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We assessed cardiovascular disease (CVD) incidence in 1474 survivors of Hodgkin lymphoma (HL) younger than 41 years at treatment (1965-1995). Multivariable Cox regression and competing risk analyses were used to quantify treatment effects on CVD risk. After a median follow-up of 18.7 years, risks of myocardial infarction (MI) and congestive heart failure (CHF) were strongly increased compared with the general population (standardized incidence ratios [SIRs] = 3.6 and 4.9, respectively), resulting in 35.7 excess cases of MI and 25.6 excess cases of CHF per 10 000 patients/year. SIRs of all CVDs combined remained increased for at least 25 years and were more strongly elevated in younger patients. Mediastinal radiotherapy significantly increased the risks of MI, angina pectoris, CHF, and valvular disorders (2- to 7-fold). Anthracyclines significantly added to the elevated risks of CHF and valvular disorders from mediastinal RT (hazard ratios [HRs] were 2.81 and 2.10, respectively). The 25-year cumulative incidence of CHF after mediastinal radiotherapy and anthracyclines in competing risk analyses was 7.9%. In conclusion, risks of several CVDs are 3- to 5-fold increased in survivors of HL compared with the general population, even after prolonged follow-up, leading to increasing absolute excess risks over time. Anthracyclines further increase the elevated risks of CHF and valvular disorders from mediastinal radiotherapy.

Purpose: To assess long-term cause-specific mortality of young Hodgkin’s disease (HD) patients. Patients and Methods: The study population consisted of 1,261 patients treated for HD before age 41 between 1965 and 1987. Follow-up was complete until October 2000. For 95% of deaths, the cause was known. Long-term cause-specific mortality was compared with general population rates to assess relative risk (RR) and absolute excess risk (AER) of death. Results: After a median follow-up of 17.8 years, 534 patients had died (55% of HD). The RR of death from all causes other than HD was 6.8 times that of the general population, and still amounted to 5.1 after more than 30 years. RRs of death resulting from solid tumors (STs) and cardiovascular disease (CVD) were increased overall (RR = 6.6 and 6.3, respectively), but especially in patients treated before age 21 (RR = 14.8 and 13.6, respectively). When these patients grew older, this elevated mortality decreased. The overall AER of death from causes other than HD increased throughout follow-up. Patients receiving salvage chemotherapy had a significantly increased RR of death from STs, compared to patients receiving initial therapy only. Conclusion: The main cause of death among HD patients was lymphoma, but after 20 years, HD mortality was negligible. The RRs and AERs of death from second primary cancers (SCs) and CVDs continued to increase after 10 years. Even more than 30 years after diagnosis, HD patients experienced elevated risk of death from all causes other than HD. Increased risk of death from SCs and CVDs was found especially in patients treated before age 21, but these risks seemed to abate with age.

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.

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.

PURPOSE: To evaluate the risk of cardiovascular events (CVE) in patients with cervical cancer treated with radiotherapy or chemoradiation.METHODS AND MATERIALS: The incidence of CVE in patients treated between 1989 and 2002 by radiotherapy or chemoradiation was compared with a Dutch reference population. Standardized incidence ratios (SIRs) were calculated for myocardial infarction (MI), angina pectoris (AP), congestive heart failure (CHF), cerebrovascular accident (CVA) separately and for any cardiac event combined (MI, AP, and CHF).RESULTS: In 277 patients with a median follow-up of 4.5 years (range, 0.1-17 years) and a median survival of 9.2 years, 27 cardiac events occurred. The 5-, 10-, and 15-year actuarial incidence of any cardiac event were 9, 14, and 16%, respectively. For the whole population, the SIR for MI was elevated (2.05, 95% CI: 1.12-3.43). The radiotherapy group (n = 132) was older and had more cardiovascular risk factors than the chemoradiation group (n = 145). The SIR for MI in the radiotherapy group was 2.88 (95% CI: 1.44-5.15) and in the chemoradiation group 1.00 (95% CI: 0.21-7.47). In multivariate analyses, there was no relation between treatment modality and the risk for MI.CONCLUSIONS: In this cohort of cervical cancer patients, an increased risk for developing a MI was observed. This increased risk of MI, in combination with the high prevalence of cardiovascular risk factors in cervical cancer patients, urges the need to explore strategies to reduce their risk for cardiovascular morbidity.

