Testing Tolerability
Medical cannabis is well tolerated – and improves sleep, functional wellbeing, and quality of life – in high-grade glioma patients, according to Phase 2 trial
Though countless studies have investigated the anti-inflammatory and anti-cancer potential of medical cannabis, clinical research into tolerability and dosing is lacking – and that’s problematic for two reasons: i) such research is needed before efficacy trials can commence, and ii) illicit use of the drug tends to increase in vulnerable populations – a category into which high-grade glioma patients certainly fall.
As the most common primary intracranial tumor of the central nervous system, gliomas account for one third of all brain tumors. The most aggressive form – glioblastoma multiforme (GBM) – is intractable because of its high risk of recurrence; patients with the disease have an average survival rate of just one year. This pessimistic outlook gives patients much to gain from medical cannabis use – which is one of the reasons Janet Schloss, Clinical Research Fellow at the National Centre for Naturopathic Medicine, Australia, and her team of researchers, decided to explore further.
The phase 2 randomized clinical trial, which set out primarily to investigate the tolerability of two medical cannabis ratios, enlisted participants (n=88) diagnosed with a high-grade glioma, no history of substance abuse, liver or kidney damage or myocardial infarction and compared them with a retrospective control group to assess secondary outcomes. The medical cannabis consisted of two standardized oil-based organic whole plant extracts of cannabis, with either a 1:1 or 4:1 ratio of THC:CBD. Participants were assessed using the Functional Assessment of Cancer Therapy for Brain Cancer (FACT-Br) questionnaire – commonly used for cancer-related issues, with quality-of-life questions specific to patients with brain cancer – in addition to a participant diary, noting any side effects, between baseline and 12 weeks.
The team found that both physical (p=0.025) and functional (p=0.014) domains were statistically significant in favor of the 1:1 ratio over the 4:1 ratio, though sleep (p=0.009) improved in both groups. Overall, the study demonstrated that a single nightly dose of THC-containing medical cannabis was safe, had no serious adverse effects, and was well tolerated. In short, medical cannabis significantly improved sleep, functional wellbeing, and quality of life. But what does this really mean for high-grade glioma patients outside of the study? We spoke to Schloss to find out.
First off, why do you think existing information regarding tolerability is lacking?
The reason is that most of the research is based on symptomology. We were looking at this trial to gather information to be able to go into an efficacy trial to see if medicinal cannabis can be used in conjunction with standard treatment for people with high-grade glioma brain tumors to assist in reducing existing tumors and preventing recurrence or regrowth. We know the GW Pharma trial was being undertaken in the UK looking at survival with a 1:1 set dose. However, with regards to tolerability, to date, there have been tolerability studies for cancer pain and chronic pain but not for potential efficacy.
The majority of in vitro studies state that it is the THC that has the anti-cancer activity; however, some other studies state that a combination of THC and CBD is more effective. We wanted to examine if a higher THC was more effective and tolerated in this cohort.
The trial enlisted patients with different tumor grades and at different disease stages; do see this as a strength or limitation of the study?
Both. On the medical front, it is seen as a limitation as we didn’t choose one genetic mutation for GBM – something that many medical studies do. However, we wanted to take a more pragmatic approach to help direct future studies; it made no sense for us to limit ourselves to one particular patient group. With a broader scope, we were able to see if certain genetic types or disease states responded better – or not. We found that patients with advanced disease did not gain benefits from cannabis beyond normal palliative care assistance. And those with mesenchymal tumors did not always respond.
What were your expectations ahead of the study?
An interesting question! My expectations were that medicinal cannabis would be of benefit for people with brain tumors, but I wasn’t sure who would benefit more. Most of the investigators thought the higher THC (4:1) would be more beneficial, but I was undecided.
How did you assess efficacy and tolerability?
We assessed tolerability by a number of aspects: compliance, side effect profile, the National Cancer Institute Common Toxicity Criteria (NCI CTC) and reduction of dose. We assessed efficacy over the 12 weeks by conducting an MRI scan at baseline and at 12 weeks.
Do you think the findings will be well received by patients and physicians?
Honestly, I think there will be a mixed response. For patients, I think the results will be well received as it gives them another potential option. For physicians, I think the reaction will be mixed; after all, this is a pragmatic study for only 12 weeks – and many physicians will see the lack of a placebo as a major limitation.
However, I’d like to point out that the primary objective under scrutiny was tolerability – secondary outcomes, as noted, will help direct our future research. In fact, we are looking at conducting the next trial as a phase IIb, which incorporates a placebo arm. We are working out the best way forward right now, but we are applying for grants and looking at joining a current trial as a study arm for newly diagnosed GBM patients. In addition, I am considering a trial on different delivery methods to see which may be better for this cohort.
