Non-curative resection for surgical T4b esophageal cancer: esophagectomy or non-esophagectomy?

National Cancer Center hospital Hiroyuki Daiko  ( [email protected] )
National Cancer Center hospital Kentaro Kubo 
National Cancer Center hospital Kyohei Kanematsu 
National Cancer Center hospital Daichi Utsunomiya 
National Cancer Center hospital Daisuke Kurita 
National Cancer Center hospital Koshiro Ishiyama 
National Cancer Center hospital Junya Oguma 
National Cancer Center hospital
Posted Date: December 8th, 2022
DOI: https://doi.org/10.21203/rs.3.rs-2347901/v1
License: This work is licensed under a Creative Commons Attribution 4.0 International License.   Read Full License
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Abstract Background
Recently, with the development of multidisciplinary treatment, the treatment outcomes of esophageal cancer (EC) have improved. However, despite advances in diagnostic imaging modalities, preoperative diagnosis of T4 EC is still dicult, and the prognosis of T4 EC remains very poor. In addition, the prognosis of surgical T4b EC (sT4b EC) after surgery remains unclear. In this study, we retrospectively reviewed sT4b EC.
Methods
We evaluated the clinical course of sT4b EC and compared palliative esophagectomy with R2 resection (PE group) with other procedures without esophagectomy (NE group) (e.g., only esophagostomy) for sT4b EC.
Results
Forty-seven patients with thoracic EC underwent R2 resection at our institution between January 2009 and December 2020. Thirty-four patients were in the PE group and 13 patients were in the NE group. The 2-year overall survival rate was 0% in the PE group and 20.2% in the NE group (p = 0.882). There was one case of long-term survival in the NE group that underwent surgery followed by denitive chemoradiation. Postoperative complications (Clavien–Dindo grade ≥3) were observed in 25 patients (73.5%) in the PE group and three patients (23.1%) in the NE group (p = 0.031). The median time to the initiation of postoperative treatment was 68.1 days in the PE group and 18.6 days in the NE group (p = 0191).
Conclusions
If EC is diagnosed as sT4b, palliative esophagectomy should be avoided because of the high complication rate and the lack of long-term survival.
Introduction Multidisciplinary treatments consisting of surgery, pharmacotherapy, and radiotherapy (RT) have improved the outcomes of advanced esophageal cancer (EC).
For clinical T4b (cT4b) EC, denitive chemoradiotherapy (dCRT) is the standard treatment [1]. In the largest study to date evaluating patterns of care for cT4b EC, compared with chemotherapy (CT) alone, the addition of denitive RT was associated with higher overall survival rates [2]. However, salvage esophagectomy after dCRT has been associated with higher postoperative mortality and morbidity rates [3]. In contrast, induction CT with docetaxel, cisplatin, and uorouracil (ind-DCF) in patients with T4 EC increased overall resectability [4]. Therefore, ind-DCF may be an effective and safe option for the initial induction treatment of T4 EC, leading to better survival than CRT alone [4]. In Japan, a phase III study of
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ind-DCF versus dCRT for locally advanced unresectable EC (JCOG1510 / TRIANgLE) by the Japan Clinical Oncology Group is currently ongoing [5].
Despite improvements in imaging modalities, the preoperative diagnostic accuracy is still not satisfactory, and there are many cases in which patients are judged to have T4b EC that is unresectable during surgery, even though they are judged to be curatively resectable preoperatively [6, 7]. Furthermore, one of the diculties of esophagectomy for esophageal cancer is that the esophagus is surrounded by vital organs, and the decision on unresectability is often made after dissection of the peri-esophageal area or disconnection of the esophagus, that is, esophagectomy with R2 resection is often performed.
The prognosis for R2 resection is very poor [8]. When intraoperative ndings indicate that a R2 resection is warranted, there is no consensus as to whether to perform a R2 resection or abandon the attempt to complete the resection. However, this is a particularly dicult question.
