Richard S. Gillies

Enhanced recovery for esophagectomy: a systematic review and evidence-based guidelines.

Objective:This article aims to provide the first systematic review of enhanced recovery after surgery (ERAS) programs for esophagectomy and generate guidelines. Background:ERAS programs use multimodal approaches to reduce complications and accelerate recovery. Although ERAS is well established in colorectal surgery, experience after esophagectomy has been minimal. However, esophagectomy remains an extremely high-risk operation, commonly performed in patients with significant comorbidities. Consequently, ERAS may have a significant role to play in improving outcomes. No guidelines or reviews have been published in esophagectomy. Methods:We undertook a systematic review of the PubMed, EMBASE, and the Cochrane databases in July 2012. The literature was searched for descriptions of ERAS in esophagectomy. Components of successful ERAS programs were determined, and when not directly available for esophagectomy, extrapolation from related evidence was made. Graded recommendations for each component were then generated. Results:Six retrospective studies have assessed ERAS for esophagectomy, demonstrating favorable morbidity, mortality, and length of stay. Methodological quality is, however, low. Overall, there is little direct evidence for components of ERAS, with much derived from nonesophageal thoracoabdominal surgery. Conclusions:ERAS in principle seems logical and safe for esophagectomy. However, the underlying evidence is poor and lacking. Despite this, a number of recommendations for practice and research can be made.

Differential clonal evolution in oesophageal cancers in response to neo-adjuvant chemotherapy

How chemotherapy affects carcinoma genomes is largely unknown. Here we report whole-exome and deep sequencing of 30 paired oesophageal adenocarcinomas sampled before and after neo-adjuvant chemotherapy. Most, but not all, good responders pass through genetic bottlenecks, a feature associated with higher mutation burden pre-treatment. Some poor responders pass through bottlenecks, but re-grow by the time of surgical resection, suggesting a missed therapeutic opportunity. Cancers often show major changes in driver mutation presence or frequency after treatment, owing to outgrowth persistence or loss of sub-clones, copy number changes, polyclonality and/or spatial genetic heterogeneity. Post-therapy mutation spectrum shifts are also common, particularly C>A and TT>CT changes in good responders or bottleneckers. Post-treatment samples may also acquire mutations in known cancer driver genes (for example, SF3B1, TAF1 and CCND2) that are absent from the paired pre-treatment sample. Neo-adjuvant chemotherapy can rapidly and profoundly affect the oesophageal adenocarcinoma genome. Monitoring molecular changes during treatment may be clinically useful.

Pragmatic staging of oesophageal cancer using decision theory involving selective endoscopic ultrasonography, PET and laparoscopy

Following CT, guidelines for staging oesophageal and gastro‐oesophageal junction (GOJ) cancer recommend endoscopic ultrasonography (EUS), PET–CT and laparoscopy for T3–T4 GOJ tumours. These recommendations are based on generic utilities, but it is unclear whether the test risk outweighs the potential benefit for some patients. This study sought to quantify investigation risks, benefits and utilities, in order to develop pragmatic, personalized staging recommendations.

Cytoplasmic β‐catenin accumulation is a good prognostic marker in upper and lower gastrointestinal adenocarcinomas

Norwood M G A, Bailey N, Nanji M, Gillies R S, Nicholson A, Ubhi S, Darnton J J, Steyn R S, Womack C, Hughes A, Hemingway D, Harrison R, Waters R & Jankowski J A
(2010) Histopathology 57, 101–111
Cytoplasmic β‐catenin accumulation is a good prognostic marker in upper and lower gastrointestinal adenocarcinomas

