Average-risk Medulloblastoma Research Articles

Reducing late effects of radiotherapy in average risk medulloblastoma.

To assess the efficacy and safety in average-risk pediatric medulloblastoma (MB) receiving tumor bed boost irradiation compared to a posterior fossa (PF) boost. Thirty patients were enrolled in the study and divided evenly into two treatment arms of 15. Both arms received 23.4 Gy craniospinal irradiation (CS) and a 32.4 Gy boost. Patients in arm 1 were given PF boosts, and those in arm 2 were given boosts to the gross target volume (GTV). Weekly oncovin was given throughout all radiotherapy (RT). Eight cycles of adjuvant chemotherapy of CCNU, oncovin and platinol were given to all patients after RT. MRI, pure tone audiogram (PTA) and intelligence quotient (IQ) tests were performed before and after RT and every three months thereafter. There were significant differences in the sparing dose to the cochlea and brain stem as well as the volume of the normal brain receiving a 100% dose. There was a significant initial improvement of hearing function in patients given the target volume boost after RT, which was lost after chemotherapy. With a median follow up of 23 months, there was no difference in progression free survival or overall survival between the two arms. Irradiation of the tumor bed after 23.4 Gy craniospinal irradiation for average-risk MB results in similar disease control as a PF boost. Dosimetric sparing for the cochleae and normal tissue is evident in patients receiving tumor bed boosts. The hearing improvement and cognitive function preservation effects of the treatment need more follow up.

Early Clinical Outcomes Demonstrate Preserved Cognitive Function in Children With Average-Risk Medulloblastoma When Treated With Hyperfractionated Radiation Therapy

To report on acute toxicity, longitudinal cognitive function, and early clinical outcomes in children with average-risk medulloblastoma. Twenty children ≥ 5 years of age classified as having average-risk medulloblastoma were accrued on a prospective protocol of hyperfractionated radiation therapy (HFRT) alone. Radiotherapy was delivered with two daily fractions (1 Gy/fraction, 6 to 8 hours apart, 5 days/week), initially to the neuraxis (36 Gy/36 fractions), followed by conformal tumor bed boost (32 Gy/32 fractions) for a total tumor bed dose of 68 Gy/68 fractions over 6 to 7 weeks. Cognitive function was prospectively assessed longitudinally (pretreatment and at specified posttreatment follow-up visits) with the Wechsler Intelligence Scale for Children to give verbal quotient, performance quotient, and full-scale intelligence quotient (FSIQ). The median age of the study cohort was 8 years (range, 5-14 years), representing a slightly older cohort. Acute hematologic toxicity was mild and self-limiting. Eight (40%) children had subnormal intelligence (FSIQ <85), including 3 (15%) with mild mental retardation (FSIQ 56-70) even before radiotherapy. Cognitive functioning for all tested domains was preserved in children evaluable at 3 months, 1 year, and 2 years after completion of HFRT, with no significant decline over time. Age at diagnosis or baseline FSIQ did not have a significant impact on longitudinal cognitive function. At a median follow-up time of 33 months (range, 16-58 months), 3 patients had died (2 of relapse and 1 of accidental burns), resulting in 3-year relapse-free survival and overall survival of 83.5% and 83.2%, respectively. HFRT without upfront chemotherapy has an acceptable acute toxicity profile, without an unduly increased risk of relapse, with preserved cognitive functioning in children with average-risk medulloblastoma.

Medulloblastoma: advances and challenges

Medulloblastoma, a cancer of the posterior fossa, is the most common malignant brain tumor in children. Although 80% of patients with average-risk medulloblastoma are cured, their quality of life is often compromised by treatment-related side effects. Recently, molecular and genomic studies have shown medulloblastoma to be a heterogeneous disease made up of distinct disease subtypes. The importance of this finding is that response to therapy appears to be subtype-specific. Nevertheless, most patients are still treated according to risk stratification methods based on the clinically defined presence or absence of disseminated disease, which take no account of these newly defined subtypes. The potential, however, to vastly reduce therapy-mediated toxicity to patients with tumor subtypes that have good outcomes, while improving therapy through targeting for the poor responders, is now palpable. Critical to this effort will be the ongoing refinement of our understanding of medulloblastoma subgroups at the molecular level and the development of mouse models that faithfully recapitulate tumor subtypes.

