Knowledge of benefits, harms of medical marijuana for cancer ‘far from complete’

The national debate about the legalization of marijuana has had broad implications for the medical community.

Thirty-three states have medical marijuana laws of some kind, with 29 of those listing cancer as a qualifying condition.

Study results estimate that about a quarter of patients with cancer used marijuana within the prior year to relieve the symptoms of their disease and its treatment. However, the ambivalent legality of tetrahydrocannabinol (THC) and cannabidiol (CBD) products has limited their research, leaving clinicians without data to provide to their patients.

“Cannabis is considered a schedule 1 drug, per federal law and the DEA,” Charles V. Pollack Jr., MA, MD, director of The Lambert Center for the Study of Medicinal Cannabis and Hemp at Thomas Jefferson University, told HemOnc Today. “That very much complicates the ability we have to study the drug.”

However, the FDA has approved THC-CBD products, including the synthetic THC analog dronabinol, used to treat anorexia and weight loss among individuals with HIV; nabilone (Cesamet, Mylan), which is approved to mitigate chemotherapy-induced nausea and vomiting; and cannabidiol (Epidiolex, GW Pharmaceuticals), which was recently approved for use in certain specific severe childhood epilepsy syndromes.

Beyond those THC-CBD products, clinicians are largely left on their own to address cannabis with their patients. Although data showing benefits in areas such as nausea and pain are encouraging, the reasons for those benefits, and whether they come with risks, remain largely unexplained.

HemOnc Today spoke with clinicians about the difficulty conducting research on cannabis in the United States, the variation in attitudes regarding medical marijuana among patients and providers, the available data on its potential harms and risks, and how clinicians can address the use of marijuana with their patients with cancer.

‘The better medicine’

Many experts, including Donald I. Abrams, MD, general oncologist at Zuckerberg San Francisco General Hospital, integrative oncologist at the UCSF Osher Center for Integrative Medicine, and member of leadership at The Lambert Center, believe that the true benefits of cannabis lie in the actual plant.

“I believe the whole plant is the better medicine, compared with the THC-CBD products and synthetics,” he said in an interview. “The emerging evidence shows so many more benefits. For example, cannabis is the only antiemetic that increases appetite.”

However, whole-plant cannabis for human study in the U.S. can only be obtained from the National Institute on Drug Abuse laboratory at University of Mississippi, according to Pollack.

“In order to conduct a study of cannabinoids in the U.S., it is necessary to go through the FDA and DEA to approach this lab,” he said. “It is extraordinarily logistically challenging and expensive. The whole process creates a substantial bottleneck.

“In Pennsylvania, we have a medicinal cannabis law, but we can’t use Pennsylvania-grown cannabis in our research,” he added. “Researchers around the country face these same obstacles.”

This impacts clinical outcomes, Abrams said.

“It works out that [the country] spends more than $100 million a year studying harmful effects of cannabis, but we can’t study potential benefits,” he said. “This is why there is a dearth of literature on the subject.

“The whole situation is rankling to oncologists,” he added. “We deal with a serious disease and strong medications that have significant side effects. Our patients need every available tool to deal with nausea, vomiting, difficulties sleeping, anxiety and other disorders, but many of them can’t legally acquire it.”

More research into the whole plant would provide much-needed data, according to Steven A. Pergam, MD, MPH, associate member of the vaccine and infectious disease and clinical research divisions at Fred Hutchinson Cancer Center, associate professor in the division of allergy and infectious diseases at University of Washington, and medical director of infection control at Seattle Cancer Care Alliance.

“[Available preparations] vary in their content of THC and other cannabinoids,” he told HemOnc Today. “This suggests that we need to consider chemical properties when assessing potential benefits. It is important to better understand methods for use, whether there are particularly benefits or risks to smoking or edible forms of cannabis.”

Research obstacles may suggest that U.S. investigators will be surpassed by their counterparts in other countries where the logistical barriers to cannabis research are less draconian.

However, it is doubtful legal hurdles will cause the U.S. to fall behind, according to Michael K. Gupta, MD, MSc,FRCSC, associate professor in the division of otolaryngology and head & neck surgery at St. Joseph’s Healthcare in Hamilton, Ontario and McMaster University.

“It is certainly possible that other countries may lead clinical trials,” he told HemOnc Today. “But it is hard to imagine Americans being left behind in this. American industry has historically been very innovative. The world models American ingenuity, entrepreneurship and quest for a dollar.”

Pergam agreed the U.S. is not necessarily behind on cannabis research, but noted that different state-level laws may impact patient-physician conversations.

