Signet Ring Cells and Efficacy of First-Line Chemotherapy in Advanced Gastric Or Oesogastric Junction Adenocarcinoma
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ANTICANCER RESEARCH 36 : 5543-5550 (2016) doi:10.21873/anticanres.11138 Signet Ring Cells and Efficacy of First-line Chemotherapy in Advanced Gastric or Oesogastric Junction Adenocarcinoma NATHALIE LEMOINE 1, ANTOINE ADENIS 2, OLIVIER BOUCHE 3, ALAIN DUHAMEL 4, ALEXANDRA HEURGUE 3, EMMANUELLE LETEURTRE 5, ERIC AMELA 2, JULIA SALLERON 4 and MOHAMED HEBBAR 1 1Department of Medical Oncology, University Hospital, Lille, France; 2Department of Digestive Oncology, Oscar Lambret Centre, Lille, France; 3Department of Digestive Oncology, University Hospital, Reims, France; 4Department of Biostatistics, EA2694, University Lille Nord de France, University Hospital, Lille, France; 5Department of Pathology, University Lille Nord de France, University Hospital, Lille, France Abstract. Aim: To evaluate the efficacy of first-line or metastatic disease at diagnostics (4). About 90% of gastric palliative chemotherapy, regarding the presence of signet tumours are adenocarcinomas that are divided into two types ring cells (SRC). Patients and Methods: Retrospective according to Lauren’s classification (5): intestinal and diffuse analysis of consecutive patients with locally advanced or types, with the latter including signet ring cell (SRC) metastatic gastric or oesogastric junction adenocarcinoma adenocarcinoma. SRC is a histological term used to describe who received first-line chemotherapy. Response to a form of mucin-secreting adenocarcinoma whose isolated chemotherapy, progression-free survival (PFS) and overall cells contain abundant cytoplasmic mucin, pushing the nucleus survival (OS) were compared between SRC and non-SRC to one side. The World Health Organization (WHO) (NSRC) groups. Results: Two hundred and three patients classification defines SRC when these mucin-rich isolated were treated, with 57 (28%) having SRC adenocarcinoma. cells represent more than 50% of the tumour cells (6). Objective response rate was significantly lower in SRC The incidence of SRC adenocarcinoma is increasing for patients (5.3% vs. 28.1%, p=0.0004). PFS was not thirty years in Western countries, conversely to the intestinal significantly different between SRC and NSRC patients type (7-10). The specific prognosis of SRC adenocarcinoma (median=3.8 vs. 4.9 months, p=0.07). OS was significantly remains controversial. Several non-comparative retrospective shorter in SRC patients (median=5.6 vs. 9.4 months, studies indicated a better prognosis in case of SRC (11-13). p<0.008). In multivariate analysis SRC was not an Other retrospective studies indicated a poor prognosis of independent prognostic factor for OS (hazard ratio SRC in all (14) or only in advanced stages (15, 16). Some (HR)=1.28, p=0.15). Conclusion: Patients with advanced studies indicated that presence of SRC was not an SRC adenocarcinomas seemed to benefit less from independent prognostic factor (17, 18). chemotherapy, whereas the presence of SRC was not an It is commonly considered that SRC adenocarcinoma is independent survival prognostic factor. less sensitive to chemotherapy, by comparison to intestinal gastric adenocarcinoma. In a recent study performed in Despite an important decrease of its incidence and mortality, patients with localized gastric adenocarcinoma, preoperative gastric cancer remains the fourth most common cancer and the chemotherapy was associated with a worse prognosis in second leading cause of cancer-related deaths worldwide (1- patients with SRC (19). We here present the results of a 3). Approximately two thirds of patients have locally advanced retrospective study assessing the efficacy of chemotherapy in advanced stages. We compared results of chemotherapy in patients with locally advanced or metastatic gastric adenocarcinoma, regarding the presence or not of SRC. Correspondence to: Professor Mohamed Hebbar, MD, PhD, Service d’Oncologie Médicale, Centre Hospitalo-Universitaire, 1 rue Michel Polonovski, 59 037 Lille, France. Tel +33 320445461, Fax +33 Patients and Methods 320445023, e-mail: mohamed.hebbar@chru-lille.fr Patients. The eligibility criteria included histologically documented Key Words: Signet ring cells, gastric adenocarcinoma, oesogastric adenocarcinoma of the stomach or the oesogastric junction; junction adenocarcinoma, prognosis. metastatic or locally advanced non resectable disease; and a WHO 0250-7005/2016 $2.00+.40 5543 ANTICANCER RESEARCH 36 : 5543-5550 (2016) performance status ≤2. Patients have been included in three centres level. In this regression model, tumour differentiation was not in Northern France. The Ethics committee of the University analyzed due to missing data and the SRC status was included in Hospital of Lille, France, has been informed of the realization of every model. Hazard ratios (HRs) and their 95% confidence this non-interventional study. intervals (CIs) were computed. Statistical analysis was performed The criteria of the WHO classification for histologic typing of by means of SAS 9.3 software (SAS Institute Inc., Cary, NC, USA). gastric tumours were used: SRC adenocarcinoma was defined as “an All tests were two-sided and statistical significance was defined as adenocarcinoma in which a predominant component (more than a p-value ≤0.05. 50% of the tumour cells) is represented by isolated or small groups of malignant cells containing intracytoplasmic mucin”(6). Tumours Results with minority SRC (less than 50% of the tumour) were not considered as SRC adenocarcinoma. Patients’ characteristics. Between January 2003 and June After informed consent, all patients received first-line 2011, 203 patients were included in this study. Among them, chemotherapy. Chemotherapy regimens included EOX (epirubicin, oxaliplatin and capecitabine), ECX (epirubicin, cisplatin and 27 (13%) had locally advanced disease and 176 (87%) capecitabine), ECF (epirubicin, cisplatin and 5-fluorouracile metastatic disease. Eighty-eight patients (43.4%) had (5-FU)), FOLFIRI (5-FU, leucovorin and irinotecan), FOLFOX oesogastric tumour and 115 patients (56.6%) gastric tumour. (5-FU, leucovorin and oxaliplatin), 5-FU-cisplatin, docetaxel and Among the 203 patients, 57 patients (28%) had a histological 5-FU alone. Tumour evaluations were performed by computed diagnosis of SRC adenocarcinoma. tomography (CT) scan every three cycles (EOX, ECX, ECC, The clinicopathologic features of the 57 patients with SRC cisplatin-5-FU regimens) or every 4 cycles (FOLFIRI, FOLFOX gastric cancer and of the 146 patients with non-signet ring regimens). Tumour responses were graded according to the RECIST criteria (20). Chemotherapy was carried on until disease cell (NSRC) adenocarcinoma are presented in Table I. The progression, limitative toxicity or patient’s refusal. After cessation SRC patients were significantly younger (mean age=53 vs. of first-line chemotherapy, subsequent chemotherapy lines were 61 years; p< 0.001). The proportion of females in the SRC allowed. All patients were seen at least every two months for group was higher (46% vs. 14%; p< 0.001). SRC tumours clinical and CT scan evaluations thereafter. Follow-up of the study were more frequently located in the lower third of the was conducted until death or until the cut-off date of October 30, stomach than NSRC tumours (37% vs. 22%; p= 0.03). 2011. Diffuse location was more frequent in the SRC group (14% vs. 1%; p< 0.001). The peritoneal carcinosis was significantly Study end-points. The primary end-point was overall survival (OS). vs. Secondary end-points were progression-free survival (PFS), more common in SRC adenocarcinomas (68.4% 30.8%; objective response rate (ORR) according to RECIST criteria and p< 0.001). SRC tumours were more frequently poorly safety according to the National Cancer Institute-common toxicity differentiated (89% vs. 36%; p< 0.001). Significantly, more criteria (NCI-CTC) (21). patients in the SRC group previously underwent curative We assessed the potent prognostic value of the presence of SRC surgery (54% vs. 36%; p= 0.02). and the following baseline clinicopathological features: age, gender, There were no significant differences between SRC and performance status, primary tumour location, prior gastrectomy, NSRC adenocarcinoma regarding the tumour stage at prior perioperative or adjuvant chemotherapy and/or adjuvant radiotherapy, tumour differentiation, tumour stage at diagnosis and diagnosis and at the beginning of the palliative at the beginning of palliative chemotherapy (locally advanced or chemotherapy, regarding (i) the performance status and the metastatic), number of disease sites, presence of peritoneal number of metastatic sites at the beginning of the carcinosis, type of chemotherapy (with our without platinum palliative chemotherapy, (ii) previous perioperative or compound). adjuvant chemotherapy and/or radiotherapy, (iii) the proportion of patients who had received chemotherapy Statistical analyses. The results were expressed by means and with platinum and (iv) the proportion of patients who were standard deviations (SD) for continuous variables and by dead at the cut-off date. In SRC adenocarcinoma, the first- frequencies and percentages for categorical variables. The two line chemotherapy regimens were FOLFIRI (26%), ECC groups defined by the presence or the absence of SRC were compared by using the unpaired Student’s t-test for continuous (14%), EOX (14%), 5-FU-cisplatin (11%), ECF (9%), variables and by the Chi-square test or Fisher’s exact test for FOLFOX (7%), docetaxel (3%) and others (16%). In categorical variables. OS was calculated from the beginning of NSRC group,