Perioperative chemotherapy with 5-FU, leucovorin, oxaliplatin, and docetaxel (FLOT) for esophagogastric adenocarcinoma: ten years real-life experience from a surgical perspective.

PURPOSE: According to the results of FLOT4 trial, perioperative FLOT chemotherapy improved overall survival (OS) in locally advanced, resectable esophagogastric adenocarcinoma (EGA) compared to perioperative ECF/ECX. We report real-life data 10 years after introduction of perioperative FLOT at our institution. METHODS: Survival of 356 consecutive EGA patients (cT3/4 and/or cN + and/or cM1) who underwent curative surgical resection was retrospectively analysed from a prospective database. A total of 263 patients received preoperative chemotherapy according to FLOT protocol and 93 patients received an epirubicin/platinum/5FU-based regimen (EPF). Propensity score matching (PSM) according to pretretment characteristics was performed to compensate for heterogeneity between groups. RESULTS: Median OS did not differ between groups (FLOT/EPF 52.1/46.4 months, p = 0.577). After PSM, survival was non-significantly improved after FLOT compared to EPF (median OS not reached/46.4 months, p = 0.156). Perioperative morbidity and mortality did not differ between groups. Histopathologic response rate was 35% after FLOT and 26% after EPF (p = 0.169). R0 resection could be achieved more frequently after FLOT than after EPF (93%/79%, p = 0.023). CONCLUSION: Overall survival after perioperative FLOT followed by surgery is comparable to clinical trials. However, collective real-life application of FLOT failed to provide a significant survival benefit compared to EPF. In clinical reality, patient selection is triggered by age, comorbidity, tumor localization, and clinical tumor stage. Yet matched analyses support FLOT4 trial findings.

Mechanical stretching and chemical pyloroplasty to prevent delayed gastric emptying after esophageal cancer resection-a meta-analysis and review of the literature.

BACKGROUND: Delayed gastric emptying (DGE) occurs in up to 40% of patients after esophageal resection and prolongs recovery and hospital stay. Surgically pyloroplasty does not effectively prevent DGE. Recently published methods include injection of botulinum toxin (botox) in the pylorus and mechanical interventions as preoperative endoscopic dilatation of the pylorus. The aim of this study was to investigate the efficacy of those methods with respect to the newly published Consensus definition of DGE. METHODS: A systematic literature search using CENTRAL, Medline, and Web of Science was performed to identify studies that described pre- or intraoperative botox injection or mechanical stretching methods of the pylorus in patients undergoing esophageal resection. Frequency of DGE, anastomotic leakage rates, and length of hospital stay were analyzed. Outcome data were pooled as odd's ratio (OR) or mean difference using a random-effects model. Risk of bias was assessed using the Robins-I tool for non-randomized trials. RESULTS: Out of 391 articles seven retrospective studies described patients that underwent preventive botulinum toxin injection and four studies described preventive mechanical stretching of the pylorus. DGE was not affected by injection of botox (OR 0.87, 95% confidence interval [CI] 0.37-2.03, P = 0.75), whereas mechanical stretching resulted in significant reduction of DGE (OR 0.26, 95% CI 0.14-0.5, P < 0.0001). CONCLUSION: Mechanical stretching of the pylorus, but not injection of botox reduces DGE after esophageal cancer resection. A newly developed consensus definition should be used before the conduction of a large-scale randomized-controlled trial.

Characteristics and Prognostic Factors of Metachronous Second Primary Upper Gastrointestinal Cancer.

