Biomarker analysis of the GATSBY study of trastuzumab emtansine versus a taxane in previously treated HER2-positive advanced gastric/gastroesophageal junction cancer.

BACKGROUND: Prespecified exploratory biomarker analyses of the phase II/III GATSBY study (NCT01641939) assessed whether patient subgroups experienced a survival benefit from trastuzumab emtansine (T-DM1) versus taxane therapy, and to advance understanding of HER2-positive advanced gastric/gastroesophageal junction cancer (AGC) disease biology. METHODS: Adults with HER2-positive AGC whose disease progressed during/after first-line therapy were enrolled and randomized to receive T-DM1 [Stage 1: 3.6 mg/kg q3w, 2.4 mg/kg qw, or taxane (docetaxel/paclitaxel); Stage 2: 2.4 mg/kg qw or taxane]. Primary efficacy endpoint was overall survival (OS). Prespecified exploratory biomarkers included HER2, HER3, PTEN, PIK3CA mutation status, FcγR, and cMET. Tumor samples from patients who received 2.4 mg/kg T-DM1 (n = 228) or taxane (n = 117) were included. RESULTS: Median OS was longer in subgroups with HER2 immunohistochemistry (IHC) 3+ [9.5 versus 8.3 months for T-DM1 versus taxane; hazard ratio (HR) 0.99 (95% CI 0.68-1.43)] versus HER2 IHC 2+/in situ hybridization-positive [5.2 versus 9.2 months for T-DM1 versus taxane; HR 1.53 (95% CI 0.94-2.50)] tumors. Trends towards increased median OS were also observed in subgroups with > versus ≤ median HER2 mRNA expression, higher versus lower HER2 gene copy number, HER2 gene ratio and H score, and homogenous or nonfocal HER2 IHC staining. T-DM1 was not associated with superior OS versus taxane in any subgroup. CONCLUSIONS: Patients with previously treated HER2-positive AGC with higher HER2 expression experienced a better treatment effect from T-DM1 than those with lower HER2 expression and may derive comparable survival benefits from T-DM1 and taxane therapy. CLINICAL TRIALS REGISTRATION: NCT01641939 ( https://clinicaltrials.gov/ct2/show/NCT01641939 ).

Cytokeratin-18 fragments predict treatment response and overall survival in gastric cancer in a randomized controlled trial.

BACKGROUND: Gastric cancer is common malignancy and exhibits a poor prognosis. At the time of diagnosis, the majority of patients present with metastatic disease which precludes curative treatment. Non-invasive biomarkers which discriminate early from advanced stages or predict the response to treatment are urgently required. This study explored the cytokeratin-18 fragment M30 and full-length cytokeratin-18 M65 in predicting treatment response and survival in a randomized, placebo-controlled trial of advanced gastric cancer. METHODS: Patients enrolled in the SUN-CASE study received sunitinib or placebo as an adjunct to standard therapy with leucovorin (Ca-folinate), 5-fluorouracil, and irinotecan in second or third line. Treatment response rates, progression-free survival and overall survival were assessed during a follow-up period of 12 months. Cytokeratin-18 fragments were analyzed in 52 patients at baseline and day 14 of therapy. RESULTS: Levels of M30 correlated with the presence of metastasis and lymph node involvement and decreased significantly during chemotherapy. Importantly, baseline levels of M30 were significantly higher in patients who failed therapy. In addition, patients who did not respond to treatment were also identifiable at day 14 based on elevated M30 levels. By stepwise regression analysis, M30 at day 14 was identified as independent predictor of treatment response. Likewise, serum levels of full-length cytokeratin-18 M65 at baseline also correlated with treatment failure and progression-free survival. The addition of sunitinib did not exert any effects on serum levels of M30 or M65. CONCLUSION: The cytokeratin-18 fragment M30 at day 14 identifies patients that fail to second- or third-line therapy for advanced gastric cancer. Validation of this non-invasive biomarker in gastric cancer is warranted.

Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study.

BACKGROUND: Although trastuzumab plus chemotherapy is the standard of care for first-line treatment of HER2-positive advanced gastric cancer, there is no established therapy in the second-line setting. In GATSBY, we examined the efficacy and tolerability of trastuzumab emtansine in patients previously treated for HER2-positive advanced gastric cancer (unresectable, locally advanced, or metastatic gastric cancer, including adenocarcinoma of the gastro-oesophageal junction). METHODS: This is the final analysis from GATSBY, a randomised, open-label, adaptive, phase 2/3 study, done at 107 centres (28 countries worldwide). Eligible patients had HER2-positive advanced gastric cancer and progressed during or after first-line therapy. In stage one of the trial, patients were randomly assigned to treatment groups (2:2:1) to receive intravenous trastuzumab emtansine (3·6 mg/kg every 3 weeks or 2·4 mg/kg weekly) or physician's choice of a taxane (intravenous docetaxel 75 mg/m2 every 3 weeks or intravenous paclitaxel 80 mg/m2 weekly). In stage two, patients were randomly assigned to treatment groups (2:1) to receive the independent data monitoring committee (IDMC)-selected dose of trastuzumab emtansine (2·4 mg/kg weekly) or a taxane (same regimen as above). We used permuted block randomisation, stratified by world region, previous HER2-targeted therapy, and previous gastrectomy. The primary endpoint (overall survival) was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01641939. FINDINGS: Between Sept 3, 2012, and Oct 14, 2013, 70 patients were assigned to receive trastuzumab emtansine 3·6 mg/kg every 3 weeks, 75 to receive trastuzumab emtansine 2·4 mg/kg weekly, and 37 to receive a taxane in the stage 1 part of the trial. At the pre-planned interim analysis (Oct 14, 2013), the IDMC selected trastuzumab emtansine 2·4 mg/kg weekly as the dose to proceed to stage 2. By Feb 9, 2015, a further 153 patients had been randomly assigned to receive trastuzumab emtansine 2·4 mg/kg weekly and a further 80 to receive a taxane. At data cutoff, median follow-up was 17·5 months (IQR 12·1-23·0) for the trastuzumab emtansine 2·4 mg/kg weekly group and 15·4 months (9·2-18·1) in the taxane group. Median overall survival was 7·9 months (95% CI 6·7-9·5) with trastuzumab emtansine 2·4 mg/kg weekly and 8·6 months (7·1-11·2) with taxane treatment (hazard ratio 1·15, 95% CI 0·87-1·51, one-sided p=0·86). The trastuzumab emtansine 2·4 mg/kg group had lower incidences of grade 3 or more adverse events (134 [60%] of 224 patients treated with trastuzumab emtansine vs 78 [70%] of 111 patients treated with a taxane), and similar incidences of adverse events leading to death (eight [4%] vs four [4%]), serious adverse events (65 [29%] vs 31 [28%]), and adverse events leading to treatment discontinuation (31 [14%] vs 15 [14%]) than did taxane treatment. The most common grade 3 or more adverse events in the trastuzumab emtansine 2·4 mg/kg weekly group were anaemia (59 [26%]) and thrombocytopenia (25 [11%]) compared with neutropenia (43 [39%]), and anaemia (20 [18%]), in the taxane group. The most common serious adverse events were anaemia (eight [4%]), upper gastrointestinal haemorrhage (eight [4%]), pneumonia (seven [3%]), gastric haemorrhage (six [3%]), and gastrointestinal haemorrhage (five [2%]) in the trastuzumab emtansine 2·4 mg/kg weekly group compared with pneumonia (four [4%]), febrile neutropenia (four [4%]), anaemia (three [3%]), and neutropenia (three [3%]) in the taxane group. INTERPRETATION: Trastuzumab emtansine was not superior to taxane in patients with previously treated, HER2-positive advanced gastric cancer. There is still an unmet need in this patient group and therapeutic options remain limited. FUNDING: F Hoffmann-La Roche.

