By Douglas Steinberg, PhD

The American Cancer Society says 30,700 new cases of pancreatic cancer, one of the worst diagnoses a doctor can deliver, will occur in the United States this year. But there are also new words emerging around pancreatic cancer, words such as promising and hopeful used to describe research and clinical trials on this deadly cancer.

Pancreatic cancer “is a hard disease to diagnose,” says James L. Abbruzzese, MD, chairman, gastrointestinal medical oncology, M. D. Anderson Cancer Center, Houston. But he identifies the “wiring” of pancreatic tumor cells—that is, their genetic patterns and internal molecular interactions—as perhaps a more calamitous factor, describing it as “so abnormal that it contributes to tremendous aggressiveness of the cancer and marked resistance to therapies.”

It might therefore come as a surprise that there is reason for cautious optimism about pancreatic cancer treatment. “We’re understanding better and better how pancreatic cancer cells work,” Dr. Abbruzzese says, “and I think that over time, that’s going to translate into some new opportunities.”

Oncologists emphasize that these therapies probably won’t cure pancreatic cancer but might make it more manageable and improve a patient’s quality of life. Pancreatic cancer is a very difficult problem, says Dr. Abbruzzese, and it’s going to require a lot more work and energy over the next 10 to 20 years.

Standard Treatments
Patients with pancreatic cancer typically complain of various non-specific symptoms, including fatigue, abdominal pain, and constipation. At first, physicians often wrongly suspect stomach-acid reflux, gallstones, or ulcers.

In 15-20% of cases, the tumor hasn’t spread to other organs (metastasized) and can be removed surgically because it has yet to entangle vital nearby structures. Patients whose tumor is in the “head” region of the pancreas then undergo a Whipple procedure, in which surgeons cut out the diseased section and hook the remainder up to the small intestine. In some cases, the entire pancreas must be removed.

“You can get along fine without it,” says John S. Macdonald, MD, medical director, St. Vincent’s Comprehensive Cancer Center, New York. “You have to take insulin and some oral enzymes to help with digestion.”

Though it’s the only chance for a complete cure, surgery is often a prelude to recurrence of the disease. Kay F. Kays, a 53-year-old from Phoenix, underwent a Whipple procedure in 1994. Her surgeon, Larry Koep, MD, recalls that the tumor’s margins were cancer-free and its cells were well differentiated—that is, they were more like normal pancreatic cells. Yet Dr. Koep had to remove Kays’ entire pancreas in 1999 after another tumor appeared, and he took out a lymph node mass in July 2002.

“Somebody will ask me, ‘How can you have pancreatic cancer? Your pancreas is gone!’” Kays recounts. “And I say, ‘It’s like boiling a chicken. You can boil the chicken and take it out, but you still have chicken broth.’ Unfortunately, even with everything they do, they can never say that they got it all.”

In 1996, Gemzar® (gemcitabine) became the first agent approved by the U.S. Food and Drug Administration (FDA) for treating inoperable pancreatic cancer. Well tolerated by patients and relatively easy to administer, Gemzar masquerades as one of DNA’s four building blocks, causing DNA replication to grind to a halt.

In clinical trials of Gemzar, about a quarter of patients experienced clinical benefit. “Their pain got better, their nutrition got better, their general quality of life got better,” Dr. Macdonald notes. The probability of one-year survival was raised as well, from only 2% with the former mainstay of treatment, 5-FU (fluorouracil), to 18% with Gemzar. The upshot, says Dr. Abbruzzese, is that “probably all patients with pancreatic cancer are getting treated with Gemzar at some point in their clinical course.”

New Chemotherapeutic Approaches
Gemzar has served as a building block for newer regimens, one of which is to combine it with other chemotherapeutic drugs such as 5-FU, Platinol® (cisplatin), and Camptosar® (irinotecan). Combination therapy might be more effective, but Dr. Macdonald warns that each drug adds some degree of toxicity.

“Since these are not curative therapies, you have to balance the side effects versus improved quality of life,” he explains.

