Childhood Cancer Registry of the Province of Torino, Italy

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1 13 Childhood Cancer Registry of the Province of Torino, Italy Survival, Incidence, and Mortality Over Years Maria Luisa Mosso, MD, Renata Colombo, MD, Livia Giordano, MD, Guido Pastore, MD, Benedetto Terracini, MD, and Corrado Magnani, MD Incident childhood cancers in the Province of Torino, Italy (population aged to 14 years averaging.5 million) have been registered since 19. Four populationbased exhaustive surveys have been done to collect cases diagnosed during the periods 19 to 1969,197 to 1975,1976 to 1981, and 198 to For each registered child, vital status on June 3,19 was assessed. This article reports incidence, mortality, and survival rates over a year period. A statistically significant trend toward an increased incidence of soft tissue sarcomas was identified. Statistically insignificant trends included an increased incidence of brain tumors (probably reflecting improved diagnostic procedures) and a decreased incidence of thyroid tumors. Incidence rates of leukemias in the first year of life tended to decrease. As expected, survival rates of some childhood cancers dramatically improved throughout the Oyear period this occurred in leukemias, brain tumors, soft tissue sarcomas, and renal tumors. Survival rates are compared with observations in comparable populationbased series. Cancer 199; 69:131. The populationbased Registry of Childhood Cancer of the Province of Torino (Registro Tumori Infantili della Provincia di Torino, RTIPT) was begun in 19. At the From the Service of Cancer Epidemiology, University of ToMo and Local Health Unit Torino 8, Torino, Italy. The Childhood Cancer Registry was supported by the Italian National Research Council (Progetto Finalizzato Oncologia, grants , , , , and.77.44); Associazione Italiana per la Ricerca sul Cancro, Milano; and Sezione Provinciale di Torino della Lega Italiana per la Lotta contro i Tumori, Torino, Italy. Computer facilities provided in part by CSI Piemonte, Torino, Italy. The authors thank Ms. Rita Giacometti for secretarial help at the Registry, the heads of the hospital units where cases were sought, and their medical and nonmedical coworkers. Address for reprints: Benedetto Terracini, MD, Servizio di Epidemiologia dei Tumori, Ente Convenzionato Universit; di Torino, USL Torino 8, via Santena 7, 116 Torino, Italy. Accepted for publication June 1, National Census, the total population of the province was,345,771; those to 14 years of age were 19% of this number. Nearly 8% lived in the metropolitan area of Torino. In 1976, registration was extended to the other provinces of Piemonte. However, our report is limited to the Province of Torino, where registration currently includes a year period. The incidence and mortality rates and survival patterns up to 1981 were reported previously.' We describe incidence and mortality data up to 1986 and cumulative survival probabilities updated to June 19. Materials and Methods At intervals, the RTIPT staff actively does a retrospective survey of files of clinical records of children (age, to 14 years) hospitalized in pediatric units and in the major departments of medicine, hematology, and neurosurgery operating in the Piemonte region and in five Italian outstanding centers located outside the region (Istituto Nazionale Tumori and Istituto Neurologico C. Besta in Milano, Istituto Giannina Gaslini in Genova, and University Services of Paediatrics in MilanoMonza and Pavia). In some hospitals of the region with a pediatric unit, the files of the services of pathology and radiation therapy also are surveyed. The registry is notified of bone cancers in children living in Piemonte histologically diagnosed in the Istituto Ortopedico Rizzoli in Bologna by its pathology service. On the occasion of the most recent surveys, the Institute GustaveRoussy of Villejuif (France) and the Cancer Registry of Geneva (Switzerland) provided the list of children living in Piemonte included in their files. Finally, the RTIPT files were cross checked with those of hospital discharges in Piemonte and Lombardia and with the file of residents (of any age) in Piemonte dying of cancer kept by the regional cancer registry. Four retrospective surveys

