[Show abstract][Hide abstract] ABSTRACT: Purpose:
The intratumoural heterogeneity of human epidermal growth factor receptor 2 (HER2) expression in gastric cancer is a major challenge when identifying patients who might benefit from HER2-targeting therapy. We investigated the significance of re-evaluation of HER2 status in primary sites and metastatic or recurrent sites in advanced gastric cancer patients whose primary tumours were initially HER2-negative.
Patients and methods:
In part I of this study, we evaluated the significance of repeat endoscopic biopsy in unresectable or metastatic gastric cancer patients whose tumours were initially HER2-negative. In part II, we examined the HER2 positivity rate in metastatic or recurrent sites in patients whose primary tumours were HER2-negative in biopsy or surgical specimens.
In part I (n = 183), we identified patients with HER2-positive tumours for a rescued HER2 positivity rate of 8.7% (95% confidence interval [CI], 4.6-12.8%) that was associated with tumour location (diffuse stomach versus other = 0% versus 11.7%, P = 0.013), Bormann type (IV versus others = 0% versus 11.7%, P = 0.013), and initial biopsy HER2 immunohistochemistry score (0 versus 1 versus 2=6.7% versus 15.4% versus 25.0%, P = 0.028). Part II (n = 175) resulted in HER2 positivity of 5.7% (95% CI 2.3-9.1%) that was significantly associated with metastatic site (liver versus others = 17.2% versus 3.4%, P = 0.012). When compared with a historical control that showed HER2 positivity on initial assessment, patients who had rescued HER2 positivity had similar treatment benefits from trastuzumab-containing first-line chemotherapy.
Repeat HER2 assessment in primary and metastatic or recurrent sites is recommended in patients with advanced gastric cancer whose primary tumour is initially HER2-negative.
Full-text · Article · Jan 2016 · European journal of cancer (Oxford, England: 1990)
[Show abstract][Hide abstract] ABSTRACT: Background
Oral fluoropyrimidine S-1 contains tegafur, which is metabolized to 5-fluorouracil by cytochrome P450 2A6 (CYP2A6). We here examined associations between CYP2A6 polymorphisms and treatment outcomes of adjuvant S-1 in gastric cancer patients.
Patients received adjuvant S-1 (40 mg/m2 twice daily, days 1–28, every 6 weeks for eight cycles) after curative surgery for pathological stage II–III gastric cancer. We analyzed the wild-type allele (W) (CYP2A6*1) and four variant alleles (V) (CYP2A6*4, *7, *9, *10) that abolish or reduce this enzyme activity.
Patients (n = 200) were enrolled between November 2007 and July 2013 with the following clinical characteristics: median age, 57 years (range, 32–83 years); 128 men, 72 women. With a median follow-up of 46.4 months, the 3-year relapse-free survival (RFS) and overall survival (OS) rates were 83.1 % (95 % CI, 77.7–88.5 %) and 94.8 % (95 % CI, 91.6–98.0 %), respectively. Genotype distributions were as follows: W/W (n = 49, 24.5 %), W/V (n = 94, 47.0 %), and V/V (n = 57, 28.5 %). Overall toxicity did not differ according to genotype for any grade (p = 0.612) or grade ≥3 (p = 0.143). However, RFS differed significantly according to CYP2A6 genotype. The 3-year RFS rates were 95.9 % for W/W, 83.1 % for W/V, and 72.5 % for V/V (p = 0.032). Carriers of W/V and V/V genotypes had a poorer RFS with a hazard ratio of 3.41 (95 % CI, 1.01–11.52; p = 0.049) and 4.03 (95 % CI, 1.16–13.93; p = 0.028), respectively, compared with the W/W genotype.
CYP2A6 polymorphisms are not associated with toxicity of S-1 chemotherapy, but correlate with the efficacy of S-1 in the adjuvant setting for gastric cancer.
[Show abstract][Hide abstract] ABSTRACT: Objective
Postoperative chemotherapy with S-1 or capecitabine plus oxaliplatin is a standard treatment for resectable gastric cancer (GC). However, survival outcomes of stage IIIB–IV (M0) GC cases are still poor. We investigated the efficacy and safety of docetaxel, capecitabine, and cisplatin (DXP) in patients with stage IIIB–IV GC.