Sunitinib added to FOLFIRI versus FOLFIRI in patients with chemorefractory advanced adenocarcinoma of the stomach or lower esophagus: a randomized, placebo-controlled phase II AIO trial with serum biomarker program.

BACKGROUND: As a multi-targeted anti-angiogenic receptor tyrosine kinase (RTK) inhibitor sunitinib (SUN) has been established for renal cancer and gastrointestinal stromal tumors. In advanced refractory esophagogastric cancer patients, monotherapy with SUN was associated with good tolerability but limited tumor response. METHODS: This double-blind, placebo-controlled, multicenter, phase II clinical trial was conducted to evaluate the efficacy, safety and tolerability of SUN as an adjunct to second and third-line FOLFIRI (NCT01020630). Patients were randomized to receive 6-week cycles including FOLFIRI plus sodium folinate (Na-FOLFIRI) once every two weeks and SUN or placebo (PL) continuously for four weeks followed by a 2-week rest period. The primary study endpoint was progression-free survival (PFS). Preplanned serum analyses of VEGF-A, VEGF-D, VEGFR2 and SDF-1α were performed retrospectively. RESULTS: Overall, 91 patients were randomized, 45 in each group (one patient withdrew). The main grade ≥3 AEs were neutropenia and leucopenia, observed in 56 %/20 % and 27 %/16 % for FOLFIRI + SUN/FOLFIRI + PL, respectively. Median PFS was similar, 3.5 vs. 3.3 months (hazard ratio (HR) 1.11, 95 % CI 0.70-1.74, P = 0.66) for FOLFIRI + SUN vs. FOLFIRI + PL, respectively. For FOLFIRI + SUN, a trend towards longer median overall survival (OS) compared with placebo was observed (10.4 vs. 8.9 months, HR 0.82, 95 % CI 0.50-1.34, one-sided P = 0.21). In subgroup serum analyses, significant changes in VEGF-A (P = 0.017), VEGFR2 (P = 0.012) and VEGF-D (P < 0.001) serum levels were observed. CONCLUSIONS: Although sunitinib combined with FOLFIRI did not improve PFS and response in chemotherapy-resistant gastric cancer, a trend towards better OS was observed. Further biomarker-driven studies with other anti-angiogenic RTK inhibitors are warranted. TRIAL REGISTRATION: This study was registered prospectively in the NCT Clinical Trials Registry (ClinicalTrials.gov) under NCT01020630 on November 23, 2009 after approval by the leading ethics committee of the Medical Association of Rhineland-Palatinate, Mainz, in coordination with the participating ethics committees (see Additional file 2) on September 16, 2009.

High Impact of Histopathological Remission for Prognosis after Perioperative Chemotherapy with ECF and ECF-Like Regimens for Gastric and Gastroesophageal Adenocarcinoma.

BACKGROUND: Perioperative chemotherapy with epirubicin, cisplatin and 5-fluorouracil (5-FU) (ECF)-like regimens is the European standard for patients with adenocarcinoma of the gastroesophageal junction (GEJ) or gastric body (GaCa) stage UICC II/III (staged according to the Union for International Cancer Control). However, limited data exist on the histopathological response and relevance of prognosis for patients homogeneously treated with ECF(-like) therapies. METHODS: All patients with GEJ/GaCa treated from September 2004 to September 2008 by perioperative ECF(-like) chemotherapy were retrospectively analyzed. Cisplatin and 5-FU were substituted with oxaliplatin or capecitabine when indicated. The histopathological response was assessed using the Becker score. RESULTS: Seventy-seven patients were analyzed with a median follow-up of 72.3 months. R0 resection was achieved in 53 of 68 operated patients. Recurrence was observed in 25 (32.5%) of these curatively treated patients, whereas 53/77 patients (68.8%) died, 39 (50.6%) of whom tumor related. The 5-year overall survival (OS) for the intention-to-treat population was 36.3%, and the 5-year tumor-specific survival was 42.2%. Pathological complete response (pCR) was seen in 10 patients (13.0%) and near pCR in 3 patients (3.9%). Patients with pCR had a significantly prolonged 5-year OS of 80.0 versus 29.7% compared to the nonhistopathological complete remission group (p = 0.01). CONCLUSION: In our retrospective analysis, ECF(-like) pretreatment resulted in a (near) pCR rate of 16.9%. In line with other regimens, our data suggest that histopathological response predicts the OS in patients treated with ECF(-like) regimens.

