Combining radioimmunotherapy and chemotherapy for treatment of medullary thyroid carcinoma: effectiveness of dacarbazine.
BACKGROUND
To enhance the efficacy of chemotherapy for medullary thyroid carcinoma (MTC), we evaluated the effect of combining radioimmunotherapy (RAIT) with 90Y-anticarcinoembryonic antigen (CEA) monoclonal antibody MN-14 and chemotherapy in nude mice bearing human MTC xenografts. A preliminary study evaluated doxorubicin, dacarbazine (DTIC), cyclophosphamide, and vincristine, singly and in combination, for their effect on the growth of MTC xenografts (TT) in nude mice. Given individually, DTIC yielded the most effective tumor growth inhibition, delaying the mean time to doubling from 1 week for untreated tumor-bearing mice to 7.5 weeks. Administering either the 4 drugs in combination or a 2-drug combination comprised of doxorubicin and DTIC significantly improved the efficacy compared with any single drug alone, increasing the mean doubling time to 10-12 weeks.


METHODS
Drug doses were selected to conform to the doses of each drug given clinically. For the combined modality therapy, administration of 90Y-labeled anti-CEA monoclonal antibody MN-14 to nude mice bearing established TT tumors was followed by various chemotherapy regimens initiated 24 hours after RAIT. Chemotherapy protocols combined with RAIT included doxorubicin or DTIC alone and in combination, and the doxorubicin, DTIC, cyclophosphamide, and vincristine 4-drug protocol. Tumor volumes were measured weekly, and toxicity was evaluated by measuring blood counts and body weight.


RESULTS
Combinations of RAIT and chemotherapy with DTIC or RAIT and chemotherapy with the drug combinations were found to augment the antitumor effects of RAIT or chemotherapy alone, without a significant increase in toxicity. The mean tumor volume doubling times were increased up to 100% compared with the results of chemotherapy alone. No significant differences in tumor growth were observed between the RAIT plus DTIC protocol and the RAIT plus two- or four-drug protocols.


CONCLUSIONS
The superiority of the combined modality treatment argues for the integration of RAIT into chemotherapeutic regimens for MTC treatment. Clinical trials are needed to assess these principles in MTC patients.
Stein
Rhona
R
Garden State Cancer Center, Belleville, New Jersey 07109, USA. rstein.gscancer@att.net
Chen
Susan
S
Reed
Linda
L
Richel
Heidi
H
Goldenberg
David M
DM
D000818:Animals; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000276:immunology; D018276:Carcinoma, Medullary / Q000628:therapy*; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000008:administration & dosage* / Q000627:therapeutic use; D005260:Female; D051379:Mice; D008819:Mice, Nude; D016499:Radioimmunotherapy; D019275:Radiopharmaceuticals / Q000627:therapeutic use*; D013964:Thyroid Neoplasms / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays; D015021:Yttrium Radioisotopes
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002272:Carcinoembryonic Antigen; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; D003606:Dacarbazine