H. Jeung

Epigenetic Therapy Using Belinostat for Patients With Unresectable Hepatocellular Carcinoma: A Multicenter Phase I/II Study With Biomarker and Pharmacokinetic Analysis of Tumors From Patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group

PURPOSE Epigenetic aberrations have been reported in hepatocellular carcinoma (HCC). In this study of patients with unresectable HCC and chronic liver disease, epigenetic therapy with the histone deacetylase inhibitor belinostat was assessed. The objectives were to determine dose-limiting toxicity and maximum-tolerated dose (MTD), to assess pharmacokinetics in phase I, and to assess activity of and explore potential biomarkers for response in phase II. PATIENTS AND METHODS Major eligibility criteria included histologically confirmed unresectable HCC, European Cooperative Oncology Group performance score ≤ 2, and adequate organ function. Phase I consisted of 18 patients; belinostat was given intravenously once per day on days 1 to 5 every 3 weeks; dose levels were 600 mg/m(2) per day (level 1), 900 mg/m(2) per day (level 2), 1,200 mg/m(2) per day (level 3), and 1,400 mg/m(2) per day (level 4). Phase II consisted of 42 patients. The primary end point was progression-free survival (PFS), and the main secondary end points were response according to Response Evaluation Criteria in Solid Tumors (RECIST) and overall survival (OS). Exploratory analysis was conducted on pretreatment tumor tissues to determine whether HR23B expression is a potential biomarker for response. RESULTS Belinostat pharmacokinetics were linear from 600 to 1,400 mg/m(2) without significant accumulation. The MTD was not reached at the maximum dose administered. Dose level 4 was used in phase II. The median number of cycles was two (range, one to 12). The partial response (PR) and stable disease (SD) rates were 2.4% and 45.2%, respectively. The median PFS and OS were 2.64 and 6.60 months, respectively. Exploratory analysis revealed that disease stabilization rate (complete response plus PR plus SD) in tumors having high and low HR23B histoscores were 58% and 14%, respectively (P = .036). CONCLUSION Epigenetic therapy with belinostat demonstrates tumor stabilization and is generally well-tolerated. HR23B expression was associated with disease stabilization.

Sunitinib for Asian patients with advanced renal cell carcinoma: a comparable efficacy with different toxicity profiles.

Objective: We aimed to describe the efficacy and safety of sunitinib in unselected Korean advanced renal cell carcinoma (RCC) patients. Patients and Methods: From November 2005 to August 2008, 132 histologically confirmed advanced RCC patients (100 in the global expanded access program) were enrolled. Response and toxicity were assessed regularly according to the protocol. Results: Within this population, 82.6% had clear cell RCC, and 28.8% were treatment naïve. Patients received a median of 5 cycles of sunitinib (range 1–30), and the mean relative dose intensity was 82.0 ± 14.20 (SD). The progression-free survival (PFS) and overall survival rates were 8.2 and 23.1 months, respectively. For the 130 evaluable patients, the objective response rate was 34.1% (n = 45); 44.7% (n = 59) exhibited stable disease. Reasons for discontinuation were disease progression (75.0%) and toxicity (7.6%). The most frequent adverse events were thrombocytopenia (75.0%), neutropenia (70.5%), and anemia (69.7%). Low body surface area (OR = 4.2, 95% CI 1.2–13.8, p = 0.02) and previously treated status (OR = 3.1, 95% CI 1.3–7.4, p = 0.01) were highly predictive of grade 3–4 toxicities. Based on these findings, a nomogram predicting the probability of 12-month PFS was constructed, giving a concordance index of 0.675. Conclusions: Despite the different toxicity profiles, maintaining adequate dose modifications and a careful follow-up enables comparable treatment outcomes for unselected Korean advanced RCC patients.

Advanced Detection of Recent Changing Trends in Gastric Cancer Survival: Up-to-date Comparison by Period Analysis

OBJECTIVE To establish a comprehensive cancer treatment and prevention policy, data collection should be performed in a timely manner, and survival analysis needs to reflect changes in treatment strategy. Therefore, we introduced the concept of period analysis for gastric cancer, the most prevalent cancer in Korea. We estimated 5- and 10-year survival trend of gastric cancer, based on data from the Yonsei Cancer Center Tumor Registry between 1990 and 2004. METHODS We compared the differences in survival between cohort, complete and period analyses for two different periods, 1995-99 and 2000-04. RESULTS A total of 11 724 cases were included. The median age of cancer diagnosis gradually increased over time, and more patients were diagnosed with Stage I disease in recent years. In the basic comparison of three estimated analytic methods (cohort, complete and period), period analysis (45.8%) was most similar to the actual 5-year observed survival rate (48.5%), when compared with cohort (43.6%) and complete (44.8%) analyses. When we compared survival between different 10-year periods (1990-99 and 1995-2004), period analysis demonstrated a greater difference than complete analysis (9.0 versus 3.9%). Subgroup analysis indicated that the survival improvement was determined by period analysis, and it was more pronounced for the age group <74 years and in Stages III-IV patients. CONCLUSIONS We observed that period analysis demonstrates the most similar results to the actual observed survival and is, therefore, a useful method to derive precise cancer survival in gastric cancer. This information is useful to understand survival differences that are influenced by changing treatment strategy.

Infusional fluorouracil, etoposide, and cisplatin (FEP) in advanced and relapsed gastric cancer

&NA; We evaluated the efficacy and tolerability of a combination chemotherapy including infusional fluorouracil (5‐FU), etoposide, and cisplatin (FEP) in 89 patients with advanced/relapsed gastric cancer. Primary endpoints were progression‐free and overall survival. Secondary endpoints were response rates, response duration, and toxicity. The treatment schedule was as follows: 5‐FU 1,000 mg/m2 and etoposide 100 mg/m2 were administered on 3 consecutive days and cisplatin at 80 mg/m2 was administered on day 2, and repeated every 3 weeks. The median times to progression and overall survival were 4 and 8 months, respectively. One‐year progression‐free and overall survival rates were 10% and 33%, respectively. The overall response rate for 25 eligible patients with measurable disease was 20% (5/25, complete response 2, partial response 3) with median response duration of 7 months. Median actual dose intensities of 5‐FU, etoposide, and cisplatin were 700 mg/m2/wk, 70 mg/m2/wk, and 21 mg/m2/wk, respectively. Median relative dose intensities of 5‐FU, etoposide, and cisplatin were 0.70, 0.70, and 0.63, respectively. In conclusion, the FEP regimen was found to produce therapeutic results similar to those of other combination chemotherapeutic studies and to have an acceptable toxicity. This regimen could be used as one of the options for advanced gastric cancer chemotherapy in patients unsuitable for doxorubicin‐based regimens.

Irradiation effect on telomerase- and angiogenesis-related gene in human umbilical vein endothelial cells.

e21048 Background: Radiotherapy is important in the treatment of many human cancers, but the effect of irradiation on angiogenesis still remains largely unknown. We investigated the effects of irradiation on telomerase- and angiogenesis-related genes in human umbilical vein endothelial cells (HUVECs). METHODS HUVECs at passage number (PN)1, PN2 and PN3, respectively, were exposed to irradiation (2 Gy). Changes in cellular growth, senescence, telomerase activity, and expression of telomerase-, angiogenesis- and pan-endothelial marker-related genes were then investigated. RESULTS Both senescence and growth delay were observed in irradiated HUVECs. Compared to controls, telomerase activity, expression of human telomerase reverse transcriptase (hTERT) and c-myc in irradiated HUVECs were down-regulated in all PNs, and Mad1 was up-regulated at PN3. Down-regulation of vascular endothelial growth factor (VEGF) was observed in irradiated HUVECs as PN increased. Other angiogenesis-related factors [vascular endothelial growth factor receptor (VEFGR)-1, VEGFR-2, VEGFR-3, Tie-1, and Tie-2] and pan-endothelial cell markers [collagen type IV alpha 2, collagen type VI alpha 1, collagen type XVIII alpha 1, insulin-like growth factor-binding protein (IGFBP)-4, IGFBP-7, connective tissue growth factor, interferon-induced transmembrane protein, melanoma cell adhesion molecule, and von Willebrand factor] were also down-regulated in irradiated HUVECs. CONCLUSIONS Irradiation at doses relevant to clinical radiotherapy can induce endothelial cell senescence. Irradiation-induced cell senescence could be related with the down-regulation of hTERT. Change in the expression of c-Myc, Mad1, and VEGF could contribute to the irradiation-induced down-regulation of hTERT.

A pilot study of SP versus FP chemotherapy in postoperative setting for histologically stage IIIb-IV(M0) gastric cancer.

e14630 Background: Although FP efficacy has not been proven, it has been used for the prevention of relapse in post-operative gastric cancer. This pilot study was conducted to investigate the safety and efficacy of SP vs FP in post-operative setting for stage IIIB-IV(M0) gastric cancer. Methods: After curative resection, stage IIIB-IV (M0) gastric cancer patients were assigned to postoperative SP or FP. Eight cycles of S-1 (40 mg/m2 two times daily, D1-14) plus cisplatin (60 mg/m2 on day 1) were administered every 3 weeks or 6 cycles of FU (1g/m2 per day, D 1-4) plus cisplatin (80 mg/m2 on day 1) were administered every 4 weeks. Results: A total of 41 patients were recruited from January 2009 to December 2009. In total, 91 cycles of SP (n = 20) and 93 cycles of FP (n = 21) were administered, with a median of five (range 1-8) in the SP arm and four (range 1-6) in the FP arm. The median relative dose intensity per patient was 75% (range, 20.08-100) for S-1, 100% (range, 50-125) for P and 100% (range, 64-100...

Global genetic pattern analysis using cDNA microarray-based CGH for prognosis prediction to FAC neoadjuvant and adjuvant chemotherapy in locally advanced breast cancer patients.

9544 Background: In locally advanced breast cancer, selection of adjuvant regimen after neoadjuvant chemotherapy and surgery is still in controversy. METHODS 46 locally advanced breast cancer patients were treated with FAC (5-fluorouracil, adriamycin, cyclophosphamide) both in neoadjuvant and adjuvant chemotherapy. We evaluated the clinical and pathologic responses, and prognosis. Genomic DNA extracted from the paraffin embedded tissues of 12 core biopsy, 46 surgically resected and 4 relapsed tissues were used for cDNA microarray-based CGH using 17K human cDNA gene chip. To identify drug-resistance related genes, we compared the genetic changes between 12 paired specimens taken before and after neoadjuvant chemotherapy in the same patient. 46 cases from surgically resected tissues were assessed to identify the prognosis signatures. RESULTS Median age of the patients was 45 (range 32-70), and 39 patients (85%) showed pathological response after neoadjuvant chemotherapy. Five-year disease-free and overall survival rates were 33% and 52%, respectively. Significant prognostic factors after the surgery were nodal state and stage. Differential patterns of gene copy number changes between before and after neoadjuvant treatment were observed, and 333 genes of differentially changed genes correlated with treatment resistance. 585 genes were distinctively changed in relapsed patients compared to disease-free patients, and most of 102 selected genes located on 1, 3p, 8q and 17q, suggesting the FAC-resistance related area. Two-way hierarchical clustering with selected genes correlated with disease recurrence (p< 0.01). With 1336 genes that had significant difference between recurred and non-recurred group, 21 of 30 recurred cases were correctly classified as the recurred group with the error rate of 30% based on the cross-validation with PAM. CONCLUSIONS We demonstrate the potential of array-CGH based global genetic patterns associated with FAC resistance, thus permitting guideline for the selection of adjuvant regimen after surgery with neoadjuvant chemotherapy. No significant financial relationships to disclose.