Health status of Polish children and adolescents after cancer treatment

In the last 40 years, considerable progress was made in the treatment of childhood cancer. Nearly 80% of children achieve long-term clinical remission or are permanently cured. This improvement is however not without sacrifice. This is the first Polish study analyzing the general health status and epidemiology of organ late effects in the cohort of Polish childhood and adolescent cancer survivors monitored by doctors and registered in the on-line national database for late effects (N = 1761). This tool collects information on previous therapy and current health status (medical history, physical examination, laboratory tests) of cancer survivors. The survivors are invited to take part in the follow-up examination 5 years after the end of treatment. In the study group, 207 survivors (11.75%) had no complaints; whereas in 1554 cases (88.25%), one or more symptoms/complaints suggesting organ dysfunction were reported. In the whole group, the circulatory problems were most common (31.7%); more than 20% of survivors presented complaints or abnormal function of the urinary tract and had skin, dental, skeletal/muscular problems, or difficulty with chewing. Obesity or short stature alone (21.4%) and a variety of endocrine problems (short stature, obesity, thyroid dysfunction, and gonads toxicity) were present in 323 patients (118 females 15.0% and 205 males 21.0%). Gonadal dysfunction, as the only problem, occurred in 75 girls (9.6%) and 131 boys (13.4%). In our cohort, severe or life-threatening health conditions (3 and 4 grade according to toxicity criteria) were present in low percentage, i.e., 0.2% in the circulatory system, 0.3% in the respiratory tract and, 0.7% in kidney insufficiency. Conclusion: Our findings indicate that many childhood cancer survivors demonstrate numerous complaints, even a short time after treatment, suggesting the importance of regular follow-up examinations in subsequent years. What is Known: • Contemporary studies indicate that a significant number of childhood cancer survivors present different long-term side effects which influence their quality of life. What is New: • This is the first nationwide study performed in the largest cohort of Polish childhood cancer survivors concerning general health status and frequency of organ dysfunction.


Introduction
In the last 40 years, we have observed progress in the treatment of different cancers during childhood-nearly 80% of children achieve long-term clinical remission or are Communicated by Peter de Winter permanently cured. This improvement is a result of more precise diagnosis (progress in radiology, molecular examinations), advances in chemotherapy, surgery, radiotherapy, and supportive care. In the growing population of childhood cancer survivors (CCS) (there are 300,000-500,000 CCS in Europe), we can find a wide range of late effects that appear after complex anticancer therapy-deterioration of life quality, late morbidity and mortality, dysfunction of different organs, endocrinopathies, and second cancers [9,15,24,25].
Research into the health status and quality of life in the cohorts of CCS is conducted in many Western countries [9,34]. In 2005, a group for late effects monitoring was formed within the Polish Society of Pediatric Oncology and Hematology; between 2006 and 2007, a platform was established as a website tool for CCS registration, which collects data on CCS from all over Poland; finally, in 2008, the Ministry of Health accepted this program, approving the structure, aims and organization of care, and health monitoring for CCS. The frequency of visits in the outpatient clinic depends on the type of cancer and aggressiveness of treatment.

Purpose
We analyzed the general health status and epidemiology of organ late effects in the cohort of Polish CCS, taking into consideration diagnosis, type of therapy, age, sex, and time interval between the end of treatment and a follow-up, as well as demand of special care for survivors.

