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G Henze

Publications and source records attributed to G Henze.

At least 55 records · Page 3Linked to original sources
PubMed2000

Potential of LightCycler technology for quantification of minimal residual disease in childhood acute lymphoblastic leukemia.

A certain quantity of residual leukemic cells at several time points during chemotherapy of childhood acute lymphoblastic leukemia (ALL) was proved to predict outcome. Future childhood ALL treatment will take minimal residual disease (MRD) into consideration for stratification aiming at an individualization of chemotherapeutic regimens. Recently, the first quantitative real-time PCR assay for MRD detection was described using T cell receptor and immunoglobulin gene rearrangements as clonal markers. Quantitative real-time PCR was performed with TaqMan technology. Here, we present for the first time the potential of LightCycler real-time PCR technology to quantify MRD. We compare and assess different approaches for real-time PCR quantification of leukemic cells, based either on clone-specific primers and general fluorescence detection with SYBR Green, TaqMan probe or hybridization probes, or based on general PCR amplification and clone-specific detection with hybridization probes. MRD quantification with LightCycler real-time PCR technology is a sensitive, specific and incomparably rapid method that needs no post-PCR handling, hence eliminating contamination risk and saving time. Working towards the establishment of MRD quantification in routine diagnostics and towards treatment strategies based on these results, LightCycler quantitative PCR seems to be a promising new technique that makes results immediately available for treatment decisions.

Base Sequence↗
PubMed2000

Relapse in childhood acute lymphoblastic leukemia is associated with a decrease of the Bax/Bcl-2 ratio and loss of spontaneous caspase-3 processing in vivo.

Dysfunction of the p53/Bax/caspase-3 apoptosis signaling pathway has been shown to play a role in tumorigenesis and tumor progression, ie the development of acquired drug resistance. Low expression of the apoptosis inducer Bax correlates with poor response to therapy and shorter overall survival in solid tumors. In the present study, we analyzed the p53/Bax/caspase-3 pathway in a paired and an unpaired sample series of children with acute lymphoblastic leukemia (ALL) at initial diagnosis and relapse. The data demonstrate that both Bax expression levels and the Bax/Bcl-2 ratio are significantly lower in samples at relapse as compared with samples at initial diagnosis (P=0.013, Wilcoxon signed rank test (paired samples); P=0.0039, Mann-Whitney U test (unpaired samples)). The loss of Bax protein expression was not a consequence of Bax frameshift mutations of the G8 tract and could not be attributed to mutations of the p53 coding sequence (exons 5 to 8) which were detected to a similar extent in de novo ALL samples and at relapse. Analysis of the downstream effector caspase-3 showed loss of spontaneous caspase-3 processing at relapse. Whereas nine out of 14 (64%, paired samples) or 37 out of 77 (48%, unpaired samples) ALL patients at initial diagnosis displayed spontaneous in vivo processing of caspase-3, this was completely absent in patients at relapse (paired samples) or detected in only one out of 34 patients at relapse (2.9%, unpaired samples). We therefore conclude that in ALL relapse a severe disturbance of apoptotic pathways occurs, both at the level of Bax expression and caspase-3 activation.

Adolescent↗
PubMed2000

Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Münster.

Four thousand, four hundred and forty eligible children of up to 18 years of age were treated in four consecutive trials between 1981 and 1995 with the treatment protocols of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). The probability for event-free survival (pEFS) at 8 years improved from 65.8% in study ALL-BFM 81 to 75.9% in study ALL-BFM 90. The cumulative incidence of recurrences with CNS involvement was 10.1% and 9.3% in studies ALL-BFM 81 and 83, but was reduced to less than 5% in study ALL-BFM 90 (for isolated CNS relapses from 5.3% in study ALL-BFM 81 to 1.1% in study ALL-BFM 90). Four major findings were derived from this series of trials performed by 37 to 96 centers in Germany, Austria, and Switzerland: (1) Reintensification is a crucial part of treatment, even in low risk patients; (2) presymptomatic cranial radiotherapy can be safely reduced to 12 Gy, or even be eliminated if it is replaced by early intensive systemic and intrathecal methotrexate applied; (3) maintenance therapy given a total of 24 months from diagnosis provides a lower rate of systemic relapses than treatment for 18 months; (4) inadequate response to an initial 7-day prednisone window (combined with one intrathecal injection of methotrexate on day 1) defines about 10% of the patients with a very high risk of relapse. For patients with adequate early response (90% of all) an 8-year pEFS of 80% has been achieved in the most recent trial ALL-BFM 90. While it has proven so far to be impossible to improve the outcome for the small group of high risk patients, the number of recurrences could be effectively reduced for the large group of patients responding adequately to the prednisone in vivo sensitivity test. Apart from inadequate prednisone response, patients with hyperleukocytosis, age <1 year, or the presence of the Philadelphia-chromosome (Ph+ ALL) are at a particularly high risk of failure.

