Role of platinum agents in the management of advanced pancreatic cancer

Pancreatic cancer, one of the most common gastrointestinal tumors, has a 5-year survival rate of < 5%. Since 1997, when gemcitabine showed superior clinical benefit to single-agent 5-fluorouracil, it has remained the only standard chemotherapy approved by the US FDA for the treatment of advanced pancreatic cancer. Numerous new agents, both cytotoxic and targeted, have been tested against and in combination with this standard. Many combination therapy regimens showed encouraging results in Phase II settings, which led to > 12 randomized Phase III trials in the last decade. Some trials showed improved response rates or progression-free survival, but there was no clear improvement in survival. Among these combinations, the combination of gemcitabine plus platinum agents showed improved progression-free survival or time-to-tumor progression, but failed to demonstrate a survival advantage over gemcitabine. This combination has regained attention after a recent pooled analysis and a meta-analysis suggested a survival benefit of gemcitabine-platinum doublets when compared with single agent gemcitabine. There are preclinical data showing synergism between gemcitabine and platinum agents. Hence, this review covers the role of platinum doublets in the treatment of metastatic pancreatic cancer.     

Role of platinum agents in the management of advanced pancreatic cancer

Pancreatic cancer, one of the most common gastrointestinal tumors, has a 5-year survival rate of < 5%. Since 1997, when gemcitabine showed superior clinical benefit to single-agent 5-fluorouracil, it has remained the only standard chemotherapy approved by the US FDA for the treatment of advanced pancreatic cancer. Numerous new agents, both cytotoxic and targeted, have been tested against and in combination with this standard. Many combination therapy regimens showed encouraging results in Phase II settings, which led to > 12 randomized Phase III trials in the last decade. Some trials showed improved response rates or progression-free survival, but there was no clear improvement in survival. Among these combinations, the combination of gemcitabine plus platinum agents showed improved progression-free survival or time-to-tumor progression, but failed to demonstrate a survival advantage over gemcitabine. This combination has regained attention after a recent pooled analysis and a meta-analysis suggested a survival benefit of gemcitabine-platinum doublets when compared with single agent gemcitabine. There are preclinical data showing synergism between gemcitabine and platinum agents. Hence, this review covers the role of platinum doublets in the treatment of metastatic pancreatic cancer.     

Emerging therapies for the treatment of patients with advanced neuroendocrine tumors

Patients with neuroendocrine tumors may pursue a number of treatment options, but there is little consensus on a single, standard treatment approach. Somatostatin analogs are generally administered to patients with symptoms of hormonal secretion, and are often highly effective in this regard. However, the administration of somatostatin analogs is only rarely associated with tumor regression, and randomized trials demonstrating a survival benefit associated with their use have not been performed. Selected patients with hepatic metastases may undergo surgical debulking, embolization or other ablative therapies. The clinical benefit associated with administration of systemic agents such as IFN-alpha or cytotoxic chemotherapy has been limited. With the possible exception of streptozocin-based therapy in patients with pancreatic neuroendocrine tumors, the widespread use of standard cytotoxic regimens has been limited by their relatively modest antitumor activity, as well as concerns regarding their potential toxicity. The modest efficacy seen with these agents in patients with advanced neuroendocrine tumors has led to great interest in the development of novel treatment approaches. One such approach is the use of radiolabeled somatostatin analogs. Recently, agents targeting the VEGF pathway and mammalian target of rapamycin have also shown promise in patients with advanced neuroendocrine tumors. Ongoing randomized studies should help better define the role these agents will play in the future treatment of patients with this disease.     

Emerging therapies for the treatment of patients with advanced neuroendocrine tumors

Patients with neuroendocrine tumors may pursue a number of treatment options, but there is little consensus on a single, standard treatment approach. Somatostatin analogs are generally administered to patients with symptoms of hormonal secretion, and are often highly effective in this regard. However, the administration of somatostatin analogs is only rarely associated with tumor regression, and randomized trials demonstrating a survival benefit associated with their use have not been performed. Selected patients with hepatic metastases may undergo surgical debulking, embolization or other ablative therapies. The clinical benefit associated with administration of systemic agents such as IFN-α or cytotoxic chemotherapy has been limited. With the possible exception of streptozocin-based therapy in patients with pancreatic neuroendocrine tumors, the widespread use of standard cytotoxic regimens has been limited by their relatively modest antitumor activity, as well as concerns regarding their potential toxicity. The modest efficacy seen with these agents in patients with advanced neuroendocrine tumors has led to great interest in the development of novel treatment approaches. One such approach is the use of radiolabeled somatostatin analogs. Recently, agents targeting the VEGF pathway and mammalian target of rapamycin have also shown promise in patients with advanced neuroendocrine tumors. Ongoing randomized studies should help better define the role these agents will play in the future treatment of patients with this disease.     