This was a single-arm phase 2 study that included patients with stage IIIB–IV GC who underwent D2 gastrectomy. Patients received six cycles of docetaxel [60 mg/m2 on day 1 (D1)], capecitabine (1,875 mg/m2/day on D1–14), and cisplatin (60 mg/m2 on D1) every 3 weeks. The primary end-point was recurrence-free survival (RFS).
A total of 46 GC patients between January 2007 and August 2008 were included. After a median follow-up of 56.1 months (range 52.2–64.1), the median RFS and overall survival (OS) were 26.9 months (95 % CI 7.5–46.4) and 43.9 months (95 % CI 29.2–58.7), respectively. The 5-year RFS and OS rates were 39.1 and 41.3 %, respectively. The most common grade 3/4 toxicities were neutropenia (40 %), anorexia (22 %), and febrile neutropenia (15 %).
Adjuvant DXP is feasible and effective for patients with stage IIIB–IV GC. A phase 3 study comparing triplet and doublet regimens for these patients is ongoing.
[Show abstract][Hide abstract] ABSTRACT: Everolimus (RAD001) is an orally administered mTOR inhibitor that is well known for its antitumor efficacy and that has been approved for the treatment of several solid tumors, including renal cell carcinoma. In gastric cancer (GC), despite previous preclinical and phase I/II studies suggesting the promising efficacy of everolimus in previously treated AGC, more recent trials revealed that only certain subsets of patients might benefit from treatment with everolimus.
A 26-year-old man with metastatic gastric cancer with multiple liver lesions was treated with everolimus after failure of 1st-line and 2nd-line chemotherapy. A durable partial response was achieved for over 2 years. After progression from initial everolimus treatment, sequential cytotoxic chemotherapies were tried but failed rapidly. Everolimus was re-tried as salvage chemotherapy (re-treatment), and the patient achieved stable disease for 1 year until his death. Subsequent mutational analysis and immunohistochemical (IHC) staining with the tumor tissues just before re-treatment with everolimus revealed a PIK3CA hotspot mutation and pS6 overexpression in the primary tumor. After two cycles of everolimus re-treatment, the overexpression of pS6 became nearly absent in follow-up IHC staining.
Everolimus monotherapy was satisfactory in a patient with refractory metastatic GC harboring PIK3CA and pS6 aberrations. These molecular alterations might be potential biomarkers that can predict the treatment response of everolimus, particularly in the terms of durable disease control. This case suggests and emphasizes that close evaluation of biomarkers in tumor tissue may be essential for identifying highly favorable groups among various subpopulations with AGC.
[Show abstract][Hide abstract] ABSTRACT: This study evaluated the incidence of imatinib-associated skin rash, the interventional outcomes of severe rash, and impact of severe rash on the outcomes of imatinib treatment in gastrointestinal stromal tumor (GIST) patients.
A total of 620 patients were administered adjuvant or palliative imatinib for GIST at Asan Medical Center between January 2000 and July 2012. This analysis focused on a group of 42 patients who developed a severe rash requiring major interventions, defined as dose interruption or reduction of imatinib or systemic steroid use.
Of the 620 patients treated with imatinib, 148 patients (23.9%) developed an imatinib-associated skin rash; 42 patients (6.8%) developed a severe rash requiring major intervention. Of these, 28 patients (66.8%) successfully continued imatinib with interventions. Serial blood eosinophil levels during imatinib treatment were associated with skin rash and severity. A significant association was observed between successful intervention and blood eosinophil level at the time of intervention initiation. In metastatic settings, patients with severe rash requiring major interventions tended to show poorer progression-free survival than patients who did not require major intervention and patients with no rash, although this finding was not statistically significant (P = 0.326).
By aggressive treatment of severe rash through modification of imatinib dose or use of systemic steroid, the majority of patients can continue on imatinib. In particular, imatinib dose intensity can be maintained with use of systemic steroid. Measuring the blood eosinophil levels may be helpful in guiding the management plan for skin rash regarding the intensity and duration of interventions.
