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.

Adolescent↗

PubMedDate not supplied

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.

Adolescent↗

PubMedDate not supplied

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.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

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.

Adolescent↗

PubMedDate not supplied

[Classification of AML by morphologic, immunologic and cytogenetic criteria. Review with reference to subtypes in the AML-BFM-87 study].

The current FAB classification of acute myelogenous leukemia (AML) by morphologic, immunologic and cytogenetic features is described and the incidence of subtypes and variant forms of AML in study AML-BFM-87 is given. In general, lymphoblastic or myeloid blast populations can be identified by morphologic, cytochemical and immunologic parameters, while immunophenotyping facilitates diagnosis in biphenotypic leukemia. Furthermore, the AML subtypes M0 and M7 (defined in 1985 and 1991) can only be ascertained by the presence of lineage-associated markers. Whereas chromosome aberrations provide an insight into the neoplastic process and assure diagnosis. Thus, next to morphologic findings, immunologic and cytogenetic studies are essential for a definite diagnosis of AML.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

[Prognostic significance of eosinophilia in children with acute myeloid leukemia in the studies AML-BFM-78 and -83].

Initial eosinophilia (greater than or equal to 3%) in the bone marrow was found in 73 out of 269 (27%) patients studied in AML studies BFM-78 and -83. It was predominantly seen in children with FAB types M2 (44%) and M4 (41%). Atypical eosinophils were mostly found in FAB type M4 (20/28 = 71%). Cytogenetic studies in eight children with FAB M4 and eosinophilia showed normal karyotypes in four patients, inversion 16 in one and other aberrations in three children. Study AML-BFM-78 did not demonstrate any differences in prognosis between patients with and without eosinophilia (event-free survival = EFS after 5 years 37%, SD 8%, vs. 38%, SD 6%). In study AML-BFM-83, however, a clear increase in EFS was seen in children with eosinophilia (EFS 72%, SD 8%, vs. 43%, SD 5%, p = 0.001). This improvement of prognosis mainly concerns patients with FAB M4 and eosinophilia (EFS 81%, SD 10%, vs. 23%, SD 11%, p = 0.006). None of the 12 children in study AML-BFM-83 with FAB M4 and atypical eosinophils has suffered a relapse, two patients belong to the early death group. Multivariate analysis shows only eosinophilia as a favorable prognostic factor in FAB type M4. According to these results FAB type M 4 with eosinophilia is a favorable prognostic parameter in children treated according to the therapy protocol of study AML-BFM-83.

Adolescent↗

PubMedDate not supplied

[Incidence and prognostic significance of Auer rods in children with acute myeloid leukemia in the studies AML-BFM-78 and -83].

The prognostic significance of Auer rods in children with AML was investigated in 129 patients of the study AML-BFM-78 and 154 patients of the study AML-BFM-83. Auer rods were found in 68 patients (53%) in the study AML-BFM-78 and 69 patients (45%) in the study AML-BFM-83. The incidence was higher in the subtypes FAB M1 (61%) and M2 (75%) compared to the subtypes FAB M4 (44%) and M5 (5%). In both studies the remission rate was higher in Auer rod-positive patients. Moreover, in the study AML-BFM-83 patients with Auer rods had a significant longer remission duration: the probability of an event-free interval (EFI) of 5 years was 77% (SD 6%) in Auer rod-positive patients compared with 44% (SD 7%) in Auer rod-negative patients (p less than 0.01). In the study AML-BFM-78 no differences regarding remission duration between both groups were detected. Analysis of the individual FAB subtypes revealed a significant higher event-free survival rate (EFS) after 5 years in Auer rod-positive compared with 18% (SD 12%) in Auer rod-negative patients (p less than 0.0001). No prognostic significance of Auer rods in other subtypes could be detected. In the overall group of all patients absence of Auer rods was associated with the unfavourable parameters hyperleucocytosis (greater than or equal to 100 x 10(3)/microliters) and acute monocytic leukemia (FAB M5) (p less than 0.01, p less than 0.001, respectively). The multivariate analysis in the study AML-BFM-83 showed that Auer rods were of prognostic significance independent from the initial leukocyte count and the FAB type M5.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMedDate not supplied

[Effect of cranial irradiation on rate of recurrence in children with acute myeloid leukemia. Initial results of the AML-BFM-87 study. The AML-BFM Study Group].

Study AML-BFM-87 compared prospectively if cranial irradiation could be abandoned by adding two blocks of intensification with high dose ARA-C and VP-16 after consolidation and furthermore, improve prognosis compared to study -83. 210 children were enrolled in study AML-BFM-87 until March 31, 1991. 164 (78%) achieved complete remission. Probabilities for event-free survival (EFS) and event-free interval (EFI) of 5 years were: .45 (SD .04) and .57 (SD .05). In the first 2.5 years of the study irradiation was randomized (n = 31), selected or refused (n = 24). However, during this period irradiation was mandatory in patients with leukocyte count greater than 70,000/mm3, and also in children with initial CNS involvement. Since July 1989 prophylactic cranial irradiation was abandoned. Patients of the group with mandatory irradiation (n = 39) presented with more unfavourable risk parameters than the group of non-irradiated children, who were enrolled in the study after randomisation had been stopped. Nevertheless, results showed in randomized and selected patient groups as well as in the total cohort a longer relapse-free interval (RFI) in irradiated (n = 66) compared to non-irradiated (n = 94) patients (RFI of 5 years: .70, SD .04 vs. .51, SD .07, p less than .05). Relapses in non-irradiated children occurred mainly in the bone marrow and less often in the CNS. The increase in relapse rate was seen especially in non-irradiated patients of the low risk group as defined in study AML-BFM-83 (RFI: .40, SD .14 vs. .79, SD .09 with irradiation, p less than .01). In the high risk group, however, the differences were not significant. Our results suggest that cranial irradiation is an important part of therapy in childhood AML, and that the good prognosis of the low risk group in study AML-BFM-83 was probably based on the combination of intensive chemotherapy and cranial irradiation.

Antineoplastic Combined Chemotherapy Protocols↗