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.     

Patterns of failure using a conformal radiation therapy tumor bed boost for medulloblastoma.

PURPOSE: To assess the patterns of failure for patients with medulloblastoma receiving a conformal tumor bed boost rather than a boost to the entire posterior fossa. PATIENTS AND METHODS: From 1994 to 2002, 32 consecutive patients with newly diagnosed medulloblastoma treated at Memorial Sloan-Kettering Cancer Center (New York, NY) received a conformal boost to the tumor bed in conjunction with craniospinal radiation therapy. Twenty-eight patients also received chemotherapy. The median age was 9 years (range, 3 to 34 years), and the male to female ratio was 3:1. Twenty-seven patients had standard-risk disease, and five patients had high-risk disease. Craniospinal doses ranged from 23.4 to 39.6 Gy, and total tumor bed doses ranged from 54 to 59.4 Gy. RESULTS: With a median follow-up of 56 months, six patients have relapsed; five relapsed outside of the posterior fossa, and one failed within the posterior fossa, outside of the high-dose boost volume. Five-year actuarial disease-free and overall survival rates were 84% and 85%, respectively. Freedom from posterior fossa failure was 100% and 86% at 5 and 10 years, respectively. Freedom from distant failure was 84% at 5 years, with a trend for improvement when full-dose craniospinal radiation (36 to 39.6 Gy) was used compared with a reduced dose (23.4 Gy) of radiation (100% v 63%, respectively; P =.06). No other predictive variables were identified. CONCLUSION: Conformal treatment to the tumor bed allows for significant sparing of critical structures. The posterior fossa failure rate in this series is similar to that reported when the entire posterior fossa is treated. This approach should be investigated further in a phase III trial.     

Preliminary results of conformal radiation therapy for medulloblastoma

Radiation therapy for medulloblastoma consists of postoperative irradiation of the intracranial and spinal subarachnoid volume with an additional boost to the primary site of disease in the posterior fossa. The entire posterior fossa is usually included in the boost volume. Conformal radiation therapy techniques may be used to boost the primary site alone and substantially reduce the dose received by normal tissues, including the supratentorial brain, the middle and inner ear, and the hypothalamus. Using these techniques to irradiate only the tumor bed or residual tumor and not the entire posterior fossa represents a new paradigm in the treatment of medulloblastoma. In this study, we examine the use of conformal radiation therapy in the treatment of 14 patients with medulloblastoma. These patients were treated with multiple static, individually shaped, noncoplanar beams directed at the primary site after craniospinal irradiation. Excluding two patients who had previously received irradiation to the posterior fossa, the mean dose delivered to the primary site was 5715 cGy. Among the medulloblastoma patients (n = 10) who received immediate postoperative radiation therapy, no failures have occurred with a median follow-up of 42 months (range from 30 to 54 months). To demonstrate the differences in the distribution of dose to normal tissues when comparing conventional and conformal techniques, dose-volume histograms of the total brain, middle and inner ear, hypothalamus, and temporal lobe were created and presented for an example case. The neurologic, neuroendocrine, and neurocognitive outcome for patients with medulloblastoma may be influenced with the use of conformal radiation therapy. The use of these techniques should be formally tested in prospective studies of rigorously staged patients with failure rate monitoring.     

Survival of very young children with medulloblastoma (primitive neuroectodermal tumor of the posterior fossa) treated with craniospinal irradiation

Purpose: Very young children with medulloblastoma are considered to have a worse prognosis than older children. As radiotherapy remains an important part of the treatment, the adverse prognosis could be due to inadequate radiation treatment rather than biological factors. We analyzed the published literature to examine the impact of radiotherapy on survival in this group.

Methods and Materials: A Medline search was performed and we reviewed studies of treatment of medulloblastoma where radiotherapy was delivered using megavoltage equipment and the minimum follow-up allowed the calculation of 5-year survival rates.