Full-text · Article · Sep 2015 · Cancer Research and Treatment
[Show abstract][Hide abstract] ABSTRACT: We conducted a phase II study to evaluate the efficacy and safety of perioperative S-1 plus docetaxel in locally advanced gastric cancer (LAGC) and to investigate the association between CYP2A6 genotype and outcome.
Patients with LAGC [clinical stage III-IV (M0) by the Japanese staging system] received three cycles of pre- and postoperative chemotherapy (S-1 40 mg/m(2) twice daily on days 1-14; intravenous docetaxel 35 mg/m(2) on days 1 and 8, every 3 weeks) followed by gastrectomy with D2 dissection. We also performed a pharmacokinetic and CYP2A6 genotyping study (*1, *4, *7, *9, *10) for S-1.
From October 2006 to June 2008, 44 patients entered the study. 43 eligible patients completed preoperative chemotherapy and 40 completed postoperative chemotherapy. The most common G3/4 toxicities during pre- and postoperative chemotherapy were neutropenia, stomatitis, and abdominal pain. The clinical response rate by RECIST was 74.4 % (95 % CI, 61.4-87.4 %), and the R0 resection rate was 97.7 %. Clinical downstaging in T or N occurred in 41.9 % of patients. The 3-year progression-free survival (PFS) rate was 62.8 % and 5-year overall survival (OS) rate was 69.6 %. PFS and OS differed significantly according to clinical response, clinical downstaging, and CYP2A6 genotype. Patients with CYP2A6 variant/variant genotypes had a higher tegafur C max and worse survival than those with wild/wild or wild/variant genotypes.
Perioperative S-1 plus docetaxel is active with a manageable toxicity in patients with LAGC receiving D2 surgery. Clinical tumor response, clinical downstaging, and CYP2A6 genotype may predict efficacy.
[Show abstract][Hide abstract] ABSTRACT: S-1 is an oral 5-fluorouracil agent containing tegafur, 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate. This study explored the pharmacokinetics of S-1 and pharmacokinetic changes after gastric surgery in patients with resectable gastric cancer who received pre- and post-operative S-1 plus docetaxel. Serial blood was drawn before and after gastrectomy from 37 patients for pharmacokinetic analysis. Pharmacokinetics of tegafur, 5-fluorouracil, and CDHP was analyzed by non-compartmental analysis (NCA) methods and by modeling. In modeling analysis CHDP concentrations were incorporated in the model as a time varying covariate that inhibits the clearance of 5-fluorouracil following an inhibitory Emax model. In NCA, pharmacokinetics of tegafur and 5-FU before and after gastric surgery were similar, although average maximum concentrations of 5-FU were decreased with statistical significance after gastrectomy. Median Tmax of tegafur was shorter after surgery without statistical significance. In modeling analysis, tegafur was best fitted by mixed zero and first-order absorption. The only difference in the final pharmacokinetic model around gastrectomy was the presence of an absorption lag of 0.23 hours before surgery. Incorporation of CDHP concentrations significantly improved the model. Although some pharmacokinetic results showed statistically significant changes after gastrectomy, these differences seems to be too small to have any clinical implication. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
No preview · Article · Mar 2015 · The Journal of Clinical Pharmacology
[Show abstract][Hide abstract] ABSTRACT: Although surgical resection remains the only curative treatment for gastric cancer, locoregional and distant recurrence are still common after surgical resection with curative intent underscoring the importance of a multimodal approach. In recent decades, there have been notable improvements in multidisciplinary treatments for gastric cancer that influence clinical decision and treatment algorithms; these include surgery, chemotherapy, and radiotherapy. Notably, multimodal and multidisciplinary approaches to gastric cancer have developed in various ways according to geographical regions in the context of variations in disease incidence, etiology/epidemiology, clinical features, and treatment outcome. Differences in surgical techniques, curative resection rate, survival outcomes after curative resection, and relapse patterns between the East and West lead to different perioperative multidisciplinary strategies. In Western countries, low rates of curative resection and high rates of locoregional recurrence following suboptimal surgery, in addition to systemic spread after surgery, provide a rationale for perioperative chemotherapy (preoperative and postoperative chemotherapy) and postoperative chemoradiation. In contrast, Eastern countries have focused on reducing systemic failures by emphasizing postoperative chemotherapy after curative resection. To further improve perioperative treatment in localized gastric cancer, more sophisticated risk stratification and novel therapeutic strategies such as molecularly targeted agents need to be investigated, based on an understanding of the molecular pathogenesis of the disease.
