Pancreatic cancer is a devastating disease. It is the fourth leading cause of cancer-related death in Germany. The incidence in 2003/2004 was 16 cases per 100.000 inhabitants. Of all carcinomas, pancreatic cancer has the highest mortality rate, with one- and five-year survival rates of 25% and less than 5%, respectively, regardless of the stage at diagnosis. These low survival rates demonstrate the poor prognosis of this carcinoma. Previous therapeutic approaches including surgical resection combined with adjuvant therapy or palliative chemoradiation have not achieved satisfactory results with respect to overall survival. Therefore, it is necessary to evaluate new therapeutic approaches. Neoadjuvant therapy is an interesting therapeutic option for patients with pancreatic cancer. For selected patients with borderline or unresectable disease, neoadjuvant therapy offers the potential for tumor downstaging, increasing the probability of a margin-negative resection and decreasing the occurrence of lymph node metastasis. Currently, there is no universally accepted approach for treating patients with pancreatic cancer in the neoadjuvant setting. In this review, the most common neoadjuvant strategies will be described, compared and discussed.
pancreas cancer; neoadjuvant therapy; adjuvant; radiotherapy; chemotherapy
Pancreatic cancer is the second most frequent gastrointestinal malignancy and carries a dismal prognosis. The current standard of care includes resection, if possible, as well as systemic chemoradiation therapy. Endoscopic ultrasound (EUS) is an established technique for the diagnosis and staging of pancreatic adenocarcinoma. Interventional EUS via fine needle injection (FNI) for the treatment of pancreatic cancer is a rapidly expanding field. The present article reviews the up-to-date developments in EUS FNI for intratumoural pancreatic cancer therapy, including antitumoural agents, immunotherapy, ablative techniques and new delivery systems. The therapeutic modalities discussed are currently under development and will hopefully reach clinical practice if benefit is demonstrated through clinical trials. EUS FNI may be an exciting new technique for the delivery of desperately needed novel therapies for pancreatic cancer.
Brachytherapy; Cytoimplant; Dendritic cells; Endoscopic ultrasound; Fiducials; Fine needle injection; ONYX-015; Pancreatic cancer; Photodynamic therapy; Radiofrequency ablation; TNFerade
Pancreatic cancer is a lethal disease characterized by multiple disease-related symptoms. Chemoradiation therapy is a standard of treatment for locally advanced pancreatic cancer. Although shown to prolong survival, there is little information about treatment-related symptoms or the palliative benefits of chemoradiation. We assessed symptoms of patients with locally advanced pancreatic cancer receiving chemoradiation to determine the prevalence, and co-occurrence, of symptoms and to identify the extent to which symptoms interfered with function. Forty-eight patients were treated with chemoradiation on a Phase I protocol. Patients received radiotherapy (50.4 Gy in 28 fractions), capecitabine (median dose 825 mg/m2 twice daily), and bevacizumab (2.5–10 mg/kg). Symptom severity and its interference with function were prospectively assessed (at presentation, during, and after chemoradiation) in 43 consenting patients using the M.D. Anderson Symptom Inventory. Results showed that 95% of patients reported at least one of the 13 symptoms assessed at presentation. The most commonly reported symptoms of moderate to severe (≥5 on a 0–10 scale) intensity at presentation were lack of appetite (24%), pain (19%), fatigue (19%), and sleep disturbance (10%). We observed an increase in patients reporting moderate to severe fatigue, nausea, and sleep disturbance during chemoradiation. McNemar tests for paired binary observations showed the proportion of patients reporting moderate to severe symptoms significantly (P < 0.001) decreased after chemoradiation at 94 days follow-up (lack of appetite = 7%, pain = 7%, fatigue = 13%, sleep disturbance = 7%). This study demonstrates the feasibility and usefulness of symptom assessment in chemoradiation protocols. Future studies with larger cohorts are needed to further characterize multiple symptoms associated with chemoradiation.