Background & Aims Although gastric cancer forms part of the Lynch syndrome tumor spectrum, the risk of developing gastric cancer in Lynch syndrome families is unknown, resulting in a lack of clear guidelines for surveillance. The aim of this study was to evaluate incidence trends and risk of developing gastric cancer among Lynch syndrome mutation carriers in a Western population. Methods Lynch syndrome mutation carriers were selected from the Dutch Hereditary Cancer Registry. The gastric cancer incidence in Lynch syndrome mutation carriers was compared to the gastric cancer incidence in the Dutch population between 1970 and 2003. Standardized incidence ratios were calculated by a Poisson model. Cumulative risks were calculated by Kaplan-Meier analysis. Results Overall, 2014 Lynch syndrome mutation carriers were identified. Gastric cancer was diagnosed in 32 (1.6%) subjects (male/female: 21/11), 22 (69%) of them had a negative family history of gastric cancer. The standardized incidence ratios of gastric cancer was 3.4 (95% confidence interval, 2.1–5.2) and showed a nonsignificant decline between 1970 and 2003 ( P = .30). Absolute risk of developing gastric cancer also showed no significant change over time ( P = .51). Lifetime risk of developing gastric cancer was 8.0% in males vs 5.3% in females ( P = .02), and 4.8% and 9% for MLH1 and MSH2 carriers, respectively. None of the 378 MSH6 carriers developed gastric cancer ( P = .002 vs MLH1 and MSH2 combined lifetime risk). Conclusions Lynch syndrome mutation carriers have a substantial risk for gastric cancer, in particular patients with an MLH1 or MSH2 mutation. Family history for gastric cancer is a poor indicator for individual risk. Surveillance gastroscopy for Lynch syndrome patients carrying an MLH1 or MSH2 mutation should therefore be considered.

Objectives. To assess the risk of second primary cancers among women with previous breast cancer and calculate the excess burden of second cancer in the population. Methods. A population-based longitudinal study was conducted using the Eindhoven cancer registry data on 9919 breast cancer patients diagnosed in the period 1972-2000 and followed until 2001. Standardised incidence ratios (SIR) and absolute excess risks (AER) were calculated. Results. In total, 1298 (13%) women developed a second primary cancer. The risk of overall second cancer was higher among breast cancer patients compared to the general population (SIR: 2.8; 95% CI: 2.6-2.9), with an AER of 115 second cancers for every 10,000 breast cancer patients per year. High SIR and AER were observed for breast cancer (SIR: 4.1; 95% CI: 3.8-4.4; AER: 64/10,000 patients/year) and ovarian cancer (SIR: 2.0; 95% CI: 1.5-2.7; AER: 4.5/10,000 patients/year). Conclusions. Our recent data show that women with previous breast cancer have an elevated risk of developing a second cancer compared to the general population. Excess burden for the population is especially high for second cancers of the breast, ovary and colon. Screening may only be justified for breast, ovary and colon cancer in certain groups of patients.

A cohort of 9919 breast cancer patients from the population-based Eindhoven Cancer Registry was followed for vital status and development of second cancer. Person-year analysis was applied to determine the risk of second primary breast or urogenital cancer among breast cancer patients and to assess its correlation with age, treatment and time since the first breast cancer diagnosis. Women with previous breast cancer have an elevated risk of overall second breast or urogenital cancer. The largest relative risk was observed for second breast cancer (SIR (standardised incidence ratio) 3.5; 95% confidence interval (CI) 3.2-3.8) and second ovarian cancer (SIR 1.7; 95% CI 1.2-2.3). The absolute excess risk was highest for second breast cancer (64/10,000 patients/year). However, breast cancer has an inverse relationship to risk of cervical cancer. Changes in behavioural risk factors are important for lowering the risk of second cancer after breast cancer.

