[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.
BMC Cancer 12/2015; 15(1):1139. DOI:10.1186/s12885-015-1139-7 · 3.36 Impact Factor
[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.
Cancer Research and Treatment 09/2015; DOI:10.4143/crt.2015.017 · 3.32 Impact Factor
[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.
Gastric Cancer 04/2015; DOI:10.1007/s10120-015-0490-3 · 3.72 Impact Factor
[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.
The Journal of Clinical Pharmacology 03/2015; 55(8). DOI:10.1002/jcph.499 · 2.48 Impact Factor
[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.
Journal of the Korean Medical Association 03/2015; 58(3):201. DOI:10.5124/jkma.2015.58.3.201 · 0.18 Impact Factor
[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.
Cancer Research and Treatment 02/2015; DOI:10.4143/crt.2014.225 · 3.32 Impact Factor
[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.
[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.
Palliative and Supportive Care 09/2014; 13(4):1-9. DOI:10.1017/S1478951514000960 · 0.98 Impact Factor
[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.
Cancer Chemotherapy and Pharmacology 09/2014; 74(5). DOI:10.1007/s00280-014-2573-y · 2.77 Impact Factor
[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.
[Show abstract][Hide abstract] ABSTRACT: Cancer, including gastric cancer, occurs predominantly in older patients. Although there is no single internationally accepted standard chemotherapy regimen for unresectable or metastatic gastric cancer (MGC), doublet combination chemotherapy using fluoropyrimidine and platinum is regarded as the reference treatment. However, most of the clinical trials that were based on the current treatment guidelines were performed in patients < 70 years of age with good performance status (PS). Therefore, the clinical application of these guidelines to elderly individuals is limited. The available data suggest that older patients with good PS are able to tolerate the same chemotherapy regimens as younger patients with MGC, and that they achieve a similar efficacy. In contrast, some studies showed that the same efficacy was achieved at the expense of increased toxicity in older patients, emphasizing the importance of patient selection. Many studies have actively investigated elderly patients with MGC, including randomized phase 3 studies comparing fluoropyrimidine and platinum doublets with fluoropyrimidine alone. Although an advanced age alone should not preclude the use of effective chemotherapy in MGC, more data regarding age-specific clinical trials are needed to guide optimal treatment in elderly patients.
[Show abstract][Hide abstract] ABSTRACT: Hypoxia-inducible factor-1 (HIF-1) facilitates the adaptation of normal and tumor tissues to oxygen deprivation. HIF-1 is frequently overexpressed in cancer cells, where it is involved in the upregulation of many genes necessary for survival. EZN-2968 is an antisense oligodeoxynucleotide that specifically targets HIF-1α, one of the subunits of HIF-1. We conducted a trial of EZN-2968 in patients with refractory solid tumors to evaluate antitumor response and to measure modulation of HIF-1α mRNA and protein levels as well as HIF-1 target genes.
Adult patients with refractory advanced solid tumors were administered EZN-2968 as a 2-h IV infusion at a dose of 18 mg/kg once a week for three consecutive weeks followed by 3-week off; in a 6-week cycle. Tumor biopsies and dynamic contrast enhanced MRI (DCE-MRI) were performed at baseline and after the third dose.
Ten patients were enrolled, of whom all were evaluable for response; one patient with a duodenal neuroendocrine tumor had prolonged stabilization of disease (24 weeks). Reduction in HIF-1α mRNA levels compared to baseline was demonstrated in 4 of 6 patients with paired tumor biopsies. Reductions in levels of HIF-1α protein and mRNA levels of some target genes were observed in two patients. Quantitative analysis of DCE-MRI from two patients revealed changes in K (trans) and k ep. The trial was closed prematurely when the sponsor suspended development of this agent.
This trial provides preliminary proof of concept for modulation of HIF-1α mRNA and protein expression and target genes in tumor biopsies following the administration of EZN-2968.
Cancer Chemotherapy and Pharmacology 11/2013; 73(2). DOI:10.1007/s00280-013-2362-z · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Anti-angiogenic therapies such as bevacizumab upregulate hypoxia-inducible factor-1α (HIF-1α), a possible mechanism of drug resistance. Camptothecin analogues, including SN-38, have been shown to reduce the expression and transcriptional activity of HIF-1α in preclinical models. We hypothesized that co-administration of pegylated SN-38 (EZN-2208) may offset the induction of HIF-1α following bevacizumab treatment, resulting in synergistic antitumor effects.
Patients and methods:
Patients with refractory solid tumors were enrolled. Objectives were to evaluate the modulation of HIF-1α protein and target genes in tumor biopsies following administration of the combination of EZN-2208 administered weekly × 3 (days 1, 8, 15) and bevacizumab administered every 2 weeks, in 28-day cycles, and to establish the safety and tolerability of the combination. Tumor biopsies and dynamic contrast enhanced MRI (DCE-MRI) were obtained following bevacizumab alone (before EZN-2208) and after administration of both study drugs.
Twelve patients were enrolled; ten were evaluable for response. Prolonged stable disease was observed in 2 patients, one with HCC (16 cycles) and another with desmoplastic round cell tumor (7 cycles). Reduction in HIF-1α protein levels in tumor biopsies compared to baseline was observed in 5 of 7 patients. Quantitative analysis of DCE-MRI from 2 patients revealed changes in K(trans) and k(ep). The study closed prematurely as further clinical development of EZN-2208 was suspended by the pharmaceutical sponsor.
Preliminary proof-of-concept for modulation of HIF-1α protein in tumor biopsies following administration of EZN-2208 was observed. Two of 10 patients had prolonged disease stabilization following treatment with the EZN-2208 and bevacizumab combination.
Investigational New Drugs 11/2013; 32(2). DOI:10.1007/s10637-013-0048-3 · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gastric cancer is the fourth most common cancer globally, and is the second most common cause of death from cancer worldwide. About three-quarters of newly diagnosed cases in 2008 were from Asian countries. With a high mortality-to-incidence ratio, management of gastric cancer is challenging. We discuss evidence for optimum management of gastric cancer in aspects of screening and early detection, diagnosis, and staging; endoscopic and surgical intervention; and the concepts of perioperative, postoperative, and palliative chemotherapy and use of molecularly targeted therapy. Recommendations are formulated on the basis of the framework provided by the Breast Health Global Initiative, using the categories of basic, limited, enhanced, and maximum level. We aim to provide a stepwise strategy for management of gastric cancer applicable to different levels of health-care resources in Asian countries.
The Lancet Oncology 11/2013; 14(12):e535-47. DOI:10.1016/S1470-2045(13)70436-4 · 24.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The prognosis of patients with positive surgical resection margins is dismal in gastric cancer. However, the influence of positive margin itself on prognosis is still uncertain, especially in advanced gastric cancer (AGC). The aims of the present study were to evaluate the prognostic impact of microscopic tumor involved resection margins in stage III-IV AGC after gastric resection in comparison with other well-known factors.
Among 1,536 consecutive gastric cancer patients who received intentional curative resection for stage III-IV AGC between April 2001 and December 2011 at the National Cancer Center, 35 patients (2.28 %) had positive resection margins on their final histology. A comparison of clinicopathologic characteristics, recurrence pattern, overall survival (OS), and disease-free survival (DFS) was made between positive margin (PM) patients and negative margin (NM) patients.
Among the 35 PM patients, 15 (42.9 %) had proximal involved margins, 21 (60.0 %) had distal involved margins, and one (2.9 %) had both involved margins. Twenty-eight PM patients (80.0 %) were stage III, and 7 (20.0 %) were stage IV. Recurrence was significantly higher in PM than NM (63.6 % vs. 39.7 %, respectively; p = 0.005). The OS and DFS rates were significantly lower in the PM group than in the NM group (14.9 vs. 36.3 months, p < 0.001 and 11.6 vs. 27.1 months, p = 0.005, respectively). The presence of PM was an independent risk factor for both OS and DFS.
The presence of PM is an independent risk factor for OS and DFS. Considering the prognostic impact of PM, a sufficient resection margin should be ensured when determining the resection line in gastrectomy with curative intent. The reoperation to secure clear resection margins should be considered as a treatment of choice in the case of PM.
World Journal of Surgery 10/2013; 38(2). DOI:10.1007/s00268-013-2301-5 · 2.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Self-expandable metallic stents are used widely to relieve malignant gastric outlet obstruction (GOO). However, restenosis or migration of first stents is a frequent complication. The purpose of this retrospective cohort study was to evaluate the effectiveness of second stents as an approach to manage failure of first stents in patients with malignant GOO.
A total of 222 patients with gastric cancer received first stents due to inoperable GOO at National Cancer Center in Korea between January 2008 and June 2011. Monthly follow-up interviews were performed, and second stents (stent-in-stent or stent-after-migration) were inserted in 59 patients by June 2012. Technical and clinical successes and long-term complications were evaluated.
The technical and immediate clinical success rates were 98.3 % (58/59) and 91.5 % (54/59), respectively. Patients who received a second stent due to late complications involving the first stent (migration, restenosis, and fracture) showed a higher clinical success rate (95.8 % [46/48]) than patients who received a second stent due to immediate clinical failure of the first stent (72.7 % [8/11], p = 0.04). The immediate clinical success rate of stent-after-migration (100 % [11/11]) was not different from that of stent-in-stent (89.6 % [43/48], p = 1.0). The stent dysfunction rate of stent-after-migration (27.3 % [3/11]) also was similar to that of stent-in-stent (29.2 % [14/48], p = 1.0). The median patencies of stent-in-stent and stent-after-migration were 27.4 and 58.4 weeks, respectively (p = 0.177). There were no significant prognostic factors for patency of second stents.
Insertion of a second stent is effective for treating the first-stent failure in gastric cancer patients with GOO, especially if the immediate outcome of the first stent was successful.