Combination chemotherapy with adriamycin and streptozotocin; I. Clinical results in patients with advanced sarcoma

Abstract

In a prospectively randomized study, 17 evaluable patients treated with adriamycin alone, 60 mg/m2 intravenously every 3 wk, were compared with 14 patients treated with adriamycin in the same dose and schedule plus streptozotocin. 500 mg/m2/day intravenously for 5 days every 3 wk. All patients had advanced sarcomas, but none had previously received either adriamycin or streptozotocin. Objective responses were seen in 9 patients on the single drug arm (4 with more than 50% tumor shrinkage and 5 with stabilization of disease), and in 8 patients given the combination drug arm (2 with more than 50% tumor shrinkage and 6 with stabilization of disease). Duration of response and survival from treatment for both treatment groups were similar. Transient hepatic dysfunction, renal function abnormalities, and nausea with vomiting were additive in the combination drug arm, the last two limiting therapy most. Leukopenia, thrombocytopenia, and mucositis appeared to be synergistically increased in patients receiving both adriamycin and streptozotocin. Patients with abnormal pretreatment renal function were able to tolerate the combination therapy without undue incidence of severity of renal toxicity. Patients who developed transient streptozotocin-related renal dysfunction were able to tolerate further doses of streptozotocin after their renal parameters normalized. Adriamycin in combination with streptozotocin did not offer any therapeutic advantage over adriamycin alone.

Doxorubicin‐Based Chemotherapy for the Palliative Treatment of AdultPatients with Locally Advanced or Metastatic Soft‐Tissue Sarcoma:A Meta‐Analysis and Clinical Practice Guideline

“…The trials ranged in size from 663 randomized patients, 9 to 33 randomized patients. 2 Results of pooling response data (Fig. 1) showed a slight trend favouring the combination therapy, though this did not reach statistical signi® cance (OR, 0.79; 95% CI, 0.60± 1.05; p=0.10).…”

Using Single-Agent Therapy in Adult Patients with Advanced Soft Tissue Sarcoma Can Still Be Considered Standard Care

“…Therefore, the results of these two studies are not completely applicable to the whole group of soft tissue sarcomas, given their heterogeneity. In the eight randomized studies, there was no superiority in terms of response rate and median overall survival over doxorubicin alone for the combinations of doxorubicin and streptozocin [3]; doxorubicin, vincristine, and cyclophosphamide [4]; doxorubicin and cyclophosphamide [7]; doxorucin and vindesine [8]; doxorubicin, mitomycin, and cisplatin [9]; or doxorubicin, vincristine, cyclophosphamide, and dacarbazine [10]. In addition, the application of these combinations was at the expense of more toxicity, in particular more bone marrow suppression.…”

“…As a single agent given in metastatic disease, it induces response rates of approximately 16%-27%, with median overall survival ranging from 7.7 to 12.0 months [3][4][5][6][7][8][9][10]. Although the few studies examining whether there is a dose-response relation of doxorubicin suffer from several methodological flaws, it is generally assumed that such a relation does exist [11].…”

Combination chemotherapy with adriamycin and streptozotocin; II. Clinicopharmacologic correlation of augmented adriamycin toxicity caused by streptozotocin

“…Up to 62% of the radioactivity of radioisotopically labeled streptozotocin can be recovered in the urine within 24 hr after administration, with 1 % in the stool and 5% in the exhaled CO 2 during the same period.! Because of the activity of streptozotocin in sarcomas, a prospectively randomized, controlled clinical trial was undertaken in patients with advanced sarcomas, comparing adriamycin alone, 60 mg/m 2 intravenously (iv) every 3 wk, with adriamycin in the same dose and same schedule plus streptozotocin, 500 mg/ 8 and showed no difference in response rate, response duration, or survival from initiation of therapy between the two treatments, although patients in each regimen who responded to therapy had significantly longer survival than nonresponding patients. 8 Certain manifestations of drug toxicity, however, appeared to be increased out of proportion to the additive side effects of the two drugs.…”

“…Because of the activity of streptozotocin in sarcomas, a prospectively randomized, controlled clinical trial was undertaken in patients with advanced sarcomas, comparing adriamycin alone, 60 mg/m 2 intravenously (iv) every 3 wk, with adriamycin in the same dose and same schedule plus streptozotocin, 500 mg/ 8 and showed no difference in response rate, response duration, or survival from initiation of therapy between the two treatments, although patients in each regimen who responded to therapy had significantly longer survival than nonresponding patients. 8 Certain manifestations of drug toxicity, however, appeared to be increased out of proportion to the additive side effects of the two drugs. Because of these findings, plasma drug concentrations of adriamycin and streptozotocin were measured in selected patients on both regimens to see whether these c1inical differences reftected a pharmacologically determined interaction.…”