Docetaxel, oxaliplatin and capecitabine (TEX regimen) in patients with metastatic gastric or gastro-esophageal cancer: results of a multicenter phase I/II study.

UNLABELLED: Three drug taxane-based regimens have shown activity in patients with metastatic or locally advanced gastric or gastro-esophageal cancer (GC/GEC). Limited tolerability of these regimens warrants treatment modification, particularly in regard of the proven equivalence of oxaliplatin and cisplatin as well as capecitabine and 5FU. Thus, a regimen with docetaxel (T), oxaliplatin (E) and capecitabine (X) was established and evaluated. METHODS: Patients with metastatic or locally advanced GC/GEC, adequate organ function, ECOG PS 0-2 were enrolled. TEX regimen was administered as defined by the phase I trial with T 35 mg/m(2) and E 70 mg/m(2) on days (d) 1, 8 and X 800 mg/m(2) bid on d 1-14 every 22 days. Primary endpoint was progression free survival (PFS) rate after 6 months. RESULTS: Altogether 70 patients (15 phase I; 55 phase II) were eligible for analysis. Results of the phase II part were as follows: most common grade toxicities diarrhea (30%), nausea/vomiting and infections, PFS rate after 6 months 56.3%, response rate 43%, median PFS 6.9 and overall survival 13 months, respectively. CONCLUSION: The TEX regimen show similar efficacy compared to other infusional 5FU-based taxane and platinum containing triplets, but the reduced tolerability, in particular grade 3 diarrhea, limits the feasibility.

Hepatic arterial infusion chemotherapy for liver metastases from gastric cancer: an analysis in Western patients.

AIMS AND BACKGROUND: The advantage of administering chemotherapy by hepatic arterial infusion is the achievement of high drug concentrations in the liver. Oxaliplatin, irinotecan and 5-flourouracil are active agents in advanced gastric cancer. Therefore a retrospective analysis was performed to investigate the effects of these drugs administered by hepatic arterial infusion in heavily pretreated gastric cancer patients with predominant hepatic metastases. Very limited data about hepatic arterial infusion exist in western gastric cancer patients. METHODS: Seven patients with advanced gastric cancer were included in the retrospective analysis. All patients had proven progressive disease prior to initiation of hepatic arterial infusion. All had an ECOG performance status of < or =2 and had received at least two previous systemic chemotherapy regimens, including the combination of cisplatin/5-fluorouracil. Patients were given chemotherapy by hepatic arterial infusion: 5-fluorouracil, 600 mg/m2, together with folinic acid, 300 mg/m2/2 h, followed by oxaliplatin, 85 mg/m2/2 h, every 2 weeks. RESULTS: Fifty-four cycles of hepatic arterial infusion (range, 2-21) with a median treatment duration of 6 cycles were administered in 7 patients. The treatment was feasible and safe, no grade 3-4 toxicity was observed. One patient showed stabilization of liver metastases over 7 months. In 6 of the 7 patients there was radiologically proven progressive disease after a median treatment time of 10 weeks. CONCLUSIONS: Chemotherapy by hepatic arterial infusion is modestly effective in heavily pretreated gastric cancer patients. Hepatic arterial infusion has a very favorable toxicity profile and can be safely administered even in elderly patients. It might be an additional therapeutic option and should be further investigated. The literature on hepatic arterial infusion in gastric cancer patients is reviewed.

