Novel approaches to target pancreatic cancer

Despite remarkable progress that has been made in the recent years in the treatment of gastrointestinal tumors, in particular colorectal cancer, the prognosis of pancreatic cancer remains dismal. Five years after diagnosis almost all patients have died. At early stages of the disease surgery is the only modality to achieve long term survival. In the palliative setting gemcitabine confers some benefit to patients with advanced pancreatic cancer. A large number of chemotherapy combinations has been tested in patients with advanced pancreatic cancer. Only one combination showed significant improvement of survival, however also increased toxicity. The introduction of targeted therapies raised hopes for a better treatment of pancreatic cancer. However, most of the compounds tested so far failed to improve the survival of patients with pancreatic cancer. This review summarizes molecular targets examined so far in pancreatic cancer including matrix metalloproteinase inhibitors, farnesyltransferase inhibitors, vascular endothelial growth factor and epidermal growth factor receptor inhibitors and points out novel promising strategies for this difficult-to-treat tumor.     

New directions in the management of advanced pancreatic cancer: a review

Complete surgical resection is the only potentially curative option for pancreatic cancer. However, most patients have advanced/metastatic disease at the time of diagnosis, or will relapse after surgery. Systemic chemotherapy is only palliative. Gemcitabine-based therapy is an acceptable standard for unresectable locally advanced/metastatic pancreatic cancer, but average median survival is only 6 months. The addition of other chemotherapies (including other antimetabolites, platinum, and topoisomerase I inhibitors) or targeted therapies (farnesyl transferase inhibitors, metalloproteinase inhibitors, cetuximab and bevacizumab) to gemcitabine has failed to improve outcome. The combination of gemcitabine and erlotinib, a small-molecule tyrosine kinase inhibitor of the human epidermal growth factor receptor, was recently approved by the US/European authorities for use in advanced disease. In a phase III trial, the combination demonstrated a significant improvement in overall survival compared with gemcitabine monotherapy. Positive efficacy results have also been observed in a phase III trial, favoring the addition of capecitabine to gemcitabine compared with gemcitabine alone. This review focuses on the recent developments in systemic treatment, and discusses how novel agents might be incorporated into future treatment strategies for pancreatic cancer.     

Advanced or metastatic pancreatic cancer: molecular targeted therapies

Patients with pancreatic cancer normally present with advanced disease that is lethal and notoriously difficult to treat. However, clinical developments over the past decade have been modest and advances are incremental at most. The core drug and the backbone of treatment in all settings of pancreatic adenocarcinoma-adjuvant, locally advanced, and metastatic-remains gemcitabine. The past decade of research focused initially on combining cytotoxic therapies with gemcitabine, and during that time a large number of studies have been published that aimed to target the molecular abnormalities implicated in pancreatic tumor growth, invasion, metastasis, angiogenesis, and resistance to apoptosis. This research is of particular importance, as data suggest that a large number of genetic alterations affect only a few major signaling pathways and processes involved in pancreatic tumorigenesis. Although laboratory results of targeted therapies have been impressive, until now only erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has demonstrated marginal survival benefit in combination with gemcitabine in phase III clinical trials. Even though the failures of targeted therapies in the clinical setting are discouraging, it is reasonable to surmise that major progress will evolve as the molecular biology of pancreatic adenocarcinoma continues to be unraveled. This review describes some of the important developments and targeted agents for pancreatic cancer that have been tested in clinical trials.     

Emerging drugs in pancreatic cancer

Improving survival in patients with pancreatic cancer remains a formidable challenge. For the few patients with localised stages of the disease, intra-operative radiotherapy, adjuvant chemoradiotherapy and neo-adjuvant therapies remain non-validated and the survival benefit conferred by 5-fluorouracil-folinic acid adjuvant chemotherapy over radical surgery alone is still a matter of debate. Gemcitabine has recently emerged as the standard single agent in advanced stages of the disease and pharmacokinetic refinements such as the use of a fixed-dose infusion rate may further improve still rather modest result figures. At present, most efforts deal with the development of more effective doublet or triplet therapies, combining gemcitabine with either conventional cytotoxic drugs--the most promising being oxaliplatin--or more innovative, targeted therapeutic agents. Among these agents, matrix metalloprotease inhibitors and farnesyltransferase inhibitors have already undergone Phase III trials, alone or in combination with gemcitabine, with rather disappointing results. However, preclinical and Phase I and II studies of cyclooxygenase-2 or lipoxygenase inhibitors, various immunotherapeutic approaches and several tyrosine kinase inhibitors or monoclonal antibodies against growth factors or their receptors are encouraging and may provide some hope for patients with pancreatic cancer.     

