Incidence of second cancers in patients treated for Hodgkin's disease.

BACKGROUND: Numerous studies of treatment for Hodgkin's disease have demonstrated large increases in the incidence of leukemia in the early years following chemotherapy, although the duration of effect and the specific agents involved are not well understood. Also, some, but not all, studies have indicated that the incidence of certain solid tumors increases following treatment for Hodgkin's disease. PURPOSE: We studied the association between treatment for Hodgkin's disease and the incidence of second cancers. METHODS: We conducted a study within a cohort that included 10,472 patients from 14 cancer centers in the United States and Canada who were first diagnosed as having Hodgkin's disease at some point from 1940 through 1987. Discounting the 1st year after diagnosis, the average length of follow-up was 7.1 years per subject. RESULTS: We observed 122 leukemias and 438 solid tumors. The relative risk (RR) of leukemia following chemotherapy, compared with no chemotherapy, was 14 (95% confidence interval [CI] = 5.6-35). Increased risks of leukemia were observed after treatment with chlorambucil (RR = 2.0; 95% CI = 1.1-3.6), procarbazine (RR = 4.9; 95% CI = 2.6-9.1), vinblastine (RR = 1.7; 95% CI = 1.1-2.8), and a group of rarely used drugs that included methotrexate, vindesine, etoposide, and 22 others (RR = 3.8; 95% CI = 1.9-7.4). RRs were also estimated for various combinations of drugs, including MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) (RR = 5.9; 95% CI = 2.9-12) and ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) (RR = 1.5; 95% CI = 0.7-3.4). The RR of leukemia associated with splenectomy was 1.6 (95% CI = 1.0-2.5). The RR of solid tumors following chemotherapy was 1.4 (95% CI = 1.1-1.8). For the group of rarely used drugs, the RR of solid tumors was 3.1 (95% CI = 1.7-5.8). Chemotherapy was associated with an increased risk of cancers of the bones, joints, articular cartilage, and soft tissues (RR = 6.0; 95% CI = 1.7-20), and cancers of the female genital system (RR = 1.8; 95% CI = 1.1-3.2). In patients followed for 10 or more years after radiotherapy, increased risks were found for cancers of the respiratory system and intrathoracic organs (RR = 2.7; 95% CI = 1.1-6.8) and for cancers of the female genital system (RR = 2.4; 95% CI = 1.1-5.4). CONCLUSIONS: Procarbazine, chlorambucil, and vinblastine are associated with increased leukemia risk. Combination drug regimens have leukemogenic effects estimated as the product of RRs for individual drugs. Chemotherapy and radiotherapy increase the risk of selected solid tumors, and the effect of chemotherapy on solid tumor risk is weaker than the leukemogenic effect. IMPLICATIONS: Without doubt, the benefits of treatment of Hodgkin's disease outweigh the risk of a subsequent malignancy, but data on the carcinogenic effects of radiation and drugs beyond 10 years after treatment continue to be sparse, and future analyses should be directed at long-term survivors.

Non-Hodgkin's lymphoma and occupational exposure.

A case-control study was conducted to assess the effect of occupational exposures on the risk of non-Hodgkin's lymphoma. Interviews were conducted with 303 persons with non-Hodgkin's lymphoma newly diagnosed from January 1, 1980, to May 31, 1982, among residents of the Boston, MA, metropolitan area and 303 age and gender matched controls. The study found an increased risk of disease among persons employed in the agriculture, forestry, and fishing industry [relative risk (RR) = 3.0]; the construction industry [RR = 2.1]; and the leather industry [RR = 2.1]. The particular job groupings at increased risk were plant farmers and gardeners (RR unbounded); painters and plasterers (RR = 6.0); and carpenters, brick and stone masons, plumbers, and roofers (RR = 12.0). Although other exposures may have led to these increased risks, the findings in this study are consistent with an increased risk of non-Hodgkin's lymphoma for workers who may be exposed to chlorophenols or phenoxyacetic acids.

Coronary artery disease mortality in patients treated for Hodgkin's disease.

