Cancer and diabetes - a follow-up study.of two populationbased cohorts of diabetic patients

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1 Journal of lnternal Medicine 1997: 241: Cancer and diabetes - a follow-up study.of two populationbased cohorts of diabetic patients H. HJALGRIM", M. FRISCH", A. EKBOMb, K. 0. KYVIK", M. MELBYE" & A. GREEN" From the 'Department of Epidemiology Research, Danish Epidemiology Science Centre, Stntens Serum lnstitut. Copenhagen: and 'Genetic Epidemiology Research Unit. Odense University. Odense: Denmark: and *Department of Cancer Epidemiology, University Hospital, Uppsala. Sweden Abstract. Hjalgrim H, Frisch M, Ekbom A, Kyvik KO, Melbye M, Green A (Statens Serum Institut, Copenhagen ; Odense University, Odense ; Denmark ; and University Hospital, Uppsala, Sweden). Cancer and diabetes - a follow-up study of two populationbased cohorts of diabetic patients. ] lntern Med 1997; 241: Objectives. To study the occurrence of cancer amongst patients with diabetes mellitus (DM). Design. Population based cohort study. Setting. Denmark. Subjects. Two cohorts of patients with DM were identifled. One cohort comprised 1659 conscripts diagnosed with type I DM before the age of 20 years. Another cohort comprised 1499 men and women with insulin treated DM identified by means of medical prescriptions on 1 July Both cohorts were followed until the end of Main outcome measures. The relative risk of cancer in the two cohorts was estimated as the ratio of observed to expected number of cancers in the cohort (SIR). Results. No unusual risk of cancer was observed amongst the conscripts (SIR 0.9, n = 13) or amongst patients with onset of DM before the age of 30 years in the prescription cohort (SIR 0.9, n = 32). Amongst those aged 30 years or more at DM onset in the prescription cohort, the overall risk of cancer did not depart from normal (SIR 1.0, n = 103), however, pancreatic cancer occurred in excess both immediately ( < 1 year) (SIR 190, n = l), and during 1-9 years after DM onset (SIR 9.0, n = 4). Similarly, the risk of non-hodgkin's lymphoma was increased significantly (SIR 3.3, n = 6), all cases occurring more than 10 years after DM onset. Conclusions. Our data suggest that there is no unusual risk of cancer associated with type I DM. Type II DM may be the first symptom of pancreatic cancer and may be associated with an increased risk of non-hodgkin's lymphoma. Keywords : cohort study, diabetes, epidemiology, non-hodgkm's lymphoma, pancreatic cancer. Introduction [8]. However, similar to previous investigations the study did not fully allow for an evaluation of whether Prompted by the wide range of metabolic, immunothe risk profile differed between different types of DM. logical and hormonal aberrations associated with To address this problem, we investigated the risk of diabetes mellitus (DM), an association between DM cancer amongst patients with insulin treated DM in and neoplastic conditions has been suspected for two different population based cohorts. many years. In particular, interest has been focused on pancreatic cancer, liver cancer, cancer of the endometrium, and of haematopoietic tissues [ Material and methods Despite the long interest in the matter, cancer morbidity amongst diabetics has been assessed only Patient cohorts in few studies [ Recently, an increased overall The two cohorts are described in detail elsewhere risk of cancer was observed amongst patients with [ In brief, one cohort comprised all men born DM in the largest cohort study undertaken to date in Denmark between 1 January 1949 and Blackwell Science Ltd 471

2 472 H. HJALGRIM et al. Table 1 Number of persons and person-years of follow-up in the two cohorts 10 ua x 10 cmoa. Men Women All Cohort Persons Person-years Persons Person-years Persons Person-years Conscript Prescription < 30 years at onset ' years at onset December 1964, who were diagnosed with DM before the age of 20 years. The cohort was identified through the National Conscript Registry. Appearance before a conscript board for examination and assessment for military and civil service is mandatory by law for all Danish men. Diabetes and suspected diabetes imply unconditional exemption from such duties (Table 1). The other cohort comprised all patients with insulin treated DM as of July 1, 1973 in Funen. County, Denmark (population of approximately persons) [12]. To identify DM patients receiving insulin, all prescriptions issued in the period from April 1 to August 31, 1973 were scrutinised. For all persons identified, the diagnosis of DM was ascertained by subsequent review of medical records and through contact to general