Staging accuracy of endoscopic ultrasound for esophageal cancer after neoadjuvant chemotherapy: a meta‐analysis and systematic review

This study aims to evaluate the accuracy of endoscopic ultrasound (EUS) in the staging of esophageal cancer after neoadjuvant chemotherapy (NAC). Articles were searched in Medline, Pubmed, Cochrane Database of Systemic Reviews, Google scholar, and EMBASE. Two reviewers independently searched and extracted data. Meta‐analysis of the accuracy of EUS was analyzed by calculating pooled estimates of sensitivity, specificity, likelihood ratios (LR), and diagnostic odds ratio (DOR). Pooling was conducted using either fixed‐effects model or random‐effects model depending on the heterogeneity across studies. Sixteen studies (n = 724) were included in this analysis. The pooled sensitivity and specificity of EUS to diagnose T1 stage tumor was 23% (95% confidence interval [CI] 16–32%) and 95% (95%CI 93–97%), respectively. For T2 stage, EUS had a pooled sensitivity and specificity of 29% (95%CI 19–41%) and 84% (95%CI 77–88%). The pooled sensitivity and specificity of EUS were 81% (95%CI 72–88%) and 42% (95%CI 33–52%) in determining T3 stage tumor. To diagnose T4 stage tumor, EUS had a pooled sensitivity of 43% (95%CI 31–56%) and specificity of 96% (95%CI 94–97%), respectively. In determining N stage, the pooled sensitivity and specificity of EUS were 69% (95%CI 58–79%) and 52% (95%CI 42–62%). EUS is a moderately accurate technique in staging esophageal cancer after NAC. Its sensitivity is relatively high in T3 while specificity is high in other T stages (T1, T2, and T4). Tumors restaged by EUS as T4 should not be assigned to surgery because it is very likely to be inoperable. EUS is not reliable for N staging with its poor sensitivity and specificity. Subgroup analysis shows that staging accuracy did not improve with time.     

Correlation between pretherapeutic d-dimer levels and response to neoadjuvant chemotherapy in patients with advanced esophageal cancer

SUMMARY.  Neoadjuvant chemotherapy may improve survival of responders in esophageal cancer patients but is useless and harmful in non-responders. Thus, it is important to predict the effect of the chemotherapy, and that any predictor must be applicable clinically. The aim of this study is to examine the correlation between pretherapeutic hypercoagulopathy as determined by plasma d -dimer levels and response to chemotherapy. In 71 patients with esophageal cancer who underwent neoadjuvant chemotherapy (cisplatin, adriamycin and 5-fluorouracil) followed by surgery, plasma d -dimer levels were measured before chemotherapy and the clinical and pathological responses to chemotherapy were assessed at 4 weeks after therapy (after surgery). Pretherapeutic plasma d -dimer level was significantly lower in clinical responders (complete response/partial response [CR/PR]; 0.62 ± 1.10 µg/mL, mean ± SD) than in non-responders (no change/progressive disease [NC/PD]; 1.15 ± 1.08 µg/mL, P  = 0.0491), and in pathological responders (Grade 1b-3; 0.62 ± 1.11 µg/mL) and non-responders (Grade 0–1a; 1.15 ± 1.05 µg/mL, P  = 0.0107). The optimal cut-off level of the plasma d -dimer levels for predicting clinical and pathological responses was 0.6 µg/mL. Then, sensitivity and specificity for the prediction of CR/PR were 68% and 73%, and those for Grade 1b–3 were 91% and 69%, respectively. Our results suggested that pretherapeutic plasma d -dimer level correlated significantly with clinical and pathological responses to chemotherapy. Pretherapeutic plasma d -dimer level can be used as a predictor for chemosensitivity.     