BACKGROUND: Patients with metachronous malignancies before carcinomas of the upper gastrointestinal tract were analyzed regarding clinical parameters, oncological outcome, and prognosis. METHODS: We analyzed the data of 1583 patients with gastroesophageal cancer who underwent oncological resections between 2002 and 2018. Of 1583 patients, 172 had a malignant tumor before the upper gastrointestinal cancer (second primary carcinomas) and 1411 without preceding malignancies served as the control group. The analyses were performed between both groups and within the subgroup of second primary carcinomas. RESULTS: Patients with second primary carcinomas were older (P < 0.0001), had more comorbidities (P < 0.0001), and underwent longer surgical resections (P = 0.0024). They had lower (y)pT-categories (P = 0.0427) and had longer stays in intensive care unit (P = 0.0002) and hospital (P = 0.0018). R0-resection was more frequent (P = 0.0275) while having more surgical complications (P = 0.0378). The median survival was 39.5 mo (primary carcinoma) versus 32.9 mo for (second primary carcinoma) and was not significantly different (P = 0.5359).In the subgroup analysis of second primaries, there were no significant survival differences depending on primary tumor entity (P = 0.4989). pT status (P = 0.0062), pN status (P < 0.0001), pM status (P < 0.0001), and R-status (P < 0.0001) were significant prognostic factors. A time period >9 y after the primary cancer could be identified as a novel and beneficial survival factor (P = 0.0496). Most patients with primary colorectal, prostate, hematogenous, or breast cancer had adenocarcinoma, whereas patients with initial otolaryngologic cancers mainly had squamous cell carcinoma. CONCLUSIONS: Second primary carcinomas of the upper gastrointestinal tract show distinct clinical and oncological characteristics. Common prognostic factors are applicable, and oncologic resection is recommended.

Expression of Angiogenic Proteins in Tumor and Stroma Affects Survival in Patients With Gastric Cancer.

BACKGROUND: Gastric cancer is one of the most frequent malignancies worldwide. Angiogenic growth factors play a crucial role in mediating the crosstalk between cancer cells and the surrounding microenvironment. In this exploratory study, we investigate the impact of angiogenic proteins within the tumor cell or stroma compartment on survival of patients with gastric cancer. MATERIALS AND METHODS: In 29 patients, tumor and stromal compartments were separated using laser capture microdissection. Angiogenic protein expression was measured using a bead-based immunoassay and correlated with tumor stage and overall survival. RESULTS: Overall survival was significantly shorter in patients with a high stroma concentration of vascular endothelial growth factor (VEGF)-A (23.5 (±17.6) versus 33.6 (±21.0) mo; P = 0.009) and stem cell factor (22.2 (±18.5) versus 33.6 (±21.8) mo; P = 0.01) compared with patients with a low stroma concentration. High stromal VEGF-D showed a trend toward worse survival (26.8 (±22.0) versus 37.2 (±19.0) mo; P = 0.09). We did not observe any significant correlation between tumor-specific expression of angiogenic cytokines and survival. CONCLUSIONS: This translational study highlights the difference in clinical impact between tumor and stromal expression of angiogenic proteins. Compartment-specific concentrations of VEGF-A and stem cell factor affect the clinical prognosis and help to identify the best therapy for patients with gastric cancer.

Diltiazem Prophylaxis for the Prevention of Atrial Fibrillation in Patients Undergoing Thoracoabdominal Esophagectomy: A Retrospective Cohort Study.

BACKGROUND: Atrial fibrillation (AF) represents the most frequent arrhythmic disorder after thoracoabdominal esophageal resection and is associated with a significant increase in perioperative morbidity and mortality. METHODS: In this retrospective cohort study, 167 patients who underwent thoracoabdominal esophagectomy at a large university hospital were assessed. We compared patients who received a 14-day postoperative course of diltiazem with a control group of patients who did not undergo diltiazem prophylaxis. Diltiazem therapy started immediately upon admission to the intensive care unit (ICU) with a loading dose of 0.25 mg/kg bodyweight (i.v.) followed by continuous infusion (0.1 mg/kg bodyweight/h) for 40-48 h. Oral administration (Dilzem® 180 mg uno retard, once a day) was started on postoperative day 3. RESULTS: A total of 117 patients were assessed. Twelve (10.3%) of all patients developed postoperative new-onset atrial fibrillation in the first 30 days after surgical intervention. Prevalence of new-onset AF showed no significant differences between the diltiazem group and control group (p = 0.74). The prevalence of bradycardia (14.7% vs. 3.6%; p = 0.03) and dose of norepinephrine required (0.09 vs. 0.04 µg/kg bodyweight/min; p = 0.04) were higher in the diltiazem group. There were no significant differences between the groups for the median postoperative duration of hospital/ICU stay or mortality. CONCLUSIONS: A prophylactic 14-day postoperative course of diltiazem was not associated with a reduction in new-onset AF or 30-day mortality following thoracoabdominal esophagectomy. Prophylactic diltiazem therapy was associated with drug-related adverse effects such as bradycardia and increased requirement of norepinephrine. German Clinical Trial Registration Number: DKRS00016631.

