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"It was the combined effect of smoking and treatment that accounted for the bulk of lung cancers in this study, underscoring the importance of smoking cessation in the management of patients with Hodgkin's disease," the authors conclude. "It is clear that the tremendous improvement in the treatment of HD far outweighs any therapy-related risks of lung cancers, especially when compared with the enormous burden imposed by tobacco," said Lois Travis, M.D., Sc.D., of the National Cancer Institute's Division of Cancer Epidemiology and Genetics in Bethesda, Md., and first author of the study.
While 7,000 people a year are diagnosed with HD in the United States, it is among the more treatable and curable types of cancer. Second cancers, which can arise after a patient is diagnosed with HD, constitute the number one cause of death in these patients. Lung cancer is the most frequent solid tumor seen in this group. However, data on the reasons behind the increased risk have been sparse and inconsistent.
For this study, the researchers looked at many different factors, but focused on three main measures: the type and cumulative amount of chemotherapy drugs, the radiation dose, and tobacco use. All three exposures contributed significantly to elevated lung cancer risks. Tobacco use, chemotherapy, and radiotherapy doses of five Gray (Gy) or more were reported in 96 percent, 63 percent, and 53 percent of case subjects (those who developed lung cancer), respectively, and in 70 percent, 52 percent, and 41 percent of patients who did not develop lung cancer.
Subjects who received either radiotherapy alone or chemotherapy with drugs called alkylating agents experienced a significantly increased risk of lung cancer. And when researchers looked at the group of patients who received both alkylating agents and radiotherapy, the numbers showed risks that were additive.
"We found that chemotherapy for Hodgkin's disease specifically treatment with alkylating agents increases risk four-fold and radiation treatment (radiotherapy) increases the risk of lung cancer almost six-fold, said Travis. "When the number of cycles and dose of either type of treatment increased, risk increased again. When we examined the combined effects of chemotherapy and radiotherapy, the risk was approximately eight-fold, suggesting that combination therapy may increase lung cancer risk in an additive fashion."
Researchers also demonstrated that lung cancer risk increased with increasing total amounts of either alkylating agents or radiotherapy dose.
In order to conduct the study, researchers from several countries collaborated to assemble over 19,000 patients diagnosed with HD between 1965 and 1994. This large group of patients represents a unique cohort, comprising information from seven cancer registries: two in the United States, one in Canada, three in Scandinavia and one in the Netherlands. Within this group, scientists identified 222 case subjects who developed lung cancer and 444 control subjects who did not develop lung cancer. In order to better examine the risk factors for lung cancer in HD patients, the researchers compared these two groups to each other, in what is called a case-control study.
Researchers also wanted to quantify the role of smoking and tobacco use in the development of lung cancer in this group. Of the lung cancers that were diagnosed, researchers estimated that approximately 10 percent were due to treatment alone, 63 percent were due to
treatment and smoking combination, 24 percent were due to smoking alone, and 3 percent were cases in which neither smoking nor therapy played a role.
In contrast to the effect of combined treatment, which showed that risks were additive with combined therapy, smoking appeared to multiply the risk of lung cancer. The largest risks for lung cancer were seen in individuals who were heavy smokers and received both radiotherapy and alkylating agents.
While the findings are consistent with the established role of tobacco in lung cancer, researchers warn that the estimated risks for treatment-associated lung cancer should be interpreted with caution. Radiotherapy and chemotherapy information was readily available in the reviewed records, but information on smoking habits was not recorded in an optimal format for retrospective studies. Additionally, because of the small number of lung cancers in nonsmokers, the interaction of chemotherapy and/or radiation with tobacco use could be evaluated only by comparing moderate-to-heavy smokers with all other patients combined.
The study also provides new information regarding the time to development of lung cancer following treatment for Hodgkin's disease. Researchers found that excess lung cancers diagnosed after chemotherapy treatment with alkylating agents occurred as early as one to four years after the first treatment. In contrast, increases in lung cancers diagnosed after radiotherapy were first noted five years after treatment and persisted for over 20 years.
Researchers plan to continue to follow the study group, since many questions remain unanswered. The way alkylating agents, a cornerstone of current HD treatment, contribute to the development of lung cancer is not entirely clear. Although several possible mechanisms were reviewed in the study, future research should address this issue and also explore whether the immunology associated with Hodgkin's disease might also somehow contribute to secondary lung cancer, and whether tissue damage and repair mechanisms seen after radiotherapy may play a role, as well.
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