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Purpose Irradiation (>3 Gy) to the breast or axillae before 30 years of age increases the risk of secondary breast cancer (SBC). The purpose of this article is to describe the clinical characteristics of SBC and the way of diagnosis in young women (before the age of national screening) in France who had received previous radiotherapy for a childhood or a young adulthood cancer. Patients and methods This retrospective, multicentre study reviewed the medical records of women with SBC before the age of the national screening who had received irradiation (≥3 Gy) on part or all of the breast before 30 years of age, for any type of tumour except BC. Results A total of 121 SBC were detected in 104 women with previous radiotherapy. Twenty percent of SBC were detected during regular breast screening and 16% of the women had a regular radiological follow-up. Conclusion Our results points out that the main proportion of childhood cancer survivors did not benefit from the recommended breast cancer screening. This result is comparable to other previously published studies in other countries. A national screening programme is necessary and should take into account the patient’s age, family history, personal medical history and previous radiotherapy to reduce the number of SBC diagnosed at an advanced stage.

Background After chest radiotherapy (RT) for Hodgkin lymphoma (HL), women experience a dose-dependent increased breast cancer (BC) risk. It is unknown whether endogenous and exogenous gonadal hormones affect the radiation dose-response relationship. Methods We conducted a nested case-control study among female 5-year HL survivors treated before 41 years between 1965-2000. Data were collected through medical records and questionnaires for 174 BC cases and 466 matched controls. RT charts, simulation films and mammography reports were used to estimate the radiation dose to the location of the breast tumor. Results The median interval between HL and BC diagnosis was 21.9 years. 98% of BC cases had received chest RT, compared to 92% of controls. We observed a linear radiation dose-response curve with an adjusted excess odd ratio (EOR) of 5.4%/Gray (95%CI:1.8%-13.37%). Women with menopause Conclusion HRT use did not appear to increase BC risk in female HL survivors with a therapy-induced early menopause. Moreover, there was no evidence for interaction between RT dose and years with intact ovarian function or HRT use. Citation Format: Krul IM, Opstal - van Winden AWJ, Aleman BMP, Janus CPM, van Eggermond AM, de Bruin ML, Hauptmann M, Krol ADG, Schaapveld M, Broeks A, Kooijman KR, Fase S, Lybeert ML, Zijlstra JM, van der Maazen RWM, Kesminiene A, Diallo I, de Vathaire F, Russell NS, van Leeuwen FE. Breast cancer after Hodgkin lymphoma: Influence of endogenous and exogenous gonadal hormones on the radiation dose-response relationship [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-06-04.

Thyroid and breast cancers share a lot of similarities in their biology: both are more frequent in women and are influenced by hormonal and reproductive factors. Moreover, individuals diagnosed with breast cancer are more likely to develop thyroid cancer as a secondary malignancy than patient diagnosed with other cancer types, and vice-versa (Nielsen et al., 2016). Genetic factors contributing to the incidence of breast cancer have been extensively studied, and 313 risk variants were identified (Mavaddat et al., 2019). On the other hand, GWAS studies on thyroid cancer have been scarce due to the lesser incidence of this disease as well as the lack of data, but it is known that thyroid cancer is the only cancer for which genetic factors contribute more than environmental factors. For thyroid cancer 10 loci were identified (Gudmundsson et al., 2017), and one of them (2q35) was previously reported to increase risk of breast cancer (Stacey et al., 2007). To date, no study has been conducted to identify common genetic factors between breast and thyroid cancer. We have access to GWAS results on thyroid cancer (EPITHYR consortium), which was coordinated by our team, and to the summary statistics of the most recent GWAS conducted by the Breast Cancer Association Consortium (BCAC, Michailidou et al., 2017). In this ongoing study, we aim at studying pleiotropy between both cancers at different scales. First, we will estimate the genome-wide genetic correlation using the LDscore and SumHer methods. Second, we will analyze the association of the polygenic risk scores of breast cancer in association to thyroid cancer risk and vice-versa. Third, we will identify the pleiotropic SNPs affecting both cancers. These analyses are still ongoing and the results will be presented. Evidence of carcinogenic pleiotropy will improve our understanding of the diseases etiology and will provide insights on the underlying common biology between both cancers. This work is supported by “La Ligue contre le Cancer” through the CCGIP (Cross Cancer Genomic Investigation of Pathway analysis and GxE interactions) project.

International audience; With the increase in survival from childhood cancer , research has increasingly focused on the educational and professional achievements of childhood cancer survivors. Yet , if large-­‐scale studies provide an acute description of the current situation of childhood cancer survivors , little is known about their trajectories and the social processes shaping these trajectories. Using a qualitative methodology , drawing from a life course perspective , this study sought to describe the role of childhood cancer and its side effects in educational trajectories , as perceived by the participants. We investigated related processes of social adjustment to cancer , that is to say , choices or decisions that survivors related to the illness in the making of their career plans. Eighty long-­‐term French childhood cancer survivors participating in the Euro2K longitudinal study were interviewed through in-­‐depth , face-­‐to-­‐face interviews undertaken in 2011-­‐2012. There were various types of impact described by respondents of the diagnosis of cancer on their occupational trajectories. These varied according to gender. In women , childhood cancer tended to result in poor educational achievement , or in steering the individual towards a health care or child care occupation. This was justified by a desire to return the support that had been offered to them as patients. In men , however , childhood cancer led to a shift in career plans , because of physical sequelae , or because of concerns about their future health. Paradoxically , this limitation had a positive impact in their occupational achievement , as most of these men disregarded blue-­‐collar jobs and chose more qualified white-­‐collar occupations. Overall , findings suggest that childhood cancer influenced educational trajectories and , thus , socioeconomic status in adulthood , through mechanisms embedded in gender norms. These mechanisms could explain gender inequalities in educational achievement after childhood cancer reported in large-­‐scale cohort studies .

