15052 Background: Taxane has been used widely in advanced gastric cancer, but toxicities are problematic. To avoid the bone marrow suppression, docetaxel could be replaced paclitaxel to reduce bone marrow suppression and to improve the efficacy, we planned to augmentation of the dose intensity. This phase II study evaluated the efficacy and safety of combination chemotherapy with paclitaxel, cisplatin, and 5-fluorouracil (5-FU) in advanced gastric cancer. Methods: Patients with histologically confirmed gastric adenocarcinoma, ECOG PS = 2, at least one measurable lesion and adequate organ functions were eligible. Paclitaxel (175 mg/m 2 ) and cisplatin (75 mg/m 2 ) were given as a 1-h intravenous infusion on day 1, followed by 5-FU (750 mg/m 2 ) as a 24-h continuous infusion for 5 days. This cycle was repeated every 3 weeks. Results: Forty-five eligible patients (median age 56 years) were treated in this way. Of the 41 patients in whom efficacy was evaluable, an objective response rate (ORR) was seen in 20 (48.8%), a complete response in two, and a partial response in 18 patients. The median time to progression was 6.9 months (95% CI, 5.86–7.94), and the median overall survival was 13.1 months (95% CI, 8.83–17.37). The main hematological toxicity was neutropenia and greater than grade 3 neutropenia was observed in 67 cycles (25%). Febrile neutropenia developed in three patients (7.3%). The major non-hematological toxicities were asthenia and peripheral neuropathy, but grade 3 or 4 toxicity was not seen. Conclusions: The combination chemotherapy with paclitaxel, cisplatin, and 5-FU is a promising regimen, and was well tolerated in patients with advanced gastric cancer. No significant financial relationships to disclose.
14154 Background: Although 5-FU and cisplatin had been widely used as radiosensitizer, the toxicities such as mucositis or bone marrow suppression were problematic. In this study, 5-FU was replaced with S-1. The primary end point of this study was to define the safety and the secondary end point was to evaluate the pathologic response and clinical efficacy as the first line therapy in locally advanced or metastatic esophageal cancer. Methods: Patients with locally advanced or metastatic esophageal cancer without history of previous chemotherapy or radiotherapy were eligible. Cisplatin was given intravenously with 75 mg/m 2 on day 1 every 3 weeks. S-1 was administered at the dose of 80 mg/m 2 /day orally divided two times for 2 weeks followed by 1 week rest. Radiotherapy was started concomittently at day 1, total dose of 5040 cGY for 6 weeks. During radiotherapy, patients received 2 cycles of chemotherapy. Results: From May 2004 to Aug 2005, 33 patients were enrolled into this study. 6 patients were dropped out due to poor compliance (3), economic problem (2) and TEF (1) during treatment. 27 patients were evaluable for response and toxicity. The median age was 66 years (range, 54–82). Clinical response was 77.8% (21 pts) and pathologic response was shown in 29.6% (8 pts). The improvement of dysphagia was shown in 22 patients (81.5%). There were 7 (25.9%) pts with grade 3 neuropenia. Grade 3–4 odynophagia during concurrent chemoradiotherapy was observed only one patient. Conclusions: The concurrent chemoradiotherapy combined with S-1 and cisplatin was well tolerated and effective in advanced esophageal cancer to relieve obstructive symptoms and tumor regression. No significant financial relationships to disclose.
Developmentally regulated GTP-binding protein 2 (DRG2) regulates microtubule dynamics and G2/M arrest during docetaxel treatment. Poly ADP-ribose polymerase (PARP) acts as an important repair system for DNA damage caused by docetaxel treatment. This study investigated whether DRG2 expression affects response to PARP inhibitors (olaparib) using prostate cancer cell lines PC3, DU145, LNCaP-FGC, and LNCaP-LN3. The cell viability and DRG2 expression levels were assessed using colorimetric-based cell viability assay and western blot. Cells were transfected with DRG2 siRNA, and pcDNA6/V5-DRG2 was used to overexpress DRG2. Flow cytometry was applied for cell cycle assay and apoptosis analysis using the Annexing V cell death assay. The expression of DRG2 was highest in LNCaP-LN3 and lowest in DU145 cells. Expressions of p53 in PC3, DU145, and the two LNCaP cell lines were null-type, high-expression, and medium-expression, respectively. In PC3 (DRG2 high, p53 null) cells, docetaxel increased G2/M arrest without apoptosis; however, subsequent treatment with olaparib promoted apoptosis. In DU145 and LNCaP-FGC (DRG2 low), docetaxel increased sub-G1 but not G2/M arrest and induced apoptosis, whereas olaparib had no additional effect. In LNCaP-LN3 (DRG2 high, p53 wild-type), docetaxel increased sub-G1 and G2/M arrest, furthermore olaparib enhanced cell death. Docetaxel and olaparib combination treatment had a slight effect on DRG2 knockdown PC3, but increased apoptosis in DRG2-overexpressed DU145 cells. DRG2 and p53 expressions play an important role in prostate cancer cell lines treated with docetaxel, and DRG2 levels can predict the response to PARP inhibitors.
4551 Background: S-1 is a fourth-generation oral fluoropyrimidine that was developed to mimic protracted continuous infusion of 5-fluorouracil (5-FU). In previous study, S-1 demonstrated promising activity which is comparable to combination chemotherapy in advanced gastric cancer. This phase II study evaluated the efficacy and safety of S-1 salvage chemotherapy, in patients with taxane and cisplatin refractory gastric cancer. The primary end point was progression free survival and secondary end points were overall survival, safety and clinical benefit. Methods: Patients were eligible if they had histologically documented gastric adenocarcinoma previously treated with taxane (docetaxel or paclitaxel) and cisplatin; age≥18; Eastern Clinical Oncology Group (ECOG) performance status of 2 or less; adequate organ function; no evidence of gastrointestinal obstruction or passage disturbance. S-1 treatment was performed according to BSA as followed; < BSA 1.25, 80 mg/day, 1.25 ≤ BSA < 1.5, 100 mg/day; BSA ≥ 1.5, 120 mg/day. Every dosage was delivered divided two times and administered for 4 weeks followed by 2 weeks of resting period. Treatment continued until progression of disease or life-threatening adverse events were occurred. Results: Fifty-four patients were enrolled in this study and of the patients, forty-eight patients were evaluable. A total 194 chemotherapy cycles were administered and median number of cycles was three. Four (8.3%) patients had a partial response and 18 (37.5%) patients had stable disease. The median progression free survival and overall survival were 3.8 and 10.2 months, respectively. Grade III/IV hematologic toxicities included neutropenia in 6 patients (12.5%) and there was no febrile neutropenia. Most of nonhematologic toxicities were diarrhea, asthenia, and mucositis, and there was no grade 3 or grade 4 except two patients, who developed grade 3 anorexia and diarrhea, respectively. The clinical benefit response was observed in 16 patients (33.3%). Conclusions: This results showed that S-1 monotherapy was active and safe salvage chemotherapy in patients with advanced gastric cancer previously treated with taxane and cisplatin. No significant financial relationships to disclose.
e15599 Background: The role of the second line chemotherapy in advanced gastric cancer was not clear, but possibility of prolongation of survival is open question. Irinotecan is promising agents in gastric cancer and this phase II study evaluated the efficacy and safety of combination chemotherapy with irinotecan, high dose of 5-fluorouracil (5-FU) and leucovorin in taxane and cisplatin based chemotherapy refractory metastatic gastric cancer. Methods: Eligible criteria were as followed; histologic confirmed adenocarcinoma of stomach, previously treated with taxane and cisplatin, age≥18, Eastern Clinical Oncology Group (ECOG) performance status of 1 or less, adequate organ function. Irinotecan (150 mg/m 2 ) as a 30-min infusion and leucovorin (200 mg/m 2 ) as a 15-min infusion were given on day 1, followed by 5-FU 400 mg/m 2 bolus infusion then 5-FU 2,400 mg/m 2 as a 48-hour continuous infusion. This cycle was repeated every 2 weeks until disease progression or unacceptable toxicities. Results: Thirty-four patients were enrolled. The median age was 57 years (range 27–73 years), and the ECOG performance status of all patients was 1. All patients were evaluable for safety and survival and twenty seven patients (79.4%) were evaluable for tumor response. The overall response rate was 18.5% (95% CI: 3.9–33.1). The median progression free survival and overall survival were 4.6 (95% CI: 2.4–6.9) and 9.3 months (95% CI: 5.2–13.4), respectively. Greater than grade 3 haematological toxicities were neutropenia in nine (26.5%), febrile neutropenia in one (2.9%) and thrombocytopenia in one patient (2.9%). The major non-haematological toxicity was asthenia, but most of patients showed grade 1 or 2. Greater than grade 3 non- haematological toxicities were elevated AST/ALT in four (11.8%), hyperbilirubinemia in two (5.9%), nausea in two patients (5.9%). Conclusions: This results showed that the combination chemotherapy with irinotecan, 5-FU and leucovorin was well tolerated and active in taxane and cisplatin refractory patients. No significant financial relationships to disclose.
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