Adolescent↗
PubMed2000

Methotrexate resistance in relapsed childhood acute lymphoblastic leukaemia.

Treatment failure in childhood acute lymphoblastic leukaemia (ALL) might be associated with methotrexate (MTX) resistance. Little is known about MTX resistance in relapsed ALL. In this study, we determined ex vivo MTX resistance in precursor-B ALL at relapse (rALL) and determined possible defects in MTX membrane transport and polyglutamylation. Using the in situ thymidylate synthase inhibition assay, 21 rALL samples were threefold more MTX resistant than 63 initial precursor-B ALL samples, both after short-term and after continuous MTX exposure (P < or = 0.01). [3H]-MTX membrane transport did not differ between eight rALL and 25 precursor-B ALL samples. Incubation for 24 h with 1 microM [3H]-MTX resulted in a trend towards a lower accumulation of MTX in 20 relapsed than in 83 initial samples of precursor-B ALL samples (906 vs. 1364 pmol/109 cells; P = 0.07). Accumulation of long-chain MTX polyglutamates (MTX-Glu4-6) did not differ between relapsed and newly diagnosed samples (746 and 889 pmol/109 cells; P = 0.1). Activities of the enzymes involved in polyglutamylation (folylpolyglutamate synthetase and folylpolyglutamate hydrolase) did not differ between rALL and untreated c/pre-B-ALL. This study demonstrates that leukaemic cells of children with relapsed precursor-B ALL are relatively MTX resistant, but that this MTX resistance is not associated with major impairments in MTX uptake or polyglutamylation.

B-Lymphocytes↗
PubMed2000

Pegylated asparaginase (Oncaspar) in children with ALL: drug monitoring in reinduction according to the ALL/NHL-BFM 95 protocols.

Hypersensitivity reactions are relevant adverse effects of asparaginase therapy. Therefore, children treated with native Escherichia coli asparaginase in induction therapy of acute lymphoblastic leukaemia (ALL) or non-Hodgkin's lymphoma (NHL) were switched to the pegylated enzyme for reinduction under drug monitoring. Seventy children, including four patients with allergic reactions during induction, were given one dose of Oncaspar 1,000 U/m2 intravenously. Activity was determined every third or fourth day until it dropped below the limit of quantification. In current reinduction protocols [ALL/NHL-Berlin-Frankfurt-Münster (BFM) 95 trials], four doses of 10,000 U/m2 E. coli asparaginase deplete asparagine for about 2-3 weeks, therefore activities of >/= 100 U/l up to day 14 and >/= 50 U/l up to day 21 were targeted. In 66 patients without an allergic reaction during induction, the mean activity was 606 +/- 313 U/l, 232 +/- 211 U/l and 44 +/- 50 U/l after 1, 2 and 3 weeks respectively. In 44/66 patients, activity was >/= 100 U/l after 14 d. A rapid decline in activity was seen in the remaining 22 patients, including 8/22 patients who showed no activity after 1 week. Toxicity was low and comparable to the native enzymes but, in contrast to about 30% of hypersensitivity reactions with conventional reinduction therapy, no allergic reaction was seen. Substituting 4 x 10,000 U/m2 asparaginase medac for one dose of 1,000 U/m2 Oncaspar was safe and well tolerated. Comparable pharmacokinetic treatment intensity was achieved in about two-thirds of patients.

Adolescent↗
PubMed2000

Childhood all blasts retain phenotypic and genotypic characteristics upon long-term serial passage in NOD/SCID mice.