Radiation-induced Glioblastoma Multiforme in Children Treated for Medulloblastoma With Characteristics of Both Medulloblastoma and Glioblastoma Multiforme

Outcomes for average-risk medulloblastoma are excellent with 5-year event-free survival and overall survival>80%. Treatment failures include radiation-induced glioblastomas (RIG), which are often diagnosed solely on imaging. Recent studies suggest that RIGs differ from spontaneous glioblastoma multiforme (GBM), based on microarray gene-expression profiling. Retrospective review of children with average-risk medulloblastoma treated from 1996 to 2003 included 16 patients with 5 treatment failures. One died of disease progression, 1 died as a result of radiation necrosis, and 3 children died of pathology-confirmed GBM. Of these 3 GBMs, one was studied with electron microscopy, cytogenetics, and gene-expression microarray analysis. This tumor had focal medulloblastoma and similarity by gene-expression microarray with other RIGs. With both components in the recurrent tumor, we suggest it was in the process of transitioning from medulloblastoma to RIG, that is, "catching the tumor in the act." Some radiation-induced nervous system tumors may develop as a direct result of severe oncologic changes within the original tumor cells, with the tumor evolving into a different phenotypic tumor type. We recommend biopsy for tissue confirmation and genetic expression profile to shed light on the etiology of radiation-induced neoplasms.

Concurrent Chemotherapy and Reduced-Dose Cranial Spinal Irradiation followed by Posterior Fossa Tumor Bed Boost for Average-Risk Medulloblastoma: Efficacy and Patterns of Failure

Concurrent Chemotherapy and Reduced-Dose Cranial Spinal Irradiation followed by Posterior Fossa Tumor Bed Boost for Average-Risk Medulloblastoma: Efficacy and Patterns of Failure

Cerebellar Mutism

Cerebellar mutism syndrome (CMS) is a unique postoperative syndrome typically arising 1 to 2 days after resection of a midline posterior fossa tumor; it consists of diminished speech progressing to mutism, emotional lability, hypotonia, and ataxia. Most descriptions have been limited to small institutional series using a retrospective chart review methodology. The authors incorporated a CMS questionnaire in two large clinical trials (Children's Cancer Group [CCG] 9931, treatment for high-risk medulloblastoma/primitive neuroectodermal tumor; and CCG/Pediatric Oncology Group [POG] A9961, treatment for average-risk medulloblastoma) to prospectively survey for incidence, severity, and possible causes of CMS in children with newly diagnosed medulloblastoma. Information pertaining to 450 of the 463 patients enrolled in the studies was available for review (82 patients in CCG 9931, and 368 patients in CCG/POG A9961). Cerebellar mutism syndrome occurred in 107 (24%) of 450 children. Symptom intensity was judged to have been severe in 43%, moderate in 49%, and mild in 8% of these 107 patients. Mutism and ataxia were the features most frequently judged as severe. In both cohorts, preoperative brainstem invasion was the only feature that correlated with risk of CMS. One year after diagnosis, nonmotor speech/ language deficits, neurocognitive deficits, and/or ataxia persisted in a significant fraction of patients. Nearly one quarter of patients who underwent resection of a medulloblastoma developed symptoms of CMS, of which 92% were judged to be of moderate or severe intensity. Brainstem invasion by tumor was the only risk factor that correlated positively with CMS occurrence; there was a negative correlation with cerebellar hemisphere tumor location. As more radical resections are attempted for medulloblastoma, the potential for increased morbidity must be carefully weighed against prognostic factors, especially in patients with brainstem invasion.

