U. Göbel

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.

Osteosarcoma Relapse After Combined Modality Therapy: An Analysis of Unselected Patients in the Cooperative Osteosarcoma Study Group (COSS)

PURPOSE To evaluate the impact of patient, tumor, and treatment-related factors on outcome in unselected patients with recurrent osteosarcoma. PATIENTS AND METHODS Five hundred seventy-six consecutive patients who had achieved a first complete surgical remission (CR) during combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group (COSS) protocols and then developed recurrent osteosarcoma were analyzed (median time from biopsy to relapse, 1.6 years; range, 0.1 to 14.3 years). There were 501 patients with metastases, 44 with local recurrences, and 31 with both. Metastases involved lungs (469 patients), bones (90 patients), and/or other sites (54 patients). RESULTS After a median follow-up of 1.2 years for all patients and 4.2 years for survivors, actuarial overall survival (OS) rates at 2, 5, and 10 years were 0.38, 0.23, and 0.18, respectively. Five-year OS was 0.39 for 339 patients with and 0.00 for 229 patients without a second surgical CR (P < .0001). A long time to relapse, a solitary lesion, and, in the case of pulmonary metastases, unilateral disease and the absence of pleural disruption, were of positive prognostic value in uni- and multivariate analyses, as were a second surgical CR and the use of second-line chemotherapy. Radiotherapy was associated with moderately prolonged survival in patients without a second CR. The very limited prognostic differences associated with the use of second-line chemotherapy appeared to be more pronounced with polychemotherapy. CONCLUSION Time to relapse and tumor burden correlate with postrelapse outcome in osteosarcoma. Complete surgery is an essential component of curative second-line therapy. Chemotherapy, particularly chemotherapy with more than one agent, may contribute to limited improvements in outcome.

Neonatal symptomatic thromboembolism in Germany: two year survey

AIMS To determine the incidence of neonatal thromboembolism in Germany. METHODS Diagnostic imaging techniques, therapeutic modalities, and short term outcome were evaluated in a prospective nationwide two year case registry study. RESULTS The reported incidence of symptomatic neonatal thromboembolism, diagnosed in most cases with Doppler ultrasonography, was 5.1 per 100 000 births, with a total of 79 cases registered: renal venous thrombosis (n=35); venous thrombosis (n=25); and arterial vascular occlusion (n=19). Fifty seven of 79 thromboses were associated with additional risk factors (central line n=25, asphyxia n=13, septicaemia n=11, dehydration n=6, maternal diabetes n=2, cardiac disease n=1). Inherited thrombophilia was also diagnosed in seven out of 35 cases investigated. Twenty three children received supportive treatment: 42 received heparin and in 13 neonates thrombolytic agents were administered. Most neonates (91%) survived; seven died. CONCLUSION Controlled multicentre studies are needed to obtain more information on treatment efficacy.

Neoadjuvant chemotherapy for osteogenic sarcoma: results of a Cooperative German/Austrian study.

From December 1979 to August 1982 158 patients were registered for an adjuvant chemotherapy (CT) study COSS -80. To compare the effect of cisplatin (CPL) to that of the drug combination bleomycin, cyclophosphamide, and dactinomycin (BCD), patients were randomized to receive either drug(s) within a course of sequential multidrug CT including doxorubicin and high-dose methotrexate (HDMTX). Definite surgery was done 10-18 weeks after the start of CT. Patients were randomized a second time to receive or not to receive fibroblast interferon in addition to CT beginning at week 16. At a median observation time of 19.5 months (range, 4-34 months), 116 (73%) of 158 patients were continuously disease-free (CDF). After exclusion of 42 patients because of some deviation in history and/or management, 86 (74%) of 116 patients actually were CDF with a 30-month calculated CDF-rate of 68%. There was no difference in CDF rates in the patients receiving BCD versus CPL or receiving interferon versus no interferon. Whereas, in comparison to the previous study COSS -77, the over-all increase in CDF rate does not reach statistical significance, it does, however, for the younger (less than or equal to 12 years) and for male patients, which is assumed to be the effect of increasing the methotrexate dose from 6 to 12 g/m2 in the COSS -80 study.

