Phase II study of pre-irradiation chemotherapy for childhood intracranial ependymoma. Children's Cancer Group protocol 9942: a report from the Children's Oncology Group.

PURPOSE: Standard therapy for childhood intracranial ependymoma is maximal tumor resection followed by involved-field irradiation. Although not used routinely, chemotherapy has produced objective responses in ependymoma, both at recurrence and in infants. Because the presence of residual tumor following surgery is consistently associated with inferior outcome, the potential impact of pre-irradiation chemotherapy was investigated. METHODS: Between 1995 and 1999, the Children's Cancer Group undertook a Phase II trial of pre-irradiation chemotherapy in children 3-21 years of age with intracranial ependymoma and radiological evidence of post-operative residual tumor. RESULTS: Of 84 patients, 41 had residual tumor, and were given four cycles of cisplatin-based chemotherapy prior to irradiation. Of 35 patients fully evaluable for response to chemotherapy, 14 (40%) demonstrated complete response, 6 (17%) partial response, 10 (29%) minor response or stable disease, and 5 (14%) demonstrated progressive tumor growth. For the entire group, 5-year overall survival (OS) and event-free survival (EFS) was 71 ± 6%, and 57 ± 6%, respectively. The pre-irradiation chemotherapy group demonstrated EFS comparable to that of patients with no residual tumor who received irradiation alone (55 ± 8% vs. 58 ± 9%, P = 0.45). Any benefit of chemotherapy was restricted to patients with greater than 90% tumor resection. CONCLUSIONS: Children with near total resection of ependymoma may benefit from pre-irradiation chemotherapy. Patients with subtotal resection have inferior outcome despite responses to chemotherapy, and should be considered for second-look surgery prior to irradiation. Pediatr Blood Cancer 2012; 59: 1183-1189. © 2012 Wiley Periodicals, Inc.

Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group.

PURPOSE: To evaluate response rate, event-free survival (EFS), and toxicity of two chemotherapeutic regimens for treatment of children younger than 36 months with malignant brain tumors and to estimate control intervals without irradiation in children with no residual tumor after initial surgery and induction chemotherapy and with delayed irradiation in patients with residual tumor or metastatic disease at diagnosis. PATIENTS AND METHODS: Patients were randomly assigned to one of two regimens of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, and etoposide v vincristine, carboplatin, ifosfamide, and etoposide). Maintenance chemotherapy began after induction in children without progressive disease. Children with no residual tumors after induction therapy and no metastatic disease at diagnosis were not to receive radiation therapy unless their tumors progressed. RESULTS: Two hundred ninety-nine infants were enrolled. Forty-two percent of patients responded to induction chemotherapy. At 5 years from study entry, the EFS rate was 27% +/- 3%, and the survival rate was 43% +/- 3%. There was no significant difference between the two arms in terms of response rate or EFS. For medulloblastoma, supratentorial primitive neuroectodermal tumor, ependymoma, and rhabdoid tumors, 5-year EFS rates were 32% +/- 5%, 17% +/- 6%, and 32% +/- 6%, and 14% +/- 7%, respectively. Fifty-eight percent of patients who were alive 5 years after study entry had not received radiation therapy. CONCLUSION: Intensified induction chemotherapy resulted in a high response rate of malignant brain tumors in infants. Survival was comparable to that of previous studies, and most patients who survived did not receive radiation therapy.

Volumetric considerations in radiotherapy for pediatric parameningeal rhabdomyosarcomas.

PURPOSE: To assess the influence of radiation volume on outcome in pediatric parameningeal rhabdomyosarcomas (PM-RMSs). METHODS AND MATERIALS: Thirty patients ranging in age from 2 to 18 years (median 6) with PM-RMS were treated at the Hospital of the University of Pennsylvania and the Children's Hospital of Philadelphia between August 1988 and December 1999. The histologic subtypes included embryonal (n = 26), alveolar (n = 3), and undifferentiated (n = 1). Twenty-seven patients had Group III and three had Group IV disease. Twenty-seven patients underwent biopsy only and three subtotal resection. All patients were treated with multiple-agent chemotherapy and external beam radiotherapy. In 8 patients, all of whom had intracranial tumor extension, the tumor and whole brain were treated as the initial volume. In the remaining patients, most of those treated before 1992 were treated to the prechemotherapy (CMT) tumor volume for the entire treatment up to the total dose, which ranged from 45 to 59.4 Gy (median dose 57.9). In contrast, patients treated after 1992 generally received radiation initially to the pre-CMT volume (30.6-40 Gy; median dose 36) followed by a conedown to the post-CMT volume to a final dose of 41.4-55.2 Gy (median 50.4). RESULTS: With a median follow-up of 6.2 years (range 2.1-13.3), the actuarial 5-year overall survival, progression-free survival, and local control rate for the entire group was 82%, 76%, and 76%, respectively. Seven failures and five deaths have been documented. In univariate analysis, histologic type, tumor size, and age at diagnosis were found to be predictive of overall survival and local control. No statistically significant difference in overall survival or local control was seen between patients who received a conedown to the post-CMT volume (n = 13) and patients in whom the pre-CMT volume was included for the entire treatment (n = 9). CONCLUSION: Radiotherapy delivered to children with PM-RMS using a shrinking field technique with a post-CMT volume boost was effective and appears to give results comparable to those of patients in whom the pre-CMT volume was treated for the entire course. The use of such tailored treatment fields is likely to lead to fewer late effects and warrants further investigation.

