Pancreatic cancer: a review of recent advances

Pancreatic cancer is one of the most common causes of cancer-related death. Despite the advances of the molecular pathogenesis, pancreatic cancer remains a major unsolved health problem. Overall, the 5-year survival rate is < 5% and only ～ 20% of the 10% of patients with resectable disease survive 5 years. Recently, the European Study Group for Pancreatic Cancer 1 trial demonstrated substantially increased survival from adjuvant chemotherapy with 5-fluorouracil–folinic acid and preliminary data showed prolonged disease-free survival from adjuvant gemcitabine. Current palliative therapeutic approaches mostly focused on evaluating chemotherapy regimens in which gemcitabine is combined with a second cytotoxic agent. Recently, large randomised trials of combinations of gemcitabine with either capecitabine or with erlotinib demonstrated prolonged survival and 1-year survival rates of ～ 25%. The advance of molecular biology has led to the elucidation of molecular events that are important for pancreatic carcinogenesis and has provided a foundation for the development of novel chemotherapeutic and biological agents that appear to be promising and are likely to play a future role in the treatment of patients with advanced pancreatic cancer.     

Adjuvant therapy in pancreatic cancer: a critical appraisal

Adenocarcinoma of the pancreas carries a grim prognosis. Surgery is currently the only curative option, but even the few patients undergoing complete resection of early localised disease run a high risk for relapse and death. Although numerous clinical trials have been conducted during the past 20 years to find an effective adjuvant treatment, thus far no general consensus on the most appropriate regimen has been reached. In a small randomised study performed in the 1980s by the GITSG (Gastrointestinal Tumor Study Group), encouraging results were obtained with fluorouracil (5-FU)-based split-course chemoradiotherapy, but these findings were not confirmed in a randomised study initiated some years later by the EORTC (European Organisation for Research and Treatment of Cancer). More recently, the ESPAC (European Study Group for Pancreatic Cancer)-1 trial even indicated a detrimental effect of chemoradiotherapy, while chemotherapy with 5-FU was shown to have a significant positive impact on long-term survival. However, this latter finding is in contrast to earlier studies of adjuvant chemotherapy with 5-FU combinations from Norway and Japan that did not suggest a prolonged beneficial effect of 5-FU on survival. Thus, the results for adjuvant regimens based on systemic 5-FU with or without external radiotherapy are conflicting. Clinical experience with intraoperative radiotherapy or regionally targeted chemotherapy to prevent local relapse, though encouraging, is still preliminary. More recently, gemcitabine, which is the most effective single agent in advanced pancreatic cancer, has also been evaluated in the adjuvant setting. The RTOG (Radiation Therapy Oncology Group)-9704 trial demonstrated that gemcitabine is superior to 5-FU as an addition to chemoradiotherapy, but the results did not allow conclusions about the value of radiation in the combined modality approach. The Charité Onkologie CONKO-001 is a randomised trial from Germany and Austria that compared adjuvant gemcitabine with observation alone. Gemcitabine was very well tolerated and almost doubled median disease-free survival and overall survival rate at 5 years, although the advantage in overall survival failed to reach statistical significance. In summary, the available data from randomised clinical trials of adjuvant therapy suggest that (i) chemoradiotherapy has no obvious advantage compared with chemotherapy alone; and (ii) chemotherapy with gemcitabine is effective and probably offers the best benefit-risk ratio of all currently available adjuvant treatment options.     

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.     

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.     

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.     

The role of gemcitabine alone and in combination in the treatment of pancreatic cancer

Pancreatic cancer, one of the most frequently reported gastrointestinal tumors, has a 5-year survival of less than 5%. Despite representing only 2-3% of the total cancer incidence, it is the fifth leading cause of cancer death. This is because it is commonly only diagnosed at an advanced stage. Until recently the traditional therapy for patients with advanced disease was palliative 5-fluorouracil (5-FU)-based chemotherapy. However, the novel antinucleoside gemcitabine (Gemzar) has demonstrated a survival benefit over 5-FU, and an improvement in disease-related symptoms and quality of life in patients with advanced disease. This review presents an overview of the clinical studies of gemcitabine, either alone or in combination, with other chemotherapeutic agents and/or radiation therapy, in the treatment of these patients. A comparison of these studies is made with those using alternative treatment regimens. The data suggest that gemcitabine in combination with biomodulated 5-FU should be considered the standard palliative treatment to which other new drug combinations or combined modality chemoradiation regimens should be compared.     

