Searching on all Fronts: Changing the Outlook for Those With Pancreatic Cancer

Sue Adkins gets two shots, one right after the other, every day. When she’s at the construction company in Whitmore Lake, Michigan, where she’s worked as a bookkeeper for 30 years, her coworker delivers the injection into the back of Adkins’ arm. At home, her husband of 43 years gives her the shot in her abdomen or thigh.

Adkins doesn’t know what’s inside the pre-filled syringes. She is part of a double-blind, randomized, placebo-controlled clinical trial, which means she could be receiving an investigational drug for pancreatic cancer called necuparanib or placebo. Either way, since joining the trial last July — a month after she learned she had stage 4 pancreatic cancer — Adkins' condition has improved.

“I had two masses (in my pancreas) and one has shrunk to about a quarter of the size it originally was,” Adkins said. In addition to the investigational drug or placebo, everyone on the trial receives the standard treatment of chemotherapy with Abraxane (nab-paclitaxel) and Gemzar (gemcitabine) once a week for three weeks followed by a week off.

Hope for Early Detection

Pancreatic cancer, typically diagnosed in late stages, is difficult to treat and has a relatively poor prognosis compared to other cancers. Necuparanib represents one of a handful of promising new and experimental drugs — in classes including targeted therapy, immunotherapy and chemotherapy — that may increase options and extend life for people with pancreatic cancer.Adkins was having digestive problems that pushed her to see her family doctor. Unable to pinpoint the cause of Adkins’ complaints, the doctor ordered blood work and a CAT scan. When the physician called Adkins back in to discuss the test results, the news wasn’t good. The doctor advised her to see an oncologist: The results pointed to pancreatic cancer.

“Because there is no screening procedure (for pancreatic cancer), patients come in when they have symptoms, and symptoms oftentimes indicate advanced disease,” says Philip A. Philip, who leads the GI and Neuroendocrine Oncology Multidisciplinary Team at the Barbara Ann Karmanos Cancer Institute in Detroit, Michigan.

Researchers are actively seeking reliable methods for early detection of pancreatic cancer. Early detection could catch a pancreatic tumor when it’s surgically removable and before it spreads. Some cancer centers try to identify these tumors in people they consider high-risk through various forms of imaging. The tests include MRI of the pancreas and bile ducts, CT scans, endoscopic ultrasound and tests that combine endoscopy and X-rays. However, to date, there is no standard screening recommendation, nor is it clear whom to screen. “These options exist, but there is no consensus as to which test to use, how often to screen and whom to screen, and most importantly how useful these tests may be in detecting earlystage pancreas cancer,” says Anna Varghese, a medical oncologist who specializes in gastrointestinal cancers at Memorial Sloan Kettering Cancer Center in New York City.

Experimental tests look for markers of pancreatic cancer in the blood. These may reveal signs of the disease long before imaging could. A 2014 study published in Nature Medicine found higher levels of branched-chain amino acids in the plasma of people who were ultimately diagnosed with pancreatic cancer up to five years before their diagnosis.

“This suggests that there may be some metabolic abnormalities years before a pancreas cancer is diagnosed, when, ideally, we could identify a cancer and hopefully still cure someone of their disease,” says Varghese.

Who Should Be Screened?

In another recent study, a blood test detected circulating pancreatic tumor DNA in almost half of the study participants who had early-stage pancreatic cancer. “There have been some promising studies that show that monitoring the level of this circulating tumor DNA in patients’ blood can be a marker of how the cancer may be responding to treatments,” says Varghese. “So one could imagine that if there is a tumor in a person’s body, and that tumor is shedding DNA into the blood, identification of this circulating tumor DNA could be a possible screening test.”Although there is no proven effective screening method, doctors might one day recommend periodic screenings of those at greatest risk of developing pancreatic cancer.

Some risk factors include tobacco use, overweight and obesity, type 2 diabetes and consistent exposure to certain dyes, pesticides and chemicals used in metal refining.

Age, gender and race are factors, too. The average age at diagnosis is 71. Men are about 30 percent more likely to develop pancreatic cancer than women. African Americans are more likely than Caucasians.