Background: A marginal interaction between sex and the type of alkylating agent was observed for event‐free survival in the Euro‐EWING99‐R1 randomized controlled trial (RCT) comparing cyclophosphamide and ifosfamide in Ewing sarcoma. To further evaluate this interaction, we performed an individual patient data meta‐analysis of RCTs assessing cyclophosphamide versus ifosfamide in any type of cancer. Methods: A literature search produced two more eligible RCTs (EICESS92 and IRS‐IV). The endpoints were progression‐free survival (PFS, main endpoint) and overall survival (OS). The hazard ratios (HRs) of the treatment‐by‐sex interaction and their 95% confidence interval (95% CI) were assessed using stratified multivariable Cox models. Heterogeneity of the interaction across age categories and trials was explored. We also assessed this interaction for severe acute toxicity using logistic models. Results: The meta‐analysis comprised 1,528 pediatric and young adult sarcoma patients from three RCTs: Euro‐EWING99‐R1 (n = 856), EICESS92 (n = 155), and IRS‐IV (n = 517). There were 224 PFS events in Euro‐EWING99‐R1 and 200 in the validation set (EICESS92 + IRS‐IV), and 171 and 154 deaths in each dataset, respectively. The estimated treatment‐by‐sex interaction for PFS in Euro‐EWING99‐R1 (HR = 1.73, 95% CI = 1.00–3.00) was not replicated in the validation set (HR = 0.97, 95% CI = 0.55–1.72), without heterogeneity across trials (P = 0.62). In the pooled analysis, the treatment‐by‐sex interaction was not significant (HR = 1.31, 95% CI = 0.89–1.95, P = 0.17), without heterogeneity across age categories (P = 0.88) and trials (P = 0.36). Similar results were observed for OS. No significant treatment‐by‐sex interaction was observed for leucopenia/neutropenia (P = 0.45), infection (P = 0.64), or renal toxicity (P = 0.20). Conclusion: Our meta‐analysis did not confirm the hypothesis of a treatment‐by‐sex interaction on efficacy or toxicity outcomes. Refereed/Peer-reviewed

Background In retrospective case-control studies performed following nuclear tests or nuclear accidents, individual thyroid radiation dose reconstructions are based on fallout and meteorological data from the residential area, demographic characteristics, and lifestyle as well as dietary information. Collecting the latter is a controversial step, as dietary declarations may be affected by the subjects’ beliefs about their risk behavior. This report analyses the potential for such bias in a case-control study performed in eastern France. Methods The study included 765 cases of differentiated thyroid carcinoma matched with 831 controls. Risk perceptions and beliefs of cases and controls were compared using Chi2 tests and differences in dietary reports were analyzed using a two-way ANOVA. Results In general, atmospheric pollution and living near a nuclear power plant were the two major risks that may influence thyroid cancer occurrence cited by cases and controls. When focusing in particular on the consequences of the Chernobyl accident, cases were more likely to think that the consequences were responsible for thyroid cancer occurrence than controls. Vegetable consumption during the two months after the Chernobyl accident was correlated with the status of subjects, but not to their beliefs. Conversely, consumption of fresh dairy products was not correlated with the status or beliefs of subjects. Conclusion We found no evidence of systematic bias in dietary reports according to the status or beliefs held by subjects about the link between thyroid cancer occurrence and Chernobyl fallout. As such, these dietary reports may be used in further studies involving individual dosimetric reconstructions.

BACKGROUND: Between 1966 and 1974, France conducted 41 atmospheric nuclear tests in Polynesia, but their potential health effects have not previously been investigated. METHODS: In a case-control study, we compared the radiation exposure of almost all the French Polynesians diagnosed with differentiated thyroid carcinoma between 1981 and 2003 (n = 229) to the exposure of 373 French Polynesian control individuals without cancer from the general population. Radiation exposures were estimated using measurements after the nuclear tests, age at time of each test, residential and dietary information. RESULTS: The average thyroid dose before 15 years of age was about 1.8 mGy, and 5% of the cases and 3% of the controls received a dose above 10 mGy. Despite this low level of dose, and after adjusting for ethnic group, level of education, body surface area, family history of thyroid cancer and number of pregnancies for women, we observed an increasing risk (P = 0.04) of thyroid cancer with increasing thyroid dose received before age of 15 years, which remained after excluding non-aggressive differentiated thyroid micro-carcinomas. This increase of risk per unit of thyroid radiation dose was higher (P = 0.03) in women who later experienced four or more pregnancies than among other women. CONCLUSION: The risk estimate is low, but is based on limited exposure data. The release of information on exposure, currently classified, would greatly improve the reliability of the risk estimation. British Journal of Cancer (2010) 103, 1115-1121. doi: 10.1038/sj.bjc.6605862 www.bjcancer.com Published online 31 August 2010 (c) 2010 Cancer Research UK

Ankle sprains are the most frequent injuries in sport and daily life, and are usually treated with anti-inflammatory drugs or compounds that have an effect on microcirculation. The efficacy and tolerability of a novel plaster containing both diclofenac epolamine (DHEP) and heparin in the treatment of acute painful ankle sprains with oedema was investigated in a randomized, double-blind, placebo-controlled study.This study, carried out in 32 French medical centres, enrolled 233 patients (148 male and 86 female, aged 18-65 years) with an ankle sprain that had occurred within the previous 48 hours. Patients were treated once daily with DHEP heparin or placebo plaster for 7 days.Reduction in ankle joint swelling measured by submalleolar circumference was the primary efficacy endpoint; secondary endpoints were pain (at rest, in active mobilization, by passive stretch and by pressure), functional disability and global judgement of efficacy and tolerability.DHEP heparin-treated patients experienced a significantly greater reduction in joint swelling compared with placebo (p = 0.005). The reduction in pain was also in favour of DHEP heparin patients, with significantly lower pain in DHEP heparin-treated than placebo-treated patients within 3 hours of the first application (p0.05). Only two patients in the DHEP heparin plaster group and six in the placebo group experienced minor adverse events, all of which resolved spontaneously. By design, the study was limited to a placebo-controlled comparison, and there was no test for possible selection bias (subsequently ruled out by choice of efficacy parameters and measures) that may have resulted in a baseline imbalance between patient groups.Results confirm the efficacy of DHEP heparin plaster compared with placebo for the treatment of painful ankle sprain with oedema. Prompt control of pain and oedema may shorten the time to initiation of a rehabilitation programme, thus reducing the risk of ankle disability recurrence and the development of chronic injury.

