FOR PATIENTS DIAGNOSED with gastrointestinal (GI) cancers, prognoses are often very hard to accept: Many of these malignancies are detected in later stages and can’t be treated nearly as effectively as we would like.

But understanding a cancer is the key to more effectively treating it — or, better yet, preventing it &mdash; and progress is being made in those areas. Particularly in gastric and esophageal cancers, we now have enough evidence to make a big difference through prevention.

We know that obesity contributes to both of these cancers; this is similar to the trend in liver cancer, where obesity can lead to a “fatty liver” and resulting inflammation, which can then spark cancer. Based on this evidence and more that is being gathered, we should have an opportunity, going forward, to help stem the tide of gastroesophageal cancers through awareness and prevention.

Specifically, we know that some esophageal cancers are preceded by a condition called Barrett’s esophagus. This can begin with obesity, which leads to reflux and then to Barrett’s esophagus; that condition, in turn, makes changes in the lining of the esophagus that sets cells on a course toward cancer. But when we’re aware that Barrett’s esophagus has developed, there are new developments to help prevent cancer from arising. Doctors can use radiofrequency ablation to remove diseased sections of the esophageal lining, or, in cases where Barrett’s esophagus is too widespread to allow this, surgeons can prophylactically remove part of a patient’s esophagus.

In gastric cancer, removal of all or part of the stomach is a common treatment for earlier-stage disease. But in the rare cases when someone’s inherited genetics predict a high chance that they will develop gastric cancer, this surgery can be used as a prevention technique. It’s something to be strongly considered in people with the CDH1 gene mutation, which can lead to both lobular breast cancer and diffuse gastric cancers. The strategy is aggressive, but it’s quite possible, after a period of adjustment, to live a normal life without a stomach.

Because these GI diseases cause only vague symptoms, the kind that also commonly occur in people who are healthy, cases are often not detected early in the United States. Things are different in countries like Japan and Korea, where gastroesophageal cancers are more common. There, education and vigilance are prioritized. People are taught the importance of avoiding alcohol and tobacco, eating a diet that emphasizes fruits and vegetables and getting checked by a doctor if they are experiencing reflux. As a result, cancers are caught earlier, treated more aggressive surgically and associated with better outcomes. In the meantime, early-detection blood and saliva tests are being developed that could further contribute to prevention efforts.

Since chemotherapy can offer only a limited amount of help in fighting gastroesophageal cancers, a growing emphasis on prevention — as well as on the development of immunotherapies &mdash; will be extremely important here in America over the next couple of years. Treating gastric and esophageal cancers as one category of disease &mdash; gastroesophageal cancer &mdash; may unite more advocates in these efforts, speeding progress along.

Chair, Department of Breast Medical Oncology

The University of Texas MD Anderson Cancer Center

>> Read the Gastrointestinal Cancers Special Issue here <<

Articles

Editor's Page

Since chemotherapy can offer only a limited amount of help in fighting gastroesophageal cancers, a growing emphasis on prevention &mdash; as well as on the development of immunotherapies &mdash; will be extremely important.

In Gastroesophageal Cancers, Better Prevention and Treatments Needed

ORIGINALLY PUBLISHED IN “GUT REACTION,” CURE WINTER 2009

*HER2 is also associated with breast cancer.

For about 20 percent of patients with advanced gastric cancer, tumors overproduce a receptor protein called HER2.

Side Note

Medical Illustration: Targeting HER2 in Gastric Cancer

MELINDA BACHINI (center), whose cholangiocarcinoma has responded to immunotherapy, mingles with attendees at the Cholangiocarcinoma Foundation Annual Conference. PHOTO BY BARR PHOTOGRAPHY (COURTESY OF THE CHOLANGIOCARCINOMA FOUNDATION)

Back in 2009, Melinda Bachini thought her job as a paramedic explained all her physical complaints — an irritable stomach from eating at odd times, exhaustion from working 24-hour shifts, right shoulder pain from lugging medical equipment.

The mother of six was dumbfounded when it turned out her symptoms were the result of a grapefruit-sized tumor in her liver. It took a while, but her doctors figured out that the mass was cholangiocarcinoma, a cancer she’d never heard of in her life. Even after treatment with surgery, Bachini was told she faced a 76 percent chance that the bile-duct cancer would recur.

When it did, in her lungs, Bachini was faced with another challenge: She wanted to join a clinical trial, but first had to convince the governor of her home state, Montana, to sign a bill requiring health insurers to cover routine patient costs associated with participating in such trials.

It was a frustrating diversion, but a fateful one. After the bill was signed and she had undergone chemotherapy, Bachini learned about a trial of a treatment that uses a patient’s own immune cells to fight cancer. In adoptive T cell therapy, researchers harvest immune cells that are naturally programmed to fight the patient’s cancer, multipy them in a lab and then reinfuse the microscopic army back into the patient’s body.

Bachini joined the trial at the National Cancer Institute and spent a month in the hospital as her immune system geared up. When she went home, she recalls, “things started improving right away. My chronic cough went away. I could walk my dog. Day by day, everything was better — it was incredible.”

The treatment didn’t cure Bachini’s cancer, but it shrank her tumors and kept the disease at bay, without any other therapies, for 18 months. Then doctors at the NCI treated her again, focusing this time on T cells targeting a specific mutation in the protein ERBB2IP, which they knew was present in her tumor. With only recent mild tumor growth, she’s been doing well for the past 28 months.

A six-year survivor of cholangiocarcinoma, Bachini is an exceptional responder, even among the 11 others in the trial. Typically, patients with advanced cholangiocarcinoma face a very poor prognosis.

But Bachini, who now works as an advocate with the Cholangiocarcinoma Foundation to offer fellow patients hope, says her experience has convinced her that “every day holds the possibility of a miracle.”

