Pippa Wysong

For Gretta Hutton of Orillia, Ontario, signing up for a clinical trial was a no-brainer. That is, once she learned about one.

Her story started in May 2014 when she was diagnosed with stage 4 mantle-cell lymphoma, a rare form of non- Hodgkin lymphoma (NHL) that affects 6 per cent of NHL patients. Her oncologist at a nearby community hospital suggested she start standard-of-care R-CHOP chemo- therapy (each letter stands for the name of a drug used).

“He gave me two to five years with treatment,” she says.

But before she began the treatment regimen, both her sister and a neighbour looked on the ClinicalTrials.gov website and found a clinical trial of the targeted drug Imbruvica (ibrutinib) that was recruiting newly diagnosed patients with her condition. Her oncologist was unaware of the trial, but once she told him about it, hospital staff provided access to phone and fax numbers for the trial nurse. Hutton received the informed consent form, which provided details about the trial, and within days, she was in Hamilton at the Juravinski Cancer Centre, one of several Canadian centres participating in the trial. Hutton underwent additional tests to make sure she qualified — and she did.

“When the trial oncologist walked in, the first thing he said was, ‘We have lots of time to talk,’” she says. He explained the study, the medications that would be used, the risks and benefits and the steps involved in being in a trial.

Hutton was placed on either Imbruvica or placebo paired with the targeted drug Rituxan (rituximab) and the chemotherapy bendamustine — a different combination of medicines than the R-CHOP regime. She isn’t certain she received Imbruvica, but suspects she did: Her condition improved significantly and her cancer is in remission. She initially made monthly trips to Hamilton and now makes the two-hour drive from her home every other month.

“I was really sick when I first went in, so there wasn’t much to lose to try a trial,” she says. Besides, she knew she could quit any time and switch to standard care. Instead, her experience was so positive that she became a patient-spokesperson for the Canadian Cancer Clinical Trials Network, also known as 

, an organization that works to increase the number of academic trials conducted in Canada and encourage patient participation.

Clinical trials, which test new treatment strategies, are opportunities for patients to “access cutting-edge technologies, new drugs and new ways of doing things (as therapies) for their cancer. We’re always trying to improve how we treat patients with cancer, be it a new drug, a new pathway (treatment protocol) or a new way of doing radiation,” says Dr. Daniel Heng, a professor of medicine at the University of Calgary and medical director of the Clinical Research Unit at the Tom Baker Cancer Centre.

A trial can investigate the effects of things like diet and lifestyle changes, new medications or novel combinations of older ones or variations in surgical techniques, he says.

“Often, patients in a clinical trial get exposed to new therapies long before they are approved or reimbursed for use,” he says — and at no cost.

According to the 2018 Cancer System Performance Report put out by the Canadian Partnership Against Cancer, between 1 per cent and 6 per cent of Canadians with cancer participated in clinical trials through 2015. Today, that number hovers between 6 per cent and 10 per cent, says Dr. Janet Dancey, a professor of medicine at Queen’s University and scientific director of 3CTN. There are multiple reasons more people don’t participate: lack of interest, worry about trying something new, concern about ending up in a trial group getting standard treatment or placebo, discomfort with being a test subject, the amount of time involved, geographic distance and the inconvenience of travelling for multiple appointments.

For Hutton, the multiple trips to Hamilton are worth it. At first, she was so unwell someone had to drive her, but now she’s healthy enough to drive herself.

According to Heng, Alberta, where his institution is located, has a higher participation rate than the United States, where it is 5 per cent. He attributes this largely to a concerted effort by the province to help patients and doctors alike become aware of clinical trials, and to find ways to help rural patients have better access. He noted that participation rates vary between different types of cancers. For example, there tend to be more trials of the more common cancers such as breast or lung, and they often recruit much larger numbers of patients. There aren’t as many trials for rare cancers.

