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

Abstract

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.