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 confirmed 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 confirm 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 classification was determined according to the American Joint Commission on Cancer/Union for International Cancer Control criteria .
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 significant 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, 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 ; therefore, Her2 expression was not routinely examined for pre-operative neoadjuvant setting in the current study. This study aimed to explore the efficacy and safety profile of preoperative CCRT in locally advanced or metastatic GC versus preoperative chemotherapy.
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.
The 65 patients were treated with an mFOLFOX-4-based regimen that comprised the following: On day 1, oxaliplatin (85 mg/m2) and leucovorin (200 mg/m2) were administered over a 2-h period, followed by a 48-h continuous infusion of 5-FU at a dose of 2400 mg/m2 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
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 fields with photon energy at 10 MV. The dose specification 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 fields 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 one-third/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 22.214.171.124 (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 fixed-jaw mode with a field 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.
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-specific 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 Efficacy 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 findings at specific 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).
Patient responses were classified according to the Response Evaluation Criteria in Solid Tumors [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 sufficient to meet the PR criteria, and the increase is not sufficient to meet the PD criteria . Finally, PFS was determined by measuring the time interval between the start of neoadjuvant CCRT or chemotherapy and the first record of progression, regardless of the patient's treatment status or final 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].
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 significant.