For children with an early bone marrow relapse or relapsed T-cell acute lymphoblastic leukemia (ALL), allogeneic bone marrow transplantation (BMT) is currently the only therapeutic option with a curative approach. Here, the graft versus leukemia (GvL) effect seems to play an important role for long-term immunological control of leukemia. If a bone marrow donor is not available, autologous stem cell transplantation after high-dose chemotherapy has been used as an alternative option. The objective of this work was the induction of tumor specific cytotoxic T-lymphocytes (CTL) against autologous leukemic cells in order to generate the missing GvL effect after autoBMT. The first step was the establishment of an optimized and reliable mouse model. The second step was the induction of a GvL effect in an allogeneic approach to serve as a basis for further GvL experiments in an autologous approach in this mouse model. Leukemic cells from 11 out of 16 different pediatric patients were successfully established in mice and in one case passaged over 19 generations without changes of genotype or phenotype. The antileukemic activity of allogeneic human MNC as a GvL reaction and an accompanying GvHD in the mouse model was shown. Xenotransplanted ALL can be considered a clinically relevant model mimicking the human conditions and as a useful preclinical tool for the evaluation of novel immuno- or genetherapeutic approaches.

Adolescent↗
PubMed2000

Non-Hodgkin's lymphoma in pediatric patients with chromosomal breakage syndromes (AT and NBS): experience from the BFM trials.

BACKGROUND: Lymphoma and leukemia are the commonest malignant diseases in patients with chromosomal breakage syndromes and immunodeficiency (Ataxia teleangiectasia (AT) and Nijmegen breakage syndrome (NBS)). With improved management of infections, malignant disease is more frequently diagnosed and has become one of the commonest causes of death in pediatric AT and NBS. PATIENTS AND METHODS: In three consecutive multicenter therapy trials for pediatric non-Hodgkin's lymphoma (NHL) (NHL-BFM), 1569 patients with newly diagnosed NHL have been registered between 1986 and 1997. Nine patients with AT (n = 5) and NBS (n = 4) were identified and analysed. RESULTS: Median age of patients with AT and NBS at diagnosis of NHL was nine years. NHL-entities differed from non-AT/NBS-patients: diffuse large B-cell lymphomas, n = 7 (78%); ALCL, n = 1; lymphoblastic T-cell lymphoma, n = 1. Cervical nodes, paranasal sinuses and epipharynx were the sites most frequently involved. Stages were: I and II in three patients, III in five and IV in one patient. All patients received polychemotherapy according to tumor-entity and stage, none received radiation. Dose reductions according to individual tolerance concerned mainly ethotrexate, alkylating agents and epipodophyllotoxines. One patient died of toxic complications, two patients relapsed and died, one patient suffered from second malignancy. Five of nine patients are in 1. CCR after a median follow-up of five years. CONCLUSIONS: Patients with AT and NBS suffer from rare entities of pediatric NHL. Curative treatment is possible and should be attempted. Intensity of therapy should be adjusted to individual risk factors and tolerance. Alkylating agents, epipodophyllotoxines should be omitted, dose of MTX should be limited to 1 g/m2. Further cooperative trials using standardized approaches are required.

Adolescent↗
PubMed1999

Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90.

In study NHL-BFM 90, we investigated whether the serum lactate dehydrogenase (LDH) concentration and early response are useful markers for stratification of therapy for childhood B-cell neoplasms in addition to stage, if the outcome of patients with abdominal stage III and LDH >/=500 U/L can be improved by high-dose (HD) methotrexate (MTX) at 5 g/m(2) instead of intermediate-dose (ID) MTX at 500 mg/m(2) in the preceding study 86; whether 2 therapy courses are enough for patients with complete resection; and whether combined systemic and intraventricular chemotherapy is efficacious for central nervous system-positive (CNS(+)) patients. After a cytoreductive prephase, treatment was stratified into 3 risk groups: patients in R1 (completely resected) received 2 5-day courses (ID-MTX, dexamethasone, oxazaphorins, etoposide, cytarabine, doxorubicin, and intrathecal therapy), patients in R2 (extra-abdominal primary only or abdominal tumor and LDH <500 U/L) received 4 courses containing HD-MTX, and patients in R3 (abdominal primary and LDH >/=500 U/L or bone marrow/CNS/multilocal bone disease) received 6 courses. Incomplete responders after 2 courses received an intensification containing HD-cytarabine/etoposide. Patients with no or necrotic tumor thereafter received 3 more courses; 6 patients with viable tumor received autologous bone marrow transplantation. From April 1990 through March 1995, 413 evaluable patients were enrolled (R1, 17%; R2, 40%; and R3, 43%). The 6-year event-free survival (pEFS) was 89% +/- 2% for all and 100%, 96% +/-2%, and 78% +/- 3% in R1, R2, and R3, respectively. The pEFS of patients with abdominal stage III and LDH >/=500 U/L was 81% +/- 4% as compared with 43% +/- 10% in study 86. Of 26 CNS(+) patients, 5 died early, but only 3 relapsed.

