Esophageal carcinoma (EC) is typically managed using curative-intent concurrent chemoradiotherapy (CCRT) as a definitive treatment option for patients who are either ineligible for or decline esophagectomy (1-3). Although CCRT is recognized as a safe and effective treatment for EC, it carries the potential for inducing adverse events, including esophageal, pulmonary, and cardiac toxicities (4).

Cardiac volume reduction (CVR) is among the observed phenomena during CCRT for EC (5-7). Suggested causes for this CVR include intravascular volume depletion attributed to dehydration which occurs when patients use or lose more fluid than they take in, and their body do not have enough water and other fluids to carry out its normal functions, a common issue encountered during hospitalization for CCRT in EC treatment (6,8,9). However, several studies have also demonstrated that acute cardiac damage may occur during CCRT for EC (6,7,10,11) and contribute to CVR (7). CVR can occur due to heart dilatation disorders caused by cardiac damage represent congestive symptoms (12). Physiological changes can also be quite different for patients with the same CVR (dehydration or heart dilatation disorders). Nevertheless, there are few reports that discuss the causes of CVR. Consequently, the cause of CVR during CCRT remains uncertain.

The left anterior descending coronary artery (LAD) is the most important coronary artery with the wide perfusion area. Recently, some studies suggested that dose to the LAD correlated with cardiac events after irradiation (13-16). In the Three-dimensional conformal radiation therapy era, CVR has not been studied extensively because the changes of dose distribution due to CVR have been reported to be small. However, in the intensity-modulated radiation therapy (IMRT) era which has dose density changes, the impact of CVR may be significant. To address these issues, we examined the correlation between factors reflecting dehydration and the parameters associated with CVR, and evaluated the cause of CVR and the impact of the CVR on movement of LAD region.

In our study, the change ratio of the IVC volume was exclusively associated with the degree of CVR during RT. Conversely, changes in blood pressure, pulse rate, BMI loss, laboratory data, and heart dose did not exhibit any significant correlation with the CVR during RT. Additionally, patients experiencing CVR of >10% demonstrated substantial LADR movements.

Dehydration stands out as the foremost reason for hospitalization in patients undergoing RT for EC (6,8,9). The IVC serves as an indicator of dehydration (21). In our study, the change ratio of the IVC volume correlated with the degree of CVR during RT. This suggests that dehydration is the primary cause of CVR during RT. However, in our study, several parameters that are typically used as indicators of dehydration, such as variations in blood pressure, pulse rate, and laboratory data, were not correlated with CVR during RT. Blood pressure and pulse rate can be influenced by diurnal variations and the degree of rest, factors that may have been challenging to control given the retrospective nature of our study. Furthermore, laboratory data are typically used to gauge dehydration in patients with normal renal function. However, the administration of cisplatin + 5-fluorouracil during CCRT in patients with EC can frequently lead to myelosuppression and/or nephrotoxicity (22-24), making it challenging to accurately assess dehydration using these parameters. Therefore, the primary cause of CVR seems to be dehydration. However, few clinical features have been presented to conveniently presume CVR during RT. In clinical practice, cisplatin + 5-fluorouracil is a chemotherapy regimen that induces dehydration and it is difficult to prevent dehydration at present. Therefore, CVR should be assessed in EC patients treated with CCRT, and re-planning should be conducted if necessary.

Several studies have demonstrated that radiotherapy to the heart can damage cardiac function, leading to cardiac impairment (6,7,10,11,13-16,25). Furthermore, some studies have suggested that cardiac damage can occur in the early stages of RT in patients with EC, and that the percentage of heart volume receiving a high dose may influence the extent of cardiac damage (7,11). Wang et al proposed that heart dilatation disorders, including cardiac impairment, contribute to CVR during RT (7). However, heart dilatation disorders generally result in a dilated IVC (12). Moreover, no studies, including ours, have demonstrated a correlation between DVH during cardiac irradiation and CVR during RT (6,7). Therefore, although cardiac impairment may also play a role, the primary cause of CVR during RT appears to be dehydration.

This suggests that CVR may occur in patients with EC treated with IMRT, even with cardiac dose reduction. Although the effect of the CVR on dose distribution is reported to be small in 3DCRT planning (6), it can significantly impact the dose distribution in IMRT, a more precise radiation method than 3DCRT. Although there were no detailed prospective analyses of adverse cardiac events, several studies have suggested that doses to the LAD may be associated with late cardiac adverse events such as major adverse cardiac events (MACEs), which include myocardial infarction, coronary revascularization, or death resulting from ischemic heart disease (13-16). In our study, because of the limited CT image quality from free breathing and the absence of cardiac synchronization, evaluating LAD movement was not feasible. Instead, we contoured the LADR as accurately as possible and evaluated its movement between the initial and off-cord boost-plan CT scans. We observed significant LADR movement caused by CVR of >10%, suggesting that substantial changes in LADR dose distribution might occur during IMRT planning and may increase the cardiac adverse event. Although further detailed evaluation with cardiac synchronization and breath-hold CT images is warranted, some studies showed that higher LAD doses may increase cardiac adverse events (13-16). Therefore, the increased LADR dose due to significant LADR movement form CVR of >10% may be associated with a higher risk of cardiac adverse events and unfavorable prognosis. To address these issues, we recommend reducing the intensity of the oblique entry beam from the front left to the back right in IMRT planning, considering the LADR as the path of the additional beam. Moreover, because few clinical features are available for predicting CVR, cone-beam CT for the evaluations of CVR 2-3 weeks after the commencement of IMRT treatment may be necessary to identify the need for replanning.

However, our study has some limitations due to its retrospective design. First, the sample size was small, which may have contributed to the discrepancies between our results and those of previous studies regarding changes in sBP, dBP, and PR. Moreover, although we used the CVR cutoff value of 10%, we believe that calculation of the appropriate clinically significant CVR cutoff value with Receiver Operating Characteristic analysis should be performed using a larger sample size in the future. Second, the use of CT images obtained during free breathing without cardiac synchronization may introduce uncertainty in LADR contouring. In our study, LADR variation from free breathing and without cardiac synchronization was judged by three observers (radiation oncologists) to be sufficiently small to have an acceptable impact on contouring. However, the variation in right coronary artery region (RCAR) due to free breathing without cardiac synchronization was deemed too large for reliable contouring. Therefore, further studies are required in the future for evaluating the changes of RCAR dose distribution. Finally, because chemotherapy was used in almost all patients (94.8%) in this study, it is unclear whether this result would apply to cases treated with radiotherapy alone. Despite these limitations, our study offers valuable insights for daily clinical practice, especially in IMRT planning, as there have been limited reports on CVR during CCRT for patients with EC and no reports on LADR movement due to CVR.

In conclusion, the primary cause of CVR during RT for patients with EC appears to be dehydration, as evidenced by the correlation between the change in IVC diameter and the degree of CVR. Notably, the substantial movement of LADR due to large CVR highlights the importance of monitoring CVR during RT, particularly in IMRT with cardiac dose reduction.