ctDNA as a biomarker of progression in oesophageal adenocarcinoma.

BACKGROUND: The incidence of oesophageal adenocarcinoma (OAC) is rapidly increasing and despite improvements in treatment, the 5-year survival rate remains poor. Prognostic biomarkers that address the genomic heterogeneity in this highly complex disease will aid the development of precision therapeutics and improve patient survival. The aim of this study was to determine whether circulating tumour DNA (ctDNA) has prognostic significance as a biomarker in OAC patients. PATIENTS AND METHODS: We profiled 209 blood and tumour samples from 57 OAC patients. Using a panel of 77 cancer genes, we sequenced ctDNA in plasma samples (n = 127) which were taken at multiple time points before and after therapy. In parallel, we sequenced matched tumour samples from 39 patients using the same gene panel. To assess whether the ctDNA profile reflected the tumour heterogeneity, we sequenced additional multi-region primary tumour samples in 17 patients. In addition, we analysed whole-genome and whole-exome sequencing data from primary tumours for a subset of 18 patients. RESULTS: Using a tumour-agnostic approach, we found that detectable ctDNA variants in post-treatment plasma samples were associated with worse disease-specific survival. To evaluate whether the ctDNA originated from the primary tumour, we carried out a tumour-informed analysis which confirmed post-treatment ctDNA variants were associated with worse survival. To determine whether ctDNA could be used as a clinical follow-up test, we assessed blood samples from multiple time points before and after treatment, in a subset of patients. Results showed that the variant allele frequency of ctDNA variants increased with disease recurrence. CONCLUSION: This study demonstrates that ctDNA variants can be detected in patients with OAC and this has potential clinical utility as a prognostic biomarker for survival.

Comparison of actionable events detected in cancer genomes by whole-genome sequencing, in silico whole-exome and mutation panels.

BACKGROUND: Next-generation sequencing is used in cancer research to identify somatic and germline mutations, which can predict sensitivity or resistance to therapies, and may be a useful tool to reveal drug repurposing opportunities between tumour types. Multigene panels are used in clinical practice for detecting targetable mutations. However, the value of clinical whole-exome sequencing (WES) and whole-genome sequencing (WGS) for cancer care is less defined, specifically as the majority of variants found using these technologies are of uncertain significance. PATIENTS AND METHODS: We used the Cancer Genome Interpreter and WGS in 726 tumours spanning 10 cancer types to identify drug repurposing opportunities. We compare the ability of WGS to detect actionable variants, tumour mutation burden (TMB) and microsatellite instability (MSI) by using in silico down-sampled data to mimic WES, a comprehensive sequencing panel and a hotspot mutation panel. RESULTS: We reveal drug repurposing opportunities as numerous biomarkers are shared across many solid tumour types. Comprehensive panels identify the majority of approved actionable mutations, with WGS detecting more candidate actionable mutations for biomarkers currently in clinical trials. Moreover, estimated values for TMB and MSI vary when calculated from WGS, WES and panel data, and are dependent on whether all mutations or only non-synonymous mutations were used. Our results suggest that TMB and MSI thresholds should not only be tumour-dependent, but also be sequencing platform-dependent. CONCLUSIONS: There is a large opportunity to repurpose cancer drugs, and these data suggest that comprehensive sequencing is an invaluable source of information to guide clinical decisions by facilitating precision medicine and may provide a wealth of information for future studies. Furthermore, the sequencing and analysis approach used to estimate TMB may have clinical implications if a hard threshold is used to indicate which patients may respond to immunotherapy.

Patient-reported outcome (PRO) results from the AGITG DOCTOR trial: a randomised phase 2 trial of tailored neoadjuvant therapy for resectable oesophageal adenocarcinoma.

