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Background: In 2004, the European Study Group for Pancreatic Cancer (ESPAC)-1 long-term data concluded that adjuvant chemotherapy provided a survival benefit for patients with pancreatic ductal adenocarcinoma (PDAC), whereas adjuvant chemoradiation was associated with worse overall survival. In this study, we investigated how long it took for US practice patterns to change following this trial., Methods: The National Cancer Database was used to identify patients with stage I-III PDAC who underwent R0 or R1 resection followed by adjuvant chemotherapy or chemoradiation between 1998 and 2015. A multivariate analysis was performed to determine predictors of receiving adjuvant chemoradiation in the post-ESPAC-1 era., Results: Between 1998 and 2015, adjuvant chemotherapy use increased from 2.9% to 51.6%, whereas adjuvant chemoradiation decreased from 49.5% to 22.9%. In 2010, adjuvant chemotherapy utilization surpassed that of chemoradiation. For patients diagnosed in the post-ESPAC-1 era, adjuvant chemotherapy (n = 7733) and chemoradiation (n = 6969) groups were compared. Patients who underwent adjuvant chemoradiation were younger, had private insurance, underwent surgery at nonacademic centers, and had more pathologically advanced cancers (all P < 0.01). After 2010, R1 resection was the strongest independent predictor of adjuvant chemoradiation use by multivariate analysis (OR 2.05, CI 1.8-2.3, P < 0.01)., Conclusions: Adjuvant chemotherapy use exceeded that of adjuvant chemoradiation 6 y after the final publication of ESPAC-1 in 2004, highlighting the challenges of disseminating and adopting clinical data. After 2010, R1 disease was the most significant predictor of receiving adjuvant chemoradiation. Prospective studies are underway to definitively address the role of adjuvant chemoradiation in PDAC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Remarkable progress has been made in treating pancreatic cancer over the past century, including refinement of our surgical techniques and improvements in adjuvant and neoadjuvant therapies. Despite these advances, the incidence of pancreatic cancer is rising globally, and it remains a deadly disease. In this review, we highlight the historical perspectives of pancreatic cancer treatment and outline the areas of future advancement that will assist progression towards better outcomes. Areas of future advancement include improving prevention strategies and early detection, refining our molecular understanding of pancreatic cancer, identifying more effective systemic therapies, and improving quality of life and surgical outcomes. Furthermore, systems need to be put in place to ensure all patients with pancreatic cancer receive high quality care and are given the appropriate options and sequence of therapy. This is best achieved through multidisciplinary care.

The surgical treatment of pancreatic cancer (PDAC) has seen sweeping changes during the past 5 decades. Up to the middle of the 20th century resection rates were below 5%, but the numbers of curative resections for PDAC are now continuously increasing due to improved neoadjuvant treatment concepts as well as progress in surgical techniques and perioperative management. During the same period, mortality rates after pancreatic surgery have decreased considerably and are now less than 5%. One of the most important cornerstones of reduced mortality has been the concentration of PDAC surgery in specialized centers. In addition, the management of postoperative complications has improved greatly as a result of optimized interdisciplinary teamwork. Adjuvant chemotherapy has become the reference treatment in resected PDAC, achieving significantly prolonged survival. Moreover, the concept of borderline resectable PDAC has emerged to characterize tumors with increased risk for tumor-positive resection margins or worse outcome. The best treatment strategy for borderline resectable PDAC is currently under debate, whereas neoadjuvant therapy has become established as a beneficial treatment option for patients with locally advanced PDAC, enabling conversion surgery in up to 60% of cases. This review article summarizes the principal changes in PDAC surgery during the past 50 years.

