The traditional concurrent chemoradiotherapy regimen has improved the local control rate and survival rate of inoperable locally advanced esophageal cancer to a certain extent, but the overall curative effect is still unsatisfactory, and further treatment strategies are urgently needed to be explored. Our trial mainly was designed to evaluate the efficacy and safety of IFI using IMRT combined with concurrent chemotherapy of paclitaxel and cisplatin in the treatment of locally advanced esophageal squamous cell carcinoma.
IMRT is considered to be superior to 3-dimensional conformal radiotherapy (3DCRT) in terms of the consistency of the prescribed dose and target volume, which provides powerful technical support for the stricter limitation of the dose of important organs such as the heart and lungs. A retrospective study showed that IMRT technology improved the 5-year OS rate of locally advanced esophageal cancer from 15 to 44% [16]. However, some retrospective studies suggested that the two radiotherapy options did not bring about differences in the efficacy of patients [17], whether related to the location of the tumor needs to be further confirmed. The use of IFI or elective nodal irradiation (ENI) in radical chemoradiotherapy for esophageal cancer has been controversial. In a prospective clinical study reported by Fudan Cancer Hospital in 2010 [5], under the 3DCRT technology, for patients with locally advanced esophageal cancer treated with concurrent chemoradiotherapy, the 3-year OS rate of patients receiving IFI was 41%, and the patients suffering regional recurrence outside the irradiation field accounted for only 8% of patients with treatment failure. Jiang et al. [18] reviewed several studies comparing IFI and ENI in chemoradiotherapy for esophageal cancer, and the results showed that IFI did not sacrifice the efficacy of patients, and the side effects of treatment are relatively reduced. In our trial, recurrence within the irradiation field occurred in 6.5% of patients, accounting for 13.7% (7/51) of patients who underwent treatment failure, and there was no case of long-term radiation-induced cardiac injury.
Also controversial is the optimal total radiation dose, which is a very hot issue and is very difficult to get a consensus among many investigators around the world. There was a trend to recommend high dose (> 60 Gy) in Asia and 50 Gy in Western countries. Many differences in patient and tumor factors could have produced those conflicting results. Recent multicenter, phase III randomized studies reported that 50 Gy is as effective as 60 Gy in ESCC, both in Europe (ARTDECO study) and China (Xu et al.) [19, 20]. In Xu et al.'s study, the incidence of radiation-related pneumonia of grade 3 or above in the 60 Gy group was higher than that in the 50 Gy group (7.5% vs 3.1%, P = 0.03). But there are still some points worth noting about these two studies. In the ARTDECO study, the difference in the radiotherapy target volume between the two experimental groups (the standard group included the primary tumor + regional lymph nodes, and the high-dose group only irradiated the primary tumor) may be related to the failure to obtain significant LRFS benefit in the high-dose group. In addition, in both studies, regional lymph nodes were selected for prophylactic irradiation, and the irradiation field was large, resulting in an increase in related radiotoxicity. In our study, based on the study design of involved field irradiation, we chose a total radiation dose of 61.2 Gy.
Additionally, with the development of proton radiotherapy, some studies had found that it can further reduce radiation lung and heart damage in patients with esophageal cancer [15]. These were still some small-sample studies and the efficacy and safety of proton radiotherapy for esophageal cancer need to be supported by data from further prospective studies, but it seems to provide a direction for our subsequent clinical research.
In routine clinical practice and worldwide trials, paclitaxel-based chemotherapy regimens have been widely adopted for concurrent chemoradiotherapy in patients with inoperable esophageal cancer. A prospective randomized controlled phase III clinical study (ESO-Shanghai1) conducted by Chen Yun et al. compared the efficacy of the concurrent chemotherapy regimen based on paclitaxel and the classical regimen of cisplatin plus fluorouracil in esophageal cancer patients receiving radical chemoradiotherapy [21, 22]. The results of the study showed that the option of paclitaxel and fluorouracil did not significantly improve the 3-year OS rate of patients compared with the regime of cisplatin and fluorouracil (55.4% vs. 51.8%), but the AE profiles significantly differed between the two regimens. The paclitaxel plus fluorouracil can significantly reduce the incidences of early gastrointestinal adverse reactions, anemia, and thrombocytopenia. Meanwhile, it had higher incidences of severe leukopenia, radiation dermatitis, and radiation pneumonitis. In another prospective phase II study of radical chemoradiotherapy for locally advanced esophageal cancer, compared with cisplatin plus fluorouracil regimen, paclitaxel combined with platinum group had lower incidences of grade 3–4 nausea, vomiting (5.88% vs. 35.29%, P = 0.003) and neutropenia (11.76% vs. 32.35%, P = 0.041) [12].
There is still a lack of high-ranking evidence on which paclitaxel-based chemotherapy regimen provides the best prognosis and the fewest adverse events. In this study, the median PFS was 39.2 months, which was significantly higher than previous similar studies involving paclitaxel and cisplatin regimen [10,11,12], and the 3-year OS rate was 63.3%, slightly better than the test group in the ESO-Shanghai1 study (55.4%). In terms of safety, the most common grade 3–4 acute adverse events were neutropenia (58.3%) and leukopenia (56.5%). The incidence was higher than that of some previous studies [11, 12], but similar to that reported by Tang et al. [10].and highly consistent with the results of a 3-group, multi-center, randomized phase III clinical trial (ESO-Shanghai2) led by Fudan University Affiliated Cancer Hospital [23].
High hematological toxicity not only requires the optimization of the combination regimen and the dose of chemotherapeutic drugs, but also poses a challenge to improve the performance of chemotherapeutic drugs themselves. As an improved new formulation, polymeric micellar paclitaxel (PM-paclitaxel) for injection had shown significant clinical benefits compared with the control group (ORR 50.33% vs. 26.4%, P < 0.0001) in the first-line treatment of non-small cell lung cancer, and its application prospect in esophageal cancer is worth looking forward to [24].
By subgroup analysis, we found that ECOG performance, the cycles of chemotherapy, pretreatment NLR, ALC nadir, and dosimetric parameters of the heart had significant effects on overall survival, suggesting that these clinical features might be prognostic factors. However, considering the impact of potential confounding factors, the results still need to be treated with caution. Fortunately, in our study, 78.7% of patients completed all 4 cycles of chemotherapy, and the vast majority of patients with low pretreatment NLR (89/108, 82%) or ECOG performance 0, which further verified the possibility of achieving higher LRFS and OS rates.
Several limitations should be considered when interpreting our findings. First, this study is a single-arm study, and no control group was set to exclude the interference of other factors. Second, the high hematological toxicity and frequent gastrointestinal reactions revealed by the study results should not be underestimated, and we did not assess the quality of life of the patients.
In conclusion, paclitaxel and cisplatin combined with concurrent involved-field irradiation in definitive chemoradiotherapy for locally advanced esophageal squamous cell carcinoma provides inspiring local control, overall survival, and high but manageable hematological toxicity.