This Workshop was organised by the Organisation of European Cancer Institutes (OECI) to provide a forum for discussing the late side-effects resulting from different cancer treatments. One of the main Workshop objectives was to generate recommendations on how to improve knowledge and, consequently, long-term care for cancer survivors.

Depuis maintenant plus de 20 ans, on assiste a une augmentation reuliere de la survie des patients apres le diagnostic d’un cancer. Malgre les efforts pour cibler leur action sur les cellules cancereuses, la chimiotherapie et la radiotherapie atteignent les tissus sains et ont des effets cancerogenes sur ces tissus. L’etude des cancers secondaires aux radiotherapies a fait l’objet d’un grand nombre d’etudes, avec ou sans estimation de la dose de radiation recue a leur siege, mais les resultats sont sou-vent contradictoires. Il n’existe tou-jours pas de modele capable de predire le risque de cancer secondaire associe a une radiotherapie donnee, ce qui implique qu’on ne peut anticiper les consequences des techniques nouvelles de radiotherapie telles que l’IMRT.

Si la publication 99 de la CIPR et le BEIR VII recommandent de maintenir l’usage d’une relation lineaire sans seuil (RLSS) pour estimer l’exces de risque relatif de cancer lie a de faibles doses de rayonnements ionisants (RI), le rapport conjoint de l’Academie des sciences et de l’Academie de medecine (2005) conclut qu’elle conduit a une forte surestimation des risques des faibles et des tres faibles doses. Les fondements de la RLSS sont remis en question par de nouvelles donnees biologiques et de l’experimentation animale qui montrent que la defense contre les RI met en jeu le micro-environnement cellulaire et le systeme immunitaire, et que les mecanismes de defense contre les faibles doses de RI sont differents et plus efficaces. Ces cellules lesees par une irradiation a faible dose sont eliminees ; la reparation s’impose a forte dose pour preserver les fonctions tissulaires. Les organismes pluricellulaires realisent ainsi une defense au moindre cout et au moindre risque contre les RI et les degâts du metabolisme oxydatif. Les differences entre les defenses contre les faibles et fortes doses sont particulierement nettes dans le cas de contamination par des emetteurs alpha qui montrent chez l’homme et l’animal des effets a seuil de plusieurs grays. Ces differences remettent en question les resultats des etudes epidemiologiques qui, pour des raisons de puissance statistique, estiment les risques en fusionnant des donnees obtenues pour des gammes de doses tres etendues, ce qui sous entend implicitement que les mecanismes de cancerogenese sont similaires quelle que soit la dose. L’estimation des risques des faibles doses de RI doit reposer sur des etudes specifiquement limitees aux faibles doses, avec une evaluation precise de facteurs de confusion potentiels. La synthese des etudes de cohorte pour lesquelles on dispose des coefficients de risque fondes sur les seules doses inferieures a 100 mSv chez l’adulte ne montre pas d’exces de risque relatif significatif, ni pour les tumeurs solides ni pour les leucemies.

AIM: The goal of this study was to estimate the cumulative activity of (131)I to be administered to patients with distant metastases from thyroid carcinoma. METHODS: A total of 444 patients were treated from 1953-1994 for distant metastases from papillary and follicular thyroid carcinoma: 223 had lung metastases only, 115 had bone metastases only, 82 had both lung and bone metastases, and 24 had metastases at other sites. Treatment consisted of the administration of 3.7 GBq (100 mCi) (131)I after withdrawal of thyroid hormone treatment, every 3-9 months during the first 2 yr and then once a year until the disappearance of any metastatic uptake. Thyroxine treatment was given at suppressive doses between (131)I treatment courses. RESULTS: Negative imaging studies (negative total body (131)I scans and conventional radiographs) were attained in 43% of the 295 patients with (131)I uptake; more frequently in those who were younger, had well-differentiated tumors, and had a limited extent of disease. Most negative studies (96%) were obtained after the administration of 3.7-22 GBq (100-600 mCi). Almost half of negative studies were obtained more than 5 yr after the initiation of the treatment of metastases. Among patients who achieved a negative study, only 7% experienced a subsequent tumor recurrence. Overall survival at 10 yr after initiation of (131)I treatment was 92% in patients who achieved a negative study and 19% in those who did not. CONCLUSION: (131)I treatment is highly effective in younger patients with (131)I uptake and with small metastases. They should be treated until the disappearance of any uptake or until a cumulative activity of 22 GBq has been administered. In the other patients, other treatment modalities should be used when tumor progression has been documented.

The purpose of this paper was to determine the cardiac status in children 15 years or more after adriamycin therapy for a solid tumour. Of the 447 pts, 229 pts were fully studied and 218 were not. The following cardiac evaluations were proposed to all the 447 consecutive patients (pts): (1) cardiac Doppler US by one of two expert cardiologists; (2) cardiac rhythm and conduction abnormalities including 24-hour holter ECG; (3) (131)l-mlBG myocardial scintigraphy; (4) serum brain natriuretic peptide levels at rest; (5) an exercise test with VO(2) max measurement. The radiation doses delivered to 6 points in the heart were estimated for all patients who had received radiotherapy. Congestive heart failure was diagnosed in 24 of 229 (10%) evaluated pts, with a median interval of 15 years (0.3-24 years) from the first symptom after adriamycin treatment. Among the 205 remaining pts, 13 asymptomatic pts (6%) had severe (n=4) (FS

OBJECTIVE: To analyse trends in diagnostic practices of thyroid diseases and to relate them to the increase in thyroid cancer incidence in France over time. DESIGN: From 1980 to 2000, a French retrospective multicentric (three endocrinology and three nuclear medicine centres) study of thyroid diseases was conducted on 20 consecutive unselected patients' records, sampled every 5 years in each centre. METHODS: Characteristics of the population and diagnosis procedures (thyroid ultrasonography (US), radionuclide scan, cytology and hormonal measurements) were described over time. Changing trends in operated patients and in cancer prevalence were analysed as well as the impact of practices on cancer incidence. RESULTS: The study included 471 patients (82% female, mean age 46.7, range 9-84 years), referred for nodular thyroid diseases (66.7%) or thyroid dysfunctions (33.3%). A significant increase in US (3 to 84.8%) and cytological practices (4.5 to 23%), and a decrease (89.4 to 49.6%) in radionuclide scan procedures were observed over time. Although the proportion of patients undergoing surgery remained constant (24.8%), the prevalence of cancer increased among operated patients from 12.5 to 37% (P=0.006). In a Cox's proportional hazard model stratified on the clinical characteristics of patients, only the cytological practice, regardless of its results, was significantly associated with the occurrence of cancer: relative risk (RR)=4.4 (95% confidence interval (CI): 1.1-16; P=0.04). CONCLUSIONS: From 1980 to 2000, a major evolution in clinical practices has led to the increase in thyroid cancer reported in France. Such changes in medical, as well as in surgical and pathological, practices must be taken into account in incidence measurement.