Teratomas in infancy and childhood

BACKGROUND AND PROCEDURE Outcomes in children with teratomas collected between October 1982 and December 1995 in cooperative protocols of the German Society of Pediatric Oncology and Hematology (GPOH) were analyzed. Teratomas were diagnosed in 329 (42%) of 780 registered patients with germ cell tumors. The annual incidence was 0.24/100,000. Main primary sites were coccygeal (n = 132, 2.2:1 female predominance), ovary (n = 81), testis (n = 40) and brain (n = 15, 2.8:1 male predominance). RESULTS Two hundred seventy cases of extracranial non-testicular teratoma were evaluated: In mature teratomas (n = 154) the observed relapse rate was 10%. Incomplete resection was the main risk factor for relapse. After complete resection, the relapse-free survival (RFS, Kaplan-Meier-estimation) was 0.96 +/- 0.01 (n = 126, observation time 18-155 months) in comparison to an RFS of 0.56 +/- 0.09 in incompletely resected teratomas grade 0 (n = 28, observation time 28-94 months) (P < 0.01). Im-mature teratomas were treated by surgery alone in 76 cases and by surgery and adjuvant chemotherapy in 40 cases. The observed relapse risk was 18%. Main risk factors for relapse were incomplete tumor resection (n = 38) as well as immaturity in incompletely resected teratomas. Fifteen of 29 relapsing patients presented with malignant tissue in the recurrent tumor (mainly yolk sac tumor); in contrast, seven of 40 patients with immature teratoma relapsed despite adjuvant chemotherapy without showing malignant components (P = 0.014). Nine of 36 (25%) relapsing patients died of disease. Eleven of the 27 (41%) surviving children suffered from mutilation after repeated surgery. COMMENTS It is suggested that an international randomized trial for patients with incompletely resected high risk teratoma be initiated to evaluate the effect of adjuvant chemotherapy on specific end-points: 1) influence on relapse rate in general; 2) reduction of the proportion of malignant relapses; 3) avoidance of mutilating surgery.

Germ-cell tumors in childhood and adolescence

Summary In mature and immature teratoma the treatment is surgical. The risk of recurrence can be estimated from the parameters primary site (with the coccygeal tumors being most at risk), histological grade of immaturity and completeness of the primary resection including the adjacent organ of origin (coccyx, ovary, testis etc.). In case of a microscopically complete tumor resection there is no role for adjuvant chemo- or radiotherapy irrespective of the histological grade of immaturity. Malignant germ-cell tumors (GCT) account for 2.9% of all malignant tumors of children younger than 15 years of age. More than half of the tumors occur at extragonadal sites such as the ovaries (26%), the coccygeal region (24%), the testes (18%) and the brain (18%) represent then primary sites. In patients with extensive tumor growth, metastatic disease or secreting intracranial tumors a delayed tumor resection after preoperative chemotherapy is preferable. In these patients malignant non-seminomatous GCT may be diagnosed clinically due to the increased serum or cerebrospinal fluid levels of the tumor markers AFT and/or [J-HCG. Current risk adapted treatment protocols containing cisplatinum allow long-term remissions in about 80% including patients with bulky or metastatic tumors. In the cisplatinum era the prognostic factors like histology, primary site of the tumor and initial tumor stage have partly lost their former impressive significance in infants and children. On the other hand the completeness of the primary tumor resection according to oncological standards has been established as the most powerful prognostic parameter superior to tumor marker levels or primary site of the tumor.

Long-Term Outcome in Children With Relapsed ALL by Risk-Stratified Salvage Therapy: Results of Trial Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group 87

PURPOSE Approximately 20% of children with acute lymphoblastic leukemia (ALL) suffer a relapse, and their prognosis is unfavorable. Between 1987 and 1990, the multicenter trial Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group (ALL-REZ BFM) 87 was conducted to establish a uniform treatment for these children in Germany and Austria. PATIENTS AND METHODS Of 207 registered patients, 183 patients were stratified into three groups according to the protocol: A, early bone marrow (BM) relapse (n = 56); B, late BM relapse (n = 101); C, isolated extramedullary relapse (n = 26). Treatment consisted of risk-adapted alternating short-course multiagent systemic and intrathecal chemotherapy, cranial irradiation, if indicated, and conventional maintenance therapy. Additionally, 24 patients with an exceptionally poor prognosis (early BM or any relapse of T-cell ALL) were treated with individual regimens. In 35 patients, stem-cell transplantation was performed. RESULTS The probability of event-free survival (EFS) and overall survival of all registered patients at 15 years was 0.30 +/- 0.03 and 0.37 +/- 0.03, respectively, with significant differences between the strategic groups (A, 0.18 +/- 0.05 and 0.20 +/- 0.05; B, 0.44 +/- 0.05 and 0.52 +/- 0.05; C, 0.35 +/- 0.09 and 0.42 +/- 0.10). Despite risk-adapted treatment, an early time point of relapse and T-lineage immunophenotype were significant predictors of inferior EFS in uni- and multivariate analyses. CONCLUSION With the ALL-REZ BFM 87 protocol, more than one-third of patients may be regarded as cured from recurrent ALL with second complete remissions lasting more than 10 years. Immunophenotype and time point of relapse are important prognostic factors that allow us to adapt more precisely treatment intensity to individual prognosis in future trials.