The Management of a Patient with an Operable Carcinoma of the Oesophagus

Patients with operable oesophageal cancer should receive a balanced discussion of the complex issues outlined above, from both the surgical and oncological teams. Patients often develop an unshakeable confidence in the treatment described during their first clinical consultation and specialist upper gastrointestinal nurses are key to maintaining equipoise in the giving of clinical information. Individual patient preferences, based on personality and previous experience, are paramount in making treatment choices. Where possible, patients should be entered into clinical trials such as the CRUK SCOPE 1 trial of definitive chemoradiotherapy with or without cetuximab and the MRC OE05 trial of chemotherapy before surgery in adenocarcinoma of the oesophagus; the availability of such trials may influence treatment recommendations. A feasibility study is due to open soon to establish whether a full multicentre randomised controlled trial comparing definitive CRT with treatment including surgery is possible in the UK. The study will establish methods for best communicating the treatment options to patients eligible for either treatment approach (Blazeby, personal communication). Outside of clinical trials, we would currently recommend the following approach: For a patient with an operable squamous cell carcinoma, we would recommend primary CRT, offering primary organ preservation in parallel with squamous cancers of other sites including the head and neck, anus and cervix, with surgery for selected patients who have residual or relapsed disease. For a similar patient with an adenocarcinoma, we would recommend pre-operative chemotherapy followed by an oesophagectomy … but then again we are biased!

Does laparoscopic antireflux surgery improve quality of life in patients whose gastro-oesophageal reflux disease is well controlled with medical therapy?

Objective Both medical therapy and laparoscopic antireflux surgery have been shown to improve quality of life in gastro-oesophageal reflux disease. Although patients with poor symptom control or side effects on medical therapy might be expected to have improved quality of life after surgery, our aim was to determine, for the first time, whether patients whose symptoms are well controlled on medical therapy but who decide to undergo surgery (patient preference) would experience improved quality of life. Methods Retrospective analysis of our patient database (1998–2003, n=313) identified 60 patients who underwent laparoscopic antireflux surgery for the indication of patient preference. Two generic quality-of-life questionnaires (Short Form 36 and Psychological General Well-Being index) and a gastrointestinal symptom questionnaire (Gastrointestinal Symptom Rating Scale) were completed preoperatively, while on medical therapy, and 6 months after surgery. Results Thirty-eight patients completed all three questionnaires at both time intervals: 31 males, seven females; mean age 42 (15–66) years. Preoperative scores while on medical therapy were significantly improved after surgery: Short Form 36 median physical composite scores 52.0 and 54.0 (P=0.034) and mental composite scores 51.0 and 56.0 (P=0.020); Psychological General Well-Being median total scores 78.0 and 90.0 (P=0.0001); Gastrointestinal Symptom Rating Scale median total scores 2.13 and 1.73 (P=0.0007) and reflux scores 2.50 and 1.00 (P<0.0001). Conclusion Laparoscopic antireflux surgery significantly improved quality of life in reflux patients whose symptoms were well controlled on medical therapy. Although on the basis of a noncomparative trial with a relatively short follow-up period, we believe such patients should be considered for laparoscopic antireflux surgery.

PREDICTING PATHOLOGICAL RESPONSE OF ESOPHAGEAL CANCER TO NEOADJUVANT CHEMOTHERAPY: THE IMPLICATIONS OF METABOLIC NODAL RESPONSE FOR PERSONALISED THERAPY

Only a minority of esophageal cancers demonstrates a pathologic tumor response (pTR) to neoadjuvant chemotherapy (NAC). 18F-FDG PET/CT is often used for restaging after NAC and to assess response. Increasingly, it is used during therapy to identify unresponsive tumors and predict pTR, using avidity of the primary tumor alone. However, definitions of such metabolic tumor response (mTR) vary. We aimed to comprehensively reevaluate metabolic response assessment using accepted parameters, as well as novel concepts of metabolic nodal stage (mN) and metabolic nodal response (mNR). Methods: This was a single-center retrospective U.K. cohort study. All patients with esophageal cancer staged before NAC with PET/CT and after with CT or PET/CT and undergoing resection from 2006 to 2014 were identified. pTR was defined as Mandard tumor regression grade 1–3; imaging parameters included metrics of tumor avidity (SUVmax/mean/peak), composites of avidity and volume (including metabolic tumor volume), nodal SUVmax, and our new concepts of mN stage and mNR. Results: Eighty-two (27.2%) of 301 patients demonstrated pTR. No pre-NAC PET parameters predicted pTR. In 220 patients restaged by PET/CT, the optimal tumor ΔSUVmax threshold was a 77.8% reduction. This was as sensitive as the current PERCIST 30% reduction, but more specific with a higher negative predictive value (P < 0.001). ΔSUVmax and Δlength independently predicted pTR, and composite avidity/spatial metrics outperformed avidity alone. Although both mTR and mNR were associated with pTR, in 82 patients with 18F-FDG–avid nodes before NAC we observed mNR in 10 (12.2%) not demonstrating mTR. Conclusion: Current definitions of metabolic response are suboptimal and too simplistic. Composite avidity/volume measures improve prediction. mNR may further improve response assessment, by specifically assessing metastatic tumor subpopulations, likely responsible for disease relapse, and should be urgently assessed when considering aborting therapy on the basis of mTR alone.

