M. Ryu

A phase I / II trial of docetaxel, capecitabine, and cisplatin as a first line chemotherapy for advanced gastric cancer

4066 Background: Combination of capecitabine and cisplatin (XP) was active and tolerable in advanced gastric cancer (AGC). We added docetaxel (D) to XP regimen and performed a phase I / II study of DXP combination. METHODS Patients (pts) with chemotherapy-naïve inoperable AGC were eligible for this study. For the phase I study, with the fixed dose of P (60 mg/m2 D1), the doses of X (D1-14) and D (D1) were escalated as following schedule: level 1: X 1,875 mg/m2/d, D 60 mg/m2; level 2: X 2,250 mg/m2/d, D 60 mg/m2; level 3: X 2,250 mg/m2/d, D 75 mg/m2; level 4: X 2,500 mg/m2/d, D 75 mg/m2. The cycle was repeated every 3 weeks. The phase II study was planned at the dose level just below the MTD in pts with measurable disease. RESULTS During 1st cycle, 1 DLT (neutropenic fever) among 6 pts at dose level 2 and 2 DLTs (asthenia) among 3 pts at dose level 4 were observed. During 2nd cycle, 2 DLTs were experienced among the 6 pts at dose level 3, which made the dose level 3 as MTD and the subsequent phase II study was begun at dose level 2. After total 17 pts were treated at dose level 2, frequent need for dose reduction made further phase II study performed at dose level 1. Total 40 pts with measurable disease, treated at dose level 1 (23) and 2 (17) were evaluated for phase II portion of the study. Four pts were not evaluable for response because of follow-up loss after 1 cycle of chemotherapy. After median 6 cycles of chemotherapy, there were 4 confirmed CRs and 23 confirmed PRs, with the overall response rate of 67.5% (95% C.I.: 52.7 - 82.3) in intention-to-treat analysis. There was no difference in response rate between the two dose levels. Ten pts underwent surgical resection after clinical response with 4 - 9 cycles of chemotherapy. Four pathologic CRs were identified. With a median follow-up of 14 mo. (range 1 to 28), median time to progression was 7.7 mo. (95% C.I.: 6.9 - 8.5), and median overall survival has not been reached. CONCLUSIONS Asthenia and neutropenia were DLTs in this DXP combination. The dose of D (60 mg/m2, D1), X (1,875 mg/m2/D, D1-14), and P (60 mg/m2, D1) was recommended for the 3 weekly DXP combination. The DXP chemotherapy was highly active and tolerable for the 1st line chemotherapy of AGC. [Table: see text].

Investigation of papulopustular eruptions caused by cetuximab treatment shows altered differentiation markers and increases in inflammatory cytokines

Background  Epidermal growth factor receptor (EGFR) critically regulates tumour cell division, survival and metastasis. Agents that inhibit EGFR have been used in the treatment of advanced‐stage malignancies, but cause variable cutaneous side‐effects, most often papulopustular eruptions and xerosis.

A phase II study of paclitaxel and capecitabine combination chemotherapy in patients with advanced gastric cancer as a first-line therapy

4051 Background: Paclitaxel and capecitabine, which have distinct mechanisms of action and toxicity profiles, showed considerable single-agent activity in gastric cancer. Synergistic interaction between these two drugs was also suggested by taxane-induced upregulation of thymidine phosphorylase. Therefore, we evaluated antitumor activity and toxicities of paclitaxel and capecitabine combination in patients with advanced gastric cancer (AGC) as a first-line therapy. METHODS Patients with histologically confirmed AGC with unresectable or metastatic diseases, measurable lesions, PS 0-2, age between 18 and 75, and no contraindication to chemotherapy were eligible in this study. Prior adjuvant chemotherapy finished at least 6 months before enrollment was allowed. Treatment included capecitabine 825 mg/m2 p.o. twice daily on days 1-14 and paclitaxel 175 mg/m2 i.v. on day 1 every 3 weeks until disease progression or unacceptable toxicities. RESULTS Between June 2002 and December 2003, total 40 pts were enrolled in this study. The median age was 57.5 years (range, 38-73). Twenty-nine pts were male. Nine pts had recurrent disease after previous curative gastrectomy and 8 had previous adjuvant chemotherapy. After a median 4 (range, 1-9) cycles of chemotherapy, thirty-four pts were evaluable for toxicity and 33 pts for response (6 pts too early for evaluation, 1 pt loss to follow-up). In intention-to-treat analysis, the overall response rate was 52.9% (95% C.I., 36.2-69.6%), including 0 CR, 18 PRs, 9 SDs, and 6 PDs. After a median follow-up of 8.6 months (range, 0.9-17.9), median time to progression was 5.3 months (95% C.I., 3.6-6.9) and median overall survival was 14.6 months (95% C.I., 8.5-20.7). The actual dose intensity was well maintained over 95% of planned during the first 4 cycles in both drugs. Commonly observed grade 3/4 adverse events were neutropenia (41.1% of patients), hand-foot syndrome (11.8%), arthralgia (8.8%). There was no neutropenic fever or treatment-related death. CONCLUSIONS Paclitaxel and capecitabine combination chemotherapy was active and highly tolerable as a first-line therapy for AGC. No significant financial relationships to disclose.

Abstract 2874: A prospective study of a repeat endoscopic biopsy to identify HER2-positive tumors following an initial HER2-negative endoscopic biopsy in unresectable or metastatic gastric cancer patients: GASTHER1 study

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: The intratumoral heterogeneity of HER2 expression in gastric cancer (GC) is a major challenge when identifying patients who will benefit from HER2-targeting therapy. The aim of this study is to evaluate the significance of re-evaluation of the HER2 status by repeat endoscopic biopsy in GC patients with an initial, HER2-negative endoscopic biopsy. Methods: Patients with unresectable or metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma and who will receive first-line chemotherapy, were eligible if the HER2 was negative on the initial endoscopic biopsy. HER2 positivity was defined as immunohistochemistry (IHC) 3+ or IHC 2+/fluorescence in situ hybridization (FISH) + using the GC scoring system. A repeat endoscopic biopsy was performed in ≥6 different primary tumor sites immediately after obtaining initial HER2-negative results. Results: From May 2011 to April 2013, a total of 183 eligible patients were enrolled. Baseline characteristics at the time of the initial biopsy were as follows: tumor location, GEJ∼fundus/body/antrum/diffuse stomach=22(12.0%)/47(25.7%)/68(37.2%)/46(25.1%); Lauren classification, intestinal/diffuse/mixed=53(29.0%)/111(60.7%)/19(10.4%); and HER2 IHC score, 0/1/2=149(81.4%)/26(14.2%)/8(4.4%). The median number of biopsy pieces per patient was 5 (range, 1-15) and 10 (range, 1-15) on the initial and repeat biopsy, respectively (P<0.0001). There was no difference in the median ratio of the number of cancer-containing pieces/total pieces; 0.86 (range, 0.13-1) vs. 0.89 (range, 0.10-1) (P=0.679). As the repeat biopsy identified 16 patients with HER2-positive tumor, the rate of rescued HER2 positivity was 8.7% (95% CI 4.6-12.8%). Rescued HER2 positivity was associated with tumor location (diffuse stomach vs. others=0% vs. 11.7%, P=0.013), Bormann type (IV vs. others=0% vs. 11.7%, P=0.013), and the HER2 IHC score on the initial biopsy (0 vs. 1 vs. 2 = 6.7% vs. 15.4% vs. 25.0%, P=0.028). In multivariate analysis, the HER2 IHC score (1/2 vs. 0, odds ratio=3.78; P=0.016) was an independent predictive factor for rescued HER2 positivity. Conclusions: Repeat endoscopic biopsy is recommended in order to check the HER2 status again even if the initial endoscopic biopsy is HER2 negative in metastatic or unresectable GC. Note: This abstract was not presented at the meeting. Citation Format: Sook Ryun Park, Young Soo Park, Baek-Yeol Ryoo, Chang Gok Woo, Hwoon-Yong Jung, Jeong Hoon Lee, Gin Hyug Lee, Min-Hee Ryu, Yoon-Koo Kang. A prospective study of a repeat endoscopic biopsy to identify HER2-positive tumors following an initial HER2-negative endoscopic biopsy in unresectable or metastatic gastric cancer patients: GASTHER1 study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2874. doi:10.1158/1538-7445.AM2014-2874

Phase II study of gemcitabine, capecitabine and cisplatin in patients with advanced pancreatic cancer

4219 Background: In advanced pancreatic cancer (APC), gemcitabine (G) monotherapy is considered as a standard chemotherapy. However, the benefit of this treatment is needed to be improved. In previous studies, gemcitabine plus capecitabine (X) or cisplatin (P) showed promising activity although there was no statistically significant survival benefit compared to gemcitabine alone. We conducted phase II study with the combination of G, X and P (GXP) in pts with APC. METHODS Pts who were chemotherapy-naive with histologically confirmed, measurable APC were enrolled. Starting doses were G (800 mg/m2, IV over 80 min, D1, 8), X (1,300 mg/m2/day, po, D1-14) and P (60 mg/m2, IV, D1) per every 3 weeks (wks). After 4 pts were treated with this dose level, toxicities were mild and the dose of G was elevated to 1,000 mg/m2 (infused over 100 min). RESULTS Between Jun 2001 and Jul 2003, 40 pts were enrolled. Median age was 53 years (range, 35-66) with 32 males. Pts with metastatic lesions were 28 and locally advanced diseases (LA) 12. Thirty eight pts were assessable for activity and 40 were assessable for toxicity. A total of 185 cycles were administered (median, 4.5; range, 1-12). Twelve pts achieved partial response giving an overall response rate of 30.0% in intention-to-treat population (95% confidence interval (CI), 15.8-44.2%) and 14 pts (35.0%) had stable disease. The median time to progression (TTP) of all patients was 5.1 months (mo) (95% CI, 3.8-6.3). In pts with LA and metastatic lesions, the median TTP was 8.1 mo and 4.4 mo, respectively. The median overall survival (OS) of all patients was 7.5 mo (95% CI, 6.7-8.3). In pts with LA and metastatic lesions, the median OS was 11.8 mo and 7.0 mo, respectively. Median duration of response in 12 responders was 3.3 mo (range, 0.7-11.0). Grade 3/4 neutropenia and thrombocytopenia were noted in 47.5% and 10.0% of the pts, respectively. Grade 2/3 non-hematologic toxicities were asthenia (45.0 % of pts), diarrhea (12.5%), stomatitis (12.5%) and hand-foot syndrome (7.5%). There was no treatment-related death. CONCLUSIONS The combination of gemcitabine, capecitabine and cisplatin is an active and tolerable regimen in pts with APC. No significant financial relationships to disclose.

Abstract B211: Comparison of detection of FGFR2 amplification by quantitative real-time-PCR (qPCR) and fluorescent in situ hybridization (FISH) in gastric cancer.

Background: Fibroblast growth factor receptor 2 (FGFR2) amplification is associated with tumorigenesis of gastric cancer and can be a promising molecular target for the treatment of FGFR2-amplified gastric cancer. So far, the most optimal single method to screen patients with FGFR2 amplification has not been determined. To screen patients with gastric cancer harboring FGFR2 amplification, we aim to investigate whether qPCR can replace the FISH method which is the golden standard but less sensitive and much more expensive than qPCR. Methods: FISH (Abnova, #FG0018) and qPCR (Applied Biosystems, HS05182482_cn) method for FGFR2 amplification were performed with formalin-fixed paraffin-embedded (FFPE) tissues of patients with gastric cancer who were diagnosed from 2007 to 2012 in Asan Medical Center, Seoul, Korea, and whose FFPE tissues contained at least 70% of tumor cells. qPCR was conducted initially in 26 patients who had both endoscopic biopsy and surgical tissues in the diagnosis to figure out which samples are better between biopsy and surgical tissues. According to the results, 182 patients with endoscopic biopsy tissues were further included. FISH was defined as positive in case of FGFR2 to CEP10 ratio > 2.0. Results: In 26 patients who had paired endoscopic biopsy and surgical samples, the qPCR-based copy number assay for FGFR2 amplification was more sensitive in biopsy samples; i.e., FGFR2 copy number by qPCR was higher in biopsy samples in 13 (50%) patients, while it was higher in surgical samples only in 3 (11.5%) patients. In a total of 208 endoscopic biopsy FFPE samples including 182 patients with biopsy tissues, copy number of FGFR2 ranged from 0.8 to 399.0 (median 15.9) by qPCR and from 0.7 to 166.9 (median 6.1) by FISH. 16 biopsy samples showing FGFR2 copy number > 10 by qPCR were all FISH-positive, while 192 biopsy samples showing FGFR2 copy number 10 in biopsy tissues by qPCR, the copy numbers were very well correlated between qPCR and FISH in all patients, and were also over 10 in surgical tissues regardless of methods in 26 patients. The positive rate of FGFR2 amplification was 7.7% with a cut-off value of 10 by qPCR. Conclusion: This study suggests that it is better to use biopsy samples than surgical tissues to detect FGFR2 amplification by qPCR; and for patient screening in gastric cancer, the optimal cut-off value for definite FGFR2 amplification by qPCR is 10 in comparison with the results of FISH. Clinical relevance of intermediate FGFR2 copy number elevation < 10 by qPCR needs to be addressed in future clinical trials using FGFR2 inhibitors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B211. Citation Format: Young-Soon Na, Young Soo Park, Min-Hee Ryu, Chae-Won Lee, Hye Jin Park, Ju-Kyung Lee, Sook Ryun Park, Baek-Yeol Ryoo, Yoon-Koo Kang. Comparison of detection of FGFR2 amplification by quantitative real-time-PCR (qPCR) and fluorescent in situ hybridization (FISH) in gastric cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B211.

Clinical significance of tumor markers as prognostic factors in patients with metastatic gastric cancer receiving first-line chemotherapy.

4035 Background: Although tumor markers are known to be associated with tumor burden and/or aggressive biology, any association of such markers with patient survival has not previously been determined in patients with metastatic or recurrent gastric cancer. METHODS Of 3,107 patients with metastatic or recurrent gastric cancer who initiated palliative chemotherapy in Asan Medical Center between January 2000 and December 2008, 1,178 were assayed for expression of three serum tumor markers, CA 19-9, CA 72-4, and CEA, prior to initiation of first-line chemotherapy. We retrospectively analyzed the relationships between tumor marker concentrations and clinicopathologic features, and treatment outcomes in such patients. RESULTS Elevated serum concentrations of CA 19-9 (>37 U/mL), CA 72-4 (>4 U/mL), or CEA (>6 ng/mL) were observed in 38.1%, 56.2%, and 33.1% of patients, respectively. Univariate analysis showed that serum positivity of all the 3 markers, CA 19-9 (p=0.001), CA 72-4 (p=0.001), and CEA (p=0.030) were associated with poor survival. However, upon multivariate analysis, only CA19-9 (HR 1.22; 95% CI, 1.08-1.37, p<0.001) was independently associated with poor survival outcome, in addition to the following clinical factors determined in previous study for gastric cancer prognostic model (Koo, et al): ECOG PS ≥ 2, no previous gastrectomy , peritoneal metastasis, bone metastasis , lung metastasis, serum alkaline phosphatase (ALP) > 120 IU/L, serum albumin < 3.3 g/dL, and total serum bilirubin > 1.2 mg/dL. In good risk group by the prognostic model, survival difference in the positivity of CA 19-9 was more significant (p < 0.001), while serum positivity of CA 19-9 did not provide clinical significance for moderate and poor groups. CONCLUSIONS The postivitiy of serum CA 19-9 for patients with metastatic or recurrent gastric cancer at the time of first line chemotherapy, especially in good prognostic group is an independent negative prognostic factor.

Abstract 2539: Antitumor effects of oral paclitaxel DHP107 on gastric cancer xenografts

Oral paclitaxel DHP107 (Daehwa, Seoul Korea), an antineoplastic agent, is effectively absorbed through the gastrointestinal tract via the lipid uptake mechanism, which is currently under clinical investigation. Oral capecitabine generates 5-fluorouracil (5-FU) by thymidine phosphorylase, preferentially in tumor tissue. Taxanes, such as paclitaxel and docetaxel, have the ability to up-regulate levels of thymidine phosphorylase which show the its increased activity in tumors compared with that of normal tissue. Accordingly, combination treatment using taxanes with capecitabine is effective in several tumors, especially in gastric cancer. In this study, we investigated the antitumor effect of DHP107 combined with capecitabine and compared the effects of DHP107 and Taxol in gastric cancer xenografts. DHP107 in combination with capecitabine dramatically inhibited tumor growth without additive toxicity compared with each agent used alone in gastric xenografts. The expression of the level of thymidine phosphorylase in tumor was markedly increased four hours after treatment with DHP107. The apoptotic effects, assessed using TUNEL and soft agar colony-formation assay on xenograft tumors, were greater with combined treatment than with either agent used alone. The antitumor effects of DHP107 were similar to those of Taxol in gastric cancer xenografts. These data indicate that DHP107 combined with capecitabine had enhanced antitumor effects in human gastric tumor xenografts and that DHP107 had antitumor effects in gastric cancer models, both of which provide support for future clinical trials of DHP107. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2539. doi:10.1158/1538-7445.AM2011-2539

Sorafenib for recurrent hepatocellular carcinoma after liver transplantation.

e14669 Background: Sorafenib is the only drug that has shown a survival benefit in patients with hepatocellular carcinoma (HCC) in randomized phase III trials. The efficacy and safety of sorafenib in the treatment of recurrent HCC after liver transplantation, however, has not been determined. Methods: We retrospectively analyzed 13 patients who were treated with sorafenib for recurrent HCC after liver transplantation. Results: All 13 patients underwent living-donor liver transplantation for HCC with underlying liver cirrhosis caused by hepatitis B virus (HBV) infection. The median model for end-stage liver disease (MELD) score at transplantation was 7.6 (range, 4.2-25.2). The median time from liver transplantation to detection of recurrent HCC was 12.3 months (range, 0.5-33.4 months). The median serum alpha-fetoprotein (AFP) concentration before sorafenib administration was 193 ng/mL (range, 1-20,500 ng/mL). Eleven of 13 patients had a starting dose of 400mg twice daily and two had a starting dose of 200 ...

Abstract 5371: Synergistic antitumor effect of HDAC inhibitor PXD101 in combination with irinotecan in colon cancer

The histone deacetylase inhibitors (HDACi), such as PXD101 or SAHA, inhibit the proliferation and stimulate the apoptosis in tumors. The enhanced effect of HDACi combined with chemotherapy or radiotherapy has been reported in several cancers. In this study, we investigated the antitumor effect of HDACi PXD101 combined with irinotecan in colon cancer. PXD101 and SN38, active form of irinotecan, had a dose-dependent anti-proliferative activity in HCT116 and HT29 colon cancer cells. PXD101 combined with SN38 had a synergistic effect in colon cancer cell lines, as shown by combination index. The combination of PXD101 with SN38 had an effect on XIAP and p21 protein expressions with time- and dose-dependent manner, more prominently in HCT116 than HT29 cells. These effects were further enhanced by the addition of PXD101 than irinotecan alone in both cell lines. In xenograft mice, PXD101 in combination with irinotecan dramatically inhibited tumor growth without additive toxicity. In addition, antiumor effect was more prominent in HCT116 than HT29 xenografts. Apoptotic effects of tumor in xenografts treated with these combinations were better than irinotecan alone. Combination of PXD101 and irinotecan resulted in 63 % of relative SUV mean in [ 18 F]FLT-PET in mice with established HCT116 xenograft. Early response to these agents can be detected with [ 18 F]FLT-PET. These data suggest that PXD101 increases the cytotoxic activity of iriontecan in colon cancer and these drug combinations should be explored in the treatment of colon cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5371.