Preoperative Versus Postoperative ChemoRadiotherapy For Locally Advanced Gastric Cancer: A Propensity Score-Matched Analysis

Background: peri-operative chemo-radiotherapy played important role in locally advanced gastric cancer. Whether preoperative strategy can improve the long-term prognosis compared with postoperative treatment is unclear. The study purpose to compare long-term oncologic outcomes in locally advanced gastric cancer patients treated with preoperative chemo-radiotherapy (pre-CRT) and postoperative chemo-radiotherapy (post-CRT). Methods: From January 2009 to April 2019, 222 patients from 2 centers with stage T3/4 and/or N positive gastric cancer who received pre-CRT and post-CRT were included. After propensity score matching (PSM), comparisons of local regional control (LC), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were performed using Kaplan-Meier analysis and log-rank test between pre- and post-CRT groups. Results: The median follow-up period was 30 months. 120 matched cases were generated for analysis. Three-year LC, DMFS, DFS and OS for pre- vs. post-CRT groups were 93.8% vs. 97.2% (p=0.244), 78.7% vs. 65.7% (p=0.017), 74.9% vs. 65.3% (p=0.042) and 74.4% vs. 61.2% (p=0.055), respectively. Pre-CRT were signicantly associated with DFS in uni- and multi-variate analysis. Conclusion: Preoperative CRT showed advantages of long-term outcome compared with postoperative CRT. Postoperative radiotherapy based on pathological stages, while preoperative radiotherapy has the advantages of down staging and lower rate of severe adverse events.

Conclusion: Preoperative CRT showed advantages of long-term outcome compared with postoperative CRT.
Trial registration: ClinicalTrial.gov NCT01291407, NCT03427684 and NCT04062058, date of registration: Feb 8, 2011 Background In China, 6.791 million new cases and 498 thousand deaths of gastric cancer every year, and 70.8% of newly diagnosed patients were locally advanced stage [1,2]. The crucial role of peri-operative chemo-radiotherapy in locally advanced gastric cancer have been concluded by studies [3][4][5][6][7][8][9]. Postoperative radiotherapy based on pathological stages, while preoperative radiotherapy has the advantages of down staging and lower rate of severe adverse events.
However, whether preoperative strategy could improve the prognosis compared with postoperative treatment is unclear [10,11]. The purpose of this study was to compare long-term outcomes in locally advanced gastric cancer patients after preoperative chemo-radiotherapy (pre-CRT) and postoperative chemo-radiotherapy (post-CRT).

Patients and eligibility
From January 2009 to April 2019, patients from 2 centers with locally advanced gastric adeno-carcinoma who received pre-CRT or post-CRT were included. The inclusion criteria were as follows: 18-75 years old, male or female; stage T3-4 and/or N + gastric cancer without distant metastasis; Karnofsky score ≥ 70; normal haematology examination. For pre-CRT patients, radiological examinations, including CT, MRI with or without PETCT, and gastroscopy should be performed for clinical TNM stage and pathology diagnosis. For post-CRT patients, pathology stage should be con rmed by post-operative histo-pathological results. All patients signed informed consent forms.

Treatment regimens
Pre-CRT patients were initially treated with radiotherapy concurrent with S-1. Three weeks after radiotherapy, patients were given neo-adjuvant chemotherapy with oxaliplatin and S-1 (SOX). Pre-operative imaging evaluation was performed 21 days after neo-adjuvant treatment. The surgical procedures were determined based on multidisciplinary team (MDT) discussion. In-operable patients continued with 3 cycles of chemotherapy, and the chemotherapy regimen was not speci ed. The patients in post-CRT group received radiotherapy concurrent chemotherapy, which with S-1 or capecitabine regimen, after radical resection. D2 resection and adjuvant chemotherapy was recommended for entire cohort. And pre-or post-operative radiotherapy dose was prescribed as 45Gy, with intensity modulated radiotherapy (IMRT) or volumetric modulated arc radiotherapy (VMAT) technique.

Evaluation and endpoints
The preoperative TNM stage was evaluated via gastric MRI, gastroscopy, endoscopic ultrasonography and CT images of thoracic, abdominal and pelvic. Diagnostic laparoscopy and PETCT scans were not mandatory.
Surgical resection specimens were subjected to a extensive evaluation of primary lesions and lymph nodes.
Follow-up was scheduled at 3-month intervals for the rst 2 years and then at 6-month intervals until 5 years.
Diagnostic evaluations were performed using CT of the chest and abdomen and MRI or gastroscopy only if necessary. The primary endpoint was disease-free survival (DFS), de ned as the interval from the date of the surgery for post-CRT group or the rst pre-CRT to the date of recurrence or death from any cause. The secondary endpoints were overall survival (OS), local control (LC) and distant metastasis free survival (DMFS).

