From OncoLog, July/August 2006, Vol. 51, No. 7/8

Pancreatic Cancer: It Takes a Village

by Sunni Hosemann

Pancreatic cancer is known to be an intractable and aggressive cancer, and its reputation is well deserved. Although there are several types (and some exotic subtypes), the most typical—95%—are exocrine adenocarcinomas. They are especially difficult cancers to diagnose and treat because they usually give no early signal to herald their presence, no definitive symptom to alert patient or physician that something is very wrong. Anatomy doesn’t help the situation: the pancreas lies deep within the body, making imaging difficult, and it is an organ rife with vital vessels and ducts that make tumor excision tricky. Thus, most pancreatic cancers are quite advanced by the time they are discovered and are difficult to treat.

“Survival rates for this cancer are low and haven’t changed dramatically in the past decade, except for patients who have surgery,” said James Abbruzzese, M.D., a professor and chair of M. D. Anderson’s Department of Gastrointestinal Medical Oncology. “We haven’t seen the major shift we’d like to see.” But, he notes, bringing about that shift is the passion of many scientists and physicians at M. D. Anderson who are collaborators in the Pancreatic Cancer Study Group, a program remarkable for the number of people involved and the diversity of disciplines represented—laboratory scientists, epidemiologists, imaging specialists, medical oncologists, and more. This group has a clinical and research agenda that is at the same time broad and focused: no gene or cell signal is unexamined, no minor tweak too unimportant, but all are focused on the larger goal as well. It is a team with a true translational research mindset, in which each contribution is interdependent on others and all members place a high value on collaboration.

The best tools today

Surgery—pancreaticoduodenectomy—is still the only measure for pancreatic cancer that can be curative. Patients who are candidates for the surgery are the ones more likely to survive. This operation—also known as a Whipple procedure—is a very serious and lengthy surgery, taking anywhere from 5 to 10 hours. A decade ago, the mortality rate for the operation alone was about 25%, but that has totally changed. “Now, it is uncommon for a patient to die following this surgery at a major center,” said Jeffrey E. Lee, M.D., a professor in the Department of Surgical Oncology.

But surgical advances, said Dr. Lee, are by no means the only significant factors. Better perioperative care—including preoperative medical assessment and anesthesia and support from specialties such as endocrinology, nursing, and nutrition service—help account for the significant reductions in both morbidity and mortality. In Dr. Lee’s view, advances in the preoperative workup—leading to better identification of patients who can successfully undergo such a major operation and are most likely to benefit from surgery—have been critically important. “We want to be as certain as possible that patients selected for this surgery do not have evidence of metastasis and that we can completely remove the tumor,” said Dr. Lee. “Our ability to do that is largely due to an improvement in the quality of preoperative imaging studies,” he said.

Eric Tamm, M.D., an associate professor in the Department of Diagnostic Radiology, describes new imaging technologies developed at M. D. Anderson that yield rapid scans, thinner slices, and smooth, “exquisite” images. “It’s like the difference between a light bulb and a searchlight,” he said. In addition to state-of-the-art equipment, he cites a new 64 detector-row helical computed tomography (CT) scanner as an example. He and his colleagues are testing software that allows the images to be viewed in planes different from those in which they were scanned. This is particularly useful in pancreatic cancers because it allows for a thorough search for tumor-caused distortions in critical veins and arteries that may not otherwise be visible. The extent and location of vessel involvement are critical determinants of operability.

A preoperative roadmap

At M. D. Anderson, the helical CT scan is the initial staging procedure for a patient with suspected pancreatic cancer. “We try to do it first, to have a baseline image before any manipulation that could cause inflammation in the organ,” said Dr. Tamm. The next common step in the workup is endoscopic ultrasound (EUS). A skilled endoscopist can precisely document the pancreatic lesion, search for smaller tumors that may have evaded CT detection, examine nearby vessels and lymph nodes, and look for evidence of local and metastatic disease spread.

Jeffrey H. Lee, M.D., an interventional endoscopist, who is an associate professor in the Department of Gastrointestinal Medicine and Nutrition, says that the combination of CT and EUS is “synergistic”—that together, they provide a thorough preoperative overview. At M. D. Anderson, an EUS is performed simultaneously with an endoscopic retrograde cholangiopancreatography. Here, the endoscopist can obtain a tissue sample by fine-needle aspiration and can also place stents in tumor-occluded bile ducts to relieve the obstructive jaundice that is usually present.