practitioners [12]. For all cases, date and age of onset of DM were available. Unfortunately the type of DM was not recorded in this database. To overcome this problem, we divided the cohort in two; one consisting of patients whose DM started before the age of 30 years (believed to represent mainly type I DM) and another comprising patients whose age at DM onset was 30 years or older (mainly patients with type II diabetes) (Table 1). Cases of cancer in the two cohorts were identified through linkage with the Danish Cancer Registry by means of the unique lodigit identification number assigned to all Danish citizens alive on April 1, The Danish Cancer Registry is considered almost 100% complete [151. For the conscript cohort, follow-up started on the 18th birthday (the approximate date of appearance before the conscript board), and for the prescription cohort on July 1, In both cohorts, follow-up continued until death, emigration, or the end of 1992, whichever came first. Statistical methods The relative risk of cancer was expressed as the ratio of observed to expected number of cancers, i.e. the standardized incidence ratio (SIR). The expected number of cancers was estimated by multiplying the person-years in the cohorts by sex, age, and period specific incidence rates in 5-year intervals obtained from the Danish Cancer Registry. Under the assumption that the cancers observed follow a Poisson distribution 95% confidence limits (CL) of the SIR were calculated [16]. Because some patients may have been included in the cohorts as the result of cancer induced DM (e.g. pancreatic cancer) we wanted to evaluate whether such selection bias was likely to have taken place. Thus, we calculated SIRS for cancer in two latency periods according to time since onset of DM, one comprising the first year after onset of DM and the other comprising longer durations of DM. Results Conscript cohort In this cohort, a total of 13 cancers were diagnosed during a total of person-years of follow-up against an expected number of 14.2 cases (SIR 0.9, 95% CL , first year after onset of DM excluded). All cancers were diagnosed more than 10 years after the diagnosis of DM. No unusual risk of cancer was observed for any specific site; oesophagus (n = l), colon (n = 2), liver (n = l), retroperitoneum (n = l), lung (n = l), testis (n = 1). nonmelanotic skin (n= 1). brain and nervous system (n = 2). connective tissue (n = l), Hodgkin's disease (n = l), and leukaemia (n = 1) Blackwell Science Ltd Journal of lnternal Medicine 241 :

3 DIABETES AND CANCER 473 Table 2 Observed and expected number of cancels in the prescription cohort, SIR and coddence limits by site and age of onset of DM. Fist year after onset of DM excluded Group Age < 30 years at onset of DM 95% Age 2 30 years at onset of DM 95% confidence confidence Observation Exp. SIR limits Observations Exp. SIR lib Buccal cavity and pharynx Digestive organs and peritoneum Respiratory system Breast Female genital organs Male genital organs Urinary system Skin Other specified sites Secondary and unspeci6ed sites Lymphatic and haematopoietic tissues All malignancies Prescription cohort For this cohort, followed over a total of person-years, initial analyses were performed for the two sexes separately. However, since no consistent differences were present the results for men and women are presented together. Amongst those diagnosed with DM before the age of 30 years, a total of 32 cancers were observed, all of which occurred more than 10 years after onset of DM. The number of cancers observed corresponded well with the expected numbers overall as well as for specific sites (Table 2). Amongst persons diagnosed with DM at the age of 30 years or older, a total of 103 cancers were observed. Two cases of cancer (one in the pancreas and one in the prostate) occurred within one year after onset of DM when only 0.14 was expected (SIR 14.0; 95% CL ). After exclusion of the first year after onset of DM the overall number of cancers did not differ from the expected (Table 2). For two specific sites, however, increased risks of cancer were observed. A total of six cases of pancreatic cancer were seen in the group with late onset DM. One case occurred less than one year after onset of DM, when was expected (SIR 190; 95% CL ), and the risk remained increased in the period 1-9 years after onset of DM (n = 4, SIR 9.0, 95% CL ). After 2 10 years of DM, the risk of pancreatic cancer was no longer increased (n = 1; SIR 0.3; 95% CL ). Also, six cases of non-hodgkin s lymphoma occurred amongst patients with onset of DM at or after the age of 30 years against 1.8 expected (SIR 3.3, 95% CL ). All