Adjuvant chemoradiotherapy vs adjuvant chemotherapy in locally advanced Siewert type ll/lll adenocarcinoma of gastroesophageal junction after D2/R0 resection

lNTRODUCTlON

In recent years,the incidence of adenocarcinoma of the gastroesophageal junction (AGE) has been increasing[1-3].The Siewert type II/III type is the most common type of AGE in Asia[4-6].At present,treatment for this type of AGE is based on the principle of gastric cancer.However,due to the special anatomical site of Siewert type II/III AGE,it differs from middle-distal gastric cancer in terms of its biological characteristics and prognosis.An increasing number of researchers have recognized AGE as an independent tumor entity[7,8].For locally advanced AGE,the local and regional recurrence and distant metastasis rates remain high after D2/R0 resection,leading to poor prognosis[9-11].As an important local treatment,radiotherapy can reduce the local recurrence rate and prolong survival time[12].Phase III clinical studies of adjuvant chemoradiotherapy after D2/R0 resection.For resectable gastric cancer in the East and West have reached different conclusions[13,14].Postoperative radiotherapy may be beneficial for patients who fail to achieve D2/R0 resection for various reasons,as well as in those with high-risk factors for local recurrence (high rate of lymph node metastasis,insufficient safe resection distance,

)[15].Although the INT-0116 trial confirmed the survival benefit of postoperative radiotherapy in patients with resectable gastric cancer,the majority of patients in this study underwent D0 or D1 gastrectomy[16].The efficacy of adjuvant radiotherapy in patients with gastric cancer undergoing D2/R0 resection is controversial[17].Neoadjuvant CRT + D2/R0 resection +adjuvant chemotherapy (CT) has been successful in the study of AGE.Long-term follow-up results from the POET study showed that preoperative CRT had the advantage of reducing local and regional recurrence and was prone to improving overall survival (OS) compared to preoperative CT[18].However,the significance of postoperative adjuvant radiotherapy for locally advanced Siewert type II/III AGE is unclear.In this study,we reviewed 316 patients with locally advanced Siewert type II/III AGE patients to determine whether CRT was superior to CT alone after D2/R0 resection,comparing the OS,relapse-free survival (RFS),and recurrence modes between the CRT and CT groups.

MATERlALS AND METHODS

Patient selection and data collection

We identified 316 patients with locally advanced Siewert type II/III AGE who were admitted to the Department of Pancreatic and Gastric Surgery,National Cancer Center,between January 2011 and May 2018.All patients underwent D2/R0 resection and did not receive neoadjuvant CT or radiotherapy.Patients were divided into a CT group and a CRT group according to whether they received postoperative adjuvant radiotherapy.Patients were followed-up by telephone,which was completed on April 30,2020.The median follow-up time was 62.7 mo.

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Pathologists determined the classification of the Siewert type.The pathological staging (pTNM)criteria were based on the 8th edition of the American Joint Committee on Cancer guidelines for esophageal adenocarcinoma (all Siewert type II adenocarcinomas invade the dentate line) and gastric cancer (Siewert type III).Patients who were lost to follow-up or were unwilling to cooperate were excluded.Patients with Siewert type I AGE were not included in this study.Patients younger than 18 years or older than 80 years,those who received neoadjuvant CT or radiotherapy,and those with less than 1 mo of postoperative survival were excluded from the study.

Adjuvant CRT and CT regimen

Patients in the CRT group received a total dose of 45–50.4 Gy in 25–28 fractions.Intensity-modulated radiation therapy or volumetric modulated arc therapy were used.For tumor margins ≤ 3 cm,the anastomosis site was included in the clinical target volume (CTV).For the T4b stage,the tumor bed should also be included.Regional draining lymph nodes according to the Japanese Gastric Cancer Association (JGCA)[19] were included in the CTV.Based on the International Commission Radiological Units report No.83[20],the planning target volume should consider not only the setup error but also the breath elements and tumor movement.Concurrent CT regimens included FU-based drugs such as 5-FU,capecitabine,or tegafur (S-1) on radiotherapy days.Patients in the CRT group received 4-6 cycles of CT,followed by CRT.

In the past,adjuvant treatment for AGE was based on the experience of esophageal adenocarcinoma or gastric adenocarcinoma.However,a growing number of researchers believe that AGE is a separate tumor[22].There have been very few randomized controlled studies on the significance of adjuvant CRT for AGE[23].In this study,we found that postoperative adjuvant CT combined with regional radiotherapy could prolong the OS of patients with locally advanced Siewert type III AGE.The local and regional recurrence rates in the CRT group were lower than those in the CT group.These results provide evidence supporting the use of postoperative adjuvant radiotherapy for AGE.

