Impact of Hypertension in Cancer Patients Treated With Anti-Vascular Endothelial Growth Factor Therapy
Article ID: CJ-22-0825
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Article ID: CJ-22-0825
Improved cancer outcomes have increased the importance of prevention, diagnosis, treatment, and follow-up of cardiac dysfunction related to cancer treatment. Hypertension (HTN) is the most common comorbidity in survivors of some cancer types, and in addition, anticancer therapies can induce blood pressure elevation through different pathways. There are no established guidelines for the management of HTN in cancer patients. Multidisciplinary collaboration and comprehensive research are needed to address complex mechanisms such as the link between HTN and cancer, cancer-related factors that raise blood pressure, and drugs and cancer risk, thereby establishing the new concept of “onco-hypertension”.1
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The incidence of cancer-related cardiac complications is increasing, with some cancers causing more deaths due to cardiovascular disease (CVD) than due to tumor recurrence. Several molecularly targeted drugs, including anthracyclines and tyrosine kinase inhibitors, have cardiotoxic potential, whereas drugs such as antimicrotubule agents may cause hypotension, thus increasing the importance of managing CVD complications in cancer patients and survivors. Vascular endothelial growth factor (VEGF) inhibitors function to inhibit angiogenesis, normalize intratumor vascular function, inhibit tumor growth, and potentiate the effects of other anticancer agents; however, cardiovascular safety remains a concern. The most common side effect of VEGF signaling pathway (VSP) inhibition is the development of HTN. The risk of severe HTN is 5-fold higher in VEGF inhibitor users than in non-users. Although HTN is likely to occur in up to 43% of patients using VEGF inhibitors,2 various trials have reported good outcomes in patients who develop HTN3 (Table).
| Cai et al3 | Moriyama et al4 | |
|---|---|---|
| Year of publication | 2013 | 2022 |
| Country | Italy, USA, Finland, UK, Israel, Japan | Japan |
| Study design | Meta-analysis | Cohort-based retrospective study (LIFE Study database) |
| Sample size | n=528 patients (7 studies) | n=3,460 patients |
| Drugs | Bevacizumab | VSP inhibitors (axitinib, bevacizumab, lenvatinib, pazopanib, ramucirumab, regorafenib sorafenib, and sunitinib) |
| Tumor type | Metastatic colorectal cancer | Colorectal, gastric, liver, lung, kidney, and thyroid cancer |
| Outcomes | Improved PFS (HR, 0.57 [95% CI, 0.46–0.72]) | Prolonged TTF (HR, 0.58 [95% CI, 0.50–0.68]) in new-onset hypertension |
| Improved OS (HR, 0.50 [95% CI, 0.37–0.68]) | Prolonged TTF (HR 0.85 [95% CI, 0.73–0.98]) in pre-existing hypertension |
CI, confidence interval; HR, hazard ratio; HTN, hypertension; PFS, progression-free survival; OS, overall survival; TTF, time to treatment failure; VSP, vascular endothelial growth factor signaling pathway.
Similarly, the analysis by Moriyama et al4 in this issue of the Journal highlights that newly developed HTN after the use of VSP inhibitors is an independent factor leading to favorable clinical outcomes in cancer patients, even in Japan. Furthermore, pre-existing HTN before VSP inhibitor initiation was also found to be associated with a favorable prognosis.4 Their study aimed to elucidate the effect of HTN on clinical outcomes in patients treated with VSP inhibitors using a Japanese claims database (Table). Although the 2019 Japanese Society of Hypertension guidelines for the management of hypertension recommend adjusting the use of anticancer and antihypertensive drugs for cancer patients with VSP inhibitor-related hypertension,5 recommendations for specific classes of antihypertensive medications in patients with VSP inhibitor-related hypertension have not been established. When previously normotensive patients develop HTN, additional treatment or titration of existing antihypertensive therapy is recommended. However, patients with active cancer have been excluded from standard HTN clinical trials. As a result, there is little outcome data to support antihypertensive therapy or blood pressure targets. However, the prolonged survival of cancer patients and the cardiovascular toxicity of many cancer chemotherapy agents make these patients more susceptible to cardiac death and future CVDs, making antihypertensive therapy a reasonable and functional consideration. In particular, the results of the study by Moriyama et al suggest that VSP inhibitors can improve the prognosis of patients with pre-existing hypertension. Therefore, it is recommended that oncologists, cardiologists, and nephrologists work together to determine the optimal antihypertensive strategy for cancer patients, based on an understanding of the characteristics and adverse effects of the drugs.
HTN associated with VSP inhibitors, called on-target toxicity, is known to be a potential clinical indicator of the effect of VSP inhibitors on cancer.6 VEGF binds to 3 tyrosine kinase receptors (VEGFR-1, VEGFR-2, and VEGFR-3).7 VEGFR-1 and VEGFR-2 are highly expressed on endothelial cells, and the binding of VEGF-A and VEGFR-2 is the main biological action.8 Although the pathophysiological mechanisms underlying the development of HTN during VSP inhibitor treatment are unknown, decreased nitric oxide production, increased expression of endothelin-1 and other pressure-elevating substances, microvascular dilution, activation of the renin-angiotensin system, oxidative stress, pressure-natriuresis system, and arterial stiffness have been proposed as possible mechanisms of VSP inhibitor-related HTN.9–11 The pathogenesis of pre-existing HTN on favorable clinical outcomes is not fully understood. Serum VEGF levels and soluble VEGFR concentrations are higher in hypertensive patients than in healthy controls.12 In addition, in colorectal cancer patients treated with VSP inhibitors, elevated plasma VEGF levels have been reported to be a potential biomarker of response to cancer therapy.13 Together with the presence of pre-existing HTN that causes a good response to VSP inhibitors, as reported by Moriyama et al, elevated serum VEGF levels in hypertensive patients may also be a favorable factor against VSP inhibitors.
Other new findings regarding cancer drugs and HTN have been reported. Immune checkpoint inhibitors (ICIs) are opening a new era in cancer therapy. Although ICIs have anti-tumor effects against a wide variety of cancer types and stages that are inadequately treated with existing drugs, they can also cause unique adverse effects known as immune-related adverse events. Myocarditis, arrhythmias, and conduction abnormalities are serious and potentially life-threatening adverse events affecting cancer patients; ICI use has also been reported to increase CVD risk but has proven not to increase the risk of HTN in the short-term.14
Common risk factors and interrelationships exist between HTN and cancer. Alone or in combination, they may lead to CVD and ultimately to a worsened quality of life and prognosis. Meanwhile, cancer therapy may be effective even in the presence of pre-existing HTN, indicating that certain types of cancer treatment may improve prognosis even when HTN develops. In addition to basic research, it is desirable to build evidence from various perspectives, including post-marketing surveillance and results obtained from actual clinical data, to optimize the management of cancer patients and improve their prognosis.
The author thanks Editage (www.editage.com) for English language editing.
The author has no conflicts of interest relevant to the content of this article.