Background: Neoadjuvant chemotherapy (NAC) is increasingly utilized to optimize survival in proximal pancreatic adenocarcinoma. However, few studies have explored the impact of NAC in distal pancreas cancer., Methods: Patients with resectable pancreatic adenocarcinoma of the body or tail treated with either upfront pancreatectomy or NAC followed by surgery were identified in the 2006-2014 National Cancer Database. Trends in utilization, predictors of use, and impact of NAC on overall survival were determined., Results: Of 1485 patients, 176 (11.9%) received NAC. Use of NAC increased from 9.3% in 2006 to 16.9% in 2013 [odds ratio 1.14; 95% confidence interval (CI) 1.05-1.24; p = 0.001]. NAC patients were younger, had higher clinical stage, and preoperative CA 19-9 levels (all p < 0.05). After adjustment for patient-, tumor-, and treatment-related factors, increased clinical stage was the greatest independent predictor of neoadjuvant approach (p < 0.001). On multivariable analysis, survival benefit from NAC did not reach threshold of significance (95% CI 0.66-1.04; p = 0.10) for the entire cohort. However, NAC was associated with a significant survival advantage in clinical stage III with a 51% decreased yearly risk of death (adjusted hazard ratio 0.49; 95% CI 0.25-0.98; p = 0.04). A trend towards improved survival with NAC was observed among stage IIA (p = 0.09) and IIB (p = 0.07) patients., Conclusions: Neoadjuvant chemotherapy is associated with improved overall survival in Stage III distal pancreatic adenocarcinoma and shows promise in earlier stage disease. However, only a small percentage of patients receive NAC. Prospective evaluation of NAC in distal pancreatic adenocarcinoma is warranted based on these findings.

Purpose: In recent years, significant progress in survival has been achieved using systemic combination chemotherapy in patients with pancreatic cancer. However, the elderly are largely underrepresented in clinical trials, and gains made from these may not necessarily apply to this important subgroup of patients. We review the currently available data regarding contemporary combination chemotherapy regimens, including FOLFIRINOX, gemcitabine plus nab-paclitaxel, nanoliposomal irinotecan plus 5-fluorouracil and leucovorin, and gemcitabine plus capecitabine, in elderly pancreatic cancer patients., Methods: We performed a search of Pubmed using the terms "pancreatic cancer", "elderly", "FOLFIRINOX", "gemcitabine", "nab-paclitaxel", "capecitabine", and "nanoliposomal irinotecan" and included articles investigating the use of combination chemotherapy in the elderly with pancreatic adenocarcinoma. Relevant abstracts from American Society of Clinical Oncology and European Society of Medical Oncology meetings were included., Results: Current clinical evidence and experience suggests that relatively fit elderly pancreatic cancer patients may derive significant benefit from contemporary combination chemotherapy regimens. Strategies to improve tolerability without decreasing efficacy include dose reduction, schedule modification, and growth factor support. Phase III clinical trials are ongoing to determine the optimal use of combination chemotherapy regimens in elderly patients with pancreatic cancer., Conclusion: Identifying elderly patients who will benefit from combination chemotherapy for pancreatic cancer remains a significant clinical challenge. An assessment of medical comorbidities and functional status plays a key role in determining fitness for intensive chemotherapeutic regimens in this important subset of patients.

Background: Multiple prospective, randomized trials have demonstrated that the addition of adjuvant therapy after surgical resection of pancreatic cancer improves survival compared to surgery alone. However, the optimal type of adjuvant therapy, chemotherapy alone, or chemotherapy combined with chemoradiation therapy remains controversial. Our aim was to examine the treatment trends for surgically resectable (stages I and II) pancreatic cancer in the USA using the National Cancer Database., Methods: The National Cancer Database (NCDB) is a national oncology outcomes database for over 1,500 Commission on Cancer accredited cancer programs. Patients diagnosed with stage I-II pancreatic adenocarcinoma between 2003 and 2010 were selected from the NCDB Hospital Comparison Benchmark Reports. Attention was paid to the initial treatment regimen, such as surgery alone, surgery plus chemotherapy, or surgery plus chemoradiation. In addition, data on hospital setting (teaching hospitals vs. community hospitals) were collected and analyzed. The Cochran-Armitage test for trend was used to assess changes in treatment over time., Results: Fifty-nine thousand ninety-four patients with stage I-II pancreatic adenocarcinoma were included in the analysis. Between 2003 and 2010, the use of surgery alone as first course treatment of stage II disease decreased significantly at both teaching hospitals and community hospitals among patients who underwent surgery (P < 0.0001 for both cases). In the same period, the use of chemotherapy in addition to surgery as treatment of stage I and II disease increased at least twofold at both hospital settings (P < 0.0001 for all cases). Treatment with surgery plus chemoradiation decreased significantly for both stages in both hospital settings (P < 0.0001 for all cases). Nonsurgical treatment for stage II disease was surprisingly high and significantly increased over time (P < 0.001 for both hospital types), ranging from approximately 30-37 % at teaching hospitals and 39-47 % at community hospitals., Conclusion: Data from the NCDB from 2003 to 2010 illustrate changes in the adjuvant treatment of pancreatic cancer. The use of chemotherapy alone as adjuvant therapy increased whereas the use of multimodality therapy decreased. In addition, there remains an alarmingly high rate of nonsurgical therapy for stage I and II disease.

