Schellong G

The effects of different cumulative doses of chemotherapy on testicular function. Results in 75 patients treated for Hodgkin's disease during childhood or adolescence.

Testicular function was evaluated in 75 boys after treatment for Hodgkins disease with involved‐field or extended‐field irradiation and stage‐dependent chemotherapy (vincristine, prednisone, procarbazine, Adriamycin [doxorubicin], and cyclophosphamide [OPPA/COPP]). Although pubertal development and testosterone levels were normal in all patients, 18 of 75 (24.0%) had elevated basal and 65/74 (87.8%) elevated stimulated luteinizing hormone (LH) levels, demonstrating chemotherapy‐induced Leydig cell damage. In addition, there was a 40.5% and 53.4% incidence of elevated basal and stimulated FSH values, respectively, indicating severe impairment of spermatogenesis as confirmed by azoospermia in four patients. Testicular dysfunction was observed in patients treated before as well as during puberty. The incidence of elevated basal follicle stimulating hormone (FSH) and LH values was significantly higher in patients who had received higher cumulative doses of chemotherapy, i.e., 28.9% and 13.2% with two OPPA, 45.5% and 36.4% with two OPPA/two COPP, and 62.5% and 43.8% with two OPPA/four to six COPP, respectively. Chemotherapy for Hodgkins disease causes a high and apparently dose‐related incidence of testicular dysfunction in prepubertal as well as in pubertal boys affecting Leydig cell function as well as spermatogenesis. Circumstantial evidence indicates that procarbazine is the major gonadotoxic agent involved.

Does Cranial Irradiation Reduce the Risk for Bone Marrow Relapse in Acute Myelogenous Leukemia? Unexpected Results of the Childhood Acute Myelogenous Leukemia Study BFM-87

PURPOSEnOne of the goals of study AMA-BFM-87 was to test prospectively in acute myelogenous leukemia (AML) patients if cranial irradiation could be replaced by late intensification therapy with high-dose cytarabine (Ara-C) and etoposide (VP-16).nnnPATIENTS AND METHODSnPatients with a low risk of CNS relapses (ie, no initial CNS disease, WBC count at diagnosis < or = 70.000/microL) were randomized for irradiation (group A, 31 patients). In 25 patients (group B), randomization was refused. As interim results showed no increase of CNS relapses in nonirradiated patients, prophylactic irradiation was discontinued after 2 1/2 years to prevent unnecessary CNS toxicity. Forty-four patients (group C) entered the study after randomization had been stopped.nnnRESULTSnIn all patients with a low risk of CNS recurrences (n = 100), a significantly higher probability of relapse-free interval (pRFI) of 5 years was found in irradiated patients (pRFI = .78) compared with nonirradiated patients (pRFI = .41) (P = .007). Moreover, a slightly higher incidence of CNS relapses was observed in nonirradiated patients. Due to the small number of patients, this was not observed when randomized patients only were analyzed. In accordance with these findings, the favorable outcome of low-risk patients in the preceding study, AML-BFM-83 (pRFI > .80), could only be reproduced in study AML-BFM-87 in patients who had received cranial irradiation.nnnCONCLUSIONnThese results indicate that cranial irradiation should be an integral part of the treatment of all AML patients not undergoing bone marrow transplantation. Residual blasts in the CNS may escape systemic chemotherapy and lead to recurrence of the initial disease not only in the CNS, but also in the bone marrow.

High cure rates and reduced long-term toxicity in pediatric Hodgkin's disease: the German-Austrian multicenter trial DAL-HD-90. The German-Austrian Pediatric Hodgkin's Disease Study Group.

