The Effect of Obesity on Response to Neoadjuvant Therapy in Locally Advanced Gastric Cancer

Introduction: The effect of obesity on response to neoadjuvant chemotherapy (NACT) remains unknown. We aimed to investigate the effect of obesity on response to NACT and survival in locally-advanced gastric cancer (GC). Methods: From 2010 to 2019, 142 GC patients with clinical stage III disease who underwent curative surgery after NACT were enrolled. Patients were divided into 3 groups according to body mass index (BMI) as follows; BMI < 25 kg/m2, BMI = 25-30 kg/m2, and BMI > 30 kg/m2. The Mandard tumor regression grading system was used for tumor regression grade (TRG). Results: Of the 142 GC patients, 45(31.7%) were female. The median age was 58 years. BMI was < 25 kg/m2 in 60 (42.3%) patients, 25-30 kg/m2 in 44 (31%) patients, and > 30kg/m2 in 38 (26.8%) patients. The numbers of patients with TRGI-II, TRGIII, and TRGIV-V were 35 (24.6%), 44 (31%), and 63 (44.4%), respectively. There was no statistically significant difference among BMI groups in terms of disease-free survival (DFS) and overall survival (OS) (p = 0.919 and p = 0.398, respectively). According to TRG groups; mDFS was 46 months in TRG I-II, 28 months in TRG III, and 18 months in TRG IV-V (p<0.001). In multivariate analysis, presence of perineural invasion and lymphovascular invasion were the factors affecting TRG. Conclusion: In our study, we found that pre-treatment obesity did not affect the TRG in clinical stage III GC patients. However, a better TRG status was associated with improved survival.


Introduction
Gastric cancer (GC) remains a major cause of cancer-related deaths globally, with high mortality rates even in the early stages. In population-based series, the 5-year survival rate for completely-resected stage I-II GC patients is approximately 35-75% (Ferlay et al., 2015;Siegel et al., 2019). Multidisciplinary team approach is the standard of care in the treatment of GC. Randomized trials and meta-analyses have indicated a significant survival benefit with adjuvant chemoradiotherapy (CRT), Neoadjuvant chemotherapy (NACT), and adjuvant chemotherapy (ACT) for locally-advanced GC patients, as compared with surgery alone (Cunningham et al., 2006;

RESEARCH ARTICLE
The Effect of Obesity on Response to Neoadjuvant Therapy in Locally Advanced Gastric Cancer spread occurs during or after NACT, particularly in patients who have a greater risk of developing distant metastases, an unnecessary surgery will be prevented .The responses to frequently-used chemotherapy (CT) regimens range from 49% to 69.7% (Kobayashi and Kimura, 2000;Cunningham et al., 2006).
The rate of (pathological complete response) pCR in GC after NACT is relatively low. Previous studies and meta-analysis have reported that pCR increases survival (Lorenzen et al., 2013;Li et al., 2018). However, it is difficult to define which patient effectively responds to NACT. The ability to predict the pathological tumor response before treatment can provide a significant clinical advantage, provide additional information to allow tailored ACT options, and help evaluate the individual prognosis (Melcher et al., 1996;Li et al., 2012;Al-Batran et al., 2016).
Obesity is an increasing global health problem. Body mass index (BMI), calculated by the patient's weight and height, is a good way to measure obesity. Moreover, BMI is an effective method in evaluating the nutritional status of cancer patients (Liedman et al., 1996;Mokdad et al., 2003). Many studies have shown that obesity is associated with poor surgical outcomes in cancer patients, including GC (Bege et al., 2009;Benns et al., 2009;Kunisaki et al., 2009).
In previous studies, the relation of obesity with postoperative complications and survival was examined (Dhar et al., 2000;Tsujinaka et al., 2007;Kunisaki et al., 2009;Kunisaki, 2010). However, the effect of obesity on response to NACT remains unknown. In the present study, we aim to investigate the effect of obesity on response to treatment and long-term survival in clinical stage III GC patients treated with NACT.

Study population
From 2010 through 2019, all patients with locallyadvanced GC, who underwent NACT followed by gastrectomy in Van Yüzüncü yıl University Hospital, were analyzed retrospectively. The inclusion criteria were defined as follows; age ≥ 18 years and having received NACT for locally-advanced (clinical stage III) GC. Patients with any of the following criteria were excluded from the study; age <18 years, those not undergoing surgery, metastatic disease, history of a second primary cancer, histologic subtypes other than adenocarcinoma (AC), [e.g., Signet ring cell carcinoma (SRCC), and Mucinous adenocarcinoma (MAC)], patients who died due to surgical complications, and those with missing data. The clinical stage of the patients was determined by computed tomography taken before treatment. Patients were restaged according to the AJCC (American Joint Committee on Cancer) Cancer Staging Manual, 8th edition.

Data collection
Demographic data of the patients including gender, age, Eastern Cooperative Oncology Group performance scale (ECOG PS), height, weight, presence of hypertension (HT) or diabetes mellitus (DM), smoking status, clinical stage, Lauren classification, primary tumor localization, histology (AC, MAC, and SRCC), tumor grade, neoadjuvant regimen, type of surgery (subtotal, total gastrectomy, D1, or D2 dissection), ypTNM stage, pathological tumor stage (ypT), pathological lymph node stage (ypN), presence of lymphovascular (LVI) and perineural invasion (PNI), tumor regression grade(TRG), human epidermal growth factor receptor 2 (HER-2) status, adjuvant regimen, recurrence status, site of recurrence, and final status were obtained from the written archive files. Patients were divided into 3 groups according to BMI as follows; BMI < 25 kg/m 2 , BMI = 25-30 kg/m 2 , and BMI > 30 kg/m 2 . In this study, no classification such as BMI <18.5 kg/m 2 as a separate group could be made since there were only 3 patients with BMI < 18.5 kg/m 2 .

