Christophe Mariette

Chemoradiation Followed by Surgery Compared With Chemoradiation Alone in Squamous Cancer of the Esophagus: FFCD 9102

PURPOSE Uncontrolled studies suggest that chemoradiation has similar efficacy as surgery for esophageal cancer. Therefore, a randomized trial was carried out to compare, in responders only, chemoradiation alone with chemoradiation followed by surgery in patients with locally advanced tumors. PATIENTS AND METHODS Eligible patients had operable T3N0-1M0 thoracic esophageal cancer. Patients received two cycles of fluorouracil (FU) and cisplatin (days 1 to 5 and 22 to 26) and either conventional (46 Gy in 4.5 weeks) or split-course (15 Gy, days 1 to 5 and 22 to 26) concomitant radiotherapy. Patients with response and no contraindication to either treatment were randomly assigned to surgery (arm A) or continuation of chemoradiation (arm B; three cycles of FU/cisplatin and either conventional [20 Gy] or split-course [15 Gy] radiotherapy). Chemoradiation was considered equivalent to surgery if the difference in 2-year survival rate was less than 10%. RESULTS Of 444 eligible patients, 259 were randomly assigned; 230 patients (88.8%) had epidermoid cancer, and 29 (11.2%) had glandular carcinoma. Two-year survival rate was 34% in arm A versus 40% in arm B (hazard ratio for arm B v arm A = 0.90; adjusted P = .44). Median survival time was 17.7 months in arm A compared with 19.3 months in arm B. Two-year local control rate was 66.4% in arm A compared with 57.0% in arm B, and stents were less required in the surgery arm (5% in arm A v 32% in arm B; P < .001). The 3-month mortality rate was 9.3% in arm A compared with 0.8% in arm B (P = .002). Cumulative hospital stay was 68 days in arm A compared with 52 days in arm B (P = .02). CONCLUSION Our data suggest that, in patients with locally advanced thoracic esophageal cancers, especially epidermoid, who respond to chemoradiation, there is no benefit for the addition of surgery after chemoradiation compared with the continuation of additional chemoradiation.

Therapeutic strategies in oesophageal carcinoma: role of surgery and other modalities

Traditionally, surgery is considered the best treatment for oesophageal cancer in terms of locoregional control and long-term survival. However, survival 5 years after surgery alone is about 25%, and, therefore, a multidisciplinary approach that includes surgery, radiotherapy, and chemotherapy, alone or in combination, could prove necessary. The role of each of these treatments in the management of oesophageal cancer is under intensive research to define optimum therapeutic strategies. In this report we provide an update on treatment strategies for resectable oesophageal cancers on the basis of recent published work. Results of the latest randomised trials allow us to propose the following guidelines: surgery is the standard treatment, to be used alone for stages I and IIa, or possibly with neoadjuvant chemotherapy or chemoradiotherapy for stage IIb disease. For locally advanced cancers (stage III), neoadjuvant chemotherapy or chemoradiotherapy followed by surgery is appropriate for adenocarcinomas. Chemoradiotherapy alone should only be considered in patients with squamous-cell carcinomas who show a morphological response to chemoradiotherapy, and produces a similar overall survival to chemoradiotherapy followed by surgery, but with less post-treatment morbidity. Although the addition of surgery to chemotherapy or chemoradiotherapy could result in improved local control and survival, surgery should be done in experienced hospitals where operative mortality and morbidity are low. Moreover, surgery should be kept in mind as salvage treatment in patients with no morphological response or persistent tumour after definitive chemoradiotherapy.

The number of metastatic lymph nodes and the ratio between metastatic and examined lymph nodes are independent prognostic factors in esophageal cancer regardless of neoadjuvant chemoradiation or lymphadenectomy extent.

