Late somatic sequelae after treatment of childhood cancer in Slovenia.

BACKGROUND: 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. METHODS: 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 Kaplan Meier estimator and Cox regression model. RESULTS: 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. CONCLUSIONS: 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.

Genotyping of BRCA1, BRCA2, p53, CDKN2A, MLH1 and MSH2 genes in a male patient with secondary breast cancer.

BACKGROUND: Some tumour suppressor genes (BRCA2) and mismatch repair genes (MSH2, MLH1) are correlated with an increased risk for male breast cancer. CASE REPORT: Our patient developed secondary breast cancer after the treatment for Hodgkin's disease in childhood. DNA was isolated from the patients' blood and screened for mutations, polymorphisms and variants in BRCA1, BRCA2, p53, CDKN2A, MLH1 and MSH2 genes. We found no mutations but common polymorphisms, and three variants in mismatch repair genes. CONCLUSIONS: Nucleotide variants c.2006-6T>C and p.G322D in MSH2 might be correlated with male breast cancer.

Gonadal function in patients treated for Hodgkin's disease in childhood.

BACKGROUND: The long-term survival of patients treated for Hodgkin`s disease (HD) in childhood is high and the chief concern is now being directed toward the late effects of the treatment, including the endocrine dysfunction. PATIENTS AND METHODS.: Testicular and ovarian functions were assessed in 64 long term survivors (24 females, 40 males) treated for HD in childhood in Slovenia between 1972 and 1994. At diagnosis they were 3-16 years old and had gonadal evaluation 4-27 years later at the age of 13-34. Fifty-four (84%) patients received chemotherapy (ChT), 49 in combination with radiation therapy (RT), 10 received RT alone. Gonadal function was assessed by the clinical examination and measurement of serum concentrations of estradiol and testosterone. Serum levels of LH and FSH were determined in the basal state and after the stimulation. RESULTS: Primary hypogonadism (PH) was found in 30 (47%) patients. Twenty-four of 40 (60%) males had PH with evidence of damage of germinal epithelium, 4 of them had evidence of damage of Leydig cells (LC) and 10 had evidence of dysfunction of LC as well. PH was found in 6 of 24 (25%) females. CONCLUSIONS: After therapy for HD PH was more frequent in males than in females. Not only RT but also alkylating agents and procarbazine alone caused damage of LC. Age of patient at the time of treatment was not an important risk factor for gonadal toxicity. Pelvic RT in combination with ChT is the most important risk factor of the development PH both, in males and females.

Prognostic value of immunohistochemistry in the Ewing's sarcoma family of tumors.

BACKGROUND: The expressions of different markers have been immunohistochemically studied in various types of the Ewing's sarcoma family of tumors, especially for diagnostic purposes. However, little is known about their prognostic value in combination with the clinicopathological data of such patients. MATERIAL/METHODS: This retrospective study investigated the immunohistochemical expressions of NSE, TdT, EMA, S-100, CK MNF116, p53, bcl-2, CD99, and CD117 on formalin-fixed paraffin-embedded material of 72 patients (age range: 2-59 years) with various types of Ewing's sarcoma family of tumors using the tissue microarray method. The immunohistochemical results were compared with clinicopathological features using survival analysis (Cox regression). RESULTS: CD99 expression was detected in 90%, CD117 in 75.8%, bcl-2 in 70.1%, NSE in 66.6%, p53 in 66.6%, EMA in 26%, S-100 in 25.4%, TdT in 22.1%, and CK MNF116 in 10.2% of the cases. No immunoreactivity was observed in the normal tissue around the tumors. CONCLUSIONS: The expressions of EMA (p=0.107), NSE (p=0.126), CD99 (p=0.14), TdT (p=0.198), bcl-2 (p=0.382), p53 (p=0.54), CD117 (p=0.612), S-100 (p=0.867), and CK MNF116 (p=0.934) had no statistically significant impact on survival. Patient age at the time of diagnosis (p=0.008) and the presence of tumor necrosis (p=0.033) were the only significant prognostic factors in this study. Tumor location was an insignificant prognostic factor (p=0.38).

Trends in survival after childhood cancer in Slovenia between 1957 and 2007.

