RADIATION DOSE, CHEMOTHERAPY AND RISK OF OSTEOSARCOMA AFTER SOLID TUMOURS DURING CHILDHOOD Be ´atrice LE VU 1 , Florent DE V ATHAIRE 1 *, Akhtar SHAMSALDIN 2 , Michael M. HAWKINS 4 , Emmanuel GRIMAUD 2 , Claire HARDIMAN 2 , Ibrahima DIALLO 2 , Gilles V ASSAL 3 , Elhadie BESSA 8 , Sarah CAMPBELL 9 , Xavier PANIS 5 , Nicolas DALY-SCHVEITZER 6 , Jean-Le ´on LAGRANGE 7 , Jean-Michel ZUCKER 8 , Franc ¸ois ESCHWE ` GE 2 , Jean CHAVAUDRA 2 and Jean LEMERLE 3 1 National Institute of Public Health and Medical Research Unit 351, Villejuif, France 2 Medical Physics and Radiotherapy Departments, Gustave Roussy Institute, Villejuif, France 3 Department of Paediatrics, Gustave Roussy Institute, Villejuif, France 4 Childhood Cancer Research Group, University of Oxford, Oxford, UK 5 Institut Jean Godinot, Reims, France 6 Centre Claudius Regaud, Toulouse, France 7 Centre Antoine Lacassagne, Nice, France 8 Department of Paediatrics, Institut Curie, Paris, France 9 Thames Cancer Registry, London, UK O steosarcoma 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. W e 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. Parametersstudied were the incidence of osteosar- coma, 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. N o interaction was noted between radiotherapy and chemotherapy. Bilateral retinoblastoma, Ewing’s sar- coma and soft tissue sarcoma were found to render patients susceptible to a higher risk of developing an osteosarcoma as a second malignant neoplasm. W e 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 radio- therapy plus high doses of chemotherapy, without focusing exclusively on the radiation field. Int. J. Cancer 77:370–377, 1998.  1998 Wiley-Liss, Inc. Osteosarcoma is the most frequent second primary cancer which occurs in teenagers or young adults up to 20 years after a first cancer during their childhood (Tucker et al., 1984; Hawkins et al., 1987; Olsen et al., 1993). Quantification of the risk of osteosar- coma as a second malignant neoplasm (SMN) and its relationships with radiotherapy and chemotherapy could provide a rational basis for the elaboration of future treatment protocols. Only a few published studies have estimated the relationship between the dose of radiotherapy received at a given site of the skeleton and the risk of osteosarcoma at this site (Tucker et al., 1987; Hawkins et al., 1996; Wong et al., 1997). We report on a case-control study, nested in a cohort of patients treated for a first solid cancer in childhood. PATIENTS AND METHODS Cohort A cohort of 4,400 at least 3-year survivors treated for a solid cancer during childhood in 8 centres in France and Great Britain, between 1942 and 1986, was recorded. The eight centres are: Institut Curie in Paris, Institut Gustave Roussy (IGR) in Villejuif, Institut Jean Godinot in Reims, Centre Antoine Lacassagne in Nice, Centre Claudius Regaud in Toulouse, Saint Bartholomew Hospital, Great Ormond Hospital, and Royal Marsden Hospital in London. Clinical and pathological characteristics of the cancer, the nature of the treatment, and detailed information about chemotherapy were recorded from hospital clinical records by physicians. Radio- therapy data were obtained from the technical records, by clinicians or hospital physicists. We obtained follow-up data of British patients from hospital records and registration of the Children Cancer Research Group (CCRG). In French centres, follow-up data were abstracted from clinical records. These centres, all members of the Fe ´de ´ration Nationale des Centre de Lutte Contre le Cancer performed active follow-up by writing to patients and linked their data-base with the national death certificates data. All second osteosarcomas were confirmed by histopathologists. In this study, only osteosarcomas which occurred as second cancers were considered, chondroblastic or not, therefore we excluded 143 patients treated for osteosarcoma as a first cancer from this cohort, because it is not possible to differentiate a second primary osteosarcoma from a relapse or a metastasis of the first one. The remaining 4,257 patients were included in the cohort analysis, 3,058 from French centres and 1,199 from British ones. The end of the cohort analysis was January 1st 1992 for patients treated in French centres, and January 1st 1991 for those treated in British centres. Radiation dosimetry The individual dose calculation, required for this study was performed with a software package, Dos_EG, which was devel- oped for retrospective studies at the IGR (Franc ¸ois et al., 1988a; b). It includes two major algorithms. The first is devoted to generating an anatomy mathematically equivalent to each patient and com- putes the organ positions using auxological methods as previously described (Sempe ´, 1979). The parameters required to construct this Grant sponsor: Europe Against Cancer; Grant number: 91CV101090–0; Grant sponsor: Radiation Protection Programs of the EEC; Grant numbers: F13P-CT92–0064 and F14P-CT95–0009; Grant sponsors: Gustave Roussy Institute, INSERM, CNAMTS, EDF, SNECMA, Framatome, Association pour la Recherche Me ´dicale, the comities ‘‘Champagne-Ardennes’’, ‘‘Essonne’’ and ‘‘Val d’Oise’’ of the Ligue Nationale Contre le cancer. *Correspondence to: INSERM U 351, Institut Gustave Roussy, 39 rue Camille Desmoulins F-94805 Villejuif Cedex, France. Fax: (33) 1–4211– 5315. E-mail: fdv@igr.fr Received 5 January 1998; Revised 20 February 1998 Int. J. Cancer: 77, 370–377 (1998)  1998 Wiley-Liss, Inc. Publication of the International Union Against Cancer Publication de l’Union Internationale Contre le Cancer