Adolescent↗
PubMed1999

Therapy for non-Hodgkin lymphoma in children with primary immunodeficiency: analysis of 19 patients from the BFM trials.

BACKGROUND: Non-Hodgkin lymphomas (NHL) represent an important complication of primary immunodeficiency (ID), posing new therapeutic challenges in this patient population. This study analyzes clinical data and therapy results of pediatric patients with primary ID and NHL in three consecutive NHL-BFM trials. PROCEDURE: Retrospective analysis of children with primary ID and NHL, treated according to protocol NHL-BFM, was performed regarding clinical presentation, diagnostic features, therapy, and outcome. RESULTS: From October, 1986, to April, 1997, 19 of 1,413 newly diagnosed patients with NHL were registered as suffering from primary ID. Age at diagnosis of NHL was lower in patients with ID. Six patients suffered from humoral ID, 13 patients from combined ID (ataxia teleangiectasia n = 3; Nijmegen breakage syndrome n = 4; PNP deficiency n = 1; IL2 receptor defect n = 1, other combined ID n = 4). Thirteen lymphomas were of B-cell and six of T-cell-lineage. Four of thirteen patients with combined ID were diagnosed with T-NHL, nine with B-NHL. Two of six patients with humoral ID presented with T-NHL and four with B-NHL. NHL entities differed significantly between ID and non-ID patients (P < or = 0.01): centroblastic and immunoblastic lymphomas (31.6% vs. 8.1%), anaplastic large cell lymphoma (26.3% vs. 10.7%), Burkitt lymphoma and B-ALL (21% vs. 47. 8%). Seventeen patients received polychemotherapy. Therapy-related toxicity was increased in ID- compared to non-ID-patients. Three patients died of sepsis; three died of tumor progression; one patient relapsed; one died of BMT-related toxicity; one died of second malignancy. Ten patients are in first continuous remission after a median follow-up of 4 years. CONCLUSIONS: Curative treatment of NHL in the presence of primary ID is possible and should be attempted.

Adolescent↗
PubMed1999

Toxicity, supportive care and costs of two chemotherapy protocols for treatment of childhood ALL in Russia: BFM 90m and MB 91.

Since the late 1980s, polychemotherapy protocols for the treatment of childhood acute lymphoblastic leukaemia (ALL) derived from Western European and American regimens have been introduced in Russian paediatric oncology centres. Whereas treatment results were significantly improved compared with the results of former non-standard treatment strategies, the substantial toxicity of these protocols required a high standard of supportive care, and the high costs of treatment became a major problem. In 1991, a new protocol was developed with the aim of reducing toxicity and costs without affecting efficacy of the treatment. Since 1991, a single-centre study comparing the new Russian Protocol, Moscow-Berlin 91 (MB), with a modified version of the protocol ALL BFM 90 (BFM) of the Berlin-Frankfurt-Münster group was performed in Moscow to evaluate possible advantages of the new protocol under Russian conditions. The aim of the present analysis was to compare toxicity, need of supportive care and expense of both regimens (BFM, 25 pts; MB, 32 pts). Hepatotoxicity (liver enzymes), nephrotoxicity (creatinine), duration of neutropenia, and platelet transfusions were similar in both protocols. The median erythrocyte transfusion level was greater in the BFM (1000 ml/m2) than the MB patients (505 ml/m2, P < 0.01), as was the length of intravenous (i.v.) antibiotic therapy (22 days BFM versus 9 days MB, P < 0.01), treatment delays (39 days BFM versus 21 days MB, P < 0.001), and duration of in-patient treatment (47 days BFM versus 18 days MB, P < 0.001). Side-effects of the MB protocol occurred mainly during induction therapy. Total costs (mean cost/person/m2 body surface) of treatment including supportive care were 1.73-fold higher for the BFM protocol than MB, whereas costs of cytostatic drugs were comparable in both groups. In Russia both protocols were feasible. During consolidation therapy tolerance to treatment was better in MB 91 compared with BFM 90m, whereas toxicity during induction therapy was similar in both protocols. With respect to costs and side-effects, the MB 91 protocol appears to be an alternative to established protocols for countries with limited financial and clinical resources.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Relationship between the intracellular daunorubicin concentration, expression of major vault protein/lung resistance protein and resistance to anthracyclines in childhood acute lymphoblastic leukemia.

