In this population-based study, we found that irradiated 5-year survivors of ALL had more hospital contacts and spent more days in hospital than both non-irradiated survivors and matched population controls. This risk increased with the amount of cranial irradiation received. In contrast, non-irradiated survivors of ALL did not have more hospital contacts, nor did they spend more days in hospital, than controls. Among those who were hospitalized at least once, a broad range of different diagnoses of the hospital contacts were significantly more frequent among ALL survivors than controls.
In the present study, comprising a follow-up from 1975 to 2009, 49% of survivors of ALL were hospitalized at least once, which is similar to the proportion found in leukemia survivors in British Columbia, Canada, where 40% had been hospitalized at least once (follow-up 1986–2000) . Leukemia survivors included in the CCSS had a standardized incidence ratio of self-reported hospitalization of 1.4 (95%CI 1.3–1.4) compared with the general U.S. population . In the BCCSS, 7.1 percent of survivors of leukemia reported having been hospitalized at least once during the observed year, a 1.4-fold risk compared with the general population (data from the National General Household Survey) . Thus, the findings of the present study are also consistent with the results of the BCCSS and the CCSS. The BCCSS has a long period of follow-up and is, like the CCSS, a large study. However, both these studies rely on self-reported outcome measures. Furthermore, the CCSS includes patients only treated at the collaborating hospitals, while the present study is distinguished by being strictly population-based and includes outcome measures that are based on comprehensive nationwide registers. An additional strength of the present study is the use of a large, matched control cohort from the general population.
Our finding of a broad range of discharge diagnoses causing hospital contacts among survivors is supported in two comparable studies [15, 16]. Clearly, the increased risk of hospital contacts among survivors of ALL compared to the controls is caused by many different diagnoses. One exception in our study is the finding of a smaller proportion of hospital contacts for pulmonary diseases in the group of ALL survivors than in the control cohort, which is in contrast to that of the two earlier studies. One may speculate that the different frequencies of pulmonary diseases in survivors and controls could be due to differences in smoking habits between cancer survivors and controls. This hypothesis is supported by the CCSS study, where survivors were found to smoke less than the general population . Unfortunately, information on smoking was not available in the current study. We also found that survivors did not have hospital contacts to a greater extent for mental disorders, injuries or poisoning than controls, which is in contrast to previously published results [15, 16].
It is well known that cranial and total body irradiation result in an increased risk of a broad range of late complications, and efforts to reduce radiotherapy in treatment protocols without compromising survival rates have been successful for ALL patients during the last three decades [22, 23]. Nevertheless, Bradley et al. could not find a specific treatment modality to be a risk factor for hospitalization when survivors of all childhood cancers were grouped together . When leukemia survivors were analyzed separately by Lorenzi et al., an increased risk of hospitalization was seen among survivors treated with chemotherapy only, as well as among those treated with both chemotherapy and cranial irradiation, compared to the control group . In contrast to both these studies, we found an increased risk of having hospital contacts only in the subgroups of survivors whose treatment included radiotherapy in addition to chemotherapy. All three studies are population- and register-based, but the follow-up period of our study is longer, and we included survivors diagnosed with ALL as early as 1970, which may in part explain the disparities.
The main finding of our study that there is no increased risk of hospital contacts of non-irradiated survivors of ALL is supported by the CCSS study where the vast majority (92%) of the non-irradiated, non-relapsed survivors did not report any severe chronic medical condition . On the basis of the results of the present study, follow-up of ALL survivors should primarily focus on developing preventive interventions, and enhancing patient counseling and follow-up care of those whose treatment included irradiation.
Our data show that, in both the survivor cohort and the control cohort, females had an increased risk for at least one hospital contact, more hospital contacts and longer hospital stays than males, which is in agreement with previous studies [15, 16]. Moreover, we found that age at diagnosis did not influence the risk of having at least one hospital contact, but in the age group ≥ 10 years at cancer diagnosis, fewer hospital contacts and shorter hospital stays were seen. In the CCSS, young age at diagnosis was found to be associated with an increase in risk of hospitalization, while Lorenzi et al. showed that age at diagnosis did not significantly influence later hospitalization [15, 16]. However, all types of childhood cancer were included in the analyses of the impact of gender and age at diagnosis in these two studies, making direct comparisons with our study difficult. In accordance with the study by Lorenzi et al., we found that the influence of socio-economic factors on hospital contacts did not differ between ALL survivors and controls.
The limitations of the current study must be considered. The Swedish National Hospital Register includes hospital-based outpatient data only since 2001, and no data from general practitioners are included, so the present study mainly captures conditions resulting in admission to hospital. In addition, the Swedish Hospital Register has national coverage only since 1987, which further reduces the number of hospital contacts included in the study. However, most parts of Southern Sweden have had complete coverage since 1970. The current study was not powered to look at the influence of treatment era on health care utilization. However, we did analyze the impact of treatment modality, which in part could be seen as a substitute for treatment era. Information on emigration and death was not considered in the follow-up of the control cohort, which could potentially have led to the underestimation of the rate of hospital contacts in this cohort. However, given the size of the control cohort, this potential underestimation should not be of any substantial significance.