Emerging therapeutic options for advanced enteropancreatic neuroendocrine tumors

INTRODUCTION: Several chemotherapy agents and combinations have proven effective in the therapy of advanced enteropancreatic neuroendocrine tumors (EP-NETs). However, their toxicity can be significant. Recent understanding of the molecular mechanisms of these tumors, especially the central role of tumor angiogenesis, has led to the identification of new therapeutic targets and agents directed at the molecular level. AREAS COVERED: This paper gives a comprehensive evaluation of the existing therapeutic armamentarium for EP-NETs. Narrated in a historical perspective, this review analyzes the available information on traditional chemotherapy agents, interferon-α and somatostatin analogs, as well as newer therapies and experimental agents. EXPERT OPINION: Despite recent advances, a curative approach for metastatic EP-NETs is yet to be discovered. To date, sunitinib and everolimus have been shown to impact progression-free survival only in pancreatic NETs, and the duration of this benefit has not yet been established. Further research is necessary to determine whether a combination of these drugs, either together or with other therapies, may yield superior outcomes. Moreover, sequential use of these agents should be explored in an attempt to improve survival. Efficacy of a variety of experimental agents is also being tested in clinical trials.     

Novel fluoropyrimidine-based chemotherapy for advanced well-differentiated neuroendocrine tumors: a clinical update

Introduction: Patients with advanced well-differentiated neuroendocrine tumors (NETs) who have bulky and/or symptomatic and/or rapidly progressive disease require chemotherapy treatment.

Areas covered: This review summarizes the accumulating evidence for treatment with fluorouracil-based chemotherapy in well-differentiated NETs. The main clinical studies, toxicity and predictors of fluorouracil- based chemotherapy regimens in well-differentiated NETs are discussed, along with the current issues, future research directions and therapeutic prospects.

Expert opinion: Somatostatin analogs may control symptoms of hormone excess and tumor growth in patients with well-differentiated metastatic NETs, and biological therapies may improve progression-free survival for these patients. However, chemotherapy leads to higher objective response rates and symptom control by reducing tumor bulk. The low response rate and significant toxicities of conventional chemotherapy regimens limit their widespread use. Fortunately, some novel fluoropyrimidine-based treatment including fluorouracil, capecitabine, or S-1 based chemotherapy with or without antiangiogenic agents have been investigated in recent years. These treatments showed significant efficacy and less toxicity in pancreatic and non-pancreatic metastatic well-differentiated NETs. Additionally, non-pancreatic well-differentiated NETs have also achieved similar tumor response or survival comparable to pancreatic NETs. Moreover, some predictors of response to these treatment regimens have been evaluated.     

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.     

Emerging therapeutic options for advanced enteropancreatic neuroendocrine tumors

Introduction: Several chemotherapy agents and combinations have proven effective in the therapy of advanced enteropancreatic neuroendocrine tumors (EP-NETs). However, their toxicity can be significant. Recent understanding of the molecular mechanisms of these tumors, especially the central role of tumor angiogenesis, has led to the identification of new therapeutic targets and agents directed at the molecular level.

Areas covered: This paper gives a comprehensive evaluation of the existing therapeutic armamentarium for EP-NETs. Narrated in a historical perspective, this review analyzes the available information on traditional chemotherapy agents, interferon-α and somatostatin analogs, as well as newer therapies and experimental agents.

Expert opinion: Despite recent advances, a curative approach for metastatic EP-NETs is yet to be discovered. To date, sunitinib and everolimus have been shown to impact progression-free survival only in pancreatic NETs, and the duration of this benefit has not yet been established. Further research is necessary to determine whether a combination of these drugs, either together or with other therapies, may yield superior outcomes. Moreover, sequential use of these agents should be explored in an attempt to improve survival. Efficacy of a variety of experimental agents is also being tested in clinical trials.     

