Late somatic sequelae after treatment of childhood cancer in Slovenia
© Erman et al.; licensee BioMed Central Ltd. 2012
Received: 3 October 2011
Accepted: 24 May 2012
Published: 24 May 2012
This is a long-term follow-up clinical study of adolescents and adults, survivors of childhood cancer. We evaluate and analyze the late somatic sequelae of childhood cancer treatment. Many such studies are susceptible to a strong selection bias, i.e., they employ a limited non-systematic sample of patients, based on a clinical hospital that provided the cancer treatment or performed the follow-up. To address the issue of selection bias, we perform here an analysis of late sequelae on a systematic database of the entire population of the children treated for cancer in Slovenia. Due to the specifics of cancer treatment procedures in Slovenia, they have all been treated and followed-up in the same clinic.
The data are based on the centralized registry of cancer patients in Slovenia and present a controlled and homogeneous collection. Late sequelae are evaluated following a modified CTCAE, i.e., the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 3.0. We use survival analysis method to estimate the incidence of and risk for late sequelae, where the time variable is measured in years from the diagnosis date, while we follow the event of incidence of late sequelae scored other than none. Survival analysis is performed using KaplanMeier estimator and Cox regression model.
The incidence of mild, moderate, or severe late sequelae of childhood cancer treatment significantly decreased from 75% in the group of patients diagnosed before 1975 to 55% for those diagnosed after 1995. The Cox regression analysis of the risk factors for the incidence of late sequelae identifies three significant factors: treatment modalities, age at diagnosis, and primary diagnosis.
The change of treatment modalities in terms of replacement of surgery and radiotherapy with chemotherapy is the main reason for the decrease of the incidence and the risk for late sequelae of childhood cancer treatment; treatment modalities including surgery significantly increase the risk ratio of late sequelae, while those based on chemotherapy only significantly decreases the risk. Risk of late sequelae increases with the diagnosis age: younger children are more susceptible to late effects of treatment. Finally, primary diagnosis significantly influences the risk for late sequelae, but mostly due to the dependency of the treatment modality on the primary diagnosis.
In Slovenia and in the rest of Europe as well as the USA, the mortality rate of chlidren with cancer is declining despite the increasing incidence rate. Survival of children treated for cancer has significantly improved after 1970 with the introduction of chemotherapy. Since 1990, however, the rate of increase might have slowed for several reasons: on one hand, new ways of treatment have been introduced and on the other hand, the mortality due to late effects of treatment and secondary tumors have emerged [1–7]. With the increasing number of childhood cancer survivors, late sequelae and quality of life have become a major concern. Approximately 50% of children cured of cancer will display one or more delayed somatic sequelae, and about one third will have severe and life threatening complications. There is therefore a general agreement for the necessity of a long-term follow-up of adolescents and adults, survivors of childhood cancer [8–12].
Childhood cancer survivors included in many long-term follow-up clinical studies do not appropriately represent the entire survivor population for different reasons. One is that not all the patients included in the follow-up respond to the questionnaires or show-up for the regular clinical checks. Another reason is selection bias; studies often address a non-systematic sample of patients based on a clinical hospital that provided the treatment or performed the follow-up. Integrating groups of patients from different follow-up programs or clinics in a more systematic sample of patients is often prohibitive, since there are many different approaches to the evaluation of the late sequelae and quality of life. Finally, that there are still many open issues related to the childhood cancer survivors, such as definitions of the terms cure, health, or quality of life. Even the excellent studies on large populations of patients and based on high-quality questionnaires may be susceptible to selection bias [13–15].
In this paper, we address the problem of selection bias by performing a study of late sequelae on the entire population of all registered children treated for cancer in Slovenia. Namely, the registration of cancer patients in Slovenia is obligatory and centralized within the Cancer Registry of Slovenia, established in 1950. Treatment of children with cancer is also centralized at the Children’s Hospital in Ljubljana. After treatment, all patients are being followed at the same single center for at least five years or until they are 18 years old, and later they are followed regularly at a single institution, the outpatient Clinic for Late Effects at the Institute of Oncology, Ljubljana. The follow-up program that includes a specifically designed questionnaire for recording data has been established in 1986 . Slovene Ministry of Science has been financing the program for “Late effects of childhood cancer treatment” since 1993. Survivors included in the program have been evaluated and analyzed as to their late somatic sequelae including neurological deficits , endocrine function deficits , renal function damage , secondary tumors [20, 21], cardiac damage , and psychosocial consequences .
