Medical Cannabis During Chemoradiation for Head and Neck Cancer

Patients undergoing intensive treatment for locally advanced Head and Neck Cancer (HNC) with definitive or adjuvant concurrent chemoradiation (CRT) typically experience high levels of acute treatment toxicity due to the unavoidable irradiation of normal tissues in the upper aerodigestive tract adjacent to tumor and nodal target structures such as pharyngeal constrictors, salivary glands, oral cavity, and the upper esophagus. Radiation dose to these structures has been substantially reduced with the widespread adoption of advanced treatment planning and delivery techniques such as intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT), however patients continue to experience significant toxicity due to local effects of radiotherapy. Treatment toxicity due to local effects increases synergistically with the addition of concurrent chemotherapy, and additional toxicities such as myelosuppression and chemotherapy induced nausea/vomiting can be introduced with the addition of concurrent chemotherapy. Acute treatment toxicities include significant mucositis, odynophagia, nausea, anorexia, weight loss leading to severe reductions in health-related quality of life (HRQoL) domains related to eating, tasting, and overall sense of wellbeing. These effects generally build up over the course of a typical radiotherapy schedule (six to eight weeks), continue to persist after treatment, and demonstrate a gradual improvement over a typical course of three to six months post-treatment.

Treatment toxicity and their resultant treatment burden are typically managed with a regimen of medications directed at specific cell receptor targets involved in pain signaling, inflammation, nausea/vomiting and occasionally supplemented by topical agents intended to protect mucosal surfaces and provide local pain relief. Notably, patients often require high dose opiate analgesics to achieve adequate pain relief, exposing patients to risks of opiate dependence and the constellation of adverse effects associated with chronic opiate use. Overall, in spite of maximal treatment with currently available agents, patients continue to experience significant reduction in QoL during and after CRT attributable to both treatment-related toxicity and adverse effects of opiate analgesics utilized to alleviate treatment-related pain.

Cannabis is defined as products derived from the Cannabis sativa plant leaf. Cannabis consists of numerous bioactive compounds collectively referred to as cannabinoids. The most studied and best characterized cannabinoids are tetrahydrocannabinol (THC) and cannabidiol (CBD). Cannabinoids interact with endogenous cannabinoid receptors to produce biologic effects. Two types of cannabinoid receptors, CB1 and CB2, have been identified and characterized to date. CB1 receptors are primarily expressed in the CNS and GI tract whereas CB2 receptors are primarily expressed in immune cells, particularly circulating B-lymphocytes. Collectively, CB receptors are involved in cellular pathways regulating pain, nausea, appetite, and mood Cannabis derivatives such as tetrahydrocannabinol (THC) and cannabidiol (CBD) have demonstrated anti-inflammatory, anti-emetic, analgesic, and appetite stimulatory activity in clinical use in humans. Pre-clinical studies with tumor cell lines have also demonstrated anti-neoplastic activity.

Trials evaluating cannabis have shown synergistic anti-emetic effects with commonly used agents such as prochloperazine and ondansetron and synergistic analgesic effects with opiates. Cannabis was also shown to reduce opiate requirements and consequent opiate related toxicity for acute and chronic cancer-related pain. Of note, cannabis and cannabinoids have a favorable safety profile compared to opioid analgesics with significantly lower addictive potential and carry a lower risk of potentially serious cardiovascular toxicity (QTc prolongation) or systemic toxicity (serotonin syndrome) compared to commonly utilized anti-emetic agents. In fact, the potential lethal dose in humans has been estimated in the range of 650-700 kg inhaled in 15 minutes, making overdose highly unlikely. As a result, cannabis has recently been approved in many states within the USA for medical use, including New York state. Physician and patient enthusiasm for medical use of cannabis is high, however clinical data clarifying the role of cannabis in the treatment armamentarium for a variety of disease conditions including cancer is currently limited.

Many of the common acute symptoms experienced by HNC patients during CRT involve physiologic pathways in which cannabinoid receptors have been implicated. Therefore, given the favorable safety profile of cannabis derivatives and potential synergistic effects with commonly used medications for relief of these treatment toxicities, we hypothesize that the addition of cannabis to the supportive care regimen will improve symptom burden during and immediately post-treatment resulting in improved HRQoL and may also decrease weight loss and opiate analgesic requirement.