Effective childhood cancer treatment: the impact of large scale clinical trials in Germany and Austria.

In Germany and Austria, more than 90% of pediatric cancer patients are enrolled into nationwide disease-specific first-line clinical trials or interim registries. Essential components are a pediatric cancer registry and centralized reference laboratories, imaging review, and tumor board assistance. The five-year overall survival rate in countries where such infrastructures are established has improved from <20% before 1950 to >80% since 1995. Today, treatment intensity is tailored to the individual patient's risk to provide the highest chances of survival while minimizing deleterious late effects. Multicenter clinical trials are internationalized and serve as platforms for further improvements by novel drugs and biologicals.

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.

Treatment strategies and long-term results in paediatric patients treated in four consecutive AML-BFM trials.

A total of 1111 children with acute myeloblastic leukaemia (AML) were treated in four consecutive Berlin-Frankfurt-Münster (BFM) studies from 1978 to 1998. The first cooperative trial AML-BFM 78 established intensive chemotherapy with seven drugs, CNS irradiation and 2-year maintenance, achieving a long-term survival (overall survival (OS)) of 40%. Induction intensification in AML-BFM 83 resulted in significant improvement of disease-free survival (DFS). The risk of haemorrhage, especially in children with hyperleukocytosis, proved the high relevance of supportive care. In AML-BFM 87, the benefit of CNS irradiation in preventing CNS/systemic relapses was demonstrated. In AML-BFM 93, the introduction of idarubicin during first induction followed by intensification with HAM increased the 5-year EFS, DFS and OS to 50+/-2, 61+/-3 and 57+/-2%, respectively. Stem cell transplantation (SCT), as applied in high-risk patients with a matched related donor, did not significantly improve the outcome compared to chemotherapy alone. In spite of treatment intensification, the therapy-related death rate decreased from trial to trial, mainly during induction. The future aim is to reduce long-term sequelae, especially cardiotoxicity, by administration of less cardiotoxic drugs, and toxicity of SCT by risk-adapted indications. The AML-BFM studies performed in three European countries with >70 cooperating centres have significantly improved the outcome in AML children; nevertheless, increasing experience with these intensive treatment regimens is of fundamental importance to reduce fatal complications.

Late effects after therapy of Hodgkin's disease: update 2003/04 on overwhelming post-splenectomy infections and secondary malignancies.

BACKGROUND: For a long time, a main focus of paediatric therapy studies for Hodgkin's disease (HD) has been on diminishing adverse late effects. Consequently, the long-term follow-up of patients after HD is very important. The HD late effects project of the GPOH, which evolved from 5 consecutive German-Austrian DAL therapy studies, was aimed at establishing a basis for the further improvement of therapy concepts and of long-term surveillance. PATIENTS AND METHODS: The original cohort consisted of 1 245 study patients from 92 centres enrolled in the DAL studies HD-78 to HD-90 between 1978 and 1995. Initially, follow-up data were submitted by the participating study centres. When the majority of the patients had reached adult age and were no longer seen by the originally treating paediatric colleagues, we contacted them directly by mail every 2-3 years. At the time of analysis (March 2004) information from the preceding 6 years was available in 78.6 % of the patients alive. RESULTS: The median follow-up period of patients at the date of last information was 11.1 years (max. 25.5 years), the median age was 23.7 years (max. 41.1 years). The present report is focused on three out of a wide range of problems evaluated, namely cause of death in 14 patients expired after 10-21 years' follow-up, overwhelming post-splenectomy infections (18 events, 11 fatal), and 46 secondary malignancies. The OS rate after 24 years is 87 % (SE 3 %) in the total group, 83 % (SE 3 %) in 335 asplenic patients, and 93 % (SE 2 %) in 910 non- or partially splenectomised patients. We have initiated activities to improve the prophylactic measures against overwhelming infections in this risk group of asplenic patients. The cumulative incidences of secondary malignancies (SM) after 22 years is 11 % (SE 2 %) for all SM, 10 % (SE 2 %) for solid tumours, 0.8 % (SE 0.5 %) for NHL, and 0.6 % (SE 0.3 %) for leukaemias. The cumulative incidence of breast cancer in female patients at the age of 35 years is 4.0 % (SE 2 %). The effect of reducing the radiotherapy doses in the studies HD-87/HD-90 will become evident within the next years.

