Introduction

Targeted therapies are a rapidly expanding group of anticancer drugs, which promise to provide better tolerated and higher efficacy medications compared with conventional systemic chemotherapy. Inhibition of novel pathways or molecules brings about some unexpected and unforeseen adverse effects which are similar, yet distinct to those seen with chemotherapy. Cutaneous toxicity is the most common adverse drug reaction seen with targeted therapy. It ranges from benign, easily reversible effects to more life-threatening toxicity, which may even require cessation of therapy. Treatment of these adverse reactions poses different challenges, and thus, it is important to understand their clinical manifestations and mechanisms of action to aid in providing appropriate therapy.

Acneiform Rash

• ■
  

  Incidence: Acneiform rash is the most common side effect of tyrosine kinase inhibitors (TKIs), reportedly seen in 50% to 100% of treated cases. This rash can affect not only the quality of life of patients but can also decrease compliance to therapy. For example, acneiform rash is very common with epidermal growth factor receptor (EGFR)–targeting agents. Both the incidence (81%–100%) and the frequency of grade 3 rash (15%) are highest with afatinib when compared with gefitinib or erlotinib. Cetuximab is reported to have a slightly lower incidence of 75% to 91%.

Mechanism of Rash and the EGFR Pathway

• ■
  

  Proliferating keratinocytes in the epidermis normally express abundant EGFR, which acts as a ligand to a number of molecules such as epidermal growth factor (EGF), transforming growth factor-α (TGF-α), heparin-binding EGF (HB-EGF), amphiregulin (AR), epiregulin (EREG), betacellulin (BTC), epigen (EPG), and neuregulin 1–4 (NRG1–4). This receptor-ligand interaction activates the intracellular tyrosine kinase domain, causing autophosphorylation, which then eventually leads to activation of intracellular signaling pathways, particularly the RAS/mitogen-activated protein kinase (MAPK) and PI3K/AKT pathways, which ultimately promote proliferation, survival, and migration.

  
  
• ■
  

  Anti-EGFR TKIs compete with ATP and inhibit EGFR tyrosine kinase activity, which in turn results in keratinocyte apoptosis, inhibiting cell growth while promoting cell adhesivity and differentiation. This also triggers release of inflammatory chemokines such as chemokine ligand 2, ligand 5, and chemokine 10/interferon gamma-inducible protein 10. These cellular changes within the keratinocytes bring about the skin changes observed clinically.

Approved EGFR–Targeting Therapies

US Food and Drug Administration (FDA)–approved EGFR-TKIs include the first-generation TKIs, gefitinib and erlotinib, the second-generation TKI, afatinib, and the third-generation TKI, osimertinib. Gefitinib and erlotinib are reversible TKIs used for metastatic non–small-cell lung cancer (NSCLC) with the EGFR exon 19 deletion or the exon 21 substitution mutation L858R. Erlotinib is also used in pancreatic cancer. Afatinib is an irreversible HER2, EGFR, and HER4 TKI used in metastatic NSCLC. Osimertinib is an irreversible TKI approved for metastatic NSCLC with T790M mutation upon progression, on or after EGFR TKI therapy. Osimertinib was also recently approved as a first-line treatment of NSCLC with sensitizing EGFR mutations. Osimertinib spares wild-type EGFR and is known to have less skin and gastrointestinal toxicities.

Cetuximab and panitumumab are FDA–approved anti-EGFR monoclonal antibodies (mAbs). Cetuximab is a mouse–human chimeric monoclonal immunoglobulin G1 (IgG1) that binds to the extracellular ligand binding domain of EGFR with higher affinity than endogenous ligands. This prevents tyrosine kinase activation and downstream EGFR signaling, and promotes EGFR internalization. This also promotes antibody-dependent cell-mediated cytotoxicity (ADCC) and induces apoptosis. Cetuximab has a long half-life of 7 days and can bind both wild-type and mutant EGFRvIII. It is used in metastatic colorectal cancer and head and neck squamous cell carcinoma. Panitumumab is a fully human immunoglobulin G2 (IgG2) that prevents ligand binding and promotes receptor internalization and degradation. It is used in metastatic colorectal cancer.

