Background: Several studies have shown that survivors of Hodgkin's disease have increased risk of lung cancer, but the factors responsible for this excess risk are not well known.
Purpose: This study was undertaken to investigate the effects of radiation dose, chemotherapy, and smoking on the risk of lung cancer following treatment of Hodgkin's disease.
Methods: We conducted a case-control study in a cohort of 1939 patients treated for Hodgkin's disease from 1966 through 1986 in The Netherlands. Detailed treatment information was collected from the medical records for 30 case patients with lung cancer following Hodgkin's disease and 82 matched control subjects who had not developed lung cancer. Multiple sources were used to obtain as complete smoking histories of the study participants as possible. For each case-control set, the radiation dose received by the area of the lung where the case patient developed the tumor was estimated on the basis of radiotherapy charts and experimental simulations of treatments. The estimates of relative risk (RR) for lung cancer associated with specific exposures were obtained from logistic regression methods, and all tests of statistical significance were two-sided.
Results: A statistically significant increase in risk of lung cancer was observed with increasing radiation dose (P for trend = .01) with an RR of 9.6 (95% confidence interval [CI] = 0.93-98) for patients who received 9 Gy or more compared with those who received less than 1 Gy. Patients who smoked more than 10 pack-years after the diagnosis of Hodgkin's disease had a sixfold increase in the risk of lung cancer compared with patients who smoked less than 1 pack-year (P = .03). Positive interaction on a multiplicative scale was observed between the carcinogenic effects of smoking and radiation. The increase in risk of lung cancer with increasing radiation dose was much greater among the patients who smoked after diagnosis of Hodgkin's disease than among those who refrained from smoking (P = .04). There was no increase in lung cancer risk in relation to the number of cycles of chemotherapy or the cumulative doses of the drugs mechlorethamine and procarbazine.
Conclusions: The excess risk of lung cancer in Hodgkin's disease patients treated with radiotherapy is related to the radiation dose received by the affected area of the lung. Smokers experience a significantly greater risk attributable to radiotherapy than nonsmokers.
Implications: Physicians in charge of patient treatment should make a special effort to dissuade Hodgkin's disease patients from smoking after receiving radiotherapy.