A FLEDGLING BUT PROMISING form of immunotherapy known as CAR T cell therapy has been adapted to hit a new biologic target in the hopes that it will effectively fight advanced pancreatic cancer. The technique is being tested in a phase 1 trial designed to enroll up to 30 patients with the disease.

In CAR (chimeric antigen receptor) T cell therapy, immune cells, also known as T cells, are removed from a patient’s body and engineered in a lab to recognize a specific biologic marker that drives a cancer, and to destroy cells that carry it; these special T cells are then returned to the patient to multiply and do that work. The therapy being tested in this trial, BPX-601, targets prostate cancer stem cell antigen.

Despite its name, the prostate stem cell antigen (PSCA), a protein-coding gene, is naturally produced by the bodies of both men and women, and it does, indeed, have a relationship to pancreatic cancer. “It is a protein found on the surfaces of cells that was initially identified as a tumor antigen in prostate cancer, but subsequent investigations have revealed an upregulation in other cancers, including pancreatic cancer,” said the trial’s principal investigator, Carlos Becerra, M.D., of Baylor Health Care System, in Dallas. In fact, he said, 60 to 80 percent of pancreatic cancers express PSCA. “Studies have shown it to be effective in treating human pancreas cancer tumors in mice.” Those studies were conducted by Bellicum Pharmaceuticals, Inc., the developer of the CAR T- cell therapy that targets PSCA and the sponsor of the new trial.

) is being conducted solely at Dallas’ Baylor Sammons Cancer Center, through the Baylor Scott & White Research Institute. It is testing BPX-601 in humans for the first time. Other CAR T cell therapies have already been tested in humans in early-phase trials for a variety of cancer types, but no such therapy has yet been approved by the U.S. Food and Drug Administration.

Four patients have been enrolled in the trial of BPX-601, and recruitment is continuing. Participants must be adults with nonresectable pancreatic adenocarcinoma, and their tumors must test positive for expression of PSCA. Patients may have experienced disease progression after surgery or while taking chemotherapy or an investigational therapy, or they may have refused standard treatments. They must have adequate organ function and a life expectancy of more than 12 weeks; as part of the trial, they will be followed for up to two years.

Autologous T cells will be collected from the patients via blood withdrawal and genetically modified using a retrovirus to express the anti-PSCA chimeric antigen receptor. Then, the T cells will be reinfused into each patient according to a dose-finding schedule, assuming the recipient has a T cell count that’s low enough to allow the engineered cells to multiply and work. The aim of the trial is to test BPX-601 for feasibility, safety and dosing. The trial will also evaluate the safety of rimiducid, a drug that will be infused after BPX-601 is administered; investigators will consider how long the engineered CAR T cells remain at work following a single rimiducid infusion.

Rimiducid, developed by Bellicum, is designed to trigger T cell activation and proliferation in patients administered BPX-601. It helps enable control over the activity and potency of the therapy.

 “It is the activation switch and has dual functions,” Becerra said. “Once administered, it dimerizes, or couples the proteins together, to create a cluster that triggers the signaling cascade. Rimiducid also increases the activation of the T cell, expanding its number and allowing it to survive longer.”

The side effects of rimiducid are similar to those of placebo, and are to be determined for BPX-601, although they may be similar to those of CAR T cell therapies, Becerra said. The most dangerous of those is cytokine release syndrome, which can cause fever, nausea, chills, low blood pressure, headache and rash.

Becerra said he’s hopeful about the trial because there’s a great need for new methods of treating pancreatic cancer. When looking at all stages of the disease combined, patients have a one-year relative survival rate of 20 percent and a five-year relative survival rate of 7 percent.

Standard treatment includes combinations of surgery, chemotherapy and/or radiation, depending on cancer stage. “It’s important because we constantly strive to find ways to improve survival for our patients,” he said. “The Baylor Scott & White Research Institute’s mission is to support research that brings innovative treatments to the bedside. This trial is one of several strategies we are using to attack one of the deadliest forms of cancer. It helps open the door for new ways of treating pancreatic cancer using a person’s own immune system.”

“We are cautiously optimistic about this trial moving forward,” Becerra said. “Although we believe this treatment holds great promise, it is only the beginning of the clinical trial process, and only through the completion of these trials will we know if it’s effective.”

Those interested in learning whether they might be eligible for the trial can find a complete list of eligibility and exclusion requirements at 

. Alternatively, prospective enrollees can contact patient navigators at the Sammons Cancer Center at (214) 820-3535.

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Experimental treatment uses engineered T cells to target prostate stem cell antigen.

Car T Cell Therapy Being Tested in Pancreatic Cancer

GASTROINTESTINAL CANCERS CAN BE particularly difficult to weather due to the invasive nature of some treatments. Specifically, surgery can remove essential organs such as the colon or rectum, permanently affecting quality of life for survivors.

Surgeons and researchers are aware of the challenges that come with adjusting to these kinds of changes, and that’s why they’re working hard to find ways to make such extensive surgeries less common. In this issue of CURE focused specifically on GI cancers, we examine efforts to preoperatively downstage GI disease using chemoradiation, so that patients will be eligible for less invasive surgeries that don’t result in ostomies. After successful chemoradiation, some patients might even do well with a “watch and wait” approach, in which surgery is, at least temporarily, put on hold.

These measures can be immensely helpful in preserving quality of life for patients who are eligible, and our article advises readers about what to consider in researching these possibilities for themselves. Elsewhere in this special issue, we look at the fascinating phenomenon of right-sided versus left-sided colorectal cancers, explaining recent discoveries about their differences. While researchers have found that those whose cancers develop on the right side of the colon have a poorer prognosis, they are also studying genetic differences between the cancer types that could lead to new treatments.

