Ibrahima Diallo

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

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

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

SummaryThe 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.

Long-Term Cardiovascular Mortality After Radiotherapy for Breast Cancer

OBJECTIVES This study sought to investigate long-term cardiovascular mortality and its relationship to the use of radiotherapy for breast cancer. BACKGROUND Cardiovascular diseases are among the main long-term complications of radiotherapy, but knowledge is limited regarding long-term risks because published studies have, on average, <20 years of follow-up. METHODS A total of 4,456 women who survived at least 5 years after treatment of a breast cancer at the Institut Gustave Roussy between 1954 and 1984 were followed up for mortality until the end of 2003, for over 28 years on average. RESULTS A total of 421 deaths due to cardiovascular diseases were observed, of which 236 were due to cardiac disease. Women who had received radiotherapy had a 1.76-fold (95% confidence interval [CI]: 1.34 to 2.31) higher risk of dying of cardiac disease and a 1.33-fold (95% CI: 0.99 to 1.80) higher risk of dying of vascular disease than those who had not received radiotherapy. Among women who had received radiotherapy, those who had been treated for a left-sided breast cancer had a 1.56-fold (95% CI: 1.27 to 1.90) higher risk of dying of cardiac disease than those treated for a right-sided breast cancer. This relative risk increased with time since the breast cancer diagnosis (p = 0.05). CONCLUSIONS This study confirmed that radiotherapy, as delivered until the mid-1980s, increased the long-term risk of dying of cardiovascular diseases. The long-term risk of dying of cardiac disease is a particular concern for women treated for a left-sided breast cancer with contemporary tangential breast or chest wall radiotherapy. This risk may increase with a longer follow-up, even after 20 years following radiotherapy.

Frequency Distribution of Second Solid Cancer Locations in Relation to the Irradiated Volume Among 115 Patients Treated for Childhood Cancer

PURPOSE To provide better estimates of the frequency distribution of second malignant neoplasm (SMN) sites in relation to previous irradiated volumes, and better estimates of the doses delivered to these sites during radiotherapy (RT) of the first malignant neoplasm (FMN). METHODS AND MATERIALS The study focused on 115 patients who developed a solid SMN among a cohort of 4581 individuals. The homemade software package Dos_EG was used to estimate the radiation doses delivered to SMN sites during RT of the FMN. Three-dimensional geometry was used to evaluate the distances between the irradiated volume, for RT delivered to each FMN, and the site of the subsequent SMN. RESULTS The spatial distribution of SMN relative to the irradiated volumes in our cohort was as follows: 12% in the central area of the irradiated volume, which corresponds to the planning target volume (PTV), 66% in the beam-bordering region (i.e., the area surrounding the PTV), and 22% in regions located more than 5 cm from the irradiated volume. At the SMN site, all dose levels ranging from almost zero to >75 Gy were represented. A peak SMN frequency of approximately 31% was identified in volumes that received <2.5 Gy. CONCLUSION A greater volume of tissues receives low or intermediate doses in regions bordering the irradiated volume with modern multiple-beam RT arrangements. These results should be considered for risk-benefit evaluations of RT.

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.

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

AbstractObjectives 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.

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 Hodgkins 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.

Risk of a Second Malignant Neoplasm After Cancer in Childhood Treated With Radiotherapy: Correlation With the Integral Dose Restricted to the Irradiated Fields

PURPOSE After successful treatment of cancers in childhood, the occurrence of second malignant neoplasm (SMN) came to the fore. Few studies have considered the relationship between the radiation dose received and the risk of developing an SMN. To take into account the heterogeneity of the dose distribution so as to evaluate the overall risk of an SMN after a childhood cancer, we therefore focused on the integral dose restricted to the irradiated fields. METHODS AND MATERIALS The study was performed in a cohort of 4,401 patients who were 3-year survivors of all types of childhood cancer treated between 1947 and 1986 in France and Great Britain. For each patient, the integral dose was estimated for the volume inside the beam edges. RESULTS We found a significant dose-response relationship between the overall risk of an SMN and the estimated integral dose. The excess relative risk for each incremental unit of the integral dose was only 0.008 in a linear model and 0.017 when a negative exponential term was considered, when adjusted for chemotherapy. The risk of SMN occurrence was 2.6 times higher in the case of irradiation. However among patients who had received radiotherapy, only those who had received the highest integral dose actually had a higher risk. CONCLUSIONS The integral dose in our study cannot be considered as a good predictor of later risks. However other studies with the same study design are obviously needed to evaluate the use of the integral dose as a tool for decision making concerning different radiotherapy techniques.

Radiation therapy and late mortality from second sarcoma, carcinoma, and hematological malignancies after a solid cancer in childhood.

PURPOSE 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. METHODS AND MATERIALS 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. RESULTS 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. CONCLUSIONS 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.

Age at menopause and its influencing factors in a cohort of survivors of childhood cancer: earlier but rarely premature

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? SUMMARY ANSWER Menopause occurred at a median age of 44 years in this cohort which is earlier than in the general population, but premature menopause was uncommon. Main risk factors for non-surgical menopause were exposure to and dose of alkylating agents, especially during adolescence, radiation dose to the ovaries and oophorectomy. WHAT IS KNOWN ALREADY While survivors of childhood cancer are known to be at increased risk for developing premature menopause, data on its risk factors are limited. STUDY DESIGN A cohort study of 1109 still-living female survivors of childhood solid cancer treated between 1945 and 1985, of whom 863 (78%) returned a follow-up questionnaire. Of them, 157 were excluded. PARTICIPANTS AND METHODS Seven hundred and six women, among whom 32% have attained 40 years of age, were included in this study. A Cox regression model was used to determine risk factors influencing the age at menopause. MAIN RESULTS Ninety seven women have reached menopause at a median age of 44 years. Menopause has been surgically induced in 36% of women. In multivariate analysis, risk factors for non-surgical menopause included exposure to alkylating agents, increasing radiation dose to the ovaries, procarbazine dose, cyclophosphamide dose and unilateral oophorectomy. The highest risk ratio for non-surgical menopause was observed for women treated after the onset of puberty with alkylating agents, either alone (RR = 9, 95% CI: 2.7-28, P = 0.0003) or associated with even a low dose of radiation to the ovaries (RR = 29, 95% CI: 8-108, P < 0.0001). Exposure to unilateral oophorectomy is associated with a 7-year earlier age at menopause. By the age of 40, only 2.1% had non-surgical premature menopause and its main risk factors were age at diagnosis, cyclophosphamide dose, exposure to melphalan and radiation dose to the ovaries. LIMITATIONS The information on menopause was based on self-reported data without confirmation by FSH levels. Participants to this study have been treated for cancer from 1945 to 1985 and one can expect an increase in premature menopause incidence with more recent protocols using high-dose alkylating agents. WIDER IMPLICATIONS OF THE FINDINGS This study provides data on risk factors for a reduced fertility window in order to inform survivors at risk and help oncologists to design new therapeutic protocols avoiding this risk. This study does not confirm the high rate of premature menopause reported by the Childhood Cancer Survivor Study, but this population differs from theirs (no leukemia and a lower percentage of lymphoma).