Statistical analysis
Since patients were not randomly assigned to either treatment group due to the retrospective nature of the analysis, propensity score matching (PSM) was used to determine the independent impact of treatment modality on long-term oncologic outcomes. First, logistic regression using these variables was performed to obtain the propensity score for each patient (de ned as the probability to be assigned to pre-or post-CRT group according to the individual pro le of these covariates). Then, patients in each group were matched according to the calculated propensity scores using a k nearest neighbours (KNN) algorithm with a threshold of c ≤ 0.05.
After matching, Kaplan-Meier analysis for LC, DMFS, DFS and OS were performed and compared between two groups using log-rank test. The Kaplan-Meier method was used to analyse the survival rate using R software (R Foundation for Statistical Computing, Vienna, Austria).

Clinical characteristics
Two hundred and twenty two patients were enrolled, and the follow-up rate was 100%. In total, 79.3% were male patients. The median age was 60 (27-75) years. 89.6% and 84.2% of patients was T3/4 lesions and clinical N positive, respectively. Table 1 summarizes the patients' baseline characteristics for each group, indicating relevant differences between the two. Patients in pre-CRT group signi cantly had a greater frequency of proximal segment gastric cancer, poorly differentiated pathological type, clinical T3/4 and N1/2 gastric cancer than in post-CRT group.
In pre-CRT group, the median duration between neo-adjuvant treatment and surgery was 52 (14-174) days. Twenty-two patients (23.9%) did not undergo a further surgical procedure because of disease progression or other personal reasons. Among these patients, 17 had distant metastasis (4 peritoneal, 4 liver, 2 para-aortic lymph nodes, 2 ovarian and 1 lung metastasis, and 5 unknown), 5 abandoned the operation due to personal reasons or other unknown reasons. Among the 70 resected patients, the rate of downstaging, ypN0 and pathologic complete response (pCR) rate was 64.1% (n = 59), 50.0% (n = 46) and 15.2% (n = 14) respectively. In post-CRT group, 119 patients (91.5%) underwent adjuvant chemotherapy, which was more than 81.5% in pre-CRT group.  *T and N stage of pre-CRT group were clinical staging.
Entire cohort prior to propensity score matching The median follow-up for survivors was 30 (range: 8-84) months in pre-CRT group and 39 (range: 6-90) months in post-CRT group, respectively. There were no signi cant differences in clinical outcomes between the two groups before PSM analysis (Table 2 and Fig. 1).  Table 3 presents the results of uni-and multi-variate Cox proportional hazards models for DFS. Clinical T/N stage and surgical procedure were associated with DFS in the univariate analysis and were included in the multivariate model. By multivariate analysis, surgical procedure was associated with improved DFS (p = 0.001).