2 Childhood Cancer Registry in Torino/Mosso et al. 131 have been done, collecting cases diagnosed during the periods 19 to 1979,197 to 1975,1976 to 1981, and 198 to In addition to all cancers (International Classification of Diseases, Ninth Revision, categories 14 to 8), the RTIPT records angiomas of the central nervous system (CNS), but histiocytosis X is not recorded. Data collection procedures were reported elsewhere.' Individual records include identification data (name, surname, date of birth, and town of residence) and cancer type, date of diagnosis, diagnostic procedures, and some major clinical information. "DCO' cases, ix., those identified only through the report of a malignant neoplasm as the leading cause of death on the death certificate (% during 19 to 1969, decreasing progressively to.% in 198 to 1986) were considered as diagnosed on the date of death. Cases registered under the same surname and name were reviewed manually, and double cancers were accepted only if both cancers were verified histologically. Cancer cases were coded both with an ad hoc code originally developed by the RTIPT and according to standard International Classification of Diseases for Oncology morphologic and topographic codes.' A case was considered to be histologically verified when a histologic report was identified during the registration procedures. In the computation of histologically verified cases, bone marrow aspiration cytology for leukemia was considered equivalent to histologic confirmation. For each child registered since 19, vital status on June 3, 19 was assessed through the Anagrafe (the Italian equivalent to Registrars of Births, Marriages, and Deaths in the United Kingdom) of the town of residence. The rates were computed on the basis of the age (1 year age classes) structure of the population during the 1971 and 1981 census and betweencensus estimates provided since 197 by the Istituto per le Ricerche Economiche e Sociali of the Piemonte region. All rates in this report are annual per million; the 1971 population of the province was used as standard for age adjustment (using four age classes:,l to 4,5 to 9, and 1 to 14 years). Survival analyses were done with the Kaplan Meier3 method, and the statistical significance of the differences between survival curves was assessed using the longrank test.4 Timerelated differences in incidence and mortality rates were analyzed with the chisquare test for trend with one degree of freedom. Results During 19 to 1986, 131 cases of childhood cancers were recorded, corresponding to an annual rate of per million children. Table 1 reports incidence rates by tumor type, age, sex ratios, and proportion of cases for which a histologic confirmation was available. Among cases diagnosed in 198 to 1986, there was his Table 1. Incidence Rates (Annual per Million) of Childhood Cancer in the Province of Torino (1986) by Age, Male to Female Ratio, Percentage of Cases Histologically Verified, and Absolute Number of Cases Agespecific rates (yr) Male to No. of * female ratio HV /%) cases Leukemias (all types) ALL ANLL Others and unspecified CNS neoplasms Neuroblastoma Hodgkin's lymphoma NonHodgkin's lymphoma Soft tissue sarcomas Bone sarcomas Renal tumors Retinoblastoma Thyroid tumors Others o All cancers No. of patients HV: histologic verification; ALL acute lymphocytic leukemia; ANLL acute nonlyrnphocytic leukemia; CNS: central nervous system. * Agestandardized on the age structure of the population of the province in

