RECURRENCE IN PN0 GASTRIC CANCER: RISK FACTORS IN THE OCCIDENT

ABSTRACT 
Background:
 Nearly 10% of node negative gastric cancer patients who underwent curative surgery have disease recurrence. Western data is extremely poor on this matter and identifying the risk factors that associate with relapse may allow new strategies to improve survival. 
Aim:
 Verify the clinical and pathological characteristics that correlate with recurrence in node negative gastric cancer. 
Methods:
 All gastric cancer patients submitted to gastrectomy between 2009 and 2019 at our institution and pathologically classified as N0 were considered. Their data were available in a prospective database. Inclusion criteria were: gastric adenocarcinoma, node negative, gastrectomy with curative intent, R0 resection. Main outcomes studied were: disease-free survival and overall survival. 
Results:
 A total of 270 patients fulfilled the inclusion criteria. Mean age was 63-year-old and 155 were males. Subtotal gastrectomy and D2 lymphadenectomy were performed in 64% and 74.4%, respectively. Mean lymph node yield was 37.6. Early GC was present in 54.1% of the cases. Mean follow-up was 40.8 months and 19 (7%) patients relapsed. Disease-free survival and overall survival were 90.9% and 74.6%, respectively. Independent risk factors for worse disease-free survival were: total gastrectomy, lesion size ≥3.4 cm, higher pT status and <16 lymph nodes resected. 
Conclusion:
 In western gastric cancer pN0 patients submitted to gastrectomy, lymph node count <16, pT3-4 status, tumor size ≥3.4 cm, total gastrectomy and presence of lymphatic invasion, are all risk factors for disease relapse.

Our study was performed in a homogeneous gastric cancer population, with low risk of bias, and indicates the pN0 patients who are at risk of disease recurrence. This data may be used to intensify postoperative screening for relapse, and also to propose adjuvant therapy. Inclusion in trials for adjuvant treatment may be guided by the presence of the risk factors here identified.

Central message
In western gastric cancer pN0 patients submitted to gastrectomy, lymph node count <16, pT3-4 status, tumor size ≥3.4 cm, total gastrectomy and presence of lymphatic invasion, are all risk factors for disease relapse.
Total gastrectomy (p=0.002), larger tumor size (p=0.002), presence of lymphatic invasion (p=0.049) and advanced pT status (p=0.004) were associate with recurrence patients. There was no difference between the groups regarding the histological type, extension of lymphadenectomy and the number of lymph nodes dissected.
The length of hospital stay was similar between the groups (10.9 and 15.4 days for non-recurrence and recurrence group, respectively; p=0.106). Major complications occurred in 6.3% of the cases (5.6% and 3% for non-recurrence and recurrence group, respectively; p=0.107).

Survival analysis
Disease-free survival and overall survival rates for the entire population were 90.9% and 74.6%, respectively ( Figure 2).

INTRODUCTION
G astric cancer (GC) has high prevalence worldwide and is a major cause of cancer-related death 2,10,20 . Lymph node metastasis is the most important prognostic factor 18,23,29 ; however, nearly 10% of pN0 patients who underwent gastrectomy have disease recurrence 18,22,23,29 . This particular subgroup may benefit from adjuvant therapy and more intensive follow-up 22,26,28 ). Nevertheless, the risk factors associated with recurrence in this population are poorly reported, especially in the western world.
The aim of this study was to evaluate the clinical and pathological characteristics related to recurrence in pN0 GC patients who underwent curative gastrectomy.

METHODS
The present study was approved by our ethics committee and is registered online at plataformabrasil.saude.gov.br under CAAE: 62915516.2.0000.0065.