Prognostic significance of microsatellite-instability in gastric and gastroesophageal junction cancer patients undergoing neoadjuvant chemotherapy.

Perioperative systemic treatment is standard of care for Caucasian patients with locally advanced, resectable gastric adenocarcinoma. The prognostic relevance of the microsatellite instability (MSI) status in patients undergoing neoadjuvant chemotherapy followed by resection is unclear. We analyzed the association of the MSI status with histological regression and clinical outcome in patients undergoing neoadjuvant systemic treatment. Tumor tissue from patients undergoing neoadjuvant chemotherapy followed by resection for gastric or gastroesophageal-junction adenocarcinoma was analyzed for MSI status using a mononucleotide marker panel encompassing the markers BAT25, BAT26, and CAT25. Histological regression, relapse-free survival and overall survival were calculated and correlated with MSI status. We identified the MSI-H phenotype in 9 (8.9%) out of 101 analyzed tumors. Though a poor histological response was observed in eight out of nine MSI-H patients, overall survival was significantly better for patients with MSI-H compared to MSS tumors (median overall survival not reached vs. 38.6 months, log-rank test p = 0.014). Among MSI-H patients, an unexpected long-term survival after relapse was observed. Our data indicate that the MSI-H phenotype is a favorable prognostic marker in gastric cancer patients undergoing neoadjuvant treatment. The benefit of perioperative cytotoxic treatment in patients with MSI-H gastric cancer, however, remains questionable. Future trials should stratify patients according to their MSI status, and novel treatment modalities focusing on MSI-H tumors should be considered.

Neoadjuvant Therapy Improves Outcomes in Locally Advanced Signet-Ring-Cell Containing Esophagogastric Adenocarcinomas.

BACKGROUND: Only a few studies have analyzed multimodal treatment concepts in the subgroup of signet-ring-cell containing upper gastrointestinal (GI) cancer. Recent retrospective, multicentric data favor primary resection without neoadjuvant chemotherapy for gastric signet-ring-cell containing carcinomas (SRCs). We compared the outcomes of primarily resected carcinomas with neoadjuvantly treated, locally advanced esophagogastric SRCs. METHODS: A total of 310 patients with esophagogastric SRC-staged cT3/4/Nany/Many from a prospective unicentric database were included in this study; 192 (61.9%) received neoadjuvant therapy (NEO group) and 118 (38.1%) were primarily resected (RES group). RESULTS: Overall, 128 (41.3%) patients presented with adenocarcinoma of the esophagogastric junction (AEG) and 182 (58.7%) presented with gastric cancer. Neoadjuvant therapy was significantly associated with resection in curative intent (NEO: 91.1%; RES: 75.4%; P = 0.001), improved (y)pT category (P = 0.035), improved (y)pN category (P < 0.001), and R0 resections (curative intent cohort: 76.0% in NEO vs. 60.7% in RES; P = 0.010), among others, but not with postoperative complications. Overall survival was significantly improved by neoadjuvant treatment {median survival 28.5 months (95% confidence interval [CI] 14.4-39.6) vs. RES: 14.9 months (10.6-17.5); P < 0.001}, as well as in subgroups (AEG and gastric tumors, R0-resected patients, and patients with and without relevant comorbidities). Independent prognostic factors were neoadjuvant therapy (hazard ratio [HR] 0.66; P = 0.023), pT4 category (HR 1.71; P = 0.041), pN2 category (HR 1.86; P = 0.013), pN3 category (HR 2.40; P < 0.001), pM1 category (HR 1.95; P = 0.003), age > 70 years (HR 1.79; P = 0.006), gastric localization (HR 0.69; P = 0.032), American Society of Anesthesiologists classification 3/4 (HR 1.71; P = 0.004), and incomplete resection R1/2 (HR 1.6; P = 0.014). CONCLUSIONS: Our results demonstrate a survival advantage for advanced-stage esophagogastric SRC patients by neoadjuvant treatment.

Prolonged antibiotic prophylaxis after thoracoabdominal esophagectomy does not reduce the risk of pneumonia in the first 30 days: a retrospective before-and-after analysis.