The concept of the GPOH-HD 2003 therapy study for pediatric Hodgkin's disease: evolution in the tradition of the DAL/GPOH studies.

Today it is possible to cure more than 90 % of children and adolescents with Hodgkin's disease with a combination of radiotherapy and chemotherapy. Since the DAL-HD 82 study, the main scientific focus has been on avoiding late effects such as the OPSI syndrome, late complications involving the heart, lungs, thyroid and/or gonads particularly sterility in men and premature onset of menopause in women, and the prevention of secondary malignancies. The GPOH-HD 2003 study will introduce FDG-PET to the initial diagnostic program and the assessment of response to therapy in order to evaluate further possibilities for reducing therapy. In this context, the central review of all clinical and radiological findings, systematically done since the DAL-HD 90 study, will be increasingly relevant in maintaining standardised stage classification and therapy group assignment which was established by the preceding studies. Continuing in the direction of the earlier studies, the indications for radiotherapy will be restricted even further. In the early stages (treatment group 1) patients with CR or a negative FDG-PET at the end of chemotherapy will receive no radiotherapy in order to reduce the risk of a secondary malignancy. In a randomized comparison, procarbazine will be replaced by dacarbazine in the COPP cycles to determine whether sterility in men and premature onset of menopause in women can be avoided by elimination of procarbazine while retaining the same clinical efficacy. Finally, relapse therapy is to be tailored according to the time of relapse, the initial therapy group, and the patient's response to the relapse therapy with more patients receiving autologous transplantation in order to further improve the results of relapse treatment.

Immunodeficiency and Hodgkin's disease: treatment and outcome in the DAL HD78-90 and GPOH HD95 studies.

BACKGROUND: Excellent treatment results have been obtained for children with Hodgkin's disease (HD). Children with immunodeficiencies who present with HD do not have such a favourable prognosis. PATIENTS AND METHODS: A systematic literature search using MEDLINE and a search for immunodeficiencies in the database of the trials DAL HD78-HD90 and GPOH HD95 (n = 2263) were carried out. Age, sex, type of immunodeficiency, disease stage, treatment and outcome of all HD cases with known immunodeficiency were recorded. RESULTS: 28 published cases and 13 children in the DAL/GPOH trials were identified. 19/28 and 6/13 patients have immunodeficiencies with increased DNA breakage (24/25 ataxia teleangiectasia, 1/25 Nijmegen breakage syndrome) who present largely with stage III - IV HD. Among the published cases with increased DNA breakage there is only one child who is surviving 16 months after diagnosis, while there are 6/9 survivors in the group of immunodeficiencies without increased DNA breakage. Similarly, only 1/6 children survives in the group of children reported to the DAL/GPOH trials suffering from HD and immunodeficiency with increased DNA breakage, while the outcome in children suffering from immunodeficiency without increased DNA breakage is much better with 5/7 survivors. CONCLUSIONS: The literature review and data analysis of the DAL/GPOH studies show that treatment outcome is almost invariably fatal in children with HD and immunodeficiency with increased DNA breakage. Thus we propose to treat children with or without increased DNA breakage differently to improve the outcome of Hodgkin's disease in the subgroup of children with immunodeficiency.

Preliminary results of the multicenter trial GPOH-HD 95 for the treatment of Hodgkin's disease in children and adolescents: analysis and outlook.

