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Anti-Hypertensives and Cancer Therapy
A Rational Approach
Topics that
will be
covered
• Grading of hypertension-therapeutic goals
• Incidence and pathophysiology of
hypertension in cancer patients
• Currently available antihypertensive agents
or malignancy associated hypertension
• Finally -Theoretical/clinically verified
anticancer effects of antihypertensive agents
ANTIHYPERTENSIVES IN CA.pptx
Grading of hypertension and therapeutic goals
• General cancer population→ goal is maintenance of pressure <140/90 if no concomitant
significant cardiovascular risk factors
• If estimated 10-year ASCVD risk of ≥10%, or additional cardiovascular
comorbidities(diabetes, chronic renal failure→goal BP < 130/80
• Patient should have their own cuff and be self-monitoring TID until stability established
• White coat hypertension and mask hypertension→ both more common in cancer patients
• 24 hour outpatient monitoring x several days may be considered if there are reliability
considerations or other variables
The nature/magnitude of the problem
• Hypertension is a well-established risk factor for heart failure and atherosclerotic cardiovascular disease
in the general population as well as cancer patients
• Hypertension increases the risk of death from stroke, heart disease, and other vascular conditions.
• Hypertensive men are at a higher risk of developing prostate/renal cancer, women at a higher risk of
for endometrial and breast cancers
• Etiological Hypothesis → elevated angiotensin II stimulates VEGF production and cancer
angiogenesis
• Hypertension,especially if poorly-controlled significantly increases the risk for chemotherapy-
induced cardiomyopathy/heart failure-especially true with anthracycline /Her-2 therapy/anti-VEGF
therapy
• Anthracycline Mechanism→Hypertension iincreases systemic vascular resistance/pressure
overload→ increased left ventricular stress wall→ release of growth factor in cytokines→ concentric
ventricular modelling and hypertrophy
• Herceptin Mechanism→inhibition epidermal growth factor receptor (HER2) activity in cardiomyocytes
interferes with nitric oxide synthesis and sarcomere preservation
• VEGF Inhibitor Mechanisms→multiple→endothelial dysfunction, renal toxicity, autonomic dysfunction
• Multi-targeted TKI inhibitor mechanisms→ endothelial dysfunction and interference renin/angiotensin
ANTIHYPERTENSIVES IN CA.pptx
ANTIHYPERTENSIVES IN CA.pptx
Specific Considerations- VEGF inhibitors
• Hypertension is the most reported cardiovascular side effect of VEGF inhibitors with incidence
ranging from 17 to 80%
• Mechanism is multifactorial but significant interference with endothelial function, especially nitric
oxide/ prostaglandin production involved in vasodilation
• Overall incidence is approximately 20% -with severe hypertension 8-10%
• Risk factors include higher dosing (15 versus 7.5 mg/kilo),Afro Canadian ancestry, renal cancer,
and age >75
• Occurs early on in drug introduction→ minimum target blood pressure <140/90→Ideal <130/80→hold
medication for >160/100
• Patients should have their own cuff and perform regular home monitoring at least 2-3 x daily
• Monitor each visit for hypertensive induced proteinuria→ follow-up + dipstick with 24 hour quantitation
• Antihypertensive of first choice is calcium channel blocker followed by ACE inhibitor
• Hypertension fortunately often reversible post therapy→80% normalization within 3 months
ANTIHYPERTENSIVES IN CA.pptx
Specific Considerations- TKI’s
• Multi-targeted TKI’s (sorafenib, sunitinib, lenvatinib, axitinib, pazopanib, cabozantinib,Ibrutinib), are used for
treating multiple cancers→RCC, hepatocellular carcinoma, metastatic melanoma, GIST and neuroendocrine
tumors
• Overall incidence varies but is approximately 20% -with severe hypertension 5%
• Amongst these agents, Axitinib has been associated with the highest incidence of hypertension
• Ibrutinib hypertension also 20% with 5% grade 3 or 4
• In real cancer, developmentof TKI hypertension may actually serve as a biomarker for overall therapeutic
efficacy
• Mechanism is multifactorial but significant interference with endothelial function, especially nitric
oxide/ prostaglandin production and activation of the renin/angiotensin system
• Occurs early on in drug introduction→ minimum target blood pressure <140/90→Ideal <130/80→hold
medication for >160/100
• Patients should have their own cuff and perform regular home monitoring at least 2-3 x daily
• Hypertension associated with TKIs usually does not require Rx interruption→antihypertensive therapy usually
sufficient
• Similar to Bevacizumab-hypertension usually reversible post therapy→80% normalization within 3 months
Specific Considerations- Other antineoplastic agents
Myeloma-Proteasome Inhibitor’s
• Carfilzomib(15%), Bortezomib (5%) Ixazomib (5%)have all been associated with hypertension
• Mechanism is thought to be the accumulation of ubiquitinated proteins producing endothelial
damage/dysfunction
Prostate cancer
• Abiraterone interferes with CYP17 , shutting off cortisone production and shunting pathway into
mineralocorticoid/aldosterone production
• Enzalutamide/Apalutamide have also been associated with hypertension possibly relating to their effects on
the androgen receptor
Corticosteroids
• Glucocorticoid-induced hypertension has been reported in up to 13% of patients
• Mechanisms → sodium / water retention, intrinsic vasoconstriction, sensitization to endogenous
vasopressors.