PURPOSE: Thoracoabdominal esophageal resection for malignant disease is frequently associated with pulmonary infection. Whether prolonged antibiotic prophylaxis beyond a single perioperative dose is advantageous in preventing pulmonary infection after thoracoabdominal esophagectomy remains unclear. METHODS: In this retrospective before-and-after analysis, 173 patients between January 2009 and December 2014 from a prospectively maintained database were included. We evaluated the effect of a 5-day postoperative course of moxifloxacin, which is a frequently used antimicrobial agent for pneumonia, on the incidence of pulmonary infection and mortality after thoracoabdominal esophagectomy. RESULTS: 104 patients received only perioperative antimicrobial prophylaxis (control group) and 69 additionally received a 5-day postoperative antibiotic therapy with moxifloxacin (prolonged-course). 22 (12.7%) of all patients developed pneumonia within the first 30 days after surgery. No statistically significant differences were seen between the prolonged group and control group in terms of pneumonia after 7 (p = 0.169) or 30 days (p = 0.133), detected bacterial species (all p > 0.291) and 30-day mortality (5.8 vs 10.6%, p = 0.274). CONCLUSION: A preemptive 5-day postoperative course of moxifloxacin does not reduce the incidence of pulmonary infection and does not improve mortality after thoracoabdominal esophagectomy.

Postoperative follow-up programs improve survival in curatively resected gastric and junctional cancer patients: a propensity score matched analysis.

BACKGROUND: To date there is no evidence that more intensive follow-up after surgery for esophagogastric adenocarcinoma translates into improved survival. This study aimed to evaluate the impact of standardized surveillance by a specialized center after resection on survival. METHODS: Data of 587 patients were analyzed who underwent curative surgery for esophagogastric adenocarcinoma in our institution. Based on their postoperative surveillance, patients were assigned to either standardized follow-up (SFU) by the National Center for Tumor Diseases (SFU group) or individual follow-up by other physicians (non-SFU group). Propensity score matching (PSM) was performed to compensate for heterogeneity between groups. Groups were compared regarding clinicopathological findings, recurrence, and impact on survival before and after PSM. RESULTS: Of 587 patients, 32.7% were in the SFU and 67.3% in the non-SFU group. Recurrence occurred in 39.4% of patients and 92.6% within the first 3 years; 73.6% were treated, and of those 17.1% underwent resection. In recurrent patients overall and post-recurrence survival (OS/PRS) was influenced by diagnostic tools (p < 0.05), treatment (p ≤ 0.001), and resection of recurrence (p ≤ 0.001). Standardized follow-up significantly improved OS (84.9 vs. 38.4 months, p = 0.040) in matched analysis and was an independent positive predictor of OS before and after PSM (p = 0.034/0.013, respectively). CONCLUSION: After PSM, standardized follow-up by a specialized center significantly improved OS. Cross-sectional imaging and treatment of recurrence were associated with better outcome. Regular follow-up by cross-sectional imaging especially during the first 3 years should be recommended by national guidelines, since early detection might help select patients for treatment of recurrence and even resection in few designated cases.

Surgical strategies in true adenocarcinoma of the esophagogastric junction (AEG II): thoracoabdominal or abdominal approach?

BACKGROUND: The optimal surgical approach for adenocarcinoma directly at the esophagogastric junction (AEG II) is still under debate. This study aims to evaluate the differences between right thoracoabdominal esophagectomy (TAE) (Ivor-Lewis operation) and transhiatal extended gastrectomy (THG) for AEG II. METHODS: From a prospective database, 242 patients with AEG II (TAE, n = 56; THG, n = 186) were included and analyzed according to characteristics and perioperative morbidity and mortality and overall survival (chi-square, Mann-Whitney U, log-rank, Cox regression). RESULTS: Groups were comparable at baseline with exception of age. Patients older than 70 years were more frequently resected by THG (p = 0.003). No differences in perioperative morbidity (p = 0.197) and mortality (p = 0.711) were observed, including anastomotic leakages (p = 0.625) and pulmonary complications (p = 0.494). There was no significant difference in R0 resection (p = 0.719) and number of resected lymph nodes (p = 0.202). Overall median survival was 38.4 months. Survival after TAE was significantly longer than after THG (median OS not reached versus 33.6 months, p = 0.02). Multivariate analysis revealed pN-category (p < 0.001) and type of surgery (p = 0.017) as independent prognostic factors. The type of surgery was confirmed as prognostic factor in locally advanced AEG II (cT 3/4 or cN1), but not in cT1/2 and cN0 patients. CONCLUSIONS: Our single-center experience suggests that patients with (locally advanced) AEG II tumors may benefit from TAE compared to THG. For further evaluation, a randomized trial would be necessary.

