ASO Visual Abstract: Survival Benefit of Surgery Versus Oncology-Only Therapy in Artery-Involving Borderline Resectable and Locally Advanced Pancreatic Cancer.

Locally Advanced Non-Metastatic Pancreatic Cancer — Can We Do More?

FOLFIRINOX: A Small Step or a Great Leap Forward?

A Population-Based Model of Local Control and Survival Benefit of Radiation Therapy for Breast Cancer

Yet Another Nucleoside Analog for Pancreatic Cancer

The combination of gemcitabine with erlotinib is viewed as one standard in the treatment of patients with advanced pancreatic cancer. However, the magnitude of the survival benefit of the combination therapy compared to single agent gemcitabine is relatively small. Whether this statistically significant survival benefit translates to a relevant clinical benefit of the combined treatment in view of increased toxicity and costs is still a matter of debate. Consequently, there has been great interest in identifying molecular biomarkers predictive for response and survival benefit from EGFR-targeted agents in advanced pancreatic cancer. No data have been published up to now concerning the value of K-RAS mutations in pancreatic cancer as a predictive marker for lack of response to EGFR targeted agents. Nevertheless, the first prospective evaluation of K-RAS status and response to erlotinib in combination with either gemcitabine or capecitabine suggest a significant improvement of overall survival only for patients with K-RAS wild type tumors suggesting a possible role of K-RAS mutational status as predictive marker in pancreatic cancer.

Single agent gemcitabine has been the mainstay of therapy for advanced pancreatic cancer over the past decade. Multiple trials of newer chemotherapeutic agents both alone and in combination have yielded disappointing results, spurring the ongoing search for new agents and combinations in this aggressive malignancy. Inhibitors of the epidermal growth factor receptor (EGFR) have shown promising activity in multiple solid tumors types, and preclinical data support a role for EGFR inhibition in pancreatic cancer. A recent phase III study by the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) demonstrated a significant survival benefit with the addition of the EGFR tyrosine kinase inhibitor, erlotinib, to gemcitabine chemotherapy for the first-line treatment of patients with advanced pancreatic cancer, becoming the first phase III study to demonstrate a survival benefit of combination therapy as well as targeted therapy in this disease. This article reviews the evidence supporting EGFR inhibition and the use of erlotinib in advanced pancreatic cancer as well as future implications of targeted therapy in this challenging malignancy.

Therapeutic Advances in Pancreatic Cancer

Genomic sequencing to inform therapy in advanced pancreatic cancer: A systematic review and meta-analysis of prospective studies

Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial

BackgroundPancreatic cancer is considered as a chemoresistant neoplasm with extremely dismal prognosis. Gemcitabine is recommended as the standard agent for locally advanced or metastatic pancreatic cancer. A series of trials have been conducted to improve the outcome of advanced pancreatic cancer with other anticancer drugs in combination with gemcitabine. Unfortunately, the designers of the clinical trials failed to improve the poor prognosis of patients with advanced pancreatic cancer. Erlotinib was the first additional drug that improved the overall survival of patients with advanced pancreatic cancer with gemcitabine. We performed this systematic review and meta-analysis to explore the efficacy and safety of the combination of gemcitabine with erlotinib (GemErlo) for patients with advanced pancreatic cancer using the currently available evidence.MethodsPubMed/MEDLINE, EMBASE, the Cochrane Library, and relevant abstracts of major conferences were comprehensively searched. Data results on objective response rate, disease control rate, and 1-year survival were pooled by using MetaAnalyst with a random-effects model. Results on progression-free survival and overall survival were only summarized descriptively.ResultsA total of 24 studies with 1,742 patients with locally advanced or metastatic pancreatic cancer treated with GemErlo were included. Combined objective response rate was 14.4% (95% CI: 11.6%–17.7%), disease control rate was 55.0% (95% CI: 51.5%–58.5%), and 1-year survival rate was 28.5% (95% CI: 24.0%–33.4%). Progression-free survival ranged from 2.63 to 9.6 months, and overall survival varied from 6 to 10 months. As for the toxicity profile, the most common adverse events (AEs) were hematologic reactions, skin rash, and gastrointestinal reactions. Other severe AEs, which had low incidence, included treatment-induced death and interstitial lung disease.ConclusionOur study showed that GemErlo is associated with reasonable activity in treating patients with locally advanced or metastatic pancreatic cancer. Most of the AEs were tolerable, while some severe AEs needed careful detection.

