CaSMO Management of Cutaneous Toxicities Associated with Immune Checkpoint Inhibitors: A Practical Primer

Maxwell B Sauder MD, FRCPC, DABD¹, Joel Claveau MD FRCPC, DABD², Marcus Butler MD³, Anneke Andriessen PhD⁴, Tarek Hijal MD, FRCPC⁵, Charles W Lynde MD, FRCPC⁶

¹Diplomate of the American Board of Dermatology, Fellow of the Royal College of Physicians of Canada, Associate Professor, Department of Medicine University of Toronto, Onco-dermatologist, Princess Margaret Cancer Centre, Director, Toronto, ON, Canada.
²Fellow of the Royal College of Physicians of Canada, Diplomate of the American Board of Dermatology, Associate Professor, Department of Medicine, Division of Dermatology, Laval University, Director Melanoma and Skin Clinic, Le Centre Hospitalier Universitaire de Québec, Hôtel-Dieu de Québec, Quebec City, QC, Canada.
³Medical Oncologist, Medical Oncology Disease Site Lead for Melanoma/Skin Oncology, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre. Assistant Professor, Department of Medicine, University of Toronto, Associate Member, Department of Immunology, University of Toronto, Toronto, ON, Canada
⁴Radboud UMC, Nijmegen and Andriessen Consultants, Malden, The Netherlands.
⁵Fellow of the Royal College of Physicians of Canada, Associate Professor, Department of Oncology, McGill University; Director, Division of Radiation Oncology, McGill University Health Centre, Montreal, QC, Canada.
⁶Fellow of the Royal College of Physicians of Canada, Diplomate of the American Board of Dermatology, Associate Professor, Department of Medicine University of Toronto, Toronto, ON, Canada, Lynderm Research, Markham, ON, Canada.

Abstract
The Canadian skin management in oncology (CaSMO) project was developed to improve cancer patients’ (both active and survivors) quality of life by offering tools to healthcare professionals for preventing, reducing and/or managing cutaneous adverse events (cAEs).
Immunotherapy, specifically immune checkpoint inhibitors (ICIs), for cancer patients is both increasing in indications and use. Similarly, the incidence and onset of cutaneous immunotherapy-related adverse events (cirAEs) vary based on the class and dose of immunotherapy administered, the type of cancer, and factors related to the patients. Dermatologists will increasingly see side effects from immunotherapy.

The CaSMO advisors developed a practical primer on prevention, identification, and treatment, including skincare for cirAEs, focusing on isolated pruritus, psoriasiform eruptions, lichenoid eruptions, eczematous eruptions, and bullous pemphigoid.
A modified Delphi approach was used for the cirAEs practical primer’s development. Recommendations given by the CaSMO advisers are based on information from the guidelines, algorithms, consensus papers, and systematic reviews coupled with their clinical experience and resulting from discussions.

According to the CaSMO group, the management of cirAEs starts with physician awareness and patient education on the occurrence of toxicities, preventive measures, and skincare using gentle cleansers, moisturizers, and sunscreen started before immunotherapy begins and ongoing thereafter as part of the lifestyle.

Keywords: Immunotherapy, cutaneous adverse events, immune checkpoint inhibitor, skin toxicity, psoriasis, pruritus, morbilliform, eczema, bullous pemphigoid

Disclosures
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this manuscript. This work was supported by an unrestricted educational grant from La Roche-Posay Canada. All authors contributed to the manuscript, reviewed it and agree with its content and publication.

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Introduction

In 2021 an estimated 229,200 Canadians were diagnosed with cancer.¹ In Canada, of the four most commonly diagnosed types of cancer (lung, breast, colorectal, and prostate), excluding non-melanoma skin cancer, lung cancer is the most lethal and expected to cause more deaths than the other types combined.^2,3

Immunotherapy activates the body’s immune system to fight cancer. Immune checkpoint inhibitors (ICIs) prevent the deactivating signal by blocking the T-cell shut-off receptors and ligands from binding to each other, thereby disrupting signaling so that T cells remain active and can then recognize and attack cancer cells.^4,5 ICIs are approved for treatment across almost every type of solid-organ tumors, many hematologic malignancies, and in many instances, first-line therapy.^4,5 In 2019, in the United States, approximately 40% of oncology patients were eligible for treatment with immunotherapy.⁶ ICIs may be administered as a single agent (anti-CTLA-4 (ipilimumab), anti-PD-1 (pembrolizumab, nivolumab), anti-PD-L1 (atezolizumab, durvalumab, and avelumab)) or as combination immunotherapy (ipilimumab and nivolumab) and even as a combination with other agents.^4-6

Oncology patients treated with immunotherapy may experience cutaneous immunotherapy-related adverse events (cirAEs) at any time during and after the cancer treatment, severely impacting the quality of life (QoL) and potentially cancer treatment outcomes.^7-24 The incidence and onset of cirAEs vary depending on the drug class, the type of cancer, and factors related to the patient.²⁵ Adverse skin reactions occur in 14%–47% of patients treated with ICIs, ranging from mild and localized to debilitating and widespread in 1%–3% of patients and even potentially causing death.^15,16,26-30 Nivolumab-related cirAEs, including isolated pruritus, occurred in approximately 13–20% of patients, of which 0.7% of patients reported grade three or higher cAEs.^29-33 Pembrolizumab-induced cirAEs occurred in 9%–27% of patients, of which 1%−4% of patients reported grade three or higher cirAEs.^34,35

