Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial
Chemotherapy is the standard of care for incurable advanced gastric cancer. Whether the addition of gastrectomy to chemotherapy improves survival for patients with advanced gastric cancer with a single non-curable factor remains controversial. We aimed to investigate the superiority of gastrectomy followed by chemotherapy versus chemotherapy alone with respect to overall survival in these patients.
Methods
We did an open-label, randomised, phase 3 trial at 44 centres or hospitals in Japan, South Korea, and Singapore. Patients aged 20–75 years with advanced gastric cancer with a single non-curable factor confined to either the liver (H1), peritoneum (P1), or para-aortic lymph nodes (16a1/b2) were randomly assigned (1:1) in each country to chemotherapy alone or gastrectomy followed by chemotherapy by a minimisation method with biased-coin assignment to balance the groups according to institution, clinical nodal status, and non-curable factor. Patients, treating physicians, and individuals who assessed outcomes and analysed data were not masked to treatment assignment. Chemotherapy consisted of oral S-1 80 mg/m2 per day on days 1–21 and cisplatin 60 mg/m2 on day 8 of every 5-week cycle. Gastrectomy was restricted to D1 lymphadenectomy without any resection of metastatic lesions. The primary endpoint was overall survival, analysed by intention to treat. This study is registered with UMIN-CTR, number UMIN000001012.
Findings
Between Feb 4, 2008, and Sept 17, 2013, 175 patients were randomly assigned to chemotherapy alone (86 patients) or gastrectomy followed by chemotherapy (89 patients). After the first interim analysis on Sept 14, 2013, the predictive probability of overall survival being significantly higher in the gastrectomy plus chemotherapy group than in the chemotherapy alone group at the final analysis was only 13·2%, so the study was closed on the basis of futility. Overall survival at 2 years for all randomly assigned patients was 31·7% (95% CI 21·7–42·2) for patients assigned to chemotherapy alone compared with 25·1% (16·2–34·9) for those assigned to gastrectomy plus chemotherapy. Median overall survival was 16·6 months (95% CI 13·7–19·8) for patients assigned to chemotherapy alone and 14·3 months (11·8–16·3) for those assigned to gastrectomy plus chemotherapy (hazard ratio 1·09, 95% CI 0·78–1·52; one-sided p=0·70). The incidence of the following grade 3 or 4 chemotherapy-associated adverse events was higher in patients assigned to gastrectomy plus chemotherapy than in those assigned to chemotherapy alone: leucopenia (14 patients [18%] vs two [3%]), anorexia (22 [29%] vs nine [12%]), nausea (11 [15%] vs four [5%]), and hyponatraemia (seven [9%] vs four [5%]). One treatment-related death occurred in a patient assigned to chemotherapy alone (sudden cardiopulmonary arrest of unknown cause during the second cycle of chemotherapy) and one occurred in a patient assigned to chemotherapy plus gastrectomy (rapid growth of peritoneal metastasis after discharge 12 days after surgery).
Interpretation
Since gastrectomy followed by chemotherapy did not show any survival benefit compared with chemotherapy alone in advanced gastric cancer with a single non-curable factor, gastrectomy cannot be justified for treatment of patients with these tumours.
Funding
The Ministry of Health, Labour and Welfare of Japan and the Korean Gastric Cancer Association.
Introduction
The prognosis of patients with advanced gastric cancer with non-curable factors, such as hepatic, peritoneal, or distant lymph node metastases, is poor—most patients die within 1 year. Chemotherapy is the standard of care for these patients. For incurable advanced gastric cancer, palliative resection or bypass surgery is generally indicated in the presence of major symptoms such as bleeding or obstruction, whereas the usefulness of gastrectomy aimed at reduction of tumour volume (ie, reductive gastrectomy) in asymptomatic patients is still unclear. Findings from studies from the early 1980s to early 2000s1, 2, 3, 4, 5, 6, 7, 8, 9 suggested that the addition of gastrectomy to chemotherapy, even in the absence of any serious symptoms such as bleeding and obstruction, might improve patient survival (median overall survival of 8·0–12·2 months with gastrectomy vs 2·4–6·7 months without gastrectomy) among patients with advanced gastric cancer with a single non-curable factor. However, most of these studies were retrospective, single institutional case series, and were confounded by substantial selection bias because patients with good Eastern Cooperative Oncology Group (ECOG) performance status, fewer comorbidities, and small tumour burden were more likely to undergo gastrectomy, thereby resulting in a positive outcome. Furthermore, in the past decade, a median overall survival of about 12 months has been reported with chemotherapy alone,10, 11, 12, 13, 14 making the role of additional gastrectomy in the treatment of non-curable advanced gastric cancer unclear.
