Sung Hoon Noh

Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial.

BACKGROUND D2 gastrectomy is recommended in US and European guidelines, and is preferred in east Asia, for patients with resectable gastric cancer. Adjuvant chemotherapy improves patient outcomes after surgery, but the benefits after a D2 resection have not been extensively investigated in large-scale trials. We investigated the effect on disease-free survival of adjuvant chemotherapy with capecitabine plus oxaliplatin after D2 gastrectomy compared with D2 gastrectomy only in patients with stage II-IIIB gastric cancer. METHODS The capecitabine and oxaliplatin adjuvant study in stomach cancer (CLASSIC) study was an open-label, parallel-group, phase 3, randomised controlled trial undertaken in 37 centres in South Korea, China, and Taiwan. Patients with stage II-IIIB gastric cancer who had had curative D2 gastrectomy were randomly assigned to receive adjuvant chemotherapy of eight 3-week cycles of oral capecitabine (1000 mg/m(2) twice daily on days 1 to 14 of each cycle) plus intravenous oxaliplatin (130 mg/m(2) on day 1 of each cycle) for 6 months or surgery only. Block randomisation was done by a central interactive computerised system, stratified by country and disease stage. Patients, and investigators giving interventions, assessing outcomes, and analysing data were not masked. The primary endpoint was 3 year disease-free survival, analysed by intention to treat. This study reports a prespecified interim efficacy analysis, after which the trial was stopped after a recommendation by the data monitoring committee. The trial is registered at ClinicalTrials.gov (NCT00411229). FINDINGS 1035 patients were randomised (520 to receive chemotherapy and surgery, 515 surgery only). Median follow-up was 34·2 months (25·4-41·7) in the chemotherapy and surgery group and 34·3 months (25·6-41·9) in the surgery only group. 3 year disease-free survival was 74% (95% CI 69-79) in the chemotherapy and surgery group and 59% (53-64) in the surgery only group (hazard ratio 0·56, 95% CI 0·44-0·72; p<0·0001). Grade 3 or 4 adverse events were reported in 279 of 496 patients (56%) in the chemotherapy and surgery group and in 30 of 478 patients (6%) in the surgery only group. The most common adverse events in the intervention group were nausea (n=326), neutropenia (n=300), and decreased appetite (n=294). INTERPRETATION Adjuvant capecitabine plus oxaliplatin treatment after curative D2 gastrectomy should be considered as a treatment option for patients with operable gastric cancer. FUNDING F Hoffmann-La Roche and Sanofi-Aventis.

Robot-assisted gastrectomy with lymph node dissection for gastric cancer: lessons learned from an initial 100 consecutive procedures.

Objective:To evaluate the technical feasibility, effectiveness, and safety of robot-assisted gastrectomy (RAG) with lymphadenectomy, using the da Vinci system through analyses of our initial series of 100 consecutive patients. Summary Background Data:The application of robotic surgery was proven to be one of the best cutting-edge technologies for successful minimally invasive surgery by providing solutions to the many drawbacks of laparoscopic surgery, yet few reports have studied robotic surgery in gastric cancer. Methods:A review of a prospectively designed database at our institute from July 2005 to October 2007 revealed a series of 100 consecutive RAG patients with a preoperative diagnosis of early gastric cancer. Clinicopathologic characteristics and surgical outcomes were analyzed. Results:All operations were performed successfully without open or laparoscopic conversion. There were 33 total gastrectomies and 67 subtotal gastrectomies with D1+&bgr; or extended lymphadenectomy (D2). The mean total operation time and console time were 231 and 150 minutes, respectively. There were 13 postoperative morbidities and 1 postoperative mortality. The first flatus was noted on postoperative day 2.9, soft diet was started on postoperative day 4.2, and the mean postoperative hospital stay was 7.8 days. Although all patients were diagnosed as early gastric cancer preoperatively, the final pathology report revealed that 19 patients exhibited a depth deeper than T2. The mean number of retrieved lymph nodes was 36.7 (range, 11–83). None of the specimens showed microscopic tumor involvement in the resection line. Conclusions:This study demonstrated that RAG with lymphadenectomy can be applied safely and effectively for patients with gastric cancer.

