Tumor-cell PD-L1 is expressed in 50% of patients with advanced EC[14, 15]. While the major clinical benefits reported from the use of PD-1/PD-L1 inhibitors[16, 17], the accompanying risk of adverse events cannot be underestimated[18]. RP is a common adverse event occurring in 10–30% of patients with chest malignancies treated with RT[2, 19]. Many clinical factors such as age, smoking history, the size of tumor, MLD, V20 and the lung volume receiving low-dose irradiation are known to be independent risk factor for the occurence of RP[20–25]. However, the introduction of immunotherapy to the standard of care in this population should lead to the re-assessment of this pattern.
In our study, the incidence of grade ≥ 2 RP in patients with EC who received RT and immunotherapy was 30.95%, which is higher compared to those who received RT alone (17.39%). Most RP occurred 106 days after RT, which was consistent with previous studies[26, 27], however patient who received RT alone developed a delayed RP compared to those in the RT-I group (87 days).
Age, the total irradiation dose, irradiation segmentation frequency and V15 are independent predictive factors for the development of grade ≥ 2 RP in patients with unresectable locally advanced EC receiving RT + Immunotherapy. Age was shown to be negatively associated with the development of RP in patients with EC in our study, which is comparable to patients with lung cancer who received chest irradiation[28]. Younger age group may possess a stronger immune response than older patients, which account for the higher risk of RP. Cytokines such as tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β), interleukin (IL)-1, IL-6 as well as reactive oxygen and growth factors released from irradiated lung cells further recruit inflammatory cells to alveoli, which could lead to the development of an acute-phase pneumonitis[29–31].
Interestingly, although a non-smoking status showed a trend to be protective from the development of RP, the statistical analysis was not significant, which may be accountable to the small cohort size. Besides, RP is associate with a radiation therapy in a dose dependent manner, which was consistent with our analysis showing that higher total irradiation doses are associated with a higher risk of RP [32].
The NCCN guidelines (Version 1.2023) recommend that the lung dose limits for EC patients are as follows: V5 ≤ 50%, V10 ≤ 40%, V20 ≤ 20%, V30 ≤ 15%, and V40 ≤ 10%. V5, V20, V30, and MLD have been identified as independent predictors of RP[33–35]. In our study, V15 was found to be related with RP occurrence, which was reported in the literature in predicting the development of grade ≥ 2 RP[36]. V15 may be an important factor to consider when discussing the benefits and adverse events that may occur after receiving RT + Immunotherapy.
In order to construct an optimistic RP prediction risk model, all clinical parameters were included in R vision for cyclic modeling inspection. Ultimately, four and five parameters were screen out in two groups. Several studies tried to establish a risk model including only one parameter: V20. Current studies showed that V20 > 20% was a risk factor for RP[37–39], however we found that 69% of RP cases occurred with a V20 ≤ 20% in patients receiving RT alone. Our risk model combines several factor to predict the risk of RP however larger cohort are required to reevaluate the predictive value of a V20>20% when combined with other factors age and N, M stage. In EC patients who received RT + immunotherapy, more paraments should be included for RP risk prediction. Except for four parameters which are significantly related to RP occurrence (age, total irradiation dose, irradiation segmentation frequency and V15), V20 was also included in RP prediction risk model. According to the coefficient value, the smaller number of irradiation segmentation frequency, the higher total irradiation dose, the higher incidence of RP. It is easy to be explained that lung tissue belongs to late responding tissue, which is more sensitive to single dose.
In summary, age and V20 are very important parameters for predicting RP risk. Whether EC patients received immunotherapy or not, age and V20 were typical factors to be evaluate while establishing the treatment plan and calculating the RP incidence risk. In the era of immunotherapy, age, total RT dose, irradiation segmentation frequency, V15 and V20 should be reevaluated.
Nevertheless, our study encountered several limitations. Including the retrospective design and the fact that all the patients received chemotherapy. Therefore, no comparison of differences in various chemotherapy regimens were available. In addition, the majority of patients included in this study were diagnosed with squamous carcinomas, which are more common in China, compared to adenocarcinomas, which are more prevalent in Europe and the United States. Therefore, the probability of RP and the risk factors for adenocarcinoma of the esophagus in the real world needs to be further explored.