Cancer; chemoradiation; symptoms; pancreas; epidemiology; fatigue; pain; appetite; nausea; toxicity
Pancreatic ductal adenocarcinoma is the 10th most common cancer and the 4th leading cause of cancer-related death in the United States. Despite great effort, the prognosis for patients with this disease remains dismal with, a 5-year survival rate of just 4-6%. While several important advances have improved our understanding of the underlying biology of pancreatic cancer, this knowledge has not translated into novel therapeutic approaches and effective systemic or targeted therapies. Pancreatic cancer is one of the malignancies most difficult to treat, with remarkable intrinsic resistance to both standard and targeted chemotherapy as well as ionizing radiation. Surgical intervention remains the only potentially curative approach. However, most patients present with inoperable and/or metastatic disease and are therefore excluded from surgery. Accordingly, new therapeutic options are desperately needed. In vivo models to study innovative and alternative treatment approaches are of major importance. A variety of genetically engineered mouse models of pancreatic cancer have been developed over the last decade. However, these models display different characteristics and not all of them are suited for preclinical studies. In this review we aim to review the mouse models currently available, their experimental use, their clinical relevance and limitations as well as future directions.
Pancreatic Cancer; genetically engineered mouse models; transgenic; preclinical testing
Pancreatic cancer is a devastating disease with the worst mortality rate and an overall 5-year survival rate lower than 5%. In the United States, this disease is the fourth leading cause of death and represents 6% of all cancer related deaths. Gemcitabine, the current standard first-line treatment offers marginal benefits to patients in terms of symptom control and prolongation of life. Since 1996, about 20 randomized phase III trials have been performed to improve the efficacy of gemcitabine with little success regarding a significant improvement in survival outcomes. The need for novel therapeutic strategies such as target therapy is obvious. Monoclonal antibodies have finally come of age as therapeutics and several molecules are now approved for cancer therapies. This review aims at giving a general view on the clinical results obtained so far by antibodies for the treatment of pancreatic cancer and describes the most promising avenues toward a significant improvement in the treatment of this frustrating disease.
Antibodies, therapy, pancreatic, bispecific, clinical trials
The disappointing results of surgical therapy alone of ductal pancreatic cancer can only be improved using multimodal approaches. In contrast to adjuvant therapy, neoadjuvant chemoradiation is able to facilitate resectability with free margins and to lower lymphatic spread. Another advantage is better tolerability which consecutively allows applying multimodal treatment in a higher number of patients. Furthermore, the synopsis of the overall survival results of neoadjuvant trials suggests a higher rate compared to adjuvant trials.
As there are no prospectively randomised studies for neoadjuvant therapy, the Interdisciplinary Study Group of Gastrointestinal Tumours of the German Cancer Aid has started such a trial. The study investigates the effect of neoadjuvant chemoradiation in locally resectable or probably resectable cancer of the pancreatic head without distant metastasis on median overall survival time compared to primary surgery. Adjuvant chemotherapy is integrated into both arms.
The protocol of the study is presented in condensed form after an introducing survey on adjuvant and neoadjuvant therapy in pancreatic cancer.
Pancreatic cancer is considered an aggressive malignancy that responds poorly to current treatments and therefore has a dismal survival rate. This disease is usually not diagnosed until a late stage, at which point palliative chemotherapy with the purine analogue gemcitabine and/or a fluoropyrimidine or a platinum agent is the standard approach. There are some new data on the molecular and genetic changes that take place in pancreatic cancer, which may facilitate the accuracy of diagnosis and efficacy of treatments. However, translational efforts in clinical practice have increased clinicians' options with a targeted agent, erlotinib, in combination with the standard gemcitabine chemotherapy. Many other novel drugs currently being tested in the field of pharmaco-oncology target various altered biological pathways and molecules. Nevertheless, the lack of clinically significant improvements in treatments is rendering efforts to develop methods of early diagnosis both more urgent and promising. The aim of this review was to summarize the molecular basis of pancreatic carcinogenesis and the latest developments in diagnosis by molecular means, focusing on the results of clinical research into targeted and personalized treatments.
Pancreatic ductal carcinoma; Molecular targets; Pharmacogenetics; Novel agents
Development of systemic treatment for advanced pancreatic cancer (APC) has been challenging. After fluorouracil, gemcitabine (GEM) became the treatment of choice based on its benefit of symptom relief. Many cytotoxic agents have been combined with GEM in search of regimens with improved survival benefit. However, there were only marginal benefits in people with good performance status. Recently, the combination regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) was found to achieve unprecedented survival benefit and has become the preferred option for patients with good clinical conditions. On the other hand, many biological agents have been combined with GEM, but only erlotinib was found to derive statistically significant survival advantage. However, the effect was too small to be appreciated clinically. The effort in development of targeted therapy in APC continues. This paper summarized key findings in the development of chemotherapy and targeted therapy for APC patients and discussed future directions in management.