Full-text · Article · Mar 2015 · Journal of the Korean Medical Association
[Show abstract][Hide abstract] ABSTRACT: This phase I trial evaluated the question of whether the standard starting dose of axitinib could be administered in combination with therapeutic doses of cisplatin/capecitabine in patients with previously untreated advanced gastric cancer, and assessed overall safety, pharmacokinetics, and preliminary antitumor activity of this combination.
Patients in dose level (DL) 1 received axitinib 5 mg twice a day (days 1 to 21) with cisplatin 80 mg/m2 (day 1) and capecitabine 1,000 mg/m2 twice a day (days 1 to 14) in 21-day cycles. Maximum tolerated dose (MTD) was the highest dose at which ≤ 30% of the first 12 patients experienced a dose-limiting toxicity (DLT) during cycle 1. Ten additional patients were enrolled and treated at the MTD in order to obtain additional safety and pharmacokinetic data.
Three DLTs occurred during cycle 1 in three (25%) of the first 12 patients: ruptured abdominal aortic aneurysm, acute renal failure, and > 5 consecutive days of missed axitinib due to thrombocytopenia. DL1 was established as the MTD, since higher DL cohorts were not planned. Common grade 3/4 non-hematologic adverse events in 22 patients treated at DL1 included hypertension (36.4%) and decreased appetite and stomatitis (18.2% each). Cisplatin/capecitabine slightly increased axitinib exposure; axitinib decreased capecitabine and 5-fluorouracil exposure. Eight patients (36.4%) each had partial response or stable disease. Median response duration was 9.1 months; median progression-free survival was 3.8 months.
In patients with advanced gastric cancer, standard doses of axitinib plus therapeutic doses of cisplatin and capecitabine could be administered in combination. Adverse events were manageable.
Preview · Article · Feb 2015 · Cancer Research and Treatment
[Show abstract][Hide abstract] ABSTRACT: This study aimed to validate the prognostic relevance of macroscopic serosal changes in patients with resected gastric cancer. Prospectively collected databases of two multicenter randomized phase III trials of adjuvant chemotherapy were analyzed.
For this study, 655 patients in the control groups of AMC 0101 and 0201 trials were selected. Macroscopic serosal changes were determined according to disruptions in serosal continuity, such as changes in color or nodular texture by the operating surgeon. Correlations with recurrence-free survival (RFS), overall survival (OS), and time to peritoneal recurrence were analyzed.
Macroscopic serosal changes were identified intraoperatively in 432 patients (66 %) and found to be significantly associated with multifocal or diffuse involvement (p = 0.001), Borrmann type 4 (p = 0.005), advanced pathologic T (p < 0.001), N (p < 0.001), overall stage (p < 0.001), and total gastrectomy (p < 0.001). In multivariate analyses, which included prognostic factors of localized gastric cancer, macroscopic serosal changes were significantly associated with poor RFS [hazard ratio (HR) 2.0; 95 % confidence interval (CI), 1.4-2.7; p < 0.001] and OS (HR 2.1; 95 % CI 1.5-3.0; p < 0.001). The changes also were significantly related to shorter time to peritoneal recurrence (HR 2.9; 95 % CI 1.7-5.0; p < 0.001).
Intraoperatively assessed macroscopic serosal changes confer a poor prognosis and increased peritoneal recurrence for patients with curatively resected gastric cancer. Macroscopic assessment of serosal changes may be a useful indicator that allows better risk stratification of patients with resected gastric cancer in terms of prognosis and peritoneal recurrence.
Full-text · Article · Jan 2015 · Annals of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: Objective:
This study examined changes in health-related quality of life (HRQoL) and quality of care (QoC) as perceived by terminally ill cancer patients and a stratified set of HRQoL or QoC factors that are most likely to influence survival at the end of life (EoL).
We administered questionnaires to 619 consecutive patients immediately after they were diagnosed with terminal cancer by physicians at 11 university hospitals and at the National Cancer Center in Korea. Subjects were followed up over 161.2 person-years until their deaths. We measured HRQoL using the core 30-item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, and QoC using the Quality Care Questionnaire-End of Life (QCQ-EoL). We evaluated changes in HRQoL and QoC issues during the first three months after enrollment, performing sensitivity analysis by using data generated via four methods (complete case analysis, available case analysis, the last observation carried forward, and multiple imputation).
Emotional and cognitive functioning decreased significantly over time, while dyspnea, constipation, and pain increased significantly. Dignity-conserving care, care by healthcare professionals, family relationships, and QCQ-EoL total score decreased significantly. Global QoL, appetite loss, and Eastern Cooperative Oncology Group Performance Status (ECOG-PS) scores were significantly associated with survival.
Significance of results:
Future standardization of palliative care should be focused on assessment of these deteriorated types of quality. Accurate estimates of the length of life remaining for terminally ill cancer patients by such EoL-enhancing factors as global QoL, appetite loss, and ECOG-PS are needed to help patients experience a dignified and comfortable death.
No preview · Article · Sep 2014 · Palliative and Supportive Care
[Show abstract][Hide abstract] ABSTRACT: Purpose:
The role of non-surgical treatments (NS), such as chemoradiotherapy or radiotherapy, for clinical T1N0M0 esophageal cancer (cT1N0M0 EC) has not been well delineated. The aim of this study was to evaluate and compare the feasibility and efficacy of NS and Surgical treatment (S) in cT1N0M0 EC patients.
The medical records of patients who received treatment for cT1N0M0 EC at Asan Medical Center between 2003 and 2012 were retrospectively reviewed. The baseline characteristics, treatment outcomes and complications, and survival were compared.
There were 264 S and 20 NS patients with respective median ages of 69.5 and 63.0. The main histologic finding was squamous cell carcinoma in both groups (97 and 100 %, respectively). The Eastern Cooperative Oncology Group performance status and Charlson comorbidity index score were poorer in the NS group. With a median follow-up of 49.0 months, 37 S patients (14 %) and 3 NS patients (15 %) exhibited recurrence. The first sites of recurrence for S and NS patients were locoregional (21 vs. 3 patients), distant (6 vs. 0), and both locoregional and distant (9 vs. 0), respectively. The median time-to-recurrence could not be calculated in either group (log-rank test P = 0.831). The estimated median overall survival was 64.4 months (95 % CI 37.2-91.6 months) in the NS group and could not be calculated in the S group (P = 0.056).
Non-surgical treatments can be an effective alternative to S for patients with cT1N0M0 EC unfit for radical surgery. The role of NS for early stage EC needs to be further verified with prospective randomized trials.
No preview · Article · Sep 2014 · Cancer Chemotherapy and Pharmacology
[Show abstract][Hide abstract] ABSTRACT: Hypoxia-inducible factor-1 alpha (HIF-1α) is an important marker of hypoxia in human tumors and has been implicated in tumor progression. Drugs targeting HIF-1α are being developed, but the ability to measure drug-induced changes in HIF-1α is limited by the lability of the protein in normoxia. Our goal was to devise methods for specimen collection and processing that preserve HIF-1α in solid tumor tissues and to develop and validate a two-site chemiluminescent quantitative ELISA for HIF-1α. We tested various strategies for HIF-1α stabilization in solid tumors including nitrogen gas-purged lysis buffer, addition of proteasome inhibitors, or the prolyl hydroxylase inhibitor 2-hydroxyglutarate, and bead homogenization. Degassing and addition of 2-hydroxyglutarate to the collection buffer significantly increased HIF-1α recovery, while bead-homogenization in sealed tubes improved HIF-1α recovery and reduced sample variability. Validation of the ELISA demonstrated intra- and inter-assay variability of less than 15% and accuracy of 99.8% ± 8.3% as assessed by spike recovery. Inter-laboratory reproducibility was also demonstrated (R2 = 0.999). Careful sample handling techniques allow us to quantitatively detect HIF-1α in samples as small as 2.5 μg of total protein extract, and this method is currently being applied to analyze tumor biopsy specimens in early-phase clinical trials.
No preview · Article · Aug 2014 · Analytical Biochemistry