BACKGROUND: AGITG DOCTOR was a randomised phase 2 trial of pre-operative cisplatin, 5 fluorouracil (CF) followed by docetaxel (D) with or without radiotherapy (RT) based on poor early response to CF, detected via PET, for resectable oesophageal adenocarcinoma. This study describes PROs over 2 years. METHODS: Participants (N = 116) completed the EORTC QLQ-C30 and oesophageal module (QLQ-OES18) before chemotherapy (baseline), before surgery, six and 12 weeks post-surgery and three-monthly until 2 years. We plotted PROs over time and calculated the percentage of participants per treatment group whose post-surgery score was within 10 points (threshold for clinically relevant change) of their baseline score, for each PRO scale. We examined the relationship between Grade 3+ adverse events (AEs) and PROs. This analysis included four groups: CF responders, non-responders randomised to DCF, non-responders randomised to DCF + RT, and "others" who were not randomised. RESULTS: Global QOL was clinically similar between groups from 6 weeks post-surgery. All groups had poorer functional and higher symptom scores during active treatment and shortly after surgery, particularly the DCF and DCF + RT groups. DCF + RT reported a clinically significant difference (-13points) in mean overall health/QOL between baseline and pre-surgery. Similar proportions of patients across groups scored +/- 10 points of baseline scores within 2 years for most PRO domains. Instance of grade 3+ AEs were not related to PROs at baseline or 2 years. CONCLUSIONS: By 2 years, similar proportions of patients scored within 10 points of baseline for most PRO domains, with the exception of pain and insomnia for the DCF + RT group. Non-responders randomised to DCF or DCF + RT experienced additional short-term burden compared to CF responders, reflecting the longer duration of neoadjuvant treatment and additional toxicity. This should be weighed against clinical benefits reported in AGITG DOCTOR. This data will inform communication of the trajectory of treatment options for early CF non-responders. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry (ANZCTR), ACTRN12609000665235 . Registered 31 July 2009.

Complications and survival after hybrid and fully minimally invasive oesophagectomy.

BACKGROUND: Minimally invasive oesophagectomy (MIO) is reported to produce fewer respiratory complications than open oesophagectomy. This study assessed differences in postoperative complications between MIO and hybrid MIO (HMIO) employing thoracoscopy and laparotomy, along with the influence of co-morbidities on postoperative outcomes. METHODS: Patients with oesophageal cancer undergoing three-stage MIO or three-stage HMIO between 1999 and 2018 were identified from a prospectively developed database, which included patient demographics, co-morbidities, preoperative therapies, and cancer stage. The primary outcome was postoperative complications in the two groups. Secondary outcomes included duration of operation, blood transfusion requirement, duration of hospital stay, and overall survival. RESULTS: There were 828 patients, of whom 722 had HMIO and 106 MIO, without significant baseline differences. Median duration of operation was longer for MIO (325 versus 289 min; P < 0.001), but with less blood loss (median 250 versus 300 ml; P < 0.001) and a shorter hospital stay (median 12 versus 13 days; P = 0.006). Respiratory complications were not associated with operative approach (31.1 versus 35.2 per cent for MIO and HMIO respectively; P = 0.426). Anastomotic leak rates (10.4 versus 10.2 per cent) and 90-day mortality (1.0 versus 1.7 per cent) did not differ. Cardiac co-morbidity was associated with more medical and surgical complications. Overall survival was associated with AJCC stage and co-morbidities, but not operative approach. CONCLUSION: MIO had a small benefit in terms of blood loss and hospital stay, but not in operating time. Oncological outcomes were similar in the two groups. Postoperative complications were associated with pre-existing cardiorespiratory co-morbidities rather than operative approach.

Preoperative cisplatin, fluorouracil, and docetaxel with or without radiotherapy after poor early response to cisplatin and fluorouracil for resectable oesophageal adenocarcinoma (AGITG DOCTOR): results from a multicentre, randomised controlled phase II trial.

