Smoking, Treatment for Hodgkin's Disease, and Subsequent Lung Cancer Risk
Authors: J.-F. Boivin
Journal: JNCI Journal of the National Cancer Institute (1995)

In this issue of the Journal, van Leeuwen et al. (/) reported a study of the effect of treatment of Hodgkin's disease and of smoking on subsequent lung cancer risk. Until now, research on secondary cancers in patients with Hodgkin's disease has almost exclusively focused on the effect of radiotherapy, chemotherapy, and splenectomy. The data provided by van Leeuwen et al. (V) bring new information in a relatively unexplored domain. A review of this article suggests that several issues need further clarification, including the measurement of smoking, particularly prior to the diagnosis of Hodgkin's disease, the assessment of interaction between smoking and radiation, and the choice of appropriate reference categories, which are discussed below. van Leeuwen et al. (1) collected smoking information from medical records, from questionnaires mailed to general practitioners, and, in a certain number of cases, from the patients themselves. The authors indicate that complete smoking history was obtained for 90% of the study population, but, as they also acknowledge, this does not preclude the presence of misclassification and, therefore, bias. The assessment of smoking through medical records or from physicians can be highly inaccurate. For example, one should be alert to possibilities of bias arising from the potential availability of more thorough information on cases of lung cancer than on controls, as was found by others (2,5). Similarly, the stronger association observed by van Leeuwen et al. (/) for smoking since diagnosis of Hodgkin's disease than for smoking before diagnosis or for lifetime smoking could be explained by a more accurate measurement of recent smoking habits than of more distant smoking habits. In spite of this, however, the expected finding of a smoking effect on lung cancer risk in these patients suggests that the available smoking information was reasonably accurate. Lung cancer risk was also found to increase with radiation dose. In subgroup analyses, the dose-response trend was statistically significant among those who smoked 1 or more pack-years after the diagnosis of Hodgkin's disease but not among those who smoked less or did not smoke, this observation suggested to the investigators the presence of a positive interaction between smoking and radiation. A strength of this study was that doses of radiation and of smoking were obtained, allowing analyses of interaction that would most likely have been impossible with simple dichotomous classifications of subjects as exposed or unexposed to smoking or to radiotherapy. In spite of this, however, the interpretation of the data as showing interaction must be examined cautiously. One difficulty is that the observed trends rest on some very small numbers. In two smoking-radiation categories, only one case was available. In addition, an examination of the point estimates of the relative risks (RRs) does not support the interpretation of the results as showing positive interaction. For the sake of illustration, the following RRs from the authors' Table 3 can be used: 0 or  5 Gy: RR = 2.5; >1 pack-years and 1-5 Gy: RR = 7.7; >1 pack-years and >5 Gy: RR = 9.1. The first category, 0 or <1 pack-year and 1-5 Gy, with an RR of unity, can be used for our purposes as the reference group. In a multiplicative model, a positive interaction would be present if the RR for the heavier smokers exposed to larger doses of radiation exceeded 19.3, i.e., 2.5 times 7.7. An RR of 9.1 was actually observed, suggesting, if anything, the presence on a multiplicative scale of a negative interaction. It can be argued, however, that, in the analysis of causal relationships in epidemiology, departure from additivity of rates represents a more relevant criterion to assess interaction than departure from multiplicativity (4). In case-control studies, additivity of rates can be assessed through estimates of the excess RR, i.e., RR minus 1 (4,5). In these data, the four excess RRs are then 0.0 (by definition), 1.5,6.7, and 8.1, respectively. If rates were additive, persons who smoked 1 or more pack-years and were exposed to 5 Gy or more would be expected to have an excess RR of 1.5 + 6.7 = 8.2, translating into an RR of 9.2 (= 8.2 + 1.0), which is practically exactly what van Leeuwen et al. (J) found. This approach leads to a conclusion of absence of interaction between smoking and radiation. All study subjects included in the analysis had received radiotherapy or chemotherapy or both. This feature of the study is important in the interpretation of the results. In particular, in the analysis of the association between chemotherapy and lung cancer risk, most subjects in the reference group had received radiotherapy to the chest. Because chest irradiation is itself associated with an increased risk of lung cancer, weak carcinogenic effects of drugs can be masked, van Leeuwen et al. (/) were, however, able to correct for the effect of chest radiotherapy because radiation dose had been obtained, allowing the inclusion of a radiation coefficient in their multivariate models; this analysis represents a good example of the usefulness of doseresponse data to control for potential confounding. This statistical correction requires, however, the assumption that the extrapolation of the dose effect to unexposed subjects is valid. Further research is clearly required on this question; at least two previous studies (2,6) have suggested that chemotherapy may be associated with an increased lung cancer risk, and alternative