Our cover story, meanwhile, considers the importance of survivorship care plans for those who have completed treatment for GI cancers. Many survivors aren’t aware that these guiding documents exist, yet the plans can make a huge difference when it comes to long-term physical and emotional health.

In addition to an article detailing the latest strategies for liver cancer, we offer a section on pancreatic cancer that delves into issues from prevention to causes to treatments — both approved and experimental. We hope this compilation is both informative and inspiring, arming you with the knowledge and hope you need to proactively manage your cancer journey. As always, thank you for reading.

From the Chairman

Surgery without ostomy, and the use of survivorship plans, can protect quality of life.


Averting Challenges for GI Patients

MANY PEOPLE ARE QUITE unaware of the facts about liver cancer, but there are aspects about the disease that everyone should consider as this rare disease becomes more common in certain segments of the population.

Liver cancer is a threat not only because its incidence, as well as deaths from the disease, are rising when rates for many others cancers are falling. It’s also a threat because it is silent in its early phases. Importantly, some cases of liver cancer could be preventable, and many others arise due to causes that are at least diagnosable, meaning that some patients could undergo surveillance and catch the disease in its earliest stages, when it’s the most curable.

In the past, liver scarring, or cirrhosis, that could lead to cancer was typically seen in heavy drinkers of alcohol. That issue remains, but, in recent years, the incidence of obesity, which can lead to fatty liver and subsequent inflammation and scarring, is causing a spike in liver cancer. Hispanics are at particular risk, due to their higher likelihood of carrying a gene that promotes fat in the liver, and people of other ethnicities that have elevated obesity rates, including Native Americans, are also being hit hard. Luckily, diet modifications and exercising can go a long way toward prevention of this condition.

In its largest numbers, liver cancers arise from infection with hepatitis B or C. This is important to understand, since many of us carry one of these viruses without even knowing it. Vaccinating infants at birth against the “B” version of the virus is crucial, and screening people at the highest risk for the “C” version (including those who have injected drugs, are at risk for sexually transmitted disease, or are “Baby Boomers”) is also extremely important, since treatments are available to eradicate the virus and reduce the risk of liver cancer.

Short of a 100 percent prevention rate, we must look with hope toward newer and novel treatment strategies. Luckily, some look very promising. In rare patients, liver transplant can bring about a cure for the disease if it has not spread beyond the liver but is too large for surgical resection alone. Alternatively, innovations in surgery, radiation and the delivery of chemotherapy and other agents into the hepatic arteries (chemoembolization) can work well for some patients. Generating a lot of interest in the scientific community are targeted drugs; with one already in use, another, Stivarga (regorafenib), seems poised for FDA approval. Finally, immunotherapy drugs, which are being studied in clinical trials, could easily become the new frontier in liver cancer treatment. Most of these treatments are not curative, but can hold cancers in check — sometimes for prolonged periods.

With further advancements in the clinic and comprehension in the community about the causes of this disease, we should finally be able to make some headway in reducing the incidence of liver cancer. For those who do develop it, the field is moving in the right direction — but we need to understand how to best monitor those at risk and continue to innovate in the development of therapeutic approaches.

Chair, Department of Breast Medical Oncology

The University of Texas MD Anderson Cancer Center

Editor's Page

Understanding liver cancer is a crucial step toward the prevention of this rare condition.


Knowledge is Power: Especially if it can help prevent disease

CUTTING-EDGE CANCER RESEARCH is often focused with pinpoint precision on tiny variations in the genetic code. It’s akin to working with typos in a phonebook. So last summer, when researchers revealed that there may be a significant difference between colorectal cancer that emerges on the right side of the body versus that arising on the left side, oncologists got very curious about this apparently much more simple discovery.

It has been observed for years that patients with rightsided colorectal cancer had worse outcomes than those with left-sided disease. Nobody knew why, and while there was some evidence of molecular differences based on where a colorectal cancer emerged, the consensus assumption seemed reasonable: Right-sided patients fared worse because their disease was less likely to be caught at an early stage.

Stool is more liquid on the right side, and the bowel is larger. “We assumed that you would need a more advanced cancer on the right side to manifest symptoms,” explains Alan Venook, M.D., a gastrointestinal (GI) oncologist at the UCSF Helen Diller Family Comprehensive Cancer Center, in California. Patients with a right-sided tumor were thus more likely to be diagnosed with later-stage disease. It was serendipity that made Venook rethink left versus right. He was invited to give a memorial lecture at Cornell Medical School in April 2016 in honor of Scott Wadler, a specialist in GI cancers who had died in 2007. While researching his talk, Venook found a 2001 paper that showed a five-month difference in survival between left- and right-handed colorectal cancers. “Now, that blew my mind,” says Venook. Because the therapy regimen in the paper was obsolete, the research never got the attention it deserved.

Venook was motivated to re-examine data he’d helped generate as the lead investigator on Cancer and Leukemia Group B/Southwest Oncology Group 80405, a trial that had studied some combination therapies for metastatic colorectal cancer. As its ponderous name and number suggests, it was one of the thousands of generally anonymous studies that, bit by bit, advance cancer treatment.

Study 80405 had largely wrapped up by 2014, but it had never looked at where the cancer had arisen. “It hadn’t occurred to us that that was relevant,” says Venook. “In almost no study in that era did we capture that information.” For six weeks, a small team combed through more than a thousand patient files, pulling out the primary disease location in the colon.