Minimally Invasive Versus Open Ivor-Lewis Esophagectomy for Esophageal Cancer or Cancer of the Gastroesophageal Junction: Comparison of Postoperative Outcomes and Long-term Survival Using Propensity Score Matching Analysis.

BACKGROUND/AIM: Esophagectomy is crucial for achieving long-term survival in patients with esophageal cancer, while being associated with a significant risk of complications. Aiming to reduce invasiveness and morbidity, total minimal-invasive esophagectomy (MIE) has been gradually implemented worldwide. The aim of the study was to compare MIE to open Ivor-Lewis esophagectomy (OE) for esophageal cancer or cancer of the gastroesophageal junction (GEJ), in terms of postoperative and oncological outcomes. PATIENTS AND METHODS: Clinicopathological data of patients undergoing oncologic transthoracic esophagectomy (Ivor Lewis procedure) between 2010 and 2019 were assessed. Postoperative outcomes and long-term survival of patients undergoing OE were compared to those after MIE using 1:1 propensity score matching. RESULTS: After excluding hybrid and robotic procedures, 90 patients who underwent MIE were compared with a matched cohort of 90 patients who underwent OE. MIE was associated with lower major postoperative morbidity (31% vs. 46%, p=0.046) and lower 90-day mortality (2% vs. 12%, p=0.010) compared to OE. MIE showed non-inferior 3-year overall (65% vs. 52%, p=0.019) and comparable disease-free survival rates (49% vs. 51%, p=0.851) in comparison to OE. CONCLUSION: Our data suggest that MIE should be preferably performed in patients with esophageal cancer or cancer of the GEJ.

A FDG-PET radiomics signature detects esophageal squamous cell carcinoma patients who do not benefit from chemoradiation.

Detection of patients with esophageal squamous cell carcinoma (ESCC) who do not benefit from standard chemoradiation (CRT) is an important medical need. Radiomics using 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a promising approach. In this retrospective study of 184 patients with locally advanced ESCC. 152 patients from one center were grouped into a training cohort (n = 100) and an internal validation cohort (n = 52). External validation was performed with 32 patients treated at a second center. Primary endpoint was disease-free survival (DFS), secondary endpoints were overall survival (OS) and local control (LC). FDG-PET radiomics features were selected by Lasso-Cox regression analyses and a separate radiomics signature was calculated for each endpoint. In the training cohort radiomics signatures containing up to four PET derived features were able to identify non-responders in regard of all endpoints (DFS p < 0.001, LC p = 0.003, OS p = 0.001). After successful internal validation of the cutoff values generated by the training cohort for DFS (p = 0.025) and OS (p = 0.002), external validation using these cutoffs was successful for DFS (p = 0.002) but not for the other investigated endpoints. These results suggest that pre-treatment FDG-PET features may be useful to detect patients who do not respond to CRT and could benefit from alternative treatment.

Laparoscopic Resection for Adenocarcinoma of the Stomach or Gastroesophageal Junction Improves Postoperative Outcomes: a Propensity Score Matching Analysis.

BACKGROUND: Minimally invasive resection for upper gastrointestinal tumors has been associated with favorable results. However, the role of laparoscopic surgery (LS) in the multimodal treatment of patients with advanced adenocarcinoma of the stomach or gastroesophageal junction needs further investigation. METHODS: Clinicopathological data of patients who underwent gastrectomy between 2005 and 2017 were assessed. Outcomes of patients undergoing LS were compared with those of patients treated with a conventional open resection (OR) using a 1:1 propensity score matching analysis. RESULTS: Curative resection for adenocarcinoma of the stomach or gastroesophageal junction was performed in 417 patients during the study period. Beginning in June 2014, the majority of patients underwent LS (n = 72) and they were matched with 72 patients who were treated with an OR. The majority of patients treated with LS (89%) had advanced cancer (UICC stages II and III) and 82% of them received neoadjuvant chemotherapy. LS was significantly associated with a higher number of harvested lymph nodes (26 (9-62) vs. 21 (4-46), P = .007), a lower 90-day major complication rate (13 vs. 26%, P = .035), and a lower length of hospital stay (14 vs. 16 days, P = .001). After a median follow-up time of 32 months, 1-year overall survival rate was higher after LS than after OR (93 vs. 74%, P = .126); however, results did not reach statistical significance. CONCLUSION: LS for adenocarcinoma of the stomach or gastroesophageal junction is feasible and significantly reduces major postoperative morbidity resulting in a reduced length of hospital stay. Therefore, LS should be preferably considered for the curative treatment of patients with these malignancies.