Pancreatic cancer is the fourth-leading cause of death in the United States and one of the most aggressive known malignancies. New and innovative advances in treatment are desperately needed. One promising area of investigational treatment for pancreatic cancer involves the use of immunotherapy. The development of immunotherapy for pancreatic cancer has been hampered by difficulty in generating tumor-reactive lymphocytes from resected specimens and by a lack of appropriate target antigens expressed on tumor cells. Innovative strategies have been developed with the use of peripheral blood lymphocytes that are genetically engineered to express T-cell receptors targeting common tumor antigens, including cancer-testis antigens, such as the MAGE-A3 antigen. Cancer-testis antigens pose excellent targets for immunotherapy because they are expressed in cancer and in the testis, an immune-privileged site, but have limited expression in normal tissue. An additional advantage in targeting cancer-testis antigens for immunotherapy is that their expression can be selectively up-regulated in tumor cells via epigenetic regulation with chromatin remodeling agents. Current interest in targeting cancer-testis antigens in pancreatic cancer is well-founded because cancer-testis antigens have been shown to be expressed in pancreatic cancer as potential targets for therapy. In our studies, we validated the expression pattern of cancer-testis antigens in resected specimens of pancreatic cancer and tested the hypothesis that treatment of pancreatic cancer cells with chromatin remodeling agents would render them more sensitive to antigen-specific T lymphocytes. We focused predominately on the MAGE-A3 antigen because it is highly expressed in pancreatic cancer, and several immunotherapeutic strategies are in clinical trials targeting this specific antigen. The results of these studies have important translational implications and provide the rationale for combined treatment with chromatin remodeling agents and immunotherapeutic approaches for pancreatic cancer.
Pancreatic cancer, although not very frequent, has an exceptionally high mortality rate, making it one of the most common causes of cancer mortality in developed countries. Pancreatic cancer is difficult to diagnose, allowing few patients to have the necessary treatment at a relatively early stage. Despite a marginal benefit in survival, the overall response of pancreatic cancer to current systemic therapy continues to be poor, and new therapies are desperately needed. Histone deacetylase (HDAC) enzymes play an important role in the development and progression of cancer and HDAC inhibitors (HDACIs) have been shown to induce differentiation and cell cycle arrest, activate the extrinsic or intrinsic pathways of apoptosis, and inhibit invasion, migration and angiogenesis in different cancer cell lines. As a result of promising preclinical data, various HDACIs are being tested as either monotherapeutic agents or in combination regimens for both solid and hematological malignancies. Vorinostat was the first HDACI approved by the Food and Drug Administration for patients with cutaneous T-cell lymphoma. The use of HDACIs in clinical trials, in pretreated and relapsed patients suffering from advanced pancreatic cancer is discussed. Unfortunately, clinical data for HDACIs in patients with pancreatic cancer are inadequate, because only a few studies have included patients suffering from this type of neoplasm and the number of pancreatic cancer patients that entered HDACIs phase II/III trials, among others with advanced solid tumors, is very limited. More studies recruiting patients with pancreatic cancer remain to determine the efficiency of these therapies.
Pancreatic cancer; Histone deacetylases; Histone deacetylase inhibitors; Clinical trials
Metastatic renal cell cancer (RCC) is a malignant disease without curative treatment. These patients are usually symptomatic and desperate for effective palliative treatment. Radiotherapy, chemotherapy, and hormonal therapy are not effective in these patients. A multimodal approach consisting of cytoreductive nephrectomy, systemic therapy (which includes cytokines or targeted molecules), and metastasectomy have been shown to be useful in prolonging the survival and improving the quality of life in a select group of patients with metastatic renal cancer. Patients with oligometastatic disease, good performance status, and delayed presentation of the secondaries have better results following this integrated approach. Although there is some controversy regarding the order in which nephrectomy and systemic therapy are to be instituted, well-controlled studies like the South West Oncology Group and European organization research and treatment of cancer have shown that upfront nephrectomy gives better survival compared to neoadjuvant systemic therapy followed by nephrectomy. This order is the standard presently. Of late, with better understanding of the genetic basis and the biology of the various subtypes of renal cell carcinoma, targeted molecular therapies have emerged as an equally effective alternative therapy to cytokines. Recent reports have proven that targeted therapy is more effective with comparable side effects. Metastasectomy in a subgroup of patients improves survival and quality of life specifically in those with lung secondaries and painful bone metastases.