When they ran the numbers, the differences leapt off the page. To double-check, he scoured other studies. “It just blew my mind. I had no clue that it was this big a difference,” says Venook.

Colleagues were similarly intrigued when Venook presented his analysis in 2016 (it hasn’t been published yet). For patients with metastatic colorectal cancer, he found, the sidedness of the primary tumor within the colon appears to affect both survival and the effectiveness of commonly used biological agents Avastin (bevacizumab) and Erbitux (cetuximab), which are designed to interfere with the formation of blood vessels that feed a tumor, and with growth factor receptor signaling. Patients with left-sided disease enjoyed a median overall survival of 33 months compared with 19.4 months in right-sided disease. And a comparison of Avastin and Erbitux showed that Erbitux might actually be harmful to patients with right-sided tumors.

Because the study was not originally designed to scrutinize sidedness, scientists believe more research is needed for confirmation. But the issue has the attention of GI oncologists. “Most of us believe this finding could be practice-changing,” says Mohamed Salem, M.D., of the Lombardi Comprehensive Cancer Center at Georgetown University, in Washington, D.C.

Anatomically, the colon, or large intestine, seems like a single organ, a unified piece of human plumbing. For years, the primary tool of colorectal cancer screening was a sigmoidoscope, which only views the left side of the colon. The premise: no polyps — potentially precancerous growths &mdash; on the left side meant that the right colon would be fine, since more cancers do, in fact, arise in the rectum, or left side of the colon. That was eventually disproven, one reason why colonoscopy, which can examine the entire colon, is now favored by many providers. Flexible sigmoidoscopy is still used for screening, but performed every five years compared to every decade for colonoscopy.

In fact, the two sides of the colon emerge from different parts of embryo. Every cell in the body descends from that first fusion between the egg and the sperm, but as the embryo grows, these cells begin to develop in different directions. Some cells become skin, while other cells become neurons in the brain. Some cells become the right colon, while others become the left colon. The right colon comes from the mid gut while the left colon comes from the hind gut, and they have different blood supplies. The cells on the left and rights sides function slightly differently, and therefore, while they possess the same genes, they may not all be turned on to express the same set of proteins. “That doesn’t mean their gene expression patterns are necessarily different, but it certainly would be believable that they are,” says Venook.

It’s also assumed that the microbiome, which affects the way the body operates, plays a role. The microbiome is composed of all the genes within the collection of microbes (mostly bacteria) that live in and on humans. The vast majority of the GI microbiome resides in the colon, where it interacts constantly with the immune system through the lining of the intestine. It can affect the chemical composition of the colon contents, including what is absorbed into the body, But the microbiome is a moving target: different in different parts of the colon, different in every person and different over time. “The microbiome is very hard to understand in colon cancer,” Venook says. It’s also disrupted by the procedures used to diagnose and treat colorectal cancer. “This is a black box. Undoubtedly this is important, but we just don’t know how.”

While colon cancer is typically a disease of older people, Salem reports “an alarming finding:” over the last 10 to 15 years, an increase in colorectal cancer for patients between the ages of 20 and 49. And while there has been a slight overall decline in colorectal cancer, the frequency of rightsided colon cancer appears to be increasing. But the right/ left divide is more complex than just patients with left-sided disease doing a little better. There is slightly more left-sided disease than right. Patients with right-sided disease also tend to be older and are more likely to be female.

Right-sided disease is also subtly different: more advanced, with larger tumors that look different and have different chemical signatures.

The information about sidedness also comes on the heels of a major upgrade in our understanding of colorectal cancer. As our ability to decode the genetics and molecular biology of tumors has gotten both cheaper and more powerful, colorectal cancer is now recognized as more than one disease. Gene mutations like HER2 and BRAF, which can be targeted with drugs, are just part of the picture, as experts are learning that the overall biology of the tumor is also important when it comes to designing treatment. In 2015, scientists divided the disease into what they call “consensus molecular subtypes:” CM1, CM2, CM3 and CM4.

Between this new classification system and left/right awareness, future clinical trials hold greater promise than ever. Among the first tasks is finding out what the sidedness means. “It’s our job to figure out what it’s a surrogate for,” says Venook. “Is it an independent prognosticator, or some kind of voodoo we don’t understand?”

“Any future clinical trials will stratify patients according to the side,” adds Salem.

But can this information be used now? First of all, it’s important to understand that right-sided disease is not a death sentence. “I’ve had patients say ‘Oh, I’ve got right-sided cancer. I’m toast,’” says Venook. “These are generalities, these are averages. There are patients within the group who do fine.” Indeed, if caught early enough, surgery to excise rightsided disease is typically less complicated than that undertaken for left-sided colorectal cancer.

Alternatively, the intel can be comforting to some with left-sided disease. While C. Damon Hecker, a Virginia-based executive, was in the midst of chemo for his stage 3 colorectal cancer, his wife, Karen, did most of the family education, reading journal articles and connecting with Colon Town and other patient communities. When she learned about the right/left difference, she happily conveyed the news to her husband — it was, after all, among the more encouraging statistics in the face of the loss of nearly a foot of his left colon.

“I didn’t give a s***, to be honest,” he confesses — the chemo was hitting him hard. “I was pretty focused on other things, but it helped her.” She agrees: “You’re always looking for an edge.”

Once the disease is metastatic, treatment options change. Salem and Venook now use sidedness as one variable of many, on a case-by-case basis.

