Comparison of survival outcomes according of patients with metastatic gastric cancer receiving trastuzumab with systemic chemotherapy.

Purpose: Currently, trastuzumab plus chemotherapy is the standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic gastric cancer (mGC) or esophagogastric junction cancer. However, it is not clear whether the prognosis of HER2-positive mGC treated with trastuzumab plus chemotherapy is better than that of HER2-negative mGC treated with chemotherapy as the first-line therapy. Methods: We performed a retrospective study comparing the prognosis of mGC according to first-line treatment with trastuzumab plus chemotherapy or chemotherapy only, at the Korea Cancer Center Hospital from 2011 to 2018. The Kaplan-Meier method and Cox proportional hazards model were used for univariate and multivariate survival analyses. Results: The median overall survival of trastuzumab group was 26.1 months and that of chemotherapy group was 14.8 months (P=0.047). Trastuzumab group had a longer median progression-free survival than chemotherapy group (23.4 vs. 9.2 months, P=0.026). By univariate analysis, sex, age, World Health Organization (WHO) histology, HER2 status, primary tumor site, extent of disease, number of lesions, number of metastatic, measurability of disease, prior gastrectomy, and chemotherapy group are statistically significant. Using multivariate analysis, number of lesions, number of metastatic, prior gastrectomy, and trastuzumab group (hazard ratio, 0.594; 95% confidence interval, 0.384-0.921; P=0.020) were found to be independent prognostic factors of overall survival. Conclusion: The result suggests prognosis of HER2-positive mGC treated by trastuzumab plus chemotherapy could be better than that of HER2-negative mGC treated by chemotherapy only. Well-designed prospective cohort studies are needed to confirm the results of this study. HER2 testing should be performed routinely in all patients newly diagnosed with mGC.

Time-Dependent Effects of Prognostic Factors in Advanced Gastric Cancer Patients.

PURPOSE: This study aimed to identify time-dependent prognostic factors and demonstrate the time-dependent effects of important prognostic factors in patients with advanced gastric cancer (AGC). MATERIALS AND METHODS: We retrospectively evaluated 3,653 patients with AGC who underwent curative standard gastrectomy between 1991 and 2005 at the Korea Cancer Center Hospital. Multivariate survival analysis with Cox proportional hazards regression was used in the analysis. A non-proportionality test based on the Schoenfeld residuals (also known as partial residuals) was performed, and scaled Schoenfeld residuals were plotted over time for each covariate. RESULTS: The multivariate analysis revealed that sex, depth of invasion, metastatic lymph node (LN) ratio, tumor size, and chemotherapy were time-dependent covariates violating the proportional hazards assumption. The prognostic effects (i.e., log of hazard ratio [LHR]) of the time-dependent covariates changed over time during follow-up, and the effects generally diminished with low slope (e.g., depth of invasion and tumor size), with gentle slope (e.g., metastatic LN ratio), or with steep slope (e.g., chemotherapy). Meanwhile, the LHR functions of some covariates (e.g., sex) crossed the zero reference line from positive (i.e., bad prognosis) to negative (i.e., good prognosis). CONCLUSIONS: The time-dependent effects of the prognostic factors of AGC are clearly demonstrated in this study. We can suggest that time-dependent effects are not an uncommon phenomenon among prognostic factors of AGC.

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.

Hepatic resection for hepatic metastases from gastric adenocarcinoma.

PURPOSE: The effects of hepatic resection on patients with metastatic tumors from gastric adenocarcinomas are unclear. Therefore, we analyzed early clinical outcomes in patients who underwent surgical resection for hepatic metastases from gastric adenocarcinomas. MATERIALS AND METHODS: From January 2003 to December 2010, 1,508 patients with primary gastric cancers underwent curative gastric resections at the Korea Cancer Center Hospital. Of these patients, 12 with liver-only metastases underwent curative hepatic resection. Their clinical data were analyzed retrospectively. RESULTS: The median follow-up period was 12.5 months (range, 1~85 months); no operative mortalities or major complications were observed. Three patients underwent synchronous resections, and 9 underwent metachronous resections. In the latter group, the median interval between gastrectomy and hepatectomy for hepatic metastasis was 10.5 months (range, 5~47 months). The overall 1- and 5-year survival rates of these 12 patients were 65% and 39%, respectively, with a median overall survival of 31.0 months; 2 patients survived for >5 years. CONCLUSIONS: Hepatic resection can be a feasible procedure for treating hepatic metastases from gastric adenocarcinomas. Although this study was small and involved only selected cases, the outcomes of the hepatic resections were comparable and long-term (>5 years) survivors were identified. Surgical resection of the liver can be considered a feasible option in managing hepatic metastases from gastric adenocarcinomas.

