Risk of melanoma following adulthood cancer: a case-control study.

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.

Cardiac abnormalities 15 years and more after adriamycin therapy in 229 childhood survivors of a solid tumour at the Institut Gustave Roussy.

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<20%) or marked (n=9) (20< or =FS<25%) systolic dysfunction. In the 192 others, the median meridional end-systolic wall stress was 91 (53-135) and it exceeded 100 g cm(-2) in 52 pts. Using a Cox model, only the cumulative dose of adriamycin and the average radiation dose to the heart, were identified as risk factors for a pathological cardiac status. In conclusion, the risk of cardiac failure or severe abnormalities increases with adriamycin treatment, radiotherapy and time since treatment, even after a follow-up of 15 years or more. In our series, after an average follow-up of 18 years, 39% of the children had a severe cardiac dysfunction or major ventricular overload conditions. The risk increases with the dose of adriamycin and radiation received to the heart, without evidence for threshold.

Radiation dose as a risk factor for malignant melanoma following childhood cancer.

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.

Radiation dose, chemotherapy, hormonal treatment and risk of second cancer after breast cancer treatment.

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 vs >or=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.

Estimation of the radiation dose from radiotherapy for skin haemangiomas in childhood: the ICTA software for epidemiology.

Radium applicators and pure beta emitters have been widely used in the past to treat skin haemangioma in early childhood. A well defined relationship between the low doses received from these applicators and radiation-induced cancers requires accurate dosimetry. A human-based CT scan phantom has been used to simulate every patient and treatment condition and then to calculate the source target distance when radium and pure beta applicators were used. The effective transmission factor psi(r) for the gamma spectrum emitted by the radium sources applied on the skin surface was modelled using Monte Carlo simulations. The well-known quantization approach was used to calculate gamma doses delivered from radium applicators to various anatomical points. For 32P, 90Sr/90Y applicators and 90Y needles we have used the apparent exponential attenuation equation. The dose calculation algorithm was integrated into the ICTA software (standing for a model that constructs an Individualized phantom based on CT slices and Auxological data), which has been developed for epidemiological studies of cohorts of patients who received radium and beta-treatments for skin haemangioma. The psi(r) values obtained for radium skin applicators are in good agreement with the available values in the first 10 cm but higher at greater distances. Gamma doses can be calculated with this algorithm at 165 anatomical points throughout the body of patients treated with radium applicators. Lung heterogeneity and air crossed by the gamma rays are considered. Comparison of absorbed doses in water from a 10 mg equivalent radium source simulated by ICTA with those measured at the Radiumhemmet, Karolinska Hospital (RAH) showed good agreement, but ICTA estimation of organ doses did not always correspond those estimated at the RAH. Beta doses from 32P, 90Sr/90Y applicators and 90Y needles are calculated up to the maximum beta range (11 mm).

Increased risk of second cancers following breast cancer: role of the initial treatment.

OBJECTIVES AND METHODS: The risk of second primary malignancies (SMN) was studied in a cohort of 4,416 one-year survivors of a breast cancer. The role of the menopausal status and of the initial treatment modalities (surgery, radiotherapy, and chemotherapy) was investigated. RESULTS: Excluding second primary breast cancer and non-melanoma skin cancer, a total of 193 (4.4%) patients developed a SMN between 1973 and 1992, compared with 136 expected (Standardised Incidence Ratio, SIR = 1.4, 95% CI (1.2-1.6)). No trend towards either an increase or a decrease was noted in the SIR with time after treatment (p = 0.2). The greatest increase in the relative risk concerned soft tissue cancers (SIR = 13.0, 95% CI: 6.8-22.3), followed by leukaemia (SIR = 3.1, 95% CI: 1.7-5.0), melanoma (SIR = 2.7, 95% CI: 1.4-4.8), kidney (SIR = 2.5, 95% CI: 1.2-4.5), ovary (SIR = 2.0, 95% CI: 1.2-3.1) and uterine tumours (SIR = 1.9, 95% CI: 1.4-2.5). The SIR was 3.0 (95% CI 1.8-4.7) in women under 40 at the time of the breast cancer, 1.9 (95% CI: 1.4-2.4) in those aged 40-49 and 1.2 (95% CI 1.0-1.4) in those aged 50 or more. In the 2,514 women who had received radiotherapy as initial treatment without chemotherapy, the SIR for all SMN was 1.6 (95% CI: 1.1-2.3) fold higher than in those who had not received radiotherapy as initial treatment. CONCLUSION: In conclusion, this study confirms the increased risk of second malignancies in women treated for a breast cancer, and particularly in those who were younger at the time of treatment for breast cancer. Our results also suggest that radiotherapy may play a role in the onset of these second lesions.