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

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. 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. 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. 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.

Incidence and severity of postoperative cerebellar mutism syndrome in children with medulloblastoma: a prospective study by the Children’s Oncology Group

Cerebellar mutism syndrome (CMS) is a unique postoperative syndrome typically arising 1 to 2 days after resection of a midline posterior fossa tumor; it consists of diminished speech progressing to mutism, emotional lability, hypotonia, and ataxia. Most descriptions have been limited to small institutional series using a retrospective chart review methodology. The authors incorporated a CMS questionnaire in two large clinical trials (Children's Cancer Group [CCG] 9931, treatment for high-risk medulloblastoma/primitive neuroectodermal tumor; and CCG/Pediatric Oncology Group [POG] A9961, treatment for average-risk medulloblastoma) to prospectively survey for incidence, severity, and possible causes of CMS in children with newly diagnosed medulloblastoma. Information pertaining to 450 of the 463 patients enrolled in the studies was available for review (82 patients in CCG 9931, and 368 patients in CCG/POG A9961). Cerebellar mutism syndrome occurred in 107 (24%) of 450 children. Symptom intensity was judged to have been severe in 43%, moderate in 49%, and mild in 8% of these 107 patients. Mutism and ataxia were the features most frequently judged as severe. In both cohorts, preoperative brainstem invasion was the only feature that correlated with risk of CMS. One year after diagnosis, nonmotor speech/language deficits, neurocognitive deficits, and/or ataxia persisted in a significant fraction of patients. Nearly one quarter of patients who underwent resection of a medulloblastoma developed symptoms of CMS, of which 92% were judged to be of moderate or severe intensity. Brainstem invasion by tumor was the only risk factor that correlated positively with CMS occurrence; there was a negative correlation with cerebellar hemisphere tumor location. As more radical resections are attempted for medulloblastoma, the potential for increased morbidity must be carefully weighed against prognostic factors, especially in patients with brainstem invasion.

Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial

Current treatment for medulloblastoma, which includes postoperative radiotherapy and 1 year of chemotherapy, does not cure many children with high-risk disease. We aimed to investigate the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma. After resection, patients were classified as having average-risk medulloblastoma (< or = 1.5 cm2 residual tumour and no metastatic disease) or high-risk medulloblastoma (> 1.5 cm2 residual disease or metastatic disease localised to neuraxis) medulloblastoma. All patients received risk-adapted craniospinal radiotherapy (23.4 Gy for average-risk disease and 36.0-39.6 Gy for high-risk disease) followed by four cycles of cyclophosphamide-based, dose-intensive chemotherapy. Patients were assessed regularly for disease status and treatment side-effects. The primary endpoint was 5-year event-free survival; we also measured overall survival. This study is registered with ClinicalTrials.gov, number NCT00003211. Of 134 children with medulloblastoma who underwent treatment (86 average-risk, 48 high-risk), 119 (89%) completed the planned protocol. No treatment-related deaths occurred. 5-year overall survival was 85% (95% CI 75-94) in patients in the average-risk group and 70% (54-84) in those in the high-risk group (p=0.04); 5-year event-free survival was 83% (73-93) and 70% (55-85), respectively (p=0.046). For the 116 patients whose histology was reviewed centrally, histological subtype correlated with 5-year event-free survival (p=0.04): 84% (74-95) for classic histology, 77% (49-100) for desmoplastic tumours, and 57% (33-80) for large-cell anaplastic tumours. Risk-adapted radiotherapy followed by a shortened schedule of dose-intensive chemotherapy can be used to improve the outcome of patients with high-risk medulloblastoma.