According to Dr. Jeffrey H. Lee, the combined power of these imaging tools helps the treatment team make decisions about surgery for a given patient. “For patients who will have surgery, it helps determine whether neoadjuvant therapy (usually chemoradiation) could be helpful and becomes a roadmap for the surgeon,” he said. For all patients, it provides staging that once had to be done surgically and more accurately pinpoints who is most likely to benefit from surgery. As the techniques become more advanced, the stage of disease can be more precisely defined and treatment tailored to the extent of the cancer in a specific patient.

One surgical advance popularized by M. D. Anderson involves the removal and replacement of blood vessels close to the pancreas that can prevent complete tumor removal. Patients whose tumors do not involve major arteries but do involve the superior mesenteric or portal vein may have the tumor removed and the veins reconstructed. “Our group helped develop criteria to select patients for this technique and refined the surgical procedures to allow successful tumor removal under these circumstances,” noted Dr. Jeffrey E. Lee. “We have found that these patients can do as well as those who did not require the resection.”

More questions than answers

“Still,” said Dr. Jeffrey E. Lee, “pancreatic cancer is one of the toughest problems in solid tumor oncology, and even patients who are candidates for surgery remain at high risk for recurrence.” Because of that, clinical work is ongoing to try to determine the best combination of treatments to use either in conjunction with surgery, when possible, or instead of surgery.

Today, the enrollment of patients with pancreatic cancer into clinical trials has dramatically increased. Currently at M. D. Anderson, there are clinical trial options for patients with every stage of disease. In addition, novel systemic therapies are being studied as more is learned about the mechanisms of the disease; examples include tyrosine kinase inhibitors, antiangiogenic agents, and vaccines. One interesting example of a novel agent is curcumin, which is currently being evaluated in a phase I trial. This compound, found in the spice turmeric, acts to suppress the transcription factor NF-kappa B, which is constitutively activated in pancreatic cancer. Studies are also under way of other agents that target NF-kappa B, as well as agents that target other transcription factors. For example, a clinical trial will soon open involving dasatinib, an inhibitor of the protein tyrosine kinase Src, which is aberrantly activated in 70% of pancreatic cancers.

There are other promising therapies in the pipeline, and discoveries are moving quickly from the laboratory into the clinic, as evidenced by the efforts of the Pancreatic Cancer Study Group at M. D. Anderson. However, at present, treatment must be highly individualized. For this reason, many physicians agree that patients with pancreatic cancer are best served by treatment in a major cancer center and, when possible, as part of a clinical trial.

Eye on the future

The research agenda in pancreatic cancer is broad. It is looking for better treatments and a better understanding of who gets this disease and why and how it might be found earlier. M. D. Anderson’s receipt of the National Cancer Institute Specialized Programs of Research Excellence (SPORE) grant for pancreatic cancer brings together a diverse team of scientists to study the equally diverse aspects of this disease, from laboratory research to clinical trials. Thus, one of the focal points of the pancreatic cancer grant is the Tumor Bank and Database. Tissue and fluid samples from every possible procedure—surgery, biopsies, endoscopy—are saved and logged, along with correlating clinical information. The result is a growing compendium of vital information that can be accessed by scientists studying pancreatic cancer. Another important data collection effort is gathering epidemiologic information aimed at answering the question, Who is at risk for this disease?

The most consistently identified epidemiological risk factor for pancreatic cancer is cigarette smoking; fully one-third of pancreatic cancers occur in smokers. There also seem to be potential relationships between the development of pancreatic cancer and other environmental carcinogens—radiation and hydrocarbon solvents, for example. These kinds of data will add a critical dimension to the laboratory and clinical studies that look into the questions of how carcinogens are metabolized—something that may differ among individuals. Epidemiological studies will also shed light on the importance of family history and heredity, because certain hereditary conditions have known associations with pancreatic cancer, as do genetic point mutations or amplifications, overexpression of oncogenes, and alterations of tumor suppressor genes. Thus, harvesting and organizing family and health history information are important.

For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

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