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.

[Central nervous system involvement at diagnosis and at relapse in children with neuroblastoma]. / Zajecie osrodkowego ukladu nerwowego w chwili rozpoznania i we wznowach u dzieci ze zwojakiem zarodkowym wspólczulnym.

Central nervous system (CNS) involvement in the course of neuroblastoma (NBL) in children is relatively rare. However, it seems to become serious clinical problem in the group of patients from high risk group. They presently achieve longer time of survival caused by employment of more intensive treatment modalities. The aim of the study was clinical evaluation of the patients over 1 year of age with stage 4 NBL with CNS involvement, both at diagnosis and at relapse. From 1997 to 2007, 117 patients (age 0.2-13.5 years) started NBL treatment. In 58 children over 1 year, stage 4 of disease was diagnosed. In 4 (6.9%) cases the CNS involvement was found at diagnosis. In 5 patients (8.6%) the isolated relapse in brain was diagnosed. The clinical symptoms caused by increased intracranial pressure were observed in all patients at relapse. In the case of initial involvement no neurological symptoms were observed. All 5 children with CNS involvement as isolated relapse did not present with infiltration of skull bones, whereas at initial diagnosis the brain lesions were continuous with bone metastases. Among 5 patients with isolated relapse 4 died because of NBL progression. Among 4 children with initial CNS involvement 1 died due to haemorrhage to CNS. Probably brain involvement at initial NBL diagnosis is not an additional negative prognostic factor. Because of extremely poor prognosis in patients with CNS relapse it should be advised to consider possible implementation of preventive treatment. It is also necessary to invent new more effective treatment methods.

[Treatment results of children with neuroblastoma: report of Polish Pediatric Solid Tumor Group]. / Wyniki leczenia dzieci ze zwojakiem zarodkowym wspólczulnym: wstepny raport Polskiej Pediatrycznej Grupy Guzów Litych.

Approximately 60 children aged 0-18 years are diagnosed of NBL each year in Poland. About 60% of all patients suffering from NBL have a chance for durable cure. Unfortunately the prognosis for patients within the high-risk group accounting for more than 50% of all NBL patients remains poor despite the introduction of more intensive chemotherapy regimens with radical surgery procedures and megachemotherapy with subsequent stem cell transplantation. Only one third of patients in this group can be cured. To improve the treatment results of the high-risk patient group and to decrease the rate of therapy related side effects current European treatment protocols have been introduced systematically in Poland. In February 2009 information about 389 patients (age 0.1-16.5 years) diagnosed between 2001 and 2008 were obtained. Results of therapy of 319 patients who started treatment from 2001 to 2007 were analyzed. Between 104 infants and 215 children over 1 year of age, stage 4 of disease was found in 25% and 54.5%, respectively. In this period additionally to European treatment protocols, two another protocols were used. Satisfactory treatment results were obtained in 104 infants (5-year event free survival /EFS/=82.6%), irrespective of the type of treatment protocol. Over 5-year EFS for children over 1 year of age in 1, 2 and 3 stage of disease was: 100%, 86.3% and 64.5%, respectively. On the contrary, 107 patients with 4 stage of disease achieved the 5-year EFS of 27% only. Treatment results obtained in patients treated according to the European HR-NBL-1/ESIOP protocol were better than for patients treated according to other treatment protocols (5-year EFS: 31.1% and 16.4%, respectively), but difference between these groups was not significant. Between 2001 and 2007 data reporting increased to 81% from 19% noted earlier. Unfortunately, results of treatment for children over 1 year of age remain still unsatisfactory. That is why there is a need of improvement of modern, unified treatment realization as well as better data reporting. For realization of these aims adequate financial support is essential.

[Opsoclonus-myoclonus syndrome in children with neuroblastoma: description of 3 cases]. / Zespól opsoklonii mioklonii u dzieci z nerwiakiem zarodkowym wspólczulnym: opis trzech przypadków.

Neuroblastoma (NBL) is one of the most common childhood malignancies. Presence of untypical symptoms is characteristic for this malignancy; therefore it may mimic many other illnesses, both malignant and nonmalignant. Particular attention should be focused on opsoclonus-myoclonus syndrome (OMS, Kinsbourne's syndrome). In this paper three children with NBL previously diagnosed with OMS are presented. There is a need to test children with OMS for NBL as more than 30% of them are diagnosed with a tumor of neural origin. Children with NBL suffering from OMS have usually a favorable outcome with respect to their malignancy. However, the neurological and cognitive deficits are present for a long time and even they may become more intensive in spite of immunosuppressive therapy.

[Can intensive induction chemotherapy eradicate retroperitoneal lymph node metastases in children over 1 year of age with stage 4 neuroblastoma?]. / Czy intensywna chemioterapia indukcyjna moze spowodowac eradykacje zmian w pozaotrzewnowych wezlach chlonnych u dzieci powyzej 1 r.z. z neuroblastoma w 4 stopniu zaawansowania?

The prognosis in patients over 1 year of age with stage 4 neuroblastoma (NBL) is poor in spite of intensive treatment. The choice of intensive chemotherapy and extension of the surgery, especially in the case when the tumor is localized in the abdomen, is still controversial. Between 1991-2001 there were 61 patients with NBL treated in our Department; 28 of them were older than 1 year and had stage 4 with the tumor localized in the abdomen. All children received intensive chemotherapy according to Japanese protocol. Three children with disease progression during intensive treatment where excluded from further analysis. In 22 children with good or very good response to chemotherapy, the surgery was performed. In 4 patients it was local surgery. In 18 patients the tumor was removed with all visible retroperitoneal lymph nodes (so called Tsuchida surgery). The histopathological evaluation was performed in 17 patients with Tsuchida surgery and in 13 cases metastases in retroperitoneal lymph nodes were found. The 5-year overall survival was significantly better in the group with Tsuchida surgery performed (0.66 vs 0.21, p=0.044) for the patients in stage 4. After the intensive induction of chemotherapy the metastases in retroperitoneal lymph nodes can still be found. The removal of the tumor with all retroperitoneal lymph nodes can improve treatment results in patients with advanced abdominal neuroblastoma, but it is necessary to investigate more patients and to prolong the observation period.