Saturday, 5 August 2017

Angiotensin system inhibitors + low dose Avastin

This June a study was published by Victor Levin et al. of Kaiser Permanente Hospital, Redwood City, which follows up on a previous study on the use of Avastin doses lower than the standard dose.  (I've uploaded the full study to the Brain Tumor Library -> Folder 1. Therapies - Human Studies -> Angiotensin System Inhibitors)

The current study looked at the use of angiotensin system inhibitors, including both ACE inhibitors (benzapril, captopril, etc.) and angiotensin II receptor blockers (losartan, telmisartan, etc.) used for hypertension simultaneously with chemotherapy and/or Avastin in newly diagnosed and recurrent glioma patients.

In a very large cohort of 1186 infiltrative glioma cases (grades 2-4), use of an angiotensin system inhibitor (ASI) was significantly associated with better survival (hazard ratio 0.82), in a multivariate analysis adjusted for other variables such as age, extent of resection, GBM versus other grade, use of Avastin, etc.  This advantage of ASI treatment was even more significant in patients who were also treated with Avastin (HR 0.75).

A previously published cohort of 181 recurrent GBM patients treated with various doses of Avastin was examined with regard to their use of ASI drugs (for hypertension).  The previous study had shown trend toward longer survival in the group treated with lower-dose Avastin, and this study has been summarized elsewhere.   (Page 90)

Remarkably, of the 89 patients treated with doses of Avastin lower than 3.6 mg/kg/week (the standard dose amounts to 5 mg/kg/week),  the 47 patients also using an ASI drug had a very impressive median survival of 99 weeks (22.8 months) versus 55.6 months (12.8 months) for the 42 patients receiving low dose Avastin without ASI drugs.

99 week (nearly 23 month) median survival (from treatment for recurrence) for a sizeable (n=47) group of recurrent glioblastoma patients in virtually unheard of.  Although all the usual caveats apply because of the retrospective, non-randomized nature of this study,  the outcomes are too impressive to ignore.

As Levin et al. conclude "Prospective clinical trials combining ASIs with low-dose BEV in GBM patients are now needed to confirm whether ASIs can enhance the efficacy of VEGF-targeted therapies and thereby improve clinical outcome."

As a side note, Victor Levin is the founder of the Society for Neuro-Oncology (SNO) and often described as the "father of neuro-oncology", at least in America.


  1. One puzzling aspect of this study is that while it did pose the caveat of being a retrospective design, it seems like they should have had the data to do a little more digging on drug interactions. It was 100% from the Kaiser patient database and so the patients full set of prescriptions should have been available. ASI's are commonly prescribed along with calcium channel blockers when treating for hypertension. Since calcium channel blockers have a mixture of effects on liver clearance and more importantly on drug efflux pumps in the tumor, it seems like this could really cloud the results by having their own positive benefit on chemo effectiveness.

    It is good though to see more studies with good indications that a more moderated dose of BEV (aka Avastin) can be more effective than current standard dosing. Seems like getting an NO to reduce a drug dose is far easier than getting one to prescribe an off-label drug.

    1. Good point about the possibility that some of these patients were simultaneously being treated with calcium channel blockers.

  2. So what is better to take with Avastin: –°aptopril or Telmisartan? After much thought, we started taking Telmisartan 40 mg twice a day, but now I noticed that Captopril is much higher on the list "Pharma and non-pharma list and ranking for GBM" by Stephen(

    By the way, the dose of Telmisartan 80 mg is well tolerated, does not affect normal blood pressure.

    1. I upgraded my estimation of ACE inhibitors based on the study:
      Angiotensin II drives the production of tumor-promoting macrophages.

      In this study they used an ACE inhibitor to reduce the number of macrophages infiltrating tumors in a mouse model. Angiotensin-II was directly stimulating the angiotensin receptors (AGTR1, or AT1) on hematopoietic stem cells and macrophage progenitors. So theoretically an agiotensin-II receptor blocker like telmisartan could work in the same way as ACE inhibitors. (ACE inhibitors prevent the production of angiotensin-II and the ARBs like telmisartan prevent the action of angiotensin-II at the receptor).

      If you already have the telmisartan I don't see any strong argument to switch over to an ACE inhibitor.