There are also other barriers to participation for many patients. Some trials require that participants have not yet taken any cancer treatment, and patients may need to meet a certain level of health or might be disqualified if the cancer is too extensive or if they have other health-complicating issues. Some groups of people are underrepresented in cancer clinical trials, including rural and Indigenous populations and those who aren’t proficient in English or French.

“We are working on initiatives that improve these issues,” Heng says. Heng points out that all trials are different, so a patient who doesn’t qualify for one might be eligible for another. Also, some trials help patients pay for travel if distance is an issue.

Patients can even participate in trials taking place in provinces they don’t live in, but it takes extra paperwork to ensure public health coverage. “It is possible,” Dancey says. “We can figure out a way to make it work, but it takes time to get that coverage in place. And then, to be in the trial may require you to relocate to a new place.”

Advantages of clinical trials include participants getting more monitoring and tests than they might in other treatment settings, as well as a very high level of care. That’s because researchers need to know if a new treatment or regimen is working, and also about any side effects.

Participating also gives patients opportunities to help move science and treatments forward.

Clinical trials in Canada are required to meet rigorous standards. “All trials have to go through a research ethics board that includes input from medical and legal experts, patient advocates and ethicists to ensure patients are being safeguarded. There is a lot of oversight for clinical trials in Canada,” says Dr. Sharlene Gill, a professor of medicine at the University of British Columbia and spokesperson for the Canadian Association of Medical Oncologists.

Because of her experience in a clinical trial, Hutton has been able to establish a new normal in her life. She has had to make some sacrifices — she continues to take medications that cause side effects, including a suppressed immune system, potential blood clots and a risk of bleeding that means she has to refrain from riding or showing her horses. However, Hutton is convinced that her outcome is better than it would have been on standard-of-care drugs, and she says she would certainly make the same choice again.

Dancey appreciates that commitment, noting that “the only reason we have treatment now is because patients went through trials before.”

One of the best ways to find a clinical trial is to go to the ClinicalTrials.gov website, Heng says. Canadian centres are required to register clinical trials on the site. It also lists trials from around the world.

The National Cancer Institute also has a 

cancer clinical trials searchable database

, which focuses on trials available to patients within Alberta. Trials in Ontario are listed 

“Definitely ask your oncologist about clinical trials,” Heng says. “They can look to see what’s available. It helps for patients to be proactive and see what they can find on the web to open up the discussion.”

Articles

Clinical trials offer a chance to try experimental treatments and move the state of science forward. Here’s what patients need to know.

Trial Run: What You Need to Know About Clinical Trials in Canada

It’s been close to four years since Daniel Malka, of Montreal, was told he had six to eight months to live.

After eight rounds of chemotherapy and 21 rounds of radiation treatment for his stage 4 small-cell lung cancer, he not only survived but has been in remission for more than two years. The fact that he’s now doing well is some- thing Malka attributes, in part, to judicious use of cannabis along with his regular therapies. He says the plant, which was legalized in Canada for medical purposes in 2001 and for recreational use in 2018, has helped him feel much better over the past three years.

While his medical and radiation treatments helped Malka fight his cancer, they also contributed to significant pain in his affected lung and his back, as well as complications including inflammation of the esophagus, the bacterial infection C. difficile, diverticulitis, appetite disturbances, sleep problems and nausea. His daughter suggested he try cannabis, and so, with some searching, he was able to find an oncologist specializing in rehabilitation who was on board with authorizing it.

Malka says the cannabis has eased his pain enough to enable him to stay away from opioids: “During the past three and a half years, I haven’t used any pain medications except for Tylenol and cannabis oil and vaping.”

There is some scientific evidence that cannabis can ease pain, as well as nausea and vomiting, according to guide- lines for medical cannabis use from the College of Family Physicians of Canada (CFPC).

But there are a lot of unknowns with respect to the immediate and long-term effects of the drug on the body and the disease, says Dr. Marc Kerba, a radiation oncologist and clinical associate professor of medicine at the University of Calgary.

