Improving individualised therapies in localised gastro-oesophageal adenocarcinoma.

Despite our increased understanding of the biological and molecular aspects of gastro-oesophageal tumourigenesis, the identification of prognostic or predictive factors remains challenging. Patients with resectable gastric and oesophageal adenocarcinoma are often treated similarly after surgical resection, regardless of their tumour biology, clinical characteristics, and histological treatment response. Substantial progress has been made in the past 5 years in managing patients with gastric or oesophageal adenocarcinoma, including the use of immune checkpoint inhibitors and new targeted therapies, leading to substantial improvements in clinical outcomes. These advancements have primarily been established in advanced and metastatic disease, while the management framework for local and locoregional disease is just beginning to shift. We provide an overview of existing data on biomarkers and tumour-related and host-related factors that are relevant to stratify patients into low-risk and high-risk recurrence groups, both before and after surgery, paving the way for more personalised treatment approaches.

Mind the target: programmed death ligand 1 in oesophagogastric cancers.

PURPOSE OF REVIEW: Metastatic oesophagogastric cancers carry a prognosis of generally less than 2 years despite current treatment. There has been recent excitement in the field focused on immune checkpoint inhibition though anti-PD-1 antibodies. In this article, we review recent phase 3 clinical trials evaluating first line PD-L1 inhibition in metastatic HER-2-negative oesophagogastric cancers and discuss future questions and challenges in the field. RECENT FINDINGS: Prior studies have shown promise using PD-L1 inhibition as third and fourth line treatment but recent phase 3 clinical trials have shown clear benefit to overall survival as first line treatment. PD-L1 inhibition as monotherapy demonstrated earlier death rates but there are a subset of patients with a long-term durable benefit when compared with chemotherapy. PD-L1 inhibition when combined with chemotherapy showed benefit in overall survival and progression-free survival and is enhanced in subsets of patients with increased PD-L1 expression. SUMMARY: Although there are still open questions how best to assess PD-L1 status, these studies provide clear evidence for use of PD-L1 inhibition combined with cytotoxic chemotherapy as first-line treatment in metastatic or unresectable oesophagogastric cancers that express PD-L1. In addition, they lay the groundwork for future studies evaluating PD-1 inhibition in earlier stages of disease.

EGFR amplification and outcome in a randomised phase III trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastro-oesophageal cancers.

OBJECTIVE: Epidermal growth factor receptor (EGFR) inhibition may be effective in biomarker-selected populations of advanced gastro-oesophageal adenocarcinoma (aGEA) patients. Here, we tested the association between outcome and EGFR copy number (CN) in pretreatment tissue and plasma cell-free DNA (cfDNA) of patients enrolled in a randomised first-line phase III clinical trial of chemotherapy or chemotherapy plus the anti-EGFR monoclonal antibody panitumumab in aGEA (NCT00824785). DESIGN: EGFR CN by either fluorescence in situ hybridisation (n=114) or digital-droplet PCR in tissues (n=250) and plasma cfDNAs (n=354) was available for 474 (86%) patients in the intention-to-treat (ITT) population. Tissue and plasma low-pass whole-genome sequencing was used to screen for coamplifications in receptor tyrosine kinases. Interaction between chemotherapy and EGFR inhibitors was modelled in patient-derived organoids (PDOs) from aGEA patients. RESULTS: EGFR amplification in cfDNA correlated with poor survival in the ITT population and similar trends were observed when the analysis was conducted in tissue and plasma by treatment arm. EGFR inhibition in combination with chemotherapy did not correlate with improved survival, even in patients with significant EGFR CN gains. Addition of anti-EGFR inhibitors to the chemotherapy agent epirubicin in PDOs, resulted in a paradoxical increase in viability and accelerated progression through the cell cycle, associated with p21 and cyclin B1 downregulation and cyclin E1 upregulation, selectively in organoids from EGFR-amplified aGEA. CONCLUSION: EGFR CN can be accurately measured in tissue and liquid biopsies and may be used for the selection of aGEA patients. EGFR inhibitors may antagonise the antitumour effect of anthracyclines with important implications for the design of future combinatorial trials.

