[Show abstract][Hide abstract] ABSTRACT: Thyroid carcinoma is a frequent complication of childhood cancer radiotherapy. The dose-response to thyroid radiation dose is now well established, but the potential modifier effect of other factors still requires further investigation.
To investigate the role of potential modifiers of the dose-response.
We followed, over an average of 27 years, a cohort of 4338 5-year survivors of solid childhood cancer treated before 1986. The dose received by the thyroid gland and some other anatomical sites during radiotherapy was estimated after reconstruction of the actual conditions in which irradiation was delivered.
Fifty-five (55) patients developed a thyroid carcinoma. The risk of thyroid carcinoma increased with a radiation dose to the thyroid of up to two tenths of Gy, then leveled off for higher doses. When taking into account the thyroid radiation dose, a surgical or radiological splenectomy (>20 Gy to the spleen) increased thyroid cancer risk (RR=2.3, 95%CI:1.3-4.0), high radiation doses (> 5 Gy) to pituitary gland lowered this risk (RR=0.2, 95%CI:0.1-0.6). Patients who received nitrosourea chemotherapy had a 6.6-fold (95%CI: 2.5-15.7) higher risk than those who did not. The excess relative risk per Gy of radiation to the thyroid was 4.7 (95%CI: 1.7 to 22.6). It was 7.6 (95%CI: 1.6 to 33.3) if body mass index at time of interview was equal or higher than 25, and 4.1 (95%CI: 0.9-17.7) if not (p-value for interaction=0.1).
Predicting thyroid cancer risk following childhood cancer radiation therapy probably requires the assessment of more than just the radiation dose to the thyroid. Chemotherapy, splenectomy, radiation dose to pituitary gland, and obesity also play a role.
The Journal of Clinical Endocrinology and Metabolism 09/2015; DOI:10.1210/jc.2015-1690 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Contexte
La télésurveillance des défibrillateurs automatiques implantables (DAI) se généralise. Les études randomisées ont démontré son utilité, mais les données manquent sur son utilisation en pratique courante avec différentes marques et des patients non sélectionnés.
Évaluer l’apport de la télésurveillance pour le suivi et l’évolution des patients appareillés d’un DAI en pratique courante.
Nous avons inclus rétrospectivement les patients appareillés d’un DAI dont la télésurveillance a débuté en 2009 dans notre centre, suivis par télésurveillance ou suivi hospitalier (SH) seul. Nous avons étudié l’apport de la télésurveillance sur le nombre de consultations programmées et en urgence, le délai entre la survenue d’un événement asymptomatique et l’intervention clinique ainsi que la pertinence clinique des consultations programmées. Nous avons également évalué la proportion d’alertes de télésurveillance traduisant un événement clinique pertinent.
Au total, 355 patients ont été inclus (télésurveillance : n = 144 ; SH : n = 211 ; 76,9 % d’hommes ; 60,3 ± 15,2 ans ; 50,1 % de DAI en prophylaxie ; fraction d’éjection ventriculaire gauche moyenne 35,5 ± 14,5 %). La durée moyenne de suivi était de 13,5 mois. Dans le groupe télésurveillance, le nombre de consultations programmées était significativement réduit (1,8 vs 2,1/patient/année ; p < 0,0001) ainsi que le délai médian entre un événement asymptomatique et l’intervention clinique (7 vs 76 jours ; p = 0,016). Parmi les 784 consultations programmées, 152 (19,4 %) seulement ont été suivies d’un changement de thérapeutique ou de programmation du DAI. La majorité des notifications de télésurveillance (61,9 %) n’avait pas de pertinence clinique.
La télésurveillance permet une prise en charge précoce des événements asymptomatiques et une diminution des consultations programmées, en pratique courante, sans une moindre sécurité des patients, soutenant son utilisation large pour les porteurs de DAI.
