Use of Cannabinoids in Cancer Patients

CINV is regulated via different pathways, one of which appears to be the endocannabinoid system. CB1 receptor agonists decrease GI motility, but may also act centrally. Cannabinoids have been shown to be efficacious at reducing CINV when compared to placebo or other antiemetics. However, there is limited evidence comparing medical cannabis to newer generation antiemetics such as serotonin antagonists and substance P/neurokinin-1 receptor antagonists. ASCO guidelines recommend using FDA approved cannabinoids for nausea and vomiting that does not respond to other agents, but cite lack of evidence for using other formulations. As reported by the National Academies of Sciences Engineering and Medicine, there is “conclusive evidence that oral cannabinoids are effective” in treating CINV. Even with systematic reviews showing benefit, the Cochrane Database review recommends only using cannabinoids when patients have failed other antiemetics. There are a lack of data for using plant cannabis, despite patient perceptions and requests. Prospective, randomized trials utilizing preparations that limit THC to avoid undesired side effects are needed. There is a randomized controlled trial underway in Australia (“Cannabis CINV”) which will compare an oral THC/CBD formulation with placebo. (II)

Upwards of 92% of patients will experience chronic neuropathy following taxane chemotherapy for ovarian cancer, and many will require long term pain medication. However, up to 50% of patients have inadequate relief of symptoms with these medications. Traditionally, GABA analogues such as gabapentin and tricyclic antidepressants have been the mainstay of therapy. Preclinical studies suggest potential benefit for THC and CBD for the prevention and treatment of neuropathic pain. In rodent models, THC eliminates the mechanical and thermal allodynia of neuropathic pain. However, psychoactive side effects are often limiting. CBD has been effective in reducing neuro- pathic pain, but has less efficacy than THC when used as monotherapy. Despite this, higher doses of CBD could be used due to the low toxicity and wide therapeutic window. CBD also was effective at preventing mechanical sensitivity induced by paclitaxel. As an example, THC and CBD in a 1:1 ratio was effective attenuating paclitaxel-induced neuropathic pain in mice. Cannabinoids have also been studied in humans as agents of prevention and/or relief of neuropathic pain. Several clinical studies have shown that low concentrations of inhaled THC have greater effect than placebo in relieving neuropathic pain. Multiple recent randomized controlled trials have demonstrated significant improvements in at least one measure of neuropathic pain. The use of CBD alone has shown less efficacy in the treatment of neuropathic pain in clinical trials. THC and CBD combinations for relief of other neurologic symptoms have conflicting results. While several studies have demonstrated improvement in sleep and disability associated with neuropathic pain, a recent meta-analysis has suggested only a modest effect on chronic pain. Additional research is necessary to determine optimal dose, route of administration, and ratio for combined cannabinoid use. (II)

In the wake of the opioid epidemic and increasing reports of opioid related deaths, providers and patients are actively seeking strategies to reduce opioid usage. In addition to alternative analgesic medications and non-medical therapies such as NSAIDs, antidepressants, acupuncture, and physical therapy, cannabinoids have emerged as a treatment strategy. While opioids are currently considered the gold standard for relief of cancer-related pain, their use is limited by side effects including constipation, sedation, addiction, and at worst, overdose. Cannabinoids exert central and peripheral effects for analgesia, in addition to muscle relaxation, anti-inflammatory effects, and anxiolysis with less risk for overdose. Cannabinoids may augment opioids and alter expression of the opioid receptor. Indeed, patients report increased pain relief with cannabis, with 97% reporting reduction in opioid medication when combined with cannabis in a non-cancer specific population. Randomized studies of THC and THC and CBD combinations show improvement in pain scores, albeit without opioid reduction. The use of cannabinoids for the reduction of opioid use warrants further investigation. (II)