Discussion
The optimal strategy for locally advanced gastric cancer is peri-operative comprehensive treatment, including peri-operative chemotherapy, radiotherapy and novel molecular agents. To our knowledge, few studies have explored to compare the long-term outcomes of preoperative with postoperative chemo-radiotherapy in gastric cancer with PSM method. The survival analysis after PSM indicated that DFS rate of pre-CRT group was signi cant higher than that of post-CRT. And the pre-CRT group showed a trend towards to better 3-year OS.
Radiotherapy plays an important role in the comprehensive treatment of locally advanced gastric cancer. Seyedin et al analyzed the prognosis of 21472 patients with stage I-IV gastric cancer in SEER database. For patients with stage II, III, or IV, those treated with radiotherapy had the best outcome compared with the other treatment modalities [12]. The study based on 21447 cases of gastric cancer from the NCDB database showed that the use of RT in addition to chemotherapy was associated with a signi cant OS advantage [13]. In randomized studies of postoperative radiotherapy, although the series of ARTIST studies did not obtain positive results, INT0116 and CRITICS studies suggested that postoperative radiotherapy was effective for patients with speci c treatment modality and disease stage [14][15][16][17]. Published clinical studies concerning neo-adjuvant treatment showed that preoperative CRT could improve the pCR rate and long-term outcomes [9]. The phase 3 randomized controlled study from our centre compared the prognosis of preoperative radiotherapy with that of surgery alone. The 5-and 10-year OS rates in the preoperative radiotherapy cohort were signi cantly better [8].
The CROSS study conducted similar results [18]. And our previous study reported the prognosis of preoperative CRT compared with that of preoperative chemotherapy. The 2-year DFS and LRFS rates of CRT group were better than preoperative chemotherapy [19]. Therefore, both the analysis based on big data and prospective randomized studies con rmed the value of radiotherapy. And radiotherapy is recommended as standard treatment for local advanced gastric cancer in NCCN and ESMO guidelines.
Local advanced gastric cancer is eligible for either pre-or post-operative CRT. However, at present, there is no large sample prospective randomized controlled study comparing these two strategies. In some pooled analysis studies, which compared pre-with post-CRT, results were inconsistent. Wong reviewed 16 randomized controlled studies, 3 meta-analyses and 1 practice guideline of preoperative CRT and postoperative CRT for gastric cancer [20]. They concluded that preoperative CRT is a very promising treatment strategy for local advanced gastric cancer. However, the results from SEER database study showed that for stage II patients the death hazard risk of treatment with adjuvant radiotherapy was the lowest. For patients with stage III-IV, there was no signi cant difference in death hazard risk between the pre-or post-operative radiotherapy strategy [12]. In the Afsaneh study, the results were similar. Twenty-one thousand four hundred and forty-seven cases of gastric cancer included in the NCDB database were divided into three groups: perioperative chemotherapy + operation group, perioperative chemotherapy + operation + adjuvant radiotherapy group and neo-adjuvant radiotherapy + operation + chemotherapy group. The results showed that the overall survival rate of the adjuvant radiotherapy group was the best (P < 0.001) [21]. Our study compared the long-term prognosis of pre-and post-operative radiotherapy patients with PSM statistical method, which could minimize the selection bias between two groups.
The results con rmed that preoperative radiotherapy had more advantages in the long-term prognosis.
The advantages of the preoperative treatment of gastric cancer include an improved R0 resection rate by downstaging, tolerable toxicities and a good long-term prognosis. However, the accuracy of the preoperative clinical staging of gastric cancer, especially the diagnosis of peritoneal metastasis, is challenging the clinical practice. In studies reported by surgeons, the incidence of intra-operative observed peritoneal metastasis could be as high as 30% in imaging diagnosed clinical M0 stage patients [22]. Patients with underestimated staging will progress during preoperative radiotherapy. Therefore, underestimating the clinical stage might be major issue, which may affect the overall prognosis of preoperative treatment modality. In the uni-and multi-variate factor analysis of our study, we found that the surgery was a good prognostic factor for long-term outcomes. And the main reason that patients did not receive surgery was disease progression, most likely caused by the underestimation of staging. After PSM, these patients without operation in pre-CRT group due to paired un-matching was excluded for further survival analysis. This might be the main cause of better DFS in pre-CRT group. Therefore, the accuracy of clinical staging before initial treatment is very important in the subsequent randomized controlled study and clinical practice.
In recent years, total neoadjuvant treatment has become a topic of high interest in the treatment of GI cancer, which can lead to downstaging and pCR [23]. The expected greater opportunity for delivering high-dose chemotherapy in the preoperative setting could theoretically improve the rate of R0 resection of the cancer, and thus increase relapse-free survival. This hypotheses was demonstrated in Stahl's study. In this study, compared with preoperative chemotherapy, higher pCR, ypN0 and better OS tendency was achieved by chemo-radiotherapy, although the study recruited only 126 patients due to a slow recruiting speed.
There were some limitations in this study. First, the chemotherapy regimen and cycles were not detailed enough to evaluate the perioperative chemotherapy intensity of all patients, which might have in uenced the long-term prognosis. Second, gastric cancer is highly heterogeneous. There were limited clinical and pathological factors that might be related to prognosis that were analysed in this study. Third, although the data come from two centers, the sample size was still not large enough, which might lead to biased results.
In conclusion, preoperative chemo-radiotherapy may have better long-term outcomes for locally advanced gastric cancer, compared with post-operative chemo-radiotherapy. Despite these encouraging results, further prospective randomized studies should be conducted. Sciences (CH-GI-121). All subjects signed a written informed consent form.
-Consent to publish Not applicable.
-Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

-Competing interests
The authors declare that they have no competing interests. Kaplan-Meier plots for disease-free survival (DFS) after PSM