PCNSL is a rare and aggressive tumor and DLBCL represents 90%-95% of all primary central nervous system lymphoma[1, 2]. There are remarkable advances in the treatment of PCNSL over the last two decades[3, 4]. The present population-based study was conducted to detect the primary treatment and survival trends in patients with PCNSL diagnosed during 1995–2016. The results of our study indicates that both the use of radiotherapy alone and the application of combined chemoradiotherapy decreased, following more extensive use of chemotherapy alone as time went by. A significant improvement in survival was also demonstrated over time during 1995–2016.
The significantly increased cancer-specific survival from the time period-1 to the time period-2 is most likely bound up with the utilization of more intense chemotherapy regimens and the utilization of autologous stem-cell transplantation as consolidation strategy. As shown in our study, the use of radiotherapy alone and combined chemoradiotherapy dropped substantially with the patients aged 18–60 years dropping most and the use of chemotherapy alone increased dramatically from the time period-1 to the time period-2. Accordingly, our results showed that the survival increased most prominently for patients aged 18–60 years who may more fit to received more intense chemotherapy or high dose-ASCT for consolidation and survival of patients aged above 70 years who may have worse functional status and greater comorbidities remained unchanged from the time period-1 to the time period-2. Although wider use of chemotherapy applicated in patients aged above 70 years, a less aggressive treatment approach may performed. Although lacking of phase III randomized controlled trials to confirm the best consolidation approach, what is clear is that the application of more intense chemotherapy and the utilization of autologous stem-cell transplantation as consolidation strategy improved survival according to our population-based study. The finding that there was no improvement in survival of patients aged above 70 years the time period-1 to the time period-2 in our study falls in line with historical findings of previous studies based on population analysis[24, 25]. A cohort study carried out by Mendez JS et al. shown that survival in the elderly population (> 70) has not changed from 1973 to 2013. Van der Meulen M et al. demonstrated that improved survival was found in PCNSL up to age 70 only by a population-based study in the Netherlands,1989–2015.
However, there was an improvement in cancer-specific survival in the most recent period in not only younger patients (< 70 years) but also the elderly patients (> 70 years). There are many causes. One of the important reasons may be that there have been no age restrictions in several clinical trials and furthermore, trials have been conducted to target the elderly patient population (Such as PRIMAIN study) in the most recent clinical trials worldwide. It guide clinicians making treatment decisions in this patient population. Instead, clinical trials are only applicable to young and fit patients in the past. Another possible reason is that some new agents which are also tolerated in the elderly patients springs up in the time period-3 as we observed that elderly patients were more likely to receive chemotherapy in the time period-3. The representative agents include an antiproliferative and immunomodulatory agent lenalidomide and an oral BTK inhibitor Ibrutinib. In a prospective multicenter study reported by Ghesquieres H et. al assessing the combined chemotherapy of lenalidomide plus intravenous rituximab in relapsed/refractory PCNSL, an OR rate of 67% and an overall survival of 17.7 months were reported. Recent results from the phase II 'proof-of-concept' iLOC study investigating single-agent ibrutinib in relapse or refractory(R/R) DLBCL-PCNSL showed an OR rate of 52% and median OS of 19.2 months in 52 patients. Monotherapy with lenalidomide or ibrutinib is also being explored as a potential consolidation or maintenance therapy, particularly in older DLBCL-PCNSL patients. It may become a clinical progress which may provide more effective treatment options and significantly improved outcome among the elderly patients with PCNSL in future.
The strength of this study is that analysis of a population-based registries SEER including a large number of DLBCL-PCNSL patients, demonstrates continuous improvement in survival during 1995–2016, which reflected developments in treatment over time. By contrast, both the use of radiotherapy alone and the application of combined chemoradiotherapy decreased in all aged groups over time. We can find that the application of radiotherapy in the treatment of PCNSL has waned over time in this large population-based study. In most recent years, and particularly after that a randomized German study (G-PCNSL-SG-1) did not show evidence of improved survival by adding radiation, the use of whole brain radiation has been questioned.
The most recent RTOG 1114 study discussing the effect of reduced-dose radiation further (R-MVP/Ara-C ± low dose WBRT) and presented orally at ASCO 2020, a better PFS was reached in the reduced-dose WBRT group compared with the chemo-alone group.
However, the analyses of toxicity, especially neurotoxicity are still ongoing, the result of which might give further insight in the use of radiation in PCNSL.
Age is one of the most major prognostic factors for PCNSL. Both of the prognostic scores of Memorial Sloan Kettering Cancer Center and the International Extranodal Lymphoma Study Group include age as a prognostic factor. Survival also differed greatly between age groups and the multivariable model demonstrated an adverse effect of older age in our study. This patient population has a less radical therapeutic method, poorer performance status, and greater complication which may contribute to worse overall survival. Our study also found distribution of PCNSL by site in the CNS is another prognostic factor. Median cancer-specific survival was worse in PCNSL patients occurred in the brain parenchyma in comparison to those occurred in the CNS except brain parenchyma. Prognostic models including these factors should be developed to help in deciding the optimal therapeutic schedule in future.
It's worthy to note that our study should be considered in the context of its potential limitations. First, because of the deficiency of the SEER database, we were incapable of obtaining granular data especially the specifics on treatment (chemotherapy regimens, the dose of radiation, receive ASCT or not receive, the intent of radiotherapy and the like). Second,information regarding prognostic factors (patient performance status, CSF protein, serum lactate dehydrogenase, and lesions within deep structures) and history of prior treatment is not available. Third, we were incapable of excluding every HIV-associated PCNSL.