Wansik Yu

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.

Prospective randomized trial of early postoperative intraperitoneal chemotherapy as an adjuvant to resectable gastric cancer.

OBJECTIVE Surgeons have postulated on numerous occasions that cancer resection may participate in the dissemination of a malignancy. This randomized trial sought to determine whether a large volume of chemotherapy solution used perioperatively to flood the peritoneal cavity could eliminate microscopic residual disease and thereby improve survival of patients with gastric cancer. SUMMARY BACKGROUND DATA Surgical treatment failures in patients with gastric cancer are confined to the abdomen in most patients. Resection site and peritoneal surface spread, along with liver metastases, are the most common areas of recurrence. Survival and quality of life of patients with gastric cancer would be improved if disease progression at these anatomic sites was reduced. METHODS In a prospective randomized trial of 248 patients, intraperitoneal mitomycin C on day 1 and intraperitoneal 5-fluorouracil on days 2 through 5 were administered after gastric cancer resection. Patients who were thought to have stage II or stage III disease were randomized after resection to surgery alone versus surgery plus early postoperative intraperitoneal chemotherapy. After final pathologic examinations, there were 39 patients with stage I, 50 with stage II 95 with stage III, and 64 with resected stage IV cancer. RESULTS The 5-year survival of the surgery-only group was 29.3%, and the surgery-plus-intraperitoneal chemotherapy group was 38.7% (p = 0.219). In a subset analysis, the patients with stage I, stage II, and stage IV disease showed no statistically significant difference in survival. The 5-year survival rate of patients with stage III disease who underwent surgery only was 18.4% versus a survival rate of 49.1% for patients who underwent surgery plus intraperitoneal chemotherapy (p = 0.011). CONCLUSIONS In a subset analysis, patients with stage III gastric cancer have shown a statistically significant improvement in survival when treated with perioperative intraperitoneal chemotherapy. Further studies in patients with gastric cancer with surgically directed chemotherapy are suggested.

Randomized clinical trial of splenectomy versus splenic preservation in patients with proximal gastric cancer.

Preservation or removal of the spleen during total gastrectomy for proximal gastric cancer is a matter of debate.

Factors related to lymph node metastasis and the feasibility of endoscopic mucosal resection for treating poorly differentiated adenocarcinoma of the stomach

BACKGROUND AND AIM Endoscopic mucosal resection (EMR) is currently not accepted as an alternative treatment to surgery in early gastric cancer (EGC) of the undifferentiated histologic type. The present retrospective analysis examined the correlation of various histologic factors with the presence of lymph node metastasis (LNM). PATIENTS AND METHODS A retrospective analysis on 234 patients with poorly differentiated EGC who underwent radical gastrectomy with D2 lymph node dissection was undertaken. Several clinicopathologic factors were investigated to identify predictive factors for LNM: age, sex, type of operation, tumor location, tumor size, gross type, ulceration, lymphatic invasion, and depth of invasion. RESULTS Of the 234 lesions with poorly differentiated EGC, half (n = 116) already showed submucosal invasion in the resection specimen; 25.9 % of those (30/116) were limited to the upper third (SM1). Of the lesions confined to the mucosa, LNM was found in 3.4 % (4/118). With minor submucosal infiltration (SM1), the LNM rate was lower (0/30) in our patient population. Only with SM2/3 infiltration did the LNM rate sharply rise to around 30 %. The cut-off for submucosal infiltration depth was 500 microm (0/32 LNM), above which LNM rates were substantial (31.2 %; 24/77). There was limited correlation between the SM1-3 classification and actual measurement of submucosal infiltration depth. In a multivariate analysis, tumor size ( P = 0.033), depth of invasion ( P = 0.004), and lymphatic invasion ( P < 0.001) were associated with LNM. CONCLUSION Poorly differentiated EGC confined to the mucosa or with minimal submucosal infiltration (<or= 500 microm) could be considered for curative EMR due to the low risk of LNM. Given the limited case number of subgroups, these findings should be confirmed by more data from other centers, which should also focus on local recurrence after EMR in poorly differentiated EGC.

