Caroline Gronnier

Oesophagogastric junction adenocarcinoma: which therapeutic approach?

Gastric and oesophageal cancers are among the leading causes of cancer-related death worldwide. By contrast with the decreasing prevalence of gastric cancer, incidence and prevalence of oesophagogastric junction adenocarcinoma (OGJA) are rising rapidly in developed countries. We provide an update about treatment strategies for resectable OGJA. Here we review findings from the latest randomised trials and meta-analyses, and propose guidelines regarding endoscopic, surgical, and perioperative treatments. Through a team approach, members from all diagnostic and therapeutic disciplines, such as gastroenterologists, surgeons, oncologists, radiologists, and radiotherapists, can effectively administer a range of treatment modalities.

Salvage Surgery After Chemoradiotherapy in the Management of Esophageal Cancer: Is It a Viable Therapeutic Option?

PURPOSE The aim of this large multicenter study was to assess the impact of salvage esophagectomy after definitive chemoradiotherapy (SALV) on clinical outcome. PATIENTS AND METHODS Data from consecutive adult patients undergoing resection for esophageal cancer in 30 European centers from 2000 to 2010 were collected. First, groups undergoing SALV (n = 308) and neoadjuvant chemoradiotherapy followed by planned esophagectomy (NCRS; n = 540) were compared. Second, patients who benefited from SALV for persistent (n = 234) versus recurrent disease (n = 74) were compared. Propensity score matching and multivariable analyses were used to compensate for differences in some baseline characteristics. RESULTS SALV versus NCRS groups: In-hospital mortality was similar in both groups (8.4% v 9.3%). The only significant differences in complications were seen for anastomotic leak (17.2% v 10.7%; P = .007) and surgical site infection, which were both more frequent in the SALV group. At 3 years, groups had similar overall (43.3% v 40.1%; P = .542) and disease-free survival (39.2% v 32.8%; P = .232) after matching, along with a similar recurrence pattern. Persistent versus recurrent disease groups: There were no significant differences between groups in incidence of in-hospital mortality or major complications. At 3 years, overall (40.9% v 56.2%; P = .046) and disease-free survival (36.6% v 51.6%; P = .095) were lower in the persistent disease group. CONCLUSION The results of this large multicenter study from the modern era suggest that SALV can offer acceptable short- and long-term outcomes in selected patients at experienced centers. Persistent cancer after definitive chemoradiotherapy seems to be more biologically aggressive, with poorer survival compared with recurrent cancer.

The impact of severe anastomotic leak on long-term survival and cancer recurrence after surgical resection for esophageal malignancy

Objective: The aim of this study was to the determine impact of severe esophageal anastomotic leak (SEAL) upon long-term survival and locoregional cancer recurrence. Background: The impact of SEAL upon long-term survival after esophageal resection remains inconclusive with a number of studies demonstrating conflicting results. Methods: A multicenter database for the surgical treatment of esophageal cancer collected data from 30 university hospitals (2000–2010). SEAL was defined as a Clavien-Dindo III or IV leak. Patients with SEAL were compared with those without in terms of demographics, tumor characteristics, surgical technique, morbidity, survival, and recurrence. Results: From a database of 2944 operated on for esophageal cancer between 2000 and 2010, 209 patients who died within 90 days of surgery and 296 patients with a R1/R2 resection were excluded, leaving 2439 included in the final analysis; 208 (8.5%) developed a SEAL and significant independent association was observed with low hospital procedural volume, cervical anastomosis, tumoral stage III/IV, and pulmonary and cardiovascular complications. SEAL was associated with a significant reduction in median overall (35.8 vs 54.8 months; P = 0.002) and disease-free (34 vs 47.9 months; P = 0.005) survivals. After adjustment of confounding factors, SEAL was associated with a 28% greater likelihood of death [hazard ratio = 1.28; 95% confidence interval (CI): 1.04–1.59; P = 0.022], as well as greater overall (OR = 1.35; 95% CI: 1.15–1.73; P = 0.011), locoregional (OR = 1.56; 95% CI: 1.05–2.24; P = 0.030), and mixed (OR = 1.81; 95% CI: 1.20–2.71; P = 0.014) recurrences. Conclusions: This large multicenter study provides strong evidence that SEAL adversely impacts cancer prognosis. The mechanism through which SEAL increases local recurrence is an important area for future research.

Impact of neoadjuvant chemoradiotherapy on postoperative outcomes after esophageal cancer resection: results of a European multicenter study.