Frequently occurring cirAEs include pruritus without primary dermatologic findings (isolated pruritus), lichen planus or lichenoid drug eruptions, psoriasiform reactions, eczematoid eruptions, morbilliform eruptions, and bullous diseases, primarily bullous pemphigoid.^7-24  

The cirAEs may indicate a therapeutic response. A multicenter retrospective study on patients with non-small-cell lung carcinoma (NSCLC) receiving nivolumab showed that AEs and cirAEs were a strong predictor of survival outcomes, and those presenting with more than 2 AEs showed more benefit than patients with fewer AEs.¹⁴  Vitiligo occurs in some patients with melanoma receiving ICIs (Figure 1), and this is significantly associated with both progression-free-survival (PFS) and overall survival (OS) which indicated a two to four times lower risk of disease progression and death.^32,36

Major guidelines^10-12 recommend the use of systemic steroids for grade 2 or higher “rash” contrary to evidence showing the use of systemic steroids reduces the anticancer effect of ICIs.³³  A secondary analysis of a randomized trial on stage III melanoma patients with cirAEs showed that patients who received treatment with systemic steroids for 30 days or longer had lower OS than those without steroid treatment.³³  Another multicenter retrospective analysis of patients treated with anti-PD-1 therapy showed that high-dose glucocorticoids used to treat AEs were associated with poorer PFS and OS.³⁵

Scope of the Canadian Skin Management in Oncology Project

The Canadian skin management in oncology (CaSMO) project was developed to improve cancer patients’ (both active and survivors) QoL by offering tools for preventing and managing cAEs.^37-39 A general management algorithm to reduce the incidence of all cutaneous toxicities and maintain healthy skin using general measures and over-the-counter agents³⁸ and an algorithm to reduce and treat acute radiation dermatitis³⁹ were previously published. These algorithms aim to support all healthcare providers treating oncology patients, including physicians, nurses, pharmacists, and other medical providers.^38,39 The next step in the project was to develop a practical primer on prevention, identification, and treatment for cirAEs, focusing on isolated pruritus, psoriasiform eruptions, lichenoid eruptions, eczematous eruptions, and bullous pemphigoid.

Table 1: Immunotherapy classes, molecules, and indications

CTLA-4 impinges on many features of T-cell biology.^43,44  The CTLA-4 signaling pathway and the PD-1/PD-L1/PD-L2 signaling pathway are critical checkpoints that are used to down-regulate the body’s immune system that tumors often exploit and activate, thereby evading the body’s immune system.^43,44 CTLA-4 dampens T-cell responses via cell-intrinsic and extrinsic pathways. Intrinsic events include, among others, inhibition of protein translation, recruitment of phosphatases, activation of ubiquitin ligases, inhibition of cytokine receptor signaling, and inhibition of lipid microdomain formation on the surface of T-cells. Cell extrinsic events include the competition for CD28 in binding to its ligands CD80/86, the removal of CD80/86, the release of suppressive indoleamine-dioxygenase, and the modulation of Treg function. Antibodies to CTLA-4 may facilitate T-cell tumor entry and alter the movement in tumors and rates of egress.^43,44

cirAEs can present as almost any dermatologic condition, but most are inflammatory dermatoses.^7-11,26 The median time to onset of cirAEs is four weeks but has a broad range from 2 to 150 weeks, including beyond treatment discontinuation.^15,17,45

cirAEs of any grade have been reported at 30-40% of patients receiving PD-1/PD-L1 and approximately 50% of patients treated with ipilimumab.³¹  Maculopapular rash and pruritus are common cirAEs related to these treatments.³¹

A systematic literature review on cancer treatment with pembrolizumab and nivolumab observed that the most frequently occurring cirAEs were inflammatory dermatitis, pruritus, and vitiligo.⁴⁶ The rate of any-grade cirAEs with pembrolizumab and nivolumab was reported at 16.7% (RR=2.6) and 14.3% (RR=2.5), respectively.⁴⁶ The cirAEs may be associated with pruritus and comprised of erythematous macules, papules, and plaques, predominantly low-grade and localized to the trunk and extremities.⁴⁶ Challenges with reports of cirAEs are accurate descriptions and diagnoses of the specific dermatoses as many are simply reported as “rash”. Additional cirAEs comprised pruritus [incidence pembrolizumab and nivolumab was 20.2% (RR=49.9) and 13.2% (RR=34.5) respectively] and vitiligo [incidence, 8.3% (RR=17.5) and 7.5% (RR=14.6) respectively].⁴⁵ The researchers noted that knowledge of cirAEs is critical in delivering optimal cancer treatment, maintaining therapeutic agent dose, and health-related QoL.⁴⁶

The advisors agreed that cirAEs are likely an indicator of ICIs treatment efficacy and should be managed with topical treatment and judicious, ideally steroid-sparing systemic treatment where possible.^33,35-38

Approaches to the most common immunotherapy-related cAEs

The advisors discussed and selected the most common cirAEs: isolated pruritus, psoriasiform eruptions, lichenoid eruptions, eczematous eruptions, morbilliform (maculopapular) eruptions, and bullous pemphigoid eruptions.^7-25,27-30

According to the advisors, the management of cirAEs starts with patient education on the occurrence of cirAEs, preventive measures, and skincare using gentle cleansers, moisturizers, and sunscreen started before ICIs treatment begins and ongoing during survival as part of the lifestyle.^9-25

Diagnosis of cirAEs

When diagnosing the cirAEs, other etiologies such as an infection, an effect of other agents, or other skin conditions should be ruled out.^8-11 

Biopsies play a role in accurately diagnosing the cirAEs when morphology is not clear. Histopathologically, cirAEs can be categorized into four broad groups, group 1: Inflammatory skin disorders, which reflect acute, subacute, or chronic inflammation of various patterns associated with variable epidermal changes, including psoriasiform or lichenoid interface chronic dermatitis.^16,50-53 Group 2: ICIs-related bullous skin lesions such as bullous pemphigoid or dermatitis herpetiformis, group 3: Keratinocyte alteration—Grover’s disease⁵⁴/acantholytic dyskeratosis, and group 4: Immune-reaction mediated by alteration of melanocytes such as regression of nevi, tumoural melanosis, and vitiligo.^29,36,48-52 For this review, we will only be focusing on the selected cirAEs.

