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Background Increasing numbers of children with cancer survive and reach reproductive age. However, the risk of cancer (other than retinoblastoma) in the offspring of survivors of childhood and adolescent cancer is uncertain.
Methods Using data from national cancer and birth registries, we assessed the risk of cancer among 5847 offspring of 14,652 survivors of cancer in childhood or adolescence diagnosed since the 1940s and 1950s in Denmark, Finland, Iceland, Norway, and Sweden. The offspring were followed up for a diagnosis of cancer for 86,780 person-years, and standardized incidence ratios were calculated.
Results Among the 5847 offspring, 44 malignant neoplasms were diagnosed (standardized incidence ratio, 2.6; 95 percent confidence interval, 1.9 to 3.5). There were 17 retinoblastomas, yielding a standardized incidence ratio of 37. There were 27 neoplasms other than retinoblastoma (standardized incidence ratio, 1.6; 95 percent confidence interval, 1.1 to 2.4). The second most common primary site of cancer among the offspring was the brain and nervous system, in which eight tumors were observed (standardized incidence ratio, 2.0; 95 percent confidence interval, 0.9 to 3.9). There were between zero and four apparently sporadic cases of cancer in other primary sites among the offspring. Excluding 4 likely cases of hereditary cancer and 2 subsequent cancers among the offspring with hereditary retinoblastoma, there were 22 sporadic cancers, for a standardized incidence ratio of 1.3 (95 percent confidence interval, 0.8 to 2.0).
Conclusions There is no evidence of a significantly increased risk of nonhereditary cancer among the offspring of survivors of cancer in childhood.
In this collaborative study from five countries — Denmark, Finland, Iceland, Norway, and Sweden — we assessed the incidence of cancer in large population-based cohorts of offspring of survivors of cancer in childhood or adolescence and compared it with the relevant rates of cancer in the general population.
Methods
The primary patient population consisted of 14,652 men and women in whom cancer was diagnosed when they were less than 20 years old and who survived until they reached reproductive age (defined as 15 years old). The data were obtained from cancer registries, which had been initiated in 1943 (Denmark), 1953 (Finland and Norway), 1955 (Iceland), and 1958 (Sweden). All the patients who were registered between those years and December 31, 1991 (1987 in Sweden), were included in the study. Patients who died before reaching 15 years of age or before the year in which national computerized registration of offspring began (Iceland, 1955; Norway, 1960; Sweden, 1961; Finland, 1967; and Denmark, 1968) were not eligible. The personal identification number, type of malignant neoplasm, and date of diagnosis of the survivors were extracted from the files of the five nationwide population-based cancer registries. The personal identification number, which is unique to every Scandinavian citizen, incorporates sex (except in Iceland) and the date of birth and permits accurate linkage of information between registries. The malignant neoplasms of the survivors were classified according to a scheme for childhood cancer prepared by the International Agency for Research on Cancer.6
The unique personal identification numbers allowed a computerized search of the central population registries (national birth registry in Sweden) for all offspring born to the 14,652 survivors of childhood cancer. As of December 31, 1991, 5847 offspring of these survivors had been identified. In Sweden, the birth registry contained data on the offspring of all female survivors but only on the offspring of the male survivors who were married at the time of the birth of their offspring.
The personal identification numbers of the 5847 offspring were linked with the files of the national cancer registries. The follow-up for cancer among these children started on the date of birth or the date of the introduction of national personal identification numbers in each country, whichever was later (Table 1). The follow-up ended on the date of death or emigration or the closing date of the study — December 31, 1994, or December 31, 1995 (Table 1).
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The expected numbers of cancers among the offspring were calculated by multiplying the number of person-years of follow-up by the cancer incidence rates for the respective national populations in five-year age groups and calendar periods of observation. Standardized incidence ratios were calculated by dividing the observed numbers of cancers (specific for sex, age, and calendar year) by the respective expected ones. Ninety-five percent confidence intervals were calculated on the basis of the assumption that the observed numbers of cancers followed a Poisson distribution.
