Catherine Guibout

Role of Cancer Treatment in Long-Term Overall and Cardiovascular Mortality After Childhood Cancer

PURPOSE The purpose of this study was to assess the role of treatment in long-term overall and cardiovascular mortality after childhood cancer. PATIENTS AND METHODS We studied 4,122 5-year survivors of a childhood cancer diagnosed before 1986 in France and the United Kingdom. Information on chemotherapy was collected, and the radiation dose delivered to the heart was estimated for 2,870 patients who had received radiotherapy. RESULTS After 86,453 person-years of follow-up (average, 27 years), 603 deaths had occurred. The overall standardized mortality ratio (SMR) was 8.3-fold higher (95% CI, 7.6-fold to 9.0-fold higher) in relation to the general populations in France and the United Kingdom. Thirty-two patients had died as a result of cardiovascular diseases (ie, 5.0-fold [95% CI, 3.3-fold to 6.7-fold] more than expected). The risk of dying as a result of cardiac diseases (n = 21) was significantly higher in individuals who had received a cumulative anthracycline dose greater than 360 mg/m(2) (relative risk [RR], 4.4; 95% CI, 1.3 to 15.3) and in individuals who received an average radiation dose that exceeded 5 Gy (RR, 12.5 and 25.1 for 5 to 14.9 Gy and > 15 Gy, respectively) to the heart. A linear relationship was found between the average dose of radiation to the heart and the risk of cardiac mortality (estimated excess [corrected] RR at 1 Gy, 60%). CONCLUSION This study is the first, to our knowledge, to establish a relationship between the radiation dose received by the heart during radiotherapy for a childhood cancer and long-term cardiac mortality. This study also confirms a significant excess risk of cardiac mortality associated with a high cumulative dose of anthracyclines.

Malignant breast tumors after radiotherapy for a first cancer during childhood.

PURPOSE To assess the specific role of treatment and type of first cancer (FC) in the risk of long-term subsequent breast cancer (BC) among childhood cancer survivors. PATIENTS AND METHODS In a cohort of 1,814 3-year female survivors treated between 1946 and 1986 in eight French and English centers, data on chemotherapy and radiotherapy were collected. Individual estimation of radiation dose to each breast was performed for the 1,258 patients treated by external radiotherapy; mean dose to breast was 5.06 Gy (range, 0.0 to 88.0 Gy) delivered in 20 fractions (mean). RESULTS Mean follow-up was 16 years; 16 patients developed a clinical BC, 13 after radiotherapy. The cumulative incidence of BC was 2.8% (95% CI, 1.0% to 4.5%) 30 years after the FC and 5.1% (95% CI, 2.1% to 8.2%) at the age of 40 years. The annual excess incidence increased as age increased, whereas the standardized incidence ratio decreased. On average, each Gray unit received by any breast increased the excess relative risk of BC by 0.13 (< 0.0 to 0.75). After stratification on castration and attained age, and adjusting for radiation dose, FC type, and chemotherapy, a higher risk of a subsequent BC was associated with Hodgkins disease (relative risk, 7.0; 95% CI, 1.4 to 30.9). CONCLUSION The reported high risk of BC after childhood Hodgkins disease treatment seems to be due not only to a higher radiation dose to the breasts, but also to a specific susceptibility.

Plasma levels of six carotenoids in nine European countries: report from the European Prospective Investigation into Cancer and Nutrition (EPIC)