Objectives:To assess the impact of neoadjuvant chemoradiotherapy (NCRT) on anastomotic leakage (AL) and other postoperative outcomes after esophageal cancer (EC) resection. Background:Conflicting data have emerged from randomized studies regarding the impact of NCRT on AL. Methods:Among 2944 consecutive patients operated on for EC between 2000 and 2010 in 30 European centers, patients treated by NCRT after surgery (n = 593) were compared with those treated by primary surgery (n = 1487). Multivariable analyses and propensity score matching were used to compensate for the differences in some baseline characteristics. Results:Patients in the NCRT group were younger, with a higher prevalence of male sex, malnutrition, advanced tumor stage, squamous cell carcinoma, and surgery after 2005 when compared with the primary surgery group. Postoperative AL rates were 8.8% versus 10.6% (P = 0.220), and 90-day postoperative mortality and morbidity rates were 9.3% versus 7.2% (P = 0.110) and 33.4% versus 32.1% (P = 0.564), respectively. Pulmonary complication rates did not differ between groups (24.6% vs 22.5%; P = 0.291), whereas chylothorax (2.5% vs 1.2%; P = 0.020), cardiovascular complications (8.6% vs 0.1%; P = 0.037), and thromboembolic events (8.6% vs 6.0%; P = 0.037) were higher in the NCRT group. After propensity score matching, AL rates were 8.8% versus 11.3% (P = 0.228), with more chylothorax (2.5% vs 0.7%; P = 0.030) and trend toward more cardiovascular and thromboembolic events in the NCRT group (P = 0.069). Predictors of AL were high American Society of Anesthesiologists scores, supracarinal tumoral location, and cervical anastomosis, but not NCRT. Conclusions:Neoadjuvant chemoradiotherapy does not have an impact on the AL rate after EC resection (NCT 01927016).

Does Timing of Surgical Procedure After Neoadjuvant Chemoradiation Affect Outcomes in Esophageal Cancer

BACKGROUND To date, for esophageal cancer (EC), the optimal timing of surgical procedures after neoadjuvant chemoradiation (nCRT) is not well defined. Data in rectal cancer suggest that a prolonged interval between treatment and operation may improve tumoral pathologic response, R0 resection rate, and survival. The aims of this study were to evaluate whether delaying operation after nCRT in EC increases pathologic response and has an impact on oncologic outcome or postoperative course. METHODS A total of 257 consecutive EC patients (n=161 squamous cell carcinomas and n=96 adenocarcinomas) undergoing nCRT followed by operation between 1997 and 2011 were retrospectively analyzed by the use of prospectively collected data. The patients were divided into two groups according to the median delay between nCRT and operation (<7 weeks, n=122; ≥7 weeks, n=135). The impact of surgical delay on outcomes was studied through univariable and multivariable analyses. RESULTS The groups were comparable regarding patient and tumor characteristics (p≥0.074). The ypT0 and R0 resection rates were similar between the two groups, as were postoperative course, median survivals, and incidence and patterns of recurrence (p≥0.332). Multivariable analysis failed to identify any impact of the surgical delay on the endpoints. Subgroup analysis according to the histologic type found similar results. CONCLUSIONS After nCRT for EC, delaying operation does not affect the ypT0 rate, postoperative course, or oncologic outcome and cannot therefore be justified by these aims.

The Impact of Preoperative Radiochemotherapy on Survival in Advanced Esophagogastric Junction Signet Ring Cell Adenocarcinoma

BACKGROUND Signet ring cell (SRC) tumors have a worse prognosis when compared with non-SRC tumors, and neoadjuvant chemotherapy has been suggested to be an ineffective treatment strategy. Preoperative radiochemotherapy, of already proven efficacy for esophagogastric junction adenocarcinomas (EGJA), could be an alternative neoadjuvant strategy for SRC EGJA. The aim of this retrospective study was to evaluate the survival impact of preoperative radiochemotherapy on patients with advanced resectable SRC EGJA. METHODS Of 3,010 patients registered in 21 French centers between January 1997 and January 2010, 2,670 underwent surgical resection, of whom 97 patients had a stage III SRC EGJA treated by either neoadjuvant radiochemotherapy followed by surgery (group RCT, n = 23) or primary surgery (group S, n = 74). RESULTS Groups were comparable by age, sex, American Society of Anesthesiologists score, malnutrition, and cTNM stage. There was evidence of significant tumoral (p = 0.003), nodal (p < 0.001), and pTNM (p < 0.001) downstaging after radiochemotherapy. In group RCT and group S, 3-year overall survival was 51% and 21% (p = 0.002), respectively, with disease recurrence rate of 30.4% versus 59.5% (p = 0.015), respectively. In multivariate analysis the sole independent favorable prognostic factor identified was the administration of neoadjuvant radiochemotherapy (hazard ratio 0.41, p = 0.020). CONCLUSIONS In the setting of locally advanced SRC EGJA, neoadjuvant radiochemotherapy is responsible for tumoral downstaging, reduced disease recurrence, and improved patient survival. A strategy of preoperative radiochemotherapy should be implemented in clinical practice to treat advanced SRC EGJA.