PURPOSEnTo further reduce therapy-related late effects in patients with pediatric Hodgkins disease (HD) while maintaining the high cure rates achieved with vincristine, prednisone, procarbazine, and doxorubicin (OPPA) or OPPA/cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) chemotherapy and involved-field radiotherapy. The risk of testicular dysfunction was addressed by substituting etoposide for procarbazine (OEPA) in the induction therapy for boys. Radiation doses and fields were further reduced.nnnPATIENTS AND METHODSnThree hundred nineteen boys and 259 girls younger than 18 years with previously untreated HD, enrolled onto the study between 1990 and 1995, were allocated to treatment group (TG)1 (early stages), TG2 (intermediate stages), or TG3 (advanced stages). All groups underwent two cycles of OEPA (boys) or OPPA (girls) for induction chemotherapy. TG2 and TG3 continued on additional two or four cycles, respectively, of COPP. Low-dose radiotherapy was given to the initially involved sites, ie, reduced involved fields.nnnRESULTSnInitial response to OPPA or OEPA induction was virtually identical. Eight of 578 patients experienced early progression of HD. Thirty-seven relapses, three secondary tumors, and no secondary leukemias have been recorded, with a median follow-up duration of 5.1 years (maximum, 8.1 years). Thirteen of 578 patients died. The probability of 5-year event-free survival/overall survival is 91%/98% in the total group, 94%/97% with OPPA, and 89%/98% with OEPA induction therapy. Risk factor analysis showed two significant prognostic factors: histologic subtype NS2 and B symptoms. OEPA induction therapy, large mediastinal tumor, and age were not significant. Preliminary studies of testicular function indicate a lower risk of germ cell damage than previously documented with OPPA.nnnCONCLUSIONnOEPA is a satisfactory alternative to OPPA. Radiotherapy can be confined to involved sites when combined with appropriate chemotherapy. The DAL-HD-90 regimen represents a comprehensive treatment program for all stages of pediatric HD and offers a favorable benefit/risk ratio, combining excellent disease control, moderate acute toxicity, and reduced long-term toxicity.

Treatment of Children and Adolescents With Hodgkin Lymphoma Without Radiotherapy for Patients in Complete Remission After Chemotherapy: Final Results of the Multinational Trial GPOH-HD95

UNLABELLEDnPURPOSE To minimize the risk of late effects in pediatric Hodgkin lymphoma (HL) by omitting radiotherapy (RT) in patients in complete remission (CR) after chemotherapy and reducing the standard radiation dose to 20 Gy in patients in incomplete remission.nnnPATIENTS AND METHODSnBetween 1995 and 2001, 925 patients with classical HL (cHL) were registered from seven European countries in German Society of Pediatric Oncology and Hematology Hodgkin Lymphoma Trial 95. Patients in treatment group 1 (TG1; early stages) received two cycles of vincristine, prednisone, procarbazine, and doxorubicin or vincristine, prednisone, etoposide, and doxorubicin chemotherapy; additional two or four cycles of cyclophosphamide, vincristine, prednisone, and procarbazine were added in TG2 (intermediate stages) or TG3 (advanced stages), respectively. Patients in CR (assessed by computed tomography or magnetic resonance imaging) did not undergo RT. Those with tumor volume reduction more than 75% received reduced involved-field RT with 20 Gy and an additional 10- or 15-Gy boost only for larger residuals.nnnRESULTSnRates of overall survival, progression-free survival (PFS), and event-free survival at 10 years were (± SE) 96.3% ± 0.6%, 88.2% ± 1.1%, and 85.4% ± 1.3%, respectively. PFS for TG1 patients without or with RT was 97.0% ± 2.1% versus 92.2% ± 1.7% (P = .214) but was unsatisfactory for nonirradiated patients in TG2 (68.5% ± 7.4% v 91.4% ± 1.9%; P < .0001), with similar but not significant results in TG3 (82.6% ± 5.4% v 88.7% ± 2.0%, P = .259). Reduction of the standard radiation dose from 25 to 20 Gy did not increase failure rate.nnnCONCLUSIONnRT can be omitted in early stage HL in so defined CR following this chemotherapy. RT with 20(-35) Gy proved to be sufficient in patients with incomplete remission following chemotherapy.

Low risk of secondary leukemias after chemotherapy without mechlorethamine in childhood Hodgkin's disease. German-Austrian Pediatric Hodgkin's Disease Group.