When assessing the severity of cirAEs, grading systems’ trial limitations need to be considered.⁹ The Common Terminology Criteria for Adverse Events (CTCAE) classification is typically used; however, in the case of clinical trials, clinicians should be cognisant of the version the trial is using as different versions of CTCAE have different definitions and categorizations.²⁶

A general approach to prevention or reduction of cirAEs as well as initial management of the previously published CaSMO algorithm is displayed (Figure 2) for reference.³⁸  

Isolated Pruritus

Immunotherapy-related isolated pruritus occurs frequently and has a significant impact on QoL (Figure 3).^{7-25,31,46,55-57}  Diagnostic criteria for pruritus have been described as core symptoms, including duration of pruritus (more than six weeks) and a history of signs of scratching.^63,64 Associated criteria comprise a range of clinical manifestations, symptoms, functions, and emotions. The function includes the extent of impaired QoL, sleep loss, and days of absence from work. Emotions include possible psychological reactions such as, depression, anxiety, anger, and helplessness.⁶⁴

Isolated pruritus should be a diagnosis of exclusion once other causes such as pre-bullous pemphigoid, bites, or other drug reactions are ruled out.

A stepwise approach includes starting with over-the-counter topical agents, topical prescription agents, systemic drugs, and phototherapy.^63,64 General principles before starting topical and/or systemic treatment comprise skincare using gentle cleansers and moisturizers, especially in the presence of xerosis.^63,48

The CaSMO algorithm educates on general measures such as avoiding skin irritants, scented products, temperature extremes, sun, and the use of sun-protective clothing (e.g., brim hats and sunglasses). The information should be provided before immunotherapy starts, and this is especially important for isolated pruritus.³⁸ The daily skincare regimen should be reinforced with emphasis on gentle cleansers, skin moisturization, and sun protection – similar counseling to a patient with atopic dermatitis.^37,38,47  

A prurigo nodularis 4-tier treatment ladder⁶⁴ addresses neutral and immunologic mechanisms that may be applicable to ICIs-induced pruritus.⁶⁴ Immunologic mechanisms are more likely to be the underlying mechanism in ICIs-induced pruritus. Patients can enter the treatment ladder at any tier and move up or down the ladder based on their clinical presentation.⁶⁴  Immunologic tier 1 is more likely mechanisms can be treated with TCS, TCI, or topical calcipotriol.⁶⁴  Moisturizers, including antipruritics such as pramoxine 1% or formulations with menthol or camphor, may be used as an adjunct therapy.⁶⁴ 

For tier 2 neural mechanisms of pruritus medications include selective nor­epinephrine reuptake inhibitors (SNRIs) (i.e., mirtazapine) and gabapentinoids (gabapentin and pregabalin), which have antipru­ritic properties.^63,64  Second-generation histamine H1 receptor antagonists were shown to be effective and safe for patients receiving ICIs.⁶⁴ 

Additional second-line systemic therapies such as neurokinin 1 inhibitors (i.e., aprepitant) and inhibi­tors of interleukins (ILs) 4, 13 may be considered for the tier 3 immunologic mechanisms approach.⁶⁴ When evaluating the need for systemic or topical treatment, possible interactions with cancer therapy are assessed together with concomitant conditions and cirAEs.^{9-11,15,16,23,24 37,38,47}

Clinicians should take caution using systemic steroids and immunomodulators for patients receiving cancer treatment with ICIs (Table 2).^9-11

Table 2: Isolated pruritus

Psoriasiform Eruptions

T helper (Th) cells producing interleukin (IL)-17, IL-22, and tumor necrosis factor (TNF) drive the pathogenesis of psoriasis by orchestrating inflammation in the skin triggering proliferation of keratinocytes and endothelial cells.⁶⁵ Besides Th17 cells, other immune cells that are capable of producing IL-17-associated cytokines participate in psoriatic inflammation.^66-70  ICIs are thought to be driven through the TH17 pathway, and this may have implications on the development of psoriasis but also on the use of systemic psoriasis medications.^64,65,71,72

Immunotherapy with anti-PD1 and anti-PDL1 can exacerbate psoriasis, although more severe flares were noted in patients treated with durvalumab.^65-68,70,71

A personal or family history of psoriasis is a significant risk factor that should be identified before starting immunotherapy.^65,66,68 These patients require regular skin monitoring enabling early diagnosis and treatment of psoriatic exacerbations.^65,66,68 Prompt diagnosis can prevent a severe impact on QoL of this cirAE that may compromise therapeutic protocols and final cancer prognosis (Figure 4).^53,65,66 A skin biopsy to confirm the diagnosis, although not required, includes parakeratosis, hypogranulosis, regular acanthosis, suprapapillary plate thinning, and neutrophils at various layers of the epidermis.^68,70