Results: Thirty-nine studies were published between 1979 and 1996 with a treatment including craniospinal irradiation and boost to the posterior fossa. Eleven studies comprising 1366 patients analyzed survival by age at diagnosis. Eight of 11 studies showed a worse 5-year survival for the younger patient group which reached statistical significance in two. There is also a suggestion of a higher proportion of children with metastatic disease at presentation in the very young age group. The usual policy in younger children was to give a lower dose of radiotherapy to the craniospinal axis (CSA) and posterior fossa (PF) with reduction of dose in the range of 15 to 25% compared to standard treatment. As dose reduction to the posterior fossa is associated with worse survival and local recurrence is the predominant site of failure, the major determinant of worse survival in very young children with medulloblastoma may be suboptimal radiotherapy. Protocols including postoperative chemotherapy with delayed, omitted, or only local tumor irradiation do not reach survival rates of protocols with standard radiotherapy, also suggesting a continued importance for irradiation.

Conclusion: Very young children with medulloblastoma have a worse prognosis than older children. Inadequate radiation dose and technique to the primary tumor region may be a major contributing factor. Current chemotherapeutic regimes alone are not sufficient to compensate for reduced radiation doses and volumes.     

The local field in infratentorial ependymoma: does the entire posterior fossa need to be treated?

INTRODUCTION: In the past decade, there have been multiple reports indicating that the predominant problem in the curative treatment of intracranial ependymoma is local failure. As a result, many have recommended local field radiotherapy. For infratentorial ependymoma, there is controversy regarding what constitutes the local field. Some radiation oncologists advocate coverage of the entire posterior fossa, whereas others recommend radiotherapy to the tumor bed and a safety margin. METHODS AND MATERIALS: From 1984 to 1998, 28 patients with posterior fossa ependymoma were diagnosed at our institution. There were 18 males and 10 females with a median age of 12 years (range, 2-81 years). Four patients (14%) had high-grade ependymoma and 3 (11%) had M+ disease at initial diagnosis. Gross total resection was achieved in 17 (61%) and postoperative radiotherapy (RT) was given to 22 (77%). Radiotherapy fields were craniospinal in 10, whole brain in 1, posterior fossa in 2, and tumor bed with a 2-cm. margin in 9. Median dose to the primary site was 54 Gy (range, 45-55 Gy). All 4 patients with high-grade ependymoma received craniospinal RT. Six patients did not receive RT after surgery. Magnetic resonance imaging (MRI) or computed tomography (CT) scans of the brain at initial diagnosis were compared to MRI or CT scans of patients at relapse to determine if the local relapse was in the tumor bed or nontumor bed posterior fossa. Median follow-up was 127 months (range, 14-188 months). RESULTS: Six patients have relapsed. For the 11 patients who had craniospinal or whole brain radiotherapy (RT), 3 recurred (tumor bed 1, spine 1, nontumor bed posterior fossa + spine 1). Both patients who failed in the spine had high-grade tumors. Neither of the 2 treated with posterior fossa fields relapsed. For the 9 patients who had tumor bed RT alone and the 6 who did not receive RT, there were 3 relapses; all were in the tumor bed. There were no relapses in the nontumor bed posterior fossa. CONCLUSION: For nondisseminated, low-grade infratentorial ependymoma, the radiotherapy volume does not need to include the entire posterior fossa. This information can be used to minimize late effects of RT in the era of three-dimensional (conformal) radiotherapy. No conclusion can be reached regarding the appropriate local field for high-grade infratentorial ependymoma because of the small number of patients.     

