Heung-Moon Chang

FCGR2A and FCGR3A Polymorphisms Associated With Clinical Outcome of Epidermal Growth Factor Receptor–Expressing Metastatic Colorectal Cancer Patients Treated With Single-Agent Cetuximab

PURPOSE Cetuximab, a chimeric immunoglobulin G 1 (IgG1) anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), has shown efficacy in 10% of patients with metastatic colorectal cancer (CRC). Recent studies demonstrate antibody-dependent cell-mediated cytotoxicity (ADCC) is one of the modes of action for rituximab and trastuzumab. Fragment c (Fc) portion of IgG1 mAb has shown to induce ADCC. Fragment c gamma receptors (FcgammaR) play an important role in initiating ADCC. Studies have shown that two IgG FcgammaR polymorphisms (FCGR2A-H131R and FCGR3A-V158F) independently predict response to rituximab in patients with follicular lymphoma. We tested the hypothesis of whether these two polymorphisms are associated with clinical outcome in metastatic CRC patients treated with single-agent cetuximab. PATIENTS AND METHODS Thirty-nine metastatic CRC patients were enrolled onto the ImClone0144 trial. Using an allele-specific polymerase chain reaction (PCR) -based method, gene polymorphisms of FCGA2A-H131R and FCGA3A-V158F were assessed from genomic DNA extracted from peripheral blood samples. RESULTS FCGR2A-H131R and FCGR3A-V158F polymorphisms were independently associated with progression-free survival (PFS; P = .037 and .055, respectively; log-rank test). Combined analysis of these two polymorphisms showed that patients with the favorable genotypes (FCGR2A, any histidine allele, and FCGR3A, any phenylalanine allele) showed a median PFS of 3.7 months (95% CI, 2.4 to 4.4 months), whereas patients with any two unfavorable genotypes (FCGR2A arginine/arginine or valine/valine) had a PFS of 1.1 months (95% CI, 1.0 to 1.4 months; P = .004; log-rank test). CONCLUSION Our preliminary data suggest that these two polymorphisms may be useful molecular markers to predict clinical outcome in metastatic CRC patients treated with cetuximab and that they may indicate a role of ADCC of cetuximab.

Pyridoxine Is Not Effective to Prevent Hand-Foot Syndrome Associated With Capecitabine Therapy: Results of a Randomized, Double-Blind, Placebo-Controlled Study

PURPOSE To determine whether concurrent pyridoxine therapy can prevent the development of hand-foot syndrome (HFS) in patients being treated with capecitabine. METHODS Chemotherapy-naive patients with GI tract cancers scheduled for capecitabine-containing chemotherapy were randomly assigned to concurrent oral pyridoxine (200 mg/d) or placebo. Patients were stratified by chemotherapy regimen and monitored until development of National Cancer Institute Common Toxicity Criteria grade 2 or worse HFS or capecitabine-containing chemotherapy ended. Patients in the placebo group who developed grade 2 or worse HFS were randomly assigned again to receive pyridoxine or placebo in the next chemotherapy cycle to determine whether pyridoxine could improve HFS. RESULTS The median number of chemotherapy cycles to grade 2 or worse HFS was three in both groups. Grade 2 or worse HFS developed in 55 (30.6%) of 180 placebo-treated patients and in 57 (31.7%) of 180 pyridoxine patients. The cumulative dose of capecitabine to grade 2 or worse HFS was not different between the two groups (median not reached in either group; hazard ratio [HR] = 0.95; P = .788). Randomization of the 44 patients in the placebo group with grade 2 or worse HFS to placebo or pyridoxine for the next cycle resulted in no significant difference in the proportion showing improvement of HFS (42.9% v 47.8%; HR = 1.12; P = .94). By multivariate analysis, age > or = 56 years (HR = 1.768; 95% CI, 1.190 to 2.628; P = .005) was an independent risk factor for grade 2 or worse HFS, and combined use of docetaxel (HR = 2.046; 95% CI, 0.880 to 4.755; P = .096) was of borderline significance. CONCLUSION Pyridoxine is not effective in prevention of capecitabine-associated HFS.

