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.
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.
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.
Dale O’Brien, MD
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. And there have been some prior preliminary research studies.
Now comes a very intriguing and elaborate pre-clinical study involving cells and mice and the blood pressure medicine losartan. This medication is an angiotensin receptor blocker (ARB) which relaxes muscle cells and causes blood vessels to dilate. Researchers at Massachusetts General Hospital and Harvard Medical School including Jain and colleagues published this study in the October issue of the journal Nature communications.
The authors find and postulate that losartan appears to be the right ARB to optimally increase vascular perfusion and oxygen delivery in the stroma laden environment of pancreatic adenocarcinomas. As a part of the study losartan was given together with chemotherapy drugs including 5-FU and doxorubicin, and appears to potentiate chemotherapy delivery to the tumor site in pancreatic cancer.
The authors end by postulating that drugs such as losartan (ARBs) might be considered for further evaluation as adjuvant to standard chemotherapy for pancreatic cancer.
This is a highly provocative and promising pre-clinical finding that is deserving of further research.
Dale O’Brien, MD
There is no universally agreed upon second line treatment for metastatic pancreatic cancer. On August 20 in the British Journal of Cancer, the results of an interesting international Phase II clinic trial using nanoliposomal irinotecan for the treatment of earlier pre-treated metastatic pancreatic cancer were published. The researchers included Dr. Margaret Tempero, who is on our Pancreatica Science Board.
The study included 40 patients with metastatic pancreatic cancer who were now considered refractory to earlier treatment with gemcitabine, and who were then given the drug agent PEP02, also known as MM-398 (or Irinotecan Sufosulcrate) as developed by the biotech companies PharmaEngine and Merrimack. This is a nanoliposome, which indicates that the drug molecule is contained in a spherical coating of a lipid or fatty-like substance.
The essential aim of this study was to ascertain the 3-month survival rate. The researchers observed 3 patients who demonstrated an objective tumor response. Over at least two treatment cycles 17 other patients showed evidence of stable disease. 10 patients (of 32) with elevated CA19-9 levels, showed a greater than fifty percent decrease in these levels. The median progression-free duration was 2.4 months. The overall 3-month survival rate was 75%. And the median overall survival was 5.2 months.
The researchers note that the more common side-effects of this treatment were asthenia, abdominal discomfort, neutropenia and diarrhea.
The authors conclude that at this stage of study the apparent activity of liposomal irinotecan coupled with a relatively tolerable side-effect profile make it a promising candidate for second-line consideration. Currently Phase III trials are underway.
Dale O’Brien, MD