CURE

WINTER / 2013

Changing Course in Pancreatic Cancer

Small, yet significant, advances are reshaping pancreatic cancer treatment.

Susan Smith is hopeful. For the first time in years, a new drug combination has put her pancreatic cancer back into remission. In May, she began receiving gemcitabine in combination with Abraxane (nab-paclitaxel), a drug already approved by the Food and Drug Administration (FDA) for treating breast and lung cancers. A recent scan showed very encouraging news—the size of the lesion was reduced by nearly half. “Both my doctor and I were extremely pleased with the results,” Smith says.

The 66-year-old resident of Vero Beach, Fla., received her pancreatic cancer diagnosis almost seven years ago and underwent surgery to remove part of her pancreas and spleen. She then received an intense regimen of chemotherapy and radiation and was followed closely by her oncologist for the next five years without further treatment, as she appeared to be in remission.

Five years after receiving her diagnosis, she no longer needed imaging scans. However, in March, Smith began experiencing back pain. Scans and a biopsy revealed that her cancer had metastasized to her liver.

Her initial treatment with Abraxane had to be halted because it made her white blood cell count plummet. She restarted treatment with an altered schedule that included doses of granulocyte colony-stimulating factors (G-CSFs) to boost her white blood cells.

Susan Smith won’t let the side effects of pancreatic cancer treatment stop her from working in her home garden in Vero Beach, Fla. Photo by Ashley Razo.

Early on, Smith struggled with other side effects, including rash, thrush, mouth sores and poor appetite. But as the treatment progressed, the side effects lessened. “Now I experience tiredness, lethargy and flu-like symptoms on the third and fourth day after chemo, but other than that I get along well,” she says.

Early Detection is Difficult

About 45,000 new cases of pancreatic cancer are estimated to be diagnosed this year in the U.S. Patients with the disease face a tough challenge due to its aggressive nature and resistance to available treatments. Moreover, it can be difficult to diagnose in its early stages (less than 20 percent of tumors are confined to the pancreas at the time of diagnosis), so all too often, the disease has already spread to the point where surgical removal of the tumor is not possible. Thus, the one-year survival rate for all stages of the disease combined is about 20 percent. Unfortunately, disease recurrence is common, and the five-year survival rate for pancreatic cancer is 6 percent.

The best predictors of long-term survival following surgery (considered the only potentially curative treatment at this time) are small tumor size, no lymph node involvement and no cancer cells surrounding the tissue where the tumor was removed. There is also increasing evidence that the best outcomes after surgery for the disease are achieved at major medical centers that perform more than 20 pancreatic surgeries annually.

Inroads into effective treatments and better diagnostics have been slower than with many other cancers, but new approaches are emerging, especially as more is learned about the biologic makeup of the disease.

There are several types of pancreatic cancer, but they fall into two major categories: exocrine and endocrine. Approximately 95 percent of pancreatic cancers begin in the exocrine cells in the ducts of the pancreas and sometimes in the cells that make pancreatic enzymes that aid digestion. Within this category, there are a number of tumor types, but about 95 percent are adenocarcinomas. Endocrine tumors, also known as pancreatic neuroendocrine tumors (PNETs), are slower growing and develop in the islet cells, which produce hormones, such as insulin. These cancers are rare, accounting for less than 4 percent of pancreatic cancers. While treatment varies depending on the specific tumor type and stage, the prognosis for PNETs is usually better than for exocrine cancers.

The Role of Diet and Diabetes

Most cases of pancreatic cancer appear to be sporadic, in that they occur in patients who do not have an inherited predisposition. Smoking, by far, is the most common modifiable risk factor, accounting for about 20 percent of cases. Some studies have found that diet can play a role, in that high consumption of processed red meat and fats might increase pancreatic cancer risks, while fruits, vegetables and dietary fiber might have a protective effect, but more research is necessary to confirm those results. Being obese has also been linked with a higher risk.

Other risk factors include long-term inflammation of the pancreas (chronic pancreatitis) and certain inherited syndromes caused by genetic abnormalities. Diabetes can be a risk factor and a symptom of pancreatic cancer. “Diabetes or glucose intolerance often predates pancreatic cancer by several months,” says Diane M. Simeone, director of the Pancreatic Cancer Center at the University of Michigan in Ann Arbor. “We are trying to understand in more detail what the link is between diabetes and pancreatic cancer, and this could help us develop an early detection test.”