Leptomeningeal carcinomatosis in gastric cancer.

We analyzed 19 cases of cytologically confirmed leptomeningeal carcinomatosis (LMC) treated at our institution over the past 11 years. LMC was the initial manifestation of gastric cancer in 2 patients. With the exception of 1 patient, the primary gastric cancer was Borrmann type III or IV, and 88% had poorly differentiated or signet-ring cell histology. The gastric cancer was progressive or a recurrent disease in most of the patients. The distribution of extraneural metastasis suggested that Batsons venous plexus might be the predominant route to the subarachnoid space. Eighty percent of the patients had multiple neuraxis syndrome, and the combination of brain plus cranial nerve syndrome was the most common manifestation. Computed tomography (CT) findings were abnormal in a minor proportion of the patients, while magnetic resonance imaging (MRI) revealed abnormality in 67% of the patients, which could help the diagnosis. LMC complicating gastric cancer was ultimately fatal. Median survival was very short, 4 weeks. By univariate analysis, good performance status, intrathecal chemotherapy, and low CSF LDH concentration favored survival. Multivariate analysis revealed that the administration of CSF chemotherapy was the independent prognostic factor for survival.

Cross-Sectional Study of Imatinib Plasma Trough Levels in Patients With Advanced Gastrointestinal Stromal Tumors: Impact of Gastrointestinal Resection on Exposure to Imatinib

PURPOSE Imatinib plasma trough levels (C(min)) have been reported to correlate with treatment outcomes in patients with gastrointestinal stromal tumors (GISTs). We therefore have evaluated the correlation between imatinib C(min) and the clinical characteristics of patients with GIST. PATIENTS AND METHODS Steady-state imatinib C(min) in 107 patients with GIST who were taking imatinib 300 to 800 mg/d was measured. RESULTS In patients treated with imatinib 400 (n = 92), 300 (n = 7), 600 (n = 2), or 800 (n = 11) mg/d, imatinib C(min) was 1,305 +/- 633 ng/mL, 1,452 +/- 830 ng/mL, 1,698 +/- 725 ng/mL, and 3,330 +/- 1,592 ng/mL, respectively. Of the 92 patients treated with 400 mg/d imatinib, 59 patients (63%) were men; the median age was 55 years (range, 28 to 76 years), and the median duration of imatinib use before sampling was 8.8 months (range, 0.5 to 67.6 months). The mean inter- and intrapatient variability rates were 44.7% and 26.5%, respectively. In univariate analyses, high C(min) was correlated with advanced age (P = .02), low creatinine clearance (P = .001), low hemoglobin (P = .03), and low albumin (P < .001) concentrations. Imatinib C(min) was also significantly lower in patients with (n = 18; 942 +/- 330 ng/mL) than without (n = 74; 1,393 +/- 659 ng/mL) major (ie, total or subtotal) gastrectomy (P = .002). In multivariate analysis, albumin (P = .001) concentrations, creatinine clearance (P = .002), and major gastrectomy (P = .003) were significantly correlated with C(min). CONCLUSION In patients with GIST, imatinib C(min) at steady state was significantly associated with albumin concentration, creatinine clearance, and previous major gastrectomy. Although its clinical impact is unclear at present time, monitoring of imatinib C(min) might be particularly important for optimal treatment with imatinib in patients who have undergone major gastrectomy.

Comprehensive analysis of HER2 expression and gene amplification in gastric cancers using immunohistochemistry and in situ hybridization: which scoring system should we use? ☆,☆☆

It has been reported that HER2 expression is different in gastric and breast cancers, and a gastric cancer scoring system (GCSS) has recently been suggested. We investigated HER2 protein expression using GCSS and a breast cancer scoring system (BCSS) and correlated it with HER2 gene amplification. HER2 status was evaluated in 1091 cases by analyzing tissue microarrays constructed using 2 different cores from each case. Polyclonal (HercepTest) and monoclonal (Pathway) antibodies were used for immunohistochemistry (IHC), and results were scored by BCSS and GCSS. Gene amplification was evaluated by automated dual-color silver-enhanced in situ hybridization (SISH) in all cases and correlated with the results from fluorescence in situ hybridization (FISH) in 590 cases. The concordance between the IHC results using polyclonal and monoclonal antibodies was high (κ = 0.785). The results of dual-color SISH and FISH showed very high concordance as well (κ = 0.918). GCSS was significantly more sensitive for detecting SISH positivity than was BCSS in both antibodies (polyclonal, P = .003; monoclonal, P < .001), but specificity was higher in BCSS than GCSS (polyclonal, P = .004; monoclonal, P < .001). It has been recently shown that HER2-overexpressing patients with unresectable gastric cancer benefited from trastuzumab therapy. Because IHC is recommended before gene amplification studies in HER2 testing, GCSS should be used for evaluating HER2 expression in gastric cancers.

Systemic chemotherapy for treatment of advanced small bowel adenocarcinoma with prognostic factor analysis: retrospective study

BackgroundWe sought to evaluate prognostic factors affecting overall survival (OS), and to investigate the role of palliative chemotherapy using propensity score-based weighting, in patients with advanced small bowel adenocarcinoma (SBA).MethodsData from a total of 91 patients diagnosed with advanced SBA at the Asan Medical Center between January 1989 and December 2009 were retrospectively analyzed. Patients were split into two groups, those who did and did not receive palliative chemotherapy.ResultsOverall, 81 patients (89.0%) died, at a median survival time of 6.6 months (95% confidence interval [CI], 5.5 - 7.5 months). The 40 patients receiving chemotherapy showed overall response and disease control rates of 11.1% and 37.0%, respectively, with OS and progression-free survival (PFS) of 11.8 months (95% CI, 4.6 - 19.0 months) and 5.7 months (95% CI, 3.5 - 8.0 months), respectively. The 41 patients who did not receive chemotherapy had an OS of 4.1 months (95% CI, 3.1 - 5.1 months) and a PFS of 1.3 months (95% CI, 0.8 - 1.7 months). Multivariate analysis showed that lack of tumor resection, non-prescription of chemotherapy, liver metastasis, and intra-abdominal lymph node metastasis, were all independently associated with poor survival outcomes. After inverse probability of treatment weighting (IPTW) adjustment, the group that did not receive chemotherapy was at a significantly higher risk of mortality (HR 3.44, 95% CI 2.03 - 5.83, p < 0.001) than were patients receiving chemotherapy.ConclusionPalliative chemotherapy may improve survival outcomes in patients with advanced SBA.

Sorafenib dose escalation in the treatment of advanced hepatocellular carcinoma.

Objective: Although sorafenib has shown survival benefits in patients with hepatocellular carcinoma (HCC), many patients require discontinuation or dose reduction due to adverse events (AEs). We applied a dose escalation scheme to increase patient compliance and avoid AEs. Methods: Of 267 HCC patients treated with first-line sorafenib, 25 at increased risk of AEs, including those with advanced liver cirrhosis, a history of liver transplantation, or cytopenia, received the dose escalation scheme. They started on a reduced dose of sorafenib which increased to the standard dosage according to tolerance in each patient. We analyzed the efficacy and safety of the dose escalation scheme. Results: Patients with risk factors showed a lower disease control rate, shorter survival, and more frequently grade 3/4 AEs. Among patients presenting risk factors, the dose scheme did not affect the efficacy of sorafenib or survival, but reduced the incidence of grade 3/4 AEs. Rates of sorafenib discontinuation and dose reduction related to AEs were also lower in the dose escalation group. Dose escalation to the standard dose of sorafenib was achieved in 16 of the 25 patients in the dose escalation group (64.0%). After 2 weeks, the dose intensity of sorafenib did not differ between the two dose schemes. Conclusions: The sorafenib dose escalation scheme may increase patient compliance and tolerance to prolonged treatment, thus enhancing the efficacy of sorafenib in patients at high risk of AEs or with poor tolerance. Further prospective analyses are needed to determine the usefulness of the dose escalation scheme.

Concurrent male gynecomastia and testicular hydrocele after imatinib mesylate treatment of a gastrointestinal stromal tumor.

We report a gastrointestinal stromal tumor (GIST) patient with male gynecomastia and testicular hydrocele after treatment with imatinib mesylate. A 42 yr-old male patient presented for management of hepatic masses. Two years earlier, he had undergone a small bowel resection to remove an intraabdominal mass later shown to be a GIST, followed by adjuvant radiation therapy. At presentation, CT scan revealed multiple hepatic masses, which were compatible with metastatic GIST, and he was prescribed imatinib 400 mg/day. During treatment, he experienced painful enlargement of the left breast and scrotal swelling. Three months after cessation of imatinib treatment, the tumors recurred, and, upon recommencing imatinib, he experienced painful enlargement of the right breast and scrotal swelling. He was diagnosed with male gynecomastia caused by decreased testosterone and non-communicative testicular hydrocele. He was given androgen support and a hydrocelectomy, which improved his gynecomastia. The mechanism by which imatinib induces gynecomastia and hydrocele is thought to be associated with an inhibition of c-KIT and platelet-derive growth factor. This is the first report, to our knowledge, describing concurrent male gynecomastia and testicular hydrocele after imatinib treatment of a patient with GIST.

Adjuvant Chemotherapy for Small Bowel Adenocarcinoma after Curative Surgery

Objectives: We evaluated prognostic factors affecting relapse-free survival (RFS) and overall survival (OS), and investigated the role of adjuvant chemotherapy in patients with small bowel adenocarcinoma (SBA). Methods: Data from 52 patients with SBA who underwent curative surgery at the Asan Medical Center between January 1989 and December 2009 were retrospectively analyzed. Patients were divided into two groups: those who did (n = 23) and did not (n = 29) receive adjuvant chemotherapy. Results: At a median follow-up of 32.2 months (range, 5.5–212.2 months), relapses had occurred in 17 patients (32.7%), with a 5-year RFS rate of 52.9% (95% CI, 39.3–66.5%), and 19 patients (36.5%) had died, with a 5-year OS rate of 59.0% (95% CI, 45.6–72.4%). The most frequent sites of relapse were the peritoneum and liver. Multivariate analysis showed that lymph node involvement was the only factor independently associated with poor RFS and OS. After inverse probability of treatment weighting adjustment, adjuvant chemotherapy did not enhance RFS [hazard ratio (HR), 1.399; 95% CI, 0.498–3.933] or OS (HR 0.797; 95% CI, 0.307–2.068). Conclusions: Lymph node involvement is a predictor of poor prognosis in patients with SBA who undergo curative surgery.

Radiofrequency ablation of liver metastasis in patients with locally controlled pancreatic ductal adenocarcinoma.

PURPOSE To evaluate retrospectively the role of radiofrequency (RF) ablation for liver metastases arising from pancreatic ductal adenocarcinoma simultaneously with pancreatic resection or after curative resection in patient survival. MATERIALS AND METHODS RF ablation of liver metastases was performed on 34 patients with pancreatic ductal adenocarcinoma postoperatively after pancreatectomy or intraoperatively at pancreatectomy between December 2002 and June 2009. Criteria for RF ablation were liver metastasis ≤ 3 cm diameter in size, five or fewer lesions, and no definite suspicious lesion other than liver metastasis. Patient survival was assessed by the Kaplan-Meier method, and prognostic factors were analyzed. RESULTS Of the patients receiving RF ablation treatment (n = 34), 18 underwent one session of RF ablation, and 16 underwent more than one session. In each session, all the targeted lesions were successfully ablated by ultrasound-guided RF ablation. Median duration of follow-up was 15 months (range, 3-65 mo). The interval between pancreatic resection and liver metastasis was 3 months (range, 0-33 mo). Median survival time after liver metastasis was 14 months. Univariate analysis of factors affecting survival showed that better patient survival after RF ablation was associated with a single, < 2 cm diameter liver metastasis (P = .007) and well or moderate differentiation (P = .032). In multivariate analysis, a single < 2 cm diameter liver metastasis and good or moderate differentiation were independent predictors for longer patient survival (P = .027, P = .016). CONCLUSIONS RF ablation in liver metastasis occurring after locally controlled pancreatic ductal adenocarcinoma can be a safe and feasible strategy for extending survival in selected patients.