Targeting EGFR in pancreatic cancer treatment

The prognosis of patients with pancreatic cancer is extremely poor, and current systemic therapies provide marginal survival benefits for treated patients. The era of targeted therapies has offered a new avenue to search for potentially more effective strategies. Epidermal growth factor receptor (EGFR) is a member of the erbB/human epidermal growth factor receptor family of tyrosine kinases, which includes erbB2/HER2, erbB3/HER3 and erbB4/HER4. Epidermal growth factor receptor overexpression may be detected in up to 90% of pancreatic tumors. Two pharmacologic approaches have been successfully used to inhibit epidermal growth factor receptor function in cancer treatment: neutralizing monoclonal antibodies and small molecule tyrosine inhibitors. The randomized trials studying the addition of EGFR targeted agents to gemcitabine compared with gemcitabine alone have been disappointing, although results with the EGFR tyrosine kinase inhibitor erlotinib were statistically significant but clinically of marginal benefit. In this article, we review the epidermal growth factor receptor signaling network in pancreatic cancer, the strategies to increase the effectiveness of epidermal growth factor receptor inhibitors, and the clinical trials of these inhibitors in pancreatic cancer.     

Cytotoxic chemotherapy for pancreatic cancer: Advances to date and future directions

Chemotherapy remains the mainstay of treatment for pancreatic cancer as most patients present with advanced disease, which precludes locoregional treatment. However, the efficacy of chemotherapy is limited. Gemcitabine is the only agent that improves symptoms and confers a modest survival advantage. Many combination therapy regimens have been studied in phase II settings. Eleven randomised phase III trials have been conducted to compare gemcitabine-containing regimens with gemcitabine monotherapy since gemcitabine became available clinically. The combination of gemcitabine plus capecitabine has demonstrated a survival advantage over gemcitabine, whereas gemcitabine plus oxaliplatin and gemcitabine plus cisplatin have shown improved progression-free survival or time to tumour progression but failed to demonstrate a survival advantage over gemcitabine. The search for effective therapy for advanced pancreatic cancer continues. Gemcitabine in combination with cytotoxic agents or molecular targeted agents hold promise.     

Neoadjuvant therapy for resectable and borderline resectable adenocarcinoma of the pancreas

For over 25 years, the standard of care for resectable pancreatic adenocarcinoma has been upfront surgery followed by delivery of post-operative therapy. Until recently however, there has been no consensus as what constituted a standard adjuvant regimen. Data from large phase III studies now support single agent gemcitabine, administered over 6 cycles, as standard. Nevertheless, the overall survival of patients undergoing upfront surgical resection followed by adjuvant therapy remains poor, with no significant improvements in median, or long term survival over the last 3 decades. Surgery as the first intervention for potentially curative pancreatic cancer has some distinct disadvantages and neoadjuvant therapy provides a mechanism to better select patients for subsequent surgical intervention. Current data suggest this approach spares patients from a morbid surgical procedure when it will be of no benefit and improves outcomes for those who do undergo surgery. Furthermore, with the increasing recognition of borderline resectable pancreatic cancer, neoadjuvant treatment should be considered as alternative to upfront surgery for this distinct clinical entity. This has the potential to maximize the chances of a margin-negative resection and minimize the number of patients harboring aggressive disease from undergoing a fruitless surgical procedure. Importantly, as the number of targeted agents available for clinical use expands, more rational, personalized neoadjuvant therapies may emerge.     

Novel non-operative treatment and treatment strategies in pancreatic cancer

Patients with advanced pancreatic cancer have traditionally been treated with palliative care only. The last decade has seen significant improvements in the surgical treatment of this disease but until the late 1990s there was no effective non-surgical treatment for these tumours. The introduction of gemcitabine has given clinicians treating patients with pancreatic cancer a new option. The published randomised data of gemcitabine in patients with pancreatic cancer has shown both a small survival advantage and significant improvements in quality of life indicators in these patients. These data have stimulated a resurgence of interest in pancreatic tumours and several studies have been or are currently investigating novel treatments or treatment strategies. The explosion in the molecular knowledge of cancer has led to the development of several ‘molecular designer drugs’ that have been tested in pancreatic cancer. The furthest advanced of these is a matrix metalloproteinase (MMP) inhibitor called marimastat. The first randomised data using this new class of agents is increasing and suggests that marimastat may have a role in the future treatment of patients with pancreatic cancer. Other agents such as gastrimmune, are about to enter Phase III studies and several other molecular treatment strategies are progressing from the in vitro stage towards the clinical arena. Each of these treatments and treatment regimens are discussed along with their current progress.     