BACKGROUND: In 5 consecutive pediatric and adolescent Hodgkin's disease trials DAL-HD since 1978 the invasive diagnostic procedures and the radiotherapy have gradually been reduced and chemotherapy modified to minimize toxicity and the risk of late effects. Since 1982 the overall survival increased up to 95%. In this trial the possibility of reducing local radiation doses to 20 Gy in patients with good response to chemotherapy and omitting radiotherapy totally for patients with complete remission after chemotherapy was tested. PATIENTS AND METHODS: Over a period of 6 years, from August 1995 to July 2001, 1018 children and adolescents with Hodgkin's disease from Germany, Austria,Switzerland, the Netherlands, Sweden, Norway and Denmark were enrolled in this trial. The chemotherapy was equivalent to previous trial DAL-HD 90. The treatment group (TG) 1 (stages I and IIA) received 2 cycles OPPA for girls and 2 cycles OEPA for boys, TG2 (stages IIEA, IIB, IIIA) and TG3 (stages IIEB, IIIEA, IIIB, IV) received additional 2 or 4 cycles COPP respectively. In contrast to trial DAL-HD 90 boys in stage IIIB and IIIEB received OPPA instead of OEPA. The initial staging as well as the restaging for evaluating tumor volume reduction after chemotherapy was reviewed by the study center. Radiotherapy was planned accordingly: patients with complete remission after chemotherapy were not irradiated (21.9%); all other patients received local radiotherapy to the initially involved sites, depending on the tu-mor response. Patients with a partial remission of> 75 tumor regression were irradiated with 20 Gy (50AX), partial remission of< 75% with 30 Gy (4.1 %), and residual masses of > 50 ml were boosted up to 35 Gy (20.2 %). RESULTS: 36 tumor progressions and 49 relapses occurred over a period of 7 1/2 years (median followup 3 years, data deadline 12/19/02). Kaplan-Meier-analysis after 5 years showed a probability for event-free survival (pEFS) for all patients of 0.88 and for overall survival (pOS) of 0.97. For the total group the pDFS (disease free survival) was lower in 222 non irradiated patients than in the 758 irradiated patients (0.88 vs. 0.92,p - 0.049). But there was a difference between the individual treatment groups. In TG 1 there was no difference between nonirradiated and irradiated patients (0.97 vs. 0.94) and the non-ir-radiated patients showed a better trend. In TG 2, and in TG 2 and TG 3 combined, the pDFS was significantly worse for non irradiated patients in comparison with the irradiated patients (TG2:0.78 vs. 0.92; TG 2 +3:0.79 vs. 0.91). Compared to former DAL-HD trials the pOS stayed stable despite therapy reduction. CONCLUSIONS: A reduction of radiotherapy to 20 Gy for patients in all stages with good response to chemotherapy is possible without deterioration of the results. The omission of radiotherapy for patients in complete remission after chemotherapy is recommended only for patients in early stages (TG1). In future trials the possibility of a wider selection for chemotherapy alone for this group needs to be evaluated. In intermediate (TG2) and advanced (TG3) stages omission of radiotherapy for patients incomplete remission results in a lower pEFS, but the pOS is not significantly reduced. Only with knowledge of the long term effects of today's therapy we can give a satisfactory answer to the question whether in future trials the primary aim should be pEFS as high as possible due to front-line-therapy or reduction of late effects.

Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report.

The purpose of our study was to investigate the efficacy of an acute lymphoblastic leukemia (ALL)-type treatment with moderate-dose, prophylactic cranial irradiation and without local radiotherapy for childhood T-cell lymphoblastic lymphoma (T-LBL). From April 1990 to March 1995, 105 evaluable patients, 1.1 to 16.4 years of age, with T-LBL were enrolled in study NHL-BFM 90 (non-Hodgkin's lymphoma-Berlin-Frankfurt-Munster 90). They received an 8-drug induction over 9 weeks followed by an 8-week consolidation including methotrexate (MTX) 5 g/m(2) x 4. Patients with stage I (n = 2) and II (n = 2) continued with maintenance therapy (6-mercaptopurine daily and MTX weekly, both orally) until a total therapy duration of 24 months. Patients with stage III (n = 82) and IV (n = 19) received an 8-drug intensification over 7 weeks and cranial radiotherapy (12 Gy for prophylaxis) after consolidation, followed by maintenance. Residual tumor after induction had to be resected. Patients received intensified chemotherapy if tumor regression on day 33 of induction was less than 70% or when vital residual tumor was present after the complete induction phase. With a median follow-up of 4.5 years, the estimated event-free survival at 5 years is 90% (95% confidence interval, 82%-100%). Events were 1 early death, 8 tumor failures, and 1 secondary acute myeloid leukemia. A total of 101 patients were evaluable for the speed of tumor response. Two patients received intensified therapy due to less than 70% tumor regression on day 33. Of 19 patients with tumor residues after induction, 2 relapsed as compared to 4 of 80 patients with complete tumor regression. We conclude that, with intensive ALL-type chemotherapy including moderate cumulative doses of anthracyclines 240 mg/m(2) and cyclophosphamide (3 g/m(2)) and moderate-dose prophylactic cranial irradiation but no local radiotherapy, an event-free survival rate of 90% can be achieved in childhood T-LBL. (Blood. 2000;95:416-421)

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.