To achieve that miracle, more attention to cholangiocarcinoma is needed, and that’s been coming in increasing doses.

In recent years, pharmaceutical companies have become more willing to offer up drugs for study in the disease diagnosed in 6,000 Americans each year, which is now treated mainly with surgery, chemotherapy and radiation. At the same time, more researchers have become committed to finding answers, and patients like Bachini have expressed an avid interest in participating in clinical trials, attendees explained during the Cholangiocarcinoma Foundation Annual Conference held in Salt Lake City, Utah, in early February.

“If you look back to 1949, there was one paper published for cholangiocarcinoma,” said Juan Valle, an oncologist and researcher with the Christie NHS Foundation Trust in England who was on hand to give attendees a research overview. “As time has gone by, there have been more and more papers published due to a greater scientific interest in cholangiocarcinoma, even within the last five years. A total of 536 papers were published in 2011, there were 918 in 2015 and I suspect that will continue to increase.”

All kinds of solutions are being explored: liver transplant, new chemotherapy combinations, chemotherapy before or after surgery, updated radiation approaches, targeted treatments and immunotherapies.

So far, though, there have been no eye-popping results. Scientists are learning more every day about the genomic variability of cholangiocarcinoma and how it responds — or doesn’t &mdash; to various types of treatments. But for now, they remain awash in more questions than answers.

Cholangiocarcinoma affects the bile ducts, tubes from the liver to the small intestine that carry bile, a fluid that helps digest fats and excrete wastes.

Half of all cholangiocarcinomas are perihilar, meaning that they occur where the left and right hepatic ducts meet upon leaving the liver. Because they occur outside the liver, these are considered extrahepatic bile duct cancers, as are distal cancers, which happen further down the duct near where it connects to the small intestine, and comprise two to three of every 10 cholangiocarcinomas.

Rarest, about one in every 10 cholangiocarcinomas, are intrahepatic cancers, which occur in smaller bile duct branches inside the liver.

Risk factors include age over 65; obesity; diabetes; inflammatory conditions including hepatitis B and C, HIV and inflammatory bowel disease; congenital abnormalities; infectious diseases such as liver flukes, which are most common in Asia; and a list of drugs, toxins or chemicals, including the radioactive Thorotrast, which in the past was used in X-rays, as well as asbestos and dioxin. Smoking and drinking alcohol are also thought to be risk factors.

All of that is “important, because a number of these we might be able to do something about,” Valle said. “In reducing the incidence of cholangiocarcionoma, we also need to focus on some of these preventive measures.”

There is no screening method for finding cholangiocarcinoma, and symptoms — which can include yellowed skin known as jaundice, itching, discolored urine or stools, belly pain or vomiting &mdash; don’t typically occur until the disease is advanced.

Five-year survival for those with intrahepatic cholangiocarcinomas is 15 percent if the cancer was localized when found, but drops down to 2 percent if it was distant. Five-year prognoses are a bit better for those with extrahepatic cholangiocarcinomas: 30 percent when localized at diagnosis, but still 2 percent if the cancer was distant when found.

“Surgery is the only chance of cure, but that’s usually not possible because the disease is too advanced” or patients, who are older, have additional illnesses that make treatment more difficult, Valle said.

Sometimes radiation and/or chemotherapy are used to shrink tumors so that they are small enough to operate on, or these techniques may be used after surgery to help control cancer. Radiation therapy can also be the main treatment, if surgery is not possible.

But the backbone of treatment for metastatic cholangiocarcinoma is combination chemotherapy with cisplatin and gemcitabine, the only regimen formally shown to improve survival.

“This is a devastating disease,” Valle said. “If we don’t do anything but give best supportive care alone, survival is twoand- a-half to four-and-a-half months. With cisplatin and gemcitabine, on average, patients survive a year. That’s still modest, but having a single standard of care allows us to be able to build on that, to add new treatments we want to explore.”

A host of techniques are, in fact, being studied, but many with less-than-optimal or uncertain results.

Liver transplant would ostensibly allow surgeons to avoid the tricky issues involved with excising tumors: conserving blood supply to the liver, getting clean margins and leaving behind an organ that is functional.

However, “it’s fair to say that initial results from transplantation have been disappointing — five-year survival was less than 50 percent,” Valle said. “This has improved to 65 to 80 percent with recent neoadjuvant approaches before transplant, but treatment is intensive,” including radiation, chemotherapy and laparoscopy before transplant to make sure the cancer hasn’t spread.

Valle cautioned that existing data is for patients with earlystage disease, making it more difficult to evaluate the success of transplantation. That’s because some early-stage patients, during surgery, were found to have no evidence of cancer, and it wasn’t possible to know whether their tumors had completely resolved due to pre-transplant radiation/chemotherapy or whether the patients had never had tumors in the first place.

Valle also cautioned that patients on waiting lists don’t always get new livers in time, and when those who die while waiting are included in statistics, the success rate with transplant drops back down to 53 percent.

Still, a number of transplant studies in cholangiocarcinoma are being conducted in the U.S. (NCT00301379), Italy, China and France.

With transplant a shaky option, patients with earlier-stage disease can expect to undergo liver resection. Might they stand a better chance of cure if they got radiation or chemotherapy after surgery?

It’s a difficult question to answer, Valle says. The bottom line is that some patients are going to either be cured or relapse, regardless of whether they undergo adjuvant therapy. Only for a small population of patients might post-surgery therapy turn a likely relapse into a cure.

To make matters worse, Valle said, “we can’t tell ahead of time who those patients are. We don’t know how big that group is. Is it different for intrahepatic or extrahepatic cholangiocarcinoma?”