European Research in Telemedicine 12/2014; 3(4). DOI:10.1016/j.eurtel.2014.10.008
[Show abstract][Hide abstract] ABSTRACT: Background. - Remote monitoring (RM) is increasingly used to follow up patients with implantable cardioverter-defibrillators (ICDs). Randomized control trials provide evidence for the benefit of this intervention, but data for RM in daily clinical practice with multiple-brands and unselected patients is lacking. Aims. - To assess the effect of RM on patient management and clinical outcome for recipients of ICDs in daily practice. Methods. - We reviewed ICD recipients followed up at our institution in 2009 with RM or with traditional hospital only (HO) follow-up. We looked at the effect of RM on the number of scheduled ambulatory follow-ups and urgent unscheduled consultations, the time between onset of asymptomatic events to clinical intervention and the clinical effectiveness of all consultations. We also evaluated the proportion of RM notifications representing clinically relevant situations. Results. - We included 355 patients retrospectively (RM: n = 144, HO: n = 211, 76.9% male, 60.3 +/- 15.2 years old, 50.1% with ICDs for primary prevention and mean left ventricular ejection fraction 35.5 +/- 14.5%). Average follow-up was 13.5 months. The RM group required less scheduled ambulatory follow-up consultations (1.8 vs. 2.1/patient/year; P < 0.0001) and a far lower median time between the onset of asymptomatic events and clinical intervention (7 vs. 76 days; P = 0.016). Of the 784 scheduled ambulatory follow-up consultations carried out, only 152 (19.4%) resulted in therapeutic intervention or ICD reprogramming. We also found that the vast majority of RM notifications (61.9%) were of no clinical relevance. Conclusion. - RM allows early management of asymptomatic events and a reduction in scheduled ambulatory follow-up consultations in daily clinical practice, without compromising safety, endorsing RM as the new standard of care for ICD recipients.
[Show abstract][Hide abstract] ABSTRACT: Bone sarcoma as a second malignancy is rare but highly fatal. The present knowledge about radiation-absorbed organ dose-response is insufficient to predict the risks induced by radiation therapy techniques. The objective of the present study was to assess the treatment-induced risk for bone sarcoma following a childhood cancer and particularly the related risk of radiotherapy. Therefore, a retrospective cohort of 4,171 survivors of a solid childhood cancer treated between 1942 and 1986 in France and Britain has been followed prospectively. We collected detailed information on treatments received during childhood cancer. Additionally, an innovative methodology has been developed to evaluate the dose-response relationship between bone sarcoma and radiation dose throughout this cohort. The median follow-up was 26 years, and 39 patients had developed bone sarcoma. It was found that the overall incidence was 45-fold higher [standardized incidence ratio 44.8, 95 % confidence interval (CI) 31.0-59.8] than expected from the general population, and the absolute excess risk was 35.1 per 100,000 person-years (95 % CI 24.0-47.1). The risk of bone sarcoma increased slowly up to a cumulative radiation organ absorbed dose of 15 Gy [hazard ratio (HR) = 8.2, 95 % CI 1.6-42.9] and then strongly increased for higher radiation doses (HR for 30 Gy or more 117.9, 95 % CI 36.5-380.6), compared with patients not treated with radiotherapy. A linear model with an excess relative risk per Gy of 1.77 (95 % CI 0.6213-5.935) provided a close fit to the data. These findings have important therapeutic implications: Lowering the radiation dose to the bones should reduce the incidence of secondary bone sarcomas. Other therapeutic solutions should be preferred to radiotherapy in bone sarcoma-sensitive areas.
[Show abstract][Hide abstract] ABSTRACT: STUDY QUESTION Is the age at menopause in a cohort of childhood cancer survivors earlier and what are the risk factors associated with earlier
age at menopause?
Human Reproduction 11/2012; 28(2). DOI:10.1093/humrep/des391 · 4.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Children and young adults treated with total body or abdominal radiotherapy have an increased risk of insulin resistance and diabetes mellitus. However, little is known of the effect of pancreas irradiation on the risk of diabetes. We assessed the relation between radiation exposure and occurrence of diabetes in a large cohort of long-term childhood cancer survivors.