Recurrence pattern

Specific imaging or pathological diagnosis is needed when defining tumor recurrence.In this study,we divided recurrence into local recurrence,regional recurrence,and metastatic recurrence according to the first site of recurrence during the follow-up period.

Recurrence in the anastomotic stoma,tumor bed,and remnant stomach was defined as a local recurrence.Recurrence in the lymphatic drainage area,according to the JGCA guidelines[19] for gastric cancer and the Japan Esophageal Cancer Research Association guidelines[21] for the esophagus,was defined as a regional recurrence.The diagnosis of recurrent lymph nodes on imaging should satisfy one of the following criteria: (1) Short diameter of lymph nodes ＞ 8 mm; (2) Ratio of the long diameter to the short diameter of lymph nodes is close to one; (3) Central lymph nodes are necrotic; (4) Multiple lymph nodes are aggregated; and (5) Lymph nodes are significantly enhanced on computed tomography.Distant recurrence was defined as distant lymph node,bone,peritoneal or pleural,and solid organ metastases such as liver,lung,and ovarian metastases.

RESULTS

Clinicopathological characteristics

Table 1 summarizes the clinicopathological characteristics of the patients enrolled in this study.There were 57 patients in the CRT group and 295 patients in the CT group.The number and proportion of patients with Siewert type II and III AGE were 148 (46.8%) and 168 (53.2%),respectively.

Survival results

Figure 1A and B summarize the OS and RFS curves of the CRT and CT groups,respectively,for all patients.Figure 1C and D summarize the OS and RFS curves of the CRT and CT groups for patients with Siewert type II AGE,respectively.Figure 1E and F summarize the OS and RFS curves of the CRT and CT groups for patients with Siewert type III AGE,respectively.

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Five-year OS rates of the CRT and CT groups for all patients were 66.7% and 41.9%,respectively (

=0.010).Five-year OS rates of the CRT and CT groups for Siewert type II AGE patients were 59.3% and 39.4%,respectively (

= 0.063).Five-year OS rates of the CRT and CT groups for Siewert type III AGE patients were 65.7% and 43.9%,respectively (

= 0.006).

Table 2 and Figure 2).

Results of recurrence

Among the 195 patients for whom recurrence information could be obtained,18 (34.6%) and 61 (42.7%)were diagnosed with recurrence in the CRT and CT groups,respectively.The local and regional recurrence rates were lower in the CRT group than in the CT group (22.2%

24.6% and 27.8%

39.3%,respectively).The distant recurrence rate was higher in the CRT group than in the CT group (100%

68.9%) (Table 3 and Figure 3).

Multivariable Cox regression analysis

For Siewert type II AGE,multivariate Cox regression analysis showed that vascular invasion was an important prognostic factor (Table 4).For Siewert type III AGE,multivariate Cox regression analysis showed that vascular invasion,nerve invasion,and adjuvant CRT were important prognostic factors(Table 5).

DlSCUSSlON

In the CT group,the main CT regimens included oxaliplatin + 5-FU (SOX,XELOX),cisplatin + 5-FU(PF,XP,SP),albumin-bound paclitaxel + S-1,and single-drug CT regimen (S-1,docetaxel,and irinotecan).Adjuvant CT is usually performed for 4-6 cycles.

The role of adjuvant radiotherapy after D2/R0 resection in gastric cancer remains controversial.The Korean ARTIST 1 study[17] suggested that patients with lymph node metastases may benefit from postoperative irradiation.However,the ARTIST 2 study[24] showed that SOX CT combined with radiotherapy did not improve outcomes in patients with lymph node metastasis after D2/R0 resection.In addition,the majority of patients enrolled in these clinical trials had distal gastric cancer,while fewer had proximal gastric cancer.Owing to the specificity of the anatomic site,the benefits of adjuvant radiotherapy in AGE may not be consistent with those in gastric cancer.Therefore,we designed this retrospective clinical study to evaluate the value of adjuvant CRT in locally advanced AGE.

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Five-year recurrence-free survival rates of the CRT and CT groups for all patients were 64.5% and 55.3%,respectively (

= 0.254).Five-year recurrence-free survival rates of the CRT and CT groups for Siewert type II AGE patients were 60.5% and 55.9%,respectively (

= 0.995).Five-year recurrence-free survival rates of the CRT and CT groups for Siewert type III AGE patients were 72.6% and 56.8%,respectively (

= 0.082) (

Because of the special location of AGE,cancer cells can metastasize to the mediastinum and abdominal cavity along the lymphatic vessels.However,for Siewert type II/III AGE,abdominal lymph node metastasis is the main direction of metastasis[25].The JCOG9502 study showed that for Siewert type II/III AGE that underwent D2/R0 lymph node dissection,the positive rate of lymph nodes at station 16 was 15.2%,and the postoperative lymph node recurrence rate was 17.4%[26].These results provide evidence for the delineation of radiotherapy targets for locally advanced AGE.