The only way to find out is by conducting randomized clinical trials, and that’s being done, Valle said. Close to reporting results is BilCap, conducted in the U.K., which recruited 360 patients and treated half with surgery alone and half with surgery plus adjuvant chemotherapy (capecitabine). Also preparing to report results is the PRODIGE12 study in France, which compared surgery with or without adjuvant gemcitabine and oxaliplatin.

A third study recently opened in Germany: ACTICCA-1, which is comparing cure-intended surgery alone versus surgery plus cisplatin and gemcitabine.

The concept of treatment with other modalities before surgery — neoadjuvant therapy &mdash; was first explored in breast cancer, where it is now a standard of care, and has been studied a lot in pancreatic cancer, noted Kabir Mody, an oncologist specializing in gastrointestinal cancers at the Mayo Clinic who discussed clinical trials in a presentation at the conference. In cholangiocarcinoma, because this tactic can shrink tumors, it might be appropriate for patients with disease that is resectable or nearly so, and those are the patients now enrolled in a pilot study of gemcitabine and cisplatin before surgery.

“It’s an area that needs more exploration,” Mody said. “It’s not clear what the best chemotherapy regimen would be.”

In radiotherapy, questions revolve around how doctors can administer higher doses and target tumors more accurately while reducing side effects and complications, Valle said.

Studies are looking at radiation with or without chemotherapy and analyzing dosage, schedules, local control, survival and toxicity, he said.

In the U.K., the phase 2 ABC-07 study will administer cisplatin/ gemcitabine to patients with tumors of 6 centimeters or less for three months, then split responders into two groups — one remaining on chemotherapy and the other additionally receiving stereotactic body radiotherapy (SBRT).

Also being explored is proton beam therapy, offered by only a handful of centers in the United States. It’s billed as a technique that delivers less radiation to healthy tissue around a tumor, thus causing fewer side effects.

In a single-arm, phase 2 study, 39 patients with non-metastatic intrahepatic cholangiocarcinoma experienced an average overall survival of 22.5 months after proton beam therapy, with few serious side effects — apparently better results than chemotherapy, Valle pointed out. A next study (NCT02200042) will start with a cisplatin/gemcitabine induction period and then add focal radiation therapy for some patients. “We will get to find out what is the extra value that proton beam or SBRT add, if at all,” Valle said.

Also being considered in intrahepatic cholangiocarcinoma is selective intra-arterial radiotherapy (SIRT), which delivers radiation on beads small enough to be injected into tumors.

In an analysis of 11 retrospective or prospective studies including nearly 300 pretreated patients, this technique shrank 28 percent of cholangiocarcinoma tumors and resulted in stable disease for 54 percent of patients; 10 percent of the tumors shrank enough to be operable. Average overall survival on the treatment was 15.5 months. However, the therapy caused fatigue, abdominal pain, fever, nausea and abnormal liver tests, as well as one treatment-related death.

“We’ve learned over the past few years to do this much more safely,” Valle said. “The important thing is to give just enough to treat the tumor but not enough to allow the liver to fail.”

An upcoming randomized phase 2 trial, SIRCCA, will start off some patients with standard chemotherapy and others with the beads followed by chemotherapy, Valle said. “We’ll really get to understand how much these radiotherapy beads add over and above chemotherapy alone.”

A different study, Mody said, will compare SIRT to TACE, or trans-arterial chemoembolization, which uses beads coated with chemotherapy instead of radiation.

Also being looked at by researchers, he said, is irreversible electroporation, which uses electrical fields to create pores in tumor cells, allowing fluids to move in and out that will eventually kill the cells by bursting their membranes.

Although standard chemotherapy with gemcitabine/cisplatin has remained unchanged in the past few years, there are suggestions that more patients with cholangiocarcinoma can benefit from it. A recent clinical trial demonstrated benefit in 33 patients with jaundice who were otherwise fit; in the past, they would have been excluded from therapy. “Jaundice can be life-threatening in three to four weeks, but these patients could live close to 10 months with the cisplatin/gemcitabine combination,” Valle said. He cautioned, though, that “that only applied if they had a tumor blocking off the bile ducts, because they could then get an improvement and their ducts drained beter. It did not work if the liver was very badly damaged already.”

Newer ways of administering chemotherapy are also being explored. Hepatic artery infusions use a pump on the surface of the abdomen to deliver chemotherapy directly to the liver through a catheter inserted into the hepatic artery. Two studies on this technique are being done at Memorial Sloan Kettering Cancer Center, Mody said.

What about new chemotherapy combinations? Is there anything out there better than cisplatin and gemcitabine? Valle says chemotherapy doublets and triplets are being explored in cholangiocarcinoma in the United States, including the modified FOLFIRINOX regimen used in pancreatic cancer, and cisplatin and gemcitabine combined with 5-fluorouracil. Another study is adding Abraxane (nab-paclitaxel), which has worked well in pancreatic cancer, to cisplatin/ gemcitabine, noted Mody. Another potential addition to regimens is Acelarin (NUC- 1031), which is similar to gemcitabine but expected to cause fewer side effects. That’s shown a “hint” of promise in a phase 1 study, and is being looked at in another early trial, Valle said. Since chemotherapy doesn’t kill all cancer cells, the bad news is that it can be expected to stop working at some point. And then what?

“We don’t really have good backup options,” Valle said. “For second-line chemotherapy, our team looked at all trials of all treatments to get a sense of how effective they were. We found quite a few studies that included close to 900 patients altogether, treated with a long list of different options, and it was disappointing that we weren’t able to come up with a conclusion regarding the best approach. One thing we found was that the amount of time that the chemotherapy controlled the cancer was probably only until the first scan — they were not very effective treatments, and we need to do better in second-line.”

In the ABC-06 study of secondline chemotherapy versus active symptom control, investigators are considering whether chemotherapy is even the right approach as a second-line treatment. “Often, patients run into problems with recurrent infections and needing a stent and a second stent,” Valle said.

