Systematic Evaluation of the Safety and Therapeutic Effects of Para-aortic Lymphadenectomy for Advanced Gastric Cancer: a Systematic Review and Meta-analysis

Background: At present, there is still no definite conclusion on whether advanced gastric cancer requires additional para-aortic nodes dissection (PAND). The purpose of this study is an attempt to provide significant data to guide clinical decision-making. Methods: The literature was searched using the terms of gastric cancer, para-aortic lymphadenectomy and D2+ lymphadenectomy and D3 lymphadenectomy. The databases searched included PubMed, Embase, Cochrane library, Web of Science, China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, VIP Database for Chinese Technical Periodicals, and China Biology Medicine disc. RevMan 5.3 software was used for the meta-analysis.Results: In total, 20 studies were included, consisting of 6 randomized controlled trials (RCT) and 14 non-randomized controlled trials (nRCT). These studies involved 5643 patients. The meta-analysis showed the following results: (1) compared with group D2 (D2 lymphadenectomy), the operating time in group D2+ (D2+ lymphadenectomy) was longer [mean difference (MD)=99.45 min, 95% confidence interval (CI) (48.93, 149.97), P<0.001], with more intra-operative blood loss [MD=262.14 mL, 95%CI (165.21, 359.07), P<0.001]; (2) there were no significant differences in five-year overall survival [HR=1.09, 95%CI (0.95, 1.25), P=0.22] and post-operative mortality [RR=0.96, 95%CI (0.59, 1.57), P=0.88] between the two groups; (3) the rate of post-operative complication in group D2+ was higher than that in group D2 [RR=1.42, 95%CI (1.11, 1.81), P<0.001]. Conclusions: It is noteworthy that the combination of perioperative chemotherapy and D2+ surgery, particularly D2+ PAND, shows some survival advantages for specific patients. Although prophylactic D2+ surgery is not recommended as it increases postoperative complications and does not improve long-term survival in patients with advanced gastric cancer.

PRODIGY: A Phase III Study of Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 Versus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer

PURPOSE Adjuvant chemotherapy after D2 gastrectomy is standard for resectable locally advanced gastric cancer (LAGC) in Asia. Based on positive findings for perioperative chemotherapy in European phase III studies, the phase III PRODIGY study (ClinicalTrials.gov identifier: NCT01515748 ) investigated whether neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 could improve outcomes versus standard treatment in Korean patients with resectable LAGC. PATIENTS AND METHODS Patients 20-75 years of age, with Eastern Cooperative Oncology Group performance status 0-1, and with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma (clinical TNM staging: T2-3N+ or T4Nany) were randomly assigned to D2 surgery followed by adjuvant S-1 (40-60 mg orally twice a day, days 1-28 q6w for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 intravenously day 1, S-1 40 mg/m2 orally twice a day, days 1-14 q3w for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary objective was progression-free survival (PFS) with CSC versus SC. Two sensitivity analyses were performed: intent-to-treat and landmark PFS analysis. RESULTS Between January 18, 2012, and January 2, 2017, 266 patients were randomly assigned to CSC and 264 to SC at 18 Korean study sites; 238 and 246 patients, respectively, were treated (full analysis set). Follow-up was ongoing in 176 patients at data cutoff (January 21, 2019; median follow-up 38.6 months [interquartile range, 23.5-62.1]). CSC improved PFS versus SC (adjusted hazard ratio, 0.70; 95% CI, 0.52 to 0.95; stratified log-rank P = .023). Sensitivity analyses confirmed these findings. Treatments were well tolerated. Two grade 5 adverse events (febrile neutropenia and dyspnea) occurred during neoadjuvant treatment. CONCLUSION PRODIGY showed that neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, is effective and tolerable in Korean patients with LAGC.

SHARED: Efficacy and safety of sintilimab in combination with concurrent chemoradiotherapy (cCRT) in patients with locally advanced gastric (G) or gastroesophageal junction (GEJ) adenocarcinoma.