Test execution variation in peritoneal lavage cytology could be related to poor diagnostic accuracy and stage migration in patients with gastric cancer.

PURPOSE: Peritoneal lavage cytology is part of the routine staging workup for patients with advanced gastric cancer. However, no quality assurance study has been conducted to show variations or biases in peritoneal lavage cytology results. The aim of this study was to demonstrate a test execution variation in peritoneal lavage cytology between investigating surgeons. MATERIALS AND METHODS: A prospective cohort study was designed for determination of the positive rate of peritoneal lavage cytology using a liquid-based preparation method in patients with potentially curable advanced gastric cancer (cT2~4/N0~2/M0). One hundred thirty patients were enrolled and underwent laparotomy, peritoneal lavage cytology, and standard gastrectomy, which were performed by 3 investigating surgeons. Data were analyzed using the chi-square test and a logistic regression model. RESULTS: The overall positive peritoneal cytology rate was 10.0%. Subgroup positive rates were 5.3% in pT1 cancer, 2.0% in pT2/3 cancer, 11.1% in pT4a cancer, and 71.4% in pT4b cancer. In univariate analysis, positive peritoneal cytology showed significant correlation with pT stage, lymphatic invasion, vascular invasion, ascites, and the investigating surgeon. We found the positive rate to be 2.1% for surgeon A, 10.2% for surgeon B, and 20.6% for surgeon C (P=0.024). Multivariate analysis identified pT stage, ascites, and the investigating surgeon to be significant risk factors for positive peritoneal cytology. CONCLUSIONS: The peritoneal lavage cytology results were significantly affected by the investigating surgeon, providing strong evidence of test execution variation that could be related to poor diagnostic accuracy and stage migration in patients with advanced gastric cancer.

Risk stratification for serosal invasion using preoperative predictors in patients with advanced gastric cancer.

PURPOSE: Although serosal invasion is a critical predisposing factor for peritoneal dissemination in advanced gastric cancer, the accuracy of preoperative assessment using routine imaging studies is unsatisfactory. This study was conducted to identify high-risk group for serosal invasion using preoperative factors in patients with advanced gastric cancer. MATERIALS AND METHODS: We retrospectively analyzed clinicopathological features of 3,529 advanced gastric cancer patients with Borrmann type I/II/III who underwent gastrectomy at Korea Cancer Center Hospital between 1991 and 2005. We stratified patients into low- (≤40%), intermediate- (40~70%), and high-risk (>70%) groups, according to the probability of serosal invasion. RESULTS: Borrmann type, size, longitudinal and circumferential location, and histology of tumors were independent risk factors for serosal invasion. Most tumors of whole stomach location or encircling type had serosal invasion, so they belonged to high-risk group. Patients were subdivided into 12 subgroups in combination of Borrmann type, size, and histology. A subgroup with Borrmann type II, large size (≥7 cm), and undifferentiated histology and 2 subgroups with Borrmann type III, large size, and regardless of histology belonged to high-risk group and corresponded to 25% of eligible patients. CONCLUSIONS: This study have documented high-risk group for serosal invasion using preoperative predictors. And risk stratification for serosal invasion through the combination with imaging studies may collaboratively improve the accuracy of preoperative assessment, reduce the number of eligible patients for further staging laparoscopy, and optimize therapeutic strategy for each individual patient prior to surgery.

Effect of bisphosphonates on bone mineral density and fracture prevention in gastric cancer patients after gastrectomy.