With scientists understanding more about the biology of various cancers, there is, of course, interest in applying targeted therapies in cholangiocarcinoma.

But in this area, too, there’s still a lot of work to be done. So far, drugs targeting mutations in the EGFR pathway, which occur in a number of cancers, have not shown benefit in cholangiocarcinoma. Also without benefit was cediranib, an experimental anti-angiogenesis drug that stops blood vessels from growing and feeding tumors, “but one problem is that adding cedirinib to standard chemotherapy added more side effects,” Valle pointed out. “Maybe we should look at a different compound that has less side effects if we want to see the benefit.”

Going forward, more distinct classification of cholangiocarcinoma subtypes may help direct the use of targeted therapy, Valle suggested.

“Intrahepatic cholangiocarcinoma has a different genomic profile than extrahepatic cholangiocarcinoma. If you look at extrahepatic, KRAS substitution (a cancer-causing mutation that activates cell growth pathways) is 42 percent — much higher than in other cancers. Is there something about these different patterns that will allow us to treat patients differently?” In that vein, a couple of techniques are being tested specifically in intrahepatic cholangiocarcinomas, due to their unique genomic codes.

One strategy is to target the FGFR2 receptor, which sends pro-growth signals to cells. Scientists now know that 11 to 15 percent of intrahepatic cholangiocarcinomas have a misplaced FGFR2 receptor gene, leading to overexpression of the protein that promotes the growth of cancer cells instead of normal ones. Based on this knowledge, there are a number of phase 1 and 2 trials testing FGFR inhibitors in intrahepatic cholangiocarcinoma, including phase 2 trials of Iclusig (ponatinib), a drug indicated for the treatment of chronic myelogenous leukemia, Mody said.

In addition, 15 to 20 percent of patients with intrahepatic cholangiocarcinoma have mutations in the IDH1 or IDH2 genes, causing the genes to secrete pro-tumorogenic substances. Targeting these mutant proteins are some novel drugs, including AG120. Last year, a small phase 1 trial showed that AG120 was well-tolerated, and one of 20 participating patients with cholangiocarcinoma had a partial response; 11 patients had stable disease on the drug, and six of them maintained that response beyond six months, Mody said.

“There’s some promise there, and a phase 2 trial is being planned and will be started soon,” he said.

Despite the success that immunotherapy has brought Bachini, such techniques are still little-studied in cholangiocarcinoma.

There are only two immunotherapy trials open that include patients with cholangiocarcinoma, Mody said, one testing Keytruda (pembrolizumab) in solid tumors (KEYNOTE-158) and the other weighing adoptive T cell transfer, which involves engineering a patient’s own immune cells to attack a specific target on cancer cells and then reinfusing them into the body to do their work.

An area of interest in immunotherapy is mismatch repair, or microsatellite instability, which is present in about 5 percent of cholangiocarcinomas. This condition prevents the repair of cellular “cuts and bruises,” allowing mutations to accumulate. This, in turn, makes these cells easier for the immune system to recognize, so they are particularly ripe for targeting with immunotherapy.

In a study of PD-1-targeted immunotherapy in patients with noncolorectal GI cancers, two of three participating patients with biliary cancers experienced durable responses, with survival significantly prolonged.

“It’s early data, but promising,” Mody said.

Progress has been slow, but the research happening in each area of interest represents a start. In the eyes of those eager to significantly extend life, it’s not enough, but the activity stands in stark contrast to the way things were when Valle joined the field.

“I spent the early part of my 16 years in this field sending letters of intent to (pharmaceutical) companies to get somebody to please share their drugs, so we could open trials and start treating patients with new compounds,” he recalled. “It’s refreshing to see some people from industry here today, and to see trials led by the (pharmaceutical) industry making accessible to us some agents we wanted access to.”

Features

Research into treatments for cholangiocarcinoma is branching out, but there are still more questions than answers.

Cholangiocarcinoma Research is Expanding, But Many Questions Are Still Unanswered

MARY ANN MACHOL, diagnosed with stage 4 colorectal cancer, has responded well to immunotherapy.

[PHOTO BY JULIE CHESHIRE (JULIECHESHIRE.COM)]

Mary Ann Machol was 44 in 2013 when she learned she had inoperable stage 4 colorectal cancer — a difficult diagnosis that left her with no choice but to undergo the harsh three-drug chemotherapy regimen known as FOLFOX. The cocktail (consisting of leucovorin, fluorouracil and oxaliplatin) helped shrink her tumors, but then she was diagnosed with uterine cancer, and had to stop all treatments. After undergoing surgery to remove her uterus, Machol, who lives in the San Francisco Bay area, was put on a different chemotherapy regimen for the colorectal cancer.

By the end of 2014, Machol had run out of options. Then she learned about a trial at Stanford University involving a drug that stimulates the immune system to fight off cancer. The drug, Keytruda (pembrolizumab), from Merck, was already on the market and being used successfully in melanoma and certain lung cancer patients. In March 2015, Machol was accepted into the trial and began receiving infusions of Keytruda every two weeks.

“After the second dose, I started feeling better,” Machol says. “I had been in severe pain — on high doses of morphine around the clock, bedridden and sleeping 16 to 20 hours a day. Then, all of a sudden, I was cutting back on the morphine. I was down to about 100 pounds because I couldn’t eat, but by summer I had gained all my weight back.” Machol’s tumors are shrinking, classifying her as a partial responder to the drug so far. She will remain in the trial through 2017.

Keytruda is among an emerging class of drugs that block “checkpoints” in the body that prevent the immune system from being able to recognize and eradicate cancer cells. Keytruda specifically targets the checkpoint PD-1, which has emerged as an important target in several types of gastrointestinal (GI) cancers, including colorectal, gastric and esophageal cancers.