Plus, cannabis and its components can have dramatically different effects on individuals, not all of them helpful.

The bottom line is that, although cannabis is now widely available in Canada, people need guidance from their doctors to help avoid adverse effects, says Dr. Antonio Vigano, director of the Cancer Rehabilitation Program and an associate professor of oncology at the McGill University Health Centre.

Cannabis contains over 400 chemical compounds. More than 60 are cannabinoids, many of which have a variety of biological effects. There are also compounds called terpenes (which give a plant its scent) and flavonoids (which are antioxidants), and many of their effects are not well understood. There are varying combinations and ratios of these compounds in the wide variety of cannabis plants available. Many of the compounds have not been studied, and how each affects people is unknown — which makes it challenging, Kerba says, to sort out the details when it comes to using cannabis to treat patients.

While many anticancer medications were initially derived from plants, those plants usually had only one active compound that was extracted and purified for clinical use, such as the chemotherapy paclitaxel, which was first derived from Pacific yew tree bark. With its large number of biologically active compounds, cannabis is far more complicated.

Some cannabis compounds may interact with chemotherapy or other medications patients are taking, Kerba said. For instance, benzodiazepines, antidepressants and all other central nervous system medications may cause adverse effects when taken with cannabis.

Some studies suggest that certain cannabis compounds may help inhibit the growth or spread of certain types of cancers. In fact, Malka is convinced that cannabis is keeping his at bay.

However, other studies show that some cannabinoids may do unhelpful things such as suppress parts of the immune system that fight cancer. In fact, cannabis may interfere with immunotherapy, Kerba says, a point illustrated by a study from Israel of patients with cancer who were taking Opdivo (nivolumab): Those who were using cannabis had a significantly reduced response rate to the treatment.

Throwing more uncertainty into the use of cannabis in cancer care is the fact that patients are free to choose any formulation they want, whether recreational- or medical-grade.

Malka selects flowers from licensed producers to make his own CBD and THC oil formulas. Being a biochemist, he identified formulations he thought were best suited for his condition.

“It’s up to the patient which products they get and how they use them — which is very different from traditional prescription medications where the molecules in the product are known and standardized, as are doses,” says Ted Findlay, a clinical assistant professor of family medicine at the University of Calgary, a consultant for Alberta Health Services Chronic Pain Centre and an author of the CFPC guidelines.

In its guidelines, the CFPC does not strongly recommend cannabis to treat any side effect. It states that there is very low evidence for the use of cannabis to treat chronic pain and low-to-moderate evidence for its use to treat chemo- therapy-induced nausea and vomiting. The organization recommends that cannabis be used only when these conditions have not sufficiently responded to other treatments.

The guidelines also suggest that synthetic cannabinoids made by pharmaceutical companies, such as Cesamet (nabilone) or Sativex (nabiximols), be tried first, because their effects are better understood.

The strongest evidence cited in the guidelines for cannabis use pertains to treating nausea and vomiting from chemotherapy. The drug eased nausea and vomiting for 47 per cent of users, compared with 13 per cent of patients who took a placebo, according to a meta-analysis of seven randomized controlled trials.

The studies on pain evaluated by the CFPC showed less obvious benefit, and it remains uncertain whether cannabis is beneficial in treating this symptom. The organization recommends that cannabinoids be used only “after patients have had a reasonable therapeutic trial of two or more established agents for cancer or palliative pain.”

But Vigano says both animal and human studies are unravelling how cannabis might help relieve certain types of pain. One way is by reducing inflammation that can cause pain. Others involve affecting pain transmission in the nervous system and altering the way the brain interprets pain. “Cannabis will help a patient to dissociate pain from their emotional reactions to it,” he said. The drug reduces the anxiety and stress around pain, which in turn reduces its impact.