Of all people age 50 or older who have diabetes, one in 100 will receive a diagnosis of pancreatic cancer within three years of their diabetes diagnosis, according to Simeone. “We need to be able to take that information and better differentiate which individuals should get a further workup for pancreatic cancer.”

Detection and Diagnosis Can Be Daunting

Pancreatic cancer can often be challenging to diagnose, as patients do not typically have symptoms when the disease is in its early stages. When symptoms develop, they are generally vague and can be attributed to other illnesses. Pain is a common symptom, which often occurs in the abdomen or the middle of the back. The pain can be unrelenting, especially at night. Individuals may also experience weight loss, jaundice and digestive problems, such as indigestion, nausea and poor appetite. Stool may become lighter and turn pale or light grayish, while urine may become darker.

About half of patients have metastatic disease at the time of diagnosis; while a third have regional spread. “Early detection would be a huge advance for pancreatic cancer,” Simeone says. “And there are high-risk groups that could benefit from a screening test.”

Unfortunately, there is a lack of established methods for early detection. While pancreatic cancer is diagnosed primarily through imaging, there is no consensus on when it should be used to detect the disease in its early stages. And unlike screening methods for other cancers, such as mammography or colonoscopy, there are also no reliable routine screening tests for pancreatic cancer.

Surgical Advances

Although surgery has been used to treat pancreatic cancer since the early 20th century, the first groundbreaking procedure wasn’t performed until 1935 when American surgeon Allen Whipple developed and later refined the procedure that still bears his name. After further modifications in the 1940s, the Whipple procedure became the standard operation for treating pancreatic cancer. This major surgery—which involves the pancreas, the duodenum, the gallbladder, the bile duct and a portion of the stomach— also comes with a historically high risk of complications and mortality. In fact, at more than 20 percent, the death rate was considered so high at one time that some surgeons suggested the operation no longer be performed. That has changed, thanks in part to advances in open operative techniques, improvement in operative and post-operative care, and the advent of minimally invasive surgery.

“The death rate has gone down to under 1 to 2 percent in major centers with open and laparoscopic surgery,” says Dilip Parekh, a professor of clinical surgery at the University of Southern California’s Keck School of Medicine. Minimally invasive or laparoscopic surgical techniques can sometimes be used in pancreatic surgery, enabling patients to recover in a shorter period of time.

The open procedure requires an incision that extends across the abdomen, explains Parekh, who helped pioneer the laparoscopic Whipple procedure. “A lot of the recovery from the surgery is related to recovery from the surgical incision,” he says. Because the recovery from open surgery tends to be lengthy, “many patients who require adjuvant therapy are not completely recovered by the time they start their chemotherapy or radiation therapy,” he adds.

“We are finding that recovery is much quicker with these patients,” Parekh says of patients who receive the laparoscopic procedure. “And generally, they are able to start chemotherapy earlier and have much better performance status when they begin adjuvant treatment.”

This is changing the treatment of pancreatic cancer in a big way, he adds. He expects the laparoscopic approach to soon become an available option for all patients.

A second major advance has been for patients whose cancer is “borderline resectable,” Parekh says.

“These are patients for whom the tumor is encroaching on, or partially obstructing, the superior mesenteric vein,” he says. “In the past, these patients were regarded as inoperable, but today, some of them will be candidates for a Whipple procedure and partially removing and reconstructing the vein. So we have extended the surgery to other patients.”

"Four years ago I was told that I had three months to live. I was fortunate to find a doctor who thinks outside the box," says Laurie MacCaskill. Photo by Mike Kitada.

Laurie MacCaskill was just such a patient. At age 55, she was in terrific shape and was doing everything “right.” So how could she have cancer?

“I was very healthy. I didn’t smoke. I’d been going to the gym regularly since I was 20 years old,” says MacCaskill, who divides her time between Los Angeles and Aspen, Colo. “This came as a complete shock to me,” she adds. “It was terrifying.”

Her initial symptom was back pain, and after her physician ran more tests, she finally received a diagnosis of stage 3 pancreatic cancer. At that point, it had already started growing outside the pancreas.

MacCaskill and her husband began doing research. She received second and third opinions. Eventually, MacCaskill underwent a Whipple procedure and then began receiving chemotherapy. She continued that treatment for three years before it became ineffective.

“Four years ago I was told that I had three months to live,” MacCaskill says. Yet instead of accepting that prognosis, she began investigating other options.

