Low-dose craniospinal radiation therapy for medulloblastoma

At the University of California, San Francisco, 65 children with medulloblastoma of the posterior fossa were treated postoperatively with craniospinal irradiation; the dose to the posterior fossa was 54 Gy. The 26 children initially treated had only radiation therapy, receiving 30 to 40 Gy to the spine and 40 to 50 Gy to the brain. Subsequently, 39 children were treated with low-dose craniospinal irradiation and chemotherapy; 24 to 30 Gy was directed to the whole brain and 24 to 26 Gy to the spinal axis. Chemotherapy generally consisted of procarbazine just before, and hydroxyurea during, radiation therapy. Poor-risk and good-risk patients (defined by tumor resection less than 75% or greater than 75%, positive or negative myelogram, positive or negative cerebrospinal fluid analysis, age less than or greater than 2 years, respectively) were evenly distributed between the low-dose and high-dose craniospinal radiation therapy groups. Median follow-up was 51 months (range, 24 to 228 months). Kaplan-Meier actuarial survival for all patients was 73% at 5 years, 70% at 10 years. Freedom from disease progression was 68% at 5 years, 65% at 10 years. Whereas poor-risk patients treated with low-dose craniospinal irradiation and chemotherapy had a 5-year survival of 58% and a 5-year freedom from disease progression of 39%, those figures in the comparable good-risk patients were 83% and 77%, respectively. For both good-risk and poor-risk patients, the posterior fossa was the primary site of recurrence. Tumors recurred in the frontal region, probably under blocks, in three patients receiving low-dose irradiation and in two receiving the higher dose. Reducing the dose of whole-brain and spinal irradiation and giving chemotherapy did not result in a higher rate of recurrence in the brain or spinal cord. Intellectual and social function appeared better in patients receiving the lower dose. We did not study whether chemotherapy benefitted good-risk patients. Craniospinal axis irradiation at a lower dose than conventionally used does not compromise local control or survival in patients with medulloblastoma, and may reduce toxicity.     

Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study.

PURPOSE: Medulloblastoma is the most common malignant brain tumor of childhood. After treatment with surgery and radiation therapy, approximately 60% of children with medulloblastoma are alive and free of progressive disease 5 years after diagnosis, but many have significant neurocognitive sequelae. This study was undertaken to determine the feasibility and efficacy of treating children with nondisseminated medulloblastoma with reduced-dose craniospinal radiotherapy plus adjuvant chemotherapy. PATIENTS AND METHODS: Over a 3-year period, 65 children between 3 and 10 years of age with nondisseminated medulloblastoma were treated with postoperative, reduced-dose craniospinal radiation therapy (23.4 Gy) and 55.8 Gy of local radiation therapy. Adjuvant vincristine chemotherapy was administered during radiotherapy, and lomustine, vincristine, and cisplatin chemotherapy was administered during and after radiation. RESULTS: Progression-free survival was 86% +/- 4% at 3 years and 79% +/- 7% at 5 years. Sites of relapse for the 14 patients who developed progressive disease included the local tumor site alone in two patients, local tumor site and disseminated disease in nine, and nonprimary sites in three. Brainstem involvement did not adversely affect outcome. Therapy was relatively well tolerated; however, the dose of cisplatin had to be modified in more than 50% of patients before the completion of treatment. One child died of pneumonitis and sepsis during treatment. CONCLUSION: These overall survival rates compare favorably to those obtained in studies using full-dose radiation therapy alone or radiation therapy plus chemotherapy. The results suggest that reduced-dose craniospinal radiation therapy and adjuvant chemotherapy during and after radiation is a feasible approach for children with nondisseminated medulloblastoma.     

Medulloblastoma and supratentorial primitive neuroectodermal tumors: an institutional experience.

