MEDULLOBLASTOMA TRIAL

Medulloblastoma Trial:
Optimizing the physical and biological parameters in craniospinal irradiation (CSI) for embryonal CNS (central nervous system) tumors: a prospective study

Background and rationale
Embryonal central nervous system (CNS) tumors comprising 25-30% of all childhood brain tumors share a common propensity of leptomeningeal dissemination. Craniospinal irradiation (CSI), therefore remains the cornerstone of adjuvant therapy following maximal safe resection. Medulloblastoma is the commonest of these high-grade embryonal CNS neoplasms (Freeman). Traditional risk classification (Deutsch) in medulloblastoma has been as follows:
? Average risk: age > 3 years, M0 disease, and no or =1.5 cm2 residual disease after surgery;
? High risk: age = 3 years, any M+ or postoperative residual tumor >1.5 cm2.
Traditionally, volume of CSI includes the entire subarachnoid space and conventionally, the standard dose of radiation has been 35-36 Gy in 20-21 fractions to the entire neuraxis with once daily fractionation, followed by boost of 18-20 Gy in 10-11 fractions to the posterior fossa in medulloblastoma (Patterson) or tumor bed in non-posterior fossa embryonal CNS tumors.
Non-cerebellar embryonal CNS tumors such as supratentorial Primitive Neuro-Ectodermal Tumor (PNET), pineoblastomas, and ependymoblastomas are generally classified and treated as high-risk disease.
Recent times have witnessed the emergence of adjuvant chemotherapy with radiotherapy in a bid to either reduce the dose of CSI in average-risk disease or improve tumor control in high-risk disease. While conventional radiation therapy is reasonably effective in achieving long-term control, it could be associated with considerable late morbidity, more so in this patient population of growing children.
Long term effects of radiotherapy could be in the form of neurocognitive impairment, neuroendocrine dysfunction, hearing disabilities and increased risk of second malignancies. Spinal component of CSI could result in impeding the growth of bones resulting in spinal deformity and short stature. Efforts have been made for the last decade or so to avoid or minimise the doses of radiation therapy.
Hyperfractionated radiation therapy (HFRT) involves the use of lower dose per fraction (1-1.2 Gy) and is administered more than once daily (with a gap of at least 6 hours); the total dose of radiation given in same overall treatment time as conventional fractionation. Using Linear Quadratic model, (assuming a/b of 10 for tumor control and 2 for late effects), the biologically equivalent dose (BED) of HFRT-CSI (36 Gy/36 fractions, 2 fractions daily, 6-8 hours apart for tumor control is 39.6 Gy10, which is similar to the standard conventional CSI dose (35 Gy/21 fractions, one fraction daily, BED=40.84Gy10). The BED for late effects HFRT-CSI is 54.2Gy2 which compares very favourably to BED=64.05Gy2 for conventional standard dose CSI. The low dose conventionally fractionated CSI (23.4Gy/13 fractions) is obviously inferior for tumor control (BED=27.6Gy10), but superior for late effects (BED=44.5Gy2).
Due to its strong radiobiologic rationale HFRT can theoretically be used to reduce late effects of radiation without compromising on tumor control increasing the therapeutic index in favour of CSI, both for average-risk (without chemotherapy) as well as high-risk disease (with chemotherapy. Trial is designed to establish this radiobiologically superior schedule.

Study design
Patients (5-15 years) with an embryonal CNS tumor requiring CSI
25 patients of embryonal CNS tumors to be accrued over a period of 24 months

Inclusion criteria
A) paediatric patients of either sex aged between the age of 5 and 15 years (inclusive)
B) histologically confirmed diagnosis of an embryonal CNS tumor (medulloblastoma & variants, PNETs, ependymoblastomas, pineoblastomas)
C) Karnofsky performance status of = 70%
D) signed informed consent
E) patient suitable for undergoing twice daily radiotherapy
F) radiotherapy starting within 6-8 weeks of surgery
G) adequate haematological and biochemical function

Exclusion criteria
A) patients with recurrent tumours either after previous surgery and/or radiotherapy
B) prior history of therapeutic irradiation
C) prior/concurrent second neoplasm
D) known predisposition to medulloblastoma e.g Gorlin’s syndrome
E) compromised haematological or biochemical function
F) any form of immunosuppression e.g HIV
G) patients requiring anaesthesia during RT

Study End point:
? To estimate the reduction in long-term sequelae of radiotherapy.
? To estimate event-free & overall survival at 2 and 5 years

Status:
On going study.