[Pediatric hematology and oncology in Germany: On the verge of a new reimbursement system].
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Child↗
Biomedical subjects
F Berthold
Publications and source records attributed to F Berthold.
Topotecan in the treatment of refractory neuroblastoma and other malignant tumors in childhood - a phase-II-study.
BACKGROUND: The topoisomerase-I-inhibitor Topotecan (TPT) has shown a broad activity in the therapy of adult malignant diseases. In pediatric oncology TPT has been rarely used. METHODS: From 1/98 to 8/99 we conducted a multicenter phase-II-study of TPT (1.5 mg/m (2)/d in 30 min i. v. for 5 days every 21 days) in pediatric patients (pts) with malignant tumors refractory to conventional therapy (either second line or any relapse). PATIENTS: A total of 20 pts received 81 cycles. The 7 female and 13 male pts had a median age of 10.2 years at the beginning of the TPT therapy. RESULTS: The median number of administered TPT cycles was 4 with an interval of 23.5 days. The median administered TPT dose was 1.48 mg/m (2)/d. No complete responses, but 2 partial responses and 9 stable diseases were observed. In 9 pts the disease progressed. The mean duration until progression for SD was 130 and not different from PR with 131 days. The median cumulative TPT dose until progression in responders was 30 mg/m (2). For all study-pts the median overall survival time was 235 days with 1 pt. still alive. The main toxicity was hematological with anemia grade III/IV (10/42 % of all evaluable TPT cycles), neutropenia grade III/IV (49/18 %) and thrombopenia grade III/IV (35/36 %). Non-hematologic toxicity was mild with the exception of 4 cycles with infection grade III and 1 grade IV. No patient died of therapy-related complications. CONCLUSIONS: TPT as monotherapy has shown an antitumor activity in pediatric pts with various malignancies. Toxicity was mainly hematological and manageable. Further evaluation of TPT treatment is planned using combinations with other cytostatic drugs.
Adolescent↗
The incidence of hearing impairment after successful treatment of neuroblastoma.
BACKGROUND: Platinum compound based chemotherapy has contributed to improved survival rates in neuroblastoma patients. We studied the association of hearing loss with the use of platinum based drugs. METHODS: Data of children from the two German neuroblastoma study cohorts, NB90 and NB97, were analyzed for the incidence of hearing impairments greater than WHO grade 2. Data from patients surviving more than 1 year after diagnosis without progression or recurrence were used. RESULTS: Of these 1,170 patients, 146 (12.5 %) had persisting hearing impairments. The incidence was low after localized neuroblastoma INSS stage 1 - 3 with 35/650 (5 %) and stage 4S with 2/113 (2 %), but high in stage 4 disease with 109/405 (27 %). Ototoxicity depended on the cumulative cisplatin dose. For doses of 1 - 200 mg/m (2), 201 - 400 mg/m (2), 401 - 600 mg/m (2) and 601 - 800 mg/m (2) we found hearing impairments in 5/39 (12 %), 28/221 (13 %), 61/230 (26 %) and 50/225 (22 %) patients, respectively. The incidence of hearing impairment was not age dependent. In stage 4 patients, there was an additional effect of high dosed carboplatin. 65/188 (40 %) patients developed hearing impairments after carboplatin containing (1,500 mg/m (2)) high dose chemotherapy with autologous stem cell reinfusion compared to only 33/217 (15 %) in patients receiving platinum free maintenance chemotherapy. Substitution of cisplatin (40 mg/m (2) x d, d 1 - 4, 96 h infusion) with carboplatin (100 mg/m (2) x d, d 1 - 4, 1 - 2 h infusion) due to otoxicity during induction chemotherapy did not reduce event free survival. CONCLUSION: One fourth of high risk neuroblastoma survivors suffer from treatment induced hearing impairments. The substitution of cisplatin with carboplatin was not associated with an increased rate of tumor recurrences.
Antineoplastic Combined Chemotherapy Protocols↗
Neuroblastoma preoperatively treated as nephroblastoma: does inadequate therapy worsen the prognosis?