Cytoreductive nephrectomy; immunotherapy; metastasectomy; metastatic renal cancer; targeted molecular therapy
Importance of the field
Head and neck squamous cell carcinoma (HNSCC) is the eighth leading cause of cancer death worldwide. Despite advances in surgery and chemoradiation therapy, there has been little improvement in survival rates over the past 4 decades. Additionally, surgery and chemoradiotherapy have serious side effects. The development of agents with greater efficacy and tolerability is needed.
Areas covered in this review
EGFR is the only proven molecular target for HNSCC therapy. Cetuximab, the sole FDA-approved molecular targeted HNSCC therapy, and other potential targeted therapies are being evaluated in preclinical, clinical and post-marketing studies. Here, we review the emerging targets for biological agents in HNSCC and the rationale for their selection.
What the reader will gain
Key information in the development of new drug targets and the emergence of new biomarkers are discussed. Readers will gain insight regarding the limitations of current therapies, the impact of recently approved targeted therapies and the influence that predictive biomarkers will have on drug development.
Take home message
The head and neck cancer drug market is rapidly evolving. Coordination between drug and biomarker development efforts may soon yield targeted therapies that can achieve the promise of personalized cancer medicine.
carcinoma; cetuximab; EGFR; erlotinib; gefitinib; HNSCC; HPV; panitumumab; SCCHN; squamous
Pancreatic cancer is the fourth leading cause of cancer related deaths in North America. The poor survival statistics are due to the fact that there are no reliable tests for early diagnosis and no effective therapies once metastasis has occurred. Surgical resection is the only curative treatment for pancreatic cancer; however, only less than 15% of the patients are eligible for surgery at diagnosis. New therapies are urgently needed for this malignant disease. And combinational therapy including surgery, chemotherapy and molecular targeted therapy may further improve the efficacy of individual therapies. However, a reliable mouse model which mimics the human disease and can be used for testing the surgical treatment and surgery-based combinational therapy is not available. In this study, we have established a mouse model for curative surgical resection of pancreatic cancer. Human pancreatic cancer cells were used to create orthotopic xenografts in nude mice, distal pancreatectomy was performed using imaging-guided technology to remove the pancreatic tumors, and sham surgery was performed in the control group. All mice survived the operation and no complication was observed. Surgical resection at early stage improved the survival rate and quality of life of the mice compared with the sham surgery and surgical resection at the late stage. If combined with other therapies such as chemotherapy and molecular targeted therapy, it could further improve the outcome of pancreatic cancer. This mouse model is a useful tool to study the surgical therapy and the tumor recurrence of pancreatic cancer, and could potentially impact the therapeutic choices for this deadly disease.
surgical resection; imaging; pancreatic cancer; mouse model; distal pancreatectomy; combinational therapy
Several advances in genetics, diagnosis and palliation of pancreatic cancer (PC) have occurred in the last decades. A multidisciplinary approach to this disease is therefore recommended. PC is relatively common as it is the fourth leading cause of cancer related mortality. Most patients present with obstructive jaundice, epigastric or back pain, weight loss and anorexia. Despite improvements in diagnostic modalities, the majority of cases are still detected in advanced stages. The only curative treatment for PC remains surgical resection. No more than 20% of patients are candidates for surgery at the time of diagnosis and survival remains quite poor as adjuvant therapies are not very effective. A small percentage of patients with borderline non-resectable PC might benefit from neo-adjuvant chemoradiation therapy enabling them to undergo resection; however, randomized controlled studies are needed to prove the benefits of this strategy. Patients with unresectable PC benefit from palliative interventions such as biliary decompression and celiac plexus block. Further clinical trials to evaluate new chemo and radiation protocols as well as identification of genetic markers for PC are needed to improve the overall survival of patients affected by PC, as the current overall 5-year survival rate of patients affected by PC is still less than 5%. The aim of this article is to review the most recent high quality literature on this topic.
Diagnosis; Epidemiology; Palliation; Pancreatic cancer; Therapy
Pancreatic cancer is a highly aggressive disease with poor survival. The only effective therapy offering long-term survival is complete surgical resection. In the setting of nonmetastatic disease, locally advanced tumors constitute a technical challenge to the surgeon and may result in margin-positive resection margins. Few studies have evaluated the implications of the latter in depth. The aim of this study was to compare the margin-positive situation to palliative bypass procedures and margin-negative resections in terms of perioperative and long-term outcome. By retrospective analysis of prospectively maintained data from 360 patients operated for pancreatic cancer at our institution, we provide evidence that margin-positive resection still yields a significant survival benefit over palliative bypass procedures. At the same time, perioperative severe morbidity and mortality are not significantly increased. Our observations suggest that pancreatic cancer should be resected whenever technically feasible, including, cases of locally advanced disease.
