Prospective Study Open Access
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Oct 15, 2021; 13(10): 1532-1543
Published online Oct 15, 2021. doi: 10.4251/wjgo.v13.i10.1532
Efficacy and toxicity of capecitabine combined with intensity-modulated radiotherapy after D1/D2 lymph node dissection in patients with gastric cancer
Xin Wang, Wei-Hu Wang, Shu-Lian Wang, Yong-Wen Song, Yue-Ping Liu, Yuan Tang, Ning Li, Wen-Yang Liu, Hui Fang, Ye-Xiong Li, Dong-Bing Zhao, Yihebali Chi, Lin Yang, Jing Jin
Xin Wang, Shu-Lian Wang, Yong-Wen Song, Yue-Ping Liu, Yuan Tang, Wen-Yang Liu, Hui Fang, Ye-Xiong Li, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Wei-Hu Wang, Department of Radiation Oncology, Peking University Cancer Hospital and Institute, Beijing 100001, China
Ning Li, Jing Jin, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, Guangdong Province, China
Dong-Bing Zhao, Department of Pancreatic and Gastric Surgery, National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Yihebali Chi, Lin Yang, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
ORCID number: Xin Wang (0000-0002-3149-108X); Wei-Hu Wang (0000-0003-4969-398X); Shu-Lian Wang (0000-0001-7322-9621); Yong-Wen Song (0000-0003-1345-8339); Yue-Ping Liu (0000-0001-6446-4291); Yuan Tang (0000-0001-5417-8988); Ning Li (0000-0002-7968-7364); Wen-Yang Liu (0000-0002-6978-7169); Hui Fang (0000-0002-9317-9761); Ye-Xiong Li (0000-0003-0985-235X); Dong-Bing Zhao (0000-0002-3011-5277); Yihebali Chi (0000-0002-8381-3554); Lin Yang (0000-0002-4829-3119); Jing Jin (0000-0003-2158-7392).
Author contributions: Jin J and Zhao DB contributed to study concepts and design and were major guarantors of integrity of the entire study; Jin J participated in funding acquisition and revised the manuscript; Wang X, Wang WH, Wang SL, Song YW, Liu YP, Tang Y, Li N, Liu WY, Fang H, Li YX, Zhao DB, Chi Y, and Yang L contributed to patient recruitment and clinical studies; Wang X performed the statistical and data analyses, and drafted the manuscript; All authors have read and agreed to the published version of the manuscript.
Supported by Beijing Hope Run Special Fund of Cancer Foundation of China, No. LC2018L03; Sanming Project of Medicine in Shenzhen, No. SZSM201612063; and Shenzhen High-level Hospital Construction Fund.
Institutional review board statement: This study was approved by the Independent Ethics Committees of Cancer Institute and Hospital, Chinese Academy of Medical Sciences (Approved No. 11-72/507).
Clinical trial registration statement: The clinical trial is registered with ClinicalTrials.gov, using identifier NCT01674959. Details can be found at https://clinicaltrials.gov/ct2/show/NCT01674959?term=NCT01674959&rank=1.
Informed consent statement: All patients signed informed consent.
Conflict-of-interest statement: The authors of this work have nothing to disclose.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at jingjin1025@163.com. Participants gave informed consent for data sharing.
CONSORT 2010 statement: The authors have read the CONSORT 2010 Statement, and the manuscript was prepared and revised according to the CONSORT 2010 Statement.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jing Jin, MD, Doctor, Professor, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 113 Baohe Avenue, Longgang District, Shenzhen 518116, Guangdong Province, China. jingjin1025@163.com
Received: April 15, 2021
Peer-review started: April 15, 2021
First decision: June 4, 2021
Revised: June 11, 2021
Accepted: August 16, 2021
Article in press: August 16, 2021
Published online: October 15, 2021

Abstract
BACKGROUND

Adjuvant chemoradiotherapy (ACRT) with oral capecitabine and intensity-modulated radiotherapy (IMRT) were well tolerated in a phase I study in patients who had undergone partial or total gastrectomy for locally advanced gastric cancer (GC). This phase II study aimed to further determine the efficacy and toxicity of this combination after radical resection and D1/D2 lymph node dissection (LND) for patients with locally advanced GC.