BACKGROUND: The current standard in the treatment of nephroblastoma is preoperative chemotherapy based on radiological appearance. After subsequent surgical removal few tumours proved histologically to be neuroblastoma. We asked whether initial chemotherapy according to nephroblastoma trials would change the prognosis for those neuroblastoma patients. RESULTS: Out of 1603 patients registered in the German neuroblastoma trials, 29 patients (1.8 %) have preoperatively been treated according nephroblastoma protocols. Advanced stages (11 stage 3, 12 stage 4) were dominant. Diagnostic work up of those patients revealed elevation of catecholamine metabolites in only 39 % (compared to 80 % of the control patients) and mIBG uptake in only 71 % (compared to 89 % of the control patients). Elevation of NSE was observed in 92 % of patients (control group 72 %). Patients with preoperative nephroblastoma treatment were older than the patients of the control group. Risk factors like MYCN amplification or elevation of LDH were more often detected. The outcome of the patients with preoperative chemotherapy according nephroblastoma trials was worse than that of the control group, but risk group adapted survival analysis revealed no disadvantage. CONCLUSION: The prognosis of children with neuroblastoma tumours, which have been radiologically classified as nephroblastoma, is inferior compared to the prognosis of patients without preoperative nephroblastoma therapy. The difference appears to be associated rather with more unfavourable biology than with the element "preoperative chemotherapy".
Adolescent↗
Infants with stage 4 neuroblastoma: the impact of the chimeric anti-GD2-antibody ch14.18 consolidation therapy.
BACKGROUND: Antibody treatment is considered tolerable and potentially effective in the therapy of neuroblastoma. We have analyzed the clinical data of infants < 1 year with stage 4 neuroblastoma with regard to the consolidation treatment. PATIENTS AND METHODS: Infants < 1 year with stage 4 neuroblastoma who completed initial treatment (6-8 chemotherapy cycles followed either by 4 cycles low dose oral chemotherapy or high dose chemotherapy with stem cell transplantation) without event were eligible for this trial. Consolidation therapy consisted of 6 cycles of antibody ch14.18 (20 mg/m(2) x d ch14.18 for 5 days every 2 months) or 12 months oral maintenance chemotherapy (MT). RESULTS: Of 59 evaluable patients, 31 received a total of 159 ch14.18 cycles, 16 received MT instead, and 12 had no further treatment. Fever (47 % of cycles), abnormal CRP without infection (25 %), rash (23 %), cough (16 %), and pain (8 %) were the main side effects. Univariate analysis found no difference in event free survival (3-year-EFS 80.5 +/- 7.1 %, 87.5 +/- 8.3 %, and 75.0 +/- 12.5 % for patients treated with antibody ch14.18, MT, and no further therapy, p = 0.433) and overall survival (3-year-OS 90.1 +/- 5.4 %, 93.8 +/- 6.0 %, and 91.7 +/- 8.0 % for patients treated with antibody ch14.18, MT, and no further therapy, p = 0.931). Multivariate analysis failed to demonstrate an advantage of antibody treatment. CONCLUSION: The outcome of infants with stage 4 neuroblastoma is good. Consolidation treatment with ch14.18 was tolerable but associated with fever, elevated CRP, rash, cough, and pain as side effects. Compared to oral maintenance chemotherapy and no consolidation treatment, ch14.18 treatment had no impact on the patients' outcome which confirms the results found in children > 1 year.
Administration, Oral↗
[Structure, use, and risks of biomaterial repositories of embryonal tumors].
