Due to the significant morbidity and potential for mortality associated with RP, it has always been a tough nut to crack for the oncologists. As described above, previous researches have made great efforts to establish reliable predictors to guide clinicians in mitigating the radiation-induced lung toxicity. And the DVH parameters of the lung has been wildly applied in clinic, such as MLD and lung V20 [7,8,9,10,11,12]. However, these factors can’t reflect the difference between individuals. In this study, we studied 31 parameters from 123 thoracic cancer patients enrolled prospectively. The results of this study demonstrated SARE, ILMLD (> 1186.78 cGy), MED were associated with SRP. And we further established an original nomogram model for symptomatic RP based on that.
To the best of our knowledge, it is the first time that SARE acts as a predictor for ≥grade 2 RP. As we all know, both the radiation-induced pneumonitis and radiation-induced esophagitis are typical radiation toxicities among thoracic RT. However, no research has linked the two together before that. The symptoms of SARE include retrosternal pain, dysphagia and odynophagia. It is easy for an experienced radiation oncologist to estimate the severity of ARE by the patient’s symptoms and physical signs during RT. SRP means that patients not only have changes on CT, but also have manifestations, such as cough, expectoration, dyspnea, etc. The assessment criteria of RP and ARE is explained in Table 1 in detail. By a long term of observation in clinic, we found a possible relation between these two inflammations and then designed a real-world study to explore the predictive value of SARE to SRP. Prior studies have explored numerous predictive factors for RP. Based on these results, we collected some of the clinical, laboratory and dosimetric parameters that we can obtain as much as possible. In order to better observe and record the initiation and development of patients’ symptoms, we chose to collect information prospectively. The results highlighted the predictive value of SARE to SRP. And we think SARE may function as an easier and earlier signal for SRP in future’s clinical work.
The high incidence of SRP was estimated to be at the range of 15 ~ 40% among patients with thoracic RT by previous studies [20], and the incidence in our study (30.8%) was consistent with it. The mortality associated with RP was reported to be less than 2% [21], which was 1.6% in our study. The lethal ratio of RP was not extremely high, however, it did decrease the quality of life and led to poor prognosis [22, 23]. Moreover, the lung tissue may become more vulnerable to virus or bacterial infection. In this study, there was a 64-year-old esophageal cancer patient who died of RP related pulmonary infection. After only 10 fractions of RT, the old man suffered intractable grade 4 ARE. He felt extremely pain when swallowing and had difficulty in eating. The symptoms become worse and worse, then he can only drink a little water in the final stage of radiotherapy. The esophagoscopy found diffuse esophagus mucosal erosion, ulceration, and hemorrhage (Fig. 6a). Moreover, the symptoms continued for the subsequent treatment and even after RT. Then the pneumonitis symptoms appeared only 4 days after RT. Unfortunately, the man got infected with pneumocystis carinii during the following treatment of RP (Fig. 6b ~ d) and died soon. This case reminds us that RP can not only reduce lung tolerance but increase the chance of severe pulmonary infection. If the doctor had realized the strong connection between SARE and SRP, he/she might modulate the radiotherapy plan timely. And the subsequent tragedy may be avoided by that.
In this real-word study, we set up both the esophagus and lung dose limits to the enrollment criteria to select those patients whose lung and esophagus tissue were both exposed to radiation. In another word, these patients have a highly likelihood of both two types of inflammation. The acute esophagus toxicity is regard as the response to the radiation exposure of esophageal mucosa. Patients often develop dysphagia and odynophagia, which may lead to appetite loss and weight loss [24, 25]. These symptoms usually appear at 2 to 4 weeks during RT, and some even occur in the first 2 weeks. In addition to reducing the quality of life, SARE may cause treatment break, which is related to inferior survival results [26, 27]. There is no specific cure for it, usually, ARE acts as a kind of self-limited complication. Symptoms can disappear in 2 to 4 weeks after the completion of RT gradually [27]. Our results showed SARE was associated with two esophagus-related dosimetric indicators, they were esophagus volume receiving more than 3000 cGy (V30) and the maximum esophagus dose. These two indicators showed a weak connection with SARE (OR: 1.000 and 1.010), which couldn’t influence SRP. Thus, SARE could be used to reflect the sensitivity of individual’s normal tissue towards the radiation directly. Patients whose radiation fields contain both the lungs and esophagus need to be more vigilant about the occurrence of SARE. If someone has developed SARE, great caution should be exercised on RP prevention. He/she should pay more attention to keep warm during and after RT to avoid catching cold. And the patient should take timely chest CT to determine the lung condition and change the patient’s treatment plan if necessary.
Numerous lung related DVH parameters for RP have been widely verified in previous studies, such as total or ipsilateral lung V5, V10, V13 and V20 [6,7,8,9,10,11,12,13,14]. Furthermore, the dosimetric parameters of esophagus, which may have not been served as predictors for RP, were also considered in this study. And we set enrollment limits on ILV5 and MED to reduce the bias of individual dose difference among the lung and esophagus, in order to avoid their affection on RP. We collected the parameters of mean esophagus dose and esophagus V30. We found that the MED made sense both in the univariate analysis and multivariate analysis. We admitted its value as a significant predictor for SRP, but that didn’t mean it was one of the causes of RP. It served as an indirect indicator that could reflect the distribution and volume of pulmonary disease surrounding the esophagus, which eventually would be reflected in the pulmonary dosimetric outcomes. And previous study had already found that esophagus dosimetric indices were positively correlated with lung dosimetric indices [7].
There are several possible reasons that may explain the predictive value of SARE to SRP. First of all, SARE can reflect the high esophageal radiation dose [27, 28], which further implicates the increase of radiation dose in the surrounding lung tissue. Secondly, the esophagus and lung are radiosensitive organs, and the early occurrence of SARE may further indicates the high radiosensitivity of the body tissue. More than this, Previous studies have confirmed multiple inflammatory cytokines were closely related to SARE as well as SRP [10, 27, 29, 30], so it may be a signal of activation of the body’s systemic inflammatory system. However, more basic experiments are needed to better explain the relation.
Although we have obtained a considerable relation between SARE and SRP from 123 patients, it is far away to get a convincing conclusion. The main limitation of this study is the relatively small number of patients. More so, we validated the nomogram model internally by Bootstraps with 1000 resample instead of an external database. In addition, some more fundamental research toward the common nature of these two inflammations are needed to finally prove it.