RT Journal Article SR Electronic T1 Comparative Toxicity and Efficacy of Combined Radioimmunotherapy and Antiangiogenic Therapy in Carcinoembryonic Antigen–Expressing Medullary Thyroid Cancer Xenograft JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 624 OP 631 DO 10.2967/jnumed.109.070714 VO 51 IS 4 A1 Françoise Kraeber-Bodéré A1 Caroline Bodet-Milin A1 Colin Niaudet A1 Catherine Saï-Maurel A1 Anne Moreau A1 Alain Faivre-Chauvet A1 Patrick Thomare A1 Gerard Deleris A1 Karine Estieu-Gionnet A1 Andréas Bikfalvi A1 Jacques Barbet A1 François Paris YR 2010 UL http://jnm.snmjournals.org/content/51/4/624.abstract AB A significant antitumor effect was previously observed with radioimmunotherapy using anti–carcinoembryonic antigen 131I-F6 monoclonal antibody in medullary thyroid cancer–bearing nude mice. Nevertheless, no complete response was observed. As seen with chemotherapy, drugs targeting the tumor microenvironment might improve radioimmunotherapy efficacy. This study evaluated the toxicity and efficacy of combining radioimmunotherapy with thalidomide or a cyclopeptidic vascular endothelial growth inhibitor (CBOP11) in mice grafted with the TT human medullary thyroid cancer cell line. Methods: Six to 10 nude mice treated with 92.5 MBq of 131I-F6 in association with 200 mg/kg/d of oral thalidomide during 20 d by force-feeding or 0.45 mg/kg/d of CBOP11 during 25 d using subcutaneous minipumps were compared with control mice receiving either treatment or naked F6 or nonspecific 131I-734. Combined therapies included 131I-F6 at day 0 followed by thalidomide between days 20 and 40, thalidomide between days 0 and 20 followed by 131I-F6 at day 25, 131I-F6 at day 0 and CBOP11 between days 0 and 25, CBOP11 between days 0 and 25 followed by 131I-F6 at day 25, and 131I-F6 at day 0 followed by CBOP11 between days 20 and 45. Animal weight, hematologic toxicity, tumor volume, and serum calcitonin were monitored for the following 3 mo. Improvement of 125I-F6 tumor biodistribution by antiangiogenic drug was studied after pretreatment by thalidomide. Follow-up of the tumor after combined antiangiogenic and radioimmunotherapy therapies was performed by histology studies. Results: Combined associations, as compared with radioimmunotherapy alone, increased leukopenia but not thrombocytopenia. Tumor volume–quadrupling time (TVQT) was 22.8 ± 3.3 d in the control group, 29.9 ± 3.6 d in the group treated with thalidomide, 34.6 ± 4.4 d in the group treated with CBOP11, and 51.0 ± 2.8 d after radioimmunotherapy alone. As compared with radioimmunotherapy, TVQT was significantly longer (P < 0.01) after thalidomide followed by radioimmunotherapy (69.83 ± 3.9), CBOP11 followed by radioimmunotherapy (71.3 ± 6.1), and CBOP11–radioimmunotherapy in concomitance (64.2 ± 6.1). Nevertheless, TVQT was not increased after radioimmunotherapy followed by thalidomide (48.8 ± 4) and radioimmunotherapy followed by CBOP11 (56.8 ± 4.8). Surprisingly, pretreatment by CBOP11 or thalidomide sensitized larger tumors (>300 mm3) to radioimmunotherapy. Change in calcitonin levels confirmed morphologic tumor response. Tumor uptake 24 h after injection of 125I-F6 was 4.5 ± 0.6 percentage injected dose per gram (%ID/g) without pretreatment and 8.7 ± 1.3 %ID/g with pretreatment by thalidomide. An increase of the antitumor effect observed using the antiangiogenic drug combined with radioimmunotherapy was correlated with a decrease of blood vessels shown by von Willebrand immunostaining. Conclusion: Pretreatment with antiangiogenic therapies improved radioimmunotherapy efficacy, with acceptable toxicity. Future investigations will be performed to understand how antiangiogenic agents sensitize large tumors to radioimmunotherapy.