cases were diagnosed 2 10 years after onset of DM. Discussion We observed no unusual risk of cancer among patients with onset of DM before the age of 30 years, neither immediately after onset nor after longer durations of DM. Amongst those with onset of DM at or after the age of 30 years, the two cases of cancer occurring during the first year of DM exceeded the expected, whereas the overall cancer risk was not increased thereafter. We know of few other studies assessing cancer morbidity among patients with DM. In a study some what smaller than the present which comprised 1135 incident cases of DM followed for a total period of over 9800 person-years, the overall risk of cancer did not differ significantly from that of the background population, neither including or excluding the first year of follow-up [lo]. However, increased risks of cancer amongst patients with DM were observed in a recent Swedish cohort, including patients identified in a hospital discharge register, followed for a total of person-years subsequent to fist registered discharge [8]. Because precise information about type and date of onset of DM was not available in that particular study, patients were grouped according to age at first discharge, the youngest group being years. For all age groups, significantly elevated risks of cancer were observed during the first year of follow Blackwell Science Ltd Journal of Internal Medicine 241:

4 474 H. HJALGRIM et al. up, in the youngest age group as much as 5.5-fold amongst women and 10-fold amongst men, the risk declining with time since beginning of follow-up. The present study has some limitations that need to be considered. Although we believe that both cohorts are characterized by a high ascertainment rate and that close to 100% of the cancers occurring in the cohorts are registered, the number of persons included in the study remains limited. Accordingly, relatively few cancers were expected and observed, restricting the conclusions that can be drawn. This consideration applies in particular to the results for the conscript cohort. However, the observation of a similar estimate [SIR 0.91 amongst those diagnosed with DM before the age of 30 years in the prescription cohort (believed to comprise mainly type I DM) supports the view of no unusual cancer risk associated with type I DM. Consequently, the present observations supplement those of the Swedish study [8] by providing risk estimates for young patients predominantly having type I DM. Being a register-based study, we were unable to address potential effects of unmeasured confounders, including behavioural factors like alcohol consumption and tobacco smoking. Another limitation was that in the prescription cohort we had no information on the type of DM in the individual patients. The appropriateness of using of age of onset as a surrogate marker for the type of DM should therefore be considered. One previous analysis of the prescription cohort clearly demonstrated that the proportion of all cases of DM that are noninsulin dependent increased with age of onset and became by far the predominant type after the age of 30 years [17]. Therefore the assumption that all cases of DM with onset at age 30 years or older are of type 11 has probably resulted in only a minor degree of misclassification between type I and type 11 patients. A temporal pattern worthy of notice was that of the association between DM and pancreatic cancer. Thus, amongst persons with onset of DM at or after the age of 30 years, we observed a markedly elevated risk of pancreatic cancer in the first 10 years after onset of DM; an association that disappeared thereafter. An increased risk of pancreatic cancer amongst patients with DM has been described in several studies (reviewed in Ref. 18) and the present study yields further evidence for the association. However, rather than suggesting DM as a cause of pancreatic cancer, our data render an opposiie causal associ- ation plausible. In some situations DM may be the fist symptom that ultimately leads to the detection of an undiagnosed pancreatic cancer. It should be mentioned, however, that in a recent hospital-based study from Sweden the risk of pancreatic cancer remained significantly increased more than 10 years after fmt hospital discharge with DM [19], in agreement with the above mentioned meta-analysis of previous studies [18]. In the prescription cohort, an excess occurrence of non-hodgkin s lymphoma was observed amongst patients with onset of DM at or after the age of 30 years or older. As type 11 is the predominant type of DM in this group, this observation is in line with other studies by indicating