“I was fortunate to find a doctor who thinks outside the box,” she says. Ultimately, she was prescribed another chemotherapy treatment that she received twice a day for one month.

Fast-forward to today, seven years after her diagnosis. MacCaskill is alive and thriving, serving as a volunteer and advocate for the Pancreatic Cancer Action Network.

Small Steps

The quest for targeted therapies has received a great deal of attention in cancer care, and deservedly so, but researchers are also looking at how to make better use of drugs and treatment regimens that already exist. One area is combining drugs or radiation therapy with surgery. Systemic chemotherapy, radiation therapy or a combination of the two are being used after surgery (adjuvant therapy) and before surgery (neoadjuvant therapy) in an effort to improve cure rates.

“We have developed combinations of chemotherapy with radiation that effectively downstages some patients who have locally advanced cancers without evidence of metastasis,” Simeone says. “We can now resect a subset of those patients and provide a significant survival benefit, where previously we weren’t able to do that.”

There have been some advancements in treating metastatic disease, although “not as significant as we would like,” she admits. However, she adds, on a positive note, there is much active research in this area.

There has also been interest in the use of FOLFIRINOX, a treatment combining several drugs that have long been used (5-FU [fluorouracil], leucovorin, irinotecan and oxaliplatin).

While gemcitabine has been a cornerstone of therapy for advanced pancreatic cancer for the past decade, it has only a modest impact on survival. A phase 3 clinical trial that compared FOLFIRINOX with gemcitabine as a first-line therapy in 342 patients with metastatic pancreatic cancer found that the combination extended survival by 4.3 months.

The downside is this approach comes with more serious side effects compared with gemcitabine alone. Ongoing and planned studies will continue to evaluate this regimen and investigate how to adjust doses to reduce toxicity.

Targeting the Stroma

Persistent research has resulted in important new leads for treatment.

“There has been a tendency to try to lump all cancers together—if we understand the signaling pathways in one type of cancer, then we can understand them in all,” Simeone says. “But many of us working with pancreatic cancer feel that isn’t the case, and we need to understand the unique biology of this disease. There is something about it that is particularly aggressive.”

An emerging strategic approach for treatment involves targeting the tumor-associated stroma—the supportive tissue surrounding pancreatic cancers. New research has shown that the stroma encases the tumor cells, which could explain why pancreatic cancer doesn’t respond well to chemotherapy. The stroma also appears to have a specific protein profile called SPARC, which has been associated with a poor clinical outcome.

There has been a tendency to try to lump all cancers together... But many of us working with pancreatic cancer feel that isn’t the case, and we need to understand the unique biology of this disease.

—Diane Simeone

An emerging strategic approach for treatment involves targeting the tumor-associated stroma—the supportive tissue surrounding pancreatic cancers. New research has shown that the stroma encases the tumor cells, which could explain why pancreatic cancer doesn’t respond well to chemotherapy. The stroma also appears to have a specific protein profile called SPARC, which has been associated with a poor clinical outcome.

Targeting the stroma might explain why the Abraxanegemcitabine combination appears to work in advanced pancreatic cancers. Abraxane is encased in a soluble protein called albumin that could help the combination infiltrate the stroma, target SPARC and get to the tumor better. The drug’s approval for pancreatic cancer in September was based on positive results of a large phase 3 study, in which participants who received a combination of Abraxane and gemcitabine lived about two months longer than those who had gemcitabine alone, but neutropenia (low white blood cell count) and neuropathy (nerve damage) were experienced more frequently by participants in the combination arm.

With Abraxane’s approval, some experts are suggesting the combination will be a new standard of care. A Japanese study of the novel 5-FU-like agent S-1 showed that it boosted survival when compared with gemcitabine alone. While S-1 might soon be considered the new standard treatment in Japan, the study findings may not be applicable to non-Asian populations.

In addition, the monoclonal antibody nimotuzumab has been evaluated in a phase 2 trial as a combination with gemcitabine in patients who have previously untreated, locally advanced or metastatic disease. The study found the combination significantly improved one-year overall survival. Nimotuzumab targets the extracellular region of epidermal growth factor receptor (EGFR), a key target in the development of cancer therapeutics. It is not yet available in the U.S. (outside of clinical trials), but it has already been approved in several other countries to treat various types of cancer.

Smith is betting on continued breakthroughs. Now in her second round of treatment with Abraxane, she is optimistic that she will achieve a second remission and accomplish one of her short-term goals: celebrating her 50th wedding anniversary next year.

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