Histopathologic Response Is a Positive Predictor of Overall Survival in Patients Undergoing Neoadjuvant/Perioperative Chemotherapy for Locally Advanced Gastric or Gastroesophageal Junction Cancers-Analysis from a Large Single Center Cohort in Germany.
ABSTRACT: There is conflicting evidence regarding the efficacy of neoadjuvant/perioperative chemotherapy (NCT) for gastro-esophageal cancer (GEC) on overall survival. This study aimed to analyze the outcomes of multimodal treatments in a large single center cohort. We performed a retrospective analysis of patients treated with NCT, followed by intended curative oncological surgery for locally advanced gastric cancer. Uni- and multivariate regression analysis were performed to identify the predictors of overall survival. From over 3000 patients, 702 eligible patients were analyzed. In the univariate analysis clinical stage, application of preoperative PLF, requirement of surgical extension, UICC-stage, grading, R-status, Lauren histotype, and HPR were the prognostic survival factors. In multivariate analysis PLF regimen, UICC-stages, R-status, Lauren histotype, and histopathologic regression (HPR) were significant predictors of overall survival. Overall HPR-rate was 26.9%. HPR was highest in the cT2cN0 stage (55.9%), and lowest in the cT3/4 cN+ stage (21.6%). FLOT demonstrated the highest HPR (37.5%). Independent predictors for HPR were the clinical stage and grading. Kaplan Meier analyses demonstrated significant survival benefits for the responding patients (p < 0.0001). HPR after NCT was an important prognostic factor to predict overall survival for locally advanced GEC. FLOT should be the preferred regimen in patients undergoing NCT ahead of surgery.
Project description:5-year survival rate in patients with early adenocarcinoma of the gastro-esophageal junction or stomach (AGE/S) in Caucasian patients is reported to be 60-80%. We aimed to identify prognostic markers for patients with UICC-I without lymph-node involvement (N0).Clinical data and tissue specimen from patients with AGE/S stage UICC-I-N0, treated by surgery only, were collected retrospectively. Tumor size, lymphatic vessel or vein invasion, grading, classification systems (WHO, Lauren, Ming), expression of BAX, BCL-2, CDX2, Cyclin E, E-cadherin, Ki-67, TP53, TP21, SHH, Survivin, HIF1A, TROP2 and mismatch repair deficiency were analyzed using tissue microarrays and correlated with overall and tumor related survival.129 patients (48 female) with a mean follow-up of 129.1 months were identified. 5-year overall survival was 83.9%, 5-year tumor related survival was 95.1%. Poorly differentiated medullary cancer subtypes (p<0.001) and positive vein invasion (p<0.001) were identified as risk factors for decreased overall-and tumor related survival. Ki-67 (p = 0.012) and TP53 mutation (p = 0.044) were the only immunohistochemical markers associated with worse overall survival but did not reach significance for decreased tumor related survival.In the presented study patients with AGE/S in stage UICC-I-N0 had a better prognosis as previously reported for Caucasian patients. Poorly differentiated medullary subtype was associated with reduced survival and should be considered when studying prognosis in these patients.
Project description:The incidence of gastric cancer (GC) is decreasing worldwide, especially for intestinal histotype of the distal third of the stomach. On the contrary, proximal location and diffuse Lauren histotype have been reported to be generally stable over time. In the west, no clear improvement in long-term results was observed in clinical and population-based studies. Results of treatment in these neoplasms are strictly dependent on tumor stage. Adequate surgery and extended lymphadenectomy are associated with good long-term outcome in early-stage cancer; however, results are still unsatisfactory for advanced stages (III and IV), for which additional treatments could provide a survival benefit. This implies a tailored approach to GC. The aim of this review was to summarize the main multimodal treatment options in advanced resectable GC. Perioperative or postoperative treatments, including chemotherapy, chemoradiotherapy, targeted therapies, and hyperthermic intraperitoneal chemotherapy have been reviewed, and the main ongoing and completed trials have been analyzed. An original tailored multimodal approach to non-cardia GC has been also proposed.
