Hypertension and renal disease during anti-cancer therapies

VEGF inhibitors

Most cancer therapeutics that have been associated with hypertension have an antiangiogenic, vascular effect in common. The classic examples of this are VEGFIs. Indeed, the introduction of VEGFIs highlighted the importance of blood pressure management in the context of cancer therapy. VEGFI treatment causes an increase in blood pressure in almost all patients (up to 60% to 80% of patients in clinical trials). In a carefully characterized registry cohort, 73% of patients with renal cell cancer receiving targeted therapy (mainly VEGFI), developed cardiovascular toxicity, 55% of which was accounted for by hypertension. VEGFI-associated hypertension develops quickly, and may be difficult to treat, interferring with the delivery of optimal anti-cancer VEGFI therapy. ^, In addition to the acute effects of hypertension, as patients survive longer and receive VEGFIs for prolonged periods, the risk of chronic end-organ effects of hypertension, including myocardial ischaemia and infarction, heart failure, renal dysfunction, and stroke, are of increasing concern.

Variability in the definitions used for clinical trial reporting, together with blood pressure thresholds that are greater than those in evidence-based hypertension guidelines, means that the incidence of VEGFI-associated hypertension may be underestimated. ^{, ,} Additionally, patients with complicated hypertension or a history of cardiovascular disease are usually excluded from clinical trials and accordingly the real world incidence of VEGFI-associated hypertension may be higher than reported. ^, There have, however, been efforts to improve standardization of the definition of VEGFI-associated hypertension, with recommendations that such a diagnosis requires that the blood pressure be greater than 140/90 mm Hg on two to three occasions at least one week apart for most patients. The threshold for diagnosis is lower (130/80 mm Hg) for patients with additional cardiovascular risk factors, such as diabetes mellitus or renal impairment. ^{, ,} These definitions are based in large part on earlier guidelines where blood pressure targets were set at 140/90 mm Hg. However, many major current guidelines have lowered the definition of hypertension to a cutoff of 130/80 mm Hg and, accordingly, the definition of VEGFI-induced hypertension may also require modification. Based on the effect of VEGFI on the endothelium and the vasculature, these patients can be viewed as being at higher risk in general.

Within hours to days of starting treatment with VEGFIs, blood pressure rises in a dose-dependent manner. ^{, ,} This is potentiated when multiple anti-angiogenic agents are used in combination. In patients with renal cell cancer treated with sunitinib, blood pressure increased by an average of 14/11 mm Hg in the first week of treatment and by 22/17 mm Hg in the second week. This effect was persistent during sunitinib treatment, but reversed rapidly once VEGFI was withdrawn. The rapid and early rise in blood pressure can provoke acute complications, for example, in patients not previously ‘conditioned’ to the effects of hypertension an acute rise in blood pressure can precipitate acute end-organ complications, such as stroke, myocardial ischaemia, heart failure, and acute kidney injury at a lower threshold than might be expected in patients with long-standing hypertension. Posterior reversible leukoencephalopathy can occur, although this is rare (<1% of patients treated with VEGFI). Clinical signs and symptoms include headache, confusion, seizures, and visual impairment. Magnetic resonance T2-weighed imaging of the brain reveals edema, classically within the posterior fossa. The underlying pathophysiology seems to be related to the combination of hypertension, impaired cerebral autoregulation and cerebrovascular permeability/endothelial dysfunction. Importantly, with early recognition/diagnosis, prompt treatment of hypertension, and withdrawal of VEGFI therapy, the, prognosis is favorable.

The mechanisms responsible for VEGFI-associated hypertension remain incompletely defined, but alterations in vascular tone appear to be of fundamental importance. Proposed mechanisms include endothelial dysfunction, oxidative stress, upregulation of the endothelin-1 system, activation of the renin angiotensin aldosterone system, capillary rarefaction, and vascular remodelling as well as renal dysfunction with impaired sodium handling and increased salt sensitivity. There is a complex relationship between these various factors, and the relative contribution of each mechanism may vary at different stages in the progression of acute hypertensive effects through to sustained and chronically elevated blood pressures. Combination of VEGFI and other anti-cancer drugs may amplify hypertension and renal toxicity. For instance, in patients with hepatocellular carcinoma, treatment with combination VEGFI (bevacizumab) and programmed death 1 inhibitors (atezolizumab), was associated with a higher rate of hypertension and proteinuria than in patients treated with VEGFI (sorafenib) alone.

Conflicting evidence exists regarding risk factors predisposing patients to VEGFI-induced hypertension. Conventional cardiovascular risk factors, including older age (>65 years), previous history of hypertension, smoking, elevated body mass index, and possibly hypercholesterolemia have been linked with an increased risk of VEGF-induced hypertension. ^, However, other studies have suggested that these factors and others, including a history of vascular disease, reduced renal function, and family history of hypertension or cardiovascular disease are not predictive. ^,

As hypertension associated with VEGFI agents occurs as a pharmacodynamic on-target effect, it has been proposed that it may reflect effective inhibition of the VEGF signalling pathway and could be gauged as an indicator of the therapeutic response. Indeed, supportive evidence indicates that the development of VEGFI-associated hypertension is associated with one to two years greater progression-free and overall survival. ^, In light of this association between the development of hypertension and improved anti-cancer responses, it has been suggested that VEGFI-induced hypertension could be used to define the optimal biologically active doses of VEGFI drugs. However, this suggestion should be considered cautiously and the development of hypertension should not be used as a measure to guide the maximum possible dose of VEGFI agents for individual patients.

Non-VEGFIs

Although VEGFIs represent the class of anti-cancer drugs most associated with treatment-induced hypertension, it may also be encountered as a result of other anti-cancer agents, including platinum-based therapies, proteasome inhibitors, and mammalian target of rapamycin (mTOR) inhibitors and as a result of corticosteroid therapy, either alone or as adjuvant therapy. ^,

Monitoring blood pressure during cancer treatment

Although blood pressure control is important for patients receiving any form of cancer therapy, the rapid and potentially substantial rise in response to VEGFI means that this group should be considered a particularly high-risk group for whom specific strategies apply ( Table 20.1 ).

In addition to blood pressure monitoring at baseline prior to beginning VEGFI therapy, blood pressure should be monitored regularly throughout treatment. Monitoring is particularly relevant in the early stages of treatment when the risk of acute rises in blood pressure is greatest. ^, It is recommended that blood pressure be monitored on a weekly basis during the first cycle of treatment and at least every two to three weeks thereafter.

Office blood pressures should be measured based on clinical guidelines, ^{, , ,} where 3 measurements should be made at least 3 minutes apart and an average taken of the two last readings. Measurements should be made using an appropriately calibrated device with a correctly sized cuff and the patient sitting at rest for 5 minutes. ^, Home blood pressure monitoring may be appropriate for some patients. If introduced, it is important to provide patients with a blood pressure diary, instructions on accurate self-measurement, and criteria for blood pressure readings that should prompt them to seek attention from their oncologist or medical practitioner. Ideally, blood pressure should be measured by ambulatory blood pressure monitoring during the first week of commencing VEGFI treatment and during each cycle of therapy.