Jörg Michaelis

Multidisciplinary treatment of primary Ewing's sarcoma of bone. A 6‐year experience of a European cooperative trial

The German Society of Pediatric Oncology in 1981 initiated the Cooperative Ewings Sarcoma Study (CESS 81) using a four‐drug combination of chemotherapy prior to definitive local control with surgery and/or radiation. From January 1, 1981 until February 28, 1985, 93 patients were registered at the trial office from 54 participating institutions in West Germany, Austria, Switzerland, and the Netherlands. On February 1, 1987, 54 of 93 patients were disease‐free. Using the Kaplan‐Meier life table analysis, the estimated disease‐free survival (DPS) rate was 60% at 36 months and 55% at 69 months. The median period of observation was 29 months, ranging from 22 months to 69 months. Twenty‐one of 93 patients (23%) had local failure, 18 of 93 patients (19%) developed systemic metastases. The local failure rate was particularly high in patients treated with radiation and was reduced when radiation planning was centralized within the study based upon the extent of disease at diagnosis. Cox regression analysis of prognostic factors showed that tumor volume was a significant factor influencing prognosis. The estimated 3‐year DFS rate was 80% for patients with small tumors (volume less than 100 ml) compared to 31% for patients with large tumors (volume greater than or equal to 100 ml). In patients who had surgery for local control, the histologic response to chemotherapy was analyzed on the surgical specimen and had a strong influence on survival: 79% DFS at 3 years for patients with less than 10% viable tumor (good responders) compared to 31% DFS for patients with more than 10% viable tumor (poor responders). Tumor load and responsiveness to chemotherapy are the two major factors influencing prognosis in patients with primary Ewings sarcoma of bone.

Population‐based epidemiologic data on brain tumors in German children

Brain tumors are the most common disease group of solid tumors in childhood, and children with brain tumors have a relatively poor survival rate. Epidemiologic data from a population‐based cancer registry provide the necessary information to obtain a full picture of the frequency of this disease, which is a great challenge in pediatric oncology.

Childhood malignancies in Germany—methods and results of a nationwide registry

Since 1980, a nationwide registry of childhood malignancies has been established in the Federal Republic of Germany. The registry combines features of a population-based and a hospital-based registry. Basic registry data are complemented and validated by data from all ongoing clinical trials in paediatric oncology. Descriptive analyses are presented for the first 13 years of operation of the registry. In addition, time trends and regional variations of incidence within the Federal Republic of Germany are shown. A brief description of completed and ongoing registry-based epidemiological studies is given.

Residential magnetic fields as a risk factor for childhood acute leukaemia: results from a German population-based case-control study.

Our objective was to investigate whether exposure to residential power‐frequency (50 Hz) magnetic fields above 0.2 μT increases a childs risk of leukaemia and to confirm or reject a finding from a previous German study on this topic, which reported increased leukaemia risk with exposure to stronger magnetic fields during the night. A population‐based case‐control study was used, covering the whole of the former West Germany. Residential magnetic fields were measured over 24 hr for 514 children with acute leukaemia identified by the German Childhood Cancer Registry and 1,301 control children taken from population registration files. Magnetic fields above 0.2 μT were relatively rare in Germany (only 1.5% of the study population). Childhood leukaemia and 24 hr median magnetic fields were only weakly related (OR = 1.55, 95% CI 0.65–3.67). A significant association was seen between childhood leukaemia and magnetic field exposure during the night (OR = 3.21, 95% CI 1.33–7.80). A dose‐response‐relationship was observed after combining the data of all German studies on magnetic fields and childhood leukaemia. The evidence for an association between childhood leukaemia and magnetic field eposure in our study comes from a measure of exposure during the night. Despite the large size of our study, the results are based on small numbers of exposed children. If the observed association stands, the effect on a population level in Germany would be small.

Risk factors for pediatric tumors of the central nervous system: Results from a German population‐based case‐control study

BACKGROUND From 1993 to 1997 we conducted two population-based case-control studies on childhood cancer and a variety of potential risk factors in Germany. One case group involved children under the age of 15 years having a tumor of the central nervous system (CNS). PROCEDURE For both studies, one conducted in the northwestern area of Germany, the other covering the whole of West Germany, incident cases were identified from the nationwide German Childhood Cancer Registry, and controls were randomly selected from complete population registration files. RESULTS In total 466 pediatric CNS tumor cases and 2,458 controls were available for analyses. We observed only few positive associations, namely, between CNS tumors and low birth weight [<2,500 g; odds ratio (OR), 1.73; 95% confidence interval (CI), 1.06-2.84], between ependymoma and maternal smoking during pregnancy (>10 cigarettes per day: OR, 4.71; 95% CI, 1.69-13.1), and between astrocytoma and exposure to wood preservatives (OR, 1.91; 95% CI, 1.22-3.01). CNS tumors were not associated with high birth weight, duration of breast feeding, maternal age at time of delivery, duration of gestation, previous fetal losses, paternal smoking during pregnancy, maternal alcohol consumption, the childs exposure to pesticides, maternal diagnostic X-ray examinations during pregnancy, X-ray examinations of the child, or exposure to residential magnetic fields. CONCLUSIONS Despite the large study population, we found only few factors that were associated with CNS tumors or one of the morphological subgroups. Therefore, our results suggest that aspects of the prenatal and neonatal period play only a minor role in the etiology of pediatric CNS tumors.

