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Effect of Neoadjuvant Chemotherapy Followed by Surgical Resection on Survival in Patients With Limited Metastatic Gastric or Gastroesophageal Junction Cancer: The AIO-FLOT3 Trial.

ABSTRACT: Surgical resection has a potential benefit for patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction.To evaluate outcome in patients with limited metastatic disease who receive chemotherapy first and proceed to surgical resection.The AIO-FLOT3 (Arbeitsgemeinschaft Internistische Onkologie-fluorouracil, leucovorin, oxaliplatin, and docetaxel) trial is a prospective, phase 2 trial of 252 patients with resectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Patients were enrolled from 52 cancer care centers in Germany between February 1, 2009, and January 31, 2010, and stratified to 1 of 3 groups: resectable (arm A), limited metastatic (arm B), or extensive metastatic (arm C). Data cutoff was January 2012, and the analysis was performed in March 2013.Patients in arm A received 4 preoperative cycles of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) followed by surgery and 4 postoperative cycles. Patients in arm B received at least 4 cycles of neoadjuvant FLOT and proceeded to surgical resection if restaging (using computed tomography and magnetic resonance imaging) showed a chance of margin-free (R0) resection of the primary tumor and at least a macroscopic complete resection of the metastatic lesions. Patients in arm C were offered FLOT chemotherapy and surgery only if required for palliation. Patients received a median (range) of 8 (1-15) cycles of FLOT.The primary end point was overall survival.In total, 238 of 252 patients (94.4%) were eligible to participate. The median (range) age of participants was 66 (36-79) years in arm A (n?=?51), 63 (28-79) years in arm B (n?=?60), and 65 (23-83) years in arm C (n?=?127). Patients in arm B (n = 60) had only retroperitoneal lymph node involvement (27 patients [45%]), liver involvement (11 [18.3%]), lung involvement (10 [16.7%]), localized peritoneal involvement (4 [6.7%]), or other (8 [13.3%]) incurable sites. Median overall survival was 22.9 months (95% CI, 16.5 to upper level not achieved) for arm B, compared with 10.7 months (95% CI, 9.1-12.8) for arm C (hazard ratio, 0.37; 95% CI, 0.25-0.55) (P?

SUBMITTER: Al-Batran SE

PROVIDER: S-EPMC5824287 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Effect of Neoadjuvant Chemotherapy Followed by Surgical Resection on Survival in Patients With Limited Metastatic Gastric or Gastroesophageal Junction Cancer: The AIO-FLOT3 Trial.

Al-Batran Salah-Eddin SE Homann Nils N Pauligk Claudia C Illerhaus Gerald G Martens Uwe M UM Stoehlmacher Jan J Schmalenberg Harald H Luley Kim B KB Prasnikar Nicole N Egger Matthias M Probst Stephan S Messmann Helmut H Moehler Markus M Fischbach Wolfgang W Hartmann Jörg T JT Mayer Frank F Höffkes Heinz-Gert HG Koenigsmann Michael M Arnold Dirk D Kraus Thomas W TW Grimm Kersten K Berkhoff Stefan S Post Stefan S Jäger Elke E Bechstein Wolf W Ronellenfitsch Ulrich U Mönig Stefan S Hofheinz Ralf D RD

JAMA oncology 20170901 9

<h4>Importance</h4>Surgical resection has a potential benefit for patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction.<h4>Objective</h4>To evaluate outcome in patients with limited metastatic disease who receive chemotherapy first and proceed to surgical resection.<h4>Design, setting, and participants</h4>The AIO-FLOT3 (Arbeitsgemeinschaft Internistische Onkologie-fluorouracil, leucovorin, oxaliplatin, and docetaxel) trial is a prospective, phase 2 trial of 252 p ...[more]

PMID: 28448662

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Project description:Gastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements, most patients die of their disease. Although immune checkpoint blockade became part of the standard-of-care for patients with metastatic G/GEJ cancers, its efficacy and impact on the tumor microenvironment (TME) in early disease remain largely unknown. We hypothesized higher efficacy of neoadjuvant immunotherapy plus chemotherapy in patients with nonmetastatic G/GEJ cancer. In the phase 2 PANDA trial, patients with previously untreated resectable G/GEJ tumors (n = 21) received neoadjuvant treatment with one cycle of atezolizumab monotherapy followed by four cycles of atezolizumab plus docetaxel, oxaliplatin and capecitabine. Treatment was well tolerated. There were grade 3 immune-related adverse events in two of 20 patients (10%) but no grade 4 or 5 immune-related adverse events, and all patients underwent resection without treatment-related delays, meeting the primary endpoint of safety and feasibility. Tissue was obtained at multiple time points, allowing analysis of the effects of single-agent anti-programmed cell death ligand 1 (PD-L1) and the subsequent combination with chemotherapy on the TME. Twenty of 21 patients underwent surgery and were evaluable for secondary pathologic response and survival endpoints, and 19 were evaluable for exploratory translational analyses. A major pathologic response (≤10% residual viable tumor) was observed in 14 of 20 (70%, 95% confidence interval 46-88%) patients, including 9 (45%, 95% confidence interval 23-68%) pathologic complete responses. At a median follow-up of 47 months, 13 of 14 responders were alive and disease-free, and five of six nonresponders had died as a result of recurrence. Notably, baseline anti-programmed cell death protein 1 (PD-1)+CD8+ T cell infiltration was significantly higher in responders versus nonresponders, and comparison of TME alterations following anti-PD-L1 monotherapy versus the subsequent combination with chemotherapy showed an increased immune activation on single-agent PD-1/L1 axis blockade. On the basis of these data, monotherapy anti-PD-L1 before its combination with chemotherapy warrants further exploration and validation in a larger cohort of patients with nonmetastatic G/GEJ cancer. ClinicalTrials.gov registration: NCT03448835 .