With increased knowledge about late effects of cancer treatment, treatment policies have been appropriately changed in order to decrease toxic sequelae . For example, Hodgkin's disease treatment with MOPP (i.e., Nitrogen Mustard, Oncovin, procarbazine, and prednisone), known for causing male sterility, has been replaced by other chemotherapy (CHT) combinations, while the doses of radiation have been diminished. In nephroblastoma, radiotherapy (RT) has been replaced in the great majority of patients by chemotherapy. The toxic dose of antracyclines has been avoided in newer combinations of CHT and RT doses have been diminished in many cases of soft tissue sarcoma as well. In more general terms, while in the first decade until 1970 the great majority of children were treated with surgery and RT, in the 1970-ies to 1980-ies for the majority of patients a combination of RT and CHT has been added to surgery. After 1985, RT was often replaced by CHT. Because RT has been shown as the major risk for late sequelae, it is reasonable to expect a decrease of late sequelae in our patients treated after 1985.
The aim of this study is to find out whether the risk for late somatic sequelae has declined with the treatment changes described above. Our study includes all children diagnosed and treated with cancer in Slovenia between 1957 and 2005. The continuous effort on systematic and unified follow-up of all childhood cancer survivors in Slovenia allows us to perform a systematic study and analyze the impact of the treatment advances and changes to the quality of their life.
The study is based on a systematic database of 2005 children aged 16 years or less registered at the Cancer Registry of Slovenia from 1957 to 2005. Twenty-two have been excluded from the study: nine were lost from follow-up immediately after treatment and for thirteen patients the revision of the primary diagnosis proved that the tumors were not malignant.
Patient database summary
Age at diagnosis up to 5 years
From 5 to 10 years
From 10 to 18 years
Malignant bone tumors
Other malignant neoplasms
No secondary tumor
The childhood cancer survivors are followed until they are 18 years old at the Center for treatment of children with cancer at the Children’s Hospital. After that, physicians that were involved in the primary treatment collaborate in the follow-up for late effects performed at the next-door Oncological Institute. The children and their parents are well informed about the necessity of a lifetime follow-up by the psychologist that joins the team during treatment. Every childhood cancer survivor is formally invited to a follow-up evaluation and receives a booklet with the necessary information . The great majority of them, 853 in total, accept our recommendation of a lifetime follow-up, resulting in data from not only newly treated patients but also those treated decades ago. The first follow-up evaluation is performed at least five years after the first treatment and at the age of 18 years.
Follow-up evaluation and scoring
Late-sequelae scoring system
No effect that can be related to cancer treatment or an effect so mild that it requires no regular medication or other healthcare intervention and does not interfere with normal life.
Mild effects related to cancer treatment that are entirely or almost entirely controlled by medicine and/or other healthcare intervention and do not lead to anything more than a minor alternation in lifestyle.
Moderate adverse effects related to cancer treatment that require continued use of medicine and/or other healthcare intervention. The patient remains able to lead an independent existence although some modifications in activity and in style of leaving are necessary.
Severe adverse effects. The patient’s life is considerably affected by the adverse effects related to cancer treatment with a considerable and continued restriction of activities. Inpatient care and major surgery might have been required.
Death related to the cancer and/or cancer treatment.
Years after treatment
Data analysis methods
To test this central hypothesis, we use survival analysis methodology that allows analysis of the survival time of patients. In general, survival analysis can tackle the occurrence of any particular event of interest and not only death. In our study, the event of interest is late sequelae; more specifically, we follow the occurrence of late sequelae. We measure the time to the occurrence of late sequelae in years from date of the diagnosis and treatment of the primary tumor. We censor data about the patients that do not reach late sequelae evaluation other than none at the time of their last follow-up evaluation. To measure the probability of late sequelae occurrence five and ten years after treatment, we use Kaplan-Meier estimator . We also analyze the hazard function that models the late-sequelae risk, i.e., the probability that the patient has late sequelae other than none at a certain time after treatment. Using a Cox’s proportional hazards model, commonly referred to as Cox regression , we analyze the impact of demographic, diagnosis, and treatment factors on the late-sequelae risk (hazard ratio). All tests of significant differences are two-sided with a significance level of 95%. The statistical analysis is performed using the R software environment for statistical computing .
Late-sequelae occurrence and risk through diagnosis periods
Since the observed change of probability seems to be correlated to the change of therapy modalities depicted in Figure 2, we continue our analysis with the analysis of the treatment modalities on the occurrence of late sequelae. Note that one patient with neuroblastoma diagnosed at birth has not received any treatment; we excluded that patient data from the further analysis.
Influence of therapy on the late-sequelae risk
These results confirm our hypothesis that the improvements of therapy combinations have a strong impact on the decrease of late-sequelae incidence. However, to test the importance of therapy combination relative to other factors, we perform a multivariate Cox regression analysis.