BACKGROUND: To the authors' knowledge there are relatively few data concerning supratentorial primitive neuroectodermal tumors (PNET). The authors retrospectively reviewed all cases of PNET of the brain treated at the study institution to determine whether there was a difference in presentation, overall survival, and recurrence-free survival with regard to tumor location (supratentorium vs. posterior fossa). METHODS: Between 1977-1996 33 patients with PNET were diagnosed and treated at 1 radiotherapy center. The median age of the patients was 9 years. The location of the tumor was in the posterior fossa in 25 patients and the supratentorium in 8 patients. The tumor had spread to the neuraxis in six patients; four patients with disseminated neuraxis disease had a supratentorial PNET and two had a posterior fossa PNET. All but three patients received craniospinal irradiation. The primary tumor received > or = 5000 centigray in 27 patients and chemotherapy was employed in 26 patients. The median follow-up was 60 months. RESULTS: The 5-year overall and recurrence-free survival rates for all patients were 77.2% and 79.6%, respectively. The 5-year overall survival rates were 86.3% for patients with medulloblastoma (posterior fossa PNET) and 46.9% for patients with supratentorial PNET (P = 0.01, log rank test). For overall survival, prognostic factors included radiotherapy dose to the primary site, metastases (M) status, and location of the primary tumor. The 5-year recurrence free survival rates were 89.8% for patients with medulloblastoma and 46.9% for patients with supratentorial PNET (P = 0.003, log rank test). For recurrence free survival, prognostic factors included M status and primary tumor site location; radiation dose to the primary tumor site and patient gender were of borderline significance. In the ten patients with inadequate posterior fossa boost fields judged by Children's Cancer Group criteria, there were two failures, both of which were in the original tumor bed. CONCLUSIONS: Supratentorial PNET has a worse overall survival and recurrence free survival than medulloblastoma. There is a suggestion that radiotherapy boosts in medulloblastoma may not need to encompass the entire posterior fossa because posterior fossa failures primarily are in the tumor bed. Larger studies with longer follow-up are needed to determine whether craniospinal irradiation followed by a boost to the tumor bed is adequate for medulloblastoma patients.     

72例标危型髓母细胞瘤放疗剂量对生存的影响

目的 回顾分析标危型髓母细胞瘤采用全脑全脊髓放疗剂量≤24 Gy和>24 Gy对预后的影响。方法 标危型髓母细胞瘤定义为年龄>3岁、未发生转移、肿瘤全切或近全切(残留≤1.5 cm³)。2003—2013年共入组72例初治儿童、青少年标危型髓母细胞瘤患者。患者术后接受全脑全脊髓+局部瘤床放疗和8个疗程辅助化疗,化疗方案为顺铂、司莫司汀或卡莫司汀联合长春新碱。按放疗剂量≤24 Gy和>24 Gy分为A、B组(20、52例),比较两组患者复发率和生存率。Kaplan-Meier法计算复发率和生存率并Logrank法检验组间差异。结果 A组接受全脑全脊髓放疗19.2~24.0 Gy,B组接受全脑全脊髓放疗24.1~30.6 Gy。放疗后66例(92%)患者完成全部辅助化疗。共11例患者复发。随访满3年患者48例,其中复发11例,死亡7例。全组3年EFS率为83%,3年OS率为86%。A组和B组患者3年EFS率分别为84%和83%(P=0.609), 3年OS率分别为85%和87%(P=0.963)。结论 标危型髓母细胞瘤经规范综合治疗效果较好,其中全脑全脊髓放疗剂量减少至19.2~24.0 Gy未影响疗效。     

Long-term survival of high-risk pediatric patients with primitive neuroectodermal tumors treated with antineoplastons A10 and AS2-1