Investigation of Vascular Endothelial Growth Factor Gene Polymorphisms and Its Association with Clinicopathologic Characteristics in Gastric Cancer

Objective: Vascular endothelial growth factor (VEGF) is known to be a potent proangiogenic factor. This study evaluates the potential association of three VEGF gene polymorphisms (–460T > C, +405G > C, and 936C > T) with the susceptibility to and clinicopathologic characteristics of gastric cancer. Methods: The VEGF genotypes were determined using paraffin-embedded tissue from 413 patients who underwent a surgical resection and peripheral blood lymphocytes from 413 healthy controls by PCR-RFLP assay. Results: There was no difference in the allele frequency of –460T > C polymorphism. However, for the +405G > C polymorphism, the +405C allele was associated with a significantly decreased susceptibility to gastric cancer [odds ratio (OR) 0.686; 95% confidence interval (CI) 0.564–0.834]. Although there was no significant difference in the distribution of the 936C > T polymorphism between the two groups, the 936T allele was associated with a decreased susceptibility to gastric cancer (OR 0.757; 95% CI 0.591–0.970). In the haplotype analyses, the haplotype TCT (OR 0.405; 95% CI 0.263–0.624) was most closely associated with a decreased susceptibility to gastric cancer. However, no significant association was observed between the frequency of the genotypes or alleles and the clinicopathologic characteristics of gastric cancer. Conclusion: These observations imply that the VEGF gene polymorphisms may be associated with the susceptibility to gastric cancer. However, further studies of other VEGF sequence variants and their biological functions are needed to understand the role of the VEGF polymorphisms in determining the susceptibility to gastric cancer.

Phase II study of docetaxel and capecitabine in patients with metastatic or recurrent gastric cancer

Objectives: A phase II study was conducted to evaluate the response rate and safety of a combination regimen of docetaxel plus capecitabine in patients with advanced gastric cancer. Patients and Methods: Patients with previously untreated metastatic or recurrent measurable gastric cancer received i.v. docetaxel 75 mg/m2 on day 1 and oral capecitabine 1,000 mg/m2 twice daily from day 1 to 14 every 3-week cycle. Results: Thirty-two patients were enrolled in the current study. Of these, 30 patients were assessable for efficacy and 31 assessable for toxicity. One complete response and 13 partial responses were confirmed, giving an overall response rate of 43.8% (95% CI; 25.6–61.9%). The median time to progression and median overall survival for all patients was 5.07 months and 8.4 months, respectively. Grade 3/4 neutropenia occurred in 3 patients (9.7%) and febrile neutropenia was observed in 2 patients (6.3%). Grade 1/2 nausea was observed in 45.2% of patients. Grade 2–3 hand-foot syndrome occurred in 4 patients (12.9%). Conclusions: The combination of docetaxel and capectabine was found to be well tolerated and effective in patients with advanced gastric cancer. Accordingly, this regimen can be regarded as an important first-line treatment option for advanced gastric cancer.

Prognostic value of Tumor-infiltrating lymphocytes in Epstein-Barr virus-associated gastric cancer

BACKGROUND This study explored the prognostic impact of tumor-infiltrating lymphocytes (TILs) and investigated whether three histologic subtypes (lymphoepithelioma-like carcinoma, carcinoma with Crohns disease-like lymphoid reaction, and conventional-type adenocarcinoma) could stratify a prognostic subset for patients with Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC). MATERIALS AND METHODS After reviewing 1318 consecutive cases of surgically resected or endoscopic submucosal dissected gastric cancers, 120 patients were identified as EBV-positive using EBV-encoded RNA in situ hybridization. The evaluation of the percentage of intratumoral (iTu-) and stromal (str-) TILs was carried out, and the cases were also subclassified into three histologic subtypes as noted above. RESULTS Among the 120 patients, 73 patients (60.8%) and 60 patients (50.0%) were determined as str-TIL-positive and iTu-TIL-positive, respectively. In a univariate analysis, str-TIL-positivity was significantly associated with longer recurrence-free survival (RFS; P = 0.002) and disease-free survival (DFS; P = 0.008), yet not overall survival (OS; P = 0.145). While iTu-TIL-positivity has a tendency of favorable outcome indicator for DFS and OS, but statistically significant differences were not shown, respectively (RFS, P = 0.058; DFS, P = 0.151; OS, P = 0.191). In a multivariate analysis using a Cox proportional hazard model adjusted for age, pTNM stage, lymphatic invasion, perineural invasion, and venous invasion; histologic subtype, WHO classification, and str-TIL-positivity were independently or tentatively associated with favorable RFS (hazard ratio [HR] = 12.193, 95% confidence interval [95% CI] 1.039-143.055, P = 0.047) or DFS (HR = 4.836, 95% CI 0.917-25.525, P = 0.063). CONCLUSION The histologic subclassification and TILs can be used to predict RFS and DFS for patients with EBVaGC.