Phase III Study of Craniospinal Radiation Therapy Followed by Adjuvant Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma

To determine the event-free survival (EFS) and overall survival of children with average-risk medulloblastoma and treated with reduced-dose craniospinal radiotherapy (CSRT) and one of two postradiotherapy chemotherapies. Four hundred twenty-one patients between 3 years and 21 years of age with nondisseminated medulloblastoma (MB) were prospectively randomly assigned to treatment with 23.4 Gy of CSRT, 55.8 Gy of posterior fossa RT, plus one of two adjuvant chemotherapy regimens: lomustine (CCNU), cisplatin, and vincristine; or cyclophosphamide, cisplatin, and vincristine. Results Forty-two of 421 patients enrolled were excluded from analysis. Sixty-six of the remaining 379 patients had incompletely assessable postoperative studies. Five-year EFS and survival for the cohort of 379 patients was 81% +/- 2.1% and 86% +/- 9%, respectively (median follow-up over 5 years). EFS was unaffected by sex, race, age, treatment regimen, brainstem involvement, or excessive anaplasia. EFS was detrimentally affected by neuroradiographic unassessability. Patients with areas of frank dissemination had a 5-year EFS of 36% +/- 15%. Sixty-seven percent of progressions had some component of dissemination. There were seven second malignancies. Infections occurred more frequently on the cyclophosphamide arm and electrolyte abnormalities were more common on the CCNU regimen. This study discloses an encouraging EFS rate for children with nondisseminated MB treated with reduced-dose craniospinal radiation and chemotherapy. Additional, careful, step-wise reductions in CSRT in adequately staged patients may be possible.

Role of amifostine as a cytoprotectant in children ≥ 3 years with average risk (AR) medulloblastoma (MB) treated with craniospinal irradiation (CSI) and 4 courses of cisplatin (CDDP)-based high dose chemotherapy

9063 Background: Therapy for MB (CSI and CDDP-based chemotherapy) results in hearing loss before completion of therapy in 30%-50% of patients, who consequently require a reduced cisplatin dose. Cytoprotection against cisplatin-induced ototoxicity may be provided by amifostine, a thiol prodrug that protects many normal tissues against therapy-induced damage without diminishing antitumor effects. Method: This study was designed to detect a 20% decrease (80% power) in CDDP induced ototoxicity (defined as needing hearing aids) in AR MB patients with the use of amifostine (n=62) compared to historical controls (n=35) one year from diagnosis. An interim analysis was conducted after accrual of 32 pts on the experimental arm. A total of 67 AR MB patients received CSI (23.4 Gy) followed by 3-dimensional conformal boost to the tumor bed (total 55.8 Gy) and 4 cycles of high-dose cyclophsophamide (4,000 mg/m2 per cycle), cisplatin (75 mg/m2 per cycle), and vincristine (two 1.5 mg/m2 doses per cycle). When used, amifostine (600 mg/m2 per cycle) was given before and 3 hours into the cisplatin infusion. Results: The median age of the 40 male, 27 female patients was 8.7 (range, 3.2–20.2) yrs. The 2 groups had similar median ages (amifostine, 9.1; control, 7.8 years) and gender (male: amifostine, 66%; control, 54%). One year after the start of treatment, the objective criteria for needing a hearing aid in at least 1 ear were met by 13 (37%) of control-group patients and 6 (18.8%) of those who received amifostine. Conclusion: The interim analysis has demonstrated that the need for hearing aids in AR MB children treated with the above-described regimen is halved by using amifostine during CDDP administration. No significant financial relationships to disclose.

Current treatment of medulloblastoma: Recent advances and future challenges

Medulloblastoma (MB) is the most common malignant brain tumor of childhood, yet it makes up only 1% of adult brain tumors. MB is uniquely sensitive to chemotherapy and radiation, but successful surgical resection continues to be an important component of therapeutic success. Progress in the treatment of MB has occurred in multiple areas from improved neurosurgical techniques, refined dosing and delivery of radiation, and optimized chemotherapy. Tumors are currently risk-stratified as average risk or high risk depending on clinical factors such as age, extent of resection, and presence of metastases. Molecular biology is beginning to improve upon clinical prognostication and may soon provide the means to accurately predict response to therapy. Treatment for average-risk MB has achieved a level of success that allows efforts to be focused on the limitation of adverse treatment effects. Therapy for high-risk and relapsed MB has been positively affected by the advent of high-dose chemotherapy with stem cell rescue. In addition, molecular targets are being elucidated and new therapeutic agents are being tested for safety and efficacy. Treatment for this disease has evolved a great deal over the preceding decades, but a great deal of work remains to be done to effect reliable cures while reducing long-term sequelae of therapy.

