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Cardiac performance was evaluated at least two years after doxorubicin treatment in childhood in 55 patients without overt congestive cardiomyopathy. None of the patients had received mediastinal irradiation. Computer-assisted analysis of digitised echocardiograms showed impaired rapid diastolic filling and an increased change of dimension between minimal cavity dimension and mitral valve opening. This impairment of diastolic function was related to the cumulative dose of doxorubicin. In contrast when angiotensin II was infused to increase the afterload the end systolic pressure-length and stress-shortening relation indicated normal left ventricular systolic function. But during baseline conditions the end systolic wall stress was significantly increased in patients in whom the cumulative dose of doxorubicin exceeded 360 mg/m2. [ABSTRACT FROM PUBLISHER]

We conducted a clinical trial and report the long-term outcome of 773 children with acute lymphoblastic leukemia upon risk-adapted therapy accrued in trial CoALL 07-03 (from the Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia). In a 2-step stratification, patients were allocated to receive either low- or high-risk treatment, based on initial white blood cell count, age, and immunophenotype. A second stratification was performed according to the results of in vitro pharmacosensitivity toward prednisolone, vincristine, and asparaginase (PVA score) and in vivo response after induction therapy (minimal residual disease [MRD]). Therapy was reduced for both risk groups in patients with a low PVA score or negative MRD result, and intensified in patients with a high PVA score. Overall outcome improved significantly compared with the predecessor CoALL 06-97 trial, with identical therapy backbone despite treatment reduction in 15.8% of patients (10-year probability of event-free survival, 83.5% vs 73.9%; overall survival, 90.7% vs 83.8%). Outcome for patients in the reduced treatment arms was superior to that of patients in the standard arms, associated with a profound reduction in frequency and severity of infectious complications. Importantly, we observed a lack of correlation between in vitro and in vivo drug response, as well as a lower predictive value of in vitro drug testing, reflecting an intrinsic limitation of this methodology that prevents its use for treatment stratification in future trials. In conclusion, it might be possible to reduce chemotherapy in children with acute lymphoblastic leukemia selected by stringent in vivo measurement of MRD without jeopardizing overall outcome., (© 2019 by The American Society of Hematology.)

Anthracyclines are integral components of antileukemic treatment. Apart from cardiotoxicity, myelosuppression and infectious complications have been described for doxorubicin (DOX) and daunorubicin (DNR) as predominant side effects, but little is known about their differential toxicities. To address the question whether DNR is associated with a lower rate of infectious complications compared with DOX, 307 children with newly diagnosed acute lymphoblastic leukemia, enrolled in trial CoALL 08-09, were randomized to receive either DOX 30 mg/m 2 (n = 153) or DNR 36 mg/m 2 (n = 154) in delayed intensification. Hematologic toxicities and stomatitis were less frequent in the DNR group resulting in a significantly lower rate of infections in the DNR arm (27% vs. 59%, p < .0001). Survival was equal in both arms (95% SE 2%) (p = .55), with an insignificant difference in the relapse rate (RR 0.12 (SE = 0.03) in the DOX arm vs. 0.16 (SE = 0.04) in the DNR arm; p = .37; Hazard ratio 1.3; 95% confidence interval 0.7-2.6). In conclusion, DNR given in delayed intensification is associated with a lower incidence of infectious complications without loss of efficacy.

Since the long-term disease-free survival rate in adjuvantly treated osteosarcoma has nowadays reached a level of about 70%, increasing interest is also being directed towards primarily disseminated forms of the disease. Primary metastases, which were confined to the lungs in 42 cases, were detected in 59 out of 421 patients from the prospective therapy trials COSS-80 and COSS-82. The primary tumors were more frequently localized in the proximal femur and flat bones as compared to patients without detectable metastases at diagnosis. Following chemotherapy and surgery of the primary tumor, 15/31 (48%) patients whose metastases were excised have survived for 4-8 years, in contrast to only 1/22 (5%) of those patients whose metastases could not be removed for a variety of reasons. Clinical or histological evidence of tumor response after primary chemotherapy significantly influenced the outcome of the metastasectomized patients.

A comparison was carried out of the value of plain radiographs, tomography and CT in 37 patients aged between five and 24 years. The majority of these patients had an osteosarcoma. Thirty-five CT examinations were performed on 16 patients and about 300 foci were demonstrated. Plain radiographs only showed 50%, and tomograms only 70% of these lesions. Surgery was carried out in 34 patients and there was agreement between the findings at thoracotomy and radiology in about half the cases. Frequently, more metastases were found at operation than could be demonstrated radiologically, in a few cases there were fewer.