AIM

To further determine the efficacy and toxicity of this combination after radical resection and D1/D2 LND for patients with locally advanced GC.

METHODS

Forty patients (median age, 53 years; range, 24-71 years) with pathologically confirmed adenocarcinoma who underwent D1/D2 LND were included in this study. The patients received ACRT comprising IMRT (total irradiation dose: 45 Gy delivered in daily 1.8-Gy fractions on 5 d a week over 5 wk) and capecitabine chemotherapy (dose: 800 mg/m² twice daily throughout the duration of radiotherapy). The primary study endpoint was disease-free survival (DFS), and the secondary endpoints were overall survival (OS), toxic effects, and treatment compliance.

RESULTS

The 3-year DFS and OS were 66.2% and 75%, respectively. The median time to recurrence was 19.5 mo (range, 6.1-68 mo). Peritoneal implantation (n = 10) was the most common recurrence pattern, and the lung was the most common site of extra-abdominal metastases (n = 5). Nine patients developed grade 3 or 4 toxicities during ACRT. Two patients discontinued ACRT, while eleven underwent ACRT without receiving the entire course of capecitabine. There were no treatment-related deaths.

CONCLUSION

The ACRT protocol described herein showed acceptable safety and efficacy for patients with locally advanced GC who received radical gastrectomy and D1/2 LND.

Key Words: Gastric cancer, Radiotherapy, Chemoradiotherapy, Clinical trial, Phase II

Core Tip: In our previous phase I study, we found that an adjuvant chemoradiotherapy (ACRT) regimen of 45 Gy radiotherapy concurrent with oral capecitabine was well tolerated in patients with locally advanced gastric cancer who had received partial or total gastrectomy. The maximum tolerated and recommended dose of capecitabine was 800 mg/m2 twice daily with oral administration. We performed this phase II study to further assess the efficacy and toxicity of this ACRT regimen as an adjuvant therapy after radical resection and D1/D2 lymph node dissection for patients with locally advanced gastric cancer.



INTRODUCTION

The Intergroup trial (INT0116) demonstrated a major survival benefit of using a combination of conventional radiotherapy (RT) and fluorouracil (5-FU) chemotherapy on the 3-year disease-free survival (DFS) in patients with locally advanced gastric cancer (GC) after radical surgery (R0) and D0/D1 lymph node dissection (LND)[1]. However, more than half of the patients developed grade 3/4 hematologic toxicity and one-third developed gastrointestinal (GI) toxicity, which may affect the prognosis. Thus, it is important to combine advanced radiation techniques with a low-toxicity chemotherapy regimen to improve compliance to adjuvant chemoradiotherapy (ACRT) among postoperative GC patients who show poor tolerability for adjuvant treatment because of partial or total loss of the stomach.

Capecitabine, which belongs to fluoropyrimidines, has been widely used for chemotherapy and concurrent with radiotherapy in GC[2,3]. It is comparable to 5-FU and has a safer side effect profile and convenient oral administration[3,4]. High tumor response rates (26%-34%) have been reported with capecitabine monotherapy in phase II studies[5-7], and the drug has been found to be more efficacious when used in combination with platinum-based drugs in some phase III trials in patients with advanced GC[4-8].

Modern intensity-modulated radiotherapy (IMRT) planning systems have made it possible to deliver radiation doses more accurately to the planning target volume (PTV) and spare critical normal tissues to a substantial degree. IMRT has also been confirmed to be superior to two- or three-dimensional RT.

In our previous phase I study, we found that the ACRT regimen of 45 Gy radiotherapy concurrent with oral capecitabine was well tolerated in patients with locally advanced GC who had received partial or total gastrectomy. The maximum tolerated and recommended dose of capecitabine was 800 mg/m2 twice daily with oral administration[9]. We performed this phase II study to further assess the efficacy and toxicity of this ACRT regimen as an adjuvant therapy after radical resection and D1/D2 LND for locally advanced GC patients.