Project description:Importance:Dysregulation of the mesenchymal-epithelial transition (MET) signaling pathway is associated with poor prognosis in gastroesophageal adenocarcinoma (GEC). We report results of METGastric, a phase 3 trial of the MET inhibitor onartuzumab plus standard first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative, MET-positive, advanced GEC. Objective:To determine whether the addition of onartuzumab to first-line fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) improves efficacy compared with mFOLFOX6 plus placebo in HER2-negative, MET-positive GEC. Design, Setting, and Participants:Randomized, double-blind, multicenter trial conducted from November 2012 to March 2014. Patients were 18 years or older with an adenocarcinoma of the stomach or gastroesophageal junction with metastatic disease not amenable for curative therapy. Tumor samples were centrally tested for MET expression using Ventana anti-Total c-MET (SP44) rabbit monoclonal antibody, HER2 status, and Lauren histologic subtype. MET-positive tumors were defined as at least 50% of tumor cells showing weak, moderate, and/or strong staining intensity (MET 1+/2+/3+, respectively) by immunohistochemistry. Interventions:Patients with HER2-negative, MET-positive GEC were enrolled and randomized 1:1 to receive mFOLFOX6 with or without onartuzumab (10 mg/kg). Main Outcomes and Measures:Co-primary end points: overall survival in the intent-to-treat (ITT) population and in patients with MET 2+/3+ GEC. Secondary end points: progression-free survival (PFS), overall response rate (ORR), and safety. Results:Enrollment was stopped early due to sponsor decision, which was agreed with an independent data monitoring committee. At the data cutoff (April 25, 2014) there were 562 patients in the ITT population (n = 283 placebo plus mFOLFOX6 [median age, 58 y; 65% male]; n = 279 onartuzumab plus mFOLFOX6 [median age, 60 y; 67% male]); 109 (38.5%) and 105 (37.6%) of the ITT population were MET 2+/3+, respectively. Addition of onartuzumab to mFOLFOX6 did not significantly improve OS, PFS, or ORR vs placebo plus mFOLFOX6 in the ITT (OS hazard ratio [HR], 0.82; 95% CI, 0.59-1.15; P = .24; PFS HR, 0.90; 95% CI, 0.71-1.16; P = .43; ORR, 46.1% vs 40.6%) or MET 2+/3+ populations (OS HR, 0.64; 95% CI, 0.40-1.03; P = .06; PFS HR, 0.79; 95% CI, 0.54-1.15; P = .22; ORR, 53.8% vs 44.6%). Safety was as expected for onartuzumab. Conclusions and Relevance:Addition of onartuzumab to first-line mFOLFOX6 did not significantly improve clinical benefits in the ITT or MET 2+/3+ populations. Trial Registration:clinicaltrials.gov Identifier: NCT01662869.
Project description:BACKGROUND AND AIMS:Patients with gastric cancer often show signs of malnutrition. We sought to evaluate the influence of sarcopenia in patients with locally advanced, not metastasized, gastric or gastro-esophageal junction (GEJ) cancer undergoing curative treatment (perioperative chemotherapy and surgery) on morbidity and mortality in order to identify patients in need for nutritional intervention. PATIENTS AND METHODS:Two-centre study, conducted in the Frankfurt University Clinic and Krankenhaus Nordwest (Frankfurt) as part of the University Cancer Center Frankfurt (UCT). 47/83 patients were treated in the FLOT trial (NCT01216644). Patients´ charts were reviewed for clinical data. Two consecutive CT scans were retrospectively analyzed to determine the degree of sarcopenia. Survival was calculated using the Kaplan-Meier method, multivariate analysis was performed using the Cox regression. RESULTS:60 patients (72.3%) were male and 23 (27.7%) female. 45 patients (54.2%) had GEJ type 1-3 and 38 (45.8%) gastric tumors, respectively. Sarcopenic patients were significantly older than non-sarcopenic patients (mean age 65.1 years vs. 59.5 years, p = 0.042), terminated the chemotherapy significantly earlier (50% vs. 22.6%, p = 0.037) and showed higher Clavien-Dindo scores, indicating more severe perioperative complications (score ?3 43.3 vs. 17.0%, p = 0.019). Sarcopenic patients had a significantly shorter survival than non-sarcopenic patients (139.6 ± 19.5 [95% CI, 101.3-177.9] vs. 206.7 ± 13.8 [95% CI, 179.5-233.8] weeks, p = 0.004). Multivariate Cox regression analysis showed that, besides UICC stage, sarcopenia significantly influenced survival. CONCLUSION:Sarcopenia is present in a large proportion of patients with locally advanced gastric or GEJ cancer and significantly influences tolerability of chemotherapy, surgical complications and survival.