PURPOSE: To further reduce therapy-related late effects in patients with pediatric Hodgkin's 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. PATIENTS AND METHODS: Three 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. RESULTS: Initial 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. CONCLUSION: OEPA 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.

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.

The effects of etoposide on testicular function in boys treated for Hodgkin's disease.

BACKGROUND: Testicular dysfunction with elevated follicle-stimulating hormone (FSH) levels (indicating oligospermia and/or azoospermia) is a major late sequelae after treatment for Hodgkin's disease (HD) with high cumulative doses of procarbazine, cyclophosphamide, or chlorambucil. Etoposide is a newer antineoplastic agent that is effective in the treatment of HD. However, little is known regarding its testicular toxicity, especially in the pediatric age group. METHODS: The authors evaluated testicular function in 46 young adults in first continuous complete remission after stage-dependent treatment for HD with the vincristine, etoposide, prednisone, and doxorubicin (OEPA) or OEPA/cyclophosphamide, vincristine, procarbazine, and prednisone [COPP] chemotherapy regimens and involved field irradiation, excluding patients with ilioinguinal radiotherapy. Pubertal development was documented and a standardized intravenous gonadotropin-releasing hormone test was performed measuring testosterone and basal and stimulated levels of FSH and luteinizing hormone (LH). RESULTS: Testicular volumes, Tanner stages of pubic hair, and genital development were found to be appropriate or slightly delayed for the patients' chronologic age. All 27 patients had normal basal levels of FSH and LH after treatment of Ann Arbor Stage I-IIA HD with 2 courses of OEPA. Stimulated FSH and LH levels were found to be elevated only in rare patients, thus indicating normal endocrine function and spermatogenesis. However, basal and stimulated FSH levels were outside the +2 standard deviation range in 37.5% and 83.3% of patients receiving 2 cycles of OEPA and 2 cycles of COPP chemotherapy, and in 36.4% and 66.7% of patients receiving 2 cycles of OEPA and 4 cycles of COPP chemotherapy, demonstrating a high risk of oligospermia or azoospermia with these regimens. Basal LH levels essentially were normal, whereas stimulated LH levels frequently were elevated. CONCLUSIONS: Testicular function was found to be normal in patients with Stage I-IIA HD when etoposide was used in combination with vincristine, prednisone, and doxorubicin (2 cycles of OEPA). Additional chemotherapy with cyclophosphamide and procarbazine (2 cycles of OEPA and 2 or 4 cycles of COPP) negatively affected spermatogenesis and possibly Leydig cell function in a considerable number of patients. This major gonadotoxic effect most likely is due to procarbazine, although an additional effect of etoposide and cyclophosphamide cannot be excluded.

[Multi-national therapy study for Hodgkin's disease in children and adolescents GPOH-DH 95. Interim report after 2 1/2 years]. / Multinationale Therapiestudie für den Morbus Hodgkin bei Kindern und Jugendlichen GPOH-HD 95. Zwischenbericht nach 2 1/2 Jahren.