4040 Background: PD-1 inhibitor and chemotherapy have shown significant clinical benefits in 1L-treatment of G/GEJ. While it is not clear for locally advanced stage. The aim of this single-arm phase Ib trial is to assess the feasibility of sintilimab (PD-1 inhibitor) in combination with cCRT in locally advanced GC. Methods: Patients (pts) with initial histopathologically confirmed G/GEJ adenocarcinoma, diagnosed as locally advanced III-IVA per AJCC 8th and ECOG PS of 0-1 were eligible. Sintilimab (200mg, iv, Q3W) was given with CRT sandwich in sequence of one induction chemotherapy (S-1+Nab-PTX), weekly Nab-PTX(80-100mg/m2, d1, d8, d15, d22), concurrent radiotherapy (45Gy/1.8Gy*25f), and one consolidation chemotherapy (S-1+Nab-PTX). Pts received three additional combinations of sintilimab and chemotherapy after surgery or investigator’s best choice for unresectable pts after planned therapy. The primary endpoint was pCR and a Simon two-stage was employed at first 9 pts. This interim analysis was pre-planned after finishing stage I assessment. Accrual is ongoing with another 25 in next stage. Results: In the first stage, 5 out of 9 pts achieved pCR and passed to next stage. As of 7th Feb 2021, 28 pts met inclusion criteria with median age 67 yrs (range 47-81), men 86%, PS 1 25%, cT3/4a/4b 28%/54%/18%, cN1/N2/N3 7%/50%/43% and Borrmann II/III/IV 57%/18%/25%. The location on GEJ and G was 14% and 86%. Of 23 pts completed neoadjuvant, all were evaluated as D2-surgery feasibility. 19 pts had completed gastrectomy (4 pts waiting for surgery) with pCR 42.1% (8/19), MPR (≤10% viable tumor cells) 73.7% (14/19) and R0 resection 94.7% (18/19). Down-staging to pT0 and pN0 were both observed in 42.1%. The median follow-up was 5.8m unavailable for survival evaluation at present. Grade (gr) 3-4 TRAE occurred in 39.3% (11/28) pts with most common events as myelosuppression (39.3%) and increased transaminase (10.7%). IrAEs occurred in 21.4% (6/28) pts with one gr 4 hepatitis and others gr 1-2. Peri-operative complications occurred in 3 pts with gr 1-2 pneumonia, increased transaminase, and ileus. No death or unexpected toxicity observed. Conclusions: SHARED interim analysis demonstrated a promising feasibility of sintilimab in combination with cCRT with preliminary impressive pCR & MPR and acceptable toxicity in phase III-IVA G/GEJ cancer. These results warrant further accrual and evaluation. Clinical trial information: ChiCTR1900024428.

Prolonged overall survival observed in patients with locally advanced gastric cancer receiving prophylactic simplified heated intraperitoneal chemotherapy after D2 surgery.

e16110 Background: Despite advances in surgery and adjuvant chemotherapy, intraperitoneal recurrence is highly frequent in gastric cancer (GC) with a dismal prognosis. In this retrospective study, we aimed to evaluate the effectiveness of adding simplified prophylactic heated intraperitoneal chemotherapy (sp-HIPEC) between surgery and systemic chemotherapy. Methods: Clinical data of 170 patients diagnosed as having locally advanced GC and receiving D2 surgery were retrospectively reviewed. Of the patients, 99 received sp-HIPEC, followed by systemic postoperative chemotherapy, and 71 received only systemic postoperative chemotherapy. Overall survival and recurrence rates between the groups were compared. Results: The median survival was 30.3 and 17.2 months for the sp-HIPEC and systemic groups, respectively (hazard ratio, 0.56; 95% CI, 0.10-0.97). The 3- and 5-year survival rates were 48.2% vs 41.4% and 22.9% vs 14.4%, respectively. Moreover, adding sp-HIPEC significantly reduced peritoneal relapse rate.Both regimens were well tolerated. Conclusions: Adding sp-HIPEC between surgery and systemic chemotherapy may benefit the overall survival without causing additional treatment toxicity.