Results
Of the 14,652 survivors of cancer in childhood and adolescence (8032 men and 6620 women; male-to-female ratio, 55:45), 3369 (23 percent) had children during the follow-up period (Table 2). The proportion of parents was lowest among the survivors of leukemia (6 percent) and highest among the survivors of carcinomas (43 percent) (Table 2). The mean numbers of offspring per survivor ranged from 1.6 to 1.8, depending on the type of cancer, except for survivors of leukemia, for whom it was 1.3 (Table 2).
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The risk of cancer among the subgroups of offspring was not significantly increased when analyzed according to the primary site of the cancer in the parent, except for retinoblastoma. No neoplasms were observed among the children of survivors of leukemia, neuroblastoma, or hepatic tumors. The overall standardized incidence ratio for nonretinoblastoma neoplasms was 3.9 (95 percent confidence interval, 2.1 to 6.7) for offspring whose parents were less than 10 years of age at the time of diagnosis, and it was 1.1 (95 percent confidence interval, 0.6 to 1.8) among the offspring of survivors who were 10 or older at the time of diagnosis. All the offspring with cancer were born at least eight years after cancer was diagnosed in their mothers except one (pair 25, Table 5).
The risk of retinoblastoma among the offspring of retinoblastoma survivors was extremely high: of the 17 offspring with retinoblastoma, 16 each had a parent who had had the disease (standardized incidence ratio, 950; 95 percent confidence interval, 540 to 1500). Only one parent with retinoblastoma had two children with retinoblastoma. Two subsequent nonretinoblastoma tumors occurred among the 16 offspring with hereditary retinoblastoma. One was a sebaceous carcinoma in the eyelid (pair 10, Table 5); the other was a rhabdomyosarcoma in the temporal region (pair 13, Table 5). Both tumors occurred in areas that were probably irradiated during treatment of the retinoblastoma. Among the offspring, there were no retinoblastomas diagnosed before the 1970s; for offspring born in the 1970s, the overall standardized incidence ratio for retinoblastoma was 37 on the basis of 5 cases, and for those born in 1980 to 1991, the standardized incidence ratio was 49 on the basis of 12 cases.
To assess only the risk of sporadic cancer among the offspring, we excluded the four offspring in whom there were features of hereditary cancer syndromes and the two patients with hereditary retinoblastoma who had solid tumors that probably arose in external-radiotherapy fields. By limiting the analysis to the 22 offspring with apparently sporadic tumors (including the 1 with sporadic retinoblastoma), we found that the standardized incidence ratio decreased from 1.6 to 1.3 (95 percent confidence interval, 0.8 to 2.0).
Discussion
In our large population-based series, the overall standardized incidence ratio for nonretinoblastoma cancers among the offspring of survivors of nonretinoblastoma cancer in childhood or adolescence was 1.6 (95 percent confidence interval, 1.1 to 2.4) on the basis of 27 observed and 16.5 expected cases — a small but statistically significant increase. However, when we limited the analysis to the 22 apparently sporadic tumors, the standardized incidence ratio was only 1.3 (95 percent confidence interval, 0.8 to 2.0). We think that this figure is more relevant to clinical practice than the overall ratio. Our study found that there was less than 1 excess case of cancer per 1000 offspring, whereas in previous, smaller studies, the numbers of observed cancers were too small to allow reliable estimates of risk.3,4,5
There were four instances in which hereditary syndromes other than retinoblastoma were likely. However, our data were limited to two generations, and for this reason we could not construct large pedigrees. These cases included two survivor–offspring pairs with features suggestive of Li–Fraumeni syndrome, one pair with von Hippel–Lindau disease, and one pair with neurofibromatosis type 1 or 2. There were no apparent hereditary cases of neuroblastoma or Wilms' tumor among the offspring, but we did not collect data on the bilateralism of Wilms' tumor among the survivors. The two survivor–offspring pairs in which both parent and offspring had soft-tissue sarcomas (pairs 20 and 21, Table 5) yielded a high standardized incidence ratio of 38, but whether this was due to a hereditary component or a chance finding could not be determined.