“GI malignancies are the next frontier for immunotherapy,” says Yelena Janjigian, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York who has been an investigator for several immunotherapy trials. “Several patients of mine with metastatic stomach cancer have failed every standard treatment and have had dramatic and durable responses to immunotherapy. It really has changed lives.”

Colorectal cancer is the third most commonly diagnosed cancer in both men and women, according to the American Cancer Society. About 90 percent of cases of the disease and 93 percent of deaths occur in people over age 50. While 20 percent of patients have some family history of the disease, a few lifestyle factors are also believed to raise the risk of colorectal cancer, including smoking, certain diets and heavy alcohol use. Obesity is another risk factor.

 In addition to chemotherapy, some monoclonal antibody-based, or targeted, drugs have been approved to treat colorectal cancer, including Avastin (bevacizumab), an “anti-angiogenic” treatment that works by targeting vascular endothelial growth factor (VEGF) and thereby cutting off the blood supply to tumors. There are also Erbitux (cetuximab) and Vectibix (panitumumab), which target epidermal growth factor receptor (EGFR), a protein that is over-expressed in some colorectal cancers.

Still, the prognosis for patients, particularly those in the late stages of the disease, is not good. The five-year survival rate for metastatic colon and rectal cancer is 11 percent and 12 percent, respectively.

One challenge with PD-1 inhibitors is that they tend to work particularly well in tumors that have a lot of mutations. The more mutated a cancer, the more foreign the cells look to the immune system and the more likely it is to go after the cancer once the checkpoint is removed. But colorectal cancer mostly resembles normal colon cells, making it difficult for the immune system to recognize them as foreign invaders that need to be eradicated, even with help from an immunotherapy.

In an early trial of Keytruda in colorectal cancer, only one out of 33 patients responded well to the drug. Researchers at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center discovered that the patient had a condition called “mismatch repair” (MMR) deficiency, which renders tumors incapable of repairing damage to their DNA. As a result, the tumors accumulate thousands of mutations.

So they designed a phase 2 study of Keytruda to prove that colorectal cancer patients with MMR would respond well to the drug. The results were dramatic: The cancer was brought under control in 90 percent of MMR-positive patients, versus just 11 percent of patients without the deficiency. In November 2015, the FDA granted breakthrough therapy status to Keytruda for colorectal cancer patients with MMR defects, and a phase 3 study has been initiated.

Half of the MMR-deficient patients in the phase 2 trial saw their tumors shrink more than 50 percent. “In several patients, the tumors are completely gone,” says Luis Alberto Diaz, Jr., associate professor of oncology at Johns Hopkins and one of the investigators for the trial. “It’s exciting to see these patients alive and thriving.”

About 3 percent of colorectal cancer patients have Lynch syndrome, an inherited genetic mutation that almost always causes mismatch repair. Machol is among those patients. Although it’s rare — about one in 30 of all cancers have MMR, Diaz estimates &mdash; he anticipates that results from the trial of Keytruda in colorectal cancer patients with the deficiency may be relevant for treating a range of solid tumors. “Over the next six to 12 months, there will be continued advances,” he predicts.

Boosting Standard Treatments With Immunotherapy

Another benefit of PD-1 inhibitors is that they are considerably less toxic than chemotherapy, typically causing mild effects like fatigue, rash, stomach upset and joint pain, and more rarely touching off other auto-immune disorders. Machol, a pediatric nurse who is married with two children, says the only major side effect she has suffered was a swollen thyroid, which was easily controlled with medication. “I have some fatigue, but otherwise I have my life back,” she says.

Keytruda is also being tested in esophageal cancer — another type of GI cancer where advances in treatment have been slow to arrive. Esophageal cancer strikes three to four times as many men as women, according to the American Cancer Society. Smoking is a major risk factor for the disease. Some people with Barrett’s esophagus, a condition caused by long-term acid reflux disease, also go on to develop this cancer.

 Along with surgery, chemotherapy combinations are commonly used to treat esophageal cancer; some of the drugs often involved are fluorouracil (FU), cisplatin or other platinumbased chemotherapies, taxanes, anthracyclines, capecitabine and sometimes irinotecan hydrochloride. Radiation may also be used. Still, the five-year survival rate, averaged across all stages of esophageal cancer, is only about 20 percent.

In January 2016, Merck announced that Keytruda produced a 30 percent response rate in an early trial in patients with previously treated esophageal tumors that overexpressed PD-L1, a protein related to PD-1 that’s believed to be a good predictor of response to Keytruda. All of the responses were partial, and the patients were only followed for seven months, but the results were deemed promising enough to warrant further study. So Merck recently launched a phase 3 study, called Keynote-181, and is currently recruiting 600 patients.

PD-L1 inhibitors are also being explored in esophageal cancers, including Medimmune’s durvalumab (MEDI4736). It is currently in phase 2 trials.

After treatment with durvalumab for his stage 4 esophageal cancer, MICHAEL KENNEY’s tumors disappeared.

Michael Kenney, who was diagnosed with stage 4 esophageal cancer in June 2013 and treated with FOLFOX, qualified for the durvalumab trial in October of that year and jumped at the chance to participate. “I was told it would supercharge my immune system so it would recognize the cancer,” recalls Kenney, 55. He received the treatment at MedStar Georgetown University Hospital every other week for a year, but it only took six months for his tumors to virtually disappear. In July of 2015, he underwent surgery to remove a small tumor that remained at the junction of his esophagus and stomach. He no longer requires any treatment.

“It’s an absolute miracle,” says Kenney, a married father of two who lives in Rockville, Maryland. Kenney got a minor rash from the immunotherapy but otherwise felt as if he was taking nothing at all, he says. “It was surreal. I felt totally fine.”