BACKGROUND: Patients with oesophageal/gastro-oesophageal junction adenocarcinoma (EAC) not showing early metabolic response (EMR) to chemotherapy have poorer survival and histological response rates <5%. We investigated whether tailoring neoadjuvant therapy can improve outcomes in these patients. PATIENTS AND METHODS: Patients with resectable EAC were enrolled and randomised into two single-arm, multicentre phase II trials. After induction cisplatin and 5-fluorouracil (CF), all were assessed by day 15 positron emission tomography (PET). Patients with an EMR [maximum standardised uptake values (SUVmax) ≥35% reduction from baseline to day 15 PET] received a second CF cycle then oesophagectomy. Non-responders were randomised 1 : 1 to two cycles of CF and docetaxel (DCF, n = 31) or DCF + 45 Gy radiotherapy (DCFRT, n = 35) then oesophagectomy. The primary end point was major histological response (<10% residual tumour) in the oesophagectomy specimen; secondary end points were overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LR). RESULTS: Of 124 patients recruited, major histological response was achieved in 3/45 (7%) with EMR, 6/30 (20%) DCF, and 22/35 (63%) DCFRT patients. Grade 3/4 toxicities occurred in 12/45 (27%) EMR (CF), 13/31 (42%) DCF, and 25/35 (71%) DCFRT patients. No treatment-related deaths occurred. LR by 3 years was seen in 5/45 (11%) EMR, 10/31 (32%) DCF, and 4/35 (11%) DCFRT patients. PFS [95% confidence interval (CI)] at 36 months was 47% (31% to 61%) for EMR, 29% (15% to 45%) for DCF, and 46% (29% to 61%) for DCFRT patients. OS (95% CI) at 60 months was 53% (37% to 67%) for EMR, 31% (16% to 48%) for DCF, and 46% (29% to 61%) for DCFRT patients. CONCLUSIONS: EMR is associated with favourable OS, PFS, and low LR. For non-responders, the addition of docetaxel augmented histological response rates, but OS, PFS, and LR remained inferior compared with responders. DCFRT improved histological response and PFS/LR outcomes, matching the EMR group. Early PET/CT has the potential to tailor therapy for patients not showing an early response to chemotherapy. TRIAL REGISTRATION: ACTRN12609000665235.

Baseline neutrophil-lymphocyte ratio holds no prognostic value for esophageal and junctional adenocarcinoma in patients treated with neoadjuvant chemotherapy.

BACKGROUND: Several studies have reported that neutrophil-lymphocyte ratio (NLR) can predict survival in esophageal and gastroesophageal junction adenocarcinoma, as it reflects systemic inflammation. Hence, we aimed to determine whether baseline NLR holds prognostic value for esophageal adenocarcinoma patients treated with neoadjuvant chemotherapy (nCT) followed by surgery. METHODS: We studied the data of 139 patients that received nCT before undergoing esophagectomy with curative intent, all identified from a prospectively maintained database (1998-2016). Pretreatment hematology reports were used to calculate the baseline NLR. A receiver operating characteristic curve (ROC-curve) was plotted to determine an optimal cutoff value. NLR quartiles were used to display possible differences between groups in relation to overall survival (OS) and disease-free survival (DFS) using the method of Kaplan-Meier. Cox regression analysis was performed to assess the prognostic value of NLR. RESULTS: The median OS and DFS times were 46 months (interquartile range [IQR]: 19-166) and 30 months (IQR: 13-166], respectively, for the entire cohort. The ROC-curve showed that NLR has no discriminating power for survival status (area under the curve = 0.462) and therefore no optimal cutoff value could be determined. There were no statistically significant differences in median OS times for NLR quartiles: 65 (Q1), 32 (Q2), 45 (Q3), and 46 months (Q4) (P = 0.926). Similarly, DFS showed no difference between quartile groups, with median survival times of 27 (Q1), 19 (Q2), 36 (Q3), and 20 months (Q4) (P = 0.973). Age, pN, pM, and resection margin were independent prognostic factors for both OS and DFS. On the contrary, NLR was not associated with OS or DFS in univariable and multivariable analyses. CONCLUSION: Baseline NLR holds no prognostic value for esophageal and gastroesophageal junction adenocarcinoma patients treated with nCT in this study, in contrast to other recently published papers. This result questions the validity of NLR as a reliable prognostic indicator and its clinical usefulness in these patients.

Patterns of Failure Following Dose-escalated Chemoradiotherapy for Fluorodeoxyglucose Positron Emission Tomography Staged Squamous Cell Carcinoma of the Oesophagus.