Among the offspring, there were no cases of Hodgkin's disease (0.8 was expected) or of malignant tumors in bone (0.5), the thyroid (0.4), the cervix uteri (0.4, in situ not included), colorectum (0.3), the liver (0.2), the breast (0.3), or the lung (0.1). Since the hereditary forms of cancer of the colorectum and breast are almost never diagnosed before the age of 20, these diseases were not encountered among the parents.
In one case, the interval from the diagnosis of the cancer in the survivor mother to the birth of the affected child was three years; the mother had had a mixed tumor of the parotid gland at the age of 19, and her daughter had mucocellular carcinoma of the stomach at the age of 33. In all other cases not involving retinoblastoma, the interval from the mother's diagnosis to the birth of the affected child was between 8 and 23 years, making a direct effect of the mother's cancer treatment on the fetus unlikely.
There was a slight trend toward increased risk with younger survivor parents' ages at the time of diagnosis. The standardized incidence ratio for nonretinoblastoma neoplasms was 3.9 for offspring of survivors whose cancers were diagnosed when they were less than 10 years of age and 1.1 for offspring of survivors whose cancers were diagnosed when they were 10 to 19 years of age. However, the cancer pattern among the offspring of survivors who were given diagnoses when they were less than 10 years old was quite heterogeneous, impeding further conclusions.
The Swedish birth-registry data did not contain information on the offspring of male survivors who were not married when the child was born. However, this limitation should not have caused a selection bias that might have affected the estimate of can-cer incidence among the identified offspring in the Swedish data. For purposes of quality control, the offspring of the Swedish male survivors were identified through the use of another registry, with data on live offspring in 1992. We found that the sex ratio of the survivors resembled that in the other countries, but we could not use the data, because the offspring who had died before 1992 were missing.
We conclude that in this series of patients the risk of cancer among the offspring of survivors of childhood cancer (excluding retinoblastoma and other hereditary cancer syndromes) was small and limited to children of survivors whose cancers were diagnosed when they were less than 10 years of age. Our confidence in concluding that the excess number of nonretinoblastoma cancers was very small is bolstered by the fact that our data represent all the cases of cancer diagnosed in a population of about 20 million people during a 25-to-35-year period. These results imply that fear of cancer in their offspring is no reason to discourage the survivors of sporadic childhood cancer from having children, and efforts to screen for cancer in offspring of the survivors of sporadic cancer in childhood or adolescence are not warranted.
Supported by a research grant from the Nordic Cancer Union.
We are indebted to Andrea Bautz from the Danish Cancer Society for technical help in statistical analyses and data management.
Source Information
From the Finnish Cancer Registry, Helsinki (R.S.); the Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen (J.H.O.); the Southern Swedish Regional Cancer Registry (H.A., T.M.) and the Department of Pediatrics, University Hospital (S.G.), Lund, Sweden; the Cancer Registry of Norway, Oslo (E.G., F.L.); the Department of Pediatrics, University Hospital, Copenhagen (H.H.); the Department of Pediatrics, University Hospital of Oulu, Oulu, Finland (M.L.); and the Icelandic Cancer Registry, Reykjavik (H.T.).
Address reprint requests to Dr. Sankila at the Finnish Cancer Registry, Liisankatu 21 B, FIN-00170 Helsinki, Finland.
References
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Related Letters:
Cancer among Offspring of Survivors of Childhood Cancer
Ross J. A., Davies S. M., Sankila R., Olsen J. H., Garwicz S.
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Full Text
N Engl J Med 1998;
339:923-924, Sep 24, 1998.
Correspondence
This article has been cited by other articles:
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