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Mortality following a brain tumour diagnosis in multiple sclerosis patients
Journal:
BMJ Open
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Date Submitted by the Author:
Complete List of Authors:
bmjopen-2013-003622 Research 19-Jul-2013
Primary Subject Heading:
Keywords:
Epidemiology, Neurology
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Secondary Subject Heading:
Epidemiology
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Montgomery, Scott; Örebro University Hospital and Örebro University, Clinical Epidemiology and Biostatistics; Karolinska Institutet, Department of Medicine Hassan, Ahmad; Örebro University, 2. School of Health and Medical Sciences Bahmanyar, Shahram; Karolinska Institutet, Clinical Epidemiology Unit and Pharmacoepidemiology Unit, Department of Medicine Brus, Ole; Örebro University Hospital, Clinical Epidemiology and Biostatistics Hussein, Oula; Örebro University Hospital, Clinical Epidemiology and Biostatistics Hiyoshi, Ayako; Örebro University Hospital, Clinical Epidemiology and Biostatistics Hillert, Jan; Karolinska Institute, Clinical Neuroscience Olsson, Tomas; Karolinska Institutet, Clinical Neuroscience Fall, Katja; Örebro University Hospital and Örebro University, Clinical Epidemiology and Biostatistics Örebro, Sweden
Multiple sclerosis < NEUROLOGY, Epidemiology < TROPICAL MEDICINE, Neurological oncology < ONCOLOGY
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Mortality following a brain tumour diagnosis in multiple sclerosis patients Scott Montgomery,1 2 3 Ahmad Hassan,2 Shahram Bahmanyar,3 5 Ole Brus,1 Oula Hussein,1 Ayako Hiyoshi,1 Jan Hillert,5 Tomas Olsson,6 Katja Fall,1 2 1. Clinical Epidemiology and Biostatistics, Örebro University Hospital, Örebro, Sweden. 2. School of Health and Medical Sciences, Örebro University, Örebro, Sweden. 3. The Clinical Epidemiology Unit & Pharmacoepidemiology Unit, Karolinska Institutet, Stockholm, Sweden. 4. Clinical Research Centre, Golestan University of Medical Sciences, Gorgan, Iran. 5. Department of Clinical Neuroscience, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden. 6. Neuroimmunology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
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Address for correspondence and reprint requests to: Prof. Scott Montgomery Clinical Epidemiology and Biostatistics S-huset Örebro University Hospital 701 85 Örebro Sweden
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Word count for paper: 1,219 Word count for abstract: 238
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[email protected] Tel: +46 19 602 6210
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Number of references: 11
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Keywords: multiple sclerosis, epidemiology
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ARTICLE SUMMARY
Article focus •
The higher brain tumour risk among multiple sclerosis (MS) patients may in part be due to enhanced detection due to more frequent examinations.
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Brain tumours may theoretically have a worse prognosis among patients with an inflammatory disease of the central nervous system like MS.
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It has been hypothesised that brain tumour treatment may worsen MS progression, which in turn may increase mortality risk.
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Key messages •
Earlier brain tumour diagnosis in MS patients may contribute to a reduction in mortality risk.
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Even after taking age at diagnosis and malignancy grade into account, the mortality risk associated with brain tumours is not worse in MS patients.
Strengths and limitations
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The majority of MS patients with brain tumours in Sweden during the study period were included and compared them with brain tumour patients without MS.
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Use of All-cause mortality identifies an increased risk of death due to both brain tumours and influences on MS disease course.
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Information on brain tumour stage and size at diagnosis was not available.
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ABSTRACT Objective Brain tumours and their treatment may theoretically have more severe adverse consequences in inflammatory CNS diseases like multiple sclerosis (MS), even though earlier detection may be enhanced through more frequent neurological examinations. Here, all-cause mortality following a brain tumour diagnosis was compared in patients with
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and without MS.
Methods Swedish national registers identified MS diagnoses (1969–2005) and each patient with MS was matched with 12 subjects without MS. Everyone with a primary brain
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tumour diagnosis was selected, 111 with MS and 907 without. Cox regression assessed the five-year mortality risk following brain tumour diagnosis, with adjustment for age at
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diagnosis, grade of malignancy, sex, region of residence and socioeconomic index. Linear
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regression examined age at brain tumour diagnosis.