Psoriasiform cirAEs can affect skin, nails, and joints and significantly impact QOL.^65-71 Psoriasis can be associated with arthritis as patients have a greater-than-expected incidence of psoriatic arthritis when it occurs as a cirAE of cancer treatment.^33,65,66 The choice of therapy takes many factors into account, including the extent and area of involvement, lifestyle, other health issues, and medications. First-line treatments include topical treatment with TCS, TCI, calcitriol, or a combina­tion of a super potent TCS with calcipotriol or tazarotene can be given.^65-71  For recalcitrant cases, consider adjuvant narrowband ultraviolet B therapy or oral treatment such as systemic retinoids [acitretin] or apremilast.^72-75  Although there is no direct evidence in ICIs treated cancer patients, methotrexate is immunosuppressive and may reduce the therapeutic effect of ICIs, similar to systemic steroids that have been shown to reduce RFS and OS.^32,33,35

Acitretin or apremilast is preferred over methotrexate; however, there is an absence of data for apremilast on the effect it may have on the anticancer treatment.^68-75  If the lesions persist, treatment with biologics may be required to treat psoriasiform cirAEs. IL-23 agents (gulselkumab, risankizumab, tildrakizumab) are considered most targeted and have the least direct evidence of immunosuppression (e.g. infection and TB reactivation). However, the risk/benefit needs to be considered before starting treatment with biologics (Table 3).^76-86

Lichen Planus

Immunotherapy-induced lichen planus is a pruritic, papulosquamous disease that can affect skin, hair, and nails (Figure 5). Treatment is required, especially if pruritic when it can severely impact QoL.^{7-19,27,33,46,63,77,78} When examining the patient exclude guttate psoriasis, mucositis, and bullous disease. Specific investigations include a detailed medical history and medication use, liver function tests including hepatitis C status, and, if required, a skin biopsy.⁷⁹

Pruritus may be treated with second-generation histamine H1 receptor antagonists (e.g., blistane, rupatadine, cetirizine and fexofendadine).^63,64,79 A retrospective analysis of clinical data investigating if commonly used medications might influence responses to checkpoint inhibitors. The researchers found that concurrent use of second-generation histamine H1 receptor antagonists correlated with significantly improved survival outcomes in those with melanoma or lung cancer. In addition, the antihistamine was effective for treating pruritus in cirAEs.^63,64,79 The choice of therapy takes many factors into account, including the extent and area of involvement, other health issues, and medications.^{8-11,67-69,78,80} First-line treatment includes moisturization and sun avoidance, antihistamines, TCS, and TCI.^80,81 Other second-line treatments include oral retinoids (acitretin), apremilast, sulfasalazine, metronidazole, hydroxychloroquine (especially for scalp or presentation with arthritis).⁸⁰ Additionally, narrowband or broadband UVB or PUVA may be used. Treatment with cyclosporine should be avoided as it may exert effects on the immune system (Table 4).^25,31,78

Table 4: Lichen planus

Eczematous Eruptions

Eczematous eruptions (EE) are associated with altered immune function, epidermal barrier dysfunction, genetic and environmental factors, and poorly understood interaction between these factors.^82-85 EE presents clinically as relapsing erythematous and pruritic patches of skin with varying severity (Figure 6).^9-11,82-85  Skin biopsies may be taken if the condition is extensive or not responding to therapy or if the diagnosis is in doubt.^9-11 Canadian and US guidelines for topical treatment of atopic dermatitis include education and avoiding triggers, routine skincare with gentle cleansers and moisturizers, and EE management foundation regardless of disease severity and prescription treatment.^82,83 Conventional moisturizers contain occlusives, humectants, and emulsions. Newer moisturizers designed to restore skin barrier defects include distinct ratios of lipids that resemble physiological compositions.^{36,38,47,82,83} If EE is not controlled with a moisturizer alone, TCS, TCI, or crisaborole ointment, an anti-inflammatory inhibitor of PDE4, is recommended while continuing skincare.^9-11,82-86   Treatment with crisaborole ointment achieved early sustained control of atopic dermatitis flares (reduced pruritus, erythema, exudation, excoriation, induration/papulation, and lichenification).^84,85  The topical PDE4 inhibitor offered a safe alternative to TCS and TCI.^84,85

For those not adequately controlled with topical treatment, nbUVB may be considered.^82,83 Dupilumab is a humanized monoclonal antibody against the shared alpha subunit of IL-4 and IL-13 receptors, blocking these cytokines commonly found in atopic dermatitis-affected skin. The use of dupilumab may be considered for extensive, moderate-to-severe EE. Two large, long-term RCTs demonstrated its efficacy and safety.^{9-11,82,83,86}  

Another option is tralokinumab (IL-13 inhibitor) which was shown to be effective and safe for the treatment of severe atopic dermatitis.⁸⁷

Treatment with the biologic is preferred to methotrexate which is an immunosuppressive and may reduce the anticancer effect.^9-11 TCS, TCI, and crisaborole can be used with any systemic treatment to address an EE flare (Table 5).^82-85,93

Morbilliform (maculopapular) Eruptions

These cirAEs may present as pruritic, nontender, erythematous papular, and macular eruptions on various body locations.^37,38,46,47 Physical examination focusing on the morphology and the distribution, starting on the trunk and then spreading to limbs, of the presented morbilliform eruptions is required to distinguish between the various cirAEs (Figure 7).^37,38,46,47 Laboratory tests may be needed and include a complete blood count, electrolytes, renal and liver function, and inflammatory markers.^37,38,46,47 Peripheral blood eosinophilia (≥500 eosinophils/microL) may be caused by numerous conditions, including allergic, infectious, inflammatory, and neoplastic disorders (Table 6).^37,38,46,47  Mild to moderate conditions may be treated with general skin care measures, TCS, TCI, and oral histamine H1 receptor antagonists to reduce pruritus.^63,64,94 Generally, this condition can be managed with aggressive topical treatment; however, for very severe and symptomatic cases, ICIs-treatment may be held, and a short course of systemic corticosteroids may be indicated.⁹⁴ 