3 13 CANCER March 1,199, Volume 69, No. 5 Table. Incidence Rates of Childhood Cancer in the Province of Torino (1986) by Period of Diagnosis (No. of (No. of (No. of (No. of Rate cases) Rate cases) Rate cases) Rate cases) Leukemias (all types) 4 (7) 48.3 (146) 46.8 (131) 47.5 (83) ALL 8. (1) 3.9 () 37. (11) 39.3 (69) ANLL. () 6. (19) 6.5 () 7.5 (1) Others and unspecified.9 (58) 11.1 (34) 3.4 (1).7 () CNS neoplasms 7.5 (41).8 (91) 3.4 (95) 34.5 (66) Neuroblastoma 14.7 () 7.7 (3) 11.5 (8) 13.1 () Hodgkin s lymphoma 6. (9) 6.5 () 7.1 (3) 4.6 (11) NonHodgkin s lymphoma 7.4 (11) (1) 9.7 () (15) Soft tissue sarcomas 6.7 (1) (1) 9.5 (6) 11. (19) Bone sarcomas 6. (9) 6.8 (1) 7.4 (5) 8.4 () Renal tumors 8.7 (13) 5.4 (16) 8.4 (1) 11.4 (17) Retinoblastoma 5.4 (8).7 (8) 4.8 (11) 1.4 () Thyroid tumors.7 (4) 1.3 (4) 1. (4).4 (1) Others 11.4 (17) 1. (31) 9.3 (6) 7.9 (15) Unspecified 6. (9). (6).8 (). () Total (3) (48) (41) 147. (69) ALL acute lymphocytic leukemia; ANLL acute nonlymphocytic leukemia; CNS central nervous system. Rates are annual per million, agestandardized on the structure of the population of the province in tologic conhation in 1% of cases for leukemias, 8% for CNS neoplasms, and 97% for other tumors. Timetrends in incidence are shown in Table. This reports rates during the periods covered by each of the four surveys done over the year period. Only the trend toward an increased incidence of soft tissue sarcomas was statistically significant (chisquare, 9.1). During 198 to 1986, the rate for CNS neoplasms was increased 5% over that estimated during 19 to 1969, but the trend was not statistically significant (chisquare, 1.48). Additional (not tabulated) trend analyses were limited to the first year of life. In this age group, there was a statistically significant (chisquare for trend, 7.8) monotonic decrease of leukemias; the rates in the four periods were 8, 58.1, 7.4, and 1.5, respectively, based on 9, 1,4, and 1 cases, respectively. Only two of these cases were DCO, and in none was the presence of Down syndrome reported. Corresponding rates for CNS tumors and soft tissue sarcomas were 19.3, 9.7, 34., and 4. (based on two, two, five, and four cases) and 19.3, 4.8, 13.7 and 5.4 (based on two, one, two, and five cases), respectively. These trends were not statistically significant. Up to 1976, leukemia typing was not always done, and its registration was unsatisfactory. The 187 cases recorded during the subsequent 1 years included 153 of acute lymphatic leukemia (47% not otherwise specified, 7% specified as acute lymphatic leukemia of Tcell origin, and 46% as nontcell nonbcell), and 7 of nonlymphatic acute leukemias (ie., 1 M1 to M,3 pro myelocytic M3, 4 myelomonocytic M4, 3 monocytic M5, and 5 nonlymphatic leukemias with no further specification). Of the remaining seven cases, four were myelocytic leukemias, and three were recorded as acute leukemias. Tables 3, 4, and 5 report respectively the distribution of histologic types of neoplasms of the CNS, soft tissue sarcomas, and other cancers. As expected, carcinomas were rare. One of the two liver adenocarci Table 3. Distribution of Neoplasms of the Central Nervous System by Subtype, Male to Female Ratio, Percentage of Cases With Histologic Verification, and Incidence Rates (AgeStandardized, Annual per Million) No. of Male to cases female ratio HV (%) Rate Medulloblastomas Astrocytomas Epend ymomas Craniopharyngiomas Hemangiomas* Otherst Not otherwise specified Total HV: histologic verification. * Nineteen benign angiomas, one hemangiopericytoma, and one hemangioblastoma. t Reported as follows: 15 gliomas, neurinomas, pinealomas, 1 pituitary adenoma, 1 chordoma, 3 meningiomas, 1 cerebral ganglioneuroma, and 1 neuroeuhithelioma.

