Cancer kidney liver

BEVERLEY BALKAU, PHD [1]

HENRY S. KAHN, MD [2]

DOMINIQUE COURBON [1]

EVELINE ESCHWEGE, MD [1]

PIERRE DUCIMETIERE, PHD [1]

The Paris Prospective Study

OBJECTIVE -- To investigate whether insulin is a risk factor for death by site-specific cancers.

RESEARCH DESIGN AND METHODS -- This was a prospective cohort study of 6,237 nondiabetic French working men between ages 44 and 55 years at baseline from the Paris Prospective Study cohort. Death by site-specific cancers was investigated in relation to baseline insulin concentrations during fasting and 2 h after a 75-g oral glucose tolerance test.

RESULTS -- Of the original 6,237 men in the cohort, 1,739 died over the 23.8 years of follow-up, 778 (45%) from cancer. Baseline hyperinsulinemia, both fasting and 2-h, was significantly associated with fatal liver cancer, with age-adjusted standardized hazards ratios of 2.72 (95% CI 1.87-3.94) and 3.41 (2.23-5.21). In contrast, fasting hyperinsulinemia was inversely associated with fatal lip, oral cavity, and pharynx cancer and larynx cancer, with hazards ratios of 0.55 (0.41-0.75) and 0.63 (0.47-0.83), respectively; 2-h insulin concentrations were inversely associated with stomach and larynx cancers (hazards ratios 0.62 [0.43-0.90] and 0.66 [0.50-0.89], respectively). These relationships were stable after adjusting for other risk factors. Insulin concentrations remained negatively associated with deaths from these cancers in analyses restricted to men who smoked and in those who were not chronic alcohol consumers.

CONCLUSIONS -- Peripheral hyperinsulinemia, indicative of very high portal insulin concentrations, predicted fatal liver cancer in these nondiabetic men, but was inversely associated with fatal lip, oral cavity, and pharynx cancer; stomach cancer; and larynx cancer.

A number of studies have examined cancer incidence (or mortality) and hyperglycemia, diabetes, and central obesity, but they have been unable to establish the biological mechanism underlying the epidemiological associations [1-11]. All of the site-specific cancers cited in these studies (pancreatic, kidney, colorectal, prostate, liver, biliary tract, stomach, and genital) showed a positive association with diabetes [1,4-10], except for the negative association found for lung cancer in men in one study [5]. A coherent argument has been offered for the role of chronic hyperinsulinemia in the initiation and promotion of cancer growth [12]; this is supported by recent evidence that incident colorectal cancer was related to hyperinsulinemia [13] and C-peptide concentrations [14]. A recent publication from the Helsinki Policeman Study [15] showed an overall positive but nonsignificant relationship between cancer death and the area under the 2-h insulin curve; there were not enough deaths in that study to look at si te-specific cancers. In a prospective analysis from the Busselton study [16], hyperinsulinemia was a risk factor for cancer mortality among men aged 60-74 years at baseline, but not among women or younger men.

In French men, cancer death is more common than cardiovascular death [17], a trend also seen in the Paris Prospective Study cohort. In this study, we explored whether peripheral insulin concentrations were a risk factor for death from site-specific cancers over 23.8 years of follow-up in a cohort of middle-aged working men.

RESEARCH DESIGN AND METHODS

Subjects and methods

The 6,237 men studied were ages 44-55 years at baseline and had undergone a 75-g oral glucose tolerance test. They were all followed up for vital status, had no missing data for the baseline variables, and were not diabetic (i.e., were not being treated for diabetes and had fasting glucose [less than]7.0 mmol/l and 2-h glucose [less than]11.1 mmol/l) [18]. Blood pressure was measured with the subjects in a seated position, and BMI was determined. The men were questioned about current and previous smoking habits, from which we reported an index of mean tobacco intake over the previous 5 years. The erythrocyte mean corpuscular volume (MCV) was used as a measure of alcohol consumption in this analysis [19], and some men were classified at baseline as chronic alcohol users, based on the judgment of the examining physician.