GOAL: To evaluate the effectiveness of bisphosphonates in preventing fractures in gastric cancer patients by increasing bone mineral density (BMD). BACKGROUND: The effectiveness of bisphosphonates is questionable in gastric cancer patients who have undergone gastrectomy, although they display a high prevalence of osteoporosis. STUDY: Forty-seven gastric cancer patients with osteoporosis were retrospectively analyzed. All patients were supplemented with calcium and vitamin D. Twenty-four patients were treated with bisphosphonate (bisphosphonate group) and 23 patients were untreated (control group). Fractures, severe bone pain, and adverse effects of bisphosphonates were monitored. BMD of the lumbar spine and femoral neck were measured before and 1-year treatment with bisphosphonates by dual-energy X-ray absorptiometry. RESULTS: During a 1-year follow-up, 7 of the 47 (15%) patients developed new fractures. The bisphosphonate-treated group had a significantly lower fracture rate than the control group (n=1 vs. 6, P<0.05). Lumbar spine BMD increased in both groups (0.047 ± 0.03 vs. 0.021 ± 0.03 g/cm², respectively), whereas femoral neck BMD increased only in the bisphosphonate group (0.032 ± 0.03 vs. -0.004 ± 0.02 g/cm², respectively). Furthermore, the bisphosphonate group showed greater increases in lumbar spine and femoral neck BMDs than the controls (P<0.05). No difference was found between alendronate and risedronate in terms of BMD at follow-up. CONCLUSIONS: Therapy using bisphosphonates might be effective at increasing BMD and reducing fracture risk in gastric cancer patients after gastrectomy. Further well-designed randomized controlled trials are needed for confirmation.

Prognosis of curatively resected pT4b gastric cancer with respect to invaded organ type.

PURPOSE: Curative resection, including gastrectomy, extensive lymph node dissection, and combined resection of invaded organs, is the mainstay of treatment for T4b gastric cancers. We sought to investigate the clinicopathologic features, surgical outcomes, and prognostic factors of curatively resected pathologic T4b gastric cancer with a focus on organs invaded. METHODS: Data of 243 pT4b gastric cancer patients who underwent curative resection at Korea Cancer Center Hospital from 1991 to 2005 were retrospectively subjected to univariate and multivariate analyses. RESULTS: Overall 5-year survival rate and median survival time were 36.8% and 26 months, respectively. Five-year survival rates were 23.3% in the pancreatic invasion group (n = 67) and 42.1% in the nonpancreatic invasion group (n = 176) (P = 0.002). Regarding operative methods used for pancreatectomy in pancreatic invasion group, 5-year survival rates were 0% in the pancreaticoduodenectomy group (n = 9) and 27.4% in the other pancreatectomies group (n = 58) (P = 0.013). Multivariate analysis revealed that advanced lymph node stages (hazard ratio [HR] 1.637 for N0 vs. N1, HR 2.177 for N0 vs. N2, HR 3.241 for N0 vs. N3a, and HR 4.000 for N0 vs. N3b), encircling type of tumor (HR 1.804), and pancreatic invasion (HR 1.463) were independently unfavorable prognostic factors. CONCLUSIONS: In pT4b gastric cancer, pancreatic invasion was found to portend the least favorable prognosis, especially in cases requiring pancreaticoduodenectomy. However, prognoses were more favorable after curative resection in patients without advanced lymph node stages (N2, N3a, and N3b), an encircling type of gastric tumor, or pancreatic invasion. We propose a novel therapeutic strategy for patients with T4b gastric cancer.

Prevalence, pathophysiology, screening and management of osteoporosis in gastric cancer patients.

Osteoporosis in gastric cancer patients is often overlooked or even neglected despite its high prevalence in these patients. Considering that old age, malnutrition, chronic disease, chemotherapy, decreased body mass index and gastrectomy are independent risk factors for osteoporosis, it is reasonable that the prevalence of osteoporosis in gastric cancer patients would be high. Many surviving patients suffer from back pain and pathological fractures, which are related to osteoporosis. Fractures have obvious associated morbidities, negative impact on quality of life, and impose both direct and indirect costs. In the era of a >55.6% 5-year survival rate of gastric cancer and increased longevity in gastric cancer patients, it is very important to eliminate common sequelae such as osteoporosis. Fortunately, the diagnosis of osteoporosis is well established and many therapeutic agents have been shown to be effective and safe not only in postmenopausal females but also in elderly males. Recently, effective treatments of gastric cancer patients with osteoporosis using bisphosphonates, which are commonly used in postmenopausal woman, were reported.

Phosphorylated S6K1 is a possible marker for endocrine therapy resistance in hormone receptor-positive breast cancer.

