Roles of radiotherapy and smoking in lung cancer following Hodgkin's disease.

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.

Leukemia risk following Hodgkin's disease: relation to cumulative dose of alkylating agents, treatment with teniposide combinations, number of episodes of chemotherapy, and bone marrow damage.

PURPOSE: The development of leukemia is one of the most serious long-term complications of modern treatment for Hodgkin's disease (HD). This study was undertaken to examine the relation between risk of leukemia and various treatment factors (including cumulative dose of cytostatic drugs and interaction with radiotherapy [RT]), while also assessing the effect of treatment-induced bone marrow damage. PATIENTS AND METHODS: We conducted a case-control study in a cohort of 1,939 patients treated for HD between 1966 and 1986 in the Netherlands. Detailed information from the medical records was obtained for 44 cases of leukemia and 124 matched controls, in whom leukemia had not developed. RESULTS: The cumulative dose of mechlorethamine was the most important factor in determining leukemia risk. As compared with patients who received RT alone, patients treated with six or fewer cycles of combinations including nitrogen mustard (mechlorethamine) and procarbazine had an eightfold increased risk of developing leukemia (P = .08), while patients who received more than six of such cycles had a greater than 40-fold excess risk (P < .001). Treatment with lomustine or a combination of teniposide and cyclophosphamide also significantly increased the risk of leukemia. Patients who had received chemotherapy (CT) during two or more time periods had a nearly 40-fold increased risk of leukemia as compared with patients treated only once. The extent of RT did not further increase leukemia risk among patients who also received CT. A significantly increased risk of leukemia was found among patients with low platelet counts, both in response to initial therapy and during follow-up. Patients who experienced 2 or more half-year periods with platelet counts less than 75 x 10(6)/mL had an approximately fivefold risk of developing leukemia, and a similar risk increase was found for patients who responded to initial treatment with a > or = 70% decrease of platelet counts (as compared with patients who had a < or = 50% decrease). CONCLUSION: In addition to mechlorethamine, lomustine and teniposide combinations were also linked to an elevated risk of developing leukemia. Since the number of CT episodes was found to be a strong determinant of leukemia risk, it is important that new therapies for HD continue to yield high initial cure rates. Further studies are warranted to investigate whether patients at high risk for developing leukemia may be identified from the response of their platelets to initial therapy for HD.

Second cancer risk following Hodgkin's disease: a 20-year follow-up study.

PURPOSE: To determine risk factors for the development of second primary cancers during long-term follow-up of patients with Hodgkin's disease (HD). PATIENTS AND METHODS: We assessed the risk of second cancers (SCs) in 1939 HD patients, who were admitted to the Netherlands Cancer Institute (NKI; Amsterdam) or the Dr Daniel den Hoed Cancer Center (DDHK; Rotterdam) between 1966 and 1986. For 97% of the cohort, we obtained a medical status up to at least January 1989. The median follow-up duration of the patients was 9.2 years; for 17% of the patients, follow-up was longer than 15 years. For more than 98% of all second tumors, the diagnosis was confirmed through a pathology report. RESULTS: In all, 146 patients developed a SC, compared with 41.9 cases expected on the basis of incidence rates in the general population (relative risk [RR], 3.5; 95% confidence interval [CI], 2.9 to 4.1). The mean 20-year actuarial risk of all SCs was 20% (95% CI, 17% to 24%). Significantly increased RRs were observed for leukemia (RR, 34.7; 95% CI, 23.6 to 49.3), non-Hodgkin's lymphoma (NHL) (RR, 20.6; 95% CI, 13.1 to 30.9), lung cancer (RR, 3.7; 95% CI, 2.5 to 5.3), all gastrointestinal cancers combined (RR, 2.0; 95% CI, 1.2 to 3.1), all urogenital cancers combined (RR, 2.4; 95% CI, 1.4 to 3.7), melanoma (RR, 4.9; 95% CI, 1.6 to 11.3), and soft tissue sarcoma (RR, 8.8; 95% CI, 1.8 to 25.8). As compared with the general population, the cohort experienced an excess of 63 cancer cases per 10,000 person-years. Cox-model analysis indicated the following as significant risk factors for developing leukemia: first-year treatment with chemotherapy (CT), follow-up treatment with CT, age at diagnosis of HD greater than 40 years, splenectomy, and advanced stage. Patients treated with CT in the 1980s had a substantially lower risk of leukemia than patients treated in the 1970s (10-year actuarial risks of 2.1% and 6.4%, respectively; P = .07). Significant risk factors for NHL were older age, male sex, and combined modality treatment as compared with either modality alone. Risk of lung cancer was strongly related to radiotherapy (RT), while an additional role of CT could not be demonstrated. After more than 15 years of follow-up, women treated with mantle-field irradiation before age 20 years had a greater than forty-fold increased risk of breast cancer (P < .001). CONCLUSION: While the long-term consequences of HD treatment as administered in the 1960s and 1970s are still evolving, it is promising that patients who received the new treatment regimens introduced in the 1980s have a much lower leukemia risk than patients treated in earlier years. Beginning 10 years after initial RT, the follow-up program of women who received mantle-field irradiation before age 30 years should routinely include breast palpation and yearly mammography.

Second cancer risk following testicular cancer: a follow-up study of 1,909 patients.

PURPOSE: Improved survival in testicular cancer has been accompanied by concern about long-term side effects of therapy. We assessed the evolution of second cancer (SC) risk over a prolonged follow-up period, which has been rarely studied in large patient series. PATIENTS AND METHODS: We estimated the risk of SCs in 1,909 patients with testicular cancer diagnosed in the Netherlands from 1971 to 1985. Complete medical information was obtained up to at least January 1988 for 92% of patients. Median follow-up was 7.7 years. For 89% of second tumors the diagnosis was confirmed through review of histologic slides; for an additional 8%, the diagnosis was verified by pathology reports only. RESULTS: Seventy-eight patients developed a SC 1 year or more after start of treatment, as compared with 47.6 expected on the basis of incidence rates in the general population (relative risk [RR], 1.6; 95% confidence interval [CI], 1.3 to 2.1). The mean 15-year actuarial risk of all SCs was 9.8% (95% CI, 7.5% to 12.8%). Significantly increased RRs were observed for all gastrointestinal cancers combined (RR, 2.6; 95% CI, 1.7 to 3.9), stomach cancer (RR, 3.7; 95% CI, 1.8 to 6.8), contralateral testicular cancer (CLTC) (RR, 35.7; 95% CI, 21.8 to 55.2), and leukemia (RR, 5.1; 95% CI, 1.4 to 13.0). Patients who had received irradiation to the paraaortic lymph nodes and who survived testicular cancer for more than 5 years were at particularly high risk of developing stomach cancer (RR, 6.9; 95% CI, 3.3 to 12.7). The median interval between the diagnosis of testicular cancer and stomach cancer was 12.4 years. Patients treated with chemotherapy (CT) did not experience an increase in SCs in general. Indeed, CT-treated patients, as compared with those who received radiotherapy (RT), or surgery alone, had significantly reduced risk of CLTC. This finding might be attributed to an eradicating effect of CT on carcinoma in situ or subclinical CLTC. The excess risk of leukemia was not found to be clearly related to CT. CONCLUSION: Testicular cancer patients who receive RT experience elevated risk of gastrointestinal tumors. CT does not seem to increase SC risk and may even decrease the risk of a CLTC. Following testicular cancer, the 15-year actuarial risk of all SCs is only about half the risk experienced by patients with Hodgkin's disease.