The late health effects associated with radioiodine ((131)I) given as treatment for thyroid cancer are difficult to assess since the number of thyroid cancer patients treated at each centre is limited. The risk of second primary malignancies (SPMs) was evaluated in a European cohort of thyroid cancer patients. A common database was obtained by pooling the 2-year survivors of the three major Swedish, Italian, and French cohorts of papillary and follicular thyroid cancer patients. A time-dependent analysis using external comparison was performed. The study concerned 6841 thyroid cancer patients, diagnosed during the period 1934-1995, at a mean age of 44 years. In all, 17% were treated with external radiotherapy and 62% received (131)I. In total, 576 patients were diagnosed with a SPM. Compared to the general population of each of the three countries, an overall significantly increased risk of SPM of 27% (95% CI: 15-40) was seen in the European cohort. An increased risk of both solid tumours and leukaemias was found with increasing cumulative activity of (131)I administered, with an excess absolute risk of 14.4 solid cancers and of 0.8 leukaemias per GBq of (131)I and 10(5) person-years of follow-up. A relationship was found between (131)I administration and occurrence of bone and soft tissue, colorectal, and salivary gland cancers. These results strongly highlight the necessity to delineate the indications of (131)I treatment in thyroid cancer patients in order to restrict its use to patients in whom clinical benefits are expected.

In total, 281 of the 7711 women who were initially treated for breast cancer between 1954 and 1983 at the Gustave Roussy Institute developed a second malignant neoplasm (SMN) other than second primary breast cancer and nonmelanoma skin cancer at least 1 year after breast cancer treatment. We carried out a nested case-control study to determine the overall relationship between the dose of radiotherapy received at a given anatomical site and the risk of SMN at the same site. In total, 75% of the cases of SMN were previously treated by radiotherapy, as compared to 73% of the controls. In the irradiated patients, the median local dose was higher among cases (3.1 Gy) than among controls (1.3 Gy). More than 40% of the irradiated patients received a local dose of less than 1 Gy. A purely quadratic relationship was observed between the dose of radiation received at an anatomical site and the risk of SMN at this site. According to the quadratic model, the excess risk of SMN was 0.2% (95% CI 0.05-0.5%) when the target organ received 1 Gy. This risk did not differ significantly according to age at the time of radiotherapy (40 vsor=40 years). The risk of SMN was 6.7-fold higher for doses of 25 Gy or more than in the absence of radiotherapy. No carcinogenic effect of chemotherapy was observed and a dose-effect relationship between the length of tamoxifen treatment and SMN occurrence was found. This relationship was limited to endometrial cancers and did not modify the relationship with radiation dose. Our results suggest that high radiation doses slightly increase the risk of second malignancies after breast cancer.

We present the data of the Cancer Registry of French Polynesia (FP) for the 1990–1995 period, highlighting the difference between the incidences among inhabitants born in FP and in immigrants. A total of 1606 incident cases of cancer were registered during the 6-year period from 1990 to 1995, about 90% of which were histologically confirmed. Among these incident cases, 1361 occurred in native French Polynesians (FPs) and 245 in immigrants. Overall cancer incidence was found to be very slightly higher among women in the native population (209/105) than among immigrants (191/105), and lower among men in the native population (186/105) than in the immigrants (241/105). Cervix, corpus uteri, and thyroid cancer incidence rates were higher among women born in FP than among immigrant women. In contrast, colorectal cancer and melanoma incidences rates were lower, and colorectal cancer was similar. Laryngeal cancer incidence was higher among men born in FP than among immigrant men. In contrast, cancers of the oral cavity, colon and rectum, prostate gland, bladder and melanoma were less frequent. This first report, based on the data from the Cancer Registry of French Polynesia, shows high cancer incidence rates in females and low incidence in males born in FP, as compared to those recorded in France; and low cancer incidence rates, as compared to New Zealand Maoris and Hawaiians. For certain cancers, for example colorectal cancer, the incidence in the immigrant population seems to be between that of the native FP population and that of the population living in France, and lower than in New Zealand Maoris and Hawaiians.

To determine the incidence of haematological malignancies in French Polynesia from 1990 to 1995, we collected cases from the local cancer registry, sanitary evacuation files and all the histopathology and clinical biology laboratories. All leukaemias, non Hodgkin's lymphomas, and multiple myelomas incidence was slightly lower among French Polynesians than among Maoris from New-Zealand and Hawaiians of Hawaii. Standardised Incidence Ratio (SIR) for Hodgkin's disease among females was 0.08 when comparing to Hawaiians and 0.33 when comparing to Maoris. Other salient features were a high proportion of high grade and Burkitt's lymphoma, the absence of Hodgkin's disease after 40 years of age, a low incidence of chronic lymphoid leukaemia, and a high non lymphoblastic/lymphoblastic acute leukaemia ratio in childhood. This study stresses the peculiar incidence of some haematological malignancies in this south pacific area.

