Radiodermatitis

Introduction

Radiation therapy (or radiotherapy) is a key component of cancer treatment and palliation for a wide variety of cancers. Radiotherapy works by delivering ionizing radiation to tumors, which damages critical cellular structures and ultimately results in the death of malignant cells. While highly effective at limiting tumor growth, the damaging effects of radiation also pose a threat to surrounding normal tissues.

Radiodermatitis is one of the most common adverse effects of radiation therapy. More severe skin manifestations can significantly impact patient quality of life and can even result in interruptions in therapy that can impact long-term outcomes (Lazarev, Adv Radiat Oncol, 2018; Bese, Oncology, 2005). Though preventative and symptomatic therapies exist to combat the symptoms of radiodermatitis, more effective therapies are needed to improve the patient experience.

Topical CBD and other cannabinoid formulations have emerged as an attractive therapeutic option for the prevention and mitigation of symptoms associated with radiodermatitis. Advantages of CBD include its beneficial safety profile (Iffland, Cannabis Cannabinoid Res, 2017) and its ability to modulate key pathways involved in the pathogenesis of radiodermatitis, including inflammation, oxidative stress, wound healing, and pain. Clinical trials are needed to evaluate the efficacy of topical CBD as well as combination therapies in the prevention and symptomatic management of radiodermatitis. If successful, such a therapy would have the potential to positively impact the lives, and potentially even the outcomes, of millions of cancer patients worldwide.

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About Radiodermatitis

Radiodermatitis collectively refers to a constellation of skin reactions that largely develop in a dose- and time-dependent manner (Bray, Dermatol Ther (Heidelb), 2016). Acute manifestations, by definition, occur within 90 days of radiation exposure, while chronic manifestations occur months to years following cessation of therapy. In an acute reaction, mild reddening of the affected area (or erythema) is usually the first symptom to develop and can be seen after the first dose of radiation (Bray, Dermatol Ther (Heidelb), 2016). With ongoing treatment, erythema may persist or worsen, and itching (pruritis), burning, and edema may develop around days 10-14 (Kole, Breast Cancer (Dove Med Press), 2017). By weeks 3 or 4, desquamation reactions can occur. Desquamation is an inflammatory response to radiation that leads to flaking or sloughing of the skin with or without associated serous drainage (termed moist and dry desquamation, respectively). Dry desquamation may appear after a lower total radiation dose and is typically less bothersome than moist desquamation, which is often painful and distressful to patients (Fuzissaki, J Pain Symptom Manage, 2019). Moist desquamation initially presents in the skin folds or creases, where skin tension and friction are greatest, but can ultimately spread to involve contiguous areas of skin (Bray, Dermatol Ther (Heidelb), 2016; Kole, Breast Cancer (Dove Med Press), 2017). The most severe skin reactions involve full thickness ulceration and necrosis of the skin, which can be life-threatening due to severe electrolyte disturbances and deficits in thermoregulation.

Besides the most severe cases, skin reactions can resolve within 4 – 8 weeks of cessation of radiotherapy with appropriate preventative and therapeutic strategies (discussed below) (Fisher, Int J Radiat Oncol Biol Phys, 2000). However, grades 2 and above carry an increased risk of superimposed infection, typically with Staph aureas, that can delay wound healing (Altoparlak, Eurasian J Med, 2011). Given the potentially devastating nature of grade 4 lesions, outcomes tend to vary greatly from person-to-person.

In addition to medical complications that can arise, skin lesions can also substantially impact patient quality of life during the treatment period, with patients citing pain, pruritis, disturbed body image, and emotional distress as key contributors to dissatisfaction (Schnur, Psychooncology, 2011, de Macedoa Rocha, Revista Gaucha de Endermagem, 2018). The negative patient experience can result in treatment interruptions and even premature cessation of therapy, both of which can negatively impact overall survival and other clinical outcomes (Lazarev, Adv Radiat Oncol, 2018; Bese, Oncology, 2005).

The same mechanisms with which radiotherapy so effectively limits tumor growth are also responsible for the complications of radiodermatitis. Ionizing radiation directed at malignant cells results in double-stranded DNA breaks and damage to other important molecules via the generation of reactive oxygen species (ROS) (Straub, J Cancer Res Clin Oncol, 2016). Cancer cells lose the capacity to repair DNA breaks due to accumulating mutations and thus undergo apoptosis in response to the irreparable cellular damage. Though healthy cells have intact DNA repair machinery, this homeostatic mechanism can be overcome by higher doses of radiation. Cells with high rates of turnover, such as those in the skin, are particularly susceptible due to their high metabolic demand and relatively rapid rate of proliferation (Hafer, Radiat Res, 2010).

The damage associated with radiodermatitis impacts the layers of the skin to varying extents. Under physiologic conditions, the epidermis provides a protective barrier against pathogens and functions in the maintenance of electrolyte/fluid balance and thermoregulation (Sotironpoulou, Cold Spring Harb Perspect Biol, 2012). The barrier is maintained by natural turnover of keratinocytes, repopulated from the differentiation and superficial migration of stem cells in the basal layer of the epidermis. Meanwhile, the dermis provides structural support to the organ with its dense network of collagen and fibroblasts. The dermis is also highly vascularized and contains lymphatic vessels for immune surveillance (Rittie, J Cell Commun Signal, 2016).