Standard of Care

People with a family history of pancreatic cancer or a genetic predisposition to some other cancers have a greater risk than others. This includes people who have gene mutations for hereditary breast and ovarian cancers (such as BRCA2); familial melanoma or pancreatitis; Lynch syndrome; Peutz-Jeghers syndrome; and Von Hippel-Lindau syndrome. People who are genetically high-risk might want to approach their doctors for advice and enrollment in surveillance trials.Surgery to completely remove the cancer from the pancreas is the only treatment that can cure pancreatic cancer. But most cases — more than four out of five – have spread beyond the pancreas by the time a doctor diagnoses them. Doctors may be able to surgically remove the cancer in the remaining cases in which tumors are strictly confined to the pancreas. Even when surgery removes all apparent tumor, recurrence rates are high. “About one in five who undergo surgery are long-term survivors. Recurrence is high because there are microscopic metastases, for example in the lining of the abdomen, that we cannot see with our naked eye or even with the fanciest scan,” Philip says.

Surgery candidates may go through chemotherapy before surgery to help shrink the tumor, or they may have the treatment after surgery to reduce the risk of recurrence.

Doctors may recommend radiation to help shrink tumors before surgery or in combination with chemotherapy for inoperable tumors.

For the majority of people with pancreatic cancer, whose disease is inoperable at the time of diagnosis, a combination of chemotherapy drugs is the standard of care. People who are healthy enough to tolerate it typically get two or more drugs, often the combination regimen FOLFIRINOX or, in cases where the cancer has become resistant to one of these regimens, gemcitabine and paclitaxel, though many other options are available. The most common side effects of chemotherapy are fatigue, nausea, vomiting, loss of appetite, hair loss, mouth sores, diarrhea and neuropathy. But chemotherapy can also damage bone marrow, which reduces blood cell counts and increases risk of infection, bleeding and bruising. People who cannot tolerate the often severe side effects of two chemotherapy drugs may get only one, such as gemcitabine (with or without Abraxane), 5-fluorouracil or capecitabine.

Clinical Trials

Quality of life is a major consideration in patient management, and increasing emphasis is placed on supportive care to address symptoms such as pain, discomfort, fatigue or loss of appetite. This kind of care can include palliative chemotherapy or radiation, whose goal is strictly to relieve symptoms; the placement of a stent to alleviate blockage of the bile duct or small intestine; or a special diet or medication to improve a patient’s digestion or appetite.Adkins was so shocked to hear she had pancreatic cancer that she sought a second opinion, which led her to Philip at Karmanos, who confirmed her diagnosis.

“He said that the treatment would be the same wherever I went, and that I was eligible for a clinical trial if I was interested,” Adkins recalls. “Because he told me I would receive the standard chemo treatment whether I was part of the clinical or not, I felt very good about (joining a trial). I’m still getting the standard treatment, which hopefully stabilizes my condition. And if there is any added benefit from the trial, then I’m all for that.”

Necuparanib

Relatively few people with pancreatic cancer, about 4.5 percent, enroll in clinical trials, Philip says. About half of those with pancreatic cancer are not healthy enough to be eligible for a clinical trial. The others simply aren’t informed about them or don’t live near enough to a trial site. Philip recommends that people who might be interested in a trial ask about them. “It might give you an opportunity to get a new drug — not always, because in randomized trials you don’t always get it — but you’re always going to get the standard treatment plus or minus an experimental drug,” he says.Necuparanib, the drug administered in the clinical trial in which Adkins is enrolled, is a form of heparin, a common blood thinner that people take to reduce the risk of heart attack and stroke. Research in animals and humans has shown that blood thinners can have anti-cancer effects. The necuparanib formulation of heparin minimizes blood-thinning while maintaining the anti-tumor effects. It also has a broad range of effects on cell growth pathways and tumor blood vessel formation.

Onivyde

Last year, the U.S. Food and Drug Administration granted the drug orphan drug designation, which helps advance the development of drugs that show promise to treat rare diseases — those that impact fewer than 200,000 people in the U.S. The FDA later gave the drug fast track designation to help speed it through the process for approval as a first-line treatment for metastatic pancreatic cancer in combination with paclitaxel and gemcitabine.For people who have already undergone treatment with gemcitabine, last year the FDA approved the new chemotherapy drug Onivyde (MM-398) for use in combination with 5-fluorouracil and leucovorin. Onivyde is a nanoliposomal form of an older drug, irinotecan. This one stays in circulation longer.

“It increases the exposure of the cancer cells to the active drug, which is still irinotecan but with better efficacy,” says Philip. “This has shown to be active in patients who have failed gemcitabine or gemcitabine plus another drug combination in the front line.”

PEGPH20

In clinical trials, when patients took Onivyde in addition to 5-fluorouracil and leucovorin, their tumors shrank more than those in patients who took the other two drugs alone.One reason people with pancreatic cancer must switch from drug to drug is because the condition is inherently more resistant to chemotherapy than some other cancers. This is due in part to substances that surround the tumor.

