Preventive HIPEC in combination with perioperative FLOT versus FLOT alone for resectable diffuse type gastric and gastroesophageal junction type II/III adenocarcinoma: The phase III “PREVENT” trial of the AIO /CAOGI /ACO.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS4149-TPS4149
Author(s):  
Thorsten Oliver Goetze ◽  
Pompiliu Piso ◽  
Sylvie Lorenzen ◽  
Ulli Simone Bankstahl ◽  
Marcin Ostrzyzek ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Western Hemisphere ◽  
Phase Iii ◽  
R0 Resection ◽  
Type Ii ◽  
Diffuse Type ◽  
Open Label ◽  
Peritoneal Seeding ◽  
Perioperative Morbidity

TPS4149 Background: The main reason for treatment failure after curative surgical resection of gastric cancer is intra-abdominal spread, with 40- 50% peritoneal seeding as primary localization of recurrence. Peritoneal relapse is seen in 60-70% of tumors of diffuse type, compared to only 20-30% of intestinal type. Hyperthermic IntraPEritoneal Chemoperfusion (HIPEC) is an increasingly used therapy method for patients with peritoneal metastases. The preventive use of HIPEC could represent an elegant approach for patients (pts) before macroscopic peritoneal seeding, since patients with operable disease are fit and may have potential risk of microscopic involvement, thus having a theoretical chance of cure with HIPEC even without the need for cytoreduction. No results from a PCRT from the Western hemisphere have yet been published. Methods: This is a multicenter, randomized, controlled, open-label study including a total of 200 pts with localized and locally advanced diffuse and mixed type (Laurens`s classification) adenocarcinoma of the stomach and Type II/III GEJ (i.e. ≥cT3 any N or any T N positive). All enrolled pts will have received 3-6 pre-operative cycles of biweekly FLOT (Docetaxel 50 mg/m²; Oxaliplatin 85 mg/m²; Leucovorin 200 mg/m²; 5-FU 2600 mg/m², q2wk). Pts will be randomized 1:1 to receive surgery only and postoperative FLOT (Arm A- Control arm) or surgery + intraoperative HIPEC (cisplatin 75mg/m2 solution administered at a temperature of 42°C for 90 minutes) and postoperative FLOT (Arm B- experimental arm). Surgery is carried out as gastrectomy or transhiatal extended gastrectomy. Primary endpoint is PFS/DFS, major secondary endpoints are OS, R0 resection rate, perioperative morbidity/mortality including VAS pain score and quality of life as assessed by EORTC QLQ C30 questionnaire. The trial starts with a safety run-in phase. After 20 patients had curatively intended resection in Arm B, an interim safety analysis is performed assessing feasibility, safety, and tolerability in Arm B. First patient was randomized on 18JAN2021. Currently one patient is recruited. EudraCT: 2017-003832-35; ClinicalTrials.gov ID: NCT04447352. Clinical trial information: NCT04447352.

scholarly journals Preventive HIPEC in combination with perioperative FLOT versus FLOT alone for resectable diffuse type gastric and gastroesophageal junction type II/III adenocarcinoma – the phase III “PREVENT”- (FLOT9) trial of the AIO /CAOGI /ACO

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Thorsten O. Götze ◽  
Pompiliu Piso ◽  
Sylvie Lorenzen ◽  
Ulli S. Bankstahl ◽  
Claudia Pauligk ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Western Hemisphere ◽  
Phase Iii ◽  
Type Ii ◽  
Diffuse Type ◽  
Open Label ◽  
Peritoneal Seeding ◽  
Link Type

Abstract Background The main reason for treatment failure after curative surgical resection of gastric cancer is intra-abdominal spread, with 40–50% peritoneal seeding as primary localization of recurrence. Peritoneal relapse is seen in 60–70% of tumors of diffuse type, compared to only 20–30% of intestinal type. Hyperthermic IntraPEritoneal Chemoperfusion (HIPEC) is an increasingly used therapy method for patients with peritoneal metastases. The preventive use of HIPEC could represent an elegant approach for patients (pts) before macroscopic peritoneal seeding, since pts. with operable disease are fit and may have potential risk of microscopic involvement, thus having a theoretical chance of cure with HIPEC even without the need for cytoreduction. No results from a PCRT from the Western hemisphere have yet been published. Methods This is a multicenter, randomized, controlled, open-label study including a total of 200 pts. with localized and locally advanced diffuse or mixed type (Laurens’s classification) adenocarcinoma of the stomach and Type II/III GEJ. All enrolled pts. will have received 3–6 pre-operative cycles of biweekly FLOT (Docetaxel 50 mg/m2; Oxaliplatin 85 mg/m2; Leucovorin 200 mg/m2; 5-FU 2600 mg/m2, q2wk). Pts will be randomized 1:1 to receive surgery only and postoperative FLOT (control arm) or surgery + intraoperative HIPEC (cisplatin 75 mg/m2 solution administered at a temperature of 42 °C for 90 min) and postoperative FLOT (experimental arm). Surgery is carried out as gastrectomy or transhiatal extended gastrectomy. Primary endpoint is PFS/DFS, major secondary endpoints are OS, rate of pts. with peritoneal relapse at 2 and 3 years, perioperative morbidity/mortality and quality of life. The trial starts with a safety run-in phase. After 20 pts. had curatively intended resection in Arm B, an interim safety analysis is performed. Recruitment has already started and first patient in was on January 18th, 2021. Discussion If the PREVENT concept proves to be effective, this could potentially lead to a new standard of therapy. On the contrary, if the outcome is negative, pts. with gastric cancer and no peritoneal involvement will not be treated with HIPEC during surgery. Trial registration The study is registered on June 25th, 2020 under ClinicalTrials.gov Identifier: NCT04447352; EudraCT: 2017-003832-35.