Based on concepts of the successful German-Austrian pediatric Hodgkin studies DAL-HD 78 until-90, a new trial was initiated addressing the question whether radiotherapy can be further reduced or can be omitted in case of complete remission after initial chemotherapy, aiming at reduction of sequelae after radiotherapy, especially radiogenic second malignancies. In respect to CHEMOTHERAPY patients are stratified into 3 therapy groups (TG) according to stage and gender: 2 courses of OPPA (girls) or OEPA (boys) in TG1 (stage IA/B, IIA), and in addition 2 (TG2: stage IEA/B, IIEA, IIB, IIIA) or 4 (TG3: stage IIEB, IIIEA/B, IIIB, IVA/B) COPP courses. Boys with stage IIIB and IIIEB receive OPPA instead of OEPA. RADIOTHERAPY is administered according to response to chemotherapy independent of stage: patients with complete remission or minimal residues do not receive irradiation; patients with more than 75% tumor regression are irradiated to involved fields at a dose of 20 Gy. Doses of 30 or 35 Gy are given to regions with tumor regression below 75% or residual bulky tumor of > 50 ml, respectively. INTERIM RESULTS: From 8/95 till 1/98 we registered 385 patients under the age of 18 years from Germany, Austria, Switzerland, Sweden and the Netherlands. Therapy has been completed in 334 patients. Three patients with solitary nodular paragranuloma were treated with surgery only. Out of 331 patients 89 (26.9%) achieved a complete remission with chemotherapy. Tumor regression of more than 75% was seen in 193 (58.3%) patients and below 75% in 39 (11.8%) patients. Tumor progression during chemotherapy occurred in 1 (0.3%) patient. Response after chemotherapy was not evaluable for 9 (2.7%) patients. Radiotherapy was omitted in 91 (27.1%) patients: in TG1 50 of 142 (34%) patients, TG2 24 of 98 (24.5%) patients and TG3 18 of 94 (19.2%) patients. Initially involved regions were irradiated at a dose of 20 Gy in 164 of 334 (49.1%) patients. Doses up to 30 Gy or 35 Gy were given to 19 (5.7%) or 57 (17.1%) patients respectively. Events (tumor progression, relapse or death) occurred in 23 of 334 patients until now. The event-free survival rate is 0.91 at 2 1/2 years for all study patients and 0.89 for patients without radiotherapy. Six relapses occurred in 91 patients without radiotherapy. No relapse occurred in TG1 (n = 49), but in 5 of 24 TG2-patients, and in 1 of 18 TG3 patients without radiotherapy. As yet, the results are not significantly inferior compared with trial DAL-HD 82. Therefore this trial aiming at omitting radiation therapy in patients with complete remission after a short lasting chemotherapy will be continued. Longer follow up is necessary for final evaluations and conclusions.

Pediatric Hodgkin's disease: treatment in the late 1990s.

BACKGROUND: For two decades now combined chemo-radiotherapy has been preferred in most of the studies on childhood Hodgkin's disease (HD), because combined modality is the precondition for (1) reducing the radiation dose, (2) reducing the radiation fields, (3) shortening chemotherapy, (4) omitting splenectomy and laparotomy, and thus, for optimizing the benefit/risk ratio between cure rates and late effects. Recently, the rationale for this approach was strengthened by worrisome data about the increasing incidence of secondary breast cancer in women treated for HD in childhood, adolescence or adult age < 30 years. Nearly all breast cancers were localized in the former radiation field, and the relative risk was much higher after doses > 40 Gy than after lower doses. These findings suggest that pediatric therapy approaches abandoning radiotherapy alone with its high doses and large fields should be extended to adolescents treated outside of pediatric studies and to adults younger than 30. The risk of chemotherapy-related secondary leukemias can be limited to < 1% by omitting mechlorethamine and restricting the cumulative doses of other drugs with leukemogenic potential, as demonstrated by the experience with ABVD and the recently published data of the German-Austrian pediatric group. PATIENTS AND METHODS: The updated results of the German-Austrian multicenter study HD-90 are presented in this paper (578 patients < 18 years, follow-up: median 4 years, maximum 7 years). Patients were allocated to three treatment groups (TG) according to disease stage. In all three TG, induction procarbazine, prednisone, adriamycin) for girls and two cycles of OEPA (etoposide instead of procarbazine) for boys. Patients of TG 2 and 3 additionally received two or four cycles of COPP (C, cyclophosphamide), respectively. CT was followed by radiotherapy to the involved sites (reduced fields if possible) of 25, 25 and 20 Gy in the 3 TG, respectively. PRELIMINARY RESULTS: For the total group of 578 pats, overall survival (OS) at 5 years is 98% and event-free survival (EFS) 91%. In TG 1, EFS for girls (2 OPPA) is 96%, and for boys (OEPA), 94%, in TG 2 and 3 (combined), 92% and 86%, respectively. Secondary leukemias were not observed so far, thirty-one male patients of TG 1 who were tested endocrinologically showed normal FSH levels. CONCLUSIONS: The especially high efficacy of OPPA and OPPA/COPP could be confirmed in study HD-90 with reduced radiation doses and fields. OEPA and OEPA/COPP CT also produced very favorable results, not significantly different from those with OPPA and OPPA/COPP. It may be anticipated that the ratio between cure rates and risks of late effects of study HD-90 will compare favorably to approaches of other groups. It would be useful for the future continued optimization of HD therapy to attain a rough consensus at an international level about principles which should be considered for pediatric approaches. Some proposals have been made for treatment of early stages.