• ■
  

  Clinical description: The rash associated with EGFR–targeting therapies presents similar to acne vulgaris and is described as painful and pruritic follicular-centered papules or pustules. Unlike acne, however, comedones are never present, and the rash has a monotonous morphology. This rash generally involves the face, scalp, upper chest, and upper back but spares the periorbital region and the palms and soles. The rash occurs in a dose-dependent pattern and is noted to disappear after discontinuation of the drug. ^, It develops in the first 1 to 2 weeks of treatment, generally peaks at 3 to 4 weeks, and eventually decreases in intensity but has been known to persist for months. It may be preceded by sensory disturbances in the form of paresthesia, erythema, or edema. Unlike Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), the rash typically does not involve the mucosal surfaces although xerophthalmia and xerostomia may be seen in 12% to 35% of cases. In terms of severity, lesions secondary to monoclonal antibodies have been reported to be more severe and extensive when compared with those secondary to small-molecule TKIs.

  
  
• ■
  

  Histopathology: A biopsy of the rash associated with EGFR–targeting therapies shows a distinct pattern when compared with acne vulgaris. Whereas acne vulgaris is characterized by sebaceous gland hypertrophy and inflammatory infiltrate related to Propionibacterium acnes colonization, this rash has been described as a sterile process as demonstrated by the absence of infective etiology. However, affected areas can get secondarily infected with herpes simplex virus or Staphylococcus aureus . It is broadly described as having two unique patterns: a hyperkeratotic follicular infundibulum surrounded by a superficial dermal inflammatory cell infiltrate or a neutrophilic suppurative folliculitis.

  
  
• ■
  

  Grading: The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 grading scale ( Table 15.1 ) is used.

  
  
  
  

  TABLE 15.1

  
  

  The NCI-CTCAE (Version 5.0) Grading Scale ^a

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Grades	Percent BSA Involved	Clinical Presentation
  1	<10%	+/− pruritic or tenderness
  2	10%–30%	Limiting self-care ADL, psychosocial impact
  3	>30%	Limiting self-care ADL, local superinfection, treated with oral antibiotics
  4	Any	Severe superinfection, life-threatening, treated with IV antibiotics
  5	Any	Death

   
  

  a This is the most commonly used criteria for assessment of dermatological toxicity from cancer directed therapies. ADL, Activities of daily living; BSA, body surface area; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.

  
  
  
  
• ■
  

  The clinical grading system is often used as a tool to describe treatment algorithms. Interestingly, the severity of the rash predicts therapy response and is often used as a surrogate marker of response to therapy.

  
  
• ■
  

  Management of acneiform rash: Treatment options are divided based on the intent—preventive versus reactive. Preventive treatments are preemptive in nature and are based on various studies conducted that showed favorable outcomes with regard to severity of the rash, although it did not have a significant impact on the absolute incidence of the rash.

  
  
• ■
  

  Pharmacological treatment: Pharmacological treatment is classified as topical therapy or oral therapy. Oral treatments primarily consist of antibiotics although other supplementary treatments have also been described. The rash grading system described previously is crucial in decision making to step-up treatment because no intervention is required for the management of mild grade (grade 1) rash, although topical steroid creams may provide potential benefit. Oral antibiotics are typically described for moderate grade (grade 2) rash along with topical steroids. ^, Severe grade (grade 3) rash often requires discontinuation of the regimen for 2 to 4 weeks, which can be resumed once the rash improves. Permanent discontinuation can be considered if the rash continues unabated despite temporary cessation.

  
  
  
  
  • ■
    

    Steroids: Topical hydrocortisone 1% is commonly prescribed for grade 1 to 3 rash. There are no randomized clinical trials to support this practice, rather its use is supported by anecdotal and expert opinion.

    
    
  • ■
    

    Antibiotics: Oral tetracyclines, such as doxycycline and minocycline, have been studied for prophylaxis and treatment of grades 2 to 3 acneiform rash. In the Pan Canadian Rash trial, the overall incidence of rash was similar in the three treatment arms (prophylactic minocycline, minocycline after rash developed, and no treatment), however, minocycline was associated with a higher “mean time to onset of any grade maximum rash.” Minocycline 100 mg has been shown to decrease lesion count and the frequency of moderate to severe pruritus in patients treated with cetuximab. Minocycline also has the added benefit of not carrying a risk of photosensitivity, compared with tetracycline and doxycycline. Doxycycline 100 mg and tetracycline 250 mg have both been described to lower the severity of grade 2 or higher rash. Notably, doxycycline in particular, is a suitable option for patients with renal dysfunction.

