[DRAFT] The Endocannabinoid System – Ch 3: Cancer & The ECS

Introduction

In 1929 Edward Hubble observed that stars and galaxies were moving away from each other. He reasoned that, if stars are continuously moving apart, they must have been closer together at earlier times, to the point that at the very beginning the entire cosmos would have been compressed into a tiny space. This led to the hypothesis that our universe could have originated from a cosmic explosion, “the Big Bang”. But where are the remnants of such an enormous blast? Surely such a phenomenon must have left its mark in today’s universe? In fact, it did. Radio astronomers, Arno Penzias, and Robert Wilson detected the Cosmic Microwave Background radiation in 1964. This is the glow of the Big Bang explosion; it permeates the whole universe at an almost uniform -270 degrees Celsius.

So, what does all of this have to do with cancer? Tumours are large collections of cancer cells that grow out of control and invade healthy tissue, thus becoming life-threatening. Like the universe, cancers expand from something tiny, a single tiny cell. Thus, an interdisciplinary study involving the University of Southern California, the University of California, the CHA University in South Korea, and the Queen Mary University in London formulated the “Big Bang” model of tumor growth in which cancer grows as a single expansion populated by a large number of intermixed clones. They used this term because this model implies that a signature of the early origins of the malignancy can be recovered from the present-day tumor, in the same way that the Cosmic Microwave Background represents a signature of the birth of our Universe. By sequencing the DNA of tumors we know that each cancer is unique to a single patient, in the same way, that the universe is unique, as far as we can tell. Additionally, there is genetic variation not only between patients but also among cells of the same tumor. Tumours are no longer seen as uniform, but rather as a collection of distinct subpopulations of cells often called “clones”. This diversity is a big challenge for tumor treatment, as therapy may only work for a subset of cells in a tumor, thus making its complete eradication impossible.

Cancer incidence and mortality are rapidly growing worldwide. Cancer is expected to rank as the leading cause of death and the single most important barrier to increasing life expectancy in every country of the world in the 21st century. In 2018 there were an estimated 18 million cancer cases around the world, of these 9.5 million cases were in men and 8.5 million in women. The most frequently diagnosed cancer and the leading cause of cancer death substantially vary across countries and within each county depending on the degree of economic development and associated social and lifestyle factors.

Cannabis use is becoming more prevalent in patients with cancer. Robust evidence has shown heightened activity of endocannabinoid (eCB) signaling pathways and increased expression of eCB receptors in various cancer types, often in correlation with prognosis. Preclinical models propose that cannabinoids contain anti-oncogenic effects, notably by inhibition of tumor proliferation, vascularization, and metastasis. However, only 30% of oncologists feel that they have sufficient training to make informed recommendations about cannabis and 85% want more education about it. In addition, there is increasing concern among healthcare communities about the misinformation online about using cannabis to cure cancer. Recent claims that cannabis can treat serious health conditions such as cancer have proliferated online, raising concerns within the oncology community. These claims represent misleading or ‘false news’, without basis in the medical literature. The development of this false news is contextualized by three intersecting societal trends: interest in alternative treatments, the proliferation of misinformation online, and the legalization of cannabis.

Literature

In a review made by Technion-Israel Institute of Technology, the Emek Medical Center in Israel, and the Division of Oncology Rambam Health Care Campus in Israel, they aimed to provide a thorough investigation of the therapeutic use of Cannabis in oncology. In this review, they classified Cannabinoids according to natural and synthetic subtypes and their mechanisms of action expounded; they took into account the variability of available products in the clinical context and the data regarding chemotherapy-induced nausea and vomiting, cancer-related pain, anorexia, insomnia, and anxiety; they addressed the immunological and antineoplastic effects in preclinical and clinical trials; explored the concepts such as synergism or opposition with conventional treatment modalities, sequence of administration and dosage, molecular cross-talk and malignancy-cannabinoid congruence; and discussed the side-effects, limitations in trial design and legislation barriers.

The collaboration of the Israel biomedical institutions found out that the cannabinoids, cannabidiol, AEA, 2-AG, and endocannabinoid transport inhibitors have been shown to induce cancer cell death through apoptosis and to inhibit proliferation and migration in numerous murine and human tumor cell lines including glioma, oligodendroglioma, glioblastoma multiforme, astrocytoma, neuroblastoma, breast cancer, prostate cancer, colon carcinoma, uterine cervix carcinoma, thyroid cancer, leukemia, and lymphoid tumors; additional research has shown inhibited growth in vivo in murine models (mice) of lung carcinoma, glioma, thyroid epithelioma, lymphoma, and skin carcinoma. On the other hand, conflicting reports have shown oncogenic cannabinoid activity as well. While high concentrations of cannabinoids have antiproliferative effects on tumors, treatment of lung, brain, and genitourinary carcinoma cell lines with low concentrations result in rapid epidermal growth factor receptor and metalloprotease-dependent cancer cell proliferation. In cholangiocarcinoma cell lines, while anandamide shows an in vitro antiproliferative effect, 2-AG stimulates growth, and the effects are apparently due to the stabilization of lipid rafts and not mediated by CB receptors. Finally, they reported multiple studies that showed the pro-cancer effects of cannabinoids in association with immunological mechanisms.

