1. 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-Lymphome G-PCNSL-SG

2. 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.

3. 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

4. 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.

5. 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 fulfilled the eligibility criteria and received HDMTX n=93 protocol violation (49 WBRT arms, 44 no WBRTarms) n=154 WBRTn=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

6. Patients characteristics (PP population, n=318) med. age61 (19-84) male/female183/135 med. Karnofsky80 (30-100) diagnostic procedure: stereotactic biopsy184 (57.8%) partial/total resection97 (30.6%) open biopsy32 (10.1%) CSF cytomorphology3 (0.9%) no data2 (0.6%) lymphoma cells in the CSF26 (8.2%) ocular involvement on slit lamp9 (2.8%)

7. PFS and OS : PP patients WBRT n=154, no WBRT n=164 PFS 18.3 vs. 12 mo (P=.13) OS 32.4 vs. 37.1 mo (P=.7)

8. 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)

9. 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)

10. PFS and OS : ITT patients WBRT = 203, no WBRT = 208 PFS 15.5 vs. 9.9 mo (P=.041) OS 34.4 vs. 32.1 (P=.94)

11. 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)

12. Late neurotoxicity (PP pts. with CR) WBRT No WBRT Clinical evaluationNeuroradiologic evaluation Clinical evaluation n=45 WBRT, n=33 no WBRT Neuroradiologic evaluation n=51 WBRT, n=36 no WBRT P=.054P=.04

13. 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