Association of childhood leukaemia with factors related to the immune system

SummaryThe childhood peak of common acute lymphoblastic leukaemia has been proposed as being a rare response to delayed exposure to a common infection. In this context, factors related to the child’s immune system are of special interest. Information on such factors was obtained in a recent German case-control study comprising more than 1000 children with acute leukaemia. Neither being the first-born child, nor a short duration of breastfeeding, indicators of a deficit in viral contacts during infancy or the number of infectious diseases, were significant risk factors. We observed a strong association with fewer routine immunizations with a 3.2-fold increase for those children getting less than four immunizations, but this association could partly be explained by reporting bias. While tonsillectomy or appendectomy increased the risk of leukaemia in our studies, a protective effect of allergies could be seen. In summary, we found only weak support for the delayed exposure hypothesis. To some extent this may be due to the chosen surrogate markers which reflect, rather indirectly, immunological isolation in infancy and delayed exposure to common viruses. However, the significant findings for routine immunizations, tonsillectomy and allergies of the child or its parents merit further investigation.

Childhood leukemia and electromagnetic fields: results of a population-based case-control study in Germany.

The investigation of an association between increased exposure toresidential extremely-low frequency elec-tromagnetic fields (ELF-EMF) andchildhood leukemia was part of a population-based case-control study carriedout between 1992 and 1995 in the northwestern part of Germany. A total of 129children with leukemia and 328 controls participated in the EMF-study.Exposure assessment comprised measurements of the magnetic field over 24hours in the childs bedroom at the residence where the child had been livingfor the longest period before the date of diagnosis, and spot measurements atall residences where the child had been living for more than one year. Themedian of the 24h-measurement in the childs bedroom was regarded as the mostvalid exposure variable. For children exposed to more than 0.2 μT, anelevated but not significant odds ratio (OR) was observed (OR = 3.2, 95percent confidence interval = 0.7-14.9). These figures are based on only fourleukemia cases and three controls since only 1.5 percent of the studypopulation was classified as highly exposed. Exploratory analyses revealedORs that were not statistically significantly increased for othercharacteristics of the magnetic field at varying cut-points. The results arecomparable with those from other studies. Although not statisticallysignificant, they may indicate a positive association between EMF andchildhood leukemia.

Atopic disease and childhood acute lymphoblastic leukemia

Our objective was to test the hypothesis that the risk of childhood leukemia is associated with allergies or a family history of allergy. We used a German population‐based case‐control study with self‐reported information on allergies of the children and their first‐degree relatives. Our study included a total of 1,130 cases of acute lymphoblastic leukemia (ALL), 164 cases of acute myeloid leukemia (AML) and 2,957 controls. A major finding of our study is that hay fever, neurodermatitis and contact eczema are underrepresented within the group of children with ALL, with respective odds ratios (OR) of 0.45 (95% confidence interval [CI] 0.31–0.66) for hay fever, of 0.49 (CI 0.34–0.71) for neurodermatitis and of 0.62 (CI 0.39–0.99) for eczema, respectively. Atopic diseases, comprising hay fever, neurodermatitis and asthma, are much stronger related with a reduced risk of ALL than other allergies (OR 0.52, CI 0.40–0.67 vs. OR 0.89, CI 0.66–1.21). The strongest association is seen with an atopy in the index child; however, ALL risk is also reduced if one of the parents or a sibling had an atopic disease. No such consistent pattern is seen for AML. Our data suggest that atopy or a family history of atopy are associated with a reduced risk of childhood ALL. Recall bias remains a concern, but sensitivity analysis provided some evidence that the protective effect is unlikely to be attributable to this bias in its entirety.

Combined risk estimates for two German population-based case-control studies on residential magnetic fields and childhood acute leukemia

From 1992 to 1996, we obtained electromagnetic field measurements in two population-based case-control studies on childhood leukemia in the northwestern part of Germany and in Berlin. Exposure assessment comprised residential 24-hour measurements and short-term measurements. We obtained 24-hour measurements for a total of 176 cases and 414 controls. We compared subjects exposed to median 24-hour measurements of 0.2 microT or more with those exposed to lower amounts. Multivariate regression analysis revealed an odds ratio of 2.3 (95% confidence interval = 0.8-6.7).

Second malignant neoplasms after treatment of childhood cancer

The aim of this study was to determine therapy-related risk factors for the development of second malignant neoplasm (SMN) after childhood cancer. The German Childhood Cancer Registry (GCCR) registers all childhood malignancies since 1980 including SMN. A nested case-control study with 238 SMN cases and 450 controls was conducted. A confirmatory, as well as an explorative, analysis was performed. Radiotherapy showed a small effect on the risk of SMN for doses >or=65 Gy. Regarding the chemotherapeutical agents, we saw increased Odds Ratios (OR) for high doses of cyclophosphamide (CP >8000 mg/m(2) OR=6.3 (95% Confidence Interval (CI): 1.3-30.2)), cisplatinum (DDP >435 mg/m(2) OR=2.8 (95% CI: 1.1-6.7)) and mercaptopurine (MP >5000 mg/m(2) OR=4.5 (95% CI: 1.1-18.9)). Patients jointly receiving high doses of MP (>5000 mg/m(2)) and dexamethasone (DEXA >or=1200 mg/m(2)) had an OR=6.9 (95% CI: 1.2-40.3). Our results could be added to those of other investigations to give indications for modifying future therapeutic strategies for childhood cancer.