Little value of surveillance magnetic resonance imaging for primary CNS lymphomas in first remission: results from a Danish Multicentre Study

Primary central nervous system lymphomas (PCNSLs) account for a very small fraction of central nervous system (CNS) neoplasms (Gittleman et al, 2015). The vast majority of PCNSL are diffuse large B-cell lymphomas (DLBCL) with an activated B-cell phenotype, and the prognosis is inferior to their non-CNS counterparts (Camilleri-Broët et al, 1998; Lin et al, 2006). Nevertheless, a considerable number of patients achieve long-lasting or temporary remissions following high-dose methotrexate (HDMTX) based treatments (Ferreri et al, 2009). There is currently no standard follow-up (FU) care for patients with PCNSL in remission, but the minimum testing often includes history, physical examination and gadolinium-enhanced magnetic resonance imaging (MRI) of the brain (Abrey et al, 2005). In a Danish multicentre study, we examined the relapse detection pattern in PCNSL with a particular focus on the value of routine MRI studies. Consecutive PCNSL patients seen in five Danish academic centres between 2002 and 2012 were retrospectively included if they fulfilled the following criteria: (i) biopsy-verified, treatment-naïve PCNSL, (ii) age ≥15 years, and (iii) complete remission (CR) following first line treatment. Baseline clinico-pathological features were retrieved from the Danish Lymphoma Registry and relapse characteristics were collected locally from medical files. As a rule, patients were seen in outpatient clinics quarterly for the first 2 years of FU and then biannually for three more years. History, clinical examination, and routine blood tests were obtained during each of these visits. MRI scans were performed at the discretion of the attending physician, but biannual routine MRI scans for 2 years was common practice many places. Routine MRI studies were defined as studies prescribed to patients in remission, whereas clinical MRI studies were defined as studies performed in response to clinical symptoms/findings. MRI studies were categorized as true negative (negative study followed by clinical remission >6 weeks), true positive (positive study with relapse confirmed by biopsy, or where imaging results were considered sufficient to initiate salvage therapy), false negative (negative study with relapse ≤6 weeks of the study date) and false positive (positive study with relapse disproved by biopsy, repeated imaging or FU). Statistical analyses were performed with R statistical software, version 3.2.0 (R Core Team, 2015) and data collection was compliant with national regulations. Eighty-six PCNSL patients with median age 64 years (range 30–84 years) were included. The histology subtypes were DLBCL in 81 patients (94%), low-grade B-cell lymphomas in two patients (2%), and T-cell lymphomas in three patients (4%). With a median FU of 4·9 years, the estimated five-year overall survival and progression-free survival values were 58% [95% confidence interval (CI) 46–69%] and 45% (95%CI 33–56%), respectively. Relapse occurred in 32/86 patients (37%, 95%CI 27–48%). Median time from diagnosis to first relapse was 1·4 years (range 0·6–5·6). Relapse was suspected due to new clinical symptoms in 31/32 relapse patients (97%, 95%CI 84–100%) whereas relapse (3%, 95%CI 0–16%) was diagnosed by a routine MRI study in one patient. The most common symptoms associated with clinical relapse were cognitive symptoms (34%) and paralysis (28%) (Table 1). When restricting the analysis to patients receiving ≥1 routine MRI study, 1/20 (5% 95%CI 0–25%) relapses were diagnosed by routine MRI imaging. In 30/32 relapse patients (94%, 95%CI 79–99%), relapse investigations were initiated outside pre-planned FU visits. During the first 5 years of FU, 189 routine MRI studies were performed in 64 patients (146 performed in year 0–2) and 81 clinical MRI studies were performed in 45 patients (Table 2). In total, 189 routine MRI studies were performed to detect one preclinical PCNSL relapse. Roadmaps for developing effective FU strategies in lymphoma do not exist, but the success of a FU programme depends on the nature of the disease, the existence of effective salvage therapies and available technologies for relapse detection. The behaviour of PCNSL is very different from the systemic lymphomas and the practices used in other lymphomas do not necessarily apply to PCNSL. Unlike many systemic lymphomas, even small PCNSL lesions can result in dramatic symptoms, which makes it difficult for random cross-sectional imaging to detect preclinical relapse. Thus, careful consultation with patients for symptoms seems far more important than relying on routine FU checks, which generally failed to identify relapse in the present cohort. Through education, patients and their relatives should be encouraged to report even discrete neurological/mental changes immediately. Pursuing early relapse detection in PCSNL is clinically important because a diagnostic delay can lead to irreversible damage. However, routine MRI studies did not contribute significantly to relapse detection in the present study where only one out of 189 routine MRI studies revealed preclinical relapse. In contrast, only 3·4 MRI studies were performed per relapse in patients with clinical symptoms. Clinical MRI studies missed pending relapse in three symptomatic patients diagnosed with recurrent PCNSL. Therefore, repeat MRI studies should be considered in case of discrepancies between MRI results and clinical findings. To the best of our knowledge, this is the first published study reporting the utility of routine MRI for PCNSL and evaluating the current FU practice in general. The present study needs to be considered within the context of its limitations. MRI studies were performed at the discretion of the attending physicians and there was no national standard FU for PCNSL. Increasing the number of MRI studies may lead to more imaging-detected relapses, although the value of this is uncertain in the absence of solid evidence indicating a survival benefit for patients with preclinical relapse detection. No central review of MRI images was organized, but the participating centres were serviced by experienced neuro-radiologists and the study utilized data upon which clinical decisions were made. In conclusion, routine FU procedures (including routine MRI scans and pre-planned visits) play a limited role in detecting relapsed PCNSL. The aggressive nature of the disease and the short asymptomatic disease period leaves little room for routine imaging to become successful. Pre-planned FU checks are appropriate for assessing late treatment toxicities and improving survivorship. Diagnosing relapsed PCNSL, however, relies mostly on the vigilance of the patients and their relatives. TCEG and KJM designed the study. KJM, TCEG, ILG, MH, PB, TBE, PDNB and AOG collected data. All authors contributed to planning of data analysis. KJM, MB, TCEG and TYM performed statistical analysis. All authors interpreted data and results. TCEG drafted the first manuscript. All authors commented, revised, and approved the final manuscript.