Should whole brain radiotherapy be considered standard of care in newly diagnosed primary
central nervous system lymphoma? The G-PCNSL-SG-1 randomized phase IV trial
E.Thiel , A. Korfel, P. Martus, L. Kanz, Griesinger F, P Rauch, L. Fischer, T. Pietsch, M. Bamberg, M. Weller
on behalf of G-PCNSL-SG
Deutsche Studiengruppe Primäre ZNS-LymphomeG-PCNSL-SG
Background
• High-dose methotrexate (HDMTX) is considered standard of care for newly diagnosed PCNSL.
• The role of whole brain radiotherapy (WBRT) is controversial.
• Delayed neurotoxicity limits the acceptance of HDMTX+WBRT as a standard of care.
CR No CR
A1: Cons. WBRT
B1: Rescue WBRT
G-PCNSL-SG-1 trial design
B2: HD-Ara-C
A2: Watch and wait
CR No CR
• newly diagnosed PCNSL • immunocompetent adult patients• creatinine clearance >50 ml/min
Randomization:A1/B1 versus A2/B2
HDMTX 4g/m2 d1 1999-2007* HDMTX 4g/m2 d1 + Ifo 1.5g/m2 d3-5 2007-2009*
* + 3 x 8 mg Dexamethasone (d1-10), 1st cycle only
Statistical considerations
• Hypothesis: omission of WBRT from first-line
treatment does not compromise OS (non-inferiority design). • Omission of WBRT was defined as non-inferior to WBRT if
the lower two-sided 95% confidence limit of the
hazard ratio of WBRT versus no WBRT was not below 0.9.• 60% power to prove non-inferiority of omission of WBRT in
case of a hazard ratio of 1.2 of WBRT versus no WBRT. • Sample size required: 151 patients per group.
n=551 entered
n=24 early drop-out / recruitment error
n=49 dropped out
n=411 entered the post-HDMTX phase (ITT)
n=318 per protocol
Flow diagram of all patients
n=526 fulfilledthe eligibility criteria
and received HDMTX
n=93 protocol violation(49 WBRT arms, 44 no WBRTarms)
n=154 WBRT n=164 no WBRT
CR 182 (34.6%)PR 101 (19.2%)SD/PD 24/123 (4.6/23.4%)
Unknown 30 (5.7%)
Died 66 (12.5%) n=66 died
Patients characteristics (PP population, n=318)
• med. age 61 (19-84)• male/female 183/135• med. Karnofsky 80 (30-100)• diagnostic procedure:
stereotactic biopsy 184 (57.8%)partial/total resection 97 (30.6%)open biopsy 32 (10.1%)CSF cytomorphology 3 (0.9%)no data 2 (0.6%)
• lymphoma cells in the CSF26 (8.2%)• ocular involvement on slit lamp 9 (2.8%)
PFS and OS : PP patientsWBRT n=154, no WBRT n=164
PFS 18.3 vs. 12 mo (P=.13) OS 32.4 vs. 37.1 mo (P=.7)
OS and PFS: PP patients with CR after HDMT
WBRT n=56, no WBRT n=96
PFS 36.3 vs. 21.5 mo (P=.038) OS 38.8 vs. 39.4 (P=.56)
OS and PFS: PP patients without CR after HDMTX
WBRT n=98, no WBRT n=68
PFS 5.6 vs. 3 mo (P=.003) OS 24.3 vs. 18.6 mo (P=.1)
PFS and OS : ITT patientsWBRT = 203, no WBRT = 208
PFS 15.5 vs. 9.9 mo (P=.041) OS 34.4 vs. 32.1 (P=.94)
The influence of age and KPS on OS (n=526)
Age (<60 n=189; ≥60 n=337) KPS (≥70 n=275; <70 n=163)
38.4 vs. 14.2 mo. (P<.005) 31.5 vs. 9.8 mo. (P<.005)
Late neurotoxicity(PP pts. with CR)
48,9
72,5
28
41,7
0
10
20
30
40
50
60
70
80
%
WBRT WBRT
No WBRT No WBRT
Clinical evaluation Neuroradiologic evaluation
Clinical evaluation n=45 WBRT, n=33 no WBRTNeuroradiologic evaluation n=51 WBRT, n=36 no WBRT
P=.054 P=.04
Conclusions
• first randomized phase IV study on PCNSL• no significant difference for OS with versus
without WBRT • PFS prolongation in subgroup analyses confirms
the role WBRT for disease control; lack of OS benefit reflects effectivity of salvage treatments
• age and KPS most important risk factors• late neurotoxicity more frequent with WBRT