Serum microRNA profiles as prognostic/predictive markers in the multimodality therapy of locally advanced adenocarcinomas of the gastroesophageal junction.

Neoadjuvant multimodality treatment is frequently applied to improve the poor prognosis of locally advanced adenocarcinomas of the gastroesophageal junction. This study aimed to asses if serum microRNA profiles are useable as response indicators in this therapeutic setting. Fifty patients with locally advanced adenocarcinomas of the gastroesophageal junction were included in the study. All patients received neoadjuvant therapy and subsequently underwent surgical resection. Histomorphologic regression was defined as major histopathological response when resected specimens contained less than 10% vital residual tumor cells. Circulating RNA was isolated from pretherapeutic/post-neoadjuvant blood serum samples. RNA from nine patients was applied to PCR microarray analyses Based on these findings possible predictive miRNA markers were validated by quantitative RT-PCR analyses. Depending on the histomorphologic regression, a differential serum microRNA profile was identified by microarray analyses. Based on the divergent miRNA pattern, miR-21, miR-192, miR-222, miR-302c, miR-381 and miR-549 were selected for further validation. During neoadjuvant therapy, there was a significant increase of miR 222 and miR-549. Although on an expanded patient cohort, the six microRNAs could not be validated as markers for therapy response, there was a significant correlation between a high miR-192 and miR-222 expression with a high T-category as well as miR-302c and miR-222 expression significantly correlated with overall survival. Comprehensive miRNA profiling showed a differential microRNA expression pattern depending on the histomorphologic regression in the multimodality therapy of locally advanced adenocarcinomas of the gastroesophageal junction. Moreover, using single RT-PCR analyses a prognostic impact of miR-222 and miR-302c was detected.

Influence of Different Neoadjuvant Chemotherapy Regimens on Response, Prognosis, and Complication Rate in Patients with Esophagogastric Adenocarcinoma.

BACKGROUND: Perioperative chemotherapy improves survival in patients with advanced esophagogastric cancer, but the optimal treatment regimen remains unclear. More intensive chemotherapy may improve outcome, but also increase toxicity and complications. METHODS: A total of 843 patients were included in this retrospective study and stratified in 4 groups: doublet therapy with cisplatin or oxaliplatin and 5-fluorouracil (groups A/B) or triplet therapy with additional epirubicin or taxane (groups C/D). The influence of the different neoadjuvant chemotherapy regimens on response, prognosis, and complications was assessed. RESULTS: Clinical and pathological response were associated with longer overall survival (OS; p < 0.001). No significant differences regarding response or OS were found, but there was a trend toward better outcome in group D (taxane-containing triplet). In the subgroup of 669 patients with adenocarcinomas of the esophagogastric junction (AEG), patients who had received taxane-containing regimens had a significantly longer OS (p = 0.037), but taxane use was not an independent factor in multivariate analysis. Triple therapy with taxanes did not result in a higher complication rate or postoperative mortality. CONCLUSIONS: Although no superior neoadjuvant chemotherapy regimen was identified for patients with esophagogastric adenocarcinoma, taxane-containing regimens should be further investigated in randomized trials, especially in patients with AEG tumors.

Association of angiogenic factors with prognosis in esophageal cancer.