Assessment of changes in tumor heterogeneity following neoadjuvant chemotherapy in primary esophageal cancer

To assess the changes in computed tomography (CT) tumor heterogeneity following neoadjuvant chemotherapy in esophageal cancer. Thirty‐one consecutive patients who received neoadjuvant chemotherapy for esophageal cancer were identified. Analysis of primary tumor heterogeneity (texture) was performed on staging and post‐chemotherapy CT scans. Image texture parameters (mean grey‐level intensity, entropy, uniformity, kurtosis, skewness, standard deviation of histogram) were derived for different levels of image filtration (0–2.5). Proportional changes in each parameter following treatment were obtained. Comparison between pathological tumor response and texture parameters was analyzed using Mann–Whitney U‐test. The relationship between CT texture and overall survival) was estimated using the Kaplan–Meier method. Tumor texture became more homogeneous after treatment with a significant decrease in entropy and increase in uniformity (filter 1.0 and 2.5). Pretreatment (filter 1.5, P = 0.006) and posttreatment standard deviation of histogram (filter 1.0, P = 0.009) showed a borderline association with pathological tumor response. A proportional change in skewness <0.39 (filter 1.0) was associated with improved survival (median overall survival 36.1 vs. 11.1 months; P < 0.001). CT tumor heterogeneity decreased following neoadjuvant chemotherapy and has the potential to provide additional information in primary esophageal cancer.     

Current concepts and future potential in neoadjuvant chemotherapy for esophageal cancer

Many trials have evaluated preoperative chemotherapy for the treatment of locally advanced esophageal cancer (LAEC). Most studies were small with conflicting results and no clear evidence of survival advantage. However, two large trials that included squamous cell carcinomas and adenocarcinomas of the esophagus produced opposite outcomes with one showing limited benefit and the other showing none. Recent meta-analyses suggest only a modest benefit from induction chemotherapy in the treatment of LAEC. Two factors associated with prolonged survival are: (1) an R0 resection and (2) pathological complete remission. Preoperative chemotherapy is preferred in Europe for adenocarcinomas; however, chemoradiation has been the treatment of choice in the US. The individualization and optimization of therapy for esophageal cancer patients may come from an in-depth understanding of molecular biology and the development of predictive biomarkers. The use of targeted and immunotherapy agents in the preoperative setting are also promising and warrant further evaluation.     

Comparison of the prognostic value of the 6th and 7th editions of the Union for International Cancer Control TNM staging system in patients with lower esophageal cancer undergoing neoadjuvant chemotherapy followed by surgery

Carcinoma of the esophagus is classified according to the Union for International Cancer Control (UICC) TNM staging system. The 7th edition of the UICC TNM staging system was published in 2009. This is the first study to compare the prognostic value of the TNM 6th and 7th editions in patients with esophageal carcinoma treated with chemotherapy followed by surgery. Two hundred forty‐three patients with esophageal carcinoma were retrospectively selected from two referral centers. All patients received chemotherapy before surgery. Histopathologic data from the resection specimens were retrieved and restaged according to the TNM 7th edition. Disease‐specific survival curves were plotted for depth of tumor invasion (ypT), lymph node status (ypN), and ypTNM stage and then compared. Median follow‐up after surgery was 2.5 years (range 0.2–9 years). Survival analysis using the log‐rank method revealed that there was a significant difference in survival between ypT4 disease and ypT3 disease (P= 0.003), but no difference between ypT0, ypT1, ypT2, and ypT3 categories irrespective of TNM edition used. Survival probability was significantly different between ypN0 and ypN1 (P= 0.001 for TNM 6th and 7th edition), as well as ypN2 and ypN3 (TNM 7th edition, P= 0.004), but not between ypN1 and ypN2 (TNM 7th edition, P= 0.89). Neither the TNM 6th nor 7th edition T staging provides accurate survival probability stratification. However, the advantage of the 7th edition is the introduction of a third tier in survival stratification for patients with nodal involvement.     