    
    
  • ■
    

    Supplementary treatments

    
    
  • ■
    

    Retinoids: Topical retinoids promote gene transcription and cause subsequent activation of a downstream retinoid signaling pathway, ^, and induction of HBEGF and amphiregulin, which are ligands for EGFR. Isotretinoin, tazarotene, and adapalene have been described in this context. Adapalene additionally inhibits proliferation of keratinocytes, reduces leukocyte migration, and has anticyclooxygenase activity, which promotes antiinflammatory effects. ^, Tazarotene not only had a low compliance rate due to local skin irritation, but also did not show significant improvement at 4 weeks and is thus not recommended. Isotretinoin and adapalene have been shown to have efficacy, albeit based on case reports rather than large prospective trials.

    
    
  • ■
    

    Vitamin K: Vit K3 (menadione) has been recommended for prophylactic use and has been studied in the context of cetuximab-related skin toxicities. A shorter median time for improvement of skin toxicity (8 vs. 18 days) was noted in one particular study.

  
  
  
  
• ■
  

  Nonpharmacological treatment: The high incidence of acneiform rashes makes patient education an important aspect of treatment to ensure continued therapy compliance. Certain instructions should be built into supportive care protocols upon prescription of these agents. These include having a skin care routine including cleanliness and use of moisturizers, application of alcohol-free and perfume-free emollient creams, and avoidance of hot showers and products that cause skin dryness. ^, In UVB-mediated skin damage due to inhibition of EGFR-mediated signaling processes lies the rationale to using sunscreen in this population. ^, Although there is not much evidence to support the use of sun protectants as a single agent preventive strategy, patients enrolled in some pharmacological trials used skin care as part of their daily care routine. Thus its effectiveness in combination with other methods cannot be discarded.

Hand-Foot Skin Reaction

• ■
  

  Incidence: There is considerable variation in the incidence of hand-foot skin reaction (HFSR) among different multikinase inhibitors ranging from up to 61% (regorafinib) to 34% (sorafinib) to as low as 4.5% (pazopanib). Even with the same drug, incidence rates differ depending on the tumor type being treated. This can be explained in part by the different molecular pathways involved and the degree of target inhibition achieved.

  
  
• ■
  

  Mechanism of HFSRs with multikinase inhibitors: Angiogenesis is essential for the growth and metastasis of tumor cells and is mediated through vascular endothelial growth factor (VEGF) and its receptor (VEGFR). The VEGF family includes five glycoproteins: VEGFA, VEGFB, VEGFC, VEGFD, and placenta growth factor (PGF), which interact with and activate three receptors belonging to the RTK family: VEGFR1, VEGFR2, and VEGFR3. Upon interaction with their ligands, VEGFRs activate downstream signaling pathways, mainly the PLCγ/PKC/RAF/MAPK and PI3K/AKT pathways. This leads to endothelial cell effects including proliferation, survival, migration, vasodilation, and increased permeability. Inhibition of these pathways causes microvascular structural changes and disruption of endothelial and vascular repair mechanisms, which result in damage to vessels in locations where skin is subjected to friction, heat, or recurrent trauma, such as the palms and soles. Antiangiogenic TKIs inhibit additional pathways involving PDGFR, C-Kit, EGFR, FGFR, RET, and RAF kinases. It is postulated that HFSR occurs as a result of blockade of multiple pathways. Thus receptor specific drugs such as bevacizumab, which targets VEGF, only rarely causes HFSR. ^,

  
  
• ■
  

  Approved multikinase inhibitors: Antiangiogenic TKIs are often multikinase inhibitors and inhibit other kinases, as well as VEGFR including PDGFR, c-KIT, EGFR, FGFR, RET, and RAF kinases. FDA–approved agents with activity against VEGFR include sorafenib, sunitinib, pazopanib, axitinib, vandetanib, regorafenib, lenvatinib, cabozatinib, and ponatinib.

  
  
• ■
  

  Clinical description: HFSR is a dose-limiting cutaneous toxicity described in patients treated with multikinase inhibitors and BRAF inhibitors. It is similar to hand-foot syndrome (HFS) seen with use of traditional cytotoxic chemotherapies, such as capecitabine and anthracyclines. HFSR, however, is clinically and histopathologically distinct from HFS. Its onset after initiation of targeted therapy is generally days to weeks versus weeks to months as seen in HFS. Some symptoms are similar to those of HFS, including dysesthesia, erythema, and scaling. In addition, HFSR is characterized by well-demarcated, significantly edematous, and painful blisters involving pressure points. Heels, metatarsal heads, and areas subject to repeated friction, and weight bearing sites are commonly involved. Several weeks later, thickening of skin and pain at the site of lesions impairs range of motion, function, and quality of life. Acral dysesthesia and paresthesia commonly precede the lesions. Just like acneiform rash, the therapeutic response has been correlated with HFSR occurrence except in the case of regorafenib.