Availability of statistically sufficient numbers of tumor samples and other biomaterials in high quality together with corresponding clinical data is crucial for biomedical research. Tumor repositories from individual scientists are mostly not sufficient to satisfy these criteria, especially since pediatric tumors are rare. In 2000 three centralized tumor repositories (neuroblastoma in Cologne, nephroblastoma in Würzburg, hepatoblastoma, brain tumors in Bonn) have been established by the "German Competence Net Pediatric Oncology und Hematology". The aim was to collect biomaterial including tumor samples, normal tissue, and blood in high quality for research and diagnostic purposes at a central institution. Informed consent of the parents or patients is a prerequisite for scientific use of the samples and is requested by the therapy trial. The samples are collected according to accepted standards and shipped in the specially designed Tumorbox. The tumor repository organizes the distribution of the samples to the cooperating diagnostic laboratories. The number of collected tumor samples has increased over the years. In 2000, samples from 200 patients were collected while the patient number increased to 321 in 2005. Over the years the tumor repositories collected more than 7,150 samples (fresh frozen tumor, fresh frozen normal tissue, and blood). Through links with clinical trial databases the samples can be connected with clinical data. 12 of 14 applications for tumor material to be used in specific scientific projects have been approved by an independent supervisory board. The establishment of central tumor repositories represents a major step for biomedical research activities and quality control in pediatric oncology.
Biocompatible Materials↗
[Measures of quality assurance for in-patient pediatric oncology units].
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Age Factors↗
[Effect of cranial irradiation on rate of recurrence in children with acute myeloid leukemia. Initial results of the AML-BFM-87 study. The AML-BFM Study Group].
Study AML-BFM-87 compared prospectively if cranial irradiation could be abandoned by adding two blocks of intensification with high dose ARA-C and VP-16 after consolidation and furthermore, improve prognosis compared to study -83. 210 children were enrolled in study AML-BFM-87 until March 31, 1991. 164 (78%) achieved complete remission. Probabilities for event-free survival (EFS) and event-free interval (EFI) of 5 years were: .45 (SD .04) and .57 (SD .05). In the first 2.5 years of the study irradiation was randomized (n = 31), selected or refused (n = 24). However, during this period irradiation was mandatory in patients with leukocyte count greater than 70,000/mm3, and also in children with initial CNS involvement. Since July 1989 prophylactic cranial irradiation was abandoned. Patients of the group with mandatory irradiation (n = 39) presented with more unfavourable risk parameters than the group of non-irradiated children, who were enrolled in the study after randomisation had been stopped. Nevertheless, results showed in randomized and selected patient groups as well as in the total cohort a longer relapse-free interval (RFI) in irradiated (n = 66) compared to non-irradiated (n = 94) patients (RFI of 5 years: .70, SD .04 vs. .51, SD .07, p less than .05). Relapses in non-irradiated children occurred mainly in the bone marrow and less often in the CNS. The increase in relapse rate was seen especially in non-irradiated patients of the low risk group as defined in study AML-BFM-83 (RFI: .40, SD .14 vs. .79, SD .09 with irradiation, p less than .01). In the high risk group, however, the differences were not significant. Our results suggest that cranial irradiation is an important part of therapy in childhood AML, and that the good prognosis of the low risk group in study AML-BFM-83 was probably based on the combination of intensive chemotherapy and cranial irradiation.
Antineoplastic Combined Chemotherapy Protocols↗
[The IgG subclass level in children and adolescents with malignant diseases].
Children with malignant disease have an increased risk for bacterial infections. We investigated a possible correlation between septic episodes and decreased IgG subclass levels in 63 patients. At diagnosis 13 of 50 children showed decreased IgG subclass levels: 10x IgG4, 2x IgG1, and 1x IgG3 + IgG4 were reduced. Bone marrow infiltration by tumor cells did not increase the frequency of subclass reductions (4/25 with, 9/25 without bone marrow infiltration). The time course of subclass levels was followed during 37 febrile episodes (mainly fever of unknown origin, septicemia, pneumonia) of 23 children under cytostatic therapy. 6 patients showed transient low IgG subclasses: 2x IgG4, 1x IgG1, 1x IgG3, 1x IgG2 + IgG4, and 1x IgG1 + IgG3 + IgG4. Children with decreased IgG subclass levels appeared to occur more independently of leucopenia. In general, febrile episodes in children with subclass decreases did not last a longer period and did not occur more frequently than in children without IgG subclass deficiencies. In conclusion, the determination of IgG subclasses in cancer children at diagnosis or during chemotherapy did not add substantial information of prognostic or therapeutic relevance.