AIMS: To analyse outcomes and patterns of failure following dose-escalated definitive chemoradiotherapy (CRT) for oesophageal squamous cell carcinoma using fluorodeoxyglucose positron emission tomography for staging and treatment planning. MATERIALS AND METHODS: A retrospective review of patients with oesophageal squamous cell carcinoma receiving definitive CRT to a dose of ≥56 Gy was conducted. Patient and tumour characteristics, treatment received and first sites of relapse were analysed. RESULTS: Between 2003 and 2014, 72 patients were treated with CRT to a median dose of 60 Gy (range 56-66 Gy). The median age was 63 years; most (61%) were stage III/IVa. The median follow-up was 57 months. Three year in-field control, relapse-free survival and overall survival was 64% (95% confidence interval 50-75%), 38% (95% confidence interval 27-50%) and 42% (95% confidence interval 30-53%), respectively. Of the 41 failures prior to death or at last follow-up date, isolated locoregional relapse occurred in 16 patients (22%) with isolated in-field recurrence in 11 patients (15%). Distant failure as first site of relapse was present in 25 patients (35%). No in-field failures occurred in the 11 patients with cT1-2, N0-1 tumours. The median survival for cT4 tumours was 8 months, with five of eight patients developing local progression within the first 6 months. CONCLUSIONS: Dose-escalated radiotherapy was associated with promising rates of in-field local control, with the exception of cT4 tumours. Distant failure remains a significant competing risk. Our data supports the need for current trials re-examining the role of dose escalation in the modern era.

Meta-analysis of radical resection rates and margin assessment in pancreatic cancer.

BACKGROUND: R0 resection rates (complete tumour removal with negative resection margins) in pancreatic cancer are 70-80 per cent when a 0-mm margin is used, declining to 15-24 per cent with a 1-mm margin. This review evaluated the R0 resection rates according to different margin definitions and techniques. METHODS: Three databases (MEDLINE from 1946, PubMed from 1946 and Embase from 1949) were searched to mid-October 2014. The search terms included 'pancreatectomy OR pancreaticoduodenectomy' and 'margin'. A meta-analysis was performed with studies in three groups: group 1, axial slicing technique (minimum 1-mm margin); group 2, other slicing techniques (minimum 1-mm margin); and group 3, studies with minimum 0-mm margin. RESULTS: The R0 rates were 29 (95 per cent c.i. 26 to 32) per cent in group 1 (8 studies; 882 patients) and 49 (47 to 52) per cent in group 2 (6 studies; 1568 patients). The combined R0 rate (groups 1 and 2) was 41 (40 to 43) per cent. The R0 rate in group 3 (7 studies; 1926 patients) with a 0-mm margin was 72 (70 to 74) per cent The survival hazard ratios (R1 resection/R0 resection) revealed a reduction in the risk of death of at least 22 per cent in group 1, 12 per cent in group 2 and 23 per cent in group 3 with an R0 compared with an R1 resection. Local recurrence occurred more frequently with an R1 resection in most studies. CONCLUSION: Margin clearance definitions affect R0 resection rates in pancreatic cancer surgery. This review collates individual studies providing an estimate of achievable R0 rates, creating a benchmark for future trials.

Impact of postoperative morbidity on long-term survival after oesophagectomy.

BACKGROUND: Oesophageal malignancy is a disease with a poor prognosis. Oesophagectomy is the mainstay of curative treatment but associated with substantial morbidity and mortality. Although mortality rates have improved, the incidence of perioperative morbidity remains high. This study assessed the impact of postoperative morbidity on long-term outcomes. METHODS: A prospective database was designed for patients undergoing oesophagectomy for malignancy from 1998 to 2011. An observational cohort study was performed with these data, assessing intraoperative technical complications, postoperative morbidity and effects on overall survival. RESULTS: Some 618 patients were included, with a median follow-up of 51 months for survivors. The overall complication rate was 64·6 per cent (399 of 618), with technical complications in 124 patients (20·1 per cent) and medical complications in 339 (54·9 per cent). Technical complications were associated with longer duration of surgery (308 min versus 293 min in those with no technical complications; P = 0·017), greater operative blood loss (448 versus 389 ml respectively; P = 0·035) and longer length of stay (22 versus 13 days; P < 0·001). Medical complications were associated with greater intraoperative blood loss (418 ml versus 380 ml in those with no medical complications; P = 0·013) and greater length of stay (16 versus 12 days respectively; P < 0·001). Median overall and disease-free survival were 41 and 43 months. After controlling for age, tumour stage, resection margin, length of tumour, adjuvant therapy, procedure type and co-morbidities, there was no effect of postoperative complications on disease-specific survival. CONCLUSION: Technical and medical complications following oesophagectomy were associated with greater intraoperative blood loss and a longer duration of inpatient stay, but did not predict disease-specific survival.

