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SRI Magazine 2016

SRI Magazine 2016

Stomach, pancreatic and other upper GI cancers: new findings are providing much-needed treatment guidance

Upper gastrointestinal cancers are under-studied in Canada. Given their grim outlook—at best, intrusive; at worst, fatal—it’s a void begging to be filled

In 2009, U.S. Supreme Court Justice Ruth Bader Ginsberg had a routine CT scan that showed a one-centimetre-wide tumour in the middle of her pancreas. The finding was part of Ginsberg’s yearly exams after having beaten colon cancer a decade earlier. She had surgery to remove the lesion and was back in the courtroom less than three weeks later. The veteran Supreme Court Justice, who’d experienced no symptoms, was lucky it was caught early. Pancreatic cancer most often is diagnosed when people report symptoms like abdominal pain and weight loss, at which point the disease has already spread, or metastasized.

Upper gastrointestinal cancers, including those of the esophagus, stomach, liver and pancreas are uncommon in Canada, but they can be fatal. Stomach cancer is often diagnosed at advanced stages, with more than one-half of patients presenting with incurable disease. Pancreatic cancer is even more pernicious; nearly 80% of these patients have disease that is so advanced that surgery cannot be offered. Moreover, it accounts for only 2.4% of all new cancer cases in Canada, yet it is the fourth leading cause of cancer death, killing 4,600 Canadians yearly—more than even prostate cancer, which arguably gets more public attention.

The challenge of managing these potentially deadly diseases is what drew Dr. Natalie Coburn, a surgical oncologist at Sunnybrook’s Odette Cancer Centre and clinician-scientist at Sunnybrook Research Institute (SRI), to the field. In particular, Coburn is working to unravel the complexities of treating stomach cancer in North America. “It’s a really interesting cancer to study epidemiologically. Worldwide it’s very common, but not one that is commonly seen in North America,” she says. Stomach cancer represents less than 2% of all new cancers in Canada, but it is the fifth most common cancer worldwide. The disease is not screened in North America, Coburn notes. “It is useful to screen for colon or breast cancer, because these are common cancers. Since stomach cancer is so rare in Canada, screening programs are not effective. In Asia, where the prevalence of stomach cancer is nearly 10 times higher, screening is effective. Unfortunately, lack of screening leads to the disease presenting at advanced stages.”

This challenge of late-stage presentation with linked metastasis prompted Coburn to lead a study on factors influencing the prognosis of people with advanced stomach cancer. The aim was to help doctors provide more accurate prognoses and identify modifiable factors that might improve outcomes. She looked at people with stage four cancer in Ontario between 2005 and 2008. Older age, tumours in the middle of the stomach and cancer that had spread widely were associated with lower rates of survival. Those who had surgery, chemotherapy or radiation, as well as those who were treated by a stomach cancer specialist with a high volume of patients, had significantly better survival, with this last factor accounting for a 15% reduction in the rate of death.

Why do these findings matter? “We can give [doctors] a ‘road map’ for the best way to treat patients,” says Coburn. “If we can identify a group of patients that exceeds expectations, that were treated in a certain manner—so with chemotherapy upfront, for example, or with aggressive therapies—then we can let other physicians know this seemed to work best across our population.”

To define these road maps, Coburn helmed the largest review of processes of care of patients with stomach cancer. The project culminated in a special issue of Gastric Cancer and a meeting of global experts who developed guidelines for best practices. Coburn is leading adaptation of these guidelines for Cancer Care Ontario’s program in evidence-based care. Having a research-based guide to treatment may be helpful especially in Ontario, where, according to Coburn, there is variation in care. “Wait times at one centre might be longer for radiation; wait times at another might be a little bit longer for surgery. Doctors’ philosophies [with respect to] aggressiveness of treatment also likely varies between centres. Those subtle differences affect what happens to patient care and outcomes,” she says.

Sometimes, even where there are guidelines to help standardize care, they are not always followed, as Coburn and her colleague Dr. Julie Hallet know. They, along with Dr. Paul Karanicolas and Dr. Calvin Law, chief of the Odette Cancer Program, form the upper gastrointestinal surgical oncology team at Sunnybrook. Hallet is also an associate scientist at SRI. One of her aims is to reduce unnecessary blood transfusions in the operating room. Blood transfusions can save lives but come with risks. They can make people more susceptible to bacterial or viral infection. In people with cancer, transfusions may stimulate isolated cancer cells to grow, leading to tumour enlargement and spread. Guidelines suggest blood transfusions only when hemoglobin, a protein in red blood cells that carries oxygen throughout the body, falls below a certain level, at which point the body is not getting enough oxygen.