  
  
• ■
  

  Histopathology: Epidermal hyperplasia, papillomatosis, and parakeratotic hyperkeratosis are detected on histopathology. Dyskeratosis and vacuolar degeneration with intraepidermal blister formation is also seen.

  
  
• ■
  

  Grading system: There is no grading specific to HFSR, however, a general consensus exists to use the grading system for HFS ( Table 15.2 ). ^,

  
  
  
  

  TABLE 15.2

  
  

  NCI-CTCAE Versions 4 and 5 Grading Scales for Hand-Foot Syndrome

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Grading	NCI-CTCAE Version 4.0 and 5.0 , ,	Symptoms
  Grade 1	•  Minimal skin changes or dermatitis (e.g., erythema, edema or hyperkeratosis) without pain	•  Numbness, unpleasant sensations when touching ordinary things, a burning or prickly feeling, tingling, painless swelling, redness, or discomfort of hands/feet; symptoms do not affect ADL
  Grade 2	•  Skin changes (e.g., peeling, blisters, edema, or hyperkeratosis) with pain; limiting instrumental ADL	•  One or more of the following: painful redness, swelling, skin thickening of the hands/feet; symptoms create discomfort, but do not affect ADL
  Grade 3	•  Severe skin changes (e.g., peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting self-care ADL	•  One or more of the following: scaling, open sores, blistering, skin thickening, severe pain of the hands/feet, severe discomfort; unable to work or perform ADL
  Grade 4	—	—
  Grade 5	—	—

   
  

  ADL, Activities of daily living; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.
  
  
  
  
• ■
  

  Management of HFSR: Management of HFSR requires a multidisciplinary approach involving a team consisting of oncologists, dermatologists, podiatrists, primary care physicians, and nurses. Prior to treatment, it is important to recognize and optimally treat risk factors that could predispose to development of HFSR such as diabetes mellitus, fungal infection, peripheral neuropathy, and other related conditions. It is also recommended that an experienced professional assess the quality of life using established tools such as Skindex or the Dermatology Life Quality Index.

  
  
  
  
  • ■
    

    Pharmacological treatment: Pharmacological treatment is determined based on the grade of symptoms. Treatment should be given in addition to continuing supportive measures. For grade 1 symptoms, keratolytics such as 10% to 40% urea or 10% salicylic acid along with topical lidocaine can be used. If progression to grade 2 toxicity is noted, then topical steroids such as clobetasol 0.05% ointment can be used. Dose reduction of targeted therapy can also be considered if symptoms persist despite topical steroid use. ^, The use of hydrocolloid dressings containing ceramide with a low-friction external surface has been shown to prolong median time to progression of grade 1 HFSR and can also be considered. Further worsening to grade 3 toxicity generally requires the use of topical antibiotics along with temporary interruption of targeted therapy for at least 7 days to observe for resolution of toxicity. It is important to reinforce patient education at each clinical visit for continued use of supportive and preventive measures to ensure patient compliance.

    
    
  • ■
    

    Nonpharmacological treatment: Supportive measures should be considered prior to the start of treatment with agents that may cause HFSR. This includes close inspection of the hands and feet for preexisting calluses or hyperkeratotic skin lesions, which could predispose to the development of HFSR. Manicure and pedicure or use of pumice stones to remove any calluses along with daily use of non–urea-based moisturizers can be recommended. Although prophylactic use of 10% urea showed a lower occurrence of any-grade rash and improvement in patient quality of life, it has not shown a change in dose reduction, interruption, or cessation of sorafenib therapy. Patient education regarding predisposing factors can mitigate or even reduce the severity of dermatological toxicity. This includes avoidance of triggers like rubbing, pinching or skin friction, vigorous activity, excessive heat, and constrictive footwear. Liberal use of moisturizers and use of thick cotton gloves and socks to prevent injury and friction are other helpful supportive measures that should be considered.

