Ian S Zagon
Professor of Neural and Behavioral Sciences
Department of Neural and Behavioral Sciences
Jill P Smith
Professor of Medicine
Division of Gastroenterology
The Pennsylvania State University
College of Medicine
Pancreatic cancer is the most lethal human cancer worldwide and continues to remain a major unsolved health problem. Pancreatic cancer is responsible for 168,000 deaths per year globally,(1,2) claiming over 40,000 lives in Europe,(2,3) 6,500 in the UK,(2) 19,000 in Japan(4) and more than 31,000 in the USA.(5) The majority of malignant pancreatic neoplasms are exocrine in origin, with 90% of these being ductal adenocarcinomas.(6) Incidence and mortality rates are virtually identical in pancreatic cancer, with median survival for all stages of pancreatic cancer being less than 3–5 months from diagnosis.(5,7) The five-year survival for pancreatic cancer is less than 4%.(5) Despite efforts in the past 50 years, conventional treatment such as surgery, radiation and/or chemotherapy have not changed survival rates.(5,8) The problem of treating pancreatic cancer is compounded by a lack of early detection tools, resulting in 80% of patients having unresectable cancer at the time of initial diagnosis.(9)
This article summarises some of the most recent achievements in the field of management and treatment of pancreatic cancer, and provides a glimpse at exciting new therapies, some of which take advantage of the body’s own machinery to modulate growth of these neoplasias.
Resectable pancreatic cancer
Surgery is the only treatment that offers the prospect of a cure for pancreatic cancer. Resectable pancreatic cancer is defined as a pancreatic tumour without evidence of involvement of the superior mesenteric artery or coeliac axis, a patent superior mesenteric–portal venous confluence, and no detection of distant metastasis.(7–10) Approximately 15–20% of patients have resectable pancreatic cancer. However, prognosis for survival is relatively poor even with surgery, and a median survival of 13–15 months and five-year survival of 15–20% have been reported. (8,9,11,12) Greater attention has been recently given to adjuvant and neoadjuvant treatment.(9) Adjuvant therapy has focused on either chemotherapy with fluorouracil or fluorouracil-based chemoradiation.(9,13,14) However, questions have been raised as to the value of chemoradiation, and some researchers support chemotherapy instead.(15) The use of gemcitabine postoperatively instead of fluorouracil is now being considered in clinical trials.
Testing of neoadjuvant therapy using preoperative chemoradiation (followed by surgery) has been reported to improve resection rate and locoregional tumour control.(16) However, more data are needed to support this conclusion, and some investigators do not endorse neoadjuvant therapy as standard practice for pancreatic cancer.(17)
Locally advanced or unresectable pancreatic cancer
Locally advanced pancreatic cancer is defined as a tumour that includes arterial involvement (low-density tumour inseparable from the superior mesenteric artery or coeliac axis) or superior mesenteric vein–portal vein confluence occlusion.(7–10) These patients are judged unresectable because of invasion of the portal or mesenteric vessels, even in the absence of demonstrable metastases. Moreover, there should be no evidence of distant metastatic disease to the chest, liver or peritoneum. Approximately 40% of patients with pancreatic cancer present with unresectable but nonmetastatic disease.(9)
The standard of care for unresectable pancreatic cancer is fluorouracil-based chemoradiation.(8,9) This combined modality of treatment improves survival compared with radiotherapy alone or chemotherapy alone. The palliative benefit of radiation seems to provide relief in more than half of the patients. Unfortunately, this intervention rarely controls pancreatic cancer, and within months of completing treatment there is evidence of local tumour progression or new metastatic disease to the liver or peritoneum.(8)
The use of gemcitabine for single-agent chemotherapy of locally advanced or unresectable pancreatic cancer is currently in clinical trials.(9)
Metastatic and recurrent pancreatic disease
Metastatic pancreatic cancer is characterised by pain, anorexia, cachexia and asthenia. Often, the patient’s clinical status can change rapidly.(7–10) Continuing problems with biliary or gastric outlet obstruction, pain and thromboembolic events are common, and peritoneal carcinomatosis with intestinal dysmotility or intractable ascites is often observed and may be difficult to manage. Gemcitabine, a deoxycytidine analogue, is the standard of care for metastatic pancreatic cancer. Although it confers only a modest survival advantage over treatment with fluorouracil, gemcitabine appears to alleviate more disease-related symptoms, such as weight loss, increased pain and decreasing quality of life, than seen with fluorouracil. Treatment with gemcitabine is not curative for metastatic disease, and treatment with this agent as to its palliative benefit must be examined in the face of such factors as toxicity.(8,9) Higher doses of gemcitabine, along with slower infusion, may offer some improvement in response rate.
Over 70 clinical trials related to treatment of advanced pancreatic cancer (see Resource) are currently in progress in the USA. Combinations of drug therapies, many of which involve a new agent plus gemcitabine, have recently gained a great deal of attention. Although some involve chemotherapy, several capitalise on our increasing knowledge on the biology of pancreatic cancer to manipulate the body’s own machinery for treatment. This exciting new frontier involves biotherapy. Some of these approaches include:
- Phase III clinical trials of Virulizin, a novel immunotherapy that stimulates a patient’s immune system through the activation of macrophages and infiltration of natural killer cells into tumours.(18)
- Phase III clinical trials of a combination of docetaxel (Taxotere) and irinotecan (Camptosar, CPT-11), which affect different stages of the cell cycle, with some patients receiving cetuximab (Erbitux, C225), which is targeted to the epidermal growth factor receptor (EGFR).(19)
- Phase II clinical trials of opioid growth factor (OGF), which serves as an inhibitory agent that stimulates (upregulates) the OGF-OGF receptor (OGFr) and targets the cell cycle.(20) Based on provocative preclinical data showing that a combination of OGF and gemcitabine has a supra-additive effect on inhibiting cell number in vitro, and delays in tumour growth using xenografts of human pancreatic cancer, the need to initiate phase I clinical trials would be timely.(21)
Pancreatic cancer remains the deadliest form of cancer worldwide. Methods for early detection of these neoplasms are needed. Diagnosis of this disease at a stage appropriate for resection would change the dynamics for survival. However, because of the aggressive nature of these cancers – even with resection – and because almost 100% of patients with pancreatic cancer develop metastases, the only recourse for extending survival will be to develop new treatment modalities. The increasing knowledge base on the cellular and molecular biology of pancreatic cancer provides an exciting opportunity to develop methods for diagnosis and treatment of this disease. Agents that interfere with the signal transduction pathways and specific pathways that mediate the growth of these neoplasms can be envisioned to be the foundation for overcoming this devastating disease. Taking advantage of the biology of these cancers has already led to the development of a variety of biotherapies whereby native growth mechanisms (eg, blockade of growth stimulators, negative growth factors) are utilised. These promising results should have considerable impact on hospital practice and prescription policies as they evolve in the next 5–10 years.
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Pancreatic Cancer Action Network (PanCAN)
Clinical trials for the treatment of advanced pancreatic cancer. For more information: