Combination Regimen Of Gemcitabine Research Articles

Clinical characteristics and blood/serum bound prognostic biomarkers in advanced pancreatic cancer treated with gemcitabine and nab-paclitaxel

BackgroundIn recent years treatment options for advanced pancreatic cancer have markedly improved, and a combination regimen of gemcitabine and nab-paclitaxel is now considered standard of care in Sweden and elsewhere. Nevertheless, a majority of patients do not respond to treatment. In order to guide the individual patient to the most beneficial therapeutic strategy, simple and easily available prognostic and predictive markers are needed.MethodsThe potential prognostic value of a range of blood/serum parameters, patient-, and tumour characteristics was explored in a retrospective cohort of 75 patients treated with gemcitabine/nab-paclitaxel (Gem/NabP) for advanced pancreatic ductal adenocarcinoma (PDAC) in the South Eastern Region of Sweden. Primary outcome was overall survival (OS) while progression free survival (PFS) was the key secondary outcome.ResultUnivariable Cox regression analysis revealed that high baseline serum albumin (> 37 g/L) and older age (> 65) were positive prognostic markers for OS, and in multivariable regression analysis both parameters were confirmed to be independent prognostic variables (HR 0.48, p = 0.023 and HR = 0.47, p = 0.039,). Thrombocytopenia at any time during the treatment was an independent predictor for improved progression free survival (PFS) but not for OS (HR 0.49, p = 0.029, 0.54, p = 0.073), whereas thrombocytopenia developed under cycle 1 was neither related with OS nor PFS (HR 0.87, p = 0.384, HR 1.04, p = 0.771). Other parameters assessed (gender, tumour stage, ECOG performance status, myelosuppression, baseline serum CA19–9, and baseline serum bilirubin levels) were not significantly associated with survival.ConclusionSerum albumin at baseline is a prognostic factor with palliative Gem/NabP in advanced PDAC, and should be further assessed as a tool for risk stratification. Older age was associated with improved survival, which encourages further studies on the use of Gem/NabP in the elderly.

Efficacy and treatment-related adverse events of gemcitabine plus nab-paclitaxel for treatment of metastatic pancreatic cancer “in a Korean” population: A single-center cohort study

Pancreatic cancer has poor prognosis because of its rapid progression and treatment resistance. Based on the results of the Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT), a combination regimen of gemcitabine with nab-paclitaxel is currently used as standard therapy for the treatment of metastatic pancreatic cancer. However, because studies in Asian populations are lacking, we investigated the treatment efficacy and safety of this combination therapy in Korean population. Patients with metastatic pancreatic cancer (n=81) treated with gemcitabine and nab-paclitaxel (1,000 and 125 mg/m2, respectively) as the first-line chemotherapy from January 2016 were identified using the Severance Hospital Pancreatic Cancer Cohort Registry. Treatment efficacy and treatment-related adverse events (AEs) were analyzed. The median follow-up period was 10.7 months (range, 1.5–23.3 months). Median overall survival, progression-free survival, and objective response rates were 12.1 months (95% confidence interval [CI], 10.7–not estimable), 8.4 months (95% CI, 5.0–11.8), and 46.9%, respectively. The incidence of grade ≥3 neurotoxicity and neutropenia were 18.5% and 46.9%, respectively. Febrile neutropenia and grade ≥3 gastrointestinal AEs occurred in 13 (16.0%) and 16 (19.8%) patients, respectively. Dose reductions because of AEs were required in 60.5% of patients. The combination of gemcitabine with nab-paclitaxel is an effective anti-cancer regimen in Korean population of patients with metastatic pancreatic adenocarcinoma. However, careful monitoring and management are required because of occurrence of treatment-related AEs.

Comparison of efficacy and toxicity of FOLFIRINOX and gemcitabine with nab-paclitaxel in unresectable pancreatic cancer.