Survival and secondary tumors in children with medulloblastoma receiving radiotherapy and adjuvant chemotherapy: results of Children's Oncology Group trial A9961

The purpose of the trial was to determine the survival and incidence of secondary tumors in children with medulloblastoma receiving radiotherapy plus chemotherapy. Three hundred seventy-nine eligible patients with nondisseminated medulloblastoma between the ages of 3 and 21 years were treated with 2340 cGy of craniospinal and 5580 cGy of posterior fossa irradiation. Patients were randomized between postradiation cisplatin and vincristine plus either CCNU or cyclophosphamide. Survival, pattern of relapse, and occurrence of secondary tumors were assessed. Five- and 10-year event-free survivals were 81 ± 2% and 75.8 ± 2.3%; overall survivals were 87 ± 1.8% and 81.3 ± 2.1%. Event-free survival was not impacted by chemotherapeutic regimen, sex, race, age at diagnosis, or gender. Seven patients had disease relapse beyond 5 years after diagnosis; relapse was local in 4 patients, local plus supratentorial in 2, and supratentorial alone in 1. Fifteen patients experienced secondary tumors as a first event at a median time of 5.8 years after diagnosis (11 >5 y postdiagnosis). All non-CNS solid secondary tumors (4) occurred in regions that had received radiation. Of the 6 high-grade gliomas, 5 occurred >5 years postdiagnosis. The estimated cumulative 10-year incidence rate of secondary malignancies was 4.2% (1.9%–6.5%). Few patients with medulloblastoma will relapse ≥5 years postdiagnosis; relapse will occur predominantly at the primary tumor site. Patients are at risk for development of secondary tumors, many of which are malignant gliomas. This may become an increasing issue as more children survive.     

Thyroid dysfunction as a late effect in childhood medulloblastoma: a comparison of hyperfractionated versus conventionally fractionated craniospinal radiotherapy

Primary hypothyroidism is a common sequela of craniospinal radiotherapy in the treatment of childhood medulloblastoma. Due to the strong radiobiologic rationale, hyperfractionation can reduce the delayed effects of radiation injury.

The authors compared the incidence of thyroid dysfunction after conventionally fractionated radiotherapy (Group A, n = 20 patients) vs. hyperfractionated radiotherapy (Group B, n = 12 patients) in a group of pediatric patients with posterior fossa primitive neuroectodermal tumor (PNET).

The mean age at the time of tumor diagnosis was 7.4 years in Group A and 8.4 years in Group B. Thyroid function was evaluated yearly, with ultrasonographic examination every 2 years. The patients were followed after diagnosis for a mean of 10.8 years for Group A and 6.0 years for Group B. Approximately 80% of the Group A (16/20) and 33.3% of the Group B (4/12) patients developed primary hypothyroidism within a similar period after irradiation (4.2 vs. 3.5 years, respectively). Analysis by cumulative incidence function demonstrated a significant difference in the risk of developing thyroid dysfunction between these two groups of patients (p < 0.05). Ultrasonography showed reduced thyroid volume in 7 Group A patients and structural changes in 21 patients (17 Group A, 4 Group B cases); a thyroid benign nodule was detected in 2 Group A patients.

The current study findings suggest that the use of hyperfractionated craniospinal radiotherapy in the treatment of childhood medulloblastoma is associated with a lower risk of these patients’ developing late thyroid dysfunction.     

Medulloblastomas and central nervous system primitive neuroectodermal tumors

Opinion statement Significant advances in the treatment of medulloblastoma and primitive neuroectodermal tumors have been made in the past three decades. Maximal surgical resection is a mainstay of therapy. However, unlike many other central nervous system neoplasms, medulloblastoma and primitive neuroectodermal tumors are radiation and chemotherapy responsive. Despite this response, the prognosis for patients with these tumors remains variable and is relatively poor in infants and patients with metastatic disease. These tumors most commonly arise in children, thus most clinical trials emphasize the reduction of long-term sequelae, in addition to improving survival. All newly diagnosed patients who are eligible should be offered participation in a clinical trial. If a patient is ineligible or declines consent/ assent for a clinical trial, the best current treatment approach is surgical resection, followed by radiation therapy (except for children younger than 3 years) with weekly vincristine. For high-risk patients, 36 Gy of craniospinal irradiation should be delivered plus a boost of 19.8 Gy to the posterior fossa/primary tumor bed and sites of bulk metastatic disease. For average-risk patients, the craniospinal irradiation dose may be lowered to 23.4 Gy plus 32.4 Gy to the posterior fossa/tumor bed. After radiation therapy, intensive multimodal chemotherapy should be used for all patients.     