Significant understaging is seen in clinically staged T2N0 esophageal cancer patients undergoing esophagectomy

This study aimed to determine the impact of preoperative staging on the treatment of clinical T2N0 (cT2N0) esophageal cancer patients undergoing esophagectomy. We reviewed a retrospective cohort of 27 patients treated at a single institution between 1999 and 2011. Clinical staging was performed with computed tomography, positron emission tomography, and endoscopic ultrasound. Patients were separated into two groups: neoadjuvant therapy followed by surgery (NEOSURG) and surgery alone (SURG). There were 11 patients (41%) in the NEOSURG group and 16 patients (59%) in the SURG group. In the NEOSURG group, three of 11 patients (27%) had a pathological complete response and eight (73%) were partial or nonresponders after neoadjuvant therapy. In the SURG group, nine of 16 patients (56%) were understaged, 6 (38%) were overstaged, and 1 (6%) was correctly staged. In the entire cohort, despite being clinically node negative, 14 of 27 patients (52%) had node‐positive disease (5/11 [45%] in the NEOSURG group, and 9/16 [56%] in the SURG group). Overall survival rate was not statistically significant between the two groups (P = 0.96). Many cT2N0 patients are clinically understaged and show no preoperative evidence of node‐positive disease. Consequently, neoadjuvant therapy may have a beneficial role in treatment.     

Survival outcomes of resected patients who demonstrate a pathologic complete response after neoadjuvant chemoradiation therapy for locally advanced esophageal cancer

A variety of strategies, using chemotherapy, radiation therapy, and surgical resection have been employed in the treatment of locally advanced esophageal cancer. No strategy has proven superior, and poor long-term survival is anticipated. A survival benefit has been suggested for patients who achieve a pathologic complete response (pCR) following neoadjuvant chemoradiation therapy. We examined the collective results at three institutions of patients who achieved a pCR following neoadjuvant chemoradiation therapy. A retrospective, chart-based review was conducted. Kaplan-Meier calculations were used to determine overall and disease-free survival. Between 1995 and 2002, 229 patients were treated with neoadjuvant chemoradiation followed by surgery as a planned approach for locally advanced esophageal cancer. Forty-one patients (18%) demonstrated pCR and were the focus of this study. Histology was adenocarcinoma in 29, squamous in 10, and adenosquamous/undifferentiated in two patients. Forty patients were staged by endoscopic ultrasound prior to neoadjuvant therapy and all demonstrated a T-stage of 2 or higher, while 19 had evidence of nodal metastasis. Four patients died in the perioperative period. The remaining patients have been followed for an average of 46 months. Overall survival at 5 years was 56.4% and a median survival has not been reached. Esophageal cancer patients who demonstrate a pCR following neoadjuvant chemoradiation are a select subset who demonstrate excellent long-term survival. Identification of clinical variables or biomarkers predictive of pCR may therefore optimize treatment strategies of patients with locally advanced esophageal cancer.     

Effects of neoadjuvant chemotherapy on primary tumor and lymph node metastasis in esophageal squamous cell carcinoma: additive association with prognosis

SUMMARY.  Neoadjuvant chemotherapy (NACT) is widely used to treat esophageal squamous cell carcinoma with lymph node metastasis (ESCC). However, NACT frequently has differential effects on primary tumor (PT) and lymph node metastasis (LNM). The clinical significance of this phenomenon remains unclear. Reduction in tumor size of PT and LNM was evaluated separately in 47 node-positive ESCC patients undergoing NACT, followed by surgical resection. We analyzed the prognostic significance and various clinicopathological parameters. NACT resulted in an average reduction rate of 45.5% for PT and 36.6% for LNM; the correlation between these rates was weak but significant ( r ² = 0.122, P  = 0.016). The reduction rates in both PT and LNM were significant prognostic factors, with the maximal significance with cut-off at 30% size reduction for PT (3-year survival, 47.3 vs. 8.3%, P  = 0.0004) and 20% for LNM (51.3 vs . 7.1%, P  = 0.0013). When these cut-off values were used to define NACT response, 28 patients (59%) were deemed responders for both PT and LNM, while 7 (15%) were nonresponders for both, and the response was inconsistent in 12 patients (26%). Only both PT/LNM responders showed good survival rates, with the remaining categories showing poor survival (3-year survival 60.5 vs . 5.3% P  < 0.0001). Multivariate analysis identified neither the PT nor the LNM response alone as an independent prognostic factor; however the combined PT/LNM response was identified as an independent prognostic factor (hazard ratio [HR] 2.861, P  = 0.0255) in addition to the number of histological lymph node metastases (HR 2.551, P  = 0.0328). The response to NACT in LNM and PT correlates closely with postoperative survival. A good response in both enhances the postoperative prognosis.     