The authors conducted a follow-up study of the association between mediastinal irradiation, chemotherapy, and mortality from coronary artery disease in 4665 patients treated for Hodgkin's disease. Study subjects were followed after the diagnosis of Hodgkin's disease until death or the closing date of the study. The average duration of follow-up was 7 years; 2415 patients died, and 124 cases of coronary artery disease were identified from death certificates, including 68 cases of acute myocardial infarction. The age-adjusted relative risks (RR) of death with any coronary artery disease after mediastinal irradiation and after chemotherapy were 1.87 (95% confidence interval [CI], 0.92 to 3.80) and 1.28 (CI, 0.77 to 2.15), respectively. A significantly increased risk of death in the subcategory myocardial infarction was observed after mediastinal irradiation (RR, 2.56; CI, 1.11 to 5.93) but not after chemotherapy (RR, 0.97; CI, 0.53 to 1.77). These results support the hypothesis that radiation therapy to the mediastinum increases the risk of coronary artery disease.

Issues in the early termination of the aspirin component of the Physicians' Health Study. Data Monitoring Board of the Physicians' Health Study.

The Physicians' Health Study is a randomized, double-blind, placebo-controlled prevention trial of 22,071 US physicians, using a factorial design to evaluate the role of aspirin in the prevention of cardiovascular mortality and beta carotene in the reduction of cancer incidence. After approximately 5 years of follow-up, the aspirin component was terminated, 3 years ahead of schedule. Several factors were considered in the decision to terminate, including a cardiovascular mortality rate markedly lower than expected in both aspirin and placebo subjects, precluding the evaluation of the primary aspirin hypothesis, and a highly significant (P < .00001) and impressive (44%) reduction in the risk of first myocardial infarction in the aspirin group. Issues in the decision to terminate are described in this report.

Radiation dose and breast cancer risk in patients treated for cancer of the cervix.

The relationship between breast cancer and radiation treatment for cervical cancer was evaluated in an international study of 953 women who subsequently developed breast cancer and 1,806 matched controls. Radiation doses to the breast (average 0.31 Gy) and ovaries (average 32 Gy) were reconstructed for exposed subjects on the basis of their original radiotherapy records. Overall, 88% of the breast cancer cases and 89% of the controls received radiation treatment [relative risk (RR) = 0.88; 95% confidence interval (CI) = 0.7-1.2]. Among women with intact ovaries (561 cases, 1,037 controls), radiotherapy was linked to a significant 35% reduction in breast cancer risk, attributable in all likelihood to the cessation of ovarian function. Ovarian doses of 6 Gy were sufficient to reduce breast cancer risk but larger doses did not reduce risk further. This saturation-type response is probably due to the killing of a critical number of ovarian cells. Cervical cancer patients without ovaries (145 cases, 284 controls) were analyzed separately because such women are at especially low natural risk for breast cancer development. In theory, any effect of low-dose breast exposure, received incidentally during treatment for cervical cancer, should be more readily detectable. Among women without ovaries, there was a slight increase in breast cancer risk (RR = 1.07; 95% CI = 0.6-2.0), and a suggestion of a dose response with the RR being 1.0, 0.7, 1.5 and 3.1 for breast doses of 0, 0.01-0.24, 0.25-0.49 and 0.50+ Gy, respectively. However, this trend of increasing RR was not statistically significant. If low-dose radiation increases the risk of breast cancer among women over age 40 years, it appears that the risk is much lower than would be predicted from studies of younger women exposed to higher doses.

Radiation dose and second cancer risk in patients treated for cancer of the cervix.