Adolescent↗
[The "Lower Saxony/Northern Rhine-Westphalia" Neuroblastoma Screening Project: on the need for epidemiologic comparison].
The proof for the general evolution of metastatic neuroblastoma from localized disease by a low-speed process is lacking. The epidemiological approach would require the decrease of neuroblastoma related mortality by reduction of the number of metastatic cases per population unit as a result of a screening program. During 1983 through 1990 the neuroblastoma incidence in the FRG was 0.85-1.09 cases per 100,000 children less than 15 years of age. The mortality rate ranged between 0.25 and 0.49 deaths per 100,000 children. The project "Niedersachsen/Nordrhein-Westfalen" started April 1st, 1992 and is investigating urinary catecholamine metabolite excretion in infants at the age of 10-12 months and for a second time in toddlers at 17-19 months. The target population includes 24.7 million inhabitants with 267,000 births per year. The urine sampled on filter paper is analyzed using thin layer chromatography. Positive and questionable positive results are confirmed by HPLC and GC-MS. The aim of the study is to demonstrate the feasibility of the chosen approach. Furthermore first epidemiological data will be obtained. Until a population-based study on neuroblastoma mortality in screened versus controlled populations has proven the usefulness of the screening it cannot be recommended as a general service to the public.
Adolescent↗
The role of chemotherapy in the treatment of children with neuroblastoma stage IV: the GPO (German Pediatric Oncology Society) experience.
340 consecutive patients with neuroblastoma stage IV were analyzed for the possible impact of chemotherapy on general condition, remission status, event free survival and survival. The children entered the trials NB 79, NB 82 and NB 85 of the German Pediatric Oncology Society (GPO). The patients did benefit from chemotherapy by considerable improvement of the general condition, by achievement of 30-40% complete and 60-70% partial remissions. The event free survival (EFS) rate 5-8 years after diagnosis was 13% for all 299 protocol patients, the survival (S) rate 10%. The median/mean EFS time were 11.6/23.8 months, the median/mean S time 17.0/29.4 months. The use of response rates as early predictors for long term survival is challenged. Addition of PCVm (cisplatinum, cyclophosphamide, Vm 26) to ACVD (adriamycine, cyclophosphamide, vincristine, dacarbazine) in trial NB 82 resulted in an improvement of the long term EFS rate from 5% to 18% (S rates 7----21%). The introduction of IVp (ifosfamide, VP16) and increase of doses (cisplatinum, Vm 26) did not further improve the results. Maintenance therapy (NB 82) revealed a positive influence on the outcome. Shorter intervals for realization of chemotherapy were associated with a trend for better EFS (NB 85). Although the group of children with bone marrow transplantation showed better EFS and S data compared to the unselected chemotherapy group, the advantage was less clear if matched pairs (remission status at the time of BMT) were compared.(ABSTRACT TRUNCATED AT 250 WORDS)
Antineoplastic Combined Chemotherapy Protocols↗
Interstitial irradiation of cerebral gliomas in childhood by permanently implanted 125-iodine--preliminary results.
19 children with a deeply located cerebral glioma were treated with continuous interstitial irradiation (stereotactically implanted 125-iodine). The accumulated dose at the tumor surface ranged in the low grade glioma group (Group A) from 55 to 100 Gy and in the high grade glioma group (group B) from 50 to 65 Gy. Patients in group B additionally received a fractionated external beam irradiation (15-20 Gy boost dose). Tumor shrinkage as seen on CT-scans 6 months postoperatively could be achieved in 100% of patients with a low grade glioma. The response rate of 6 children with a high grade glioma was 83%. With a mean follow up of 57.0 months (group A) and 56.2 months (group B) respectively the estimated 4.5 year survival probability was 92% for low grade gliomas and 83% for grade III/grade IV lesions. Permanent interstitial irradiation offers the possibility of local tumor control with low risk of severe side effects. The survival rates are promising and comparable with results of other study groups. For gliomas grade I and grade II a dose reduction may be feasible.
