariate analysis were induction chemotherapy response ( p = 0.002) and extent of surgical resection ( p = 0.045). There was a trend toward improved DFS on univariate analysis with the use of TBI as part of myeloablative therapy ( p = 0.07). The one factor associated with improved OS on univariate analysis was induction chemotherapy response ( p = 0.007). Multivariate analysis revealed that induction chemotherapy response is the only factor that remains significant for DFS ( p = 0.032) as well as for OS ( p = 0.017). Patients with complete response to induction therapy had 40% probability of survival versus all other patients who had 10% survival ( p = 0.05). Conclusion: Consolidative radiotherapy is feasible in primary metastatic or recurrent pediatric sarcoma patients treated with myeloablative therapy with or without TBI. CRT to sites amenable to irradiation provided an improved 3-year actuarial local control than that seen in sites amenable to CRT that did not undergo radiotherapy. There was a trend for improved DFS with the use of TBI. Improved DFS and OS can be predicted by response to induction therapy. This intensive regimen may improve the cure rate of advanced pediatric sarcomas in select patients.

To evaluate the patterns of failure and outcome of patients undergoing high-dose chemotherapy, total body irradiation (TBI), and bone marrow transplantation (BMT) for advanced/relapsed pediatric neuroblastoma, with emphasis on the impact of a radiotherapy boost to primary and metastatic sites.Between May 1986 and June 1993, 26 patients with advanced neuroblastoma underwent high-dose chemotherapy and TBI followed by BMT at our institution. The majority of patients were over the age of 2 years (73%) and were Stage IV at diagnosis (81%). Multiple metastatic sites were involved including bone (17), bone marrow (15), distant nodes (11), liver (5), lung (4) and brain (1). Twenty patients (77%) received cyclophosphamide (50 mg/kg x 4 days) and TBI as consolidation therapy. TBI was delivered to a total dose of 12 Gy given in 2 Gy twice daily (b.i.d.) fractions over the 3 days preceding bone marrow infusion. A local radiotherapy boost of 8-24 Gy was given to 13 out of 26 patients (50%) to the primary and/or metastatic sites immediately prior to or following induction chemotherapy according to physician judgement. Sites not amenable to a radiotherapy boost included the bone marrow, diffuse/bilateral lung involvement, and multiple bone metastases (four sites).The actuarial overall survival of the 26 patients was 40.4% at 3 and 5 years, with a progression-free survival at 5 years of 38.5%. Six patients died of transplant-related toxicity (23%). The use of cyclophosphamide as high-dose consolidation chemotherapy was significantly better than other multidrug regimens used in terms of overall survival (p0.0001) and progression-free survival (p = 0.0004). The presence of liver involvement prior to BMT was a significant adverse prognostic factor by multivariate analysis. Of the 20 patients surviving the transplant, 10 (50%) underwent a local radiotherapy boost. The patterns of failure were as follows: 3 out of 10 "boost" patients failed overall, none in previous (old) sites of disease only, 1 in new sites only, and 2 in old and new sites; 6 out of 10 "no boost" patients failed overall, 4 in old sites only, none in new sites only, and 2 in old and new sites. There was a trend toward improved 5-year progression-free survival in patients surviving the transplant that received a boost (68% vs. 33%, p = 0.24). A failure analysis was also performed for each of the 59 initially involved sites, of which the majority (64%) were amenable to a radiotherapy boost. Overall, there is a trend toward less failure in sites amenable to a radiotherapy boost that were irradiated (1 out of 10) vs. those not irradiated (6 out of 28). Failure in the liver occurred in three out of four of the patients with liver involvement that did not receive boost radiotherapy, whereas all seven patients with distant nodal involvement were controlled without a boost. Long-term sequelae include learning difficulties (2), cataract formation (1), and hearing loss (2). Sequelae attributable to a radiotherapy boost occurred in only one patient who received whole brain radiotherapy and developed a cataract and learning difficulties.We have found an actuarial 5-year survival rate of 40.4% for patients with advanced neuroblastoma treated with BMT, which compares favorably with results of other published series. Disease recurrence following BMT was most common in previous sites of disease. The majority (64%) of these sites were amenable to a radiotherapy boost. An analysis of failure suggests that a low-dose radiotherapy boost improves control of these sites.

