RT Journal Article
SR Electronic
T1 Prediction of Myelotoxicity Based on Bone Marrow Radiation-Absorbed Dose: Radioimmunotherapy Studies Using <sup>90</sup>Y- and <sup>177</sup>Lu-Labeled J591 Antibodies Specific for Prostate-Specific Membrane Antigen
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 850
OP 858
VO 46
IS 5
A1 Vallabhajosula, Shankar
A1 Goldsmith, Stanley J.
A1 Hamacher, Klaus A.
A1 Kostakoglu, Lale
A1 Konishi, Shota
A1 Milowski, Mathew I.
A1 Nanus, David M.
A1 Bander, Neil H.
YR 2005
UL http://jnm.snmjournals.org/content/46/5/850.abstract
AB In radioimmunotherapy, myelotoxicity due to bone marrow radiation-absorbed dose is the predominant factor and frequently is the dose-limiting factor that determines the maximum tolerated dose (MTD). With 90Y- and 131I-labeled monoclonal antibodies, it has been reported that myelotoxicity cannot be predicted on the basis of the amount of radioactive dose administered or the bone marrow radiation-absorbed dose (BMrad), estimated using blood radioactivity concentration. As part of a phase I dose-escalation study in patients with prostate cancer with 90Y-DOTA-J591 (DOTA = 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid) (90Y-J591) and 177Lu-DOTA-J591 (177Lu-J591), we evaluated the potential value of several factors in predicting myelotoxicity. Methods: Seven groups of patients (n = 28) received 370–2,775 MBq/m2 (10–75 mCi/m2) of 177Lu-J591 and 5 groups of patients (n = 27) received 185–740 MBq (5–20 mCi/m2) of 90Y-J591. Pharmacokinetics and imaging studies were performed for 1–2 wk after 177Lu treatment, whereas patients receiving 90Y had these studies performed with 111In-DOTA-J591 (111In-J591) as a surrogate. The BMrad was estimated based on blood radioactivity concentration. Myelotoxicity consisting of thrombocytopenia or neutropenia was graded 1–4 based on criteria of the National Cancer Institute. Results: Blood pharmacokinetics are similar for both tracers. The radiation dose (mGy/MBq) to the bone marrow was 3 times higher with 90Y (0.91 ± 0.43) compared with that with 177Lu (0.32 ± 0.10). The MTD was 647.5 MBq/m2 with 90Y-J591 and 2,590 MBq/m2 with 177Lu-J591. The percentage of patients with myelotoxicity (grade 3–4) increased with increasing doses of 90Y (r = 0.91) or 177Lu (r = 0.92). There was a better correlation between the radioactive dose administered and the BMrad with 177Lu (r = 0.91) compared with that with 90Y (r = 0.75). In addition, with 177Lu, the fractional decrease in platelets (FDP) correlates well with both the radioactive dose administered (r = 0.88) and the BMrad (r = 0.86). In contrast, with 90Y, there was poor correlation between the FDP and the radioactive dose administered (r = 0.20) or the BMrad (r = 0.26). Similar results were also observed with white blood cell toxicity. Conclusion: In patients with prostate cancer, myelotoxicity after treatment with 177Lu-J591 can be predicted on the basis of the amount of radioactive dose administered or the BMrad. The lack of correlation between myelotoxicity and 90Y-J591 BMrad may be due to several factors. 90Y-J591 may be less stable in vivo and, as a result, higher amounts of free 90Y may be localized in the bone. In addition, the cross-fire effect of high-energy β−-particles within the bone and the marrow may deliver radiation dose nonuniformly within the marrow.