Yusuke Shimodaira

18-fluorodeoxy-glucose positron emission computed tomography as predictive of response after chemoradiation in oesophageal cancer patients.

INTRODUCTION The purpose of this study was to evaluate if a baseline, an interim or a post-chemoradiation (CTRT) 18-fluorodeoxy-glucose positron emission computed tomography (18F-FDG PET/CT) studies could provide information on pathologic response to CTRT and overall survival (OS). MATERIALS AND METHODS Thirty-one patients with histologically proven adenocarcinoma or squamous cell carcinoma of the oesophagus, fit for trimodality therapy were prospectively enrolled. Most were men (93.5%), and had a stage III cancer (74.2%). Chemotherapy consisted of oxaliplatin/5-fluorouracil (45.2%) and taxane/5-fluorouracil (54.8%). All patients underwent a baseline, an interim (performed 12 ± 2 days after the onset of CTRT) and a post-CTRT 18F-FDG PET/CT study. The 18F-FDG PET/CT variables evaluated were at baseline, interim and post-CTRT studies maximum standardised uptake value (SUV max) and total lesion glycolysis (TLG). Clinical and 18F-FDG PET/CT parameters were correlated with pathologic complete response (pathCR) and OS. RESULTS Among the 31 patients studied, 61.3% achieved a clinical complete response (cCR) and 87.1% had surgery. The median OS was 35.1 months (95% confidence interval (CI): 19.9-NA). PathCR rate was 22.2%. There was only a marginal association between cCR and pathCR (p = 0.06). None of the other variables was predictive of pathCR. There was association between OS and baseline TLG (p = 0.03) at the optimal cutoff TLG value of 75.15. Additionally, TLG and ΔTLG post-CTRT were also associated with OS (p = 0.01 and 0.03, respectively). CONCLUSION None of the PET parameters is predictive of pathCR but TLG at baseline and post-CTRT are prognostic of OS.

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.

Prognosis of gastric adenocarcinoma patients with various burdens of peritoneal metastases

Peritoneal metastases (PM) in patients with gastric adenocarcinoma (GAC) may be identified by diagnostic laparoscopy (DL) or imaging (I). Although prognosis is poor, some patients have excellent outcome. We compared the overall survival (OS) of patients in 3 groups: those with positive cytology (CY+) by DL (DL‐CY+), those with gross PM (GPM) by DL (DL‐GPM+) and with GPM obvious on I (I‐GPM+).

Evolution of gastric surgery techniques and outcomes.

Surgical management of gastric cancer improves survival. However, for some time, surgeons have had diverse opinions about the extent of gastrectomy. Researchers have conducted many clinical studies, making slow but steady progress in determining the optimal surgical approach. The extent of lymph node dissection has been one of the major issues in surgery for gastric cancer. Many trials demonstrated that D2 dissection resulted in greater morbidity and mortality than D1 dissection. However, long-term outcomes demonstrated that D2 dissection resulted in longer survival than D1 dissection. In 2004, the Japan Clinical Oncology Group reported a pivotal trial which was performed to determine whether para-aortic lymph node dissection combined with D2 dissection was superior to D2 dissection alone and found no benefit of the additional surgery. Gastrectomy with pancreatectomy, splenectomy, and bursectomy was initially recommended as part of the D2 dissection. Now, pancreas-preserving total gastrectomy with D2 dissection is standard, and ongoing trials are addressing the role of splenectomy. Furthermore, the feasibility and safety of laparoscopic gastrectomy are well established. Survival and quality of life are increasingly recognized as the most important endpoints. In this review, we present perspectives on surgical techniques and important trials of these techniques in gastric cancer patients.

The Proportion of Signet Ring Cell Component in Patients with Localized Gastric Adenocarcinoma Correlates with the Degree of Response to Pre-Operative Chemoradiation

Background: Patients with localized gastric adenocarcinoma (LGAC), who get pre-operative therapy, have heterogeneous/unpredictable outcomes. Predictive clinical variables/biomarkers are not established. Methods: We analyzed 107 LGAC patients who had chemoradiation and surgery. LGACs were grouped for (1) presence/absence of signet ring cell histology (SRC) and (2) histologic grade: G2 or G3. %SRC was assessed (0, 1-10, 11-49, and 50-100%) and correlated with pathologic complete response (pathCR) or <pathCR in the resected specimens. Results: Most patients were men (60%), had stage cIII LGAC (50%), and received chemotherapy before chemoradiation (93%). Most had G3 tumors (78%) and SRC (58%). Presence of SRC was associated with a lower rate of pathCR (11 vs. 36%, p = 0.004), and the association remained significant even with a low percentage of SRC (1-10%; p = 0.014). The higher the fraction of SRC, the lower was the probability of pathCR (p = 0.03). G3 and SRC led to a shorter overall survival (OS) (p = 0.046 and p = 0.038, respectively). yp stage independently prognosticated OS and recurrence-free survival (p < 0.001). Conclusion: Our novel findings suggest that LGACs with SRC are relatively chemoradiation resistant compared to LGACs without SRC. A higher fraction of SRC is associated with higher resistance. Upon validation/biomarker(s) evaluation, reporting of the fraction of SRC may be warranted.

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

The best timing for administering systemic chemotherapy in patients with locally advanced rectal cancer

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.

Exploiting Molecular and Immune Biology of Gastric and Gastroesophageal Adenocarcinomas to Discover Novel Therapeutic Targets

Over the past several decades, outcomes for patients with rectal cancer have improved considerably. However, several questions have emerged as survival times have lengthened and quality of life has improved for these patients. Currently patients with locally advanced rectal cancer (LARC) are often recommended multimodality therapy with fluoropyrimidine-based chemotherapy (CT) and radiation followed by total mesorectal excision (TME), with consideration given to FOLFOX before chemoradiotherapy (CRT). Recently, Garcia-Aguilar and colleagues reported in Lancet Oncology that the addition of mFOLFOX6 administered between CRT and surgery affected the number of patients achieving pathologic complete response (pathCR), which is of great interest from the standpoint of pursuit of optimal timing of systemic CT delivery. This was a multicenter phase II study consisting of 4 sequential treatment groups of patients with LARC, and they reported that patients given higher number CT cycles between CRT and surgery achieved higher rates of pathCR than those given standard treatment. There was no association between response improvement and tumor progression, increased technical difficulty, or surgical complications. Ongoing phase III clinical trial further assessing this strategy might result in a paradigm shift.