Concomitant chemo-radiotherapy and local dose of radiation as risk factors for second malignant neoplasms after solid cancer in childhood: a case-control study.

Radiotherapy and chemotherapy are associated with an increased risk of a second malignant neoplasm (SMN) after a cancer during childhood. This study specified the dose-effect relationship between radiotherapy, chemotherapy and the risk of a SMN, and investigated the effect of chemo-radiotherapy on the risk of SMN. A case-control study nested in a European cohort of 4,581 patients treated for a solid cancer during childhood was conducted. One hundred and fifty three cases with a SMN and 442 controls were matched according to sex, age at first cancer, calendar year, type of first cancer and follow-up. The local radiation dose was estimated at the site of the SMN, for each case and at the same site, for the matched controls. The local dose of radiation significantly increased the risk of a SMN. The best model was linear with an excess relative risk per Gray equal to 0.13 (95% CI, 0.06; 0.26). Any chemotherapy significantly increased the risk of a SMN, odd ratio(adjusted) (OR(adjusted)) = 2.4 (95% confidence interval (95% CI), 1.4-4.1), but no dose-effect relationship was observed between any drug category and the risk of a SMN. Patients who had received concomitant chemo-radiotherapy were significantly more at risk of developing a SMN than patients who had been treated with sequential chemo-radiotherapy, even after adjustment for the local dose of radiation and the 6 most frequently administered drugs, OR(adjusted) = 2.3 (95%CI, 1.1-4.8). Radiation was found to be the foremost treatment-related risk factor for the occurrence of a SMN. Compared to sequential treatment, concomitant chemo-radiotherapy may lead to a higher risk of a SMN.

Anthracyclines, mitoxantrone, radiotherapy, and granulocyte colony-stimulating factor: risk factors for leukemia and myelodysplastic syndrome after breast cancer.

PURPOSE: To determine the risk factors for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after breast cancer. PATIENTS AND METHODS: We conducted a case-control study among women treated for breast cancer between 1985 and 2001 in French general hospitals, cancer centers, or clinics. We included 182 AML and MDS patients and 534 matched controls. Breast cancer characteristics, type of treatment, and family history of cancer were compared in both groups. RESULTS: The risk of AML/MDS was increased after topoisomerase-II inhibitor-based chemotherapy (P < 10-16) and was higher for mitoxantrone-based chemotherapy than for anthracycline-based chemotherapy (relative risk [RR] = 15.6; 95% CI, 7.1 to 34.2; and RR = 2.7; 95% CI, 1.7 to 4.5, respectively). After adjustment for other treatment components, the risk of AML/MDS in patients who received radiotherapy was multiplied by 3.9 (95% CI, 1.4 to 10.8) but was not increased by alkylating agents. Patients receiving granulocyte colony-stimulating factor (G-CSF) support had an increased risk of AML/MDS (RR = 6.3; 95% CI, 1.9 to 21), even when controlling for chemotherapy doses. Similar results were obtained when AML and MDS were considered separately. CONCLUSION: This large case-control study demonstrates that the risk of AML/MDS is much higher with mitoxantrone-based chemotherapy than with anthracyclines-based chemotherapy in a population of women recently treated for breast cancer. The risk of AML/MDS associated with mitoxantrone must be kept in mind when using this drug to treat diseases other than breast cancer (eg, prostate cancer or multiple sclerosis). In addition, our study suggests the need to monitor the long-term effects of G-CSF therapy.

Radiation dose and long term risk of cardiac pathology following radiotherapy and anthracyclin for a childhood cancer.

PURPOSE: To determine the cardiac status in children 15 years (yrs) or more after a solid tumour treatment. PATIENTS AND METHODS: Of the 447 patients, 229 were fully studied and 218 were not. The following cardiac evaluation was proposed to all the 447 consecutive patients: (1) cardiac Doppler US by one of two expert cardiologists; (2) cardiac rhythm and conduction abnormalities including 24-h holter ECG; (3) (131)I-mIBG myocardial scintigraphy; (4) serum brain natriuretic peptide levels at rest; (5) an exercise test with VO(2)max measurement. The radiation dose delivered to 7 points in the heart was estimated for all patients who had received radiotherapy. RESULTS: Cardiac disorder was diagnosed in 89 evaluated patients (39%) including 24 heart failures and 65 other asymptomatic cardiac diseases. When adjusting on potential confounders, cardiac disorder and cardiac failure risks were respectively linear (ERR at 1 Gy: 26%) and linear-quadratic (ERR at 1 Gy: 19%) functions of the average radiation dose received to the heart. No interaction between cumulative dose of adriamycin and average radiation dose was evidenced for cardiac disorders, but the ERR/Gy of cardiac failure was higher for patients receiving less than 350 mg/m(2) of Adriamycin. CONCLUSION: Long term heart pathologies are probably one of the major iatrogenic risks encored by patients who survived a childhood cancer. This study strongly emphasizes the need to limit the heart irradiation during radiotherapy, particularly, for patients who also received or were susceptible to later received adriamycin.