The MUC1 mucin regulates the tumorigenic properties of human esophageal adenocarcinomatous cells

MUC1 is a membrane-bound mucin known to participate in tumor proliferation. It has been shown that MUC1 pattern of expression is modified during esophageal carcinogenesis, with a progressive increase from metaplasia to adenocarcinoma. The principal cause of development of esophageal adenocarcinoma is gastro-esophageal reflux and MUC1 was previously shown to be up-regulated by several bile acids present in reflux. In this report, our aim was thus to determine whether MUC1 plays a role in biological properties of human esophageal cancer cells. For that, a stable MUC1-deficient esophageal cancer cell line was established using a shRNA approach. In vitro (proliferation, migration and invasion) and in vivo (tumor growth following subcutaneous xenografts in SCID mice) biological properties of MUC1-deficient cells were analyzed. Our results show that esophageal cancer cells lacking MUC1 were less proliferative and had decreased migration and invasion properties. These alterations were accompanied by a decreased activity of NFKB p65, Akt and MAPK (p44/42, JNK and p38) pathways. MCM6 and TSG101 tumor-associated markers were also decreased. Subcutaneous xenografts showed a significant decrease in tumor size when cells did not express MUC1. Altogether, the data indicate that MUC1 plays a key role in proliferative, migrating and invasive properties of esophageal cancer cells as well as in tumor growth promotion. MUC1 mucin appears thus as a good therapeutic target to slow down esophageal tumor progression.

Operatively induced chronic reflux in rats: A suitable model for studying esophageal carcinogenesis?

BACKGROUND The mechanisms of esophageal reflux leading to esophageal adenocarcinoma (EA) remain poorly understood. This study appraises critically an operatively induced chronic reflux rat model. METHODS We randomized 108 Sprague-Dawley rats into 2 experimental groups; one was performing esophagoduodenal (ED) anastomosis with or without gastrectomy to induce duodeno-esophageal reflux (DER group; n = 63), and the other involved duodeno-gastro-esophageal reflux (DGER group; n = 45). Control groups included (i) Roux-en-Y esophagojejunal anastomosis, (ii) laparotomy alone, (iii) subtotal gastrectomy to induce duodenogastric reflux (DGR group), and (iv) the same procedure as in the DGER group plus proton pump inhibition (PPI group). The esophagus underwent histologic and molecular analyses. RESULTS The prevalence of Barretts esophagus (BE), dysplasia, and EA in the experimental groups was 41%, 7%, and 11%, respectively. Histologic and molecular analyses in groups DER, DGER, and DGR suggested that BE occurred through de novo intestinal metaplasia and proximal migration of duodenal cells. No distant metastases were identified. The molecular characteristics of both BE and EA were similar to humans. BE was more common, and dysplasia and EA less frequent in the DER group when compared with the DGER group (44% vs 24% [P = .038] and 7% vs 25% [P = .012], respectively). Compared with the DGER group, carcinogenic sequence occurred less frequently in the PPI-treated group (P = .019). CONCLUSION Despite pathophysiologic differences with humans, the rat model of esophagoduodenostomy reproduces accurately histologic and molecular lesions in the carcinogenetic sequence of BE and allowed us to identify novel, tumor-associated proteins that may be potential biomarkers and new therapeutic targets in EA.

Multicentre study of neoadjuvant chemotherapy for stage I and II oesophageal cancer

The benefit of neoadjuvant chemotherapy (NCT) for early‐stage oesophageal cancer is unknown. The aim of this study was to assess whether NCT improves the outcome of patients with stage I or II disease.

Esophageal Adenocarcinoma: Impact of a Large Hiatal Hernia on Outcomes After Surgery.

Objective: To evaluate complete tumor resection rate (primary objective), 30-day postoperative outcomes, and survival (secondary objectives) in patients with a hiatal hernia (HH) ≥5 cm (HH group) compared with those who did not have a HH or presented with a HH <5 cm (control group). Background: HH is a risk factor for esophageal and junctional adenocarcinoma (EGJA). Its impact on the outcomes after EGJA surgery is unknown. Methods: Among 367 patients who underwent surgery for EGJA, a HH was searched for on computerized tomography scan and barium swallow, with comparison between the HH (n = 42) and control (n = 325) groups. Results: In the HH group, EGJAs exhibited higher rates of incomplete resection (50.0% vs 4.0%; P < 0.001), of pN3 stages (28.5% vs 10.1%; P = 0.002), and lower median survival (20.9 vs 41.0 mos; P = 0.001). After adjustment, a HH ≥5 cm was a predictor of incomplete resection (odds ratio 21.0, 95% confidence interval 9.4–46.8, P < 0.001) and a poor prognostic factor (hazard ratio 1.6, 95% confidence interval 1.1–2.5, P = 0.025). In the HH group, 30-day mortality was significantly higher in patients who received neoadjuvant radiotherapy (20.0% vs 0%; P = 0.040), which was related to greater cardiac and pulmonary toxicity. Conclusions: For the first time, we showed that a HH ≥5 cm is associated with a poor prognosis in patients who had surgery for EGJA, linked to greater incomplete resection and lymph node involvement. Neoadjuvant radiotherapy was associated with a significant toxicity in patients with a HH ≥5 cm.