Nieder Carsten, Wiedenmann Nicole, Andratschke Nicolaus, Molls Michael
Department of Radiation Oncology, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
Cancer Treat Rev. 2006 Aug;32(5):348-64. doi: 10.1016/j.ctrv.2006.03.006. Epub 2006 May 19.
Angiogenesis inhibitors combined with cytotoxic chemotherapy have recently entered routine oncological practice. Several rationales exist for combining these agents with ionizing radiation, a primary curative cancer treatment, either in bimodal or trimodal fashion, i.e. with or without additional chemotherapy. More than 20 different anti-angiogenic agents have been studied in preclinical animal tumor models. This systematic review compares the results of preclinical studies published before February 2006. The combination of vascular endothelial growth factor (VEGF) inhibitors with irradiation consistently resulted in improved tumor growth delay (at least additive effects), despite different radiation schedules, drugs and doses, and combination regimens. Only two studies evaluated tumor control dose (TCD)50 as a measure of tumor cure (radiation dose yielding permanent local control in 50% of the tumors). While anti-VEGF receptor (VEGFR) antibody treatment improved the outcome, a VEGFR tyrosine kinase inhibitor showed negative results. For agents interfering with other pathways, the results are also not consistent, although most studies were positive. Trimodal approaches seem to improve tumor growth delay even further. Importantly, both radiotherapy schedule and sequence of the modalities in combined treatment may impact on the outcome. Hence, further preclinical studies examining these parameters need to be conducted. While preclinical research is ongoing, phase I and II clinical trials with bevacizumab, combretastatin A-4, thalidomide and different receptor tyrosine kinase inhibitors, usually combined with radio- and chemotherapy, have been designed. Early results suggest that acute toxicity is acceptable, planned surgery after such treatment is feasible, and that further evaluation of such combined modality treatment is warranted.
血管生成抑制剂与细胞毒性化疗药物联合使用最近已进入肿瘤学常规实践。将这些药物与作为主要癌症治愈性治疗手段的电离辐射以双峰或三峰方式联合使用，即联合或不联合额外化疗，存在多种理论依据。超过20种不同的抗血管生成药物已在临床前动物肿瘤模型中进行了研究。本系统评价比较了2006年2月之前发表的临床前研究结果。尽管放疗方案、药物和剂量以及联合方案各不相同，但血管内皮生长因子（VEGF）抑制剂与放疗联合使用始终能改善肿瘤生长延迟（至少有相加效应）。只有两项研究评估了肿瘤控制剂量（TCD）50作为肿瘤治愈的指标（使50%的肿瘤实现永久局部控制的辐射剂量）。虽然抗VEGF受体（VEGFR）抗体治疗改善了疗效，但一种VEGFR酪氨酸激酶抑制剂显示出阴性结果。对于干扰其他途径的药物，尽管大多数研究结果为阳性，但结果也不一致。三峰联合治疗方法似乎能进一步改善肿瘤生长延迟。重要的是，联合治疗中的放疗方案和治疗模式的顺序都可能影响疗效。因此，需要进行进一步的临床前研究来考察这些参数。在临床前研究仍在进行的同时，已经设计了针对贝伐单抗、康普瑞他汀A - 4、沙利度胺以及不同受体酪氨酸激酶抑制剂的I期和II期临床试验，这些药物通常与放疗和化疗联合使用。早期结果表明，急性毒性是可接受的，这种治疗后计划进行的手术是可行的，并且这种联合治疗模式值得进一步评估。
