Journal of Clinical Oncology, Vol 1, 701-705, Copyright © 1983 by American Society of Clinical Oncology
High-dose VP-16-213 and autologous bone marrow transplantation for refractory malignancies: a phase I study
SN Wolff, MF Fer, CM McKay, KR Hande, JD Hainsworth and FA Greco
VP-16-213, a congener of epipodophyllotoxin, is a useful chemotherapeutic
agent especially against small-cell carcinoma of the lung, germ cell
carcinoma, and lymphoma. The standard dose of this drug is limited by
myelosuppression. Autologous transplantation of cryopreserved bone marrow
assures the restoration of hematopoiesis after marrow ablative cytotoxic
therapy. By using this technique, VP-16- 213 was dose-escalated using a
Fibonacci scheme from the previous highest dose administered to humans
(1,500 mg/m2) to 2,700 mg/m2 (900 mg/m2 per day for three consecutive
days). At 2,700 mg/m2, severe extramedullary toxicity of the mucous
membranes was observed in three of three courses. At the next highest dose
(2,400 mg/m2), two of 18 courses (11%, p less than 0.01) resulted in severe
mucositis, thus defining this dose as the maximally tolerated dose based on
extramedullary toxicities. As anticipated, myelotoxicity was severe but
based on the kinetics of marrow recovery, VP-16-213 in these doses appeared
not to be marrow ablative. Based on responses observed in this study,
high-dose VP-16-213 should be explored in phase II studies or used in
combination chemotherapy.