Irinotecan, oxaliplatin and leucovorin-modulated fluorouracil (FOLFIRINOX) and the combination regimen of gemcitabine and nanoparticle albumin-bound paclitaxel (GnP) (nab-PTX) improve the prognosis of patients with metastatic pancreatic cancer. However, no study has compared the efficacy of the two regimens. We compared retrospectively the efficacy and safety of the two regimens in patients with unresectable pancreatic cancer. Thirty-eight patients with unresectable locally advanced or metastatic pancreatic cancer received FOLFIRINOX or GnP as first-line chemotherapy between December 2013 and September 2015. In the FOLFIRINOX group, patients received 85 mg/m2 oxaliplatin followed by 180 mg/m2 irinotecan and 200 mg/m2 L-leucovorin, and by 400 mg/m2 fluorouracil as a bolus and 2,400 mg/m2 fluorouracil as a 46-h continuous infusion every 14 days. In the GnP group, patients received 125 mg/m2 nab-PTX followed by 1 g/m2, and gemcitabine on days 1, 8 and 15, repeated every 28 days. Response rate was 6.3% in the FOLFIRINOX group and 40.9% in the GnP group (P=0.025). Median progression-free survival (PFS) was 3.7 months [95% confidence interval (CI), 3.0-4.5] in the FOLFIRINOX group and 6.5 months (95% CI, 6.2-6.9 months) in the GnP group (P=0.031). Drug toxicity in the GnP group was less than in the FOLFIRINOX group. Efficacy and safety of GnP compare favorably to those of FOLFIRINOX in patients with pancreatic cancer. Additional prospective trials are warranted.

A phase II study of biweekly gemcitabine at fixed dose rate infusion plus S1 as first-line chemotherapy in patients with locally advanced or metastatic pancreatic cancer.

357 Background: The combination regimen of gemcitabine plus S1 (GS) as first-line chemotherapy has shown good efficacy in advanced pancreatic cancer. However, it is inconvenient to deliver gemcitabine on days 1 and 8 within one treatment cycle. In addition, previous studies have demonstrated that the gemcitabine administration by fixed dose rate infusion of 10 mg/m2/min should maximize the rate of intracellular accumulation of gemcitabine triphosphate and might improve clinical efficacy. The aim of this study was to evaluate the efficacy and safety of biweekly gemcitabine at fixed dose rate infusion combined with S1 (FGS) in chemonaive patients with locally advanced or metastatic pancreatic cancer. Methods: Forty-three eligible patients with locally advanced or metastatic pancreatic cancer received gemcitabine at a fixed dose of 10 mg/m2/min intravenously over a 2-h period on day 1, together with oral S1 40mg/m2twice daily on days 1 to 10, every 2 weeks. Tumor assessment was performed for every 3 cycles of chemotherapy. Results: All patients were evaluable for toxicity and 42 patients for efficacy. The overall response rate was 35.7% with 1 complete response, 14 partial responses, 17 stable diseases, and 10 progressions. Median time to progression was 5.9 months and median overall survival was 9.6 months. The main grade 3/4 toxicities included neutropenia (30.2%), thrombocytopenia (6.9%), anemia (2.3%), nausea (4.6%), diarrhea (2.3%). Conclusions: The biweekly FGS regimen is active, well tolerated and conveniently delivered as first-line chemotherapy for patients with locally advanced or metastatic pancreatic cancer.