Using Biomarkers to Improve Gastric Cancer Outcomes

Michael Pishvaian, the oncologist at Georgetown who treated Kenney in the trial, says immunotherapy seems to be particularly beneficial in patients with cancers of the upper GI tract, though scientists have not quite figured out why yet. And more than 70 percent of patients report no side effects, he says. Although oncologists are still trying to figure out how to predict who will best respond to these therapies, Pishvaian says, “there’s a good chance they will be part of the armamentarium in esophageal cancer.”

 Immunotherapy is also being tried along with either chemotherapy or radiation, Pishvaian adds. “That’s based on the premise that giving chemotherapy or radiation, even if doesn’t completely kill the cancer, might kill enough of the cancer cells to cause an immune response,” Pishvaian says. “That would enhance the response to the immunotherapy.”

In January 2016, data was released showing a 14 percent response rate to another anti-PD-1 drug, Opdivo (nivolumab), in patients with metastatic gastric, esophageal or gastroesophageal junction cancers — a relatively low success rate. However, 27 percent of patients whose tumors expressed PD-L1 did respond, raising hope among oncologists that PD-L1 may be an important prognosticator of treatment response.

The quest to understand PD-L1 and other biomarkers of tumor response to immunotherapy is particularly pressing in gastric cancer, where there have been few advances in recent years. The disease is most common in men over 65, and it is more prevalent in Hispanic Americans, African Americans and Asian/Pacific Islanders than it is in Caucasians. Infection with 

), a type of bacteria that can lead to ulcer, seems to raise the risk of gastric cancer, as does smoking. Less than 3 percent of cases have an inherited component.

The five-year survival rate for gastric cancer at the earliest stages is 71 percent, according to the American Cancer Society, but because its symptoms often aren’t noticeable until it has spread, the disease is rarely diagnosed until it is in stage 4, at which point the survival rate drops to 4 percent. As many as nine different chemotherapy drugs can be tried in various combinations, along with radiation and targeted antibodybased treatments such as Herceptin (trastuzumab), which is approved to treat metastatic or gastroesophageal junction tumors that test positive for the HER2 oncogene. About 20 percent of gastric tumors exhibit HER2 overexpression or gene amplication.

Other antibodies have shown modest survival benefits in gastric cancer, including the approved drug Cyramza (ramucirumab) and an experimental molecule called apatanib, both of which target the angiogenic factor VEGFR2. Still, “the landscape in gastric cancer in the second- and third-line setting is so bare. We can’t enrich treatments based on biomarkers beyond HER2,” says Janjigian, who is an investigator for the Opdivo trials. More in-depth data on that drug will be released this summer, which will clarify the potential role of PD-L1 inhibition in treating gastric cancer, she says.

Using genomic sequencing to identify patients whose gastric tumors have hundreds of mutations — and therefore might be most susceptible to treatment with immunotherapy &mdash; is an approach that some oncologists have started to embrace, Janjigian adds.

Even though targeted antibodies haven’t produced much of a survival benefit on their own, or in combination with chemotherapy, oncologists have observed that they seem to activate the immune system. The hope is that combining them with checkpoint inhibitors will strengthen that response. Memorial Sloan Kettering is planning a trial, for example, combining Herceptin and Keytruda in HER2-positive gastric cancer patients.

A wide range of combination treatments are being tested across all of the GI cancers. Opdivo is in an early trial in combination with Yervoy (ipilimumab), which inhibits another checkpoint called CTLA-4, in patients with colon cancer. And Roche is currently testing its drug Avastin with an experimental anti-PD-L1 antibody, atezolizumab, in esophageal cancer.

And it’s not just drug treatments that can activate the immune system to combat GI tumors. One of the biggest developments in cancer immunotherapy in recent years is the ability to take immune-boosting T cells from the blood of patients, re-engineer them to be able to recognize unique antigens, or proteins on cancer cells, and then infuse them back into the body so they can home in on tumors and destroy them.

The technology, known as chimeric antigen receptor T cell (CAR T cell) therapy, has worked well in blood-based cancers like leukemia and lymphoma — even curing some patients in clinical trials who had failed all other therapies &mdash; but it has been difficult to translate to GI cancers and other solid tumors because there is no single antigen that drives them.

Scientists at the National Cancer Institute (NCI) are working on a method for engineering cells that might get around that problem. The technique, called “adoptive cell transfer,” involves removing tumor samples from individual patients and isolating tumor-reactive lymphocytes, which are naturally occurring white blood cells that can recognize the specific mutations in that cancer and launch an immune attack against them. The cells are then grown outside the body, engineered to enhance the immune response, and infused back into patients.

The technique has been used only in a small number of patients with gastrointestinal cancers, including one with a type of GI cancer called cholangiocarcinoma, or bile duct cancer, who had failed multiple chemotherapy regimens. The patient’s lung and liver metastases have shrunk by greater than 80 percent, and she remains progression-free more than two years after treatment. Researchers continue to perfect the technique, says Steven Rosenberg, a senior investigator at the NCI who is leading the research.

“It’s highly personalized — we have to create a new drug for each patient,” Rosenberg says. “But 90 percent of all patients who die of cancer die of solid tumors, so we’re in desperate need of new treatments. In my view, cell-transfer therapy is a promising area.”

In the oncology world, gastrointestinal cancers may be the next in line to realize the promise of immunotherapy.

The Next Frontier: The Promise of Immunotherapy in Gastrointestinal Cancers

When she was diagnosed with a metastatic gastrointestinal sarcoma nearly 20 years ago, Marina Symcox was 38, with a 2-year-old daughter and two sons, aged 6 and 8. Her doctors weren’t entirely sure of the exact type of sarcoma it was — there are more than 70, and only a few are well understood. Traditional chemotherapy and multiple surgeries did nothing to stop her disease.

