Kidney Cancer Patients on ASI Antihypertensives Live Longer

Only Applies to Patients on VEGF Inhibitors

Zosia Chustecka

January 29, 2014

A retrospective analysis of 4736 patients with metastatic kidney cancer has found that patients who were taking antihypertensive drugs that act as angiotensin system inhibitors (ASIs) lived significantly longer than patients who were not taking such drugs.

The overall survival among patients taking ASIs was 27 months vs 17 months for patients who were not talking these drugs (P < .0001; hazard ratio [HR], 1.258).

ASIs have been associated with improved survival in other cancers, but the new study is the largest analysis of ASIs and cancer to date.

The findings will be presented at the 2014 Genitourinary Cancers Symposium in San Francisco, and were highlighted at a presscast ahead of the meeting held by the American Society for Clinical Oncology.

One of the take-home messages for clinicians from this study is that for patients with metastatic renal cell carcinoma who need treatment for the comorbidity of hypertension, the "go-to" drug should be an ASI, said lead investigator Rana McKay, MD, a clinical fellow at the Dana-Farber Cancer Institute in Boston.

ASI antihypertensives include angiotensin-converting-enzyme (ACE) inhibitors such as captopril and lisinopril, and also angiotensin-receptor blockers such as losartan. Both classes of drugs act to reduce levels of the peptide hormone angiotensin II.

Antihypertensive drugs with actions other than ASIs, such as beta blockers, calcium-channel blockers, and diuretics, did not appear to have an effect on survival. A subgroup of 783 patients taking non-ASI antihypertensive drugs had an overall survival of 18 months, similar to the 17 months seen in the larger group of all patients not taking ASIs (n = 2736).

So it is the impact on angiotensin II that appears to be important. "That is what we believe is driving the survival difference that we observed," Dr. McKay told Medscape Medical News. There is increasing evidence that angiotensin II is involved in carcinogenesis, she commented. In preclinical models, the use of ASIs reduced tumor growth, inhibited angiogenesis, and inhibited metastatic spread. In addition, improved survival has been associated with ASIs in another meta-analysis involving patients with many different cancer types, she said.

Important Caveat: Effect Requires VEGF Inhibitors

The data for the current analysis in patients with metastatic renal cell carcinoma came from prospective phase 2 and 3 clinical trials sponsored by Pfizer. These trials had investigated a variety of drugs, including inhibitors of vascular endothelial growth factor (VEGF) such as sunitinib (Sutent, Pfizer), sorafenib (Nexavar, Bayer), axitinib (Inlyta, Pfizer), and bevacizumab (Avastin, Roche/Genentech), as well as mTOR-targeted agents such as temsirolimus (Torisel, Pfizer) and interferon alfa.

The researchers performed a subset analysis according to the drug therapies used for kidney cancer.

They found that the difference in survival for the different types of antihypertensives was statistically significant only in the subset of patients who were on VEGF inhibitors.

Specifically, in this subgroup, the median overall survival in patients taking ASIs was 31 months vs 20 months in patients not taking ASIs (HR, 1.35; P < .001).

Notably, there was no significant increase in survival seen with ASIs in patients who were on mTOR inhibitors and/or interferon alfa.

This suggests a synergistic interaction between the ASIs and the VEGF inhibitors, Dr. McKay said. She explained that VEGF inhibitors inhibit the process of angiogenesis, and "we suspect that this is the point at which the ASIs are also acting. Blocking the pathway at multiple points may be beneficial."

"These are early data and are hypothesis-generating," Dr. McKay said. The next step would be a prospective trial exploring VEGF inhibitors in metastatic renal cell carcinoma with or without an ASI in a phase 2 study to see if the same signal is seen.

At this stage, the ASIs would be given only to patients who had hypertension, and not for prophylaxis, she explained.

"There would be great interest in such a trial," suggested Charles Ryan, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, who acted as moderator for the presscast. "This is quite a significant effect here, and one that makes sense when you consider the mechanism of action of the ASIs and the VEGF inhibitors," she added.

Dr. Ryan noted that about half of the renal cell carcinoma patients in this analysis had hypertension at baseline. Dr. McKay also noted that hypertension can arise as an adverse effect of treatment with the VEGF inhibitors (a factor that was adjusted for in the above analysis). These results suggest that if hypertension does develop, it should be treated with an ASI, she said.

Dr. McKay has disclosed no relevant financial relationships. Senior author Toni Choueri, MD, reports acting as a consultant for Pfizer and several other pharmaceutical firms. One of the study coauthors is a Pfizer employee. Dr. Ryan reports receiving honoraria from Astellas Pharma, Janssen Biotech, Millennium, and Sanofi.

2014 Genitourinary Cancers Symposium (GUCS): Abstract 437. To be presented February 1, 2014.

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