Improved survival in primary central nervous system lymphoma up to age 70: a population-based study on incidence, primary treatment and survival in the Netherlands, 1989-2015 Matthijs van der Meulen, A.G. Dinmohamed, O. Visser, J.K. Doorduijn, J.E.C. Bromberg Erasmus Medical Centre, the Netherlands Netherlands comprehensive cancer organisation June 24, 2017

Disclosures No disclosures

Primary central nervous system lymphoma Aggressive form of non-Hodgkin lymphoma Brain, leptomeninges, eyes and/or spinal cord 3% of all brain tumors Focal deficits, neuropsychiatric symptoms and headache Mostly diffuse large B-cell lymphoma Clinical presentation concerns mostly focal neurological deficits, neuropsychiatric symptoms and headache and, in contrast to glioma’s , in only a minority of the cases the patient will present with a seizure MRI shows mostly a single or multiple space occupying lesions with homogenous contrast enhancement. Batchelor TT, 2006; Colocci, 2004 Central Brain Tumor Registry of the US

Rationale Findings from the few available prospective studies demonstrated improved outcome in PCNSL over the past decades1-4 However, the results from such studies may not reflect daily practice Population-based studies are useful to complement prospective intervention studies by addressing a non-selected group of patients May not reflect actual daily practice because of stringent inclusion criteria in prospective trials A non selected group of patients from a specific geographic area 1Ferreri AJ et al. Lancet. 374: 1512-20 (2009); 2Thiel E et al. Lancet Oncol. 11: 1036-47 (2010); 3Omuro A et al. Lancet Haematol. 2: 251-9 (2015); 4Fritsch K et al. Leukemia. Epub ahead of print (2016).

Rationale Large representative population-based studies in PCNSL are scarce Comprehensive information on incidence, treatment and survival at the population level are virtually lacking We assessed trends in incidence, primary treatment and survival among adult PCNSL patients diagnosed in the Netherlands from 1989 to 2015 reported to the nationwide Netherlands Cancer Registry (NCR)

The Netherlands Cancer Registry We selected all adult PCNSL patients diagnosed between 1989-2015 from the NCR with survival follow-up through February 1, 2016 The NCR includes all newly diagnosed malignancies since 1989 all pathology laboratories in the Netherlands (PALGA) Nationwide Registry of Hospital Discharges (LMR/LBZ) Coverage >95% The NCR contains Dates of birth, sex and vital statistics Diagnosis, stage, morphology and primary treatment The primary central nervous system lymphoma’s has to be confirmed by pathology or cytology NCR, founded in 1989 has access to the Nationwide Network of Histopathology and Cytopathology and the National Registry of Hospital Discharges. Earlier research showed an overall coverage of >95% The registry contains age, sex, diagnosis, stage and primary treatment. Unfortunately details about the treatment administered are only available from 2014 onwards

Statistical methods Patients divided into 4 periods (1989-1995, 1996-2002, 2003-2008 and 2009-2015) and 3 age groups (18-60, 61-70 and >70 years) Primary treatment was defined as: no anti-neoplastic therapy, chemo-therapy (CT), radiotherapy (RT), CT+RT, and other/unknown therapy Relative survival as a measure of disease-specific survival Patient survival corrected for the expected survival of a comparable group from the general population (i.e. sex, age and period matched)

Results Total Number of patients 1,673 Men 885 Women 788 Median age 65 years (19-87)

Age-specific incidence of PCNSL Males and females together Incidence per 100,000 Over the past 28 years there is a increasing incidence of PCNSL among patients over 60 years old only The increase among women is slightly less The incidence of PCNSL steadily increased for patients >60 years In part due to improved diagnostic practices among the elderly over time, however the incidenc of glioma’s and lymphoma’s elsewhere in the body is not increasing a the speed. Changes in etiologic factors cannot be completely ruled out So, the increase is not completely understood, bit is a clear trend of over a long period Year of diagnosis

