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Survivors of childhood cancer are at risk of anthracycline-induced cardiotoxicity, which might be prevented by dexrazoxane. However, concerns exist about the safety of dexrazoxane, and little guidance is available on its use in children. To facilitate global consensus, a working group within the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the existing literature and used evidence-based methodology to develop a guideline for dexrazoxane administration in children with cancer who are expected to receive anthracyclines. Recommendations were made in consideration of evidence supporting the balance of potential benefits and harms, and clinical judgement by the expert panel. Given the dose-dependent risk of anthracycline-induced cardiotoxicity, we concluded that the benefits of dexrazoxane probably outweigh the risk of subsequent neoplasms when the cumulative doxorubicin or equivalent dose is at least 250 mg/m 2 (moderate recommendation). No recommendation could be formulated for cumulative doxorubicin or equivalent doses of lower than 250 mg/m 2 , due to insufficient evidence to determine whether the risk of cardiotoxicity outweighs the possible risk of subsequent neoplasms. Further research is encouraged to determine the long-term efficacy and safety of dexrazoxane in children with cancer., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: The International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer was established in 2018 to address gaps in knowledge of risk and risk factors for breast cancer subsequent to childhood/adolescent cancer by pooling individual patient data from seven cohorts. Initially, the pooled cohort will focus on three clinically relevant questions regarding treatment-related subsequent breast cancer risk in female survivors, which are the risk related to low-dose radiotherapy exposure to the chest, specific chemotherapy agents and attained age., Participants: The consortium database includes pooled data on 21 892 female survivors from seven cohorts in North America and Europe with a primary cancer diagnosis at <21 years of age, and survival ≥5 years from diagnosis., Findings to Date: This is a newly established pooled study. The cohort profile summarised the data collected from each included cohort, including childhood cancer diagnosis information and treatment details (ie, radiotherapy fields and cumulative doses, and chemotherapy agents and cumulative doses for each agent). Included cohorts' follow-up started 1951-1981 and ended 2013-2021, respectively, for a median follow-up duration of 24.3 (IQR 18.0-32.8) years since primary cancer diagnosis. The median age at primary cancer diagnosis was 5.4 (IQR 2.5-11.9) years. And the median attained age at last follow-up was 32.2 (IQR 24.0-40.4) years. In all, 4240 (19.4%) survivors were treated with radiotherapy to the chest and 9308 (42.5%) with anthracyclines. At the end of the follow-up, 835 females developed a first subsequent breast cancer, including 635 invasive breast cancer only, 184 carcinomas in situ only (172 ductal carcinomas in situ and 12 lobular carcinomas in situ), and 16 with both an invasive and in situ diagnosis at the same moment. The cumulative incidences of subsequent breast cancer (both invasive and in situ) 25 and 35 years after primary cancer diagnosis were 2.2% and 6.2%, respectively., Future Plans: The consortium is intended to serve as a model and robust source of childhood/adolescent cancer survivor data for elucidating other knowledge gaps on subsequent breast cancer risk, and risk of other subsequent malignancies (including data on males) in the future., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: Cancer survival is improving along with an increase in the potential for adverse kidney effects from antineoplastic treatments or nephrectomy. We sought to describe recent trends in the incidence of kidney failure related to antineoplastic treatments and urinary tract cancers and evaluate patient survival and kidney transplantation access., Design, Setting, Participants, & Measurements: We used the French Renal Epidemiology and Information Network registry to identify patients with kidney failure related to antineoplastic treatments or urinary tract cancer from 2003 to 2015. We identified 287 and 1157 cases with nephrotoxin- and urinary tract cancer-related kidney failure, respectively. The main study outcomes were death and kidney transplantation. After matching cases to two to ten controls ( n =11,678) with other kidney failure causes for age, sex, year of dialysis initiation, and diabetes status, we estimated subdistribution hazard ratios (SHR) of each outcome separately for patients with and without active malignancy., Results: The mean age- and sex-adjusted incidence of nephrotoxin-related kidney failure was 0.43 (95% CI, 0.38 to 0.49) per million inhabitants and 1.80 (95% CI, 1.68 to 1.90) for urinary tract cancer-related kidney failure; they increased significantly by 5% and 2% annually, respectively, during 2006-2015. Compared with matched controls, age-, sex-, and comorbidity-adjusted SHRs for mortality in patients with nephrotoxin-related kidney failure were 4.2 (95% CI, 3.2 to 5.5) and 1.4 (95% CI, 1.0 to 2.0) for those with and without active malignancy, respectively; for those with urinary tract cancer, SHRs were 2.0 (95% CI, 1.7 to 2.2) and 1.1 (95% CI, 0.9 to 1.2). The corresponding SHRs for transplant wait-listing were 0.19 (95% CI, 0.11 to 0.32) and 0.62 (95% CI, 0.43 to 0.88) for nephrotoxin-related kidney failure cases and 0.28 (95% CI, 0.21 to 0.37) and 0.47 (95% CI, 0.36 to 0.60) for urinary tract cancer cases. Once on the waiting list, access to transplantation did not differ significantly between cases and controls., Conclusions: Cancer-related kidney failure is slowly but steadily increasing. Mortality does not appear to be increased among patients without active malignancy at dialysis start, but their access to kidney transplant remains limited., (Copyright © 2020 by the American Society of Nephrology.)