Primitive neuroectodermal tumors (PNETs) are usually successfully treated with craniospinal radiation and chemotherapy; however, difficulties with standard treatment can be encountered in very young children, in adult patients at high risk of complication from standard treatment, and in patients with recurrent tumors. Thirteen children, either with recurrent disease or high risk, were treated in phase II studies with antineoplastons (ANP). The median age of patients was 5 years, 7 months (range, 1-11). Medulloblastoma was diagnosed in 8 patients, pineoblastoma in 3 patients, and other PNET in 2 patients. Previous treatments included surgery in 12 patients (1 had biopsy only, suboccipital craniotomy), chemotherapy in 6 patients, and radiation therapy in 6 patients. Six patients had not received prior chemotherapy or radiation. The treatment consisted of intravenous infusions of 2 formulations of ANP, A10 and AS2-1, and was administered for an average of 20 months. The average dosage of A10 was 10.3 g/kg/d and of AS2-1 was 0.38 g/kg/d. Complete response was accomplished in 23%, partial response in 8%, stable disease in 31%, and progressive disease in 38% of cases. Six patients (46%) survived more than 5 years from initiation of ANP; 5 were not treated earlier with radiation therapy or chemotherapy. The serious side effects included single occurrences of fever, granulocytopenia, and anemia. The study is ongoing and accruing additional patients. The percentage of patients' response is lower than for standard treatment of favorable PNET, but long-term survival in poor-risk cases and reduced toxicity makes ANP promising for very young children, patients at high risk of complication of standard therapy, and patients with recurrent tumors.     

Suprateutorial primitive neuroectodermal tumors in children

A retrospective review of 36 children diagnosed with a supratentorial primitive neuroectodermal tumor (PNET) at the Hospital for Sick Children was performed for the period 1970-1995. All children but one received their initial treatment at our institution. There were 18 males and 18 females and the median age at diagnosis was 35 months. Twenty-two PNETs were lobar, 3 were deep in the hemisphere, and 10 were located in the pineal region. One child presented with intracranial leptomeningeal disseminated disease. The tumors were mostly undifferentiated although 22 had some evidence of differentiation along one or more neuroepithelial lines. Five children had a biopsy, 24 had subtotal resection, and 7 had gross total resection. Twenty-six children had adjuvant radiotherapy and 13 had chemotherapy. At last follow-up 30 patients were dead and 6 were alive. The median survival was 23 months and the 2, 3, and 5 year survivals were 50%, 34%, and 18% respectively. All of the survivors received craniospinal radiation and 4 received chemotherapy. There was a statistically significantly worse survival in young children. There was a trend to better survival in children treated since 1984, and in children undergoing gross total resection. Because of the extremely poor survival, we recommended that all children undergo gross total resection followed by chemotherapy. For children older than 3 years of age craniospinal radiation should also be given.     

Conformal radiotherapy, reduced boost volume, hyperfractionated radiotherapy, and online quality control in standard-risk medulloblastoma without chemotherapy: results of the French M-SFOP 98 protocol

PURPOSE: Between December 1998 and October 2001, patients <19 years old were treated for standard-risk medulloblastoma according to the Medulloblastome-Société Fran?aise d'Oncologie Pédiatrique 1998 (M-SFOP 98) protocol. Patients received hyperfractionated radiotherapy (36 Gy in 36 fractions) to the craniospinal axis, a boost with conformal therapy restricted to the tumor bed (to a total dose of 68 Gy in 68 fractions), and no chemotherapy. Records of craniospinal irradiation were reviewed before treatment start. RESULTS: A total of 48 patients were considered assessable. With a median follow-up of 45.7 months, the overall survival and progression-free survival rate at 3 years was 89% and 81%, respectively. Fourteen major deviations were detected and eight were corrected. No relapses occurred in the frontal region and none occurred in the posterior fossa outside the boost volume. Nine patients were available for volume calculation without reduction of the volume irradiated. We observed a reduction in the subtentorial volume irradiated to >60 Gy, but a slight increase in the volume irradiated to 40 Gy. No decrease in intelligence was observed in the 22 children tested during the first 2 years. CONCLUSION: This hyperfractionated radiotherapy protocol with a reduced boost volume and without chemotherapy was not associated with early relapses in children. Moreover, intellectual function seemed to be preserved. These results are promising.     

