Phase IV Study on the Role of Whole Brain Irradiation in Primary CNS Lymphoma (PCNSL) After High-dose Methotrexate
Six 14-day cycles of high-dose MTX will be given at the beginning of the study.
Randomization will be performed centrally at the study headquarters in UKBF Berlin already
at study inclusion. Patients meeting all inclusion criteria will receive the first systemic
treatment with 4 g/m2 MTX i.v. over 4 hours within 14 days. Dexamethasone in a dose of 3 x 8
mg/day orally for 10 days will additionally be given in the first cycle. This dexamethasone
dose will be started 3 days before the first MTX application. Ten to 14 days after the 3rd
and 6th MTX dose, the response to MTX therapy will be evaluated by MRI and a repeated CSF
examination in the case of renewed CSF involvement. Assessment can also be made at any other
time point if there is clinical deterioration. In all cases, the neuroradiological reference
center (Department of Neuroradiology, University of Tübingen) will decide about the response
to MTX therapy. MRI and CT scans should be sent to the neuroradiological reference center
after HD MTX is terminated for central response evaluation. If complete remission is
achieved after completing high-dose MTX therapy, patients will be treated with WBI (45 Gy in
1.5 Gy fractions) starting a minimum of 4 and a maximum of 7 weeks after the end of
chemotherapy (arm A1) or WBI at first recurrence (arm A2). If primary therapy is not
successful (partial remission, stable disease after the 6th cycle, progression at any time
of MTX therapy), patients will receive WBI (45 Gy in 1.5 Gy fractions; arm B1) or high-dose
AraC chemotherapy 3 g/m2 i.v. over 3 hours every 12 hours for 2 days (arm B2) according to
the randomization. If high-dose MTX therapy leads to termination before the application of 6
cycles of MTX (see termination criteria) but allows further AraC therapy or WBI, further
treatment is given in the non-CR arm according to the randomization. High-dose AraC therapy
will be administered in four 3-week cycles. If complete remission occurs already after one
or two cycles, only one additional cycle will be applied. Patients will not be crossed over
into the B arms.
If there is a recurrence or progression after finishing a complete treatment arm, the
patient can be treated with chemotherapy according to PCV protocol or WBI in the B2 arm.
This decision is left up to the individual study center.
The G-PCNSL-SG-1 study is a prospective, controlled phase IV study with central
randomization. Patients in both arms will be submitted to stratified randomization according
to age (< 60; > 60) and center to minimize the effect of important therapy-related
prognostic factors. The study is not blinded. Randomization will be performed centrally at
study inclusion at the Institute of Medical Informatics, Biometry and Epidemiology,
University Hospital Benjamin Franklin of the Free University of Berlin.
The planned study duration is 7 years - 4 years in the recruitment phase with a subsequent
3-year follow-up period and a 6-month evaluation phase. For an individual patient, the
treatment time in arm A1 is 12 weeks for 6 cycles of MTX therapy, followed by a 4-7-week
resting period and then 6 weeks until the completion of WBI (arm A1). In arm A2, the patient
is irradiated (a total of 6 weeks) only in the case of recurrence. Up to that point, the
patient will be followed up in fixed intervals like those patients in A1 after WBI. In arm
B, MTX therapy is immediately followed by 6 weeks of WBI (arm B1) or the maximal 3 months of
AraC therapy. After completing the protocol of the planned therapy, all patients will be
followed-up for at least three years.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Eckhard Thiel, MD
Charite Campus Benjamin Franklin
Germany: Federal Institute for Drugs and Medical Devices