Additional systemic treatments for locally advanced or metastatic pancreatic cancer are needed, as current treatment options produce only modest survival benefits. Rubitecan (Orathecin; Supergen Inc., Dublin, CA, http://www.supergen.com) is an orally active camptothecin derivative with demonstrated responses in patients with pancreatic cancer in early clinical trials. This phase II, open-label trial was developed to assess the safety and efficacy of rubitecan in patients with locally advanced or metastatic pancreatic cancer refractory to conventional chemotherapy. Fifty-eight patients with failed or relapsed advanced pancreatic cancer after receiving at least one prior chemotherapy regimen were enrolled to receive eight consecutive weeks of treatment with rubitecan at a dose of 1.5 mg/m2 orally on five consecutive days per week, followed by 2 days off therapy, repeatedly. The primary end point was response rate. Time to progression, overall survival, changes in CA19-9 levels, and the composite measure of clinical benefit response were evaluated as secondary end points. Among 43 patients with measurable disease, 7% (3/43) achieved partial responses and 16% (7/43) had disease stabilization for an overall response and disease stabilization rate of 23%. All responses were confirmed by independent radiology review. Median survival was longer in responding patients than in the overall study cohort (10 months versus 3 months). Gastrointestinal and hematologic toxicities were the most commonly reported adverse events. Oral rubitecan produced responses and was well tolerated by heavily pretreated patients with refractory pancreatic cancer. The overall risk-benefit profile of oral rubitecan appears promising, supporting further evaluation in phase III trials in patients with refractory and chemotherapy-naive pancreatic cancer.

Pancreatic cancer: cause for optimism?

The incidence of pancreatic cancer has increased in recent years, and the mortality has ranked the third among malignant tumors. Advances have been made in the diagnosis and treatment of pancreatic cancer in the past decade, however, the current situation is still severe due to the uneven medical level in different regions of China. In 2018, Pancreatic Cancer Committee of Chinese Anti-cancer Association formulated the "Chinese comprehensive guidelines for the diagnosis and treatment of pancreatic cancer (2018 version)", with the view for standardizing and improving the level of diagnosis and treatment of pancreatic cancer in China. In 2020, the committee worked out the latest version of "Chinese comprehensive guidelines for the diagnosis and treatment of pancreatic cancer (2020 version)", based on the development in the past two years. These updates were mainly reflected in the following aspects: breakthroughs in targeted therapy and immunotherapy, and genetic screening and genetic sequencing has been firstly applied in the comprehensive diagnosis and treatment of pancreatic cancer. The practicability and accuracy of the 8th edition of AJCC-TNM staging system for pancreatic cancer has been validated in multi-center of China and has been used in clinical practice. Preoperative neoadjuvant therapy has become the standard treatment for borderline resectable and locally advanced pancreatic cancer, and it is gradually applied to the resectable pancreatic cancer. The surgical exploration after neoadjuvant therapy is particularly important. Chemotherapy-based systemic treatment modality, including targeted therapy and immunotherapy, has been carried out in clinical trial setting, and the benefits of maintenance therapy have been confirmed in advanced pancreatic cancer. The multi-disciplinary and multi-regional collaborative diagnosis and treatment pattern is widely popularized in China and runs through the entire diagnosis and treatment process. The development of domestic clinical trials and multi-center, cross-regional cooperation provides high-level evidence of evidence-based medicine for the new drug development and regimen optimization of pancreatic cancer. By incorporating the above latest advances into the new guideline, we aim to provide further guidance for the comprehensive diagnosis and treatment of pancreatic cancer in China.