Epirubicin, cyclophosphamide and weekly paclitaxel as neoadjuvant chemotherapy for stage II and III breast cancer

Purpose: To assess the efficacy and the toxicity of a new combination of epirubicin, cyclophosphamide and paclitaxel as neoadjuvant chemotherapy for breast cancer. Methods: Patients with stage II and III breast cancer received 3–4 cycles of epirubicin 75 mg/m² plus cyclophosphamide 600 mg/m² on day 1, and paclitaxel at a dose of 100 mg on days 1, 8, 15 and 22 on a 28-day cycle. Results: Forty-nine patients were enrolled in the study. Stage II was present in 16 patients (32.7%) and stage III in 33 patients (67.3%). Relevant toxicities were nausea/vomiting grades III–IV in 6 patients (12.2%) and neutropenia grade III–IV in 33 patients (67.3%). The overall clinical response rate was 83.7%. Partial response was observed in 25 patients (51%), complete response in 16 patients (32.7%), stable disease in 7 patients (14.3%) and progression in 1 patient. Thirty-three non-inflammatory breast cancer patients underwent surgery, 29 with breast-conserving surgery (87.9%). Pathological complete response was found in 5 patients (15.1%). Conclusions: The combination of epirubicin, cyclophosphamide and weekly paclitaxel as given in this study is safe and shows good activity in the neoadjuvant setting of stage II and III breast cancer patients.     

Increasing the interval between neoadjuvant chemoradiotherapy and surgery in esophageal cancer: a meta‐analysis of published studies

The aim of this meta‐analysis was to clarify whether a longer interval between the end of neoadjuvant chemoradiotherapy (nCRT) and surgery is associated with better outcomes in esophageal cancer. nCRT followed by surgery is the most common approach for patients with resectable esophageal cancer. Operations are performed within 2–8 weeks after nCRT; however, the optimal interval between nCRT and surgery for esophageal cancer is unknown. We performed a systematic literature search in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Clinical Trials database for studies published between January 2000 and December 2014. Eligible studies were prospective or retrospective studies of esophageal cancer that assessed the effects of intervals longer or shorter than 7–8 weeks between the end of nCRT and surgery. The primary end‐points were the overall survival (OS) and pathologic complete response (pCR). Secondary end‐points were anastomotic leak, R0 resection, and postoperative mortality rate. A meta‐analysis was performed to estimate odds ratios (ORs) using fixed‐effect and random‐effect models, with Review Manager 5.2. The five studies that met the eligibility requirements included 1,016 patients: 520 in the shorter interval group (≤7–8 weeks) and 496 in the longer interval group (>7–8 weeks). The results of our meta‐analysis indicate that a longer interval between nCRT and surgery may be disadvantageous for 2‐year OS (OR = 1.40, 95% confidence interval [CI]: 1.09–1.80, P = 0.010) and R0 resection rate (OR = 1.71, 95% CI: 1.14–2.22, P = 0.009). The pCR, anastomotic leak rate, and postoperative morbidity were similar in the two groups. A longer interval (more than the standard 7–8 weeks) from the end of preoperative nCRT to surgery did not increase the rate of pCR in esophageal cancer, and the different intervals had similar effects on anastomotic leak rate and postoperative mortality rates. However, the longer interval between nCRT and surgery may be disadvantageous for long‐term OS. These results should be validated prospectively in a randomized trial.     