MATERIALS AND METHODS
Eligibility

Participants were recruited if they met the following inclusion criteria: received partial (proximal or distal subtotal gastrectomy) or total gastrectomy with D1/D2 LND; had not received neoadjuvant anti-cancer treatment; postoperative pathologic diagnosis of adenocarcinoma; pathologic classification of T3-4N0 or any TN+M0 according to the 7th edition of the American Joint Committee on Cancer TNM classification; age ≤ 75 years and good performance (Eastern Cooperative Oncology Group performance status ≤ 1); no prior or concurrent history of malignant disease (except non-melanoma skin cancers or in situ carcinoma of the cervix); no prior abdominal radiation; and leukocyte count ≥ 3.5 × 109/L, neutrophil count ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, hemoglobin level ≥ 10.0 g/L, and normal alanine aminotransferase/aspartate aminotransferase and creatinine level.

All patients entering the trial received physical examinations, computed tomography (CT) scans of the chest/abdomen/pelvis, a complete blood count, and biochemical profile before treatment began. A complete blood count and biochemical profile were conducted every 1 and 2 wk, respectively. Adverse events terms and grade were coded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. The follow-up interval for patients was once every 3 mo for the first 2 years and every 6 mo thereafter. Permission to conduct the study was obtained from the institutional ethics committees, and the study was registered at clinicaltrials.gov (NCT01674959). All patients provided signed informed consent.

Surgery

All patients were recommended D2 LND, which requires resection of all perigastric LNs, left gastric artery, common hepatic artery, celiac artery, proximal splenic artery, and proper hepatic artery, depending on the primary tumor location.

Radiotherapy

The prescription dose and fraction were 45 Gy in daily 1.8 Gy (5 d a week over 5 wk) by IMRT techniques. To enable visualization of the small intestine, patients needed to fast for 4 h before CT simulation, and take an oral positive contrast (300 mL) 30 min before the simulation. A normalized meal (300 mL of ready-to-eat canned porridge) was given to the patients 15 min before CT simulation and each treatment daily to decrease heterogeneity in gastric filling. The patients were placed in the supine position with thermoplastic immobilization masks; intravenous contrast was recommended but no 4D-CT planning or motion management was required during IMRT with 6-MV photon beam.

Clinical target volume (CTV) for each patient was contoured in accordance with recommendations from the Japanese Gastric Cancer Association depending on the extension and location of the primary tumor and the LN region involved status[10]. The CTV generally covered anastomoses, duodenal stump, tumor bed (only for stage T4b, if present), and regional LNs (Table 1). The remnant stomach was not routinely included in the target volume. The PTV typically includes the CTV plus a 5-7 mm margin in the radial direction and a 10 mm margin in the superior-inferior direction. Dose limitations for an organ at risk (OAR) were as follows: volume percentage receiving over 30 Gy (V30) < 40% for the liver, V20 < 30% or a mean dose of < 20 Gy for both kidneys, and V30 < 30% for the heart; the maximal dose for the spinal cord planning OAR volume was < 40 Gy. The maximal dose was less than the prescribed dose for the small intestine and colon. An experienced physicist did the IMRT plans design using a five-to-seven–field, coplanar, sliding window technique using the Pinnacle system, version 8.0.

Table 1 Clinical target volume for elective nodal regions according to the Japanese Gastric Cancer Association guidelines.
Tumor location
CTV for elective nodal regions
Upper 1/3rd or gastroesophageal junction110, 1-3, 7, 9-11
Middle 1/3rd1-3, 5-13, 141, 16a
Lower 1/3rd3, 5-9, 11p, 12-13, 141, 16a
Chemotherapy

Oral capecitabine was delivered twice daily (after breakfast and after dinner) at a dose of 800 mg/m² from the beginning to end of the radiation period based on the results of a previous phase I study[9]. Adjuvant chemotherapy (ACT) was required for a maximum of 6 mo and was conducted before or after ACRT depending on the performance status, clinical comorbidities, and toxicity profile of the patient; however, the regimens were open.