Adolescent↗
[Intensive combined drug therapy and beta-interferon in the treatment of children with metastasizing neuroblastoma: GPO-NB 79/82 study].
From June 1979 to June 1982 72 children with metastatic neuroblastoma older than 1 year of age at diagnosis were treated according to the protocol NB 79 of the German Society for Paediatric Oncology. The chemotherapy included three cycles of adriamycine, cyclophosphamide, vincristine, dacarbazine and five cycles of adriamycine and cyclophosphamide. 34 patients were randomized for additional beta-Interferon (Fiblaferon) treatment (10(5) U/kg daily for 3 weeks followed by 3 times a week for 21 weeks). 38 patients were not treated with Fiblaferon. The response rate was 96% including 35% complete and 61% partial remissions. Preoperative chemotherapy improved remarkably the resectability of the primary tumor without enhancing complication rates. The cumulative proportion surviving was 21% for the interferon group and 6% for the patients not treated with interferon. The cumulative recurrence free survival rate, however, was 5% for both groups. The median survival time was 19 months and the median recurrence free survival time 10 months. A serious side effect of chemotherapy was bone marrow depression (73%) resulting in 1 week delay of drug administration per cycle. The median of administered drug dosages was 87-100% of the recommended dosages. Side effects of beta-Interferon commonly decreased with time and were fever reactions (55%), shaking chills (29%), cardiovascular reactions (16%).(ABSTRACT TRUNCATED AT 250 WORDS)
Age Factors↗
[Corticosteroid-dependent reduction of leukocyte count in blood as a prognostic factor in acute lymphoblastic leukemia in childhood (therapy study ALL-BFM 83)].
In therapy study ALL-BFM 83 a total of 630 patients with acute lymphoblastic leukemia (ALL) have prospectively been evaluated for initial response on therapy with corticosteroids. It was the aim to qualify the in vivo cytoreduction as a new predictor for therapy failure. All patients were exposed for 7 days to prednisone before combination chemotherapy at day 8 has been started. At day 0 one additional dose of Methotrexate was given intrathecally. Therapy for all patients with non-B-ALL has been stratified according to initial tumor burden (risk factor) providing four therapy branches: standard risk low (SR-L), standard risk high (SR-H), medium risk (MR), high risk (HR). After a median duration of study of 21 months, event-free survival (EFS) is for all 630 patients 73%, 81% for SR-L, 76% for SR-H, 69% for MR, and 35% for HR patients (date of evaluation Jan. 1, 1987). In this prospective study, a small subgroup of patients (n = 48; 7.6% of total group) is characterized by greater than 1000 leukemic blasts/mm3 peripheral blood at day 8 after exposure to prednisone. In this subgroup the EFS is only 43% in contrast to 76% in the complementary group of 582 patients with less than 1000 leukemic blasts/mm3 peripheral blood at day 8. Patients of that risk group are derived from therapy branches SR-H, M and HR, the latter contributing relatively most patients. In this negatively selected group all patients with an initial high white blood count, CNS disease at diagnosis, immune subtypes as prae-T-ALL (n = 6), T-ALL (n = 18), null-ALL (n = 5), and males clearly dominate. Of 48 patients with greater than 1000 blasts/mm3 at day 8 4 subsequently failed to enter remission and 8 were qualified as lateresponders. 18 patients relapsed, most of them earlier compared to those of the complementary group. The initial in vivo response on corticosteroid therapy is considered a supplementary prognostic predictor for early failure. It will be utilized in trial ALL/NHL-BFM 86 to qualify patients at the highest risk for relapse. This group of patients is supplemented in addition by non- and lateresponders and children with acute undifferentiated leukemia (AUL). The in vivo corticosteroid test is simple, generates early and reliable results and can be obtained almost always. Thus it may be recommended for use in a multicenter trial.