We evaluated the safety and outcomes of palliative esophagectomy with R2 resection (PE group) versus other procedures (e.g., esophagostomy only) without esophagectomy (NE group).
Materials And Methods Forty-seven patients with thoracic EC who underwent R2 resection at our institution between January 2009 and December 2020 were retrospectively evaluated. They were divided into two groups: palliative esophagectomy with R2 resection (PE group) and other procedure without esophagectomy (NE group). In the NE group, diagnostic thoracotomy, thoracoscopy, or laparotomy was performed in eight cases; esophagogastric bypass in four cases; esophagostomy in one case.
The primary endpoint was the overall survival (OS) rate, and the secondary endpoints were perioperative complications (Clavien–Dindo grade ≥ 3), postoperative hospital stay, and the presence, type, and timing of additional postoperative treatment [9]. EC was staged according to the 8th edition of the Union for International Cancer Control (UICC) classication [10].
This study was conducted with the approval of the ethics committee of National Cancer Center hospital.
Results Patient characteristics are shown in Table 1. Thirty-four patients were in the PE group and 13 patients were in the NE group. The median age was 65.6 years in the PE group and 66 years in the NE group, and both groups were predominantly male (25 cases = 73.5% in the PE group and 11 cases = 84.6% in the NE group). One patient in the PE group had adenocarcinoma of the esophagogastric junction, which required R2 resection due to aortic and hepatic invasion during the abdominal procedure after completion of thoracotomy. In the NE group, Siewert type 1 adenocarcinoma, which was unresectable due to aortic invasion, was found. According to the UICC 8th staging system, the majority of patients in both groups had cStage III cancer. Patients diagnosed with cStage IVA preoperatively had either bronchial or aortic
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invasion, but all of them had undergone dCRT or had an absence of feasibility for strong chemotherapy (CT), and only palliative CT or best supportive care was available. The preoperative diagnosis of stage IVB was metastasis to the supraclavicular lymph nodes (no.104) in both groups. Most postoperative tumor remnants were found in the trachea, bronchus, and macrovasculature (aorta and/or pulmonary vein and/or pulmonary artery). Fifteen cases of bronchial invasion and 15 cases of macrovascular invasion were observed in the PE group. In the NE group, tracheal and aortic invasion were observed in six patients each. In the other group, tracheal and aortic invasion were found in six patients each, and bronchial invasion was found in ve patients.
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Age (Median) 65.6 66
Histological diagnosis    
adenocarcinoma 1 (2.9%) 1 (7.7%)
Location of primary tumor      
Ae 1 (2.9%) 0
Clinical Stage (UICC 8th )    
Preoperative therapy      
radiotherapy   1 (2.9%) 0
neoadjuvant chemoradiotherapy 0 1(7.7)
surgery alone 4 (11.8%) 2(15.4)
Remaining gross tumor sites (including duplicates)    
trachea 6 6
Both groups are predominantly male and have squamous cell carcinoma. The preoperative diagnosis of stage IVB was metastasis in supraclavicular lymph nodes (no.104) in both groups. PE, palliative esophagectomy with R2 resection; NE, other procedures (e.g., esophagostomy only) without esophagectomy.
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vertebra     3 0
liver 1 0
Both groups are predominantly male and have squamous cell carcinoma. The preoperative diagnosis of stage IVB was metastasis in supraclavicular lymph nodes (no.104) in both groups. PE, palliative esophagectomy with R2 resection; NE, other procedures (e.g., esophagostomy only) without esophagectomy.
The 1-year OS rate was 31.5% in the PE group and 20.2% in the NE group, and the 2-year OS rate was 0% in the PE group and 20.2% in the NE group (p = 0.882) (Fig. 1 and Table 2). However, there was one case of long-term survival in the NE group that underwent surgery followed by dCRT.
