A Randomized Comparison of two Short Intensive Chemotherapy Regimens in Children and Young Adults With Osteosarcoma: Results in Patients With Metastases: A Study of the European Osteosarcoma Intergroup.

Purpose. To report the outcome of 37 patients with metastatic osteosarcoma entered into a large randomized trial (EOI 80831/MRC B002) comparing two different regimens of chemotherapy in patients with osteosarcoma.Methods. Patients with biopsy-proven osteosarcoma localized and metastatic, age 40 years or younger, were randomized to receive either two-drug treatment with doxorubicin/cisplatin (DOX 25 mg m(-2) day(-1) x 3 + DDP 100 mg m(-2) on day 1 q 3 weeks x 6 courses) or three-drug treatment comprising high-dose methotrexate (HDMTX 8 mg m(-2) administered every 4.5 weeks x 4 courses) given 10 days before DOX/DDP.Results. Twenty-four patients with metastatic disease received the two-drug arm treatment and 13 received three-drug treatment. Despite chance imbalance in numbers, there were no major differences in age, sex, primary site or performance status. Baseline alkaline phosphatase (AP) was elevated more frequently (96 vs 42%) in the two-drug arm. Twenty-one of 24 patients in the two-drug arm and 11/13 patients in the three-drug arm had evaluable primary tumors concurrent with metastases. Respective clinical response rates for the two- and three-drug arms were 48% and 40% for primary tumors, and 33% and 55% for metastases. Respective survivals at 2 and 4 years were 36% and 9% for the two-drug arm, and 69% and 52% for the three-drug arm, and survival was better for patients with normal AP at presentation. When adjusted for AP, survival was not significantly different between the two treatments (hazard ratio 0.52, 95% confidence interval 0.22-1.23, p = 0.14). There were three long-term survivors among the metastatic patients, all of whom received the three-drug therapy.Discussion. It is likely that random bias in the population (small numbers, imbalance in size of groups, uneven distribution of AP) accounts for the difference in outcome favoring the three-drug treatment in patients with metastatic disease. More reliance can be placed on the finding that disease-free and overall survival in the adjuvant component of this study (Bramwell et al., J Clin Oncol 1992; 10: 1579-91) were better after two-drug treatment.

Prognostic significance of erythrocyte sedimentation rate in clinical stages I-II of Hodgkin's disease.

A prospective study was undertaken in 1963 on the respective prognostic significances of erythrocyte sedimentation rate (ESR) and presence or absence of systemic symptoms in Hodgkin's disease. Six hundred seventy-six patients with clinical stages I or II were included in this study; 376 from 1963 to 1971 who were included in the H1 trial of the European Organization for Research and Treatment of Cancer (EORTC) and 300 who had been enrolled in the EORTC H2 trial from 1972 to 1976. All relevant data and long-term follow-up are available from 649 patients who were analyzed in this study. Multivariate analysis (Cox model) was carried out to assess the prognostic value of ESR independently of the other prognostic parameters and of the treatment. The results showed that of all the prognostic indicators studied, ESR is the one which has the highest correlation with relapse-free survival; however, initial ESR is not correlated with the probability of death after relapse. The presence or absence of systemic symptoms has less prognostic impact. Despite a close correlation between systemic symptoms and ESR, the two are not redundant and it is useful to combine both.

Misonidazole in the preoperative and radical radiotherapy of bladder cancer.

Measurement of intercapillary distances suggests the presence of significant cell hypoxia in Bilharzial bladder cancer. This tumor seems to be capable of reoxygenation in view of the existence of a correlation between prognosis and immediate tumor shrinkage after irradiation. Two programs are presented: 1) Use of misonidazole with concentrated preoperative irradiation where the reoxygenation properties are not used fully. A prospective randomized study is presented whereby cystectomy alone is compared with cystectomy plus preoperative irradiation (6.5 Gy X 2F/1 week) with or without misonidazole. the drug is given either orally (in two doses 3 g/m2 each given 3.5 hours prior to each fraction; blood levels: 90-110 micrograms/ml) or intravesically. The intravesical administration is designed in the light of penetration studies and seems to have the advantage of the complete lack of systemic drug toxicity. Twenty-eight patients were included in this study and no drug toxicity was recorded. A second preoperative irradiation study is presented whereby cystectomy alone is compared with cystectomy plus preoperative irradiation (4.0 Gy X 5F) with or without misonidazole in individual doses of 2 g/m2. 2) Two radical radiotherapy regimes are presented. One protocol involves a split course (SC) protracted regime making full use of spontaneous reoxygenation. The drug is given in 0.5 g/m2 daily doses (total dose 14 g/m2 spread over 61 days, blood level: 15-20 micrograms/ml). A second protocol involves hyperfractionation stimulating continuous low-dose-rate irradiation. Higher blood levels are attained (60-80 micrograms/ml) after daily doses of 2 g/m2 (total dose: 14 g/m2 spread over 35 days). In a phase II study using SC technic, reversible grade 1 peripheral neuropathy was encountered in 5 of 22 patients. Complete tumor regression 3 months after irradiation was achieved in 18 of 22 patients with 3T tumors. No neuropathy was encountered in four patients subjected to the HF regimen who also showed complete tumor regression.

Cell proliferation of carcinoma in Bilharzial bladder: an autoradiographic study.

The rate of cell production in thirty-five cases of carcinoma in Bilharzial bladder was evaluated from the labelling index after in vitro incubation with [3H]TdR. Squamous cell carcinoma was the most frequent histological type in this series and had a median LI of 8.0% which corresponds to a potential doubling time of 5.9 days. In squamous cell tumours the LI increased with the histological grade. Transitional cell tumours had a somewhat greater LI. In all histological types the LI was significantly greater in the deep infiltrating parts of the tumour than in the superficial parts. The discrepancy between the estimated potential doubling time and the growth rate normally attributed to such tumours suggests the existence of an extensive cell loss factor. Areas of focal or diffuse mucosal hyperplasia were associated with increased LI.

The dose-time relationship in the radiotherapy of carcinoma of the cervix uteri: an application of the CRE formalism.

A correlation could be obtained between the likelihood of control of central and nodal disease and the corresponding local CRE levels attained in a group of 79 cases of carcinoma of the cervix uteri treated according to a multistage protocol involving a combination of external telecobalt irradiation and intracavitary radium application. A nodal CRE level of 1700 reu and a central CRE value of 2900 reu seemed to be optimal for control of modal metastases and central disease respectively. These CRE levels seemed to be well tolerated even if salvage surgery had to be performed.

Penetration of misonidazole after intravesical administration in cases of carcinoma of the bilharzial bladder.

The penetration of misonidazole was studied by a semiquantitative T.L.C. method after intravesical administration 2 h before total cystectomy in cases of carcinoma of the Bilharzial bladder. In 5 out of 7 cases misonidazole was found at a concentration of the order of 0.4 mg/g in the superficial and deep parts of the tumour, but not in normal bladder tissues.