Cardiotoxicity in Cancer Patients: Often More Malignant Than Cancer—Part 2

[Hopeful]

Interview by L Scott Zoeller. 2012 Aug 24, Joerg Herrmann, MD

In Part 1 of this interview, Dr. Herrmann discussed the need for specialized experience in cardio-oncology and optimal use of imaging and biomarkers in monitoring cardiac damage associated with cancer therapies. In Part 2, Dr. Herrmann discusses the evidence behind cardioprotective agents and patient lifestyle.

Cardioprotective agents

OncologySTAT: Do you think dexrazoxane (Zinecard) or other cardioprotective agents should be used more widely, and do you have any concerns about this drug compromising antineoplastic efficacy?

Dr. Herrmann: The American Society of Clinical Oncology (ASCO) developed guidelines for the use of dexrazoxane,¹ and it’s currently indicated for breast cancer patients with metastatic disease who received a cumulative dose of doxorubicin of at least 300 mg/m², and who may yet benefit from further therapy. It’s not recommended outside of clinical trials, really. The recommendations include adults and the pediatric community.

The main concern that drove this conservative recommendation, indeed, relates to what you expressed in your second question: Is there some compromise of the antineoplastic efficacy? Now, I think the best data that address this question are from the Cochrane Database of Systematic Reviews. There was an article published last year, and, of the agents listed, dexrazoxane was the only one with sufficient data to draw conclusions, even though most of the studies included were of adult patients with advanced breast cancer.²

So this, in a way, actually reflects the ASCO recommendation on the use in breast cancer patients. Subgroup analyses (ie, pediatric vs adult and solid vs hematologic malignancies) were not possible; so, one can’t comment on that. With these caveats in mind, dexrazoxane reduced the incidence of clinical and subclinical heart failure by 70%. When the five primary trials were included in this analysis, interestingly enough, there was a trend (P=0.08) for a reduced response rate with dexrazoxane. Three years earlier, the same group published a similar review article in the Cochrane Database of Systematic Reviews, and, at that point, the P value for the impact on response rate was actually 0.06; so, a little more concern emerged that dexrazoxane would compromise antineoplastic efficacy. On the other hand though, differences in progression-free and overall survival between patients receiving and not receiving this agent were not noted.

One might therefore say: if survival is our endpoint, dexrazoxane doesn’t seem to make patients live longer, even though we prevent clinical and subclinical heart failure; so, why bother? One could also question if chemotherapy-induced heart failure is all that clinically relevant after all.

The decisive point in the analysis is clinical heart failure. So, dexrazoxane may not be as efficacious in preventing clinical heart failure, although, when we combine data from all of the studies, it is efficacious overall. That’s why there might not be an overall survival benefit if we consider, as studies have shown, that chemotherapy-induced, anthracycline-induced, heart failure is one of the worst forms of cardiomyopathy someone can acquire, with a 50% survival rate for less than 2 years. There is also a time factor that needs to be taken into consideration when analyzing these studies.

Another explanation for the overall lack of benefit is that dexrazoxane may have prevented heart failure–related mortality at the cost of attenuating the survival benefits of cancer therapy. However, this is hard to construct from the current data, as indicated. Nevertheless, the issue that changed the mind of the European Medicines Agency to restrict the use of dexrazoxane is the concern for a risk association with acute myeloid leukemia and myelodysplastic syndrome in children who received the drug.³ That’s why the recommendations on the use of dexrazoxane remain confined to those individuals with the presumed highest benefit from this intervention.

OncologySTAT: What do you think about pentoxifylline’s role in minimizing radiation-induced cardiotoxicity?

Dr. Herrmann: Mechanistically, one could think of ways that the inhibitory effect of pentoxifylline on NF-κB activation and activation of the TGF-beta pathway could have some potential merit. There are a number of studies that looked at superficial radiation-induced fibrosis, some looked at proctitis, and other studies looked at lung injury— pulmonary fibrosis—to see how pentoxifylline might be beneficial.

But, really, there are just a few preclinical studies that may draw our attention. One, in particular, showed that the combination of pentoxifylline and vitamin E—they are usually combined—significantly reduced radiation-induced myocardial fibrosis and left ventricular diastolic dysfunction in a rat model.⁴ This was true regardless of whether these two interventions, pentoxifylline plus vitamin E, were started before or 3 months after irradiation (ie, at a time point when histopathologic changes were not or were already apparent).

