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  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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. Specific Algorithm for Bevacizumab-Calcium Channel Blockers often agents of first choice
  10. Putting it together-therapeutic recommendations based on purported hypertensive mechanisms
  11. 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