Clinical Results of Gemox-R in Mantle CELL Lymphoma: The Role of Oxaliplatin

Introduction: Mantle cell lymphoma (MCL) is mostly incurable. The current standard therapy achieves a high rate of complete remission (CR), but the pattern of continuous relapses still marks this disease as a challenge. We previously reported the efficacy of GemOx-R, a combination regimen of gemcitabine, oxaliplatin and rituximab, in patients with refractory and relapsing MCL. Our aim is to confirm our previous results in a larger retrospective series and evaluate the efficacy of each component of GemOx-R in a panel of MCL cell lines and in patient-derived primary cells.Methods: Between 2003 and 2015, 30 patients with MCL were included in a retrospective study of treatment with GemOx-R from the University Hospital Son Espases: 10 cases frontline and 20 in the salvage setting. Frontline cohort was consolidated with radioimmunotherapy and received maintenance therapy with rituximab. The translational study was performed in established cell lines as well as primary MCL lines from patients by cell viability, cell cycle, apoptosis and western blot analysis. Drug synergy was determined by the isobologram and combination index methods.Results: This is a high risk series of patients: median age 70 years, 87% stage IV and 86% intermediate or high risk MIPI. Overall response rate and CRR was 80% and 60% in the frontline cohort as well as 85 % and 60% for salvage patients, respectively. Median progression-free survival was 28 months in the entire series: 66 and 22 months, respectively, for the two cohorts. Median overall survival was 34 months in the entire series: not reached and 20 months, respectively, for the two cohorts. Grade 3 and 4 toxicity was as follows: neutropenia (63%), anemia (34%) and thrombocytopenia (30%) as well as 24% of grade 1 and 2 neurotoxicity. Cell viability and apoptosis analysis showed that oxaliplatin is the most effective drug in this regimen in contrast to the poor responses induced by gemcitabine and rituximab. Oxaliplatin had a profound effect on cellular viability, consistent with the induction of caspase activityand the downregulation of pro-survival proteins. We further present synergistic efficacy of oxaliplatin combined with cytarabine in MCL cells.Conclusions: (1) GemOx-R shows excellent results in MCL both in the frontline and salvage settings considering the high risk patients included. (2) Oxaliplatin is the most effective drug in GemOx-R; (3) oxaliplatin has a robust in vitro activity comparable to that of cytarabine, and the combination of both oxaliplatin and cytarabine shows a significant synergism; (4) taken together, our findings suggest that oxaliplatin alone or combined with cytarabine could constitute a new or alternative backbone for promising new regimens in MCL. DisclosuresNo relevant conflicts of interest to declare.

First-line chemotherapy with gemcitabine, etoposide, and cisplatin in combined-multimodality treatment for patients with advanced urothelial carcinoma.

262 Background: We had previously reported the phase I/II study of a combination regimen of gemcitabine, etoposide, and cisplatin (GEP) in second-line treatment for patients with advanced UC. This study sought to examine the combination chemotherapy of GEP as first-line treatment for advanced urothelial carcinoma (UC) to assess efficacy, feasibility, prognostic factors, and the impact of postchemotherapy surgery on outcomes. Methods: Forty-two patients were treated with GEP as first-line treatment for metastatic or unresectable locally advanced UC. GEP was recycled every 4 weeks. Etoposide and cisplatin were given on days 1 through 3 at doses of 60 mg/m2 and 20 mg/m2, respectively, and gemcitabine was given on days 1, 8, and 15 at a dose of 800 mg/m2. Results: The median patient age was 64 years. Twenty-three male patients and 19 female patients were included. The primary cancer site is urinary bladder in 21 patients, and upper urinary tract in 21 patients. Nineteen had visceral/bone metastases, 16 had disease restricted to lymph nodes, and the remaining 7 had unresectable disease at primary site. The median number of GEP courses was 4. Thirty of 42 assessable patients (71.4%) demonstrated objective responses. At a median follow-up of 14.6 months, the median overall survival time (OS) was 16.2 months. Twenty-four of 30 responders underwent postchemotherapy surgeries. Median OS in the patients with postchemotherapy surgery was 25.4 months. In the multivariable analysis, anemia and visceral/bone metastasis were significant pretreatment prognostic factors for OS. In addition, being male and anemic were independent poor prognostic factors in patients with postchemotherapy surgery. Grade 3-4 neutropenia, anemia and thrombocytopenia occurred in 84%, 73% and 57%. There were no treatment-related deaths. Conclusions: GEP as first-line chemotherapy in combined-multimodality treatment is active and moderately tolerable for advanced UC. Postchemotherapy surgery may yield favorable outcomes in patients who achieved objective responses. Anemia and visceral/bone metastasis were independent pretreatment predictors for OS.

Treatment of gemcitabine combined with nedaplatin and paclitaxel for patients with metastatic cisplatin-resistant nasopharyngeal carcinoma

Objective To assess the short-term effects and adverse reactions of combination regimen of gemcitabine, nedaplatin and paclitaxel for patients with metastatic cisplatin-resistant nasopharyngeal carcinoma (NPC). Methods A total of 15 patients with metastatic cisplatin-resistant NPC were enrolled. All patients were treated with a combination regimen including gemcitabine with 1000 mg/m2 on day 1st and 8th, nedaplatin with 70 mg/m2 on day 1st and paclitaxel with 135 mg/m2 on day 1st, repeated every 21 days. Response was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 3.0. Results The overall response rate was 40.0 %, with a complete response rate of 6.7 % (1/15) and a partial response rate of 33.3 % (5/15). Six patients (40.0 %) had stable disease and 3 patients (20.0 %) had progressive disease. The median time to progression (TTP) was 4.7 months and the median overall survival was 6.3 months. Hematological toxicities were the adverse reaction with 40.0 % of leucopenia, 6.7 % of anemia and 20.0 % thrombocytopenia. One patient needed for platelet transfusion. Other adverse reactions were mild. Conclusion The combination regimen of gemcitabine, nedaplatin and paclitaxel is feasible as second-line chemotherapy in patients with metastatic cisplatin-resistant NPC. Key words: Nasopharyngeal neoplasms; Drug therapy,combination

Phase II study of carboplatin and gemcitabine as adjuvant chemotherapy in patients with completely resected non-small cell lung cancer: a report from the Central Japan Lung Study Group, CJLSG 0503 trial

The aim of this phase II study was to evaluate the feasibility and safety of a carboplatin and gemcitabine combination regimen in the treatment of completely resected non-small cell lung cancer (NSCLC). Patients with completely resected pathologically documented stage IB, II or IIIA NSCLC were treated with carboplatin and gemcitabine. Chemotherapy consisted of 4 cycles of carboplatin at an area under the curve of 5 (level 1) or 4 (level 2) on day 1 combined with gemcitabine 1,000 mg/m(2) on days 1 and 8 every 3 weeks. The primary endpoint of this study was the completion rate of 4 cycles. Twenty patients were treated, and the patient's demographics were: median age 61 years (range 51-74), gender male (n = 13, 65%)/female (n = 7, 35%), stage IB (n = 8, 40%), IIA (n = 1, 5%), IIB (n = 6, 30%), IIIA (n = 5, 25%). Seventeen patients (85%, 95% confidence interval 64.0-94.8) received the planned 4 cycles of the chemotherapy regimen at level 1 every 3 weeks. Among the 3 patients who failed to complete 4 cycles, the reasons for stopping were refusal (n = 1), thrombocytopenia (n = 1) and rash (n = 1). The main adverse effects were hematological toxicity as well as grade 3/4 neutropenia and thrombocytopenia (which occurred in 65% and 40% of the patients, respectively). Adjuvant chemotherapy with a carboplatin and gemcitabine combination regimen has an acceptable toxicity profile, and the majority of patients completed 4 cycles of therapy.

Synergistic inhibitory effect of gemcitabine and angiotensin type-1 receptor blocker, losartan, on murine pancreatic tumor growth via anti-angiogenic activities

Pancreatic cancer is one of the leading causes of cancer death, and represents a challenging chemotherapeutic problem. The crucial role of angiogenesis in tumor growth has been widely recognized, and several reports have revealed that the combination treatment of the conventional chemotherapeutic drugs and anti-angiogenic agents exerted synergistic anti-cancerous effects. It has been reported that the clinically used angiotensin type-1 receptor blocker (ARB) exerted potent anti-angiogenic activity. The aim of our current study was to examine the combination effect of gemcitabine (GEM), a widely used conventional chemotherapeutic drug against pancreas cancer, and losartan (Lo), an ARB, on murine pancreatic tumor growth, especially in conjunction with angiogenesis. When used individually, GEM and Lo at clinically comparable low doses moderately suppressed pancreatic tumor development. The combination treatment with GEM and Lo exerted a marked inhibitory effect as compared with single agent treatments even after the tumor was fully established. Neovascularization and the expression of the vascular endothelial growth factor (VEGF), a central angiogenic factor, in the tumor were both markedly suppressed in a magnitude similar to the inhibitory effects against the tumor growth. Since both agents are widely used in the clinical practice, the combination regimen of GEM and Lo may represent a potential new therapeutic strategy for pancreatic cancer in the future.

Gemcitabine and lenalidomide combination in a patient with metastatic pancreatic cancer: a case study

The proportion of people surviving pancreatic cancer is extremely low, with just 10% of patients diagnosed with any stage of the disease living beyond 1 year and a 5-year relative survival rate of <5%. The lack of effective therapy is one the main reason for such a bleak outlook. Herein, we report on a patient with pancreatic adenocarcinoma and metastatic disease treated with a combination regimen of gemcitabine and lenalidomide, without major complications. We also present in vitro data that highlight a hyper-additive effect of the two drugs when used in combination. To date, 33 months after diagnosis, the patient remains well and continues in full-time employment.

Phase I trial of oral S-1 plus gemcitabine in elderly patients with nonsmall cell lung cancer

We conducted a phase I study to determine the maximum tolerated dose, the recommended dose and the safety profile of S-1 and gemcitabine combination regimen in the treatment of elderly patients (> or = 70 years) with advanced nonsmall cell lung cancer (NSCLC). Chemotherapy-naive patients with advanced NSCLC were treated with S-1 and gemcitabine. S-1 was administered orally twice daily for 14 days and gemcitabine on days 1 and 15 of each cycle, and this was repeated every 4 weeks. Doses of each drug were planned as follows: level 1, 800/60; level 2, 1000/60; level 3, 1000/70; and level 4, 1000/80 [gemcitabine (mg/m2/ day)/S-1 (mg/m2/day)]. The dose-limiting toxicity (DLT) of the regimen was assessed during the first chemotherapy cycle. Sixteen patients were enrolled in this study. The main grade 3 toxicities observed during the first cycle were neutropenia (43.7%), leukopenia (18.7%), and hyperglycemia. One of six patients in level 3 had DLT. Although no patients in level 4 experienced DLT, this level was considered the maximum tolerated dose. Level 4 was selected as the recommended dose. Objective responses were seen in four patients (response rate, 42.9%). The combination of S-1 plus gemcitabine is a feasible and well-tolerated regimen for the treatment of elderly patients with advanced NSCLC.

A phase 2 study of gemcitabine and epirubicin for the treatment of pleural mesothelioma

The North Central Cancer Treatment Group (NCCTG) conducted a phase 2 study to evaluate the antitumor activity of the combination of gemcitabine and epirubicin in patients with pleural mesothelioma who received no more than 1 prior chemotherapy regimen. A total of 23 patients were accrued between August 2001 and April 2002 and received gemcitabine at a dose of 1000 mg/m(2) intravenously over 30 minutes weekly every 2 weeks and epirubicin at a dose of 90 mg/m(2) intravenously on Day 1 on an every-21-days cycle (high-dose patient group). Between August 2002 and April 2004, an additional 45 patients were treated at a reduced dose of gemcitabine of 750 mg/m(2) and epirubicin at a dose of 70 mg/m(2) with the same schedule (low-dose patient group). In the high-dose patient group, the confirmed response rate was 13% (95% confidence interval [95% CI], 3-34%). The median survival was 9.3 months (95% CI, 7.4-10.7 months) and the median time to disease progression was 6.3 months (95% CI, 3.0-7.6 months). In the low-dose patient group, the confirmed response rate was 7% (95% CI, 0-28%). The median survival was 5.7 months (95% CI, 4.7-8.7 months) and the median time to disease progression was 4.2 months (95% CI, 2.7-5.6 months). Toxicity was moderate to severe. In the high-dose and low-dose groups, 87% and 60% of patients, respectively, experienced at least 1 adverse event of grade 4 or higher (according to National Cancer Institute Common Toxicity Criteria [version 2.0]). The quality of life remained similar from baseline to the end of the 2 cycles of treatment in the high-dose group but worsened in the low-dose group. In the current study, the combination regimen of gemcitabine and epirubicin was found to demonstrate minimal antitumor activity against pleural mesothelioma.