With the first dose of radiation, there is damage to cellular DNA, production of free radicals, and initiation of an inflammatory response within the skin. The proliferating basal cells are most susceptible to DNA damage, which impairs their ability to repopulate and repair the damaged epidermis. Damaged tissue-resident cells and endothelial cells release pro-inflammatory cytokines and upregulate adhesion molecules on blood vessels thereby promoting the infiltration and activation of circulating neutrophils and macrophages (Bray, Dermatol Ther (Heidelb), 2016; Straub, J Cancer Res Clin Oncol, 2016; Borrelli, Ann Plas Surg, 2019). These activated immune cells further propagate the local inflammatory response and oxidative stress by producing more ROS and other pro-inflammatory mediators. Continued radiation exposure incites further damage and overwhelms the already impaired ability of basal keratinocytes to repair and restore the barrier function of the skin. Together, these cellular changes result in the acute manifestation of radiodermatitis described above.

Dysregulated, chronic inflammation is also responsible for the development of radiation-induced fibrosis. During the initial inflammatory reaction, macrophages, endothelial cells, and fibroblasts, release the cytokine transforming growth factor beta (TGFbeta). TGFbeta stimulates the migration and differentiation of fibroblasts into myofibroblasts, which promote the deposition of extracellular matrix proteins (Borrelli, Ann Plas Surg, 2019; Straub, J Cancer Res Clin Oncol, 2016). Over time, the proliferation of myofibroblasts and excess deposition of collagen leads to chronic fibrosis in some patients.

Current standard of care consists of a combination of preventative routines and symptomatic management based on dermatitis grade, as outlined above. Preventative skin care routines generally involve keeping the area clean and dry while avoiding skin irritants and unnecessary friction or skin stress (Salvo, Curr Onvol, 2010; Wong, Supp Care Canc, 2013). Applying lanolin-free moisturizer 2-3 times a day throughout the duration of treatment is also recommended, with some evidence suggesting that topical corticosteroids used after radiotherapy sessions may provide some benefit as well (Salvo, Curr Onvol, 2010; Wong, Supp Care Canc, 2013).

In terms of management once skin lesions present, patients with grade 1 dermatitis do not frequently require additional intervention beyond maintaining their skincare routine. The moist desquamation in grade 2 and 3 dermatitis indicates compromised barrier function and increased risk for infection. Treatment is therefore aimed at accelerating tissue healing using bandage dressings to keep the area moist (Macmillan, Int J Radiat Oncol Biol Phys, 2007). Grade 4 dermatitis, as mentioned above, is severe and potentially life-threatening. The full thickness ulcerations may require skin grafts, surgical debridement, or other surgical interventions that must be assessed on a case-by-case basis.

Despite the use of these interventions, up to 85% of individuals will experience a moderate to severe skin reaction during their disease course (Salvo, Curr Oncol, 2010). This highlights the need for better preventative strategies to reduce the incidence and severity of skin toxicity. The incomplete success of therapies to date likely relates to the multiple toxic mechanisms of radiation, including direct DNA toxicity, oxidative stress, and both acute and chronic inflammatory reactions. Therapies that can address multiple aspects of radiation toxicity on the cellular level are likely to have the most success as prophylaxis and treatment for these patients.

CBD/CBG as an Adjunct to Standard of Care Treatment

In recent years, cannabis and its active constituents have gained popularity in the treatment of a wide variety of conditions due to their documented anti-inflammatory, antioxidant, and analgesic properties (Pellati, Biomed Res Int, 2018). The cannabis plant contains a number of active compounds, termed cannabinoids, that include tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabigerol (CBG).

Cannabinoids exert their diverse effects through a series of receptors and signaling pathways, collectively referred to as the endocannabinoid system (ECS). Receptors of the ECS include the G protein-coupled receptors, CB1 and CB2, as well as other cannabinoid-responsive receptors like TRPV1 (Zou, Int J Mol Sci, 2018). CB1 is found predominantly in the nervous system, while CB2 is highly expressed on immune cells and lymphoid tissue, although both receptors are expressed on many cells throughout the body (Zou, Int J Mol Sci, 2018).

In the skin, cannabinoid receptors were recently shown to be expressed on keratinocytes, sebaceous glands, immune cells, and sensory nerves, and the ECS is now appreciated for its important role in normal skin homeostasis (Biro, Trends Pharmacol Sci, 2009; Toth, Molecules, 2019). Additionally, cannabinoid signaling in multiple cell types was shown to have a profound immunosuppressive effect both in vitro and in murine models of dermatitis and dermal fibrosis (Pellati, Biomed Res Int, 2018; Akhmetshina, Arthritis Rheum, 2009; Karsak, Science, 2007; Oka, J Immunol, 2006). Therapeutic administration of either oral or topical cannabinoids are now being studied for a variety of inflammatory skin conditions, with some initial success demonstrated in clinical trials for atopic dermatitis (Yuan, Clin Interv Aging, 2014), acne vulgaris (Spleman, J Invest Dermatol, 2018; Ali, Pak J Pharm Sci, 2015), and epidermal bullosa (Chelliah, Pediatr Dermatol, 2018).

