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In Vivo

Cancer Research

Columbia's All-Out Assault on the Deadliest Cancer

As surgeon John Chabot, M.D., looks at his patient's CT scans, he knows what lays ahead in the OR. "That will be an all day affair," he says to the 15 physicians who have assembled to discuss their latest patients.

The CT scans reveal that the tumor has wrapped itself around not one, but two large blood vessels that run through the pancreas. To remove the tumor, Dr. Chabot, associate professor of surgery, will have to reconstruct both of those vessels in a long and difficult procedure.

Most surgeons are not willing to go to such lengths, but surgery – despite advances in therapy and early detection that have raised the survival rates of other cancers – is still a pancreatic cancer patient's best hope. Twenty percent will still be alive after five years, odds that don't seem very good until they are contrasted with the 0.5 percent odds patients face without surgery.

The fact that Dr. Chabot will do the operation is testimony to just how far surgeons at CUMC are pushing the boundaries of the traditional standards for pancreatic cancer patients. In most places, surgery is reserved for the 15 percent of patients who have only one uncomplicated tumor. "The 30 percent who still lack metastases but whose tumors are more complicated have been abandoned," says Dr. Chabot. "We can't accept that."

Getting More Mileage Out of Chemotherapy

The Whipple procedure
The Whipple procedure

Surgery gives a patient with pancreatic cancer the best odds for survival. Pictured above is the Whipple procedure, the most common operation for pancreatic cancer. This difficult procedure involves removing the head of the pancreas, the lower part of the stomach, the entire duodenum and, sometimes, the spleen. The five-year survival rate after this operation is 20 percent. The Whipple procedure was developed in 1935 by P&S surgeon Allen O. Whipple, who was chairman of surgery from 1921-1946.

Optimism for converting inoperable patients (40 percent of all patients) to an operable status has come from seminal research in the lab of Robert Fine, M.D., associate professor of medicine, who has found a treatment that has produced the highest response rates and survival in the United States and Europe.

"In my opinion, we're not using chemotherapy correctly," says Dr. Fine. "We're just throwing drugs at patients. What's needed is a more rational approach. More chemo is not better, what's better is smarter chemo. Our approach is to give specific chemotherapy on a schedule that promotes pancreatic cell death by circumventing the myriad mechanisms of drug resistance in pancreatic cancer."

Once pancreatic cancer has spread to the liver or lymph nodes (cancer is discovered in about half of all patients only after it has metastasized) median survival is four to five months even when patients are aggressively treated with Gemzar, the only drug approved for pancreatic cancer in the past 30 years.

For Dr. Fine, creating smarter chemotherapy meant taking a step back from clinical trials and returning to the lab. For two years, Dr. Fine and associate research scientists Yuehua Mao and Richard Dinnen, and Paul Brandt-Rauf, chairman of environmental health at the Mailman School of Public Health, looked for targets that, when hit, would bypass the tumor's resistance mechanisms and kill the cells.

What came out of these bench studies is a complex chemotherapy regimen, called GTX, which has, in Phase II trials, more than doubled the life expectancy of patients with metastatic disease and increased response rates more than four-fold. In addition, GTX and radiation can convert more than 50 percent of inoperable patients to operable status.

So far, the GTX regimen has been the most successful treatment for patients with metastatic disease, more than doubling life expectancy. In a soon-to-be-published Phase II trial of 35 of Dr. Fine's patients, the tumors shrank in about half and median survival rose to nearly one year, the longest survival rate ever achieved for metastatic pancreatic cancer. Four patients have now survived over three years and one for over four years after their diagnosis of liver metastases.

"What our trials confirm is that the application of scientific principles is vital to getting higher response rates and we can still get a lot of mileage out of chemotherapy," Dr. Fine says. Still, better treatments for metastatic disease may only be possible with more targeted therapies. A gene therapy created by Dr. Fine and Dr. Mao that kills tumors cells without harming normal ones is being prepared for animal testing. The researchers hope to offer the therapy to patients in clinical trials in two years if the therapy, which consists of a virus that delivers a toxic synthetic gene to cancer cells, performs well in mice.

A Cure Through Early Detection?

Until better chemo or targeted therapies are developed, the only way to make a big impact in increasing survival may be through early detection.

Early detection is not a concept that is generally embraced by the medical community at the moment, but CUMC has already started offering screening to people at high risk for pancreatic cancer.

"I think it's not embraced because it's not well known that 10 to 15 percent of cases have a genetic basis," says Harold Frucht, M.D., associate professor of medicine, who works with Peter Stevens, M.D., associate professor of medicine in the gastrointestinal division. "And even if doctors realize some people have an increased genetic risk, the hospitals that see most patients don't have our expertise in detecting small abnormalities with endoscopic ultrasound and MRI. Finally, if you get to the point of finding a lesion, what do you do with it? The Whipple surgical procedure has a high mortality across the country except here at Columbia."

CUMC's venture into early detection is based partly on increasing knowledge about pancreatic cancer risk factors. In the last 10 years, researchers have found that several other inherited cancer syndromes give people a 10- to 100-fold increased risk. People with a family history of the disease, even if they don't carry known genetic markers, also have an increased risk, which increases exponentially with the number of affected relatives.

"I don't want to scare everybody, but the general public should be more aware of the disease," says Dr. Frucht. "Certainly anyone with a first degree relative who has had pancreatic cancer should be aware that they're at greater risk."

Dr. Chabot, with surgeons John Allendorf, M.D., assistant professor of surgery, and Beth Shrope, M.D., assistant professor of surgery, are leading the way in developing techniques that remove parts of the pancreas while preserving function as much as possible. Their results show that a new technique to remove the central part of the pancreas can safely remove the growth with only a few patients developing minor glucose intolerance.

Ending the Hopelessness

With daunting statistics to overcome – 31,860 people in the United States were diagnosed with pancreatic cancer last year, and 31,270 died – many physicians and researchers have given up on pancreatic cancer, and research dollars to fund much-needed research are scarcer compared with other kinds of cancer research.

"One of our biggest challenges is reversing some of the nihilistic beliefs doctors and researchers have about pancreatic cancer, that nothing can be done," Dr. Chabot says.

"I think the future for pancreatic cancer looks promising," Dr. Fine adds. "There have been great advancements in creating animal models that let's us study the molecular changes in early and late cancer, and I'm confident we'll soon identify targets that can stop malignancy."

—Susan Conova