We sent a questionnaire to 3468 survivors of a childhood cancer treated in eight centres in France and the UK between 1946 and 1985, of which 2520 were returned. Each self-declaration of diabetes was confirmed by contacting the patients' medical doctors. We estimated the radiation dose received by the tail, head, and body of the pancreas and 185 other anatomical sites during each course of radiotherapy from 1990 to 1995 for each child after reconstruction of the conditions in which irradiation was delivered. We investigated the relation between radiation dose to the pancreas and the risk of a subsequent diabetes diagnosis.
65 cases of diabetes were validated. The risk of diabetes increased strongly with radiation dose to the tail of the pancreas, where the islets of Langerhans are concentrated, up to 20-29 Gy and then reached a plateau for higher radiation doses. The estimated relative risk at 1 Gy was 1·61 (95% CI 1·21-2·68). The radiation dose to the other parts of the pancreas did not have a significant effect. Compared with patients who did not receive radiotherapy, the relative risk of diabetes was 11·5 (95% CI 3·9-34·0) in patients who received 10 Gy or more to the tail of the pancreas. Results were unchanged after adjustment for body-mass index, despite its strong independent effect (p<0·0001), and were similar between men and women. Children younger than 2 years at time of radiotherapy were more sensitive to radiation than were older patients (relative risk at 1 Gy 2·1 [95% CI 1·4-4·3] vs 1·4 [95% CI 1·1-2·2] in older patients; p=0·02 for the difference). For the 511 patients who had received more than 10 Gy to the tail of the pancreas, the cumulative incidence of diabetes was 16% (95% CI 11-24).
Our study provides evidence of a dose-response relation between radiation exposure of pancreas and subsequent risk of diabetes. Because of the risks observed and the frequency of diabetes in general population, this finding raises important public health issues. The pancreas needs to be regarded as a critical organ when planning radiation therapy, particularly in children. Follow-up of patients who received abdominal irradiation should include diabetes screening.
Ligue Nationale Contre le Cancer, Institut de Recherche en Santé Publique, Programme Hospitalier de Recherche Clinique, Institut National du Cancer, Agence Française de Sécurité Sanitaire et des Produits de Santé, Fondation Pfizer pour la santé de l'enfant et de l'adolescent.
The Lancet Oncology 08/2012; 13(10):1002-10. DOI:10.1016/S1470-2045(12)70323-6 · 24.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Very few childhood cancer survivor studies have been devoted to thyroid adenomas. We assessed the role of chemotherapy and the radiation dose to the thyroid in the risk of thyroid adenoma after childhood cancer.
A cohort of 3254 2-year survivors of a solid childhood cancer treated in 5 French centers before 1986 was established. The dose received by the isthmus and the 2 lobes of the thyroid gland during each course of radiation therapy was estimated after reconstruction of the actual radiation therapy conditions in which each child was treated as well as the dose received at other anatomical sites of interest.
After a median follow-up of 25 years, 71 patients had developed a thyroid adenoma. The risk strongly increased with the radiation dose to the thyroid up to a few Gray, plateaued, and declined for high doses. Chemotherapy slightly increased the risk when administered alone but also lowered the slope of the dose-response curve for the radiation dose to the thyroid. Overall, for doses up to a few Gray, the excess relative risk of thyroid adenoma per Gray was 2.8 (90% CI: 1.2-6.9), but it was 5.5 (90% CI: 1.9-25.9) in patients who had not received chemotherapy or who had received only 1 drug, and 1.1 (90% CI: 0.4-3.4) in the children who had received more than 1 drug (P=.06, for the difference). The excess relative risk per Gray was also higher for younger children at the time of radiation therapy than for their older counterparts and was higher before attaining 40 years of age than subsequently.
