Breitz H B, Fisher D R, Goris M L, Knox S, Ratliff B, Murtha A D, Weiden P L
Division of Nuclear Medicine, Virginia Mason Medical Center, Seattle, WA 98111, USA.
Cancer Biother Radiopharm. 1999 Oct;14(5):381-95. doi: 10.1089/cbr.1999.14.381.
Pretargeted radioimmunotherapy permits the administration of doses of 90Y five times higher than is possible with antibodies directly labeled with 90Yttrium (90Y). These high doses of 90Y introduced new issues for dosimetry that were not encountered in prior studies using conventional radioimmunotherapy. We have addressed these issues here and correlated dosimetry estimates with observed toxicity and tumor responses.
The pretargeted radioimmunotherapy (PRIT) system employed the antibody NR-LU-10 conjugated with streptavidin, a glycoprotein clearing agent and 90Y-DOTA-biotin. A single dose of 90Y was escalated to 140 mCi/m2. Indium-111(111In) (3-5 mCi) DOTA-biotin was co-injected for gamma camera imaging and dosimetry assessment. The effect of bremsstrahlung radiation from increasing 90Y activity levels with a constant dose of 111In was studied using a phantom. Patient images identified the intestinal tract and the kidneys as potential organs at risk of clinically significant radiation toxicity. A method of measuring the activity localized in the intestinal tract was developed, and S values were calculated to estimate intestinal wall dose from radioactivity present in the intestine. Intestinal, bone marrow and renal toxicity were observed. Coefficients were derived for correlating the relationships between observed intestinal and marrow toxicity and the estimated radiation absorbed doses.
At an 90Y:111In ratio of 50:1, bremsstrahlung radiation accounted for 12% of the counts in the images. Grade IV diarrhea was observed in patients estimated to have received 6850-14,000 cGy to the large intestinal wall. The correlation coefficient of intestinal toxicity with absorbed dose was 0.64. Myelotoxicity (measured as grade of suppression of absolute neutrophil count) correlated better with marrow dose (r = 0.72) than with the whole body dose, (r = 0.44). Delayed renal toxicity was observed in two patients 8 and 11 months following therapy. Tumor response was seen in the two patients with the highest estimated dose to tumor, 4,000-6,000 cGy.
Dosimetry is feasible using 111In as a tracer in the presence of high 90Y activity. The absorbed dose estimates derived in the PRIT schema correlated moderately well with clinically observed toxicity and response.
预靶向放射免疫疗法允许给予的钇-90（90Y）剂量比直接用钇-90（90Y）标记抗体时高出五倍。这些高剂量的90Y给剂量测定带来了新问题，而在以往使用传统放射免疫疗法的研究中并未遇到这些问题。我们在此解决了这些问题，并将剂量测定估计值与观察到的毒性和肿瘤反应相关联。
预靶向放射免疫疗法（PRIT）系统采用与链霉亲和素偶联的抗体NR-LU-10、一种糖蛋白清除剂和90Y-DOTA-生物素。90Y的单次剂量递增至140 mCi/m²。同时注射铟-111（111In）（3 - 5 mCi）DOTA-生物素用于γ相机成像和剂量测定评估。使用体模研究了在111In剂量恒定的情况下，随着90Y活度水平增加产生的轫致辐射的影响。患者图像确定肠道和肾脏为有临床显著辐射毒性风险的潜在器官。开发了一种测量肠道内局部活度的方法，并计算S值以根据肠道内存在的放射性估计肠壁剂量。观察到肠道、骨髓和肾脏毒性。得出了观察到的肠道和骨髓毒性与估计的辐射吸收剂量之间关系的相关系数。
在90Y:111In比例为50:1时，轫致辐射占图像计数的12%。估计大肠壁接受6850 - 14000 cGy辐射的患者出现了IV级腹泻。肠道毒性与吸收剂量的相关系数为0.64。骨髓毒性（以绝对中性粒细胞计数抑制等级衡量）与骨髓剂量（r = 0.72）的相关性优于与全身剂量（r = 0.44）的相关性。两名患者在治疗后8个月和11个月出现延迟性肾脏毒性。在估计肿瘤接受剂量最高的两名患者中观察到肿瘤反应，剂量为4000 - 6000 cGy。
在高90Y活度存在的情况下，使用111In作为示踪剂进行剂量测定是可行的。PRIT方案中得出的吸收剂量估计值与临床观察到的毒性和反应有适度的良好相关性。