Most patients with adenocarcinoma of the pancreas present with locally advanced or metastatic disease. Although single agent gemcitabine is widely accepted as first-line therapy, there is no current standard of care for gemcitabine-refractory patients. Common second-line chemotherapy regimens included oxaliplatin and 5-FU/leucovorin (OFF), gemcitabine and oxaliplatin (GEMOX), oxaliplatin and capecitabine (XELOX), and irinotecan-oxaliplatin. At the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting, several new second-line chemotherapy regimens were presented, including gemcitabine and oxaliplatin with imatinib, single agent nab-paclitaxel, and the combination of high-dose capecitabine with oxaliplatin and sorafenib. These abstracts provide exciting new directions for the treatment of gemcitabine-refractory advanced pancreatic cancer.

Background: Pancreatic cancer is the fourth leading cause of cancer-related death in the US. However, there is a growing belief that novel biological agents could improve survival of patients with this cancer. Gemcitabine-based chemotherapy remains the cornerstone treatment for advanced pancreatic cancers. So far, the current targeted agents that have been used in combination with gemcitabine have failed to improve clinical outcomes. This failure may stem from the heterogeneous molecular pathogenesis of pancreatic cancers, which involves several oncogenic pathways and defined genetic mutations., Objective: The aims of this review are: i) to define the existing treatments available at present for patients with pancreatic cancers in the neo-adjuvant, adjuvant, locally advanced and metastatic settings; ii) to highlight the molecular heterogeneity of the cancers and the rationale for targeting specific oncogenic pathways; iii) to give an overview of targeted agents that may potentially have an impact in the treatment of pancreatic cancers., Conclusions: Molecular pathogenesis of pancreatic cancer involves several pathways and defined genetic mutations. Targeting these complex molecular pathways with a combination of novel biological and chemotherapeutic agents could potentially improve patient outcome.

Pancreatic cancer has a very high mortality rate and affects approximately 230,000 individuals worldwide. Gemcitabine has become established as the standard therapy for advanced pancreatic cancer; however, the survival advantage is small. Adjuvant chemotherapy using either 5-fluorouracil or gemcitabine is now established in pancreatic cancer as an alternative therapy. Combinations of gemcitabine with either platin agents or capecitabine may be advantageous. Anti-EGFR and anti-VEGF agents have been unsuccessful but multiple tyrosine kinase inhibitors are under investigation. Of the increasing number of immunological agents, the GV1001 antitelomerase vaccine holds some interest. Targeted agents against important mitogenic pathways, including MEK/ERK, Src, PI3K/Akt, mTOR, Hedgehog and NF-kappaB, as well as agents targeting histone deacetylase, poly(ADP-ribose) polymerase, heat shock protein 90 and other agents such as beta-lapachone, hold considerable interest for further development. However, the probability of individual success is low.

Background: Pancreatic cancer is an aggressive malignancy with a dismal prognosis. Radical surgery provides the only chance for a cure with a 5-year survival rate of 7%-25%. An effective adjuvant therapy is urgently needed to improve the surgical outcome. This review describes the current status of adjuvant therapy for pancreatic cancer, and highlights its controversies., Data Sources: A Medline database search was performed to identify relevant articles using the keywords "pancreatic neoplasm", and "adjuvant therapy". Additional papers were identified by a manual search of the references from the key articles., Results: Eight prospective randomized controlled trials (RCTs) on the use of adjuvant chemotherapy and chemoradiation for pancreatic cancer could be identified. The results for adjuvant regimens based on systemic 5-fluorouracil with or without external radiotherapy were conflicting. The recent two RCTs on gemcitabine based regimen gave promising results., Conclusions: Based on the available data, no standard adjuvant therapy for pancreatic cancer can be established yet. The best adjuvant regimen remains to be determined in large-scale RCTs. Future trials should use a gemcitabine based regimen.

Ductal adenocarcinoma of the pancreas is one of the leading causes of cancer death in the UK, Europe and US, with incidence closely paralleling mortality. Until recently, enthusiasm for treating these patients was limited for a number of reasons: the majority of patients undergoing surgery would relapse early, adjuvant treatment was of unproven value and systemic therapy in advanced disease had only a small chance of a short-term benefit. More recently, however, it has become recognised that specialist surgery can improve results and there is evidence that adjuvant chemotherapy has a significant advantage in terms of 5-year survival. In particular adjuvant systemic 5-fluorouracil with folinic acid can result in 5-year survival of < or = 29% (compared with 11% for controls) and adjuvant gemcitabine can improve disease-free survival to 13.4 months from a median of 6.9 months in controls, but not overall survival. In contrast the role of adjuvant chemoradiation in addition to chemotherapy remains unproven and the survival results appear to be inferior to systemic chemotherapy alone. New agents, such as capecitabine and erlotinib, are emerging with some activity in this dismal disease signalling hope for the future.