The variation in the risk of solid second malignant neoplasms (SMN) with time since first cancer during childhood has been previously reported. However, no study has been performed that controls for the distribution of radiation dose and the aggressiveness of past chemotherapy, which could be responsible for the observed temporal variation of the risk. The purpose of this study was to investigate the influence of the treatment on the long-term pattern of the incidence of solid SMN after a first cancer in childhood. We studied a cohort of 4400 patients from eight centres in France and the UK. Patients had to be alive 3 years or more after a first cancer treated before the age of 17 years and before the end of 1985. For each patient in the cohort, the complete clinical, chemotherapy and radiotherapy history was recorded. For each patient who had received external radiotherapy, the dose of radiation received by 151 sites of the body were estimated. After a mean follow-up of 15 years, 113 children developed a solid SMN, compared to 12.3 expected from general population rates. A similar distribution pattern was observed among the 1045 patients treated with radiotherapy alone and the 2064 patients treated with radiotherapy plus chemotherapy; the relative risk, but not the excess absolute risk, of solid SMN decreased with time after first treatment; the excess absolute risk increased during a period of at least 30 years after the first cancer. This pattern remained after controlling for chemotherapy and for the average dose of radiation to the major sites of SMN. It also remained when excluding patients with a first cancer type or an associated syndrome known to predispose to SMN. When compared with radiotherapy alone, the addition of chemotherapy increases the risk of solid SMN after a first cancer in childhood, but does not significantly modify the variation of this risk during the time after the first cancer. © 1999 Cancer Research Campaign

Objective To determine the efficacy and safety of using natural platelet-activating factor receptor antagonist (PAFra), BN 52021, to treat patients with severe Gram-negative bacterial sepsis. Design A prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial. Setting Fifty-nine academic medical center intensive care units in Europe. Patients Six hundred nine patients with severe sepsis, suspected to be related to Gram-negative bacterial infection, who received PAFra or placebo. Interventions Patients were randomized to receive either a dose of PAFra (120 mg iv) every 12 hrs over a 4-day period or placebo over a 4-day period. Measurements and Main Results The patients were well matched at study entry for severity of illness and for risk factors known to influence the outcome of sepsis. Among all randomized patients, the 28-day, all-cause mortality rate was 49% (152/308) in the placebo group, and 47% (140/300) in the PAFra group (p = .50). When analyzed on the basis of the previously defined target population, the 28-day, all-cause mortality rate was 50% (115/232) in the placebo group and 44% (94/212) in the PAFra group, yielding a 12% reduction in mortality rate (p = .29). In patients with documented infection involving other organisms, there was no difference between treated and placebo groups. When the outcomes of organ dysfunctions were examined in the overall population and in the documented Gram-negative bacterial infection population, the number of patients who resolved hepatic dysfunction tended to be higher in the treated group than in the placebo group (p = .06). The number of adverse events reported were not different between the two groups. Conclusions A 4-day administration of the studied PAFra (BN 52021) failed to demonstrate a statistically significant reduction in the mortality rate of patients with severe sepsis suspected to be related to Gram-negative bacterial infection. If PAFra treatment has any therapeutic activity in severe Gram-negative bacterial sepsis, the incremental benefits are small and will be difficult to demonstrate in a patient population as defined by this clinical trial. (Crit Care Med 1998; 26:1963-1971)

We studied 1771 patients treated for a thyroid cancer in two institutions. None of these patients had been treated with external radiotherapy and 1497 had received (131)I. The average (131)I cumulative activity administered was 7.2 GBq, and the estimated average dose was 0.34 Sv to the bone marrow and 0.80 Sv to the whole body. After a mean follow-up of 10 years, no case of leukaemia was observed, compared with 2.5 expected according to the coefficients derived from Japanese atomic bomb survivors (P = 0.1). A total of 80 patients developed a solid second malignant neoplasm (SMN), among whom 13 developed a colorectal cancer. The risk of colorectal cancer was found to be related to the total activity of (131)I administered 5 years or more before its diagnosis (excess relative risk = 0.5 per GBq, P = 0.02). These findings were probably caused by the accumulation of (131)I in the colon lumen. Hence, in the absence of laxative treatment, the dose to the colon as a result of (131)I administered for the treatment of thyroid cancer could be higher than expected from calculation of the International Commission on Radiological Protection (ICRP). When digestive tract cancers were excluded, the overall excess relative risk of second cancer per estimated effective sievert received to the whole body was -0.2 (P = 0.6). Images Figure 1

Because genetic predisposition probably plays an important role in the aetiology of most of childhood cancers, studies of second primaries occurring after these cancers may be particularly informative about possible common genetic mechanisms in both of these cancers. We have studied the incidence of thyroid tumours occurring after cancer in childhood in a cohort of 592 children treated before 1970. Among these children, six later developed a thyroid carcinoma, and 18 developed a thyroid adenoma. Radiation doses received to the thyroid by each of the irradiated children have been estimated using individual radiotherapeutic technical records. Thyroid carcinomas and thyroid adenomas were five times more frequent after irradiation for neuroblastoma than after irradiation for any other first cancer. This ratio did not depend on sex, nor on time elapsed since irradiation, nor on dose of radiation received for the thyroid gland. This result suggests that there is a common mechanism for the occurrence of neuroblastoma and of differentiated thyroid tumour.

This study presents a method aimed at creating radiotherapy (RT) patient-adjustable whole-body phantoms to permit retrospective and prospective peripheral dose evaluations for enhanced patient radioprotection. Our strategy involves virtual whole-body patient models (WBPM) in different RT treatment positions for both genders and for different age groups. It includes a software tool designed to match the anatomy of the phantoms with the anatomy of the actual patients, based on the quality of patient data available. The procedure for adjusting a WBPM to patient morphology includes typical dimensions available in basic auxological tables for the French population. Adjustment is semi-automatic. Because of the complexity of the human anatomy, skilled personnel are required to validate changes made in the phantom anatomy. This research is part of a global project aimed at proposing appropriate methods and software tools capable of reconstituting the anatomy and dose evaluations in the entire body of RT patients in an adapted treatment planning system (TPS). The graphic user interface is that of a TPS adapted to obtain a comfortable working process. Such WBPM have been used to supplement patient therapy planning images, usually restricted to regions involved in treatment. Here we report, as an example, the case of a patient treated for prostate cancer whose therapy planning images were complemented by an anatomy model. Although present results are preliminary and our research is ongoing, they appear encouraging, since such patient-adjusted phantoms are crucial in the optimization of radiation protection of patients and for follow-up studies.

