Antiangiogenic therapies, such as bevacizumab, have significantly improved the treatment
landscape of various cancers, including gynecological types. Bevacizumab is a humanized
monoclonal IgG1 antibody targeting all forms of human vascular endothelial growth
factor-A (VEGF), essential for angiogenesis in healthy and cancerous tissues. This drug
inhibits angiogenesis primarily by blocking VEGF from activating its receptors, VEGFR, on
endothelial cells, thus limiting tumor growth by cutting off their blood supply and
aiding the effectiveness of cytotoxic drugs by reducing tumor interstitial pressure and
abnormal blood vessels.
For advanced ovarian cancer, bevacizumab was found to improve the median progression-free
survival of 4 months. However, targeting tumor vessels will eventually modify the
patients' vasculature, leading to hypertension in 2 to 19% of patients as per a
meta-analysis. VEGF-VEGFR pathway inhibition can cause hypertension by inhibiting the
production of nitric oxide in the arterial wall or by capillary rarefaction and increased
afterload. Several retrospective studies support a correlation between the occurrence of
a bevacizumab-associated hypertension (BIH) and outcomes, highlighting the link between
tumor and patient vasculature. However, bevacizumab-associated hypertension can lead, in
some rare cases, to major adverse cardiovascular events (MACE).
Multiple treatments have been proposed to control this adverse reaction. Calcium channel
blockers (CCBs) such as amlodipine have been proposed and offers a way to control
bevacizumab-associated hypertension. Angiotensin-converting enzyme inhibitors (ACEi),
which targets the renin-angiotensin-aldosterone system (RAAS) to control hypertension,
could also constitute an interesting option and could be more efficient.
However, there is both caution against the use of CCBs and ACEis, since nifedipine has
been shown to induce VEGF secretion in vitro, and ACEi (enalapril and perindopril) have
been associated in a case report with CA125 increase.
Current guidelines vary on the preferred class of medication for initial management of
antiangiogenic-associated hypertension. The European Society of Cardiology (ESC)
guidelines favor ACEis as the first-line treatment, whereas guidelines for gynecological
cancers suggest CCBs for managing BIH in patients without other comorbidities. This
discrepancy highlights the need for direct comparisons of oncologic and cardiologic
outcomes in this context.
Randomized controlled trials (RCTs), despite being the gold standard, face practical and
financial constraints that may limit their use. In the absence of RCT, observational data
can serve as a crucial alternative for estimating real-world causal effects. However,
observational studies come with challenges, such as confounding factors due to the lack
of randomization and the risk of immortal-time bias. A recent advancement in addressing
these challenges is the use of emulated trials, which strive to replicate the conditions
of a target RCT. This approach, employing propensity-score adjustment methods, has shown
promise in extracting the highest level of evidence from observational data. The SNDS,
covering 98.8% of the French population, offers extensive and detailed demographic,
health condition, and healthcare utilization data, enabling a thorough and representative
analysis of healthcare outcomes in oncology.
In this study, to address measured confounding at baseline, an exact copy of each
patient's record will be created and allocated to each arm of the study, ensuring
identical baseline characteristics across the study groups. Clones will be artificially
censored when their observed trajectories deviated from the treatment strategy of the arm
to which they were assigned. This informative artificial censoring introduces selection
bias over time, which will be addressed using inverse probability of censoring (IPC)
weights. Standardized mean differences (SMDs) will be derived to assess adjustment
quality after IPC weighting.
The per-protocol average treatment effect (ATE) will be estimated by the one- and
three-year differences in PFS probability and three-year restricted mean survival time
(RMST) differences in the IPC-weighted population. This will be visually assessed using
weighted Kaplan-Meier survival curves. Similar steps will be performed for overall
survival (OS) at one, three, and five years for survival probability differences, and at
five years for RMST.
This study focuses on comparing the effects of antihypertensive drugs - ACEi vs CCBs- on
the risk of relapse in patients undergoing adjuvant maintenance treatment with
bevacizumab for ovarian cancer after debulking surgery. It employs an emulation of a
clinical trial using data from the French National Health Data System (SNDS). Secondary
objectives will include examining the causal impact of these antihypertensive classes on
overall survival, the incidence of MACE and the time to treatment failure.