Project description:BACKGROUND:The 5-FU, Leucovorin, Oxaliplatin and Docetaxel (FLOT) protocol provides superior oncologic results compared to other perioperative chemotherapeutic protocols for the treatment of non-metastatic esophagogastric cancer (EGAC). Survival and the pattern of recurrence of EGAC after FLOT and curative tumor resection are analyzed in a collective of patients treated outside clinical trials. METHODS:Two-hundred-seventy-seven patients with EGAC (cT3-4 and/or cN+) were treated with perioperative FLOT-chemotherapy plus curative surgery between 2009 and 2018. Data were analyzed retrospectively from a prospective database. RESULTS:Two-hundred-twenty-eight patients were included in the analysis. Postoperative in-hospital mortality was 2%. The median survival was 61-months, and median recurrence-free survival was 42 months. Multivariate analysis identified postoperative nodal status and T-stage as independent predictors of improved overall and recurrence-free survival. Administration of adjuvant chemotherapy failed to be significant for overall survival but was an independent predictor of recurrence-free survival. Recurrence occurred after a median of 9 months (range 1-46 months). Eighty-nine percent of recurrence occurred during the first 24 months. The rate of local recurrence was low. After surgery for gastric cancer, the major recurrence site was peritoneal carcinomatosis (56%), while esophageal cancer recurred mostly as metastasis to distant organs (78%). The specific site of recurrence had no impact on overall survival time. CONCLUSION:Real-life application of FLOT shows oncologic results comparable to clinical trials. Recurrence after FLOT and surgery for EGAC occurs predominantly early within the first two years after surgery and in the form of distant organ metastasis for esophageal tumors or peritoneal carcinomatosis for gastric tumors.
Project description:The aim of this study was to investigate immune response and its prognostic significance in colon carcinomas using the previously described Immunoscore (IS). A population-based series of 779 colorectal cancers, operated on between 2000 and 2010, were classified according to tumour, node, metastasis (TNM) status, mismatch repair (MMR), and BRAF mutation status. Rectal cancer cases (n = 203) were excluded as a high proportion of these patients received preoperative neoadjuvant chemoradiotherapy. Tissue microarray (TMA) samples collected from the tumour centre and invasive front were immunostained for CD3 and CD8. Lymphocytes were then digitally calculated to categorize IS from grade 0 to 4. Samples adequate for IS were available from 510 tumours. IS was significantly associated with AJCC/UICC stage, T stage, lymph node and distant metastases, perineural and lymphovascular invasion, MMR status, and BRAF mutation status. For IS0, IS1, IS2, IS3 and IS4, respectively, the 5-year disease-free survival (DFS) rates were 59, 68, 78, 83 and 94% (p < 0.001); 5-year disease-specific survival (DSS) rates were 47, 55, 75, 80, and 89% (p < 0.001); and 5-year overall survival (OS) rates were 40, 44, 66, 61, and 76% (p < 0.001). IS was also prognostic for DFS, DSS, and OS within subsets of microsatellite-stable (MSS) and microsatellite-instable (MSI) disease. Multivariable analysis showed that IS, AJCC/UICC stage, lymphovascular invasion, and lymph node ratio in AJCC/UICC stage III disease were independent prognostic factors for DFS, DSS, and OS. Age was an independent prognostic factor for DSS and OS. Gender and BRAF mutation were independent prognostic factors for OS. In conclusion, IS differentiated patients with poor versus improved prognosis in MSS and MSI disease and across AJCC/UICC stages. IS, AJCC/UICC stage, lymphovascular invasion, and lymph node ratio in AJCC/UICC stage III disease were independent prognostic factors for DFS, DSS, and OS.