Background and purpose A cohort study was performed to investigate the carcinogenic effect of treatment with ionizing radiation of skin hemangioma in early childhood. This study presents the incidence of differentiated thyroid and breast cancers after radiotherapy in this cohort. Methods and Materials: Of a total of 8307 patients treated for a skin hemangioma between 1940 and 1973 at the Institut Gustave-Roussy, 4 767 (3 317 women) were included in an incidence study, among whom 3 795 (2 698 women) received radiotherapy. External radiotherapy, Radium 226, Strontium 90, Yttrium 90, and Phosphorus 32 were used as treatment. The mean age at first exposure was 0.7 years and the mean absorbed dose to the breast was 70 mGy and 41 mGy to the thyroid. Breast and Thyroid tumors cases were obtained by sending a questionnaire, and verified from pathological reports. Estimation of breast and thyroid cancer specific incidence rates in French population was obtained from French cancer registry network. External and internal analyses were performed. Results: During an average follow-up of 35 years, a total of 11 patients developed a differentiated thyroid carcinoma and 19 women developed BC, i.e. respectively 2.5 (95%CI: 1.4-4.4) and 2.5 (95% CI 1.5-3.8) more than expected from French general population. An association between weight and BMI at age 18 and BC risk was observed. Thyroid carcinoma incidence was higher in non-smoker patients. As compared with patients who had not received radiotherapy, those who had, had a 3.5 times higher (9%CI : 2.2-5.4 ) risk of developing a BC. Despite the risk of BC was multiplied by 3.6, 6.0, 7.9, for dose of radiation to breast varying, respectively from, 0 to 10, from 10 to 100, and > 100 (mGy), as compared to patients who did not received radiotherapy, the dose response was not significant. However, a significant dose response relationship was estimated between the radiation dose received to thyroid and the risk of thyroid cancer (Excess Relative Risk per GY, ERR/Gy: 14.7, 95%CI: 1.6 - 62.9). Conclusion: This study confirms that radiation treatment performed in the past for hemangioma during infancy increased the risk of thyroid and breast cancers.

Background: Radiation is known to be mutagenic. In thyroid cancer treatment, 131I is usually administered, for the first treatment, at a 3700MBq activity, corresponding to an estimated radiation dose of 140mGy to the ovaries. However data on the effects of 131I therapy on pregnancy outcomes, especially untoward, are scarce. Methods: Data on 2673 pregnancies were obtained by interviewing female patients treated for thyroid carcinoma who had not received significant external radiation to the ovaries, in three French hospitals and one Italian hospital. Results: The incidence of miscarriages was 10% before any treatment for thyroid cancer ; this percentage increased after surgery for thyroid cancer, both before (20%) and after (19%) 131I treatment, with no variation according to the cumulative dose. Miscarriages were not significantly more frequent in women treated with 131I during the year before conception, even in subjects who had received more than 370MBq during that year, as compared to women never treated with 131I. The incidence of stillbirths, preterm births, a low birth weight, congenital malformation and death during the first year of life was not significantly different before or after 131I therapy. The incidence of thyroid and non thyroidal cancers was similar in children born either before or after the mother’s exposure to 131I. Conclusion: In our data, we found no evidence that exposure to 131I affects the outcome of subsequent pregnancies and offspring. Whether the number of malformations, or thyroid and non thyroidal cancers are related to gonadal irradiation remains to be established. Our findings allowed us to fuel the debate on the doubling dose: the concept is still heatedly debated and the value of 1 Gy as the doubling dose in humans should be rediscussed.

Background Childhood cancer survival has increased considerably during the last 3 decades. Until now, little has been known about the risk factors for death due to cardiovascular diseases in long-term survivors of a childhood cancer. Methods We investigated long-term mortality in a cohort of 4 122 5-year survivors (aged 0-15 years) of a childhood cancer treated between 1942 and 1986 in 8 centres in France and Great Britain as having a solid cancer and followed up over an average of 26 years. 98% of vital status were obtained from INSEE and 95% of causes of death from Cepi-Dc. Information about chemotherapy was collected, and the radiation dose received in all except for 159 of the 2 870 patients, who had received radiotherapy was estimated, The radiation dose received at 188 anatomical sites are estimated for each radiotherapy course of every child. The classification of causes of death was based on a comparison between the code topographic first cancer and the leading cause of death. The causes of death from heart disease the most common are: heart disease, heart failure and acute myocardial infarction Results A total of 603 patients died during the follow-up, i.e. 8.3-fold (95% CI 7.6-9.0) more than that expected in the general population. A total of 32 patients died of cardiovascular diseases, i.e. 4.8-fold (95% CI 3.3-6.7) more than expected, 21 of which were cardiac diseases, i.e. 6.0-fold (95% CI 3.8-9.0) more than expected. Patients who had received radiotherapy had a 5.4-fold (95% CI 1.6-33.0) higher risk of mortality due to cardiovascular disease than those who had not. Mortality due to cardiac disease was related to the administration of anthracyclines, alkylating agents and/or vinca alkaloids. Patients who had received between 5 to 14.9 Gy to the heart during radiotherapy had a 14.5-fold (95% CI 2-291) higher risk of mortality from cardiac diseases than patients who had not received radiotherapy. Patients who had received on average, more than 5 Gy to the brain were at a higher risk of developing vascular diseases (n=11). Conclusions Childhood cancer survivors are at a high long-term risk of mortality from cardiac diseases when treated with radiotherapy if the average radiation dose to the heart is higher than 5 Gy, or with anthracyclines, alkylating agents and/or vinca alkaloids. The cardiovascular diseases are the causes non-cancerous most frequent in the very long term after treatment for cancer of the child.