Baseline nutritional status is prognostic factor after definitive radiochemotherapy for esophageal cancer

Identify prognostic factors for survival and patterns of treatment failure after definitive radiochemotherapy for esophageal cancer. Between 2003 and 2006, 143 patients with squamous cell carcinoma and adenocarcinoma of the esophagus were retrospectively reviewed. Median age was 65 years (42–81). Median radiation dose was 62.5 Gy (38–72) with 1.8–2 Gy fraction. Median follow‐up was 20.8 months (2.8–92.4). Three and 5‐year local recurrence‐free survival rates were 58.3% and 50.9%. In univariate analysis, traversable esophageal stricture was a prognostic factor. Three, 5‐year locoregional recurrence‐free survival rates were 42.4% and 34.9%. In multivariate analysis, traversable esophageal stricture and stage < IIB were independent prognostic factors. Three and 5‐year disease‐free survival rates were 30.5% and 25.9%. In multivariate analysis, Nutritional Risk Index (NRI) ≥ 97.5 and performance status (PS) = 0 were independent prognostic factors. Median, 3, and 5‐year overall survival rates were 22.1 months, 34.4%, and 19.8%. In multivariate analysis, independent prognostic factors were NRI ≥ 97.5 and PS = 0. Median survival times for the NRI classes (no denutrition, moderate and severe denutrition) were 29.5, 19.7, and 12 months (P = 0.0004), respectively. A major impact of baseline NRI was found in terms of survival; it should be included in future prospective trials.     

Inflammation-based prognostic score is a useful predictor of postoperative outcome in patients with extrahepatic cholangiocarcinoma

Background/purpose

Recent studies have revealed that the Glasgow prognostic score (GPS), an inflammation-based prognostic score, is useful for predicting outcome in a variety of cancers. This study sought to investigate the significance of GPS for prognostication of patients who underwent surgery with extrahepatic cholangiocarcinoma.

Methods

We retrospectively analyzed a total of 62 patients who underwent resection for extrahepatic cholangiocarcinoma. We calculated the GPS as follows: patients with both an elevated C-reactive protein (>10 mg/L) and hypoalbuminemia (<35 g/L) were allocated a score of 2; patients with one or none of these abnormalities were allocated a score of 1 or 0, respectively. Prognostic significance was analyzed by the log-rank test and a Cox proportional hazards model.

Results

Overall survival rate was 25.5 % at 5 years for all 62 patients. Venous invasion (p = 0.01), pathological primary tumor category (p = 0.013), lymph node metastasis category (p < 0.001), TNM stage (p < 0.001), and GPS (p = 0.008) were significantly associated with survival by univariate analysis. A Cox model demonstrated that increased GPS was an independent predictive factor with poor prognosis.

Conclusions

The preoperative GPS is a useful predictor of postoperative outcome in patients with extrahepatic cholangiocarcinoma.     

Effects of an immuno‐enhanced diet containing antioxidants in esophageal cancer surgery following neoadjuvant therapy

Neoadjuvant therapy‐induced immunological deterioration may be a key factor in postoperative morbidity in patients with esophageal cancer. This study aimed to determine the effects of perioperative feeding with an immuno‐enhanced diet on immune competence in patients treated with neoadjuvant therapy followed by surgery. Because an immuno‐enhanced diet that contained several antioxidants was used, perioperative oxidative stress and the effects of the immuno‐enhanced diet on this stress were also investigated. Of 39 patients with esophageal cancer who underwent similar surgical procedures, 26 patients who received chemotherapy or chemoradiation therapy before surgery were randomly divided into two groups: group 1 (n= 14) was given an immuno‐enhanced diet for 5 days before surgery, and group 2 (n= 12) received no enteral feeding products before surgery. Group 3 (n= 13) consisted of patients that did not receive neoadjuvant therapy and received no enteral feeding products before surgery. Several markers for coagulation and fibrinolysis were determined and immunological assessments were performed for each patient. To measure reactive oxygen metabolites and the total antioxidant capacity, diacron‐reactive oxygen metabolites (d‐ROMs) and OXY‐adsorbent tests were performed using a free radical elective evaluator. Significant depression in lymphocyte numbers was observed in groups 1 and 2 before and early after surgery as compared to group 3. Numbers of B cells, CD4/CD8 ratio, and phytohemagglutinin‐induced lymphocyte transformation tests were also significantly decreased in groups 1 and 2 on postoperative day 1. Fibrin and fibrinogen degradation products were significantly elevated in group 2 compared to group 1. d‐ROMs and OXY‐adsorbent test values were elevated before surgery and were decreased transiently early after surgery. Compared to groups 2 and 3, d‐ROMs values were significantly lower in group 1 patients throughout the postoperative period, while OXY‐adsorbent test values were significantly higher in group 2 patients. Oxidative index was significantly suppressed in group 1 compared to group 3. No significant intergroup differences were observed with regard to morbidity after surgery. Although the baseline levels of immunological function might have been different because of less‐advanced cancer stages in group 3, neoadjuvant therapy significantly affected several immunological parameters. Preoperative administration of an immuno‐enhanced diet did not significantly prevent neoadjuvant therapy‐induced immunological deterioration prior to esophageal cancer surgery. Patients with esophageal cancer had elevated levels of oxidant and antioxidant activities before surgery, which were transiently decreased early after surgery. Although the underlying mechanisms for these perioperative changes are unclear, this study showed that an immuno‐enhanced diet containing several antioxidants may reduce oxidative stress following esophageal cancer surgery. After these mechanisms are studied further, oxidative stress control may become another tool for perioperative management to reduce morbidity after esophageal cancer surgery.     