Statistical analyses

The primary endpoint of our phase II study was DFS, which was defined as the length of time after surgery ends that the patient’s disease progresses or dies from any cause. The secondary endpoints were overall survival (OS), toxic effects, and treatment compliance. We hypothesized that the 3-year DFS rate would improve from 50% to 70% based on the results of INT0116. The use of Fleming’s design (P1 = 0.50 and P2 = 0.70, setting α = 0.05 [two-sided], 80% power) revealed that 37 study participants were needed. At least 40 patients were required for this study with assumption of a 10% dropout rate.

The first site of recurrence was recorded to analyze treatment failure patterns. Locoregional recurrence was defined as reappearance of cancer at the anastomosis site, remnant stomach, duodenal stump, tumor bed, or regional LNs within the radiation field. Outside radiation field LNs region relapse, peritoneal implantation, liver metastasis or any other extra-abdominal site metastasis were regarded as distant metastases. Survival analysis were assessed with Kaplan–Meier curves using SPSS for Windows, version 20.0 (IBM SPSS Inc., Armonk, NY, United States).

RESULTS
Patient characteristics

From October 2011 to June 2013, 40 patients were recruited for the study. The patients’ general characteristics are shown in Table 2. The median age was 53 years (range, 24-71 years). Thirty-seven (92.5%) patients had positive LNs. The median number of positive LNs was 7 (range, 1-26 nodes), and the median number of LNs resected was 24 (range, 15-56 nodes). D2 LND was performed in 22 (55%) patients. The median interval between surgery and ACRT was 5.5 mo (1.4-8 mo).

Table 2 Patient characteristics.
Characteristic
n
%
Age in yr, median (range)53 (24-71)
Men2870.0
Tumor size in cm, median (range)5.0 (2-20)
Location of primary tumor
Upper 1/3rd of stomach820
Middle 1/3rd of stomach820
Lower 1/3rd of stomach1435
≥ 2 sites involved1025
Surgery type
Partial gastrectomy3690
Total gastrectomy410
Positive LNs, median (range)7 (1-26)
LNs resected, median (range)24 (15-56)
LN ratio, median (range)0.27 (0-0.86)
Extent of dissection
D11845
D22255
Lauren type
Intestinal type1230
Diffuse type1640
Mixed type1230
Tumor differentiation
Good12.5
Moderate820
Poor3177.5
Lymphatic/vascular invasion
Absent1640
Present2460
Perineural invasion
Absent3075
Present1025
Signet ring cells
Absent2972.5
Present1127.5
Tumor deposit
Absent3485
Present615
Stage (AJCC 7th)
IIa25
IIb615
IIIa1127.5
IIIb1127.5
IIIc1025
Stage (AJCC 6th)
Ib25
II1435
IIIa1025
IIIb25
IV1230

The patients received the following ACT regimens based on docetaxel and/or oxaliplatin and 5-FU analogues, with a median of six cycles (range, 3–10 cycles) before or after ACRT: oxaliplatin/cisplatin and S-1 (n = 18, 45%); docetaxel, oxaliplatin, and capecitabine/S-1/5-FU (n = 13, 32.5%); oxaliplatin and capecitabine (n = 6, 15%); and oxaliplatin, 5-FU, and leucovorin (n = 3, 7.5%).

Toxicities and treatment compliance

During ACRT, nine patients (22.5%) developed grade 3-4 toxicities and there were no treatment-related deaths. The most common grade 3-4 toxicities were leukopenia (5 patients, 12.5%), vomiting (4 patients, 10%), nausea (3, 7.5%), esophagitis (3, 7.5%), and thrombocytopenia (3, 7.5%).

