Anthracycline-Based Chemotherapy Linked to Valve Disease, Even in Absence of Radiation

Adult survivors of lymphoma have a 3-fold increased risk of developing valvular dysfunction following treatment with anthracyclines, even if they did not receive cardiac radiation therapy as part of their treatment, according to a study published online February 17, 2016 ahead of print in JACC: Cardiovascular Imaging.  

Several studies have suggested that anthracycline-based chemotherapy may induce heart failure, but researchers led by Klaus Murbraech, MD, of Oslo University Hospital (Oslo, Norway), sought to determine if there was a direct connection between the chemotherapy and valvular dysfunction. While radiation therapy is known to increase the risk of valvular dysfunction, the relationship between chemotherapy alone and valvular dysfunction is less clear.

Murbraech and colleagues looked at 274 adult survivors of Hodgkin’s or non-Hodgkin’s lymphoma who received high-dose chemotherapy with autologous hematopoietic stem cell transplantation with (35%) or without (65%) radiation therapy involving the heart between 1987 and 2008, and an equal number of healthy, age- and sex-matched controls. Patients who received cardiac radiation therapy were further grouped by radiation doses of ≤ 30 Gy or > 30 Gy.

Survivors and controls had similar general risk factors for cardiovascular disease, including smoking and hypertension.

Three-Fold Increased Risk

The overall prevalence of valvular dysfunction in the entire lymphoma survivor cohort—defined on echocardiography as more than mild regurgitation or any stenosis—was 22.3% and consisted of primarily left-sided valvular regurgitation, with few dysfunctional changes that were considered severe (3.3%). In the chemotherapy-only group, the rate of valvular dysfunction was 16.7%, which was three-fold higher than what was seen in controls (OR 3.3; 95% CI 1.7-6.2).

Survivors who received either no radiation or low doses (≤ 30 Gy) had an equal distribution of valvular degenerative changes. When the no-radiation group was compared with controls, there was a much higher degree of degeneration involving the aortic valve (13% vs 2.9%; P< .001). While no differences in the incidence of mitral regurgitation were seen between no-radiation patients and controls, aortic and tricuspid regurgitation were much higher (6.2% vs 1.5% and 6.2% vs 1.1%, respectively; P < .001 for both).

In multivariable analysis, independent predictors for valvular dysfunction in all lymphoma survivors compared with controls were female gender, age > 50 years at lymphoma diagnosis, ≥ 3 lines of chemotherapy before autologous hematopoietic stem cell transplantation, and radiation >30 Gy. For the chemotherapy alone group, however, the only independent predictors were age ≥ 50 years at primary diagnosis (OR 5.7; 95% CI 1.8-17.8) and ≥ 3 lines of chemotherapy before stem cell treatment (OR 4.4; 95% CI 1.1-17.5).

Building the Knowledge Base

According to the study authors, their finding of an increased risk of valvular dysfunction independent of radiation adds to knowledge of MI and heart failure risk in patients with lymphoma, but stands in contrast to a larger study of survivors showing that those who received cardiac radiation therapy had a 2-fold risk for valvular dysfunction compared with patients who received anthracycline-based chemotherapy alone.

Furthermore, they suggest that cardiotoxic therapy with anthracyclines likely accelerates the valvular aging process, thereby explaining why patients who are 50 years or older at time of diagnosis are at higher risk for dysfunction. The finding of gender as a risk factor in survivors compared with controls is also of interest, they say, because it suggests gender differences in tolerance for cardiotoxic treatment and subsequent risk of valvular dysfunction. Lastly, Murbraech and colleagues say their findings support recommendations to restrict radiation doses to 30 Gy or lower in children and adults with lymphoma.

In an accompanying editorial, Michael H. Crawford, MD, of the University of California, San Francisco (San Francisco, CA), says the data supporting a direct link between anthracycline-containing chemotherapy and valve injury are compelling.

“Ventricular function and left ventricular volumes were significantly different between chemotherapy patients and controls, but the changes were modest and of doubtful biologic significance, which suggests that myocardial toxicity was not the only explanation for the higher incidence of regurgitant valve disease in the chemotherapy alone group,” Crawford writes. “Also, comorbidities that could explain valve disease risk were no different between the patients and controls.”  

Crawford concludes that it “seems prudent” to consider valve disease in long-term lymphoma survivors whether they received radiation or chemotherapy or both, especially at high doses under the age of 25. 

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Sources: 
1. Murbraech K, Wethal T, Smeland KB, et al. Valvular dysfunction in lymphoma survivors treated with autologous stem cell transplantation—a national cross-sectional study. JACC: Cardiovascular Imaging. 2016;Epub ahead of print.
2. Crawford MH. Chemotherapy induced valvular heart disease. JACC: Cardiovascular Imaging. 2016;Epub ahead of print.  

Disclosures:

• The study was supported by South-Eastern Norway Regional Health Authority. 
• Murbraech and Crawford report no relevant conflicts of interest. 

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