Targeted therapies have allowed oncologists to reduce their use of anthracyclines. Clinicians have always had concerns about anthracycline toxicity. But , founder of the Canadian Cardiac Oncology Network, from the University of Ottawa, discusses in this video the latest strategies for managing anthracycline toxicity.
The following is a transcript of her remarks:
Small molecules and targeted therapies have really improved the outcome of patients over the last 10 to 15 years, but the important thing to realize is that we are still using anthracyclines. There are those clinicians out there who think that anthracyclines are no longer valuable, but we know they are still utilized in many of the solid and hematological malignancies that we treat. The reason this is important is because of the concern that clinicians have of cardiotoxicity.
Anthracycline Toxicity Strategies
We've known for many years that if you give high doses of anthracyclines or if you give lower doses to patients who have other cardiovascular risk factors that patients can develop drops in their left ventricular ejection fraction, and ultimately, they can develop heart failure, which is permanent. We do not want to cure people from their cancer but then have them end up with end-stage heart failure.
Over the years, there have been a number of strategies that have been looked at trying to decrease the risk of developing cardiotoxicity from anthracyclines. One of them has been looking at giving anthracyclines as an infusion over 48 to 96 hours. However, this is not really practical because it requires patients to have a central line, and they have to be admitted to hospital.
Another way that clinicians have looked at this is by giving a liposomal formulation of doxorubicin, but this is expensive and it really hasn't been adopted by clinicians. Finally, the third approach that has been looked at is a drug called dexrazoxane. It's called a cardioprotectant, and what it does is, it's an iron chelator. It combines to the anthracycline or the iron portion of that, and prevents dissemination of oxygen-free radicals, so it tries to prevent the anthracyclines from causing cardiac damage.
The problem with that has been earlier when this drug was developed, there was concerns that it may decrease the efficacy of the cancer therapy. That has since been disproven. In a meta-analysis, however, it was shown that clinicians have not really adopted this approach, and the FDA has approved dexrazoxane only for women with metastatic breast cancer who have had over 300 milligrams per meter squared of doxorubicin.
Biomarkers and Imaging
Where do we go from here? Knowing that we're still using anthracyclines, what is the future and how can we protect our patients from developing cardiotoxicity? Daniela Cardinale from Italy has looked at very close monitoring of patients who are on anthracyclines. What she demonstrated is that if you measure cardiac biomarkers and if you do cardiac imaging very stringently, that at the earliest signs of drop in ejection fraction, she gives cardiac medications, [and this shows] that you can actually reverse some of the cardiotoxicity if you do it early in the first 6 months of exposure to these drugs.
Primary Prevention
There also recently have been three randomized phase III studies looking at what I'll call primary prevention strategies. This is where you take patients who are receiving anthracyclines and you give them cardiac medication upfront to see if that can prevent drops in left ventricular ejection fraction.
Two of those studies were relatively small. One was called MANTICORE, done in Canada. One was called PRADA, done in the U.S. They looked at giving beta blockers or ACE inhibitors to women who were receiving anthracyclines with or without trastuzumab. What they found was they could prevent drops in left ventricular ejection fraction anywhere from 2% to 4%.
The third study, just recently presented at the American College of Cardiology meeting, was a CECCY study that was done in Brazil. In that study, researchers took 200 women with breast cancer, so no trastuzumab, and randomized them to carvedilol or a placebo. They found no difference in that study. It was relatively short-term follow up.
Next: At Risk Patients
We're left with three studies now looking at a total of maybe 400 patients that show that these drugs might be beneficial. However, my only critique of that is they looked at very well, healthy, young women receiving treatment for early-stage breast cancer. I think moving forward it's not a bad strategy, but what we really need to do is look at this primary prevention strategy in patients who are at risk.
By that I mean patients might be older, have underlying history of diabetes, heart disease, high blood pressure. These are the patients who are at risk, and I think these are the patients you often do not see included in clinical trials. This is the population we're worried about in our clinic, and this is a population that we really need to focus on as to how can we prevent cardiotoxicity with anthracyclines.