Intrinsic Subtypes of Gastric Cancer, Based on Gene Expression Pattern, Predict Survival and Respond Differently to Chemotherapy

BACKGROUND & AIMS Gastric cancer (GC) is a heterogeneous disease comprising multiple subtypes that have distinct biological properties and effects in patients. We sought to identify new, intrinsic subtypes of GC by gene expression analysis of a large panel of GC cell lines. We tested if these subtypes might be associated with differences in patient survival times and responses to various standard-of-care cytotoxic drugs. METHODS We analyzed gene expression profiles for 37 GC cell lines to identify intrinsic GC subtypes. These subtypes were validated in primary tumors from 521 patients in 4 independent cohorts, where the subtypes were determined by either expression profiling or subtype-specific immunohistochemical markers (LGALS4, CDH17). In vitro sensitivity to 3 chemotherapy drugs (5-fluorouracil, cisplatin, oxaliplatin) was also assessed. RESULTS Unsupervised cell line analysis identified 2 major intrinsic genomic subtypes (G-INT and G-DIF) that had distinct patterns of gene expression. The intrinsic subtypes, but not subtypes based on Laurens histopathologic classification, were prognostic of survival, based on univariate and multivariate analysis in multiple patient cohorts. The G-INT cell lines were significantly more sensitive to 5-fluorouracil and oxaliplatin, but more resistant to cisplatin, than the G-DIF cell lines. In patients, intrinsic subtypes were associated with survival time following adjuvant, 5-fluorouracil-based therapy. CONCLUSIONS Intrinsic subtypes of GC, based on distinct patterns of expression, are associated with patient survival and response to chemotherapy. Classification of GC based on intrinsic subtypes might be used to determine prognosis and customize therapy.

Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial

BACKGROUND The CLASSIC trial was done to compare adjuvant capecitabine plus oxaliplatin versus observation after D2 gastrectomy for patients with stage II or III gastric cancer. The planned interim analysis of CLASSIC (median follow-up 34 months) showed that adjuvant capecitabine plus oxaliplatin significantly improved disease-free survival, the primary endpoint, compared with observation after D2 gastrectomy. We report the 5-year follow-up data from the trial. METHODS CLASSIC was a phase 3, randomised, open-label study done at 35 cancer centres, medical centres, and hospitals in China, South Korea, and Taiwan. Patients with stage II-IIIB gastric cancer who underwent curative D2 gastrectomy were randomly assigned (1:1) after surgery to receive adjuvant chemotherapy with capecitabine and oxaliplatin (eight 3-week cycles of oral capecitabine 1000 mg/m(2) twice daily on days 1-14 plus intravenous oxaliplatin 130 mg/m(2) on day 1) for 6 months or observation alone. Randomisation was stratified by country and disease stage with a permuted block (size four) design. Neither patients nor investigators were masked to treatment assignment. The primary outcome was 3-year disease-free survival in the intention-to-treat population. This analysis presents the final preplanned assessment of outcomes after 5 years. The study is registered with ClinicalTrials.gov, NCT00411229. FINDINGS We enrolled 1035 patients: 520 were randomly assigned to adjuvant capecitabine and oxaliplatin, and 515 to observation. Median follow-up for this analysis in the intention-to-treat population was 62·4 months (IQR 54-70). 139 (27%) patients had disease-free survival events in the adjuvant capecitabine and oxaliplatin group versus 203 (39%) patients in the observation group (stratified hazard ratio [HR] 0·58, 95% CI 0·47-0·72; p<0·0001). Estimated 5-year disease-free survival was 68% (95% CI 63-73) in the adjuvant capecitabine and oxaliplatin group versus 53% (47-58) in the observation alone group. By the clinical cutoff date, 103 patients (20%) had died in the adjuvant capecitabine and oxaliplatin group versus 141 patients (27%) in the observation group (stratified HR 0·66, 95% CI 0·51-0·85; p=0·0015). Estimated 5-year overall survival was 78% (95% CI 74-82) in the adjuvant capecitabine and oxaliplatin group versus 69% (64-73) in the observation group. Adverse event data were not collected after the primary analysis. INTERPRETATION Adjuvant treatment with capecitabine plus oxaliplatin after D2 gastrectomy should be considered for patients with operable stage II or III gastric cancer. FUNDING F Hoffmann La-Roche and Sanofi.