Changes of quality of life after gastric cancer surgery.

Purpose The aim of this study was to evaluate chronological change of quality of life after surgery in patients with gastric cancer during one year postoperatively. Materials and Methods Quality of life data were obtained from 272 gastric cancer patients who underwent curative gastrectomy between September 2008 and February 2011 at the Kyungpook National University Hospital. The Korean versions of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core (QLQ) 30 with gastric cancer-specific module, the EORTC QLQ-STO22 were used to assess quality of life. All patients had no evidence of recurrence or metastasis during the first postoperative year. Patients were asked to complete the questionnaire, by themselves preoperatively, 3-, 6-, 9-, and 12-months postoperatively. Results Physical functioning score and role functioning score significantly decreased at first 3 months after surgery and the significant differences were noticed until 12 months after surgery. Emotional functioning score started with the lowest score before surgery and significant improvement was shown 6 months after surgery. Most symptom scores and STO-22 scores were highest at 3 months after surgery and gradually decreased, thereafter. Eating restriction, anxiety, taste, body image scores was highest at 3 months after surgery without significant decrease afterwards. Conclusions Most scales worsened after surgery and gradually recovered afterwards with some differences in rate of recovery. However the scales did not fully recover by 1 year period. Further follow-up after 1 year would be helpful in determining which scales are permanently damaged and which are just taking longer time to recover.

Quality of Life of Long-Term Survivors after a Distal Subtotal Gastrectomy

PURPOSE The aim of this study was to investigate the impact of a distal subtotal gastrectomy on the quality of life (QoL). MATERIALS AND METHODS The QoL data of 126 patients were obtained on their 5th annual follow-up visit after a curative distal subtotal gastrectomy for gastric cancer (Group A). The QoL data of 130 age- and gender-adjusted healthy population were obtained from the individuals who visited the health screening center for a medical check-up (Group B). There were 42 women and 84 men in the study group and their mean age was 56.0±11.1 years. QoL was assessed using the Korean versions of the European Organization for Research and Treatment of Cancer (EORTC) QoL Questionnaire Core 30 (QLQ-C30) and QLQ-STO22. RESULTS The EORTC QLQ-C30 global health status and QoL scores of Group A and Group B were 63.9±22.7 and 61.3±22.1, respectively (p=0.361). Group A revealed a better score for emotional functioning (84.1±16.1 and 75.2±21.4, respectively; p<0.001), cognitive functioning (82.0±16.4 and 75.0±21.4, respectively; p=0.004) and fatigue (27.7±20.8 and 33.8±23.2, respectively; p=0.028). However, Group A revealed a worse score for nausea and vomiting (14.8±20.0 and 10.2±16.0, respectively; p=0.042), financial difficulties (14.8±22.9 and 7.1±16.1, respectively; p=0.002), reflux (16.7±17.7 and 10.1±17.0, respectively; p=0.003), eating restrictions (13.6±15.2 and 6.6±10.2, respectively; p<0.001) and body image (23.3±25.4 and 16.2±24.6, respectively; p=0.023). CONCLUSION The QoL of long-term survivors after a distal subtotal gastrectomy is still influenced by the surgery itself even though they are considered to be free of disease.

No Association of Vascular Endothelial Growth Factor-A (VEGF-A) and VEGF-C Expression with Survival in Patients with Gastric Cancer

PURPOSE Although the vascular endothelial growth factor (VEGF) superfamily has been identified to critically influence tumor-related angiogenesis, the prognostic significance of a VEGF expression in gastric cancer is still controversial. Accordingly, the present study analyzed the VEGF-A and VEGF-C expressions and their impact on the prognosis of patients with gastric cancer. MATERIALS AND METHODS Three hundred seventy-five consecutive patients who underwent surgical resection for gastric adenocarcinoma with a curative intent were enrolled in the present study. Immunohistochemical staining for VEGF-A and VEGF-C was performed using the formalin fixed, paraffin embedded tumor tissues. RESULTS Positive VEGF-A and VEGF-C expressions were observed in 337 (90.1%) and 278 (74.9%) cases, respectively. The survival analysis showed that the expression of VEGF-A and VEGF-C had no effect on the OS and DFS. On the multivariate analysis that included age, gender and the TNM stage, no significant association between the grade of the VEGF-A or VEGF-C expression and survival was observed. CONCLUSION The current study suggests that the tissue expression of VEGF-A or VEGF-C alone is not an independent prognostic marker for patients with surgically resected gastric adenocarcinoma.