Topical cannabinoids have yet to be explored in the treatment of radiodermatitis, though the demonstrated benefit in other similar inflammatory and wound-forming conditions suggests they may represent a novel and successful adjunctive therapy. Of the potential cannabinoids to be used in therapeutic formulations, THC, which is responsible for the psychoactive properties of marijuana, can result in undesirable mood effects. CBD and CBG, on the other hand, are not psychotropic and are therefore more attractive candidates for translation into therapeutic practice.

Preclinical Data

A growing body of literature indicates that cannabinoids, and CBD in particular, may target key pathways disrupted in the development of radiation-induced skin toxicity. Most notably, CBD was shown to have a profound anti-inflammatory effect in the skin. In one study using stimulated HaCaT keratinocytes, CBD dose-dependently decreased the production of the pro-inflammatory mediators CCL8, IL-6, IL-8, and TNF-α (Petrosino, J Pharmacol Exp Ther, 2018). Additionally, CBD was shown to inhibit neutrophil migration in vitro (McHugh, Mol Pharmacol, 2008). These effects are highly relevant to the pathophysiology of radiodermatitis, as damaged keratinocytes, among other cells, produce the pro-inflammatory cytokines that ultimately recruit other immune cells to the irradiated site. Importantly, CBD was also shown to have anti-inflammatory effects in a mouse model of dermatitis, demonstrating that these properties can be recapitulated in vivo (Tubaro, Filoterapia, 2010).

CBD administration may also support wound healing and resolution of oxidative stress. Multiple in vitro studies have demonstrated that cannabinoids can influence the proliferation and differentiation of keratinocytes in a dose- and receptor-dependent manner, with some interactions promoting and others attenuating keratinocyte response (Wilkinson, J Dermatol Sci, 2007; Paradisi, J Biol Chem, 2008). Evidence from in vivo murine studies, which is perhaps a better proxy for the response in humans, demonstrates that topical administration of CBD and other synthetic cannabinoids promote keratinocyte proliferation and restoration of barrier function (Kim, Int J Dermatol, 2015; Casares, Redox Biol, 2019).

More specifically, to model the effects of commercially available CBD creams on skin homeostasis, topical formulations of CBD in concentrations similar to those available (0.1-1%) were applied to the skin of adult mice. CBD not only stimulated the proliferation of keratinocytes thereby increasing skin thickness, but also enhanced the production of the anti-oxidant molecule heme oxygenase 1 (HMOX1) as well as the production of keratins 16 and 17, which are important for wound repair (Casares, Redox Biol, 2019). HMOX1, in addition to its anti-oxidant effects, also possesses anti-inflammatory and anti-fibrotic properties via the downregulation of TGFbeta-mediated collagen synthesis (Nakamura, Am J Respir Cell Med Biol, 2011). In fact, HMOX1 mutations that render the gene less transcriptionally active have been associated with increased risk of late effects of radiation-induced skin toxicity (Alam, Int J Radait Oncol Biol Phys, 2016). CBD may therefore have both direct and indirect effects that promote wound repair.

Beyond attenuating toxic reactions initiated by radiotherapy, CBD and other cannabinoids may help soothe the pain and pruritis associated with this condition. The pain of desquamation may result from frank tissue destruction as well as inflammation, and cannabinoids have been shown to modulate both pathways. Cannabinoids have a well-documented analgesic effect, acting through CB1 receptors in the central and peripheral nervous system, as well as CB2 and TRPV1 receptors on peripheral nerves and immune cells (Walker, Life Sci, 1999; Baker, Lancet Neurol, 2003). Topical CBD has been explored in the treatment of chronic cancer-associated pain, and initial success has been demonstrated in a small clinical trial of patients with pyoderma gangrenosum, an inflammatory disorder leading to chronic painful ulcerations (Maida, J Pain Symptom Manage, 2017). Nonetheless, clinical trials are now needed to study the effects of topical cannabinoids in the management of radiodermatitis specifically.

Though most research to date has focused on CBD, other cannabinoids, such as CBG, are also gaining attention in the field. CBG, like CBD, is not psychoactive and was shown to have anti-inflammatory properties both in vitro and in vivo (Borrelli, Biochem Pharmacol, 2013; Ruhaak, Biol Pharm Bull, 2011). Furthermore, combination therapies of multiple cannabinoids are thought to confer a greater therapeutic benefit due to additive or synergistic effects (Scott, Anticancer Res, 2013; Russo, Br J Pharmacol, 2011).

Clinical Program

Jay Pharma researchers are exploring the development of a clinical program to evaluate CBD/CBG alongside conventional therapies.