First of all, learning that Erbitux is riskier for right-sided patients bodes well in the long term. “As a physician, the first directive is to not harm your patient,” says Salem. The patient’s ideas about quality of life and ambition of treatment are also very important. Often enough — and in the absence of confirmed guidelines suggesting that Erbitux not be used in right-sided colorectal cancers &mdash; treatment choice is governed by side effects, like the desire to avoid a rash, or pre-existing medical conditions such as hypertension. Also, Erbitux is not used in colon cancers bearing KRAS mutations.

“We cannot cure most colon cancer patients,” admits Salem. “Yet the median overall survival has increased from six months 20 years ago to almost three years. The main change is that we have more drugs. It is important to receive all lines of therapy. The more options available, the better you do.”

Right-sided disease might also mean choosing clinical trials. “We may treat you more aggressively,” says Venook. The breast cancer drug Herceptin, which targets an overexpression of the protein HER2, is in trial for colorectal cancer now, and immune therapy options are blossoming. And it should not take long for the research community to incorporate left/right dynamics and the new molecular subtypes into a whole raft of new trials.

“This is a reason to make sure that you are in contact with, or actually see, a doctor at a major center,” says Venook. “This is an evolution, and they are the people that know about it.”

Salem agrees: “Clinical trials give you an opportunity for 2018 therapy.”

Whether a cancer arises on the left or right side of the colon can affect both prognosis and treatment.

Side Matters in Colorectal Cancer

It’s not unusual these days to hear good news about various cancer types as novel treatments bring about significant reductions in the rates of new cases and deaths.

Liver cancer, though, has been heading in the other direction. In 2016, the world mourned the loss of legendary musician David Bowie, who reportedly died of the disease. And just a few years prior, it was a major factor in the death of Lou Reed, another influential musician.

But it’s not just rock stars who succumb to liver cancer. This year, about 40,710 people in the United States will be diagnosed with the disease, and it will be responsible 28,920 deaths. Among common cancers, its incidence is increasing at a rate second only to that of thyroid cancer, and liver cancer deaths are rising at the highest rate in this group.

This is particularly troubling to the medical community because it’s tough to catch liver cancer in its early stages, when potentially curative surgery is an option.

“Unfortunately, liver cancer does not commonly have early warning signs. Symptoms of liver cancer often do not appear until it is in its later stages, where it is harder to treat,” says Bassel El-Rayes, M.D., an oncologist at Emory Winship Cancer Institute, in Atlanta. These symptoms include pain in the upper right side of the belly, bloating, loss of appetite, feelings of fullness, weight loss, fatigue, nausea and vomiting, and yellow skin and eyes.

Avoiding risks such as hepatitis and obesity-related fatty liver may be the most effective and straightforward approach to lowering risk. But for those who have developed liver cancer, the good news is that researchers are working to improve existing treatments for the disease — and to develop new ones. In particular, experts say, targeted drugs and immunotherapies look promising.

While most treatments besides surgery are not considered curative, they may delay progression of cancer, and some remissions might be long-lasting.

“There have been many advances in understanding how to treat liver cancer,” says Ghassan K. Abou-Alfa, M.D., a medical oncologist at Memorial Sloan Kettering Cancer Center, in New York. “I always tell my patients that this is a very hopeful time.”

Treatment options are available for people with all stages of liver cancer. Early-stage disease is often treatable with surgery, which offers the best chance of a cure, but advanced stages usually require alternative strategies.

Surgical tumor removal is an option for patients who have a single malignant liver tumor that has not grown into nearby blood vessels. Once the cancer is removed, a healthy liver has the capacity to grow back and, over time, can even regain some of the function it lost when part of it was taken out.

 Potential side effects of surgery include bleeding, infections, complications from anesthesia, blood clots and pneumonia. However, newer laparoscopic and roboticassisted surgical techniques typically cause fewer side effects and are associated with faster recovery times. These are options for patients whose liver tumors are not close to main vessels, or who have not had extensive liver surgery in the past.

Liver Transplantation may be an option for any patient whose cancer has not spread beyond the liver, or for many whose livers are cirrhotic. To be considered eligible, a patient must have either a) a single tumor that is 5 cm or smaller, or b) three or fewer tumors, none of which is larger than 3 cm. However, researchers are investigating the possibility of expanding the criteria for liver transplantation. Liver donors are rare and the wait lists can be long, so transplantation is not always an option, even for those who meet the eligibility criteria.

Possible side effects of this procedure include failure of the bile ducts, blood clots or bleeding, infection and the body’s rejection of the donated organ. High-energy radiation can kill cancer cells and shrink tumors. External beam radiation therapy uses a machine outside the body to deliver the radiation to liver tumor(s).

In internal radiation therapy, also known as brachytherapy, radioactive material is injected into or near the tumor(s). The radiation doesn’t travel far, so it’s less likely to damage nearby normal tissues.

Side effects associated with liver radiation can include skin irritation, stomach upset, low blood counts and fatigue.

Some cancer centers offer minimally invasive techniques that are particularly useful if surgery is not an option, and these may also be administered by a radiation oncologist. One is ablation, which kills small tumors by cutting, vaporizing, melting or using intense heat or cold; this may be done in combination with surgery, or without any surgery at all. Side effects can include infection and internal bleeding. Another minimally invasive technique is NanoKnife, which uses electrical currents to make holes in the cancer cells and destroy them.

 lessens or blocks the flow of blood to liver cancer cells, so that they cannot survive. There are two kinds of embolization:

 or chemoembolization is a procedure by which particles meant to cause an obstruction, or those particles plus a high dose of chemotherapy, are injected through a catheter directly into the hepatic artery, the blood vessel that feeds the liver cancer tumor. This strategy is commonly used to treat patients whose liver tumor(s) cannot be removed surgically. It is also increasingly used in many cancer centers, says El-Rayes, as a “bridge to transplant,” meaning it can often either shrink liver cancer tumors or keep them from growing until a liver is available for transplant.

 is a procedure by which small radioactive beads are injected through a catheter into the hepatic artery, through which they travel to reach the liver.

