Explaining the unexplainable: discrepancies in results from the CALGB/SWOG 80405 and FIRE-3 studies
Explaining the unexplainable: discrepancies in results from the CALGB/SWOG 80405 and FIRE-3 studies
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DOI：
10.1016/s1470-2045(19)30172-x
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发表时间：
2019-05-01
期刊：
影响因子：
51.1
通讯作者：
Heinemann, Volker
中科院分区：
文献类型：
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作者：
Aderka, Dan;Stintzing, Sebastian;Heinemann, Volker
我们提出了一个工作假设，整合了CALGB/SWOG 80405和FIRE-3研究的数据，以解释其结果中的明显差异。两项试验均评估了西妥昔单抗或贝伐珠单抗与不同化疗方案的联合治疗：FIRE-3研究中所有患者接受伊立替康，CALGB/SWOG 80405研究中75%的患者接受奥沙利铂。该假设分为三个部分。首先，除了肿瘤的生物学或微环境以及两项试验所共有的生物靶向药物的选择之外，化疗本身也是决定治疗疗效的重要变量，因为生物疗法、化疗和微环境之间存在复杂的相互作用。其次，肿瘤微环境，如由共有分子亚型（CMS）分类所定义的，决定了化疗剂与生物靶向剂如贝伐单抗和西妥昔单抗的相互作用。尽管伊立替康与西妥昔单抗在所有CMS亚型中协同作用，但奥沙利铂可能具有不同的作用，在成纤维细胞贫乏的微环境中与西妥昔单抗协同作用，如CMS 2和CMS 3，但激活成纤维细胞丰富的微环境，如CMS 1和CMS 4，释放可能拮抗一些西妥昔单抗作用的细胞因子。第三，前面的假设整合成一个最终的概念，即总生存期不仅取决于生物治疗或一线治疗，而且具体取决于一线和二线方案的顺序以及它们之间的协同作用程度。在临床环境中，生物治疗和化疗的最佳一线组合预先决定了特定二线治疗的交叉，这会影响特定肿瘤亚型患者的总生存期。我们的工作假设表明，CALGB/SWOG 80405和FIRE-3研究是互补的，而不是不一致的，它提供了一个解释，他们的相反的解释。总之，正确解释CALGB/SWOG 80405和FIRE-3结果需要深入研究复杂的相互作用，不仅是靶向生物制剂和化疗药物之间的相互作用，而且是治疗与肿瘤生物学和微环境之间的相互作用。
We propose a working hypothesis that integrates data from the CALGB/SWOG 80405 and FIRE-3 studies to explain apparent discrepancies in their results. Both trials assessed the combination of either cetuximab or bevacizumab with a different chemotherapy backbone: irinotecan in all patients in the FIRE-3 study, or oxaliplatin in 75% of the patients in the CALGB/SWOG 80405 study. The hypothesis is divided into three parts. Firstly, in addition to the biology or microenvironment of the tumour and the selection of the biologically targeted agents common to both trials, chemotherapy itself is an important variable that determines treatment efficacy because of a complex interplay between the biological therapy, the chemotherapy, and the microenvironment. Secondly, the tumour microenvironment, as defined by the Consensus Molecular Subtypes (CMS) classification, determines the interaction of chemotherapeutic agents with biologically targeted agents such as bevacizumab and cetuximab. Whereas irinotecan synergises with cetuximab across all CMS subtypes, oxaliplatin might have variable effects, synergising with cetuximab in fibroblast-poor microenvironments, such as CMS2 and CMS3, but activating fibroblast-rich microenvironments, such as CMS1 and CMS4, to release cytokines that might antagonise some of the cetuximab effects. Thirdly, the previous assumptions integrate into a final concept, which is that overall survival is determined not only by the biological therapy or the first-line treatment, but specifically by the sequence of first-line and second-line regimens, and the degree of synergism between them. In a clinical setting, the optimal first-line combination of biological therapy and chemotherapy predetermines the crossover to a specific second-line treatment, which affects the overall survival of a patient with a specific tumour subtype. Our working hypothesis suggests that the CALGB/SWOG 80405 and FIRE-3 studies are complementary rather than discrepant, and it provides an explanation for their opposing interpretations. In conclusion, proper interpretation of the CALGB/SWOG 80405 and FIRE-3 results requires an in-depth examination of the complex interplay, not only between the targeted biological agents and chemotherapeutic drugs, but also between therapies and the tumour biology and microenvironment, for each line of treatment.