Thyroid carcinomas after irradiation for a first cancer during childhood.

BACKGROUND: The thyroid gland is among the most radiosensitive organs. However, little is known about the long-term risk of developing a thyroid tumor after fractionated external radiotherapy for cancer during childhood. OBJECTIVE: To study the long-term risk of developing a thyroid tumor in 4096 three-year survivors of childhood cancer treated between May 1942 and December 1985 in 8 centers in France and the United Kingdom, 2827 of whom had received external radiotherapy. METHODS: A wide range of radiation doses were given to the thyroid: 1164 children received less than 0.5 Gy and 812 received more than 5.0 Gy, the average dose being 7.0 Gy. RESULTS: After mean follow-up of 15 years (range, 3-45 years), 14 patients-all of whom had received radiotherapy-developed a clinical thyroid carcinoma. Within the cohort, the relation between radiation dose to the thyroid and risk of thyroid carcinoma and adenoma was similar to that observed in patients who received radiotherapy during childhood for other reasons, such as an excess relative risk per gray of 4 to 8, up to a few gray. In contrast, compared with thyroid cancer incidence in the general population, the standardized incidence of thyroid carcinoma was much higher than expected from the dose-response relationship estimated within the cohort and from patients who received radiotherapy during childhood for other reasons: a dose of 0.5 Gy was associated with a standardized incidence ratio of 35 (90% confidence interval, 10-87) and a dose of 3.6 Gy with a standardized incidence ratio of 73 (90% confidence interval, 28-153). We did not show a reduction in excess relative risk per gray with use of an increasing number of fractions. CONCLUSION: Although we cannot estimate the exact proportion, it is probable that some or all children who are treated for cancer are predisposed to developing a thyroid carcinoma.

Second malignant neoplasms after a first cancer in childhood: temporal pattern of risk according to type of treatment.

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.

Risks of brain tumour following treatment for cancer in childhood: modification by genetic factors, radiotherapy and chemotherapy.

A cohort of 4,400 persons treated for various cancers of childhood in France and the UK was followed up over an extended period to assess risks of subsequent brain tumour in relation to the radiotherapy and chemotherapy that the children received for their first cancer. Elevated risks of subsequent brain tumours were associated with first central nervous system (CNS) tumour (two-sided p = 0.0002) and neurofibromatosis (two-sided p = 0.001). There was also elevated brain tumour risk (two-sided p = 0.003) associated with ionising radiation exposure, the risk being concentrated among benign and unspecified brain tumours. The radiation-related risk of benign and unspecified brain tumours was significantly higher than that of malignant brain tumours (two-sided p< or =0.05); there was no significant change of malignant brain tumour risk with ionising radiation dose (two-sided p > 0.2). In general, there were no strong associations between alkylating agent dose and brain tumour risk. The only significant association between brain tumour risk and alkylating agent dose was in relation to compounds used (bleomycin, chloraminophen) that are thought not to deliver substantial doses to the brain; the statistical significance of the trend with dose depended on a single case, and thus must be considered a weak result.

Radiation dose, chemotherapy and risk of osteosarcoma after solid tumours during childhood.

Osteosarcoma is the most frequent second primary cancer occurring during the first 20 years following treatment for a solid cancer in childhood. Using a cohort study of children treated for a solid cancer, we investigated the incidence and etiology of osteosarcoma as a second malignant neoplasm after childhood cancer in a cohort and a case-control study. We analysed the relationship between the local dose of radiation and the risk of osteosarcoma, taking into account chemotherapy received. A cohort study of 4,400 3-year survivors of a first solid cancer during childhood diagnosed in France or the United Kingdom, between 1942 and 1986, revealed 32 subsequent osteosarcomas. In a nested case-control study, we matched 32 cases and 160 controls for sex, type of first cancer, age at first cancer and the duration of follow-up. Parameters studied were the incidence of osteosarcoma, the cumulative local dose of irradiation and the cumulative dose of chemotherapy received by cases and controls. The risk of a osteosarcoma was found to be a linear function of the local dose of radiation (excess relative risk per gray=1.8), and was found to increase with the number of moles of electrophilic agents per square meter but not with other drugs. No interaction was noted between radiotherapy and chemotherapy. Bilateral retinoblastoma, Ewing's sarcoma and soft tissue sarcoma were found to render patients susceptible to a higher risk of developing an osteosarcoma as a second malignant neoplasm. We recommend long-term surveillance of patients who were treated during childhood for bilateral retinoblastoma, Ewing's sarcoma, soft tissue sarcoma, as well as other first cancer treated with radiotherapy plus high doses of chemotherapy, without focusing exclusively on the radiation field.

