The standard of care for locally advanced resectable esophageal squamous cell carcinoma (ESCC) is neoadjuvant chemotherapy (NAC) in Japan (1,2) and neoadjuvant chemoradiotherapy (NACR) in western countries (3). More evidence available is supporting the use of NACR worldwide, especially for locally advanced disease (4). Even in Japan, NACR is recommended in patients whose disease is suspected to be borderline resectable (5). However, the side effects of NACR cannot be ignored. In the Francophone de Cance’rologie Digestive 9901 (FFCD 9901) trials, the in-hospital postoperative mortality of NACR group was 11.1% (6). Surgical procedures following NACR were challenging, reflected in prolonged surgical times and blood loss. Also concerning was an increase in major postoperative complications (7).
Docetaxel achieved significantly longer survival in SCC of the head and neck (8) and locally advanced ESCC (9). A phase II study also suggested that preoperative docetaxel, cisplatin and fluorouracil (DCF) was well tolerated in ESCC (10). The regimen exhibited a response rate of 60.0% with no treatment-related deaths (10). In our retrospective data, paclitaxel + cis-platinum (TP) achieved an overall clinical response rate of 77.1%. The pathological complete response (pCR) rate was 20.5%, in contrast to 29% for similar patients receiving chemoradiotherapy alone reported by CROSS trial (3). These data suggested that, in addition to NACR, nowadays many patients could achieve a response only by chemotherapy.
Therefore, we designed NAC with or without NAR (NAC ± NAR) combined treatment to avoid unnecessary NACR. The curative surgery was performed in patients who responded to NAC. Otherwise, NAR was employed.
We hypothesized that NAC ± NAR compared with NACR combined treatment mode could significantly reduced the postoperative complications and postoperative hospital stays. Furthermore, they might have the same survival benefits.
The project was approved by the Review Board and Ethics Committee of Henan Cancer Hospital (HCH)/The affiliated Cancer Hospital of Zhengzhou University. The ethical approval number is 2018122. At our institution, we have occasionally seen patients with locally advanced ESCC that the longest diameter of transverse section of the tumor was longer than 3.3 cm and was suspected of uneasy surgery by computed tomography (CT) scan, however which was diagnosed as T3 disease by electronic ultrasonic esophagoscopy (EUS), bronchofiberscope, chest magnetic resonance imaging (MRI), and other preoperative tests. We refer to these cases as borderline-resectable cT3 cancer. We retrospectively collected the data of patients with borderline-resectable cT3 ESCC who received NAC ± NAR and surgery in the First Ward Thoracic Surgery Department of HCH between June 30, 2015 and October 31, 2016. The control group was the patients with borderline-resectable T3 ESCC who received NACR and surgery in our department during the same time. The inclusion criteria were: clinical stage borderline-resectable T3N0-1M0 according to the 2012 TNM classification; aged 17 to 80 years; esophagectomy was done through right thoracic cavity; with sufficient bone marrow function; and without any contraindications due to conditions of the liver, kidneys, heart, or lungs.
Figure 1 shown the clinical pathways of the NAC ± NAR and NACR routes. In NAC ± NAR group, therapy was started with NAC. According to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (11), if patients achieved a response, partial response (PR)/complete response (CR), we proceeded to surgery. If the patients were instead found to have SD/progressive disease (PD), we defined it as no response and suggested the patients receive 30–45 Gy radiotherapy. After NAR, if the patients achieved response (PR/CR), surgery was employed. If the patients achieved no response (SD/PD), we suggested them to receive definitive radiotherapy or surgery. Reevaluation after all of these treatments, surgeries were accessed, and further treatments or palliative therapy were provided as necessary.
NAC ± NAR
The NAC included two cycles of TP, consisting of paclitaxel at a dose of 175 mg/m2 and cisplatin at 75 mg/m2 by continuous infusion. No response patients would receive 35–40 Gy radiotherapy.
The concurrent NACR was performed with 6 MV photons to a total dose of 35–40 Gy over less than 5 weeks. If the patients could not undergo surgery, the radiotherapy was performed to a total dose of 60–65 Gy. During the course of NACR, docetaxel + cisplatin (DP) chemotherapy was administered with radiotherapy. Two cycles of DP consisted of docetaxel at 50 mg/m2 and cisplatin at 60 mg/m2.
Right thoracotomy esophagectomy and regional lymphadenectomy was performed. Thoracolaparoscopic esophagectomy was accepted. Transhiatal esophagectomy and left thoracotomy was excluded. Total two-field lymphadenectomy was adopted. The left recurrent laryngeal nerve, right recurrent laryngeal nerve, paraesophageal, paratracheal, subcarinal, supradiaphragmatic, posterior mediastinal lymph nodes, celiac, left gastric artery, common hepatic artery and splenic artery lymph nodes were all defined as the regional lymph nodes (12). Li’s anastomosis (13) and gastric conduit were used for all patients.