Two patients discontinued ACRT due to disease progression (total dose, 25.2 Gy) and serious fatigue (total dose, 5.4 Gy). The remaining 38 patients (95%) received 45 Gy as planned, including 3 patients who developed grade 3 thrombocytopenia (2 cases) and grade 3 vomiting (1 case) but finally completed RT (not with capecitabine) after a break. Besides the treatment discontinuation mentioned above, an additional 8 patients did not finish the whole course of capecitabine because of the reasons below: leukopenia (maximum grade, 3), 2 patients; thrombocytopenia (maximum grade, 3), 2 patients; anemia (maximum grade, 2), 1 patient; gastritis (maximum grade, 3), 1 patient; vomiting (maximum grade, 3), 1 patient; and anorexia (maximum grade, 3), 1 patient. The overall toxicities are showed in Table 3.

Table 3 Overall toxicities at the recommended dose, n = 40.
Toxicity
Grade 1-2, n (%)
Grade 3-4, n (%)
Nausea22 (45)3 (7.5)
Vomiting15 (37.5)4 (10)
Anorexia27 (67.5)2 (5)
Esophagitis6 (15)3 (7.5)
Diarrhea5 (12.5)0
Abdominal pain1 (2.5)1 (2.5)
Gastritis9 (22.5)2 (5)
Fatigue21 (52.5)1 (2.5)
Weight loss8 (20)0
HFS14 (35)0
Leukopenia27 (67.5)5 (12.5)
Neutropenia7 (17.5)1 (2.5)
Anemia3 (7.5)0
Thrombocytopenia17 (42.5)3 (7.5)
ALT/AST2 (5)0
Survival and relapse

In total, 19 patients died during the follow-up period (median 80 mo; range, 8.4-96 mo): 18 died of disease and 1 of gastrorrhagia. The 3-year DFS, the primary endpoint of this study, was 66.2 (95% confidence interval [CI]: 58.6-73.8). The survival outcomes of OS, locoregional recurrence-free survival (RFS), and distant metastasis-free survival are listed in Figure 1 and Table 4. During the follow-up period, the following recurrence patterns were observed in the 18 patients (45%, 18/40): peritoneal implantation (n = 10, 25%), hematogenous spread (n = 8, 20%), and locoregional recurrence (n = 7, 17.5%). A single recurrence pattern was noted in 13 patients and multiple recurrence patterns were observed in 5 patients. Among the 7 patients with locoregional recurrence, 4 showed recurrences at the regional LNs, 3 at the anastomosis, and 1 at the gastric stump. The most common site of extra-abdominal metastases was the lung, which was noted in 5 (12.5%) patients. The median time to first recurrence was 19.5 mo (range, 6.1-68 mo). The median time from first recurrence to death was 5.9 mo (range, 0.5-60 mo).

Figure 1
Figure 1 Overall survival rates and disease-free survival rates according to the Kaplan-Meier technique. A: Overall survival rates; B: Disease-free survival rates.
Table 4 Survival outcomes.
Time
DFS (95%CI)
OS (95%CI)
LRFS (95%CI)
DMFS (95%CI)
3 yr66.2 (58.6-73.8)75 (68.2-81.8)80.8 (74.2-88.6)72.4 (64.9-79.9)
5 yr55.2 (47.1-63.3)58.9 (51.0-66.8)80.8 (74.2-88.6)60.4 (52.1-68.7)
7 yr152.3 (44.1-60.5)48.2 (39.5-56.9)80.8 (74.2-88.6)57.2 (48.8-65.6)
DISCUSSION

Our results suggest that ACRT with 45 Gy IMRT and concurrent oral capecitabine at a dose of 800 mg/m2 twice daily had an acceptable efficacy and toxicity profile in patients with locally advanced GC after radical gastrectomy and D1/2 LND. The 3-year DFS was 66.2%, which did not reach the primary hypothesis endpoint of our phase II study.

