Multimodality therapy: potentiation of high linear energy transfer radiation with paclitaxel for the treatment of disseminated peritoneal disease.
OBJECTIVE
Studies herein explore paclitaxel enhancement of the therapeutic efficacy of alpha-particle-targeted radiation therapy.


METHODS
Athymic mice bearing 3 day i.p. LS-174T xenografts were treated with 300 or 600 microg paclitaxel at 24 h before, concurrently, or 24 h after [213Bi] or [212Pb]trastuzumab.


RESULTS
Paclitaxel (300 or 600 microg) followed 24 h later with [213Bi]trastuzumab (500 microCi) provided no therapeutic enhancement. Paclitaxel (300 microg) administered concurrently with [213Bi]trastuzumab or [213Bi]HuIgG resulted in median survival of 93 and 37 days, respectively; no difference was observed with 600 microg paclitaxel. Mice receiving just [213Bi]trastuzumab or [213Bi]HuIgG or left untreated had a median survival of 31, 21, and 15 days, respectively, 23 days for just either paclitaxel dose alone. Paclitaxel (300 or 600 microg) given 24 h after [213Bi]trastuzumab increased median survival to 100 and 135 days, respectively. The greatest improvement in median survival (198 days) was obtained with two weekly doses of paclitaxel (600 microg) followed by [213Bi]trastuzumab. Studies were also conducted investigating paclitaxel administered 24 h before, concurrently, or 24 h after [212Pb]trastuzumab (10 microCi). The 300 microg paclitaxel 24 h before radioimmunotherapy (RIT) failed to provide benefit, whereas 600 microg extended the median survival from 44 to 171 days.


CONCLUSIONS
These results suggest that regimens combining chemotherapeutics and high linear energy transfer (LET) RIT may have tremendous potential in the management and treatment of cancer patients. Dose dependency and administration order appear to be critical factors requiring careful investigation.
Milenic
Diane E
DE
Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA. dm71q@nih.gov
Garmestani
Kayhan
K
Brady
Erik D
ED
Baidoo
Kwamena E
KE
Albert
Paul S
PS
Wong
Karen J
KJ
Flynn
Joseph
J
Brechbiel
Martin W
MW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000473:pathology / Q000628:therapy*; D017239:Paclitaxel / Q000008:administration & dosage*; D010534:Peritoneal Neoplasms / Q000556:secondary / Q000628:therapy*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D016499:Radioimmunotherapy / Q000379:methods; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D011838:Radiation-Sensitizing Agents; D000068878:Trastuzumab; D017239:Paclitaxel