可能切除性胰腺体尾部癌的外科手术治疗研究

目的 探讨可能切除性胰腺体尾部癌行外科手术治疗的技术方法及临床疗效。方法 11例伴有局部侵 犯的可能切除性胰腺体尾部癌患者,均以逆行切除方式施行根治性切除手术,同时辅以术后化疗并追踪随访。结 果 11例患者中10例达到R0切除,1例为R1切除。3例切除了受累的腹腔干血管（CA）及肝总动脉（CHA）,其中2 例联合了全胃切除、空肠代胃术,1例因切口感染延长了住院时间外,其余病例均无严重并发症发生。术后除2例患 者未能坚持规律化疗外,其余患者均行吉西他滨规律化疗。术后全部患者腹痛症状消失,中位生存时间28（14,36） 个月,术后1年、3年生存率分别为90.9%、36.3%。结论 可能切除性胰腺体尾部癌患者手术切除率低并长期被腹痛 困扰,以逆行切除手术方式,必要时扩大手术切除范围的方法并辅助术后化疗可以一定程度延长患者的生存时间并 显著改善患者的生活质量。     

Adjuvant therapy for pancreatic cancer

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.     

Adjuvant therapy for pancreatic cancer

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 ≤ 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.     

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.     

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: advances in medical therapy

Progress in the treatment of pancreatic cancer has been notably slow and modest in contrast to other cancers of the GI tract over the last 5 years. Pancreatic cancer still continues to be a devastating illness that is marked by the appearance of early metastatic disease, despite curative surgery and the relative chemoresistance of the disease. However, small incremental benefits have been seen, and point to areas of research and development over the subsequent years. Developments in adjuvant chemotherapy and the use of gemcitabine in combination with other cytotoxic agents or with biological agents have changed clinical practice. Given its poor outlook and the paucity of active therapies, even modest gains can lead to regulatory approval and, therefore, pancreatic cancer represents a common target for pharmaceutical companies. Newer agents are in development with the promise of further refinement in treatment selection based on molecular tumor characteristics.     

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.     

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.     

吉西他滨及其增效剂对胰腺癌细胞作用机制的研究进展

胰腺癌是全世界公认的高度恶性疾病之一。由于胰腺癌疾病隐匿、病情发展较快,目前尚无明确有效的治疗方案,基于吉西他滨的联合化疗仍是最主要的临床手段。研究发现胰腺癌细胞对吉西他滨有高度化疗耐药性,因此治疗效果并不理想,而且与细胞毒性药物的联用方案对患者有较强的机体损伤。深入研究发现与吉西他滨可联用于治疗胰腺癌,安全合理并能增加吉西他滨治疗效果的增效剂成为领域重点问题。关注不同增效剂与吉西他滨联合应用的作用机制,分析其应用效果,可为吉西他滨促胰腺癌细胞凋亡作用的发挥提供有利影响,有望为胰腺癌患者带来福音。     

Drugs in preclinical and early-stage clinical development for pancreatic cancer

INTRODUCTION: Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths in the US and Europe, and the lethality of this cancer is demonstrated by the fact that the annual incidences are approximately equal to the annual deaths. Current therapy for PC is multimodal, involving surgery and chemotherapy. Clinical symptoms are unspecific, and consequently about 85% of patients with PC are diagnosed at advanced tumor stages without any surgical therapy options. Since the therapeutic rates for PC are so dismal, it is essential to review the clinical targets for diagnosis and treatment of this lethal cancer. AREAS COVERED: In this review, we discuss potential treatment options for PC by identifying molecular targets including those involved in cell proliferation, survival, migration, invasion and angiogenesis. Targeting these molecules in combination with surgery could improve the clinical outcome for PC patients. EXPERT OPINION: For a decade, gemcitabine has remained the single first-line chemotherapeutic agent for advanced adenocarcinoma of the pancreas; however, less than 25% of patients benefit from gemcitabine. The reason for frequent reoccurrence of PC after conventional methods such as surgery, radiation and/or chemotherapy is due to the lack of understanding of the basic underlying metabolic cause of the cancer and thus consequently remains uncorrected. Our understanding of drug resistance in PC is still not clear and may be answered by focusing on new useful biomarkers and their role in chemo- and radioresistance.     

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.