Gastric cancer.

Gastric cancer is the fifth most common cancer and the third most common cause of cancer death globally. Risk factors for the condition include Helicobacter pylori infection, age, high salt intake, and diets low in fruit and vegetables. Gastric cancer is diagnosed histologically after endoscopic biopsy and staged using CT, endoscopic ultrasound, PET, and laparoscopy. It is a molecularly and phenotypically highly heterogeneous disease. The main treatment for early gastric cancer is endoscopic resection. Non-early operable gastric cancer is treated with surgery, which should include D2 lymphadenectomy (including lymph node stations in the perigastric mesentery and along the celiac arterial branches). Perioperative or adjuvant chemotherapy improves survival in patients with stage 1B or higher cancers. Advanced gastric cancer is treated with sequential lines of chemotherapy, starting with a platinum and fluoropyrimidine doublet in the first line; median survival is less than 1 year. Targeted therapies licensed to treat gastric cancer include trastuzumab (HER2-positive patients first line), ramucirumab (anti-angiogenic second line), and nivolumab or pembrolizumab (anti-PD-1 third line).

Changes in the therapeutic landscape of oesophago-gastric cancers.

PURPOSE OF REVIEW: This article reviews recent randomised clinical trials on systemic treatment of oesophago-gastric cancers in the perioperative and metastatic setting. RECENT FINDINGS: Adding nivolumab to first-line chemotherapy improved survival in patients with metastatic gastric/gastro-oesophageal junction/oesophageal adenocarcinoma with PD-L1 combined positive score (CPS) ≥ five in a global trial and progression-free survival in metastatic gastric/gastro-oesophageal junction cancers in an Asian trial. The addition of pembrolizumab to first-line chemotherapy improved survival in metastatic oesophageal cancer patients, with the most benefit in oesophageal squamous cancer and tumours with high PD-L1 expression (CPS ≥ 10). Adjuvant nivolumab improved disease-free survival (DFS) in resectable oesophageal cancer patients with residual pathologic disease after neoadjuvant chemoradiation. In human epidermal growth factor receptor 2 (HER2)-positive oesophago-gastric adenocarcinoma, a phase II trial showed improved DFS when pertuzumab and trastuzumab were added to perioperative FLOT (5-fluorouracil/leucovorin, oxaliplatin, docetaxel). Another phase II trial showed improved response rates and survival in pretreated metastatic HER2-positive gastric and gastrooesophageal junction cancer patients who received the antibody-drug conjugate trastuzumab deruxtecan compared to physician's choice of chemotherapy. SUMMARY: Chemo-immunotherapy combinations will become the new standard of care for some patients with metastatic oesophago-gastric cancers. Adjuvant nivolumab is a new option for oesophageal cancer patients with poor response after neoadjuvant chemoradiation.

Adjuvant therapy following neoadjuvant chemotherapy and surgery for oesophageal adenocarcinoma in patients with clear resection margins.

BACKGROUND: The role of adjuvant therapy in patients with oesophagogastric adenocarcinoma treated by neoadjuvant chemotherapy (NAC) and surgery is contentious. In UK practice, surgical resection margin status is often used to classify patients into receiving adjuvant treatment. This study aimed to assess any survival benefit of adjuvant therapy in patients with clear resection margins. METHODS: This was a retrospective collaborative cohort study combining two prospectively collected UK institutional databases of patients with oesophageal adenocarcinoma. Multivariable Cox regression and propensity matched analyses were used to compare overall and recurrence-free survival according to the adjuvant treatment. RESULTS: Of 374 patients with clear resection margins, 221 patients (59%) had no adjuvant treatment, 137 patients (37%) had adjuvant chemotherapy and 16 patients (4%) had adjuvant chemoradiotherapy. For patients who had received NAC (290, 76%), when adjuvant chemotherapy was compared to no adjuvant treatment, hazard ratios (HRs) favoured adjuvant chemotherapy but did not reach independent significance (overall survival [OS] HR 0.65 95% confidence interval [CI] 0.40-1.06; p .0.087). Responders to NAC (Mandard 1-3) were seemingly more likely to demonstrate a survival benefit from adjuvant chemotherapy (HR 0.42 95% CI 0.15-1.11; p .1.081). CONCLUSIONS: Although no independent survival benefit was observed, the point estimates favoured adjuvant treatment, predominantly in patients with chemo-responsive tumours.

Multimodality treatment for localized gastric cancer: state of the art and new insights.

PURPOSE OF REVIEW: Surgery represents the only curative approach for resectable gastric cancer. However, rates of recurrence remain high. This review summarizes the state of the art and future perspectives regarding perioperative, neoadjuvant and adjuvant chemotherapy for localized gastric cancer with insights regarding precision medicine. RECENT FINDINGS: Perioperative chemotherapy with FLOT has significantly improved outcomes for non-Asian patients with resectable gastric cancer, removing the role for anthracyclines. Preliminary results demonstrate that the perioperative approach is an option for Asian patients; however, long-term outcomes are awaited. For adjuvant treatment in Asian gastric cancer patients, S-1 as well as docetaxel may be a new treatment option. In this context, the right selection of patients is crucial. Among several biomarkers, microsatellite instability/mismatch repair deficiency has been linked with a lack of benefit from chemotherapy as well as better prognosis. SUMMARY: Multimodality treatment represents the standard of care for resectable gastric cancer. Perioperative chemotherapy with FLOT is the standard treatment in western countries; in patients who are not suitable for triplet, a platinum-fluoropyrimidine doublet can be considered. In Asian countries, adjuvant chemotherapy based on fluoropyrimidine monotherapy or in association with oxaliplatin/docetaxel are options. Validation of prognostic and predictive biomarkers is needed in order to improve patient selection.

The Role of Microsatellite Instability in Positive Margin Gastric Cancer Patients.

PURPOSE: A positive resection margin (RM+) is acknowledged as a poor prognostic factor after gastrectomy. Microsatellite instability (MSI-H) gastric cancer has been identified as a subgroup of gastric cancer that may be associated with an improved prognosis. The aim of the study was an analysis of MSI status on patients with margin involvement after gastrectomy and examination of the association between MSI, margin status, and survival outcomes. METHODS: From a large prospectively annotated surgical database we collected clinicopathological and survival data on patients who had undergone a potentially curative resection for gastric cancer. MSI status was assessed using a standard 5-marker quasi-monomorphic mononucleotide repeat panel. Patients who were R+ and either microsatellite stable (MSS) or MSI-H were identified and clinicopathological characteristics and disease specific survival was compared. RESULTS: Three hundred and eighty-six patients were identified; 102 (26.4%) cancers were MSI-H. The proportion of R+ resections was not significantly different in MSS and MSI-H groups. For MSS patients 3-, 5-, and 10-year disease-specific survival rates were 9.1%, 0%, and 0%, respectively; for patients with MSI-H R+ tumors these were 38.5%, 30.8%, and 15.4%, respectively. In Cox analysis MSI-H, female gender, and T ≥3 were significantly associated with survival. CONCLUSIONS: Patients with MSI-H gastric cancer may have long-term survival despite R+ margin status. The molecular division of gastric cancer may be an important step in identifying possible tailored surgical treatments corresponding to clinical and pathological factors.

Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial.

BACKGROUND: Peri-operative chemotherapy and surgery is a standard of care for patients with resectable oesophagogastric adenocarcinoma. Bevacizumab, a monoclonal antibody against VEGF, improves the proportion of patients responding to treatment in advanced gastric cancer. We aimed to assess the safety and efficacy of adding bevacizumab to peri-operative chemotherapy in patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. METHODS: In this multicentre, randomised, open-label phase 2-3 trial, we recruited patients aged 18 years and older with histologically proven, resectable oesophagogastric adenocarcinoma from 87 UK hospitals and cancer centres. We randomly assigned patients 1:1 to receive peri-operative epirubicin, cisplatin, and capecitabine chemotherapy or chemotherapy plus bevacizumab, in addition to surgery. Patients in the control group (chemotherapy alone) received three pre-operative and three post-operative cycles of epirubicin, cisplatin, and capecitabine chemotherapy: 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 and 1250 mg/m2 oral capecitabine on days 1-21. Patients in the investigational group received the same treatment as the control group plus 7·5 mg/kg intravenous bevacizumab on day 1 of every cycle of chemotherapy and for six further doses once every 21 days following chemotherapy, as maintenance treatment. Randomisation was done by means of a telephone call to the Medical Research Council Clinical Trials Unit, where staff used a computer programme that implemented a minimisation algorithm with a random element to establish the allocation for the patient at the point of randomisation. Patients were stratified by chemotherapy centre, site of tumour, and tumour stage. The primary outcome for the phase 3 stage of the trial was overall survival (defined as the time from randomisation until death from any cause), analysed in the intention-to-treat population. Here, we report the primary analysis results of the trial; all patients have completed treatment and the required number of primary outcome events has been reached. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 46020948, and with ClinicalTrials.gov, number NCT00450203. FINDINGS: Between Oct 31, 2007, and March 25, 2014, 1063 patients were enrolled and randomly assigned to receive chemotherapy alone (n=533) or chemotherapy plus bevacizumab (n=530). At the time of analysis, 508 deaths were recorded (248 in the chemotherapy alone group and 260 in the chemotherapy plus bevacizumab group). 3-year overall survival was 50·3% (95% CI 45·5-54·9) in the chemotherapy alone group and 48·1% (43·2-52·7) in the chemotherapy plus bevacizumab group (hazard ratio [HR] 1·08, 95% CI 0·91-1·29; p=0·36). Apart from neutropenia no other toxic effects were reported at grade 3 or worse severity in more than 10% of patients in either group. Wound healing complications were more prevalent in the bevacizumab group, occurring in 53 (12%) patients in this group compared with 33 (7%) patients in the chemotherapy alone group. In patients who underwent oesophagogastrectomy, post-operative anastomotic leak rates were higher in the chemotherapy plus bevacizumab group (23 [10%] of 233 in the chemotherapy alone group vs 52 [24%] of 220 in the chemotherapy plus bevacizumab group); therefore, recruitment of patients with lower oesophageal or junctional tumours planned for an oesophagogastric resection was stopped towards the end of the trial. Serious adverse events for all patients included anastomotic leaks (30 events in chemotherapy alone group vs 69 in the chemotherapy plus bevacizumab group), and infections with normal neutrophil count (42 events vs 53). INTERPRETATION: The results of this trial do not provide any evidence for the use of bevacizumab in combination with peri-operative epiribicin, cisplatin, and capecitabine chemotherapy for patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. Bevacizumab might also be associated with impaired wound healing. FUNDING: Cancer Research UK, MRC Clinical Trials Unit at University College London, and F Hoffmann-La Roche Limited.

Characterising timing and pattern of relapse following surgery for localised oesophagogastric adenocarcinoma: a retrospective study.

BACKGROUND: Oesophagogastric adenocarcinoma (OGA) has a poor prognosis, even for patients with operable disease. However, the optimal surveillance strategy following surgery is unknown. METHODS: We performed a retrospective review of all patients with OGA who had undergone surgery with radical intent at the Royal Marsden between January 2001 and December 2010. RESULTS: Of the 360 patients with OGA who underwent potentially curative surgery, 100/214 patients (47%) with oesophageal/gastro-oesophageal junction (GOJ) adenocarcinoma and 47/146 patients (32%) with gastric adenocarcinoma developed recurrent disease. 51, 79 and 92% of relapses occurred within 1, 2 and 3 years respectively and the majority of patients relapsed at distant sites. Of the patients who relapsed, 67% (67/100) with oesophageal/GOJ adenocarcinoma and 72% of patients with gastric cancer (34/47) were symptomatic at the time of relapse. The majority of asymptomatic relapses were first detected by a rise in tumour markers. There was no difference in disease-free survival between asymptomatic and symptomatic patients, but asymptomatic patients were more likely to receive further treatment and had a longer survival beyond relapse. CONCLUSION: The majority of relapses occur within the first 3 years and at distant sites. Monitoring of tumour markers should be considered as part of a surveillance program.

Improved survival in resected oesophageal and gastric adenocarcinomas over a decade: the Royal Marsden experience 2001-2010.

BACKGROUND: Oesophageal and gastric adenocarcinoma (OGA) treatment remains challenging. Improvements in early diagnosis, staging and management might have contributed to survival prolongation. To examine this hypothesis, we assessed outcomes of resected OGA patients in our institution over 10 years, comparing two time periods, 2001-2005 and 2006-2010. METHODS: Records from patients who had undergone surgery with radical intent and follow-up for OGA were retrospectively reviewed. Patients followed up at hospitals other than the Royal Marsden Hospital were excluded. Two different cohorts were identified: patients with oesophageal and type I or type II oesophagogastric junction (OGJ) tumours, and patients with gastric and type III OGJ tumours. RESULTS: We identified 360 patients: 147 from 2001-2005 and 213 from 2006-2010. The characteristics were comparable across the two time periods. Between 2001-2005 and 2006-2010, the percentage of R0 resections increased (from 67.1 to 81.1 % for proximal tumours and from 76.3 to 95.9 % for gastric and type III OGJ tumours). The mean number of lymph nodes retrieved increased over time. The 5-year overall survival rate increased significantly from 42.3 to 56.6 % for proximal tumours and from 38.8 to 55.3 % for gastric and type III OGJ tumours. Similarly, the disease-free survival rate significantly increased from 34.6 to 53.5 % for proximal tumours and from 35.9 to 51.1 % for gastric and type III OGJ tumours. CONCLUSION: This study comprehensively describes the improvement in survival outcomes in a major UK referral centre over a 10-year period, identifying potentially relevant factors such as increased number of R0 resections and higher lymph node yield.

Esophagogastric Adenocarcinoma: Is More Chemotherapy Better?

OPINION STATEMENT: Two cycles of neoadjuvant cisplatin and fluoropyrimidine (CF) and 6 cycles of perioperative CF with or without epirubicin are an evidence-based approach in operable esophageal and esophagogastric junctional adenocarcinomas. Three-drug regimens with anthracycline or taxane are associated with significantly higher tumor regression rates, with an expected increase in toxicity. In order to achieve an R0 resection and consequently a survival advantage, in selected patients having a risk of a threatened margin or incomplete resection, chemotherapy might be continued beyond 2 cycles if a response has been demonstrated. In metastatic setting, multidrug combination regimens have demonstrated a significant survival benefit when compared to single-agent regimes. A three-drug regimen should be considered for fit patients and/or when a response is required for symptom control. The expected increase in toxicity needs to be carefully considered and discussed with patients. The choice to use a taxane in first-line setting may limit the options of second-line treatment to irinotecan-containing regimens and also precludes the use of anthracyclines in the first line. For this reason, we prefer to reserve taxane-based therapy for the second-line setting.

The Preoperative Lymphocyte-to-Monocyte Ratio is Prognostic of Clinical Outcomes for Patients with Liver-Only Colorectal Metastases in the Neoadjuvant Setting.

BACKGROUND: Circulating monocyte-derived, tumor-associated macrophages are associated with a poor prognosis for various cancers. Conversely, circulating lymphocytes are the source of tumor-infiltrating lymphocytes, which are associated with an improved prognosis. This study evaluated the prognostic value of the preoperative blood lymphocyte-to-monocyte ratio (LMR) for patients undergoing hepatectomy for liver-only colorectal metastases. METHODS: This retrospective study examined 140 consecutive patients with liver-only colorectal metastases. Disease-free survival (DFS), post-recurrence survival (PRS), cancer-specific survival (CSS), and overall survival (OS) were analyzed in relation to LMR values using both Kaplan-Meier and multivariate Cox-regression methods. RESULTS: In the multivariate analysis, high LMR (>3) was significantly associated with increased OS [hazard ratio (HR), 2.43; 95 % confidence interval (CI), 1.32-4.48; P = 0.004], CSS (HR 2.15; 95 % CI 1.13-4.10; P = 0.020), and PRS (HR 2.15; 95 % CI 1.15-4.01; P = 0.016) but not with DFS. An LMR lower than 3 may have been associated with decreased CSS and PRS by increasing the rate of multifocal recurrence (P = 0.063). In the multivariate analysis comparing LMR, the neutrophil-lymphocyte ratio, and the platelet-lymphocyte ratio, LMR remained the only significant prognostic variable of CSS. CONCLUSION: This study identified preoperative LMR as an independent prognostic factor for PRS, CSS, and OS but not for DFS in patients undergoing hepatectomy for liver-only colorectal metastases. In the future, interventions to augment immune function could improve survival for low-LMR patients.

A case of metastatic pancreatic adenocarcinoma with prolonged survival after combination of neoadjuvant FOLFIRINOX therapy and synchronous distal pancreatectomy and hepatectomy.

In this case report we detail the treatment of a patient with pancreatic ductal adenocarcinoma and a solitary liver metastasis who received nine cycles of FOLFIRINOX therapy with favourable response. The patient subsequently underwent synchronous distal pancreatectomy and hepatectomy with an R0 resection followed by three further cycles of FOLFIRINOX. At the last follow-up, 2 years from operation and 28 months from the diagnosis of metastatic pancreatic adenocarcinoma the patient remains disease free.

Adjuvant or neoadjuvant therapy for operable esophagogastric cancer?

Esophagogastric cancer encompasses proximal squamous cell carcinoma of the esophagus, distal esophageal/junctional adenocarcinoma of the esophagus and gastric adenocarcinoma. These diseases have different etiologies, geographic incidences and biologies. This review mainly focuses on the treatment of operable esophagogastric adenocarcinoma. In Asia, adjuvant chemotherapy is commonly used for patients with gastric cancer following the landmark ACTS-GC trial. In contrast, perioperative chemotherapy is a standard of care in many Western countries based on the results of the MAGIC trial. Neoadjuvant chemotherapy is better tolerated than adjuvant therapy, and therefore dose intensity is likely to be maintained in a greater proportion of patients. In addition, neoadjuvant treatment can lead to tumor downstaging, increasing the likelihood of achieving a complete surgical resection. This may be particularly important in Western populations, as these patients often present with more advanced tumors than Asian patients. Adjuvant chemoradiotherapy is a standard treatment option in the USA for adenocarcinoma of the stomach or gastroesophageal junction as a result of the INT-0116 trial, but the benefit of this approach after a D2 resection has not been confirmed. Neoadjuvant chemoradiotherapy may reduce the risk of local recurrence and may be particularly beneficial for patients with squamous cell carcinoma as these tumors are more radiosensitive. However, patients with esophagogastric adenocarcinoma are more likely to relapse with distant disease, and therefore a systemic disease approach with chemotherapy is likely to be more beneficial than a purely localized treatment strategy for these patients.