Project description:Background:The understanding of ovarian cancer pathogenesis has recently shifted to recognize distinct changes in how ovarian cancer histotypes are defined. Using the 2014 World Health Organization (WHO) diagnostic guidelines, we classified ovarian cancer histotypes in Surveillance, Epidemiology, and End Results (SEER) cancer registry data and examined survival patterns by histotype and disease stage. Methods:We extracted data on 28 118 incident epithelial ovarian cancer cases diagnosed in 2004-2014 from SEER and defined histotype using the 2014 WHO guidelines (high-grade serous, low-grade serous, endometrioid, clear cell, mucinous, carcinosarcoma, and malignant Brenner tumors). By histotype and disease stage, we estimated Kaplan-Meier survival curves and calculated age-adjusted overall and cause-specific survival estimates. Cox proportional hazards regression models were used to estimate histotype-specific hazard ratios (HRs) and 95% confidence intervals (CIs) by disease stage while adjusting for age at diagnosis, region, race/ethnicity, and receipt of surgery. Results:Within two years after diagnosis, localized/regional-stage carcinosarcoma and distant-stage mucinous, clear cell, and carcinosarcoma had a higher risk of mortality compared with high-grade serous, with the most pronounced association for localized/regional carcinosarcoma (>1-2-year time period: HR = 3.81, 95% CI = 2.74 to 5.30) and distant-stage mucinous (0-1-year time period: HR = 3.87, 95% CI = 3.45 to 4.34). In the time period more than four to 10 years after diagnosis, hazard ratios for all histotypes relative to high-grade serous, irrespective of disease stage, were less than 1.00. Cumulatively, both localized/regional and distant-stage low-grade serous and endometrioid carcinomas had the most favorable outcomes. Conclusions:Our large study, which is representative of the United States population and incorporates the most current knowledge of ovarian cancer pathogenesis, highlights the need to recognize ovarian cancer as a set of distinct diseases and not a single entity. Only then will we be able to effectively target the unique features of each histotype to reduce ovarian cancer mortality.
Project description:BACKGROUND:Regulatory T cells(Tregs) and myeloid-derived suppressor cells(MDSCs) represent two immunosuppressive cell populations that are important in the establishment and maintenance of cancer immune tolerance. MDSCs can express IDO and promote immune tolerance via expansion of Treg cell. METHOD:We use needle biopsy breast cancer tissues prior to neoadjuvant chemotherapy(NCT) staining for CD33, Foxp3 and IDO by immunohistochemistry to evaluate whether they were correlated with subsequent treatment responses in breast cancer. RESULTS:Expressions of IDO, CD33+MDSCs and Foxp3+Tregs were correlated with each other. Immunohistochemical double staining revealed that IDO expression in CD33+MDSCs was positively correlated with Foxp3+Tregs (P < 0.05). CD33+MDSCs, Foxp3+Tregs, and IDO expression in tumor tissues were associated with advanced clinical stage prior to NCT (P < 0.05). CD33+MDSCs, Foxp3+Tregs, IDO expression, IDO expression in CD33+MDSCs and clinical T3-T4 stage prior to NCT, pathological T3-T4 stage, ER(+), luminal type were correlated with clinical responses of PD+SD (P < 0.05). Multivariate analysis showed that CD33+MDSCs, IDO expression, IDO expression in CD33+MDSCs, and advanced pathological T stage were risk factors for PD+SD. Focusing on the pCR of NCT, only CD33+MDSCs, clinical T3-T4, and N1-N3 stage prior to NCT were associated with no-pCR (P < 0.05). The multivariate analysis showed that advanced clinical T stage and N stage were risk factors for no-pCR. Clinical stage prior to NCT were significantly correlated with progression free survival (P = 0.021), while Foxp3+Tregs and clinical T stage were significantly correlated with overall survival (P = 0.022 and P = 0.001, respectively). Foxp3+Treg was significant risk factor for overall survival after adjusting covariates by COX regression. CONCLUSION:Tumor-infiltrating MDSCs, Tregs, IDO expression and IDO expression in MDSCs were correlated with clinicopathological features, NCT response, and prognosis of breast cancer patients, suggesting that they might be potential markers for clinical outcomes of NCT and help clinical decision-making for improved therapies for breast cancer.