OBJECTIVES: To evaluate childhood cancer survival in Slovenia, to provide results comparable to ACCIS studies, and to study the effect of recorded variables on 5-year survival. METHODS: The data are registry-based and present a unique collection in terms of control and homogeneity. Survival was explored using Kaplan-Meier estimates and the Cox model. Restricted cubic splines were used to illustrate the nonlinearity of the age and year of diagnosis effect for the four chosen diagnoses. RESULTS: The data set includes 1827 children examined from 1957 to 2002 with the follow-up ending 2007. The overall 5-year survival increased from 0.26 (95%CI [0.21, 0.33]) before 1973 to 0.8 (95% CI [0.74, 0.85]) for patients diagnosed in the period 1998-2002. It is best for Hodgkin disease and leukemia; for non-Hodgkin lymphoma (NHL) and intracranial and intraspinal neoplasms (CNS) the rate of improvement has been slowing down since 1990. Survival is significantly associated with age at diagnosis for patients with leukemia, CNS, NHL, and neuroblastoma (p < .001), the association varies between diseases. Hazard decreases with age for children with CNS and NHL, increases for children with neuroblastoma, and is quadratic with its lowest point at the age of about 5 years for children with leukemia. CONCLUSIONS: The survival experience in Slovenia compares well with those of large samples in the United States SEER program 1975-1995 and the data collected by ACCIS from 62 population-based cancer registries in Europe. The hazard of dying has been decreasing constantly, mainly due to improvements in leukemia treatment.

Cardiac damage after treatment of childhood cancer: a long-term follow-up.

BACKGROUND: With improved childhood cancer cure rate, long term sequelae are becoming an important factor of quality of life. Signs of cardiovascular disease are frequently found in long term survivors of cancer. Cardiac damage may be related to irradiation and chemotherapy.We have evaluated simultaneous influence of a series of independent variables on the late cardiac damage in childhood cancer survivors in Slovenia and identified groups at the highest risk. METHODS: 211 long-term survivors of different childhood cancers, at least five years after treatment were included in the study. The evaluation included history, physical examination, electrocardiograpy, exercise testing and echocardiograpy. For analysis of risk factors, beside univariate analysis, multivariate classification tree analysis statistical method was used. RESULTS AND CONCLUSION: Patients treated latest, from 1989-98 are at highest risk for any injury to the heart (73%). Among those treated earlier are at the highest risk those with Hodgkin's disease treated with irradiation above 30 Gy and those treated for sarcoma. Among specific forms of injury, patients treated with radiation to the heart area are at highest risk of injury to the valves. Patients treated with large doses of anthracyclines or concomitantly with anthracyclines and alkylating agents are at highest risk of systolic function defect and enlarged heart chambers. Those treated with anthracyclines are at highest risk of diastolic function defect. The time period of the patient's treatment is emerged as an important risk factor for injury of the heart.

Classification tree analysis of second neoplasms in survivors of childhood cancer.

BACKGROUND: Reports on childhood cancer survivors estimated cumulative probability of developing secondary neoplasms vary from 3.3% to 25% at 25 years from diagnosis, and the risk of developing another cancer to several times greater than in the general population. METHODS: In our retrospective study, we have used the classification tree multivariate method on a group of 849 first cancer survivors, to identify childhood cancer patients with the greatest risk for development of secondary neoplasms. RESULTS: In observed group of patients, 34 develop secondary neoplasm after treatment of primary cancer. Analysis of parameters present at the treatment of first cancer, exposed two groups of patients at the special risk for secondary neoplasm. First are female patients treated for Hodgkin's disease at the age between 10 and 15 years, whose treatment included radiotherapy. Second group at special risk were male patients with acute lymphoblastic leukemia who were treated at the age between 4.6 and 6.6 years of age. CONCLUSION: The risk groups identified in our study are similar to the results of studies that used more conventional approaches. Usefulness of our approach in study of occurrence of second neoplasms should be confirmed in larger sample study, but user friendly presentation of results makes it attractive for further studies.

Ewing sarcoma/PNET: 27 years of experience in Slovenia.

The study includes 91 patients treated for Ewing sarcoma between 1972 and 2002. Forty were younger and 51 were older than 16. The overall 5-year survival was 36%: 53.5% in the younger and 22.5% in the older age group. Among patients with localized disease, 5-year survival was 58% in younger and 25.5% in the older. Survival was similar whether patients received three treatment modalities or chemotherapy combined with either surgery or radiotherapy. Recurrence was noted in 47 out of 75 patients with localized disease, most commonly as local recurrence or lung metastases. Among 18 evaluated patients, 14 had minor physical defects and 4 had severe late treatment effects (sterility in 3 and secondary osteogenic sarcoma in 1).