“The differences among state laws make this a bit confusing for sure, and no doubt have a definite impact on use patterns around the U.S.,” he said. “Particularly in states where cannabis isn’t legal, patients may be less likely to use and, if they do, they may be less likely to tell their doctors.”

The U.S. can’t afford to lag behind in this arena, according to Prasanna Ananth, MD, MPH, pediatric oncologist at Yale Cancer Center and assistant professor of pediatrics at Yale School of Medicine.

“We are entering an era in which we are not able to ignore widespread marijuana availability and use,” she told HemOnc Today. “As providers and institutions, we ought to come up with policies on how to approach marijuana inquiries from patients and families. These approaches may vary from one institution to the next, recognizing that the scientific evidence may lag behind state policies around medical marijuana.”

‘Keep the dialogue open’

The societal taboo surrounding marijuana may complicate clinicians’ willingness to recommend it for their patients.

Study data suggest that attitudes about marijuana vary wildly in the United States.

Keyhani and colleagues surveyed 16,280 U.S. adults in 2017 and found that 14.6% of respondents reported using marijuana in the past year.

Just over 80% believed the drug had at least one benefit, compared with 17% who believed it had no benefits. Two-thirds of the cohort (66%) used it for pain management, whereas 48% used it for treatment of a disease — such as epilepsy and multiple sclerosis — and 47% used it as relief from anxiety, stress and depression.

Still, 91% of respondents reported belief that the drug has at least one risk, whereas 9% believed there are no risks involved with cannabis use. About half of respondents believed that legal problems and/or addiction may result from marijuana use, and 42% suggested that it may impair memory. Just under 30% agreed that health problems can be prevented with marijuana use, and 22.4% believed it is not addictive.

Source: McMaster University.

“I tell my patients there are still a lot of unknowns,” Gupta said. “One thing I can tell them for certain is that smoking always makes me a little more nervous because of combustion. There is almost certainly harm in that. But, we are still far from complete understanding of the risks.”

However, Abrams noted no such harms other than cough and phlegm have been identified.

Research also has revealed variation in attitudes among oncologists and in use among patients with cancer.

Braun and colleagues surveyed 400 medical oncologists in November 2016 to determine their attitudes about medical marijuana use and whether they believed it to be it an effective adjunct to standard pain management strategies.

Working from a 63% response rate, results showed that just 30% of oncologists felt sufficiently informed to make recommendations about medical marijuana use. That said, 80% reported conducting discussions about the drug, and 46% recommended it clinically. Other findings showed that 67% felt that marijuana is helpful in managing pain, and 65% suggested it may be useful in anorexia/cachexia.

“Most people can figure out how to get it, and how to use it,” Abrams said. “We don’t prescribe it, we recommend it. But, even in this context, things need to change. Dr. Braun noted that it’s still not in the dropdown menu of electronic medical records. It needs to become more mainstream.”

In a study published this year in Pediatrics, Ananth and colleagues found that providers were largely open to considering medical marijuana for children with cancer.

Researchers sent a cross-sectional survey to 564 pediatric oncology providers in Illinois, Massachusetts and Washington, 44% of whom were included in the analysis.

Thirty percent of provided had received one or more requests from a patient for medical marijuana in the last month, and 92% reported willingness to help children with cancer access it.

“They tended to be more open to using medical marijuana in the later stages of illness, when illness is not curable, it is being treated with palliative intent, or near the end of life,” Ananth said.

Results also showed that providers who were legally eligible to certify patients for medical marijuana were less likely to approve patient use by smoking, orally, as cancer-directed therapy or to manage symptoms (P < .005 for all).

“The other interesting finding of our study was that there seemed to be a difference of attitudes between providers who were legally able to recommend marijuana vs. those who are not,” Ananth added. “Providers who are not legally able to recommend medical marijuana were actually more open to considering medical marijuana in oral forms, smoked and as a cancer-directed treatment. This is quite interesting because, unfortunately, there is not a lot of evidence for medical marijuana use in cancer treatment.”

Pergam and colleagues surveyed 926 patients from the Seattle Cancer Care Alliance to determine cannabis habits.

Results showed that 61% of respondents reported prior cannabis use, with 24% using it in the previous year, 21% using it the last week, and 24% reporting habitual usage. Weekly users comprised 74% of the habitual user group, whereas 56% reported daily use and 31% used cannabis more than once per day.

