Impact of Antihypertensive Therapy on Recurrence Risk of Ovarian Cancer for Bevacizumab-associated Hypertension
- Conditions
- Antiangiogenic-Associated HypertensionAdjuvant BevacizumabOvarian CancerHypertension
- Interventions
- Drug: arm A - angiotensin converting enzyme inhibitors (ACEi)Drug: arm B - calcium channel blockers (CCBs)Drug: arm R - angiotensin receptor blockers ARB
- Registration Number
- NCT06515678
- Lead Sponsor
- Groupe Hospitalier Pitie-Salpetriere
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- Female
- Target Recruitment
- 9464
- 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
- 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
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Main analysis - antihypertensive therapy with bevacizumab (ACEi or CCBs) arm A - angiotensin converting enzyme inhibitors (ACEi) Adjuvant/maintenance bevacizumab after ovarian cancer debulking surgery with antihypertensive therapy monotherapy. Any patients with bevacizumab treated with monotherapy ACEi (arm A) or CCB (arm B) up to 6 months following debulking surgery Complementarity analysis - 1st-line CCB vs ACEi vs ARBs arm A - angiotensin converting enzyme inhibitors (ACEi) Adjuvant/maintenance bevacizumab after ovarian cancer debulking surgery with antihypertensive therapy monotherapy. Any patients with bevacizumab treated with Renin Angiotensin Aldosterone System (RAAS) inhibitor drug among ACEi (arm A) versus angiotensin receptor blocker ARB (arm R) versus CCB (arm B) Complementarity analysis - 1st-line CCB vs ACEi vs ARBs arm B - calcium channel blockers (CCBs) Adjuvant/maintenance bevacizumab after ovarian cancer debulking surgery with antihypertensive therapy monotherapy. Any patients with bevacizumab treated with Renin Angiotensin Aldosterone System (RAAS) inhibitor drug among ACEi (arm A) versus angiotensin receptor blocker ARB (arm R) versus CCB (arm B) Main analysis - antihypertensive therapy with bevacizumab (ACEi or CCBs) arm B - calcium channel blockers (CCBs) Adjuvant/maintenance bevacizumab after ovarian cancer debulking surgery with antihypertensive therapy monotherapy. Any patients with bevacizumab treated with monotherapy ACEi (arm A) or CCB (arm B) up to 6 months following debulking surgery Complementarity analysis - 1st-line CCB vs ACEi vs ARBs arm R - angiotensin receptor blockers ARB Adjuvant/maintenance bevacizumab after ovarian cancer debulking surgery with antihypertensive therapy monotherapy. Any patients with bevacizumab treated with Renin Angiotensin Aldosterone System (RAAS) inhibitor drug among ACEi (arm A) versus angiotensin receptor blocker ARB (arm R) versus CCB (arm B) Sensitivity analysis arm B - calcium channel blockers (CCBs) Sensitivity analysis S1 - Impact of Antihypertensive Treatment Switching. The investigators will utilize time-varying inverse probability of censoring weights (IPCW). The first step of the IPCW method consists in censoring patients who interrupt their initially assigned treatment. The second step of the IPCW method is thus to use IPCW with baseline covariates and time-dependent covariates linked to the treatment switching. (i) Number of cardiology consultations, (ii) Number of nephrology consultations or proteinuria, (iii) Number of cardiovascular events related to hypertension (MACE broad) Sensitivity analysis S2 - Exclusion of patients with isolated proteinuria or elevated proteinuria: The investigators will reproduce the main analysis, excluding patients with signs of isolated proteinuria or elevated proteinuria. Sensitivity analysis arm A - angiotensin converting enzyme inhibitors (ACEi) Sensitivity analysis S1 - Impact of Antihypertensive Treatment Switching. The investigators will utilize time-varying inverse probability of censoring weights (IPCW). The first step of the IPCW method consists in censoring patients who interrupt their initially assigned treatment. The second step of the IPCW method is thus to use IPCW with baseline covariates and time-dependent covariates linked to the treatment switching. (i) Number of cardiology consultations, (ii) Number of nephrology consultations or proteinuria, (iii) Number of cardiovascular events related to hypertension (MACE broad) Sensitivity analysis S2 - Exclusion of patients with isolated proteinuria or elevated proteinuria: The investigators will reproduce the main analysis, excluding patients with signs of isolated proteinuria or elevated proteinuria.