The challenge of targeted therapies for gastric cancer patients: the beginning of a long journey

Introduction: Despite significant improvements in systemic chemotherapy over the last two decades, the prognosis of patients with advanced disease remains dismal. Collaborative, high-quality research and advances in high-throughput technologies have contributed to elucidate molecular pathways underpinning disease progression and have stimulated many clinical studies testing target therapies in the advanced disease setting. Although progress has been made thanks to trastuzumab in HER2 positive tumours, antiangiogenic drugs have produced conflicting results and EGFR-inhibitors have failed to show major improvements.

Areas covered: While commenting on the results of many key Phase III randomized trials, the Authors discuss the most promising classes of novel targeted agents and present the current challenges toward a customized treatment.

Expert opinion: Palliative chemotherapy became the worldwide standard of care for patients with advanced gastric cancers, producing significant life prolongation and improvement of life quality. Nevertheless, long-term outcomes of those patients remain poor. Because of the encouraging advancement in novel targeted therapies, such a disappointing scenario is now evolving. While results serve as a springboard for future research, more comprehensive efforts are needed to clarify the biological mechanisms underpinning cancer progression and help clinicians to develop new effective treatments.     

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.     

Novel combination chemotherapy in the treatment of non-small cell lung cancer

Treatment of patients with advanced non-small cell lung cancer (NSCLC) remains a vexing problem and long-term survival beyond 5 years is extremely rare. Five new agents, paclitaxel, docetaxel, vinorelbine, gemcitabine and irinotecan, have been introduced for the treatment of NSCLC and investigated extensively both preclinically and clinically. Monotherapy with one of these agents has produced survival benefits over the best supportive care in Phase III studies. Combination chemotherapy with a new agent and platinum produced a higher response rate than conventional cisplatin-based chemotherapy and improved survival was observed in some randomised trials. There was little difference in efficacy and toxicity between the chemotherapeutic regimens with a new agent and a platinum in Phase III trials, suggesting the clinical utility of these regimens is similar. Many trials have focused on regimens containing two new agents, with or without platinum. Preliminary results of Phase III trials of three drug combinations versus two drug combinations suggested the former to be more promising, in terms of response rates and survival. Whether the era of platinum-based chemotherapy in the treatment of NSCLC should continue or not must be determined by Phase III trials, evaluating the use of a platinum agent with one of the new agent combinations. These aggressive chemotherapeutic combinations will hopefully improve survival and quality of life for patients with advanced NSCLC.     

Novel combination chemotherapy in the treatment of non-small cell lung cancer

Treatment of patients with advanced non-small cell lung cancer (NSCLC) remains a vexing problem and long-term survival beyond 5 years is extremely rare. Five new agents, paclitaxel, docetaxel, vinorelbine, gemcitabine and irinotecan, have been introduced for the treatment of NSCLC and investigated extensively both preclinically and clinically. Monotherapy with one of these agents has produced survival benefits over the best supportive care in Phase III studies. Combination chemotherapy with a new agent and platinum produced a higher response rate than conventional cisplatin-based chemotherapy and improved survival was observed in some randomised trials. There was little difference in efficacy and toxicity between the chemotherapeutic regimens with a new agent and a platinum in Phase III trials, suggesting the clinical utility of these regimens is similar. Many trials have focused on regimens containing two new agents, with or without platinum. Preliminary results of Phase III trials of three drug combinations versus two drug combinations suggested the former to be more promising, in terms of response rates and survival. Whether the era of platinum-based chemotherapy in the treatment of NSCLC should continue or not must be determined by Phase III trials, evaluating the use of a platinum agent with one of the new agent combinations. These aggressive chemotherapeutic combinations will hopefully improve survival and quality of life for patients with advanced NSCLC.     

Emerging drugs in the treatment of advanced gastric cancer

Background: Gastroesopheal cancer is one of the most common cancers worldwide. If detected early, curative treatment is possible. Often, gastroesophageal cancer is detected at an advanced stage when therapy is palliative. Objectives: To provide a critical evaluation of historic and recently developed chemotherapy regimens for the treatment of advanced gastroesophageal cancer (AGC). Methods: Published clinical trials in AGC as well as selected abstracts presented at international oncology meetings were selected. Results/conclusion: Chemotherapy has demonstrated a benefit over best supportive care alone by improving the quality and quantity of life for patients with advanced disease. Recent Phase III trials investigating cytotoxic chemotherapy and Phase II trials incorporating biotherapy for the treatment of AGC show promise for the future.     