This article reviews the published literature on the use of chemoradiation as a modality in various stages of pancreatic adenocarcinoma and highlights areas that future trials in this field should target for a way forward in this malignancy.
Adenocarcinoma of the exocrine pancreas has an annual incidence of 7,400 cases in the U.K. In comparison with other common cancers of solid organs, namely, breast, colorectal, and prostate cancer, pancreatic cancer has a high morbidity and mortality. Radical resection is possible in only 15%–20% of patients, and only 3%–4% of all patients presenting with this condition achieve long-term control and cure. Various strategies in the form of neoadjuvant and adjuvant treatment have been employed over the years to improve outcome, with limited success. Systemic chemotherapy remains the gold standard in the metastatic setting in good performance status patients, and adjuvant chemotherapy after resection of localized and locally advanced cancer has been found to improve outcome. The role of radiotherapy, however, remains controversial and is an area that merits further investigation in well-conducted multicenter trials at various stages of the disease in combination with systemic agents and exploiting recent advances in the delivery of radiotherapy. In this article, we review the published literature on the use of chemoradiation as a modality in various stages of pancreatic adenocarcinoma and highlight areas that future trials in this field should target for a way forward in this malignancy.
Pancreatic cancer; Chemoradiation; Chemoradiotherapy; IMRT
Adenocarcinoma of the pancreas only rarely is associated with inflammatory myopathy. In this setting, polymyositis may be treated with glucocorticoids in combination with cancer specific treatment.
We present the case of a 52-year-old man with stage IIA pancreatic tail adenocarcinoma who underwent surgical treatment and six months into therapy with gemcitabine he developed symmetrical, painful, proximal muscle weakness with peripheral oedema. Re-evaluation with imaging modalities, muscle histology and biochemistry conferred the diagnosis of polymyositis associated with pancreatic cancer progression. The patient was treated with glucocorticoids along with gemcitabine and erlotinib which resulted in complete remission within six months. He remained in good health for a further six months on erlotinib maintenance therapy when a new computer tomography scan showed pancreatic cancer relapse and hence prompted 2nd line chemotherapy with gemcitabine.
Polymyositis associated with pancreatic cancer may respond to glucocorticoids along with cancer specific treatment.
This paper discusses the rationale for phase III testing of neoadjuvant therapy in patients affected by resectable pancreatic adenocarcinoma. The therapeutic management of patients affected by resectable pancreatic cancer is particularly troublesome due to the aggressiveness of the disease and to the limited efficacy and sometimes unfavourable risk-benefit ratio of the available therapeutic tools. Conflicting data on the role of adjuvant chemoradiation have been reported, while adjuvant single-agent chemotherapy significantly improved overall survival (OS) when compared to surgery alone. However, the OS figures for adjuvant chemotherapy remain disappointing. In effect, pancreatic cancer exhibits a prominent tendency to recur after a brief median time interval from surgery and extra-pancreatic dissemination represents the predominant pattern of disease failure. Neoadjuvant treatment has a strong rationale in this disease but limited information on the efficacy of this approach is available from single arm trials with low levels of evidence. Thus, in spite of two decades of investigation there is currently no evidence to support the routine use of pre-surgical therapy in clinical practice. To foster knowledge on the optimal management of this disease, and to produce evidence-based treatment guidelines, there is no alternative to well designed randomized trials. Systemic chemotherapy is a candidate for testing because it is supported by a more robust rationale than chemoradiation. Combination chemotherapy regimens with elevated activity in advanced disease warrant investigation. Caution would suggest the running of an exploratory phase II randomized trial before embarking on a large phase III study.