Patients
All GC patients submitted to gastrectomy with curative intent between 2009 and 2019 at the Instituto do Cancer de São Paulo, São Paulo, SP, Brazil were considered. Data were available in a prospective database. Inclusion criteria were: gastric adenocarcinoma, absence of lymph node metastasis (pN0), gastrectomy with D1 or D2 lymphadenectomy. Palliative surgery and patients with postoperative mortality were excluded from the analysis.
The number of lymph nodes dissected was evaluated according to the minimum values recommended for examination by the American Joint Committee on Cancer and the Japanese Gastric Cancer Association (at least 16 and 25, respectively) 1,13 .
Postoperative complications were graded by Clavien-Dindo classification, and Clavien >II were considered as major ones 8 .
Total or subtotal gastrectomy and lymphadenectomy extension were performed according to the Japanese Guidelines 13 . Specimens were fixed in Carnoy's solution and pathologic analysis followed the recommendations of the College of American Pathologists 6,24 . The 8 th edition of the TNM was used for staging 1 .

Statistical analysis
Chi-square or Fisher exact tests were used for qualitative variables and t-student test for quantitative ones. Receiver Operating Characteristic (ROC) curve was used to determine the cut-off value for tumor size that correlated with disease recurrence. The area under the curve (AUC) was employed as a measure of accuracy. Overall survival and disease-free survival were estimated by the Kaplan-Meier test and differences examined by the log rank test. Survival was determined from the day of the surgery until death, recurrence or the or date of last contact. Variables independently affecting prognosis were investigated by multivariate analysis using the Cox proportional hazards model. Variables with p<0.100 univariate analysis were included in the multivariate model. SPSS was used for statistical analysis. All tests were two-sided and p<0.05 was considered significant.

2/4 FIGURE 3 -Disease-free survival according to extent of surgery, lesion size and pTNM
In multivariate analysis, total gastrectomy, tumor size ≥ 3.4 cm, advanced pT status and <16 lymph nodes resected were independent risk factors for worse disease-free survival ( Table 2).

DISCUSSION
Following gastrectomy with curative intent, pN0 GC patients have good prognosis, even if they were N+ before an eventual neoadjuvant therapy 2,21 . For those with advanced stage (T3-4 lesions) adjuvant therapy is indicated, but this is not usually recommended for the rest and some of them will relapse. By identifying this subgroup of patients, we may intensify their follow-up and/or refer them for adjuvant treatment, hoping to extend their survival. Besides the pT status 3,7,15 , inadequate lymphadenectomy 3,15 , low number of lymph nodes examined 11,12,14,26 , diffuse histology 16,25 and neural or lymphatic invasion 6,13,14,16,30 have been correlated with recurrence.
In our cohort, relapse occurred in 7% of the studied population and, besides pT and lymphatic invasion, total gastrectomy and lesions ≥3.4 cm also correlated with disease recurrence. Larger tumors require total gastrectomy more frequently, so the type of surgery must be considered in this context. Tumor size has been described as a predictor of prognosis in GC; however, there is no consensus on the cut-off value 17,27,31 .
Lymphatic invasion is considered a high-risk feature 9 , so that adjuvant therapy may be recommended for pT2N0 patients 12,15,19 . In its presence we strongly advice additional investigation, with further cuts and immunohistochemical analysis of the lymph nodes retrieved 6,13,22 .
Low lymph node count (<16) was more frequent in the recurrence group (8.4% vs. 21.1%), however with no significance, probably due to the low number of patients with recurrence. At multivariate analysis it was the most important independent risk factor for worse disease-free survival (HR=5).
The main limitations of our study are its retrospective nature and the low number of patients with relapse. Nevertheless, to assess the real impact of the studied factors in survival, palliative procedures, R1/2 resections and stage IV patients were not included. Lymph node count was also high certifying that adequate staging as performed. Also, available western data concerning recurrence in pN0 GC is extremely poor 4 ; so, our findings provide further evidence to help guide decision in the studied population.

CONCLUSION
In western GC pN0 patients submitted to gastrectomy with curative intent, lymph node count <16, pT3-4 status, tumor size ≥3.4 cm, total gastrectomy and presence of lymphatic invasion are all risk factors for disease relapse.