The overall pattern of thyroid adenoma after radiation therapy for a childhood cancer appears to be similar to that observed for thyroid carcinoma.
International journal of radiation oncology, biology, physics 06/2012; 84(2):e209-15. DOI:10.1016/j.ijrobp.2012.03.044 · 4.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Resting heart rate has been related to the risk of cardiovascular disease and sudden death in several large prospective studies. To investigate prospectively the association of novel heart rate parameters and of carotid artery stiffness with sudden death and other cardiovascular disease. The Paris Prospective Study III (PPS3) is a new, ongoing French prospective study. From June 2008 to December 2011, 10,000 men and women aged 50-75 years who will have a preventive medical check-up at the Centre d'Investigations Préventives et Cliniques in Paris (France), will be enrolled in the study, after signing an informed consent. In addition to the general health examination, each subject's heart rhythm will be recorded during the course of the health check-up (approximately 2(1/2) h) and an echo-tracking of the right carotid bulb will be performed by trained technicians. A bio bank and DNA bank will be established for further biomarker and genetic analyses. The occurrence of cardiovascular disease including acute coronary syndrome, stroke, peripheral artery disease and sudden death, and of mortality, of the participants will be followed up during 20 years. With an estimated mean annual rate of sudden death of 0.1% and its increasing incidence rate with age, between 250 and 300 sudden deaths are expected. This unique study should provide new insights into the regulation of heart rate and blood pressure and should enable to identify novel heart rate parameters that are associated with sudden death.
European Journal of Epidemiology 10/2011; 26(11):887-92. DOI:10.1007/s10654-011-9618-x · 5.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To compare patterns of long-term deaths due to secondary carcinomas, sarcomas, and hematological malignancies occurring after childhood cancer in a cohort of patients followed over a median of 28 years.
The study included 4,230 patients treated at eight institutions, who were at least 5-year survivors of a first cancer, representing 105,670 person-years of observation. Complete clinical, chemotherapeutic, and radiotherapeutic data were recorded, and the integral radiation dose was estimated for 2,701 of the 2,948 patients who had received radiotherapy. The integral dose was estimated for the volume inside the beam edges. The causes of death obtained from death certificates were validated.
In total, 134 events were due to second malignant neoplasm(s) (SMN). We found that the standardized mortality ratio decreased with increasing follow-up for second carcinomas and sarcomas, whereas the absolute excess risk (AER) increased for a second carcinoma but decreased for second sarcomas. There was no clear variation in SMN and AER for hematological malignancies. We found a significant dose-response relationship between the radiation dose received and the mortality rate due to a second sarcoma and carcinoma. The risk of death due to carcinoma and sarcoma as SMN was 5.2-fold and 12.5-fold higher, respectively, in patients who had received a radiation dose exceeding 150 joules.
Among patients who had received radiotherapy, only those having received the highest integral radiation dose actually had a higher risk of dying of a second carcinoma or sarcoma.
International journal of radiation oncology, biology, physics 06/2011; 80(2):339-46. DOI:10.1016/j.ijrobp.2010.02.004 · 4.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To date, very little is known about the long-term risk of death from cerebrovascular sequelae following childhood cancer treatment. The purpose of this study was to assess the role of treatment in very long-term cerebrovascular mortality following childhood cancer. We studied 4227 5-year survivors of a childhood cancer. Information on chemotherapy was collected and the radiation dose delivered to 11 anatomical sites in the brain was estimated. The main outcome that was considered was death due to cerebrovascular disease occurring before 1 January 2008. After a median follow-up of 29 years, 23 deaths due to cerebrovascular diseases had occurred. In the brain, the radiation dose delivered to the prepontine cistern seemed to play a greater role than the average radiation dose received throughout the brain or the dose to any other specific anatomical site in the brain. The risk of death from cerebrovascular disease increased linearly with the local radiation dose to the prepontine cistern. Each unit of absorbed radiation (Gray) delivered to this area increased the risk by 22% (95% confidence interval: 1-44%). Compared with patients who had not received radiotherapy or who had received <0.1 Gray in the prepontine cistern area, those who had received >50 Gray had a 17.8-fold (4.4-73.0) higher hazard ratio of death from cerebrovascular disease. In conclusion, among 5-year survivors of childhood cancer, the radiation dose to the brain during radiotherapy was significantly associated with long-term cerebrovascular mortality.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to assess the role of treatment in long-term overall and cardiovascular mortality after childhood cancer.
