Human equilibrative nucleoside transporter 1 is not predictive for gemcitabine efficacy in advanced pancreatic cancer: Translational results from the AIO-PK0104 phase III study with the clone SP120 rabbit antibody

2014 ◽  
Vol 50 (11) ◽  
pp. 1891-1899 ◽  
Author(s):  
Steffen Ormanns ◽  
Volker Heinemann ◽  
Mitch Raponi ◽  
Jeff Isaacson ◽  
Rüdiger P. Laubender ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Advanced Pancreatic Cancer ◽  
Phase Iii ◽  
Nucleoside Transporter ◽  
Rabbit Antibody ◽  
Equilibrative Nucleoside Transporter ◽  
Phase Iii Study

Updated results of the GEST study: Randomized phase III study of gemcitabine plus S-1 (GS) versus S-1 versus gemcitabine (GEM) in unresectable advanced pancreatic cancer in Japan and Taiwan.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4035-4035 ◽  
Author(s):  
Akira Fukutomi ◽  
Takuji Okusaka ◽  
Kazuya Sugimori ◽  
Hideki Ueno ◽  
Tatsuya Ioka ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Primary Endpoint ◽  
Advanced Disease ◽  
Performance Status ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Phase Iii ◽  
Locally Advanced Disease ◽  
Phase Iii Study

4035 Background: The GEST study (Ioka et al. ASCO 2011, Abstract 4007) demonstrated the non-inferiority of S-1 to GEM with respect to the primary endpoint of overall survival (OS) in patients with pancreatic cancer (PC). We now report the updated results of this study. Methods: The GEST study was a randomized, 3-arm, phase III study. Chemotherapy-naive patients with unresectable advanced PC, an ECOG Performance status (PS) of 0-1, and adequate organ functions were randomly assigned to receive GEM (1000 mg/m2, iv, d1, 8 and 15, q4w), S-1 (80/100/120 mg/day based on BSA, po, d1-28, q6w), or GS (GEM 1000 mg/m2, iv, d1 and 8 plus S-1 60/80/100 mg/day based on BSA po, d1-14, q3w). The primary endpoint was OS, used to assess the non-inferiority of S-1 and the superiority of GS to GEM. Patient information was updated in July 2011. Results: At the time of this follow-up analysis, median follow-up was 29.8 months with 795 OS events, compared with 18.4 months with 710 OS events out of 832 patients at the previous analysis. Median OS was 8.8 months (95% CI: 8.0–9.7) in the GEM group and 9.7 months (95% CI: 7.6-10.8) in the S-1 group (HR=0.96, 97.5% CI: 0.79-1.17, p<0.001 for non-inferiority), which is consistent with prior results (HR=0.96, 97.5% CI: 0.78-1.18, p<0.001). In the GS group, median OS was 9.9 months (95% CI: 9.0-11.2). The HR was 0.91 (97.5%CI: 0.75-1.11, p=0.28 for superiority versus the GEM group). On subgroup analysis, GS was associated with a non-statistically significant trend toward better OS compared with GEM among patients with locally advanced disease and those with a PS of 1. Median OS was 12.7 months (95% CI: 9.7–14.9) in the GEM group and 15.9 months (95% CI: 13.0-19.7) in the GS group (HR=0.72, 95% CI: 0.51-1.03) among patients with locally advanced disease, and 6.2 months (95% CI: 4.9–8.3) in the GEM group and 9.6 months (95% CI: 8.0-10.9) in the GS group (HR=0.62, 95% CI: 0.46-0.83) among patients with a PS of 1. Conclusions: The non-inferiority of S-1 to Gem in terms of the primary endpoint of OS was reconfirmed. Monotherapy with S-1 can be used as one of the standard treatments for advanced PC. As for GS therapy, there is room for further investigation.

scholarly journals Novel Strategy with Gemcitabine for Advanced Pancreatic Cancer

ISRN Oncology ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Shuji Komori ◽  
Shinji Osada ◽  
Kazuhiro Yoshida
Keyword(s):  
Pancreatic Cancer ◽  
Advanced Pancreatic Cancer ◽  
Metabolic Enzymes ◽  
Interindividual Variation ◽  
Nucleoside Transporter ◽  
Standard Drug ◽  
Equilibrative Nucleoside Transporter ◽  
Nucleotide Pools ◽  
Novel Strategy

5-fluorouracil (5-FU) is widely used in chemotherapy for gastric and colorectal cancer, but gemcitabine (GEM), and not 5-FU, is approved as a standard drug for use in pancreatic cancer. Interindividual variation in the enzyme activity of the GEM metabolic pathway can affect the extent of GEM metabolism and the efficacy of GEM chemotherapy. Human equilibrative nucleoside transporter 1 (hENT1) is recognized as a major transporter of GEM into cells. In addition, a factor that activates hENT1 is the inhibition of thymidylate synthase (TS), one of the 5-FU metabolic enzymes; TS inhibition mediates depleting intracellular nucleotide pools, resulting in the activation of the salvage pathway mediated through hENT1. In this paper, the role of 5-FU in GEM-based chemotherapy for pancreatic cancer is discussed with special emphasis on enzymes involved in the 5-FU and GEM metabolic pathways and in the correlation between GEM responsiveness and the expression of 5-FU and GEM metabolic enzymes.