Objective:To investigate whether the number of lymph nodes metastasis (LNMs) and the ratio between metastatic and examined lymph nodes (LNs) are better prognostic factors when compared with traditional staging systems in patients with esophageal carcinoma. Summary Background Data:The accuracy of the 6th UICC/TNM classification is suboptimal, especially when not taking into account neoadjuvant therapy and lymphadenectomy extent. Methods:For 536 patients who underwent curative en bloc esophagectomy, in whom 51.5% (n = 276) received neoadjuvant chemoradiation, LNMs were classified according to the 6th UICC/TNM classification and systems based on the number (≤4 and >4) or the ratio (≤0.2 and >0.2) of LNMs. Survival of the respective stages, predictors of survival, and influence of both chemoradiation and number of examined LNs were studied. Results:After a median follow-up of 50 months, the 5-year survival rates were 47% for the entire population, significantly poorer for patients with >4 LNMs (8% vs. 53%, P < 0.001) or a ratio of LNMs >0.2 (22% vs. 54%, P < 0.001). After adjustment for confounding variables, a number of LNMs >4 and a ratio of LNMs >0.2 were the only predictors of poor prognosis. The prognostic role of both the number and the ratio of LNMs was maintained whether patients received neoadjuvant chemoradiation or not. Moreover, LN ratio is shown to be more accurate for inadequately staged patients (<15 examined LNs), whereas the number of LNMs is pertinent for adequately staged patients (≥15 examined LNs). Conclusion:Staging systems for esophageal cancer that use the number (≤4 or >4) and the ratio (≤0.2 or >0.2) of LNMs have greater prognostic importance than the current staging systems because of the good stratification of the groups and their clinical utility, taking into account neoadjuvant therapy and lymphadenectomy extent.

Surgery Alone Versus Chemoradiotherapy Followed by Surgery for Stage I and II Esophageal Cancer: Final Analysis of Randomized Controlled Phase III Trial FFCD 9901

PURPOSE Although often investigated in locally advanced esophageal cancer (EC), the impact of neoadjuvant chemoradiotherapy (NCRT) in early stages is unknown. The aim of this multicenter randomized phase III trial was to assess whether NCRT improves outcomes for patients with stage I or II EC. METHODS The primary end point was overall survival. Secondary end points were disease-free survival, postoperative morbidity, in-hospital mortality, R0 resection rate, and prognostic factor identification. From June 2000 to June 2009, 195 patients in 30 centers were randomly assigned to surgery alone (group S; n = 97) or NCRT followed by surgery (group CRT; n = 98). CRT protocol was 45 Gy in 25 fractions over 5 weeks with two courses of concomitant chemotherapy composed of fluorouracil 800 mg/m(2) and cisplatin 75 mg/m(2). We report the long-term results of the final analysis, after a median follow-up of 93.6 months. RESULTS Pretreatment disease was stage I in 19.0%, IIA in 53.3%, and IIB in 27.7% of patients. For group CRT compared with group S, R0 resection rate was 93.8% versus 92.1% (P = .749), with 3-year overall survival rate of 47.5% versus 53.0% (hazard ratio [HR], 0.99; 95% CI, 0.69 to 1.40; P = .94) and postoperative mortality rate of 11.1% versus 3.4% (P = .049), respectively. Because interim analysis of the primary end point revealed an improbability of demonstrating the superiority of either treatment arm (HR, 1.09; 95% CI, 0.75 to 1.59; P = .66), the trial was stopped for anticipated futility. CONCLUSION Compared with surgery alone, NCRT with cisplatin plus fluorouracil does not improve R0 resection rate or survival but enhances postoperative mortality in patients with stage I or II EC.

Life-threatening postoperative pancreatic fistula (grade C) after pancreaticoduodenectomy: incidence, prognosis, and risk factors.

BACKGROUND Pancreatic fistula (PF) is one of the most common postoperative complications of pancreatoduodenectomy (PD). A recent International Study Group on Pancreatic Fistula (ISGPF) definition grades the severity of PF according to the clinical impact on the patients hospital course. Although PF is generally treated conservatively (grade A), some cases may require interventional procedures (grade B) or may be life-threatening and necessitate emergency reoperation (grade C). The aim of the present study was to evaluate the incidence of postoperative grade C PF after PD and to assess the prognosis and risk factors for this life-threatening condition. STUDY DESIGN Between January 2000 and December 2006, 680 consecutive patients underwent PD in 5 digestive surgery departments in the northwest region of France (Lille, Amiens, Rouen, and Caen). PF was defined as drain output of any measurable volume of fluid on or after postoperative day 3 with amylase content greater than 3 times the serum amylase activity (ISGPF guidelines). To identify possible risk factors for grade C PF, we reviewed the records of 111 (16.3%) patients with postoperative PF and compared grade C cases with grade A+B cases. RESULTS The median age was 59 years (range 22-87). The male-to-female ratio was 1.6:1. Fifty-six (50.4%) PDs were performed via pancreaticogastrostomy and 55 via pancreaticojejunostomy. Overall mortality was 2% (n = 14). Grade C PF was observed in 36 (32%) patients, of whom 17 (47%) had sepsis due to an abdominal collection, 16 (44%) had postoperative bleeding, 10 (27.7%) had bleeding associated with abdominal collection, and 3 (9%) had multi-organ failure due to other causes. Of these 36 patients, 35 (97%) underwent reoperation. The mortality rate in grade C PF patients was 38.8%. The major causes of death were sepsis (n = 6) and recurrent bleeding after reoperation (n = 5). Grade C PF increased the duration of postoperative hospitalization (46 vs 29 days, P < .001). Univariate analysis showed that peroperative soft pancreatic parenchyma, peroperative blood transfusion, and postoperative bleeding were significant risk factors for grade C PF, with P values of .011, .003, and .001, respectively. No risk factors for grade C PF were identified in a multivariate analysis. The sensibility, specificity, positive predictive value, and negative predictive value of the presence of the 3 risk factors for grade C PF were 13.89%, 100%, 100%, and 70.75%, respectively. CONCLUSION Sixteen percent of patients had PF after PD. Among them, 30% had grade C PF, with a mortality rate of about 40%. Achievement of a 100% predictive positive value for grade C PF after PD in individuals with 3 discriminant risk factors (peroperative soft pancreatic parenchyma, peroperative transfusion, and postoperative bleeding) is a first step towards the identification of high-risk patients who should be managed differently from other patients with PF during or after PD.