Public Health Codes more and more require that any information relevant to the estimation of the high doses delivered within the target volumes and low doses delivered outside should be recorded. In this context, the availability for each radiotherapy patient of the magnitude of the unavoidable low doses delivered outside the target-volumes becomes an important issue. However, to date, Treatment Planning Systems (TPS) are not designed for this issue. Therefore, we have developed a new version of the ISOgray TPS which can provide, in addition to the doses distributions in the fields, the magnitude of the doses to distant healthy tissues in the course of common radiotherapeutic procedures. Our strategy involves 3 modules: A library of adjustable whole-body patient models in treatment position which allows different patient anatomies to be simulated; A multi-sources beam model, which allows the description of the irradiation field to be extended to the whole body; A dose calculation engine producing the distributions of doses in the fields and in any organ outside. This paper describes the principles of the system and provides data on doses distributions to distant organs for various common radiotherapeutic procedures. At this stage of development, the agreement of measured and calculated doses reaches ±3% in the radiation field and is better than ±15% outside. In the case of a 17 years aged girl treated for Hodgkin's disease using two 6MV opposite photon beams, when a dose of 20 Gy was delivered to the target volume, outside the beam, the dose to the brain was 0.37 Gy (1.85% of the tumor dose), the kidney 0.06 Gy (0.30%) and the ovaries below 0.02 Gy (

We conducted a case-control study of nasopharyngeal carcinoma (NPC) in Tunisia, on diet, dietary patterns and life style, the characteristics of which had been defined by an anthropological study. Eighty incident cases, diagnosed in Tunisia between November 1986 and November 1987, were each matched for sex, age and place of residence to 2 controls. The subjects were asked for dietary data referring to the year preceding the diagnosis of NPC and, with help of their families, during childhood and after weaning. After adjustment for an empirical living conditions score, the following food items were found to be associated with an increased risk for NPC: preserved spiced meat (quaddid), basic stewing preparation (mixture of red and black pepper, garlic, oil, caraway and coriander), and harissa (red pepper, olive oil, garlic, caraway, salt) taken with bread as a snack during childhood and youth. Moreover, subjects who had been directly weaned from mother's milk on to an adult diet were found to be at higher risk for NPC.

Melanoma is a severe skin cancer related to sun exposure. Whether this malignancy is linked to exposure to ionising radiation during adulthood is still controversial. This case-control study examined the risk of melanoma following treatment for an adulthood first malignant neoplasm (FMN). Cases were patients who presented with cutaneous melanoma after a first cancer in adulthood. Controls (3 per case) were patients free of melanoma, matched for age, duration of follow-up since the FMN, type of FMN, and followed in the same institution. A total of 57 cases and 171 controls were included. In the final multivariate analysis, no risk of melanoma was associated with radiotherapy (odds ratio (OR) for 1 Gy = 1.01, 95% confidence interval (95%CI) 0.96-1.07) nor hormonotherapy, whereas chemotherapy use (OR = 2.3, 95%CI 0.93-5.6) and having a history of familial cancer (OR = 2.8, 95%CI 1.3-5.9) exhibited a nearly significant risk. In conclusion, unlike the evidence for risk of exposure to ionising radiation during childhood, we did not substantiate a risk for association of melanoma with exposure to ionising radiation during adulthood. The risk associated with chemotherapy should justify the implementation of skin surveillance for early detection of melanoma in these patients.

Metastases outside the neck occur in 10 to 15% of patients with differentiated thyroid cancer (1). Almost half of them are present initially. The lungs and bones are the most frequent locations. Metastases in the brain, liver or skin tend to appear late in patients who already have multiple bone or lung metastases. In patients with metastatic disease, the main prognostic factor for cure and for survival is the treatment of metastases at a stage when they are not visible on X-rays (2). Their early detection is based on the combined use of serum thyroglobulin (Tg) measurement and total body 1311 scan (1311-TBS).

The aim of this study was to evaluate the frequency of chromosomal abnormalities in thyroid cancer patients before and after radioactive iodine administration in order to assess cytogenetic particularity in Polynesian thyroid cancer patients. Chromosomal abnormalities were studied in 30 Polynesian patients with differentiated thyroid cancer, prior to and 4 days after 131I administration. Unstable chromosomal abnormalities were counted in peripheral blood lymphocytes using a conventional cytogenetic method. Peripheral blood was irradiated in vitro at different doses (0.5, 1 and 2 Gy) in order to establish the dose-response of the lymphocytes. Control groups were composed of 50 European thyroid cancer patients before and after first administration of 131I, and of ten European healthy donors. In addition, in vitro irradiation assays were performed at different doses (0.5, 1 and 2 Gy). The relative risk of spontaneous dicentrics before any radiation treatment was 2.9 (95% CI 1.7–5.1) times higher among Polynesian thyroid patients than among European thyroid cancer patients. After in vitro irradiation, the rise in frequency of dicentrics was similar in the Polynesian thyroid cancer group and the European thyroid patients and healthy donors. Four days after administration of 3.7 GBq 131I, the relative risk for a dicentric per cell was 1.3 (95% CI 1.0–1.5) times higher in Polynesian than in European patients. This can be explained by higher 131I retention in Polynesian compared with European patients. The results obtained revealed an increased frequency of cytogenetic abnormalities in Polynesian thyroid cancer patients compared with European control patients. These preliminary findings are compatible with possible previous environmental aggression and therefore imply a need for further investigations on larger series including, in particular, French Polynesian healthy donors. In addition to French Polynesians, Maori and Hawaiian control groups could be useful.

The aim of this study was to determine therapy-related risk factors for the development of melanoma after childhood cancer. Among 4401 3-year survivors of a childhood cancer in eight French and British centres and 25120 patients younger than 20 years old at first malignant neoplasm (FMN) extracted from the Nordic Cancer Registries, 16 patients developed a melanoma as a second malignant neoplasm (SMN). A cohort study of the French and British cohorts was performed. In a nested case-control study, the 16 patients who developed a melanoma as a SMN (cases) were matched with 3-5 controls in their respective cohort according to gender, age at the first cancer, the calendar year of occurrence of the first cancer and follow-up. Radiotherapy appeared to increase the risk of melanoma for local doses >15 Gy, Odds Ratio (OR)=13 (95% Confidence Interval (CI): 0.94-174). Regarding chemotherapy, we observed an increased OR for both alkylating agents and spindle inhibitors, OR=2.7 (95% CI: 0.5-14). Children treated for a gonadal tumour as a FMN were found to be at a higher risk of melanoma, OR=8.7 (95% CI: 0.9-86). The adjusted OR for the local radiation dose was 1.07 (95% CI: 1.00-1.15). In conclusion, radiotherapy may contribute to an increased risk of melanoma as a SMN, but only at very high doses of low linear energy transfer radiation. Common genetic origins between gonadal tumours and malignant melanomas are likely.

