Phase II/III multicentre randomised controlled trial evaluating a strategy of primary surgery and adjuvant chemotherapy versus peri-operative chemotherapy for resectable gastric signet ring cell adenocarcinomas – PRODIGE 19 – FFCD1103 – ADCI002

Abstract

BackgroundA dramatic increase in the incidence of the diffuse form of gastric adenocarcinomas and particularly signet ring cell carcinomas has been observed in Western countries. Evidence is accruing that signet ring cell carcinomas may have inherent chemo resistance leaving many clinicians unsure of the benefits of delaying surgery to pursue a neoadjuvant approach.Methods/designPRODIGE-19-FFCD1103-ADCI002 is a prospective multicentre controlled randomised phase II/III trial comparing current standard of care of perioperative chemotherapy (2x3 cycles of Epirubicin, cisplatin, 5-fluorouracil) with a strategy of primary surgery followed by adjuvant chemotherapy (6 cycles of Epirubicin, cisplatin, 5-fluorouracil) in patients with a stage IB-III gastric signet ring cell tumour. The principal objective of the phase II study (84 patients) is to determine if the experimental arm (primary surgery followed by adjuvant chemotherapy) has sufficient interest in terms of percentage of living patients at 24 months to be evaluated in a phase III trial. If 7 or less patients in the experimental arm are alive at 24 months, phase III will not be initiated. The primary objective of phase III (230 additional patients) is to demonstrate superiority of the experimental arm in terms of overall survival. Secondary endpoints include overall survival at 36 months, disease free survival at 24 and 36 months, R0 resection rates, treatment tolerance, postoperative mortality and morbidity evaluated by Clavien-Dindo severity index, the prognostic impact of positive peritoneal cytology and the assessment of quality of life. An ancillary study will assess the emotional and cognitive impact of surgery and perioperative chemotherapy for both the patient and their partner.DiscussionAs inherent chemo resistance of signet ring cell tumours and delay in definitive surgery may favour tumour progression we hypothesise that a policy of primary surgery followed by adjuvant chemotherapy will improve overall survival compared to a standard perioperative chemotherapeutic strategy. This randomised phase II/III trial is the first dedicated to this histological subtype. Whilst the development of new biomarkers and targeted therapies are awaited, the results of this trial should further help in devising individualised protocols of patient care in a tumour group whose diversity increasingly demands assessment of alternative strategies.Trial registrationClinicalTrials.gov, NCT01717924

Tumor response evaluation after neoadjuvant chemotherapy in locally advanced gastric adenocarcinoma: a prospective, multi-center cohort study

“…Our experience indicates no difference in terms of DFS and OS between diffuse and intestinal carcinoma and both Lauren types present comparable results in terms of TRG and clinical response ( Table 4). An ongoing phase II/III controlled randomized trial (22), in which perioperative treatment is compared to a strategy of primary surgery followed by adjuvant chemotherapy for locally advanced signet ring cell carcinoma, will probably provide more evidences for a different approach for this type of tumor in the next years. Today perioperative chemotherapy remains the standard of care.…”

Is signet-ring cell carcinoma a specific entity among gastric cancers?

“…Moreover, important prognostic factors identified in our more recent analysis, such as age, involvement of adjacent organs, extent of lymphadenectomy, and T, N, and M components of the TNM classification, were not included in the multivariate analysis performed in the first study. To better investigate the chemosensitivity of SRC carcinoma, an ongoing prospective randomized multicentric trial has been launched by our FREGAT group (NCT01717924) [57].…”

International comparison of the German evidence-based S3-guidelines on the diagnosis and multimodal treatment of early and locally advanced gastric cancer, including adenocarcinoma of the lower esophagus

“…Additionally, a comparative French multicenter study suggested a worse outcome for patients with a signet ring cell type of gastric carcinoma after perioperative chemotherapy versus surgery [60]. Therefore, the Prodice-FFCD group started a randomized controlled trial of perioperative versus adjuvant therapy in these subtype patients [61]. In esophageal cancer, a more detailed analysis of postoperative mortality of preoperative RCT showed increased mortality after RCT and resection only for patients with squamous cell carcinoma [62,63], whereas studies that predominantly included patients with adenocarcinoma had no increase or reduction in mortality [46][47][48]55].…”