Follow-up methods

Follow-up for vital status and causes of death were complete until the end of 1993, an average follow-up of 23.8 years. Enquiries were made through official sources to ascertain the date of death of deceased subjects; revisions 8 and 9 of the International Classification of Diseases (ICD) [20] were used to code the causes of death, which up until the end of 1988 were based on information from the treating physician, hospital records, and the family of the deceased. For those with missing causes of death before this date and for deaths after 1989, the officially certified causes of death were used.

The 6,237 men studied differed significantly from the 1,068 men with missing vital status or values on some variables: mean age, 47.0 vs. 47.2 years (P [less than] 0.05); smokers, 58 vs. 61% (P [less than] 0.01); chronic alcohol users, 5 vs. 8% (P [less than] 0.001).

Statistical analysis

The characteristics of the men according to vital status and causes of death were compared by analysis of variance; the logarithms of the insulin concentrations were used to ensure more symmetric distributions. Standardized hazards ratios from Cox proportional hazards models were used to describe the age-adjusted effect of baseline fasting and 2-h insulin concentrations (one standard deviation change in the logarithm of the insulin concentrations). Men with missing causes of death or causes other than cancer were censored. The log-likelihood ratios were used to test whether a quadratic term in the insulin concentrations was statistically significant and should be included in the Cox model for all site-specific cancer deaths. Further adjustment was made for other possible risk factors: BMI, tobacco smoking (never, ex-smoker, and [less than or equal to] and [greater than]20 cigarettes per day), erythrocyte MCV and chronic alcohol use, and all factors together (all the aforementioned factors as well as glucose c oncentrations and systolic blood pressure). For those cancers that were negatively and significantly related with insulin concentrations, the insulin-cancer relationship was studied in the subgroup of smokers and in the men who were not likely to be very heavy alcohol consumers. Analysis of covariance was used to examine the age- and age-and BMI-adjusted mean insulin concentrations, according to smoking habits. In additional analyses, only those men dying of cancer [greater than or equal to]5 years after baseline were analyzed to be more certain of the time sequence between hyperinsulinemia and cancer. SAS software was used for all analyses.

RESULTS -- After 23.8 years of follow-up, 1,739 of the 6,237 men had died; the most common cause of death was neoplasm-related (45%), followed by circulatory causes (30%). The site-specific cancer deaths were grouped according to the major ICD categories [20], and the characteristics of the men studied were grouped according to whether they were still alive or had died from circulatory fatal causes or fatal cancers (Tables 1 and 2). Tobacco and alcohol intake was high in the men with fatal lip, oral cavity, and pharynx cancer; esophagus cancer; and larynx cancer. Tobacco intake alone was high in men with fatal trachea, bronchus, and lung cancer; bladder cancer; kidney cancer; and cancers of secondary and unspecified sites.

After adjusting for age, fasting hyper-insulinemia did not have a significant linear effect on mortality from all neoplasms (Table 3), but there was a significant overall curvilinear relationship ([[chi].sup.2] = 8.4; df = 2; P [less than] 0.02) (Fig. 1A). For the 2-h insulin concentration, the relationship was negative, with an age-adjusted standardized hazards ratio of 0.91 (95% CI 0.85-0.98), but there was no statistically significant curvilinearity and no dosage-response relationship (Fig. 1B).

Fatal lip, oral cavity, and pharynx cancers were inversely associated with both fasting and 2-h hyperinsulinemia (hazards ratios 0.55 [CI 0.41-0.75]) and 0.75 [0.55-1.02], respectively) (Table 3). There were nonsignificant trends for fasting insulin, with an inverse relationship to esophagus cancer (hazards ratio 0.74 ([0.55-1.01]) and positive relationships for fatal colorectal and pancreatic cancers (hazards ratios 1.22 [0.95-1.56] and 1.18 [0.84-1.66], respectively). The 2-h insulin level was inversely associated with stomach cancer (hazards ratio 0.62 ([0.43- 0.90]). There were no significant curvilinear relations with any of these cancers.