Analysis of patients with supratentorial primitive neuro-ectodermal tumours entered into the SIOP/UKCCSG PNET 3 study

The SIOP PNET 3 study was designed to determine whether 10 weeks of moderately intensive chemotherapy given after surgery and before radiotherapy (RT) would improve the outcome for patients with primitive neuroectodermal tumours (PNETs) compared with RT alone. Patients with a histological diagnosis of supratentorial PNET (StPNET) and no radiological evidence of metastatic disease were initially eligible for randomisation to either chemotherapy followed by craniospinal RT 35 Gy in 21 fractions with a boost of 20 Gy in 12 fractions to the primary site, or RT alone. In respect of the increasing recognition that StPNET were high-risk tumours, randomisation for this group closed in November 1999. This analysis includes both randomised and non-randomised patients with StPNET entered into the study database. Sixty-eight patients aged 2.9-16.6 years (median 6.5 years) were included in the analysis (chemotherapy+RT: 44, RT alone: 24). Fifty-four patients (79%) had a non-pineal and 14 (21%) a pineal site. At a median follow-up of 7.4 years, for all patients overall survival (OS) at 3 and 5 years was 54.4% and 48.3%, respectively. Event-free survival (EFS) at 3 and 5 years was 50.0% and 47.0%, respectively. There was no statistically significant difference in OS or EFS according to treatment received. OS (P=0.05) and EFS (P=0.03) were significantly better for patients with pineal primary sites. EFS for pineal tumours were 92.9% at 3 years and 71.4% at 5 years and for non-pineal primaries 40.7% at 3 years and 40.7% at 5 years. This study confirmed the relatively good survival for non-metastatic pineal PNETs but poor survival of non-pineal StPNETs. There was no evidence that pre-radiation chemotherapy improved outlook. Future treatment programs should be directed at the particular natural history of these tumours, to further define prognostic factors and to explore further biological characteristics.     

Results of radiation therapy for medulloblastoma

Results of radiation therapy for cerebellar medulloblastoma at Kyoto University Hospital were reviewed. Between 1962 and 1988, 30 patients with histologically-proven medulloblastoma completed radiotherapy. Before 1971, the treatment volume was either the posterior fossa only or posterior fossa plus spinal axis, but after 1972, it was extended to include the entire neuraxis. The mean dose was 48 Gy to the posterior fossa, 36 Gy to the whole brain, and 25 Gy to the spinal axis. The 5-year survival rate and 5-year relapse-free survival rate estimated by the Kaplan-Meier's method were 36% and 37%, respectively, for total cases, but were as high as 79% and 80%, respectively, for the recent 10 patients. This improvement in the treatment results appeared to be due to extensive tumor resection and improved radiotherapy technique, and not to the use of chemotherapy. The prognosis was significantly better in patients treated with craniospinal irradiation than in those otherwise treated. There was a trend towards better survival in patients who received 50 Gy or more to the posterior fossa or 24 Gy or more to the spinal axis, compared to the patients who received lower doses to each site. No significant morbidity of radiotherapy was seen. Four of the six surviving patients who were treated below age 12 have a mental retardation and/or a short stature, but one patient treated at age 5 has a normal growth and a good intelligence. From these analysis, it is recommended to irradiate craniospinal axis and posterior fossa up to 25-35 Gy and 50-55 Gy, respectively.     

Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children's Cancer Group study.

PURPOSE: To investigate the intellectual outcomes of children with medulloblastomas/primitive neuroectodermal tumors (MB/PNET) treated with reduced-dose craniospinal radiotherapy (RT) plus adjuvant chemotherapy. PATIENTS AND METHODS: Forty-three children with average-risk posterior fossa MB/PNETs underwent longitudinal intelligence testing. All had been treated with a reduced-dose craniospinal RT regimen (23.4 Gy to the neuraxis, 32.4-Gy boost to the posterior fossa) and adjuvant chemotherapy. RESULTS: The estimated rate of change from baseline was significant for Full Scale Intelligence Quotient (FSIQ), Verbal IQ (VIQ), and Nonverbal IQ (NVIQ) (P <.001 for all three outcomes). The rate of change was estimated to be -4.3 FSIQ points per year, -4.2 VIQ points per year, and -4.0 NVIQ points per year. Females were more subject to VIQ decline than were males (P =.008), and young children (< 7 years of age) were more negatively affected than were older children, with a significant decline in NVIQ (P =.016). Finally, patients with higher baseline evaluations suffered greater declines in IQ than did those with lower baseline scores. CONCLUSION: This study represents the largest series of patients with average-risk MB/PNETs treated with a combination of reduced-dose RT and adjuvant chemotherapy whose intellectual development has been followed prospectively. Intellectual loss was substantial but suggestive of some degree of intellectual preservation compared with effects associated with conventional RT doses. However, this conclusion remains provisional, pending further research.     