Seventy percent of active users smoked cannabis, whereas 70% used edibles and 40% used both methods. Three-quarters of the active-user group suggested they used cannabis primarily for physical symptoms, and 63% reported use for neuropsychiatric symptoms.

“Our study showed that over 70% of patients wanted to get information about cannabis and cancer from their cancer providers but, in Dr. Braun’s study, 70% of cancer physicians didn’t feel sufficiently informed about cannabis to make medical recommendations for its use,” Pergam said. “This dichotomy is part of the problem with the lack of research.

“There is a need for education for both physicians and patients, and we need to keep the dialogue open,” he added. “It is important that we ask patients about use and advise them the best we can with the data available. If we close the door, patients will seek information from sources outside of the medical field.”

Potential benefits

Some research suggests medical marijuana can help address anxiety, depression and fatigue among patients with cancer.

“Our patients know that there is a wide range of uses for medical cannabis,” Abrams said. “As oncologists, we also understand these benefits.”

In a single-center, case-matched control study, Zhang and colleagues evaluated 74 patients newly diagnosed with head and neck cancer who reported marijuana use and 74 patients who reported no use.

Univariable analysis results showed users had lower EuroQol-5D scores for anxiety and depression (1.34 vs. 2.08; difference, 0.74; 95% CI, 0.55-0.93) and pain and discomfort (1.53 vs. 1.82; difference, 0.29; 95% CI, 0.03-1.54).

Using the Edmonton Symptom Assessment System questionnaire, marijuana users showed less pain (1.85 vs. 2.72; z score = 2.36), decreased lack of appetite (1.7 vs. 3.57; z score = 4.17), and overall improved well-being (4.05 vs. 2.12; z score = 4.43). Patients in the marijuana group reported less fatigue (1.66 vs. 3.88; z score = 5.02), anxiety (0.77 vs. 5.3; z score = 10.04), depression (0.72 vs. 3.19; z score = 5.96) and drowsiness (0.56 vs. 2.68; z score = 5.51).

“As far as the depression and anxiety outcomes go, the data are coming,” Gupta, a researcher on the study, said. “The important thing about cancer as a disease is that the survivorship experience is so significant. We treat them for this terrifying disease, and then survivors face anxieties and depression. Our hope is that marijuana or CBD fits into that paradigm.”

This may be particularly true for patients with head and cancer, treatment for which impacts speech, swallowing and facial structures, according to Gupta.

“These very much impact people’s social interactions and sense of self-worth,” he said, suggesting that data looking into these parameters also will be useful.

Because the Israeli Ministry of Health began approving medical cannabis for the palliation of cancer symptoms in 2007, Bar-Lev and colleagues were able to evaluate its safety and efficacy among 2,970 patients with cancer, 20.7% of whom had breast cancer, 13.6% lung cancer, 8.1% pancreatic cancer and 7.9% colorectal cancer. Just over half of the cohort had stage 4 disease.

Results showed that 78.4% of patients used medical cannabis to help them sleep, 77.7% wanted treatment for pain, 72.7% for weakness, 64.6% for nausea, and 48.9% to improve their appetite.

“We have seen in our own research that cannabis works better than other antiemetics,” Abrams said, noting that oncologists have a long history of using THC-CBD in this context.

Among 1,211 patients who were still using cannabis after 6 months, 60.6% reported a response, 95.9% reported an improvement in their condition, 3.7% reported zero change, and only 0.3% suggested that cannabis worsened their condition.

“Clearly, in this cohort from Israel, there are superior outcomes in patients who used cannabis,” Abrams said. “The plant also seems to be effective in neuropathic pain.”

But the benefits may go beyond palliation.

Previous data have shown that cannabinoids may enhance the process of cell self-destruction, particularly in the AKT/mTOR pathway, which is overactive in certain cancers. Such a mechanism may suggest a potential to improve cancer outcomes.

GW Pharmaceuticals announced top-line data results from a phase 2, placebo-controlled, proof-of-concept study evaluating its proprietary combination of THC and CBD among 21 patients with glioblastoma.

Results showed 83% of the 12 patients who received THC-CBD achieved 1-year survival compared with 53% of nine patients receiving placebo (P = .042). Median survival was 550 days in the treatment group compared with 369 days in the placebo group.

Vomiting occurred in three-quarters of the THC-CBD group. Other adverse events included dizziness (67%), nausea (58%), headache (33%) and constipation (33%).