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.
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%).
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.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
A significantly increased risk of developing any SMN was observed after Hodgkin's 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 Hodgkin's 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.
Survivors of Hodgkin's lymphoma, retinoblastoma, malignant bone tumor, STS, and germ cell tumor should receive close surveillance because they are at increased risk of developing any SMN.
[Show abstract][Hide abstract] ABSTRACT: Radiotherapy and chemotherapy are associated with an increased risk of a second malignant neoplasm (SMN) after a cancer during childhood. This study specified the dose-effect relationship between radiotherapy, chemotherapy and the risk of a SMN, and investigated the effect of chemo-radiotherapy on the risk of SMN. A case-control study nested in a European cohort of 4,581 patients treated for a solid cancer during childhood was conducted. One hundred and fifty three cases with a SMN and 442 controls were matched according to sex, age at first cancer, calendar year, type of first cancer and follow-up. The local radiation dose was estimated at the site of the SMN, for each case and at the same site, for the matched controls. The local dose of radiation significantly increased the risk of a SMN. The best model was linear with an excess relative risk per Gray equal to 0.13 (95% CI, 0.06; 0.26). Any chemotherapy significantly increased the risk of a SMN, odd ratio(adjusted) (OR(adjusted)) = 2.4 (95% confidence interval (95% CI), 1.4-4.1), but no dose-effect relationship was observed between any drug category and the risk of a SMN. Patients who had received concomitant chemo-radiotherapy were significantly more at risk of developing a SMN than patients who had been treated with sequential chemo-radiotherapy, even after adjustment for the local dose of radiation and the 6 most frequently administered drugs, OR(adjusted) = 2.3 (95%CI, 1.1-4.8). Radiation was found to be the foremost treatment-related risk factor for the occurrence of a SMN. Compared to sequential treatment, concomitant chemo-radiotherapy may lead to a higher risk of a SMN.
International Journal of Cancer 01/2007; 120(1):96-102. DOI:10.1002/ijc.22197 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to determine the therapy-related risk factors for the occurrence of leukaemia after childhood solid cancer. Among 4204 3-year survivors of a childhood cancer treated in eight French and British centres before 1986, 11 patients developed leukaemia as a second malignant neoplasm (SMN). Compared with the leukaemia incidence in the general French and British populations, the standardised incidence ratio (SIR) of leukaemia was 7.8 (95% CI 4.0-13.4). It decreased from 20.3 (95% CI 8.3-41.2) during the first years of follow-up, to 2.2 (95% CI 0.1-9.7) between 10 and 20 years, but rose again to 14.8 (95% CI 3.7-38.3) 20 or more years after the first cancer. Radiotherapy appeared to increase the risk of leukaemia at moderate weighted doses to active bone marrow; the relative risk (RR) was 4.2 (95% CI 0.8-20.7) for doses ranging from 3 to 6.6 Gy. A greater RR was observed for epipodophyllotoxins and for vinca alkaloids. No specific type of first malignant neoplasm (FMN) was found to lead to a higher risk of secondary leukaemia. Epipodophyllotoxins and vinca alkaloids at high doses and moderate weighted radiation doses to active bone marrow may contribute independently to an increased risk of leukaemia for patients treated for childhood cancer. Our results suggest that the long-term risk of secondary leukaemia could be higher than previously reported.
European Journal of Cancer 12/2006; 42(16):2757-64. DOI:10.1016/j.ejca.2006.05.034 · 5.42 Impact Factor