Cross-talk between the estrogen receptor and the mammalian target of rapamycin (mTOR) pathway is one of the mechanisms of endocrine therapy resistance, and the phosphorylated S6 kinase 1(p-S6K1) is known to be a marker of the mTOR pathway activation. The authors assessed the prognostic significance of p-S6K1 according to the hormone receptor (HR) status. The expression of p-S6K1 was evaluated in 304 breast cancer tissues, and the association between its expression and patient outcomes was investigated. Among 197 cases with the HR (+) tumor, 70 (35.5%) were positive for p-S6K1. Most of the patients (97.5%) with the HR (+) tumor received adjuvant endocrine therapy. The expression of p-S6K1 was found to be an independent worse prognosticator affecting overall survival (OS) and breast cancer-specific survival (BCSS) in the HR (+) group (hazard ratio, 2.62; 95% confidence interval [CI], 1.19-5.76; P = 0.017 and hazard ratio, 3.25; 95% CI, 1.20-8.82; P = 0.020, respectively). In the HR (-) group, however, the p-S6K1 expression was not associated with patients' survival. The expression of p-S6K1 is a worse prognostic factor in patients with HR (+) tumors. These results suggest that the p-S6K1 expression might be a marker for endocrine therapy resistance in patients with HR (+) tumors.

Phenotypic Differences of Gastric Cancer according to the Helicobacter pylori Infection in Korean Patients.

PURPOSE: Infection with Helicobacter pylori is an important risk factor for gastric cancer in humans. We compared the clinicopathologic features of gastric cancer patients based on H. pylori infection. MATERIALS AND METHODS: We prospectively studied 155 patients who had gastric cancer and underwent gastrectomies in 1 hospital in Korea. We examined H. pylori infections using the rapid urease test (RUT) with gastrectomy specimens and collected clinical and pathologic data. RESULTS: The number of H. pylori infections based on the RUT was 137 (88%). The H. pylori-negative group was significantly associated with AGC and tumor histology. H. pylori infection was significantly correlated with type I/IIa in EGC and type III/IV/V in AGC. AGC was significantly correlated with larger tumor size, lymphatic invasion, perineural invasion, and H. pylori infection based on univariate and multivariate analyses. CONCLUSIONS: We report the prevalence of H. pylori based on the RUT in gastric cancer patients. H. pylori infection influences the tumor histology, progression, and growth type of gastric cancer.

Stereotactic body radiotherapy for isolated para-aortic lymph node recurrence after curative resection in gastric cancer.

The aim of this study was to investigate whether stereotactic body radiotherapy (SBRT) can salvage gastric cancer patients with para-aortic lymph node (PALN) recurrence. From January 2003 to December 2006, 7 patients were treated for isolated PALN recurrence from gastric cancer after curative resection. Follow up durations ranged from 19 to 33 months (median; 26 months), and SBRT doses from 45 Gy to 51 Gy (median 48 Gy) in 3 fractions. Disease progression-free and overall survivals and toxicities were recorded. Response to treatment was assessed by computed tomography. Final patient outcomes were as follows: 2 were alive without evidence of disease, 3 remained alive with disease, and 2 patients died of disease. Five of 7 patients showed complete response and 2 patients partial response between 3 and 11 months after SBRT. Three-year overall and disease progression-free survival rates post-SBRT were 43% and 29%, respectively. No severe complication was detected during follow-up. Selected patients with isolated PALN recurrence can be salvaged by SBRT without severe complications.

Randomized controlled trial comparing gastrectomy plus chemotherapy with chemotherapy alone in advanced gastric cancer with a single non-curable factor: Japan Clinical Oncology Group Study JCOG 0705 and Korea Gastric Cancer Association Study KGCA01.

A randomized controlled trial has started in both Japan and Korea to evaluate the role of gastrectomy in the management of incurable advanced gastric cancer (AGC). Patients with AGC diagnosed as having a single non-curable factor are randomized to gastrectomy plus chemotherapy or chemotherapy alone. Surgeons at 33 specialized centers in Japan and at 15 high-volume hospitals in Korea will recruit 330 patients. Primary end-point is overall survival, and secondary end-points are progression-free survival and adverse events associated with either gastrectomy or chemotherapy.

High prevalence of osteoporosis in patients with gastric adenocarcinoma following gastrectomy.