BACKGROUND In addition to their possible direct biological effects, plasma carotenoids can be used as biochemical markers of fruit and vegetable consumption for identifying diet-disease associations in epidemiological studies. Few studies have compared levels of these carotenoids between countries in Europe. OBJECTIVE Our aim was to assess the variability of plasma carotenoid levels within the cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS Plasma levels of six carotenoids--alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene, lutein and zeaxanthin--were measured cross-sectionally in 3043 study subjects from 16 regions in nine European countries. We investigated the relative influence of gender, season, age, body mass index (BMI), alcohol intake and smoking status on plasma levels of the carotenoids. RESULTS Mean plasma level of the sum of the six carotenoids varied twofold between regions (1.35 micromol l(-1) for men in Malmö, Sweden vs. 2.79 micromol l(-1) for men in Ragusa/Naples, Italy; 1.61 micromol l(-1) for women in The Netherlands vs. 3.52 micromol l(-1) in Ragusa/Naples, Italy). Mean levels of individual carotenoids varied up to fourfold (alpha-carotene: 0.06 micromol l(-1) for men in Murcia, Spain vs. 0.25 micromol l(-1) for vegetarian men living in the UK). In multivariate regression analyses, region was the most important predictor of total plasma carotenoid level (partial R(2)=27.3%), followed by BMI (partial R(2)=5.2%), gender (partial R(2)=2.7%) and smoking status (partial R(2)=2.8%). Females had higher total carotenoid levels than males across Europe. CONCLUSIONS Plasma levels of carotenoids vary substantially between 16 different regions in Italy, Greece, Spain, France, Germany, the UK, Sweden, Denmark and The Netherlands. Compared with region of residence, the other demographic and lifestyle factors and laboratory measurements have limited predictive value for plasma carotenoid levels in Europe.

Long-term risk of second malignant neoplasms after neuroblastoma in childhood: Role of treatment

The aim of our study was to quantify the risk of second malignant neoplasms (SMNs) among long‐term survivors of neuroblastoma and to study the influence of treatment on this risk. We studied data from 544 5‐year survival patients diagnosed with neuroblastoma before age 16 years at 8 French and British treatment centres from 1948 to 1986. After an average follow‐up of 15 years (range, 5–38 years), 12 children developed a total of 13 SMNs, whereas 1.19 were expected from general population rates. Among these SMNs, there were 5 thyroid and 3 breast cancers. Increases of the risks of SMN were observed with time since neuroblastoma diagnosis and attained age. In a multivariate analysis, the relative risk of SMN associated with radiotherapy was 4.3 (95% CI 0.8–78), whereas no increased risk of SMN was associated with the administration of chemotherapy as a whole (RR = 0.4, 95% CI 0.1–1.9). Young children treated for a neuroblastoma have significantly increased risks of SMN over 3 decades of follow‐up. Radiotherapy treatment was found to be an important risk factor for developing SMNs, whereas no effect of chemotherapy was evidenced. Although our findings reflect the late effects of past therapeutic modalities, they underscore the importance of long‐term surveillance of young children treated for a neuroblastoma. For these patients, many more years of follow‐up are required to appreciate their overall risks of treatment‐related SMNs.

Long-term Mortality from Second Malignant Neoplasms in 5-Year Survivors of Solid Childhood Tumors: Temporal Pattern of Risk according to Type of Treatment

Background: The temporal pattern in mortality from late second malignant neoplasms in solid childhood cancer survivors, according to the type of treatment, has not been investigated in detail. Methods: We studied 4,230 5-year survivors of solid childhood cancer diagnosed between 1942 and 1986 in France and the United Kingdom. Complete clinical, chemotherapy, and radiotherapy data were recorded and the integral radiation dose was estimated for 2,701 of the 2,948 patients who had received radiotherapy. Results: After a median follow-up of 28 years, 134 fatal events were due to second malignancies, compared with the 13.3 expected from the general France-UK population rates. The standardized mortality ratio was of a similar magnitude after radiotherapy alone and chemotherapy alone and higher after both treatments. The standardized mortality ratio decreased with follow-up, whereas the absolute excess risk increased significantly over a period of at least 25 years after the first cancer. This temporal pattern was similar after chemotherapy alone, radiotherapy alone, or both treatments. We observed a similar long-term temporal pattern among survivors who had died of a second malignant neoplasm of the gastrointestinal tract and breast. Survivors who had received a higher integral radiation dose during radiotherapy were at a particularly high risk, as well as those who had received alkylating agents and epipodophyllotoxins. Conclusions: Five-year survivors of childhood cancer run a high long-term mortality risk for all types of second malignant neoplasms whatever the treatment received and require careful long-term screening well beyond 25 years after the diagnosis. Cancer Epidemiol Biomarkers Prev; 19(3); 707–15