“The findings from this well-designed controlled study suggest that the addition of a combination of THC and CBD to patients on dose-intensive temozolomide produced relevant improvements in survival compared with placebo and this is a good signal of potential efficacy,” study principal investigator Susan Short, PhD, professor of clinical oncology and neuro-oncology at Leeds Institute of Cancer and Pathology at St. James’s University Hospital, said in a press release. “Moreover, the cannabinoid medicine was generally well tolerated. These promising results are of particular interest as the pharmacology of the THC-CBD product appears to be distinct from existing oncology medications and may offer a unique and possibly synergistic option for future glioma treatment.”

Understanding pain, addiction

Pain is the most common reason why patients with cancer report using cannabis, according to Pergam.

“To date there are currently only small studies that suggest cannabis could play a role in pain management, but very little data that directly relates to cancer patients,” he said. “To better understand if cannabis can be used in supportive care for cancer pain, we need well designed clinical trials. This type of research will help us to better advise patients.”

This research also includes whether cannabis might play a role as an alternative to opioids, Pergam added.

“The most important thing is controlling cancer pain,” he said. “If cannabis can help, that might be a good thing.”

Researchers are beginning to look at how cannabis may synergize with morphine or oxycodone, according to Abrams.

“The findings are as yet inconclusive, but this may decrease opiate use,” he said.

Pollack was cautiously optimistic about the switch from opioids to marijuana.

“There may be some biologic plausibility to the idea of associations between cannabis receptors and opioid receptors,” he said. “But there is still so much more research to be done in this space. Still, it is very attractive, given the current opioid crises.”

Gupta agreed.

“I think this is everyone’s hope, but there are no studies looking at it at the moment,” he said. “I share that hope.”

Once patients are taking opioids, it is difficult to get them to stop, according to Pollack.

“To think of cannabis as a silver bullet to replace opioids is probably wishful thinking,” he said.

It is important to keep in mind that treatment also differs for acute and chronic pain, Abrams said.

“Cannabis is more effective in chronic than acute pain,” he said. “Short-term opioids may be a better option for someone who has undergone surgery. For this reason, it is unlikely that cannabis will ever completely replace opioids.”

Potential harms

Most experts with whom HemOnc Today spoke acknowledged that adverse effects of cannabis will ultimately emerge as more studies are conducted.

Nugent and colleagues conducted a systematic review of MEDLINE, Cochrane Database of Systematic Reviews, and other sources through March 2017. They found 27 studies evaluating cannabis as a method of improving pain and quality of life.

Results showed “low-strength” evidence that cannabis may improve neuropathic pain, and insufficient evidence for other pain parameters. Potential harms included increased motor vehicle accidents, psychotic symptoms and short-term cognitive impairment. Data on possible adverse pulmonary outcomes were inconclusive.

“There are concerns about whether marijuana is carcinogenic, but there is not a lot of proof in the data,” Gupta said, adding that there also is a concern among some psychiatrists that increased marijuana use may exacerbate psychiatric issues.

He spoke to HemOnc Today on the brink of Canada legalizing marijuana nationwide.

“The government is definitely trying to find this out to determine how it will impact the health of the population in terms of potential secondary cancer incidence, or a Breathalyzer to deal with a possible increase in car accidents, but the literature is unclear,” he said.

A lot of the data that do exist are not specific to patients with cancer, according to Pergam.

“But even the data for cannabis affecting nausea and vomiting has had both positive and negative results,” he said. “Most of the data has used synthetic THC, but there are even fewer studies which look at cannabis for treatment of cancer symptoms.”

Regarding other potential dangers, Pergam noted that cannabis can have an effect on thinking and has been associated with delirium in some patients, particularly in those already at risk for such conditions.

“Cannabis hyperemesis syndrome can affect patients who use cannabis, where instead of helping with nausea and vomiting it can actually trigger these symptoms, particularly when using strains that are more potent,” he said. “Drug-drug interactions, instability or falls, and other possible complications concern us.”

Yet another concern is that marijuana can harbor mold and put patients at risk for infections, according to Pergam.

“I definitely wouldn’t recommend use, particularly smoking cannabis, for patients with leukemia, those undergoing bone marrow transplant or those with very weakened immune systems,” he said. “Still, these side effects are better assessed in clinical trials, so that users have a better sense of what to expect.”

Gupta looked at this issue more holistically.

“Maybe we’ll find out that the risks actually do outweigh the benefits,” he said. “Maybe someday down the road, we will see that legalization was the wrong thing. We have to consider all possible outcomes.”

Having the conversation

The lack of data on cannabis specifically for patients with cancer may leave some clinicians to feel ill-equipped to discuss its use with their patients.