The protocol of a prospective, multicenter, randomized, controlled phase III study evaluating different cycles of oxaliplatin combined with S-1 (SOX) as neoadjuvant chemotherapy for patients with locally advanced gastric cancer: RESONANCE-II trial

Background Curing locally advanced gastric cancer through surgery alone is difficult. Adjuvant and neoadjuvant chemotherapy bring potential benefits to more patients with gastric cancer based on several clinical trials. According to phase II studies and guidelines, SOX regimen as neoadjuvant chemotherapy is efficient. However, the optimal duration of neoadjuvant chemotherapy has not been established. In this study, we will evaluate the efficacy and safety of different cycles of SOX as neoadjuvant chemotherapy for patients with locally advanced gastric cancer. Methods RESONANCE-II trial is a prospective, multicenter, randomized, controlled phase III study which will enroll 524 patients in total. Eligible patients will be registered, pre-enrolled and receive three cycles of SOX, after which tumor response evaluations will be carried out. Those who show stable disease or progressive disease will be excluded. Patients showing complete response or partial response will be enrolled and assigned into either group A for another three cycles of SOX (six cycles in total) followed by D2 surgery; or group B for D2 surgery (three cycles in total). The primary endpoint is the rate of pathological complete response and the secondary endpoints are R0 resection rate, three-year disease-free survival, five-year overall survival, and safety. Discussion This study is the first phase III randomized trial to compare the cycles of neoadjuvant chemotherapy using SOX for resectable locally advanced cancer. Based on a total of six to eight cycles of perioperative chemotherapy usually applied in locally advanced gastric cancer, patients in group A can be considered to have completed all perioperative chemotherapy, the results of which may suggest the feasibility of using chemotherapy only before surgery in gastric cancer. Trial registration Registered prospectively in the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) with registration number ChiCTR1900023293 on May 21st, 2019.

Is D2 surgery necessary for clinical T1 gastric cancer with nodal swelling?

288 Background: D2 surgery is required for clinical T1 gastric cancer with nodal swelling, however, D2 has a higher risk for morbidity than D1/D1+. Moreover, previous study demonstrated that the false positive rate for nodal diagnosis in clinical T1 was very high. To select optimal surgery with high probability, we explored risk factors for false positivity in clinical T1 disease. Methods: Patients who underwent radical gastrectomy for clinical T1 gastric cancer between April 2015 and June 2019 were enrolled. Accuracy, sensitivity, specificity, positive predictive value, and negative predictive values for nodal diagnosis were retrospectively investigated. The risk factors for false positivity were also analyzed by the following factors; age, sex, histological type, tumor size, tumor depth, location, tumor type, presence of ulcer, and timing of CT that is (1) the patients who underwent primary endoscopic mucosal dissection (ESD) but resulted in non-curative resection, then received CT to proceed to surgery (delayed CT group) or (2) the other patients who had received CT before primary surgery or before non-curative ESD (primary CT group). Results: A total of 679 patients were examined in the present study. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 83.5% (567/679), 14.3% (13/91), 94.2% (554/588), 27.7% (13/47), and 87.7% (554/632), respectively. The false positive rate was 72.3% (34/47). In univariate analysis, differentiated tumor ( p= 0.012) and delayed CT (p < 0.001) were associated with the false positivity. Multivariate analysis revealed that delayed CT (OR, 4.534; p < 0.001) was a sole significant risk factor for false positivity. False positive rate was 100% (13/13) in the delayed CT group and 61.8% (21/34) in the primary CT group ( p= 0.009). Conclusions: False positive rate was high in clinical T1 disease, especially when the patients received delayed CT after non-curative ESD. D2 surgery would be unnecessary even though nodal swelling was detected in CT after non-curative ESD.

Safety and feasibility of S-1 adjuvant chemotherapy for pancreatic cancer in elderly patients.

486 Background: The safety and feasibility of starting S-1 adjuvant chemotherapy for pancreatic cancer has not been evaluated in elderly patients. Methods: The patients who underwent curative D2 surgery for pancreatic cancer were selected to this retrospective study. The patients were diagnosed within stage I to III disease, and received adjuvant S-1 at our hospital. Patients were categorized into two groups; non-elderly patients (age<70 years: group A) and elderly patients (age≥70 years: group B). The toxicity and drug continuation rates in the two groups were compared. Results: Total 40 patients were evaluated in this study. There were no grade 3 and 4 toxicities. The incidences of grade 2 hematological toxicities were 0% in group A and 11% in group B. The incidences of grade 2 non-hematological toxicities were 50% in group A and 27.8% in group B. The differences in both groups were not significant. The continuation rate at 6 months was 55.7% in group A and 72.7% in group B, and there was also no significant difference in the groups. Conclusions: These results suggest that S-1 adjuvant chemotherapy for pancreatic cancer is safe and feasible, regardless of the age of the patient; especially in elderly patients.