Radiation dose and relapse are predictors for development of second malignant solid tumors after cancer in childhood and adolescence: a population-based case-control study in the five Nordic countries.

The aim of the study was to assess the risk with radiation therapy and chemotherapy of the first cancer in childhood and adolescence for the development of a second malignant solid tumor (SMST). Also, the role of relapse of the primary tumor was studied. It is a nested case-control study within a Nordic cohort of patients less than 20 years of age at first diagnosis 1960-1987. SMSTs were diagnosed in 1960-1991. There were 196 cases and 567 controls. The risk was increased only for radiotherapy given more than five years before the development of the SMST. A significantly increased relative risk of 1.8 was found already at doses below 1 Gy. The risk increased rapidly up to a maximum of 18.3 for doses above 30 Gy. Chemotherapy alone did not increase the risk to develop an SMST. However, in combination with radiotherapy, chemotherapy showed a significant potentiating effect. Relapse was found to be an independent risk factor for development of an SMST, with a higher relative risk for females than for males.

High cumulative rate of secondary leukemia after continuous etoposide treatment for solid tumors in children and young adults.

BACKGROUND: In a national pediatric case-control study, we observed a very high relative risk of leukemia in patients who had received continuous etoposide (CE) over 6 months or more, but we could not estimate the absolute risk. The purpose of the present study was to estimate this absolute risk after CE. PROCEDURES: We report a study of 18 patients with refractory or recurrent tumors who received CE over 6 months or more between 1995 and 1997. It was administered either 3 days a week for 3/4 weeks ("3 x 3", 14 patients) or 7 days a week for 3/4 weeks ("7 x 3", four patients). RESULTS: Five patients developed secondary leukemia 10-25 months after the initiation of CE. All the others died of their first tumor. The cumulative incidence of leukemia at 30 months was 28% (95% CI, 10%-53%). A chromosome 11q23 rearrangement was found in 3/5 cases. All four patients who received the "7 x 3" CE schedule developed leukemia compared to 1/14 treated with the "3 x 3" CE schedule (P = 0.002). CONCLUSIONS: Given its efficacy, CE may still have a place as a palliative treatment. However, the risk of leukemia must be borne in mind when considering its use in patients with a better prognosis.

Radiation dose and risk of soft tissue and bone sarcoma after breast cancer treatment.

BACKGROUND: To quantify the risk of soft tissue and bone sarcomas after breast cancer according to the doses and technical modalities of irradiation. METHODS: We followed a cohort of 6597 breast-cancer patients for 8.3 years on average. The number of soft tissue and bone sarcomas was compared to the expected number based on the incidence rates in the general French population. We also estimated the risk of sarcoma according to the radiation dose received at site of the sarcoma in a nested case control study of 14 breast-cancer patients who subsequently developed a sarcoma and 98 controls matched for age at diagnosis of breast cancer, period of initial treatment and length of follow-up. RESULTS: In the cohort-study, 12 women who had initially received radiotherapy treatment developed a bone or soft tissue sarcoma during the follow-up period. The expected number of cases during this period was 1.7 (SIR = 7.0, 95% CI: 3.7-11.7) and the mean annual excess incidence during the same period was 21 per 100,000 person-years. The 15-year cumulative incidence of sarcoma was 0.28% (95% CI: 0.10-0.45%). In the case-control study, all the 14 cases had received at least 11.8 Gray at the site of the sarcoma, which was always located in the irradiated field or in the upper ipsilateral extremity of the arm. A dose-effect relationship was observed (p < 0.001). The best fit was obtained for a quadratic dose-response relationship, without a negative exponential term for cell killing at high doses. The risk of sarcoma was 30.6 higher for doses of more than 44 Gray than for doses of less than 15 Gray. CONCLUSIONS: High doses of radiation strongly increase the risk of bone and soft tissue sarcoma.