Research in context
Evidence before this study
We searched PubMed, Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials databases without language restrictions for studies published between Jan 1, 1985, and Dec 31, 2014, using the terms “gastric cancer”, “non-curative OR advanced”, “gastrectomy OR surgery”, “chemotherapy”, and “randomized”. We also searched clinical trial registers (ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform) for ongoing randomised trials. The final search was done on April 30, 2015. Although in the past 30 years there has been much interest in the safety and efficacy of gastrectomy in patients with non-curative gastric cancer, most studies were retrospective case series involving selected patients, spanning a wide timeframe, and with variable methods and reporting, and none was randomised. We identified only one relevant ongoing randomised trial comparing gastrectomy plus metastasectomy followed by systemic therapy versus systemic therapy alone in advanced gastric cancer.
Added value of this study
To our knowledge, REGATTA is the first randomised controlled trial to address the survival benefit of reduction surgery before chemotherapy as first-line treatment of advanced gastric cancer. We recruited patients with a single non-curable factor since this population was the most likely to obtain a survival benefit from a surgically reduced tumour burden. Patients were randomly assigned to receive either D1 gastrectomy plus chemotherapy or chemotherapy alone with S-1 plus cisplatin as first-line treatment. Findings from this study showed that primary surgery before chemotherapy does not yield any survival benefit and is not recommended in the clinical management of incurable gastric cancer.
Implications of all the available evidence
To our knowledge, this study provides the first high-quality evidence for reduction surgery before chemotherapy in patients with non-curative gastric cancer. Patients with incurable gastric cancer should undergo upfront chemotherapy. Our findings could change the practice of reduction surgery for non-curative gastric cancer and are applicable to a broad population of patients with advanced gastric cancer worldwide.
Theoretically, gastrectomy might reduce a large and potentially immunosuppressive tumour burden, remove the source of new metastases, and ameliorate symptoms caused by the gastric lesion, thereby facilitating durable systemic chemotherapy. By contrast, gastrectomy could enhance the growth of metastatic lesions by inducing immunosuppression, delay the start of systemic chemotherapy because of postoperative complications, increase toxicity, and decrease tolerability of chemotherapy. In the past decade, findings from several clinical studies of first-line chemotherapy for metastatic or recurrent gastric cancer15, 16, 17, 18 have shown that past gastrectomy along with a small number of metastatic sites are independent favourable prognostic factors, which suggest the relevance of reducing tumour burden for achieving longer overall survival in patients with advanced gastric cancer.
To the best of our knowledge, no randomised controlled trial has investigated whether additional gastrectomy confers a survival benefit over chemotherapy alone in patients with non-curable advanced gastric cancer.19 Here, we report the final results of a multi-institutional, randomised, controlled trial (REGATTA) that was done to establish whether the addition of gastrectomy to standard chemotherapy improves survival among patients with advanced gastric cancer with a single non-curable factor.