Material and methods
After the end of the therapy, each patient should receive complex information for their general practitioner (or for specialists) concerning the history of illness, treatment, acute side effects, and guidelines for future follow-up. This information is prepared by the attending physician. The monitoring starts 2 years after the end of treatment simultaneously with cancer remission monitoring and is performed by the attending physician. The "actual" follow-up starts 5 years after the treatment. This task is delegated to the dedicated physician working in the outpatient setting, who has a direct contact with the attending physician and a complete insight into the patient's medical history.
The frequency of follow-up visits depends on the type of cancer and its therapy-from minimum once a year for survivors with high probability of side effects to once every 2-5 years for patients who received less aggressive treatment. CCS are followed in outpatient clinics in children's hospitals until they are 18 years old; sometimes, however rarely, up to the age of 24 years or even longer. At the beginning of the visit, every patient receives a detailed questionnaire on the present complaints, referring to every system/organ in the body. The application of additional investigations depends partly on the type of diagnosis and mostly on the previous treatment (e.g., echocardiogram for patients receiving anthracyclines, audiogram for survivors treated with platinbased agents or irradiation to the central nervous system, flow-cytometry for patients after hematopoietic stem cell transplantation, abdominal ultrasound for solid tumors located in the abdomen, and spirometry if there was surgery within the lung tissue or chest wall). No official international guidelines were used in our patients, but rather the recapitulation of the already published studies that were gathered into a logical plan for the respective survivor [21]. The visit ends with the verification of the complaints marked in the questionnaire and interpretation of the laboratory and additional test findings. On-line database is then filled in by a physician who follows survivors and registers the information on the previous therapy and current health status.
Analysis was performed in the cohort of 1761 registered CCS from 2016, who had complete datasets in the web-based tool. When the child visited the outpatient clinic for follow-up more than once, the results from the last visit were taken into consideration. This registry collects data on the medical history of disease and treatment, current medical history, physical examination and results of laboratory findings, radiological examinations, and functional investigations, allowing the analysis of the function of all organs and general health status of the survivors. The necessity to perform different analysis, e.g., echocardiography, audiometry, spirometry, and hormonal analysis, depends on risk-based recommendations.
The description of the health condition was classified according to the Common Terminology Criteria for Adverse Events (CTCAE) as the following: grade 1 (mild), grade 2 (moderate), grade 3 (severe), and grade 4 (serious/life-threatening) [33].
Typical statistical tests were used to calculate the number of different pathologies in the subgroups of the study patients. For comparison of the non-continuous data, chi-square test was used. STATA 2011 program was applied for statistical analysis.
The characteristics of the cohort of cancer survivors are presented in Table 1.
High percentage of patients after treatment for Hodgkin's lymphoma (HL) (17.32%) was due to the fact that we started the follow-up from this group of patients in the initial period of database functioning. Epidemiological data show that in Poland patients treated for HL account for approximately 7%.
On the other hand, lower (3.63%) percentage of patients after brain tumors is due to their registration in separate database.
Normal function of all organs without complaints was observed in 207 (11.75%) survivors; whereas, in 239 (13.57%) cases, we found at least one symptom or complaint suggesting organ dysfunction, in 274 (15.56%)-dysfunction of two organs occurred, in further 249 (14.14%) three organs, and in 792 (44.97%)-four or more organs were affected.

Sex
The frequency of different organ dysfunctions according to sex is presented in Fig. 1. A higher frequency of complaints or organ abnormalities was observed in males than in females in the circulatory system (p = 0.029), the gonads (p < 0.0001), the immune system (p < 0.0001), the liver (p = 0.038), and dentition/the masticatory system (p < 0.0001).

Age at diagnosis
A higher frequency of late effects was found in survivors diagnosed at younger age; the circulatory and immune system abnormalities were observed most often in children diagnosed between the age of 1 and 4 years (35%, p < 0.0001 and 27.3%, p = 0.005, respectively). The same tendency was noted for dental problems/difficulty with chewing (33%, p < 0.0001); whereas, infants were most frequently diagnosed with hearing problems (20.6%, p < 0.0001) and vision problems (22.9%, p = 0.012; Table 2). The thyroid gland dysfunction was present most frequently in children diagnosed between the age of 5 and 9 years (24. 5%, p = 0.001).

Time of follow-up
The group of long-term survivors (more than 15 years) was not very numerous (N = 21). Those who ended their treatment between 5 and 10 years to the follow-up showed more late effects in the immune system (p < 0.0001), male gonads (p = 0.003), and dentition/the masticatory system (p = 0.002). The highest incidence of complaints/symptoms was found 11 to 15 years after the treatment completion: in the circulatory system (p < 0.0001), the respiratory system (p = 0.024), the thyroid gland (p < 0.006), the digestive tract (p < 0.0001), and the nervous system (p < 0.0001) ( Table 3).

Diagnosis
In the most numerous group of survivors, after treatment for acute lymphoblastic leukemia (ALL), more than 25% of patients presented symptoms/complaints suggesting the follow-  (Table 4).
Taking into consideration CTCAE for the description of health condition, 99.7% of the survivors presented mild (1) and moderate (2) grade sequelae and 0.30% severe (3) or serious (4) grade of respiratory tract dysfunction. Grades 1 and 2 symptoms/complaints from the circulatory system were found in 99.9% and grades 3 and 4 in 0.1%. Symptoms from the urinary tract in 1 and 2 grades were observed in 96.42% and in grade 3 or 4 in 3.58%. Thyroid dysfunction in grade 1 or 2 was present in 99.29%, in grade 3 or 4 in 0.71%.
After the end of treatment, the largest group of survivors was followed-up in pediatric oncology outpatient clinic-over 70%. Nearly 20% were followed-up in endocrinological outpatient clinic due to thyroid or gonadal disorders. The smallest number participated in follow-up in gastrological or/and liver diseases outpatient clinics (5.3%).

