Impact of Antihypertensive Therapy on Recurrence Risk of Ovarian Cancer for Patients Treated With Bevacizumab Maintenance: A Target Trial Emulation
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 9,464
- 试验地点
- 2
- 主要终点
- Progression-free survival for ovarian cancer
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Other
- 时间视角
- Retrospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Main analysis - antihypertensive therapy with bevacizumab (ACEi or 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
干预措施: arm A - angiotensin converting enzyme inhibitors (ACEi) (Drug)
Main analysis - antihypertensive therapy with bevacizumab (ACEi or 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
干预措施: arm B - calcium channel blockers (CCBs) (Drug)
Complementarity analysis - 1st-line CCB vs ACEi vs ARBs
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)
干预措施: arm A - angiotensin converting enzyme inhibitors (ACEi) (Drug)
Complementarity analysis - 1st-line CCB vs ACEi vs ARBs
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)
干预措施: arm B - calcium channel blockers (CCBs) (Drug)
Complementarity analysis - 1st-line CCB vs ACEi vs ARBs
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)
干预措施: arm R - angiotensin receptor blockers ARB (Drug)
Sensitivity analysis
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.
干预措施: arm A - angiotensin converting enzyme inhibitors (ACEi) (Drug)
Sensitivity analysis
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.
干预措施: arm B - calcium channel blockers (CCBs) (Drug)
结局指标
主要结局
Progression-free survival for ovarian cancer
时间窗: 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
次要结局
- Major Cardiovascular Event (MACE) - narrow definition(Time from ovarian cancer first surgery to the time of MACE-narrow, assessed up to 7 years)
- Overall survival(OS is defined as the time, from ovarian cancer first surgery to death from any cause, assessed up to 7 years)
- Time to treatment failure (TTF)(Time from bevacizumab initiation to the first antihypertensive treatment switch or change to bitherapy, assessed up to 7 years)
- Major Cardiovascular Event (MACE) - broad definition(Time from ovarian cancer first surgery to the time of MACE-broad, assessed up to 7 years)
研究者
Paul Gougis
Principal Investigator
Groupe Hospitalier Pitie-Salpetriere