PCNSL represents a rare but highly aggressive NHL with poor prognosis. In light of the rarity of PCNSL, current understanding of PCNSL is mainly based on retrospective analysis with small series. Therefore, we conducted a study based on a large population. In the current study, there were 5166 PCNSL patients from SEER database.
The mean age at diagnosis was 63.1±14.9 years, and the male to female ratio was 1.1:1.0, which was largely consisting with population-based study from Australia. Previous studies have demonstrated that age was a significant and adverse prognostic factor[11–13]. In the present study, inferior OS and DSS were significantly associated with older age, consisting with previous results. Interestingly, our study revealed that married patients tend to have better outcomes than single patients (including divorced/widowed/separated patients). The mechanism between marital status and survival is unclear, social-psychological factors may contribute to it. The married patients may have better socioeconomic status and more emotional support than single patients.
Although the introduction of HD-MTX has significantly improved PCNSL prognosis, numerous patients still die attributed to treatment-related mortality, chemotherapy-resistant disease and relapse. Recent progress in understanding the pathophysiology of PCNSL has led to novel therapeutics introduced into clinical trials and have shown promising clinical responses. Based on population analysis, we found that patients diagnosed between 2009-2018 had better OS and DSS than those diagnosed 2000-2008, which reflected developments in treatment.
PCNSL is characterized by a frequent early wide dissemination and the involvement of deep brain that leads to poor efficacy of surgery. Previous research suggested that surgical resection (including complete and partial surgical resection) have no significant survival advantage and even be associated with higher mortality that should be avoided[17, 18]. The role of surgery is to only establish a diagnosis by stereotactic biopsy. However, with the large number of applications of new techniques and practices in recent years, including increased use of MRI, frameless stereotyping and tumor visualization, the effectiveness and tolerability have greatly improved. Survival advantage was proven and the traditional view has been questioned in some studies[19–21]. Therefore, the role of surgery in PCNSL should be reevaluated. In our study, surgical excision was associated with significantly better OS and DSS, and was an independent risk factor for survival. Moreover, combining surgical excision and chemotherapy can bring favourable OS and DSS than chemotherapy alone, which suggested that multimodal therapy may be more beneficial. However, this results should be interpreted with caution because of unknown operation mode and variations in the technical level of operators, and more prospective research is needed to verify it.
Due to the high sensitivity to radiation, newly diagnosed patients with PCNSL have historically received whole-brain radiotherapy (WBRT). However, WBRT-associated delayed neurotoxicity has limited its use, especially for age older than 60 years[7, 22, 23]. Given the higher risk of neurotoxicity and the limited durability of treatment responses, WBRT is not considered as the standard initial therapy for PCNSL patients[24, 25]. Recently, many clinical studies have engaged in whether different radiotherapy regimens (including reduced-dose and partial‐brain radiotherapy) combination with chemotherapy can bring better clinical outcomes[26–30]. However, the results still remain controversial. Analysis based on a large population, radiotherapy did not improve long-term effects and associated with inferior OS and DSS compared with no radiotherapy according to univariate analysis. Multivariate analysis revealed radiotherapy was an independent prognostic factor for OS, but not for DSS. We further explored the combination of radiotherapy and chemotherapy, then found that patient may benefit from combination therapy in the early stage of the treatment, unfortunately, the long-term outcomes were not superior to chemotherapy alone because of the high incidence of delayed neurotoxicity and short-term responses. Giving above, the benefit of radiotherapy in establishing local control of tumors must be weighed against the increased risk of long‐term neurotoxicity. Due to unknown information about detailed radiotherapy and chemotherapy regimens, subgroup analysis could not be performed. Therefore, these results should be interpreted cautiously.
The nomogram has become a useful tool for clinical decision-making and visualized and quick risk assessment for clinicians. In this study, it was found that race, age, sex, marital status, chemotherapy and surgery were independent prognostic factors for OS and DSS in DLBCL patients, and we constructed the nomograms to predict 1-, 3-, and 5-year survival based on these factors. The significantly higher C-index 0.704 and 0.698 of the nomograms proved discriminative power. Moreover, the calibration curve exhibited good consistency among the predicted survival and the actual survival. However, due to manual calculations, the nomograms are not easy to apply to clinical practice, so we further developed a dynamic web-based survival rate calculator that can predict the long-term OS dynamically at different time points for DLBCL patients based on the nomogram (https://tangdongshengarticle.shinyapps.io/DynNomapp/).
This study has several limitations. Firstly, potential biases were unavoidable as a retrospective study. Secondly, other potential prognostic factors, such as Karnofsky performance status score, size and number of lesions, LDH level are not registered in SEER database, and cannot combine these factors to predict prognosis. Thirdly, detail chemotherapy, surgical operation mode and radiotherapy regimens for patients are not available. We are unable to further analyze the impact of different treatment regimen on prognosis. Lastly, the nomograms were established and verified by using the same database, so it is necessary to prospectively verify the nomogram in another independent data set for reliable evaluation. Therefore, the results of the present study should be interpreted with caution given above limitations. Whereas, our study still provided useful information and important insights in PCNSL despite these limitations based on a large population.
In conclusion, age, race, sex, use of chemotherapy, surgery and radiation were independent prognostic factors for OS, but radiotherapy was no longer an independent prognostic factor for DSS based on the SEER database. Surgery might be a therapeutic benefit for PCNSL patients. Radiotherapy was effective in therapeutic initial stage, but the long-term outcome was not satisfactory. We also developed a predictive nomogram and a web-based survival rate calculator predicting the long-term OS in DLBCL patients which showed favorable applicability and accuracy that could help in the prediction of mortality and the choice of treatment.