Alkylating agents
• May result in long-lasting hypertension in more than 50% of those treated-especially Cisplatin
• Mechanism is thought to be endothelial damage and nephrotoxicity
Available antihypertensive agents-overview
A number of chemotherapeutic agents have been associated with an increased incidence of
hypertension
Antihypertensive drugs available to manage cancer associated hypertension-major
pharmacological categories:
• diuretics
• angiotensin-converting enzyme inhibitors
• angiotensin II receptors
• direct aldosterone antagonists b-blockers
• calcium channel blockers
Agents of first choice tend to be calcium channel blockers and ARB/ACE inhibitors and diuretic
should be used with caution because of their potential effects on vascular volume and renal
function
Beta-blockers may be useful if there is concomitant left ventricular dysfunction (HER2 agents)
Smaller doses of multiple agents may be preferable to full therapeutic dose of a single agent
Target blood pressures have been well defined for the cancer population
ANTIHYPERTENSIVES IN CA.pptx
Specific Algorithm for Bevacizumab-Calcium Channel Blockers often agents of first choice
Putting it together-therapeutic recommendations based on purported hypertensive mechanisms
All is not Doom and Gloom-Antihypertensive
Possible anti-tumoral mechanisms/benefits
• Calcium channel blockers maybe associated with intracellular calcium accumulation
promoting apoptosis so theoretically useful for cancer treatment
• ACE inhibitors are anti-RAS agents, anti-angiogenic (suppressing VEGF) and appear to
potentially limit the amount of DNA damage in colon cancer
• Spironolactone has a direct antiangiogenic effect which accounts for its side effect of
gynecomastia
• A systematic review suggested ACE and ARB may be associated with improved
outcomes in non-small cell lung cancer, pancreatic cancer, and breast cancer
• Beta-blockers have been reported to reduce both angiogenesis and oncogenesis
• Calcium channel blockers promote apoptosis by increasing intracellular calcium
accumulation –they also inhibit P glycoprotein function-so there is a question of re-sensitize
chemo-resistant cells by inhibiting the intracellular removal of chemotherapeutic agents
• Summary: there is significant evidence that not only is there a beneficial effect in oncology
from antihypertensive agents regarding the control of hypertension/cardiovascular toxicity,
but these drugs may also function as therapeutic adjuvants in a number of tumor types
ANTIHYPERTENSIVES IN CA.pptx

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ANTIHYPERTENSIVES IN CA.pptx

  • 1. Anti-Hypertensives and Cancer Therapy A Rational Approach
  • 2. Topics that will be covered • Grading of hypertension-therapeutic goals • Incidence and pathophysiology of hypertension in cancer patients • Currently available antihypertensive agents or malignancy associated hypertension • Finally -Theoretical/clinically verified anticancer effects of antihypertensive agents
  • 4. Grading of hypertension and therapeutic goals • General cancer population→ goal is maintenance of pressure <140/90 if no concomitant significant cardiovascular risk factors • If estimated 10-year ASCVD risk of ≥10%, or additional cardiovascular comorbidities(diabetes, chronic renal failure→goal BP < 130/80 • Patient should have their own cuff and be self-monitoring TID until stability established • White coat hypertension and mask hypertension→ both more common in cancer patients • 24 hour outpatient monitoring x several days may be considered if there are reliability considerations or other variables
  • 5. The nature/magnitude of the problem • Hypertension is a well-established risk factor for heart failure and atherosclerotic cardiovascular disease in the general population as well as cancer patients • Hypertension increases the risk of death from stroke, heart disease, and other vascular conditions. • Hypertensive men are at a higher risk of developing prostate/renal cancer, women at a higher risk of for endometrial and breast cancers • Etiological Hypothesis → elevated angiotensin II stimulates VEGF production and cancer angiogenesis • Hypertension,especially if poorly-controlled significantly increases the risk for chemotherapy- induced cardiomyopathy/heart failure-especially true with anthracycline /Her-2 therapy/anti-VEGF therapy • Anthracycline Mechanism→Hypertension iincreases systemic vascular resistance/pressure overload→ increased left ventricular stress wall→ release of growth factor in cytokines→ concentric ventricular modelling and hypertrophy • Herceptin Mechanism→inhibition epidermal growth factor receptor (HER2) activity in cardiomyocytes interferes with nitric oxide synthesis and sarcomere preservation • VEGF Inhibitor Mechanisms→multiple→endothelial dysfunction, renal toxicity, autonomic dysfunction • Multi-targeted TKI inhibitor mechanisms→ endothelial dysfunction and interference renin/angiotensin