Gemcitabine and irinotecan in patients with previously treated carcinoma of unknown primary site: A Minnie Pearl Cancer Research Network phase II trial

4167 Background: Three sequential phase II trials done by the Minnie Pearl Cancer Research Network of taxane, platinum, and etoposide combinations for carcinoma of unknown primary site (CUP) have produced median survivals of about 10 months, and 1, 2, 3, 5, and 8-year survivals of 42%, 22%, 18%, 12%, and 10%, respectively. In an effort to improve efficacy, we evaluated second-line treatment with a new combination regimen of gemcitabine and irinotecan. Methods: The primary objective was to evaluate the toxicity and response rate in CUP as second-line therapy. Eligible patients (pts) had adenocarcinoma, poorly differentiated adenocarcinoma, poorly differentiated carcinoma, or poorly differentiated neuroendocrine carcinoma (PDNE); one prior chemotherapy regimen, not including recent irinotecan and/or gemcitabine; absence of brain metastasis; and adequate organ function. Gemcitabine 1000 mg/m2 IV days 1, 8 and irinotecan 100 mg/m2 IV days 1, 8 were given every 21 days. Pts with objective responses or stable tumor after 2 cycles (6 weeks) continued additional 3-week cycles for a recommended 6 cycles. Results: 31 pts were treated and 27 were evaluable for response; median age 50 years (range 24–74); performance status (0=1, 1=28, 2=2); men - 15; women - 16. The response rate was 15% with 3 (11%) partial responses, 1 (4%) complete response. 11 pts had stable disease and 12 progressive disease. Of the 2 pts with PDNE, both had stable disease. The median time-to-progression, median survival, and 1-year survival were 3.5 months, 4 months, and 15%, respectively. Grade 3/4 toxicities included: neutropenia (30%), thromobcytopenia (8%), diarrhea (8%), anemia (9%), neutropenic fever (3%), nausea/vomiting (8%), and fatigue (8%). Conclusions: Gemcitabine/irinotecan is an active and well-tolerated second-line treatment for pts with CUP. A randomized prospective phase III study of gemcitabine/irinotecan compared to paclitaxel/carboplatin/etoposide in the first-line setting is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly; Pfizer-Pharmacia

Gemcitabine and irinotecan in patients with previously treated carcinoma of unknown primary site: A Minnie Pearl Cancer Research Network phase II trial

4167 Background: Three sequential phase II trials done by the Minnie Pearl Cancer Research Network of taxane, platinum, and etoposide combinations for carcinoma of unknown primary site (CUP) have produced median survivals of about 10 months, and 1, 2, 3, 5, and 8-year survivals of 42%, 22%, 18%, 12%, and 10%, respectively. In an effort to improve efficacy, we evaluated second-line treatment with a new combination regimen of gemcitabine and irinotecan. Methods: The primary objective was to evaluate the toxicity and response rate in CUP as second-line therapy. Eligible patients (pts) had adenocarcinoma, poorly differentiated adenocarcinoma, poorly differentiated carcinoma, or poorly differentiated neuroendocrine carcinoma (PDNE); one prior chemotherapy regimen, not including recent irinotecan and/or gemcitabine; absence of brain metastasis; and adequate organ function. Gemcitabine 1000 mg/m2 IV days 1, 8 and irinotecan 100 mg/m2 IV days 1, 8 were given every 21 days. Pts with objective responses or stable tumor after 2 cycles (6 weeks) continued additional 3-week cycles for a recommended 6 cycles. Results: 31 pts were treated and 27 were evaluable for response; median age 50 years (range 24–74); performance status (0=1, 1=28, 2=2); men - 15; women - 16. The response rate was 15% with 3 (11%) partial responses, 1 (4%) complete response. 11 pts had stable disease and 12 progressive disease. Of the 2 pts with PDNE, both had stable disease. The median time-to-progression, median survival, and 1-year survival were 3.5 months, 4 months, and 15%, respectively. Grade 3/4 toxicities included: neutropenia (30%), thromobcytopenia (8%), diarrhea (8%), anemia (9%), neutropenic fever (3%), nausea/vomiting (8%), and fatigue (8%). Conclusions: Gemcitabine/irinotecan is an active and well-tolerated second-line treatment for pts with CUP. A randomized prospective phase III study of gemcitabine/irinotecan compared to paclitaxel/carboplatin/etoposide in the first-line setting is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly; Pfizer-Pharmacia