BACKGROUNDnIn the last two decades, it has become evident that secondary leukemias after Hodgkins disease (HD) are mainly caused by the treatment with alkylating agents, especially mechlorethamine. Since 1978, the German-Austrian trials for childhood HD have used combined chemoradiotherapy without mechlorethamine.nnnPATIENTS AND METHODSnThe risk of secondary hematologic malignancies (SHM) was assessed in the total cohort of 667 children treated in four consecutive German-Austrian trials between 1978 and 1990. Primary chemotherapy for stages IA/B and IIA consisted of two cycles of vincristine, procarbazine, prednisone, and doxorubicin (OPPA) or OPA (without procarbazine) and, for more advanced stages, of two cycles of OPPA or OPA plus two, four, or six cycles of COPP or COMP (C, cyclophosphamide; M, methotrexate). Radiotherapy was given in the first study to extended fields, and in later trials to involved fields only. In 591 patients, only primary therapy was given; 76 patients (11%) needed additional salvage therapy. The actuarial survival rate at 15 years is 94%.nnnRESULTSnSHM developed in 5 of 667 patients: four acute myeloid leukemias (AMLs) and one myelodysplastic syndrome (MDS). The estimated cumulative risk for SHM at 15 years is 1.1% (95% CI, 0.0% to 2.2%). Salvage therapy was a significant risk factor for SHM (relative risk, 7.25; P = .03), whereas age, sex, stage of HD, splenectomy, and amount of alkylating agents were not.nnnCONCLUSIONnThe observed risk of SHM is smaller than in other studies (adults and children) in which chemotherapy with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) was given. This difference can be attributed to the lower cumulative doses of alkylating agents, the absence of mechlorethamine in the chemotherapy, and the small number of patients who needed salvage therapy in the presented cohort. In general, differences in the incidence of SHM after HD reflect complex differences between treatment strategies.

Up-front centralized data review and individualized treatment proposals in a multicenter pediatric Hodgkin's disease trial with 71 participating hospitals: the experience of the German–Austrian pediatric multicenter trial DAL-HD-90

BACKGROUND AND PURPOSEnA systematic procedure for up-front centralized data review and the set-up of individualized treatment proposals was integrated prospectively into the German-Austrian multicenter trial DAL-HD-90 for pediatric Hodgkins disease (HD) in order to introduce local radiotherapy according to the individual patients spread of disease within a combined-modality treatment. This paper investigates the feasibility of such a procedure and its impact on the final definition of the extent and stage of disease as well as on the choice of treatment.nnnPATIENTS AND METHODSnBetween October 1990 and July 1995, 578 children and adolescents <18 years (259 girls, 319 boys, median age 12.9 years) with HD were enrolled into the HD-90 trial. After clinical and pathological staging (66.4/33.6%), patients were allocated to treatment groups (TG) 1 early stage, TG2 intermediate stage, or TG3 advanced stage. All groups underwent two cycles of OPPA (vincristine, prednisone, procarbazine, doxorubicin) (girls) or OEPA (E, etoposide) (boys) for induction chemotherapy. TG2 and TG3 continued on as two or four cycles, respectively, of COPP (C, cyclophosphamide). Low-dose local radiotherapy was given to the initially involved sites, with radiation doses of 25 Gy in TG1/TG2, and 20 Gy in TG3. All documentation forms, radiographs, and chest and abdominal computed tomography (CT) scans were centrally reviewed, addressing in particular the individual patients extent and stage of disease. This review and the set-up of individualized treatment proposals were in the hands of the study coordinator, one additional pediatrician and two radiation oncologists and radiologists at the study center. During a time slot of at least 8 weeks (two cycles of standard chemotherapy in all three TGs) the individualized treatment proposals were to be sent to the participating hospital.nnnRESULTSnComplete sets of documentation from 564/578 patients (97.6%) were submitted sufficiently early to the study center. A total of 285 out of 574 chest radiographs, 468 out of 553 chest CT scans and 421 out of 548 abdominal CT scans were available from 71 hospitals. A total of 564 individualized treatment proposals were worked out by the review group and sent to the hospitals before radiotherapy began. Re-analysis of images and documentation forms, including laboratory and clinical data, resulted in a revision of stage in 115/571 patients (20.1%) and of TG in 76/571 patients (13.3%). A total of 67/76 patients were shifted into a higher TG, 60 patients on account of additionally detected extralymphatic involvement, five patients because of additionally detected lymph node involvement and two patients due to clinical data which had to be classified as B-symptoms. A total of 9/76 patients were shifted into a lower TG; in three patients extranodal disease and in six patents local lymph node involvement could not be confirmed.nnnCONCLUSIONSnThe up-front centralized review of patient data and consecutive set-up and delivery of individualized treatment proposals for almost every patient are feasible within a large multicenter trial. Sufficient time and manpower at the study center are needed for the review process and the set-up of individualized treatment proposals. Such a procedure has a significant impact on the homogeneity of stage definition, allocation to TG, and individualized treatment proposals.