The role of radiotherapy in the treatment of childhood intracranial germinoma: long-term survival and late effects.

BACKGROUND: The aim of the present report was to evaluate the role of radiotherapy in the treatment of childhood intracranial germinoma in view of long-term survival and functional outcome. PROCEDURE: Nine children with histologically verified intracranial germinomas treated in Slovenia between 1983 and 1995 were reviewed. The four boys and five girls were 8.8-16.9 years old (median, 11.3 years). Five tumors were suprasellar, three were in the pineal region, and one patient had bifocal disease. Two patients had disseminated tumor. All patients received radiotherapy: six to the tumor bed, one to the whole brain, and two to the whole central nervous axis (CNA). The doses to the tumor bed ranged from 30 to 46 Gy (median, 44 Gy) and to the CNA were 24 and 34.5 Gy. Five patients received neoadjuvant cyclophosphamide and three patients, all with beta-human chorionic gonadotropin secreting tumors, received neoadjuvant cisplatin-based chemotherapy. RESULTS: Six patients are alive 12.8-21.8 years (median, 19 years) from diagnosis. The causes of death in three patients were disseminated disease, toxicity of salvage chemotherapy, and secondary etoposide-induced leukemia. All patients with suprasellar tumors presented with overt endocrinopathy. Results of psychological evaluation were subnormal in one out of five patients tested. Estimate of mental deterioration due to therapy ranged from 0% to 30% (median, 15%). Emotional disorder was registered in four patients and psycho-organic syndrome in three. CONCLUSIONS: Our results on long-term survival and functional outcome confirm the efficacy and relative safety of limited-field and reduced-dose radiotherapy for childhood intracranial germinoma when supplemented with chemotherapy.

Pediatric osteosarcoma: a 35-year experience in Slovenia.

The purpose of this study was to review all the children and adolescents treated for osteosarcoma in Slovenia between 1968 and 1997. Seventy-four patients were included in this retrospective study and classified according to the newly devised classification based on clinical and imaging studies. The overall survival rate is 48%. The stage of the disease and the treatment, including chemotherapy, are the only prognostic factors significantly influencing survival. The survival of patients with osteosarcoma has improved with chemotherapy, but new therapeutic strategies should be found for different stages of disease. The authors' newly devised classification based on clinical and imaging studies proved to be adequate.

Gonadal function in patients treated for leukemia in childhood.

Ovarian and testicular function were assessed in 67 long-term survivors (37 females, 30 males) treated for leukemia between 1973 and 1992. At diagnosis they were 1-16 (median 5) years old and had evaluation of gonadal function 4-25 (median 13) years later at the age of 13-31 (median 19). All had been treated with various combinations of chemotherapy (ChT) (including cyclophosphamide (CYC) and cytarabine in 32 patients), 62 patients had received prophylactic cranial irradiation with 12-49 (median 18) Gy, 2 patients had had craniospinal irradiation with 24 and 10 Gy respectively. Nine patients were treated for relapse; 2 boys had testicular irradiation (RT) with 12 Gy in 3 fractions and 1 girl whole-abdomen RT with 20 Gy as a part of this treatment. Three patients were treated for second malignancies. Gonadal function was assessed by clinical examination and measurement of serum concentrations of estradiol and testosterone. Serum levels of LH and FSH were determined in basal state and after stimulation. Primary hypogonadism was found in 6 (9%) patients. Five (16,5%) males had primary hypogonadism with evidence of damage to the germinal epithelium, 2 of them, treated with testicular RT, had evidence of damage to the Leydig cells and 2 had evidence of dysfunction of Leydig cells as well. Primary hypogonadism was found in 1 female, who was heavily treated for relapse (ChT containing CYC, abdominal RT and craniospinal RT). She was amenorrhoic and needed substitutional estrogen therapy but delivered a child anyway. Five females had early puberty after cranial RT. One female had secondary hypogonadism and hyposomatotropism after cranial RT with 30 Gy, one male had hyposomatotropism after receiving cranial RT twice (49 Gy total). Primary treatment for leukemia does not produce primary hypogonadism in girls, but it does in boys. Alkylating agents and gonadal RT are the most damaging factors. Not only RT to gonads but also alkylating agents alone cause dysfunction of Leydig cells.

Second neoplasms after treatment of childhood cancer in Slovenia.

