Observational Study Comparing Ecacy and Safety Between Preoperative Neoadjuvant Concurrent Chemoradiotherapy and Chemotherapy for Patients with Unresectable Locally Advanced or Metastatic Gastric Cancer

Dismal outcomes in patients with locally advanced or metastatic gastric cancer (GC) highlights the need for effective systemic neoadjuvant treatment strategies to improve clinical results. Neoadjuvant multimodality strategies vary widely. This study compared the ecacy, safety, and clinical outcomes of preoperative neoadjuvant CCRT and chemotherapy for such patients. Sixty-ve patients with histologically locally advanced or metastatic GC following neoadjuvant or

more precise treatment protocol that appropriately selects patients and provides speci c therapy is ongoing.
Patients with more locally advanced GC who underwent gastrectomy after preoperative CCRT experienced outcomes that varied between favorable and poor. In this study, we presented our experience with preoperative neoadjuvant CCRT versus chemotherapy alone in patients with unresectable locally advanced or metastatic GC and compared baseline characteristics, e cacy, and safety between the two groups.

Data Source and Study Design
This study was conducted at Kaohsiung Medical University Hospital with approval from the hospital's institutional review board (KMUHIRB-20130022) and informed consent was obtained from all patients. The study started in January 2010 and as of April 2019, 65 patients with histologically con rmed locally advanced T4 or metastatic GC have been included. In the current study that diagnostic laparoscopy is not routinely performed in metastatic GC patients with dissemination, but diagnostic laparoscopy will be performed that image studies cannot con rm if the curative-intent resection will be performed in locally advanced T4 GC patients. Baseline investigations consist of blood tests, gastroendoscopy with tumour biopsy samples, complete history review and physical examination, and image studies (i.e., chest radiography, abdominal computed tomography [CT], and additional magnetic resonance imaging [MRI] if the CT scan could not clarify the cancer stage). TNM classi cation was determined according to the American Joint Commission on Cancer/Union for International Cancer Control criteria [9].

Patient Selection
Patients with histologically proven locally advanced T4 or metastatic GC are eligible for this study. Patients should be at least 18 years old with an Eastern Cooperative Oncology Group performance status of 0-2. Patients must have adequate hematological, renal and liver function. Exclusion criteria include: central nervous system metastases or previous malignancy, active infections or serious concurrent medical illness (i.e., clinical signi cant cardiac disease or liver disease, known peripheral neuropathy), life expectancy <3 months, prior radiotherapy or chemotherapy, and inability to receive neoadjuvant therapy.
Considering eligibility criteria of patient, neoadjuvant chemoradiotherapy or chemotherapy were chosen after shared decision-making with patients and family meeting according to real-world situation in Taiwan.

Clinicopathological Characteristics
Clinicopathological characteristics, such as age, sex, tumor size, tumor invasion depth, lymph node metastasis, clinical TNM status, vascular invasion, perineural invasion, tumor location, histological tumor differentiation grade, pretreatment metastasis site, and pretreatment serum carcinoembryonic antigen (CEA) level were analyzed. Her2 expression was not often tested as Trastuzumab was not reimbursed in Taiwan. Additionally, positive Her2 expression was approximately only 6% in Taiwan [10]; therefore, Her2 expression was not routinely examined for pre-operative neoadjuvant setting in the current study. This study aimed to explore the e cacy and safety pro le of preoperative CCRT in locally advanced or metastatic GC versus preoperative chemotherapy.

Treatment Modalities
Currently, no particular neoadjuvant protocol is internationally regarded as superior in the multimodal therapeutic armamentarium. Interpretation of trial results is controversial, which results in strong interinstitutional differences concerning radiotherapy and chemotherapy sequence for the treatment of patients with locally advanced T4 or metastatic GC. Whether preoperative chemotherapy or CCRT should be recommended for the treatment of patients with locally advanced T4 or metastatic GC remains uncertain. Furthermore, both options are suggested by guidelines supported by the National Comprehensive Cancer Network. In this study, we compared the survival data of patients with locally advanced T4 or metastatic GC, treated either with CCRT or chemotherapy, based on real world data from one institution, and we additionally reviewed the current literature.