Table 2 overall survival rate
  PE (n = 34) NE (n = 13) p value
1-year 31.5% 20.2%  
2-year 0% 20.2% 0.882
There are no signicant differences, but there is one case of long-term survival in the NE group that underwent surgery followed by denitive chemoradiation. PE, palliative esophagectomy with R2 resection; NE, other procedures (e.g., esophagostomy only) without esophagectomy.
Postoperative complications (Clavien–Dindo grade ≥ 3) were observed in 25 patients (73.5%) in the PE group and three patients (23.1%) in the NE group, and were signicantly fewer in the NE group (p = 0.031) (Table 3) [10]. In the PE group, pyothorax and mediastinitis were observed in nine patients (25%), anastomotic leakage in eight patients (29.4%), and postoperative pneumonia in ve patients (14.7%). In addition, fatal complications such as tracheal or bronchial necrosis were observed in two patients (5.9%), and perioperative death was observed in three patients (8.8%). In the NE group, postoperative pneumonia was observed in two patients, but no severe complications or perioperative deaths were observed.
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Table 3 Postoperative complications (Grade 3 according to Clavien-Dindo classication)
  PE (n = 34) NE (n = 13) p value
All 25 (73.5) 3 (23.1) 0.031
pyothorax, mediastinitis 9 (26.5) 0  
anastomotic leakage 8 (23.5) 0  
recurrent nerve palsy 3 (8.8) 0  
pneumonia 5 (14.7) 2 (15.4)  
tracheal or bronchial necrosis 2 (5.9) 0  
perioperative death 3 (8.8) 0  
Postoperative complications (Clavien–Dindo grade ≥ 3) is observed in 25 patients (73.5%) in the PE group and three patients (23.1%) in the NE group, and is signicantly fewer in the NE group (p = 0.031). PE, palliative esophagectomy with R2 resection; NE, other procedures (e.g., esophagostomy only) without esophagectomy.
The postoperative hospital stay was 32.4 days in the PE group and 25 days in the NE group, and additional postoperative treatment was introduced in 15 (44.1%) and seven (53.8%) patients in the PE and NE groups, respectively (Table 4). The median time to the initiation of postoperative treatment was 68.1 days in the PE group and 18.6 days in the NE group (p = 0.191). Although there was no signicant difference, the NE group tended to be able to introduce postoperative treatment earlier than the PE group. There were six cases of CT alone or RT alone in the PE group, whereas denitive CRT could be introduced in all cases in the NE group, partly due to the inuence of preoperative treatment. Three patients in the PE group and one patient in the NE group did not complete dCRT; one patient in the NE group discontinued treatment due to progression of the primary disease, whereas two patients in the PE group discontinued treatment due to progression of the primary disease and one patient due to an adverse event (decrease in performance status due to anorexia and neutropenia).
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Table 4 Postoperative hospital stays, introductive rate, and type of postoperative additional treatment.
  PE (n = 34) NE (n = 13) p value
Postoperative hospital stay (days, median) 32.4 25 0.47
Introduction of additional treatment (%) 44.1 53.8 0.51
Time to initiation of postoperative treatment (days, median) 68.1 18.6 0.191
Postoperative additional treatment      
- chemotherapy 4 0 0.548
- radiotherapy 2 0 0.892
Although there is no signicant difference, the NE group tended to be able to introduce postoperative treatment earlier than the PE group.
PE, palliative esophagectomy with R2 resection; NE, other procedures (e.g., esophagostomy only) without esophagectomy.
Discussions In recent years, multidisciplinary treatment combining surgery, CT, and RT has been performed for EC, and its prognosis has improved. Thorough esophagectomy with three-eld lymphadenectomy also contributes to better prognosis, especially in Japan [11]. Additionally, for resectable EC, preoperative adjuvant DCF followed by radical esophagectomy has become the standard therapy, following the report of the NExT study (JCOG1109) [12]. The results of the Checkmate 577 trial also suggest that nivolumab will become the standard care for radical esophagectomy followed by adjuvant therapy [13]. The prognosis of resectable EC is expected to improve further.
