Chest radiation exposure associated with severe valvular disease commonly aortic stenosis has been under the area of active research recently owing to the lack of plausible data, and the dilemma of opting for a suitable surgical approach for valvular repair after the consequent development of challenges, such as mediastinal fibrosis and pericardial constriction rendering the feasibility of surgical intervention questionable despite the necessity. The lack of significant clinical trials and credible research data leaves cancer survivors with debatable options for suitable surgical intervention, the judgment mostly based on the prognosis of cancer itself. The findings of our updated meta-analysis appraising the outcomes of TAVR in patients with versus without prior C-XRT had discerned notable findings regarding short, and long-term mortality, safety, and efficacy of the procedure. We demonstrated TAVR to be safe in cancer survivors with a history of C-XRT, with similar all-cause mortality at 30-days, and 1-year interval, post-procedural safety in terms of stroke, and major bleeding events, as well as efficacy of the procedure in improving LVEF, and mean aortic valve gradient. We further found that exacerbation of CHF post-procedurally was higher among patients with C-XRT compared to the control groups.
Our updated analysis showed that the mortality rate at both the 30-day, and 1-year interval was similar in the radiation group compared to the control group. This is in contrast with the findings of a previous meta-analysis by Zafar et al. which indicated higher mortality at 1-year follow-up among TAVR patients with prior C-XRT [16]. These conflicting findings can be explained by the addition of two new large-scale observational studies by Kherallah et al., and Mohanty et al. both of which followed cancer survivors for a duration of 2-years and found no significant differences in all-cause death between those with prior C-XRT, and control groups [6, 7]. However, previously published observational studies have indicated radiation therapy [14], and malignancy progression as potential factors for higher long-term mortality outcomes for TAVR in the cancer population [17]. A recent study by Strange et al. found that the risk of 1-year mortality in patients with the low burden of co-morbidities undergoing TAVR was found to be 5.5%, and contrarily, in patients with high co-morbidity burden was found to be 25% [17]. Together with this, Siddiqui et al., also found that patient baseline co-morbidities are a considerable factor in the readmissions of patients who underwent TAVR and survived their index hospitalizations [18] putting forward that the risk factor assessment for underlying co-morbidities in cancer survivors considered for TAVR may remarkably allow physicians to predict a far better long-term prognosis.
Individual phenotyping of patients and consideration of appropriate personalized rehabilitation with effective monitoring may improve co-morbidity associated with increased long-term mortality after TAVR together with better assessment of prognosis. Further studies are suggested to evaluate the incidence and type of comorbidity most associated with poor post-procedural prognosis. Different peri-procedural management plans can be explored and tailored to the individual phenotyping of patients according to demographic and clinical factors to increase the probability of long-term survival. In addition, further studies on co-morbidities particularly associated with cancer survivors such as cardio metabolic co-morbidities may be of additional benefit in drawing better conclusions regarding the prognosis of TAVR in cancer survivors.
The post-procedural safety outcomes including stroke, major bleeding events, access-related vascular complications, PPM implantation, and acute kidney injury at 30-days were similar in both groups. It has been previously established that TAVR can be theoretically a better surgical intervention in patients with prior C-XRT due to its advanced, and minimally invasive technique bearing advantage over open-heart surgery in patients with extensive chest radiation, and mediastinal fibrosis. These better peri-procedural safety outcomes can be linked to the recent advancements in TAVR techniques, closer monitoring, and anticoagulative therapy that has particularly reduced the incidence of stroke in this cohort [16]. Our analysis revealed no significant differences in the incidence of PPM implantation between the two groups. These findings parallel the observations from the PARTNER 2 registry which analyzed 3987 cancer survivors undergoing TAVR and found no difference in rates of PPM implantation [7]. In contrast, the study by Agrawal et al. indicated higher incidence of pacemaker implant in cancer survivors with prior C-XRT at a mean follow-up of 17 months [14]. C-XRT is also notoriously reported to cause damage to the conduction pathways via fibrosis consequently leading to arrhythmias. Hence, watchful monitoring is essential in these patients for earlier detection, and treatment of these conduction abnormalities. The remarkably higher incidence of exacerbation of post-procedural CHF was a characteristic finding in patients with prior C-XRT despite paralleling aortic valve gradients, and LVEF before and after TAVR as the control groups. Several possible causative factors can be put forward for the finding, including the radiation exposure associated diastolic dysfunction, contribution of post-procedural anemia, blood transfusions, pulmonary hypertension, and atrial dilation in worsening of heart failure while also considering the cardiotoxic effect of some chemotherapeutic agents delineating that the plausible exacerbation may be possibly caused by independent post-procedural, and post-radiotherapeutic phenomena rather than the procedure itself.
There are a few limitations of our study that warrant consideration. First, all of the studies included in our analysis were observational, and hence associated with confounders, and risk of bias. Randomized control trials comparing TAVR with standard medical therapy in cancer survivors are critical to resolve this clinical enigma. Second, our study population displays a widely heterogeneous, and relatively smaller number of patients with different thoracic malignancies, variable therapies, and underlying comorbidities. Thus, it was difficult to stratify them based on types of malignancy. This would obligate access to an outsized patient database, which is not presently available. Third, we could not evaluate the influence of the amount of radiation dosage, the time duration between last chest radiation therapy and TAVR and laterality of the tumor on the clinical outcomes due to limited data reported in the included studies. The studies also did not report data for cancer-related and non-cancer specific deaths hence this could not be evaluated for all-cause mortality. Fourthly, we were unable to compare the outcomes of TAVR versus surgical aortic valve intervention in cancer survivors with prior C-XRT due to lack of optimal number of available studies to analyze them meta-analytically. Finally, we cognize that data on long-term valve dysfunction are essential, but unfortunately, they were not conferred in the included studies.
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