Does bulky disease at diagnosis influence outcome in childhood Hodgkin’s disease and require higher radiation doses? Results from the German–Austrian Pediatric Multicenter Trial DAL-HD-90

PURPOSEnThe identification of risk factors is required for risk-adapted treatment strategies in the treatment of Hodgkins disease. To assess the influence of bulky disease at diagnosis as compared with other risk factors on event-free survival (EFS) in pediatric Hodgkins disease such as stage, B-symptoms, number of involved lymph node regions, histology, and remission status after chemotherapy, we analyzed the outcome of 552 patients treated with a risk-adapted treatment strategy consisting of OPPA(OEPA)/COPP (vincristine, procarbazine, etoposide, prednisone, adriamycin, cyclophosphamide) and involved-field radiotherapy.nnnMETHODS AND MATERIALSnBetween 1990 and 1995, 578 patients with primary Hodgkins disease (HD) were enrolled in the German/Austrian Pediatric Hodgkins Disease Study Group (DAL) Multicenter Study (HD-90). Patients were stratified into three treatment groups (TGs) for early, intermediate, and advanced stage. All patients received induction chemotherapy (CT) with two cycles of OEPA for boys and two cycles of OPPA for girls. Patients in TG2 and TG3 received another two or four cycles, respectively, of COPP. Chemotherapy was followed by involved-field radiotherapy. The radiation field, which was prescribed by the study center, was treated with a dose of 25 Gy/25 Gy/20 Gy (TG1/TG2/TG3), and in case of insufficient remission with a local boost of 5 Gy to 10 Gy. The following prognostic factors were analyzed with regard to their impact on EFS: bulky disease, mediastinal tumor, number of involved lymph node regions, histology, treatment group, B-symptoms, sex, age, and remission status after chemotherapy.nnnRESULTSnSignificant univariate predictive factors for the EES were: nodular sclerosis type 2 (NS2) histology (relative risk [RR] 3.43; p = 0.0002), presence of B-symptoms (RR 2.70; p = 0.0014), number of involved regions (1.55; p = 0.019), and treatment groups (RR 1.33; p = 0.017). There was a higher risk (RR 1.92; p = 0.040) for patients with bulky compared with nonbulky disease (5-year EFS 89.6%/94.6%). In the multiple regression model, only NS2 and B-symptoms remained strong predictive factors. The remission status after chemotherapy did not correlate with EFS (p = 0.66).nnnCONCLUSIONnTreatment strategies in Hodgkins disease have an impact on different risk factors. In the risk-adapted treatment strategy of the HD-90 study, tumor burden indicated as bulky disease or as number of involved lymph nodes loses its importance, whereas NS2 histology and B-symptoms have a major impact on treatment outcome. Bulky disease at diagnosis might require higher radiation doses only in case of insufficient remission.

Prediction of splenic involvement in children with Hodgkin's disease. Significance of clinical and intraoperative findings. A retrospective statistical analysis of 154 patients in the German therapy study DAL-HD-78.