Furthermore, in a review made by the Minnesota Department of Health, the University of Minnesota, and the Park Nicollet Oncology Research in Minneapolis, they analyzed cannabis use specifically in patients with cancer and provided an accessible guide for clinicians, researchers, and patients. Their study included thirty states plus the District of Columbia, all of which had already established comprehensive medical cannabis programs, each with different regulations and products available. Unfortunately, despite anecdotal reports and extensive online websites/blogs claiming that cannabis has a significant antitumor effect, there is little direct clinical evidence. Only two case reports have been published documenting a potential antitumor impact of cannabis (one in relapsed/refractory acute lymphoblastic leukemia and another in pilocytic astrocytomas). Moreover, Evidence of antitumor impact in patients is limited to two main studies, both in glioblastoma multiforme (GBM). These studies demonstrated that THC injected into tumors may affect tumor growth and clinical outcomes. Because patients did not consume cannabis products directly, one cannot assume that more typical use of cannabis would lead to similar outcomes. Conversely, large observational studies suggest patients with cancer using cannabis report significant improvement in many common symptoms. Cannabis use appears well-tolerated, with few serious adverse effects reported.

Finally, in a study made by Stanford University and the Kaiser Interstate Radiation Oncology Center in Portland, it was characterized the growing online interest in using cannabis as a cancer cure, the relationship between cannabis legalization and online interest, and the role of physicians and leading cancer organizations in clarifying misinformation. Using Google Trends, they characterized the global internet interest in cannabis and cancer from January 2011 through July 2018 among several states in the US. Among the 32 states included in their analysis, 22 states had legalized medical cannabis and seven states had legalized recreational cannabis at the time of our analysis. The online search volume for cannabis and cancer increased at 10 times the rate of standard therapies, more so in states where medical or recreational cannabis is legal. The use of cannabis as a cancer cure represented the largest category (23.5%) of social media content on alternative cancer treatments. The top false news story claiming cannabis is a cancer cure generated 4.26 million engagements on social media, while the top accurate news story debunking this false news generated 0.036 million engagements. Cancer organizations infrequently addressed cannabis, with low influence compared to false news.

Limitations

A thorough investigation of research regarding Cannabis and associated drugs is hampered by high variability and lack of standardization in trial construction and drug formulation. Studies analyzing the relation Cancer-Cannabinoids differ in timing of drug administration in relation to chemotherapy exposure, specific chemotherapy regimen, and cannabinoid composition and dosage. Furthermore, a varying pharmacokinetic profile for different cannabinoid products and subjects causes serious intra and interpatient inconsistency in terms of bioavailability of the drug, and consequently, in result interpretation. The dose delivery of smoked marijuana, for instance, varies by number and duration of inhalations and breath-hold – determining the spectrum of reactions from lack of effect to toxicity. The palliative oncological patient population, in particular, may be especially vulnerable to toxicity, often exhibiting lowered muscle mass and tending to extremes in weight, resulting in unexpected pharmacodynamic interactions.

Additionally, the study by Stanford University and the Kaiser Interstate Radiation Oncology Center in Portland had several limitations. Social media and online search activity around cannabis did not represent the actual use of cannabis. Further, not all states had RSV data available due to periods with low search volume, limiting generalizability. Finally, they could not determine what proportion of the audience of social media news stories about cannabis as a cancer cure were actual patients.

Conclusion

These findings reveal a growing interest in cannabis use as a cancer cure, and a crucial opportunity for physicians and medical organizations to communicate accurate information about the role of cannabis in cancer to patients, caregivers, and the general public. Sufficient evidence supports the use of Cannabis for palliative indications in oncology, however, patients should be carefully selected, guided, and followed. It should be noted that a serious limitation pertains to patients’ preconceived notions regarding cannabis. Often those who may benefit resist treatment due to stigma or fear of side effects. Contrastingly, other patient populations may demand treatment for recreational usage or due to false beliefs about a “miracle drug” that could lead to self-medication with extremely high dosages in place of conventional treatment.

Strong evidence exists for the endocannabinoid system’s involvement in cancer growth. Cannabinoids have shown antineoplastic effects in preclinical studies in a wide range of cancer cells and some animal models, and distinct signaling pathways are implicated in these results. Furthermore, combining Cannabis with conventional cancer treatment modalities may cause enhancing or diminishing effects. In oncology, sufficient evidence supports its use as add-on therapy for chemotherapy-induced nausea and vomiting to achieve a synergistic effect with conventional medicines, as well as for the treatment of refractory chronic or neuropathic pain with evidence of advantageous neurological interactions. Synergism between cannabinoids and conventional cancer treatment has been also shown to a lesser extent in radiotherapy.