Prognostic significance of tumor volume in localized Ewing's sarcoma of bone in children and adolescents

SummaryA total of 60 consecutive patients with localized Ewings sarcoma of bone who were entered into the Cooperative Ewings Sarcoma Study of the German Society of Pediatric Oncology from January 1981 until April 1985 were evaluable for tumor volume at diagnosis. The tumor volume was calculated from plain X-rays and CT scans as ellipsoidal or cylindrical depending on the tumor configuration and presence or absence of a soft tissue component. The 3-year disease-free survival rate according to Kaplan-Meier life table analysis was 78% for tumors with a volume <100 ml compared to 17% for tumors ≧100 ml volume. These results were independent of the site of the tumor, though larger tumors were primarily located in central and proximal extremity sites. Maximal tumor extension was less precise than tumor volume in predicting prognosis. The radio of tumor volume to body surface area, body length, or body weight did not increase the ability to separate prognostic groups compared to tumor volume. The better prognosis for patients following radical surgery seems to be in part due to a biased distribution of tumor volumes within local therapy groups, since more patients with smaller tumors had surgery for local control.

Radiation Therapy for Intracranial Germinoma: Results of the German Cooperative Prospective Trials MAKEI 83/86/89

PURPOSE A multicenter prospective trial was conducted (Maligue Keimzelltümoren [MAKEI] 83/86/89) to assess outcome in intracranial germinoma after treatment with radiotherapy alone at reduced doses. PATIENTS AND METHODS Between 1983 and 1993, 60 patients with histologically (n = 58) or cytologically (n = 2) confirmed germinoma were enrolled onto the study. Patients received radiotherapy alone (craniospinal axis/local boost). In the MAKEI 83/86 study (involving 11 patients), the dose to the craniospinal axis was 36 Gy and the dose to the tumor region was 14 Gy. In the MAKEI 89 study (involving 49 patients), doses were 30 and 15 Gy, respectively. RESULTS Median patient age was 13 years (range, 6 to 31 years). Complete remission was achieved in all patients. The estimated (Kaplan-Meier) 5-year relapse-free survival rate was 91.0% +/- 3.9% at a mean follow-up of 59.5 months (range, 3 to 180 months); the estimated overall survival rate was 93.7% +/- 3.6%. Relapse occurred in five patients 10 to 33 months (mean, 18.4 months) after diagnosis (one patient developed a spinal canal metastasis and underwent salvage radiotherapy and chemotherapy; four patients had metastases outside the CNS and underwent salvage chemotherapy alone). Four patients died: one died from disease, two died from therapy-related complications, and one committed suicide. Acute complications with long-lasting sequelae were tumor or surgery related (three cases of blindness, six of reduced vision, two of hemiparesis). Psychosocial development was normal in the majority of patients. CONCLUSION Radiotherapy directed toward the craniospinal axis or tumor site alone at decreased dose levels is effective. To reduce the risk of late side effects, further attempts to decrease total doses are justified. In cases of recurrent disease, chemotherapy administered outside the CNS is the treatment of choice.

Malignant peripheral neuroectodermal tumors. A retrospective analysis of 42 patients.

The clinical presentation of the disease and the results of treatment in 42 patients with malignant peripheral neuroectodermal tumors (MPNT) entered into the Cooperative Ewings, soft tissue, and neuroblastoma trials of the German Society of Pediatric Oncology were retrospectively analyzed. Within the Ewings sarcoma trial, patients with chest wall lesions were particularly analysed for MPNT features. The period of observation ranged from 15 to 86 months; the median relapse‐free time was 24 months. There were 28 male and 14 female patients, the median age of patients was 15 years (range, 9 months‐23 years). Thirty‐two patients had localized disease (M0), and ten patients presented with primary metastases (M1). The predominant location of the tumors was the thoracopulmonary region, followed by the extremities, the abdominal/pelvic, and head and neck region. Thirty‐one of 42 tumors involved the adjacent bone. The disease‐free survival according to Kaplan‐Meier life‐table analysis was 56% ± 11% for Stage M0 patients at 3 years. Nine of ten patients with M1 disease showed progression of their disease. Most patients had combined modality treatment with surgery, chemotherapy and radiation therapy. Best results were obtained with extensive surgery. Radiation doses ranged from 20 to 60 Gy and could not be correlated with the outcome of the disease. Most recurrences occurred at the site of the primary tumor. In patients with primary chemotherapy after biopsy‐proven diagnosis, the responsiveness of this disease to chemotherapy could be demonstrated. Combination chemotherapy containing anthracyclines and high doses of alkylating agents appeared superior.