Smoking is not considered a risk factor for chronic lymphocytic leukemia (CLL) yet increased lung cancer risk has been reported for these patients. Little data exist on the temporal variation in lung cancer risk after CLL, or its histological composition. We investigated the occurrence of second cancers in a large cohort of CLL patients with particular emphasis on lung cancer and its major subtypes. We followed all patients diagnosed with CLL in Denmark in the period 1943-2003 (n 5 12,373) for the occurrence of second cancers. The relative risk was expressed as the standardized incidence ratio (SIR), i.e. the ratio of observed to expected number of cancers, based on incidence rates for the Danish population. During follow-up 1,105 cancers occurred among the CLL patients (SIR 5 1.59 (95% CI 1.50-1.69)). SIR for all cancers combined remained elevated more than 10 years after CLL (SIR 5 1.80 (1.56-2.08)). Lung cancer occurred in 141 patients (SIR 5 1.61 (1.37-1.90)). The relative risk of lung cancer did not vary by gender, or time of follow-up, but was higher in younger (SIR <60 years 5 2.22 (1.62-3.06)) than in older (SIR 70-79 years 5 1.21 (0.88-1.68)) age-groups. Elevated risks were observed for adenocarcinoma (SIR 5 2.20 (1.57-3.08)) and squamous cell carcinoma (SIR 5 1.52 (1.06-2.17)) of the lung. We speculate that shared genetic risk factors may explain the accumulation of lung and other cancers in CLL patients. ' 2007 Wiley-Liss, Inc.Key words: CLL; second cancer; cohort study; epidemiology In Western countries chronic lymphocytic leukemia (CLL) accounts for 25-30% of all leukemias.1 Clinically the disease varies substantially: while in many patients it remains indolent with no need for treatment, in others it displays an aggressive clinical course. Consequently the 7-years median survival time for CLL ranges from a few months to several decades. 2The causes of CLL largely have remained unestablished, 3-5 but there is increasing evidence that its development involves both constitutional and environmental factors. 6,7 Little is known about the nature of these factors, but important clues could emanate from studies of comorbidity in CLL patients, e.g. the occurrence of second cancers.Previous studies have indicated that patients with CLL have an increased risk of subsequent cancer, in particular cancers of the skin and lung. [8][9][10][11][12] Several mechanisms have been discussed for the association between these cancers. The increased risk of lung cancer is particularly noteworthy, because smoking has so far not been linked with CLL risk. 13,14 In previous Danish 11 and American 10 studies, the increased risk of lung cancer was found to be independent of time since CLL diagnosis, leading to the conclusion that it could not be attributed to CLL treatment offered no explanation for the observed increased lung cancer risk. However, concomitant with the introduction of new treatment strategies including the nucleoside analog Fludarabine, other studies have reported both increased risk of lung cancer, 15-17 an...
Background: Studies have shown that patients with chronic lymphocytic leukemia (CLL) are at increased risk of developing second lung cancer. The underlying mechanisms for this increased risk have yet not been identified. Risk factors may differ between histological lung cancer subtypes. However, though relevant to the clarification of the association between the two malignancies, little is known about the lung cancer subtype distribution in CLL patients. Methods: We investigated the occurrence of second lung cancer overall and its major histological subtypes in all patients diagnosed with CLL in Denmark between 1943 and 1999 in a retrospective registry-based cohort study. The relative risk was expressed as the standardized incidence ratio (SIR), i.e. the ratio of the observed to the expected number of lung cancer cases, based on age-, sex-, and calendar year specific incidence rates for the Danish population, available from the Danish Cancer Registry. Results: Overall, 9,541 patients diagnosed with CLL between 1943 and 1999 were followed for lung cancer occurrence. The median age at onset was 70 years and the male-to-female ratio was 1.6. Second lung cancer occurred in 147 patients (122 men and 25 women) during 36,604 person-years of follow-up (median 2.5 years) corresponding to a statistically significantly increased relative risk (SIR=1.83, 95% CI 1.55–2.15). There was no difference in risk between women and men (phom=0.27). The relative risk for lung cancer varied slightly by age at CLL being particularly high in younger age groups (≤59 years SIR=2.18 (1.53–3.10), 60–69 years SIR=2.26 (1.78–2.86), 70–79 years SIR=1.28 (0.93–1.76), ≥80 years SIR=1.51 (0.79–2.90); phom=0.02). In contrast, SIR for lung cancer did not vary by time since CLL diagnosis (phom=0.64). In 95 cases (72 men, 23 women) of second lung cancer information about major histological subtypes were available. We found a statistically significantly elevated risk for all major subtypes, except small-cell carcinoma (adenocarcinoma SIR=2.85 (2.04–3.99), large-cell carcinoma SIR=2.31 (1.04–5.15), squamous cell carcinoma SIR=2.30 (1.68–3.14), small cell carcinoma SIR=1.47 (0.90–2.39)). Discussion: In one of the largest and most detailed register-based cohort studies so far, we found an increased occurrence of lung cancer among CLL patients, which was apparent for major lung cancer subtypes. While increased medical surveillance of the CLL patients cannot be ruled out as explanation for the increased risk, the uniform distribution over time since CLL diagnosis suggests that it is unrelated to initial therapy. Tobacco smoking is the major risk factor in lung cancer. Data on smoking history were not available in our study, however, previous studies suggest that smoking is not associated with CLL. Family aggregation found for both lung cancer and CLL may indicate hereditary predisposition to the two conditions. Furthermore, individual susceptibility to malignant diseases may be influenced by polymorphisms in enzymes metabolizing carcinogenes, suggested independently for CLL and lung cancer. Given the prolonged survival of patients with CLL, further studies are needed to address the causal relationship between CLL and second malignancies, including lung cancer.
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