Medulloblastoma/primitive neuroectodermal tumor in adults: prognostic factors and treatment results: a single-center experience from Turkey

We performed retrospective review of 29 adult patients with cerebellar medulloblastoma/primitive neuroectodermal tumor (PNET) who received craniospinal radiotherapy in Ankara Oncology Hospital between years 2000 and 2005. All patients were operated followed by craniospinal irradiation; 11 of 29 patients also received chemotherapy. All patients had no distant or spinal metastases at the time of diagnosis. Median follow up time was 26 months. Progression-free survival was 86% at 2 years, 55% at 5 years. Mean progression-free survival was 25 months in patients with PNET; 61.4 months in patients with medulloblastoma (P = 0.0016). Mean survival was 61.33% months in patients <25 age, 38 months in patients >25 age. (P = 0.04). Overall mean survival was 59.80 months in patients who received chemotherapy and 41.4 months in patients who did not have chemotherapy (P = 0.15). Cranial relapses were observed in 3 of 29 patients, and 3 of 29 patients had distant metastases. The mean time to cranial recurrence was 19 months; to distant metastases was 18 months. In conclusion, adult patients with PNET have worse survival rates than patients with medulloblastoma, like in childhood patients. Patients younger than 25 years of age also had statistically significant better survival.     

Phase II study of 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine chemotherapy with radiotherapy for treating malignant glioma in children

We conducted a single-arm phase II study to evaluate the efficacy and safety of radiotherapy combined with 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine (TPDCV) chemotherapy for treating malignant astrocytoma in children and anaplastic ependymoma in patients of all ages. Between 1984 and 1992, 42 patients who had malignant astrocytomas (glioblastomas multiforme, anaplastic astrocytomas, or mixed anaplastic oligoastrocytomas) were treated with TPDCV chemotherapy and radiation therapy. Of these patients, 40 were younger than 18 years, but 2 were older (22 and 23 years) when treated. Cranial radiation averaged 58 Gy. TPDCV chemotherapy was given for 1 year or until progression. Between 1989 and 1991, 17 patients with malignant ependymoma were treated with TPDCV chemotherapy and craniospinal radiation. Radiation was given at an average dose of 54 Gy to the tumor, 28 Gy to the whole brain, and 31 Gy to the spinal axis. TPDCV chemotherapy was given for 1 year or until tumor progressed. Of the patients with glioblastoma multiforme, 13 of 17 died; the median time to progression was 49 weeks, and median survival was 85 weeks. The four patients surviving at this writing were followed a median 537 weeks (range 364-635 weeks). Of the patients with nonglioblastoma malignant astrocytoma, 14 of 25 died; the median time to progression was 224 weeks. Median survival was not reached in this group. The median follow-up for those surviving was 494 weeks. For the patients with ependymoma, 11 of 17 died with a median time to progression of 141 weeks. The median follow-up for the eight who survive was 469 weeks. Nine patients died with a median survival of 183 weeks. The combination of TPDCV and radiotherapy has activity against childhood anaplastic astrocytoma, glioblastoma multiforme, and anaplastic ependymoma. The results of this study for children with glioblastoma were comparable to results in the literature, while the results for children with anaplastic astrocytoma appeared better than most reports. The combination of TPDCV chemotherapy and radiation therapy for anaplastic ependymomas appears to be active and at least as good as published reports using radiation therapy alone.     

