BACKGROUND: Lung cancer is a frequent cause of death in patients cured of 
Hodgkin's disease, but the contributions of chemotherapy, radiotherapy, and 
smoking are not well described. We quantified the risk of treatment-associated 
lung cancer, taking into account tobacco use.
METHODS: Within a population-based cohort of 19 046 Hodgkin's disease patients 
(diagnosed from 1965 through 1994), a case-control study of lung cancer was 
conducted. The cumulative amount of cytotoxic drugs, the radiation dose to the 
specific location in the lung where cancer developed, and tobacco use were 
compared for 222 patients who developed lung cancer and for 444 matched control 
patients. All statistical tests were two-sided.
RESULTS: Treatment with alkylating agents without radiotherapy was associated 
with increased lung cancer risk (relative risk [RR] = 4.2; 95% confidence 
interval [CI] = 2.1 to 8.8), as was radiation dose of 5 Gy or more without 
alkylating agents (RR = 5.9; 95% CI = 2.7 to 13.5). Risk increased with both 
increasing number of cycles of alkylating agents and increasing radiation dose 
(P for trend <.001). Among patients treated with mechlorethamine, vincristine, 
procarbazine, and prednisone (MOPP), risk increased with cumulative amounts of 
mechlorethamine and procarbazine (P<.001) when evaluated separately. 
Statistically significantly elevated risks of lung cancer were apparent within 
1-4 years after treatment with alkylating agents, whereas excess risk after 
radiotherapy began 5 years after treatment and persisted for more than 20 years. 
Risk after treatment with alkylating agents and radiotherapy together was as 
expected if individual excess risks were summed. Tobacco use increased lung 
cancer risk more than 20-fold; risks from smoking appeared to multiply risks 
from treatment.
CONCLUSIONS: Past treatments with alkylating agents and radiation therapy for 
Hodgkin's disease were associated with an increased risk of lung cancer in a 
dose-dependent and additive fashion. The precise risk estimates, however, should 
be interpreted cautiously, given the possible residual and enhancing effects of 
tobacco.