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A Setback for ARBs for the Treatment of Pancreatic Cancer?

Again, for more than a decade there have been theoretical discussions about the use of drugs commonly used to treat high blood pressure for use in the treatment of cancer – pancreatic cancer (ductal adenocarcinoma of the pancreas).

And having just published a Pancreatica blog entry based on the pre-clinical study and work by Jain and colleagues from Harvard on the use of the angiotensin receptor blocker (ARB) high blood pressure medication losartan in the treatment of pancreatic cancer, we now present a kind of refutation of this premise in the form of actual Phase II clinical trial results using a different ARB, candesartan. By way of refresher, angiotensin receptor blockers relax muscle cells and cause blood vessels to dilate – possibly potentiating the effects of chemotherapy agents.

ARBs for the Treatment of Pancreatic Cancer?

In the October 1st 2013 issue of the journal Investigational New Drugs, Koike and Japanese colleagues from the University of Tokyo have published the results of a Phase II multi-center clinical trial called GEGA2. These researchers enrolled 35 patients with confirmed advanced adenocarcinoma of the pancreas who had not received any prior chemotherapy. The patients were treated with a combination of gemcitabine and the ARB candesartan (up to 16 milligrams given orally).

The median progression-free survival was found to be 4.3 months; the overall median survival was 9.1 months. The one-year overall median survival rate of these patients was 34.2 %. The median progression-free survival was found to be significantly increased in those who received 16 mg of candesartan versus those who received just 8 mg. Modest or more low blood pressure was seen in three patients, and the candesartan was stopped in two of these. The primary side-effects were found to be hematological.

The authors conclude that the addition of candesartan did NOT significantly benefit patients over what would likely have been seen with the gemcitabine alone.

Does this doom the ARB hypothesis? No, this result was somewhat anticipated by the Harvard study. There, the researchers found that the significant effect that losartan had on the pancreatic adenocarcinoma stromal tissue in the vicinity of the tumor itself – appeared to be somewhat extreme and unique in the ARB family, including in the specific cited case of candesartan.

So the issue still remains: not as much about candesartan (given the results of this study by Koike et al.), but about the ARB losartan. Losartan as a potentiator of the effects of chemotherapy in the treatment of pancreatic cancer awaits further research.

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Dale O’Brien, MD