Antineoplastic Combined Chemotherapy Protocols↗
[Combination chemotherapy and chemoembolization in the treatment of primary inoperable hepatoblastoma].
A 33 months old girl and a 5 months old boy presented with unresectable hepatoblastoma (group III) and were treated with combination chemotherapy using Adriamycin, Cyclophosphamide, Cisplatinum (regimen I) and Adriamycin, Etoposide, Cisplatinum (regimen II). In both patients tumor size and alpha-fetoprotein levels decreased remarkably. Tumor regression was considerably enhanced by selective chemoembolization (Ethibloc, Adriamycin) of the right hepatic artery in one patient. After preoperative chemotherapy hepatoblastomas could be removed surgically. Local recurrence in the older patient was treated again successfully by surgery and chemotherapy. The patients are surviving disease-free 17 and 28 months from diagnosis. The efficacy of the treatment warrants prospective clinical trials in patients with unresectable hepatoblastoma.
Antineoplastic Combined Chemotherapy Protocols↗
[Myeloablative chemo- and radiotherapy with autologous and allogenic bone marrow reconstitution in children with metastatic neuroblastoma].
22 children with metastatic neuroblastoma received myeloablative chemoradiotherapy followed by bone marrow transplantation (BMT). The duration of preceding chemotherapy was 4-30 months and included treatment of recurrences in 10 children. At BMT 12 patients were in CR, 9 in PR and one had tumor progression. 10/15 of autologous bone marrows were purged using immunomagnetic bead method of Kemshead and 2/15 using 4 hydroperoxycyclophosphamide. Myeloablative therapy consisted of melphalan and total body irradiation (TBI) in 13 patients (three each supplemented by vincristine or adriamycin/etoposide), in one child of melphalan and mIBG and in 3 children of melphalan alone. 3 children received double autograft and 2 cyclophosphamide (and TBI). 10 patients survived 0-32 months from BMT and 5-48 months from diagnosis, respectively. 12 patients died including 7/12 of tumor progression and 5/12 of toxicity (venoocclusive disease, gut toxicity, septicemia, pneumonia). We conclude that at this point BMT after conventional high dose chemotherapy may provide the only real chance of survival for a significant number of children with metastatic neuroblastoma.
Abdominal Neoplasms↗
[131(I)-meta-iodobenzylguanidine treatment of 32 children with therapy-refractory neuroblastoma].
The selective uptake and accumulation of 131J-Metaiodobenzylguanidine in neuroblastoma cells in vivo may be utilized for targeted irradiation. The experience with 32 neuroblastoma patients refractory to conventional high dose chemotherapy is reported. At diagnosis 8 patients had Evans stage III and 22 stage IV. 11/32 experienced recurrences after complete tumor disappearance and before mIBG treatment, 16/32 progressed from residual or nonresponding tumor and in 3/32 insufficient tumor regression by chemotherapy was observed. 2 children received one mIBG course each with no evidence of disease. Mean applied activity was 128 mCi per course (35-300 mCi), 360 mCi per patient (80-1033 mCi) and 19.2 mCi/kg per patient (3.2-37.9 mCi/kg), respectively. A total of 84 courses was given (mean 2.6 per patient). Pain relief was noticed in 14/14 patients with bone pain. Complete or very good partial remission was achieved in 5/32, partial remission in 11/32 and stable disease in 6/32 patients. In 8 children progression occurred and 2 patients were not evoluable. 20 children died, 12 are still alive (6 patients with initial stage IV, 6 with stage III disease). Main side effect was transient thrombocytopenia, which became more severe with increasing number of courses. We conclude that mIBG treatment is effective in some patients with refractory neuroblastoma and may be utilized in the future as front line therapy for patients achieving only incomplete regressions after high dose chemotherapy.
3-Iodobenzylguanidine↗
[Neuroblastoma study NBL 79 of the German Society for Pediatric Oncology. Report after 2 years].
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Child↗