Elena Elimova

Importance of Surveillance and Success of Salvage Strategies After Definitive Chemoradiation in Patients With Esophageal Cancer

PURPOSE Patients with esophageal carcinoma (EC) who are treated with definitive chemoradiotherapy (bimodality therapy [BMT]) experience frequent relapses. In a large cohort, we assessed the timing, frequency, and types of relapses during an aggressive surveillance program and the value of the salvage strategies. PATIENTS AND METHODS Patients with EC (N = 276) who received BMT were analyzed. Patients who had surgery within 6 months of chemoradiotherapy were excluded to reduce bias. We focused on local relapse (LR) and distant metastases (DM) and the salvage treatment of patients with LR only. Standard statistical methods were applied. RESULTS The median follow-up time was 54.3 months (95% CI, 48.4 to 62.4). First relapses included LR only in 23.2% (n = 64), DM with or without LR in 43.5% (n = 120), and no relapses in 33.3% (n = 92) of patients. Final relapses included no relapses in 33.3%, LR only in 14.5%, DM only in 15.9%, and DM plus LR in 36.2% of patients. Ninety-one percent of LRs occurred within 2 years and 98% occurred within 3 years of BMT. Twenty-three (36%) of 64 patients with LR only underwent salvage surgery, and their median overall survival was 58.6 months (95% CI, 28.8 to not reached) compared with those patients with LR only who were unable to undergo surgery (9.5 months; 95% CI, 7.8 to 13.3). CONCLUSION Unlike in patients undergoing trimodality therapy, for whom surveillance/salvage treatment plays a lesser role,(1) in the BMT population, approximately 8% of all patients (or 36% of patients with LR only) with LRs occurring more than 6 months after chemoradiotherapy can undergo salvage treatment, and their survival is excellent. Our data support vigilant surveillance, at least in the first 24 months after chemotherapy, in these patients.

Medical management of gastric cancer: A 2014 update

Gastric cancer represents a serious health problem on a global scale. It is the second leading cause of cancer-related death worldwide. Novel therapeutic targets are desperately needed because the meager improvement in the cure rate of about 10% realized by adjunctive treatments to surgery is unacceptable as > 50% patients with localized gastric cancer succumb to their disease. Either postoperative chemoradiotherapy (United States), pre-and post-operative chemotherapy (Europe), and adjuvant chemotherapy after a D2 resection (Asia) can all be regarded as standards of care in the localized gastric cancer management. In metastatic disease the addition of trastuzumab to chemotherapy is standard of care in Her2 positive disease. In the HER2 negative population, the treatments remain limited. In the first line setting, the standard of care is a combination of fluoropyrimidine and platinum containing chemotherapy, with or without epirubicin or docetaxel. The results of targeted therapy trials have by and large been disappointing, but none of these trials looked at an appropriately enriched population. Finally there is a meager overall survival benefit in treating patients with metastatic disease in the second line setting, with either irinotecan, docetaxel or ramucirumab however none of these drugs have been compared head to head in a well-powered randomized controlled trial.

A validated miRNA profile predicts response to therapy in esophageal adenocarcinoma

In the current study we present a validated miRNA signature to predict pathologic complete response (pCR) to neoadjuvant chemoradiation in esophageal adenocarcinoma.

Distribution and Timing of Distant Metastasis after Local Therapy in a Large Cohort of Patients with Esophageal and Esophagogastric Junction Cancer

Background: Patients with localized esophageal and esophagogastric junction cancer (EAC) receive chemoradiation and then surgery (trimodality, TMT) or definitive chemoradiation (bimodality, BMT). Distant metastases (DMs) are common but the details of their distribution and timing in a large cohort have not been described. Methods: 629 patients with localized EAC who had TMT or BMT were analyzed. Standard statistical methods were used to define the end points. Results: The median follow-up time was 37.2 months (interquartile range 17.8-65.0). Of 356 TMT patients, 33% (119) developed DM as their first relapse and of 273 BMT patients, 40% (109) developed DM; 91% (TMT) and 96% (BMT) of the DMs were diagnosed within 2 years of local therapy. The most common sites of DM were: lung, distant nodes, liver, peritoneal cavity, bone, brain and pleura in order of frequency. The median overall survival of TMT patients with DM was 10.2 months (95% CI 7.8-12.7) and that for BMT patients with DM was 7.8 months (95% CI 5.7-9.9). Conclusions: Following TMT or BMT, ≥33% of patients developed DMs and most of these occurred within 2 years (>90%) of local therapy. A clinical model is desirable that associates clinical parameters with a high risk for DM in TMT-eligible patients prior to surgery.

Comprehensive geriatric assessment in patients with gastric and gastroesophageal adenocarcinoma undergoing gastrectomy

The purpose of this study was to identify clinical and geriatric assessment variables associated with outcome in patients with gastric adenocarcinoma who have undergone gastrectomy.

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.

Anti-angiogenic agent ramucirumab: meaningful or marginal?

Ramucirumab (IMC-1121B) targets VEGFR-2. Ramucirumab is being investigated in many malignancies including gastric cancer. The Phase III trial in patients with advanced breast cancer failed to improve the primary end point The REGARD trial, a Phase III study, in patients with advanced gastric cancer in the second line setting, had a marginal improvement in overall survival but did not achieve the expected hazard ratio target (of 0.69) and the median duration of therapy with ramucirumab was meager 8 weeks (only 2 weeks longer than the placebo’s). Other notable agents in the second line setting are docetaxel and irinotecan. Preliminary results of the RAINBOW trial suggest that ramucirumab may be providing more than marginal advantage. In this review, we briefly summarize the process of angiogenesis and address the emerging cost-benefit issues that surround all newly developed agents including ramucirumab.