Craniospinal radiation in the treatment of biopsy-proven intracranial germinomas: twenty-five years' experience in a single center.

PURPOSE: The optimal treatment for intracranial germinomas remains controversial. We report on our 25-year experience using craniospinal irradiation (CSI) for this disease. METHODS AND MATERIALS: Between September 1976 and May 2001, 39 patients with biopsy-proven intracranial germinomas seen at the Children's Hospital of Philadelphia/Hospital of the University of Pennsylvania received CSI. Thirteen of 36 patients (36%) had evidence of spinal dissemination. Median doses to the whole brain, primary site, and spine were 36 Gy (range, 18-44.2 Gy), 50.4 Gy (range, 44-55.8 Gy), and 30.6 Gy (range, 18-40 Gy), respectively. RESULTS: With a median follow-up of 7.1 years (range: 1.5-20.2 years), there have been no documented relapses. This includes 5 patients without spinal dissemination who received 18-19.8 Gy to the craniospinal axis; for these patients, the median length of follow-up was 5.5 years (range, 1.3-6.8 years). One patient, who had no evidence of disease 12.9 years after CSI, died of unknown causes 4 months later. CONCLUSIONS: Our treatment of intracranial germinomas with CSI has yielded outstanding results with no known relapses during a long follow-up period. These results must be considered when evaluating other approaches, such as chemotherapy only or local field irradiation.

Surgery with or without radiation therapy in the management of craniopharyngiomas in children and young adults.

PURPOSE: The optimal management of craniopharyngiomas remains controversial, especially in children and young adults. This study reports a single institution's experience with such patients. METHODS AND MATERIALS: Between 1974 and 2001, 76 patients were treated for craniopharyngioma at the Children's Hospital of Philadelphia and the Hospital of University of Pennsylvania (HUP). Of these, 75 patients (97%) were evaluable with long-term follow-up. Although all patients underwent attempted gross total resection, 27 had documentation of less than total resection with 18 of these patients receiving immediate postoperative radiotherapy (RT). An additional 22 patients received RT at HUP after failing surgery alone. RESULTS: Median follow-up for all patients was 7.6 years. The 10-year actuarial overall survival, relapse-free survival, and local control (LC) rates for all patients were 85%, 48%, and 53%, respectively. When comparing the 57 patients treated with surgery alone to the 18 treated with subtotal resection (STR) followed by RT, a significant difference in LC rates at 10 years (42% vs. 84%, respectively; p = 0.004) was noted. However, no statistically significant difference in overall survival was found between the two groups, because RT was highly effective as salvage therapy. Twenty-two patients at HUP treated with RT after relapse had a 10-year ultimate LC rate comparable to that of patients who received RT immediately after STR. CONCLUSION: RT given either immediately after STR or at relapse is effective in controlling craniopharyngiomas.

Intensity modulated radiation therapy--the shape of things to come?

Over the past century, the field of radiation oncology has seen tremendous technological advances. Some of these advances relate to biomedical accomplishments, while many are directly related to those achieved in computing and information technology. For example, developments in radiation treatment planning systems are intimately connected to progress in all of computing, and have culminated in the ability of radiation oncologists to accurately plan even the most complex therapy. Treatment machines, themselves tooled with embedded computer chips and processors, have evolved from rigid monstrosities to highly flexible, compact, machines capable of moving with robotic-like precision. The addition of multi-leaf collimators to these treatment machines has added yet another dimension to the picture. The ability to coordinate the fine motor movements of these collimators along with the coarser movements of the machine itself has required a level of control not possible manually. Computers again have provided a solution, and the result was not just a new means of directing the radiation beam, but a revolution in how radiation itself was delivered Intensity Modulated Radiation Therapy. Now, Intensity Modulated Radiation Therapy (IMRT) is practiced in hundreds of radiation oncology departments worldwide. The administration process, which challenges the most sophisticated computer planning and treatment control systems, requires not just proficient technical support, but also a dedicated administrative infrastructure. The payoff, however, promises to be big. Preliminary clinical outcome reports suggest that significant reductions in toxicity will be achievable, making increased control rates more likely. In addition, favorable CMS reimbursement changes make it probable that the technology will spread rapidly throughout the radiation oncology community. Studies are ongoing to help identify the most appropriate use of the therapy. Ultimately, IMRT is likely to become a readily available treatment for use in select cases.