BACKGROUND: Despite multimodal therapy esophageal cancer often presents with poor prognosis. To improve outcome, tumor angiogenesis and anti-angiogenic therapeutic agents have recently gained importance. However, patient subgroups who benefit from anti-angiogenic therapy are not yet defined. In this retrospective exploratory study we investigated 9 angiogenic factors in patients' serum and tissue samples with regard to their association with clinicopathological parameters, prognosis and response in patients with locally advanced preoperatively treated esophageal cancer. METHODS: From 2007 to 2012 preoperative serum and corresponding tumor tissue (n = 54), only serum (n = 20) or only tumor tissue (n = 4) were collected from esophageal squamous cell carcinoma (SCC) (n = 34) and adenocarcinoma of the esophagogastric junction (AEG) (n = 44) staged cT3/4NanyM0/x after preoperative chemo(radio)therapy. Angiogenic cytokine levels in both tissue and serum were measured by multiplex immunoassay. RESULTS: Median survival in all patients was 28.49 months. No significant difference was found in survival between SCC and AEG (p = 0.90). 26 patients were histopathological responders. Histopathological response was associated with prognosis (p = 0.05). Angiogenic factors were associated with the following clinicopathological factors: tumor tissue expression of Angiopoietin-2 and Follistatin was higher in SCC compared to AEG (p = 0.022 and p = 0.001). High HGF and Follistatin expression in the tumor tissue was associated with poor prognosis in all patients (p = 0.037 and p = 0.036). No association with prognosis was found in the patients' serum. Neither patients' serum nor tumor tissue showed an association between angiogenic factors and response to neoadjuvant therapy. CONCLUSION: Two angiogenic factors (HGF and Follistatin) in posttherapeutic tumor tissue are associated with prognosis in esophageal cancer patients. Biological differences of AEG and SCC with respect to angiogenesis were evident by the different expression of 2 angiogenic factors. Results are promising and should be pursued prospectively, optimally sequentially pre- and posttherapeutically.

Surgery of gastric cancer and esophageal cancer: Does age matter?

INTRODUCTION: In the past, elderly patients with upper GI cancers were excluded from surgery or multimodal treatment only due to their advanced age. In an aging society this way of patient selection seems to be questionable. The aim of this retrospective exploratory study was to investigate how patients with upper GI cancer over the age of 70 years differ from younger patients in the postoperative course and which parameters influence overall survival in older patient populations. PATIENTS AND METHODS: From 2002 to 2012 1,005 patients underwent resection of esophageal or gastric cancer at the University of Heidelberg. 272 patients were older than 70 years and analyzed in subgroups (70-74 years: n = 146; 75-79 years: n = 82; 80 years or older: n = 44). Patients older than 70 years were compared to patients under 70 years (n = 733) with focus on differences in patients characteristics and outcome. Statistical analyses were made retrospectively on a prospective database. RESULTS: Fewer older patients were treated neoadjuvantly (< 70 years: 41.5%; > 70 years: 24.7%, P < 0.001) and extended resection (abdominothoracic approach) was applied less frequently compared to patients under 70 years (< 70 years: 38.9%; > 70 years: 19.9%, P < 0.001). The pNM-category (HR 1.41/2.56) and R-status (HR 1.78) remain the most important predictive factor for survival (all < 0.001). Female patients had a longer survival than men over the age of 70 (84.9 vs. 23.5 months, P < 0.01). Patients over 80 years had a significant shortened overall survival (> 80 years: 16.7 vs. < 70 years: 37.4 months) compared to the other subgroups (P < 0.001) and a significant increased in-hospital mortality (> 80 years: 20.5% vs. < 70 years: 6.0%, P = 0.002). CONCLUSIONS: An exclusion from surgical therapy due to advanced age in general seems not to be justified. However, the decision for a surgical resection in patients over 80 years should be made with caution. pNM-categories and R0-resection remain the most important predictive factors for overall survival in all subgroups. No survival benefit for neoadjuvant treatment in patients over 70 years was found, while women survived longer than men. However, the decision concerning a (radio) chemotherapy should be made individually in each patient.

Post-therapeutic response evaluation by a combination of endoscopy and CT scan in esophagogastric adenocarcinoma after chemotherapy: better than its reputation.