One hundred two patients with recurrent and/or metastatic head and neck squamous cell cancer were entered into four consecutive phase II trials, all cisplatinum (C-DDP, 100 mg/m2/cycle)-based. The two combinations tried were C-DDP, bleomycin, and fluorouracil (CFB) on 54 patients, and cisplatinum and vindesin in 36 patients (CV). The CFB combination was given with C-DDP by continuous infusion over 96 hours (23 patients) or on day 1 (31 patients). The CV regimen was also given in two different schedules, with VDS at 3 mg/m2/g weekly (12 patients) or by a 96-hour continuous infusion (0.6 to 1.0 mg/m2/d) in 24 patients. The following variables: sex, age, performance status, previous therapy, local recurrence, length of disease-free interval (DFI), distant metastases, weight loss, primary site, histological differentiation, type of chemotherapy, previous chemotherapy, evaluable/measurable disease, erythrosedimentation rate, and their relation with response to chemotherapy (WHO) and survival were submitted to both univariate and multivariate analysis (Cox). Overall response rate (RR:CR + PR) was 25 (28%) of 90. In the CFB protocols, RR was 12 (22%) of 54 vs. 13 (38%) of 36 (P = 0.15, NS) in the CV combination group. For the four different combinations the RR was CFB C-DDPci 7 (30%) of 23, CFB C-DDP 1 hour 5 (16%) of 31, CV VDS weekly 2 (17%) of 12, CV VDSci 11 (45%) of 24. The patient populations were very different, with the latest combination consisting of metastatic patients exclusively. Univariate analysis of multiple variables showed age less than 60 years, PS:0 or 1, no previous therapy, absence of local relapse, metastatic disease, long DFI, and that measurable disease was significant for the probability of response. Median survival was 7 months for the 90 evaluated patients, 5 months for nonresponders, and 9 months for responders (P = 0.01). In the univariate analysis, significant factors for survival were PS:0 or 1, a weight loss below 10%, long DFI, response to chemotherapy, erythrosedimentation rate (ESR) of less than 30 mm/1st hr, presence of bone metastasis, and the number of metastases. Multivariate analysis shows PS, the absence of local relapse, and disease-free interval as significant prognostic factors for response. Multivariate analysis factors of significance for survival were PS, weight loss, and response to chemotherapy. The analysis of the clinical pattern showed an evolution in RR from 3 (8%) of 36 on previously irradiated local recurrent disease to 8 (73%) of 11 in previously untreated patients with metastatic disease at presentation.(ABSTRACT TRUNCATED AT 400 WORDS)

Fifty-four clinically euthyroid patients were evaluated 1 up to 17 yr after external irradiation to the neck for Hodgkin's disease. T4 level was decreased in 6%, while basal TSH level was increased in 44%, and TSH response to TRH was increased in 66% of the patients with normal basal TSH level. Thyroid iodine content (TIC), measured in 50 patients, was below 5 mg in 18. The 29 patients with normal basal TSH level had a mean TIC (6.8 +/- 2.7 mg) significantly lower (p less than 0.01) than the control population (14.6 +/- 5 mg). A significant positive correlation was found between log T4 and log TIC (r = 0.55, p less than 0.01). Thyroglobulin (Tg) level was increased in 53% of the patients with no palpable thyroid abnormality. It was not related to TSH level but was related to younger age at irradiation. T4 treatment decreased Tg level to the normal range in 5 of 8 patients. These facts suggest subclinical thyroid abnormalities and patients with elevated Tg levels should be considered at risk for developing a thyroid tumor.

9520 Background: A multi-centre French cohort study was performed to evaluate the role of treatment in the long-term overall and cause-specific mortality among childhood cancer survivors. Methods: This study cohort included 3,057 patients treated for a solid tumours before the age of 17 between 1942–1986, in 5 French centres and who survived at least 5 years from diagnosis. Detailed clinical and therapeutic data were extracted for each patients from medical records. For 2,081of the 2,178 patients who received radiotherapy, radiation doses were estimated at 188 anatomical sites, including heart (7 sites) and lungs (10 sites). 98% of patients were identified in French National Registry of Physical Persons (RNIPP) and we obtained the death causes of 95% of dead patients. Overall and cause-specific mortality standardized ratios (SMR), absolute excess risk (AER) of death were studied using Poisson regression. Results: 50% of patients were treated by chemotherapy (CT) plus radiotherapy (RT), 22% by CT alone and 21% by RT alone. During an average follow-up of 25 years, 465 patients dead. The overall SMR was 7.3 (95% CI: 6.7–8.0) and AER was 6 deaths per 1,000 person-years. SMR for death due to cancer other than the 1st cancer (SC) was 16.1 (95%, CI 13.5–18.9). SMRs were significantly elevated for non-cancer overall mortality, infectious and parasitic diseases, diseases of the circulatory, nervous and respiratory system, congenital anomalies, symptoms, signs and ill- defined conditions’ (SMRs of 2.6, 15.7, 6.4, 8.5, 4.6, 3.2, respectively). RT was associated an increase in the risk for overall and SC related deaths (RR = 2.0; 95% CI: 1.5–2.7; RR = 1.8; 95% CI: 1.1–2.9; respectively). CT was associated with an increased risk for overall, SC and non- cancer related deaths (RR = 1.6; 95% CI: 1.3–2.0; RR = 1.9; 95% CI: 1.2–3.0; RR = 1.8; 95% CI: 1.1–2.9 respectively). We were not able to find any evidence for an interaction between CT and RT, whatever the end point considered. Among the 26 circulatory deaths, 24 received RT, the mean radiation dose of the heart (P=0.0006) and treatment with spindle inhibitors (P=0.009) were significantly associated to death by cardiac disease. Conclusions: In the future, death due to cardiac pathologies could be an important issue for long term survivors of childhood cancer. No significant financial relationships to disclose.

A mortality study of French Polynesia in the period 1984-92, although limited by the small population living close to the test sites and the high proportion of deaths attributed to ill-defined causes, found no excess of cancer that could confidently be attributed to the 41 atmospheric test explosions in 1966-74. A study of cancer incidence is planned.