Therapy For Advanced Pancreatic Cancer Research Articles

First-in-man Phase 1 Clinical Trial of Gene Therapy for Advanced Pancreatic Cancer: Safety, Biodistribution, and Preliminary Clinical Findings

This phase 1 trial was aimed to determine the safety, pharmacokinetics, and preliminary clinical activity of CYL-02, a nonviral gene therapy product that sensitizes pancreatic cancer cells to chemotherapy. CYL-02 was administrated using endoscopic ultrasound in 22 patients with pancreatic cancer that concomitantly received chemotherapy (gemcitabine). The maximum-tolerated dose (MTD) exceeded the maximal feasible dose of CYL-02 and was not identified. Treatment-related toxicities were mild, without serious adverse events. Pharmacokinetic analysis revealed a dose-dependent increase in CYL-02 DNA exposure in blood and tumors, while therapeutic RNAs were detected in tumors. No objective response was observed, but nine patients showed stable disease up to 6 months following treatment and two of these patients experienced long-term survival. Panels of plasmatic microRNAs and proteins were identified as predictive of gene therapy efficacy. We demonstrate that CYL-02 nonviral gene therapy has a favorable safety profile and is well tolerated in patients. We characterize CYL-02 biodistribution and demonstrate therapeutic gene expression in tumors. Treated patients experienced stability of disease and predictive biomarkers of response to treatment were identified. These promising results warrant further evaluation in phase 2 clinical trial.

Identifying microRNA-mRNA regulatory network in gemcitabine-resistant cells derived from human pancreatic cancer cells.

Pancreatic cancer is unresectable in over 80 % of patients owing to difficulty in early diagnosis. Chemotherapy is the most frequently adopted therapy for advanced pancreatic cancer. The development of drug resistance to gemcitabine (GEM), which is always used in standard chemotherapy, often results in therapeutic failure. However, the molecular mechanisms underlying the gemcitabine resistance remain unclear. Therefore, we sought to explore the microRNA-mRNA network that is associated with the development of gemcitabine resistance and to identify molecular targets for overcoming the gemcitabine resistance. By exposing SW1990 pancreatic cancer cells to long-term gemcitabine with increasing concentrations, we established a gemcitabine-resistant cell line (SW1990/GEM) with a high IC50 (the concentration needed for 50 % growth inhibition, 847.23 μM). The mRNA and microRNA expression profiles of SW1990 cells and SW1990/GEM cells were determined using RNA-seq analysis. By comparing the results in control SW1990 cells, 507 upregulated genes and 550 downregulated genes in SW1990/GEM cells were identified as differentially expressed genes correlated with gemcitabine sensitivity. Gene ontology (GO) analysis showed that the differentially expressed genes were related to diverse biological processes. The upregulated genes were mainly associated with drug response and apoptosis, and the downregulated genes were correlated with cell cycle progression and RNA splicing. Concurrently, the differentially expressed microRNAs, which are the important player in drug resistance development, were also examined in SW1990/GEM cells, and 56 differential microRNAs were identified. Additionally, the expression profiles of selected genes and microRNAs were confirmed by using Q-PCR assays. Furthermore, combining the differentially expressed microRNAs and mRNAs as well as the predicted targets for these microRNAs, a core microRNA-mRNA regulatory network was constructed, which included hub microRNAs, such as hsa-miR-643, hsa-miR-4644, hsa-miR-4650-5p, hsa-miR-4455, hsa-miR-1261, and hsa-miR-3676. The predicted targets of these hub microRNAs in the microRNA-mRNA network were also observed in the identified differential genes. As a result, a differential gene and microRNA expression pattern was constructed in gemcitabine-resistant pancreatic cancer cells. Therefore, these data may be useful for the detection and treatment of drug resistance in pancreatic cancer patients, and the microRNA-mRNA network-based analysis is expected to be more effective and provides deep insights into the molecular mechanism of drug resistance.

Advanced pancreatic cancer: flourishing novel approaches in the era of biological therapy.

The progress in the development of systemic treatment for advanced pancreatic cancer (APC) has been slow. The mainstream treatment remains using chemotherapy including gemcitabine, FOLFIRINOX, and nab-paclitaxel. Erlotinib is the only approved biological therapy with marginal benefit. Studies of agents targeting epidermal growth factor receptor, angiogenesis, and RAS signaling have not been satisfying, and the usefulness of targeted therapy in APC is uncertain. Understanding in molecular processes and tumor biology has opened the door for new treatment strategies such as targeting insulin-like growth factor 1 receptor, transforming growth factor β, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathway, and Notch pathway. New directions also include the upcoming immunotherapy and many novel agents that act on the microenvironment. The practice of personalized medicine using predictive biomarkers and pharmacogenomics signatures may also enhance the effectiveness of existing treatment. Future treatment approaches may involve comprehensive genomic assessment of tumor and integrated combinations of multiple agents to overcome treatment resistance.

Allogeneic cell-based immunotherapy combined with chemotherapy and targeted therapy in advanced pancreatic cancer with metastases: A case report.

Immunotherapy may be an effective and potentially less toxic treatment for cancer in addition to the traditional therapies. The current study presents a case of advanced pancreatic cancer that was treated with cell-based immunotherapy using expanded activated allogeneic lymphocytes (EAAL*) in vitro with cluster of differentiation (CD)3(+) and CD8(+) cytotoxic T lymphocytes, and CD3(−) and CD56(+) natural killer cells as the major effector cells, together with chemotherapy and targeted agents. A 46-year-old female was diagnosed at the Chinese PLA General Hospital (Beijing, China) with stage IV pancreatic cancer with multiple metastases in October 2012. After receiving one cycle of chemotherapy plus nimotuzumab (Nimo), the patient received 14 infusions of EAAL*, which was obtained from a related donor, combined with seven cycles of chemotherapy with gemcitabine plus oxaliplatin and targeted therapy with Nimo. The patient was followed up for eight months. One day prior to the cell infusion, targeted therapy was administered and 48 h following the cell infusion, chemotherapy was administered. Following this treatment, carbohydrate antigen 19-9 levels decreased from 4,136 U/ml to within the normal ranges, along with the significant regression of the lesions. Occasionally mild upset was observed following the EAAL* transfusion. For the entire combined modality, grade II hematological and gastrointestinal toxicities plus grade I liver function damage and skin rash were identified. The present study demonstrated that combining allogeneic cell-based immunotherapy with conventional therapies is effective and safe, even in patients with end-stage pancreatic cancer. Therefore, this strategy is recommended for the treatment of similar cases.

A phase 1 trial of GSL (gemcitabine, S-1, LV) combination therapy in advanced pancreatic cancer.

290 Background: Our previous randomized controlled trial, GEMSAP study (Br J Cancer. 2012 5;106:1934-9), showed a combination therapy of gemcitabine (Gem) & S-1 (GS) for advanced pancreatic cancer was superior to Gem monotherapy in terms of progression-free survival (PFS) but not overall survival (OS). Leucovorin (LV) is known to enhance efficacy of S-1 and we conducted this phase 1 trial of combination therapy of Gem, S-1 and LV (GSL). Methods: A primary endpoint of this classical “3+3” design phase 1 trial is to determine recommended dose of GSL. Inclusion criteria were 1. histologically-confirmed advanced pancreatic cancer without prior treatment, 2.PS 0-2, 3. age over 20. Treatment schedule was S-1 80 mg/m2 2x p.o. days 1-7, LV50mg 2x p.o. days 1-7, Gem 600(Level1), 800(Level2), 1000 mg/m2(Level3) div 30-min day 1 in a 2-week schedule. Dose-limiting toxicities were Grade 4 hematological and Grade ≥3 non-hematological toxicities, or delay of recovery from treatment-related toxicity for more than 2 weeks. Results: Between May 2012 and Feb 2013, 15 patients (Level 1/2/3: 6/6/3 patients) were enrolled; 7 males, a median age of 66, PS 0/1: 5/10, locally advanced/metastatic: 5/10. DLT was observed in 2/6 in Level 1 (Grade 3 anorexia in 1 and Grade 3 anorexia/stomatitis/diarrhea in 1) and 1/6 in Level 2 (Grade 3 pulmonary embolism). No DLT was observed in Level 3 and RD was determined as 1,000 mg/m2of Gem. Tumor response by RECIST was PR 5, SD 9, NE 1 with response rate of 33% and disease control rate of 93%. Overall toxicities greater than 3 were neutropenia 20%, anemia 7%, anorexia 13%, diarrhea 7%, stomatitis 7% and pneumonitis 7%. Conclusions: RD of GSL was determined as GEM 1000 mg/m2 div 30 min day 1, S-1 80 mg/m2 2x, LV50mg 2x p.o. days 1-7. GSL was tolerable and showed promising tumor response in advanced pancreatic cancer. Clinical trial information: UMIN000007556.

A multicenter phase II trial of gemcitabine and candesartan combination therapy in patients with advanced pancreatic cancer: GECA2

Our retrospective study and phase I trial of gemcitabine and candesartan combination therapy suggested the inhibition of renin-angiotensin system potentially has a role in the treatment of advanced pancreatic cancer. The aim of this multicenter phase II trial was to assess the efficacy and toxicity of gemcitabine and candesartan combination therapy for advanced pancreatic cancer. Chemotherapy-naive patients with histologically or cytologically proven advanced pancreatic cancer were enrolled. Gemcitabine was administered at a dose of 1,000 mg/m(2) over 30 min on days 1, 8, and 15 and oral candesartan at a dose of 16 mg in normotensive patients, and 8 mg initially in hypertensive patients, with dose escalation to 16 mg allowed, from days 1 to 28, repeated every 4 weeks. A total of 35 patients with advanced pancreatic cancer were enrolled. Overall response rate and disease control rate were 11.4 % and 62.9 %. The median PFS and OS were 4.3 and 9.1 months with 1-year survival rate of 34.2 %. The median PFS was significantly longer in patients receiving 16 mg compared with 8 mg of candesartan (4.6 vs. 3.5 months, p=0.031). Major severe toxicities were neutropenia (23 %), leukopenia (17 %) and thrombocytopenia (11 %). Grade 2 hypotension was observed in 3 patients (9 %) and candesartan was discontinued in 2 patients due to hypotension. Conclusions In this multicenter phase 2 trial, gemcitabine and candesartan combination therapy was tolerable but failed to demonstrate activity against advanced pancreatic cancer. (UMIN CTR: UMIN000005580).

Effect of the addition of platinum to gemcitabine on outcome in patients with advanced pancreatic cancer who progress on gemcitabine: A comprehensive analysis of published trials.

275 Background: Pancreatic cancer is one of the deadliest cancers with an estimated 5 years survival rate of 5%. Until recently gemcitabine had been considered the first line treatment for locally advanced or metastatic disease. Although many chemotherapy regimens have been used there is no standard of care for second line therapy. The aim of this analysis was to identify superior regimen in the second line setting. Methods: We conducted a general search on PubMed for “second line therapy in advanced pancreatic cancer”. We limited our search to trials published in English from 2000 through 2012. Studies presented as abstracts in major meetings were also included. Trials that used targeted therapy other than erlotinib were excluded. We compared in an exploratory fashion the RR, PFS and OS of BSC and each of the following regimens to the rest of the treatments: 5FU+platinum, gemcitabine+platinum, taxol, erlotinib. In addition, we compared the combinations of platinum with either 5FU or gemcitabine. Finally, we explored the trend of these treatments outcomes over time. Results: Forty-four trialswere identified, of which 34 trials (T) met the inclusion criteria treating 1503 patients (N). There was a trend toward an improved overall survival with treatments (T: 33; N: 1269) compared to BSC (T: 2; N: 234) only (P= 0.013). The combination of gemcitabine and platinum (T: 5; N: 154) was the only regimen that showed a trend toward superior outcomes compared to the other regimens (T: 28; N: 1115) in terms of RR and PFS (P= 0.006 and 0.059, respectively). However, there was no difference in overall survival (P= 0.10). When compared to 5FU+platinum (T: 12; N: 450) the regimen of gemcitabine+platinum (T: 5; N: 154) showed only a trend toward significance in terms of improved RR (P= 0.030) with no difference in PFS or OS (P= 0.60 and 0.22, respectively). Overall, there was a trend toward a worse RR and PFS with no change in OS over the past 13 years. Conclusions: The combination of gemcitabine and platinum may provide a valid second line option in patients with locally advanced or metastatic pancreatic cancer who progress on gemcitabine.

Selective Induction of Apoptosis: Promising Therapy in Pancreatic Cancer

Pancreatic cancer is one of lethal and poor prognostic malignancies. Due to the absence of effective detecting methods, quite a number of efforts have been made to improve a survival advantage for treatment in patients with pancreatic cancer. Over the past decade, single-agent gemcitabine and gemcitabine-containing combinations were considered standard first-line therapies for advanced pancreatic cancer. Although these routine uses of chemotherapy failed to significantly improve survival benefit for most therapies, these trials provided insights into the molecular mechanisms involved in the development of pancreatic cancer and therefore opened up new therapeutic avenues. Apoptotic inducer as a therapeutic concept has been widely proposed and experimentally identified in some works. Some reviews have revealed that apoptosis-inducing was a promising therapy in cancers with the least side effects and more effectiveness. Apoptosis is a highly controlled physiological mechanism and proceeds through two major pathways for apoptosis-inducing. Some anticancer drugs kill cancer cells by inducing apoptosis via death receptor pathway; however, other chemotherapeutic drugs trigger apoptosis via mitochondrial pathway. In this review, we summarize briefly current chemotherapy in pancreatic cancer, describe the apoptotic mechanisms, and provide a novel therapeutic strategy by targeting Ras intermediate.

Randomized phase II trial of S-1 versus S-1 plus irinotecan (IRIS) in patients with gemcitabine-refractory pancreatic cancer.

263 Background: Gemcitabine (Gem) monotherapy or Gem-based combination therapy is a standard first-line therapy for advanced pancreatic cancer (PC). There is no consensus on second-line therapy in patients (pts) with disease progression (PD) after Gem-based therapy. S-1, an oral fluoropyrimidine derivative, is commonly used for the second-line treatment of PC in Japan. Shitara et al previously reported that IRIS regimen showed that 44% of response rate (RR), 4.9 mo of median progression free survival (PFS), and 11.3 mo of median overall survival (OS), respectively. Therefore a randomized phase II trial was conducted to evaluate the efficacy and safety of IRIS compared with S-1 alone in the second-line setting. Methods: The inclusion criteria were as follows: (1) histologically or cytologically proven pancreatic adenocarcinoma or adenosquamous carcinoma; (2) confirmed PD after Gem treatment; (3) ECOG PS, 0-1; (4) measurable metastatic lesion based on RECIST criteria; (5) age ≥ 20 years; (6) total bilirubin < 2.0 mg/dL. Patients were randomized to receive either IRIS (CPT-11 100 mg/m2, iv, d1,15 plus S-1 80/100/120 mg/day based on BSA, po, d1-14, q4w; Arm A) or S-1 (80/100/120 mg/day based on BSA, po, d1-28, q6w; Arm B). The primary endpoint was to compare PFS in Arm A and Arm B. Results: Of a total of 137 pts enrolled between Nov 2008 and Mar 2011, 127 were eligible (60 randomized to Arm A and 67 to B). Median PFS in Arm A and B was 107 and 58 days, respectively (HR= 0.767; 95% CI, 0.527-1.114; p=0.1750). Median OS in Arm A and B was 208 and 176 days, respectively (HR=0.749; 95% CI, 0.512-1.093; p=0.1338). RR was 18.3% in Arm A (11/60; 95% CI, 9.5-30.4) and 6.0% in Arm B (4/67; 95% CI, 1.7-14.6)(p=0.0311). The incidences of grade 3/4 toxicities were as follows: neutropenia (15.6% and 4.3%), anorexia (23.4% and 17.3%), nausea (6.3% and 2.9%), and diarrhea (3.1% and 2.9%) in Arm A and B, respectively. Both regimens were tolerable. Conclusions: Although IRIS showed no significant improvement in PFS or OS compared with S-1 alone in this study, it showed significant advantage in RR, and favorable HR in both of PFS and OS. IRIS might have potential power to treat second-line PC patients. Further study is warranted. Clinical trial information: JapicCTI-080657.

Gene Therapy of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with a 5-year survival rate of less than 5%. The poor prognosis of the disease is associated with late diagnosis and a high degree of drug resistance has not been overcome during the past decades. Gemcitabine-based regimens are the first line therapy for advanced pancreatic cancer but are not curative. Recent new combination chemotherapies achieved significant benefits but toxicity makes their use controversial. Novel approaches are currently being developed; in particular cancer gene therapies are undergoing preclinical and clinical validation and are the topic of the present review. We will present different ways to design gene therapy against pancreatic cancers that have been validated in preclinical studies. We also reviewed the clinical trials already published or still ongoing.

O3-005 - Phase 1 and 2 Trials of Combination Therapy with Gemcitabine and Candesartan in Advanced Pancreatic Cancer

ABSTRACT Background Inhibition of renin-angiotensin (RA) system is one of the attractive targets in the treatment of pancreatic cancer (PaC). Our retrospective analysis showed the association of inhibition of RA system with better prognosis in advanced PaC (Br J Cancer. 2010;103: 1644–8). Here we reported the results of phase 1 and 2 trials of gemcitabine and candesartan (GECA) therapy in advanced PaC. Patients In phase 1 trial in normotensive patients, candesartan was administered orally at escalating dose (4, 8, 16 and 32 mg) qd daily and gemcitabine was administered 1000 mg/m2 30 min i.v. day 1, 8, 15, repeated every 4 weeks. DLT was defined as grade 4 hematological toxic effects, Grade 2 hypotension, abnormal creatinine or potassium and grade 3 or 4 other non-hematological toxic effects. In phase 2 trial, candesartan was administered 16 mg in normotensive patients and 8 mg in patients with hypertension, followed by increase up to 16 mg in cases without adverse events. Eligible criteria were unresectable locally advanced or metastatic PaC without any prior treatment, ECOG PS 0-2, normal renal function and without hypotension. Results In phase 1 trial, 14 patients (locally advanced/metastatic 7/7, candesartan 4 mg: 3 patients, 8 mg: 3 patients, 16 mg: 6 patients, 32 mg: 2 patients) were enrolled between July 2009 and October 2010. One of six patients at 16 mg demonstrated DLT of grade 4 neutropenia and two of two patients at 32 mg demonstrated DLT of grade 2 hypotension. The response rate (RR) and the disease control rate (DCR) were 0% and 79%. Progression-free survival and overall survival were 7.6 and 22.9 months. In phase 2 trial, 35 patients (locally advanced/metastatic 9/26) were enrolled between May 2011 and December 2011. Major severe adverse events were neutropenia 24% and thrombocytopenia 18%. Grade 2 hypotension was seen in three patients. RR and DCR were 11% and 63%. Median PFS and OS were 4.3 and 7.7 months. Conclusion GECA in advanced PaC appeared safe and promising, though a phase 2 study failed to meet our primary objective of 5-month median PFS.

728P - Randomized Phase II Trial of S-1 versus S-1 Plus Oxaliplatin (SOX) in Patients with Gemcitabine Refractory Pancreatic Cancer

ABSTRACT Background Gemcitabine (Gem) monotherapy or Gem-based combination therapy is used as standard first-line therapy for advanced pancreatic cancer (PC). There is no consensus on second-line therapy in patients (pts) with disease progression (PD) after Gem-based therapy. The addition of oxaliplatin (L-OHP) to 5-FU/LV, however, yielded a significant improvement in overall survival (OS) and progression-free survival (PFS) in a second-line setting in the CONKO 003 trial. As S-1, an oral fluoropyrimidine derivative, is commonly used to treat advanced PC rather than 5-FU/LV in Japan, we conducted a randomized phase II trial to evaluate the efficacy and safety of S-1 plus L-OHP (SOX) compared with S-1 alone in a second-line setting. Material and methods The inclusion criteria were as follows: 1) histologically or cytologically proven pancreatic adenocarcinoma or adenosquamous carcinoma; 2) confirmed PD after Gem treatment; 3) ECOG PS, 0-1; 4) measurable metastatic lesion based on RECIST criteria; 5) age ≥ 20 years. Patients were randomized to receive either S-1 (80/100/120 mg/day based on BSA, po, d1-28, q6w; Arm A) or SOX (L-OHP 100 mg/m2, iv, d1 plus S-1 80/100/120 mg/day based on BSA, po, d1-14, q3w; Arm B). The primary endpoint was PFS to detect the superiority of Arm B over Arm A. Results Of a total of 271 pts enrolled between January 2009 and July 2010, 264 were eligible (130 randomized to Arm A and 134 to Arm B). Median PFS in Arm A and B was 2.8 and 3.0 months, respectively (HR= 0.838; 95% CI, 0.649-1.082; P = 0.1795) with a median follow-up time of 12.6 months. Median OS in Arm A and B was 7.0 and 7.5 months, respectively (HR = 1.031; 95% CI, 0.791-1.344; P = 0.8235) with a median follow-up time of 13.8 months. Response rate (RR) was 11.5% in Arm A (15/130; 95% CI, 6.6-18.3) and 20.9% in Arm B (28/134; 95% CI, 14.4-28.8)(P = 0.0395). The incidences of grade 3/4 toxicities were as follows: neutropenia (11.4% and 14.0%), thrombocytopenia (3.8% and 9.8%), anorexia (11.4% and 12.5%), diarrhea (4.5% and 5.1%) and nausea (3.0% and 9.8%) in Arm A and B, respectively. Both regimens were tolerable. Conclusions Although SOX showed an advantage in RR, it provided no significant improvement in PFS or OS compared with S-1 alone. Disclosure T. Okusaka: The study detailed in the abstract was funded by a pharmaceutical company. S. Ohkawa: The study detailed in the abstract was funded by a pharmaceutical company. H. Isayama: The study detailed in the abstract was funded by a pharmaceutical company. A. Fukutomi: The study detailed in the abstract was funded by a pharmaceutical company. K. Yamaguchi: The study detailed in the abstract was funded by a pharmaceutical company. M. Ikeda: The study detailed in the abstract was funded by a pharmaceutical company. A. Funakoshi: The study detailed in the abstract was funded by a pharmaceutical company. M. Nagase: The study detailed in the abstract was funded by a pharmaceutical company. S. Nakamori: The study detailed in the abstract was funded by a pharmaceutical company. Y. Hamamoto: The study detailed in the abstract was funded by a pharmaceutical company.

Tumor IGF-1 expression as a predictive biomarker for IGF1R-directed therapy in advanced pancreatic cancer (APC).

4054 Background: IGF-1 up-regulates PC proliferation and invasiveness through activation of PI3K/Akt signaling pathway and down-regulates PTEN. We investigated IGF-1 expression in tissue and blood as potential predictive markers in phase II study of IGF1R-directed monoclonal antibody, MK-0646 in APC. Prior phase I established the MTD of MK0646 at 5 mg/kg with gemcitabine (G) and erlotinib (E) and 10 mg/kg with G alone. Methods: Patients (pts) with stage IV, previously untreated APC, ECOG PS 0-1, adequate hematologic and organ function were enrolled. Arm A: G 1,000 mg/m2 over 100 min, weekly x 3, MK-0646 weekly x 4; Arm B: G 1000 mg/m2 and MK-0646 + E 100 mg daily. Arm C (control) was G 1,000 mg/m2 + E 100 mg. Cycles were repeated every 4 weeks. Pts were equally randomized in the 3 arms. Primary study objective was progression-free survival (PFS). Pre-treatment peripheral blood samples were measured for IGF-1 level by ELISA; archival core biopsies were analyzed for IGF-1 mRNA expression. RNA extraction from FFPE samples used Roche Transcriptor First Strand cDNA Synthesis Kit. TaqMan PreAmp technique was used to amplify target cDNA prior to TaqMan RT-PCR analysis. Cox proportional hazards model for PFS analyzed the interaction between tissue IGF-1 expression and treatment. Results: 50 pts were enrolled (A=15, B=16,C=16 pts, 3 ineligible). Median PFS of arms A, B and C were 5.5 months (95% CI: 3.9 – NA), 3.0 months (95% CI:1.8 – 5.6) and 2.0 months (95% CI: 1.8 – NA), respectively (log-rank test; p = 0.17). Median OS of A was 11.3 months (95% CI: 8.9 – NA), B 8.9 months (95% CI: 5.3 – NA) and C 5.7 months (95% CI: 2.0 – NA) (log-rank test; p = 0.44). 35 archival core biopsies were analyzed, 21 had adequate tissue for analysis. Using a Multivariable Cox proportional hazards model for PFS, where IGF-1 was dichotomized at the median, there was a 76% reduction in the risk of disease progression or death in arm A as compared with the control (arm C) at high IGF-1 level (p = 0.16). When IGF-1 was fitted as a continuous variable, this reduction was 96% (p = 0.08). There was no correlation between tissue and serum IGF-1. Conclusions: Tissue expression of IGF-1 level may represent a promising predictive biomarker for IGF1R-directed therapy in APC.

A multicentre randomised phase II trial of gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer: GEMSAP study

Background:This randomised phase II trial compared gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer.Methods:Patients were randomly assigned to 4-week treatment with gemcitabine alone (1000, mg m−2 gemcitabine by 30-min infusion on days 1, 8, and 15) or gemcitabine and S-1 combination therapy (1000, mg m−2 gemcitabine by 30-min infusion on days 1 and 15 and 40 mg m−2 S-1 orally twice daily on days 1–15). The primary end point was progression-free survival (PFS).Results:Between July 2006 and February 2009, 106 patients were enrolled. The PFS in gemcitabine and S-1 combination arm was significantly longer than in gemcitabine arm (5.4 vs 3.6 months), with a hazard ratio of 0.64 (P=0.036). Overall survival (OS) for gemcitabine and S-1 combination was longer than that for gemcitabine monotherapy (13.5 vs 8.8 months), with a hazard ratio of 0.72 (P=0.104). Overall, grade 3 or 4 adverse events were similar in both arms.Conclusion:Gemcitabine and S-1 combination therapy demonstrated longer PFS in advanced pancreatic cancer. Improved OS duration of 4.7 months was found for gemcitabine and S-1 combination therapy, though this was not statistically significant.

Meta-analysis of Phase III randomized trials of molecular targeted therapies for advanced pancreatic cancer

ObjectivesFor patients with unresectable pancreatic cancer (PC), the efficacy and safety of molecular targeted agents (MTAs) in combination with gemcitabine are still unclear. Published randomized controlled trials (RCTs) have reported conflicting results. This study aimed to conduct a systematic review of the literature and to perform a meta-analysis if appropriate. MethodsSeven electronic databases were searched using a standard technique to November 2011 without restriction on publication status or language. The primary aim was to assess overall survival (OS). Secondary aims were to assess progression-free survival (PFS), overall response rates (ORRs) and grade 3, 4 and 5 toxicities. A random-effects model was used for the meta-analysis. ResultsSeven Phase III RCTs were identified; 1981 patients were treated with MTAs and gemcitabine, and 1992 patients received gemcitabine with or without placebo. No statistically significant difference in OS was found between the two groups [hazard ratio (HR)=0.93, 95% confidence interval (CI) 0.85–1.02; P=0.13]. The addition of MTAs improved PFS (HR=0.86, 95% CI 0.79–0.93; P=0.000) and ORR (odds ratio 1.35, 95% CI 1.05–1.74; P=0.01). However, these benefits were accompanied by significantly higher toxicity (P=0.001). ConclusionsThe findings of this study suggest that the palliation of PC with gemcitabine and MTAs does not provide a significant survival benefit and is associated with increased grade 3 and 4 toxicities.

Activity of fractionated radioimmunotherapy (RAIT) with 90Y clivatuzumab tetraxetan (90Y-hPAM4) plus gemcitabine (Gem) in advanced pancreatic cancer (APC): Final results from a two-part study.

