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Pancreatic Cancer: The Prognosis Is ChangingBy Sunita Patterson
“If you get it, you die of it.” That’s the traditional view regarding pancreatic cancer, and by and large, that view has been justified. Although pancreatic cancer ranks 10th in men and 11th in women in incidence among cancers, it ranks 4th in cancer-related deaths, and the 5-year overall survival rate is only 5%.But within the past few years, significant progress has been made in helping patients with operable disease. Further, recent insights into pancreatic cancer have led to clinical trials of a range of new treatment approaches for patients with advanced disease. The reasons that pancreatic cancer presents such a challenge are well known. First, it is almost always diagnosed after it has spread. Patients tend to present with vague symptoms—for example, gastrointestinal distress or pain—that more commonly arise from other medical conditions such as gallstones, ulcers, or reflux. By the time these symptoms have developed and other causes have been excluded, the cancer is often locally advanced or metastatic, at which point the likelihood of surviving the disease drops dramatically. A second reason that pancreatic cancer is challenging is that surgery—the treatment option that, when feasible, gives the best prognosis—is often precluded by the complexity of the anatomy in the area, the extent of disease, and the older age of many patients. Only 10%–15% of patients are able to undergo surgery. For patients who can’t undergo surgery, chemotherapy (usually with gemcitabine [Gemzar]) is part of the standard treatment. But these patients face a third reason that pancreatic cancer is so challenging: even if tumors respond to gemcitabine initially, almost all rapidly become resistant to the drug. Together, these reasons explain why most patients diagnosed with pancreatic cancer die within the first year—and hence, pancreatic cancer’s historically dismal reputation. What’s encouraging today is that there are a number of new approaches to pancreatic cancer treatment, according to James L. Abbruzzese, M.D., a professor in and chair of the Department of Gastrointestinal Medical Oncology at The University of Texas M. D. Anderson Cancer Center. Some of these approaches—such as a new strategy for multidisciplinary care for operable disease—have been demonstrated to be effective, and others—such as new types of anticancer agents—are being tested in clinical trials at M. D. Anderson. These strategies approach the disease from many angles, with many mechanisms of action. “We’re trying to be as comprehensive as we can,” Dr. Abbruzzese said. Timing surgery for better results In the United States, most patients with resectable pancreatic cancer undergo surgery as their first treatment and then receive systemic chemotherapy or chemoradiation. At M. D. Anderson, however, many patients are being treated on protocols that involve chemotherapy or chemoradiation first and then surgery. Clinicians are excited about the increased survival durations they’ve obtained with this approach. Initial studies of this treatment approach have shown benefits for two groups of patients. For patients with resectable cancers, two phase II trials with a total of 176 patients have been completed. In one trial, patients received gemcitabine and radiation before pancreaticoduodenectomy; in the second, patients received gemcitabine and cisplatin, then gemcitabine and radiation, before surgery. The median overall survival durations in the patients who completed treatment were 34 months in the first trial and 31 months in the second. Some patients with borderline resectable cancers—those who were not clear candidates for surgery initially because of the extent or location of disease—also benefited from this treatment strategy, the M. D. Anderson team found. One hundred sixty such patients were enrolled in a trial of chemotherapy or chemoradiation as initial therapy. In the 66 patients whose tumors were clearly operable after systemic therapy, the median survival duration was 40 months. “We’re really starting to see some tangible improvements,” said Dr. Abbruzzese.
There are several rationales for starting with preoperative chemotherapy or chemoradiation. “For one, most patients likely have small numbers of metastatic cells that we can’t see on our x-rays,” said Jason B. Fleming, M.D., an associate professor in the Department of Surgical Oncology. “Giving systemic therapy first is a chance to treat those micrometastases.” A second rationale is that the response to systemic therapy helps clinicians better assess which patients will receive the most benefit from surgery. The decision to perform surgery isn’t taken lightly. Pancreaticoduodenectomy, also called the Whipple procedure, is a major operation that involves removal of portions of the pancreas, stomach, duodenum, common bile duct, and gallbladder and then reconstruction of connections between the pancreas, jejunum, common bile duct, and stomach. A typical hospital stay at M. D. Anderson is 11 days, and the recovery period is several weeks. Although the in-hospital death and complication rates are lower at M. D. Anderson than the national average, “the surgery carries significant risk,” Dr. Fleming said. “So our treatment philosophy is to get the most out of the operation that we can, and our recent studies suggest that patients who receive preoperative therapy followed by surgery benefit more than when the surgery is performed first.” A third rationale for giving preoperative therapy—specifically, chemoradiation—is that the rate of positive resection margins may be reduced. The local recurrence rate for pancreatic cancer after surgery has been as high as 50%. One reason for this high rate is that it’s hard for the surgeon to remove all the tumor cells close to the major blood