PANCREOX: A Randomized Phase III Study of Fluorouracil/Leucovorin With or Without Oxaliplatin for Second-Line Advanced Pancreatic Cancer in Patients Who Have Received Gemcitabine-Based Chemotherapy

2016 ◽  
Vol 34 (32) ◽  
pp. 3914-3920 ◽  
Author(s):  
Sharlene Gill ◽  
Yoo-Joung Ko ◽  
Christine Cripps ◽  
Annie Beaudoin ◽  
Sukhbinder Dhesy-Thind ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Adverse Events ◽  
Group Performance ◽  
Advanced Pancreatic Cancer ◽  
Phase Iii ◽  
Life Questionnaire ◽  
Second Line ◽  
European Organization ◽  
Phase Iii Study ◽  
Previously Treated

Purpose The standard of care for second-line therapy in patients with advanced pancreatic cancer after gemcitabine-based therapy is not clearly defined. The CONKO-003 phase III study reported a survival benefit with second-line fluorouracil (FU) and oxaliplatin using the oxaliplatin, folinic acid, and FU (OFF) regimen. 1 PANCREOX was a phase III multicenter trial to evaluate the benefit of FU and oxaliplatin administered as modified FOLFOX6 (mFOLFOX6; infusional fluorouracil, leucovorin, and oxaliplatin) versus infusional FU/leucovorin (LV) in this setting. Patients and Methods Patients with confirmed advanced pancreatic cancer who were previously treated with gemcitabine therapy and with an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. A total of 108 patients were randomly assigned to receive biweekly mFOLFOX6 or infusional FU/LV until progression. Progression-free survival (PFS) was the primary end point. Results Baseline patient characteristics were similar in both arms. No difference was observed in PFS (median, 3.1 months v 2.9 months; P = .99). Overall survival (OS) was inferior in patients assigned to mFOLFOX6 (median, 6.1 months v 9.9 months; P = .02). Increased toxicity was observed with the addition of oxaliplatin, with grade 3/4 adverse events occurring in 63% of patients who received mFOLFOX6 and 11% of those who received FU/LV. More patients in the mFOLFOX6 arm withdrew from study due to adverse events than in the FU/LV arm (20% v 2%), whereas the use of postprogression therapy was significantly higher in the FU/LV arm (25% v 7%; P = .015). No significant differences were observed in time to deterioration on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 global health scale. Conclusion No benefit was observed with the addition of oxaliplatin, administered as mFOLFOX6, versus infusional FU/LV in patients with advanced pancreatic cancer previously treated with first-line gemcitabine.

scholarly journals Application of two lines of chemotherapy: gemcitabine with nab-paclitaxel and liposomal irinotecan with 5-fluorouracil and leucovorin in patient with advanced pancreatic adenocarcinoma

Oncoreview ◽  
2021 ◽  
Vol 11 (3(43)) ◽  
pp. 68-72
Author(s):  
Krystyna Ostrowska-Cichocka ◽  
Marek Z. Wojtukiewicz
Keyword(s):  
Pancreatic Cancer ◽  
Therapeutic Option ◽  
Advanced Pancreatic Cancer ◽  
Distant Metastases ◽  
Phase Iii ◽  
Phase Iii Study ◽  
Previously Treated ◽  
Liposomal Irinotecan ◽  
Line Of Therapy ◽  
Advanced Pancreatic Adenocarcinoma

Pancreatic cancer is a disease with high mortality. It is predicted to become the second leading cause of cancer death in some regions of the world. Frequent diagnosis at an advanced stage contributes to 5-year survival at a highly unsatisfactory level of 2–9%. Due to the lack of early symptoms, nearly 80% of patients receive a diagnosis when distant metastases develop. So far, the most frequently used programs in the treatment of patients with pancreatic cancer in the stage of neoplastic spreading include: FOLFIRINOX (oxaliplatin, 5-fluorouracil, irinotecan, leucovorin), gemcitabine alone or in combination with nab-paclitaxel or erlotinib. Based on the results of the phase III study NAPOLI-1, liposomal irinotecan in combination with 5-fluorouracil (5-FU) and leucovorin (LV ) was approved as the first regimen for use in the second or subsequent line of therapy in patients with advanced pancreatic cancer previously treated with gemcitabine. This paper presents a case of a patient with advanced pancreatic cancer who was treated with two lines of chemotherapy – gemcitabine in combination with nab-paclitaxel and liposomal irinotecan with 5-FU/LV . The treatment was well tolerated and was considered a valuable therapeutic option. A 2-year overall survival was obtained from the diagnosis of the disease.