 Side effects of embolization for liver cancer can include fever, abdominal pain, nausea, an inflamed gallbladder, liver infection and blood clots.

Nexavar (sorafenib) is the only FDA-approved targeted drug for those with liver cancer; it’s indicated for patients with hepatocellular carcinoma for whom surgery is not an option. Nexavar works by blocking signals that tell cancer cells to grow, while also helping to prevent tumors from forming the new blood vessels that feed them.

Side effects can include, but are not limited to, skin problems, stomach upset, hair loss or thinning, dry mouth, diarrhea and fatigue.

For patients who are resistant to Nexavar, or for whom it is not an option, several targeted drugs are being explored in clinical trials.

“The clinical trials of today are testing the drugs that will become standards of care in 10 years, so it’s important for patients to consider clinical trials,” El-Rayes says.

Among the most promising targeted therapies in clinical trials, says Abou-Alfa, is cabozantinib, a drug that is already approved to treat thyroid and kidney cancers. Cabozantinib is under investigation in a phase 3 clinical trial, called CELESTIAL, for patients with advanced hepatocellular carcinoma who have already received Nexavar. A MET inhibitor, it works by blocking proteins that encourage the cancer to grow. Like Nexavar, it also stops tumors from growing blood vessels.

Abou-Alfa says he is also “very encouraged” by data on Stivarga (regorafenib), “a cousin to Nexavar,” and on the MET inhibitor tivantinib. In January, the U.S. Food and Drug Administration granted a priority review to Stivarga as a treatment for liver cancer, and expects to make a decision about whether to approve the drug by this summer.

While there is much enthusiasm about new targeted therapies, it is unclear how much these will extend remission times or improve survival until larger-scale trials are carried out. In addition, it is hoped that tissue or blood testing might personalize therapy and be able to match the right drug to the right situation.

Another area of “great interest,” says Abou-Alfa, is immunotherapy, which capitalizes on the body’s immune system — its natural defense system &mdash; to fight cancer.

However, he notes that immunotherapy’s full range of “side effects are unknown and should not be underestimated, especially given that liver cancer patients so often have hepatitis or cirrhosis.”

 The known side effects can include cough, fatigue, nausea and skin problems. In rare cases, the boosted immune system can attack healthy organs in the body, and that can lead to serious complications.

Mark Yarchoan, M.D., an oncologist at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, says a class of immunotherapeutic drugs called checkpoint inhibitors is “highly promising” for the treatment of liver cancer. These drugs, which inhibit proteins that would otherwise hold the immune system in check, are already approved for several cancers, including lung cancer, melanoma, kidney cancer and head and neck cancers.

Data from the CheckMate-040 study, a phase 3 clinical trial of the checkpoint inhibitor Opdivo (nivolumab) in patients with liver cancer, showed that “one in five patients had measurable tumor shrinkage with Opdivo, while many other patients got their disease to remain stable for sometimes a long time,” Yarchoan says. The results were “so positive,” he says, that “many in the field are hopeful that Opdivo will be better than any treatment that came before it for liver cancer.”

In addition, Abou-Alfa noted that Keytruda (pembrolizumab) and the experimental immunotherapies durvalumab and tremelimumab have “shown promise, but are being studied in clinical trials as well.”

In the future, Yarchoan says, there will likely be trials that combine targeted therapies and immunotherapies for the treatment of liver cancer, as there are for other cancers. “Different drugs destroy cancer cells in different ways,” Yarchoan says. “Using a combination of drugs can increase the chance more cancer cells will be destroyed. Many times, one drug will even help the other drug work better.”

Liver cancer diagnoses and mortality have been rising, but new treatments are designed to help reverse the trend.

Changing Direction on Liver Cancer Trends

When Martha Raymond, M.A., CPN, executive director of Michael’s Mission and co-chair of the GI Cancers Alliance, conducted an anonymous online survey to explore the unmet needs of patients with gastrointestinal (GI) cancers, she was shocked at their gutwrenchingly honest and disheartening responses.

“Fifty-one percent didn’t even know what a survivorship care plan was,” Raymond says of the 507 participants in the six-week national survey conducted in the fall of 2016. “Another 23 percent said their health care provider never mentioned the need for one.” Based on Raymond’s data, only 8 percent of those who survive GI cancer have a survivorship care plan in place.

Yet in 2005, the Institute of Medicine recommended that each cancer patient, upon completing treatment, be equipped with such a roadmap; now, centers that want accreditation from the Commission on Cancer are required to provide survivorship plans, including treatment summaries and follow-up/surveillance recommendations.

The survey — which included surviors of colon, stomach, rectum and other cancers, most of whom had been diagnosed at stage 3 or 4 &mdash; found that such plans could be helpful to this population, as most said their struggle didn't end once treatment did.

That struggle comes in many different forms: Over 50 percent of respondents reported feeling anxiety, depression, fear and sadness during treatment or survivorship, with 20 to 40 percent reporting hopelessness, denial and anger; in addition, many didn’t understand the steps they needed to take to help safeguard against cancer's return. Because GI cancer consists of 10 different diseases with varying stages and side effects, no two patients will ever have the same follow-up plan. And because there is no single set of guidelines across oncology on how to follow GI survivors, most patients feel uneducated and uncomfortable when it comes to their own survival.

