Thyroid radiation doses during radioimmunotherapy of CEA-expressing tumours with 131I-labelled monoclonal antibodies.
A number of radioimmunotherapy (RAIT) trials with iodinated antibodies have shown a high variability in the radiation doses to the thyroid. Therefore, the aim of this study was to evaluate which factors influence these thyroid doses during RAIT with 131iodinated monoclonal anti-carcinoembryonic antigen (CEA) antibodies. Data from 36 patients with CEA-expressing tumours were analysed. The patients underwent RAIT with the 131I-labelled IgG1 anti-CEA antibody, MN-14 (Ka = 10(9) l mol-1) or its F(ab')2 fragment (activity range 45.8-220.0 mCi). The thyroid was blocked with 120 mg iodine (lugol's orSSKI solution) and 400 mg perchlorate per day, starting 1 day prior to the first study. Blood clearance and molecular composition of labelled plasma compounds were determined by blood sampling and size-exclusion high-performance liquid chromatography analysis. The cumulated activities of tissues were determined from daily imaging and blood clearance data. Doses were derived from the MIRD scheme. Thyroid radiation doses showed a high variability, between 1.2 and 37.7 cGy mCi-1 (mean +/- S.D.: 11.1 +/- 8.3 cGy mCi-1), corresponding to absolute doses between 2.5 and 43.6 Gy. However, the maximal iodine uptake in the thyroid was 2.4 +/- 1.9 microCi mCi-1 (range 0.2-10.0 microCi mCi-1), which was less than 1% of the injected activity, indicating that more than 99% of the thyroid was blocked in all cases. No correlation was found between these thyroid doses and conditions leading to an enhanced exposure to free radioiodine, such as unbound I- in the mAb preparation, rapid metabolic breakdown of the labelled antibody due to human anti-mouse antibodies (HAMA), or immune complex formation with circulating antigen. However, a relationship between the thyroid doses and the patients' compliance in taking their Lugol's and perchlorate blocking medications, as well as to a relatively high variability in the biological half-life of the iodine in the thyroid (range from 31.1 h to virtual infinity), is indicated. No rising TSH titres or other signs of (latent) hypothyroidism were seen in these patients during a 2 year follow-up period. Longer follow-up was not possible because of the terminal condition of most of the patients. These data show that thyroid doses in an appropriately blocked individual given a standard, non-myeloablative dose of RAIT, are generally lower than those assumed to be required to cause late hypothyroidism. Even if higher activities are used, potential hypothyroidism may be overcome easily by hormone replacement. Thyroid doses are independent of parameters leading to an enhanced exposure of the thyroid to free radioiodine, suggesting that patient compliance in taking their blocking medication may be the most crucial factor for reducing thyroid doses in RAIT with 131I-labelled antibodies.
Garden State Cancer Center, Center for Molecular Medicine and Immunology, Newark, NJ 07103-2763, USA.
T M
TM
Behr
M E
ME
Juweid
R M
RM
Sharkey
R M
RM
Dunn
Z
Z
Ying
W S
WS
Becker
J A
JA
Siegel
D M
DM
Goldenberg
D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy*; D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use; D000936:Antigen-Antibody Complex / Q000097:blood; D002272:Carcinoembryonic Antigen / Q000378:metabolism*; D005260:Female; D006801:Humans; D007037:Hypothyroidism / Q000209:etiology / Q000517:prevention & control; D007074:Immunoglobulin G / Q000378:metabolism / Q000627:therapeutic use; D007205:Indium Radioisotopes / Q000009:adverse effects / Q000627:therapeutic use*; D007454:Iodides / Q000627:therapeutic use; D008297:Male; D051379:Mice; D010349:Patient Compliance; D010472:Perchlorates / Q000627:therapeutic use; D017680:Potassium Compounds / Q000627:therapeutic use; D011829:Radiation Dosage; D011832:Radiation Injuries / Q000209:etiology / Q000517:prevention & control; D016499:Radioimmunotherapy / Q000009:adverse effects*; D013961:Thyroid Gland / Q000293:injuries / Q000528:radiation effects*; D013972:Thyrotropin / Q000097:blood
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D002272:Carcinoembryonic Antigen; D007074:Immunoglobulin G; D007205:Indium Radioisotopes; D007454:Iodides; D010472:Perchlorates; D017680:Potassium Compounds; C009006:potassium perchlorate; D013972:Thyrotropin; C010389:Lugol's solution