Efficacy
Primary central nervous system lymphoma (PCNSL) represents an aggressive subset of lymphoma exclusively affecting the central nervous system (brain parenchyma, spinal cord, eyes, cranial nerves and/or meninges).r Diffuse large B-cell lymphoma comprises the majority (90%) of PCNSL.r
Landmark prospective randomised clinical trials have led to the accepted standard of high-dose methotrexate chemotherapy, and later the addition of high-dose cytarabine chemotherapy for the management of PCNSL.rrr High dose chemotherapy with autologous stem cell transplant (ASCT) or whole brain radiation therapy (WBRT) are options for consolidation therapy following induction therapy with chemotherapy.r
Consolidation with WBRT vs observation
G-PCNSL-SG1 was a randomised non-inferiority trial (N = 551) that compared patients who achieved a complete remission (CR) after HDMTX, with or without ifosfamide, and were randomly allocated between consolidative WBRT (45 Gy in 30 fractions) and observation.r This study suggested that WBRT can prolong progression free survival (PFS) (median PFS, 18.3 vs 11.9 months) but not overall survival (OS) with a reported median OS of 32.4 vs 37.1 in the WBRT and observation arms, respectively. Neurotoxicity in patients with sustained complete response was more common in WBRT arm (49% by clinical assessment and 71% by neuroradiology) vs observation arm (26% and 46%). There was also a suggestion that WBRT improved PFS, but not OS, in patients who did not achieve CR after chemotherapy. However, caution should be used in the interpretation of these results as the limit for non-inferiority was not met and there were several methodological limitations with this study, including an underpowered design and issues with the per-protocol and intention-to-treat analyses.
Consolidation with WBRT vs ASCT
The IELSG32 trial is an international randomised phase 2 study.r Between February 2010 and August 2014, 227 patients were recruited with 219 of these assessable in the trial. The second randomisation of the study looked at the efficacy of myeloablative chemotherapy supported by ASCT as an alternative to WBRT, as consolidation after high-dose-methotrexate-based chemoimmunotherapy. Of the 122 patients eligible for the second randomisation, 118 patients were randomly assigned to WBRT (group D) or ASCT (group E) with 59 patients per group. The WBRT group were prescribed 36 Gy to the whole brain, two cervical vertebrae and posterior 2/3 of orbits. The orbits were shielded after 30 Gy (or 36 Gy in patients with intraocular disease). A 9 Gy tumour-bed boost was given in patients with partial response.
Both arms of the study met the predetermined efficacy threshold of at least 40 progression-free survivors at 2 years amongst the first 52 patients in both groups D and E. There were no significant differences in 2-year PFS between the groups: 80% (95% CI:70–90) in group D and 69% (59–79) in group E (hazard ratio 1.50, 95% CI:0.83–2.71, p=0.17). Both consolidation therapies were reported to be well tolerated. Grade 4 non-haematological toxicity was uncommon. In the ASCT arm, haematological toxicity was more common, and two patients died of infection. Acute neurotoxicity was grade 3 or less in both arms, and more common in the WBRT arm (18% vs 7%, p=0.089). They concluded that both consolidation therapies are feasible and effective after high-dose methotrexate based chemoimmunotherapy and the risks of cognitive impairment from WBRT should be considered when determining treatment options.
The PRECIS trial is a randomised phase II study in patients (age 18-60 years) with newly diagnosed primary CNS lymphoma.r Patients were treated with high-dose methotrexate-based induction chemotherapy followed by WBRT, 40 Gy in 20 fractions, or high-dose chemotherapy (thiotepa-busulfan-cyclophosphamide) with ASCT. The PRECIS trial has published long-term outcome and toxicity data (8 years median follow-up). Fifty-three patients received consolidation WBRT and 44 patients received consolidation ASCT. The 8-year event-free survival (from random assignment) was 67% (ASCT arm) and 39% (WBRT arm) (P =.03). There was a significantly lower risk of relapse after ASCT (hazard ratio 0.13, P <.001). Of the patients that relapsed after WBRT, one third were alive after salvage treatment. Five ASCT and four WBRT patients died of treatment related toxicities. OS was 69% and 65% at 8-years in the ASCT and WBRT arms, respectively (not significant). During follow-up balance (52% v 10%, P ≤ 0.001) and neurocognition (64% v 13%, P < .001) significantly deteriorated after WBRT compared with ASCT. This publication concluded that 40 Gy WBRT should be avoided due to toxicity and suboptimal efficacy in reducing relapses compared to ASCT.
A single-centre phase-2 study demonstrated excellent response rates in patients who underwent ASCT after R-MPV (2-year PFS and OS of 81%) with stable cognitive function post-transplant (median age: 57 years).r
These studies show that consolidative WBRT and HDC/ASCT are 2 effective consolidation options, and that ASCT may be a better alternative to WBRT. Therapeutic choice should be based on age, comorbidity, and tolerability to induction chemotherapy. Consolidative WBRT may be preferred in select patients aged 60-70 years old with responsive disease and relevant comorbidities and/or poor induction tolerability. WBRT is an unavoidable option for poor autologous peripheral blood stem cell mobilisers.