Clinical and pathological tumor response
The esophagography, EUS, contrast-enhanced thoracic CT scan, abdominal echography, brain MRI, cervical color ultrasound and emission computed tomography (ECT) were essential pre-treatment examinations. PET/CT was used instead of abdominal echography, cervical color ultrasound and ECT if the patient had good financial circumstances. The common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 was used to assess the adverse events of NAC and NAR (14). The evaluation of the clinical tumor responses were conducted by the RECIST 1.1 (11). No evidence of viable cancer cells was defined as pCR (15).
A research nurse contacted all patients by phone and ensured that each patient would be followed at outpatient clinics. The surveillance examinations included chest CT scans and abdominal, cervical echography routinely. The clinical and laboratory examinations were repeated every 3 months for first 3 years, every 6 months for the next 2 years. The end point was defined as death or being lost to follow-up.
The statistical analyses were conducted using SPSS 17.0 software for Windows (SPSS Inc., Chicago, IL, USA). Statistical significance was defined as a two-sided P value of 0.05. The pretreatment data were compared using a Mann-Whitney U test and a Chi-square test for qualitative data and the student’s t-test for all quantitative data. Kaplan-Meier curves and the log-rank test were used for statistical analysis of overall survival (OS). The OS was defined as the first date from the NAC/NACR to the tumor recurrence or most recent follow-up.
There were 60 patients included into the retrospective study. Thirty-one patients were treated with the NAC ± NAR, and 29 patients commenced the NACR. Baseline characteristics of all 60 patients are summarized in Table 1. Most patients were male (66.7%), and the median age was 65 years old (range, 47–79 years old). There were no significant differences between the two groups.
The response rate was summarized in Table 2. The overall response rate of NAC ± NAR was 93.5%. After NAC, six patients were evaluated as SD. These patients received the followed NAR. Four of them got clinical PR, and 2 of them got SD. One of the clinical PR patients was evaluated pCR after surgery. All of the two group patients achieved R0 resection.
The median follow-up period in all patients surviving without tumor progression was 15.5 months (range, 3–26 months). The median OS for all patients was not reached. A point estimate of the 2-year OS rate of the NAC ± NAR group was 84.0%, whereas 80.7% in the NACR group (Figure 2). The OS of NAC ± NAR and NACR were not significantly different (mean OS time: 21.672±0.710, 95% CI, 20.281–23.063 vs. 22.899±1.274 months, 95% CI, 20.402–25.395; P=0.410).
The overall toxicities during treatment were listed in Table 3. The major toxicities were leukopenia and gastrointestinal symptoms. There were three in the NAC ± NAR group (9.7%) and seven in the NACR group (24.1%) got adverse events of grade four. There was no significant difference between two groups. Surgical data for both groups are shown in Table 4. There was longer surgical time (mean, 237.26±73.369 vs. 268.38±53.189 min, P=0.024), more blood loss (median, 100 vs. 200 mL, P<0.001) and longer postoperative stays (median, 9 vs. 16 d, P<0.001) in the NACR group. The total complication rates (32.3% vs. 69%, P=0.004), the rates of arrhythmia (6.5% vs. 37.9%, P=0.003) and pneumonitis (25.8% vs. 51.7%, P=0.039) were higher in the NACR group. The anastomotic leakage only developed in NACR patients (0% vs. 13.8%, P=0.049). There are no treatment related deaths.
This retrospective study was designed to compare the long-term and short-term outcomes of a new combined mode NAC ± NRC with the standard NACR for ESCC. Finally we demonstrated NAC ± NRC and NACR may have same 2-year OS rates. We also demonstrated NAC ± NRC had significantly better surgical data, post operation complication rates, as compared with the standard NACR for ESCC.
The most controversial part of locally advanced resectable ESCC is whether to use NAC or NACR. More evidence supports the survival benefit of NACR compared with surgery alone (4). There were 2 clinical trials compared NAC and NACR for EC. They all got negative results, one of the trial got P value of 0.37 (16), the other P=0.07 (17). Two meta analysis which focus on this topic also got a negative result P=0.07 (4,18). A study reported that the addition of radiotherapy to NAC resulted in higher pCR rate, R0 resection rate, and a lower frequency of lymph-node metastases, however contributed nothing significant to survival (19). The difference of survival benefits between NAC and NACR may not be significant. As the high response rate of NACR for ESCC was observed, Japan started to do NExT Study (20) and Qun wang has launched to do NACR versus NAC for ESCC in China (21). Although they all expected a better survival results of NACR, the conclusion is still unclear. In this study, the NAC had become an induction chemotherapy for radiotherapy in no response patient. The induction chemotherapy prior to NACR also got a comparable survival benefit with NACR for ESCC (22). NAC ± NAR was increased the response rate of NAC alone and comparable data of NACR. These reasons may contribute to our survival data. The NAC ± NAR and NACR achieved a same survival benefits of 2-year OS rate of 84% and 80.7% (P=0.025). Furthermore, the 2-year survival rate in the NAC ± NAR group was higher than that in the group of standard-dose cisplatin, 5-Fu-radiotherapy in the CROSS trial (3). These data suggested that NAC ± NAR might be a sufficiently powerful combine model that results in a high rate of response and 2-year OS.