AIM: To evaluate the prevalence and predictive factors of osteoporosis in patients with gastric adenocarcinoma after gastrectomy. METHODS: The study included 133 patients diagnosed with gastric adenocarcinoma but who did not undergo prior diagnostic work-up for osteoporosis. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) and vertebral deformity was assessed by plain X-rays. We evaluated the effects of age, sex, body mass index (BMI), anemia, back pain, vertebral deformity, tumor staging, reconstruction type, and past medical history to determine predictive factors of osteoporosis in these patients. RESULTS: The prevalence of osteoporosis in the lumbar spine was 38.3% (male, 28.9%; female, 54.0%), and 15.0% in the femoral neck (male, 10.8%; female, 22.0%). The vertebral deformity rate was 46.6% (male, 43.4%; female, 52.0%). Age, BMI and hemoglobin correlated with BMD (P < 0.01). In males, anemia and age > 64 years were independent predictive factors of osteoporosis in multivariate analysis. In females, back pain was an independent factor for osteoporosis. CONCLUSION: The results of this study revealed that prevalence of osteoporosis and vertebral bone deformity rate were high in gastric cancer patients, regardless of post-gastrectomy duration and operation type. Early diagnosis and a proper management plan must be established in these patients.

Ipsilateral breast tumor recurrence after breast-conserving therapy: A comparison of quadrantectomy versus lumpectomy at a single institution.

The aims of study were to compare the rates of ipsilateral breast tumor recurrence (IBTR), for patients treated with either quadrantectomy or lumpectomy at a single institution, and to identify predictors of IBTR after breast-conserving therapy (BCT). The database and medical records of 807 patients who underwent BCT for breast cancer between 1987 and 2002 were reviewed. The age of the patient, tumor size, lymph node status, extensive intraductal component (EIC), re-excision, final margin status, and the extent of surgery were examined in reference to IBTR rates. Of the total 807 patients, 456 (56.5%) had undergone quadrantectomy and 351 patients (43.5%) had lumpectomy. Apart from the higher re-excision rate in the lumpectomy group (p < 0.001), there were no significant differences in clinical and pathologic characteristics between the patients in the two groups. At the median follow-up time of 72 months, 28 cases of IBTR (3.4%) and 56 cases of systemic recurrence (6.9%) had developed in 72 patients (8.9%). On multivariate analysis, young age (< or =35) (p = 0.041), positive lymph node (p < 0.001), and the presence of EIC (p = 0.004) were independent predictors of IBTR. However, we could not find a significant difference in IBTR rate between the two groups (p = 0.546). Thus, the extent of breast surgery (quadrantectomy or lumpectomy) did not make a significant difference in IBTR if adequate surgical margins could be achieved.

Combined Cytoreductive Surgery and Early Postoperative Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis of Gastric Cancer.

PURPOSE: Peritoneal seeding is the most common type of metastasis or recurrence and one of the poor prognostic factors in gastric cancer. Moreover, there are as yet no effective treatment modalities available. Recently some research groups suggested the benefit of combined cytoreductive surgery and intraperitoneal chemotherapy, but the related experiments remain in the trial stage. Therefore, we assessed the safety and evaluated the efficacy of combined cytoreductive surgery and early postoperative intraperitoneal chemotherapy (EPIC) in gastric cancer patients with peritoneal carcinomatosis of gastric cancer. MATERIALS AND METHODS: From Nov. 1997 to May. 2002, eighteen cases of combined cytoreduction and EPIC were performed in the Korea Cancer Center Hospital due to gastric cancer with peritoneal carcinomatosis. The control group consisted of 33 patients who had no resection without EPIC during the same periods. After combined cytoreductive surgery and EPIC, all patients received systemic chemotheraphy with the exception of 2 patients who could not tolerate the treatment. We retrospectively investigated the clinicopathologic features and analyzed the factors affecting the prognosis. Median follow-up period was 11.9 months (range 0.5~61 months). Statistical analysis was performed by SPSS 11.0 for Windows. A P-value less than 0.05 was considered as statistically significant. RESULTS: There was one case of the treatment-related mortality (5.5%) and seven cases of treatment-related complications (38%) in the combined cytoreductive surgery and intraperitoneal chemotherapy group. One-, 3- and 5-year survival rates of cytoreductive surgery plus EPIC were 57.6%, 25.9% and 13.0%, respectively, and those of the control group were 18.2%, 3% and 0%, respectively. Survival of the combined cytoreductive surgery plus EPIC group was better than that of the control group (p=0.0026). In multivariate analysis of prognostic factors affecting the survival, combined cytoreductive surgery plus EPIC (p=0.02) and systemic chemotherapy (p=0.019) were independent prognostic factors. CONCLUSION: Although a small number of cases were included in this study, combined cytoreductive surgery plus EPIC showed survival benefit and retained a comparable complication rate compared with the control group.