Evaluation of the Glasgow Prognostic Score in patients receiving chemoradiotherapy for stage III and IV esophageal cancer

High Glasgow Prognostic scores (GPSs) have been associated with poor outcomes in various tumors, but the values of GPS and modified GPS (mGPS) in patients with advanced esophageal cancer receiving chemoradiotherapy (CRT) has not yet been reported. We have evaluated these with respect to predicting responsiveness to CRT and long‐term survival. Between January 2002 and December 2011, tumor responses in 142 esophageal cancer patients (131 men and 11 women) with stage III (A, B and C) and IV receiving CRT were assessed. We assessed the value of the GPS as a predictor of a response to definitive CRT and also as a prognostic indicator in patients with esophageal cancer receiving CRT. We found that independent predictors of CRT responsiveness were Eastern Cooperative Oncology Group (ECOG) performance status, GPS and cTNM stage. Independent prognostic factors were ECOG performance status and GPS for progression‐free survival and ECOG performance status, GPS and cTNM stage IV for disease‐specific survival. GPS may be a novel predictor of CRT responsiveness and a prognostic indicator for progression‐free and disease‐specific survival in patients with advanced esophageal cancer. However, a multicenter study as same regime with large number of patients will be needed to confirm these outcomes.     

Optimal surgical approach for esophageal cancer in the era of minimally invasive esophagectomy and neoadjuvant therapy

The optimal surgical technique for the potentially curative treatment of patients with esophageal cancer is still under debate. The transhiatal esophagectomy (THE) with limited lymphadenectomy mainly focuses on a decrease of postoperative morbidity and mortality by preventing a formal thoracotomy. The transthoracic esophagectomy (TTE) with extended two‐field lymphadenectomy attempts to improve the radicality of the resection and thus to increase locoregional tumor control, but is associated with increased postoperative morbidity. The recent introduction of different minimally invasive techniques probably decreases postoperative morbidity following TTE, with reduction of especially pulmonary complications, but high‐quality evidence is still limited. It is widely agreed that extended lymphadenectomy as performed during TTE provides the benefit of more accurate staging, but its effect on improvement of survival is still debated. The literature on this topic is contradictory and the choice of surgical approach is primarily driven by personal opinions and institutional preferences. Moreover, the available evidence is mainly based on patients who underwent surgery alone without neoadjuvant therapy. Results of recent studies suggest that neoadjuvant chemoradiotherapy abolishes any possibly positive effect of extended lymphadenectomy as performed during TTE on survival, but this effect should be confirmed in future research. This review gives an overview and reflects the authors' personal view on the role of TTE and THE in the treatment of potentially curative treatment of patients with locally advanced esophageal cancer in the era of minimally invasive esophagectomy and neoadjuvant treatment and outlines future research perspectives.