Dose distribution throughout the body from radiotherapy for Hodgkin's disease in childhood.

BACKGROUND AND PURPOSE: The individual dosimetry performed for a multicentre European cohort study of second malignant neoplasm following radiotherapy for a solid cancer in childhood demonstrated a large variation in the radiation doses estimated to any site. MATERIALS AND METHODS: From this study we have extracted the present work, i.e. estimation of doses for patients who underwent radiotherapy for Hodgkin's disease in their childhood. These patients were treated using high energy X-rays from linear accelerators (MV group), gamma-radiation from Cobalt machines (Cobalt group), soft X-rays from orthovoltage machines (kV group) and electron beams from accelerators (MeV group) at six French and UK centres. All patients started their radiotherapy between 1955 and 1985 and about 12% of them received more than one beam quality. Most of the patients were irradiated with large mantle AP/PA or partial mantle fields. Patients with transdiaphragmatic extension were also irradiated using inverted-Y paraaortic fields. The absorbed doses at the 91 skeleton points are used to calculate the mean dose to the active bone marrow. RESULTS: Estimates of the median and mean doses, standard deviations and ranges to 13 specific sites of the body and to the active bone marrow are reported. Depending upon the size and sex of patients, target volume and position and radiotherapy techniques, the estimated doses are highly spread, attaining 0.19-106.07% of the target dose. This study underscores the need for individual dosimetry in epidemiological studies. Comparison with the available measured and calculated doses to the ovary and testis shows good agreement. CONCLUSION: This study underscores the need for individual dosimetry in epidemiological studies.

Individualized phantom based on CT slices and auxological data (ICTA) for dose estimations following radiotherapy for skin haemangioma in childhood.

BACKGROUND AND PURPOSE: Before 1974 about 5000 children were treated by radiotherapy at the Institut Gustave-Roussy (IGR) for a skin haemangioma. A human model whose characteristics are as close as possible to those of the patient at the time of the treatment is necessary to effectuate an accurate retrospective estimation of the radiation doses received at distant organs. METHODS: We have developed a software package which constructs an individualized phantom based on CT slices and auxological data (ICTA) for this purpose. A set of real CT slices is used to produce a 3-D representation of the human body which is then adjusted to fit the dimensions supplied by published auxological data relative to sex and age for each patient. One hundred sixty-one anatomical landmarks of epidemiological interest have been defined inside the phantom for dose estimation. RESULTS: The transverse, frontal and sagittal views of the phantom displayed permit accurate positioning of radioactive applicators. The software calculates the relevant parameters required for dose estimation based on the patient's probable anatomy.

Estimation of the radiation dose delivered to any point outside the target volume per patient treated with external beam radiotherapy.

The methodology we have developed to study dose distribution outside the target volume during external beam radiotherapy allows us to determine the dose received by the patient arising from leakage radiation and scattered radiation from both the head of the treatment machine and from the treatment room. It also allows us to evaluate the dose due to photon scattering in the patient by means of a dedicated 3-D algorithm permitting computations for the whole body of the patient and taking into account height, sex and anatomical data at the time of the treatment, dosimetric data and lung heterogeneity parameters. This methodology offers solid criteria for recommendations concerning radiation protection.

Solid malignant neoplasms after childhood irradiation: decrease of the relative risk with time after irradiation.

The pattern of the temporal distribution of solid cancer incidence after irradiation in childhood is not well known, although, its importance in radioprotection is well known. We studied a cohort of 1,055 children from 8 European cancer centres, who received radiotherapy between 1942 and 1985 for a first cancer in childhood. After a mean follow-up of 19 years, 26 children developed a solid second malignant neoplasm (SMN), as compared to 5.6 expected from general population rates. Both the excess relative risk and the excess of absolute risk of solid SMN were higher among children who were younger at time of the irradiation. After reaching a maximum 15 to 20 years after irradiation, the excess relative risk of SMN decreased with time after irradiation, when controlling for age at irradiation and sex. The analysis of the risk of thyroid, brain and breast cancer together, as a function of the dose averaged on these 3 organs lead to similar results.