The aim of this study was to evaluate whether patients with salivary gland tumours are at increased risk of developing breast cancer. A retrospective cohort study was performed. Female patients (n = 439) with a salivary gland tumour (major and minor) were included. The diagnosis was confirmed histologically. The median follow-up was 5.4 years. Fifteen patients out of 439 with a salivary gland tumour subsequently developed breast cancer, with a mean time interval of 64 months. On the basis of incidence rates in the general population 5.93 breast cancers would be expected. The standardised incidence ratio (SIR) was 2.5 (95% confidence interval: 1.4-4.2; P = 0.003). Increased SIRs were also observed for other solid malignancies, but the numbers were small (n

Background: Female survivors of Hodgkin’s disease (HD) have a strongly elevated risk of breast cancer, but factors responsible for the increased risk are not well known. Methods: We investigated the effects of radiation dose, chemotherapy (CT), and reproductive factors on breast cancer risk in a nested case–control study in The Netherlands in a cohort of 770 female patients who had been diagnosed with HD before age 41. Detailed treatment information and data on reproductive factors were collected for 48 case patients who developed breast cancer 5 or more years after diagnosi so f HD and 175 matched control subjects. The radiation dose was estimated to the area of the breast where the case patient’s tumor had developed and to a comparable location in matched control subjects. Relative risks (RRs) of breast cancer were calculated by conditional logistic regression. Statistical tests were two-sided. Results: The risk of breast cancer increased statistically significantly with radiation dose (Ptrend = .01); patients who received 38.5 Gy or more had an RR of 4.5 (95% confidence interval [CI] = 1.3 to 16) times that of patients who received less than 4 Gy. Patients who received both CT and radiotherapy (RT) had a statistically significantly lower risk than those treated with RT alone (RR = 0.45, 95% CI = 0.22 to 0.91). Breast cancer risk increased with increasing radiation dose among patients who received RT only (RR = 12.7, 95% CI = 1.8 to 86, for patients receiving 38.5 Gy) but not among patients treated with CT and RT. Sixty-nine percent of control subjects treated with RT and more than six cycles of CT, but only 9% of those who received RT alone, reached menopause before age 41. Reaching menopause before age 36 was associated with a strongly reduced risk of breast cancer (RR = 0.06, 95% CI = 0.01 to 0.45). Conclusion: Breast cancer risk increases with increasing radiation dose up to at least 40 Gy. The substantial risk reduction associated with CT may reflect its effect on menopausal age, suggesting that ovarian hormones promote tumorigenesi sa fter radiation has produced an initiating event. [J Natl Cancer Inst 2003;95:971–80]

PURPOSE: To estimate the risk of ischemic stroke in patients irradiated for head and neck tumors. PATIENTS AND METHODS: The incidence of ischemic stroke was determined in 367 patients with head and neck tumors (162 larynx carcinomas, 114 pleomorphic adenomas, and 91 parotid carcinomas) who had been treated with local radiotherapy (RT) at an age younger than 60 years. Relative risk (RR) of ischemic stroke was determined by comparison with population rates from a stroke-incidence register, adjusted for sex and age. Other risk factors for stroke (hypertension, smoking, hypercholesterolemia, diabetes mellitus [DM]) were registered. The median follow-up time after RT was 7.7 years (3,011 person-years of follow-up). RESULTS: Fourteen cases of stroke occurred (expected, 2.5; RR, 5.6; 95% confidence interval [CI], 3.1 to 9.4): eight in patients with laryngeal carcinoma (expected ,1.56; RR, 5.1; 95% CI, 2.2 to 10.1), four in pleomorphic adenoma patients (expected, 0.71; RR, 5.7; 95% CI, 1.5 to 14.5), and two in parotid carcinoma patients (expected, 0.24; RR, 8.5, 95% CI, 1.0 to 30.6). Five of six strokes in patients irradiated for a parotid tumor occurred at the ipsilateral side. Analysis of other risk factors for cerebrovascular disease showed hypertension and DM to cause an increase of the RR after RT. After more than 10 years’ follow-up, the RR was 10.1 (95% CI, 4.4 to 20.0). The 15-year cumulative risk of stroke after RT on the neck was 12.0% (95% CI, 6.5% to 21.4%). CONCLUSION: This is the first study to demonstrate an increased risk of stroke after RT on the neck. During medical follow-up, preventive measures should be taken to reduce the impact of the risk factors for cerebrovascular disease, to decrease stroke in these patients.