Primary therapy of PCNSL % of patients Among the youngest group More patients received treatment the administration of Chemoradiotherapy and chemotherpay has increased the most Among elderly (over 60 years old) More patienst were treated with chemotherapy, instead of radiotherapy The question is, whether these changes in primary treatment has influenced their prognosis Age and period at diagnosis

Relative survival of PCNSL 18-60 years >70 years % relative survival Years after diagnosis 61-70 years The 1-, 3 and 5 year relative survival has increased significantly over the past decades The blue line is the first period The pink line is the last period of our cohort Unfortunately the prognosis of patients over 70 years old did not improve at all Years after diagnosis

Relative excess risk of mortality (EMR) Model without therapy Covariate EMR 95% CI p Period of diagnosis 1989-1995 1 Reference 1996-2002 1.10 0.93-1.31 0.269 2003-2008 0.73 0.61-0.86 <0.001 2009-2015 0.59 0.50-0.70 Sex Male Female 1.05 0.93-1.18 0.451 Age at diagnosis 18-60 61-70 1.67 1.44-1.93 >70 3.11 2.70-3.60 Primary treatment No anti-neoplastic therapy CT+RT CT alone RT alone Other/ unknown therapy Model with therapy EMR 95% CI p 1 Reference 1.18 0.98-1.41 0.076 1.04 0.87-1.25 0.650 0.86 0.72-1.03 0.100 0.98 0.87-1.11 0.774 1.26 1.08-1.48 <0.003 1.50 1.28-1.76 <0.001 0.08 0.06-0.09 0.14 0.12-0.17 0.22 0.19-0.26 0.28 0.19-0.39

Summary and conclusions Incidence of PCNSL steadily increased for patients >60 years Survival improved over the past decades for patients up to age 70 ↑ chemoradiotherapy for patients age 18-60 ↑ chemotherapy alone for patients age 61-70 Use of chemotherapy alone gradually ↑ for patients >70 years Their survival remained poor and essentially unchanged Specific trials for >70 years are needed to improve outcomes Incidence However, changes in etiologic factors cannot be completely ruled out Although the use of chemotherapy alone is gradually increasing among patients above age 70, their survival remained poor and essentially unchanged over the past decades. Therefore, there is a need to design specific trials for patients above age 70 in order to improve their survival.

Acknowledgements Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, the Netherlands All data managers of the NCR X

Patient characteristics at diagnosis Calendar period of diagnosis Total 1989-1995 1996-2002 2003-2008 2009-2015 No. (%) Total No. of patients 300   316 416 641 1,673 Sex Male 155 (52) 177 (54) 217 (53) 336 885 Female 145 (48) 139 (46) 199 (47) 305 788 Age, years Median (range) 62 (20-87) 65 (19-87) 64 (25-87) 66 (21-87) 18-60 136 (45) 108 (34) 153 (37) 188 (29) 585 (35) 61-70 83 (28) 112 130 (31) 242 (38) 567 >70 81 (27) 96 (30) 133 (32) 211 (33) 521

Relative excess risk of mortality (EMR)   Model without therapy Covariate EMR 95% CI P Period of diagnosis 1989-1995 1 Reference 1996-2002 1.10 0.93-1.31 0.269 2003-2008 0.73 0.61-0.86 <0.001 2009-2015 0.59 0.50-0.70 Sex Male Female 1.05 0.93-1.18 0.451 Age at diagnosis, years 18-60 61-70 1.67 1.44-1.93 >70 3.11 2.70-3.60 Primary therapy No anti-neoplastic therapy CT+RT CT alone RT alone Other/unknown therapy Model with therapy EMRa 95% CI P   1.18 0.98-1.41 0.076 1.04 0.87-1.25 0.650 0.86 0.72-1.03 0.100 1 Reference 0.98 0.87-1.11 0.774 1.26 1.08-1.48 0.003 1.50 1.28-1.76 <0.001 0.08 0.06-0.09 0.14 0.12-0.17 0.22 0.19-0.26 0.28 0.19-0.39 Relative excess risk of mortality during first five years after diagnosis