The role of ACRT in patients with locally advanced GC remains debatable. The benefits or drawbacks of this scenario mainly depend on whether a D1 or D2 lymphadenectomy has been performed. The INT0116 study was the first trial to prove the benefit of ACRT in patients after radical gastrectomy and D0/1 LND; it showed that the 3-year OS and DFS increased from 41% to 50% and 31% to 48%, respectively[1]. Even after 10 years of follow-up, ACRT was associated with superior DFS and OS[11]. Dikken et al[12] suggested that the addition of ACRT after D1 LND has a major impact on local recurrence in GC. Zhang et al[13] suggested that patients with D1 or D1 plus LND benefit from adjuvant RT, and adjuvant RT may be beneficial for some patients with D2 LND. Yu et al[14] re-analyzed the ARTIST study and concluded that adjuvant RT after D2 resection in GC reduces locoregional recurrence risk, especially in group 3 LNs, and improves locoregional RFS Patients with positive LN benefited more from the adjuvant RT than the other subgroup[14]. The National Comprehensive Cancer Network (NCCN) guideline recommends ACRT as an adjuvant treatment in patients with less than D2 LND.

In China, D2 LND is considered a routine surgical procedure for locally advanced GC, because it is the most widely accepted surgical procedure in Asian and European countries[15]. However, given the many differences between centers or institutions in terms of hospital volume, patient populations, surgical practices and training, postoperative nursing experience, and pathological identification and examination of LNs, it is difficult to standardize and generalize D2 LND, even in our specialized cancer hospital. In our previous retrospective study of 297 patients with locally advanced GC who received radical surgery alone, the median number of LNs resected was 18 (range, 4-68 nodes) with a 27.6% 5-year locoregional recurrence rate[16]. In our phase I trial (performed between 2007 and 2009), D2 LND was performed in only 16.7% (3/18) of patients with GC, with a median of 19 LNs (range, 5-35) examined in our hospital. The median number of LNs resected in this study (performed between 2011and 2013) reached up to 24 nodes (range, 5-56 nodes). In a large observational study conducted in patients who underwent radical resection for GC, the survival benefits were significantly associated with an increase in the number of LNs resected, even when as many as 40 LNs were examined[17]. According to published reports[18,19], the greater number of LNs resected in our study may have provided better locoregional control and possibly a survival advantage, although this number was still much smaller than that reported in studies conducted in Japan and Korea (D2 LND with a median of more than 40 LNs examined)[2,3]. Furthermore, although patients underwent a very high-quality D2 LND, the ARTIST trial (ACRT Trial of Capecitabine Plus Cisplatin for Gastric Cancer) demonstrated that DFS could be further improved by ACRT in LN-positive GC. A randomized trial published in 2013 showed RFS benefit (median time 36 mo vs 50 mo, P = 0.029, 95%CI: 1.03-1.78) in ACRT group after D2 LND, which did not provide the resected LN number[20]. Thus, it is reasonable that ACRT could be considered as an adjuvant treatment for patients with LN metastasis or those who did not undergo a high-quality D2 LND.

In the past decade, capecitabine has been widely used in GI cancer, as it has a much safer side effect profile and does not require invasive delivery[21,22]. Oral capecitabine was not inferior to infusional 5-FU in randomized control trials for patients with advanced GC[4]. Therefore, capecitabine has been considered as a standard chemotherapy regimen for the treatment of advanced GC worldwide. The NCCN guidelines also suggest that infusional 5-FU can be replaced by oral capecitabine in GC. Our previous study determined that the maximum tolerated dose and recommended dose of capecitabine was 800 mg/m2 twice daily when administered concurrently with IMRT for GC as adjuvant therapy[9], which is similar to the dose used in the ACRT group concurrent with RT in the ARTIST trial[2]. Lee et al[23] evaluated the efficacy and toxicity of ACRT using FP (5-FU+cisplatin) chemotherapy and capecitabine combined with RT for advanced GC; in their study, capecitabine was administered at a dose of 825 mg/m2 twice daily throughout the duration of RT. Jansen et al[24] evaluated the dose escalation of capecitabine monotherapy concurrently with postoperative RT in GC, and recommended a capecitabine dose of 1000 mg/m2 twice daily on each treatment day during the RT period.