Project description:PURPOSE:The outcomes of locoregionally advanced nasopharyngeal carcinoma patients treated with concurrent chemoradiation (CCRT) using intensity-modulated radiotherapy (IMRT) with/without neoadjuvant chemotherapy (NCT) were evaluated. MATERIALS AND METHODS:Eighty-three patients who underwent NCT followed by CCRT (49%) or CCRT with/without adjuvant chemotherapy (51%) were reviewed. To the gross tumor, 67.5 Gy was prescribed. Weekly cisplatin was used as concurrent chemotherapy. RESULTS:With a median follow-up of 49.4 months, the 5-year local control, regional control, distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival rates were 94.7%, 89.3%, 77.8%, 68.0%, and 81.8%, respectively. In multivariate analysis, the American Joint Committee on Cancer stage (p = 0.016) and N stage (p = 0.001) were negative factors for DMFS and DFS, respectively. Overall, NCT demonstrated no benefit and an increased risk of severe hematologic toxicity. However, compared to patients treated with CCRT alone, NCT showed potential of improving DMFS in stage IV patients. CONCLUSION:CCRT using IMRT resulted in excellent local control and survival outcome. Without evidence of survival benefit from phase III randomized trials, NCT should be carefully administered in locoregionally advanced nasopharyngeal carcinoma patients who are at high-risk of developing distant metastasis and radiotherapy-related mucositis. The results of ongoing trials are awaited.
Project description:BACKGROUND:To estimate the efficacy of neoadjuvant chemotherapy (NCT) in stage T3-4N1 nasopharyngeal carcinoma (NPC). METHODS:Data on stage T3-4N1 NPC patients treated with concurrent chemoradiotherapy (CCRT) with or without NCT at the Sun Yat-sen University Cancer Center between January 2006 and December 2013 were retrospectively reviewed. Propensity score matching (PSM) was carried out to balance prognostic factors in NCT followed by CCRT (NCT?+?CCRT) group and CCRT group in a 1:1 ratio. Survival outcomes of matched patients in the two groups were compared, and prognostic factors were identified using Cox regression model. RESULTS:A total of 282 patients were involved in this study, with 136 of NCT?+?CCRT group and 146 of CCRT group. After PSM, 85 pairs of patients were selected. There were no significant differences in 5-year overall survival (OS), locoregional recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), and recurrence-free survival (RFS) between NCT?+?CCRT group and CCRT group (81.0% vs. 77.5%, P =?0.750; 85.8% vs. 88.1%, P =?0.495; 92.5% vs. 93.9%, P =?0.759; 81.0% vs.77.5%, P =?0.919, respectively). Multivariate analysis found that smoking history (P =?0.044) and T classification (P =?0.027) were independent prognostic factors for OS, lymph node diameter (P =?0.032) was independent prognostic factor for LRFS, positive pretreatment lymph node condition (PLNC), which was defined as the lymph node necrosis or confluent, was independent prognostic factor for DRFS (P =?0.007), and RFS (P =?0.009). Lower 5-year OS (82.7% vs. 94.1%, P =?0.014), DRFS (79.3% vs. 96.2%, P =?0.003), and RFS (62.4% vs. 86.8%, P =?0.001) were found in positive PLNC group compared with negative PLNC group. In terms of toxicities, the incidences of acute hematological Grade 3-4 adverse events (AEs) were higher in NCT?+?CCRT group compared with CCRT group (P <?0.05), while no significant difference was observed in the rates of non-hematological Grade 3-4 AEs between these two groups (P >?0.05). CONCLUSIONS:Additional NCT is not associated with improved survival outcomes for patients with stage T3-4N1 NPC, but bring increased hematological Grade 3-4 AEs. PLNC is independent prognostic factor in stage T3-4N1 NPC, with positive PLNC correlating with poor survival outcomes.