Novel non-operative treatment and treatment strategies in pancreatic cancer

Patients with advanced pancreatic cancer have traditionally been treated with palliative care only. The last decade has seen significant improvements in the surgical treatment of this disease but until the late 1990s there was no effective non-surgical treatment for these tumours. The introduction of gemcitabine has given clinicians treating patients with pancreatic cancer a new option. The published randomised data of gemcitabine in patients with pancreatic cancer has shown both a small survival advantage and significant improvements in quality of life indicators in these patients. These data have stimulated a resurgence of interest in pancreatic tumours and several studies have been or are currently investigating novel treatments or treatment strategies. The explosion in the molecular knowledge of cancer has led to the development of several 'molecular designer drugs' that have been tested in pancreatic cancer. The furthest advanced of these is a matrix metalloproteinase (MMP) inhibitor called marimastat. The first randomised data using this new class of agents is increasing and suggests that marimastat may have a role in the future treatment of patients with pancreatic cancer. Other agents such as gastrimmune, are about to enter Phase III studies and several other molecular treatment strategies are progressing from the in vitro stage towards the clinical arena. Each of these treatments and treatment regimens are discussed along with their current progress.     

Novel targeted therapies for the treatment of penile cancer

Introduction: The treatment of penile cancer has changed over the past decade in that it was primarily a surgically managed disease and those with locally advanced or metastatic disease uniformly had a very poor prognosis. However, with the use of better traditional systemic chemotherapeutic agents in the neoadjuvant and adjuvant settings, the disease-specific survival and general outlook has improved. However, there is still a large group of patients who will progress even while on systemic therapy. It is in those patients where the application of targeted therapies has been investigated with some experiencing partial or even complete responses. With the improvement seen in patients with chemotherapy refractory disease, the application of novel targeted agents in the neoadjuvant setting may have a resultant positive impact on patient survival.

Areas covered: This review includes research pertaining to targeted therapies, biomarkers and signaling pathways involved with penile cancer. The article was based on a literature search using the keywords ‘penile cancer’ and ‘targeted therapies’.

Expert opinion: Penile cancer at the advanced stages of the disease has a high mortality. The utilization of novel targeted therapies in these situations is warranted in combination with, or sequentially with, traditional cytotoxic chemotherapy to improve the patient survival rate. Personalized therapy is nearly here for penile cancer and should be made real within the next decade.     

Anti-angiogenic agents in pancreatic cancer: a review

Pancreatic cancer is the fourth leading cause of cancer related death in the United States, with a 5-year survival of less than five percent. Since the majority of patients have locally advanced or metastatic disease at the time of diagnosis, there has been little progress made to extend survival. For over ten years, chemotherapy with gemcitabine has been standard treatment for those patients with advanced pancreatic cancer, prolonging survival by only 5-6 months. To improve upon this modest benefit, several investigations have explored other strategies aimed at curbing pancreatic cancer growth. Because pancreatic cancer has been found to have a profoundly hypoxic environment with high vascular in-growth, several agents have been developed to target the angiogenesis process. Major emphasis has been placed on anti- vascular endothelial growth factor (VEGF) models and the epidermal growth factor receptor (EGFR) signaling pathway. Over the past several years, a number of phase II and phase III trials have combined gemcitabine with these novel treatments, with the hope of prolonging survival in patients with pancreatic cancer. This review will discuss these therapies and their potential application in a clinical setting.     

