Assessment of combined radioimmunotherapy and chemotherapy for treatment of medullary thyroid cancer

We have shown previously significant antitumor effects using Y-90-MN-14 ant i-CEA monoclonal antibody (MAb) for radioimmunotherapy (RAIT) of human medu llary thyroid cancer (MTC) xenografts using the TT cell line. The purpose o f this investigation was to determine the effect of combining chemotherapy and RAIT with 90Y-MN-14 in MTC. In particular, the toxicity and efficacy of various dose schedules of RAIT and doxorubicin were examined and compared with that at the maximum tolerated dose (MTD) of each single modality treat ment. The MTD of RAIT of 105 mu Ci of Y-90-MN-14 was given alone and combin ed with 100 and 75% of the MTD of doxorubicin (60 mg/m(2)); and the MTD of doxorubicin was given alone and combined with 100 and 75% of the MTD of RAI T. In addition, 75% of each agent was also administered in combination, The MTD of RAIT was also evaluated in combination with 58 and 78% of the MTD o f Taxol. Whereas Y-90-MN-14 (105 mu Ci) led to significant antitumor effect s (P < 0.0001), doxorubicin at 60 mg/m(2) or Taxol at 225 mg/m(2) yielded o nly a slight tumor growth delay, The combinations of 100% of the MTD of RAI T and 75% of the MTD of doxorubicin and 100% of the MTD of doxorubicin and 75% of the MTD of RAIT were equitoxic to the MTD of RAIT alone and appear t o result in improved efficacy compared with either RAIT or doxorubicin alon e. For the 100% RAIT and 75% doxorubicin combination, the therapeutic effic acy was similar when doxorubicin was administered on the same day or 1 day after RAIT, but the treatment was less effective when doxorubicin was admin istered 2 days after RAIT (P < 0.03). Prolonged retardation of tumor progre ssion was also observed in animals treated with the MTD of RAIT combined wi th 175 mg/m(2) of Taxol, without increases in toxicity above that observed with RAIT alone. In conclusion, the combination of RAIT and chemotherapy ap pears to augment the antitumor effects of either treatment alone without a significant increase in toxicity, In addition, the timing of drug administr ation relative to RAIT in the combined therapy appears to be important.