Chemotherapy
The 65 patients were treated with an mFOLFOX-4-based regimen that comprised the following: On day 1, oxaliplatin (85 mg/m 2 ) and leucovorin (200 mg/m 2 ) were administered over a 2-h period, followed by a 48-h continuous infusion of 5-FU at a dose of 2400 mg/m 2 every 2 weeks. The primary endpoints of this study were response rate, PFS, and OS. The secondary endpoints were acute toxicities during preoperative CCRT or chemotherapy Radiotherapy Three-dimensional conventional radiotherapy (3D-CRT) was delivered using a 2100 C/D linear accelerator (Varian Medical Systems, Palo Alto, CA, USA). For the 3D-CRT plan, we used anterior-posterior and posterior-anterior elds with photon energy at 10 MV. The dose speci cation for 3D-CRT encompassed the planning target volume (PTV) in all directions within the 95% isodose line. Volumes receiving more than 110% of the dose prescribed to the PTV were minimized. Reference points were selected either in the central part of PTV or at the intersection of beam axes from the International Commission on Radiation Units and Measurements (ICRU; Reports 50 and 62). The radiation portal elds were designed as follows: (i) proximal one-third/ cardia/esophagogastric junction primaries included 3-5 cm of distal esophagus, medial left hemidiaphragm, adjacent pancreatic body, and nodal areas at risk including adjacent paraesophageal, perigastric, suprapancreatic, and celiac lymph nodes; (ii) middle one-third/body primaries included pancreatic body should and nodal areas at risk including perigastric, suprapancreatic, celiac, splenic hilar, porta hepatic, and pancreaticoduedenal lymph nodes; and (iii) distal onethird/antrum/pylorus primaries included pancreatic head, 3-5 cm margin duodenal stump margin if gross lesions extended to the gastroduodenal junction, and nodal areas at risk including perigastric, suprapancreatic, celiac, splenic hilar, porta hepatic, and pancreaticoduedenal lymph nodes. Radiotherapy consisted of 45-50.4 Gy in 25-28 fractions over 5 weeks.
Image-guided (IG) intensity-modulated radiotherapy (IMRT) plans were generated either with a Hi-Art helical tomotherapy unit, version 2.2.4.1 (TomoTherapy, Inc., Madison, WI, USA), or Eclipse, version 8.6 (Varian Medical Systems). The tomotherapy unit combined rotational IMRT with translational movement from the couch. A xed-jaw mode with a eld width of 2.5 or 5 cm was used for treatment planning. The pitch varied from 0.215 to 0.287. The modulation factor ranged from 2 to 3 depending on homogeneity and conformity. The gross tumor volume encompassed gastric tumors and clustered lymph nodes or lymph nodes with diameters greater than 1 cm. The clinical target volume (CTV) included the primary tumor, and adjacent lymphatic drainage depended on primary tumor location. Superior, inferior, and radial margins of 5-7 mm outside the CTV were added to form the PTV.
In the IG-IMRT group, the tumor and boost beams were combined into one integrated treatment plan; thus, these patients were treated with the same plan for each fraction throughout the entire course of radiotherapy. Fractionation schemes comprised 25 daily fractions of 1.8 Gy to the pelvis and 2 Gy to the gastric tumor and involved nodes. Optimization reduced doses for the bowel, kidney, liver, and spinal cord. These constraints were also applied to IMRT treatment plans on Varian and comprised beams with multileaf collimator shielding conforming to the PTV. The goal was to encompass the PTV in all directions within the 95% isodose line. Volumes receiving more than 110% of the dose prescribed to the PTV were minimized. Volumetric arc therapy was used when suitable. IMRT plans were reviewed using ICRU 83 recommendations. Before each RT fraction, patients were repositioned according to image guidance through megavoltage or cone beam CT, which was coregistered with a planning kilovoltage CT. A dose of 50 Gy was administered to the PTV50 (tumor and enlarged nodes) and 45 Gy to the PTV45 (adjacent high risk nodal area) through a simultaneous integrated boost scheme in the IG-IMRT group. All dose schedules were administered 5 days per week.

Toxicity
Safety and toxicity were evaluated in each cycle by using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 (https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm, accessed in 2018). Peripheral neuropathy was graded according to the following oxaliplatin-speci c scale: grade 1, paresthesia or dysesthesia of a short duration with complete recovery before the next cycle; grade 2, paresthesia persisting between two cycles without functional impairment; and grade 3, permanent paresthesia interfering with function [2,3]. Neoadjuvant chemotherapy was discontinued in cases of unacceptable toxicity (>grade 3), disease progression, or patient refusal to continue treatment [2,3].