Anti-inflammatory effects with cannabinoids and potential interfer- ence with immunosuppressive medications, immunotherapy and other chemotherapies Effects of cannabinoids on standard chemotherapy and immunotherapies are largely unknown. Chemotherapy agents metabolized by the liver may share similar metabolic pathways to cannabinoids and pharmacodynamic interactions cannot be excluded. Interestingly, a retrospective study suggested concurrent treatment with medical cannabis and the immunotherapy drug nivolumab in non-gynecologic malignancies was associated with a reduced overall response rate. An open discussion with patients regarding the possible risks and benefits of treatment with cannabis is strongly encouraged. In addition to direct effects on neuropathic pain and cancer-related pain, cannabinoids possess anti-inflammatory properties. Endocannabinoid system receptors, CB1 and CB2, both play a role in immune function. The highest levels of CB2 are expressed in B lymphocytes, but other immune cells, including macrophages, monocytes, NK cells, and polymorphonuclear cells, express CB2. The immunomodulatory effects of THC and other cannabinoids are primarily through the CB2 receptor. Immunomodulation is accomplished through induction of apoptosis, suppression of cell proliferation, inhibition of pro-inflammatory cytokines and chemokine production, increase in anti-inflammatory cytokines, and induction of regulator T-cells. CBD has been further studied for its anti-inflammatory or immunomodulating effects, as its limited psychoactive side effects allow for expanded use. CBD has shown inverse agonistic effects on tissues with CB2 receptors, which can block migration of immune cells and thus decrease inflammation. CBD has also exhibited agonistic effects at the CB2 receptor. Clinically, CBD demonstrates immunosuppressive effects through the CB2 receptor and other pathways. Various studies have demonstrated immunosuppression to noxious stimuli, reducing pro-inflammatory cytokines such as TNF-alpha, interleukin-6, interleukin-1Beta, and IFN-beta, with potential benefit for chronic inflammatory disease such as Crohn's Disease. Remarkably, CBD has also stimulated NK T cell production and increased production of IL-12, thus acting as an immune stimulator. This effect may account for the proposed anti-tumor properties of CBD. Despite the therapeutic effects of CBD for inflammatory conditions, the complex interplay of CBD and other cannabinoids with the immune system raises many questions within the changing environment of oncology care. Immunotherapies, including PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, and CAR-T cells, have recently been approved or are currently being tested in clinical trials for gynecologic cancers. These therapies allow for T cell activation for the elimination of cancer cells. The potential exists for muted response or enhanced toxicity of immunotherapy by cannabinoids. Additional studies of cannabinoid use with immunotherapy are urgently needed. Cannabinoids may also dampen the ability to respond to infections encountered during cancer treatment. However, controversy surrounds this concept, as cannabinoids have also demonstrated antibacterial properties in vitro and may control a damaging sepsis response. ​​​​Antitumor properties of cannabis In addition to symptom relief, much attention has been focused on the direct antitumor properties of cannabis. In vitro studies, as well as in vivo studies, in rodent models have demonstrated antiproliferative activity in tumor cell cultures and xenografts with exposure to cannabinoids. Direct and indirect mechanisms of action for these observed antitumor properties have been reported, included halting of angiogenesis and impaired metastasis.. The concept of combination anticancer therapy has recently been applied to cannabinoids. Recent studies have reported combined THC and temozolomide administration in glioma xenografts had a profound antitumor action. Combination THC and CBD has also been studied with promising activity in in vitro studies. Clinical trials in humans are in their infancy, but early studies have demonstrated safety and reduction in tumor progression. The majority of evidence for the antitumoral effect of cannabinoids is in pre-clinical studies, and caution should be exercised when discussing these effects with patients. Interactions with current treatment strategies and potential for improved efficacy should be explored with phase I and II trials. Risks of using medical cannabis in high risk populations Special consideration should be given to “at risk” populations when discussing the risks and benefits of cannabinoids. Use in adolescent patients carries an increased risk of mental illness (anxiety, depression, schizophrenia) and an increased risk of addiction to other substances. There are additional cognitive and brain development risks that are incompletely understood. The risk of female infertility is increased due to the central effects on the hormonal axis resulting in oligo-ovulation. Elderly patients should be counseled about side effects including cardiovascular risk, abnormal cognition, and falls risk. In patients diagnosed with mental health conditions great caution should be exercised, especially with THC-containing products. Although some research has demonstrated improvements in certain behavioral conditions, such as anxiety and PTSD, there is evidence that there is increased risk of manic episodes in bipolar illness, panic attacks and increased anxiety, and hallucinations or psychosis. Providers are directed to carefully review the updated literature as more information is published regarding adverse effects of cannabinoids, especially in higher risk populations. (III)