Primary intraspinal primitive neuroectodermal tumor: report of two cases and review of the literature

Background. Primary intraspinal primitive neuroectodermal tumor (PNET) is a very rare tumor entity. The optimal therapeutic approach is not known yet. We report on two women with primary intraspinal PNETs and review the literature. We describe the typical course of the disease, compare our patients to the other 17 cases reported until today, and discuss therapeutic options. Patients and method. Case A: In a 49-Year-old woman with an intraspinal PNET at L2, laminectomy and a gross tumor removal was accomplished. Postoperative radiation was performed from T12 to L3 to a dose of 50.4Gy. Subsequently she was treated with chemotherapy containing vincristine, cisplatinum and lomustine. Case B: A 29-Year-old woman presented with intramedullary PNET lesions at T1–3 and T10–11. Due to the multifocal location, she received a primary craniospinal axis irradiation to a dose of 35.2Gy plus a boost to the tumor region to a total dose of 53.2Gy. Results. Both patients developed multilocular intraspinal relapses with meningeosis neoplastica 17 and 6 months from radiation therapy and underwent palliative chemotherapy. Case A died 23 months, case B 17 months after primary diagnosis. Conclusion. Despite modern treatment with microsurgery, irradiation and chemotherapy in primary intraspinal PNETs, local relapse or dissemination in most cases lead to death within a few months. An improvement of treatment outcome can only be achieved by intensification through multidisciplinary treatment.     

Current diagnostic and therapeutic management of CNS metastasis in childhood primitive neuroectodermal tumors and ependymomas

Metastatic disease is a major problem in the management of the most frequent childhood brain tumors, in ependymoma and primitive neuroectodermal tumors (PNET). Today, contrast enhanced craniospinal MRI and careful analysis of craniospinal fluid are a prerequisite for correct staging of both tumors and imply therapeutic consequences. So far metastatic spread of medulloblastoma and some ependymomas is prevented by conventional chemotherapy and radiotherapy. However, some forms of diffuse metastatic dissemination in medulloblastoma are resistant to conventional therapeutic regimens and require new experimental strategies.     

Common strategy for adult and pediatric medulloblastoma: a multicenter series of 253 adults

PURPOSE: To assess prognostic factors for adults with medulloblastoma in a multicenter, retrospective study. METHODS AND MATERIALS: Data were collected by file review or mail inquiry for 253 adults treated between 1975 to 2004. Radiologists or surgeons assessed disease characteristics, such as volume and extension. Patients were classified as having either high- or standard-risk disease. Prognostic factors were analyzed. RESULTS: Median patient age was 29 years. Median follow-up was 7 years. Radiotherapy was delivered in 246 patients and radiochemotherapy in 142. Seventy-four patients relapsed. Respective 5- and 10-year overall survival rates were 72% and 55%. Univariate analysis showed that survival significantly correlated with metastasis, postsurgical performance status, brainstem involvement, involvement of the floor of the fourth ventricle (V4), and radiation dose to the spine and to the posterior cerebral fossa (PCF). By multivariate analysis, brainstem, V4 involvement, and dose to the PCF were negative prognostic factors. In the standard-risk subgroup there was no overall survival difference between patients treated with axial doses of >or=34 Gy and patients treated with craniospinal doses <34 Gy plus chemotherapy. CONCLUSION: We report the largest series of medulloblastoma in adults. Prognostic factors were similar to those observed in children. Results suggest that patients with standard-risk disease could be treated with radiochemotherapy, reducing doses to the craniospinal area, maintaining at least 50 Gy to the PCF. The role of chemotherapy for this group is still unclear. A randomized study should be performed to confirm these results, but because frequency is very low, such a study would be difficult.     

Feasibility of four consecutive high-dose chemotherapy cycles with stem-cell rescue for patients with newly diagnosed medulloblastoma or supratentorial primitive neuroectodermal tumor after craniospinal radiotherapy: results of a collaborative study.