Gene expression signature-based prognostic risk score in gastric cancer

Purpose: Despite continual efforts to develop a prognostic model of gastric cancer by using clinical and pathologic parameters, a clinical test that can discriminate patients with good outcomes from those with poor outcomes after gastric cancer surgery has not been established. We aim to develop practical biomarker-based risk score that can predict relapse of gastric cancer after surgical treatment. Experimental Design: Microarray technologies were used to generate and analyze gene expression profiling data from 65 gastric cancer patients to identify biomarker genes associated with relapse. The association of expression patterns of identified genes with relapse and overall survival was validated in independent gastric cancer patients. Results: We uncovered two subgroups of gastric cancer that were strongly associated with the prognosis. For the easy translation of our findings into practice, we developed a scoring system based on the expression of six genes that predicted the likelihood of relapse after curative resection. In multivariate analysis, the risk score was an independent predictor of relapse in a cohort of 96 patients. We were able to validate the robustness of the six-gene signature in an additional independent cohort. Conclusions: The risk score derived from the six-gene set successfully prognosticated the relapse of gastric cancer patients after gastrectomy. Clin Cancer Res; 17(7); 1850–7. ©2011 AACR.

Putative chromosomal deletions on 9p, 9q and 22q occur preferentially in malignant gastrointestinal stromal tumors

To characterize the type of genetic alterations in gastrointestinal stromal tumors (GISTs), we performed a comprehensive allelotype study of 14 GISTs (2 benign, 7 borderline and 5 malignant) by polymerase‐chain‐reaction and loss‐of‐heterozygosity (PCR‐LOH) analysis using 102 microsatellite markers, and compared the results with comparative‐genomic‐hybridization (CGH) analysis. Among the 38 evaluated chromosomal arms, 16 (42.1%) showed LOH in at least one patient. Most frequent LOH was observed at chromosome 14p and 14q (9/14, 64%) and this was demonstrated in all types of GISTs (50% in benign, 71% in borderline and 80% in malignant). Additional chromosomal deletions were found in several chromosomal arms. Among them, deletions on chromosomal arms of 22q (3/14, 21.4%), 9p (2/14, 14.3%) and 9q (2/14, 14.3%) were the most frequent, and were detected only in malignant GISTs both by PCR‐LOH and by CGH analysis. Additionally, 2 malignant GISTs with LOH on 9p showed homozygous deletions in the restricted area of 9p by multiplex PCR‐LOH analysis. Thus, several putative chromosomal changes were preferentially present in malignant GISTs but rare in benign and borderline GISTs. These findings suggest that accumulated chromosomal changes may contribute to the progression and/or malignant transformation of GISTs. Int. J. Cancer 85:633–638, 2000.

Correlation of KIT and platelet-derived growth factor receptor |[alpha]| mutations with gene activation and expression profiles in gastrointestinal stromal tumors

Activating mutations of KIT and platelet-derived growth factor receptor α (PDGFRA) are known to be alternative and mutually exclusive genetic events in the development of gastrointestinal stromal tumors (GISTs). We examined the effect of the mutations of these two genes on the gene expression profile of 22 GISTs using the oligonucleotide microarray. Mutations of KIT and PDGFRA were found in 17 cases and three cases, respectively. The remaining two cases had no detectable mutations in either gene. The mutation status of KIT and PDGFRA was directly related to the expression levels of activated KIT and PDGFRA, and was also related to the different expression levels of activated proteins that play key roles in the downstream of the receptor tyrosine kinase III family. To evaluate the impact of mutation status and the importance of the type of mutation in gene expression and clinical features, microarray-derived data from 22 GISTs were interpreted using a principal component analysis (PCA). Three relevant principal component representing mutation of KIT, PDGFRA and chromosome 14q deletion were identified from the interpretation of the oligonucleotide microarray data with PCA. After supervised analysis, there was at least a two fold difference in expression between GISTs with KIT and PDGFRA mutation in 70 genes. Our findings demonstrate that mutations of KIT and PDGFRA affect differential activation and expression of some genes, and can be used for the molecular classification of GISTs.