Non-radical, stepwise complete endoscopic resection of Barrett’s epithelium in short segment Barrett’s esophagus has a low stricture rate

Background and aims: Radical endoscopic excision of Barrett’s epithelium performing 4 – 6 endoscopic resections during the same endoscopic session results in complete Barrett’s eradication but has a high stricture rate (40 – 80 %). Therefore radiofrequency ablation is preferred after endoscopic mucosal resection (EMR) of visible nodules. We investigated the clinical outcome of non-radical, stepwise endoscopic mucosal resection with a maximum of two endoscopic resections per endoscopic session. Methods: We analysed our prospectively maintained database of patients undergoing esophageal EMR for early neoplasia in Barrett’s esophagus from 2009 to 2014. EMR was performed using a maximum of two band ligation mucosectomies per endoscopic session; thereafter, follow-up was 3-monthly and EMR was repeated as required for Barrett’s eradication. Results: In total, 118 patients underwent staging EMR for early Barrett’s neoplasia. Subsequently, 27 patients underwent surgery/chemotherapy due to deep submucosal or more advanced tumor stages or were managed conservatively. The remaining 91 patients with high grade dysplasia (48), intramucosal (38) or submucosal cancer (5) in the resected nodule underwent further endoscopic therapy with a mean follow-up of 24 months. Remission of dysplasia/neoplasia was achieved in 95.6 % after 12 months treatment. Stepwise endoscopic Barrett’s resection resulted in complete Barrett’s eradication in 36/91 patients (39.6 %) in a mean of four sessions; 40/91 patients (44.0 %) had a short circumferential Barrett’s segment (< 3 cm). In this group, repeated EMR achieved complete Barrett’s excision in 85.0 %. One patient developed a stricture (1.1 %), one a delayed bleeding, and there were no perforations. Conclusion: In patients with a short Barrett’s segment, non-radical endoscopic Barrett’s resection at the time of scheduled endoscopy follow-up allows complete Barrett’s eradication with very low stricture rate.

Translational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma.

Oxaliplatin-based chemotherapy is used to treat patients with esophageal adenocarcinoma (EAC), but no biomarkers are currently available for patient selection. We performed a prospective, clinical trial to identify potential biomarkers associated with clinical outcomes. Tumor tissue was obtained from 38 patients with resectable EAC before and after 2 cycles of oxaliplatin-fluorouracil chemotherapy. Pre-treatment mRNA expression of 280 DNA repair (DNAR) genes was tested for association with histopathological regression at surgery, disease-free survival (DFS) and overall survival (OS). High expression of 13 DNA damage repair genes was associated with DFS less than one year (P < 0.05); expression of 11 DNAR genes were associated with worse OS (P < 0.05). From clinical associations with outcomes, two genes, ERCC1 and EME1, were identified as candidate biomarkers. In cell lines in vitro, we showed the mechanism of action related to repair of oxaliplatin-induced DNA damage by depletion and knockout of protein binding partners of the candidate biomarkers, XPF and MUS81 respectively. In clinical samples from the clinical trial, pre-treatment XPF protein levels were associated with pathological response, and MUS81 protein was associated with 1-year DFS. XPF and MUS81 merit further validation in prospective clinical trials as biomarkers that may predict clinical response of EAC to oxaliplatin-based chemotherapy.

Challenges in assessing response of oesophageal cancer to neoadjuvant therapy, and the potential of composite PET-CT and multimodal metrics

We read with interest Dr. Wlodarczyk and Professor Kuzdzal’s appraisal of the potential for composite positron emission tomography-computed tomography (PET-CT) metrics to improve the assessment of oesophageal cancer to neoadjuvant therapy, in particular that of a new metric we recently described: metabolic nodal response (mNR) (1,2).