The risk of cancer associated with a broad range of organ doses was estimated in an international study of women with cervical cancer. Among 150,000 patients reported to one of 19 population-based cancer registries or treated in any of 20 oncology clinics, 4188 women with second cancers and 6880 matched controls were selected for detailed study. Radiation doses for selected organs were reconstructed for each patient on the basis of her original radiotherapy records. Very high doses, on the order of several hundred gray, were found to increase the risk of cancers of the bladder [relative risk (RR) = 4.0], rectum (RR = 1.8), vagina (RR = 2.7), and possibly bone (RR = 1.3), uterine corpus (RR = 1.3), cecum (RR = 1.5), and non-Hodgkin's lymphoma (RR = 2.5). For all female genital cancers taken together, a sharp dose-response gradient was observed, reaching fivefold for doses more than 150 Gy. Several gray increased the risk of stomach cancer (RR = 2.1) and leukemia (RR = 2.0). Although cancer of the pancreas was elevated, there was no evidence of a dose-dependent risk. Cancer of the kidney was significantly increased among 15-year survivors. A nonsignificant twofold risk of radiogenic thyroid cancer was observed following an average dose of only 0.11 Gy. Breast cancer was not increased overall, despite an average dose of 0.31 Gy and 953 cases available for evaluation (RR = 0.9); there was, however, a weak suggestion of a dose response among women whose ovaries had been surgically removed. Doses greater than 6 Gy to the ovaries reduced breast cancer risk by 44%. A significant deficit of ovarian cancer was observed within 5 years of radiotherapy; in contrast, a dose response was suggested among 10-year survivors. Radiation was not found to increase the overall risk of cancers of the small intestine, colon, ovary, vulva, connective tissue, breast, Hodgkin's disease, multiple myeloma, or chronic lymphocytic leukemia. For most cancers associated with radiation, risks were highest among long-term survivors and appeared concentrated among women irradiated at relatively younger ages.

Radiation dose and leukemia risk in patients treated for cancer of the cervix.

To quantify the risk of radiation-induced leukemia and provide further information on the nature of the relationship between dose and response, a case-control study was undertaken in a cohort of over 150,000 women with invasive cancer of the uterine cervix. The cases either were reported to one of 17 population-based cancer registries or were treated in any of 16 oncologic clinics in Canada, Europe, and the United States. Four controls were individually matched to each of 195 cases of leukemia on the basis of age and calendar year when diagnosed with cervical cancer and survival time. Leukemia diagnoses were verified by one hematologist. Radiation dose to active bone marrow was estimated by medical physicists on the basis of the original radiotherapy records of study subjects. The risk of chronic lymphocytic leukemia, one of the few malignancies without evidence for an association with ionizing radiation, was not increased [relative risk (RR) = 1.03; n = 52]. However, for all other forms of leukemia taken together (n = 143), a twofold risk was evident (RR = 2.0; 90% confidence interval = 1.0-4.2). Risk increased with increasing radiation dose until average doses of about 400 rad (4 Gy) were reached and then decreased at higher doses. This pattern is consistent with experimental data for which the down-turn in risk at high doses has been interpreted as due to killing of potentially leukemic cells. The dose-response information was modeled with various RR functions, accounting for the nonhomogeneous distribution of radiation dose during radiotherapy. The local radiation doses to each of 14 bone marrow compartments for each patient were incorporated in the models, and the corresponding risks were summed. A good fit to the observed data was obtained with a linear-exponential function, which included a positive linear induction term and a negative exponential term. The estimate of the excess RR per rad was 0.9%, and the estimated RR at 100 rad (1 Gy) was 1.7. The model proposed in this study of risk proportional to mass exposed and of risk to an individual given by the sum of incremental risks to anatomic sites appears to be applicable to a wide range of dose distributions. Furthermore, the pattern of leukemia incidence associated with different levels of radiation dose is consistent with a model postulating increasing risk with increasing exposure, modified at high doses by increased frequency of cell death, which reduces risk.

Leukemia after radiotherapy for first primary cancers of various anatomic sites.

The authors conducted a case-control study designed to evaluate the association between radiotherapy for a first primary cancer and subsequent leukemia risk. Study subjects were selected from four tumor registries (California, Connecticut, Kansas, and Massachusetts). Cases were subjects with two primary cancers; the second cancer was a leukemia diagnosed one year or more after the diagnosis of the first primary cancer. Control subjects were patients with single cancers. Two control subjects were chosen for each case matched for tumor registry, site of the first primary cancer, date of diagnosis of the first primary cancer, age, sex, and duration of survival after the first primary cancer. Separate analyses were carried out for chronic lymphatic leukemia (166 cases) and all other leukemias (232 cases). The relative risk of chronic lymphatic leukemia after radiotherapy was 0.7 and did not differ significantly from unity. For all other leukemias, relative risks were 1.6 after radiotherapy for first primary cancers of all sites, 2.4 after radiotherapy to trunk sites, 2.2 after radiotherapy for breast cancer, and 10.3 after radiotherapy for cancer of the corpus uteri. These relative risks for leukemias other than chronic lymphatic leukemia all differed significantly from unity.

Dietary animal fat in relation to ovarian cancer risk.