In vitro resistance to anthracyclines is related to a poor prognosis in childhood acute lymphoblastic leukemia (ALL), but the underlying mechanisms are poorly understood. Using flow cytometry, we studied the contribution of daunorubicin (DNR) accumulation and retention, cell size, expression of the major vault protein/lung resistance protein (LRP), P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) to the cytotoxicity of DNR (by MTT assay) in childhood ALL. The accumulated and retained DNR content was not related to the degree of DNR resistance, nor did the content differ between 53 initial and 20 relapse ALL samples (P >0. 05), although the latter were median two-fold more resistant to DNR (P = 0.004). Leukemic cell volume correlated with resistance to the anthracyclines DNR (Rs 0.32, P = 0.012) and idarubicin (Rs 0.46, P = 0.011) but not to other classes of drugs such as prednisolone, vincristine, L-asparaginase and etoposide. Relapsed patients had 1. 5-fold larger cells than patients at initial diagnosis of ALL (P = 0. 001). After cell volume correction, the intracellular DNR concentration was lower in relapsed compared with initial ALL cells (eg 60 min accumulation, P = 0.003). Moreover, the intracellular DNR concentration inversely correlated with DNR resistance, both in the accumulation (Rs -0.44, P < 0.001) and retention (Rs -0.33, P = 0. 016) test condition. The accumulated DNR concentration inversely correlated with expression of LRP (Rs -0.36, P = 0.012) but not with P-gp and MRP. Expression of LRP, but not of P-gp and MRP, significantly correlated with DNR resistance in childhood ALL (Rs 0. 33, P = 0.03). In conclusion, the intracellular DNR concentration and the expression level of LRP may contribute to DNR resistance in childhood ALL. The strength of the correlations also indicates that resistance to anthracyclines can not be explained by one single mechanism.

Antibiotics, Antineoplastic↗
PubMed1999

Different expression of glutathione S-transferase alpha, mu and pi in childhood acute lymphoblastic and myeloid leukaemia.

Expression of three major classes of glutathione S-transferases (GSTs), i.e. alpha, mu and pi class, P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) were studied in childhood acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML) and normal peripheral blood lymphocytes by flow cytometry. In vitro cytotoxicity of 4-hydroxy-ifosfamide (IFOS), daunorubicin (DNR) and prednisolone (PRED) was assessed by the MTT assay. Expression of alpha, mu and pi class GST did not significantly differ between leukaemic cells from 100 initial and 14 unrelated relapse ALL patients (GSTalpha P=026; GSTmu P=O009; GSTpi P=0.13). The expression of GSTalpha (1.4-fold, P=0.0004), GSTpi (13-fold, P = 0001) and to a lesser extent also GSTmu (1.1-fold, P=0.03) was higher in ALL compared with normal peripheral blood lymphocytes. Expression of GSTmu and GST7pi was significantly higher in 18 AML compared with 100 ALL patients at initial diagnosis (respectively 1.3-fold, P=0.0005 and 2-fold, P<0.0001). In contrast, GSTalpha was median 2-fold lower expressed in the AML samples (P< 0.0001). Expression levels of alpha, mu and pi class GSTs were not related to the degree of resistance to IFOS, DNR and PRED nor to immunophenotype, white blood cell count or age at presentation of childhood ALL. One exception was a remarkably low expression of GSTalpha in IFOS-sensitive samples compared with a heterogenous expression in IFOS-resistant samples (P= 0.02). Expression of GSTpi, but not of GSTalpha or GSTmu, weakly correlated with the expression of MRP (Rs 0.36, P = 0.002, n = 74) but not with P-gp. However, a high expression of both GSTpi and MRP was not associated with in vitro resistance to IFOS, DNR or PRED. The present data suggest that expression of GSTs is not linked to the degree of resistance to IFOS, DNR and PRED or clinical risk factors in childhood ALL. Whether the high expression of GSTmu and GSTpi in AML cells contributes to the relative resistance to IFOS, DNR and PRED compared with ALL samples (P < or = 0.0001) warrants further study.

Acute Disease↗
PubMed1999

Definition of a standard-risk group in children with AML.