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

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

Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: a case-control study by the Société Française d'Oncologie Pédiatrique.

PURPOSE: To estimate the risk of secondary leukemia as a function of the dose of epipodophyllotoxins and anthracyclines. METHODS: We conducted a case-control study of the risk of secondary leukemia or myelodysplasia after a solid tumor in childhood within the Société Française d'Oncologie Pédiatrique, including 61 patients with leukemia matched with 196 controls. The characteristics of the first cancer, the patient's family history of cancer, and the treatment (type, cumulative dose of chemotherapy, schedule of etoposide administration, and radiation dose delivered to active bone marrow) were compared in the two groups. RESULTS: Only two factors were found to increase the risk of leukemia in multivariate analysis, namely, the type of the first tumor, with an excess risk in patients with Hodgkin's disease (relative risk 6.4; 95% confidence interval [CI], 1.6 to 24) or osteosarcoma (relative risk 5; 95% CI, 1.3 to 19), and exposure to epipodophyllotoxins and anthracyclines. The risk of leukemia increased regularly with the cumulative dose of etoposide. In summary, patients who received between 1.2 and 6 g/m(2) of epipodophyllotoxins or more than 170 mg/m(2) of anthracyclines had a seven-fold higher risk (95% CI, 2.6 to 19) compared with patients who received lower doses or none of these drugs. The risk of leukemia in patients who received more than 6 g/m(2) of epipodophyllotoxins was multiplied by 197 (95% CI, 19 to 2,058). The risk of leukemia was not increased by exposure to alkylating agents or radiotherapy. CONCLUSION: Both epipodophyllotoxins and anthracyclines increase the risk of secondary leukemia. The current challenge is to minimize the mutagenic effects of these drugs by diminishing cumulative doses without losing the therapeutic benefits.

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

It is of particular concern to evaluate the risk of lung cancer occurrence after breast cancer treatment as women with breast cancer quite often undergo radiation therapy as part of their initial treatment and their life expectancy remains long. From a roster of 7711 women initially treated for breast cancer between 1954 and 1984, a cohort-study was performed among 4171 1-year survivors followed during the period 1975-1995. The relationship between the radiation dose received by the lung and the risk of lung cancer was then evaluated in a nested case-control study of 11 breast-cancer patients who developed lung cancer and 22 controls matched for age at diagnosis of breast cancer, period of initial treatment and length of follow-up. Among the 4171 women, six developed lung cancer during the entire follow-up as compared to 5.4 cases expected (SIR = 1.1, 95% CI: 0.4-2.3). When considering only the women initially treated by radiotherapy with or without adjunction of chemotherapy and excluding the 10 first years of follow-up, the SIR was significantly increased (SIR = 3.2, 95%CI: 1.0-7.4). In the case-control study, nine of the 11 lung cancers occurred in the ipsilateral lung and two in the trachea. The overall odds ratio (OR) of lung cancer associated with initial radiotherapy was 1.4 (95% CI: 0.2-11.1) and an excess in the OR of 7% (90% CI: ? to 41%, p = 0.10) per gray delivered to the site of lung cancer was evidenced. Our results agree with previous studies in favor of an increased risk of lung cancer after radiation therapy for breast cancer.

Characteristics of follicular cell-derived thyroid carcinomas occurring after external radiation exposure: results of a case control study nested in a cohort.

Radiation exposure is the only well-established risk factor for follicular cell-derived thyroid carcinoma. To compare the clinical characteristics and outcome of thyroid carcinoma in patients with and without a history of radiation exposure, we performed a case control study nested in a cohort of 2,196 patients treated for a papillary or a follicular thyroid cancer at the Institut Gustave Roussy. The study was performed on 91 cases (71% females) and their 273 controls matched for gender, age at thyroid cancer diagnosis (+/-3 years), and period of initial thyroid cancer treatment (+/-6 years). More than 85% of the cases have been first exposed to external radiation before the age of 30 years. Thyroid cancers were more frequently multifocal in cases than in controls (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.3-4.8), and local residual tumor was more frequently observed in cases, but the other clinical features did not differ overall. Female cases with a history of radiation exposure more frequently had a tumor of follicular histology than female controls (OR = 2.7, 95% CI: 1.1-6.5), and conversely the frequency of follicular histology was similar in male cases and in male controls (OR = 0.3, 95% CI: 0.1-1.4). The risks of recurrence and of thyroid cancer related death were similar in cases and in controls.