Immune Checkpoint Inhibition in Gastro-Oesophageal Cancer.

Recently some progress has been made in the palliative treatment of gastric cancer. It was shown that second-line chemotherapy and VEGF-R2-directed treatment can prolong survival. Despite these advances most patients with metastatic gastric cancer live for less than 2 years. Immune-checkpoint blockade with anti-CTLA4, anti-PD-1 and anti-PD-L1 antibodies has revolutionised the treatment of many cancers. Significant benefit was also proven in gastric adenocarcinomas. Nivolumab improves overall survival as third-line treatment in Asian gastric cancer patients and is already registered in Japan. Pembrolizumab shows significant efficacy, especially in PD-L1-positive patients as third-line treatment and is FDA approved for this indication. Trials with avelumab are promising and studies with atezolizumab and durvalumab are also on the way. To extend the subgroup of benefitting patients combinations of PD-1/PD-L1 antibodies with CTLA4, or VEGF-R2 antibodies or combination with chemotherapy are investigated and show promising results. In this article, the existing evidence of PD1 and PD-L1 blockade as monotherapy or in combination with anti-CTLA4, anti-VEGF-R2 and chemotherapy in gastro-oesophageal adenocarcinoma is reviewed and put into perspective.

Docetaxel and continuous-infusion fluorouracil versus epirubicin, cisplatin, and fluorouracil for advanced gastric adenocarcinoma: a randomized phase II study.

PURPOSE: A combination of docetaxel and fluorouracil (DF) was evaluated in an outpatient setting and compared with epirubicin, cisplatin, and fluorouracil (ECF), which served as an internal control arm to avoid selection bias. PATIENTS AND METHODS: Patients with metastatic or locally advanced gastric adenocarcinoma without prior chemotherapy were randomly assigned to receive either ECF (epirubicin 50 mg/m(2) day 1, cisplatin 60 mg/m(2) day 1, and fluorouracil 200 mg/m(2) days 1 through 21, every 3 weeks) or DF (docetaxel 75 mg/m(2) day 1, and fluorouracil 200 mg/m(2) days 1 through 21, every 3 weeks). RESULTS: Ninety patients were randomly assigned. Toxicity was rarely severe. Major toxic effects included diarrhea, stomatitis, and leukopenia in the DF arm and nausea, vomiting, and leukopenia in the ECF arm. Forty-three of 45 patients in each arm were assessable. In the DF arm, two patients (4.4%, intent to treat) experienced a confirmed complete tumor remission as best response, and 15 patients (33.3%) experienced a confirmed partial remission (overall response rate [ORR], 37.8%; 95% CI, 25.9% to 51.9%). Two patients (4.4%) in the ECF arm showed confirmed complete remission, and 14 (31.1%) showed confirmed partial remission (ORR, 35.6%; 95% CI, 24.8% to 48.7%). For the DF and ECF arms, the median survival was 9.5 and 9.7 months, and the median time to tumor progression 5.5 and 5.3 months, respectively. CONCLUSION: DF can be safely given in an ambulant setting. Compared with ECF, the dual combination of DF shows promising efficacy and may be an alternative treatment option that avoids cisplatin.