Hallet cites research that found one-half of all blood transfusions during surgeries to remove tumours of the liver, pancreas, gallbladder and bile ducts are avoidable. Some reasons why guidelines aren’t always followed include lack of understanding of the risks and a doctor’s belief that transfusion is critical, notes Hallet. “Often people know about guidelines but don’t use them because they don’t see the relevance to their practice,” says Hallet. She led a large study highlighting the risks of transfusions during surgery to remove liver tumours arising from colorectal cancer. Coburn, Karanicolas and Law are co-authors of the study, which was published in the Annals of Surgical Oncology. It focused on 483 people who had the operation at Sunnybrook between 2003 and 2012. People who received a blood transfusion during or right after surgery had a five-year survival rate that was 15% lower than that of people who didn’t have one, Hallet found. Moreover, the percentage of people who remained cancer free five years after surgery was 32% among those who didn’t get a transfusion—twice that of the transfused patients. “The reality is that some patients will never avoid a blood transfusion. But for some people, if it can be avoided, why give it and expose them to unnecessary potential risks? That’s what we’re trying to highlight,” says Hallet, who shows no signs of fatigue from having performed an emergency appendectomy late the night before.

Hallet and Coburn are working with the department of surgery at the University of Toronto to create best practice guidelines for transfusions around the time of surgery to reduce the percentage of patients who are transfused annually in Toronto. Hallet is also filling a knowledge gap for a relatively rare and poorly understood disease: neuroendocrine tumours (NETs). About one-third of her practice is devoted to people with NETs, which is cancer that’s found in the cells of the hormonal and nervous systems. Neuroendocrine tumours are most common in the lung or gastrointestinal tract, although they can occur anywhere in the body. She is one of two surgical oncologists in Sunnybrook’s Susan Leslie Clinic for Neuroendocrine Tumours. It is the only multidisciplinary clinic of its kind in Canada where people with NETs see specialists in radiation, surgery and medical oncology simultaneously. The clinic, which treated more than 300 new patients in 2015, is co-led by Dr. Simron Singh.

“It’s actually the second most common gastrointestinal cancer in terms of prevalence,” notes Singh. Neuroendocrine tumours often grow slowly, with symptoms that are vague, including diarrhea and flushing, which contribute to misdiagnosis. Hallet says she sees patients who have lived with the disease for years before it is identified, at which point symptoms are intrusive and have a severe impact on people’s lives. Singh recalls one patient who was given a psychiatric diagnosis before she came to the clinic and was diagnosed with a small bowel NET. Unfortunately, it was beyond the stage where cure was an option, he says. A distinctive feature of NETs is excess production of hormones. Chronically high hormone levels can damage the heart’s valves or cause heart failure, when the muscle is too weak to pump blood as it should.

People who don’t have access to neuroendocrine centres of expertise may not be getting the optimal care that they deserve.

Using databases of provincial health records, Hallet and Singh looked at 5,619 cases of NETs in Ontario that were diagnosed between 1994 and 2009. They found the rate of new cases more than doubled in Ontario in those 15 years. They also found people from a low socioeconomic background and who lived in rural areas had worse overall survival. The results of the research are compelling, says Law, who co-authored the study and also treats NETs. “Sometimes people forget that the population of Ontario is as large as a lot of the European countries … What’s powerful about that [study] is not just the number, but the ability to start understanding what are the barriers to getting better treatment and how to deliver better care to these people,” says Law.

On the back of this research Hallet, Singh, Law and Karanicolas compared outcomes of people with NETs living in rural versus urban areas. They found those in rural regions and who had lower socioeconomic status had worse overall survival and were more likely to have cancer that returned—even though they didn’t have more advanced disease at presentation. “It’s important to study because we worry that people who don’t have access to neuroendocrine centres of expertise may not be getting the optimal care that they deserve,” says Singh. They are looking into whether poorer outcomes in this patient group is due to less follow-up care, as treatment of NETs occurs over many years. “We have to keep patients enrolled in surveillance and active maintenance therapy programs. Maybe that’s where we’re missing something with patients with lower incomes or living in rural areas, and that’s where we should focus our efforts in improving outcomes for them,” says Hallet.

The NET clinic at Sunnybrook sees most of the people in Ontario who have this cancer. Such a high volume of patients provides an opportunity to do groundbreaking clinical trials. Singh led the gastrointestinal portion of the RADIANT-4 trial, a global Phase 3 study of the safety and efficacy of the drug everolimus in treating advanced NETs in the lung or gastrointestinal tract (for more on this see p. 30). Researchers found treatment with everolimus was associated with a 52% reduced risk of disease progression or death compared to placebo, astonishing results that led to regulatory approval of the drug in the U.S. “I don’t think [the trial’s organizers] expected our centre to be anywhere near the powerhouse of a recruiter it was. For this particular trial of a relatively rare disease, they actually stopped Simron because he was recruiting too fast, and they couldn’t believe it,” says Law, smiling.

Singh says the next step is to study the cost of NETs treatment, research that is challenging to do because of, well, costs. Funding for research into NETs is hard to get because it is less common, says Hallet. With incidence of the disease rising worldwide, however—in the U.S., it has increased nearly fivefold since 1974—we can’t afford to ignore it.

Coburn’s research was supported by the Canadian Cancer Society Research Institute, Canadian Institutes of Health Research and the Ontario Ministry of Health and Long-Term Care. She holds the Sherif and MaryLou Hanna Chair in Surgical Oncology Research. Hallet and Singh’s research was supported by the Ontario Institute for Cancer Research.