an increased risk of non- Hodgkin s lymphoma amongst patients with type I1 DM. Originally, Ragozzino et al. [lo] reported an increased risk of non-hodgkin s lymphoma in their study, but later revised both the data and the conclusion [9]. Whilst Adami et al. [8] do not report risk estimates specifically for non-hodgkin s lymphoma, our observations are in accordance with those of two case-control studies, both of which suggested an increased risk of such lymphomas amongst patients with type I1 DM [6, 71. One possible mechanism may be the impaired immune response observed in diabetics as suggested previously [7], because non-hodgkin s lymphoma occurs particularly amongst patients with immunological dysfunctions [20, 211. In conclusion, the present study suggests that patients with type I DM are not at any unusual cancer risk (at least during the first 4 4 decades of life) compared with that prevailing in the background population. Amongst patients with onset of DM at the age of 30 years or older, DM may be the first symptom of pancreatic cancer, and may in the long run also be associated with an increased risk of non- Hodgkin s lymphoma. References 1 Gdo L. Pezzilli R. MorseUi-Labate M. Diabetes and risk of pancreatic cancer. N Engl J Med 1994; 331: La Vecchia C. Negri E, Pranceschi S. DAvanzo B, Boyle P. A case-control study of diabetes mellitus and cancer risk. Br J Cancer 1994: 70: Cuzick J, Babiker AG. Pancreatic cancer. alcohol, diabetes meuitus and gall-bladder disease. Int J Cancer 1989; 43: Lawson DH. Gray JMB. McKillop C. Clarke J, Lee FD, Patrick Blackwell Science Ltd Journal of Internal Medicine 241 :

5 DIABETES AND CANCER 475 RS. Diabetes mellitus and primary hepatocellular carcinoma. QJ Medicine 1986; 61: OMara BA. Byers T, Schoenfeld E. Diabetes mellitus and cancer risk: a multisite case-control study. J Chron Dis 1985; 38: Cartwright RA. McKinney PA, O Brien C. Richards IDG. Roberts B, Lauder I et al. Non-Hodgkin s lymphoma: case control epidemiological study in Yorkshire. Leukemia Res 1988; 12: Natazuka T, Manabe Y, Kono M. Murayama T, Matsui T. Chihara K. Association between non-insulin dependent diabetes mellitus and non-hodgkin s lymphoma. Br Med J 1994; 309: Adami HO, McLaughlin J, &born A. Berne C. Silverman D. Hacker D, Persson I. Cancer risk in patients with diabetes mellitus. Cancer Causes Control 1991; 2: Ragozzho MW. Melton III. LJ. Palumbo PJ, Chu CP. Risk of lymphoma in individuals with diabetes mellitus. I Chron Dis 1983: 36: Ragozzino MW, Melton III. LJ, Chu CP. Palumbo PJ. Subsequent cancer risk in the incidence cohort of Rochester. Minnesota, residents with diabetes mellitus. J Chon Dis 1982 : 35: Hiatt RA. Klatsky AL. Armstrorng MA. Pancreatic cancer. blood glucose and beverage consumption. Znt J Cancer 1988: 41: Green A. Hauge M, Holm NV, Rasch LL. Epidemiological studies of diabetes in Denmark: 2. A prevalence study based on insulin prescriptions. Diabetologia 1981; 20: Green A, Andersen PK. Svendsen AJ, Mortensen K. Increasing incidence of early onset type 1 (insulindependent) diabetes mellitus: a study of Danish male birth cohorts. Diabetologia 1992; 35: Green A. Hauge M. Holm NV, Rasch LL. Epidemiological studies of diabefes mellitus in Denmark: 1. A case finding method based on the National Service Conscript Registry. Diabetologia 1980: 19: Storm HH. The Danish Cancer Registry, a self-reporting national cancer registration system with elements of active data collection. In: Jensen OM, Parkin DM. Macknnan R. Muir CS. Skeet RG. eds. Cancer Registration Principles and Methods. Lyon: IARC. 1991; Breslow NE. Day NE. Statistical methods in cancer research, Vol II. Lyon: IARC Green A. Hougaard P. Epidemiological studies of diabetes mellitus in Denmark: 4. Clinical characteristics of insulin treated diabetic patients. Diabetologia 1983: 25: Everhart J, Wright D. Diabetes mellitus as a risk factor for pancreatic cancer. I Am Med Assoc 1995: 273: Chow WH. Gridley G. Nyrkn 0. Linet MS. Ekbom A, Fraumeni JF, Jr., Adami HO. Risk of pancreatic cancer following diabetes mellitus : a nationwide cohort study in Sweden. J Natl Cancer Znst 1995: 87: Kinlen LJ. Immunosuppression and cancer. In: Vainio H, Magee PN. McGregor DB. McMichael AJ, eds. Mechanisms of carcinogenesis in risk identi$cation Lyon: IARC, 1992; Penn I. The Occurrence of Cancer in Immune Deficiencies. Curr Probl Cancer 1982; 6: Received 2 October 1996; accepted 30 December Correspondence: Henrik Hjalgrim MD, Afdeling for Epidemiologisk Forskning. Statens Serum Institut Artillerivej 5. DK-2300 K~benhavn S. Danmark (fax: : hhjalgrim@desc.ssi.dk) Blackwell Science Ltd Journal of Internal Medicine 241: