Dilsa Mizrak Kaya

Advanced gastric adenocarcinoma: optimizing therapy options

ABSTRACT Introduction: Gastric adenocarcinoma (GAC) is the fifth most common cancer and third leading cause of cancer related mortality worldwide. When localized, cure is achievable with surgery and adjunctive therapies in some patients, however, once advanced, GAC is not a curable condition. Only two targeted agents (trastuzumab and ramucirumab) have been approved and apatinib was approved only in China. Because of the heterogeneous nature of GAC, it is not possible to assess a standard therapeutic approach. Areas covered: In this review, we aimed to describe the optimal systemic therapy regimens for advanced GAC. A literature search was performed to identify all phase II-III studies about advanced GAC from PubMed, clinicaltrials.gov, American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) websites. Expert commentary: A combination of a platinum compound and a fluoropyrimidine is ideal as first line therapy. Trastuzumab should be added if the tumor is HER2 positive. In the second line setting, paclitaxel/ramucirumab is preferred over ramucirumab alone. Recently, two similar molecular classifications for GAC have been proposed. A better understanding of molecular and immune biology of GAC could identify new therapeutic targets.

Metastatic Gastroesophageal Adenocarcinoma Patients Treated with Systemic Therapy Followed by Consolidative Local Therapy: A Nomogram Associated with Long-Term Survivors

Objective: Patients with metastatic gastroesophageal adenocarcinoma (MGEAC) have a poor but heterogeneous clinical course. Some patients have an unusually favorable outcome. We sought to identify clinical variables associated with more favorable outcomes. Methods: Of 246 patients with MGEAC, we identified 64 who received systemic therapy and eventually received local consolidation therapy. Univariate and multivariate Cox regression models were used, and a nomogram was developed. Results: Of these 64 patients, 61% had received consolidation chemoradiation (CRT) with doses of 50-55 Gy and 78% did not undergo surgery. The median follow-up time of survivors was 3.9 years, and the median overall survival (OS) from CRT start was 1.5 years (95% CI, 1.2-2.2). Surgery (as local consolidation) was an independent prognosticator for longer OS in the multivariate analysis (p = 0.02). The 5-year OS rate was 25% (SE = 6%). The contributors to the nomogram were longer duration of systemic therapy before CRT and the type of local therapy. Conclusions: Our data suggest that a subset of patients with MGEAC have an excellent prognosis (OS >5 years). However, these patients need to be identified during their clinical course so that local consolidation (CRT, surgery, or both) may be offered.

Nuclear expression of Gli-1 is predictive of pathologic complete response to chemoradiation in trimodality treated oesophageal cancer patients

Background:Predictive biomarkers or signature(s) for oesophageal cancer (OC) patients undergoing preoperative therapy could help administration of effective therapy, avoidance of ineffective ones, and establishment new strategies. Since the hedgehog pathway is often upregulated in OC, we examined its transcriptional factor, Gli-1, which confers therapy resistance, we wanted to assess Gli-1 as a predictive biomarker for chemoradiation response and validate it.Methods:Untreated OC tissues from patients who underwent chemoradiation and surgery were assessed for nuclear Gli-1 by immunohistochemistry and labelling indices (LIs) were correlated with pathologic complete response (pathCR) or <pathCR (resistance) and validated in a unique cohort.Results:Initial 60 patients formed the discovery set (TDS) and then unique 167 patients formed the validation set (TVS). 16 (27%) patients in TDS and 40 (24%) patients in TVS achieved a pathCR. Nuclear Gli-1 LIs were highly associated with pathCR based on the fitted logistic regression models (P<0.0001) in TDS and TVS. The areas under the curve (AUCs) for receiver-operating characteristics (ROCs) based on a fitted model were 0.813 (fivefold cross validation (0.813) and bootstrap resampling (0.816) for TDS and 0.902 (fivefold cross validation (0.901) and bootstrap resampling (0.902)) for TVS. Our preclinical (including genetic knockdown) studies with FU or radiation resistant cell lines demonstrated that Gli-1 indeed mediates therapy resistance in OC.Conclusions:Our validated data in OC show that nuclear Gli-1 LIs are predictive of pathCR after chemoradiation with desirable sensitivity and specificity.

Liquid biopsies in gastrointestinal malignancies: when is the big day?