Treatment-Adjusted Predisposition to Second Malignant Neoplasms After a Solid Cancer in Childhood: A Case-Control Study

PURPOSE Previous therapy, genetic susceptibility, and the type of first malignant neoplasm (FMN) are known to be associated with the risk of second malignant neoplasm (SMN) among patients treated for a childhood cancer. The aim of this study was to investigate the independent role of the FMN in the onset of any SMN. PATIENTS AND METHODS A case-control study nested in a European cohort of 4,581 patients treated for a solid cancer during childhood was conducted. One hundred forty-six patients with an SMN and 417 controls were matched for sex, age at FMN, chemotherapy, radiotherapy, the local radiation dose received at the site of SMN for patient cases and at the same site for the matched controls, and follow-up. RESULTS A significantly increased risk of developing any SMN was observed after Hodgkins lymphoma, retinoblastoma, malignant bone tumor, soft tissue sarcoma (STS), and germ cell tumor as FMN, after adjustment for chemotherapy and family cancer syndrome. No significant risk of developing a carcinoma was observed among patients who had developed Hodgkins lymphoma as FMN. A significantly increased risk of developing a sarcoma was observed among patients who had developed a retinoblastoma (adjusted odds ratio [ORa] = 7.5; 95% CI, 1.2 to 46), a malignant bone tumor (ORa = 13.3; 95% CI, 1.5 to 117), an STS (ORa = 4.8; 95% CI, 1.3 to 18), or a carcinoma (ORa = 9.4; 95% CI, 1.1 to 82) as FMN. CONCLUSION Survivors of Hodgkins lymphoma, retinoblastoma, malignant bone tumor, STS, and germ cell tumor should receive close surveillance because they are at increased risk of developing any SMN.

Cardiac Diseases Following Childhood Cancer Treatment Cohort Study

Background— Cardiac disease (CD) is one of the major side effects of childhood cancer therapy, but until now little has been known about the relationship between the heart radiation dose (HRD) received during childhood and the risk of CD. Methods and Results— The cohort comprised 3162 5-year survivors of childhood cancer. Chemotherapy information was collected and HRD was estimated. There were 347 CDs in 234 patients, 156 of them were rated grade ≥3. Cox and Poisson regression models were used. The cumulative incidence of any type of CD at 40 years of age was 11.0% (95% confidence interval [CI], 9.5–12.7) and 7·4% (95% CI, 6.2–8.9) when only the CDs of grade ≥3 were considered. In comparison with patients who received no anthracycline and either no radiotherapy or an HRD<0·1Gy, the risk was multiplied by 18·4 (95% CI, 7.1–48.0) in patients who had received anthracycline and no radiotherapy or a HRD <0.1Gy, by 60.4 (95% CI, 22.4–163.0) in those who had received no anthracycline and an HRD≥30Gy, and 61.5 (95% CI, 19.6–192.8) in those who had received both anthracycline and an HRD≥30Gy. Conclusions— Survivors of childhood cancers treated with radiotherapy and anthracycline run a high dose-dependent risk of developing CD. CDs develop earlier in patients treated with anthracycline than in those treated without it.

Educational and occupational outcomes of childhood cancer survivors 30 years after diagnosis: a French cohort study

