VASCular Impact of Angiogenic Treatment in Patients With Advanced Colorectal Cancer

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    University Hospital, Rouen
Updated on 3 April 2021


Antiangiogenic treatments are used in many tumor locations such as metastatic colorectal cancer (mCRC) with a significant improvement in carcinological results on overall survival and / or progression-free survival. However, their use is characterized by an increase in side effects and in particular cardiovascular effects such as high blood pressure (hypertension). One of the main classes of antiangiogens used in this indication is that of monoclonal antibodies, the leader of which is bevacizumab (Avastin, Roche, Bale, Switzerland). Bevacizumab works by inhibiting endothelial vascular growth factor-dependent neoangiogenesis (vascular endothelial growth factor VEGF). In the reference studies, the inhibition of VEGF, whether extracellular (monoclonal antibody directed against VEGFA) or intracellular (receptor inhibitors with tyrosine kinase activity), induces hypertension of all grades, observed in 25% to 40 % of patients including 8 to 17% of severe grades ( grade 3 NCI-CTCAE). In terms of pathophysiology, inhibition of VEGFA results in a decrease in the availability of nitric oxide (NO) at the endothelial level and the appearance of arteriolar rarefaction. This induces an increase in peripheral resistance responsible ultimately for an increase in blood pressure. The occurrence of hypertension induced by anti-VEGF treatment seems to be predictive of the carcinological response in certain oncological situations such as metastatic breast cancer9, glioblastoma and mRCC. Furthermore, it has also been shown that there is an early attack on the elastic conductance arteries (branches of the aorta and its main ones) characterized by an increase in their rigidity in patients exposed to a VEGF receptor inhibitor with tyrosine activity. kinase or bevacizumab. This increase, whose poor prognostic impact is known at the cardiovascular level is largely independent of the rise in blood pressure and reflects a direct toxicity of treatments at the level of the artery wall. This increase in rigidity, refused when the pressure rises, would be predictive of a low carcinological response rate at 6 months. However, these data are based on populations that are heterogeneous in terms of carcinology and the position prior to or concomitant with other antineoplastic treatments.

In this context, the evaluation of arterial stiffness in the same patient population would make it possible to better define the involvement of the conductive arteries in a clearly defined clinical situation. Joint measurements of the plasma concentration of the treatment as well as those of factors derived from the endothelium and circulating tumor markers which, to our knowledge, have never been carried out in these patients, would make it possible to better specify the mechanisms of involvement and the links between exposure, arterial toxicity and carcinologic efficacy of bevacizumab. Of course, in order to assess more precisely the inherent impact of chemotherapy on the conductance arteries, the evolution of arterial stiffness must take into account the possible effects in patients receiving, for essentially clinical and biological reasons, systemic treatment without antiangiogenic.

Condition Oncology
Treatment Bevacizumab in combination with chemotherapy based on fluoropyrimidine IV
Clinical Study IdentifierNCT04813913
SponsorUniversity Hospital, Rouen
Last Modified on3 April 2021


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Inclusion Criteria

Patient at least 18 years old
Patient with colorectal cancer of the adenocarcinoma type, stage IV, histologically confirmed, mutated or wild tumor RAS status (exons 2, 3 and 4 of the KRAS and NRAS genes), mutated or wild BRAF status, naive in antineoplastic treatment
Patient eligible to start systemic carcinological treatment including bevacizumab in combination with chemotherapy based on IV fluoropyrimidine
General condition WHO grade less than or equal to 3
Life expectancy greater than 4 months
Patient who has read and understood the information letter and signed the consent form
Patient affiliated to a social security scheme
Effective contraception (see WHO definition) in women of childbearing age (negative pregnancy test). For postmenopausal women, a confirmatory diagnosis should be obtained (amenorrhea not medically induced for at least 12 months before the inclusion visit)

Exclusion Criteria

Previous exposure to anti-VEGF
Exposure to treatment for metastatic disease in the 12 months prior to inclusion
Other histologically proven neoplasia not considered in complete remission or considered in complete remission for less than two years
Bilateral carotid breath
Absence of peripheral pulse of the two upper limbs
Contraindication to AVASTIN 25 mg / ml concentrate for solution for infusion
Hypersensitivity to the active substance or to any of the excipients
Hypersensitivity to Chinese hamster ovarian cell products or other human or humanized recombinant antibodies
having undergone a major surgical intervention in the 28 days preceding the inclusion or as long as the surgical wound is not completely healed
Unhealed ulcer or wound
having uncontrolled pre-existing hypertension (PAS> or = 170 mm Hg after three repeated measurements at rest)
having a history of arterial thromboembolism (transient ischemic attack (TIA), cardiovascular accident (stroke) or recent (<6 months) and / or symptomatic myocardial infarction (MI)
having had an invasive dental procedure in the 28 days preceding inclusion
with known proteinuria> 2g / 24h or in whom proteinuria> 2g / 24h is discovered in the case of a positive urine strip 3+ for proteins (excluding urinary tract infection)
on aspirin> 325 mg / d
with a colonic prosthesis in place
Systemic treatment with anti-EGFR monoclonal antibodies
Presence or history of lymphedema of the bilateral upper limbs
Patient with poor understanding of spoken or written French
Patient deprived of liberty by an administrative or judicial decision or patient placed under the protection of justice, under guardianship or curatorship
Pregnant or lactating woman or wishing to breastfeed within 6 months after the last administration of the treatment
Patient participating in another drug trial / having participated in another drug trial within 30 days of inclusion
History of illness or psychological or sensory abnormality likely to prevent the subject from fully understanding the conditions required for his participation
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