Intraperitoneal alpha-particle radioimmunotherapy of ovarian cancer patients: pharmacokinetics and dosimetry of (211)At-MX35 F(ab')2--a phase I study.
The alpha-emitter (211)At labeled to a monoclonal antibody has proven safe and effective in treating microscopic ovarian cancer in the abdominal cavity of mice. Women in complete clinical remission after second-line chemotherapy for recurrent ovarian carcinoma were enrolled in a phase I study. The aim was to determine the pharmacokinetics for assessing absorbed dose to normal tissues and investigating toxicity.


METHODS
Nine patients underwent laparoscopy 2-5 d before the therapy; a peritoneal catheter was inserted, and the abdominal cavity was inspected to exclude the presence of macroscopic tumor growth or major adhesions. (211)At was labeled to MX35 F(ab')(2) using the reagent N-succinimidyl-3-(trimethylstannyl)-benzoate. Patients were infused with (211)At-MX35 F(ab')(2) (22.4-101 MBq/L) in dialysis solution via the peritoneal catheter. gamma-Camera scans were acquired on 3-5 occasions after infusion, and a SPECT scan was acquired at 6 h. Samples of blood, urine, and peritoneal fluid were collected at 1-48 h. Hematology and renal and thyroid function were followed for a median of 23 mo.


RESULTS
Pharmacokinetics and dosimetric results were related to the initial activity concentration (IC) of the infused solution. The decay-corrected activity concentration decreased with time in the peritoneal fluid to 50% IC at 24 h, increased in serum to 6% IC at 45 h, and increased in the thyroid to 127% +/- 63% IC at 20 h without blocking and less than 20% IC with blocking. No other organ uptakes could be detected. The cumulative urinary excretion was 40 kBq/(MBq/L) at 24 h. The estimated absorbed dose to the peritoneum was 15.6 +/- 1.0 mGy/(MBq/L), to red bone marrow it was 0.14 +/- 0.04 mGy/(MBq/L), to the urinary bladder wall it was 0.77 +/- 0.19 mGy/(MBq/L), to the unblocked thyroid it was 24.7 +/- 11.1 mGy/(MBq/L), and to the blocked thyroid it was 1.4 +/- 1.6 mGy/(MBq/L) (mean +/- SD). No adverse effects were observed either subjectively or in laboratory parameters.


CONCLUSIONS
This study indicates that by intraperitoneal administration of (211)At-MX35 F(ab')(2) it is possible to achieve therapeutic absorbed doses in microscopic tumor clusters without significant toxicity.
Andersson
Håkan
H
Department of Oncology, University of Gothenburg, Gothenburg, Sweden.
Cederkrantz
Elin
E
Bäck
Tom
T
Divgi
Chaitanya
C
Elgqvist
Jörgen
J
Himmelman
Jakob
J
Horvath
György
G
Jacobsson
Lars
L
Jensen
Holger
H
Lindegren
Sture
S
Palm
Stig
S
Hultborn
Ragnar
R
D000328:Adult; D000368:Aged; D000512:Alpha Particles / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001246:Astatine / Q000627:therapeutic use*; D001822:Body Burden; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000532:radiotherapy*; D016499:Radioimmunotherapy / Q000379:methods; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000627:therapeutic use; D011879:Radiotherapy Dosage; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D019275:Radiopharmaceuticals; D001246:Astatine