It Is Time to Stop Using Epirubicin to Treat Any Patient With Gastroesophageal Adenocarcinoma

TO THE EDITOR: We read the CALGB (Cancer and Leukemia Group B) 80403 study results with interest. This randomized threearm trial added cetuximab to each of three chemotherapy regimens: ECF (epirubicin, cisplatin, and fluorouracil [FU]), IC (irinotecan plus cisplatin), and FOLFOX (oxaliplatin, leucovorin [LV], and FU). The intention of this trial design was to establish a biochemotherapy regimen that might be suitable as an experimental arm in a future phase III trial. However, none should be considered for further development, because several phase III trials have documented the lack of benefit from the empiric addition of epidermal growth factor receptor inhibitior (in a variety of combinations and in different settings) in patients with gastroesophageal cancer. In theCALGB80403 study, IC plus cetuximab was considered most toxic, and ECF plus cetuximab was not better than FOLFOX plus cetuximab for any efficacy end point. In another related study, ECF was compared with FOLFIRI and was not superior in efficacy; however, both regimens produced considerable toxicities, including 4% treatment-related mortality. We summarize the mounting evidence against the use of epirubicin in the treatment of patients with gastric or gastroesophageal adenocarcinoma (GEAC). For patients with advanced GEAC, only three drugs have demonstrated prolonged overall survival (OS) in the first-line therapy setting, forming the level I evidence. These agents are docetaxel, cisplatin, and trastuzumab. Epirubicin has never achieved this distinction. ECF has had a wobbly start. In the first prospective randomized phase III trial, 274 patients with advanced GEAC received FAMTX (methotrexate, FU, and doxorubicin) or ECF. The median OS duration was 8.9 months with ECF and 5.7 months with FAMTX (P, .001). However, in this comparison, rather than ECF establishing a new OS benchmark, FAMTX had worse outcomes compared with previous results. Despite this poor performance, ECF is regularly prescribed in certain locations for advanced GEAC in the first-line setting. In patients with localized GEAC, ECF increased the cure rate by approximately 10%. After this trial, ECF use gained momentum. However, this ECF trial provided evidence only that preoperative chemotherapy was better than surgery alone; it did not exclude similar benefits from other chemotherapy combinations. A subsequent French study in which cisplatin and FU were administered as preoperative chemotherapy demonstrated similar benefits, as did the trial with ECF. Two important studies provide further documentation that epirubicin does not provide anOS advantage for patients with localized GEAC. The first trial was conducted by CALGB. Patients with resected GEAC were randomly assigned to either one cycle of FU plus LV, followed by 45-Gy radiotherapy (1.8 Gy per day) and concurrent FU (200mg/m per day as infusion throughout radiotherapy), followed by two additional cycles of FU plus LVor one cycle of ECF followed by 45-Gy radiotherapy (1.8 Gy per day) and concurrent FU, followed by two additional cycles of reduced-dose ECF. The trial enrolled 546 patients.With 242 deaths reported, therewas no advantage for ECF over FU (hazard ratio, 1.03; 95% CI, 0.80 to 1.34; P5 .80). In the second study, the Medical Research Council OEO5 trial, 897 patients with localized GEAC were randomly assigned to either two cycles of preoperative cisplatin and FU or four cycles of preoperative ECX (epirubicin, cisplatin, and capecitabine). The primary end point was the 3-year OS rate, which was 39% for cisplatin plus FU and 42% for ECX (P5 .30). Clearly, epirubicin can no longer be recommended in the localized GEAC setting based on these two studies. Additionally, administration of more than two cycles of preoperative chemotherapy does not provide an advantage. One can argue that a trial comparing ECF (or a modified version of ECF) with a platinum compound and FU in advanced GEAC is needed to settle the issue of whether epirubicin provides an OS advantage for patients with GEAC. However, considering the overall poor performance of epirubicin combinations in the many trials we have described (in which it never showed benefit against two-drug combinations or even single-agent FU), we cannot justify the use of precious resources to launch a new trial to address this issue. We do not recommend epirubicin-based treatment for any patient with GEAC.

Medical management of gastric cancer: a 2017 update

Gastric cancer remains a considerable health burden throughout the world. The Cancer Genome Atlas (TCGA) analysis has recently unveiled 4 genotypes of gastric cancer with data not ready to change treatment strategy yet. A multimodality approach to therapy is the cornerstone of screening, diagnosing, staging, treating and supporting patients with gastric cancer. The evidence‐based approach to localized gastric cancer (>cT1b) is to use an either preoperative or postoperative strategy to maximize the benefit of surgery. The focus of future research is to optimize chemotherapy regimens, determine the role of radiation therapy and investigate the effect of treatment timing. In metastatic gastric cancer, biologic therapies have been introduced targeting markers shown to be prognostic. The results of ongoing randomized controlled phase 3 trials using targeted and immunotherapy agents, either in combination or alone, have the potential to alter the current treatment landscape of advanced gastric cancer.

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.