Prognostic value of maximum standardized uptake values from preoperative positron emission tomography in resectable adenocarcinoma of the esophagus treated by surgery alone.

Preoperative staging for esophageal adenocarcinoma is suboptimal for predicting outcomes when compared with pathological data. The aim of this study was to assess if the quantitative values obtained by preoperative 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) are independent prognostic indicators for survival in patients with resectable adenocarcinoma of the esophagus undergoing surgical treatment without neoadjuvant therapy. Patients were identified from a prospective database, survival analyses were undertaken using log rank and Cox method. The median follow-up was 44 months (range 18-61 months). Between November 2002 and November 2005, 45 consecutive patients underwent FDG-PET followed by surgery. The median age was 72 years (range 38-82 years). On univariate analysis of overall survival and disease-free survival, preoperative FDG-PET maximum standardized uptake value (SUV(max); P= 0.008 and P= 0.015, respectively) and postoperative pathological stage (P= 0.001 and P= 0.001, respectively) as well as postoperative histological grade (P= 0.001 and P= 0.001, respectively) were significantly associated with outcome. Multivariate analysis demonstrated that only the postoperative pathological variables were independent predictors of outcome (Wald 11.81, P= 0.001). Preoperative FDG-PET SUV(max) is associated with outcome after esophageal adenocarcinoma resection but remains less accurate than postoperative variables. A high FDG-PET SUV(max) could be used to identify a high-risk population who would benefit most from neoadjuvant therapies.

Health-related quality of life among patients with adenocarcinoma of the gastro-oesophageal junction treated by gastrectomy or oesophagectomy.

BACKGROUND: Tumours of the gastro-oesophageal junction may be resected by total gastrectomy (TG) or transthoracic oesophagectomy (TTO). This study compared health-related quality of life (HRQL) following these procedures. METHODS: Prospective clinical and HRQL data (European Organization for Research and Treatment of Cancer QLQ-C30) were collected from 63 consecutive patients (20 TG and 43 TTO) before and 6 months after surgery for Siewert type I-III gastro-oesophageal tumours. RESULTS: Questionnaire response rates exceeded 90 per cent. Patients were similar with respect to disease stage, treatment-related mortality and survival, but those selected for TTO were younger with less co-morbidity than those undergoing TG. These differences were reflected in baseline HRQL scores, which were better in patients selected for TTO. Six months after surgery, however, HRQL showed a greater deterioration after TTO than after TG in terms of role and social function, global quality of life and fatigue. Symptom scores for pain and diarrhoea increased in both groups. CONCLUSION: TTO had a greater negative impact on HRQL than TG for tumours of the gastro-oesophageal junction.

Outcomes from salvage esophagectomy post definitive chemoradiotherapy compared with resection following preoperative neoadjuvant chemoradiotherapy.

Chemoradiotherapy (CRT) as a definitive treatment for esophageal cancer, is being used with increasing frequency and as a result, surgeons will be required to assess more patients who have residual or recurrent local malignancy. This article aimed to assess outcomes after esophagectomy following definitive CRT (dCRT) and compare any difference between them and patients who had preoperative neoadjuvant CRT (nCRT) using a similar regimen of chemotherapy. From a prospective database the details of patients who had a resection following nCRT and dCRT were analyzed. The main therapeutic difference between the groups was the dose of radiotherapy (35 vs 60 Gy) and the timing of the resection following completion of the CRT (median 4 vs 28 weeks). Fourteen patients had an esophagectomy following a dCRT and 53 had one following a nCRT. Preoperatively, the dCRT group had worse respiratory function and more ECG abnormalities. Preoperative tumor length, pathological TNM staging and R0 resection rates were the same in both groups. Post resection, the dCRT group had greater morbidity than the nCRT group, spending longer in the intensive care unit (median 48 vs 24 h), more days in hospital (median 31 vs 13) and having more severe respiratory complications (37%vs 6%). The operative mortality was higher in the dCRT group (7%vs 0%). The three-year survival was 24% after dCRT. Patients selected for salvage esophagectomy following dCRT are a major challenge in postoperative care. However, some patients survive for a reasonable period of time, making resection a worthwhile option.