Patterns of failure in relation to radiotherapy fields in supratentorial primitive neuroectodermal tumor

PURPOSE: Supratentorial primitive neuroectodermal tumor (PNET) accounts for 2-3% of all pediatric brain tumors. We retrospectively reviewed all supratentorial PNET cases treated with radiotherapy (RT) at our institutions. METHODS AND MATERIALS: A total of 25 patients (17 males and 8 females, median age 9 years) were treated with RT between 1980 and 2001. The primary site location was the pineal region in 7 (28%), temporal lobe in 5 (20%), thalamus in 5 (20%), frontal lobe in 4 (16%), parietal lobe in 2 (8%), and suprasellar region in 2 (8%). Five patients (20%) had neuraxis dissemination (M+ disease) at initial diagnosis. The RT treatment volumes were craniospinal (CS) in 17 (68%), whole brain (WB) followed by a boost in 2 (8%), and primary site (PS) alone in 6 (24%). The median dose to the primary site was 54 Gy (range, 31-55.8 Gy). The median dose to patients receiving WB and spinal fields was 36 Gy (range, 23.4-39.6 Gy). Sixteen patients (64%) received chemotherapy; the most common type was the "8 in 1" chemotherapy regimen in 9 children. The median follow-up of surviving patients was 70 months (range, 34-251 months). RESULTS: The 5-year and 10-year progression-free survival rate was 36% and 27%, respectively, and the median time to progression was 22 months. The 5-year and 10-year progression-free survival rate was 47.1% and 47.1% for those receiving CSRT and 12.5% and 0% for those receiving WBRT or PSRT, respectively. The 5-year and 10-year progression-free survival rate for those with M0 disease was 40.0% and 30.0%, respectively; for those with M+ disease, the corresponding figures were 20.0% and 0%. On multivariate analysis, only M status (p = 0.01) and RT volume (p = 0.02) were statistically significant according to the Cox proportional hazards model. The primary site control rate at 5 and 10 years was 62%. Failure at nontreated neuraxis sites was a common cause of progression in patients receiving WBRT or PSRT, as seen in 6 (75%) of 8 cases. Of the 17 patients undergoing CSRT, 8 had no recurrence. Eight of the nine CSRT relapses had a leptomeningeal component. Four (80%) of 5 M+ children and 4 (33%) of 12 M0 children who underwent CSRT developed recurrence in the neuraxis (p = 0.1, Fisher's exact test). CONCLUSION: The craniospinal axis is the standard volume that needs to be treated in supratentorial PNET. Leptomeningeal dissemination was the main obstacle for cure even in patients receiving CSRT, regardless of M status.     

64例髓母细胞瘤放疗的回顾性分析

目的分析髓母细胞瘤放疗疗效及预后影响因素,观察最常见的放疗副反应。方法回顾性分析接受放疗的髓母细胞瘤64例,年龄均≥4岁。术前中枢神经系统MRI检查无蛛网膜下腔播散迹象,属Chang’sM分期M0～M1期。所有病例均在外院接受了原发肿瘤的全切或次全切除手术。放疗先予全脑全脊髓照射30Gy,然后缩野至后颅窝局部加量20～25Gy,中位分次剂量为180cGy。结果所有病例均完成了放疗,全组3、5年总生存率分别为68.8%和55.7%,无病生存率分别为57.8%和51.4%,27例(42.2%)在3年内复发。通过分析年龄、性别、原发肿瘤大小、手术与放疗间隔时间对生存率影响发现,只有手术与放疗间隔时间有一定影响,手术与放疗间隔时间≤25、>25d的3年总生存率分别为81.5%、59.5%(P=0.110),3年无病生存率分别为74.1%、46.0%(P=0.030)。放疗中最常见的副反应主要为白细胞下降,92.2%的病例在治疗中出现了白细胞下降(<4.0×109/dl),其中2～3级的血液系统毒性占64.0%。结论髓母细胞瘤通过手术与放疗结合能取得较好疗效,但治疗失败率较高。手术与放疗间隔延长对总生存率和无病生存率均有影响,年龄、性别、原发肿瘤大小不是明显预后因素,放疗中最常见的副反应为血液毒性。     

