Impact of Antihypertensive Therapy on Recurrence Risk of Ovarian Cancer for Bevacizumab-associated Hypertension

Impact of Antihypertensive Therapy on Recurrence Risk of Ovarian Cancer for Patients Treated With Bevacizumab Maintenance: A Target Trial Emulation

Antiangiogenic therapies like bevacizumab, have notably improved cancer treatment, including for gynecological cancers, by inhibiting the vascular endothelial growth factor and thus limiting tumor growth. In treating advanced ovarian cancer, bevacizumab has been shown to extend progression-free survival by four months, though it also induces or worsens hypertension in 2 to 19% of patients by affecting vascular nitric oxide production or by capillary rarefaction. This hypertension may result in severe cardiovascular events, necessitating the use of antihypertensive drugs like calcium channel blockers and RAAS inhibitors (angiotensin converting enzyme - ACE - inhibitors mainly), despite some concerns about their effects on VEGF secretion and CA125 levels. Clinical guidelines vary, with some favoring ACE inhibitors while others recommend calcium channel blockers, underlining the need for comparative studies on these drugs' oncological and cardiovascular impacts. To address these issues, this study utilizes an emulated trial approach, leveraging comprehensive data from the French National Health Data System to compare the efficacy of these antihypertensive classes in reducing relapse and improving survival in ovarian cancer patients treated with bevacizumab.

The investigators will emulate a target clinical trial to compare the impact of antihypertensive treatments on outcomes of patients with bevacizumab-associated hypertension by ACE inhibitors (arm A) versus calcium channel blockers (CCBs, arm B) on the risk of ovarian cancer withdrawal after surgery.

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.

Inclusion Criteria:

• women with newly ovarian cancer diagnosis (FIGO III to IV)
• age over 18 years old at time of ovarian cancer diagnosis
• diagnosed between January 1, 2011 and December 31, 2020
• with debulking ovarian cancer surgery and adjuvant chemotherapy

Exclusion Criteria:

• not in the "Regime general" "Sécurité Sociale" reimbursement system
• without standard chemotherapy protocol (carbotaxol every 3 weeks or weekly)
• history of heart failure or heart surgery, cardiovascular infarction or any coronaropathy disease, cerebro-vascular disease, arteriopathy of the lower limb, within the year before ovarian cancer surgery. Patients with history of hypertension without any complications were not excluded.
• bevacizumab initiation prior to debulking surgery
• combination of antihypertensive classes prior bevaizumab or as the first-line hypertensive therapy of bevacizumab-associated hypertension
• antihypertensive monotherapy from other classes than CCBs and ACEi (ARBs, beta-blockers, diuretics etc...) as the anti-hypertensive therapy. Therapy could be initiated before ovarian surgery.

Complementary analysis :

- patients treated by ARBs