Does bevacizumab impact anti-EGFR therapy efficacy in metastatic colorectal cancer?

Abstract

Anti-EGFR therapy and antiangiogenic therapies are used alone or in combination with chemotherapies to improve survival in metastatic colorectal cancer. However, it is unknown whether pretreatment with antiangiogenic therapy could impact on the efficacy of anti-EGFR therapy.We selected one hundred and twenty eight patients diagnosed with advanced colorectal cancer with a KRAS and NRAS unmutated tumor. These patients were treated with cetuximab or panitumumab alone or with chemotherapy as second or third-line. Univariate and multivariate Cox model analysis were performed to estimate the effect of a previous bevacizumab regimen on progression free survival and on overall survival during anti-EGFR therapy. In vitro studies using wild type KRAS and NRAS colon cancer cells were performed to evaluate the impact of VEGF-A on cetuximab-induced cell death.The median progression free survival (PFS) during anti-EGFR treatment was significantly different between the bevacizumab group and the non-bevacizumab group (2.8 and 4 months respectively; p = 0.003). The median overall survival from the beginning of the metastatic disease was similar in the two groups (41.3 and 42 months respectively; p = 0.7). In vitro, VEGF-A induced a resistance toward cetuximab cytotoxicity on three KRAS and NRAS wild type colon cancer cell lines in a VEGFR2 and Stat-3-dependent manner.All in all, our clinical data, supported by in vitro procedures, suggest that a previous anti-VEGF therapy decreases anti-EGFR efficacy. Although these results are observed in a limited cohort, they could be taken into consideration for a better strategy of care for patient suffering from metastatic colorectal cancer.

Sequential cetuximab/bevacizumab therapy is associated with improved outcomes in patients with wild‐type KRAS exon 2 metastatic colorectal cancer

“…Similar to our study, the Prodige 18 study and several retrospective studies have also demonstrated that prior bevacizumab therapy decreases the efficacy of subsequent cetuximab therapy. Although Modest et al reported that the application of anti‐EGFR therapy as first‐line therapy may represent a favorable condition for promoting the effectiveness of subsequent antiangiogenic agents, the diversity of second‐line therapy and imbalance of later‐line regimens contributed to the uncertainness of this result.…”

“…Preclinical studies in animal models and cancer cell lines have shown that after resistance to EGFR inhibitors was developed, constitutively high expression of VEGF, vascular endothelial growth factor receptor‐1(VEGFR‐1), and placental growth factor (PlGF) were noted, and inhibition of the VEGF pathway by VEGF inhibitor treatment was shown to be effective . In contrast, after bevacizumab pretreatment, hypoxia was induced in cancer cell lines, and subsequent EGFR‐independent RAS activation rendered the cells less sensitive to subsequent EGFR blockade . These phenomena might explain this study results; bevacizumab as third‐line therapy leads to prolonged duration of SD because this therapy alters the tumor microenvironment through the inhibition of VEGF/VEGFR.…”

“…Furthermore, subgroup analysis suggested that the OS improvement resulting from first‐line anti‐EGFR therapy may be the impact of subsequent later‐line therapies and the sequence of targeted therapies . Several retrospective studies have also indicated that cetuximab ( after bevacizumab failure may decrease the efficacy of cetuximab . However, a phase III trial (the CALGB study) comparing cetuximab‐based first‐line regimens with bevacizumab‐based first‐line regimens showed contradictory results; that is, no differences were observed in OS or progression‐free survival (PFS) between the two regimens .…”

“…16,17 Several retrospective studies have also indicated that cetuximab ( after bevacizumab failure may decrease the efficacy of cetuximab. [18][19][20] However, a phase III trial (the CALGB study) comparing cetuximabbased first-line regimens with bevacizumab-based first-line regimens showed contradictory results; that is, no differences were observed in OS or progression-free survival (PFS) between the two regimens. 21 The imbalance and diversity of later-line therapy in the FIRE3 study are critical issues that affect OS, instead of the therapy sequence.…”

S3-Leitlinie – Kolorektales Karzinom

“…Unter der Behandlung mit Bevacizumab plus Chemotherapie traten im Vergleich zur alleinigen Behandlung mit Chemotherapie folgende Grad-3 -5-Ereignisse häufiger auf: Blutungen/Hämorrhagie (2 vs. < 1 %), gastrointestinale Perforationen (2 vs. < 1 %) und venöse thromboembolische Ereignisse (5 vs. 3 %). Retrospektive klinische Untersuchungen weisen darauf hin, dass eine anti-EGFR-Therapie dann weniger wirksam ist, wenn ihr eine anti-VEGF-Therapie voranging [1168]. Präklinische Daten stützen diese Hypothese [1169,1170].…”