BACKGROUND: Neoadjuvant chemotherapy is an accepted standard of care for locally advanced esophagogastric cancer. As only a subgroup benefits, a response-based tailored treatment would be of interest. The aim of our study was the evaluation of the prognostic and predictive value of clinical response in esophagogastric adenocarcinomas. METHODS: Clinical response based on a combination of endoscopy and computed tomography (CT) scan was evaluated retrospectively within a prospective database in center A and then transferred to center B. A total of 686/740 (A) and 184/210 (B) patients, staged cT3/4, cN0/1 underwent neoadjuvant chemotherapy and were then re-staged by endoscopy and CT before undergoing tumor resection. Of 184 patients, 118 (B) additionally had an interim response assessment 4-6 weeks after the start of chemotherapy. RESULTS: In A, 479 patients (70%) were defined as clinical nonresponders, 207 (30%) as responders. Median survival was 38 months (nonresponders: 27 months, responders: 108 months, log-rank, p < 0.001). Clinical and histopathological response correlated significantly (p < 0.001). In multivariate analysis, clinical response was an independent prognostic factor (HR for death 1.4, 95% CI 1.0-1.8, p = 0.032). In B, 140 patients (76%) were nonresponders and 44 (24%) responded. Median survival was 33 months, (nonresponders: 27 months, responders: not reached, p = 0.003). Interim clinical response evaluation (118 patients) also had prognostic impact (p = 0.008). Interim, preoperative clinical response and histopathological response correlated strongly (p < 0.001). CONCLUSION: Preoperative clinical response was an independent prognostic factor in center A, while in center B its prognostic value could only be confirmed in univariate analysis. The accordance with histopathological response was good in both centers, and interim clinical response evaluation showed comparable results to preoperative evaluation.

Outcome, complications, and mortality of an intrathoracic anastomosis in esophageal cancer in patients without a preoperative selection with a risk score.

BACKGROUND: Esophagectomy for esophageal cancer remains a challenge with relatively high morbidity. We analyzed outcome, complications, and mortality after abdominothoracic esophagectomy with intrathoracic anastomosis. No routine preoperative risk stratification was performed. METHODS: One hundred eighty-seven consecutive patients (105 AEG I, 21 AEG II, 58 SCC, and 3 other entities) underwent standardized right abdominothoracic esophagectomy with intrathoracic anastomosis and two field lymphadenectomy between 2003 and 2009. Reconstruction was performed mostly with a gastric tube (n = 126) or a fundus rotation gastroplasty (n = 57). Seventy-four patients underwent neoadjuvant treatment (36 patients chemotherapy; 38 patients chemoradiotherapy). RESULTS: Postoperative morbidity was high (73.2 %). Ninety-two patients (49.2 %) suffered from surgical complications, 50 patients had major (26.7 %), and 42 minor (22.5 %) complications. Thirty-day mortality was 9/187 (4.8 %) while in-hospital mortality was doubled with 9.6 %. Six of 19 of the patients died without surgical complications. Preoperative treatment did not increase morbidity or mortality. Surgical complications with subsequent death were tracheobronchial fistula (2/3), ischemia of the gastric tube (3/6), anastomotic leakage (6/30), chylothorax (1/6), and intraoperative bleeding from the aorta (1/1). The median overall survival was 25.0 months. The occurrence of surgical or medical complications did not influence overall survival. In multivariate analysis, cT-category, pN-category, R-category, and re-intubation were independent prognostic factors. CONCLUSIONS: Abdominothoracic esophagectomy with intrathoracic anastomosis without preoperative patient selection is associated with a high risk for complications and subsequent death but ranges still within the upper range of published data. Strict patient selection is accepted to reduce postoperative morbidity and mortality but excludes a subgroup of patients from potentially curative resection.

A multifactorial histopathologic score for the prediction of prognosis of resected esophageal adenocarcinomas after neoadjuvant chemotherapy.

BACKGROUND: For esophageal adenocarcinoma treated with neoadjuvant chemotherapy, postoperative staging classifications initially developed for non-pretreated tumors may not accurately predict prognosis. We tested whether a multifactorial TNM-based histopathologic prognostic score (PRSC), which additionally applies to tumor regression, may improve estimation of prognosis compared with the current Union for International Cancer Control/American Joint Committee on Cancer (UICC) staging system. PATIENTS AND METHODS: We evaluated esophageal adenocarcinoma specimens following cis/oxaliplatin-based therapy from two separate centers (center 1: n = 280; and center 2: n = 80). For the PRSC, each factor was assigned a value from 1 to 2 (ypT0-2 = 1 point; ypT3-4 = 2 points; ypN0 = 1 point; ypN1-3 = 2 points; ≤ 50 % residual tumor/tumor bed = 1 point; >50 % residual tumor/tumor bed = 2 points). The three-tiered PRSC was based on the sum value of these factors (group A: 3; group B: 4-5; group C: 6) and was correlated with patients' overall survival (OS). RESULTS: The PRSC groups showed significant differences with respect to OS (p < 0.0001; hazard ratio [HR] 2.2 [95 % CI 1.7-2.8]), which could also be demonstrated in both cohorts separately (center 1 p < 0.0001; HR 2.48 [95 % CI 1.8-3.3] and center 2 p = 0.015; HR 1.7 [95 % CI 1.1-2.6]). Moreover, the PRSC showed a more accurate prognostic discrimination than the current UICC staging system (p < 0.0001; HR 1.15 [95 % CI 1.1-1.2]), and assessment of two goodness-of-fit criteria (Akaike Information Criterion and Schwarz Bayesian Information Criterion) clearly supported the superiority of PRSC over the UICC staging. CONCLUSION: The proposed PRSC clearly identifies three subgroups with different outcomes and may be more helpful for guiding further therapeutic decisions than the UICC staging system.