PURPOSE: This study was designed to determine the feasibility and safety of delivering four consecutive cycles of high-dose cyclophosphamide, cisplatin, and vincristine, each followed by stem-cell rescue, every 4 weeks, after completion of risk-adapted craniospinal irradiation to children with newly diagnosed medulloblastoma or supratentorial primitive neuroectodermal tumor (PNET). PATIENTS AND METHODS: Fifty-three patients, 19 with high-risk disease and 34 with average-risk disease, were enrolled onto this study. After surgical resection, high-risk patients were treated with topotecan in a 6-week phase II window followed by craniospinal radiation therapy and four cycles of high-dose cyclophosphamide (4,000 mg/m2 per cycle), with cisplatin (75 mg/m2 per cycle), and vincristine (two 1.5-mg/m2 doses per cycle). Support with peripheral blood stem cells or bone marrow and with granulocyte colony-stimulating factor was administered after each cycle of high-dose chemotherapy. Treatment of average-risk patients consisted of surgical resection and craniospinal irradiation, followed by the same chemotherapy given to patients with high-risk disease. The expected duration of the chemotherapy was 16 weeks, with a cumulative cyclophosphamide dose of 16,000 mg/m2 and a planned dose-intensity of 1,000 mg/m2/wk. RESULTS: Fifty of the 53 patients commenced high-dose chemotherapy, and 49 patients completed all four cycles. The median length of chemotherapy cycles one through four was 28, 27, 29, and 28 days, respectively. Engraftment occurred at a median of 14 to 15 days after infusion of stem cells or autologous bone marrow. The intended dose-intensity of cyclophosphamide was 1,000 mg/m2/wk; the median delivered dose-intensity was 1,014, 1,023, 974, and 991 mg/m2/wk for cycles 1 through 4, respectively; associated median relative dose-intensity was 101%, 102%, 97%, and 99%. No deaths were attributable to the toxic effects of high-dose chemotherapy. Early outcome analysis indicates a 2-year progression-free survival of 93.6% +/- 4.7% for the average-risk patients. For the high-risk patients, the 2-year progression-free survival is 73.7% +/- 10.5% from the start of therapy and 84.2% +/- 8.6% from the start of radiation therapy. CONCLUSION: Administering four consecutive cycles of high-dose chemotherapy with stem-cell support after surgical resection and craniospinal irradiation is feasible in newly diagnosed patients with medulloblastoma/supratentorial PNET with aggressive supportive care. The early outcome results of this approach are very encouraging.     

Hyperfractionated radiotherapy with concurrent chemotherapy for advanced esophageal cancer

The clinical efficacy and safety of hyperfractionated radiotherapy with concurrent chemotherapy were studied retrospectively in patients with primary advanced esophageal cancer. The subjects were 31 patients who were treated with hyperfractionated radiotherapy and concurrent chemotherapy in our institution between 1990 and 2001. The chemoradiotherapy consisted of cisplatin 70-80 mg/m2 on day one, and continuous infusion of 5-fluorouracil 700-800 mg/m2/24 hours on days 1 to 3, with concurrent hyperfractionated radiotherapy (57.6-72 Gy). Complete remission (CR) was observed in 17 cases, and partial response in 13 cases (response rate: 96. 7%). Three-year survival rate and 5-year survival rate were 35.5% and 26.3%, respectively. Grade 3/4 hematological toxicities included leukocytes in 7 patients (22.6%), hemoglobin in 6 patients (19.4%), and platelets in 4 patients (12.9%). Grade 3 dysphagia-esophageal related to radiation was observed in 3 patients (9.7%). Late toxicities occurred with the following incidences: hypothyroidism in 2 patients, benign esophageal strictures in 2 patients, pericardial effusion in 8 patients, and pleural effusion in 8 patients. The results suggest that combined chemotherapy and hyperfractionated radiotherapy is an effective and well-tolerated regimen.     