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., (© 2017 Wiley Periodicals, Inc.)

Background: Cardiac disease (CD) is one of the major side effects of childhood cancer therapy, but until now little has been known about the relationship between the heart radiation dose (HRD) received during childhood and the risk of CD., Methods and Results: The cohort comprised 3162 5-year survivors of childhood cancer. Chemotherapy information was collected and HRD was estimated. There were 347 CDs in 234 patients, 156 of them were rated grade ≥3. Cox and Poisson regression models were used. The cumulative incidence of any type of CD at 40 years of age was 11.0% (95% confidence interval [CI], 9.5-12.7) and 7·4% (95% CI, 6.2-8.9) when only the CDs of grade ≥3 were considered. In comparison with patients who received no anthracycline and either no radiotherapy or an HRD<0·1Gy, the risk was multiplied by 18·4 (95% CI, 7.1-48.0) in patients who had received anthracycline and no radiotherapy or a HRD <0.1Gy, by 60.4 (95% CI, 22.4-163.0) in those who had received no anthracycline and an HRD≥30Gy, and 61.5 (95% CI, 19.6-192.8) in those who had received both anthracycline and an HRD≥30Gy., Conclusions: Survivors of childhood cancers treated with radiotherapy and anthracycline run a high dose-dependent risk of developing CD. CDs develop earlier in patients treated with anthracycline than in those treated without it., (© 2015 American Heart Association, Inc.)

Purpose: To investigate the roles of radiation therapy and chemotherapy in the occurrence of subsequent leukemia after childhood cancer., Methods and Materials: We analyzed data from a case-control study with 35 cases and 140 controls. The active bone marrow (ABM) was segmented into 19 compartments, and the radiation dose was estimated in each. The chemotherapy drug doses were also estimated to enable adjustments. Models capable of accounting for radiation dose heterogeneity were implemented for analysis., Results: Univariate analysis showed a significant trend in the increase of secondary leukemia risk with radiation dose, after accounting for dose heterogeneity (P=.046). This trend became nonsignificant after adjustment for doses of epipodophyllotoxins, alkylating agents, and platinum compounds and the first cancer on multivariate analysis (P=.388). The role of the radiation dose appeared to be dwarfed, mostly by the alkylating agents (odds ratio 6.9, 95% confidence interval 1.9-25.0). Among the patients who have received >16 Gy to the ABM, the radiogenic risk of secondary leukemia was about 4 times greater in the subgroup with no alkylating agents than in the subgroup receiving ≥10 g/m(2)., Conclusions: Notwithstanding the limitations resulting from the size of our study population and the quite systematic co-treatment with chemotherapy, the use of detailed information on the radiation dose distribution to ABM enabled consideration of the role of radiation therapy in secondary leukemia induction after childhood cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Kidney carcinoma is a rare second malignancy following childhood cancer., Materials and Methods: We sought to quantify risk and assess risk factors for kidney carcinoma following treatment for childhood cancer. We evaluated a cohort of 4,350 patients who were 5-year cancer survivors and had been treated for cancer as children in France and the United Kingdom. Patients were treated between 1943 and 1985, and were followed for an average of 27 years. Radiation dose to the kidneys during treatment was estimated with dedicated software, regardless of the site of childhood cancer., Results: Kidney carcinoma developed in 13 patients. The cumulative incidence of kidney carcinoma was 0.62% (95% CI 0.27%-1.45%) at 40 years after diagnosis, which was 13.3-fold higher (95% CI 7.1-22.3) than in the general population. The absolute excess risk strongly increased with longer duration of followup (p <0.0001). Compared to the general population, the incidence of kidney carcinoma was 5.7-fold higher (95% CI 1.4-14.7) if radiotherapy was not performed or less than 1 Gy had been absorbed by the kidney but 66.3-fold higher (95% CI 23.8-142.5) if the radiation dose to the kidneys was 10 to 19 Gy and 14.5-fold higher (95% CI 0.8-63.9) for larger radiation doses to the kidney. Treatment with chemotherapy increased the risk of kidney carcinoma (RR 5.1, 95% CI 1.1-22.7) but we were unable to identify a specific drug or drug category responsible for this effect., Conclusions: Moderate radiation dose to the kidneys during childhood cancer treatment increases the risk of a second kidney carcinoma. This incidence will be further increased when childhood cancer survivors reach old age., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

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.

