Concepts for systemic treatment of micrometastases
Concepts for systemic treatment of micrometastases
复制标题
微转移的系统治疗概念
作者：
F. Schabel
如果完全杀死肿瘤细胞是“治愈”的必要条件，至少对某些肿瘤来说可能是这样，那么治疗含有1006个活肿瘤细胞的微转移是所有癌症治疗师面临的问题。106细胞的转移性肿瘤细胞灶，特别是如果广泛散布，大体上是不可检测的，因此是化疗师和免疫治疗师的适当靶点。目前对肿瘤细胞群体生长动力学的了解表明，生长分数（经历活跃细胞复制的活细胞）与群体大小呈负相关。因此，微转移瘤对抗代谢物（细胞周期特异性）抗癌药物的敏感性应高于其来源的较大、肉眼可见的原发性肿瘤。事实上，原发性肿瘤的药物反应可能无法可靠地预测微转移对细胞周期特异性药物的敏感性。此外，针对临床公认的肿瘤的有效但非治愈性药物的最佳药物治疗方案可能无法预测针对微转移的相同药物的最佳方案。这在细胞周期特异性药物中尤其明显，因为小群体病灶（< 107个细胞）中肿瘤细胞的生成时间通常显著短于较大群体病灶（> 107个细胞）。由于一级细胞杀伤动力学表征了药物对肿瘤细胞的有效杀伤，并且目前已知的最佳抗癌药物具有可变但通常有限的肿瘤细胞杀伤潜力，因此应在可能的非治愈性放射学或手术治疗结束后尽快开始可能的微转移的药物治疗。实验数据表明，与不存在放射灭活肿瘤细胞相比，存在放射灭活肿瘤细胞的情况下，存活肿瘤细胞数量显著减少，这表明放射治疗肿瘤部位残留的少量存活肿瘤细胞可能比手术后原位残留的类似大小的细胞群对临床治愈的威胁更大。实验数据支持上述概念，并进行了讨论。
If total tumor cell kill is a requirement for “cure,” as it probably is for at least some tumors, treatment of micrometastases containing ≦ 106 viable tumor cells is a problem facing all cancer therapists. Metastatic tumor cell foci of ≦ 106 cells, particularly if widely disseminated, are, in the main, grossly undetectable and are, therefore, the proper targets for the chemotherapist and the immunotherapist. Current knowledge of tumor cell population growth kinetics indicates that the growth fraction (viable cells undergoing active cell replication) is inversely related to population size. Micrometastases should, therefore, be more sensitive to antimetabolite (cell‐cycle‐specific) anticancer drugs than the larger, grossly apparent, primary tumor from which they were derived. In fact, drug response of the primary tumor may not reliably predict the sensitivity of micrometastases to cell‐cycle‐specific drugs. In addition, optimal drug treatment scheduling for effective, but noncurative, drugs against clinically recognized tumors may not predict optimal scheduling of the same drugs against micrometastases. This is shown particularly in cell‐cycle‐specific drugs, since the generation time of tumor cells in small population foci (< 107 cells) is often significantly shorter than in larger population foci (> 107 cells). Since first‐order cell kill kinetics characterizes effective drug kill of tumor cells and the best currently known anticancer drugs have variable but generally limited tumor cell kill potential, drug treatment of likely micrometastases should be started as soon after the end of likely noncurative radiologic or surgical treatment as possible. Experimental data indicating that significantly smaller numbers of viable tumor cells can establish lethal tumors in the presence of radiation‐inactivated tumor cells than in their absence suggest that small populations of residual viable tumor cells in radiation‐treated tumor sites may be a greater threat to clinical cure than similar sized populations remaining in situ after surgery. Experimental data supporting the above concepts are presented and discussed.