A single-arm, phase II feasibility study of neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy in potentially resectable gastric or gastroesophageal junction adenocarcinoma.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 96-96
Author(s):  
M. Ryu ◽  
Y. Choi ◽  
B. Kim ◽  
Y. Park ◽  
H. Kim ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Advanced Gastric Cancer ◽  
Residual Disease ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Phase Iii ◽  
R0 Resection ◽  
Locally Advanced Gastric Cancer ◽  
Grade 3

96 Background: The aim of this study was to evaluate feasibility and safety of neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy in patients with potentially resectable adenocarcinoma of stomach or gastroesophageal junction. Methods: Forty-one patients with clinical stage T3-4N0M0 or T2-4N+M0 determined by CT, endoscopic ultrasonography, and laparoscopy were enrolled between DEC 2008 and MAR 2010. Gastrectomy with D2 lymph node dissection was conducted after 3 cycles of DOS chemotherapy. DOS chemotherapy consists of docetaxel 50 mg/m2 iv (day1), oxaliplatin 100 mg/m2 iv (day1), and S-1 40 mg/m2 po bid (days1-14) at 3 weeks interval. After curative gastrectomy, the patients were given 1 year of adjuvant chemotherapy with S-1 (40 mg/m2 D1-28, every 6 weeks). Results: All patients finished the planned neoadjuvant chemotherapy. Twenty-three (56%) patients achieved a partial response, and the remaining 18 patients had stable disease by CT scan after 3 cycles of DOS chemotherapy. No disease progression was observed during the neoadjuvant chemotherapy. A median 4.7 weeks (range, 4.0-7.6) after the start of the 3rd cycle of DOS chemotherapy, 39 (95%) patients underwent R0 resection with no pathologic residual disease in 4 (10%) patients. Hematologic toxicities were common including grade 4 neutropenia (32%), grade 3 thrombocytopenia (17%), and febrile neutropenia (10%). However, hematologic toxicities were generally transient and manageable. There were no grade 3 or 4 non-hematologic toxicities with frequency > 5% of patients. With all toxicities taken together, 21 (51%) patients experienced grade 3 or 4 toxicities (except grade 3 neutropenia). There was no treatment-related death, and surgical complications included only mild wound problem in 4 (10%) patients. Conclusions: In this study, neoadjuvant DOS chemotherapy could induce a sufficient down-staging and R0 resection of locally advanced gastric cancer with mild and manageable toxicities. A phase III randomized trial is planned for evaluating the benefit of neoadjuvant DOS chemotherapy in patients with locally advanced gastric cancer. [Table: see text]

KEYNOTE-062: Phase III study of pembrolizumab (MK-3475) alone or in combination with chemotherapy versus chemotherapy alone as first-line therapy for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. TPS185-TPS185 ◽  
Author(s):  
Josep Tabernero ◽  
Yung-Jue Bang ◽  
Charles S. Fuchs ◽  
Atsushi Ohtsu ◽  
Uma Kher ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Phase Iii ◽  
Primary Study ◽  
First Line ◽  
Open Label ◽  
Double Blind ◽  
End Points ◽  
First Line Therapy ◽  
Line Therapy

