Initial tumor size is an important and easily obtainable prognostic factor in osteosarcoma and may serve as a basis for risk-adapted therapy. It is best represented by the absolute three-dimensional measure ATV. There is a cut-off point regarding the incidence of metastases at a tumor volume of approximately 150 cm3 as calculated from two-plane x-ray films.

In a multicenter setting, intensive treatment of osteosarcoma according to protocol COSS-86 led to long-term disease-free survival for two thirds of patients. We saw no benefit of using the intraarterial route to administer cisplatin.

Summary. Haemophagocytic lymphohistiocytosis (HLH) isan autosomal recessive disease with histiocytic and lymphocytic in®ltrations in multiple organs. Cure seems possible only by allogeneic bone marrow transplantation (BMT), but matched sibling donors (MSD) are restricted and high mortality rates are associated with BMT from unrelated donors (URD). We report on 12 consecutive HLH patients with an improved outcome following URD transplants. Eight patients received BMT from URD, four from MSD. Five patients had signs of active HLH at the time of BMT. The conditioning regimen consisted of 20 mg/kg busulphan, 60 mg/kg VP-16 and 120 mg/kg cyclophosphamide and, in case of URD, 90 mg/kg antithymocyte globulin. The doses of busulphan and VP-16 were reduced during the programme to 16 mg/kg and 30 mg/kg, respectively. Using a ®vefold graft-versus-host disease (GVHD) prophylaxis, GVHD was absent or mild in 10, and moderate or severe in two patients undergoing unrelated transplants. One patient with URD experienced graft failure and was retransplanted on day 37. Major toxicities were hepatic veno-occlusive disease in ®ve, capillary leak syndrome in two, pneumonia in three, sepsis in one, severe mucositis in one and seizures in two patients. All patients are alive without HLH after a median follow-up of 24´5 months. One patient has chronic GVHD, another patient has severe retardation. Three patients show slight to moderate development delay. These results indicate that in HLH, BMT from matched unrelated donors should be performed. Incomplete resolution of disease activity need not impede a successful outcome.

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In a retrospective analysis on 128 patients from the trials COSS-80, -82, -85 and -86 initial x-ray pictures were evaluated for tumor diameters in three planes and the prognostic meaning on survival was assessed. In a subset of patients (n = 27) the measured values were compared to values obtained by CT-Scan and a good correlation (r = 0.69) was found. Several parameters for tumor size were defined: absolute tumor length (ATL), relative tumor length (RTL, proportion of tumor to the length of the involved bone), absolute tumor volume (ATV, calculated by the ellipsoid formula) and relative tumor volume (RTL, tumor volume referred to the body surface area) and univariate and multivariate survival analysis were performed. Univariate analysis of metastasis free survival (MFS) revealed a high prognostic significance of the ATL, the ATV and the RTV. The RTL in this patient group demonstrated a tendency only toward an inferior prognosis in larger tumors. None of the patients with a ATV < 70 ml (n = 19) and only one of 33 patients with an ATV < 100 ml relapsed. Cox regression analysis was performed including the variables age, sex, site and response (> 90% tumor necrosis) in 84 patients. ATL and RTL do not enter the model, while the response proves its significance as a valid prognostic factor with a p-value of 0.0004. Adding the ATV as the measure of tumor size to the model it enters as the first term (p = 0.0000) followed by the response (p = 0.0002).(ABSTRACT TRUNCATED AT 250 WORDS)

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Intensified adjuvant chemotherapy increased the 4-year metastasis-free survival probability from 50% (COSS-77) to roughly 80% (COSS-86). Preoperative chemotherapy was found without recognizable hazard and promoting conservative surgery. Following resection the local failure rate ist significantly higher than after demolitive procedures, including rotation plasty (10.5% vs. 2.5%). Local failures bare a very poor prognosis (19/23 DOD). The acute therapy related mortality is less than 3%. Late toxicities like ototoxicity and cardiotoxicity are intriguing and deserve increased attention. The management of the osteosarcoma patient is a complex and difficult interdisciplinary task which is best performed in centers experienced in the treatment of malignant musculo-skeletal tumors.

The neoadjuvant study COSS-86 was undertaken aiming at (1) improving the cure rate in osteosarcoma by early intensification of chemotherapy in high risk patients and (2) investigating the effect of intraarterial (i.a.) versus intravenous (i.v.) administration of cisplatinum. (1) Ifosfamide was added to the well proven drugs in osteosarcoma such as doxorubicin, high-dose methotrexate and cisplatinum in patients with large tumor size or/and high portion of chondroid groundsubstance or/and scintigraphic nonresponse after 4 weeks of preoperative chemotherapy. It was given in combination with cisplatinum. (2) The same patients were allocated to either the intraarterial study arm or the intravenous control arm of the study. The response rate (greater than 90% tumor necrosis) of all patients was 75% (88/118). No advantage in response rate was achieved by i.a. infusion of cis-platinum within this highly efficient 4-drug regimen (i.a. 75% (33/44) vs. i.v. 74% (35/47)). The significantly improved response rate in this study results in a better metastasis free survival (MFS) of 77% (+/- 4) at 4 years.