In 154 splenectomized children and adolescents with histologically proven Hodgkins disease in the therapy study DAL‐HD‐78, the incidence of splenic involvement was 39%. In single‐parameter analyses 6 of 16 examined pre‐ and intraoperative findings showed significant correlation to splenic involvement: B‐symptoms, palpable splenic enlargement, mediastinal/lung hilus involvement, nodular changes of splenic surface, enlarged lymph nodes at splenic hilus/pancreatic tail, or enlargement of other upper‐abdominal lymph nodes. The results of multivariant analyses (Cox regression model) of these six parameters showed that the two most significant intraoperative parameters—changes of splenic surface and enlargement of lymph nodes at splenic hilus/pancreatic tail‐gave almost all of the information which can be obtained about splenic involvement. With these two parameters, an intraoperative decisional strategy for selective splenectomy has been developed which allows the omission of splenectomy in about two thirds of children with Hodgkins disease while still obtaining detailed information about infradiaphragmatic spread of disease. Since minor splenic involvement remains undetected in about 10% of the nonsplenectomized patients (i.e., 6% of all patients), this method should be used only in combination with chemotherapy.

Development of a curative treatment within the AML-BFM studies.

The first multicenter treatment study for AML in childhood in Germany was performed from 1978 onwards. The therapy plan was designed similar to that for the acute lymphoblastic leukaemia (ALL). The drugs with the highest efficacy in AML, cytarabine cutting catara-bine and anthracyclines, were combined during induction and consolidation, followed by preventive cranial irradiation and maintenance therapy similar to that in ALL. The remission rate of the initial study was 80%, and the 5-year survival rate increased from less than 10% before 1970 to 40%. 5 subsequent trials have further increased the 5-year survival to now 70% and even 90% in the subgroup of core-binding factor leukaemias by using an intensified and optimised treatment schedule.The AML-BFM studies were the only prospective study sequence testing the benefit of cranial irradiation. Results from study -87 including the non-randomized patients showed an increased risk of CNS and/or bone marrow relapses in non-irradiated patients. Later on there was evidence that 12 Gy resulted in the same relapse rate as 18 Gy. The AML-BFM studies always used the experience from the previous study to optimize the next study. This approach was essential together with improved supportive treatment and experience of the medical staff for the step-wise and considerable increase of longterm survival within the 6 subsequent AML-BFM studies.

Proliferation characteristics in pediatric Hodgkin's lymphoma point to a cell cycle arrest in the G 1 phase

This study was undertaken to determine the prognostic relevance of the proliferation rate in neoplastic cells in children and adolescents with Hodgkins lymphoma. Paraffin-embedded biopsy specimens were immunostained with the proliferation-associated monoclonal antibodies Ki-S5 (Ki-67 antigen) and Ki-S2 (which detects the repp86 protein). Repp86 is a protein of about 100u2009kDa encoded by a gene located on human chromosome band 20q11.2. In contrast to the Ki-67 antigen, repp86 expression is restricted to the cell cycle phases G2, S and M. Immunohistochemical results on diagnostic lymph node biopsy specimens from 224 patients included in two pediatric multicenter Hodgkins trials, GPOH HD-90 and HD-95, were compared with clinical data. High Ki-67 antigen expression was a striking feature of Hodgkins and Reed–Sternberg cells as well as lymphocytic and histiocytic cells (median: 80%, range: 20–100%), in contrast to low repp86 expression (median: 20%, range: 10–80%; P<0.001). The proliferation rate was independent of histological subtype, stage and presence of B symptoms. The probability of event-free and overall survival (±standard error) of all patients at 5 years was 91.6±2.0 and 98.1±1.0%, respectively. The proliferation rate of tumor cells did not influence the outcome. The difference between Ki-67 and repp86 expression in Hodgkins and Reed–Sternberg or lymphocytic and histiocytic cells points to a possible cell cycle arrest in the G1 phase, which may explain the obvious paradox of a highly proliferating but slowly growing paucicellular tumor. High Ki-67 expression does not seem to be an adverse prognostic factor in pediatric and adolescent patients with Hodgkins lymphoma treated by effective risk-adapted chemo-radiotherapy regimens.