The prognosis of patients with esophageal recurrence after definitive chemoradiotherapy for ESCC is poor, and re-RT with or without chemotherapy has been considered as one of the most common treatments. However, only a few studies with small cohorts of selected patients have investigated the efficacy of re-RT in locoregional recurrent Esophageal Cancer, and the patterns of recurrence in esophagus, within or outside initial PTV, were not detailed[6, 7, 9]. To our knowledge, the present study is the first to assign esophageal recurrence to the in-PTV and out-of-PTV recurrence after definitive chemoradiotherapy, depending on the positional relationship between the recurrent tumor center and the initial PTV margin. Our research proved that there were significant differences in the clinical characteristics between these two groups. Re-RT was much safer and more effective for patients with out-of-PTV esophageal recurrence. Based on the results, it implied that more active definitive treatment should be performed in patients with out-of-PTV esophageal recurrence.
There were differences in the clinical characteristics between patients with the in-PTV and out-of-PTV esophageal recurrence. Firstly, patients with out-of-PTV recurrence had more family history of cancer than the in-PTV group; Secondly, pathological inconsistency was more common in patients with out-of-PTV recurrence. All patients in the in-PTV group had the same pathology before and after recurrence. Thirdly, the clinical stage of the out-of-PTV group was earlier than that of the in-PTV group. However, it is worth pointing out that the post-treatment changes made the diagnosis of in-PTV recurrence extremely difficult[10–13]. At last, the ratio of the number of patients in the in-PTV group to the out-of-PTV group is 326:53.
Compared with the in-PTV group, the re-RT efficacy for the out-of-PTV group was much better. The local control rates were higher, indicating better radiosensitivity of the out-of-PTV group, while almost all patients in the in-PTV group experienced recurrence again within 3 years. The OS rates of the in-PTV group are in consist with previous reports exploring salvage treatments for recurrent EC[5, 14]. In contrast, the OS rates after recurrence in the out-of-PTV group were much better. There is no previous research reporting the efficacy of re-RT for patients with out-of-PTV esophageal recurrence. We found that the therapeutic safety and efficacy of re-RT for the out-of-PTV group were close to that of definitive chemoradiotherapy for newly diagnosed locally advanced EC[1, 15, 16]. The main reason for the poor therapeutic efficacy of the in-PTV group is that after radiation for esophageal lesions, radiation-resistant cell lines relapse and the recurrent tumor mass is not sensitive to radiotherapy[17, 18]. The local control of the initial radiation was much better than that of the re-RT in the in-PTV group, which also proved this.
Re-RT for the out-of-PTV group is safer than that for the in-PTV group. Previous researches reported that the esophageal hemorrhage was 4.3%-11.8% with esophageal fistula/perforation 8.5%-19.4% in re-RT for recurrent EC after initial radiotherapy[5, 7, 8]. These complications were considered similar to the in-PTV group in our research. Though the prescribed dose of re-RT and the cumulative dose of esophagus (except the cumulative mean dose) were significantly higher in the out-of-PTV group, the rate of severe esophageal hemorrhage or perforation was lower reversely. The most important reason was that the overlap length of the irradiated esophagus was remarkably longer in case of the in-PTV group than out-of-PTV group, for it was reported that the longer length of the re-irradiated esophagus was a significant predictor of the toxicity. It was worth noting that the cumulative dose of the esophagus had significant correlations with toxicities of the esophagus. As such more attention should be paid to esophageal related complications in re-RT. Besides the repair disability of re-irradiated tissues, tumor progression might be associated with perforation and hemorrhage[14]. The severe radiation-induced pneumonitis, and cardiac disorders were similar between the two groups. Nonetheless, most patients in the in-PTV group died within 1 year and it was the most important interference factor. Besides, the recurrence free interval between the initial radiotherapy and re-RT was various, and it might affect the radiosensitivity of the organs at risk.
Although the out-of-PTV and in-PTV recurrences are both generally regarded as esophageal recurrences after chemoradiotherapy, our findings indicate that the out-of-PTV recurrence is remarkably different from the in-PTV recurrence. Out-of-PTV recurrence is usually considered as submucosal infiltration or submucosal lymphatic metastasis. Under this assumption, out-of-PTV esophageal recurrence may like an oligometastatic lesion in the esophagus. A recent study reported that the 1 and 2-year OS rates were 76.2% and 58.0%, respectively of patients with oligometastatic lesions after radical treatment for ESCC[19]. This OS is close to that of the out-of-PTV group in our research. However, as per the characteristic of EC, it is prevalently associated with multiple primary tumors in the esophagus[20, 21]. Out-of-PTV recurrence is actually a SPT in esophagus could be another possibility. In most of the cases, the pathology of out-of-PTV esophageal recurrence is consistent with that of the primary tumor, therefore it is difficult to distinguish between submucosal infiltration, submucosal lymphatic metastasis and SPT. But in either case, the radiosensitivity and therapeutic efficacy of re-RT for out-of-PTV recurrence should be better than that of re-RT for in-PTV recurrence, because the emergence of radiation-resistant cells is the main reason for in-PTV recurrence. Regardless of the origin of out-of-PTV recurrence, the radiosensitivity is more likely to be good because it has not been irradiated, and the OS of re-RT for out-of-PTV recurrence is satisfied. Thus, it is important to confirm the location of esophageal recurrence. If the out-of-PTV recurrence is still staged as a locoregional disease, a radical treatment plan should be taken, just as the newly diagnosed locally advanced EC [20, 22].
In conclusion, it will benefit the esophageal recurrence patients once exerting re-RT and classifying patients into the out-of-PTV and in-PTV groups. The out-of-PTV group has the better safety, radiosensitivity and efficacy from re-RT, and more active definitive treatment should be performed in future clinical practice.