For cT4b EC, dCRT is considered the standard treatment. The addition of denitive RT was associated with a higher OS rate than CT alone [2]. Tumors often persist, even after dCRT. If the EC does not respond completely after dCRT and the tumor remains but T4b has been released, salvage esophagectomy is usually performed. Salvage esophagectomy improves the prognosis of patients with EC remnants after dCRT. However, salvage esophagectomy after high-dose dCRT is associated with high postoperative mortality and morbidity rates [3]. In contrast, ind-DCF increases overall resectability in patients with T4 EC [4]. Therefore, ind-DCF may be an effective and safe option for the initial induction treatment of T4 EC, leading to better survival rates than CRT alone. Although causation is clearly not implied, well-selected responders to CT and/or RT may be able to undergo resection and have prolonged survival; however, patient selection remains paramount. The results of the JCOG1510 trial are awaited [5].
However, the prognosis of patients with EC treated with R2 resection remains poor [8]. In recent years, advances in magnetic resonance imaging (MRI) and computed tomography (CT) equipment as well as
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the development of methods such as cine-MRI have improved the accuracy of preoperative diagnosis [6, 7, 14]. However, it is still not perfect, and the invasion of other organs is often diagnosed only during surgery. On the other hand, surgery for EC is characterized by resection of the esophagus, which is surrounded by vital organs, such as the trachea and major blood vessels. If the EC invades these vital organs, resection of the esophagus in combination with other organs is almost impossible. Thus, preoperative diagnosis, including the determination of the presence or absence of invasion of other organs, is important to avoid R2 resection.
During surgery for EC, the esophagus is often dissected from the peri-esophageal area or disconnected, except for the invasion of other organs, followed by dissection of the EC invasion site. Sucient peri- esophageal dissection and evaluation of the mobility of the tumor can often improve the certainty of determining whether the invasion of other organs is unresectable. In such cases, it is often dicult to decide whether to attempt resection even if there is a high possibility of R2 resection, or to consider other treatment methods without resection. This study retrospectively examined this issue.
In our study, there was no signicant difference in the OS between the PE and NE groups. Postoperative complications were signicantly more frequent in the PE group than in the NE group. There was no signicant difference in the rate of introduction of additional postoperative treatment. However, all patients in the NE group received dCRT, and one of them survived for a long time, whereas six patients in the PE group received only CT or RT. In the NE group, fewer complications contributed to a greater chance of denitive treatment and longer survival. It is worth mentioning that there were no cases of long-term survival in the PE group, even including dCRT.
This report does not reject esophagectomy with R2 resection. It is important to note that many severe postoperative complications occurred in the PE group, which may interfere with postoperative treatment and even lead to perioperative death. Therefore, it is necessary to further study and formulate the concept of “the point of no return” in surgery for EC according to the localization of EC [15].
Limitations This was a single-center retrospective study. The PE and NE groups were based on the judgment of the attending physician, and the presence of prior treatment, its contents, and comorbidity were the selection bias. In addition, the choice of postoperative treatment, including the intensity of activity, was based on the judgment of the attending physician.
Conclusion The complication rate of palliative esophagectomy with R2 resection is high, and should be avoided as much as possible. In cases of non-curative resection of EC, palliative surgery without esophagectomy and the introduction of smooth postoperative denitive therapy may contribute to improved prognosis.
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Declarations Acknowledgments
The authors would like to thank Editage (www.editage.jp) for the English language review. The authors would like to thank Takako Koshika and Yoko Asahi, staff members at the Department of Esophageal Surgery, National Cancer Center hospital, for their help in the preparation of this manuscript. The authors received no nancial support for the research, authorship, and/or publication of this article. 
Compliance with Ethical Standards
Funding: None
Conict of interest: All authors declare no conict of interest.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent:  Informed consent was obtained from all individual participants included in the study.
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