Is neoadjuvant chemotherapy followed by surgery the appropriate treatment for esophagogastric signet ring cell carcinomas? A systematic review and meta-analysis.

Background: The impact of neoadjuvant chemotherapy (nCTX) on survival and tumor response in patients with esophagogastric signet ring cell carcinoma (SRCC) is still controversial. Methods: Two independent reviewers performed a systematic literature search in Medline, CENTRAL, and Web of Science including prospective and retrospective two-arm non-randomized and randomized controlled studies (RCTs). Data was extracted on overall survival (OS) and tumor regression in resected esophagogastric SRCC patients with or without nCTX. Survival data was analyzed using published hazard ratios (HR) if available or determined it from other survival data or survival curves. OS and histopathological response rates by type of tumor (SRCC vs. non-SRCC) were also investigated. Results: Out of 559 studies, ten (1 RCT, 9 non-RCTs) were included in this meta-analysis (PROSPERO CRD42022298743) investigating 3,653 patients in total. The four studies investigating survival in SRCC patients treated with nCTX + surgery vs. surgery alone showed no survival benefit for neither intervention, but heterogeneity was considerable (HR, 1.01; 95% CI, 0.61-1.67; p = 0.98; I2 = 89%). In patients treated by nCTX + surgery SRCC patients showed worse survival (HR, 1.45; 95% CI, 1.21-1.74; p < 0.01) and lower rate of major histopathological response than non-SRCC patients (OR, 2.47; 95% CI, 1.78-3.44; p < 0.01). Conclusion: The current meta-analysis could not demonstrate beneficial effects of nCTX for SRCC patients. Histopathological response to and survival benefits of non-taxane-based nCTX seem to be lower in comparison to non-SRC esophagogastric cancer. However, certainty of evidence is low due to the scarcity of high-quality trials. Further research is necessary to determine optimal treatment for SRCC patients. Systematic Review Registration: https://www.crd.york.ac.uk/, PROSPERO (CRD42022298743).

Prognostic impact of lymph node involvement and the extent of lymphadenectomy (LAD) in adenocarcinoma of the esophagogastric junction (AEG).

BACKGROUND: The prognostic importance of lymph node (LN) involvement for patients with adenocarcinoma of the esophagogastric junction (AEG) is well-known. In the latest edition of the UICC staging system, the number of metastatic LNs was taken into account, while the extent of lymphadenectomy (LAD) remains unaddressed. Removal of at least six LNs is recommended, but there is no defined minimum number as to classify as (y)pN0. We examined the prognostic value of the number of positive LNs, number of LNs removed, and LN ratio (LNR) in order to determine the influence of an adequate LAD on overall survival (OS). METHODS: We analyzed data of 316 patients with AEG treated in our institution (2001-2011) regarding clinicopathological data, treatment, morbidity, mortality, and long-term prognosis. Univariate and multivariate analysis was performed using Cox regression to evaluate the prognostic impact of(y)pN category, number of LNs removed and LNR. RESULTS: OS decreased with higher count of positive LNs (p < 0.001) and higher LNR (p < 0.001). Whether >6, >15, or >30 LNs were removed did not influence OS, neither in the entire study population nor within individual (y)pT or (y)pN categories. Multivariate analysis revealed LNR (p < 0.001) besides M category (p = 0.015) and tracheotomy during the postoperative course (p = 0.005) as independent predictors of OS. CONCLUSION: The classification according to the number of involved LNs in the latest edition of the UICC staging system improves prognostication in patients with AEG. The importance of an adequate LAD is shown by the high prognostic relevance of the LNR rather than the absolute number of LNs removed.