[Results of treatment in primary disseminated osteosarcoma. Analysis of the follow-up of patients in the cooperative osteosarcoma studies COSS-80 and COSS-82]. / Behandlungsergebnisse bei primär disseminiertem Osteosarkom. Verlaufsanalyse von Patienten aus den cooperativen Osteosarkom-Studien COSS-80 und COSS-82.

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.

Long term doxorubicin cardiotoxicity in childhood: non-invasive evaluation of the contractile state and diastolic filling.

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.

Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response.

Following observation of the predictive value of the histologic extent of tumor cell destruction after preoperative chemotherapy for metastasis-free survival (MFS) in osteosarcoma, a randomized study was undertaken with the aim of (1) sparing some patients the unpleasant side effects of highly toxic drugs like doxorubicin (DOX) and cisplatin (CPDD) by administering these drugs postoperatively only after poor response with a milder preoperative regimen, and (2) improving the prognosis of patients responding poorly to the initial treatment by use of a salvage chemotherapy postoperatively. The available patients were divided into two groups. Those in the study arm received a preoperative chemotherapy consisting of high-dose methotrexate (HDMTX) and the triple drug combination of bleomycin, cyclophosphamide, and dactinomycin (BCD) and were switched to DOX/CPDD postoperatively in case of poor response. DOX/CPDD was used besides HDMTX for initial treatment in the control arm, and BCD alternatively with CPDD/ifosfamide (IFO) for postoperative salvage treatment. The response rate of the study arm was significantly inferior to the control arm (26% v 60%; P less than .001). The actuarial 4-year MFS rate of poor responders after salvage chemotherapy also was poorest in the study arm (41%); it was unchanged in the control arm (53%) as compared with that of poor responders from the COSS-80 study without salvage chemotherapy (52%). The actuarial 4-year MFS rate of good responders was 73% in the study arm, 79% in the control arm, and not significantly different from that of the COSS-80 study (84%), although postoperative chemotherapy of good responders had been markedly shortened as compared with the COSS-80 study. The actuarial 4-year MFS rate of the study arm as a whole was inferior to that of the control arm (49% v 68%; P less than .1) and also inferior to the COSS-80 study (68%; P less than .01), indicating a failure of the employed salvage strategy in general and especially of the effort to restrict the use of the very effective but highly toxic drugs DOX and CPDD to patients resistant to a less toxic initial treatment.

[Effect of a local surgical procedure on the incidence of metastases following neoadjuvant chemotherapy of osteosarcoma]. / Einfluss des lokalchirurgischen Vorgehens auf die Inzidenz von Metastasen nach neoadjuvanter Chemotherapie des Osteosarkoms.

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.

[Results of the COSS-77 and COSS-80 studies on adjuvant chemotherapy in osteosarcoma of the extremities]. / Ergebnisse der Studien COSS-77 und COSS-80 für die adjuvante Chemotherapie bei Osteosarkom der Extremitäten.

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)

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.

[Comparison of x-ray plain films, x-ray tomograms and computed tomograms in lung nodules in children and adolescents]. / Vergleich von Röntgenübersichtsaufnahmen, Röntgenschichtaufnahmen und Computer-tomogrammen bei pulmonalen Rundherden im Kindes- und Jugendalter.

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.

[COALL-80 therapy in the management of acute lymphoblastic leukemia in childhood--an interim report]. / COALL-80-Studie zur Behandlung der akuten lymphoblastischen Leukämie (ALL) im Kindesalter--Zwischenbericht.

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.

[Therapy of acute lymphoblastic leukemia in childhood. Multicenter prospective therapy study COALL-80]. / Therapie der akuten Lymphoblastenleukämie im Kindesalter. Multizentrische prospektive Therapiestudie COALL-80.

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).

Morphological grades of regression in osteosarcoma after polychemotherapy - study COSS 80.

The histologic grade of regression of 50 osteosarcomas after polychemotherapy - according to the protocol study, COSS 80 - was classified on a six-stage regression scale; 56% of all patients responded well to chemotherapy regression grades I, II, and III and no significant difference between BCD- and CPL-treated patients could be found. Tumors under 10 cm in length responded better to chemotherapy than those of greater length and there was a good correlation between the clinical estimation of tumor regression and progression and the histologic grade of regression.

Toxicity associated with combination chemotherapy for osteosarcoma: a report of the cooperative osteosarcoma study (COSS 80).

The treatment-associated toxicity in 189 patients entered in the COSS-80 Study was analyzed. The sequential use of high-dose methotrexate (HDMTX) with citrovorum factor rescue (CFR) and cis-platinum may be additive or synergistic in causing renal toxicity. However, evaluation of the 48-h serum methotrexate level and the incidence of elevated serum creatinine levels throughout treatment failed to indicate prolonged methotrexate elimination or severe kidney damage from this regimen where an interval of 3 weeks between cis-platinum administration and the next course of HDMTX was mandatory. The treatment-related mortality was 3.2% (6 out of 189 patients). Three patients died of septicemia during chemotherapy-induced bone-marrow depression following treatment with adriamycin or the combination of bleomycin, cyclophosphamide, and dactinomycin (BCD). Three deaths occurred following the use of high-dose methotrexate with citrovorum factor rescue. Two of these deaths were associated with delayed excretion of methotrexate. The toxicity is within the range reported in the literature.

Adjuvant chemotherapy in osteosarcoma - effects of cisplatinum, BCD, and fibroblast interferon in sequential combination with HD-MTX and adriamycin. Preliminary results of the COSS 80 study.

In a cooperative adjuvant chemotherapy study of osteosarcoma (COSS-80), 192 patients were registered from December 1979 to March 1982. Forty-one patients have been excluded from study because of their nonadjuvant situation, therapy-limiting clinical conditions, or inadequate diagnosis. One hundred and fifty-one patients have been randomized to receive either the drug combination bleomycin + cyclophosphamide + dactinomycin (BCD) or cisplatinum (CPL) within a course of sequential multidrug chemotherapy including adriamycin (ADR) and high dose methotrexate (HDMTX). After exclusion of 51 patients with some deviation in history and/or management 100 selected patients were randomized once more to receive in addition or not fibroblast interferon after preoperative chemotherapy and surgical removal of the primary tumor. Patients were stratified for age and sex and for site and extension of tumor as well in both randomizations. Median follow up is now 12 (1-16) months. The expected 2-year disease free survival (DFS) rate of the total doubly randomized group is 78% and of the single randomized group 76%. No difference could be discerned between recombined groups receiving BCD vs CPL or interferon vs no interferon. The effect of preoperative chemotherapy on the tumor was evaluated clinically and by histopathologic grading; 66/85 (78%) patients were judged clinically as responders with pathohistologic verification of this finding in 71% of these cases. No adverse effect arose from delaying definite surgery for preoperative chemotherapy, but initial application of chemotherapy as well as planning, preparing, and performing of the surgical procedure have been facilitated. The majority of patients received some kind of limb-salvage treatment without local recurrences so far. A statistically insignificant but intriguing tendency for a slightly higher incidence of pulmonary metastases after resection as opposed to amputation could be detected. Similar to observations in the previous study COSS-77.

[Cooperative osteosarcoma study COSS-77: results after 4 years]. / Kooperative Osteosarkomstudie COSS-77: Ergebnisse nach über 4 Jahren.

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.