Discussion
The first reports from the British CCSS were based on a cohort of 17,981 individuals diagnosed with childhood cancer HSCT hematopoietic stem cell transplantation between 1940 and 1991, who survived at least 5 years. Other large registries were created in some European countries, the USA and Canada. In 2011, there were nearly 388,501 CCS in the USA, of whom 83.5% were ≥ 5 years post-diagnosis [4,25,27,28,34]. The results of anticancer treatment of Polish children have also changed in the last 40 years. Currently, nearly 80% of children with cancer achieve long-time clinical remission or are cured. In the USA or Great Britain, the observation of survivors started as Childhood Cancer Survivors Studies (CCSS) many years ago; they are focused on physical and psychological late effects, such as organ dysfunction, second neoplasms, endocrine problems, or mental and social consequences [23,27,34]. Unfortunately, there are no such investigations in Central and Eastern Europe.
This is the first nationwide study performed in the largest cohort of Polish CCS. The arrangement of the Polish followup guidelines is similar to the Scottish Intercollegiate Guidelines Network (SIGN): the frequency of visits in outpatient clinics and range of examinations depend on diagnosis, previous anticancer treatment, and the risk of late effects [30]. Generally, the follow-up of survivors over 18 years old has to be carried out in the outpatient clinics for adults. Therefore, our study group consists mainly of children and adolescents, and only a small number of young adults. Moreover, in other countries, the long-term observations were started with the cohorts diagnosed in 1970s or even earlier [28,34]; whereas, our study period is short and the population is young. The strength of our study is that the observations were based on physicians' interviews and reports (history and physical examination), biochemical, hormonal testing, and radiological examinations. We used not only patient self-completion questionnaires. The information given by patients was verified at the end of each follow-up visit, the reason for marking a respective complaint was made clear and only confirmed complaints appeared in the database. If the examinations performed ruled out the reason for the complaint, test results were also added to the database. Finally, information concerning the referral to a specialist, if the complaints were true, was marked. We found that only 11.75% of the survivors were in very good general health, without complaints or signs of any organ dysfunction, whereas 29.13% demonstrated. Complaints or symptoms of dysfunction of one or two organs and nearly 45% presented the signs of abnormal function of four or more organs. The American multi-institutional CCSS based on interviews and questionnaires, including 10.397 adult CCS, reported that 62.3% had at least one, 37.6% at least two, and 23.8% multiple chronic health conditions [25]. In the Dutch cohort (1.315 survivors), 70% presented at least one chronic health condition, including 40% with severe or disabling condition [11]. A Japan nationwide study reported that 56% of young CCS (mean age 23.6 years) experienced at least one late effect. A similar observation was reported from Korea (59.8%) [13,26]. In our cohort, severe or life-threatening health conditions (3 and 4 grade according to CTCAE) were rare-from 0.2% for the circulatory system, 0.3% for the respiratory tract, and 0.7% for kidney insufficiency. Analysis made in Korea in a younger population showed severe late effects in 10.8% of survivors [13]. In another Dutch study, higher frequency of severe late effects was observed in older survivors, after very long follow-up time (> 20 years, 47.8% patients), as compared to a shorter follow-up time (< 20 years, 27.9%) [6]. In the American cohort, the incidence of severe life-threatening conditions or death caused by a chronic condition occurred in 27.5% survivors at the mean age of 26.6 years; whereas, late sequelae were present in 42.4% of survivors at the median of 30 years after cancer diagnosis [25]. The results from Southern California showed that 15 years after diagnosis, nearly 40% of survivors developed at least one chronic condition [7]. The age at follow-up and the time after therapy completion seem to be very important; organ senescence, faster tissue aging after chemo-and radiotherapy, health behaviors, and differences in anticancer treatment exert their effects. Observations from different studies have indicated a growing prevalence and severity with time after diagnosis [7], which has not achieved plateau [25]. Amstrong et al. showed that a group of 24-year-old survivors of childhood cancer had the same cumulative incidence of grades 3 to 5 health conditions as their 50-year-old siblings. It was especially visible in a group of survivors older than 35 years, where nearly 20% experienced higher incidence of cardiovascular events and second cancers. The authors predict that 50% of childhood cancer survivors older than 50 years will have experienced severe diseases as a result of multiple organs dysfunction [3]. In the USA, in one of the latest studies, the prevalence of any chronic condition in survivors of more than 5 years ranged from 66% (in survivors aged 5 to 19 years) to 88% (in survivors aged 40-49 years) [27]. Our study revealed the highest incidence of cardiovascular problems (reported by 31.7%) and endocrinological problems (18.3%). They were especially visible in patients after most aggressive treatment, such as bone marrow transplantation or after complex treatment including radiotherapy. In comparison with other reports, our study group was younger and the follow-up period shorter. However, even though the percentage of survivors with health problems is high, the degree of abnormalities is low (grade 1 or 2). In the studies conducted in other countries, based on older populations of survivors, cardiovascular problems are identified as one of the most serious and frequent complications leading to higher mortality [1,2,8,9,12,16,31,32].
We found higher frequency of late effects in survivors diagnosed in younger age. The most common symptoms included circulatory, thyroid, neurological and immune abnormalities, dental problems/difficulty with chewing, hearing and vision problems, and osteopenia. In a study conducted by Han et al., where the median time after diagnosis was shorter (7.8 years), and the age at diagnosis and current age showed a positive correlation with the number of late effects [13]. The latest data from EUROCARE-5 focused on adolescents and young adults diagnosed between 2000 and 2007 exhibited improved survival in children and adolescents, but relatively poorer in adolescents and young adults than in children [31]. Similarly, in a Slovenian study, older age at diagnosis decreased the risk for late sequelae [10].
We observed higher frequency of complaints and symptoms of some organ dysfunctions (circulatory system, gonadotoxicity, hepatotoxicity, immune, and dental problems) in males. It remains in opposition to the results obtained by Oeffinger et al. in adult CCS, who found that females were more predisposed to have any adverse conditions, including 1.5 times more severe (3 or 4 grade) late effects [25]. American registries showed similar prevalence of chronic disorders in both sexes, from grade 1 or 2 to severe conditions, with a frequency increasing with age, especially in women [27].
A Korean study showed no differences between sexes in the frequency of late effects in younger CCS (mean age 14.2 years) [13]. Similarly, the results from Slovenia in younger CCS did not indicate the sex impact on the frequency of late effects [1], but suggest the effect of age at the follow-up and time after the end of treatment on the prevalence of chronic conditions. In our group, where the time of follow-up was not very long, the highest incidence of complaints/symptoms was observed in survivors who completed their treatment between 11 and 15 years of age (from the circulatory and respiratory systems, thyroid gland, female gonads, digestive tract, liver, and nervous system). According to Hudson et al., poor general status and chronic health conditions increase with age, particularly among females [18].
The type of anticancer therapy, especially most aggressive treatment (radiotherapy in complex treatment or megachemotherapy), seems to be most important. We observed a vast array of complaints and organ dysfunctions in these groups of survivors, especially after bone marrow transplantation. Other authors reported a large spectrum of serious chronic conditions and impairments involving different organs even in younger age [14]. In a Dutch study, severe adverse events were observed in 55% of survivors after radiotherapy and only in 15% after chemotherapy alone [11]. Poorer health status, physical condition, and quality of life have also been demonstrated in other studies [5,13,29]. Radiotherapy affects the function of all the exposed organs leading to endocrinopathies, mental and growth problems, obesity, pulmonary and cardiac complications, and second neoplasms [5,18,25]. This problem is especially known in older CCS, particularly in those treated with older techniques of irradiation [2,11,18,19,31], and contributes to changes in anticancer treatment during childhood, reducing indications for radiotherapy in early childhood. Phillips et al. defined the susceptibility to different chronic conditions and the magnitude of health challenges for CCS. Their analysis of results from the US population indicated high morbidity (70% mild or moderate chronic condition and 32% severe chronic condition) [27]. This results in earlier senesce and shorter life expectancy of CCS [17,20].
In conclusion, our observations made in Poland in a group of survivors shortly after treatment completion showed that many survivors demonstrated numerous organ dysfunctions, thus indicating the necessity of regular follow-up examinations in subsequent years.
Taking into consideration that some of the presented late effects, even shortly after the end of treatment, can manifest and/or progress in the future, long-term monitoring is necessary for early detection of the symptoms of organ dysfunction. Our analysis indicates that most survivors and their parents receive basic information on health status, prophylaxis, and treatment at the time of treatment, as well at the time of transition to adulthood [22]. Similarly, adult primary healthcare providers and other specialists are informed about general late effects of anticancer treatment, although there is no official funding for special outpatient clinics dedicated to the CCS. In Poland, pediatric care covers patients up to the age of 18, and for childhood cancer survivors it can be extended up to the age of 24 years; after that age, the survivors make the transition to general practitioners and specialists (if need be). The most difficult problem is the organization of outpatient clinics and/or departments for adult childhood cancer survivors where they could receive adequate education and multidisciplinary care. Patient and doctor awareness and knowledge are essential for prophylaxis, early detection of adverse late effects, normal functioning, and good life quality. The development of effective model of care for young cancer survivors, transition program suitable for an individual survivor, continuation of the follow-up beyond early twenties, and care started in childhood seem to be most crucial for Polish childhood cancer survivors.
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