Myocardial degeneration was not observed in this study. There was a trend toward a lower mast cell count in the late treatment group, which may not be desirable because these cells are actually thought to be beneficial. Hence, the results are not as clear-cut from this study, and, for now, we don’t have any clear-cut clinical trials that we can rely on. In fact, there are no clinical trials listed on clinicaltrials.gov that would address this question.

Pragmatically, one could say that nausea and vomiting are the main side effects of pentoxifylline, and so the chance that you would do a lot of harm is low, and you might have some benefit, so why not just go ahead? But, I would note that we just don’t know at this point.

OncologySTAT: I think there’s a real concern that dexrazoxane decreases the incidence of heart failure, but also decreases the efficacy of the chemotherapy, and maybe that’s done for a survival advantage. But, I think, by treating patients with pentoxifylline—as you said— we could accomplish both goals, if we want.

Dr. Herrmann: Pentoxifylline is potentially more of a win/win option than dexrazoxane; I think we just need more evidence.

Diet and exercise

OncologySTAT: What can cancer patients themselves do to minimize their likelihood of acute and late cardiotoxicity from treatment, and can lifestyle and diet affect their outcomes in this regard?

Dr. Herrmann: Patients always ask, “What can I do? How am I responsible for all of this?” And, most often, they are not. Obviously, there are some coexisting risk factors. For instance, obesity, heart diseases, and colon cancer overlap in the US. There might be some issues that could have been addressed earlier; but, once patients are on cancer therapy and get this collateral damage, it’s hard to say, “Do this or that and things will be better.”

The main thing is the awareness and the collaboration necessary to deal with whatever we are facing. The pediatric cancer community is really the only group with structured guidelines. They have a very nice set of guidelines for patients to follow, particularly after radiation therapy, and even after chemotherapy with anthracyclines, including risk factors to look for, screening tests that need to be done, and various health behaviors to incorporate. They clearly advocate diet and physical activity.

One benefit of exercise might be to help patients detect some limitations early on. They would replicate what some exercise, oxygen-consumption stress tests have demonstrated: an increased sensitivity to detect subclinical cardiomyopathy. In other words, these patients might be just fine at baseline but, when put to the test, it becomes evident that their heart is not functioning quite as well as it is supposed to.

If patients are physically active, they might have the advantage that we’ll pick up on these cardiomyopathic processes earlier on. And, there are some studies that showed that early detection really is key for restoration of cardiac function, particularly, within the first few months of its onset. The chance for restoration of LVEF to more than 50% is actually fairly good with the initiation of appropriate therapy within the first 2 months of onset. But, if we miss that time point, and things are smoldering for more than 6 months, we really miss the chance to treat these patient appropriately and improve their overall outcome. So, in that way, an active lifestyle has two benefits.

When it comes to diet, I would say the same rules apply as for the general population: Diabetes can lead to diabetic cardiomyopathy. The same is true in these patients; they’re more vulnerable to begin with to any additional insult. Hyperlipidemia is especially important after radiation therapy, given the potentiation of atherosclerosis risk. There’s a clear recommendation that these patients should get fasting glucose and lipid profiles every 2 years because the risks of coronary artery disease and ischemic cardiomyopathy are so high. I do think that lifestyle and diet are really key to overall outcome, particularly after radiation therapy.

When it comes to chemotherapy, the damage is pretty much done, and there’s less that lifestyle and diet can restore. But there are things we can do that can certainly help. It can help to detect heart dysfunction earlier on and treat it earlier on, which then would mean a better outcome. And we can minimize the likelihood of acute and late cardiotoxicity by changing the way we give the therapy and by using other treatment modalities, adjuvant therapies that we have now and maybe, in the future, other drugs.

References

1. Hensley ML, Hagerty KL, Kewalramani T, et al. American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol. 2009;27(1):127-145.
2. van Dalen EC, Caron HN, Dickinson HO, Kremer LC. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev. 2011;(6):CD003917.
3. Tebbi CK, London WB, Friedman D, et al. Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol. 2007;25(5):493-500.
4. Boerma M, Roberto KA, Hauer-Jensen M. Prevention and treatment of functional and structural radiation injury in the rat heart by pentoxifylline and alpha-tocopherol. Int J Radiat Oncol Biol Phys. 2008;72(1):170-177.

Hopeful