Background: The temporal pattern in mortality from late second malignant neoplasms in solid childhood cancer survivors, according to the type of treatment, has not been investigated in detail., Methods: We studied 4,230 5-year survivors of solid childhood cancer diagnosed between 1942 and 1986 in France and the United Kingdom. Complete clinical, chemotherapy, and radiotherapy data were recorded and the integral radiation dose was estimated for 2,701 of the 2,948 patients who had received radiotherapy., Results: After a median follow-up of 28 years, 134 fatal events were due to second malignancies, compared with the 13.3 expected from the general France-UK population rates. The standardized mortality ratio was of a similar magnitude after radiotherapy alone and chemotherapy alone and higher after both treatments. The standardized mortality ratio decreased with follow-up, whereas the absolute excess risk increased significantly over a period of at least 25 years after the first cancer. This temporal pattern was similar after chemotherapy alone, radiotherapy alone, or both treatments. We observed a similar long-term temporal pattern among survivors who had died of a second malignant neoplasm of the gastrointestinal tract and breast. Survivors who had received a higher integral radiation dose during radiotherapy were at a particularly high risk, as well as those who had received alkylating agents and epipodophyllotoxins., Conclusions: Five-year survivors of childhood cancer run a high long-term mortality risk for all types of second malignant neoplasms whatever the treatment received and require careful long-term screening well beyond 25 years after the diagnosis.

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.

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.

The aim of this study was to determine the therapy-related risk factors for the occurrence of leukaemia after childhood solid cancer. Among 4204 3-year survivors of a childhood cancer treated in eight French and British centres before 1986, 11 patients developed leukaemia as a second malignant neoplasm (SMN). Compared with the leukaemia incidence in the general French and British populations, the standardised incidence ratio (SIR) of leukaemia was 7.8 (95% CI 4.0-13.4). It decreased from 20.3 (95% CI 8.3-41.2) during the first years of follow-up, to 2.2 (95% CI 0.1-9.7) between 10 and 20 years, but rose again to 14.8 (95% CI 3.7-38.3) 20 or more years after the first cancer. Radiotherapy appeared to increase the risk of leukaemia at moderate weighted doses to active bone marrow; the relative risk (RR) was 4.2 (95% CI 0.8-20.7) for doses ranging from 3 to 6.6 Gy. A greater RR was observed for epipodophyllotoxins and for vinca alkaloids. No specific type of first malignant neoplasm (FMN) was found to lead to a higher risk of secondary leukaemia. Epipodophyllotoxins and vinca alkaloids at high doses and moderate weighted radiation doses to active bone marrow may contribute independently to an increased risk of leukaemia for patients treated for childhood cancer. Our results suggest that the long-term risk of secondary leukaemia could be higher than previously reported.

Soft tissue sarcoma (STS) is one of the most frequent second primary cancer that occurs during the first 20 years following treatment for a solid cancer in childhood. Our aim was to quantify the risk of STS as a second malignant neoplasm and to investigate its relationship with radiotherapy and chemotherapy. A cohort study of 4,400 3-year survivors of a first solid cancer diagnosed during childhood in France or the United Kingdom, between 1942 and 1985, was followed 15 years on average. In a partially nested case-control study, we matched 25 cases of STS and 121 controls for sex, type of first cancer, age at first cancer and duration of follow-up. Sixteen STS occurred in the cohort, as compared to 0.3 expected from the general population (Standardized Incidence Radio, SIR = 54 (95%CI: 34-89)). The SIR was 113 (95% CI: 62-185) after chemotherapy plus radiotherapy (13 STS), whereas it was 28 (95%CI: 2-125) after chemotherapy alone (1 STS) and 19 (95%CI: 3-60) after radiotherapy alone (2 STS). After adjustment for treatment, there was no evidence of variation in the annual excess of incidence or in the SIR with either age at first cancer or time since 1st cancer. In the case-control study, the risk of a STS was increased with the square of the dose of radiation to the site of STS development and with the administration of Procarbazine. The increased risk of soft tissue sarcoma that occurred after childhood cancer is independently related to exposure to radiotherapy and Procarbazine. A closer surveillance of children treated with this treatment combination is strongly recommended., (Copyright 2004 Wiley-Liss, Inc.)