Successful treatment of gallbladder neuroendocrine carcinoma with combined chemo-radiotherapy: a case report and literature review

Neuroendocrine tumors (NETs) occur in the bronchopulmonary system. Extrapulmonary NETs are rare and are considered to ac count for 2.5 - 5% of all NETs, with more than 60% of these tumors occurring along the gastro intestinal tract, including primary NET of the gall bladder. Pri mary NETs of the gall bladder have been classified as carcinoid, neuroendocrine carcinoma or heterogeneous carcinoma. Currently, the main treatment of neuroendocrine car ci noma re mains surgery. The role of radiotherapy and chemotherapy is undefined be cause of the paucity of data. In advanced cases, chemotherapy has been prescribed with such effective agents as cisplatin, carboplatin, etoposide and paclitaxel. Here we re port a case of a 64-year-old Taiwanese male patient with neuroendocrine carcinoma of the gall bladder who received combined chemoradiotherapy (CCRT) with cisplatin, 5- fluorouracil and leucovorin (PFL) from June 2009 un til now, and whose disease is stable. CCRT with PFL may be a possible reg i men for high-grade neuroendocrine carcinoma of the gall bladder.     

The role of EGFR tyrosine kinase inhibitors in the first-line treatment of advanced non small cell lung cancer patients harboring EGFR mutation

Lung cancer continues to be the leading cause of cancer death worldwide. Among lung cancers, 80% are classified as nonsmall- cell lung cancer (NSCLC) and are mostly diagnosed at an advanced stage (either locally advanced or metastatic disease). In the last years, the discovery of the pivotal role in tumorigenesis of the Epidermal Growth Factor Receptor (EGFR) has provided a new class of targeted therapeutic agents: the EGFR tyrosine kinase inhibitors (EGFR-TKIs). Since the first reports of an association between somatic mutations in EGFR exons 19 and 21 and response to EGFR-TKIs, treatment of advanced NSCLC has changed dramatically. Histologic profile, clinical characteristics, and mutational profile of lung carcinoma have all been reported as predictive factors of response to EGFR-TKIs and other targeted therapies. In advanced NSCLC patients harboring EGFR mutations, the use of EGFR TKIs in first-line treatment has provided an unusually large progression-free survival (PFS) benefit with a negligible toxicity when compared with cytotoxic chemotherapy in phase III randomized trials. Considering the findings regarding the excellent benefit and better safety profile of EGFR TKIs in EGFR mutation positive patients, these targeted therapeutic agents can be now considered as first-line treatment in this setting of patients. This review will discuss the new evidences in the role of EGFR-TKIs in the first-line treatment of advanced NSCLC and their implication in the current clinical decision-making.     

Sorafenib in locally advanced or metastatic breast cancer

INTRODUCTION: Sorafenib is an oral multikinase inhibitor with anti-angiogenic and anti-proliferative activity that is indicated for use in hepatocellular and renal cell carcinomas. Sorafenib is being developed in a number of solid tumors, including breast cancer (BC). AREAS COVERED: A series of four randomized, double-blind, placebo-controlled Phase IIb screening Trials were developed to Investigate the Efficacy of Sorafenib (TIES) when added to select chemotherapies for patients with HER2-negative advanced BC with a primary endpoint of progression-free survival (PFS). Results have been varied. SOLTI-0701 reported significant PFS benefit for sorafenib plus capecitabine as first- or second-line treatment, and AC01B07 reported a modest but significant PFS benefit when sorafenib was combined with gemcitabine or capecitabine for patients whose disease had progressed during or after bevacizumab. Sorafenib plus first-line paclitaxel did not significantly improve PFS (NU07B1 study), nor did its addition to first-line docetaxel and/or letrozole (FM-B07-01 study). A Phase III trial of sorafenib plus capecitabine has been initiated. EXPERT OPINION: Phase IIb data indicate a potential role for sorafenib in combination with select chemotherapies for HER2-negative advanced BC, but Phase III confirmatory trials are necessary. The variability in results across studies with sorafenib may be related to the chemotherapy combination and/or patient population.     