  • 8. Specific Considerations- VEGF inhibitors • Hypertension is the most reported cardiovascular side effect of VEGF inhibitors with incidence ranging from 17 to 80% • Mechanism is multifactorial but significant interference with endothelial function, especially nitric oxide/ prostaglandin production involved in vasodilation • Overall incidence is approximately 20% -with severe hypertension 8-10% • Risk factors include higher dosing (15 versus 7.5 mg/kilo),Afro Canadian ancestry, renal cancer, and age >75 • Occurs early on in drug introduction→ minimum target blood pressure <140/90→Ideal <130/80→hold medication for >160/100 • Patients should have their own cuff and perform regular home monitoring at least 2-3 x daily • Monitor each visit for hypertensive induced proteinuria→ follow-up + dipstick with 24 hour quantitation • Antihypertensive of first choice is calcium channel blocker followed by ACE inhibitor • Hypertension fortunately often reversible post therapy→80% normalization within 3 months
  • 10. Specific Considerations- TKI’s • Multi-targeted TKI’s (sorafenib, sunitinib, lenvatinib, axitinib, pazopanib, cabozantinib,Ibrutinib), are used for treating multiple cancers→RCC, hepatocellular carcinoma, metastatic melanoma, GIST and neuroendocrine tumors • Overall incidence varies but is approximately 20% -with severe hypertension 5% • Amongst these agents, Axitinib has been associated with the highest incidence of hypertension • Ibrutinib hypertension also 20% with 5% grade 3 or 4 • In real cancer, developmentof TKI hypertension may actually serve as a biomarker for overall therapeutic efficacy • Mechanism is multifactorial but significant interference with endothelial function, especially nitric oxide/ prostaglandin production and activation of the renin/angiotensin system • Occurs early on in drug introduction→ minimum target blood pressure <140/90→Ideal <130/80→hold medication for >160/100 • Patients should have their own cuff and perform regular home monitoring at least 2-3 x daily • Hypertension associated with TKIs usually does not require Rx interruption→antihypertensive therapy usually sufficient • Similar to Bevacizumab-hypertension usually reversible post therapy→80% normalization within 3 months
  • 11. Specific Considerations- Other antineoplastic agents Myeloma-Proteasome Inhibitor’s • Carfilzomib(15%), Bortezomib (5%) Ixazomib (5%)have all been associated with hypertension • Mechanism is thought to be the accumulation of ubiquitinated proteins producing endothelial damage/dysfunction Prostate cancer • Abiraterone interferes with CYP17 , shutting off cortisone production and shunting pathway into mineralocorticoid/aldosterone production • Enzalutamide/Apalutamide have also been associated with hypertension possibly relating to their effects on the androgen receptor Corticosteroids • Glucocorticoid-induced hypertension has been reported in up to 13% of patients • Mechanisms → sodium / water retention, intrinsic vasoconstriction, sensitization to endogenous vasopressors. Alkylating agents • May result in long-lasting hypertension in more than 50% of those treated-especially Cisplatin • Mechanism is thought to be endothelial damage and nephrotoxicity
  • 12. Available antihypertensive agents-overview A number of chemotherapeutic agents have been associated with an increased incidence of hypertension Antihypertensive drugs available to manage cancer associated hypertension-major pharmacological categories: • diuretics • angiotensin-converting enzyme inhibitors • angiotensin II receptors • direct aldosterone antagonists b-blockers • calcium channel blockers Agents of first choice tend to be calcium channel blockers and ARB/ACE inhibitors and diuretic should be used with caution because of their potential effects on vascular volume and renal function Beta-blockers may be useful if there is concomitant left ventricular dysfunction (HER2 agents) Smaller doses of multiple agents may be preferable to full therapeutic dose of a single agent Target blood pressures have been well defined for the cancer population
  • 14. Specific Algorithm for Bevacizumab-Calcium Channel Blockers often agents of first choice
  • 15. Putting it together-therapeutic recommendations based on purported hypertensive mechanisms
  • 16. All is not Doom and Gloom-Antihypertensive Possible anti-tumoral mechanisms/benefits • Calcium channel blockers maybe associated with intracellular calcium accumulation promoting apoptosis so theoretically useful for cancer treatment • ACE inhibitors are anti-RAS agents, anti-angiogenic (suppressing VEGF) and appear to potentially limit the amount of DNA damage in colon cancer • Spironolactone has a direct antiangiogenic effect which accounts for its side effect of gynecomastia • A systematic review suggested ACE and ARB may be associated with improved outcomes in non-small cell lung cancer, pancreatic cancer, and breast cancer • Beta-blockers have been reported to reduce both angiogenesis and oncogenesis • Calcium channel blockers promote apoptosis by increasing intracellular calcium accumulation –they also inhibit P glycoprotein function-so there is a question of re-sensitize chemo-resistant cells by inhibiting the intracellular removal of chemotherapeutic agents • Summary: there is significant evidence that not only is there a beneficial effect in oncology from antihypertensive agents regarding the control of hypertension/cardiovascular toxicity, but these drugs may also function as therapeutic adjuvants in a number of tumor types