The investigation of issues related to the sequence of ACT or ACRT is important since poor compliance to adjuvant treatment after gastrectomy is the main problem that may affect patient prognosis. Theoretically, for patients with high-risk pathological features (e.g., poorly differentiated cancer, lymphovascular invasion, or multiple LN metastasis) leading to a higher probability of distant failure, more cycles of ACT may be administered soon after surgery to avoid more cancer cell micrometastasis; however, excessive chemotherapy before RT would reduce patient tolerance to ACRT. Soyfer et al[25] reported an association between total RT treatment time, and to some extent, the time of the initiation of RT for local control and distant metastases. McMillan et al[26] reported that prolonged intervals between surgery and RT initiation were not associated with inferior OS in GC, while prolonged RT treatment duration were. In the studies reported by Jansen et al[24,27,28], RT started one 21-d cycle of ACT after surgery, which means that patients might tolerate ACRT well compared to the tolerance observed in those who received several cycles of combination chemotherapy before RT. With recent randomized evidence reinforcing the benefit of ACRT in node-positive GC[11,29], it is desirable to explore issues related to the proper sequence of ACT and ACRT, since poor compliance to adjuvant treatment after gastrectomy is the main problem that may impact patient prognosis. Based on our clinical experience, compliance to ACRT would be better if it started after no more than four cycles (21 d/cycle) of ACT for patients with many adverse prognostic factors. Furthermore, monotherapy administered as concurrent chemotherapy during RT, rather than as part of a combination chemotherapy regimen, would also improve patient compliance to ACRT. Thus, in our opinion, the adjuvant treatment design of the ACRT arm in the ARTIST trial seems reasonable (two cycles of capecitabine plus cisplatin followed by capecitabine-based ACRT and then two additional cycles of capecitabine plus cisplatin)[2].

The most commonly observed grade 3/4 hematologic and GI toxicities in this study were leukopenia (12.5%) and vomiting (10%), which were much less frequent than those in INT 0116 (54% and 32% of the patients developed grade 3/4 hematologic and GI toxicity) and CALGB 80801 study (about 50% and 16% of the patients developed grade 3/4 hematologic and GI toxicity)[1,30]. The exclusion of the remnant stomach from the target volume and the use of IMRT technology and capecitabine monotherapy (noninferior efficacy and lower GI toxicity than 5-FU) may account for the relatively lower rate of severe toxicities. Nam et al[31] demonstrated that the exclusion of the remnant stomach from the radiation field could significantly reduce acute side effects without compromising long-term survival rates. After the long-term follow-up of ARTIST study which CTV did not include remnant stomach, local recurrence in the remnant stomach was seen in only 2% of all patients, and this result was similar to Nam et al[14]. Several studies have found that IMRT was superior to two- or three-dimensional RT, providing a more conformal and homogeneous dose to the PTV and accordingly minimizing the probability of toxicity[32-34].We had previously determined that tomotherapy is a better option for adjuvant treatment of GC due to its superior bowel and bone marrow dose sparing, dose conformity, and dose homogeneity[6,7,35,36]. Given this evidence, this study showed acceptable safety and comparable compliance with the treatment course. Our study showed that 95% (38/40) and 72.5% (29/40) of patients completed RT and concurrent capecitabine monotherapy, respectively.

The 3-year DFS of the ACRT arm in INT 0116 was used in the power calculation for the present phase II study, as this is the only randomized trial evaluating the effect of ACRT in GC patients with an LND level less than D2. However, the final 3-year DFS in our study was 66.2%, which did not meet the primary endpoint (3-year DFS = 70%). This could be attributable to the maximum number of positive LNs found (as high as 7) and the fact that only 55% of our patients had D2 LND. Despite previous findings, our results are still better than those obtained with ACRT treatment by Janson et al[27,28]. The 2-year OS of their phase II trials evaluating capecitabine/cisplatin chemotherapy with concurrent RT after D0/1/2 LND (18%-22% of patients had D2 LND) was 45%-61%[37]. National Cancer Data Base analysis showed that patients with adjuvant RT 5-year OS rate was 45%. While our study showed a 3-year OS of 75% and 5-year OS of 58.9%. The higher incidence of D2 LND performed during radical gastrectomy in this study may have contributed to our better prognosis. Subgroup analysis of the ARTIST trial showed that the significant 3-year DFS effect of ACRT in node-positive disease improved from 72% to 78%, which may be due to the very high-quality D2 LND (median number of LNs dissected was 40) and relatively lower rate of metastatic LNs (median number was 3)[2].