Advanced Gastric Carcinoma with Signet Ring Cell Histology

Background: Gastric signet ring cell carcinoma (SRC) is a histological type based on microscopic characteristics and not on biological behavior. This study compared the clinicopathological features and prognosis of advanced SRC with non-signet ring cell adenocarcinoma (NSRC) of the stomach. Methods: We reviewed the records of 4,759 consecutive patients diagnosed with advanced gastric adenocarcinoma who were resected surgically from 1987 to 2003. Of these, 662 patients (13.9%) had SRC and were compared with 4,097 patients with NSRC. Results: Significant differences were noted in tumor size, Borrmann type, depth of invasion, lymph node metastasis, peritoneal dissemination and TNM stage. The cumulative 5-year survival rate for advanced SRC was 42.4%, compared with 50.1% in NSRC (p = 0.009). Multivariate analysis showed that tumor size ≧5 cm, Borrmann III and IV, T3–4 invasion and SRC histology were independent risk factors for lymph node metastasis. Depth of invasion, lymph node metastasis, hepatic and peritoneal metastasis and surgical curability were significant factors affecting survival. SRC histology alone was not an independent prognostic factor. Conclusions: Advanced gastric SRC tends toward deeper tumor invasion and more lymph node and peritoneal metastasis than NSRC. Advanced gastric SRC had a worse prognosis than NSRC. Therefore, curative surgical operation with extended lymph node dissection is recommended.

Prognostic significance of metastatic lymph node ratio in T3 gastric cancer

The fifth International Union Against Cancer tumor node metastasis (UICC TNM) classification, basedon the number of metastatic lymph nodes (LN), has proved to be areliable and objective method for predicting the prognosis of patientswith gastric cancer. However, the prognosis of patients with T3 gastriccancer is still heterogeneous. This study was carried out toinvestigate the validity of metastatic LN ratio as a prognostic factorin T3 gastric cancer. A retrospective analysis was performed on a totalof 833 patients that had either T3N1M0 (n = 504) orT3N2M0 (n = 329) gastric cancer by the fifth UICCclassification. A preliminary analysis revealed the cutoff values forT3N1M0 to be 10% and for T3N2M0 to be 25%. The mean metastatic LNratio was 9.0% for T3N1M0 cancer and 26.9% for T3N2M0 cancer. For theT3N1M0 stage, the patients who showed less than 10% of the metastaticLN ratio were grouped as N1-low with the others grouped as N1-high. Forthe T3N2M0 stage group, those who had less than 25% of the metastaticLN ratio were grouped as N2-low, the remainder as N2-high. Themetastatic LN ratio decreased in proportion to the extent oflymphadenectomy and it increased in relation to the increasing scale ofthe fourth N classification. The rates of recurrence were significantlydifferent according to the metastatic LN ratio in N1 and N2classification of the fifth UICC classification (p < 0.05). The5-year survival rates after gastrectomy decreased significantly byincreasing the metastatic LN ratio in both T3N1M0 cancers (p =0.0026) and T3N2M0 cancers (p = 0.0057). The metastatic LN ratiowas an independent risk factor for recurrence and poor prognosis. Ourdata suggest that the metastatic LN ratio is a significant prognosticfactor for T3 gastric cancer. Furthermore, the application of themetastatic LN ratio can provide information not only about the extentof LN metastasis but also about the extent of lymphadenectomy in T3gastric cancer.

Gastric cancer surgery without drains: A prospective randomized trial

Prophylactic drain placement during major abdominal surgery has been widely practiced without clear scientific evidence to support it. We hypothesized that prophylactic drain placement is not necessary in gastric cancer surgery. A randomized prospective trial was conducted between February 1, 2001, and July 30, 2001. Patients were randomly assigned to either the drain group or the no-drain group. One hundred seventy patients completed the study by undergoing either subtotal or total gastrectomy with D2 lymph node dissection. Surgical outcome between the two groups was compared within the subtotal and total gastrectomy subgroups. Postoperative complication within 30 days was the primary end point of the study. No significant difference was noted in the incidence of postoperative complication between the drain group and the no-drain group. The results of this study suggest that prophylactic drain placement does not offer additional benefit for patients undergoing gastric cancer surgery with extended lymph node dissection.