  
  

Stomatitis

• ■
  

  Incidence: Stomatitis is a common adverse drug effect reported with almost all targeted therapies. All-grade stomatitis in angiogenesis inhibitors ranges from 7% to 29%, varying based on the drug used. A higher incidence is reported with sunitinib, where any-grade stomatitis ranges from 16.5% to 27%, which is higher than other multi-TKIs when compared. Of note, the incidence of high grade (≥3) stomatitis is reported to be up to 4% with multitargeted angiogenesis inhibitors. A high relative risk has been documented with CDK 4/6 inhibitors in a systematic meta-analysis ranging from 2.62 to 4.87. Mammalian target of rapamycin (mTor) inhibitor-associated stomatitis (mIAS) is considered a class effect, with an overall incidence of any grade and high grade (≥3) ranging from 33.5% to 52.9% and from 4.1% to 5.4%, respectively, irrespective of the specific mTOR inhibitor used.

  
  
• ■
  

  Clinical presentation: Although stomatitis is specifically defined as inflammation of the inner lining of the mouth, resulting in swelling and painful sores, it is used more broadly to include any mucosal injuries including mucosal sensitivity, taste alterations, dry mouth, and necrosis of jaw. Symptoms of stomatitis are dose-dependent depending on the type of targeted therapy utilized. Symptoms associated with angiogenesis inhibitors include diffuse mucosal hypersensitivity and dysesthesia, moderate erythema, and painful inflammation of the oral mucosa. Stomatitis may also manifest as a burning sensation in the mouth, particularly triggered by hot or spicy foods. Symptoms have been reported as early as 9 to 16 days after treatment with EGFR inhibitors or several weeks after treatment initiation in the case of angiogenesis inhibitors. Ulcerous lesions are seen more commonly with classical chemotherapy, but ulcerations of the nonkeratinized mucosa have also been noted with sunitinib or sorafenib and are referred to as linear lingual ulcers. Commonly affected areas are nonkeratinized labial and buccal mucosa, the mucosa of the tongue, of the floor of the mouth, and the soft palate.

  
  
• ■
  

  Grading of stomatitis: The Common Terminology Criteria for Adverse Events grading system sets out five grades of oral mucositis ( Table 15.3 ). ^, This grading system helps guide optimal treatments for affected patients.

  
  
  
  

  TABLE 15.3

  
  

  The NCI-CTCAE Grading System Often Used to Characterize Grade of Oral Mucositis ^,

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Grade 1	Asymptomatic or mild symptoms; intervention not indicated
  Grade 2	Moderate pain not interfering with oral intake, modified diet indicated
  Grade 3	Severe pain; interfering with oral intake
  Grade 4	Life-threatening consequences; urgent intervention indicated
  Grade 5	Death

   
  

  NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.
  
  
  
  
• ■
  

  Mechanism of action: Stomatitis develops by a similar mechanism as does HFSR. EGF plays a major role in the maintenance of mucosal integrity by acting as a mitogen and by inducing mucus and prostaglandin synthesis. EGF promotes cell growth and regular turnover in response to the daily wear and tear. Further, inhibition of squamous epithelium maturation in the gastrointestinal tract promotes ulcer formation. For mIAS, the exact pathobiology has not been determined, however, it is postulated to be secondary to altered downstream effects of the mTOR signaling pathway. The mTOR pathway normally functions as a central modulator of extracellular and intracellular signaling of mediators and growth factors, thereby controlling downstream cellular events of translation, metabolism, and ultimately, growth. mTOR inhibition can disengage these extracellular and intracellular events with a resultant decrease in expression of CD4+, CD25+ regulatory T cells, and increase in CD8+ T cell infiltration and upregulation of heat shock protein 27 and interleukin-10, with a resultant recurrent aphthous ulceration. ^, There are other possible explanations, however. The oral microbiota mechanism suggests that the predominance of certain species such as bacteroidales may be involved in the pathogenesis of recurrent ulcers. Another proposed mechanism is that specific gene polymorphisms that code for certain proinflammatory cytokines may drive risk for stomatitis development.

  
  
• ■
  

  Antiangiogenic TKIs are often multikinase inhibitors and inhibit other kinases as along with VEGFR, including PDGFR, c-KIT, EGFR, FGFR, RET, and RAF kinases. FDA–approved agents with activity against VEGFR include: sorafenib, sunitinib, pazopanib, axitinib, vandetanib, regorafenib, lenvatinib, cabozatinib, and ponatinib. Sorafenib and sunitinib, in particular, are known for causing mucositis.

  
  
• ■
  

  mTOR inhibitors in combination with endocrine agents (everolimus plus exemestane) have been approved for the treatment of metastatic breast cancer. They have also been approved for different kinds of solid tumors and tuberous sclerosis complex. As described previously, mTOR inhibitors are associated with mIAS.