Three years later, Symcox was in hospice care. She remembers often covering her head with a pillow, because it was so painful to listen to kids playing in the nearby schoolyard, and thinking how she would not live to see her youngest through kindergarten.

Then, through the wife of another patient in Pennsylvania, Symcox heard a rumor of a new drug that might work for patients like her. Her husband, a professor of chemistry at the University of Tulsa in Oklahoma, started trying to figure out if his wife might qualify for a trial, even though she was so sick. Her cancer turned out to have a mutation in a cell receptor — cKIT &mdash; that was the focus of research.

So Symcox and her husband traveled to Oregon Health & Science University in Portland. Symcox, who’s 5-foot-10, then weighed only 95 pounds.

“I basically was carried from Tulsa to Oregon,” Symcox remembers. “My tumors were huge, my belly was swollen with them. But it turns out that my cancer was a perfect match for Gleevec (imatinib), the drug they were testing. Within 48 hours, my tumors were liquefying and my belly was sagging as if I’d just had a baby. I knew it was working.”

Fifteen-and-a-half years later, it’s still working. Symcox has not only lived to see her daughter through kindergarten, but to see all her kids into college. In the 1990s, there really were no treatment options for patients like Symcox. Today, there is not only Gleevec, but two other FDAapproved drugs and more options on the way.

“The patient experience is radically different now,” says Robert Maki, professor of hematology and medical oncology at the Icahn School of Medicine at Mt. Sinai in Manhattan. “It’s changed the whole realm of how these tumors are treated.”

Symcox’s disease initially had been lumped into a group called leiomyosarcomas, but doctors now categorize her cancer as gastrointestinal (GI) stromal tumor, or GIST. These cancers start in special cells — “interstitial cells of Cajal” &mdash; that signal the muscles of the GI tract to repeatedly contract, pushing food through the system.

GIST is a rare cancer: It’s estimated that, in the United States, between 4,000 and 5,000 new cases occur each year. However, GIST is one of the most common kinds of GI sarcomas, cancers that start in connective tissue. Carcinomas, cancers that start in the epithelial cells that line the inside and outside of body cavities and organs, are much more common that sarcomas. GIST accounts for 80 percent of GI sarcomas. It can occur at any age, but it most commonly affects those older than 50.

GIST initially causes few symptoms. There are very rare cases of the disease being passed down through families, but in general, there are no known risk factors for it, and no definite ways to prevent it. The disease is often caught during scans for other conditions, such as a CAT scan or a colonoscopy. Sometimes these tumors are even unexpectedly found on autopsy. Approximately 50 to 70 percent of GISTs occur in the stomach and 20 to 30 percent in the small intestine, with the rest scattered in various other places, such as the esophagus or the rectum. The hallmark of most GISTs — 85 percent &mdash; are changes, or mutations, in the genes that code for a protein called c-KIT (CD117) and another protein, platelet-derived growth factor (PDGFRA). Gleevec, the drug that has made such a difference for Marina Symcox, targets the binding sites of KIT, PDGFRA and BCR-ABL &mdash; a gene prevalent in some blood cancers that is formed when parts of chromosomes 9 and 22 switch places &mdash; interrupting cell signaling and thus leading to cell death. Gleevec, along with next-generation drugs like Sutent (sunitinib) and Stivarga (regorafenib), which are also approved to treat GIST, make up a class of drugs called tyrosine kinase inhibitors (TKIs).

“These drugs block the signal from the surface into the interior of the cell,” explains Maki of Mt. Sinai. “The drug fits into the receptor like a key into a lock.”

Those GISTs that don’t have KIT, PDGFRA or BCRABL mutations, some 10 to 15 percent, are called “wild type.” These overwhelmingly account for GISTs found in children and young adults.

The story of TKIs is in a sense the origin story of GIST, or, at least, the origin of our understanding of this disease. In the mid-1990s, Gleevec was just sitting on a shelf at a Swiss drug company, with scientists unsure how to use it. Then a researcher at OHSU, Brian Druker, wondered if it might be useful in fighting chronic myelogenous leukemia (CML) by blocking BCR-ABL. Of the CML patients first treated with Gleevec, a large portion went into remission, proving the principle of Druker’s idea.

Not long after this, another researcher heard a talk about Gleevec and noted that not only did the drug block BCRABL, but it also blocked KIT. This researcher had a line of GI tumor cells with KIT mutations in his lab. When he dosed them with Gleevec, all the cell samples died. Then in 1998, a Japanese researcher wrote a breakthrough paper definitively linking the KIT mutations to increased expression of c-KIT proteins that led to GI tumors.

Word of this work started to percolate around the patient community. The wealthy husband of a patient in Finland sent a doctor to America to learn about the new developments, and, if possible, to get a sample of Gleevec. When the doctor returned to Finland and treated his patient with Gleevec, she went into remission. That positive result quickly led to clinical trials in America and Europe.

Over the next couple of years, sarcoma specialists would begin to group those GI tumors with KIT mutations under the name GIST. FDA approvals for Gleevec in GIST cases followed, in 2002 for metastatic patients and in 2008 for patients who’d had surgery to remove their tumors. It was the first targeted therapy for cancer.

“Before imatinib, metastasized GIST patients had a median survival of nine to 18 months, depending on what source you quote,” explains Anthony P. Conley, a sarcoma specialist at The University of Texas MD Anderson Cancer Center in Houston. “Now the expected median survival is about 60 months. About 40 percent of patients may live 10 years or more.”

Prognosis and treatment are generally determined by where the cancer occurs, how advanced it is and how actively the tumor cells are dividing. Because this cancer is more rare, and not as well understood, as more common cancers such as breast and lung, specialists emphasize that it’s important for patients to be treated at a large medical center with experience in GIST and access to a multidisciplinary team of specialists who can collaborate in care. These specialists can tailor drug doses and other treatments to each particular case.