Table 6: Morbilliform eruptions

cirAE BP can occur at any time, including after discontinuation of ICI. The onset to developing BP is within days or weeks of ICI exposure or may be delayed several months after starting ICI.³¹ Upon diagnosis ICIs is to be held and may require permanent discontinuation.^3,15,46 In milder cases, aggressive topical treatments with class I TCS may be as effective as systemic steroids.⁹²  cirAE BP may require systemic treatment and temporary, if not permanent, cessation of immunotherapy.^3,15,46 Systemic corticosteroids may be used the achieve control quickly while waiting for steroid-sparing treatments to take effect.^88,90-92 Non-immunosuppressive systemic treatment includes oral tetracycline-class antibiotics combined with oral niacinamide 500 mg twice a day, omalizumab, IVIg, and dupilumab.^31,88,90-92 However, steroid-sparing agents that are immunosuppressive may be required in order to control BP ongoing, including methotrexate, mycophenolate mofetil or rituximab.⁹¹ While rituximab may be immunosuppressive, it works on B-cells and may not hinder the T-cell activation from ICIs. In patients with cirAE BP, obtaining disease control as quickly as possible is ideal not only for improved QoL, and decreased morbidity but also if treatment is to be reinitiated (Table 7).^93,95

Table 7: Bullous eruptions

Limitations

The details provided on the mode of action of ICIs were limited to what is clinically relevant for this primer on cirAEs. Clinical studies on prescription medications and skin care for cirAEs frequently are case reports, case series, or have small sample sizes. For this reason, grading the evidence resulting from the literature searches was irrelevant. Therefore, recommendations given by the CaSMO project advisers are based on information from the guidelines, algorithms, consensus papers, and systematic reviews coupled with their clinical experience and resulting from discussions. More work is required to identify the best practice evidence-based management of cirAEs.

Summary and Conclusions

Immunotherapy for cancer patients is fast-developing into the standard of care for many malignancies. Although many publications are available on cirAEs, publications on the treatment using prescription medications and skincare are scarce.

The CaSMO practical primer focuses on isolated pruritus, psoriasiform eruptions, lichenoid eruptions, eczematous eruptions, and bullous pemphigoid. The practical primer addresses the need for physician awareness, patient education on the occurrence of cirAEs, prompt diagnosis, prevention, treatment, and ongoing skincare started before ICI.

References

1. https://cdn.cancer.ca/-/media/files/cancer-information/resources/publications/2021-canadian-cancer-statistics-special-report/0835-2976-2021-canadian-cancer-statistics-en.pdf?rev=8e016fe8c5ea4c23b05ea08bf1018ca6&hash=C5BAEC543E496EDD8460CBBF6D44A010&_ga=2.47880293.391373246.1644172159-1100777747.1644172159
2. Canadian Cancer Society; 2021. Available at: https://www.cancer.ca/en/cancer-information/cancer-101/cancer-statistics-at-a-glance/
3. Mittmann N, Liu N, Cheng SY, Seung SJ. Health system costs for cancer medications and radiation treatment in Ontario for the most 4 most common cancers: a retrospective cohort study. Can Med Association J Open 2020;8:E191-8. Epub 2020 March 16 doi: https://doi.org/10.9778/cmajo.20190114
4. Dine J, Gordon R, Shames Y, et al: Immune checkpoint inhibitors: An innovation in immunotherapy for the treatment and management of patients with cancer. Asia Pac J Oncol Nurs 2017; 4:127-135.
5. American Society of Clinical Oncology (ASCO). Understanding immunotherapy therapy. Accessed at https://www.cancer.net/ navigating-cancer-care/how-cancer-treated/immunotherapy-and-vaccines/understanding-immunotherapy on January 16, 2022.
6. Haslam A, Gill J, Prasad V: Estimation of the percentage of US patients with cancer who are eligible for immune checkpoint inhibitor drugs. JAMA Netw Open 2020;3:e200423.
7. Malviya N, Tattersall IW, Leventhal J, et al. Cutaneous immune-related adverse events to checkpoint inhibitors. Clin Dermatol 2020;38:660-678.
8. Lacouture ME, Sibaud V. Toxic side effects of targeted therapies and immunotherapies affecting the skin, oral mucosa, hair, and nails. Am J Clin Dermatol. 2018 Nov;19(Suppl 1):31-39.
9. Haanen J, Carbonnel F, Robert C, et al. management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(7) (suppl_4):119-142.
10. Schneider BJ, Naidoo J, Santomasso BD, et al. management of immunotherapy-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology (ASCO) guideline update. J Clin Oncol 2021;39(12):4073-4126. PIMD: 34724392.
11. Thompson JA, Schneider BJ, Brahmer J et al. NCCN Guidelines insights: Management of immunotherapy-related toxicities, Version 1.2020. J Natl Compr Cancer Netw. 2020;18(3):230-241.DOI: 10.6004/jnccn.2020.0012
12. Lacouture ME, Mitchell EP, Piperdi B, et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol. 2010 March 10;28(8):1351-7.
13. Qin Q, Patel VG, Wang B, et al. Type, timing, and patient characteristics associated with immune-related adverse event development in patients with advanced solid tumors treated with immune checkpoint inhibitors. J Clin Oncol 2020;38:e15160.
14. Ricciuti B, Genova C, de Giglio A, et al. Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab. J Cancer Res Clin Oncol. 2019 Feb;145(2):479-48
15. Sibaud V. Dermatologic Reactions to Immune Checkpoint Inhibitors : Skin Toxicities and Immunotherapy. Am J Clin Dermatol. 2018 Jun;19(3):345-361.
16. Curry JL, Tetzlaff MT, Nagarajan P, et al. Diverse types of dermatologic toxicities from immune checkpoint blockade therapy. J Cutan Pathol. 2017;44(2):158-76.
17. Tang SQ, Tang LL, Mao YP, et al: The pattern of time to onset and resolution of immune-related adverse events caused by immune checkpoint inhibitors in cancer: A pooled analysis of 23 clinical trials and 8,436 patients. Cancer Res Treat 2021;53:339-354.
18. Druyts E, Boye M, Agg H, et al. Immune-related adverse events and efficacy outcomes in patients treated with immunotherapy: A systematic review and meta-analysis. J Clin Oncol 2020;38.
19. Patel AB, Pacha O: Skin reactions to immune checkpoint inhibitors. Adv Exp Med Biol 2018;995:117-129.
20. Geisler AN, Phillips GS, Barrios DM, et al. Immune checkpoint inhibitor-related dermatologic adverse events. J Am Acad Dermatol 2020; 83:1255-1268.
21. Kaul S, Kaffenberger BH, Choi JN, et al. Cutaneous adverse reactions of anticancer agents. Dermatol Clin 2019;37:555-568.
22. Wang LL, Patel G, Chiesa-Fuxench ZC, et al. Timing of onset of adverse cutaneous reactions associated with programmed cell death protein 1 inhibitor therapy. JAMA Dermatol 2018;154:1057-1061.
23. Simonsen AB, Kaae J, Ellebaek E, et al. Cutaneous adverse reactions to anti-PD-1 treatment—A systematic review. J Am Acad Dermatol 2020;83:1415-1424.
24. Hussaini S, Chehade R, Boldt RG, et al. Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors—A systematic review and meta-analysis. Cancer Treat Rev 2021;92:102134.
25. Raschi E, Gatti M, Gelsomino F, et al. Lessons to be learned from real-world studies on immune-related adverse events with checkpoint inhibitors: A clinical perspective from pharmacovigilance. Target Oncol 2020;15:449-466.
26. National Cancer Institute: Common Terminology Criteria for Adverse Events Version 5.0. NIH Publication, Bethesda, MD, 2018
27. Schaberg KB, Novoa RA, Wakelee HA, et al. Immunohistochemical analysis of lichenoid reactions in patients treated with anti-PD-L1 and anti-PD-1 therapy. J Cutan Pathol. 2016 Apr;43(4):339-46.
28. Voudouri D, Nikolaou V, Laschos K, et al.Anti-PD1/PDL1 induced psoriasis. Curr Probl Cancer. Nov-Dec 2017;41(6):407-12
29. Rofe O, Bar-Sela G, Keidar Z, et al. Severe bullous pemphigoid associated with pembrolizumab therapy for metastatic melanoma with complete regression. Clin Exp Dermatol. 2017 Apr;42(3):309-12.
30. Vivar KL, Deschaine M, Messina J, et al. Epidermal programmed cell death-ligand 1 expression in TEN associated with nivolumab therapy. J Cutan Pathol. 2017 Apr;44(4):381-84.
31. Puzanov I, Diab A, Abdallah K et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations for the Society for immunotherapy of Cancer (SITC) Toxicity Management Working group. J Immuno Therapy Cancer 2017;5:95 DOI 10.1186/s40425-017-0300-z