Section snippets
Study design and participants
REGATTA was an open-label, randomised, phase 3 trial done by the Japan Clinical Oncology Group (JCOG; JCOG0705) and the Korean Gastric Cancer Association (KGCA; KGCA01). Patients aged 20–75 years with histologically proven primary gastric adenocarcinoma and presence of a single non-curable factor confirmed by both enhanced abdominal CT and exploratory laparoscopy or laparotomy were eligible. A single non-curable factor was defined as hepatic metastasis (H1; two to four lesions of maximum
Results
Between Feb 4, 2008, and Sept 17, 2013, 175 patients (95 in Japan and 80 in South Korea) were enrolled and randomly assigned to chemotherapy alone (86 patients) or gastrectomy plus chemotherapy (89 patients; figure 1) at 44 cancer centres, medical centres, university hospitals, and general hospitals in Japan, South Korea, and Singapore. Seven patients in the chemotherapy alone group were ineligible, as was one patient in the gastrectomy plus chemotherapy group. Two patients assigned to
Discussion
In this study, gastrectomy plus chemotherapy did not provide a survival advantage compared with chemotherapy alone in the treatment of advanced gastric cancer with a single non-curable factor. The study was terminated after the interim analysis because patients assigned to gastrectomy plus chemotherapy were unlikely to have improved overall survival compared with those assigned to chemotherapy alone. 2-year overall survival did not differ between patients assigned to chemotherapy alone and
Diagnostic laparoscopy (DL) with peritoneal lavage has been adopted as a standard staging procedure for patients with gastric cancer (GC). Evaluation of the value of DL is important given ongoing improvements in diagnostic imaging and treatment. As contemporary data from European centres are sparse, this retrospective cohort study aimed to assess the yield of DL in patients with potentially curable gastric cancer, and to identify predictive factors for peritoneal metastases.
Patients with adenocarcinoma of the stomach, treated between January 2016 and December 2018, were identified from institutional databases of two high volume European Upper-GI centres. Patients who underwent a DL with peritoneal lavage for potentially curable disease after clinical staging with imaging (cT1-4N0-3M0) were included. The primary outcome was the proportion of patients with a positive DL, defined as macroscopic metastatic disease, positive peritoneal cytology washings (PC+) or locally irresectable disease.
Some 80 of 327 included patients (24.5%) had a positive DL, excluding these patients from neoadjuvant treatment (66 of 327; 20.2%) and/or surgical resection (76 of 327; 23.2%). In 34 of 327 patients (10.3%), macroscopic metastatic disease was seen, with peritoneal deposits in 30 of these patients. Only 16 of 30 patients with peritoneal disease had positive cytology. Some 41 of 327 patients (12.5%) that underwent DL had PC+ in the absence of macroscopic metastases and five patients (1.5%) had an irresectable primary tumour. Diffuse type carcinoma had the highest risk of peritoneal dissemination, irrespective of cT and cN categories.
The diagnostic yield of staging laparoscopy is high, changing the management in approximately one quarter of patients. DL should be considered in patients with diffuse type carcinoma irrespective of cT and cN categories.
A comprehensive understanding of gastric signet ring cell carcinoma (SRCC) is limited. The aim of our study was to analyze metastatic patterns of gastric SRCC and evaluate impacts of gastrectomy and chemotherapy for metastatic gastric SRCC.
We obtained data of gastric cancer patients between 2010 and 2017 in the Surveillance, Epidemiology, and End Results database. Chi-square tests were used to compare data significance. Kaplan–Meier, Cox proportional hazards regression and Fine–Gray competing risk analysis were used to analyze the difference in the overall survival (OS) and cancer-specific survival (CSS). Propensity-score matching was used to adjust numerical difference.
Among 36,459 eligible gastric cancer patients, 6264 (17.2 %) were SRCC patients. Bone metastasis was more common in SRCC patients than in non-SRCC patients. The multivariate analysis showed that chemotherapy (HR = 0.30, 95 %CI = 0.27–0.33, p < 0.01) and gastrectomy (HR = 0.51, 95 %CI = 0.45–0.59, p < 0.01) were protective prognostic factors in certain stage Ⅳ SRCC patients. For the effect of gastrectomy, survival benefits could be found in patients with liver metastasis. The gastrectomy was not associated with improved OS in patients with lung or multiple metastases. In subgroup analysis, SRCC patients with metastasis who received gastrectomy and chemotherapy (HR = 0.17, p < 0.01; HR = 0.03, p < 0.01) had a better OS and CSS than those who had chemotherapy only (HR = 0.30, p < 0.01; HR = 0.18, p < 0.01).
Our study analyzed the unique metastatic patterns of gastric SRCC and recommended chemotherapy as the first choice in metastatic SRCC. For patients with liver metastasis, gastrectomy plus chemotherapy can be considered.
Gastric cancer is one of the most frequent and deadly tumours worldwide. However, the evidence that currently exists for the treatment of older adults is limited and is derived mainly from clinical trials in which older patients are poorly represented.