“Multidisciplinary care is key,” Conley says. “GIST is rare. I hear doctors say they’ve never heard of it, or never seen one in person. This is a disease in which experience can help. For instance, a radiologist who looks at images of sarcomas all day long may key into something that a less experienced person could miss.”

The first-line treatment in many cases is surgery. GIST is resistant to conventional chemotherapy drugs and to radiation.

“If they’re caught early, we surgically resect, with a hope for cure,” says Joseph Ruggiero of Weill Cornell Medical College and New York Presbyterian Hospital. 

However, since many GIST cancers have metastasized by the time they’re noticed, and may have grown very large, medical teams sometimes use a targeted drug like Gleevec to shrink the tumor or tumors before surgery, making these operations less risky. Surgeons say that rupture of large tumors is a common risk in GIST cases.

Risk of recurrence after surgery is high in most cases, specialists say. Approximately 80 percent of patients who have radical surgery may find that the tumor grows back or metastasizes to the liver and/or the peritoneum, the membrane that covers the abdominal cavity and internal organs.

So patients with the appropriate mutations in their tumors are usually then treated post-surgically with a targeted TKI agent like Gleevec. Recent studies recommend that this be done for three years, but in practice, physicians say, patients basically stay on Gleevec until it stops working. Eventually, all patients develop a resistance to Gleevec. How long that takes varies. In some patients, the drug may stop working after a year or two. Others may stay on it for a decade or more.

“There are different ways to develop resistance,” Maki explains. “The predominant mechanism is like when you break up with a boyfriend and change the lock, so you need a new key. The new drugs are the new key. But the new keys don’t fit into all the locks. And over time, none of the keys will fit into the locks. That’s why people still die of GIST.”

Most patients progress from taking Gleevec to trying Sutent. When Sutent stops working, they go on to Stivarga. These newer drugs not only block KIT but also angiogenesis (the development of blood vessels that supply the tumor) and other mutations in various locations as the cancer cells become ever more deranged.

Unfortunately, the newer drugs also come with more severe side effects. Gleevec commonly causes puffiness around the eyes, skin rashes, fatigue and muscle cramps. Sutent may cause skin and hair to blanch white, damage the heart and cause low white and red blood cell counts. Stivarga may cause painful neuropathy in the hands and feet (often described as feeling like a cross between a callous and a blister) and high blood pressure, among other problems.

“When I was on Sutent, I got terrible mouth sores and couldn’t eat,” says Lee Ann Lamb, co-founder, with Symcox, of GIST Support International. “After two years, Stivarga started eating up my intestines, causing fistulas and perforations (bulges and holes).”

Lamb spent all of last November in the hospital dealing with those complications. In some cases, patients at this stage may go back to Gleevec with some success, but this wasn’t possible for Lamb, who is now waiting to be admitted to a clinical trial.

“It’s scary to be at this point, when you don’t have anything more,” Lamb says.

There are currently at least a dozen phase 1 trials recruiting GIST patients, and 50-plus studies recruiting in various phases. Many of these are testing the FDA-approved drugs in combination with other agents, or trying to target more recently identified mutations in tumors.

A couple dozen studies are exploring Tasigna (nilotinib), a TKI approved for the treatment of chronic myeloid leukemia, when used alone in metastatic cases of GIST, and also when used in conjuction with Gleevec. Half a dozen other studies are exploring the use of Votrient (pazopanib), an agent indicated for use in soft tissue sarcoma — but not GIST, due to lack of sufficient testing &mdash; that disrupts the development of blood vessels that supply tumor cells.

A 2012 Phase 3 study explored the use of another TKI, masatinib, showing that this drug was less toxic than Sutent (sunitinib) and improved overall survival. Other Phase 3 masatinib studies may soon be recruiting patients: One compares masatinib to Gleevec as a first-line treatment in patients who’ve had successful surgery but also have a high risk of the cancer returning.

“There are lots of options to be tried,” says Ruggiero. “In the near future, I believe there will be more targeted therapies, more anti-angiogenic agents, more tyrosine kinase inhibitors.”

“Even within GIST, it’s a lot of diseases: KIT mutation, PDGFRA mutation, BRAF, KRAS, NF1, succinate dehydrogenase, glucose metabolism (how cells convert sugar into energy) — numerous different genes,” says Jason Sicklick, a surgeon-scientist at the University of California San Diego. “And there are others that we’re just learning about.”

Sicklick is hoping to use tumor genomics — study of a tumor’s entire genetic code &mdash; to find new targets for treatment. “We are now tearing GIST apart in terms of genetics,” Sicklick says. “We’re getting a better understanding as to next steps.”

Identified only a decade-and-a-half ago, GIST is already treatable with several targeted therapies, and scientists are researching more.

Gastrointestinal Stromal Tumors Already Proving to Be Treatable With Targeted Therapies

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 &mdash; 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.

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 &mdash; 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.

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.

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.

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.”

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 &mdash; 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.

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.”

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.

Scientists are investigating a host of new treatment types that may change the outlook for those with pancreatic cancer.

Gastrointestinal Special Issue | CURE

In Gastroesophageal Cancers, Better Prevention and Treatments Needed

Medical Illustration: Targeting HER2 in Gastric Cancer

Cholangiocarcinoma Research is Expanding, But Many Questions Are Still Unanswered

The Next Frontier: The Promise of Immunotherapy in Gastrointestinal Cancers

Gastrointestinal Stromal Tumors Already Proving to Be Treatable With Targeted Therapies

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

Right in the Gut: New Clues About Preventing and Treating Gastric Cancer

An Insight Into Gastric Cancers and Life Without a Stomach

Changing Lives With Immunotherapy

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