vessels. Radiation therapy may help kill those tumor cells before the surgeon even goes in. “In our experience so far,” Dr. Fleming said, “the local recurrence rate is much lower—11%–25% in our recent reports—when chemoradiation precedes surgery.” A randomized trial to confirm these initial findings will start soon. Doing surgery after preoperative chemotherapy or chemoradiation has another advantage for investigators. “The nice thing about this approach,” Dr. Fleming noted, “is when you take the tumor out in the end, you can look at it and see how well the systemic therapy performed. You can also study the resistant cells that survived all that treatment.” Systemic therapy: looking for the right combination Unfortunately, many resistant cells do survive existing systemic therapies for pancreatic cancer, including the standard agent, gemcitabine. This resistance is the reason that inoperable disease has had such a poor prognosis: patients with locally advanced pancreatic cancers have a median overall survival duration of about 12 months from the time of initial diagnosis; those with metastatic disease, only about 6 months. Use of gemcitabine has not prolonged survival durations substantially but has been helpful with palliation of disease symptoms. To try to improve survival in patients with advanced disease, M. D. Anderson researchers are testing a range of chemotherapeutic and biologic agents, often in combination with gemcitabine, in hopes of finding synergistic anticancer mechanisms. For example, a phase II trial now under way for patients with resectable disease combines gemcitabine and erlotinib (Tarceva) with or without radiation as preoperative therapy. These agents attack tumor cells in different ways. Gemcitabine disrupts DNA replication in tumor cells and sensitizes them to radiation. Erlotinib inhibits epidermal growth factor receptor, a cell-surface protein that signals cells to divide and is overexpressed in many cancers, including those of the pancreas. In another trial, designed for patients with locally advanced disease, erlotinib is being combined with bevacizumab (Avastin), which inhibits tumor angiogenesis; capecitabine (Xeloda), which inhibits DNA synthesis; and radiation therapy. Other mechanisms being evaluated in current clinical trials are prevention of DNA repair (with BSI-201) and inhibition of cell division (with everolimus). Each of these agents has shown promise in preclinical studies or in patients with tumors at other sites. Countering chemoresistance
The key to success in pancreatic cancer may be combining anticancer drugs with agents that reverse chemoresistance. The phenomenon of chemoresistance is of central interest to M. D. Anderson researchers Gary E. Gallick, Ph.D., and Craig Logsdon, Ph.D., professors in the Department of Cancer Biology, and David J. McConkey, Ph.D., professor in the departments of Cancer Biology and Urology. The three meet weekly to compare notes. “You can kill some pancreatic cancer cells with standard chemotherapy, but most you can’t,” Dr. Logsdon said. “Why is one cell resistant and another one not? That’s the question we want to answer.” In searching for the mechanisms involved, through gene expression profiles and molecular biology studies, M. D. Anderson researchers have obtained results that suggest that gemcitabine chemoresistance is characterized by a predictable pattern of changes. For example, “one of the striking things that appears to happen is that some of the tumor cells undergo epithelial-mesenchymal transition (EMT),” Dr. Gallick said. “And one of the properties of mesenchymal cells is they are much more migratory, much more invasive”—a property essential to a tumor cell becoming metastatic. In addition, this property is associated not only with resistance to gemcitabine but also with resistance to many other agents. This new understanding of the nature of resistance has prompted several new approaches to treatment. “We think we will be able to reverse the resistance phenotype and resensitize the cells,” Dr. Gallick said. “That’s where I think things are going to go. That’s why we’re excited.” One treatment approach being tested involves targeting substances involved in EMT. Dr. Gallick’s lab has been studying c-Met, a growth factor receptor that is overexpressed in pancreatic tumors. c-Met levels are increased in cells that have undergone EMT. Dr. McConkey’s lab has been studying the histone deacetylase (HDAC) class of cellular enzymes, which appear to be involved in EMT and gemcitabine resistance. Lab studies involving inhibition of c-Met and HDACs in cancer cells have now led to clinical trials. The c-Met inhibitor XL184 and the HDAC inhibitor suberoylanilide hydroxamic acid (vorinostat) are being tested in ongoing and upcoming clinical trials at M. D. Anderson. With both c-Met and HDAC inhibitors, investigators hope that EMT can be undone—that the transformed mesenchymal cells will revert to the epithelial phenotype and thereby become sensitive to gemcitabine and other agents. This work addressing reversal of chemoresistance and the potential benefits to patients with pancreatic cancer is still hypothetical, Dr. McConkey said. However, “the good news is we have a lot of excellent models, we have good collaborations in place, and we do expect to get some answers quickly. We think we’re really onto something here.” In most cases, the diverse projects in progress in M. D. Anderson’s labs have clinical components, Dr. Abbruzzese said. “We’re trying to be very translational, to take applications from the laboratory to the clinic.” With active research on so many fronts and the clinical gains already seen, it seems only a matter of time before pancreatic cancer’s prognosis improves.For more information, call Dr. Abbruzzese at 713-792-2828. Other articles in OncoLog, October 2008 issue:
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