Our study featured the largest sample size among existing studies involving patients with ESCC undergoing nCRT. Our findings showed no notable variation in survival duration between ENI and IFI. Notably, the IFI group exhibited reduced radiation toxicity and no notable increase in out-of-field LNs.
With the widespread implementation of neoadjuvant therapies, the survival rates of patients with esophageal cancer have improved significantly [20–22]. Concurrently, researchers have reported side effects resulting from neoadjuvant radiotherapy, including myocardial infarction, arrhythmia, radiation-induced myocarditis, radiation pneumonitis and leukopenia [6, 23, 24], which may diminish patient quality of life and, in severe cases, even lead to patient mortality. Therefore, controlling the side effects of radiation therapy and preventing missed irradiation are crucial.
nCRTs are currently the main treatment modalities for patients with locally advanced stage III–IVA ESCC. Nevertheless, researchers have focused on the irradiation range of the LN drainage areas during radical radiotherapy. In their prospective cohort study, Jing et al. reported that IFI provided similar OS and PFS with smaller volumes and lower toxicity than ENI. This is particularly beneficial in older patients as a smaller CTV can help reduce treatment-related toxicities [25]. Yamashita et al. found that missed irradiation rates in clinically uninvolved nodal stations did not increase with IFI compared to ENI. Moreover, IFI resulted in significantly decreased esophageal toxicity [26]. However, research on lymphatic drainage areas in the context of neoadjuvant radiotherapy is limited, and large-scale cohort studies are lacking. Moreover, with advancements in radiotherapy techniques, the complications and side effects induced by radiotherapy are also changing.
Our preliminary results demonstrated that the survival outcomes did not differ significantly, consistent with the results of other studies [27]. Before 2021, our center mainly adopted ENI irradiation (168/208 patients, 80.0%). However, after 2021, with the advancement of lymphatic drainage area-related studies and recommendations from Chinese experts, IFI irradiation has gradually been adopted (64/98 patients, 65.3%). Substantial evidence has shown that the conventional approach of expanding the irradiation field to prolong survival is unnecessary. Post-neoadjuvant treatment frequently involves comprehensive three-field dissections that effectively clear suspicious positive LNs. Neoadjuvant chemotherapy may also play an important role.
We also observed a significantly lower incidence of bone marrow suppression and Grade ≥ 2 treatment-related esophagitis in the IFI group than in the ENI group. In our study, compared to ENI, IFI significantly reduced the CTV and mean dose to the lungs, as well as the lung V20, V30, and V40 (p<0.05). Volume reduction leads to decreased doses to critical organs, offering the potential for reduced symptoms such as radiation-induced myocarditis and pneumonitis in the lungs. Moreover, reduced doses to the spinal cord may result in decreased hematological toxicity. IFI may improve patient tolerance and the quality of life during treatment. This reduced toxicity provides a foundation for expeditious surgical intervention after neoadjuvant therapy, thereby minimizing surgical complications.
Meanwhile, in our center, the rate of out-of-field LN irradiation for patients with ESCC undergoing nCRT was 9.5%, whereas the missed irradiation rate in radical radiotherapy was 30.0% [28]. This may be related to the advancement of radiotherapy technology in recent years and the increased precision of postoperative pathology. Our study shows that out-of-field LN irradiation is not related to the method of LN irradiation and survival time and the missed irradiation rate is highest in abdominal LNs. Therefore, we should use a combination of various radiological examinations and pay attention to the abdominal LNs to clinically reduce the missed irradiation rate. Nonetheless, this research has some limitations: (1) it is a retrospective study and (2) patients underwent examinations or treatment at external institutions, which may have led to potential inaccuracies in the statistics of recurrence patterns and side effects. Moreover, while the reduction in treatment-related toxicities is promising, the impact on long-term survival outcomes is yet to be established. Further research, including larger-scale prospective studies with longer follow-up periods, is warranted to comprehensively evaluate the efficacy and safety of IFI in the treatment of ESCC.