External pancreatic duct stent decreases pancreatic fistula rate after pancreaticoduodenectomy: prospective multicenter randomized trial.

Objective: Pancreatic fistula (PF) is a leading cause of morbidity and mortality after pancreaticoduodenectomy (PD). The aim of this multicenter prospective randomized trial was to compare the results of PD with an external drainage stent versus no stent. Methods: Between 2006 and 2009, 158 patients who underwent PD were randomized intraoperatively to either receive an external stent inserted across the anastomosis to drain the pancreatic duct (n = 77) or no stent (n = 81). The criteria of inclusion were soft pancreas and a diameter of wirsung <3 mm. The primary study end point was PF rate defined as amylase-rich fluid (amylase concentration >3 times the upper limit of normal serum amylase level) collected from the peripancreatic drains after postoperative day 3. CT scan was routinely done on day 7. Results: The 2 groups were comparable concerning demographic data, underlying pathologies, presenting symptoms, presence of comorbid illness, and proportion of patients with preoperative biliary drainage. Mortality, morbidity, and PF rates were 3.8%, 51.8%, and 34.2%, respectively. Stented group had a significantly lower overall PF (26% vs. 42%; P = 0.034), morbidity (41.5% vs. 61.7%; P = 0.01), and delayed gastric emptying (7.8% vs. 27.2%; P = 0.001) rates compared with nonstented group. Radiologic or surgical intervention for PF was required in 9 patients in the stented group and 12 patients in the nonstented group. There were no significant differences in mortality rate (3.7% vs. 3.9%; P = 0.37) and in hospital stay (22 days vs. 26 days; P = 0.11). Conclusion: External drainage of pancreatic duct with a stent reduced. PF and overall morbidity rates after PD in high risk patients (soft pancreatic texture and a nondilated pancreatic duct). This study is registered at http://www.clinicaltrials.gov: Clinical trial ID# NCT01068886.

Signet ring cell histology is an independent predictor of poor prognosis in gastric adenocarcinoma regardless of tumoral clinical presentation.

Objective:To test the hypothesis that signet ring cell (SRC) histology has a negative prognostic value in patients with gastric adenocarcinoma (ADC). Summary Background Data:In western countries, gastric ADC with SRC often occurs after the disease has advanced. Consequently, the prognosis of SRC is generally regarded as poor, although survival studies comparing SRC and non-SRC have yielded inconsistent results. Methods:An intent to treat analysis was performed among 215 patients with gastric ADC scheduled for surgical resection from 1996 to 2007. Of these, 180 patients underwent the resection and 35 were not resected due to diffuse metastatic illness. From 59 resected patients with SRC (SRC group), control non-SRC resected patients matched by age, gender, American Society of Anaesthesiologists (ASA) classification, tumoral location, and pTNM stage were randomly selected by computer (non-SRC group: n = 100) during the same study period. Results:The overall median survival was 21 months, which was significantly higher in resected compared to non-resected patients (31 vs. 5 months, P < 0.001). In non-resected patients, SRC histological subtype was associated with higher rates of diffuse peritoneal carcinomatosis (90.1% vs. 62.5%, P = 0.053) and neoplastic ascitis (63.6% vs. 34.7%, P = 0.059) and poorer median survival (5 vs. 7 months, P = 0.062). For resected patients, the 2 groups (SRC and non-SRC) were comparable regarding matching variables, demographic variables, and postoperative course. The median survival was significantly lower for SRC patients (21 vs. 44 months, P = 0.004). SRC resected patients exhibited higher rates of localized peritoneal carcinomatosis (P = 0.013) and lymph node involvement (P < 0.001) at diagnosis, lower R0 resection rate (P = 0.019) and earlier tumor relapse (P = 0.009), which was generally in a peritoneal carcinomatosis form (P = 0.011). By multivariate analysis, we concluded that SRC histology was independently associated with a dismal prognosis after adjustment on confounding variables (hazard ratio = 1.5, 95% confidence interval 1.1–2.0, P = 0.004). The prognostic role of SRC was maintained after exclusion of patients with advanced stage at initial diagnosis such as localized peritoneal carcinomatosis or lymph node invasion. Conclusions:This study is currently the best evidence showing that SRC is a major and independent predictor of poor prognosis due to specific characteristics such as more infiltrating tumors showing affinity for lymphatic tissue accompanied by a higher rate of peritoneal carcinomatosis. Our results suggest the need for a specific therapeutic strategy for such tumors.