One of those survivors is Scott Murchie, who was diagnosed with stage 3 rectal cancer in April of 2011, when he was 48. After a fecal occult blood test, colonoscopy and upper endoscopy ordered due to a family history of polyps, Murchie’s GI doctor found a lime-sized tumor, immediately launching the resident of northern Virginia into a full-scale treatment plan.

“There were no signs or symptoms,” Murchie says. “I got the luckiest break in the world … If he didn’t order that test, who knows what would have happened?”

After four and a half months, during which he underwent two separate chemotherapy regimens, six weeks of daily radiation and two surgeries, Murchie then had to face an equally hard, yet lesser-known battle: survivorship. “You’re so focused on the treatment every step of the way, just getting through it,” Murchie says. “Then you’re done, and you don’t want to feel ungrateful, but this is in some ways when all the hard work happens. You ask yourself: What’s supposed to happen to me now? What am I supposed to do? How do I deal with the aftereffects both psychologically and physically?”

 Although colorectal cancer is the third leading cause of cancer-related deaths in both men and women in the U.S., that death rate has been dropping steadily over the last few decades due to advanced screening and improved treatment options. However, even though there are more than a million survivors of GI cancers, many health care professionals are battling the unknown when it comes to follow-up care and helping patients to navigate the longterm side effects of treatment.

“This poses many challenges,” says Lei Zheng, M.D., Ph.D., associate professor of oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. “These patients survive cancer, but they’re left dealing with consequences, even though [treatment] is what led to their cure.”

For example, surgery is the main treatment option for the 80 percent of colorectal cancers that are nonmetastatic, or have not spread from the primary site. While this is potentially curative, more than 40 percent of patients in stage 2 or 3 will have a disease recurrence, making follow-up care critical to catch the recurrence before it spreads, while it may be curable with surgery. This care is also important in helping survivors to deal with chronic functional gastrointestinal issues, such as the management of colostomy bags. Zheng notes that the side effects of radiation, chemotherapy and even CT scans (which employ radiation) are also a cause of concern, because the long-term effects of many treatment options are still unknown. In some cases, it is possible that treatments for an initial GI cancer can contribute to the development of a secondary cancer.

“Those things that you were so grateful to receive to cure you also cause you concern moving forward,” Murchie says. “Just going away and knowing that my appointments were done didn’t feel safe to me. Because even if you’re cured, there’s always the question of: ‘What happens now?’”

Finally, other forms of GI cancer that are less treatable than colorectal cancer pose a different set of problems — for example, while survival rates have been improving decade to decade, pancreatic cancer, detected most commonly at an advanced stage, is still considered largely lacking in significantly effective treatment options, with a one-year survival rate of 20 percent and a five-year survival rate of only 7 percent.

“Not many patients actually survive pancreatic cancer, and very few patients are cured,” Zheng says. “Therefore, the follow- up of these patients forms a different challenge, because of the stress caused by the high recurrence rate of this deadly illness and by the uncertainty of the recurrence time.”

Raymond discovered her passion for helping GI cancer patients and survivors after both her parents were diagnosed with colon cancer during her intermediate school and college years.

“There was no information, obviously no Internet back then,” Raymond says. “It was very isolating, to say the least.”

 Now, finding strength in her motto to “turn your pain into your purpose,” Raymond is partnering with the GI Cancers Alliance to develop the first survivorship care plan that will be tailored to the specific needs of patients with GI cancers. The plan will be customizable for each disease state and address specific needs of patients with GI cancers and their caregivers.

A draft version of the plan will be available in June at the annual meeting of the American Society of Clinical Oncology (ASCO), where members of the GI Cancers Alliance will review the document and offer comments, edits and suggestions. Those interested in using the plan can look for it on the GI Cancers Alliance website at GICancersAlliance.org, where it will be posted when ready.

“It will encompass things like helping patients know when they need to go back for blood work, scans, colonoscopies or endoscopies,” Raymond says.

“But it’ll also cover things such as the emotional and psychosocial aspects of survivorship … because the quality of life concerns are just as important as the physical concerns.”

In the meantime, although it does not broadly apply to patients who have survived any variety of GI cancer, ASCO offers a survivorship care plan template that is specific to those who have had colorectal cancer (https:// tinyurl.com/hhzjk9b).

There are also online guides, such as one from Livestrong (https://tinyurl.com/j6rrllm), that can help people who have had cancer, with the help of their doctors, to create their own survivorship care plans.

In general, Zheng and Raymond advise survivors to take a few simple steps to keep up with their own follow-up care. “Always consult with your health care professionals and really ask questions,” Raymond says. “Get as much education on your disease as you can from trusted sources like the National Cancer Institute, and find out what all your options are. The more information you have up front, the better prepared you are.”

Zheng stresses that followup care looks different for every patient, but suggests that many survivors undergo surveillance CT scans, colonoscopies or endoscopies and participate in clinical follow- ups to analyze their family history. For example, if it is found that the patient has Lynch Syndrome, a genetic condition associated with a higher risk of GI cancer, the patient will likely need a more rigid and comprehensive follow-up plan.

In order to manage the emotional and psychosocial consequences of GI cancer, Raymond suggests that all survivors should focus on regaining control where they can, and seek out support among a variety of sources.