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

BACKGROUND: In the last two decades, it has become evident that secondary leukemias after Hodgkin's 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. PATIENTS AND METHODS: The 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%. RESULTS: SHM 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. CONCLUSION: The 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.

Treatment of children and adolescents with Hodgkin's disease: the experience of the German-Austrian Paediatric Study Group.

In treatment strategies adapted to the specific problems in children with Hodgkin's disease (HD) high priority has been given to the reduction of late effects caused by radio- and chemotherapy, without sacrificing high survival rates. Combined modality treatment, as a standard option, has enabled reduced doses and fields of radiotherapy and lower cumulative total doses of critical cytotoxic agents. In Germany and Austria 1242 children and adolescents with HD have been treated in five consecutive multicentre studies since 1978. The main general objectives were to determine the extent to which radio- and chemotherapy can be reduced within a combined modality treatment concept and to find an effective chemotherapy of low long-term toxicity. Mechlorethamine in MOPP was replaced by adriamycin (OPPA) in the first 2 cycles of CT and by cyclophosphamide (COPP) in the additional cycles. The total number of cycles was reduced for early and intermediate stages. From the second study (HD-82) onward, patients were allocated to three treatment groups (2, 4 or 6 cycles, respectively) according to disease stage, and involved-field instead of extended-field irradiation was given. With radiation doses of 35, 30 and 25 Gy, high rates for event-free survival (97, 92 and 85%, respectively) at 14 years were achieved, demonstrating that microfoci in adjacent fields are safely eradicated by the chemotherapy used. Late effects of OPPA and OPPA/COPP: the cumulative risk of secondary leukaemias in 686 patients after 15 years was 0.9% for all patients and 0.8% for those who remained in first remission. Cardiomyopathies have not been observed (cumulative total dose of adriamycin 160 mg/m2). Increased FSH-levels indicating impaired spermatogenesis were found in 40% of the male patients without relapse. The prevalence was related to the number of procarbazine containing cycles (29% after 2 cycles, 46% after 4, and 63% after 6). In study HD-90, procarbazine in OPPA was replaced by etoposide (OEPA) for the boys (cumulative dose 1000 mg/m2), whereas girls received OPPA again. In TGs 2 and 3, both boys and girls received an additional 2 or 4 COPP cycles. Standard doses of involved-field irradiation were reduced to 25, 25 and 20 Gy. The preliminary evaluation after nearly 5 years reveals that the reduction in radiation doses did not affect the results with OPPA and OPPA/COPP chemotherapy. In localized stages, 2 OEPA (boys) and 2 OPPA (girls) cycles produced identical results. An additional objective of the German-Austrian trials was to re-evaluate the relevance of exploratory laparotomy and splenectomy within a combined modality treatment concept for all patients. While all children were laparotomized and splenectomized in the first study, the frequency of splenectomy and laparotomy was reduced step by step on the basis of retrospective analyses of the study data regarding infra-diaphragmatic involvement. Splenectomy has been completely abandoned since 1990. In conclusion, the ratio of cure rates and late effects has been favourably balanced with OPPA and OPPA/COPP plus low-dose involved-field irradiation, especially in female patients. In boys, the risk of testicular dysfunction can be further reduced by substituting OEPA for OPPA. Age up to 18 years does not appear to bear any prognostic significance for the treatment results under the conditions of the therapy concept described.

