Traditional treatments for HL have been associated with a high risk of developing CVD.3 Reducing adverse cardiac effects, without compromising the efficacy of cancer treatment, has been an important area of research.6,17 Our findings suggests that steps taken to reduce cancer therapy-related adverse cardiac effects in the treatment of HL have been successful. Although adverse cardiac effects have not been eliminated, the average HLS treated after the late 1990s is now less likely to experience CVD than those treated in preceding decades.
Cardiac function and morphology
We found no difference between HLS and controls regarding EF, the most commonly used measure of LV function. While a drop in EF is a late sign of cancer therapy-related cardiac dysfunction (CTRCD), it is closely associated to overt symptoms of heart failure and is an important predictor of prognosis.11 The lack of adverse effects about 16 years after modern treatment of HL on EF is thus a positive development.
While adverse cardiac effects have been mitigated, a substantial number of HLS in our study have a GLS outside the normal range, in fact, the risk for borderline or impaired GLS was more than three-fold compared to controls. It did not seem to matter whether the HLS had received MRT, as the prevalence of borderline or low GLS did not differ between treatment groups. Average GLS was lower in HLS receiving MRT, suggesting that although not more prevalent, those with impaired GLS after MRT had slightly worse function. It should be noted, however, that in most of these cases, GLS was borderline low, and although there is some evidence that this is associated with later adverse cardiac events, the clinical significance on prognosis is debatable.18
Tsai et al. performed an echocardiographic study in 2011 which assessed HLS treated with MRT (mean 41 Gy) with or without anthracyclines between 1980 and 1988.19 Unlike the HLS in the present study, these patients had worse cardiac function and outcomes. Patients treated with both anthracyclines and radiation, usually mantle field radiation, had an average GLS of 16.1 ± 1.9%. Although they were slightly older (51 ± 9 years) and had slightly longer observation time (22 ± 2 years) than in the present study, the difference is substantial. CTRCD from treatment with anthracyclines is highly dependent on cumulative dose, with little CTRCD below 200 mg/m2, and a steep increase in CTRCD above 400 mg/m2.20 However, even lower cumulative doses of anthracyclines can amplify the CTRCD of adjuvant radiation therapy. This has previously also been shown in survivors of breast cancer.21
Even though a direct comparison is not possible, our findings would suggest that HLS treated with both AC and MRT using contemporary treatment, with lower radiation doses and smaller fields, fared better with respect to cardiac function than those treated with only radiation therapy in the 2011 study (GLS − 19.3 vs. -17.5).
Morphology in the AC-group was very similar to controls, but this was not the case for patients in the AC + MRT-group. These patients had smaller chamber volumes, thinner posterior walls and lower LV mass compared to both controls and the AC-group. It would suggest at least a mild degree of cardiac atrophy. Similar observations have been made in prior studies both in cancer survivors treated with anthracyclines and those treated with mediastinal radiotheraphy.22,23 It is noteworthy that the combination seem to be more potent in inducing such effects than anthracycline treatment alone.
Valve disease
Perhaps the most convincing evidence of adverse effects of treatment was the prevalence of valve disease in HLS treated with MRT. Cardiac valves are particularly susceptible to radiation damage, a well-known issue in traditional treatment of both HL and left-sided breast cancer.24 It is therefore not surprising that HLS who underwent MRT had more valve pathologies than both controls and those treated with chemotherapy alone. Even so, the prevalence is drastically lowered compared to that found in earlier studies. In 2003, Heidenreich et. al found a 29% prevalence of significant valve disease in irradiated HLS.23 Even though the present cohort had a longer observation time, which is strongly correlated with increased prevalence of valve disease following radiation therapy, the prevalence of valve disease was less than half (12% vs 29%).25
As with cardiac function, the improvement in accuracy of radiation treatment is likely to be an important contributing factor to the reduction in valve disease.
While earlier studies have found an increase in valve disease from treatment with anthracyclines, we found no evidence of such an effect.26 As changes in cardiac morphology in heart failure patients can cause valve insufficiencies, it could be that earlier results were simply secondary to the development of heart failure and cardiac dilatation. This was first proposed by van Nimwegen et. al., and our findings support that theory.1
Coronary artery disease, cardiovascular risk factors and biochemistry
We found no significant differences between treatment groups or between HLS and controls with regards to most cardiovascular risk factors. There is strong evidence for an increased incidence of CAD in HLS, which is most pronounced in those treated with radiotherapy.27 However, it is likely that this increase in risk is caused by direct endothelial damage, rather than indirectly through adversely modified risk factors. Nonetheless, the higher baseline risk for CAD would suggest that close monitoring and treatment of modifiable risk-factors is of particular importance in HLS.3
Although not significant, there was a trend towards more CAD in the AC + MRT group compared to controls in the present study. As this study was not powered to assess rare outcomes, one should be careful about inferring too much from these findings. It would, however, at least suggest that CAD could still be an issue in HLS, particularly those treated with both AC and MRT.
Both treatment groups had a higher NT-proBNP than controls, and the HLS treated with both AC and MRT had a higher NT-proBNP than those treated with AC alone. This would be expected from the higher prevalence of borderline and impaired GLS on echocardiography.
Limitations
Cross sectional studies are susceptible to survival bias. Similarly, a paper recently assessed the risk of selection bias in longitudinal studies and found that those who for various reasons failed to participate in the follow-ups are at higher risk for death.28 This study combine elements of both, but is likely less affected by these issues, as measurable clinical or subclinical long-term adverse cardiac effects on echocardiographic examinations are likely to precede critical illness and death by several years.
Although the HLS were matched with controls on several risk factors, there were significant differences between the two treatment groups. Patients treated with both AC and MRT were more likely to be male and more likely to be current or former smokers. Although a potential bias, this was adjusted for in all the major analyses.
While this was a large echocardiographic study, it is not powered to reliably assess rare outcomes. Although we did not find a statistically significant difference in CAD or heart failure, we cannot conclude that such a difference does not exist, nor that the HLS are not at increased risk for CVD later in life.