“When someone is diagnosed with cancer in general, that feeling of control is gone,” she says. “But doing something as easy and as simple as putting together a binder of your health care information, blood work, scan results and appointment follow-ups … it gives the patient that feeling of control again. They start to feel like, ‘OK, I got this.’”

 From the patient perspective, Murchie agrees. “I made sure the information shared between all of my providers continued to flow together after treatment,” he says. “Every single provider I went to, I wanted to make sure that the information got hooked up together to try to figure out if anything was particularly meaningful, or if it was just information they could use to put together a picture of treating me long-term.”

Due to the wide array of symptoms, side effects and health concerns that accompany GI cancers, Raymond, Zheng and Murchie all agree: Being your own best advocate is the most effective form of follow-up care.

“A lot of folks will have opinions on what you should do, so be true to yourself about what feels comfortable,” Murchie says. “Gather information so you feel comfortable with the game plan moving forward. If it doesn’t sound right, feel right, or you’re not getting scheduled for follow-ups, you really have to advocate for yourself.”

“Be the co-captain of your own health care,” Raymond echoes. “Seek support, get education and really let your oncologist know that you want to have a say at the table.”

A survey about life after GI cancer has sparked the creation of specialized survivorship care plan.

Turning Pain Into Purpose With GI Cancer

After living just a few days with an ostomy — a bag designed to catch waste through a hole created in the stomach wall &mdash; Marjorie Wassermann knew it was not the type of lifestyle she wanted to have permanently, if she could avoid it.

“I would frequently wake up in the morning to find that the bag hadn’t done its job overnight,” she recalls. Diagnosed at age 43 with a large tumor low in her rectum, Wassermann had just completed six weeks of radiation and chemotherapy to shrink her tumor before undergoing sphincter-sparing surgery, which removed the tumor but spared the muscle that allowed her to squeeze and hold stool. In order to give what remained of her bowel enough time to heal after the surgery, Wassermann received a temporary ostomy and was told that there was a 90 percent chance that the ostomy would be reversed in a few weeks.

An ostomy is a surgically created opening in the body used for the discharge of body wastes, in this case stool. Through the ostomy, surgeons leave a small piece of exposed bowel to which patients must attach an ostomy bag to catch waste. Patients with colorectal cancer may have a colostomy, an opening where the remaining large intestine (colon) is brought through the abdominal wall, or an ileostomy, an opening where the small intestine (ileum) is brought through the abdominal wall.

Although every effort is made to preserve the intestines during surgery, for some patients with colorectal cancer, a permanent ostomy may be the only life-saving option. People living with ostomies often face issues with body image and depression, odor control and sexual activity. However, in recent years, the use of neoadjuvant radiation and chemotherapy — treatment given prior to surgery &mdash; and improved surgical techniques have led to an increase in the proportion of sphincter-sparing procedures.

It is estimated that, in 2016, about 135,000 people were diagnosed with colorectal cancer, and about 50,000 people died from the disease. If the disease is caught early, when it is localized (stage 1), the five-year relative survival rate is greater than 90 percent. If the disease has spread to local lymph nodes (stage 2 or 3), the five-year relative survival decreases to about 71 percent. In cases where the cancer has metastasized or spread to other parts of the body (stage 4), the five-year relative survival is only about 13 percent.

Surgical resection is the most common treatment for colorectal cancer and typically involves removal of the tumor, some surrounding healthy tissue and nearby lymph nodes. A majority of patients with locally advanced disease will also undergo chemoradiation treatment prior to surgery to attempt to shrink the tumor, according to Johanna Bendell, M.D., director of the gastrointestinal cancer research program at Sarah Cannon Research Institute, in Tennessee.

This approach was established based on the results of a study published in 2004 that showed that patients with locally advanced rectal cancer who were treated with a combination of radiation and a chemotherapy drug called fluorouracil prior to undergoing surgery experienced improved local control of their disease and reduced toxicity. These treatments also lower the long-term risk of recurrence and mortality.

 “We saw from this study that the rates of patients needing abdominoperineal resection decreased using neoadjuvant chemoradiation compared with post-surgical treatment,” Bendell says.

Abdominoperineal resection (APR) is a surgical procedure that completely removes the lower portion of the colon, the rectum and the anal sphincter, resulting in the need for a permanent colostomy. The past few years have seen advances in ostomy management, and today’s survivors have a wide variety of products to choose from, including bags designed to be compatible with athletic activity. Still, ostomy can decrease quality of life for some patients, at least temporarily.

In addition to patients having to live with the ostomy, the surgery itself is very complex and is associated with a variety of complications, according to Feza H. Remzi, M.D., director of the Inflammatory Bowel Disease Center at NYU Langone Medical Center in New York.

“When surgery with an ostomy is indicated, we have to remember that it is about life, about curing cancer,” Remzi says. “Anybody with an ostomy can do most of the things someone else can do, but if it can be avoided, it is good to avoid both the ostomy and the morbidities associated with the surgery.”

Instead of undergoing an APR procedure, certain patients may be eligible for sphincter-sparing procedures like the one Wassermann received. These procedures, called low anterior resections, are more commonly performed in patients with a tumor 6 to 10 cm from the anal verge, and in selected patients with a tumor less than 5 cm from the anal verge, according to Remzi. Preoperative chemoradiotherapy can help shrink the tumor and thereby enhance the surgeon’s ability to resect the tumor and leave more bowel in place.

When Marra Rodriguez, 42, was diagnosed with a massive tumor low in her rectum at age 39, only one of the physicians she spoke with believed that, through careful medical and surgical treatment, an ostomy could be temporary. Her tumor was less than 2 cm from the anal verge.

