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Radioimmunotherapy of Prostate Cancer Using ⁹⁰Y- and ¹⁷⁷Lu-Labeled J591 Monoclonal Antibodies: Effect of Multiple Treatments on Myelotoxicity

Authors' Affiliations: ¹ Department of Radiology, Division of Nuclear Medicine; ² Division of Hematology and Medical Oncology, and ³ Laboratory of Urological Oncology, Department of Urology, New York Presbyterian Hospital, Weill Medical College of Cornell University, New York, New York

Requests for reprints: Shankar Vallabhajosula, Professor of Radiochemistry and Radiopharmacy, New York Weill Cornell Medical Center, 525 East 68th Street, STARR-221, New York, NY 10021. Phone: 212-746-4533; Fax: 212-746-9010; E-mail: svallabh{at}med.cornell.edu.

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.