227 Background: A Phase I/II trial was undertaken to evaluate repeated cycles of 90Y-labeled anti-mucin humanized mAb (90Y-hPAM4) plus Gem as first-line therapy in Stage 3-4 APC. Methods: Pts received Gem once-weekly x 4 with 90Y-hPAM4 on wks 2, 3 and 4, with cycles repeated until progression or unacceptable toxicity. In Part I, pts were treated in cohorts with escalating 90Y doses and Gem fixed at a low 200 mg/m2 dose for radiosensitization. In Part II, the Gem doses were increased up to standard levels, with 90Y doses fixed for first cycle, but decreased for subsequent cycles. Tumor responses were assessed by CT, FDG/PET and serum CA19-9; safety by NCI-CTCv3. Results: Of 100 untreated pts enrolled, 10 withdrew early, while 90 (73 stage IV) received 1-4 cycles. In Part I, 38 pts received 90Y-hPAM4 weekly x 3 at 90Y doses of 6.5 (N=4), 9 (N=12), 12 (N=17) or 15 (N=5) mCi/m2, with the same cycle repeated 1-3 times in 13 pts. Grade 3-4 platelets or ANC developed in 20/38 (53%) after cycle 1 (all reversible to Grade 1) and in all retreated pts (irreversible in 4/9 pts at 12 or 15 mCi/m2). There were 3 febrile neutropenias, 4 other infections treated with IV antibiotics, but no major bleeding or other AEs. By CT-RECIST criteria, 6 pts (16%) had PRs and 16 (42%) had stabilization as best response (58% disease control). After cycle 1, 52% (13/25) with PET-avid images became negative or had >25% SUV reduction, and 33% (9/27) with elevated CA19-9 levels decreased by >50%. The median overall survival was 7.7 mo., but 11.8 mo. for retreated pts [46% (6/13) survived ≥1 yr.], with improved efficacy at higher 90Y doses. In Part II, 52 pts received 12 mCi/m2 90Y-hPAM4 x 3 with Gem doses of 200 (N=17), 600 (N=8) or 1000 mg/m2 (N=27), with 13 pts now retreated at 90Y doses of 6.5 or 9 mCi/m2. Results so far indicate no advantage to giving higher doses of Gem with RAIT. Toxicity, response and survival data for this group will be presented at the conference. Conclusions: Fractionated RAIT with 90Y-hPAM4 combined with low-dose gemcitabine appears to be a manageable and active first-line therapy for APC. It may provide comparable efficacy yet less toxicity compared to other regimens.

Metastatic Pancreatic Cancer: Are We Making Progress in Treatment?

Development of systemic treatment for advanced pancreatic cancer (APC) has been challenging. After fluorouracil, gemcitabine (GEM) became the treatment of choice based on its benefit of symptom relief. Many cytotoxic agents have been combined with GEM in search of regimens with improved survival benefit. However, there were only marginal benefits in people with good performance status. Recently, the combination regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) was found to achieve unprecedented survival benefit and has become the preferred option for patients with good clinical conditions. On the other hand, many biological agents have been combined with GEM, but only erlotinib was found to derive statistically significant survival advantage. However, the effect was too small to be appreciated clinically. The effort in development of targeted therapy in APC continues. This paper summarized key findings in the development of chemotherapy and targeted therapy for APC patients and discussed future directions in management.

Combinational therapy: New hope for pancreatic cancer?

Pancreatic cancer is a devastating disease with a low overall survival rate. Chemotherapy is the most common treatment for patients presenting with advanced pancreatic cancer. Gemcitabine achieves a modest improvement in overall survival and is the gold standard for advanced pancreatic cancer treatment. Capecitabine and S-1, derivatives of 5-fluorouracil (5-FU), offers minimal clinical benefits. Folfirinox represents a new and aggressive regimen that might benefit patients of metastatic pancreatic cancer with good performance status. Other chemotherapy drugs such as platinums and irinotecan do not provide significant improvement in overall survival, but have been used as part of combinational therapies. Comparing to systemically delivered chemotherapy, regional intra-arterial chemotherapy achieves higher local drug concentration in tumors with lower systemic drug toxicity, and may serve as a better treatment regimen. Although there have been progress made in chemotherapeutic strategies against pancreatic cancer, the overall survival is not significantly improved in the last decade. Recently, development of chemotherapy in combination with molecular targeted therapies holds great promise in pancreatic cancer treatment, especially in patients with metastatic disease. Growing bodies of preclinical and clinical evidences indicate that the combination of conventional modalities with specific molecular targeted therapy increase the efficacy of the monotherapy without an increase in toxicity. In this review, we summarized the current regimens of chemotherapy and molecular targeted therapy for advanced pancreatic cancer and highlighted the novel combinational treatments tested in recent clinical trials.

Mistletoe therapy for advanced pancreatic cancer. A group-sequential, randomised, open label study phase III ISRCTN 70760582

Mistletoe therapy for advanced pancreatic cancer. A group-sequential, randomised, open label study phase III ISRCTN 70760582

Pancreatic cancer: current standards, research updates and future directions.

Pancreatic cancer: current standards, research updates and future directions.