Relative importance of late-sequelae risk factors
Late-sequelae hazard ratios for different risk factors
Gender: Female (reference group)
Age: from 0 to 5 years (reference group)
From 5 to 10 years
From 10 to 16 years
Diagnosis period: 1957-1975 (reference group)
Treatment: Surgery only (S, reference group)
Radiotherapy only (RT)
Chemotherapy only (CHT)
Surgery and Radiotherapy (S_RT)
Surgery and Chemotherapy (S_CHT)
Radio and Chemotherapy (RT_CHT)
Surgery, Radio and Chemotherapy (S_RT_CHT)
Primary diagnosis: Leukemia (reference group)
Other malignant neoplasms
Malignant bone tumors
Results on the impact of treatment reconfirm our findings about the significant impact of the treatment modality on the late-sequelae risk. Following the results, we can identify three categories of treatment modalities. The first category of patients treated with S only and CHT only has low late-sequelae risk (the hazard ratio of 1 and 0.96). Furthermore, the second category has medium risk and includes patients treated with RT only (hazard ratio of 1.91), a combination of RT and CHT (hazard ratio of 2.29), or a combination of surgery and CHT (hazard ratio of 2.49). Finally, patients in the third category with high risk for late sequelae include those treated with the combinations of surgery and RT (hazard ratio of 3.25) or surgery, RT, and CHT (hazard ratio of 3.80).
Treatment modality by primary diagnosis
Other malignant neoplasms
Malignant bone tumors
The survival analysis of childhood cancer patients has been used in a number of other studies, including a study of the same data in Slovenia . In the context of late sequelae, survival analysis has been recently used in , where CTCAE has been applied to evaluate late somatic sequelae of 519 childhood cancer survivors with late sequelae other than none. The results on the incidence of late sequelae are similar to the results of our study; most of the late sequelae other than none are mild or moderate. The study also identifies four risk factors for severe sequelae of childhood cancer treatment: minority race, diagnosis of other tumor, older age at diagnosis, and a history of stem cell transplant. The comparison with our analysis of risk factors for any late sequelae other than none, reveals a single common factor of age. However, in our study, results show that higher age at diagnosis lowers the risk for late sequelae.
Other studies of childhood cancer survival and sequelae confirm our results on significant improvements gained through different diagnosis periods especially after 1980, while no decrease in the late mortality rate by treatment period (the periods being 1960–1970 and 1971–1984) has been identified in .
Although there is general agreement on the need for lifelong follow-up of childhood cancer survivors, the transfer of former patients from pediatric to satisfactory adult cancer care is not easy to accomplish [31–33] and the majority of childhood cancer survivors do not receive recommended risk-based care . The small country of Slovenia is, in this respect, in an advantageous position, with one pediatric center for treatment in close cooperation with the adult outpatient clinic at the Oncological Institute. The main advantage of the study presented here is that it is performed on a systematic database of the entire population of the children cancer patients in Slovenia  that have been continuously followed-up in the same clinic under the unique opportunity for an » ongoing communication between the cancer center that provided acute care for the patient and the healthcare facility providing follow-up care » .
The results of the Kaplan-Mayer analysis show that the incidence of late sequelae in childhood cancer patients five and ten years after treatment in Slovenia steadily decreases from 75% in the group of patients diagnosed before 1975 to 55% in the patients diagnosed after 1995 (see Table 3). The results show that the impact of individual therapies on late sequelae incidence differs: we observe a high and significant impact of surgery on the incidence of late sequelae five and ten years after treatment, a lower but still significant impact of radiotherapy, and almost no impact of chemotherapy (see Figure 4).
The Cox regression analysis of late-sequelae risk reveals that three studied factors significantly influence the risk. The most important factor is the treatment modality. Combinations of treatments that include surgery significantly increase the risk for late sequelae: the estimated hazard ratio of 3.80 for the combination of surgery, radio-, and chemotherapy, 3.25 for the combination of surgery and radiotherapy, and 2.49 for surgery and chemotherapy (see Table 4). Furthermore, age at diagnosis also significantly influences the hazard ratio for late sequelae from 1 for the reference group of patients diagnosed when below 5 years of age to significantly lower ratios of 0.65 and 0.40 for the patients diagnosed between 5 and 10 years as well as 10 and 16 years of age, respectively (see Table 4). Finally, the primary diagnosis also significantly influences the risk for late sequelae, with Leukemia leading to significantly lower late-sequelae risk as compared to all other diagnoses and renal tumors leading to the highest hazard ratio (see Table 4). However, deeper analysis of these results (see Table 5) shows that this is mostly due to the selection of the appropriate treatment modality for the specific primary cancer diagnosis.
In this paper, we focus on the influence of individual risk factors on incidence of and risk for late sequelae other than none. Two directions for immediate further work are evident. First, survival analysis can be used to explore the incidence of and risk for more serious (mild, moderate, or severe) somatic sequelae. Second, survival analysis can be combined with multivariate statistical methods to further explore the interactions among different risk factors with respect to their joint influence on the late sequelae of childhood cancer treatment.
The research on humans performed in the paper is in compliance with the Helsinki Declaration and approved by the National Medical Ethics Committee of the Republic of Slovenia.
The first author acknowledges the support of the Slovenian Research Agency through a young researcher grant.
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