[Recent progress in the treatment of colorectal cancer]. / Jüngste Fortschritte in der Therapie des Kolonkarzinoms.

BACKGROUND: Considerable progress has been made in the treatment of colorectal cancer. Many new results have been presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in May 2005 at Orlando, FL, USA. METHODS: This update describes the highlights of the ASCO 2005 conference and the most recent publications in this field. RESULTS AND CONCLUSION: Therapy of metastatic colorectal cancer: studies could demonstrate that capecitabine can possibly replace 5-fluorouracil (5-FU) in combination regimens with oxaliplatin. The EGF receptor antibody cetuximab shows activity as single agent and in combination with irinotecan. Combination with oxaliplatin/5-FU is under investigation. The VEGF antibody bevacizumab leads to improved efficacy in combination with all chemotherapies investigated so far, but shows no efficacy as single agent. Adjuvant therapy of colon cancer: oxaliplatin and 5-FU improves the disease-free survival compared with 5-FU regimens and is the new standard adjuvant treatment for stage III disease. Capecitabine demonstrates better tolerability and at least equal efficacy as 5-FU bolus regimens and should replace these regimens whenever an oxaliplatin-based therapy is not chosen. Irinotecan does not improve disease-free survival and has no proven benefit in the adjuvant setting. Monoclonal antibodies are integrated in new adjuvant trials.

Anastomotic leak predicts diminished long-term survival after resection for gastric and esophageal cancer.

BACKGROUND: Previous studies have reported on the association between perioperative morbidity and diminished oncologic outcomes in patients undergoing resection for colorectal or pancreatic cancer. However, the effect of anastomotic leak (AL) on the survival of patients with gastric or esophageal cancer remains unclear. METHODS: Clinicopathologic data of patients who underwent resection for gastric or esophageal cancer between 2005 and 2012 were assessed, and predictors for overall survival and disease-free survival were identified. In addition, we evaluated the impact of AL on oncologic outcomes. RESULTS: Curative resection for gastric or esophageal cancer was performed in 471 patients. The primary tumor was located in the stomach and esophagus in 53% and 47% of the patients, respectively. Forty-one patients (8.7%) suffered an AL. The AL rate was significantly higher following resection for esophageal cancer compared with the resection for gastric cancer (12.9% vs 5.3%, P = .001). Postoperative mortality (4%) was not significantly associated with the occurrence of AL (4% without AL vs 7% with AL, P = .2). After a median follow-up time of 35 months, the median overall survival and disease-free survival were 101 and 93 months, respectively. Factors associated with worse overall survival in multivariate analysis included AL (P = .001), American Society of Anesthesiologists physical status (P < .0001), advanced Union for International Cancer Control (UICC) stage (P < .0001), and poorly differentiated carcinoma (G3; P = .04). In the multivariate analysis for predictors of disease-free survival, AL (P = .037), advanced UICC stage (P < .0001), poorly differentiated carcinoma (G3; P = .044), and lymphangiosis carcinomatosa (P = .004) were independently associated with a high risk for recurrence. CONCLUSION: AL following resection for gastric and esophageal cancer has a negative prognostic impact on long-term survival, independent from tumor stage and biology. Further investigation of the interactions between AL and the development of tumor recurrence as well as the establishment of standardized perioperative care protocols are necessary for the improvement of outcomes after gastric and esophageal resection.

Response to preoperative chemotherapy predicts survival in patients undergoing hepatectomy for liver metastases from gastric and esophageal cancer.