After Jed Mattes, then a 45-year-old literary agent in New York, had a Whipple procedure in June 1998, he received Gemzar and 5-FU for four months of adjuvant therapy. His CT scans were clean until early 2000 when small tumors were detected in his right lung. Gemzar, this time combined with cisplatin, checked these malignancies for two and a half years before they began growing again. Mattes tried different strategies to bring the tumors under control, but died in July 2003. In February, however, he had remained positive about chemotherapy, saying, “I know I’m an anomaly to be alive at all, and needless to say, I’m grateful.”

Combining Gemzar with Taxotere® (docetaxel) and Xeloda® (capecitabine, the oral drug that metabolizes into 5-FU within tumor cells) shows intriguing signs of efficacy, according to Robert L. Fine, MD, director of the experimental therapeutics program, Columbia College of Physicians and Surgeons, New York. Xeloda sabotages the DNA replication needed for tumor growth in a different way than Gemzar, and Taxotere gums up one of the cancer cell’s structural proteins.

Together, the “GTX” drugs, as they are known, are synergistic in their antitumor effects, explains Dr. Fine. “When you have synergy in chemotherapy, you can reduce the dosages, so you have less toxicity to the patient.” For patients whose cancer didn’t respond to GTX, Dr. Fine devised a novel way of administering the drugs, which he has dubbed “alternating GX-T,” that induces independent cell death.

In a recent pilot study, Dr. Fine and his colleagues administered the GTX combination to 44 patients with advanced pancreatic cancer. A “partial response”—which, he explains, is more than 50% shrinkage at tumor sites—was observed in the liver metastases of 15 of 32 patients. Liver metastases completely disappeared on CT and MRI scans in three of the original 15 patients when the GTX regimen was continued for a total of eight to nine cycles. Another 28% of patients had minor response to GTX or stable disease in their liver tumors.

Dr. Fine says tumors in 12 other subjects were initially inoperable but hadn’t spread to the liver. After drug treatment and radiation, eight of these patients had successful Whipple surgery with negative margins and showed no signs of disease. For patients who failed GTX and received alternating GX-T
chemotherapy, a 30% response rate and 40% stable disease rate was seen.

Dr. Fine says these results are quite exciting in pancreatic cancer, considering that 30% of the patients had failed previous Gemzar chemotherapy.

Enid Goldman is a 72-year-old psychotherapist in New York and a GTX success story. Diagnosed with pancreatic cancer in January 2002, she was told by two leading New York hospitals that her artery-hugging tumor was inoperable and to put her affairs in order.

She recalls getting prepared to die, before a family friend steered her to Dr. Fine, who says GTX therapy shrank her tumor by 75% so that she could have a Whipple procedure. Six months later, she was still disease-free and receiving an adjuvant pancreatic cancer vaccine to prevent a recurrence. She had even resumed weight-training twice a week, a regimen her illness had forced her to suspend.

A multicenter phase II study of GTX for advanced pancreatic cancer is already in place, and by next year Dr. Fine hopes to initiate a phase III trial that assigns patients to GTX or Gemzar alone.

Another chemotherapeutic agent, Orathecin™ (rubitecan) is being compared to drugs such as Gemzar and 5-FU in three separate phase III trials after early studies showed evidence of activity against pancreatic cancer.

Results from one of those trials comparing Orathecin to “best choice” therapy were released earlier this year. The study found that 7%, or 13 of 196 patients, receiving Orathecin experienced either a complete or partial response compared to less than 1%, or one of 211 patients, receiving “best choice.”

Ramesh K. Ramanathan, MD, director of the colon and gastrointestinal cancer program, University of Pittsburgh Cancer Institute, explains that Orathecin belongs to a family of chemotherapeutic agents known as topoisomerase 1 inhibitors.

By inhibiting the activity of the topoisomerase enzyme, these compounds prevent DNA from unraveling, a step required for both normal and cancerous cells to grow.

Other members include Camptosar, Hycamtin® (topotecan), and exatecan (DX-8951f). In laboratory and clinical studies, the four compounds have exhibited different activity levels against different cancers, says Dr. Ramanathan. Besides Orathecin’s effect on pancreatic tumors, its main advantage, he says, is that it’s an oral drug.