Food and beverage frequency questionnaires were administered to 215 white women with epithelial ovarian cancer and to 215 control women matched by age, race, and residence. Women with ovarian cancer favored foods higher in animal fats and consumed significantly greater amounts of animal fat and significantly less vegetable fat compared with control subjects. Adjusted for potential confounding due to differences between case and control subjects in weight and parity, there was a significant trend for increasing risk for ovarian cancer with increasing animal fat consumption. No major differences were noted between patients and control subjects in coffee, alcohol, and tobacco use. Dietary factors may partially explain variation in the international incidence of this disease and suggest a new pathway for its etiology.

Second primary cancers following treatment of Hodgkin's disease.

A cohort study designed to evaluate the carcinogenicity of treatment for Hodgkin's disease (HD) was conducted. This report describes 2,591 patients with HD diagnosed in 1940-75 and presents an analysis of follow-up findings through 1978. Seventy-four second primary cancers (excluding basal cell and squamous cell cancers of the skin and in situ carcinomas of the cervix uteri) were observed 1 year or more after diagnosis of HD, including 21 leukemias. Twenty leukemias occurred after chemotherapy. The relative risk (RR) of leukemia after intensive chemotherapy with or without radiotherapy was 136 relative to general population incidence rates. In the subgroup with both intensive chemotherapy and intensive radiotherapy, the RR of leukemia was 125. Both RR estimates differed significantly from unity. The RR of cancers other than leukemia 10 years or more after intensive radiotherapy relative to no intensive therapy was 19.5 (95% confidence limits: 4.8-80).

Determinants of ovarian cancer risk. I. Reproductive experiences and family history.

Reproductive experiences and family history were assessed in 215 white females with epithelial ovarian cancer and in 215 control women matched by age, race, and residence. Pregnancy exerted a strong protective effect against ovarian cancer, which increased with the number of live-born children. After adjustment for parity, an effect of age at first live birth and breast-feeding was not apparent. Menstrual events did not differ significantly between cases and controls, although cases were more likely to have had an earlier menopause and less likely to have had a surgical menopause. Women with ovarian cancer had more frequently used menopausal hormones in cyclic fashion compared to controls. Regarding family history, women with ovarian cancer more frequently reported consanguinity in their ancestry and a highly frequency of primary relatives with cancer of the colon, lung, ovary, and prostate gland.

Factors affecting the association of oral contraceptives and ovarian cancer.

We investigated the relation between epithelial ovarian cancer and the use of oral contraceptives in a case-control study of 144 white women under the age of 60 who had ovarian cancer and 139 white women under 60 who were selected from the general population. We observed a decreased risk for ovarian cancer associated with the use of oral contraceptives in subjects 40 through 59 years of age at the time of the study. The relative risk, adjusted for parity, was 0.11, with 95 per cent confidence limits of 0.04 to 0.33. In contrast to the findings in older women, a decreased risk for ovarian cancer associated with oral-contraceptive use was not found in women under 40. In this group, the adjusted relative risk associated with any use of oral contraceptives was 1.98, with 95 per cent confidence limits of 0.74 to 5.27. The lowest risk for ovarian cancer associated with the use of oral contraceptives was observed in older parous subjects and in women who had discontinued use more than 10 years previously.

PIP: Results of a case-control study of histologically verified ovarian cancer including details about oral contraceptive (OC) use are presented. 144 white Massachusetts residents under age 60 with primary epithelial ovarian cancer were matched with 139 control women randomly selected from lists of Massachusetts residents who matched the cases by residence, age within 2 years, and race. Twice as many cases as controls were single and nulliparous. 34 cases had at some time used OCs compared with 48 controls. The relative risk of ovarian cancer associated with OC use, standardized for age and parity, was .38 with 95% confidence limits of .15 to .96. A decreased risk associated with OC use in subjects 40-59 years at the time of the study was observed; the relative risk, adjusted for parity, was .11, with 95% confidence limits of .04 to .33. A decreased risk associated with OC use was not found in women under 40, whose adjusted relateive risk associated with OC use was 1.98, with 95% confidence limits of .74 to 5.27. No significant differences were observed between parous and nonparous subjects. Differences in histological characteristics of cancer in OC users and nonusers were not significant, but a larger study might have uncovered differences. The lowest risk for ovarian cancer associated with the use of OCs was observed in older parous subjects and in women who had discontinued use more than 10 years previously. Potential biases that should be considered in this study include the high refusal rate among controls and the possibility that underlying infertility might confound any association of OCs and ovarian cancer.