Another concern is the side-effects and safety of preoperation treatment. The treatment related deaths cannot be ignored in the FFCD9901 trial (6). The side effects of neoadjuvant therapy are shown in Table 3. Three (9.7%) NAC+NAR patients had grade 4 leukopenia. Four (13.8%) NACR patients also developed grade 4 leukopenia. The side effects in two groups were quite acceptable. Compared with the data reported in other studies (23), it appears that the number of side effects in our study was quite low. In this study, we used paclitaxel 87.5 mg/m2, d1, d8 and cisplatin 25 mg/m2, d2–d4 every 3 weeks for 2 cycles. The weekly paclitaxel and the divided cisplatin could dramatically reduce the toxicity of TP, which might be the reason why we achieved such minimal side effects. The surgical data for patients were listed in Table 4. The operation procedure for NACR was challenging, the surgical time and blood loss were statistically different. Postoperative pneumonia was more likely in NACR patients (P=0.039). Similar to FFCD9901, the lungs and heart were the main organs injured after NACR for ESCC (6). The results were also consistent with ESCC subgroup meta-analysis of Kumagai et al. (7). They suspected the ESCC usually had a long history of smoking and alcohol abuse which may be harmful to heart and lung (7). The number of postoperative days in the hospital was significantly prolonged in NACR group.
Additionally, ESCC is more common in developing regions worldwide (24,25). Even within China, ESCC occurs more frequently in poor areas (26). It is clear that NAC has low side effects, acceptable, affordable, and therefore may easily be promoted (7). In another our retrospective study, we could achieve a 20.5% PCR rate and a 77.1% response rate in ESCC by NAC alone; the data was promising. We learned that many patients could achieve enough response from NAC only. They do not need NACR for surgery. Why not combine NAC and NACR together? Since June of 2016 in our hospital, we have explored the NAC ± NAR model.
In our study, the NAC-SD patients could still attain high response rates from the followed NAR treatment. The NAR was not too late for the NAC SD patients (response rate 66.7%). The combined NAC ± NAR group achieved a highest response rate (93.5%) than the NACR group (86.2%). The clinical response rate of two-cycle CF in 9907 patients was 38% (1). The clinical response rate of two-cycle DCF was 64.3% (10). In our retrospective study of NAC for ESCC, the clinical response rate of two cycle TP was 77.1%. The pCT of NACR in CROSS study was 29%, 33.3% in FFCD9901 (6). All the data shown above demonstrate that, with the development of a new chemotherapy regimen paclitaxel, more patients could obtain enough response from NAC for surgery. They did not need additional radiotherapy for local control. In our retrospective study, TP not only achieved a high response rate but also had low toxicity.
There were some limitations in this study that need to be acknowledged. One of the major concerns was that it was a retrospective study. There could have been a selection bias especially for response rates of neoadjuvant treatment. Secondly, this is a single institution study based on a small number of patients and a short observation period. Thirdly, for advanced esophageal cancer, the standard preoperation treatment in our department is NAC right now. The number of patients who received NACR was limited. We had more experiences to do surgery and postoperative care after NAC than NACR. The results need to be confirmed in multicenter randomized control trials in the future.
China has the highest incidence of ESCC worldwide (27,28), and Henan Province contributes more than half of the number of cases in China (26). In our department, there were about 1,500 esophagectomies for cancer last year. That is an advantage to do clinical trials. Our aim was to explore the best preoperative combined treatment model for locally advanced resectable ESCC. The Academic Committee of HCH has already passed the randomized controlled trials protocol of NAC ± NAR versus NACR. NAC ± NAR might deserve to be included in standard armamentarium for the treatment of locally advanced ESCC in the future.
In the present study, the NAC ± NAR combined treatment model was tolerable. This model got the same survival benefits as NACR, avoids unnecessary chemoradiotherapy and achieved lower postoperative complication rates. In the future, it might be determined to be the best combined preoperative treatment for locally advanced ESCC, and for this reason, it deserves further exploration.
Funding: This project was supported by the Henan provincial public health authority (Grant number. 201501003), Henan province ministry of education (Grant number. 17A320048) and Wu Jieping Fund (Grant number. 320.6799.15062). Wu Jieping Fund (Grant number. 320.2730.1892).
Conflicts of Interest: The authors have no conflicts of interest to declare.
Ethical Statement: The project was approved by the Review Board and Ethics Committee of Henan Cancer Hospital (HCH)/The affiliated Cancer Hospital of Zhengzhou University. The ethical approval number is 2018122.
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