scholarly journals Biologically effective doses of 60-70Gy vs. >70Gy of stereotactic body radiotherapy (SBRT) combined with chemotherapy in locally advanced pancreatic cancer: protocol of a phase III study

2020 ◽  
Author(s):  
Yusheng Ye ◽  
Xiaofei Zhu ◽  
Xianzhi Zhao ◽  
Lingong Jiang ◽  
Yangsen Cao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
Locally Advanced Pancreatic Cancer ◽  
Phase Iii ◽  
Phase Iii Study ◽  
Radiation Induced ◽  
Gi Toxicity ◽  
Effective Doses

Abstract Background: There is controversial on the correlation between biologically effective dose (BED, α/β=10) of stereotactic body radiation therapy (SBRT) and clinical outcomes of patients with locally advanced pancreatic cancer (LAPC). Therefore, the aim of the study is to compare the survival benefits of BED10 of 60-70Gy with those of BED10＞70Gy.Methods: This study is a multicenter study. Patients with LAPC are randomly allocated into two groups. Arm1: SBRT with BED10 of 60-70Gy in 5-6 fractions combined with gemcitabine plus albumin-bound paclitaxel; Arm2: SBRT with BED10＞70Gy in 5-6 fractions combined with gemcitabine plus albumin-bound paclitaxel. The primary outcome is progression-free survival (PFS). The secondary outcomes are radiation-induced gastrointestinal (GI) toxicity, local control (LC) and overall survival (OS).Discussion: The pilot phase Ⅲ study could provide evidence for further decision making of prescription doses of SBRT for LAPC, which may improve survival outcomes without compromise of quality of life. The trial protocol has been approved by the Ethics committee of Shanghai Changhai hospital. The ethics number is CHEC2020-100.Trial registration: Clinical trials number: NCT04603586. Date of registration: 10/27/2020.

Gemcitabine in Combination With Oxaliplatin Compared With Gemcitabine Alone in Locally Advanced or Metastatic Pancreatic Cancer: Results of a GERCOR and GISCAD Phase III Trial

2005 ◽  
Vol 23 (15) ◽  
pp. 3509-3516 ◽  
Author(s):  
C. Louvet ◽  
R. Labianca ◽  
P. Hammel ◽  
G. Lledo ◽  
M.G. Zampino ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Benefit ◽  
Performance Status ◽  
Combined Treatment ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Phase Iii Study ◽  
Grade 3

Purpose Gemcitabine (Gem) is the standard treatment for advanced pancreatic cancer. Given the promising phase II results obtained with the Gem-oxaliplatin (GemOx) combination, we conducted a phase III study comparing GemOx with Gem alone in advanced pancreatic cancer. Patients and Methods Patients with advanced pancreatic cancer were stratified according to center, performance status, and type of disease (locally advanced v metastatic) and randomly assigned to either GemOx (gemcitabine 1 g/m2 as a 100-minute infusion on day 1 and oxaliplatin 100 mg/m2 as a 2-hour infusion on day 2 every 2 weeks) or Gem (gemcitabine 1 g/m2 as a weekly 30-minute infusion). Results Three hundred twenty-six patients were enrolled; 313 were eligible, and 157 and 156 were allocated to the GemOx and Gem arms, respectively. GemOx was superior to Gem in terms of response rate (26.8% v 17.3%, respectively; P = .04), progression-free survival (5.8 v 3.7 months, respectively; P = .04), and clinical benefit (38.2% v 26.9%, respectively; P = .03). Median overall survival (OS) for GemOx and Gem was 9.0 and 7.1 months, respectively (P = .13). GemOx was well tolerated overall, although a higher incidence of National Cancer Institute Common Toxicity Criteria grade 3 and 4 toxicity per patient was observed for platelets (14.0% for GemOx v 3.2% for Gem), vomiting (8.9% for GemOx v 3.2% for Gem), and neurosensory symptoms (19.1% for GemOx v 0% for Gem). Conclusion These results confirm the efficacy and safety of GemOx, but this study failed to demonstrate a statistically significant advantage in terms of OS compared with Gem. Because GemOx is the first combined treatment to be superior to Gem alone in terms of clinical benefit, this promising regimen deserves further development.

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