RT Journal Article
SR Electronic
T1 Cure of Human Ovarian Carcinoma Solid Xenografts by Fractionated α-Radioimmunotherapy with <sup>211</sup>At-MX35-F(ab′)<sub>2</sub>: Influence of Absorbed Tumor Dose and Effect on Long-Term Survival
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 598
OP 604
DO 10.2967/jnumed.116.178327
VO 58
IS 4
A1 Tom Bäck
A1 Nicolas Chouin
A1 Sture Lindegren
A1 Helena Kahu
A1 Holger Jensen
A1 Per Albertsson
A1 Stig Palm
YR 2017
UL http://jnm.snmjournals.org/content/58/4/598.abstract
AB The goal of this study was to investigate whether targeted α-therapy can be used to successfully treat macrotumors, in addition to its established role for treating micrometastatic and minimal disease. We used an intravenous fractionated regimen of α-radioimmunotherapy in a subcutaneous tumor model in mice. We aimed to evaluate the absorbed dose levels required for tumor eradication and growth monitoring, as well as to evaluate long-term survival after treatment. Methods: Mice bearing subcutaneous tumors (50 mm3, NIH:OVCAR-3) were injected repeatedly (1–3 intravenous injections 7–10 d apart, allowing bone marrow recovery) with 211At-MX35-F(ab′)2 at different activities (close to acute myelotoxicity). Mean absorbed doses to tumors and organs were estimated from biodistribution data and summed for the fractions. Tumor growth was monitored for 100 d and survival for 1 y after treatment. Toxicity analysis included body weight, white blood cell count, and hematocrit. Results: Effects on tumor growth after fractionated α-radioimmunotherapy with 211At-MX35-F(ab′)2 was strong and dose-dependent. Complete remission (tumor-free fraction, 100%) was found for tumor doses of 12.4 and 16.4 Gy. The administered activities were high, and long-term toxicity effects (≤60 wk) were clear. Above 1 MBq, the median survival decreased linearly with injected activity, from 44 to 11 wk. Toxicity was also seen by reduced body weight. White blood cell count analysis after α-radioimmunotherapy indicated bone marrow recovery for the low-activity groups, whereas for high-activity groups the reduction was close to acute myelotoxicity. A decrease in hematocrit was seen at a late interval (34–59 wk after therapy). The main external indication of poor health was dehydration. Conclusion: Having observed complete eradication of solid tumor xenografts, we conclude that targeted α-therapy regimens may stretch beyond the realm of micrometastatic disease and be eradicative also for macrotumors. Our observations indicate that at least 10 Gy are required. This agrees well with the calculated tumor control probability. Considering a relative biological effectiveness of 5, this dose level seems reasonable. However, complete remission was achieved first at activity levels close to lethal and was accompanied by biologic effects that reduced long-term survival.