Conventional chemotherapy of advanced pancreatic cancer

The vast majority of patients with pancreatic cancer present with locally advanced unresectable or metastatic disease, and in this setting only a palliative treatment can be offered. Single-agent gemcitabine has been considered the standard chemotherapy for patients with advanced pancreatic cancer since the results of a pivotal phase III trial showing superior clinical benefit compared to bolus 5-fluorouracil were published in 1997. In recent years, many randomized trials have attempted to improve results obtained with gemcitabine exploring a different schedule (fixed dose rate) of its administration, or testing the addition of one or more drugs to gemcitabine. Unfortunately, none of these trials produced a statistically significant and clinically relevant improvement in overall survival compared to the standard. A randomized phase III trial has recently shown a survival advantage using a combination of more drugs (FOLFIRINOX: irinotecan, oxaliplatin, folinic acid and 5-fluorouracil) compared to single-agent gemcitabine, suggesting that regimens without gemcitabine can be successfully used in patients with advanced pancreatic cancer. FOLFIRINOX was associated with worse toxicity than gemcitabine, and the available data suggest that this regimen may be considered for patients with metastatic pancreatic cancer who are fit enough to withstand potential side effects. The best option for these patients remains the enrolment in prospective clinical trials. Improvements in the treatment of the advanced disease will possibly derive from new combinations or from new drugs, but certainly from a better knowledge of the multiple molecular pathways implicated in pancreatic carcinogenesis and in invasion and metastasis.     

Molecular targeted approaches for treatment of pancreatic cancer

Human pancreatic cancer remains a highly malignant disease with almost similar incidence and mortality despite extensive research. Many targeted therapies are under development. However, clinical investigation showed that single targeted therapies and most combined therapies were not able to improve the prognosis of this disease, even though some of these therapies had excellent anti-tumor effects in pre-clinical models. Cross-talk between cell proliferation signaling pathways may be an important phenomenon in pancreatic cancer, which may result in cancer cell survival even though some pathways are blocked by targeted therapy. Pancreatic cancer may possess different characteristics and targets in different stages of pathogenesis, maintenance and metastasis. Sensitivity to therapy may also vary for cancer cells at different stages. The unique pancreatic cancer structure with abundant stroma creates a tumor microenvironment with hypoxia and low blood perfusion rate, which prevents drug delivery to cancer cells. In this review, the most commonly investigated targeted therapies in pancreatic cancer treatment are discussed. However, how to combine these targeted therapies and/or combine them with chemotherapy to improve the survival rate of pancreatic cancer is still a challenge. Genomic and proteomic studies using pancreatic cancer samples obtained from either biopsy or surgery are recommended to individualize tumor characters and to perform drug sensitivity study in order to design a tailored therapy with minimal side effects. These studies may help to further investigate tumor pathogenesis, maintenance and metastasis to create cellular expression profiles at different stages. Integration of the information obtained needs to be performed from multiple levels and dimensions in order to develop a successful targeted therapy.     

Management of advanced pancreatic cancer

Each year, approximately 37,000 new patients are diagnosed with pancreatic cancer (PC) in the USA. The incidence has been increasing since the 1930s. Prognosis of PC is extremely poor. In the USA, approximately 34,000 patients die from PC each year, making it the fourth leading cause of cancer-related death in the USA. The 5-year overall survival rate for advanced pancreatic cancer is less than 5%. Poor prognosis has been attributed to the inability to diagnose, while the tumor is resectable and its propensity toward early vascular dissemination and spread to regional lymph nodes. One of the greatest challenges in the treatment of pancreatic cancer remains its inherent lack of beneficial response to cytotoxic chemotherapy. For inoperable PC, gemcitabine is the only cytotoxic agent approved by the US FDA since 1997. Several trials have evaluated whether there is any benefit for gemcitabine-based combinations, including molecular targeted agents, over gemcitabine alone. Although several of these have shown a higher response rate favoring the combined regimens, a clear benefit in overall survival has yet to be shown. Despite the benefit of gemcitabine, most patients with advanced disease still do poorly, with a median time-to-tumor progression between 2 and 3 months and median overall survival of 4–6 months. The authors review slow progress and the recent developments with newer chemotherapeutic and molecular-targeted agents in the management of pancreatic cancer.     