4 Childhood Cancer Registry in Torino/Mosso et al. 1 Table 4. Distribution of Histologic Diagnoses of Soft Tissue Sarcomas Rhabdomyosarcoma 34 Fibrosarcoma 13 Liposarcoma 9 Leiomyosarcoma 3 Synovial sarcoma Chondrosarcoma Malignant mesenchymoma 1 Malignant schwannoma 1 Myxosarcoma 1 Hemangiopericytoma 1 Soft tissue sarcoma, no further specification 6 Histologic report untraced 3 Total 76 nomas occurred in a child previously diagnosed as having a neuroblastoma. Among bone cancers, 6% and 34% were specified respectively as osteosarcomas and Ewing s sarcomas. All renal tumors were reported as Wilms tumor (two were specified as bilateral) except for two diagnosed as dear cell cancers. Among the retinoblastomas recorded over the entire period, only 6 were identified as bilateral. However, this is an underestimate because no systematic effort was made to identify metachronous bilateral retinoblastomas. During 19 to 1986, a total of 731 deaths from cancer in patients aged to 14 years were recorded (these included cases diagnosed before 19). Mortality rates by period of death are reported in Table 6. The trend was statistically significant (P <.1) for leuke Table 5. Distribution of Cases Included Under Others in Tables 1 and by Histologic Diagnosis Primary liver tumor Malignant reticulohistiocytosis Ovarian tumor Extragonadal immature teratoma Yolk sac tumors Testicular tumor Melanoma Nasopharyngeal undifferentiated carcinoma Pheochromocytoma Thymoma Adrenocortical tumor Adenocarcinoma in the liver, no further specification Others, with histologic diagnosis Histologic report untraced Total * One each of the following: carcinoid of the appendix, chorionepithelioma, adenocarcinoma of the colon, basalioma of the skin, adenocarcinoma of the pancreas, adenocarcinoma of the salivary glands, dermoid, undifferentiated carcinoma in lymph node, undifferentiated carcinoma in the connective tissue of the abdomen. Table 6. Mortality Rates of Childhood Cancer in the Province of Torino (1986) Leukemias (all types) ALL ANLL Others and unspecified CNS neoplasms Neuroblastoma Hodgkin s lymphoma NonHodgkin s lymphoma Soft tissue sarcomas Bone sarcomas Renal tumors Retinoblastoma Others and unspecified Total No. of uatients ~ ALL acute lymphocytic leukemia; ANLL acute nonlymphocytic leukemia; CNS: central nervous system. Rates are annual per million, agestandardized on the structure of the population of the province in mias considered as a whole, CNS neoplasms, and all tumors. Finally, Table 7 reports cumulative survival at 3 and 5 years after diagnosis, over six 3year periods of diagnosis. Survival for leukemias and CNS neoplasms is described in greater detail in Figures 1 and. In the logrank test, differences were significant for both leukemias (chisquare, 8.7; df, 3; P <.1) and CNS neoplasms (chisquare, 18; df, 3 df; P <.1). Discussion Over years, the RTIPT has maintained uniform criteria of registration of incidence, mortality, and survival. Thus, timerelated trends are unlikely to be biased. However, changes in incidence rates may reflect improvements in diagnostic procedures. The dramatic increase in efficacy of therapeutic protocols for several childhood cancer types largely explains the corresponding changes in mortality and survival rates. Two statistically significant timerelated trends in incidence were found. Assessing whether the increase in time of incidence rates of soft tissue sarcomas was real or reflected diagnostic improvement requires conhation during subsequent periods of registration. In addition, in the first year of life, there was a downward trend in incidence rates of leukemias, which was not determined by cases either exclusively registered through the death certificate or associated with Down syndrome. A similar timerelated trend in chil

5 ~~ 134 CANCER March 1, 199, Volume 69, No. 5 Table 7. Cumulative Survival Percentages and Standard Error at 3 and 5 Years Since Diagnosis by Period of Diagnosis % SE % SE Yo SE % SE % SE % SE Leukemias (all types) ALL ANLL Other leukemias CNS neoplasms Neuroblastoma Hodgkin's lymphoma NonHodgkin's lymphoma Soft tissue sarcomas Bone sarcomas Renal tumors Others All neoplasms 5 Y' 5 Y' 5 vr SE standard error; ALL acute lymphocytic leukemia; ANLL acute nonlymphocytic leukemia; CNS central nervous system dren younger than 1 year of age, but not in older children, was found for acute lymphatic leukemia in a cumulative sum analysis covering a 4year period of activity of the Manchester Children's Tumour Regi~try.