TPS185 Background: Pembrolizumab (pembro) is a monoclonal antibody against PD-1 designed to block its interaction with PD-L1 and PD-L2 and permit an antitumor immune response. In KEYNOTE-012, pembro showed a 22% ORR (RECIST v1.1, central review) and a manageable safety profile in patients (pts) with advanced gastric cancer. The randomized, phase 3 KEYNOTE-062 study (NCT02494583) is designed to compare the efficacy and safety of pembro alone or in combination with cisplatin + a fluoropyrimidine with those of cisplatin + a fluoropyrimidine as first-line therapy for PD-L1+/HER2– advanced gastric or GEJ adenocarcinoma. Methods: Key eligibility criteria include age ≥ 18 y, locally advanced or metastatic PD-L1+/HER2– gastric or GEJ adenocarcinoma, ECOG PS 0-1, no active autoimmune disease or brain metastases, and no prior therapy for advanced disease. Pts are randomized 1:1:1 to pembro 200 mg Q3W (arm 1), pembro + cisplatin 80 mg/m2 Q3W + 5-fluorouracil (5-FU) 800 mg/m2 on days 1-5 of each Q3W cycle (arm 2), or placebo Q3W + cisplatin + 5-FU (arm 3); 5-FU may be replaced with capecitabine 1000 mg/m2 twice daily on days 1-14 of each cycle. Randomization is stratified by region (Europe/North America/Australia vs Asia vs rest of world), disease status (locally advanced vs metastatic), and chosen fluoropyrimidine (5-FU vs capecitabine). Arm 1 is open label; in arms 2 and 3, assignment to pembro vs placebo is double blind. In all arms, treatment will continue for 35 cycles or until progressive disease, unacceptable toxicity, or pt/investigator decision. Response will be evaluated every 6 wk per RECIST v1.1 by central review and per RECIST adapted for immunotherapy response patterns; eligible pts may continue treatment beyond initial RECIST-defined progression. AEs will be assessed throughout treatment and for 30 d thereafter (90 d for serious AEs) and graded per NCI CTCAE v4.0. Pts will be followed for survival every 3 mo. OS and PFS per RECIST v1.1 are the primary study end points; secondary end points include ORR and duration of response. Enrollment in KEYNOTE-062 is ongoing and will continue until ~750 pts have enrolled. Clinical trial information: NCT02494583.

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

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4040-4040
Author(s):  
Jia Wei ◽  
Xiaofeng Lu ◽  
Qin Liu ◽  
Yao Fu ◽  
Song Liu ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Phase Iii ◽  
R0 Resection ◽  
Clinical Benefits ◽  
D2 Surgery ◽  
Ecog Ps ◽  
Clinical Trial Information

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.

scholarly journals Phase III Trial of Avelumab Maintenance After First-Line Induction Chemotherapy Versus Continuation of Chemotherapy in Patients With Gastric Cancers: Results From JAVELIN Gastric 100

2020 ◽  
pp. JCO.20.00892
Author(s):  
Markus Moehler ◽  
Mikhail Dvorkin ◽  
Narikazu Boku ◽  
Mustafa Özgüroğlu ◽  
Min-Hee Ryu ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Phase Iii ◽  
First Line ◽  
Open Label ◽  
Phase Iii Trial ◽  
Gastroesophageal Junction Cancer ◽  
Positive Population

PURPOSE The role of maintenance therapy for gastric (GC) or gastroesophageal junction cancer (GEJC) is unclear. We investigated avelumab (anti–programmed death ligand-1 [PD-L1]) maintenance after first-line induction chemotherapy for GC/GEJC. PATIENTS AND METHODS JAVELIN Gastric 100 was a global, open-label, phase III trial. Eligible patients had untreated, unresectable, human epidermal growth factor receptor 2–negative, locally advanced or metastatic GC or GEJC. Patients without progressive disease after 12 weeks of first-line chemotherapy with oxaliplatin plus a fluoropyrimidine were randomly assigned 1:1 to avelumab 10 mg/kg every 2 weeks or continued chemotherapy, stratified by region (Asia v non-Asia). The primary end point was overall survival (OS) after induction chemotherapy in all randomly assigned patients or the PD-L1–positive randomly assigned population (≥ 1% of tumor cells; 73-10 assay). RESULTS A total of 805 patients received induction; 499 were randomly assigned to avelumab (n = 249) or continued chemotherapy (n = 250). Median OS was 10.4 months (95% CI, 9.1 to 12.0 months) versus 10.9 months (95% CI, 9.6 to 12.4 months) and 24-month OS rate was 22.1% versus 15.5% with avelumab versus chemotherapy, respectively (hazard ratio [HR], 0.91; 95% CI, 0.74 to 1.11; P = .1779). In the PD-L1–positive population (n = 54), the HR for OS was 1.13 (95% CI, 0.57 to 2.23; P = .6352). In an exploratory analysis of the PD-L1–positive population, defined as combined positive score ≥ 1 (22C3 assay; n = 137), median OS was 14.9 months (95% CI, 8.7 to 17.3 months) with avelumab versus 11.6 months (95% CI, 8.4 to 12.6 months) with chemotherapy (unstratified HR, 0.72; 95% CI, 0.49 to 1.05). With avelumab and chemotherapy, treatment-related adverse events (TRAEs) occurred in 149 (61.3%) and 184 (77.3%) patients, including grade ≥ 3 TRAEs in 31 (12.8%) and 78 (32.8%) patients, respectively. CONCLUSION JAVELIN Gastric 100 did not demonstrate superior OS with avelumab maintenance versus continued chemotherapy in patients with advanced GC or GEJC overall or in a prespecified PD-L1–positive population.

624 A PHASE III STUDY ON NEOADJUVANT TORIPALIMAB PLUS CHEMOTHERAPY VERSUS NEOADJUVANT CHEMOTHERAPY FOR LOCALLY RESECTABLE ESOPHAGEAL SQUAMOUS CELL CARCINOMA

2021 ◽  
Vol 34 (Supplement_1) ◽  
Author(s):  
Yan Zheng ◽  
Jiangong Zhang ◽  
Wenqun Xing
Keyword(s):  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Disease Free Survival ◽  
Complete Response ◽  
Phase Iii ◽  
R0 Resection ◽  
Phase Iii Trial ◽  
Free Survival

Abstract   In recent years, immune checkpoint inhibitors (ICIs) have shown promising results in the treatment of ESCC. More than 20 phase II clinical trials have been launched to explore combinations of ICIs in the neoadjuvant setting for ESCC. Based on our phase II clinical trial, a two-arm phase III trial was launched in our Hospital. Methods A two-arm phase III trial was launched in April 2020 in our Hospital. Patient recruitment will be completed within 18 months. The primary endpoint is event-free survival (EFS). The secondary endpoints include pathologic complete response (pCR), disease-free survival (DFS) rate, overall response rate (ORR), R0 resection rate, major pathologic response (MPR), adverse events (AEs), complication rate and quality of life (QOL). A biobank of pretreatment, resected tumor tissue and paired blood samples will be built for translational research in the future. Results Until Dec. 2021, one hundred and twenty ESCC patients recruited in the trial. The trial is ongoing. Conclusion This RCT directly compares NAC with neoadjuvant toripalimab plus chemotherapy in terms of EFS for locally advanced ESCC. The results may usher in a new era of resectable ESCC treatment.

scholarly journals Neoadjuvant Chemotherapy Compared With Surgery Alone for Locally Advanced Cancer of the Stomach and Cardia: European Organisation for Research and Treatment of Cancer Randomized Trial 40954

2010 ◽  
Vol 28 (35) ◽  
pp. 5210-5218 ◽  
Author(s):  
Christoph Schuhmacher ◽  
Stephan Gretschel ◽  
Florian Lordick ◽  
Peter Reichardt ◽  
Werner Hohenberger ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Lymph Node ◽  
Neoadjuvant Chemotherapy ◽  
Preoperative Chemotherapy ◽  
Survival Benefit ◽  
Locally Advanced ◽  
Postoperative Chemotherapy ◽  
Phase Iii ◽  
R0 Resection ◽  
Resection Rate

PurposePatients with locally advanced gastric cancer benefit from combined pre- and postoperative chemotherapy, although fewer than 50% could receive postoperative chemotherapy. We examined the value of purely preoperative chemotherapy in a phase III trial with strict preoperative staging and surgical resection guidelines.Patients and MethodsPatients with locally advanced adenocarcinoma of the stomach or esophagogastric junction (AEG II and III) were randomly assigned to preoperative chemotherapy followed by surgery or to surgery alone. To detect with 80% power an improvement in median survival from 17 months with surgery alone to 24 months with neoadjuvant, 282 events were required.ResultsThis trial was stopped for poor accrual after 144 patients were randomly assigned (72:72); 52.8% patients had tumors located in the proximal third of the stomach, including AEG type II and III. The International Union Against Cancer R0 resection rate was 81.9% after neoadjuvant chemotherapy as compared with 66.7% with surgery alone (P = .036). The surgery-only group had more lymph node metastases than the neoadjuvant group (76.5% v 61.4%; P = .018). Postoperative complications were more frequent in the neoadjuvant arm (27.1% v 16.2%; P = .09). After a median follow-up of 4.4 years and 67 deaths, a survival benefit could not be shown (hazard ratio, 0.84; 95% CI, 0.52 to 1.35; P = .466).ConclusionThis trial showed a significantly increased R0 resection rate but failed to demonstrate a survival benefit. Possible explanations are low statistical power, a high rate of proximal gastric cancer including AEG and/or a better outcome than expected after radical surgery alone due to the high quality of surgery with resections of regional lymph nodes outside the perigastic area (celiac trunc, hepatic ligament, lymph node at a. lienalis; D2).

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