 “Typically, the patient will report that maybe the pain intensity remained at a certain level, but the patient can still cope with it, can still live with it, can have a better quality of life, can be more functional,” he says.

Because of this, he has seen patients take less of their other pain medications, many of which have their own potential side effects.

Reducing those side effects can contribute to improved feelings of well-being, a result that was shown to be the most significant advantage of cannabis in patients with cancer attending Vigano’s medical cannabis clinic at the McGill University Health Centre.

Quality-of-life outcomes were the focus of a study out of McMaster University that looked at marijuana use among 148 patients with newly diagnosed head and neck cancer. Approximately half the patients used marijuana and half did not. Results showed that the marijuana users experienced less pain, fatigue, depression, anxiety, appetite problems and drowsiness and reported better general well-being.

Cannabis may also help some patients with advanced cancer who are experiencing cachexia (weight loss associated with decreased appetite and muscle wasting). A study Vigano worked on showed that some patients with cachexia experienced an improved appetite and quality of life after being treated with cannabinoids.

More studies are needed to sort out regimens and which type of cannabis may be the most helpful to patients with cancer, Vigano says.

When patients with cancer discuss cannabis with their care teams, doctors don’t write prescriptions, Findlay explains. Instead, they write letters of authorization. These letters allow patients to purchase medical-grade cannabis products from licensed vendors.

Not all doctors can provide authorization letters. Many provinces require registration for physicians or nurse practitioners who want to give them. In addition, many health-care providers aren’t comfortable with cannabis and don’t provide authorizations. Many are concerned about potential risks or simply don’t feel they know enough.

When patients do get authorization, they should start with low doses and slowly work their way to up a dose that has the effect they want in order to minimize possible side effects, Findlay says.

It’s hard to say whether legalization of cannabis has influenced more people to “self-medicate,” but Findlay, who specializes in non-cancer pain, frequently sees patients who have tried it before consulting him for help.

A survey of cannabis use that included almost 2,000 patients with cancer, published in June 2018 by Alberta researchers, found that 43 per cent reported using cannabis at least once in their life. Four in five acquired cannabis through friends, and only 10 per cent acquired it through regulated medical dispensaries. Of the 356 patients who reported cannabis use within six months before the survey, about 36 per cent were new users, with 46 per cent of those saying they tried it for cancer-related pain, 34 per cent for nausea, 31 per cent for other cancer symptoms and 56 per cent for non-cancer-related reasons (some reported multiple reasons).

Findlay urges any patient trying cannabis to stick with medical-grade products because they are standardized and without contaminants. He encourages patients to avoid recreational cannabis products or those sold on the street and to make sure their medical teams know about their cannabis use.

Now that it’s legal for both medicinal and recreational use in Canada, cannabis is widely available to patients with cancer. How much it can help them is largely undetermined.

Weeding Out Uncertainty

Cancer brain fog — the fuzzy, slow thinking that often accompanies cancer and its treatments &mdash; is no picnic.

The condition, referred to in scientific circles as cancer- related cognitive impairment or cancer&#8208;related cognitive dysfunction, can involve trouble with remembering things such as words and problems with attention, problem- solving speed and executive function — the mental processes that enable us to plan, focus, remember instructions and multitask.

For most, it’s a temporary issue that gradually improves over time, but for some the “chemo brain” lingers long after treatment stops. The problem affects upwards of 75 per cent of patients during treatment and 35 per cent for months afterwards.

Studies show correlations between “chemo fog” and changes in brain function through imaging techniques, and it is increasingly recognized by health-care providers.

Nevertheless, there are no medications or standard protocols or programs for treating it, and resources can vary between centres across Canada.

There is help for people with the condition, though. Strategies — mainly physical and mental exercises &mdash; exist to help with specific aspects of the problem, and experts recommend that patients ask for them if they aren’t offered.

