Multimodality therapy: Potentiation of high linear energy transfer radiation with paclitaxel for thetreatment of disseminated peritoneal disease

Abstract

Purpose: Studies herein explore paclitaxel enhancement of the therapeutic efficacy of a-particle-targeted radiation therapy. Experimental Design: Athymic mice bearing 3 day i.p. LS-174T xenografts were treated with 300 or 600 μg paclitaxel at 24 h before, concurrently, or 24 h after [213Bi] or [213Pb]trastuzumab. Results: Paclitaxel (300 or 600 μg) followed 24 h later with [213Bi]trastuzumab (500 μ.Ci) provided no therapeutic enhancement. Paclitaxel (300 μg) administered concurrently with [213Bi]trastuzumab or [213Bi]HulgG resulted in median survival of 93 and 37 days, respectively; no difference was observed with 600 μg paclitaxel. Mice receiving just [213Bi]trastuzumab or[ 213Bi] HulgG 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 μg) 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 μg) followed by [213Bi]trastuzumab. Studies were also conducted investigating paclitaxel administered 24 h before, concurrently, or 24 h after [212Pb]trastuzumab (10 μCi). The 300 μg paclitaxel 24 h before radioimmunotherapy (RIT) failed to provide benefit, whereas 600 μg 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. © 2008 American Association for Cancer Research. These investigations reported herein show the potential of combining chemotherapeutics with high-LET RIT for the management and treatment of cancer patients who present with disseminated peritoneal disease at the time of their diagnosis. These studies are a natural progression to prior studies that established the efficacy of paclitaxel administered in conjunction with β-radiation RIT for the treatment of ovarian patients. Chemotherapy in conjunction with α-particle RIT using the appropriate targeting vehicle would be an effective adjuvant therapy following procedures such as cytoreductive surgery or peritoneal external beam radiation therapy. The intent of developing a treatment regimen using α-targeted radiation is to expand the repertoire to patient populations. Such a strategy would be potentially beneficial for not only those with pancreatic or ovarian cancer but also those with cancers of the colon, stomach, and small intestine, which result in peritoneal carcinomatosis as well as those with peritoneal mesothelioma. In general, the results obtained define a potentiating interaction between paclitaxel and the high-LET α-radiation-labeled trastuzumab. The studies also illustrate the necessity of establishing the optimal administration sequence of the treatment components and that dose dependency and administration order are critical factors that require careful investigation. © 2008 American Association for Cancer Research.