Research is hampered by high variability and lack of standardization in trial construction and drug formulation and pharmacodynamics. Clinical trials and in-depth drug and patient analyses are needed to find the right constellation of drug composition, dose, and means of administration, to tailor specific Cannabis-based medicine per indication and per patient. As with most medications, cannabis is not risk-free. Possible adverse effects are generally short-term and include somnolence, nausea, dizziness, dry mouth, and disorientation, as well as euphoria, anxiety, and hallucination. Memory and cognition problems, addiction, and exacerbation or provocation of nascent psychiatric illness, such as depression and anxiety disorders, have also been associated with Cannabis use. Adverse events are mostly attributed to Δ9 -THC, while the opposing cannabinoid CBD is thought to alleviate its effects, and rather facilitate learning, prevent psychosis and ease anxiety. Street Cannabis notoriously contains high levels of Δ9 -THC and negligible CBD, in contrast to CBMs supplied for research or patient use. In Nabiximols (Sativex) studies, the most common adverse events were dizziness, dry mouth, nausea/vomiting, somnolence, and confusion. Rare but severe events may develop in susceptible or naïve patients. Caution should be taken in susceptible patients, such as the elderly or those with cardiac and psychiatric comorbidities. With further research into the potential benefits of cannabis usage for cancer patients will come a further understanding of the risks. However, the risks currently seem relatively low in comparison with many medications commonly prescribed to patients with cancer (e.g., chemotherapy, opioids, benzodiazepines).

While doctor-patient interactions are a crucial venue for the communication of accurate information, many patients who use cannabis may find their primary sources of information outside this relationship. Given the prominence of online information – particularly for those with cancer – it may be especially important for major oncology organizations to have a robust online engagement policy. However, social media posts by these organizations are minimal and generated significantly less engagement than false news stories. A physician should prescribe cannabis only if a careful explanation can be provided, and a follow-up response evaluation is ensured. Though prospective clinical trials are needed to provide the robust data required to establish the proper role of cannabinoid and cannabis-based therapy in cancer patients, physicians can draw upon the knowledge currently available to have informed discussions with their patients. When starting cannabis, one should try the lowest dose and titer slowly. Oral Cannabis may be easier to dose compared with smoked Cannabis but with a longer effect and slower onset of action. Oral Cannabis contains variable bioavailability depending on the drug and patient characteristics. Smoked Cannabis should be avoided in smokers or those with lung disease due to respiratory side effects. Novel mechanisms for drug delivery offer less toxic alternatives such as vaporizers or inhalers.

Although robust, the main problem with anti-cancer research today is that it is still limited to cell lines and animal studies, precluding meaningful conclusions and extrapolations in human cancer. We expect that in the coming years, this information will shift from the theoretical and preclinical arena to concrete clinical research, by combining comprehensive cannabinoid data with those obtained from next-generation sequencing of tumors. In this way, potentially potent combinations of cannabis formulations and tumors with specific characteristics may be identified. Moreover, increased patient data will elucidate populations that are most responsive to Cannabis. Upcoming investigations will undertake studies to advance in the understanding of cannabis’ role in oncological therapy. Three main sources of data will be investigated: the bioactive chemicals in a cannabinoid product will be isolated, their levels in patient serum determined, and finally, patient and physician-reported drug effects analyzed. These data may determine which patients are responsive to which cannabinoid formulation, and ultimately lead to tailored treatment per patient and per indication. They will aid physicians in making effective evidence-based decisions in prescribing cannabinoids for patients. Moreover, they will be grounded on and built upon the rich scientific foundation of cannabis research available today.

Sottoriva A, Kang H, Ma Z, Graham TA, Salomon MP, Zhao J, Marjoram P, Siegmund K, Press MF, Shibata D, Curtis C (2015) A Big Bang model of human colorectal tumor growth. Nat Genet, 47(3):209-16.

Ferlay, Jacques, et al. “Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.” CA: A Cancer Journal for Clinicians, American Cancer Society, 12 Sept. 2018, onlinelibrary.wiley.com/doi/full/10.3322/caac.21492.

Shi S, Brant A R, Sabolch A, et al. (January 19, 2019) False News of a Cannabis Cancer Cure. Cureus 11(1): e3918. DOI 10.7759/cureus.3918

Ilit Turgeman & Gil Bar-Sela (2018): Cannabis for cancer – illusion or the tip of an iceberg: a review of the evidence for the use of Cannabis and synthetic cannabinoids in oncology, Expert Opinion on Investigational Drugs, DOI: 10.1080/13543784.2019.1561859

Steele, Grant, et al. “A Comprehensive Review of Cannabis in Patients with Cancer: Availability in the USA, General Efficacy, and Safety.” SpringerLink, Springer US, 1 Feb. 2019, link.springer.com/article/10.1007/s11912-019-0757-7.