Background:
Metastatic colorectal cancer (mCRC) is one of the most common and deadly cancers
worldwide. For most patients diagnosed with mCRC and managed with 5-fluorouracil (5-FU)/leucovorin plus
oxaliplatin (FOLFOX), the median survival time is still less than 2 years. Small molecule selective vascular endothelial
growth factor receptor (VEGFR) inhibitors have been demonstrated to have strong anti-tumour activity in
various cancer models.
Objective:
To demonstrate the efficacy and safety of selective VEGFR inhibitors in the management of mCRC.
Methods:
A comprehensive search in PubMed, EMBASE, Web of Science, Ovid MEDLINE, Google Scholar,
Springer and Cochrane Central databases was performed for randomized controlled trials (RCTs) focusing on the
effect of selective VEGFR inhibitors on mCRC. The primary outcome measures were progression-free survival
(PFS) rates, overall survival (OS) rates, complete response (CR), partial response (PR), stable disease (SD), progressive
disease (PD), objective response rates (ORRs), disease control rates (DCRs) and adverse effect (AE)
rates. The dates of the included studies ranged from the inception of the database to January 15, 2020.
Results:
Twenty-two RCTs were included. A total of 9362 patients met the inclusion criteria. Compared with
placebo, selective VEGFR inhibitors significantly increased the PFS rate, SD, PR and DCR, reduced PD, caused
more treatment-emergent adverse events (TEAEs), hypertension, hand-foot skin reaction, diarrhoea, fatigue, and
thrombocytopaenia and increased aspartate aminotransferase(AST) concentration. There was no significant difference
between selective VEGFR inhibitors and placebo regarding OS rate, CR, ORR, proteinuria, hyperbilirubinaemia
or alkaline phosphatase(ALP) concentration. Additionally, compared with FOLFOX4+placebo, FOLFOX4+
selective VEGFR inhibitors, clearly reduced PD, and caused more 3-4 AEs, serious AEs, hypertension,
hand-foot syndrome, diarrhoea, nausea, vomiting, decreased appetite, dehydration, fatigue, dizziness, neutropaenia
and thrombocytopaenia. For PFS rate, OS rate, CR, PR, SD, ORR, abdominal pain, peripheral sensory
neuropathy, asthaenia, anaemia and hypokalaemia rates, there was no significant difference between FOLFOX4+
selective VEGFR inhibitors and FOLFOX4+placebo. However, compared with FOLFOX4+bevacizumab,
FOLFOX4+selective VEGFR inhibitors, led to increased hypertension, neutropaenia, fatigue, thrombocytopaenia
and asthaenia. There is no clear difference between FOLFOX4+selective VEGFR inhibitors and FOLFOX4+
bevacizumab with regard to PFS rate, OS rate, CR, PR, SD, PD, ORR, diarrhoea, nausea, vomiting, peripheral
neuropathy and abdominal pain rates. Selective VEGFR inhibitors+cetuximab increased PFS and PR and
reduced PD compared to cetuximab, but there was no statistical difference between the two groups for OS and
SD.
Conclusion:
Compared with placebo or cetuximab, selective VEGFR inhibitors alone or combined with cetuximab
seemed to be more efficacious for mCRC respectively; however, the effects were not better than FOLFOX4
alone or when combined with bevacizumab for mCRC. Additionally, selective VEGFR inhibitors were not as safe
as placebo or FOLFOX4 alone or in combination with bevacizumab in mCRC.
Are All Anti-Angiogenic Drugs the Same in the Treatment of Second-Line Metastatic Colorectal Cancer? Expert Opinion on Clinical Practice