Radioimmunotherapy of prostate cancer using 90Y- and 177Lu-labeled J591 monoclonal antibodies: effect of multiple treatments on myelotoxicity.

Abstract

PURPOSE:

Bone marrow is the dose-limiting organ in radioimmunotherapy. Fractionated dose regimens may decrease myelotoxicity and increase greater total administered dose. We have studied the effect of two or three treatments of 177Lu-J591 and 90Y-J591 monoclonal antibodies (mAb) on myelotoxicity.

EXPERIMENTAL DESIGN:

J591 is a deimmunized anti-PSMA mAb. Seven groups of patients with prostate cancer (n = 35) received 10 to 75 mCi/m2 of 177Lu-J591 and five additional groups (n = 28) received 5 to 20 mCi/m2 of 90Y-J591. Fifteen patients received two to three treatments of 177Lu-J591 (30, 45, or 60 mCi/m2) and four patients received two or three doses of 90Y-J591 (17.5 or 20 mCi/m2). Re-treatment consisted of patients receiving the same 177Lu or 90Y dose as their initial cycle. Time between treatments was 2 to 4 months.

RESULTS:

The single dose maximum tolerated dose was 70 mCi/m2 with 177Lu-J591 and 17.5 mCi/m2 with 90Y-J591. With a single dose of 177Lu, no severe toxicity was observed below 60 mCi/m2. With 177Lu, two doses of 45 or 60 mCi/m2, totaling 90 to 120 mCi/m2, proved to be quite toxic. Three doses of 30 mCi/m2 (total 90 mCi/m2), however, were well tolerated. With 90Y, four patients tolerated two to three doses of 17.5 or 20 mCi/m2. Thrombocytopenia increased at higher doses and after repeat treatments. At higher doses, the nadir was lower and the time to reach nadir was longer. Time for recovery of platelets seems related to the total dose.

CONCLUSIONS:

Multiple (two or three) administrations of 177Lu-J591 (30-60 mCi/m2) or 90Y-J591 (17.5 mCi/m2) over a 4- to 6-month period were tolerated by the patients with manageable thrombocytopenia. Although a single large dose may deliver optimal radiation dose to kill a larger fraction of tumor cells, fractionated therapy offers the advantage of lower myelotoxicity and prolonged tumor response. With 177Lu-J591, dose fractionation in combination with taxanes should be considered as an alternative approach to achieve optimal therapeutic efficacy in patients with prostate cancer.

• Authors: Shankar Vallabhajosula, Stanley J Goldsmith, Lale Kostakoglu, Mathew I Milowsky, David M Nanus, Neil H Bander
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 19 Pt 2 Pg. 7195s-7200s (Oct 01 2005) ISSN: 1078-0432 [Print] United States
• PMID: 16203821 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• J591 monoclonal antibody
• Radioisotopes
• Yttrium Radioisotopes
• Lutetium
• Prostate-Specific Antigen

Topics

• Antibodies, Monoclonal (administration & dosage, chemistry, therapeutic use)
• Blood Platelets (metabolism)
• Bone Marrow (drug effects, radiation effects)
• Dose Fractionation, Radiation
• Follow-Up Studies
• Humans
• Lutetium (administration & dosage, therapeutic use)
• Male
• Maximum Tolerated Dose
• Prostate-Specific Antigen (blood, metabolism)
• Prostatic Neoplasms (immunology, therapy)
• Radioimmunotherapy (methods)
• Radioisotopes (administration & dosage, therapeutic use)
• Thrombocytopenia (chemically induced)
• Time Factors
• Yttrium Radioisotopes (administration & dosage, therapeutic use)