William B. Robb

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.

Is there a role for surgery for patients with a complete clinical response after chemoradiation for esophageal cancer? An intention-to-treat case-control study.

Objective:To compare the outcomes of a strategy of surveillance versus surgical resection in patients with esophageal cancer (EC) experiencing complete clinical response (cCR) after chemoradiation (CRT). Background:In EC, it remains unclear whether a strategy of surveillance or esophagectomy is appropriate after cCR to CRT. Methods:From 1995 to 2009, 222 operable patients had a cCR based on the results of a computed tomographic scan, endoscopy with biopsies and, when performed, a positron emission tomographic scan. Through an intention-to-treat case-control study, 59 patients treated with CRT and surveillance (group Surv) were matched 1:2 with 118 patients treated by CRT followed by surgery (group Surg), according to age, gender, tumor location and stage, histology, American Society of Anesthesiologists score, and nutritional status. Results:The 2 groups were comparable according to the matched variables (P > 0.276). In group Surg, the postoperative mortality rate was 4.2% with evidence of residual tumor in 34.6% of specimens. In group Surv, 2 salvage esophagectomies were performed. Despite the higher dose of radiotherapy received in group Surv (50 vs 45 Gys, P = 0.003), median survival was lower (31 vs 83 months, P = 0.001), with disease recurrence that was more frequent (50.8% vs 32.7%, P = 0.021), occurred earlier (7.8 vs 19.0 months, P = 0.002) and more often locoregional (46.7% vs 16.2%, P = 0.007) in nature. Surgical resection was independently associated with less recurrence [odds ratio = 0.4, 95% confidence interval (CI): 0.2–0.8, P = 0.006] and better survival (hazard ratio = 0.5, 95% CI: 0.3–0.8, P = 0.006). Conclusions:Survival of EC patients with a cCR after CRT is better after surgery compared to simply surveillance. In patients of low operative risk and operable disease, surgery should be considered to improve control of locoregional disease and to overcome the inherent limitations of clinical response assessment.

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.

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

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

Strategies in the prevention of the formation of postoperative adhesions in digestive surgery: a systematic review of the literature.

BACKGROUND: Postoperative intra-abdominal adhesions after GI surgery constitute a major burden for health care provision globally, causing chronic abdominal symptoms and necessitating repeated surgical intervention. OBJECTIVE: This systematic review examines safety and efficacy data for current anti-adhesion strategies after GI surgery. DATA SOURCES: PubMed, Medline, and Embase databases were searched for randomized control trials and nonrandomized clinical studies of anti-adhesion products from January 1980 to October 2013. STUDY SELECTION: A list of predefined search terms was combined with the Cochrane Highly Sensitive Search Strategy to identify studies. INTERVENTION: The use of an anti-adhesion strategy was investigated. MAIN OUTCOME MEASURES: The primary outcome was the safety profile of anti-adhesion products. Secondary outcomes included the analysis of the reduction in the incidence, extent, and severity of adhesions; incidence of bowel obstruction; quality-of-life data; and oncological outcomes. RESULTS: In total, 24 articles were included in the qualitative analysis: 17 randomized controlled trials and 7 nonrandomized studies, reporting on 5 anti-adhesion products. Data suggest that anti-adhesive products may be used safely; however, hyaluronic acid-based products should not be placed in contact with an anastomosis. The most studied product, a hyaluronic acid/carboxymethylcellulose membrane, reduces the incidence, extent, and severity of adhesions but without strong evidence of prevention of bowel obstruction. LIMITATIONS: The size and quality of available studies varied greatly, reflected by the Jadad and MINORS scores. The majority of studies reported the use of a single product, hyaluronic acid/carboxymethylcellulose membrane. CONCLUSIONS: Limiting adhesion formation after GI surgery is feasible. More evidence is needed regarding the efficacy in reducing chronic abdominal symptoms, repeated operative intervention, and improving quality of life.

Advanced tumor stage is an independent risk factor of postoperative infectious complications after colorectal surgery: arguments from a case-matched series.

BACKGROUND: Patient and technical factors influencing postoperative infectious complications after elective colorectal resections for cancer are well described. Tumor related factors, however, have not been extensively evaluated. OBJECTIVE: This study aimed to measure the effect of tumor stage on postoperative surgical site and extra surgical site infections after elective colorectal cancer resection. DESIGN: This was a retrospective matched-cohort analysis of prospectively gathered data. SETTINGS: The study was conducted in a tertiary referral center and a private hospital specializing in colorectal surgery. PATIENTS: Between 2004 and 2011, 740 consecutive patients underwent elective resection for colorectal cancer in 2 centers. Patients undergoing resection for advanced tumors (group A, ≥stage IIB, n = 177) were matched to randomly selected patients with localized disease (group L, <stage IIB, n = 354). Matching variables were age, sex, American Society of Anesthesiologists score, malnutrition, and surgical approach. MAIN OUTCOME MEASURES: We compared 30-day infectious complications rates between patients with advanced (group A) and localized (group L) tumors. Multivariable logistic regression analysis was performed to identify risk factors for infectious complications. RESULTS: Group A had a higher overall rate of IC (44.6 vs 25.4 %, p < 0.001), with a higher risk of infectious complications at both the resection site (p < 0.001) and distant to the resection site (p = 0.015). Independent risk factors for infectious complications were advanced tumors (OR = 2.70; p < 0.001), obesity (OR = 1.89; p = 0.018), malnutrition (OR = 2.22; p = 0.008), and open rather than laparoscopic procedure (OR = 5.11; p < 0.001). LIMITATIONS: This study is limited by its retrospective methodology. CONCLUSION: Advanced tumors increase the risk of infectious complications after colorectal resection, with other risk factors including malnutrition, obesity, and resection by laparotomy. Optimization of modifiable risk factors through nutritional repletion and the choice of a minimally invasive operation should be considered.