Pancreatic cancer; Neoadjuvant therapy; Phase III trial; Chemotherapy
In the past 15 years, we have seen few therapeutic advances for patients with pancreatic cancer, which is the fourth leading cause of cancer-related death in the United States. Currently, only about 6% of patients with advanced disease respond to standard gemcitabine therapy, and median survival is only about 6 mo. Moreover, phase III trials have shown that adding various cytotoxic and targeted chemotherapeutic agents to gemcitabine has failed to improve overall survival, except in cases in which gemcitabine combined with erlotinib show minimal survival benefit. Several meta-analyses have shown that the combination of gemcitabine with either a platinum analog or capecitabine may lead to clinically relevant survival prolongation, especially for patients with good performance status. Meanwhile, many studies have focused on the pharmacokinetic modulation of gemcitabine by fixed-dose administration, and metabolic or transport enzymes related to the response and toxicity of gemcitabine. Strikingly, a phase III trial in 2010 showed that, in comparison to gemcitabine alone, the FOLFIRINOX regimen in patients with advanced disease and good performance status, produced better median overall survival, median progression-free survival, and objective response rates. This regimen also resulted in greater, albeit manageable toxicity.
Chemotherapy; Palliative therapy; Metastasis; Biomarkers; Pancreatic neoplasms
Single agent gemcitabine has been the mainstay of therapy for advanced pancreatic cancer over the past decade. Multiple trials of newer chemotherapeutic agents both alone and in combination have yielded disappointing results, spurring the ongoing search for new agents and combinations in this aggressive malignancy. Inhibitors of the epidermal growth factor receptor (EGFR) have shown promising activity in multiple solid tumors types, and preclinical data support a role for EGFR inhibition in pancreatic cancer. A recent phase III study by the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) demonstrated a significant survival benefit with the addition of the EGFR tyrosine kinase inhibitor, erlotinib, to gemcitabine chemotherapy for the first-line treatment of patients with advanced pancreatic cancer, becoming the first phase III study to demonstrate a survival benefit of combination therapy as well as targeted therapy in this disease. This article reviews the evidence supporting EGFR inhibition and the use of erlotinib in advanced pancreatic cancer as well as future implications of targeted therapy in this challenging malignancy.
erlotinib; EGFR; pancreas; pancreatic; Tarceva
The rationale for and outcomes associated with the use of adjuvant and neoadjuvant therapy for resectable and borderline resectable cancer of the pancreatic head and uncinate process are reviewed.
After completing this course, the reader will be able to:
Explain the rationale for the use of adjuvant and neoadjuvant chemoradiation and/or chemotherapy in the treatment of patients with potentially resectable pancreatic cancer.Describe the limitations of prior prospective, randomized trials of adjuvant therapy strategies and the clinical implications of these limitations.Compare modern strategies for the multidisciplinary management of potentially resectable and borderline resectable pancreatic cancer.
This article is available for continuing medical education credit at CME.TheOncologist.com.
In this article, we review the rationale for and outcomes associated with the use of adjuvant and neoadjuvant therapy for resectable and borderline resectable cancer of the pancreatic head and uncinate process. Localized pancreatic cancer is a systemic disease that requires nonoperative therapies to minimize the local and systemic recurrences that almost invariably occur in the absence of such therapy, even following complete surgical resection. A well-defined role exists for the systemic administration of gemcitabine or 5-fluorouracil in the postoperative setting. Although the survival benefit associated with adjuvant chemoradiation has not been as rigorously defined, its use is supported by extensive historic experience; chemoradiation should be considered particularly for patients at high risk for local recurrence. Delivery of chemotherapy and/or chemoradiation prior to surgery has multiple potential advantages, although the superiority of neoadjuvant therapy over standard postoperative therapy has yet to be demonstrated. Neoadjuvant therapy may be particularly beneficial among patients with borderline resectable cancers. Although the existing literature is confusing, and indeed controversial, available evidence suggests that systemic chemotherapy and/or chemoradiation should be offered to all patients with pancreatic cancer who undergo potentially curative resection. Well-designed prospective trials are needed to define the optimal adjuvant or neoadjuvant therapy strategy for these patients.