32. Teulings HE, Limpens J, Jansen SN et al. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol. 2015 March 1;33(7):773-81.
33. Eggermont AMM, Kicinski M, Blank CU et al. Association between immune-related adverse events and recurrence-free survival among patients with stage III melanoma randomized to receive pembrolizumab or placebo. A secondary analysis of a randomized clinical trial. JAMA Oncol. 2020;6(4):519-527. Doi: 10.1001/jamaoncol.2019.5570 PMID: 31895407
34. Herbst RS, Baas P, Kim DW et al. Pembrolizumab versus docetaxel for previously treated, PD‐L1‐positive, advanced non‐small‐cell lung cancer (KEYNOTE‐010). Lancet 2016;387:1540–1550.
35. Bai X, Hu J, Betof Warner A et al. Early Use of High-Dose Glucocorticoid for the management of irAE Is Associated with Poorer Survival in Patients with Advanced Melanoma Treated with Anti-PD-1 Monotherapy. Clin Cancer Res. 2021 Nov 1;27(21):5993-6000. doi: 10.1158/1078-0432.CCR-21-1283. Epub 2021 August 10. PMID: 34376536.
36. Hua C, Boussemart L, Mateus C et al. Association of virtiligo with tumor response in patients with metastatic melanoma treated with pemobrolizumab. JAMA Dermatol. 2016;15(1)45-51. Doi: 10.1001/jamadermatol.2015.2707
37. Sauder MB, Addona M, Andriessen A, et al. The role of skin care in oncology patients. Skin Ther Letter; 2020 S Oct(10):1-12.
38. Sauder MB, Andriessen A, Claveau J, et al. Canadian skin management in oncology (CaSMO) algorithm for patients with oncology treatment-related skin toxicities. Skin Ther Letter; 2021 S March 21:1-10.
39. Hijal T, Sauder MB, Andriessen A, Claveau J, Lynde CW. Canadian Skin Management in Oncology Group (CaSMO) algorithm for the prevention and management of acute radiation dermatitis. Skin Ther Letter; 2021 S.
40. Brouwers M, Kho ME, Browman GP, et al. AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in healthcare. Can Med Association J 2010,182:E839-42
41. Trevelyan EG, Robinson N. Delphi methodology in health research: how to do it? Eur J Integrative Med 2015;7(4):423-428.
42. Smith Begolka W, Elston DM, Beutner KR. American Academy of Dermatology evidence-based guideline development process: responding to new challenges and establishing transparency. J Am Acad Dermatol.2011 Jun;64(6):e105-12. doi: 10.1016/j.jaad.2010.10.029.
43. Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51–60.
44. Digklia A, Duran R, Homicsko K et al. Cancer Immunotherapy: A Simple Guide for Interventional Radiologists of New Therapeutic Approaches. Cardiovasc Intervent Radiol. 2019 Sep;42(9):1221-1229. doi: 10.1007/s00270-018-2074-1.
45. Qin Q, Patel VG, Wang B, et al. Type, timing, and patient characteristics associated with immune-related adverse event development in patients with advanced solid tumors treated with immune checkpoint inhibitors. J Clin Oncol 2020;38:e15160.
46. Belum VR, Benhuri B, Pastow MA et al. Characterization and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60(6) 12–25. doi:10.1016/j.ejca.2016.02.010.
47. Lacouture ME, Choi J, Ho A et al. US cutaneous oncodermatology management (USCOM) a practical algorithm. J Drugs Dermatol 2021; 20(9)(Suppl):s3-19.
48. Larkin J et al. Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34.
49. Anforth RM, Blumetti TCMP, Kefford RF, et al. Cutaneous manifestations of dabrafenib in patients with metastatic melanoma. Br J Dermatol. 2012 Nov;167(5):1153-60.
50. Shi VJ, Rodic N, Gettinger S et al. Clinical and histologic features of lichenoid mucocutaneous eruptions due to anti-programmed cell dealth 1 and anti-programmed cell death ligand 1 immunotherapy. J Am Med Assoc Dermatol 2016; 152: 1128–1136.
51. Tetzlaff MT, Nelson KC, Diab A et al. Granulomatous/sarcoid-like lesions associated with checkpoint inhibitors: a marker of therapy response in a subset of melanoma patients Am J Dermatopathol 2017; 39: 121–129.
52. Koelzer VH, Buser T, Willi N et al. Grover’s-like drug eruption in a patient with metastatic melanoma under ipilimumab therapy. J Immunother Cancer 2016;4(8): 47. DOI: 1186/s40425-016-0151-z
53. Boada A, Carrera C, Segura S, et al. Cutaneous toxicities of new treatments for melanoma. Clin Transl Oncol. 2018;20:1373-1384.
54. Bayer V, Amaya B, Baniewicz D, et al. Cancer immunotherapy: An evidence-based overview and implications for practice. Clin J Oncol Nurs 2017;21:13-21.
55. Keiser MF, Patel AB, Altan M: Cutaneous toxicities in lung cancer patients on immune checkpoint inhibitor therapy. Clin Lung Cancer 2021;22:195-e1.
56. Ala-Leppilampi K, Baker NA, McKillop C, et al. Cancer patients’ experiences with immune checkpoint modulators: A qualitative study. Cancer Med 2020;9:3015-3022.
57. Kumar V, Chaudhary N, Garg M, et al. Current diagnosis and management of immune-related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front Pharmacol 2017; 8:49.
58. Prior LM et al. Toxicities in immunotherapy: Can they predict response? J Clin Oncol. 2016;34(15 suppl):e14534-e14534.
59. Muntyanu A, Netchiporouk E, Gerstein W, et al. Cutaneous immune-related adverse events (irAEs) to immune checkpoint inhibitors: A dermatology perspective on management. J Cutan Med Surg 2021;25:59-76.
60. Ai L, Gao J, Zhao S et al. Nivolumab-associated DRESS in a genetic susceptible individual. J Immunother Cancer 2021;9:e002879. doi:10.1136/jitc-2021-002879
61. Das S, Johnson DB. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer 2019;7:306
62. Matsubara T, Uchi H, Takamori S et al. Acute Generalized Exanthematous Pustulosis Caused by the Combination of Pembrolizumab Plus Chemotherapy in a Patient With Squamous-Cell Carcinoma. Clin Lung Cancer 2020;21(2):e54-e56.