Predicting the response to chemotherapy in gastric adenocarcinoma: who benefits from neoadjuvant chemotherapy?

Despite a decline in the overall incidence, gastric adenocarcinoma remains the second most common cause of cancer death worldwide and thus a significant global health problem. Even in early-stage locoregional confined disease the 5-year survival rarely exceeds 25-35 %. Randomized trials have demonstrated a benefit from neoadjuvant and perioperative chemotherapy. However the optimal approach in individual patients is not clear and remains controversial. A consistent finding is that patients who have a histopathological response to neoadjuvant therapy are more likely to receive a survival benefit. These clinical data provide a strong argument for the urgent development of methods to predict histopathological response to neoadjuvant therapies for gastric adenocarcinomas. Published data demonstrate that clinico-pathological features (tumour histology and location), imaging through metabolic response by FDG-PET and tissue/molecular biomarkers may all have a predictive value for neoadjuvant therapies. However it is still uncertain from published data whether or not they will be useful for clinical decision making in individual patients. Existing candidate biomarkers need to be properly qualified and validated and novel biomarkers are required and an optimal approach should involve the combination and integration of clinical, imaging, pathological and molecular biomarkers.

Use of biological mesh versus standard wound care in infected incisional ventral hernias, the SIMBIOSE study: a study protocol for a randomized multicenter controlled trial

BackgroundIn infected incisional ventral hernias (IVHs), the use of a synthetic non-absorbable mesh is not recommended and biological meshes hold promise. However, the level of evidence for their safety and efficacy remains low.MethodsThe SIMBIOSE trial is a multicenter, phase III, randomized, controlled trial comparing the use of a biological mesh versus traditional wound care in patients with an IVH. The primary end point is 6-month infectious and/or wound morbidity. Secondary end points are wound infection and recurrent hernia rates, post-operative pain, quality of life, time to heal, reoperation need, impact of the cross-linked mesh structure, and a medico-economic evaluation. One hundred patients need to be included.ResultsThe main results expected with biological mesh use are a significant decrease of post-operative morbidity, hernia recurrence, time to heal, and costs with an improved quality of life.ConclusionsFor the first time, the impact of biological meshes in the treatment of IVHs will be evaluated in an academic, randomized, phase III trial to provide scientific evidence (NCT01594450).Trial registrationClinicalTrial.gov,NCT01594450

Predictive Factors of Postoperative Mortality After Junctional and Gastric Adenocarcinoma Resection

IMPORTANCE Postoperative mortality after junctional and gastric adenocarcinoma resection remains a significant issue. OBJECTIVE To identify factors predictive of mortality within 30 days of junctional and gastric adenocarcinoma resection in a large national multicenter cohort. DESIGN A retrospective study collecting data from a multicenter database of patients who underwent resection for junctional and gastric adenocarcinoma from January 1, 1997, through January 31, 2010. A stepwise logistic regression model was built to identify, by multivariate analysis, variables independently predictive of 30-day postoperative mortality (POM). SETTING Nineteen university teaching hospitals in France. PARTICIPANTS Two thousand six hundred seventy patients with available data. MAIN OUTCOME MEASURES The primary end point was POM. Secondary end points included (1) late mortality (30-90 days after resection) and (2) postoperative morbidity. RESULTS One thousand eight hundred ninety-six patients (71.01%) had gastric adenocarcinoma and 774 (28.99%) had junctional tumors. Neoadjuvant treatment was given to 655 patients (24.53%), and 114 patients (4.27%) died within 30 days of surgery. Postoperative mortality was higher in patients who experienced grades III and IV toxic effects during neoadjuvant treatment compared with those who did not (8.7% vs 2.9%, respectively; P = .007). Multivariate analysis revealed metastatic disease at diagnosis (odds ratio, 9.13 [95% CI, 3.29-25.35]; P < .001) and poor tolerance of neoadjuvant treatment (3.33 [1.25-8.85]; P = .02) as being independently predictive of POM. Centers performing at least 10 resections per year were found to be protective against POM (odds ratio, 0.29 [95% CI, 0.12-0.72]; P = .008). CONCLUSIONS AND RELEVANCE This large national cohort study confirms that advanced disease heightens the risk of POM; centralization of junctional and gastric adenocarcinoma resection is warranted. The novel finding that grades III to IV toxic effects during neoadjuvant therapy increase POM has significant implications for decision making in this subgroup of patients. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01249859.

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.