Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, 56126, Italy.
Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori - Via Venezian, 20100, Milano, Italy.
Br J Cancer. 2018 Apr;118(7):955-965. doi: 10.1038/s41416-018-0015-z. Epub 2018 Mar 13.
Many factors, including histopathologic parameters, seem to influence the prognosis of patients undergoing resection of colorectal cancer liver metastases (CRCLM), although their relative weight is unclear. Histopathologic growth patterns (HGPs) of CRCLM may affect sensitivity to antiangiogenics. We aimed at evaluating differences in histopathologic parameters of response according to the use of bevacizumab or cetuximab as first-line targeted agents, and at exploring the prognostic and predictive role of HGPs.
We performed a comprehensive histopathologic characterisation of CRCLM from 159 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) or COI (capecitabine, oxaliplatin, and irinotecan) plus bevacizumab (N = 103) vs cetuximab (N = 56) in five first-line no-profit clinical trials.
Both major histopathologic response (tumour regression grade TRG1-2, 32 vs 14%, p = 0.013) and infarct-like necrosis (80 vs 64%, p = 0.035) were significantly higher in the bevacizumab than in the cetuximab group. Achieving major response positively affected relapse-free survival (RFS) (p = 0.012) and overall survival (OS) (p = 0.045), also in multivariable models (RFS, p = 0.008; OS, p = 0.033). In the desmoplastic HGP (N = 28), a higher percentage of major response was reported (57 vs 17% in pushing and 22% in replacement HGP, p < 0.001) and an unsignificant advantage from cetuximab vs bevacizumab was evident in RFS (p = 0.116). In the pushing HGP (N = 66), a significant benefit from bevacizumab vs cetuximab (p = 0.017) was observed. No difference was described in the replacement HGP (N = 65, p = 0.615).
The histopathologic response is the only independent determinant of survival in patients resected after triplets plus a biologic. When associated with triplet chemotherapy, bevacizumab induces a higher histopathologic response rate than cetuximab. The assessment of HGPs should be further explored as a predictor of benefit from available targeted agents.
包括组织病理学参数在内的许多因素似乎都影响着接受结直肠癌肝转移（CRCLM）切除术患者的预后，尽管其相对权重尚不清楚。CRCLM 的组织病理学生长模式（HGPs）可能会影响对血管生成抑制剂的敏感性。我们旨在评估根据贝伐珠单抗或西妥昔单抗作为一线靶向药物的使用情况，在组织病理学参数反应方面的差异，并探讨 HGPs 的预后和预测作用。
我们对 159 例接受二线切除术的患者的 CRCLM 进行了全面的组织病理学特征分析，这些患者在五项非营利临床试验中接受了三联奥沙利铂（亚叶酸、5-氟尿嘧啶、奥沙利铂和伊立替康）或 COI（卡培他滨、奥沙利铂和伊立替康）加贝伐珠单抗（N=103）或西妥昔单抗（N=56）治疗。
贝伐珠单抗组的主要组织病理学反应（肿瘤消退分级 TRG1-2，32%比 14%，p=0.013）和梗死样坏死（80%比 64%，p=0.035）均显著高于西妥昔单抗组。获得主要反应对无复发生存（RFS）（p=0.012）和总生存（OS）（p=0.045）均有积极影响，在多变量模型中也是如此（RFS，p=0.008；OS，p=0.033）。在促结缔组织增生型 HGP（N=28）中，报告的主要反应百分比更高（57%比推挤型和替代型的 17%和 22%，p<0.001），并且在 RFS 中，西妥昔单抗与贝伐珠单抗的优势不明显（p=0.116）。在推挤型 HGP（N=66）中，贝伐珠单抗与西妥昔单抗的疗效差异有统计学意义（p=0.017）。在替代型 HGP（N=65，p=0.615）中，没有观察到差异。
组织病理学反应是接受三联化疗加生物治疗后切除患者生存的唯一独立决定因素。当与三联化疗联合使用时，贝伐珠单抗诱导的组织病理学反应率高于西妥昔单抗。HGPs 的评估应进一步作为现有靶向药物获益的预测因子进行探索。
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