Sorafenib and Hypertension: Meta-Analysis

Abstract & Commentary

By William B. Ershler, MD

Synopsis: Sorafenib is a multikinase inhibitor approved for treatment of renal cell and hepatocellular carcinomas. The occurrence of hypertension has been mentioned in a number of clinical reports, but the precise risk has not yet been determined. In the current study, Wu et al have reviewed published experience with this drug, and performed a meta-analysis. The results indicate approximately one in four cancer patients will develop hypertension, and that severe hypertension occurs in just under 6%. Physicians need to monitor blood pressure closely and institute antihypertensive medications promptly to avoid cardiovascular and neurologic complications.

Source: Wu S, et al. Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. Lancet Oncol. 2008;9:117-123.

Sorafenib is a multikinase inhibitor that exhibits a broad spectrum of anti-tumor activity, including inhibition of cellular proliferation and angiogenesis.1 The clinical benefit of sorafenib seems to rest primarily on the basis of its anti-angiogenesis effects,2 and demonstrable and meaningful benefit was observed in renal cell and hepatocellular carcinoma clinical trials.3,4 Hypertension is one of the major side-effects of this drug, and frequencies vary substantially between clinical trials. To gain a better understanding of the overall risk of hypertension in patients with cancer who receive sorafenib, Wu et al performed a systematic review and meta-analysis of published clinical trials to establish the incidence of hypertension associated with sorafenib.

For this, databases, including Medline (July, 1966, to July, 2007) and Web of Science, and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004-2007, were searched to identify relevant studies. Eligible studies were prospective clinical trials of cancer patients treated with single-drug agent sorafenib at 400 mg twice daily with data on hypertension available. Phase I studies were excluded because of the dose variability inherent in that type of trial, and studies with hepatocellular carcinoma because of incomplete recording of blood pressures. For the remainder, incidence and relative risk (RR) of hypertension were calculated using a random-effects or fixed-effects model, depending on the heterogeneity of the included studies.

Of 223 screened articles, there were nine studies published between January 2006 and July 2007, including a total of 4,599 patients with RCC, or other solid tumors, that met criteria for this analysis. For patients assigned sorafenib, the overall incidence of all-grade and high-grade (ie, grade 3 or 4) hypertension was 23.4% (95% CI 16.0%-32.9%) and 5.7% (2.5%-12.6%), respectively. No significant difference was noted between patients with RCC or a non-RCC malignancy (all grade: RR 1·03 [95% CI 0.73-1.45], p = 0·89; high-grade: RR 1·23 [0.76-1.99], p = 0·40) who were assigned sorafenib. Sorafenib was associated with a significantly increased risk of all-grade hypertension in patients with cancer with an RR of 6.11 (2.44-15.32], p < 0·001), compared with controls.

Thus, patients with cancer-assigned sorafenib have a significant risk of developing hypertension. Appropriate monitoring and treatment is strongly recommended to prevent cardiovascular complications.

Commentary

Although not a described toxicity in phase I trials, larger phase II and III trials, as well as the expanded access program, have indicated that hypertension is a common observation in sorafenib-treated patients, occurring in 16.0%-42.6% of treated subjects. By the current analysis, the occurrence is expected in nearly one in four treated patients. Although the mechanism is not established, it is notable that other angiogenesis inhibitors, including sunitinib and bevacizumab, demonstrate similar rates of hypertension.5 Possible mechanisms include the effect of impaired angiogenesis leading to a decrease in the density of microvessels (rarefaction), damage to endothelial cells resulting in decreased nitric-oxide production and oxidative stress, and changes in neuro-hormonal factors or rennin/aldosterone. The latter mechanism seems less likely in light of the findings of Veronese et al, in which no significant change in humoral factors, including serum total catcholamines, epinephrine, norepinephrine, endothelin 1, renin and aldosterone were observed among 20 patients after three weeks of sorafenib treatment despite the occurrence of hypertension in 15 (75%).6

The optimal management of sorafenib-associated hypertension remains unresolved. What is clear is that blood pressure should be carefully monitored from the beginning of therapy and promptly treated. By this analysis, severe hypertension occurred in 5.7% of treated patients, and adverse outcomes, including myocardial infarction4 and posterior leukoencephalopathy syndrome,7 have been noted to occur under such circumstances. Until there is data available to guide in the choice of pharmacological agents to manage sorafenib-associated hypertension, it might be prudent to avoid drugs metabolized by the cytochrome P450 enzyme system (such as non-dihydropyridine calcium channel blockers such as verapamil and diltiazem). In contrast, dihydropyridine calcium channel blockers (amlodipine and nifedipine), ACE inhibitors, and angiotensin-receptor blockers are reasonable choices for initial management.

Thus, sorafenib treatment is associated with a significant risk of developing hypertension. Oncologists must be aware of this, monitor blood pressure carefully, and institute antihypertensive management promptly.

References

1. Wilhelm SM, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099-7109.

2. Chang YS, et al. Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol. 2007;59:561-574.

3. Abou-Alfa GK, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006;24:4293-300.

4. Escudier B, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-34.

5. Zhu X, et al. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis. 2007;49:186-193.

6. Veronese ML, et al. Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol. 2006;24:1363-1369.

7. Govindarajan R, et al. Reversible posterior leukoencephalopathy syndrome induced by RAF kinase inhibitor BAY 43-9006. J Clin Oncol. 2006;24:e48.