The balance between cure and late effects in childhood Hodgkin's lymphoma: the experience of the German-Austrian Study-Group since 1978. German-Austrian Pediatric Hodgkin's Disease Study Group.

BACKGROUND: For more than 20 years now treatment strategies geared to the specific problems in children with Hodgkin's disease (HD) have been tested by different pediatric oncologic groups. In these approaches high priority was given to the reduction of late effects caused by radio- and chemotherapy, next to the goal of achieving high survival rates. Combined modality treatment as a standard option has enabled reduced dosages and fields of radiotherapy and lowered cumulative total doses of critical cytotoxic agents. METHODS: In Germany and Austria more than 1,200 children and adolescents with HD have been treated in 5 consecutive multicenter studies since 1978. The main general objectives were to determine the extent to which radio- and chemotherapy can be reduced within a combined treatment concept and to find an effective chemotherapy (CT) of low long-term toxicity. Nitrogen-mustard in MOPP was replaced by adriamycin (OPPA) in the first 2 cycles of CT and by cyclophosphamide (COPP) in the additional cycles. The total number of cycles was reduced for early and intermediate stages. From the second study (HD-82) onward, patients were allocated to 3 treatment groups (2, 4, 6 cycles, respectively) according to disease stage, and involved-field irradiation (IFI) was given instead of extended-field irradiation (EFI). RESULTS: In study HD-82 standard doses of IFI in the 3 treatment groups (TG) after 2, 4, or 6 cycles of CT were 35, 30, or 25 Gy. In a total of 203 patients probabilities for event-free survival (pEFS) and survival (pSV) were 95% and 93% at 13 years. In the 3 TG pEFS was 97%, 92% and 85%. In an international study (SIOP-HD IV-87) 65 stage IV patients were treated according to the TG 3 schedule of HD-82 (2 OPPA, 4 COPP, 20 Gy IFI). After 7 years pEFS is 77% and pSV 93%. Late effects of OPPA respectively, OPPA/ COPP: The cumulative risk for secondary leukemias after 10 years is 0.5% for all patients and 0.3% for those who remained in first remission. Cardiomyopathies have not been observed (cumulative total dose of adriamycin 160 mg/m2). Increased FSH-levels indicating impaired spermatogenesis were found in 40% of the male patients without relapse. The frequency was related to the number of procarbazine containing cycles (29% after 2 cycles, 46% after 4, and 63% after 6). In study HD-90, procarbazine in OPPA was replaced by etoposide (OEPA) for the boys (cumulative dose 1,000 mg/ m2), whereas girls received OPPA again. In TG2 and 3, both boys and girls received COPP. Standard doses of IFI were reduced to 25, 25, and 20 Gy. The preliminary evaluation after nearly 5 years reveals that the reduction of radiation doses did not impair the results after OPPA and OPPA/ COPP. In localized stages 2 OEPA (boys) and 2 OPPA (girls) produced the same results. In the 15-18 years age group compared to the younger patients identical values for pEFS were achieved. CONCLUSIONS: The ratio between cure rates and late effects has been favourably balanced with OPPA, respectively, OPPA/COPP plus low-dose IFI, especially in female patients. In boys the risk of testicular dysfunction can be further reduced by substituting OEPA for OPPA. Age up to 18 years does not appear to be of any significance for the treatment results with our therapy concept.

Clinical significance of surface antigen expression in children with acute myeloid leukemia: results of study AML-BFM-87.