To define paediatric AML patients with a favourable outcome in order to design a risk-adapted therapy, we analysed 489 children under 17 years of age treated similarly in studies AML-BFM 83 and 87. 369 patients (75.4%) achieved remission. Estimated probabilities of survival, event-free survival (EFS) and disease-free survival (DFS) at 5 years were 50% (SE 2%), 43% (SE 2%) and 58% (SE 3%), respectively. Multivariate analysis revealed bone marrow blasts on day 15, morphologically defined risk groups and hyperleucocytosis to be of prognostic value. EFS at 5 years estimated for patients with < or = 5% and >5% blasts on day 15 were 56% (SE 3%) v 27% (SE 4%); for the favourable morphological subgroups (M1/M2 with Auer rods, M3 and M4eo) it was 60% (SE 4%) compared with other patients (33%, SE 3%), P (Kaplan-Meier) = 0.0001 each. Hyperleucocytosis proved to be an independent prognostic factor, indicating a high risk, especially for early failure. The specific karyotypes t(8;21), t(15;17) and inv16 were closely related to the favourable morphology and outcome was in the same range. We conclude that for the definition of a standard-risk group a combination of morphological and response criteria may be sufficient. The standard-risk group defined by favourable morphology and a blast cell reduction on day 15 (not required for M3) comprises 31% of all patients, P survival, pEFS and pDFS at 5 years were 73% (SE 4%), 68% (SE 5%) and 76% (SE 4%), respectively.

Acute Disease↗
PubMed1999

Extensive alternative splicing of interleukin-7 in malignant hematopoietic cells: implication of distinct isoforms in modulating IL-7 activity.

Interleukin-7 (IL-7) plays a pivotal role in early stages of normal B and T cell development. In addition, IL-7 stimulates the proliferation of both antitumor reactive cells and a number of T and B cell malignancies, underlining its significance for leukemogenesis. However, its exact role in the process of pathologic maturation of lymphocytes and regulation of the immune response is not completely understood. As alternative splicing of pre-mRNA has been shown to be involved in the control of gene expression, and splicing-derived protein isoforms with antagonistic activity have been found, we assessed the mRNA-expression of IL-7 and its previously described alternative splice variant lacking exon 4, IL-7delta4, in leukemic cells from children with acute lymphoblastic leukemia (ALL). PCR of full-length IL-7 cDNA enabling the competitive amplification of both variants led to the amplification of diverse unexpected PCR products. The sequence data demonstrated the existence of three additional in-frame splice variants resulting from exon skipping of exon 3 or exon 5 or both in combination with exon 4. We named these IL-7delta3/4, IL-7delta4/5, and IL-7delta3/4/5. Furthermore, three out-of-frame splice variants were identified, IL-7(-56bpExon2), IL-7delta4(-56bpExon2), and IL-7delta3/4/5(-56bpExon2), in which, in addition to the aforementioned exon skipping, 56 bp of the 3' end of exon 2 are omitted. Our results led us to assume that splicing-derived IL-7 isoforms play a potential role in modulating IL-7-mediated biologic effects. Further studies are required to clarify the significance of the diverse IL-7 protein isoforms for the regulation of IL-7 function and the pathogenesis of leukemia.

Alternative Splicing↗
PubMed1999

Results of treatment for soft tissue sarcoma in childhood and adolescence: a final report of the German Cooperative Soft Tissue Sarcoma Study CWS-86.

PURPOSE: The goal of the second German Soft Tissue Sarcoma Study CWS-86 (1985 to 1990) was to improve the prognosis in children and adolescents with soft tissue sarcoma by means of a clinical trial comprising intensive chemotherapy and risk-adapted local therapy. PATIENTS AND METHODS: There were 372 eligible patients. A staging system based on the postsurgical extent of disease was used. Chemotherapy consisted of vincristine, dactinomycin, doxorubicin, and ifosfamide. Radiotherapy was administered early at 10 to 13 weeks simultaneously with the second chemotherapy cycle (32 Gy or 54. 4 Gy). The single dose was reduced to 1.6 Gy and given twice daily (accelerated hyperfractionation). RESULTS: The event-free survival (EFS) and overall survival rates at 5 years were 59% +/- 3% and 69% +/- 3%, respectively. The 5-year EFS rate according to stage was as follows: stage I, 83% +/- 5%; stage II, 69% +/- 6%; stage III, 57% +/- 4%; and stage IV, 19% +/- 6%. The outcome for patients with stage III disease who required radiotherapy was much better in the CWS-86 study compared with the CWS-81 study (5-year EFS, 60% +/- 5% v 44% +/- 6%; P =.053). The most common treatment failure was isolated local relapse, with 14% of patients relapsing at the primary tumor site. CONCLUSION: The improved design of the study incorporating risk-adapted radiotherapy allowed treatment to be reduced for selected groups of patients without compromising survival.

Adolescent↗