Ojective. Data from the literature about the incidence of stroke after radiotherapy on carotid arteries is limited and controversial. We investigated in a systematic manner the risk of stroke after radiotherapy to the neck. Patients and methods. Stroke is recorded in patients with T1 or T2 laryngeal carcinoma, pleomorphic adenoma, and parotid carcinoma, who have been treated with local radiotherapy, and from whom complete follow-up is available. TIA and subarachnoid haemorrhage are excluded. The relative risk of stroke is determined by comparison with population stroke-incidence register, adjusted for sex and age. Risk factors for stroke (hypertension, smoking, hypercholesterolaemia, diabetes) are registered. Results. Two hundred and fifty-five patients were analysed: follow-up period 0–22 years (median 6 years); 120 laryngeal carcinoma (778 follow-up years); 65 pleomorphic adenoma (625 follow-up years); 70 parotid carcinoma (384 follow-up years). Incidence of stroke: laryngeal carcinoma, eight (expected 0.923; OR 8.67; 95% CI 3.74–17.07); pleiomorphic adenoma, three (all on the radiotherapy side; expected 0.330; OR 9.09; 95% CI 1.88–26.57); parotid carcinoma, 0 (exp. 0.097). The analysis risk factors remains inconclusive as the sample size is too small. Conclusion. Radiation to the neck increases the risk of stroke significantly (P

PURPOSE: To quantify the long-term risk of second primary cancers (SCs) in patients diagnosed with Hodgkin’s disease (HD) during adolescence or young adulthood. PATIENTS AND METHODS: The risk of SCs was assessed in 1,253 patients diagnosed with HD before the age of 40 years and treated in two Dutch cancer centers between 1966 and 1986. The median follow-up duration was 14.1 years. RESULTS: In all, 137 patients developed SCs, compared with 19.4 cases expected on the basis of incidence rates in the general population (relative risk [RR] = 7.0; 95% confidence interval, 5.9 to 8.3). The 25-year actuarial risk of SC overall was 27.7%. The RR of solid tumors increased greatly with younger age at the first treatment of HD, not only for breast cancer but also for all other solid tumors, with RRs of 4.9, 6.9, and 12.7 for patients first treated at ages 31 to 39 years, 21 to 30 years, and ≤ 20 years, respectively. Among patients first treated at the age of 20 years or younger, the RR of developing a solid tumor before the age of 40 years was significantly greater than the RR of solid tumor development at ages 40 to 49 years (RR = 27.9 v RR = 4.2; P = .0001). Patients who received salvage chemotherapy had significantly greater risk of solid cancers other than breast cancer than did patients whose treatment was restricted to initial radiotherapy or initial combined-modality treatment (RR = 9.4 and 4.7, respectively; P = .004). CONCLUSION: After more than 20 years of follow-up, the risk of solid tumors is still much greater in survivors of HD than in the population at large. Reassuringly, the greatly increased risk of solid tumors in patients who were young (≤ 20 years of age) at the first treatment seems to decrease as these patients grow older. Our data suggest that chemotherapy may increase the risk of solid tumors from radiotherapy.