  
  
• ■
  

  Management of stomatitis

  
  
  
  
  • ■
    

    Nonpharmacological treatment: Mucosal sensitivity is a common patient complaint that may require dietary modifications, such as avoiding irritating foods and tobacco. Before the start of treatment, a thorough assessment of the patient’s oral cavity should be made, not only to assess existing risk factors such as dental caries, dentures, and broken teeth, but also to establish a baseline in order to identify new changes that might occur after therapy. This assessment should be made by a health care professional and must be continued throughout treatment. Patient education regarding maintaining good oral hygiene is essential. A good oral routine includes brushing the teeth and tongue with a soft-bristle brush, flossing, and rinsing. Special care should be taken for using softer, nonabrasive materials or a foam swab/gauze to maintain good oral hygiene if ulcers restrict use of a toothbrush. Also, mouthwashes containing alcohol could potentially irritate and dry mucosal membranes and thus should be avoided.

    
    
  • ■
    

    Pharmacological treatment: Treatment is based on the grade of stomatitis. In general, no intervention is recommended for grade 1 lesions. Triamcinolone in dental paste can be applied two to three times daily for pain and inflammation arising from ulcers. In addition to this oral regimen, topical steroids in the form of mouth rinse or magic mouthwashes have been recommended. ^, For grade 2 mIAS, which persists or is associated with significant pain, intralesional steroid injections or low-level laser therapy (wavelength of 633–685 or 780–830 nm, energy density 2–3 J/cm ² on the tissue surface) has been observed to provide relief. Either oral erythromycin (250–350 mg) or minocycline should be added for grade 2 toxicity. For grade 3 toxicity, clobetasol ointment is used instead of triamcinolone in dental paste, and the erythromycin dose is increased to 500 mg daily or the minocycline dose to 100 mg. Additionally, systemic corticosteroids in the form of high-dose pulse therapy with 30–60 mg or 1 mg/kg oral prednisone for1 week followed by tapering has been recommended for mIAS. Antifungal agents may be administered depending on individual case assessments. As with acneiform rash, the dose of targeted therapy should be maintained for grades 1 and 2 stomatitis and may require temporary discontinuation for 2 to 4 weeks in case of grade 3 events.

  
  

Alopecia

• ■
  

  Incidence: Alopecia is a common side effect seen with many targeted therapy drugs. The incidence of all-grade alopecia is much less (14.7%) when compared with cytotoxic chemotherapy (65%). Although not life-threatening, alopecia significantly affects the self-image of patients and overall quality of life. There are reports suggesting poor compliance and even refusal to continue therapy due to the traumatizing nature of this adverse drug reaction. ^, The highest incidence of alopecia is reported with vismodegib (59.9%), followed by sorafenib (29%), and vemurafenib (23.7%). Of note, the incidence varies among drugs targeting the same primary molecule, as is observed between sunitinib (6.9%) and sorafenib. This is explained by the fact that these drugs often work on multiple pathways. Among the CDK 4/6 inhibitors, considerable incidence of alopecia (up to 33%) has been reported in a systematic meta-analysis including 2007 patients.

  
  
• ■
  

  Clinical presentation: The onset and pattern of alopecia associated with targeted therapies is not uniformly reported. The alopecia may be in a frontal, diffuse, or patchy pattern but is usually reversible and is not associated with complete baldness. The alopecia is generally nonscarring ^, and may be accompanied by pruritus. Scarring may be seen, however, with alopecia associated with infection such as folliculitis decalvans, as seen with erlotinib. ^, The onset after the start of therapy ranges from a few weeks to months and generally resolves in 1 to 6 months after the discontinuation of therapy. The quality of hair (brittle), rate of regrowth, hair structure (thin, curly), and color (brown to orange or red); however, may be affected in the regrowth process. ^{, ,} These changes mainly apply to scalp hair but have also been noted in other areas of the body. Although not common with immunotherapy, significant alopecia involving the scalp, eyebrows, face, pubic region, and trunk has been reported with ipilimumab, in a manner mimicking alopecia areata, clinically and histologically.

  
  
• ■
  

  Grading of alopecia: Alopecia is assigned two levels of grade depending on the amount of hair loss since the initiation of treatment. Grade 1 alopecia is defined as loss of less than 50% of the initial volume of hair, not requiring wearing a wig. Grade 2 alopecia is defined as loss of more than 50% of the initial volume of hair, requiring wearing a wig, and is associated with psychosocial sequelae. Further, the grade of alopecia was not detailed in most studies of CDK4/6 inhibitors except for the PALOMA-3 trial, where it was mostly grade 1 and only 1% of patients exhibited grade 2 alopecia.