ABSTRACT Introduction: Tumor tissue sample is currently the gold standard for diagnosing gastrointestinal cancers, but also for genomic/immune component analyses that can help in the selection of therapy. However, this approach of studying a ‘representative’ sample of the tumor does not address inherent heterogeneity. Liquid biopsies, mainly represented by circulating tumor cells, circulating tumor DNA, tumor exosomes, and microRNAs, have the potential to assess various biomarkers for early detection of cancer, carrying out genomic/immune profiling for not only selection of appropriate therapy but also to monitor effect of therapy. Areas covered: This review summarizes the current evidence in the literature on liquid biopsies in gastrointestinal cancers concerning diagnosis, prognosis, and response to therapy. The following terms were used in PubMed: ‘esophageal’, ‘gastric’, ‘colorectal’, ‘cancer’, ‘circulating tumor cells’, ‘circulating tumor DNA’, microRNA’, ‘diagnosis’, ‘prognosis’, ‘response’, ‘resistance’. Expert commentary: Data increasingly supports the potential of liquid biopsies for early detection, selection of therapy, and monitoring response to therapy. One major question is whether assaying various components of the blood would accommodate considerable context-dependent heterogeneity of gastrointestinal tumors. There are many potential strategies to exploit liquid biopsy use. To put them in to perspective, well-designed and meticulous prospective studies will be needed to prove their usefulness.

101 Long-Term Survivors Who Had Metastatic Gastroesophageal Cancer and Received Local Consolidative Therapy

Background: Through a multidisciplinary decision-making process, we developed a strategy of systemic therapy followed by local consolidative therapy (chemoradiation with/without surgery) in selected patients with metastatic gastroesophageal carcinoma (mGEAC). Only after a consensus during multidisciplinary discussions, local therapy was initiated. Methods: We identified 101 patients with mGEAC who had local consolidation. We evaluated the association between various clinical variables (location of the primary, location of metastases, duration of initial chemotherapy, histologic grade, and radiation dose) and overall survival (OS). Results: Of 101 patients, 71 had a proximal primary (esophageal, Siewert type I or II), and 30 patients had a distal primary (Siewert type III or distal). The median OS was 25.7 months (95% confidence interval [CI] 22.3-32.8). The OS rates at 2 and 5 years were 53.8% (95% CI 44.7-64.8) and 20.7% (95% CI 13.4-31.9), respectively. OS was highly associated with the location of the primary (median of 22.8 months for Siewert I/II vs. 41.5 months for Siewert III or distal, p = 0.03). The duration of initial chemotherapy was highly associated with OS (median of 21.8 months for <3 months vs. 32.5 months for ≥3 months, p = 0.004). Conclusion: Some mGEAC patients with a favorable clinical course can achieve a ∼20% 5-year survival rate with an approach that uses initial chemotherapy followed by multidisciplinary discussion to proceed with consolidation with local therapy. Patients with distal GEAC and those who receive initial chemotherapy for ≥3 months are the maximum beneficiaries.

Is targeted therapy possible for patients with gastric adenocarcinoma

Gastric adenocarcinoma (GAC) is a major global health problem with an estimated 951,600 new cases and 723,100 deaths in 2012 [1]. Treatment of GAC depends on the stage at diagnosis. At early stage (e.g. stage I), it can be potentially cured by endoscopic therapy or minimal surgery; however, at more advanced stage (e.g. stages II and III), it requires adjunctive therapy, in addition to surgery [2]. However, for all potentially curable cases, multidisciplinary evaluation and discussions are essential to determine the best initial approach. One should begin by completing thorough staging [2]. Once the clinical stage is determined, a consensus should be developed for optimized therapy for all patients with localized GAC. We also emphasize that patients with localized GAC are best treated at high-volume centers and be operated by high-volume surgeons [2]. Despite the application of multimodality treatment, recurrence rate is not negligible for localized GAC [2]. Adjunctive approaches vary in different regions of the world such as neoadjuvant chemotherapy or postoperative chemoradiotherapy are popular in the United States, preand postoperative chemotherapy is popular in Europe, and adjuvant chemotherapy in Asia [2,3]. For advanced-stage patients, outcome is more troublesome with an overall survival (OS) of less than 12 months despite the availability of active cytotoxic agents (fluoropyrimidines, platinum compounds, taxanes, and irinotecan) for GAC [3]. Today, a fluoropyrimidine and a platinum combination with or without trastuzumab according to human epidermal growth factor receptor (HER)-2 status is the standard of care in the first-line setting for advanced GAC [4]. Ramucirumab plus paclitaxel is the suggested second-line therapy as this combination provides better benefit than ramucirumab alone which has a marginal/negligible effect [5]. The survival prolongations provided by these agents are not satisfactory, and more targets and therapeutic agents need to be discovered.