Results A lower mortality risk following a brain tumour diagnosis among MS patients
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produced a hazard ratio (and 95% confidence interval) of 0.73 (0.54-0.99) with loss of
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statistical significance after adjustment (explained by adjustment for age at tumour diagnosis): 0.90 (0.66-1.23). On average MS patients received their first brain tumour
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diagnosis at an earlier age and the reduction in mortality risk was among those with highor uncertain-grade malignancy, but not low-grade malignancy.
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Conclusions Younger age at tumour diagnosis may contribute to mortality reduction in those with high- and uncertain-grade brain tumours. Survival following a brain tumour is not worse in MS patients even after age at brain tumour diagnosis and grade of malignancy are taken into account.
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INTRODUCTION It has been reported that brain tumours are diagnosed more frequently in multiple sclerosis (MS) patients than among the general population, despite lower overall cancer risk in MS.(1) An earlier study identified an increase in detection of brain tumours of low-grade rather than high-grade malignancy in Swedish MS patients. Some of the increased frequency of brain tumours may have been due to relatively frequent neuro-imaging of the central nervous system (CNS) in MS patients, resulting in an increased tumour detection
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rate, including for asymptomatic tumours.(1)
Despite the apparently lower proportion of high-grade brain tumour types in MS,(2)
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prognosis following a brain tumour diagnosis in patients with an inflammatory degenerative disease of the central nervous system (CNS) remains a concern. It has been suggested
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that associated treatments including brain surgery, radiotherapy, and chemotherapy may
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be relevant to the course of MS: it is plausible that surgery and radiotherapy result in the liberation of brain-specific antigens which might promote autoimmunity and thus adversely
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influence disease course in MS.(2) We therefore investigated mortality following a first
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brain tumour diagnosis in MS patients, compared with people without MS who also had a first brain tumour diagnosis. Age at first brain tumour diagnosis as an explanatory factor for variation in mortality risk was also investigated.
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PATIENTS AND METHODS
The individuals included in this study were drawn from two larger Swedish cohorts, described previously.(1) Diagnoses of MS between 1969 and 2005 were identified using the National Inpatient Register(3) and the national Swedish Multiple Sclerosis Register.(4) Patients with MS were individually matched with 12 individuals (fewer in a small minority) by year of birth, sex, vital status, and region of residence, at the time of diagnosis in the 5 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
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matched case. The Total Population Register provided information on date of death or migration. The national Swedish Cancer Register(5) identified cancer diagnoses, classified as high malignancy, low malignancy and uncertain level of malignancy (table 1). A six-category socioeconomic index was based on occupation identified from the census nearest in time to study entry (manual workers, non-manual workers, professionals, selfemployed, farmers, and others).
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From among the original 20,543 with and 204,163 without MS, we excluded 479 due to missing information. We then identified all those with a brain tumour who did not have a prior cancer diagnosis at any other site. A total of 111 with MS and 907 without had a
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primary brain tumour diagnosis.
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This study was approved by Karolinska Institutet regional ethics committee.
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Statistical analysis
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Cox proportional hazard regression was used to estimate mortality risk in the five years
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following brain tumour diagnoses in MS patients compared with the reference cohort. Follow-up was from diagnosis to death, emigration, five years duration or December 31,
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2005, whichever occurred first. Adjustment was for age at brain tumour diagnosis
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(continuous), level of malignancy, sex, geographical region (Northern, Central and Southern Sweden) and socioeconomic index. Further analyses were stratified by grade of malignancy. Mortality risk for 10 years was also examined and a Kaplan-Meier curve was produced. The proportionality of hazards assumption was verified for all analyses.
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To investigate variation in age at brain tumour diagnosis, age was the dependent variable in linear regression analysis. Adjustment was for level of malignancy, sex, geographical region and socioeconomic index.
The analysis used SPSS statistical software.
RESULTS
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Table 1 shows the characteristics of the study population. The MS patients were on average younger at brain tumour diagnosis and fewer had high-grade tumour types. There was a lower mortality risk in the five years following brain tumour diagnosis among MS
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patients, which is statistically significant before but not after adjustment (table 1 and figure 1). Adjustment for age at cancer diagnosis accounts for the loss of significance.
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When stratified by grade of malignancy, there is no difference in mortality by MS for the low-grade malignancy group. There is a statistically significantly lower mortality risk in MS
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patients among those with high and undetermined grade tumours. Adjustment for the
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potential confounding factors eliminated statistical significance, but the mortality risk remained lower among MS patients.
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Linear regression indicated MS patients were on average 4.7 years younger at brain tumour diagnosis, after adjustment for the potential confounding factors (p
