EARLY AND LATE DEATHS AFTER ELECTIVE END OF THERAPIES FOR CHILDHOOD CANCER IN ITALY Riccardo HAUPT 1,2 * , M. Grazia VALSECCHI 3 , Daniela SILVESTRI 4 , Paola DE LORENZO 4 , Silvio NAPOLI 2 , Giuseppe MASERA 4 , Benedetto TERRACINI 5 and Momcilo JANKOVIC 4 for the Italian Registry of Off-Therapy Patients (OTR) 1 Scientific Directorate, G. Gaslini Children’s Hospital, Genoa, Italy 2 Division of Hematology/Oncology, G. Gaslini Children’s Hospital, Genoa, Italy 3 Department of Public Health, University of Verona, Verona, Italy 4 Department of Pediatrics, University of Milan-Monza, Monza, Italy 5 Department of Biomedical Sciences and Human Oncology, University of Turin, Turin, Italy The first cohort of subjects treated for cancer during child- hood is now entering adulthood, and it is necessary to deter- mine whether treatment has been sufficient to completely eradicate the neoplastic clone, and whether the cancer itself or treatment-related toxicity may have increased the risk of premature death. For these reasons, long-term survival and causes of death were evaluated in a cohort of subjects treated for childhood cancer who reached the elective end of therapy in continuous remission and were registered until 1992 in the Italian Registry of off-therapy subjects (OTR). The vital status of OTR subjects was ascertained in 1996 by a postal survey through census bureaux; for deceased subjects, the cause of death was defined and compared with the ex- pected rates in the general population. At follow-up, out of 6402 eligible and evaluable subjects, 890 were found to have died; the estimated overall survival at 20 years was 80.7% (95% CI 79.3– 82.1). Most of the patients (84.6%) died due to recurrence of the primary cancer, usually within the first 5 years after the OT. The cumulative incidence of death due to recurrence of the primary tumor was greater among sub- jects treated for solid tumor than among those treated for leukemia/lymphoma (p  0.0001); in contrast, OT subjects after leukemia and lymphoma were more likely to die due to of medical complications of therapy (p < 0.02). Second can- cers were the second most frequent cause of death, with a 12-fold risk compared with the general population; the fig- ures were similar in the 2 cancer groups. Compared with the general population, OT subjects were 32 times more likely than same-age subjects to die. The SMR decreased to 6.1 when only non-cancer deaths were considered. Deaths due to external or avoidable causes occurred among survivors at a rate similar to that of the general population. Int. J. Cancer 86: 393–398, 2000. © 2000 Wiley-Liss, Inc. During the last 2 decades, advances in anti-cancer therapy have led to an increasing number of children reaching the elective end of therapy, becoming long-term survivors, and entering into adult- hood (Magnani et al., 1997; Novakovic, 1994). Follow-up of this first cohort of survivors after childhood cancer is important to determine whether therapies have been sufficient to completely eradicate the neoplastic clone, and whether cancer itself or treat- ment-related toxicity may have increased the risk of premature death. The follow-up of these subjects may be difficult; in fact, after entering adulthood, survivors are less likely to seek medical care in pediatric oncology units, and are more likely to migrate than are pediatric patients. Thus, important information on long- term survivors may be difficult to retrieve using only data available at the referring pediatric institution, and must be sought in other ways. Here we report on the follow-up through census bureaux of a large cohort of subjects enrolled in the Italian Off-Therapy Reg- istry (OTR) and on their survival after the end of therapies; we compare their death rate and causes of death with those expected in the general population. MATERIAL AND METHODS The registry The OTR was established in July 1980, when 40 Italian insti- tutions engaged in pediatric oncology, and affiliated to the Italian Association of Pediatric Hematology and Oncology (AIEOP), agreed to create at the Pediatric Clinic of the University of Monza a centralized registry of children (aged 0 –15) who, regardless of subsequent disease evolution, had reached the end of treatment in the absence of clinical signs of disease, i.e., the off-therapy stage (OT) (Zurlo et al., 1986). Each institution contributed prevalent subjects at the start of the registry, and prospectively includes new OT cases. Cancer types originally considered for the OTR were: acute lymphoblastic leukemia (ALL), acute non-lymphoblastic leukemia (AnLL), Hodgkin’s disease (HD), non-Hodgkin lym- phoma (NHL), neuroblastoma (NB) and Wilms’ tumor (WT). In 1986 the registration was expanded to include neoplasms of the central nervous system (CNS) and soft-tissue sarcomas (STS). The central registry collects information on the original cancer and its treatment, and on major clinical events, i.e., relapses, second malignant tumors, or death, if it occurs, and periodically updates follow-up through clinical records. Follow-up and definition of the unique cause of death For this study, follow-up was updated by a postal survey among the Italian town registrars. In Italy, every citizen is registered in the census bureau of the place of birth, and in those of any town of residence if he migrates; in this way, it is possible to trace every subject having his/her correct demographic data. During 1996 the vital status of each subject registered as OT until 1992 was ascertained through the census bureau of his/her place of residence or of birth. Subjects not traced through census bureaux were assigned the living status recorded in the clinical follow-up data already available in the registry. For deceased subjects, death certificates with specifications of causes of death were sought and reviewed by one of us (R.H.). The cause of death of each case was coded according to the International Classification of Diseases, 9th revision (ICD-9). Priority was given to the information given by the treating institution if the death occurred in the same hospital; otherwise the unique cause of death was defined according to the initial, intermediate and final cause as reported in the death cer- tificates. In particular, if not otherwise specifically reported from the treating institution, both deaths occurring within 6 months from the date of BMT, and infectious deaths occurring within 2 months from the end of therapies or during treatment for a relapse were defined as due to the primary cancer. Deaths occurring more than Grant sponsors: Italian Association for Cancer Research (AIRC); Istituto Superiore di Sanit` a; Fondazione Tettamanti; Comitato M. Letizia Verga. *Correspondence to: Direzione Scientifica, Istituto G. Gaslini, Largo G. Gaslini, 5, 16147 Genoa - Italy. Fax: +39 (010) 3776590. E-mail: riccardohaupt@ospedale-gaslini.ge.it Received 7 July 1999; Revised 12 October 1999 Int. J. Cancer: 86, 393–398 (2000) © 2000 Wiley-Liss, Inc. Publication of the International Union Against Cancer