Primitive neuroectodermal tumors in the central nervous system following cranial irradiation: a report of four cases

BACKGROUND: Radiation induced intracranial neoplasms are uncommon but well described and include gliomas, meningiomas, and sarcomas. The development of primitive neuroectodermal tumors (PNETs) following prophylactic craniospinal irradiation has been infrequently reported previously. The authors present four additional cases of PNETs that developed after previous cranial irradiation. METHODS: Four patients who had previously been irradiated were determined to have PNETs of the central nervous system characterized by histopathologic and immunohistochemical features. The average patient age at diagnosis of the initial tumors and cranial irradiation was 17 years. The PNETs developed 5, 11, 11, and 18 years after completion of radiation. RESULTS: Three patients had posterior fossa tumors, one pilocytic astrocytoma, one low grade astrocytoma, and one malignant ependymoma, which had been diagnosed and treated in childhood. Two of those patients developed supratentorial PNETs and the third a cerebellar hemispheric PNET. The fourth patient developed a posterior fossa PNET following irradiation for a temporal astrocytoma, which was initially diagnosed and resected at 37 years of age. Mean survival was 12 months after diagnosis. CONCLUSIONS: The development of PNETs after cranial irradiation may be more common than thought previously and should be considered in the differential diagnosis of irradiation induced neoplasms. Survival after diagnosis of these radiation induced PNETs was short, and this may reflect an inability to provide standard therapy used for primary PNETs.     

Survival and recurrence factors in adult medulloblastoma: the M.D. Anderson Cancer Center experience from 1978 to 1998

Medulloblastoma is a rare adult primary brain tumor for which limited retrospective studies are available to elucidate natural history or to guide therapy. A retrospective chart and imaging review of adult patients (aged >18 years) with medulloblastoma was performed to identify survival and prognostic factors. Fifty-seven patients were evaluated at the University of Texas M.D. Anderson Cancer Center from 1978-1998. Statistical analysis of prognostic factors and overall survival was performed for a subgroup of 28 patients who were followed exclusively at our institution from the time of diagnosis until death or last follow-up. These 28 patients had an overall survival of 91% at 3 years and 84% at 5 years, whereas median survival was not reached after a median follow-up of 168 weeks (range, 9-602 weeks). Progression-free survival for all patients was 68% at 3 years and 62% at 5 years, and was not statistically different between poor- and standard-risk patients. Univariate analysis of clinical features, such as age, sex, extent of local disease, extent of resection, and use of adjuvant chemotherapy, did not identify any prognostic variables for survival among the 28 patients. Patterns of recurrence revealed that the posterior fossa was the most common site (56%), followed by bone marrow (25%). Adult medulloblastoma appears to have a favorable prognosis after treatment with maximally surgically feasible resection followed by craniospinal irradiation. Optimal treatment remains to be clarified, as both standard-risk and poor-risk patients have prolonged disease-free survival. The marked difference between survival and progression-free survival suggests that salvage therapy, usually with combination chemotherapy in this cohort of patients, is of benefit. More formal analysis of the survival benefit was not possible, however, because of the small number of patients treated at recurrence with any one therapeutic regimen.     

Late radiation injury following hyperfractionated craniospinal radiotherapy for primitive neuroectodermal tumor

PURPOSE: To document the late radiographic change following hyperfractionated craniospinal radiotherapy for primitive neuroectodermal tumor. METHODS AND MATERIALS: We reviewed long-term MRI scans on 21 patients with standard risk and high risk primitive neuroectodermal tumor treated with hyperfractionated radiotherapy following surgical resection. High risk patients also received adjuvant chemotherapy. Long-term scans were defined as scan obtained at least 1 year from diagnosis. Clinical follow-up data was available on all patients. RESULTS: Twelve of 21 patients had MRI evidence of necrosis, telangiectasia, white matter changes, basal ganglia change, or cerebral atrophy consistent with radiation injury. No patient required treatment for the radiographic change. CONCLUSIONS: Slightly over half of the patients had evidence of long-term radiation effect following craniospinal axis radiotherapy. However, no patient had frank clinical symptoms related to the radiographic findings.