15523 Background: Most patients (pts) with pancreatic cancer present with advanced disease with a survival range of about 6–7 months (mo). Currently gemcitabine (gem) or gemcitabine plus erlotinib is standard treatment for pts with advanced pancreatic disease. The benefits of combination therapy with gemcitibine have been modest. Nab-paclitaxel (nab-pac) is a novel formulation of paclitaxel approved for the treatment of breast cancer. It allows for the preferential delivery of active drug to the site of the tumor, as demonstrated in many preclinical tumor models. In this phase I study, the combination of nab-pac and gem in pts with pancreatic cancer is evaluated. Methods: Pts with no prior chemotherapy except as a radiation sensitizer received nab-pac + gem on days 1, 8, 15 every 28 days, with a dose of 100 mg/m2 and 1,000 mg/m2 respectively in this modified Phase I trial (cohort 1). Cohort 2 (nab-pac 125 mg/m2) is ongoing. Results: 20 pts have been enrolled on cohort 1. All are evaluable for toxicity, 16 for response. Pts had a median (med) age 57 (30–86); gender: M:F 55%/45%. (Med cycles administered 5 (range 1–8). Response by radiographic review and RECIST criteria was assessed in 16 pts: 9 PR, 6 SD, 1 PD. The med cycles to response was 2 (1 -5). The MTD has not been reached and a DLT has not been reached. The most frequent Grade 3/4 adverse event (AE) was neutropenia (n=3, 2, respectively). Other grade 3 AEs include febrile neutropenia (1), fatigue (1) and hyperglycemia (1). In addition, 2 cases of grade 2 anemia and 2 cases of thrombocytopenia were observed. To date, no grade 3/4 sensory neuropathy was observed. Additional follow up data on cohort 1 and results from cohort 2 will be presented. Conclusions: These preliminary results suggest that nab-pac in combination with gem is very active in pts with advanced pancreatic cancer. Toxicities were tolerable and manageable. This combination will be further evaluated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Concordia, Genentech™ BioOncology Abraxis, Bunso, Cell Genesys, Cenis, Concordia, Genentech™ BioOncology, Genvec

e13049 Background: WT1 is expressed in various kinds of cancers and serves as a potent antigen for cancer immunotherapy. Methods: We performed a clinical phase I trial of gemcitabine (GEM) and WT1 vaccine combination therapy for advanced pancreatic cancer or biliary tract cancer. Patients with HLA-A 0201, HLA-A 0206, and/or HLA-A 2402 positive inoperable advanced pancreatic or biliary tract cancer, who has not received GEM previously were eligible. Six doses of GEM and 4 doses of WT1 vaccination were administered with the following schedule in 2 months: GEM (1000 mg/m2) was administered intravenously on days 1, 8, and 15 with 1-week rest. WT1 peptide (1 mg or 3 mg) in Montanide adjuvant was injected intradermally on day 8 and day 22. Results: Between November 2007 and September 2009, 25 patients (13 male, 12 female) were enrolled in this study. Nine patients had inoperable advanced pancreatic cancer, 8 had gallbladder cancer, 4 had intrahepatic bile duct cancer, and 4 had extrahepatic bile duct cancer. Out of 18 patients who completed the study 15 had stable disease and 3 had progressive disease at the end of this study. Seven patients could not complete the study, because of rapid disease progression (6) or patient's preference (1). Grade 1 or 2 skin reaction at the site of vaccination was observed in all patients. Patients also experienced grade 1 to 4 cytopenia, which was considered to be caused by GEM. No other adverse events above grade 3 were seen. The median survival time and disease control rate at 2 months for overall patients, pancreatic cancer, gallbladder cancer, intrahepatic bile duct cancer, and extrahepatic bile duct cancer were 275 days, 193 days, 196 days, 374 days, 225 days, and 64%, 89%, 25%, 100%, 50%, respectively. Although WT1-specific T cells were not detectable in the fresh whole blood either by multimer assay or intracellular IFN-γ staining, tetramer analysis of peptide cultured cells showed an expansion of WT1 specific T cells in 59% (13/22) of the patients. Conclusions: GEM and WT1 vaccine combination therapy is safe enough to be applied to patients with advanced pancreatic or biliary tract cancer, and that may provide a long-term survival in some patients. No significant financial relationships to disclose.