BACKGROUND: The number of long time survivors of childhood cancer treatment is constantly increasing over the last decades as a result of advances in diagnosis and treatment. The occurrence of second neoplasms is one of most serious late effects observed in cancer survivors. METHODS: The risk of secondary neoplasm was studied in a cohort of 1,577 patients treated for childhood cancer registered in the Cancer Registry of Slovenia (CRS) between 1961 and 2000. The time at risk was defined from the date of diagnosis of first malignancy to the time of death or the end of the study. RESULTS: The most frequent primary malignancies were: acute leukemia 28.5%, central nervous system (CNS) tumors 21.3%, and lymphomas 16.6%. Median observation time was 7.8 years. Forty-eight patients developed second neoplasms. CNS tumors, acute leukemias, and thyroid carcinoma were most frequent second neoplasms. The cumulative risk for second neoplasm in the entire cohort was 0.06% at 5 years, 5.1% at 15 years, and 12.6% at 25 years after diagnosis of first cancer. The overall survival after second neoplasm was 65% 10 years after the diagnosis of second neoplasm. CONCLUSIONS: Patients after treatment of childhood cancer are at special risk for subsequent neoplasms and long-term follow-up is mandatory.

Medulloblastoma in children 0-3 years old: forty years' experience in slovenia.

Twenty-one children 0-3 years with MB were admitted 1960-1996, of 14 before treated 1984, 3 had no treatment, 5 had postoperative RT, one had radioactive gold IT. Seven treated 1986-1996 had preradiation Cht, 5 with HDCy. Of the 14 treated before 1984, 12 died within 1 year, one after 42 years in hypopharynx cancer, one is alive, of normal height and working. Of the 7 treated 1986-1996, 3 with disseminated disease died. Four are longtime survivors, 2 treated with reduced doses of RT of normal development. Preradiation Cht with HDCy and reduced doses of RT seems to be a reasonable approach.

Long-term sequelae in children treated for brain tumors: impairments, disability, and handicap.

Sixty-one long-term survivors, treated for brain tumors in childhood, were evaluated in term of neurological impairments, disability, and handicap. Thirty-eight patients (pts) (62%) had at least one impairment. Visual impairment was detected in 14 pts (24%), associated with recurrence (p = .012). Thirty-four patients (56%) had motor impairment, associated with sex (female) in irradiated patients; 13 (21%) had epilepsy, associated with supratentorial tumor site (p = .001). The same number of patients had brain atrophy; risk factors were hydrocephalus at diagnosis and perioperative complications. Sixteen patients (30%) had IQ score < 80, associated with young age at first treatment (p = .006) and recurrence (p = .043). Twenty-seven out of 61 of our patients (44%) were disabled: 12 mildly, 14 moderately, and 1 severely. Epilepsy was the most important risk factor for disability. Cognitive impairment, motor impairment, and epilepsy were associated with employment (43%); cognitive impairment was also associated with education.

Topical topic: value of fine needle aspiration biopsy in childhood rhabdomyosarcoma: twenty-six years of experience in Slovenia.

BACKGROUND: Chemotherapy (Cht) for rhabdomyosarcoma (RMS) given before local treatment can prevent mutilating surgery and high-dose irradiation (RT). Fine needle aspiration biopsy (FNAB) can confirm the diagnosis and neoadjuvant treatment can start without delay. The purpose of our study was to assess the role of FNAB in the management of childhood RMS in Slovenia. PROCEDURE: A total of 78 children and young adults were included. FNAB provided the pre-treatment diagnosis in 37 and surgical biopsy in 41 patients. In 61 cases recurrent/metastatic disease was aspirated. Cytological diagnoses were compared to the original histological diagnoses. All case histories, cytological and histological material were reviewed and immunocytochemical staining performed when necessary. RESULTS: FNAB provided a correct diagnosis of malignancy in all 37 primary tumours, a specific diagnosis of RMS was given in 29 (78%). With the use of immunocytochemistry during the last 15 years, the accuracy has risen to 87%. FNAB provided the diagnosis of recurrence/metastasis in 57/61 cases. No complications of FNAB were noted. Review of histology reclassified five original diagnoses of RMS into one malignant rhabdoid tumour and four sarcomas NOS. In review of cytology we were able to sub classify 80% of RMS. CONCLUSIONS: FNAB is a safe method, which enables us to establish the pre-treatment diagnosis of RMS, and to some extent even its type, without delay. In our study, FNAB successfully replaced surgical biopsy in 87% of RMS patients during the last 15 years. Neoadjuvant Cht was started immediately, surgery was delayed and more conservative. Consequently, the risk for treatment sequelae was considerably reduced.