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.

Open versus laparoscopically-assisted oesophagectomy for cancer: a multicentre randomised controlled phase III trial - the MIRO trial

BackgroundOpen transthoracic oesophagectomy is the standard treatment for infracarinal resectable oesophageal carcinomas, although it is associated with high mortality and morbidity rates of 2 to 10% and 30 to 50%, respectively, for both the abdominal and thoracic approaches. The worldwide popularity of laparoscopic techniques is based on promising results, including lower postoperative morbidity rates, which are related to the reduced postoperative trauma. We hypothesise that the laparoscopic abdominal approach (laparoscopic gastric mobilisation) in oesophageal cancer surgery will decrease the major postoperative complication rate due to the reduced surgical trauma.Methods/DesignThe MIRO trial is an open, controlled, prospective, randomised multicentre phase III trial. Patients in study arm A will receive laparoscopic-assisted oesophagectomy, i.e., a transthoracic oesophagectomy with two-field lymphadenectomy and laparoscopic gastric mobilisation. Patients in study arm B will receive the same procedure, but with the conventional open abdominal approach. The primary objective of the study is to evaluate the major postoperative 30-day morbidity. Secondary objectives are to assess the overall 30-day morbidity, 30-day mortality, 30-day pulmonary morbidity, disease-free survival, overall survival as well as quality of life and to perform medico-economic analysis. A total of 200 patients will be enrolled, and two safety analyses will be performed using 25 and 50 patients included in arm A.DiscussionPostoperative morbidity remains high after oesophageal cancer surgery, especially due to major pulmonary complications, which are responsible for 50% of the postoperative deaths. This study represents the first randomised controlled phase III trial to evaluate the benefits of the minimally invasive approach with respect to the postoperative course and oncological outcomes in oesophageal cancer surgery.Trial RegistrationNCT00937456 (ClinicalTrials.gov)

The impact of perioperative chemotherapy on survival in patients with gastric signet ring cell adenocarcinoma: a multicenter comparative study.

Objective:The aim of this retrospective study was to evaluate the survival impact of perioperative chemotherapy (PCT) in patients with gastric signet ring cell (SRC) adenocarcinoma. Background:PCT is a standard treatment for advanced resectable gastric adenocarcinoma (GA). SRC has a worse prognosis compared to non-SRC and the chemosensitivity of SRC is uncertain. Methods:Among 3010 patients registered in 19 French centers between January 1997 and January 2010, 1050 (34.9%) were diagnosed with SRC. Of those treated with curative intent (n = 924), 171 (18.5%) received PCT with surgery (PCT group), whereas 753 (81.5%) were treated with primary surgery (S group). PCT was based mainly on a fluorouracil-platinum doublet or triplet regimen. Results:The groups were comparable regarding age, gender, American Society of Anesthesiologists (ASA) score, malnutrition, tumor location and cTNM stage. 60 patients did not undergo resection because of tumor progression (10) or metastases (50) found at operation. The R0 resection rates were 65.9% and 62.3% in the S and PCT groups, respectively (P = 0.308). Fewer patients received adjuvant chemotherapy in the S group than in the PCT group (35.2% vs. 66.5%, P < 0.001). At a median follow-up of 31.5 months, the median survival was shorter in the PCT group (12.8 vs. 14.0 months, P = 0.043). On multivariate analysis, PCT was found to be an independent predictor of poor survival (HR = 1.4, 95% CI 1.1–1.9, P = 0.042). Conclusions:PCT provides no survival benefit in patients with gastric SRC. Clinical Trial.gov record: ADCI001, Clinical Trial.gov identifier NCT01249859.