While the terms “chemo brain” and “chemo fog” are commonly used, “cancer-related brain fog” is a better name for it, says Lori Bernstein, an assistant professor of psychiatry at the University of Toronto who also works in the Department of Supportive Care at Princess Margaret Cancer Centre. “Chemo fog makes it sound like chemotherapy is the sole cause, but it’s not necessarily the cause in everyone. It’s only one of many things that can lead to the problem.”

Its causes can also include other cancer treatments (radiation, targeted drugs, immunotherapies, hormonal therapies or stem cell transplants), low red blood cell counts, poor sleep, fatigue, medications that generate drowsiness such as sleeping pills or pain medications, poor nutrition, dehydration, anxiety and the anesthesia used during surgery. It can even be a side effect of the cancer.

The effects and intensity of cancer- related brain fog vary from person to person. Even people who’ve had the same type of cancer and treatments have different experiences, making the condition difficult to predict.

This uncertainty remains because the exact mechanisms of how chemo brain happens are not well under- stood, Bernstein says.

Still, there is some data about the bodily processes that result in chemo brain. Some studies suggest that cancer treatments may cause central nervous system toxicity, which could have both direct and indirect effects on the brain. A 2017 study on animals by researchers in Alberta supports this, suggesting that chemotherapy leads to a process that essentially causes the brain to age during therapy. In addition, a 2018 study conducted at the University of California Los Angeles with breast cancer survivors found a link between cognitive decline and the biological aging of cells due to chemo- therapy and radiation.

Other studies suggest that inflammation is associated with cancer-related brain fog and may be an effect of medications or simply part of the cancer disease process.

Cognitive problems can occur before chemo- therapy, too. In a study from 2011, researchers at the University of Ottawa did brain scans of women with early-stage breast cancer while they performed neuropsychological tests. The scans were done after the patients had undergone surgery but before they began chemotherapy. Results were compared to those of a group of women who didn’t have cancer. While both groups had similar results on some of the tasks, the breast cancer patients were slower to respond on others and made more mistakes in visuospatial activities. The study showed that cognitive changes started before chemotherapy, as did differences in activity in several parts of the brain.

There are no quick medication fixes to help with brain fog. Some researchers have investigated using medications such as memantine, used in patients with Alzheimer’s disease, but “the jury is still out” on its effectiveness, says Kristin Campbell, a physical therapist and director of the Clinical Exercise Physiology Laboratory at the University of British Columbia.

Campbell is investigating the role of moderate-to-vigorous aerobic exercise, such as walking or cycling, on cognition in patients with brain fog. “There is emerging research suggesting physical activity can improve cognition in patients,” she says.

A 2016 review of 19 studies investigating the effects of physical activity on brain fog in animals and humans found that forms of exercise such as yoga may help reduce both symptoms and inflammation. And a 2017 study on women treated for breast cancer found that moderate-to-vigorous exercise can help ease both chemo brain and fatigue.

Generally, you can’t go wrong with being active to a level that feels comfortable, according to Campbell. Walking is a great place to start, she says, and besides yoga, activities such as gardening or tai chi may help, though there are additional benefits for those who can do more intense aerobic exercise.

“Tell your health-care providers if you are having problems and ask what help is available locally,” Campbell says. Sources of help include occupational or physical therapists, patient counsellors, support groups and psychologists. Some larger cancer centres have programs designed to help with brain fog. Help generally focuses on teaching strategies to cope with brain fog, such as doing memory exercises or creating reminder systems such as using sticky notes.

There are also online resources, including the Princess Margaret Cancer Centre’s “

” booklet, which Bernstein authored. It discusses the condition, causes and practical tips for managing the difficulties brain fog causes.

Patients can also find resources through the 

Cancer brain fog, or chemo brain, interferes with daily life for many patients. Help can take the form of mental or physical exercise.

Pippa Wysong

Trial Run: What You Need to Know About Clinical Trials in Canada

Weeding Out Uncertainty

Out of the Haze of Chemo Brain

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