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.     

Medulloblastoma: staging and treatment outcome

Fifty-two newly diagnosed patients with medulloblastoma were prospectively staged with myelography. Fifty also had at least one CSF cytology study. Twenty-four patients (46%) had evidence of dissemination beyond the posterior fossa at diagnosis. Patients under age 5 years were more likely to have dissemination at diagnosis than older patients (61% vs 38%). The 5-year disease-free survival for 45 patients diagnosed at least 1 year ago and treated with craniospinal irradiation was 62.6%. Overall 5-year survival for this group was 76.7%. Patients without evidence of dissemination at diagnosis had a 5-year disease-free survival of 73.3% compared to 49.1% for patients with M1-3 disease. Eighteen patients relapsed, 16 within 3 years of diagnosis. Eight patients had recurrent tumor in the posterior fossa, eight in the supratentorial compartment, seven in the cord, and five had systemic metastasis. Patients with initial cord involvement were more likely to develop systemic metastasis (4/12) than patients without initial cord involvement (1/33).     

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.     

Medulloblastoma in Adults: A Series from Brazil

We retrospectively reviewed 15 adult patients (11 males, median age 34 years; range 23–48) who had been treated and followed in our Institution since 1991 from the time of diagnosis until death or last follow-up in December 2001. Headache was the most frequent symptom (93%). The tumor was hemispheric in 11 patients. Complete resection was achieved in eight. CSF in 12 patients and craniospinal MRI in 6 did not show metastatic disease. Two patients refused adjuvant treatment and died with progressive disease. Thirteen patients received adjuvant craniospinal radiotherapy and 11 systemic chemotherapy. After initial treatment only 2 of the 13 patients relapsed in the posterior fossa. Recurrence was probably related to sub-optimal radiotherapy planning: inadequate low dose in the posterior fossa (37.5Gy) and long delay in initiating treatment. Two of the 13 patients that received adjuvant treatment died: one from meningitis, and one from recurrent disease. Eleven patients remained alive, and disease-free with Karnofsky performance status ranging 80–100. The median overall survival was not reached after a median follow-up of 5.6 years (range 0.7–10.8 years). Estimated 1-, 5- and 10-year overall survival rates were 86.7%, 72.7%, and 72.7%, respectively. Adult medulloblastoma was predominant in males and the majority of patients had hemispheric tumors. Long-term survival was not uncommon. Although chemotherapy may be useful and well tolerated, radiotherapy remains the mainstay adjuvant treatment as suggested by our two recurrences associated with a delay or inadequate dose.     

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。     

Concurrent chemotherapy and reduced-dose cranial spinal irradiation followed by conformal posterior fossa tumor bed boost for average-risk medulloblastoma: efficacy and patterns of failure