“From my first appointment with a colorectal surgeon, who would not guarantee a temporary ostomy, to what I read about the location of my tumor, everything was indicating that I would most probably live with a permanent ostomy bag. Yet, I was not willing to accept this as a final definite outcome,” Rodriguez says. “I did a lot of research and advocated for myself and found the physician who was confident that (permanent ostomy could be avoided).”

At the time of her surgery, Rodriguez had experienced a complete response to the chemoradiation, meaning there was no evidence of residual tumor. Her physician did the resection with a J-pouch reconstruction, which provides a small reservoir as an alternate way to store and pass stool, and she was given a temporary ostomy for six months to allow the area to heal.

 According to Remzi, Rodriguez’s case reflects the lack of consensus within the field of rectal surgery care. Remzi is part of the OSTRiCh Consortium (Optimizing the Surgical Treatment of Rectal Cancer), a group of health care institutions that are working to improve the quality of rectal cancer care in the United States.

With today’s pathology and imaging technology, surgeons should be able to decide whether to perform an APR, or a sphincter-sparing procedure, ahead of any chemoradiation, Remzi believes. The neoadjuvant treatment simply makes the chosen surgery easier, he says.

“For a surgeon to change their mind about the procedure after radiation therapy can be misleading,” Remzi says. “That is why these procedures should generally be done at a center where they perform them frequently.”

In fact, research has shown that high-volume hospitals are associated with improved outcomes for colon cancer compared with low-volume hospitals. In addition, patients who have their surgery at a high-volume hospital are more likely to recover and go home, rather than to skilled care facilities, after surgery than people who have operations at low-volume hospitals. “If these surgeries are not done with a stringent protocol, the patient may be missing an incredible opportunity, because the tumor may bypass a treatable period,” Remzi says.

Missing the window for effective treatment is also a concern for Remzi when it comes to the emerging practice of “watch and wait” for colorectal tumors.

The watch-and-wait management approach is being studied in patients with colorectal cancers that achieve clinical complete response after preoperative chemoradiation. “We have learned that some rectal tumors respond very well to radiation and chemotherapy, and by the time we remove the rectum, we find no cancer cells are left,” says Julio Garcia-Aguilar, M.D., Ph.D., chief of the Colorectal Service and Benno C. Schmidt Chair in Surgical Oncology at Memorial Sloan Kettering Cancer Center. “This experience has caused some to ask whether chemotherapy and radiation could potentially be the only treatment necessary for those selected patients with a dramatic response.”

A minority, maybe 25 to 30 percent of patients, treated with chemoradiation will achieve complete response and be candidates for this approach, Garcia-Aquilar says. And, as with any new treatment approach, more research is needed.

For example, while the appearance of a scar in place of the tumor in endoscopic examination — categorized as a clinical complete response — may suggest that the tumor is gone, in some of these cases a few cancer cells remain and the tumor may grow back.

Garcia-Aguilar and colleagues at Memorial Sloan Kettering have been using a watch-and-wait approach for years in patients with clinical complete response.

 “In cases where the tumor does grow back, it usually grows back slowly, and since we see patients at frequent intervals, we can detect that growth in time to do the same operation that we would have done at the beginning,” Garcia-Aguilar says. For some, he says, that could mean undergoing surgery that preserves the sphincter; the ability to go that route will depend on the stage of the tumor before starting the neoadjuvant chemotherapy and radiation, the amount of tumor left after the chemotherapy and radiation, and how far the tumor is located from the anus (farther away means more likelihood of avoiding a colostomy).

Memorial Sloan Kettering is also conducting the only prospective, multi-institutional study on this watch-and-wait approach, but data on its effectiveness likely will not be available for another three years.

Until more is known, Remzi suggests that patients should still undergo surgical resection as a standard of care for colorectal cancer, and that they should seek treatment at centers familiar with these procedures.

Years out from their initial diagnoses, surgeries and temporary ostomies, both Wassermann and Rodriguez have few regrets about their treatment decisions; however, both acknowledge that, although they avoided getting a permanent ostomy, there are still aftereffects from their disease.

Wassermann lives with nerve damage to her sphincter that affects her ability to sense when she is having a bowel movement.

“I found through my own experiments with avoiding certain foods that gluten is a big trigger for me,” Wassermann says. “I also have to avoid fibrous things like raw vegetables, or super-dense foods like steak.”

Rodriguez also has a semi-compromised sphincter and no longer has sacral nerve function for bowel control, resulting in some fecal incontinence “My brain does not always communicate with my J-pouch and allow me to evacuate properly,” Rodriguez says. Because of that, she has had to makes changes to her life, such as conducting daily colon cleanses to avoid accidents. “That is my way of living,” Rodriguez says. “Some people view it as an inconvenience, but it is my choice and the way I want to live. I prefer that to an ostomy.”

Both women say that one of the things that helped them through the experience was finding joy and laughter in their situation. As Wassermann says when discussing the adverse effects of her surgery, “Cancer is the gift that keeps on giving.” She and Rodriguez both work to give back, as well, through their involvement with patient advocacy groups like the Colon Cancer Alliance and Fight Colorectal Cancer.

“It is hard not to think of your mortality, but I made it my mantra to find joy in the entire journey,” Rodriguez says. “My advice to others would be to advocate for themselves, not focus on the negative and find joy in the milestones along the way.”

Preoperative chemoradiation and advanced surgical techniques can prevent the need for ostomies in some with colorectal cancer.

GI-Special-Issue | CURE