- Primary Outcome Measures
Name Time Method Progression-free survival for ovarian cancer PFS is defined as the time, from ovarian cancer first surgery to death, progression or recurrence, whichever occurres first, assessed up to 7 years The per-protocol average treatment effect (ATE) will be estimated by the one-, two-, and three-year differences in PFS probability, and three-year restricted mean survival time (RMST) differences in the IPC-weighted population.
The main outcome will be at three-year.
Covariate adjustment :
Covariates included in the inverse probability weighting are: (i) age at trial inclusion, (ii) number and type of comorbidities, (iii) economic deprivation level, (iv) number of general practitioner consultations the year before, (v) number of gynecologist consultation the year before, (vi) number of cardiology consultation at inclusion, (vii) number of nephrology consultation at inclusion, (viii) FIGO stage, (ix) surgical strategy, (x) hospital annual ovarian cancer volume, and (xi) hospital academic status
- Secondary Outcome Measures
Name Time Method Major Cardiovascular Event (MACE) - narrow definition Time from ovarian cancer first surgery to the time of MACE-narrow, assessed up to 7 years MACE-narrow is defined any acute myocardial infarction or cerebrovascular infarction. A competing risk model will be used for the occurrence of MACE narrow and broad, with death as a competing event. The investigators will utilize time-varying inverse probability of censoring weights (IPCW). The first step of the IPCW method consists in censoring patients who died. The death censoring mechanism may depend on the baseline and time-dependent factors. The IPCW method introduces weights to correct for this dependent censoring. The second step of the IPCW method is thus to use inverse probability of censoring weights with baseline covariates and time-dependent covariates : (i) Number of cardiology consultations, (ii) Number of nephrology consultations. MACE will be analyzed up to 36 months to assess the direct impact of bevacizumab use. Longer-term outcomes will be available in the supplemental only.
Overall survival OS is defined as the time, from ovarian cancer first surgery to death from any cause, assessed up to 7 years The per-protocol average treatment effect (ATE) will be estimated by the one-, two-, three-, and five-year differences in OS probability, and five-year restricted mean survival time (RMST) differences in the IPC-weighted population.
Time to treatment failure (TTF) Time from bevacizumab initiation to the first antihypertensive treatment switch or change to bitherapy, assessed up to 7 years Treatment failure is defined as the necessity to switch antihypertensive therapy, add a new antihypertensive therapy (bitherapy), the occurrence of a MACE-broad, recurrence or death. Time to antihypertensive treatment failure (TTF) will be assessed by the median TTF in each study arm (CCBs and ACEi). Dose increase was not considered a treatment failure. TTF is censored at bevacizumab withdrawal.
Major Cardiovascular Event (MACE) - broad definition Time from ovarian cancer first surgery to the time of MACE-broad, assessed up to 7 years MACE-narrow is defined any acute myocardial infarction or cerebrovascular infarction. A competing risk model will be used for the occurrence of MACE narrow and broad, with death as a competing event. The investigators will utilize time-varying inverse probability of censoring weights (IPCW). The first step of the IPCW method consists in censoring patients who died. The death censoring mechanism may depend on the baseline and time-dependent factors. The IPCW method introduces weights to correct for this dependent censoring. The second step of the IPCW method is thus to use inverse probability of censoring weights with baseline covariates and time-dependent covariates : (i) Number of cardiology consultations, (ii) Number of nephrology consultations. MACE will be analyzed up to 36 months to assess the direct impact of bevacizumab use. Longer-term outcomes will be available in the supplemental only.
Trial Locations
- Locations (2)
Institut Curie
🇫🇷Paris, France
Pitié-Salpêtrière
🇫🇷Paris, France