This article summarizes the important past and ongoing adjuvant therapy trials for pancreatic cancer. The recent developments in the fields of radiosensitization, chemotherapy, and molecular-targeted therapy are outlined. Finally, the future study strategies for adjuvant therapy trials are discussed.

This article summarizes the results of recent studies using newer agents, including farnesyl transferase inhibitors, matrix metalloproteinase inhibitors, inhibitors of the epidermal growth factor pathway, antiangiogenic therapeutics by inhibition of vascular endothelial growth factor, and some forms of immunotherapy. Although some results have been disappointing, others seem to be promising, serving as a basis for planned larger trials.

Background: The incidence of pancreatic cancer nearly equals its death rate (97%). Two-year survival is about 10%. Chemotherapy treatment is problematic because of the palliative and limited duration of response., Material and Methods: The article analyzes the objective response and median survival time (MST) for old and new drugs in the treatment of pancreatic cancer., Results: The most encouraging results to date come from studies of 5-fluorouracil (5FU) as an adjuvant therapy and of gemcitabine in the advanced disease, which is one of the most active and best tolerated drugs in recent years. However, with the introduction of new drugs or with different old drug associations, interesting results are also becoming evident., Conclusions: New approaches to CT treatment are necessary. Patient enrollment into rigorous and well conducted clinical trials, either at tumor diagnosis or after tumor recurrence, will generate new information regarding investigational therapies and it will offer improved therapies for patients with this disease.

In western countries, carcinoma of the pancreas remains the most lethal of the common malignancies. Even the favorable "organ-confined" tumors present a considerable challenge. The lack of anatomic barriers to local infiltration and the biological propensity for early lymphatic, perineural, and vascular invasion are nearly insurmountable obstacles to complete surgical eradication of this malignancy. Various combinations of chemotherapy and radiotherapy (RT) have been used with marginal but measurable success. Earlier trials conducted by the Gastrointestinal Tumor Study Group established roles for 5-fluorouracil chemotherapy and RT in the treatment of patients with resectable or locally advanced pancreatic cancer. More recently, computed tomography-guided conformal RT and a variety of intraoperative RT techniques have enabled more reliable sterilization of the local surgical field and escalation of doses to potentially curative levels (7000 cGy) for unresectable lesions. Chemotherapy dose intensification through the use of portable programmable pumps for protracted venous infusions and the development of active systemic agents in addition to 5-fluorouracil suggest that an effective combination chemotherapeutic regimen might soon be developed. This report reviews the current standards of practice and integrates recent developments to construct a modern algorithm for the use of chemoradiotherapy in the management of localized (nonmetastatic) pancreatic cancer. The likely directions of future investigations are also discussed.

Only 5% to 15% of patients with pancreatic adenocarcinoma are candidates for a potentially curative resection. Evidence that postoperative adjuvant therapy improves outcome has been limited to a single randomized trial of a well tolerated split-course, 5-Fluorouracil (5-FU) based, chemoradiation regimen. More aggressive regimens have since been developed and are associated with, at best, a modest improvement in patient outcome. The potentially significant morbidity associated with pancreaticoduodenectomy, which can compromise the delivery of postoperative adjuvant chemoradiation, has led to the development of preoperative (adjuvant/neoadjuvant chemoradiation) regimens in these patients. Although experience suggests that such an approach is feasible, the ultimate impact warrants further evaluation. In addition, despite evolving experiences towards more dose intensive pre or postoperative adjuvant chemoradiation regimens, the problem of distant metastases remains significant. New chemotherapeutic agents, such as gemcitabine, appear to have the potential to produce better results than those achieved over the last quarter century with 5-FU. A cooperative group study has recently been activated and is evaluating its impact in an adjuvant setting when given in addition to 5-FU based chemoradiation. In the meantime, ongoing investigations into optimal integration of different therapeutic modalities, along with advances in surgery, radiation, and systemic therapy, should lead us towards further improvements in outcomes for these patients.