PURPOSE: To review the efficacy and patterns of failure in average-risk medulloblastoma patients treated with concurrent chemotherapy and reduced-dose cranial spinal irradiation and a conformal tumor bed boost. METHODS AND MATERIALS: Thirty-three patients with average risk (defined as < or =1.5 cm(2) of residual tumor after resection, age >3 years, and no involvement of the cerebrospinal fluid or spine [M0]) medulloblastoma were diagnosed at our institution between January 1994 and December 2001. They were enrolled in an institutional pilot protocol consisting of concurrent chemotherapy (vincristine), reduced-dose cranial spinal irradiation (2340 cGy), a conformal primary tumor bed boost (3240 cGy), followed by eight cycles of chemotherapy (vincristine, cisplatin, and lomustine or cyclophosphamide). The median age at diagnosis of the 33 patients was 7 years (range, 3-21 years). The male/female patient ratio was 2.4:1. The median follow-up of the entire group was 37 months (range, 6-96 months), and the median follow-up of the survivors was 44 months (range, 10-96 months). RESULTS: The 5-year estimated disease-free survival rate, as determined by Kaplan-Meier plots, was 86% (+/-12.6%, 95% confidence interval). The 5-year estimated disease-free posterior fossa control and primary tumor bed control rates were both 94% (+/-8.2%, 95% confidence interval). The patterns of failure included 2 patients with distant central nervous system failure only, 1 patient who developed local primary tumor bed failure, posterior fossa failure, and diffuse leptomeningeal spread simultaneously, and 1 patient with failure in the high-dose, primary tumor bed field. No patient experienced isolated posterior fossa failure outside the high-dose boost region. CONCLUSION: The treatment of average-risk medulloblastoma with chemotherapy, reduced-dose cranial spinal irradiation, and a conformal tumor bed boost results in survival rates and local control rates comparable to those in contemporary studies. A reduction in the amount of posterior fossa treated to the high dose is possible. These results need to be corroborated in a large, cooperative group study.     

Multi-institution prospective trial of reduced-dose craniospinal irradiation (23.4 Gy) followed by conformal posterior fossa (36 Gy) and primary site irradiation (55.8 Gy) and dose-intensive chemotherapy for average-risk medulloblastoma

PURPOSE: Limiting the neurocognitive sequelae of radiotherapy (RT) has been an objective in the treatment of medulloblastoma. Conformal RT to less than the entire posterior fossa (PF) after craniospinal irradiation might reduce neurocognitive sequelae and requires evaluation. METHODS AND MATERIALS: Between October 1996 and August 2003, 86 patients, 3-21 years of age, with newly diagnosed, average-risk medulloblastoma were treated in a prospective, institutional review board-approved, multi-institution trial of risk-adapted RT and dose-intensive chemotherapy. RT began within 28 days of definitive surgery and consisted of craniospinal irradiation (23.4 Gy), conformal PF RT (36.0 Gy), and primary site RT (55.8 Gy). The planning target volume for the primary site included the postoperative tumor bed surrounded by an anatomically confined margin of 2 cm that was then expanded with a geometric margin of 0.3-0.5 cm. Chemotherapy was initiated 6 weeks after RT and included four cycles of high-dose cyclophosphamide, cisplatin, and vincristine. RESULTS: At a median follow-up of 61.2 months (range, 5.2-115.0 months), the estimated 5-year event-free survival and cumulative incidence of PF failure rate was 83.0% +/- 5.3% and 4.9% +/- 2.4% (+/- standard error), respectively. The targeting guidelines used in this study resulted in a mean reduction of 13% in the volume of the PF receiving doses >55 Gy compared with conventionally planned RT. The reductions in the dose to the temporal lobes, cochleae, and hypothalamus were statistically significant. CONCLUSION: This prospective trial has demonstrated that irradiation of less than the entire PF after 23.4 Gy craniospinal irradiation for average-risk medulloblastoma results in disease control comparable to that after treatment of the entire PF.     

