Seeking a Systematic Approach To One of the Deadliest Tumors

Actor Michael Landon. Jazzman Count Basie. Opera legend Luciano Pavarotti. American professor Randy Pausch. These four well-known men have one thing in common: all were killed by pancreatic cancer, one of the deadliest forms of the disease. Pausch in fact gave his well-known “Last Lecture” speech — which became a New York Times bestseller — in 2007 after learning that his pancreatic cancer had become terminal.

With a dismal five-year survival rate of less than 5 percent — a rate that has remained essentially unchanged for the past two decades — pancreatic cancer is the fourth leading cause of cancer deaths in the United States. This year, more than 38,000 Americans will be diagnosed with pancreatic cancer and nearly 34,000 will die from it. The remainder face a bleak outlook, with complete remission still extremely rare.

Why is pancreatic cancer so deadly? For one thing, it is rarely detected in its early stages because the initial symptoms are often confusing and non-specific — loss of appetite, weight loss, vague abdominal discomfort. As with ovarian cancer, it can often be confused with other illnesses, such as gastrointestinal disorders.

“I saw a 51-year-old woman yesterday who was just diagnosed with metastatic pancreatic cancer,” said Dr. A. James Moser, co-director of the Pancreatic Cancer Center and assistant professor of surgery at the University of Pittsburgh School of Medicine. “She had been recently diagnosed with diabetes, when there was none in her family,” Moser recalled. “Then she started to lose her appetite, wasn’t feeling well, and had vague belly pains that were hard to describe. She slowly lost 40 pounds, which people were attributing to her new diet for diabetes, but in fact, it was metastatic pancreatic cancer.”

The woman’s story is not uncommon, says Moser, who with his partner Dr. Herbert Zeh treated professor Randy Pausch until his death this past summer. In fact, only about 10 percent to 15 percent of pancreatic cancer cases are caught early — sometimes, because the tumor is close enough to the bile duct to block it and create obvious and severe jaundice.

Because the incidence of pancreatic cancer is not high enough for screening tests such as mammograms to be beneficial, Moser stressed that it’s essential for people at elevated risk of pancreatic cancer to be vigilant should unsettling symptoms arise.

One of the biggest risk factors for pancreatic cancer is simply advancing age. The overall risk of pancreatic cancer in the general population is 10.7 in 100,000, while at the age of 80, the risk jumps to 104 in 100,000. (But age is no guarantee; Moser’s youngest pancreatic cancer patient is 27.)

Other important risk factors include two or more close relatives who have had pancreatic cancer; cigarette smoking; being of Ashkenazi Jewish descent; having chronic pancreatitis; and having the genetic mutations BRCA2, p16, and STK11, which are currently known to be associated with pancreatic cancer.

And just recently, researchers at the University of Texas M.D. Anderson Cancer Center discovered that exposure to the hepatitis B virus may increase the risk of pancreatic cancer. The study, published in the Oct. 1 edition of the Journal of Clinical Oncology, also suggests that patients with this lethal form of cancer who are treated with chemotherapy may face an increase in the reactivation of their hepatitis B virus.

“If this study is validated, it will give us more information about the risk factors of pancreatic cancer and possibly even help prevent it in some cases,” said lead author Dr. Manal Hassan, assistant professor in M.D. Anderson’s Department of Gastroin-testinal Medical Oncology.

There didn’t seem to be an association between pancreatic cancer and hepatitis C, but “with hepatitis B, the study demonstrated that there was a two- to three-fold increase in risk for pancreatic cancer for patients who have had evidence in their blood of prior exposure to hepatitis B,” Hassan’s colleague, Dr. James Abbruzzese, recently told Voice of America.

The good news is that there’s a vaccine for hepatitis B; the bad news is that additional research is needed to verify the results.

That’s why early detection is still key and can make all the difference. Moser recalled the case of a young man in his early 40s who sought help because his mother and aunt had died of pancreatic cancer. “He said, ‘I’m having these funny pains and I’m worried.’ We screened him and sure enough, there was a cystic tumor in his pancreas. Given his significant risk, we operated and he had noninvasive pancreatic cancer,” said Moser. “His first cousin didn’t want to be screened, and subsequently went on to die of the disease.”

So to make screening easier for high-risk patients such as these, Moser and his colleagues at Pitt, along with a growing multi-institution pancreatic cancer research team, have been working to make it less invasive. Currently, the most advanced method is called endoscopic ultrasound, which uses a thin, flexible tube passed through the patient’s mouth or anus to create an image of the pancreas using sound waves. Moser’s group at Pitt has been the leader in using genetic analysis aspirated fluid collected during an endoscopic ultrasound to identify the pancreatic cysts at highest risk of developing cancer.

Another minimally invasive tool for identifying pancreatic cancer is called optical coherence endoscopy. Using a fixed frequency of light through the endoscope, doctors can see changes in pancreatic cells indicating that they are abnormal and on their way to becoming cancerous.

But nothing as simple as a blood test or a stool test for pancreatic cancer is currently on the horizon. “That would be the Holy Grail, but neither exists,” Moser said.