Project description:BackgroundDespite obvious advances over the last decades, locally advanced adenocarcinomas of the gastroesophageal junction (GEJ) still carry a dismal prognosis with overall 5-year survival rates of less than 50% even when using modern optimized treatment protocols such as perioperative chemotherapy based on the FLOT regimen or radiochemotherapy. Therefore the question remains whether neoadjuvant chemotherapy or neoadjuvant radiochemotherapy is eliciting the best results in patients with GEJ cancer. Hence, an adequately powered multicentre trial comparing both therapeutic strategies is clearly warranted.MethodsThe RACE trial is a an investigator initiated multicenter, prospective, randomized, stratified phase III clinical trial and seeks to investigate the role of preoperative induction chemotherapy (2 cycles of FLOT: 5-FU, leucovorin, oxaliplatin, docetaxel) with subsequent preoperative radiochemotherapy (oxaliplatin weekly, 5-FU plus concurrent fractioned radiotherapy to a dose of 45 Gy) compared to preoperative chemotherapy alone (4 cycles of FLOT), both followed by resection and postoperative completion of chemotherapy (4 cycles of FLOT), in the treatment of locally advanced, potentially resectable adenocarcinoma of the gastroesophageal junction. Patients with cT3-4, any N, M0 or cT2 N+, M0 adenocarcinoma of the GEJ are eligible for inclusion. The RACE trial aims to enrol 340 patients to be allocated to both treatment arms in a 1:1 ratio stratified by tumour site. The primary endpoint of the trial is progression-free survival assessed with follow-up of maximum 60 months. Secondary endpoints include overall survival, R0 resection rate, number of harvested lymph nodes, site of tumour relapse, perioperative morbidity and mortality, safety and toxicity and quality of life.DiscussionThe RACE trial compares induction chemotherapy with FLOT followed by preoperative oxaliplatin and 5-Fluorouracil-based chemoradiation versus preoperative chemotherapy with FLOT alone, both followed by surgery and postoperative completion of FLOT chemotherapy in the treatment of locally advanced, non-metastatic adenocarcinoma of the GEJ. The trial aims to show superiority of the combined chemotherapy/radiochemotherapy treatment, assessed by progression-free survival, over perioperative chemotherapy alone.Trial registrationClinicalTrials.gov ; NCT04375605 ; Registered 4th May 2020.

Project description:BACKGROUND:The benefit of neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy for treating cancer of the esophagus or the gastroesophageal junction remains controversial. In the present study, we conducted a comprehensive meta-analysis to examine the efficacy of these two management strategies. METHODS:The MEDLINE (PubMed), SinoMed, Embase, and Cochrane Library databases were searched for eligible studies. We searched for the most relevant studies published until the end of September 2017. Data were extracted independently and were analyzed using RevMan statistical software version 5.3 (Cochrane Collaboration, http://tech.cochrane.org/revman/download). Weighted mean differences, risk ratios (RRs), and 95% confidence intervals (CIs) were calculated. Cochrane Collaboration's risk of bias tool was used to assess the risk of bias. In this comprehensive meta-analysis, we examined the efficiency of neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy for the treatment of cancer of the esophagus or the gastroesophageal junction as reported in qualified clinical trials. RESULTS:Six qualified articles that included a total of 866 patients were identified. The meta-analysis showed that for 3-year and 5-year survival rates in primary outcomes, the results favored neoadjuvant chemoradiotherapy strategies compared with neoadjuvant chemotherapy (RR = 0.78, 95% CI = 0.62-0.98, P = 0.03; RR = 0.69, 95% CI = 0.50-0.96, P = 0.03, respectively). In terms of secondary outcomes, neoadjuvant chemoradiotherapy significantly increased the rate of R0 resection and pathological complete response as well (RR = 0.87, 95% CI = 0.81-0.92, P < 0.0001; RR = 0.16, 95% CI = 0.09-0.28, P < 0.00001, respectively). However, there were no significant differences in postoperative mortality between the two groups (RR = 1.85, 95% CI = 0.93-3.65, P = 0.08). For the results of postoperative complications, revealed that there was a statistically significant difference between the two groups in the incidence of postoperative complications such as pulmonary, anastomotic leak and cardiovascular complications. The subgroup analysis of patients with esophageal adenocarcinoma or squamous cell carcinoma showed that both esophageal adenocarcinoma and squamous cell carcinoma patients achieved a high rate of R0 resection (RR = 0.85, 95% CI = 0.77-0.93, P = 0.0006; RR = 0.88, 95% CI = 0.81-0.96, P = 0.005, respectively) and pathological complete response benefit of neoadjuvant chemoradiotherapy (RR = 0.23, 95% CI = 0.09-0.57, P = 0.001; RR = 0.18, 95% CI = 0.03-0.96, P = 0.05, respectively). CONCLUSION:Our findings suggested that compared with neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy should be recommended with a significant long-term survival benefit in patients with cancer of the esophagus or the gastroesophageal junction. In view of the clinical heterogeneity, whether these conclusions are broadly applicable should be further determined.

Dataset Information

Effect of Neoadjuvant Chemotherapy Followed by Surgical Resection on Survival in Patients With Limited Metastatic Gastric or Gastroesophageal Junction Cancer: The AIO-FLOT3 Trial.

Publications

Effect of Neoadjuvant Chemotherapy Followed by Surgical Resection on Survival in Patients With Limited Metastatic Gastric or Gastroesophageal Junction Cancer: The AIO-FLOT3 Trial.

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