Background:Although survival from childhood cancer has increased, little is known on the long-term impact of treatment late effects on occupational attainment or work ability.Methods:A total of 3512 five-year survivors treated before the age of 19 years in 10 French cancer centres between 1948 and 2000 were identified. Educational level, employment status and occupational class of survivors were assessed by a self-reported questionnaire. These outcome measures were compared with sex–age rates recorded in the French population, using indirect standardisation. Paternal occupational class was also considered to control for the role of survivors’ socioeconomic background on their achievement. Multivariable analyses were conducted to explore clinical characteristics associated with the outcomes.Results:A total of 2406 survivors responded to the questionnaire and survivors aged below 25 years were included in the current analysis. Compared with national statistics adjusted on age and sex, male survivors were more likely to be college graduates (39.2% vs 30.9% expected; P<0.001). This higher achievement was not observed either for leukaemia or central nervous system (CNS) tumour survivors. Health-related unemployment was higher for survivors of CNS tumour (28.1% vs 4.3%; P<0.001) but not for survivors of other diagnoses. Survivors of non-CNS childhood cancer had a similar or a higher occupational class than expected.Conclusions:Survivors treated for CNS tumour or leukaemia, especially when treatment included cranial irradiation, might need support throughout their lifespan.

Ideal Cardiovascular Health and Subclinical Markers of Carotid Structure and Function: The Paris Prospective Study III.

Objective— We hypothesized that subclinical markers of vascular structure and function, which are independent predictors of cardiovascular disease, would be less frequent in subjects with ideal than poor cardiovascular health (CVH) as defined by the American Heart Association (AHA). Approach and Results— Carotid parameters were measured using high-precision echotracking device in 9155 nonreferred participants attending a health checkup in a large health center in Paris (France) between 2008 and 2012. According to the AHA, participants with 0 to 2, 3 to 4, and 5 to 7 metrics (smoking, physical activity, body mass index, diet, blood glucose and total cholesterol, blood pressure) at the ideal level were categorized as having poor, intermediate, and ideal CVH. Carotid parameters were dichotomized according to their median value, and multivariable logistic regression analysis was performed. Mean age was 59.5 (SD 6.3) years; 39% were females, and ideal CVH was present in 10.11% of the study participants. After adjustment for age, sex, education, and living alone and compared with a poor CVH, an ideal CVH was associated with lower common carotid artery intima–media thickness (odds ratio=1.64; 95% confidence interval 1.40, 1.93), absence of carotid plaques (odds ratio=2.14; 95% confidence interval 1.60, 2.87), lower Young’s elastic modulus (odds ratio=2.43; 95% confidence interval 2.07, 2.84), and higher carotid distensibility coefficient (odds ratio=2.90; 95% confidence interval 2.47, 3.41). Conclusions— In community subjects aged 50 to 75 years, ideal CVH was associated with substantially less arterial stiffness and thickness. These associations might contribute to the lower risk of cardiovascular diseases in subjects with ideal CVH.

Ideal Cardiovascular Health and Subclinical Markers of Carotid Structure and Function

Objective— We hypothesized that subclinical markers of vascular structure and function, which are independent predictors of cardiovascular disease, would be less frequent in subjects with ideal than poor cardiovascular health (CVH) as defined by the American Heart Association (AHA). Approach and Results— Carotid parameters were measured using high-precision echotracking device in 9155 nonreferred participants attending a health checkup in a large health center in Paris (France) between 2008 and 2012. According to the AHA, participants with 0 to 2, 3 to 4, and 5 to 7 metrics (smoking, physical activity, body mass index, diet, blood glucose and total cholesterol, blood pressure) at the ideal level were categorized as having poor, intermediate, and ideal CVH. Carotid parameters were dichotomized according to their median value, and multivariable logistic regression analysis was performed. Mean age was 59.5 (SD 6.3) years; 39% were females, and ideal CVH was present in 10.11% of the study participants. After adjustment for age, sex, education, and living alone and compared with a poor CVH, an ideal CVH was associated with lower common carotid artery intima–media thickness (odds ratio=1.64; 95% confidence interval 1.40, 1.93), absence of carotid plaques (odds ratio=2.14; 95% confidence interval 1.60, 2.87), lower Young’s elastic modulus (odds ratio=2.43; 95% confidence interval 2.07, 2.84), and higher carotid distensibility coefficient (odds ratio=2.90; 95% confidence interval 2.47, 3.41). Conclusions— In community subjects aged 50 to 75 years, ideal CVH was associated with substantially less arterial stiffness and thickness. These associations might contribute to the lower risk of cardiovascular diseases in subjects with ideal CVH.