Response to treatment
The Mandard tumor regression grading system was used for TRG, which was defined as follows; TRG I= Complete regression, fibrosis with no evidence of tumor cells in the specimen, TRG II= Fibrosis and rare residual tumor cells in the specimen, TRG II= Fibrosis outgrowing residual tumor in the specimen, TRG IV= Rare fibrosis and residual tumor outgrowing fibrosis, and TRG V= Tumor without evidence of regressive changes. The patients were divided into 2 groups according to TRG status; Group 1= TRG I-II and group 2= TRG III-IV-V.

Follow-up
Disease-free survival (DFS) was calculated from the date of diagnosis to the date of progression or last followup. Overall survival (OS) was calculated from the date of diagnosis to the date of death or last follow-up.

Ethics committee approval
This study was conducted in accordance with the Declaration of Helsinki and it was reviewed and approved by the Ethics Committee of the Van Yüzüncü Yıl University Faculty of Medicine (2020/03-52).

Statistical analysis
Statistical Package for Social Sciences 22.0 for Windows software (Armonk NY, IBM Corp. 2013) was used for all statistical analysis. Student's t test was used when the numerical variable provided the normal distribution condition in two independent groups, whereas Mann Whitney U test was used when the normal distribution condition was not provided. Chi-square analysis was used to compare the ratios in the groups. Survival analyzes were performed by Kaplan Meier Analysis. For the determinant factors, logistic regression analysis was used. Statistical significance level was accepted as p <0.05.

Clinicopathological features in TRG groups
Thirty-five (24.6%) patients were TRG I-II, 44 (31%) patients were TRG III, and 63 (44.4%) patients were TRG IV-V. There was no significant difference between the TRG groups in terms of age, gender, comorbidity, Lauren classification, tumor localization, tumor grade, NACT regimen, the numbers of NACT cycles, surgical margin, the numbers of lymph nodes removed, HER-2 status, and ACT regimen. There was a statistically significant difference among the groups in terms of ypTNM, ypT, ypN, the number of lymph nodes removed, LVI, PNI, development of recurrence, and exitus rates ( Table 2).

Discussion
In this study, we investigated the effect of obesity on response to NACT and long-term survival in clinical stage III GC patients. In addition, we evaluated the prognostic effect of TRG in GC patients with real life data and found that BMI did not affect both TRG and long-term survival. However, we observed that survival was significantly better in those with an increased response to NACT. In addition, the presence of PNI and LVI were determined as the predictive factors affecting TRG.
Previous studies have reported that the obesity affects the response to NACT in various solid tumors such as prostate cancer, rectal cancer, breast cancer, and pancreas cancer (Farr et al., 2017;Park et al., 2017;Duconseil et al., 2019;Sun et al., 2020). Park et al., (2017) reported that obesity reduced the complete response rate by 40% in their study with rectal cancer patients receiving neoadjuvant CRT. Likewise, another study of pancreatic cancer by Duconseil et al., (2019) has reported that obesity is determined as the factor affecting survival. Similarly, Karatas et al., (2017) has reported that obesity is an independent prognostic factor for pCR, with a poor survival in breast cancer patients who received NACT.
Previous studies regarding GC patients have only investigated the effects of obesity on either post-surgical complications or mortality (Dhar et al., 2000;Kunisaki et al., 2009;Bickenbach et al., 2013;Wong et al., 2014;Palmela et al., 2017). Some of these studies also examined the relationship between obesity and long-term survival (Bickenbach et al., 2013;Wong et al., 2014). Wong et al. reported that obesity may cause technical difficulties to achieving R0 resection during gastric cancer surgery. However, an increased BMI did not affect DFS or OS (Wong et al., 2014). A study from Memorial Sloan-Kettering Cancer Center conducted by Bickenbach et al. evaluated the impact of obesity on survival in GC patients and reported fewer lymph node dissection rates and higher complication rates in patients with BMI > 25 kg/m 2 ; however, survival was similar between the BMI groups (Bickenbach et al., 2013). In our study, patients who died due to surgical complications were not included. Furthermore, in our study, the ratio of number of positive   In this study, mOS could not be reached in patients with TRG I-II, whereas mOS was 20 months in patients with TRG III-IV-V. Additionally, pathologic response to NACT was not correlated with any clinicopathological variable, including sex, age, tumor location, or histologic type (Smyth et al., 2016). Similar to these studies, in our study, TRG was correlated with survival. In our study, mDFS was 46 months in TRG I-II, while it was 18 months in TRG IV-V. Likewise, the TRG response was correlated with OS. Moreover, the presence of PNI and LVI were determined as the factors affecting TRG in our study.
In the literature, we could not find any study that examined the effect of BMI on TRG. Unlike the other studies, our study included a more heterogeneous patient group. We included only clinical stage III patients in our study. However, there were some limitations in our study.
Our study was single-centered and had a retrospective nature. Since there were only 3 patients with BMI <18 in our study, they were not evaluated as a separate group.
In conclusion, we found that pre-treatment obesity status did not affect the response to NACT or long-term survival in clinical stage III GC patients. However, presence of PNI and LVI were determined as the factors negatively affecting response to treatment. In our study, DFS and OS were significantly greater as the response to NACT increased.

Main Points
-The relation of obesity with postoperative complications and survival in solid cancers were examined in many studies -The effect of obesity on response to neoadjuvant chemotherapy(NACT) in Gastric cancer(GC) remains unknown.
-In the study, we found that pre-treatment obesity status did not affect the response to NACT or long-term survival in clinical stage III GC patients.
-Presence of perineural invasion and lymphovascular invasion affected the response to NACT.
-Survival was significantly greater as the response to NACT increased