Immunophenotyping using a panel of 15 antibodies was performed in 267 (87%) and cytogenetic analysis in 196 (64%) of 307 children under 17 years of age enrolled in the AML-BFM-87 study. Treatment consisted of cytosine arabinoside, daunorubicin, etoposide induction and a 6-week seven-drug consolidation chemotherapy, followed by two blocks of high-dose cytosine arabinoside with or without cranial irradiation and maintenance therapy for 1 year. Five-year event-free survival for patients with immunophenotypic data was .43 +/- .03 SE. The diagnostic value of the pan-myeloid reagents CD13, CD33, and CDw65 for the recognition of childhood acute myeloid leukemia (AML) was high with a sensitivity of 98% (positivity of at least one of these antigens), whereas, with the exception of CD41 for French American British (FAB) subtype M7, the expression of single cell-surface antigens showed no correlation with morphologic or cytogenetic subgroups. On the other hand, characteristic subgroups of AML defined by morphologic features and karyotypes could be described by low or high rates of surface antigen expression compared with those of other patients. These immunophenotypic features most probably associated with specific entities include expression of CD34 or CD13 and absence of CD14 or CD4 in M2 with Auer rods/t(8;21); absence of HLA-DR, CD34, and CD14, but expression of CD33 in M3/t(15;17); positivity of either CD34 or CD13 and either CD14 or CD2 for M4Eo/inv(16); and absence of either CD34 or CD13 and expression of either CD33 or CDw65 and either CD15 or CD4 for M5/t(9;11). In FAB M0, negativity of one or two of the three panmyeloid-associated markers (CD13/33/w65) was common; and cytogenetic results frequently showed random abnormalities. Expression of lymphoid-, progenitor- and most myeloid-associated antigens had no influence on the prognosis, whereas the outcome was significantly better for children with M2 with Auer rods, M3, or M4Eo or for those with the associated karyotypes t(8;21);t(15;17) and inv(16) than for other patients.

[Reducing radiation dosage to 20-30 Gy in combined chemo-/radiotherapy of Hodgkin's disease in childhood. A report of the cooperative DAL-HD-87 therapy study]. / Reduzierung der Strahlendosen auf 20-30 Gy im Rahmen einer kombinierten Chemo-/Radiotherapie beim Morbus Hodgkin im Kindesalter. Ein Bericht der kooperativen Therapiestudie DAL-HD-87.

UNLABELLED: The main objective of the multicenter study DAL-HD-87 was to evaluate for the involved-field irradiation a dose reduction by 5 Gy compared with the precursor studies HD-82 and HD-85. Moreover, the decisional strategy for selective laparotomy developed on the basis of retrospective analyses in study HD-82 was to be tested in a prospective design. Chemotherapy in group 1 (stages I, IIA) consisted in 2 OPA cycles (vincristine, prednisone, adriamycin). Group 2 (stages IIEA, IIB, IIIA) received 2 x OPA + 2 x COP(P), and group 3 (stages IIEB, IIIB, IV) 2 x OPPA (with procarbacine) + 4 x COP(P). For the subsequent radiotherapy, doses of 30, 25, and 20 Gy respectively were applied in the 3 groups. Fields with incomplete lymphoma regression were to receive an additional boost of 5-10 Gy. -Exploratory laparotomy was considered indicated in the event of abnormal findings in abdominal CT/ultrasonography and/or enlargement of lymph nodes at the pulmonary hilus. RESULTS: From Dec. 1986 to Sept. 1990, 204 pts from 51 centres were enrolled in the study. 196 were evaluable. 109 pts (55.6%) were laparotomized, 58 (29.6%) splenectomized. The accuracy for the prediction of an abdominal involvement was 72.3% in case of abnormal findings in abdominal CT/ultrasound but only 36.4% in case of enlarged lymph nodes at the pulmonary hilus without abdominal abnormalities. 91.2% of the removed spleens were proven involved. -2 out of 196 pts suffered progression under treatment, and 22 relapsed (as of 1 Jan, 1994). 6 pts died, 4 of whom succumbed to Hodgkin's disease, and 2 to intercurrent infections. 2 pts in first remission developed a secondary malignancy, namely 1 malignant histiocytoma in radiation field and 1 ANLL. Another patient developed a thyroid carcinoma following salvage therapy for a relapse. The probabilities of event-free survival (EFS) and survival after 7 years are for the total group: 85% and 97%, in group 1: 84% and 99%, in group 2: 82% and 93%, and group 3: 89% and 95%. Comparison with the precursor studies HD-82 and HD-85 reveals that the dose reduction in radiotherapy has not affected the results. Differences in EFS are exclusively correlated with changes in chemotherapy.