In the study by Pergam and colleagues, the researchers found that 74% of patients wanted information on cannabis from their cancer team, but only 15% actually received information that way. Rather, patients received information via friends and family, periodical publications, websites and from fellow cancer patients. More than one-third of patients received no information.

Regardless of the conversations that occur in the clinic, patients often have other routes of accessing cannabis, Ananth said.

“I would never say that a provider should recommend it, because it is difficult to recommend something for which we do not have adequate evidence,” she said. “At the same time, we want to maintain open dialogue about it.”

This means that she will often ask her patients whether they are taking any complementary or herbal remedies.

“I generally tell my patients to avoid smoked or vaporized forms of marijuana to reduce risk of exposure to carcinogens, fungi or mold,” she said. “I also would urge providers to tell patients that strengths of medical marijuana formulations can vary, so sometimes things like edibles can be quite strong. I also let my patients know that marijuana is metabolized through the liver and that it can interact with certain medications, so it is important to let us know if they are using marijuana, whether medicinally or for recreation.”

Regardless of how this conversation comes about, it is important that it goes well, Gupta said.

“Patients seem to understand that there’s no evidence one way or the other,” he said. “If you are honest with them about this, they generally appreciate that you’re concerned about their well-being. They understand that recreational use could be putting them at risk for a second primary malignancy.”

Ultimately, it appears patients and families are interested in medical marijuana and providers are being asked about it frequently, Ananth said.

“Therefore, it is important for providers to have at least a basic understanding of how to access medical marijuana, what the state laws are, how marijuana is metabolized and how it interacts with other medications,” she said.

Having a more nationwide policy would make these conversations easier for clinicians, Pollack said.

“There are 33 states with laws, and they’re all different,” he said. “It would be in patients’ best interest and good public health to have a more uniform policy across the country. Patients using cannabis, even in those 33 states, are in direct violation of federal law.”

Shifting attitudes could lead to forward motion, Pergam said.

“New studies using psilocybin [mushroom] for clinical trials of depression and the approval of Epidiolex are developments that suggest the potential for future trials,” he said.

The potential widespread benefits of cannabis may have a great impact on patients with cancer if the data are confirmed, Abrams said.

“The associations between improved nausea, vomiting, appetite and pain are well-established,” he said. “If the trends we are seeing in benefits for mood, anxiety and sleep continue, it will be difficult to ignore. If I have one medicine that does all this — as opposed to five different pharmaceutical products with varying effects and drug-drug interactions — this is something I’m going to recommend.” – by Rob Volansky

Click here to read the , “Can medical marijuana replace opioids to relieve cancer pain?”

References:

Ananth P, et al. Pediatrics. 2017;doi:10.1542/peds.2017-0559.

Bar-Lev L, et al. Eur J Intern Med. 2018;doi:10.1016/j.ejim.2018.01.023.

Braun IM, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2017.76.1221.

Keyhani S, et al. Ann Intern Med. 2018;doi:10.7326/M18-0810.

Nugent SM, et al. Ann Intern Med. 2017; doi:10.7326/M17-0155.

Pergam S, et al. Cancer. 2017;doi:10.1002/cncr.30879.

Zhang H, et al. JAMA Otolaryngol Head Neck Surg. 2018;doi:10.1001/jamaoto.2018.0486.

For more information:

Donald I. Abrams, MD, can be reached at 1001 Potrero Ave., San Francisco, California 94110; email: donald.abrams@ucsf.edu.

Prasanna Ananth, MD, MPH, can be reached at Yale Cancer Center, 333 Cedar St., LMP 2082C, New Haven, CT 06510; email: prasanna.ananth@yale.edu.

Michael K. Gupta, MD, MSc, FRCSC, can be reached at St. Joseph’s Healthcare Hamilton, G836, 50 Charlton Ave. E, Hamilton, ON L8N4A6, Canada; email: mgupta@mcmaster.ca.

Steven A. Pergam, MD, MPH, can be reached at Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. North, E4-100, Seattle, WA 98109; email: spergam@fhcrc.org.

Charles V. Pollack Jr., MA, MD, can be reached at Jefferson University Hospitals; 2301 South Broad St., Philadelphia, PA 19148; email: charles.pollack@jefferson.edu.

Disclosures: Abrams reports serving as a scientific advisor to AXIM Biotechnologies, INSYS, Intec, Maui Wellness Group, Scriptyx, Tikun Olam and Vivo Cannabis. Pergam reports grant support from Merck and Optimer/Cubist Pharmaceuticals. Ananth, Gupta and Pollack report no relevant financial disclosures.