63. Ständer S, Pereira MP, Yosipovitch G et al. IFSI-guideline on chronic prurigo including prurigo nodularis. Itch 2020;5:e42 http://dx.doi.org/10.1097/itx.0000000000000042
64. Elmariah S, Kim BS, Yosipovitch G, et al. Practical approaches for diagnosis and management of prurigo nodularis: United States expert panel consensus. J Am Acad Dermatol 2021;(3):747-760. doi.org/10.1016/j.jaad.2020.07.025
65. Guven DC, Kilickap S, Guner G, et al. Development of de novo psoriasis during nivolumab therapy in a patient with small-cell lung cancer. J Oncol Pharm Pract 2020;26:256-258.
66. Voudouri D, Nikolaou V, Laschos K, et al. Anti-PD1/PDL1 induced psoriasis. Curr Probl Cancer 2017;41:407-412.
67. Choi Y, Jang D, Byun HJ et al. Psoriasiform dermatitis related with T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains inhibitor in a patient with non-small-cell lung cancer. Ann Dermatol 2020;32(2):172-174. PMID: 33911733 | PMCID: PMC7992544
68. Amaris N, Geisler BS, Lacouture ME et al. Immune checkpoint inhibitor-related dermatologic adverse events. J Acad Dermatol 2020;83(5):1255-1268.
69. Phillips GS, Wu J, Hellmann MD, et al. Treatment outcomes of immune-related cutaneous adverse events. J Clin Oncol. 2019;37:2746–2758.
70. Kato Y, Otsuka A, Miyachi Y, Kabashima K. Exacerbation of psoriasis vulgaris during nivolumab for oral mucosal melanoma. J Eur Acad Dermatol Venereol. 2016;30:e89–e91.
71. Totonchy MB, Ezaldein HH, Ko CJ, Choi JN. Inverse psoriasiform eruption during pembrolizumab therapy for metastatic melanoma. JAMA Dermatol. 2016;152:590–592.
72. Brahmer JR, Lacchetti C, Schneider BJ, et al. management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of clinical oncology clinical practice guideline. J Clin Oncol 2018;36:1714–68.doi:10.1200/JCO.2017.77.6385
73. Elmets CA, Leonardi CL, Davis DMR, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with awareness and attention to comorbidities. J Am Acad Dermatol. 2019; 80: 1073–113. x
74. Siciliano MA, Dastoli S, d’Apolito M et al. Pembrolizumab-Induced Psoriasis in Metastatic Melanoma: Activity and Safety of Apremilast, a Case Report. Front. Oncol. 2020;10:579445. doi: 10.3389/fonc.2020.579445
75. Fattore D, Annunziata MC, Panariello L, Marasca C, Fabbrocini G. Successful treatment of psoriasis induced by immune checkpoint inhibitors with apremilast. Eur J Cancer 2019;110:107–9. doi: 10.1016/j.ejca.2019.01.010
76. Frieder J, Kivelevitch D, Menter A: Secukinumab: a review of the anti-IL-17A biologic for the treatment of psoriasis. Ther Adv Chronic Dis. 2018;9:5-21. 1177/2040622317738910
77. De Bock M, Hulstaert E, Kruse V, Brochez L: Psoriasis vulgaris exacerbation during treatment with a PD-1 checkpoint inhibitor: case report and literature review. Case Rep Dermatol. 2018;10:190-197. 10.1159/000491572
78. Martinez-Domenech A, Garcia-Legaz Martinez M, Magdaleno-Tapial J, et al. Digital ulcerative lichenoid dermatitis in a patient receiving anti-PD-1 therapy. Dermatol Online J 2019;25.
79. De la Paz Sarasola M, Taquez Delgado MA, Medina VA et al. Histamine in cancer immunology and immunotherapy. Current status and new perspectives. Pharmacol Res Perspect. 2021;9(5):e00778.
80. Tziotzios C, Lee JYW, Brier T, et al. Lichen planus and lichenoid dermatoses. J Am Acad Dermatol 2018; 79: 789–818.
81. Tattersall IW, Leventhal JS: Cutaneous toxicities of immune checkpoint inhibitors: The role of the dermatologist. Yale J Biol Med 2020;93:123-132.
82. Lynde CW, Bergman J, Fiorillo L, et al. Clinical insights about topical treatment of mild-to-moderate pediatric and adult atopic dermatitis. J Cutan Med Surg. 2019 May/Jun;23(3_suppl):3S-13S.
83. Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014;71:116–132.
84. Yosipovitch G, Simpson EL, Tan H et al. Effect of crisaborole topical ointment, 2%, on atopic dermatitis–associated pruritus: an extended analysis of 2 phase 3 clinical trials. Itch 2019;4(1)p e12.
85. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016 Sep;75(3):494-503.e6
86. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two phase 3 trials of Dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335–2348
87. Wollenberg A, Blauvelt A, Guttman-Yassky E et al. Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2). Br J Dermatol. 2021;184(3):437-449.
88. Fontecilla NM, Khanna T, Bayan CY, et al. Bullous pemphigoid associated with a new combination checkpoint inhibitor immunotherapy. J Drugs Dermatol 2019;18:103-104.
89. Kubicki SL, Welborn ME, Garg N, et al. Granulomatous dermatitis associated with ipilimumab therapy (ipilimumab associated granulomatous dermatitis). J Cutan Pathol 2018;45:636-638.
90. Siegel J, Totonchy M, Damsky W, et al: Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: A retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy. J Am Acad Dermatol 2018;79:1081-1088.
91. Lopez AT, Khanna T, Antonov N, et al. A review of bullous pemphigoid associated with PD-1 and PD-L1 inhibitors. Int J Dermatol 2018;57:664-669.
92. Joly P, Roujeau JC, Benichou J et al. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med 2002; 346:321-327
    DOI: 10.1056/NEJMoa011592
93. EsfahaniK, Elkrief A, Calabrese C, et al. Moving towards personalized treatments of immune-related adverse events. Nat Rev Clin Oncol 2020;17:504–15. doi:10.1038/s41571-020-0352-8
94. Fatima S, Veenstra J, Antonyan AS et al. Severe recalcitrant morbilliform eruption from dual immune checkpoint blockade. JAAD Case Rep 2018;4(6):593-595. PMID: 29955646
95. Aizman L, Nelson K, Sparks AD, et al. The influence of supportive oncodermatology interventions on patient quality of life: A Cross-Sectional survey. J Drugs Dermatol. 2020May 1;19(5):477-82.