Taxanes for advanced non-small cell lung cancer

The emergence of novel chemotherapeutic agents with promising anticancer activity in non-small cell lung cancer (NSCLC) during the 1990s has led to an expanded role for chemotherapy in the management of this disease. The taxanes (paclitaxel and docetaxel) are novel microtubule stabilising agents, and have become an integral part of several commonly-used chemotherapy regimens in NSCLC. Taxanes inhibit the growth of lung cancer cell lines, exhibit synergistic interaction with other chemotherapy agents and enhance the efficacy of radiation in vitro. When used in low doses (metronomic dosing), they have important antiangiogenic properties. Several Phase II and III clinical trials have established the efficacy of the taxanes, as single agents and when used in combination with a platinum compound, in the treatment of advanced NSCLC. The use of a taxane in combination with a platinum compound has become an acceptable standard for patients with advanced or metastatic NSCLC. In addition to its efficacy in the first-line therapy of NSCLC, docetaxel is also the FDA-approved second-line agent for recurrent or relapsed NSCLC in the US. Several ongoing trials are comparing the efficacy of combining molecularly targeted agents with taxane-based regimens for the treatment of advanced NSCLC.     

Taxanes for advanced non-small cell lung cancer

The emergence of novel chemotherapeutic agents with promising anticancer activity in non-small cell lung cancer (NSCLC) during the 1990s has led to an expanded role for chemotherapy in the management of this disease. The taxanes (paclitaxel and docetaxel) are novel microtubule stabilising agents, and have become an integral part of several commonly-used chemotherapy regimens in NSCLC. Taxanes inhibit the growth of lung cancer cell lines, exhibit synergistic interaction with other chemotherapy agents and enhance the efficacy of radiation in vitro. When used in low doses (metronomic dosing), they have important antiangiogenic properties. Several Phase II and III clinical trials have established the efficacy of the taxanes, as single agents and when used in combination with a platinum compound, in the treatment of advanced NSCLC. The use of a taxane in combination with a platinum compound has become an acceptable standard for patients with advanced or metastatic NSCLC. In addition to its efficacy in the first-line therapy of NSCLC, docetaxel is also the FDA-approved second-line agent for recurrent or relapsed NSCLC in the US. Several ongoing trials are comparing the efficacy of combining molecularly targeted agents with taxane-based regimens for the treatment of advanced NSCLC.     

Emerging drugs for esophageal cancer

Background: Cancer of the esophagus and gastro-esophageal junction is a disorder with a poor prognosis and increasing incidence. Objective: To provide a critical evaluation of current treatment strategies and new developments including targeted therapy for esophageal cancer. Methods: Published clinical trials as well as abstracts were selected regarding chemoradiation or targeted therapy for esophageal cancer. Results/conclusions: Preoperative chemotherapy may offer a survival advantage compared to surgery alone, but the evidence is inconclusive. For preoperative chemoradiation, only 2 of 10 randomized trials showed advanced survival compared to surgery alone, and, therefore, more Phase III trials and, consequently, meta-analyses are needed. Until now, for palliative chemotherapy, no survival benefit has been shown. This is largely due to a lack of studies and difficulties in performing randomized trials. The application of targeted therapy is widespread and reported for several tumor types. For esophageal cancer, most studies have been performed with EGFR inhibitors, including cetuximab, gefitinib, erlotinib and trastuzumab. Limited experience is available with angiogenesis inhibitors, apoptosis inhibitors and COX-2 inhibitors. As yet, targeted therapies are proven to be safe often in combination with chemoradiation, but modestly effective for esophageal cancer. Phase III trials have not been published yet and, therefore, for targeted therapies also, possibly using new concepts, more studies are needed.     

Current adjuvant and targeted therapies for pancreatic adenocarcinoma

Pancreatic cancer is one of the deadliest malignancies, costing the lives of more than 30,000 patients every year. It often presents in advanced stages not amenable to surgery. Gemcitabine is currently considered to be the standard of care for the treatment of advanced pancreatic cancer. Combination of gemcitabine with certain other cytotoxic drugs, including cisplatin, oxaliplatin, capecitabine, and 5-fluorouracil have been undertaken, but all have failed to provide substantial increases in survival benefit. However, neoadjuvant algorithms and targeted therapies, including combinations of gemcitabine with erlotinib suggest more promising results. New targeted therapies in combination with gemcitabine are currently in Phase II and III trials, possibly implicating a primary position for them in future treatment. In this paper we present an overview of the current treatment options for the different presenting stages of pancreatic cancer, including adjuvant, neoadjuvant, and targeted therapies, and attempt to provide a comprehensive analysis of the disparate research indicated on this front.