Pancreatic cancer; Adjuvant therapy; Neoadjuvant therapy; Chemoradiation; Chemotherapy; Pancreaticoduodenectomy
Despite recent research and advances in the understanding of the molecular and genetic basis of pancreatic cancer, the poor outcomes experienced by pancreatic cancer patients have changed little during the past 30 years. Adenocarcinoma of the pancreas is the fourth leading cause of cancer-related death in the United States, with only a small fraction of patients achieving long-term survival. According to data from the American Cancer Society, 5-year survival for pancreatic cancer patients is 5%; an estimated 33,730 newly diagnosed cases of pancreatic cancer will be nearly equaled by an estimated 32,300 pancreatic cancer deaths in the United States. This underscores the continued need to develop novel multimodality treatment approaches for this disease. Surgery has proved vital to a curative-intent treatment approach for these patients. However, only 10% to 20% of newly diagnosed patients present with potentially resectable nonmetastatic disease. In light of the minority of patients with resectable disease, there has been considerable debate over the potential advantages of adjuvant chemotherapy and radiotherapy. In recent decades, cooperative groups both in the United States and abroad have conducted randomized clinical trials seeking to define the potential benefit of adjuvant chemotherapy or adjuvant chemoradiotherapy vs. surgery alone for patients with resectable disease. Unfortunately, the results of these trials have been conflicting and no definitive consensus has yet been reached regarding optimal adjuvant therapy. This article reviews cooperative group data pertinent to this debate. It is suggested that (1) patients do benefit from adjuvant therapy, and (2) optimal adjuvant therapy should include gemcitabine-based chemoradiotherapy for select patient subgroups.
Pancreatic cancer is the fourth leading cause of cancer death with a median survival of 6 months and a dismal 5-year survival rate of 3–5%. The development and progression of pancreatic cancer are caused by the activation of oncogenes, the inactivation of tumor suppressor genes, and the deregulation of many signaling pathways. Therefore, the strategies targeting these molecules as well as their downstream signaling could be promising for the prevention and treatment of pancreatic cancer. However, although targeted therapies for pancreatic cancer have yielded encouraging results in vitro and in animal models, these findings have not been translated into improved outcomes in clinical trials. This failure is due to an incomplete understanding of the biology of pancreatic cancer and to the selection of poorly efficient or imperfectly targeted agents. In this review, we will critically present the current knowledge regarding the molecular, biochemical, clinical, and therapeutic aspects of pancreatic cancer.
pancreas; oncogenes; suppressor genes; signaling; cancer; surgery; neoadjuvants; chemoprevention
Erlotinib is an oral, small-molecule targeting therapy that inhibits epidermal growth factor tyrosine kinase receptors. Erlotinib has been administered for the treatment of advanced pancreatic cancer and non-small cell lung cancer. In the present trial, erlotinib was administered as second-line monotherapy in pretreated patients with advanced non-small cell lung cancer. Our objectives were to determine response, survival and toxicity. Fifty-four patients pretreated with cisplatin or its analogue-based combinations were evaluated. The disease stage of the patients was IIIB and IV. Thirty-eight patients were male, 16 were female, the median age was 65 years, and the WHO performance status was 0–2. Twenty-five cases were adenocarcinomas, 19 squamous cell carcinomas and 10 were undifferentiated. Erlotinib was administered at a dose of 150 mg daily. In case of intolerable adverse reactions, the dose was either reduced to 100 mg daily or treatment was interrupted for a maximum of two weeks. A partial response was observed in 10 (18.52%) and stable disease in 40 (74.07%) patients. The median time to disease progression was 3 months (95% CI 1.7–10.3), and the median survival was 6 months. Concerning toxicity, 53 patients (98.15%) developed a grade 1–2 skin rash, and 1 (1.85%) grade 3. Diarrhea occurred in 9 (16.67%) patients, nausea and vomiting in 4 (7.41%) and gastritis in 2 (3.70%). The majority of patients tolerated the erlotinib treatment. Of note were the 18.52% response rate and 74.07% stable disease.
erlotinib; non-small cell lung cancer
Pancreatic adenocarcinoma is a common malignancy that remains refractory to available therapies. Gemcitabine has long been the standard, first-line agent in advanced disease. The epidermal growth factor receptor (EGFR) is a commonly expressed target in pancreatic cancer that is involved in tumor proliferation, metastasis, and induction of angiogenesis. The addition of the EGFR inhibitor erlotinib to gemcitabine has recently been demonstrated to provide a small, yet statistically significant, survival benefit in advanced disease. This has prompted further research into the applications of EGFR-targeted therapy in pancreatic cancer, albeit with disappointing results. Resistance to these therapies seems highly prevalent and has been implicated in their limited efficacy. The development of rash is associated with treatment efficacy and suggests that predictive factors may one day be identified to guide appropriate patient selection for these agents. Preclinical research has shown promise that resistance to EGFR-targeted therapies can be overcome through a variety of approaches. Application of this research in clinical trials may ultimately yield an unquestioned role for EGFR-targeted therapy in the management of this disease.
cetuximab; drug resistance; epidermal growth factor receptor; erlotinib; gemcitabine; pancreatic cancer