Evaluation of Response and E cacy Assessment
Physical examination, liver and kidney function tests, complete blood count and serum CEA level examination, and electrocardiogram were performed before and after every two weeks of treatment.
Abdominal CT and additional MRI are performed every 3 months during chemotherapy, if necessary, chest X-ray is performed annually. A bone scan or positron emission tomography scan is selectively performed to display images of suspicious ndings at speci c locations of CT or MRI and suspicious metastases. All enrolled patients were followed up every 3 months until the last visit or death. The median follow-up time for all patients was 12 months (range, 6-48 months). [2,3]. Complete remission (CR) is the disappearance of treatment for all target cancer lesions. Partial response (PR) is a reduction of at least 30% of the sum of the longest diameters of metastatic lesions, with no signs of new lesions. Progressive disease (PD) is a cumulative increase in the longest diameter of the target lesion by at least 20%, and the smallest sum of the longest diameters recorded before the patient begins treatment is used as a reference. The PD can also recognize one or more new lesions. The contraction rate of stable disease (SD) is not su cient to meet the PR criteria, and the increase is not su cient to meet the PD criteria [2]. Finally, PFS was determined by measuring the time interval between the start of neoadjuvant CCRT or chemotherapy and the rst record of progression, regardless of the patient's treatment status or nal follow-up, while OS was measured by neoadjuvant CCRT or chemotherapy to chemotherapy. The starting time interval is determined. Date of death or last follow-up [2,3].

Statistical Analysis
Continuous variables are presented as the mean ± SD, and dichotomous variables are presented as numbers and percentage values. All data were analyzed using SPSS (version 20.0, SPSS Inc., Chicago, IL, USA). The chi-square test was used to compare toxicity and outcomes. Univariate analyses and a mutltivariate Cox proportional hazard regression were performed to evaluate independent predictors. PFS and OS were calculated and plotted according to Kaplan-Meier methods, and the log-rank test was used to compare time-to-event distribution. A P value of less than 0.05 was considered statistically signi cant.

Patient Demographics
From January 2010 to April 2019, 65 patients with locally advanced or metastatic GC who received rstline neoadjuvant preoperative CCRT and chemotherapy were enrolled. Their characteristics are listed in Table 1. All 65 patients received at least six chemotherapy cycles with or without preoperative radiotherapy and were eligible for e cacy and toxicity analysis. The patients included 42 men and 22 women who had a mean age of 65.4 years (ranging 31-85 years). Upon baseline gastroesophagoscopy and abdominal CT, 47 patients (72.3%) were observed to have T4 tumors, 24 patients exhibited distant metastasis (36.9%), and all patients had N+ disease.  Table 2. Major grade 3/4 hematological toxicities included neutropenia, febrile neutropenia, and thrombocytopenia, which appeared in four (6.2%), three (4.6%), and one (1.5%) patient, respectively. Other nonhematological toxicities reaching grade 3/4 status were nausea/vomiting (15.4%), anorexia/fatigue (13.8%), abnormal liver function (7.7%), abnormal renal function (7.7%), peripheral neuropathy (6.2%), stomatitis (6.2%), diarrhea (6.2%), and constipation (4.6%). All treatment-related toxicities were treated with proper medical care, and no treatment-related deaths occurred. No additional safety concerns were identi ed in the current study. These results revealed no statistical difference of toxicities between the two groups (all P > 0.05).

Clinicopathological Correlation
Preoperative neoadjuvant CCRT was performed in 30 patients (46.2%) and chemotherapy in 35 patients (53.8%). No signi cant association was observed between these two preoperative neoadjuvant treatment modalities and baseline clinicopathological features, namely age, sex, tumor size, clinical T status, clinical N status, vascular invasion, perineural invasion, clinical TNM stage, pretreatment serum CEA level, and posttreatment serum CEA level (Table 3, all P > 0.05). Moreover, no signi cant association was observed between these two preoperative neoadjuvant treatment modalities and surgical outcomes, such as operative time, estimated blood loss (Table 3,  (72.3%) into the nonresponse group (29 SD and 18 PD). From univariate analysis of the correlation between the response group and clinicopathological features, we observed no signi cant differences between preoperative CCRT and chemotherapy (Table 4). No signi cant differences in age, sex, tumor size, clinical T status, clinical N status, vascular invasion, perineural invasion, clinical TNM stage, pretreatment serum CEA level, and post-treatment serum CEA level were observed (all P > 0.05). In addition, the multivariate logistic regression analysis revealed no independent predictor of response between CCRT and chemotherapy groups (all P > 0.05).
Notably, both OS and PFS in patients with CCRT were better than those in patients with chemotherapy (P = 0.011 and P = 0.008, respectively). CCRT, rather than chemotherapy, appeared effective for achieving better survival bene t.

