Engel Ryan H, Kaklamani Virginia G
Department of Medicine, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Robert H Lurie Comprehensive Cancer Center, 676 North Street Clair Street, Suite 850, Chicago, IL 60622, USA.
Expert Rev Anticancer Ther. 2006 Apr;6(4):477-85. doi: 10.1586/14737140.6.4.477.
Brain metastases from breast cancer are common and cause significant morbidity and mortality. Treatment with whole-brain radiotherapy provides a median survival of only 4-6 months. One mechanism affecting sensitivity to radiation is tumor oxygenation. Hypoxic tumor cells are more likely to be resistant to radiation and adversely affect prognosis. For nearly 70 years, all attempted modalities have failed to circumvent tumor hypoxia and increase tumor death. Abraham and colleagues developed a fibric acid derivative that would cause the displacement of oxygen from hemoglobin and improve tissue oxygenation. After modifications to enhance absorption into the red blood cell, RSR13 (efaproxiral) was developed. Efaproxiral was found to be safe and improved tumor oxygenation in preclinical studies. Early Phase I and II trials supported the earlier preclinical evidence while demonstrating that efaproxiral was safe and effective. A randomized Phase III study, Radiation Enhancing Allosteric Compounds of Hypoxic brain metastases (REACH, RT-009), failed to show a significant improvement in overall survival in all eligible patients treated with efaproxiral and whole-brain radiation. However, there was a statistically significant improvement in median survival and quality of life within a subset of metastatic breast cancer patients. Efaproxiral is currently being studied with radiotherapy in a confirmatory trial in the treatment of brain metastases from breast cancer. Furthermore, the combination of efaproxiral with radiotherapy is being investigated in other solid tumors.
乳腺癌脑转移很常见，会导致严重的发病率和死亡率。全脑放疗的中位生存期仅为4至6个月。影响辐射敏感性的一个机制是肿瘤氧合作用。缺氧的肿瘤细胞更有可能对辐射产生抗性，并对预后产生不利影响。近70年来，所有尝试的方法都未能规避肿瘤缺氧并增加肿瘤死亡。亚伯拉罕及其同事开发了一种纤维酸衍生物，它能使氧从血红蛋白中置换出来并改善组织氧合。在经过修饰以增强其进入红细胞的吸收能力后，RSR13（依氟普胺）被研制出来。在临床前研究中发现依氟普胺是安全的，并能改善肿瘤氧合。早期的I期和II期试验支持了早期的临床前证据，同时表明依氟普胺是安全有效的。一项随机III期研究，即缺氧性脑转移的放射增强变构化合物（REACH，RT - 009），在接受依氟普胺和全脑放疗的所有符合条件的患者中，未能显示总生存期有显著改善。然而，在一部分转移性乳腺癌患者中，中位生存期和生活质量有统计学上的显著改善。目前正在进行一项确证性试验，研究依氟普胺与放疗联合治疗乳腺癌脑转移。此外，依氟普胺与放疗的联合应用正在其他实体瘤中进行研究。