“It’s a mix of fibroblasts and other elements that provide a shelter for the tumor to grow unabated,” says Daniel Laheru, co-director of the Skip Viragh Center for Pancreas Cancer at Johns Hopkins University.

Among these elements is a chemical called hyaluronan, which researchers believe forms a shield that keeps chemotherapy drugs away from cancer cells. An investigational medication PEGPH20, which is an enzyme called hyaluronidase, may help break that chemical down and allow chemotherapy medications better access to the cancer cells.

In a clinical trial, people with pancreatic cancer that was high in hyaluronan benefited from this drug. Compared with people who went on chemotherapy alone with the standard nab-paclitaxel and gemcitabine, those who received PEGPH20 along with chemotherapy halted the progress of their cancer for almost five months longer.

Immunotherapy

The drug brings an increased risk of blood clots, however, so it may not be appropriate for people with other risk factors for blood clots.Any cancer is, in large part, hard to fight because the immune system doesn’t recognize it as a foreign invader as it would a viral or bacterial infection. Therapeutic vaccines for pancreatic cancer are intended to trigger an immune-system response to antigens associated with the cancer so that the immune system will fight the disease. Several such vaccines are currently in clinical trials.

“Over the last few years, immunotherapy and vaccines have been the thing that patients ask about most,” says Philip.

In a phase 2 clinical trial, the vaccine algenpantucel-L, added to chemotherapy and radiation, extended survival. The vaccine is currently in phase 3 trials, which include people with borderline resectable cancer or cancer that has spread to the nearby abdominal cavity.

Two other vaccines — GVAX and CRS- 207 — may be more effective together than alone. Previous research has shown that, in people whose cancer never came back after receiving GVAX, the immune system recognized the cancer-related protein mesothelin as a foreign invader. “It’s thought to be very important in early invasion. In patients whose cancers have come back for reasons we don’t know, their immune systems don’t ever see this mesothelin protein as foreign,” says Laheru.Building on this understanding, more recent studies have found that GVAX combined with a mesothelin-based vaccine, CRS-207, works even better. CRS-207 inoculates patients with listeria that has been genetically engineered — first to not make anyone sick, and second to contain the protein mesothelin.

PF-04136309

“Listeria is something the immune system can see very well. The idea is that, in the process of destroying the listeria, the immune system is processing this important pancreas cancer protein,” says Laheru.A targeted therapy currently in clinical trials, PF-04136309 may also benefit people whose cancer is borderline resectable or locally advanced. This means the cancer would be operable if it weren’t for the tumor’s proximity to or encasement of important blood vessels. PF-04136309 blocks a key process in the progress of pancreatic cancer. In this disease, a molecule called CCR2 attaches to an activating molecule called CLL2. Together, they promote the entry of cells called macrophages into the tumors, which in turn result in progress of the cancer and its resistance to drugs, including immunotherapies.

PF-04136309, an oral medication, latches onto CCR2 (a chemokine receptor) present on the macrophages and prevents it from being turned on by CLL2. In this way, the drug helps to stop the advancement of cancer by blocking macrophages from accessing the tumor environment, where it participates in cancer-promoting processes such as inflammation and angiogenesis (tumor blood vessel formation). In a clinical trial, people with borderline resectable or locally advanced unresectable pancreatic cancer received the chemotherapy drug combination FOLFIRINOX with or without the investigational drug PF-04136309.

Increasing Options, Extending Life

Out of 29 patients who took the investigational drug, 14 experienced stable disease and another 14 experienced a reduction in tumor size or the amount of cancer present in the body.The latest advancements in pancreatic cancer treatment do not represent a cure, but they offer patients more options than any time before. While we clearly need more effective options, the uptick in activity and early results is encouraging.

“Not too long ago, when someone failed gemcitabinebased treatment, then oftentimes they were told, ‘We have only one other drug available,’” says Philip. “Now, we have additional treatments they can benefit from.”

Moving from one option to the next, when the previous treatment stops bringing benefits, can be life-extending. And that’s infinitely meaningful to people like Adkins, who are committed to taking advantage of every day. She wears a necklace with a pendant that says, “Never, ever give up.”

“That sums it up for me,” she says of her attitude toward pancreatic cancer. It’s not only that she doesn’t give up on the treatment itself. She hasn’t given up many of the things she loves to do.

“I went snowmobiling this winter,” Adkins says. “We were in Florida two weeks ago. Last Christmas, my daughters, my niece and my great-niece and I got together to make 30 pints of apple butter. There really hasn’t been much of anything that I’ve wanted to do that I haven’t done.”