Still, researchers are working to develop biomarkers associated with an increased risk of the disease. For instance, Pitt doctors have developed a panel of five proteins found in the blood that appear to be associated with a significantly increased risk of pancreatic cancer. “Other such panels have been identified elsewhere, but so far, none have passed muster” with the Food and Drug Administration, according to Moser. “They’re all still being fine tuned.”

Efforts to find such biomarkers though got a boost in September, when investigators with the Sidney Kimmel Cancer Center at Johns Hopkins and with Duke University reported the results of an attempt to sequence nearly all the known protein-making genes in pancreatic cancers.

The researchers found that the typical pancreatic cancer contained 63 genetic alterations — with each individual tumor having its own peculiar assortment of genetic modifications. The researchers suggested that a small number of commonly mutated genes — which they called “mountains” — and a much larger number of rarer, low-frequency gene changes — dubbed “hills” — interact to cause these cancers.

“That’s the challenge,” said Moser. “There are so many different genes involved that no one knows the primary event.”

Early detection is only part of the puzzle. Moser’s program collaborates with other researchers from the Pancreatic Cancer Ac-tion Network (PanCan) to put patients on clinical trials, most involving new therapies that fall under the rubric of “biologics” — therapies aimed at attacking specific tumor targets while producing fewer side effects than traditional chemotherapy.

A notably successful example in breast cancer is the drug Herceptin, which is extremely potent in attacking the approximately one-fourth of all breast cancers that make too much of a particular protein called HER2/neu.

There’s no Herceptin yet for pancreatic cancer, but scientists are working on it. “We don’t yet know the targets for pancreatic cancer as well as we do with breast cancer. HER2/neu, for example, is over-expressed in pancreatic cancer too, but not nearly as much,” Moser said. “There’s been no systematized approach to clinical trials for pancreatic cancer as there has been for breast cancer, but we’re working to change that. We want to bring a 21st-century biologics approach to this disease.”

For example, there is a particular oncogene (a gene that causes the transformation of normal cells into cancerous tumor cells) called KRAS. People who have a “wild type” of the KRAS oncogene appear to respond better to drugs targeting a pathway called the epidermal growth factor receptor, which has been identified as an important target for cancer treatment. A multi-institution study now under way is investigating potential drug treatments for patients with wild-type KRAS.

Moser and his colleagues at Pitt are also studying hybrid approaches to treating pancreatic cancer, combining what he calls the “Buck Rogers future agents” with current chemotherapy drugs, including those that starve tumors of their blood supply.

One such drug aimed at choking off new blood vessels, EndoTAG-1, more than doubles survival time from 7.2 months to 13.6 months in patients with inoperable pancreatic cancer, according to results presented at the 33rd Congress of the European Soci-ety for Medical Oncology.

Researchers are even looking at an HIV drug as a possible treatment because it’s been shown to increase chances of recovery from pancreatic cancer. In fact, trials are under way across the country and around the world to fight this “silent killer” at every stage — including advanced surgical techniques for early stage pancreatic cancer.

“We can’t forget that surgery is the only known treatment that currently leads to significant long-term survival and actually, in some cases, leaves the patient cancer free,” said Moser. “Often, the problem with pancreatic cancer is like real estate. Tumors arise near major blood vessels to the liver and intestine, and involve those vessels. That’s why many of these tumors that involve a vein called the portal vein have been thought to be essentially inoperable.”

But in specialized cancer centers such as Pitt, that’s no longer the case. “We treat patients with portal vein-involvement chemotherapy before surgery, then operate, take the vein out and replace it,” Moser explained. “If we have to remove too much, then we replace it with one of the jugular veins from the neck — you only need one, and God gave you two.”

Pancreatic cancer needs a “Thomas Edison approach,” Moser concluded. “A reporter asked Edison if he was discouraged be-cause he’d made 10,000 different light bulbs that didn’t work. He said, ‘I haven’t failed. I’ve just found 10,000 ways that don’t work.’ He pulled a hair out of his head, and that was the first filament of a light bulb, which worked for 24 hours.

“There’s nothing wrong with doing trials and when things don’t work, they don’t work. New agents like those we are investi-gating … put properly into clinical trials with large numbers of patients have the potential to show us the way.”

SIDEBAR

Legislation Pending to Push Pancreatic Cancer Research

On Sept. 24, 2008, the first substantive piece of legislation aimed at pancreatic cancer was introduced in Congress.

The National Plan to Advance Pancreatic Cancer Research Act (H.R. 7045), seeks to launch a Pancreatic Cancer Research Ini-tiative to provide a national focus on finding a cure for pancreatic cancer by better targeting research, developing a cadre of committed scientists, and promoting physician and public awareness.

It would also create a new five-year grant pilot project specifically for research into the most lethal cancers (pancreatic cancer and potentially others), as well as strengthen and expand centers of excellence for pancreatic cancer research.

To find out how to support the bill, contact the Pancreatic Cancer Action Network at (877) 272-6226, or visit http://pancan.org/Public/take.html.

About the Author

Gina Shaw is the medical writer for The Washington Diplomat.