To assess frequency of neural stem cell compartment (NSC) involvement in adult and pediatric gliomas [World Health Organization (WHO) grades 1–4], and to assess whether NSC involvement at presentation impacts on survival, recurrence rates, and/or transformation from low grade (WHO grade 1–2) to high grade disease (WHO grades 3–4). Cranial MRIs for 154 pediatric and 223 adult glioma patients treated from 2000 to 2012 were reviewed. NSC involvement was documented. Tumors were stratified by age (adult vs. pediatric), histology, tumor grade, tumor location, and involvement of midline structures. Odds ratios (OR) for death were calculated based on NSC status at presentation. Rates of transformation and recurrence rates (ORR) were compared using Fisher’s Exact Test. Time to recurrence (TTR) was calculated using student t test. Among recurrent and transformed tumors, we also assessed the rate of NSC involvement at time of recurrence or transformation. 74.8 % of tumors had NSC involvement. Higher rates of NSC involvement were seen among adult (p = .0001); high grade (p = .0001)); grade 2 versus grade 1 (p = .0001) and other grade 1 histologies (p = .0001) versus JPA (juvenile pilocytic astrocytoma) patients); grade 2–4 tumors (p = .0001); and supratentorial tumors (p

Purpose: Two-thirds of neuroblastoma patients present in advanced stages of disease. The treatment of advanced or recurrent neumblastoma remains controversial, with the roles of bone marrow transplant (BMT), total body irradiation (TBI), and local boost radiotherapy (RT) currently undefined. The purpose of this study is to review our experience with TBI and BMT, and to examine the role of local boost RT. Methods Between 5/86 and 6/93,26 patients with advanced nemoblastoma underwent high-dose chemotherapy and TBI followed by BMT at our institution. The majority of the patients (20/26) received Cytoxan alone as their induction regimen. TBI was delivered using 18 MV photons at an extended SSD, a dose rate of 12 cGy/min, a Lexan spoiler, custom partial transmission lung blocks, and bolus to improve homogeneity around the head, neck, and legs. The total dose delivered was 1200 cGy given in 200 cGy fractions BID via opposed lateral fields over the 3 days preceding the BM infusion. A local RT boost was given to 13/26 patients prior to TBI with doses of 8002400 cGy, in 200 cGy daily fractions. Results: The actuarial overall survival (OS) of the 26 patients was 40.4% at 3 and 5 years, with a progression-free survival (PFS) at 5 years of 28.1%. Six patients died of transplant-related toxicity (23%) leaving 20 patients evaluable for treatment response. Neither the extent of resection (gross total vs. subtotal/none) or BMT type (autologous vs. allogeneic) was significant in terms of OS or PPS. Of the 20 evaluable patients, 10 underwent a local RT boost and had an improved 5 year PFS (67.5%) than those who had no boost (0%) @=0.04). A local RT boost had no significant impact on OS (60% vs. 43.8% at 5 years, p=O.61). ‘Ihe patterns of failure were as follows: 3/10 “boost” patients failed overall, O/10 in old sites only, l/IO in new sites only, and 2/10 in old+new sites; 8/10 “no boost” patients failed overall, 5/10 in old sites only, l/10 in new sites only and 2/10 in old+new sites. A failure analysis was also performed for all 59 initially involved sites and is shown in the table. Overall, their is a trend towards decreased failure in irradiable sites that were irtadiated (l/10) vs. those not irradiated (7/28). The single patient who failed in an irradiated site failed simultaneously in the lungs, liver, and diffusely throughout the abdomen (including the irradiated primary site).