~ The upward trend in time of incidence rates of CNS neoplasms we observedalthough not statistically sig nificantreproduces findings described in other registries in Europe and North AmericaG8 and probably reflects improved diagnostic procedures.6 Although statistically not significant and based on only 13 cases, the downward trend of incidence rates (Table ) of thyroid tumors was interesting because it paralleled the dilution of radioactive pollution from nuclear tests done in the early 196s. The affected children included 6 boys and 7 girls, all of whom were 9+ years of age. No case was observed among children born after 197. The 13 cases included 1 carcinomas (7 papillary, 1 follicular, papillary and follicular, and 1 medullary) and adenomas. The case of medullary carcinoma also had a pheochromocytoma, as in the Sipple syndrome. The time trends for survival rates should be mentioned, although some estimates reported in Table 7 are based on small absolute numbers. In particular, 3year and 5year survival rates of children with leukemia increased sharply for diagnosis up to the late 197s and remained constant in subsequent periods. For Wilms' tumors, there was a marked difference between those diagnosed before and after A trend toward improved prognosis was suggested for CNS neoplasms and nonhodgkin's lymphomas. The prognosis of children with Hodgkin's disease was good throughout the whole period. There was no prognostic improvement for neuroblastomas, with the exception of those diagnosed after 198. (This observation requires confirmation over a longer period of registration and observation.) In comparison with similar populationbased estimates on white children in the United States diagnosed after 198: 5year survival rates of children living in the Province of Torino diagnosed in 1979 to 1981 were lower for acute lymphatic leukemia (% versus 71%), neuroblastomas (1% versus %YO), renal tumors (% versus 81%), and bone sarcomas (7% versus 47%). The rates were similar for Hodgkin's lymphoma (89% ver

6 Childhood Cancer Registry in Torino/Mosso et al. 135 Figure 1. Survival for children with leukemias (all types). (3 z $.8 3 v, z g.6.4 W W I I I I I I I I I I i 5 1, 1,5,.5 3, 3,5 4, 4,5 5, 5, DAYS AFTER DIAGNOSIS sus 89%) and nonhodgkin's lymphoma (53% versus 5%). The survival of children with soft tissue sarcomas was similar in the two series." Survival from childhood brain tumors diagnosed during the 197s was similar in our registry and in the Manchester Children's Tumor Registry," but the comparison was biased by the different criteria of registration. In our series, with the exception of acute lymphatic leukemia, standard errors of survival rates exceeded 1%. Given the rarity of childhood cancer, this is to be expected even in a relatively large pediatric population, such as that of the Province of Torino. However, for an overall evaluation of effectiveness of childhood cancer care, populationbased studies are more informative than hospitalbased series. Although current etiologic investigations on cancer in children are based mainly on understanding biologic mechanisms, we believe that maintenance of popula CASES UNDER OBSERVATION YEARS AFTER DIAGNOSIS RRlOD 3 5 Figure. Survival of children with CNS tumors. 1 $.8 3 v, Z f.6.4 W M ,6 1,5,6,5 3, 3,5 4, 4,5 5, 5,5 6, 6,5 7. 7,5 DAYS AFTER DIAGNOSIS

7 1 CANCER March,199, Volume 69, No. 5 tionbased childhood cancer registries is important to monitorat a population levelboth incidence rates and therapeutic success, in a domain where cancer therapy has been promising. References Pastore G, Magnani C, Ghisetti V, Terracini B, Mosso ML, Zanetti R. Childhood Cancer Registry of the Province of Torino: Survival patterns since 19 and update of incidence rates. Pediatric Hematology and Oncology 1986; 3:1954. International Classification of Diseases for Oncology. Geneva: World Health Organization, 1976; Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. ]Am Stat Assoc 1958; 53:4481. Peto R, Pike MC, Armitage P et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient: Part 11. Analysis and examples. Br J Cancer 1977; 35:l Birch JM, Swindell R, Marsden HB, MomsJones PH. Childhood leukaemia in northwest England Epidemiology, incidence and survival. Br J Cancer 1981; 43: Breslow NE, Langholz B. Childhood cancer incidence: Geographical and temporal variations. Int J Cancer 1983; 3: Ericsson JLE, Karnstrom L, Mattsson B. Childhood cancer in Sweden : I. Incidence and mortality. Acta Paediatr Scand 1978; Teppo L, Salonen T, Hakulinen T. Incidence of childhood cancer in Finland. J Null Cancer lnst 1975; 55: National Cancer Institute, Division of Cancer Prevention and Control Surveillance Program. Cancer Statistics Review Bethesda, MD: National Institutes of Health, Myers MH, Gloeckler Ries LA. Cancer patient survival rates: SEER program results for 1 years of followup. In: Cancer Statistics. Atlanta: American Cancer Society, 1989; Birch JM, Marsden HB, MomsJones PH, Pearson D. Improvements in survival from childhood cancer: Results of a population based survey over 3 years. Br Med J 19; 6: