Late effects of childhood cancer treatment in long-term survivors diagnosed before the age of 3 years - A multicenter, nationwide study.

BACKGROUND: The effect of age on the incidence of late sequelae that occur after anticancer treatment in childhood is still not fully elucidated. In this multicenter study of long-term survivors diagnosed before age of three, we investigated the prevalence of late effects many years after treatment. METHODS: The study group (n = 561) was selected from the Polish National Childhood Cancer Survivors Registry (n = 1761) created in 2007. A survivor was defined as an individual who has survived at least 5 years after completion of anticancer treatment. All children were diagnosed between 1991 and 2016, mean age at diagnosis was 1.82 years (range 0.03-2.99) and median follow up time - 9.85 years (range 5.0-23.6). They were treated in accordance with international protocols approved by the Polish Pediatric Leukemia and Lymphoma Group and Polish Solid Tumor Group. Chemotherapy alone was used in 192 (34.2%), chemotherapy and radiotherapy - 56 (10%), chemotherapy and surgery - 176 (31.4%), chemotherapy, radiotherapy, and surgery - 79 (14.1%), and surgery alone in 58 patients (10.3%). RESULTS: Of all patients enrolled to the study, only 94 (16.8%) had normal function of all organs. Seventy-six (13.5%) children developed dysfunction in one organ, another 83 (14.8%) had symptoms or complaints suggestive of dysfunction in two organs or systems, 88 (15.7%) had abnormalities in three organs, and 220 (39.2%) had at least four or more dysfunctions. In the entire study group, dysfunctions most frequently (> 20% of cases) involved the following organs/systems: circulatory - 21.8%, urinary - 30.8%, gastrointestinal - 20.8%, immune - 23.5%, vision - 20.7%, hearing - 21.8%, and oral and masticatory dysfunction - 26.9%. We did not find any significant differences in organ dysfunction between children diagnosed under the age of 1 and those diagnosed at the age of 1-3, except for a lower incidence of thyroid abnormalities (p = 0.007) and the higher prevalence of liver dysfunction in youngest patients. In the subset with longer follow-up period (> 10 years) more frequent thyroid abnormalities (p = 0.019), male (p = 0.002) and female (p = 0.026) gonads dysfunction, as well as musculoskeletal problems (p < 0.001) were observed. Among subjects who received radiotherapy compared to those who did not, short stature (p = 0.001), and dysfunction of the following systems/organs - circulatory (p = 0.049), urinary (p = 0.012), thyroid gland (p < 0.0001), nervous (p = 0.007), immunological (p = 0.002), liver (p = 0.03), dental or chewing difficulties (p = 0.001), hearing (p = 0.001) and musculoskeletal (p = 0.026) were more frequently reported. When multimodal therapy was applied (chemotherapy, radiotherapy, and surgery) a higher incidence of short stature (p = 0.007), urinary system disorders (p < 0.0001), thyroid dysfunction (p < 0.0001), hearing loss (p < 0.0001), and skin problems (p = 0.031) were observed. CONCLUSION: This study confirms that radiotherapy and some specific toxicity of cytostatics are the most important factors affecting organ function. Apart from a higher incidence of liver dysfunction in the youngest patients, there were no significant differences in organ and system toxicities between children diagnosed under the age of 1 and those diagnosed at the age of 1-3. We have shown that this group requires systematic, careful and long-term follow-up.

Analysis of incidence and risk factors of the multidrug resistant gastrointestinal tract infection in children and adolescents undergoing allogeneic and autologous hematopoietic cell transplantation: a nationwide study.

The aim of this multi-center study was to evaluate the incidence, clinical course, and risk factors for bacterial multidrug-resistant (MDR) gastrointestinal tract infections (GTI) among children undergoing allogeneic and autologous hematopoietic cell transplantation. A total number of 175 pediatric patients (aged 1-18 years), transplanted between January 2018 and December 2019, who were tested for bacterial colonization/infection were enrolled into this multi-center analysis. Episodes of MDR GTI occurred in 77/175 (44%) patients. In multivariate analysis for higher GTI incidence, the following factors were significant: matched-unrelated donor (MUD) transplantation, HLA mismatch, presence of graft-versus-host disease (GVHD), and gut GVHD. The most common GTI were Clostridium difficile (CDI), multidrug-resistant Enterobacteriaceae (Klebsiella pneumoniae, Escherichia coli extended-spectrum ß-lactamase), and Enterococcus HLAR (high-level aminoglycoside-resistant). No MDR GTI-attributed deaths were reported. MDR GTI is a frequent complication after HCT among children, causes prolonged hospitalization, but rarely contributes to death. We identified risk factors of MDR GTI development in children, with focus on GVHD and unrelated donor and HLA mismatch. We conclude that the presence of Clostridiales plays an important anti-inflammatory homeostatic role and decreases incidence of GVHD or alleviate its course.

Melphalan, Etoposide, and Carboplatin Megatherapy with Autologous Stem Cell Transplantation in Children with Relapsing or Therapy-Resistant Extracranial Germ-Cell Tumors-A Retrospective Analysis.

Pediatric germ cell tumors (GCTs) are a group of chemosensitive malignancies with a 90% curability rate. We report a series of children with relapsing or therapy-resistant GCT treated with melphalan-etoposide-carboplatin high-dose chemotherapy (HDCT) and autologous stem cell transplantation. This consisted of 18 children, either with GCTs after relapse (nine patients) or with an unsatisfactory response to first-line chemotherapy (nine patients), who underwent HDCT. The HDCT regimens MEC1 (carboplatin 1500 mg/m2, etoposide 1800 mg/m2, and melphalan 140 mg/m2) and MEC2 (carboplatin 800 mg/m2, etoposide 800 mg/m2, and melphalan 140 mg/m2) were each used in nine patients. The median observation time was 81 months, the 5-year overall survival (OS) was 76%, and the event-free survival (EFS) was 70.8%. Non-relapse mortality was 0%, and four patients died after HDCT due to progression of the malignancy. No difference in OS or EFS was noted between the MEC1 and MEC2 protocols. The 5-year OS and 5-year EFS were higher in children treated with autologous stem cell transplantation before the age of four years. The presence of metastatic disease or time of HDCT consolidation during first/subsequent line chemotherapy did not affect patient survival. The melphalan-etoposide-carboplatin protocol is feasible in pediatric GCT, but is associated with potentially life-threatening complications. In conclusion, the use of HDCT must be examined in well-designed clinical trials, and the identification of patients who can benefit from this approach is critical to avoid overtreatment.

Eltrombopag Therapy in Children With Rare Disorders Associated With Thrombocytopenia.

Eltrombopag (ELT) is a thrombopoietin receptor activator that has shown efficacy in chronic immune thrombocytopenia. We report the outcome of ELT therapy in 4 children who were treated for rare hematologic disorders, including Pearson syndrome, DiGeorge syndrome, posttransplant allogeneic poor graft function (PGF), and Wiskott-Aldrich syndrome. The ELT tolerance in the analyzed group was good, with the exception of the child with Pearson syndrome, who experienced an exacerbation of cataracts and had to discontinue treatment. Thromboembolic events were observed in one child, who continued ELT therapy despite achieving normalized platelet counts. Independence from PLT transfusions was observed at the 4-week timepoint of therapy in patients with DiGeorge syndrome and PGF who responded to ELT. Discontinuation of therapy was successful in one child, who sustained the normal CBC values afterward. In 2 patients, an increase in neutrophil counts was observed during ELT therapy without additional intervention, and a positive correlation between neutrophil and platelet values during ELT therapy was observed in the child with PGF. ELT is effective in rare pediatric disorders, but response patterns are determined by the underlying disease. ELT shows promising results in patients, but constitutional hematopoiesis defects reduce the chances of a response.

Metabolic Disturbances in Children Treated for Solid Tumors.

Metabolic disturbances are among the most common disorders diagnosed in pediatric patients after anti-cancer therapy (ACT). The aim of our study was to evaluate the prevalence of metabolic disturbances among patients after ACT. The study group comprised 44 patients (31 boys) treated for solid tumors and 31 patients in the control group. Body weight, height, body mass index (BMI) values, lipid parameters are expressed in Standard Deviation Score (SDS), based on centile charts. Indicators of risk to atherosclerosis were calculated. Obesity/overweight was observed in one third of the patients. Hypercholesterolemia occurred in half of them, elevated tryglicerides (TG) SDS in 11, and elevated low-density lipoprotein cholesterol (LDL-C) SDS in nine of the patients. Increased levels of both cholesterol SDS and LDL SDS were found in nine patients and four of them also showed elevated levels of TG SDS. There were significant differences in lipid parameters between the sexes. Risk indicators of lipid disorders defined by statistical distances (τ) were determined for the study group and the control group. The sum of the risk ratios of lipid disorders in the study group was 150 times higher than in the control group. Patients after ACT require special monitoring of lipids profiles and thyroid function as they are at higher risk for dyslipidemia and atherosclerosis than healthy people.

Correction to: Health status of Polish children and adolescents after cancer treatment.

The first and family names of the authors were interchanged. The correct author names are now correctly presented in this article.

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.

Assessment of gonadal function in boys and adolescents at the diagnosis of neoplastic disease.

OBJECTIVE: We assessed the gonadal function in boys with a newly diagnosed neoplastic disease prior to chemotherapy. Eighty-four boys (48 prepubertal and 36 pubertal) were evaluated, including 50 with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL), 10 with Hodgkin lymphoma (HL), and 24 with solid tumors. The control group consisted of 24 healthy prepubertal and 24 pubertal boys. The levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), inhibin B, and testosterone were determined, and testicular volumes were measured. RESULTS: Patients in prepuberty and early puberty (Tanner stages 1-3) diagnosed with ALL/NHL or solid tumor presented normal serum reproductive hormone levels, whereas in ALL/NHL patients in Tanner stages 4-5, the mean values of inhibin B were significantly lower (45.18 +/- 33.85 vs. 153.57 +/- 71.44 ng/L, p = 0.0027). In patients with HL in Tanner stages 4-5, a statistically significant lower mean inhibin B level (100.44 +/- 67.45 versus 153.57 +/-71.44 ng/L, p = 0.0027), higher mean FSH level (6.3 +/- 3.6 versus 4.6 +/- 2.2 mIU/mL, p = 0.05), and higher mean LH level (5.9 +/- 4.0 versus 3.6 +/- 1.8 mIU/mL, p = 0.05) were observed. No statistically significant differences were noted in assessed hormones in patients with solid tumors, independently of Tanner stage. CONCLUSION: Our analysis indicates that adolescents with ALL/NHL and HL prior to treatment, exhibit reduced levels of inhibin B, which indirectly suggests the possibility of spermatogenesis dysfunction.

Testicular function after treatment for acute lymphoblastic leukemia (all) in prepubertal and pubertal boys.

Testicular function was evaluated in 59 male (27 prepubertal and 32 pubertal) survivors treated for ALL according to two different protocols. Serum inhibin B, FSH, testosterone, LH, and testicular volume were measured. In both groups the mean values of inhibin B were lower than control, whereas the other analyzed parameters were comparable. The inhibin B-to-FSH ratio was reduced as compared to the control. Testicular volume was lower than in healthy pubertal patients. The results show that treatment for ALL has a negative effect on spermatogenesis, regardless of the age at treatment and type of therapy.

[Gonadal function in young men after the treatment for Hodgkin lymphoma]. / Czynnosc gonady meskiej u mlodocianych po leczeniu choroby Hodgkina.

INTRODUCTION: The survival rate after the treatment for Hodgkin lymphoma improved in the last three decades and the late effects of anticancer therapy, particularly gonadal toxicity, became an important problem. THE AIM OF WORK: Assessment of the influence of chemo- and radiotherapy on gonadal function in young male survivors after the treatment for Hodgkin lymphoma (HL). MATERIAL AND METHODS: Levels of inhibin B, testosterone, FSH, LH and testicular volume were measured in 26 HL survivors aged from 15.6 to 25.2, who had been treated for HL in prepubertal (n=8) or pubertal (n=18) period. RESULTS: 1. In all groups, comparing to control one, we found higher FSH concentration (15.2+/-12.3 IU/l vs. 3.3+/-1.2 IU/l); p=0.0004, lower inhibin B (60.9+/-44.5 ng/l vs. 198.1+/-58.1 ng/l); p=0.0001, lower testicular volume (18.2+/-2.6ml vs. 21.3 +/-5.1ml) p=0.01 and normal LH as well as testosterone values. 2. Higher >+2SD FSH and LH were found in 62% and 23%, respectively, and lower <-2SD inhibin B - in 72% of survivors. 3. We did not observe the differences between the patients: a) treated before and during puberty and b) the patients in different stages of disease. 4. Persistently lowered inhibin B concentration and higher, but gradually normalized values of FSH were found >6 years after the end of therapy, 5. Azoospermia was observed in 4/10 patients, oligospermia - in 4/10 and normospermia - only in 2/10. CONCLUSIONS: Anticancer treatment for HL, independently of the age at diagnosis and clinical stage, leads to serious and persistent gonadal dysfunction. The patients should be informed about the problem of gonadal toxicity and possibility of fertility preservation at the moment of diagnosis.

[Testicular function in young men treated in prepubertal period for childhood malignancy]. / Czynnosc gonad u chlopców i mlodych mezczyzn leczonych przed pokwitaniem z powodu choroby nowotworowej.

INTRODUCTION: A complex anticancer treatment leads to different late effects e.g. gonadal damage in adulthood. The information about gonadal function (steroido- and spermatogenesis) after the treatment in prepubertal period are ambiguous. THE AIM OF STUDY: was to evaluate testicular function in young men (Tanner puberty stages IV and V) treated in prepubertal period for childhood malignancies. MATERIAL AND METHODS: In thirty-two pubertal and postpubertal male survivors of childhood cancer (acute lymphoblastic leukemia, ALL - 14, non-Hodgkin lymphoma, NHL - 6, Hodgkin lymphoma, HL and solid tumors - 4) testicular volume and serum FSH, LH, testosterone, inhibin B and calculated quotient inhibin B:FSH were measured. Controls were 15 healthy boys matched by age and Tanner stage. RESULTS: In the whole studied group the mean values of FSH, LH and testosterone did not differ from control, while inhibin B was lower (87.5+/-96.3 vs. 196.5+/-66.8 ng/l; p<0,0003). The lowest values of inhibin B were found in HL (46,15+/-35,12 ng/l) and after ALL treatment (71,1+/-39,8 ng/l). We did not observe differences in hormonal parameters after NHL treatment. The inhibin B-to-FSH ratio was lower, especially after treatment for HL. CONCLUSIONS: Inhibin B is a sensitive marker of gonadal damage. Anticancer therapy in prepubertal period may lead to disturbances in spermatogenesis.

[Evaluation of selected endocrine complications in patients treated with auto- and allo-haematopoietic stem cell transplantation]. / Ocena wybranych powiklan endokrynologicznych u pacjentów po autologicznym i allogenicznym przeszczepie krwiotwórczych komórek macierzystych.

AIM: The aim of this study was to evaluate the endocrine complications, in particular disorders of growth and thyroid function and glucose metabolism dysfunctions in patients treated with allo- and auto-haematopoietic stem cell transplantation (HSCT). MATERIAL AND METHODS: The investigated group consisted of: I. 16 patients after auto-HSCT (6 girls, 10 boys) aged 3-20 years (average 10,8+/-) because of acute myelogenous leukaemia (n=5), non Hodgkin lymphoma (n=3), neuroblastoma (n=3), embryonal cancer (n=2), medulloblastoma (n=1), Ewing's sarcoma/PNET (n=1), hyper eosinophilic syndrome (n=1). High dose chemiotherapy (HDC/T) included: BU/MEL (busulfan/melfalan) (n=7), BEAM (carmustine, eteposide, cytosine arabinose, melfalan) (n=3). II. 30 patients after allo-HSCT (20 girls, 10 boys) aged 3-17 years (average 9,56). Indication for HSCT was acute lymphoblastic leukaemia (n=11), acute myelogenous leukaemia (n=5), chronic myeloid leukaemia-CML (n=6), myelodysplastic syndromes (n=2), non Hodgkin lymphoma (n=1), juvenile myelomonocytic leukemia (n=1), severe aplastic anaemia (n=1), Blackfan-Diamond anaemia (n=1), severe combined immune deficiency (n=1), rhabdomyosarcoma (n=1). The patients underwent the following types of transplantation: HSCT of matched sibling donor (n=13), HSCT of matched unrelated donor (n=11) and HLA-mismatched related donor (n=6). The preparative regimens consisted of HDC/T usually BU/MEL (n=3); BU/CY/VP (busulfan, cyclophosphamide, etoposide) (6); BU/CY/ATG (anti-thymocyte globulin) (n=5), VP/ATG/TBI (total body irradiation) (n=3). 19 children received CI (cranial irradiation) prior to grafting: auto-HSCT (n=6) and allo-HSCT (n=13) and 6 patients underwent TBI. 18 children received high steroid doses at least 28 days before transplant, 4 patients in the auto-HSCT group, and in the allo-HSCT group 14 patients before and 20 after HSCT procedure. The analysis of thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), hemoglobin A1c (HbA1c), prolactine (PRL), oral glucose tolerance test, growth hormone (GH test) and thyrotropin releasing hormone (TRH) test was performed in each case. RESULTS: Hypothyroidism was found in 5 patients (3 after allo-HSCT, 2 after auto-HSCT). Thyroid hormone substitution was applied. No case of hyperthyroidism was diagnosed. Growth deficit was found in 8 patients (6 girls, 2 boys) between 13 to 70 months after allo-transplantation (average 36 months). Three children from the above group received CI. Growth hormone substitution was applied in 1 girl (ALL, HLA MM REL, CI). An impaired excretion of GH after stimulation was diagnosed in 14 pts (10 after allo-HSCT, 4 after auto-HSCT). The growth process should still be observed in this subgroup. Glucose intolerance was found in 7 patients: in 4 treated with auto-HSCT and in 3 after allo-HSCT. Diabetes mellitus was diagnosed in none of them. An impaired glucose tolerance curve with increased excretion of insulin was diagnosed in 12 children. CONCLUSIONS: Early endocrinological care is necessary in patients treated both with auto-HSCT and allo-HSCT due to high risk of hormonal disorders.

[Analysis of selected undesirable effects of cytostatic drugs in treatment of the central nervous system tumours in children. Preliminary report]. / Analiza wybranych niepozadanych dzialan cytostatyków w trakcie leczenia dzieci z nowotworami osrodkowego ukladu nerwowego.

INTRODUCTION: During treatment of children with brain tumours there is a large risk of occurrence of side effects related to the narrow therapeutic range of cytostatic drugs and irradiation of the central nervous system. AIM: Determination of the patients' risk of undesirable effects and determination of intensification of myelosuppression and hepatocellular damage during treatment of central nervous system tumours, depending on the used therapeutic protocol and the time of chemotherapy. MATERIAL AND METHODS: The investigated group consisted of 17 patients (5 girls, 12 boys) aged 1.5-16 yrs, treated for primary brain tumour. The patients were treated according to different protocols. Protocol I (vincristine, etoposide, carboplatin, cyclophosphamide, ifosfamide and cisplatin) in 4 children with medulloblastoma and with PNET. Protocol II (etoposide, ifosfamide, adriamycin) in 4 children with glioblastoma multiformae, astrocytoma anaplasticum and ependymoma. Protocol III (carboplatin and vincristine) in 3 children with medulloblastoma, ependymoma and glioblastoma multiformae. Protocol IV (vincristine and carboplatin) in 4 children with astrocytoma fibrillare and astrocytoma pilocyticum. 10 patients were given radiotherapy. Frequency of occurrence and intensification of undesirable effects were valuated according to the WHO classification after each cycle of chemotherapy (average 8 cycles) during the whole treatment period (average 8 months): 1. Leucopenia (mm3): 0 grade [gr] (>4.000), 1 gr. (3.000-3.900), 2 gr. (2.000-2.900), 3 gr. (1.000-1.900), 4gr. ( 100000), 1 gr. (75-99000), 2 gr. (50-74000), 3 gr. (25-49000), 4 gr. (<25000) 3. Anaemia (g/dl): 0 gr. (N), 1 gr. (>10), 2 gr. (8-10), 3 gr. (6.5-7.9), 4 gr. (<6.5) 4. Hepatocellular damage (GPT, GOT/bilirubin): 0 gr. (N/N), 1 gr. (2.5xN/-), 2 gr. (2.6-5xN/1.5xN), 3 gr. (5.1-20xN/1.5-3xN), 4 gr. (>20xN/>3xN). RESULTS: In patients treated in accordance with the therapeutic protocols there was no appearance or exacerbation of undesirable side effects. During receiving adriamycin mild hyperbilirubinemia (R=0.53; p<0.05 bilirubin 1 degree) occurred statistically significantly more often. Correlation between usage of temodal and the activity of hepatic enzymes was noticed, meeting the requirements of 1st degree of toxicity according to WHO rates (R-0.66). Consequently, after the usage of temodal, more frequent abnormalities in liver function were shown. During treatment with cyclophosphamide, iphosphamide, etoposide, carboplatin, lomustine and vincristine, complications such as myelotoxicity and hepatotoxicity were not more frequent by statistical significance methods. CONCLUSIONS: Current results of treatment of central nervous system tumours in children showed, that patients tolerated cytostatic therapy relatively well. The observed undesirable effects were abnormal liver enzyme activity and bilirubin levels, higher after adriamycin and temodal therapy. Due to the small group of patients, these results are of preliminary significance. In future, a more in depth analysis of early and late effects of oncological treatment in children with cns tumours is needed.