Discussion
GC remains a leading malignancy worldwide, and management of patients with locally advanced or metastatic GC has not substantially changed in the last few decades. A neoadjuvant strategy may increase the likelihood of completing multimodality therapy, particularly when surgical management is associated with signi cant morbidity and complications that may preclude timely adjuvant therapy [9][10][11][12][13][14][15]. Preoperative concurrent chemoradiotherapy (CCRT) is a well-established primary treatment modality in other gastrointestinal malignancies including esophageal [9,11] and rectal cancer [12,13]. This treatment approach involves sterilizing the surgical eld, potentially reducing the risk of local tumor dissemination at resection. Preoperative CCRT may also allow smaller and more accurate radiation treatment elds, which could improve treatment tolerance and chemotherapy effects [14]. Application of neoadjuvant radiotherapy for patients with unresectable locally advanced or metastatic GC has several additional and distinct advantages. The presence of intact tumors and preserved normal anatomy facilitates treatment planning and may limit toxicity to adjacent organs. By contrast, adjuvant radiotherapy mandates high doses and large treatment elds that may increase toxicity.
In recent years, a multidisciplinary treatment approach including preoperative chemotherapy, radiotherapy, and target therapy has emerged for advanced or metastatic GC, resulting in increased curability and improved survival 14 . Recent studies have suggested that neoadjuvant chemotherapy in patients with locally advanced or metastatic GC can enable curative resection and improve survival [15,16]. In our previous study, we observed that survival and quality of life of patients with locally advanced or metastatic GC who received neoadjuvant chemotherapy were superior to those of patients who received only supportive care [2,3].
Low resectability is largely responsible for the poor prognosis of patients with unresectable locally advanced or metastatic GC. Patients who underwent curative surgery experienced better outcomes than did those who did not undergo surgery [2,17]. However, radical surgery in patients with locally advanced or metastatic GC is limited because of the high risk of perioperative and postoperative morbidity and mortality and the low rate of resection [18]. Timely implementation of the radical resection of cancer is a key step toward favorable therapeutic results. Therefore, improving survival rates to increase resection rates for treatment of advanced GC is necessary.
A neoadjuvant approach can be applied broadly; however, its advantages may be most pronounced in these speci c patient sunsets. In previous prospective studies, patients treated with neoadjuvant CCRT have exhibited higher response rates than did those with chemoradiotherapy alone. Numerous clinical trials have shown that preoperative neoadjuvant CCRT is feasible, and resection rates are higher in patients treated with CCRT [19,20]. Many ndings are expected from trials that explore ways of improving preoperative treatment strategies for locally advanced or metastatic GC [21][22][23][24][25]. Another main reason for the addition of radiotherapy to preoperative chemotherapy is to achieve better local control. Radiotherapy may reduce focal in ammatory edema and brous adhesion of the tumor after chemotherapy. A previous phase clinical trial reported that neoadjuvant CCRT signi cantly reduced locoregional recurrence from 34-14%, with only 1% in-eld recurrence [20,21]. In a Japanese pilot study, no local recurrence was observed after neoadjuvant CCRT [22].
The present study demonstrated favorable OS and PFS responses for patients with locally advanced or metastatic GC treated with CCRT. In our study, 18 (27.7%) of the 65 patients were categorized into the response group and the remaining 47 patients (72.3%) into the nonresponse group. The results of this study indicated that patients who had locally advanced or metastatic GC with treatment of neoadjuvant CCRT tended to have better PFS and OS than did patients with neoadjuvant chemotherapy alone. We did not observe any difference in the morbidity rate between the two treatments with tolerable toxicity and safety. Our study has several limitations. First, this was a relatively small study of limited sample size. Neoadjuvant CCRT achieved a more favorable OS and PFS than did neoadjuvant chemotherapy alone, but without signi cant increases of toxicity, response rate, disease control rate, resectability.
Therefore, these results supported the use of neoadjuvant CCRT in the treatment of patients with locally advanced or metastatic GC. However, additional studies conducted with larger sample sizes and careful patient monitoring are required to con rm these ndings. More specially designed studies and reliable biological indicators of real functional status are needed to properly select patients for multimodal treatment. The results of such studies could be used to signi cantly demonstrate therapeutic e cacy in the treatment of patients with locally advanced or metastatic GC.

Conclusion
Neoadjuvant CCRT achieved a more favorable OS and PFS than did neoadjuvant chemotherapy alone, without signi cant increases of toxicity in patients with locally advanced or metastatic GC. A prospective randomized trial comparing both treatment modalities was conducted to demonstrate the e cacy of preoperative neoadjuvant CCRT.     Figure 1 Cumulative overall survival rates of the 65 enrolled patients with unresectable locally advanced or metastatic gastric cancer undergoing preoperative neoadjuvant concurrent chemoradiotherapy or chemotherapy, as assessed using the Kaplan-Meier method. The differences in survival rates were analyzed using the log-rank test.