  
  
• ■
  

  Mechanism of action: Alopecia has been described in two ways. The first is telogen effluvium, which occurs when a large percentage of scalp hair moves from the anagen to the telogen phase of the hair cycle, leading to no more than 50% hair loss. The second is anagen effluvium, which occurs when root sheath cells are damaged, resulting in severe hair weakening and ultimately hair loss. The mechanism of action of alopecia induced by chemotherapy is predominantly secondary to nonselective cytotoxicity, however, this is not the case with targeted therapies. Rather, the pathogenesis of targeted therapy-related alopecia is due to blockage of a wide spectrum of oncogenic molecules and pathways. Inhibitors of the Sonic Hedgehog (Shh), vascular endothelial growth factor receptor (VEGFR), and mitogen-activated protein kinase (MAPK) signaling pathways are among the most commonly associated. EGFR pathways play a pivotal role in hair follicle biology and epidermal homeostasis. EGFR is located in the outer root sheath of a hair follicle and is critical to anagen to catagen transition, and its blockage results in follicular disintegration by pushing the hair follicle to the telogen phase. ^, Fibroblast growth factor (FGF) stimulates anagen hair growth and PDGF signaling helps in induction and maintenance of the anagen phase in hair follicles. Shh pathway inhibition in the skin can lead to (reversible) alopecia and arrest of hair growth in the telogen phase, which explains the occurrence of alopecia with vismodegib.

  
  
• ■
  

  CDK 4/6 inhibitors: CDK 4/6 inhibitors are associated with a considerable incidence of alopecia. CDK4 and CKD6 have been successfully targeted in ER+ HER2−breast cancer. Three agents selective for CDK4 and CDK6 inhibitors that are currently approved for treatment of advanced estrogen receptor–positive (ER+) breast cancer in combination with antiestrogen therapy are palbociclib, ribociclib, and abemaciclib. Abemaciclib is also approved as monotherapy after progression on chemotherapy and/or hormonal therapy.

  
  
• ■
  

  Management of alopecia

  
  
  
  
  • ■
    

    Pharmacological treatment: No pharmacological treatment is available to prevent alopecia, however, topical minoxidil 5% twice daily is sometimes used off-label. Minoxidil has been shown to shorten the duration of hair loss but, cannot prevent it. ^, Off-label use of clobetasol in shampoo or solution has also been used. Alopecia, irrespective of grade, does not require dose modification or cessation because it is not life-threatening. However, it still requires frequent monitoring and should be assessed periodically. Additionally, adequate workup of alopecia includes evaluation for nutritional deficiencies, as these may cooccur due to chemotherapy- or targeted therapy-induced poor gastrointestinal absorption. This workup should include thyroid function testing, vitamin D levels, iron studies, and assessment for protein deficiency.

    
    
  • ■
    

    Nonpharmacological treatment: Patients should be counseled regarding alopecia as a potential adverse effect of targeted therapy. This is necessary to maintain compliance and ensure continued therapy. ^, Some patients may require support in the form of formal counseling to alleviate distress and trauma associated with alopecia. Furthermore, frequent brushing is recommended, which helps loosen scalp hair kinkiness, making it less brittle. In cases where eyelashes are affected, it might be important to trim them because inward curling may result in keratitis. Use of depilatory treatments, including laser depilation and eflornithine creams, can also be used.

  
  

Cutaneous Squamous Cell Carcinoma

• ■
  

  Incidence: Individual studies have reported varying incidences of cutaneous squamous cell carcinoma (cuSCC) in patients treated with BRAF inhibitors ranging from a low of 3.92% to as high as 33.33%. In a meta-analysis including 7442 patients from 24 studies, the incidence of BRAF inhibitor–associated squamous cell carcinoma was reported to be about 12.5% for all-grade and 11.6% for high-grade cuSCC. Subgroup analysis revealed no difference in incidence when considering tumor type, particular drug used, or the study design chosen. Interestingly, the use of dual BRAF inhibitors resulted in a lower incidence of cuSCC than single agent use for all-grade and high-grade lesions.