Coronary heart disease mortality after irradiation for Hodgkin's disease.

The authors conducted a study designed to evaluate the hypothesis that irradiation to the heart in the treatment for Hodgkin's disease (HD) is associated with increased coronary heart disease (CHD) mortality. This report describes 957 patients diagnosed with HD in 1942-75 and analyzes follow-up findings through December 1977. Twenty-five coronary heart disease deaths have been observed, and 4258.2 person-years of experience at risk have been accrued. The relative death rate (RDR), defined as the CHD mortality for heart-irradiated subjects divided by the mortality for nonirradiated subjects, was estimated. After adjustment for the effect of interval of observation, age, stage, and class, the RDR estimate is 1.5 but does not differ significantly from unit (95% confidence limits: 0.59, 3.7).

Collaborative clinical trial for stage I and II Hodgkin's disease: significance of mediastinal and nonmediastinal disease in laparotomy- and non-laparotomy-staged patients.

In this study, 460 eligible patients with stage I and II Hodgkin's disease were randomized to treatment with involved field (IF) and extended field (EF) radiotherapy. Lymphangiogram was a requisite of the study. One hundred and seventy-seven patients were staged by laparotomy. The value of EF radiotherapy in improving survival over a 10-year followup was studied. This effect was considered separately for patents staged by laparotomy, for patients staged by lymphangiogram alone, and for patients with and without initial mediastinal involvement. A substantial benefit was seen for the subgroup staged by lymphangiogram alone and without mediastinal disease, with 10-year survival rates of 80% for EF and 56% for IF. For all other groups staged by laparotomy or having mediastinal presentations 10-year survival rates were essentially the same, differing by less than ten percentage points for IF and EF regimens. The advantage of EF treatment in lymphangiogram-staged nonmediastinal disease was realized only when the extended fields included the abdominal para-aortic area.

Leukemia in women following radiotherapy for cervical cancer: ten-year follow-up of an international study.

An international collaborative study of 31,219 women treated for cervical cancer from 30 radiotherapy centers in nine countries was conducted. Patients were followed clinically and with blood studies between 1960 and 1970, and 148,000 woman-years (WY) were accumulated. Among 28,490 women treated with either intercavitary radium, external radiation, or both, 134,000 WY were accumulated and 13 cases of leukemia were observed. On the basis of general population rates, 15.5 cases were expected [relative risk (RR) = 0.8; 95% confidence limits (CL) = 0.4-1.4]. A twofold risk could thus be excluded, but a 1.4-fold risk remained possible. In absolute terms, risks larger than 0.1 leukemia cases per 10(6) WY-rad could be excluded. Among 2,729 cervical cancer patients not irradiated but similarly evaluated, 14,000 WY were accumulated and 2 cases of leukemia were observed as compared with 1.0 expected. In the interval 4-8 years after exposure, the period in which any leukemogenic effect might be most apparent, 7 cases of leukemia were observed among exposed patients as compared with 5.4 expected (RR - 1.3; 95% CL = 0.5-2.7). The absence of an increased leukemia risk suggested that the radiation regimens used to treat cervical cancer are not so effective in inducing leukemia as are other radiation exposures that have been studied.

Survival and complications of radiotherapy following involved and extended field therapy of Hodgkin's disease, stages I and II. A collaborative study.

A collaborative trial with random assignment to involved field or extended field radiotherapy for localized Hodgkin's disease was begun in 1967. Case accession was completed in 1973, with 224 eligible patients assigned to involved field and 243 to extended field. With a median follow-up time of 27 months no significant survival difference is found between involved and extended field regimens for the total patient group or for most subgroups defined by age, sex, histology, stage, class, and use of laparotomy for staging. A single exception is an improved survival in the involved field group for female patients. Survival free of distant extension shows a similar lack of treatment effect, but survival free of any extension, local or distant, shows a significant benefit from extended field treatment. Complications of radiotherapy are significantly increased following extended field treatment. Survival following local extension is similar to survival following periods free of any extension.