This study had several limitations that warrant emphasis. Due to the poor patient recruitment for this study, we did not limit the regimens or cycles of adjuvant chemotherapy administered before or after ACRT. Accordingly, this may have influenced the results for the toxicity profile of ACRT and led to different intervals between surgery and initiation of ACRT. However, patients were presumably recruited postoperatively, yielding a subgroup of patients who had undergone surgery. This is relevant if comparisons are to be made with other treatment strategies where patients are recruited preoperatively.

CONCLUSION

In conclusion, we considered that ACRT with 800 mg/m2/d oral capecitabine twice daily combined with 45 Gy IMRT was safe and efficacious. The use of advanced techniques such as IMRT or tomotherapy, an appropriate irradiation field, and low-toxicity single-agent chemotherapy regimens such as capecitabine chemotherapy is highly recommended. A randomized phase III study in our hospital comparing ACT with ACRT for node-positive locally advanced GC after D2 LND is ongoing (NCT 02648841), and its results are highly awaited.

ARTICLE HIGHLIGHTS
Research background

Capecitabine has been widely used for chemotherapy and concurrent with radiotherapy in gastric cancer (GC) treatment, while modern intensity-modulated radiotherapy (IMRT) has also been confirmed to be superior to two- or three-dimensional radiotherapy (RT). In our previous phase I study, we found out adjuvant chemoradiotherapy (ACRT) regimen of IMRT concurrent with oral capecitabine was well tolerated in patients with locally advanced GC who had received partial or total gastrectomy.

Research motivation

We performed this phase II study to further assess the efficacy and toxicity of this ACRT regimen as an adjuvant therapy after radical resection and D1/D2 lymph node dissection (LND) for locally advanced GC patients.

Research objectives

The aim of this study was to evaluate the efficacy and toxicity of IMRT combined with capecitabine after radical resection and D1/D2 LND for patients with locally advanced GC.

Research methods

Forty patients with locally advanced GC, who underwent radical resection and D1/D2 LNDwere included in this study. The patients received ACRT comprising IMRT (total irradiation dose: 45 Gy delivered in daily 1.8-Gy fractions on 5 d a week over 5 wk) and capecitabine chemotherapy (dose: 800 mg/m² twice daily throughout the duration of RT). The primary study endpoint was disease-free survival (DFS) and the secondary endpoints were overall survival (OS), toxic effects, and treatment compliance.

Research results

The 3-year DFS and OS were 66.2% and 75%, respectively. Nine patients developed grade 3 or 4 toxicities during ACRT. Two patients discontinued ACRT, while 11 underwent ACRT without receiving the entire course of capecitabine.

Research conclusions

ACRT with oral capecitabine and IMRTwas safe and efficacious.

Research perspectives

The use of IMRT and low-toxicity single-agent chemotherapy regimens such as capecitabine is highly recommended in patients who had undergone partial or total gastrectomy for locally advanced GC. Moreover, to further determine the efficacy of this combination therapy, a randomized phase III study in our hospital is ongoing.

Footnotes

Manuscript source: Unsolicited manuscript

Specialty type: Gastroenterology and hepatology

Country/Territory of origin: China

Peer-review report’s scientific quality classification

Grade A (Excellent): 0

Grade B (Very good): B, B

Grade C (Good): C, C, C

Grade D (Fair): 0

Grade E (Poor): 0

P-Reviewer: Dimofte GM, Kim HS, Lee KG, Mohamed SY S-Editor: Wu YXJ L-Editor: Filipodia P-Editor: Yuan YY

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