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 ≤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.

A 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/Objective: Limiting the neurocognitive sequelae of radiation therapy has been a primary objective in the treatment of medulloblastoma (MB). Post-operative treatment for children with average-risk MB has evolved to include low-dose (23.4 Gy) craniospinal irradiation (CSI), posterior fossa (PF) irradiation (RT) to 54–55.8 Gy and combination chemotherapy. Despite the reduction in CSI dose from 36.0 Gy, neurocognitive effects of RT are significant. Conventional PF treatment using parallel-opposed portals delivers the prescribed dose to nearly 30% of the brain and the majority of the temporal lobes. Conformal RT to less than the entire PF is a potential means to further reduce neurocognitive sequelae. The primary objective of this study was to reduce the volume of posterior fossa irradiation without affecting the rate of tumor control for children with average-risk medulloblastoma treated with 23.4 Gy craniospinal irradiation and dose-intensive chemotherapy. Materials/Methods: Between October 1996 and September 2002, 73 consecutive patients, 3–21 years of age, with newly diagnosed, average-risk MB (residual tumor < 1.5cm2 and no metastases) were treated on a prospective, IRB-approved, multi-institution trial of risk-adapted radiation therapy and dose-intensive chemotherapy with peripheral blood stem cell support. RT commenced within 28 days of definitive surgery and consisted of CSI (23.4 Gy), conformal PF RT (36.0 Gy) and primary site RT (55.8 Gy) at 1.8 Gy per day. The clinical target volume (CTV) for the PF component was the anatomic PF including the cerebellar hemispheres, brainstem to the level of the midbrain and upper cervical spinal cord at the level of the foramen magnum. The planning target volume (PTV) expanded the CTV by a geometric margin of 0.3–0.5 cm. The gross tumor volume (GTV) for the primary site component included the post-operative tumor bed; the CTV included the GTV with an anatomically confined margin of 2 cm in adjacent brain; the PTV expanded the CTV with a geometric margin of 0.3–0.5 cm. Conformal treatment consisted of forward-planned, multi-field, non-coplanar, individually shaped beam arrangements incident on the PTV. The field edge (cerrobend or MLC) was 0.6–0.8 cm outside the PTV. The homogeneity of dose (95%–110%) was optimized across the PTV with beam modifiers that included physical or virtual wedges. Dose to the upper cervical spinal cord was limited to 54 Gy. Chemotherapy was initiated 6 weeks after RT and included 4 cycles of cyclophosphamide, cisplatin and vincristine. Results: With a median follow-up of 32.4 months (2.2–74.4 months), the estimated 3-year cumulative incidence of PF failure as a component of failure was 5.27% + 3.13% (SE). Two patients had isolated PF failure at 2.8 and 32.1 months, one patient failed in the PF with simultaneous neuraxis failure at 3.1 months and eight patients failed with neuraxis dissemination with a median time of 25.2 months (4.2–38.4 months). There was one death without failure. Conclusions: This is the largest prospective trial to demonstrate the efficacy of reducing the treatment volume after 23.4 Gy CSI for average-risk MB. Patients who received a minimum dose of 36 Gy to the PF and focal treatment of the post-operative tumor bed to 55.8 Gy with an anatomically defined margin of 2.0 cm do not appear to have an increased risk of failure when compared to results from large contemporary trials, providing a basis for further dose reductions in normal tissue irradiation.

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

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