A pilot study of risk-adapted radiotherapy and chemotherapy in patients with supratentorial PNET

We undertook this study to estimate the event-free survival (EFS) of patients with newly diagnosed supratentorial primitive neuroectodermal tumor (SPNET) treated with risk-adapted craniospinal irradiation (CSI) with additional radiation to the primary tumor site and subsequent high-dose chemotherapy supported by stem cell rescue. Between 1996 and 2003, 16 patients with SPNET were enrolled. High-risk (HR) disease was differentiated from average-risk (AR) disease by the presence of residual tumor (M(0) and tumor size > 1.5 cm(2)) or disseminated disease in the neuraxis (M(1)-M(3)). Patients received risk-adapted CSI: those with AR disease received 23.4 Gy; those with HR disease, 36-39.6 Gy. The tumor bed received a total of 55.8 Gy. Subsequently, all patients received four cycles of high-dose cyclophosphamide, cisplatin, and vincristine with stem cell support. The median age at diagnosis was 7.9 years; eight patients were female. Seven patients had pineal PNET. Twelve patients are alive at a median follow-up of 5.4 years. The 5-year EFS and overall survival (OS) estimates for all patients were 68% +/- 14% and 73% +/- 13%. The 5-year EFS and OS estimates were 75% +/- 17% and 88% +/- 13%, respectively, for the eight patients with AR disease and 60% +/- 19% and 58% +/- 19%, respectively, for the eight with HR disease. No deaths were due to toxicity. High-dose cyclophosphamide-based chemotherapy with stem cell support after risk-adapted CSI results in excellent EFS estimates for patients with newly diagnosed AR SPNET. Further, this chemotherapy allows for a reduction in the dose of CSI used to treat AR SPNET without compromising EFS.     

Medulloblastoma: time–dose relationship based on a 30-year review

Purpose: Time–dose relationships have proven important in many cancer sites. This study evaluates the time factors involved in the successful postoperative radiotherapy of medulloblastoma, based on a 30-year experience in a single institution.Methods and Materials: Fifty-three patients with medulloblastoma received postoperative craniospinal radiotherapy with curative intent between 1963 and 1993. Seven patients (13%) underwent biopsy alone, 28 patients (53%) had subtotal excision, and 18 patients (34%) had gross total excision. Eleven patients received adjuvant chemotherapy. The mean posterior fossa dose was 53.1 Gy; most patients received 54.0 Gy (range, 34.3 to 69.6 Gy). For 41 patients receiving once-a-day therapy, the mean dose was 50.6 Gy (range, 34.3 to 56.0 Gy). For 12 patients receiving twice-a-day therapy, the mean dose was 61.8 Gy (range, 52.6 to 69.6 Gy). Minimum follow-up was 2 years, and median follow-up was 10.7 years. Survival, freedom from relapse, and disease control in the posterior fossa were calculated using the Kaplan-Meier method, and multivariate analysis was performed for prognostic factors. Variables related to radiotherapy were examined, including dose to the craniospinal axis, dose to the posterior fossa, fractionation (once-a-day vs. twice-a-day), use of adjuvant chemotherapy, risk group [high (≥T3b or ≥M1) or low (≤T3a and M0-MX)], interval between surgery and radiotherapy (excluding patients receiving chemotherapy before radiotherapy), and duration of radiotherapy.Results: At 5 and 10 years, overall survival rates were 68 and 64%, respectively, and freedom-from-relapse rates were 61 and 52%, respectively. Rates of disease control in the posterior fossa at 5 and 10 years were 79 and 68%, respectively. At 5 years, absolute survival rates after biopsy alone, subtotal excision, and gross total excision were 43, 67, and 78%, respectively (p = 0.04), and posterior fossa control rates were 27, 89, and 83%, respectively (p = 0.004). Duration of the treatment course was the only radiotherapy-related variable with a significant impact on freedom from relapse and posterior fossa control. For patients whose radiation treatment duration was ≤45 days, posterior fossa control was 89% at 5 years, compared with 68% for those treated for >45 days (p = 0.01). Duration of treatment also affected freedom from relapse at 5 years: ≤45 days (76%) compared with >45 days (43%), p = 0.004.Conclusion: Our study demonstrates that if adequate doses are used, then radiotherapy treatment duration will significantly affect the outcome in terms of control of disease in the posterior fossa and freedom from relapse. Fractions of at least 1.75 Gy given once a day, or a twice-a-day regimen should yield optimal local control results.