Our study found that adjuvant radiotherapy did not significantly improve RFS in all patients or OS in patients with Siewert type II AGE.However,we observed a significant extension of OS in patients with Siewert type III AGE after adjuvant CRT.A possible explanation is that adjuvant radiotherapy reduceslocal and regional recurrence rates.The overall recurrence rate in the CRT group was lower than that in the CT group.Compared with the CT group,more attention should be paid to distant metastasis during postoperative reexamination in the CRT group.We found that patients with Siewert type III AGE were more sensitive to adjuvant radiotherapy.The difference between Siewert type II and III AGE in adjuvant CRT requires further study.Multivariable Cox regression analysis showed that adjuvant CRT was an important factor affecting the prognosis of patients with Siewert type III AGE,further verifying the necessity of adjuvant CRT.

Our study has several limitations.First,this was a single-center retrospective study,and thus inherently has a lower level of evidence than a multicenter prospective clinical trial.Furthermore,did not compare surgical approaches for different types of AGE.In addition,the toxic effects of radiotherapy were not investigated in this study.

CONCLUSlON

For locally advanced Siewert type III AGE,adjuvant CRT following D2/R0 resection may prolong OSand reduce the local and regional recurrence rate.Postoperative radiotherapy may be feasible for Siewert type III AGE patients.Multicenter prospective clinical trials should be conducted to investigate the significance of adjuvant CRT in AGE.

ARTlCLE HlGHLlGHTS

Research background

The role of adjuvant chemoradiotherapy (CRT) in adenocarcinoma of gastroesophageal junction (AGE) is unclear.

Research motivation

Radiotherapy may reduce the local recurrence rate and prolong survival time for locally advanced Siewert II/III type adenocarcinoma of AGE.

Research objectives

To evaluate the effect of adjuvant CRT vs adjuvant chemotherapy (CT) on overall survival (OS),relapsefree survival (RFS),and recurrence pattern in locally advanced Siewert II/III type adenocarcinoma of AGE patients undergoing D2/R0 resection.

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Research methods

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Research results

Adjuvant CRT improves the 5-year survival rate of adenocarcinoma of AGE,especially Siewert type III adenocarcinoma of AGE,and reduces local and regional recurrence rates.

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Research conclusions

National Natural Science Foundation of China,No.82072734.

Research perspectives

Multicenter prospective clinical trials should be conducted to investigate the significance of adjuvant CRT in adenocarcinoma of AGE.

We sincerely thank all the researchers of Department of Pancreatic and Gastric Surgery,Department of Radiation Oncology,and Department of Pathology in National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences,and Peking Union Medical College.We are also grateful to the patients enrolled in the study.

Tian YT and Jin J designed the research; Kang WZ,Shi JM,Wang BZ,Xiong JP and Shao XX analyzed the data and wrote the paper; Hu HT collected the patient’s clinical data; Kang WZ and Shi JM contributed equally to this work.

We compared the OS,RFS,and recurrence modes between the adjuvant CRT and adjuvant CT groups.

Adjuvant CRT may be appropriate for adenocarcinoma of AGE,especially for Siewert type III adenocarcinoma of AGE.

The study was reviewed and approved by the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College Institutional Review Board,No.17-156/1412.

Patients were not required to give informed consent to the study because the analysis used anonymous data that were obtained after each patient agreed to treatment by written consent.

That s just where it is, sighed the Caliph, whose wings drooped94 in a dejected manner; how do you know she is young and lovely? I call it buying a pig in a poke26

All the authors report no relevant conflicts of interest for this article.

Dataset available from the first author at kwz@whu.edu.cn.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license,which permits others to distribute,remix,adapt,build upon this work non-commercially,and license their derivative works on different terms,provided the original work is properly cited and the use is noncommercial.See: https://creativecommons.org/Licenses/by-nc/4.0/

China

Wen-Zhe Kang 0000-0001-9965-8109; Jin-Ming Shi 0000-0001-6870-1995; Bing-Zhi Wang 0000-0001-9622-7151; Jian-Ping Xiong 0000-0001-6593-6377; Xin-Xin Shao 0000-0002-1826-3832; Hai-Tao Hu 0000-0003-0585-6070; Jing Jin 0000-0003-2158-7392; Yan-Tao Tian 0000-0001-6479-7547.

Fan JR

A

Wu RR

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