In order to reduce the toxicity of the otherwise very effective childhood ALL treatment protocol BFM 76/79 asparaginase was omitted from the 4-drug induction regimen and placed as single drug before the intensification phase. In addition the effect of 3-monthly intermediate dose methotrexate (ID-MTX) pulses versus conventional vincristine (VCR) pulses during maintenance therapy was studied. Of 145 evaluable patients 124 (85.5%) survive in continuous and complete remission (CCR) at a median observation time of 21 (1,5-47) months. The expected rate of patients in CCR at 4 years is 75% respectively 80% after exclusion of 4 patients with fatal complications and one remission failure. These relapse free survival data re equal to the BFM 76/79 and 79/81 results. There was very few therapy related morbidity and no mortality from the COALL-80 induction therapy modification. The intensification phase, however, which was adopted from the BFM study without modification was difficult to manage and was not free of life threatening mostly infectious complications which were fatal in 4 cases. ID-MTX pulses did not prove superior to conventional VCR pulses. The relapse rate in patients with the c-ALL subtype was markedly lower than in any other subtype, remarkably also than in the undifferentiated type.

In the first study, COSS-77, 100 patients with OS were treated for 12 months according to a CT-protocol consisting of high-dose methotrexate (HD-MTX), adriblastine (ADR) and cyclophosphamide (CP). At 40 months the expected continuous disease-free survival (CDFS) rate of the 71 evaluable patients was 55%. After exclusion of local recurrences (n = 2) and fatal chemotherapy toxicities (n = 0) a reduced group of 69 patients remained and the expected CDFS rate at 40 months became 56%. In the second study, COSS-80, the MTX dose was doubled. Two groups were randomly selected, one of which received cisplatinum (CPL) and the other the triple drug combination bleomycin + CP + dactinomycin (BCD) in addition to MTX and ADR, both groups being treated for 8 months. Furthermore some randomly selected patients received fibroblaste-interferon (IF). The expected CDFS rate at 40 months of the 115 evaluable COSS-80 patients was 67%. 106 patients remained in a reduced group defined as above (4 local recurrences and 5 CT toxicities) in which the expected CDFS rate at 40 months was 73%. This is significantly better (p less than 0.05) than the results obtained from the COSS-77 group. No differences were found between the CPL and BCD arms of the COSS-80 group or between the arms receiving or not receiving IF. A significant increase in the CDFS rate for young (less than 12 years) and male patients over that in COSS-77 was observed in COSS-80, probably due to the increased MTX dose.(ABSTRACT TRUNCATED AT 250 WORDS)

71 patients with resectable osterosarcoma received chemotherapy for one year including high-dose methotrexate (18 x 200 mg/kg), adriamycin (5 x [2 x 45] mg/m2) and cyclophosphamide (6 x 1200 mg/m2). During the initial 15 weeks adriamycin was used preferentially and cytostatic agents were applied in a higher frequency than later on. 41/71 patients are continuously free of disease with a median follow up of 39 (24-54) months. The latest appearance of pulmonary metastases was observed at 28 months so far. 18/27 (67%) patients with extension of tumor lesion beyond 1/3 long bones length by x-ray examination relapsed in contrast to 12/43 (28%) patients with smaller lesions. 1 patient died from adriamycin induced cardiomyopathy. Generally therapy was well tolerated. An average of 70-80% of planned drug dosages could be realized without measurable influence of individual differences on outcome.

Since 1979 in a cooperative study (COALL-80) 110 children with acute lymphoblastic leukemia (ALL) and 13 children with high grade malignant non Hodgkin's lymphoma (NHL) have been treated with a less aggressive modification of the Westberlin Study Program BFM 76/79. Asparaginase has been delayed from the initial 4 drugs regimen and interposed in between induction therapy and treatment of central nervous system (CNS). Induction therapy that way was well tolerated and realized mostly on an outpatient basis. The expected 2 1/2 years disease free survival rate for ALL is 86% and no worse than the results of the original BFM study. We were able to define by age (greater than 2, less than 7 years), initial blast count (less than 25000/mm3) and immunological typing (cALL Ag+) a great group of patients (52%) which has remained in continuous remission as a whole. For this group further reduction of therapy intensity is planned (omission of cyclophosphamide during CNS-phase and use of intermediate dose methotrexate (MTX-mHD) instead of CNS-irradiation).

Following preoperative chemotherapy of 9-18 weeks duration limb salvage procedures were performed instead of ablative surgery in about 1/2 of the patients (pts). Overall continuous disease-free survival rate is 69% (80/115) at 37 (21-51) months. 5 pts died from therapy related complications, 4 developed a local failure (2 following amputation and 2 following limb salvage each) and 26 pts developed pulmonary metastases. The incidence of pulmonary metastases after en bloc resection, but not after shank rotation plasty, was found to be significantly increased over that after ablative surgery (83% vs 60% metastases free survival (MFS) at 40 months, p less than 0.05). The outcome was most unfavourable following en bloc resection of large tumors (36% MFS) and of tumors poorly responding to preoperative chemotherapy. Delaying surgery for preoperative chemotherapy in itself did not influence MFS-rate but it enabled a thorough planing and preparation of surgical procedures. Chemotherapy has very much improved the prognosis of osteosarcoma, trials on limb salvage surgery are indicated therefore. However, these procedures appear to be hazardous by increasing the rate of pulmonary metastases. Until the underlying mechanisms are not uncovered and preventive strategies worked out, limb salvage surgery in osteosarcoma has to be regarded and handled as an experimental procedure.