In this article, a group of experts selected from the Oncogeriatrics Section of the Spanish Society of Medical Oncology (SEOM), the Spanish Group for the Treatment of Digestive Tumours (TTD), and the Spanish Multidisciplinary Group on Digestive Cancer (GEMCAD) reviews the existing scientific evidence for older patients (≥65 years old) with gastric cancer and establishes a series of recommendations that allow optimization of management during all phases of the disease. Geriatric assessment (GA) and a multidisciplinary approach should be fundamental parts of the process. In early stages, endoscopic submucosal resection or laparoscopic gastrectomy is recommended depending on the stage. In locally advanced stage, the tolerability of triplet regimens has been established; however, as in the metastatic stage, platinum- and fluoropyrimidine-based regimens with the possibility of lower dose intensity are recommended resulting in similar efficacy. Likewise, the administration of trastuzumab, ramucirumab and immunotherapy for unresectable metastatic or locally advanced disease is safe. Supportive treatment acquires special importance in a population with different life expectancies than at a younger age. It is essential to consider the general state of the patient and the psychosocial dimension.
The clinical significance of tumor-positive peritoneal cytology (CYT+) in gastric cancer (GC) patients is unclear. This nationwide cohort study aimed to i) assess the frequency of cytological analysis at staging laparoscopy; ii) determine the prevalence of CYT+GC; and iii) compare overall survival (OS) in CYT+ patients versus those with (PM+) and those without (PM-) macroscopic peritoneal disease.
All patients diagnosed with cT1–4, cN0–2 and M0 or synchronous PM GC between 2016–2021 were identified in the Netherlands Cancer Registry database and linked to the nationwide pathology database.
A total of 4397 patients was included, of which 40 % underwent cytological assessment following staging laparoscopy (863/1745). The prevalence of CYT+ was 8 %. A total of 69 patients had CYT+(1.6 %), 789 (17.9 %) had PM+ and 3539 (80.5 %) had PM- disease. Hazard ratio for OS in CYT+ versus PM+ was 0.86 (95 %CI 0.64–1.17, p-value=0.338), and in PM- versus PM+0.43 (95 %CI 0.38–0.49, p-value<0.001). No survival difference was found between systemic chemotherapy versus surgical resection in CYT+ patients.
In this nationwide study, OS for gastric cancer patients with CYT+ was equally unfavorable as for those with PM+ and significantly worse as compared to those with PM-. The optimal treatment strategy has yet to be established.
The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer (GC), published in late 2022 and the updated ESMO Gastric Cancer Living Guideline published in July 2023, were adapted in August 2023, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with GC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with GC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), coordinated by ESMO and the Japanese Society of Medical Oncology (JSMO). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian regions represented by the 10 oncological societies. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with GC across the different regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling and age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different regions of Asia.
Recent advances in chemotherapy have resulted in successful conversion surgery (CS) for clinical stage (cStage) IVB gastric cancer (GC). This study aimed to evaluate the success rate of CS in clinical practice and determine optimal treatment strategies.
Totally, 166 patients with cStage IVB gastric and gastroesophageal junction adenocarcinoma, who underwent chemotherapy at Hyogo Medical University Hospital between January 2017 and June 2022, were included. CS was performed after confirming tumor to be M0 based on imaging and/or staging laparoscopy, except for resectable liver metastases. Preoperative chemotherapy was continued for at least 6 months provided that adverse events were manageable.
Of 125 eligible patients, 23 were treated with CS, achieving a conversion rate of 18.4% and an R0 resection rate of 91.3%. The median duration of preoperative chemotherapy was 8.5 months; the median number of cycles was eight. The highest conversion rate was observed in patients receiving first-line treatment (14.4%), followed by those receiving second and third lines (5.8% and 2.3%, respectively). The median survival time in patients who received CS was significantly longer than that in patients who continued chemotherapy alone (56.7 versus 16 months, respectively, P < 0.0001). There was no significant difference in the 3-year overall survival between the patients who achieved CS after first-line treatment (63.2%, n = 18) and those who achieved CS after second- or third-line treatment (66.7%, n = 5).
Consistent chemotherapy strategies could lead to successful CS and improved prognosis in a greater number of patients with cStage IVB GC, regardless of line of treatment.