  
  
• ■
  

  Clinical presentation: cuSCC has been reported to occur between 2 and 6 months after BRAF inhibitor therapy initiation. ^, On average, lesions occur within 3 months of treatment with a median time of diagnosis of 61 to 68 days. Although lesions occur equally in both genders, there is preponderance for older individuals, and as such, lesions are uncommon in individuals less than 40 years. ^, At the time of detection, lesions are generally noninvasive, measure 8.7 mm on average, and are described as papular or nodular in appearance. Invasive lesions can be distinguished from noninvasive lesions because they are characterized by centrally located thrombosed vessels, adherent scales, and an erythematous halo. No cases of metastatic cuSCCs resulting from BRAF inhibitor therapy have been reported to date. ^,

  
  
• ■
  

  Histopathology: Most cuSCCs are well-differentiated, but a few cases of unusually aggressive spindle cell variants have been reported. Histopathologically, lesions can be grouped as keratoacanthoma-like or wart-like, both of which demonstrate invasive lobules and atypical keratinocytes. These can be differentiated by the presence of papillomatosis, hyperkeratosis, acanthosis, and koilocytosis, which are characteristic of wart-like lesions. ^,

  
  
• ■
  

  Mechanism of action of cuSCC and the BRAF pathway: BRAF alterations are found in about 8% of human cancers including melanomas, thyroid, ovarian, and colorectal cancers. ^, The substitution of glutamic acid to valine at position 600 (V600E) is involved in 90% of BRAF mutant melanomas. This results in sustained activation of the mitogen-activated protein kinase (MAPK) and activation of downstream cellular pathways in the absence of growth factor signals, causing unregulated cell growth, proliferation, and differentiation of cancer cells. BRAF inhibitors inhibit the MAPK pathway and inadvertently result in an increased incidence of cuSCC. The exact pathogenesis is not known, but there are two mechanisms that have been proposed. Both hypothesized mechanisms essentially occur in wild-type BRAF cells and those that have oncogenic RAS mutations due to UV damaged skin. The first hypothesis involves RAS-mediated dimerization of BRAF-CRAF and the consequent activation of a pathway through CRAF. ^, The second hypothesis involves an activated RAS (activated upstream by EGFR) and transactivation of a BRAF-inhibitor-bound BRAF/BRAF homodimer or a BRAF-inhibitor-bound BRAF/CRAF heterodimer. ^, This activation is suggested to be dose dependent, occurring at low concentrations of BRAF inhibitors. Further, it has been elucidated in vitro that mutant RAS cell lines hyperproliferate after treatment with BRAF inhibitors. There is evidence that BRAF inhibitors paradoxically activate MAPK pathways in cells that lack a BRAF mutation.

  
  
• ■
  

  Approved BRAF inhibitors: Vemurafenib and dabrafenib are reversible inhibitors of BRAF that compete with ATP for binding to the kinase domain. Vemurafenib is approved for the treatment of melanoma with BRAF V600E mutation, where valine is substituted for glutamate at codon 600. Dabrafenib is approved as monotherapy for melanoma with V600E mutation. It is also approved for treatment of melanoma with BRAF V600E/K mutations in combination with trametinib, a MEK inhibitor. The combination of dabrafenib and trametinib has also been FDA–approved for metastatic NSCLC with BRAF V600E mutation and anaplastic thyroid cancer with BRAF V600E mutation.

  
  
• ■
  

  Management of cuSCC

  
  
  
  
  • ■
    

    Nonpharmacological treatment: It is important to educate patients about the known adverse effects of BRAF inhibitor therapy to avoid cessation or interruption of tumor therapy. Preventive methods include avoidance of prolonged sun exposure and avoidance of alcohol-containing skin products. Patients should undergo regular dermatological follow-up for continued evaluation of possible cuSCC. Supportive measures include use of sunscreen to protect against UVB damage, use of daily moisturizers, and a good skin care routine through use of nonalcoholic, nonirritant skin care products.

    
    
  • ■
    

    Pharmacological treatment: Dual therapy with BRAF inhibitors and MEK inhibitors has been reported to be associated with a much lower incidence of cuSCC compared with BRAF inhibitors alone. Surgical treatment is the current standard of care for BRAF inhibitor-induced cuSCCs. This approach is appropriate for single, first-time lesions, but the relative inconvenience of excision of multiple or recurrent lesions has made way for the use of pharmacological agents. This includes use of systemic retinoids such as acitretin and 5-fluorouracil. Both agents have been successful in treating existing lesions, and follow-up studies also indicate a reduction in the rate of cuSCC recurrence. There is growing evidence linking human papilloma virus (HPV) ^, and human polyoma virus (HPyV) ^, in BRAF inhibitor-associated cuSCCs, and the possible use of antiviral therapy has been raised.