Antifolate agents also inhibit DNA replication, though by a different route. For Alex A. Adjei, MD, PhD, associate professor of oncology, Mayo Clinic, Rochester, Minnesota, Alimta® (pemetrexed) is the most promising such agent for use against pancreatic cancer. He notes that, unlike other antifolates that inhibit a single enzyme, Alimta affects at least three.

“Because cancer cells are so complex, you’re more likely to get an effect—at least in theory—if you block more than one enzyme,” he says. Drug resistance, he adds, is less probable if a drug attacks a cancer cell at different points.

In a phase II study released last year, 42 patients with advanced pancreatic cancer received a Gemzar/Alimta combination, and about 32% survived for one year. A 520-patient phase III trial that compares the combination versus Gemzar alone is currently under way.

Targeted Agents
New medications, known as targeted agents, impact cancer-related proteins that are either mutated or overexpressed in cancerous cells, the “faulty wiring” in the conglomeration of abnormalities in pancreatic cancer.

Perhaps the most prominent of these agents are those targeting a protein on the cell’s surface called the epidermal growth factor receptor (EGFR). Many pancreatic tumors produce abnormally high levels of this receptor, and its activity is believed to contribute to their uncontrolled growth. The new agents inhibit EGFR’s activity.

Two EGFR inhibitors have been tested against advanced pancreatic cancer: Tarceva™ (erlotinib) and Erbitux™ (cetuximab or C225). In 2001, Dr. Abbruzzese and his colleagues reported on a 41-patient study of Erbitux. Five patients showed a partial response, and 16 had stable disease or a minor response.

Several targeted agents inhibit the activity of an enzyme known as farnesyl protein transferase (FPT), which helps activate Ras, a protein whose mutated form in tumor cells triggers unrestrained growth. Although agents like Zarnestra™ (tipifarnib) and Sarasar™ showed promise in laboratory experiments, they have proven disappointing so far in studies on pancreatic cancer patients. According to Dr. Adjei, one reason is that cells in some types of tumors—pancreatic adenocarcinomas, for instance—compensate for FPT inhibition by activating another enzyme.

Researchers are testing several other targeted agents on patients with advanced pancreatic cancer:

• Avastin™ (bevacizumab) is an antibody that inhibits angiogenesis, the process by which new blood vessels sprout to feed growing tumors. A recent study combining Avastin and Gemzar resulted in six of 16 pancreatic cancer patients having a partial response and seven having stable disease.
  
• Velcade™ (bortezomib), a drug that inhibits the proteosome, has recently been approved for treatment of multiple myeloma. It is being studied in patients with pancreatic cancer.
  
• BMS-247550 decommissions the protein tubulin, a vital part of the cellular scaffold necessary for tumor growth, and is currently in phase II clinical trials.

These are some of the more prominent targeted agents, but others exist, as Jerry Jordahl of St. Ansgar, Iowa, learned three and a half years ago at the age of 64.

During a Whipple procedure, Jordahl’s surgeon detected liver metastases and opted not to remove any malignant growths. Dr. Adjei then enrolled Jordahl in an early clinical trial of a pill containing the compound CI-1040. This targeted agent inhibits MEK, an enzyme whose activation stimulates cancer cells to replicate. For 15 months, CI-1040 worked, shrinking Jordahl’s pancreatic tumor by 60% and eliminating visible liver lesions.

“It felt good,” he recalled. “No side effects. I thought, man, I’m set for life.” In February 2002, however, the liver spots returned, and Jordahl tried various combination therapies involving such drugs as Camptosar, Tarceva, Xeloda, and the anti-inflammatory agent, Celebrex® (celecoxib). Until his death in April 2003, he continued to encourage other pancreatic cancer patients to phone him for support.

Nine-year survivor Kay Kays has her own advice for pancreatic cancer patients. “Never give up hope. Because if you do, you might be that one who’s going to make it, and you’re throwing away your lottery ticket. Go beat it!”