The aim of our study was to quantify the risk of second malignant neoplasms (SMNs) among long-term survivors of neuroblastoma and to study the influence of treatment on this risk. We studied data from 544 5-year survival patients diagnosed with neuroblastoma before age 16 years at 8 French and British treatment centres from 1948 to 1986. After an average follow-up of 15 years (range, 5-38 years), 12 children developed a total of 13 SMNs, whereas 1.19 were expected from general population rates. Among these SMNs, there were 5 thyroid and 3 breast cancers. Increases of the risks of SMN were observed with time since neuroblastoma diagnosis and attained age. In a multivariate analysis, the relative risk of SMN associated with radiotherapy was 4.3 (95% CI 0.8-78), whereas no increased risk of SMN was associated with the administration of chemotherapy as a whole (RR = 0.4, 95% CI 0.1-1.9). Young children treated for a neuroblastoma have significantly increased risks of SMN over 3 decades of follow-up. Radiotherapy treatment was found to be an important risk factor for developing SMNs, whereas no effect of chemotherapy was evidenced. Although our findings reflect the late effects of past therapeutic modalities, they underscore the importance of long-term surveillance of young children treated for a neuroblastoma. For these patients, many more years of follow-up are required to appreciate their overall risks of treatment-related SMNs., (Copyright 2003 Wiley-Liss, Inc.)

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.

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.

Chemotherapy has considerably improved the prognosis of solid tumours in children, but may have very adverse effects, particularly on fertility. A study was conducted at the Gustave Roussy Institute to identify the toxic effect of chemotherapy on male fertility. At present, 205 patients, treated during childhood have entered the study. Basal FSH-LH have been assayed to assess possible germ cell damage although azoosperia can not be eliminated. Results were normal in 127 patients (62%) and increased basal FSH levels were found in 78 (38%). Endocrine function was not altered: all patients were either impubertal or intrapubertal at diagnosis and subsequently achieved normal puberty. Multivariate analysis revealed an obvious toxic effect of 2 alkylating drugs: cyclophosphamide and procarbazine. No toxic effect was observed for vincristine, dohorubicin or actinomycin D. Age and pubertal status at diagnosis were not correlated with toxic effects. At present, no conclusion for other drugs may be made but results high dose metotrexate are promising. For lomustine and cisplatin, less favourable, though nonsignificant, results have been obtained. Complete recovery is possible several years later.

Of a cohort of 634 children treated from 1942 to 1969 at the Gustave Roussy Institute for a first cancer and alive 5 years after treatment, 32 later developed second malignant neoplasms (SMN). A case-control study was performed to determine the relationship between the dose of radiotherapy received on a given anatomical site for the treatment of a first cancer, and the risk of SMN development at the same anatomical site. Another aim of the study was to analyse the effects of the association of radiotherapy with chemotherapy on the risk of SMN. The 32 cases of second malignant neoplasms were individually matched with one to nine patients of the cohort (a total of 162) who did not develop a SMN after a first cancer, matching on age, sex, type of first cancer and follow-up duration. The doses of radiotherapy delivered for the treatment of the first cancer were retrospectively estimated at the 26 anatomical sites of SMN. When the SMN was a leukaemia, the mean active bone-marrow dose was estimated as a weighted mean of the doses received by 20 bone sites. As compared to anatomical sites in children who had not received radiotherapy, the sites which had received 50 Gy or more had a relative risk of SMN of 5.8 (P less than 0.05). When taking into account the dose received at the site of the SMN, neither the number of fractions nor the type of radiations were related to the risk of SMN. Children who had received chemotherapy had a relative risk of SMN of 2.7 (95% CI: 1.2-6.4), adjusted for the dose of radiotherapy, as compared to those who had not. The relative risk of SMN did not vary with the dose nor the duration of the chemotherapy. Dactinomycin was found to increase the relative risk of second soft tissue and bone sarcomas. Cyclophosphamide was found to be less carcinogenic than the other alkylants. The relative risk of SMN was equal to 2.0 (n.s.) after radiotherapy of more than 25 Gy, to 4.4 (n.s.) after chemotherapy, and to 21.4 (P less than 0.01) after the combination of these two treatments modalities, as compared to patients treated by surgery alone. This study suggests that the oncogenic effect of radiations might be increased by chemotherapy, and that the combination of the two treatment modalities might be one of the major factors responsible for overall risk of SMN.