BACKGROUND: The role of hepatectomy for patients with liver metastases from gastric and esophageal cancer (GELM) is not well defined. The present study examined the morbidity, mortality, and long-term survivals after liver resection for GELM. METHODS: Clinicopathological data of patients who underwent hepatectomy for GELM between 1995 and 2012 at two European high-volume hepatobiliary centers were assessed, and predictors of overall survival (OS) were identified. In addition, the impact of preoperative chemotherapy for GELM on OS was evaluated. RESULTS: Forty-seven patients underwent hepatectomy for GELM. The primary tumor was located in the stomach, cardia, and distal esophagus in 27, 16, and 4 cases, respectively. Twenty patients received preoperative chemotherapy before hepatectomy. After a median follow-up time of 76 months, 1-, 3-, and 5-year OS rates were 70, 37, and 24%, respectively. Postoperative morbidity and mortality rates were 32 and 4%, respectively. Outcomes were comparable between the two centers. Preoperative chemotherapy for GELM (5-year OS: 45 vs 9%, P = .005) and the lack of posthepatectomy complications (5-year OS: 34 vs 0%, P < .0001) were significantly associated with improved OS in univariate and multivariate analyses. When stratifying OS by radiologic response of GELM to preoperative chemotherapy, patients with progressive disease despite preoperative treatment had significantly worse OS (5-year OS: 0 vs 70%, P = .045). CONCLUSION: For selected patients with GELM, liver resection is safe and should be regarded as a potentially curative approach. A multimodal treatment strategy including systemic therapy may provide better patient selection resulting in prolonged survival in patients with GELM undergoing hepatectomy.

Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

BACKGROUND: The value of second-line therapy for metastatic gastric cancer is unclear. So far there are no randomised phase III data comparing second-line chemotherapy to best supportive care (BSC). In this prospective, multicenter, open label, randomised phase III study we compared irinotecan to BSC to evaluate the impact on survival of second-line chemotherapy. METHODS: Eligible patients (pts) had metastatic or locally advanced gastro-oesophageal junction or gastric adenocarcinoma, objective tumour progression during or within 6months after first-line chemotherapy and ECOG performance status 0-2. Stratification for time of progression after first-line therapy, ECOG PS and pretreatment secured even distribution of important prognostic factors. TREATMENT: Arm A: Irinotecan 250mg/m(2)q3w (first cycle) to be increased to 350mg/m(2), depending on toxicity. Arm B: BSC. FINDINGS: Between 10/2002 and 12/2006 40 pts were randomised. The study was closed prematurely due to poor accrual. Responsefor arm A (19 pts evaluable): No objective responses, SD 53%, PD 47%. Improvement of tumour related symptoms: Arm A 50% of pts, arm B 7%. Overall Survival: (all events in 40 pts have occurred): The hazard ratio for death was reduced to 0.48 (95%CI 0.25-0.92) in the irinotecan-arm (p=0.012). Median survival arm A: 4.0months (95% CI 3.6-7.5), arm B: 2.4months (95% CI 1.7-4.9). INTERPRETATION: Irinotecan as second-line chemotherapy significantly prolongs overall survival compared to BSC in the studied pts. Second-line chemotherapy can now be considered as a proven treatment option for metastatic or locally advanced gastric cancer. FUNDING: The study was supported by a research grant from Aventis and Pfizer.

Docetaxel in the treatment of gastric cancer.

Docetaxel is part of the standard chemotherapy in breast, non-small cell lung cancer and androgen-independent metastatic prostate cancer and has recently been approved for advanced gastric cancer. It demonstrated promising single-agent efficacy in gastric cancer and was therefore investigated in different combination regimens. The combination of docetaxel with 5-fluorouracil (5-FU), capecitabine, irinotecan or cisplatin demonstrated high efficacy. The triple combination of docetaxel/cisplatin and 5-FU (DCF) was investigated in randomized Phase II trials and a randomized Phase III study (TAX325). In TAX325, DCF demonstrated superiority in terms of time to tumor progression, response rate and survival against a cisplatin/5-FU combination. Docetaxel was therefore approved for advanced gastric cancer by the US FDA and the European Agency for the Evaluation of Medicinal Products and will evolve as an integral part of routine combination regimens against gastric cancer. This review will discuss and interpret the different Phase II and III trials of docetaxel in gastric cancer.