Patterns of relapse in patients with localized gastric adenocarcinoma who had surgery with or without adjunctive therapy: Costs and effectiveness of surveillance

Purpose After therapy of localized gastric adenocarcinoma (GAC) patients, the costs of surveillance, relapse patterns, and possibility of salvage are unknown. Materials and Methods We identified 246 patients, who after having a negative peritoneal staging, received therapy (any therapy which included surgery) and were surveyed (every 3–6 months in the first 3 years, then yearly; ∼10 CTs and ∼7 endoscopies per patient). We used the 2016 Medicare dollars reimbursed as the “costs” for surveillance. Results Common features were: Caucasians (57%), men (60%), poorly differentiated histology (76%), preoperative chemotherapy (74%), preoperative chemoradiation (59%), and had surgery (100%). At a median follow-up of 3.7 years (range, 0.1 to 18.3), the median overall survival (OS) was 9.2 years (95% CI, 6.0 to 11.2). Tumor grade (p = 0.02), p/yp stage (p < 0.001), % residual GAC (p = 0.05), the R status (p = 0.01), total gastrectomy (p = 0.001), and relapse type (p = 0.02) were associated with OS. Relapse occurred in 79 (32%) patients (only 8% were local-regional) and 90% occurred within 36 months of surgery. P/yp stage (p < 0.001) and total gastrectomy (p = 0.01) were independent prognosticators for OS in the multivariate analysis. Only 1 relapsed patient had successful salvage therapy. The estimated reimbursement for imaging studies and endoscopies was

Potentially Curable Cancers of the Esophagus and Stomach

1,761,221.91 (marked underestimation of actual costs). Conclusions The median OS of localized GAC patients was excellent with infrequent local-regional relapses. Rigorous surveillance had a low yield and high “costs”. Our data suggest that less frequent surveillance intervals and limiting expensive investigations to symptomatic patients may be warranted.

Barrett’s Esophagus after Bimodality Therapy in Patients with Esophageal Adenocarcinoma

Gastric and gastroesophageal adenocarcinomas continue to be a major health burden globally and collectively represent the third leading cause of cancer death. Among patients with metastatic disease, most die of their cancer because of the limited number of modestly effective treatment regimens available today. The progress against these cancers has been slow compared with many other solid tumors despite many attempts. In-depth molecular profiling has also not been completed. Even when these cancers are localized, they impose considerable challenges for the patient, relatives, and treatment team alike. Localized gastric or gastroesophageal cancer is best managed with a multidisciplinary approach. This review focuses on the management of localized cancers by reviewing the current literature and explaining certain principles that help guide therapy for these patients. The future, however, will afford numerous opportunities, including exploitation of initial data from The Cancer Genome Atlas, to identify novel targets and drugs, harness the prowess of the immune system, and customize therapy for each patient.

Immune checkpoint blockade therapy for esophageal squamous cell carcinoma

Introduction: Barrett’s esophagus (BE) may be present in patients with esophageal adenocarcinoma (EAC) after bimodality therapy (BMT). There is no specific guidance for follow-up of these patients with regard to the presence of BE or dysplasia. In this study, we assessed the outcomes of patients who, after BMT, had BE and those who did not. Method: Patients with EAC who had BMT were identified and analyzed retrospectively in two groups, with and without BE. We compared patient characteristics and outcome variables (local, distant, and no recurrence). Results: Of 228 patients with EAC, 68 (29.8%) had BE before BMT. Ninety-eight (42.9%) had BE after BMT, and endoscopic intervention was done in 11 (11.2%). With a median follow-up of 37 months, the presence of post-BMT BE was not significantly associated with overall survival (OS) and local recurrence-free survival (LRFS). Similarly, endoscopic intervention was not significantly associated with OS and LRFS. Fifty (73.5%) patients with BE before BMT had BE after BMT (p < 0.0001). Conclusion: The presence of BE after BMT was not associated with increased risk of local recurrence. The local recurrence rate was not influenced by endoscopic intervention. Prospective studies are warranted to generate guidance for intervention, if necessary, for this group of EAC patients.