Management of advanced pancreatic cancer

Each year, approximately 37,000 new patients are diagnosed with pancreatic cancer (PC) in the USA. The incidence has been increasing since the 1930s. Prognosis of PC is extremely poor. In the USA, approximately 34,000 patients die from PC each year, making it the fourth leading cause of cancer-related death in the USA. The 5-year overall survival rate for advanced pancreatic cancer is less than 5%. Poor prognosis has been attributed to the inability to diagnose, while the tumor is resectable and its propensity toward early vascular dissemination and spread to regional lymph nodes. One of the greatest challenges in the treatment of pancreatic cancer remains its inherent lack of beneficial response to cytotoxic chemotherapy. For inoperable PC, gemcitabine is the only cytotoxic agent approved by the US FDA since 1997. Several trials have evaluated whether there is any benefit for gemcitabine-based combinations, including molecular targeted agents, over gemcitabine alone. Although several of these have shown a higher response rate favoring the combined regimens, a clear benefit in overall survival has yet to be shown. Despite the benefit of gemcitabine, most patients with advanced disease still do poorly, with a median time-to-tumor progression between 2 and 3 months and median overall survival of 4-6 months. The authors review slow progress and the recent developments with newer chemotherapeutic and molecular-targeted agents in the management of pancreatic cancer.     

Advanced stage pancreatic cancer: novel therapeutic options

Despite advances in our understanding of the molecular and genetic basis of pancreatic cancer, it continues to be a therapeutic challenge. Gemcitabine approved by FDA in 1997, offers modest improvement of tumor-related symptoms and marginal advantage of survival. Many chemotherapeutic agents have been compared against or combined with gemcitabine in randomized Phase III trials and no drug was shown to be superior to single-agent gemcitabine except FOLFIRINOX and nab-paclitaxel plus gemcitabine. On the other hand, efforts to integrate targeted agents such as BAY 12-9566, SCH 66336, bevacizumab, cetuximab, axitinib and sorafenib have been quite dismal despite extensive pre-clinical and clinical research over the last decade in the field of novel agents. To date, erlotinib remains the only biological agent that has demonstrated a small, but significant, added benefit to single agent gemcitabine. However, numerous new agents, including monoclonal antibodies and tyrosine kinase inhibitors, are currently being tested in an attempt to achieve better response, while maintaining a safe toxicity profile. In this article, the author discusses the management of advanced pancreatic and the current role of novel agents in this setting.     

Emerging drugs in the treatment of 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: the evolving role of systemic therapy

Pancreatic adenocarcinoma is the fourth leading cause of cancer mortality in the US. The outcome for patients with pancreatic cancer has not essentially altered over the past few decades. Several new drugs with activity against pancreatic cancer have recently been identified for use in palliative settings. Of these, gemcitabine is the most widely used agent against the disease, but its benefit is very modest. Pilot Phase II studies combining gemcitabine with 5-fluorouracil (5-FU), irinotecan, docetaxel or cisplatin show improved outcomes that need to be confirmed in randomised studies. Concurrent administration of gemcitabine and external beam radiation therapy (EBRT) for locally advanced pancreatic cancer is feasible and is currently undergoing efficacy evaluations. Current research in pancreatic cancer involves newer dosing schedules of gemcitabine, and combinations of gemcitabine with novel agents. Ultimately, better understanding of the molecular biology of pancreatic neoplasia will identify potential cellular targets for future development of new agents for pancreatic cancer.     

Clinical trials of VEGF receptor tyrosine kinase inhibitors in pancreatic cancer

Pancreatic cancer is the fourth leading cause of cancer-related deaths in Western countries and is among the deadliest diseases in humans. At present, gemcitabine is the standard chemotherapy for advanced pancreatic cancer, although (despite its use) prognosis continues to be dismal with a median survival of < 6 months. While targeting tumor vasculature has provided improved outcomes in colon, lung, breast and renal cell cancers, trials of angiogenesis inhibitors have lagged behind in pancreatic cancer. This review provides the rationale for exploring antiangiogenic therapies in the treatment of pancreatic cancer as well as summarizes present clinical development of VEGF receptor tyrosine kinase inhibitors and their application to pancreatic cancer.     

Clinical trials of VEGF receptor tyrosine kinase inhibitors in pancreatic cancer

Pancreatic cancer is the fourth leading cause of cancer-related deaths in Western countries and is among the deadliest diseases in humans. At present, gemcitabine is the standard chemotherapy for advanced pancreatic cancer, although (despite its use) prognosis continues to be dismal with a median survival of < 6 months. While targeting tumor vasculature has provided improved outcomes in colon, lung, breast and renal cell cancers, trials of angiogenesis inhibitors have lagged behind in pancreatic cancer. This review provides the rationale for exploring antiangiogenic therapies in the treatment of pancreatic cancer as well as summarizes present clinical development of VEGF receptor tyrosine kinase inhibitors and their application to pancreatic cancer.