American Journal of Clinical Dermatology (2018) 19 (Suppl 1):S31–S39

https://doi.org/10.1007/s40257-018-0384-3

REVIEW ARTICLE

Toxic Side Effects of Targeted Therapies and Immunotherapies

Affecting the Skin, Oral Mucosa, Hair, and Nails
Mario Lacouture1 · Vincent Sibaud2

Published online: 30 October 2018

© The Author(s) 2018

Abstract
Targeted therapies and immunotherapies are associated with a wide range of dermatologic adverse events (dAEs) resulting
from common signaling pathways involved in malignant behavior and normal homeostatic functions of the epidermis and
dermis. Dermatologic toxicities include damage to the skin, oral mucosa, hair, and nails. Acneiform rash is the most common
dAE, observed in 25–85% of patients treated by epidermal growth factor receptor and mitogen-activated protein kinase kinase
inhibitors. BRAF inhibitors mostly induce secondary skin tumors, squamous cell carcinoma and keratoacanthomas, changes
in pre-existing pigmented lesions, as well as hand-foot skin reactions and maculopapular hypersensitivity-like rash. Immune
checkpoint inhibitors (ICIs) most frequently induce nonspecific maculopapular rash, but also eczema-like or psoriatic lesions,
lichenoid dermatitis, xerosis, and pruritus. Of the oral mucosal toxicities observed with targeted therapies, oral mucositis is
the most frequent with mammalian target of rapamycin (mTOR) inhibitors, followed by stomatitis associated to multikinase
angiogenesis and HER inhibitors, geographic tongue, oral hyperkeratotic lesions, lichenoid reactions, and hyperpigmentation.
ICIs typically induce oral lichenoid reactions and xerostomia. Targeted therapies and endocrine therapy also commonly induce
alopecia, although this is still underreported with the latter. Finally, targeted therapies may damage nail folds, with paronychia
and periungual pyogenic granuloma distinct from chemotherapy-induced lesions. Mild onycholysis, brittle nails, and a slower
nail growth rate may also be observed. Targeted therapies and immunotherapies often profoundly diminish patients’ quality
of life, which impacts treatment outcomes. Close collaboration between dermatologists and oncologists is therefore essential.

1 Introduction
Key Points
An estimated 14 million individuals were diagnosed with
Although dermatologic toxicities with systemic cancer cancer (excluding non-melanoma skin cancers) worldwide
therapies are very frequent, a minority of cancer patients in 2012 (http://gco.iarc.fr/today​/ home), of which more
are referred to a dermatologist during their therapy. than 10 million received systemic anticancer therapy.
Dermatologic toxicities related to targeted therapies Anticancer therapies including targeted therapies and
and immune checkpoint inhibitors profoundly dimin- immune checkpoint inhibitors (ICIs) are designed to tar-
ish patients’ quality of life, which impacts adherence to get alterations in DNA repair pathways and defects in the
the treatment, jeopardizing its success and thus patient immune system to treat cancer. However, those treatments
progression-free survival. Closer collaboration between target signaling pathways involved in both cell malig-
dermatologists and oncologists is essential. nant behavior and normal homeostatic functions of the
epidermis and dermis. Consequently, although intended
* Vincent Sibaud
to treat cancer, targeted therapies and immunotherapies
sibaud.vincent@iuct‑oncopole.fr also damage the skin and its appendages, resulting in the
Mario Lacouture
consistent report of cutaneous, oral mucosal, hair, and/
[email protected] or nail toxicities in nearly all patients, irrespective of the
pathway being blocked. Those dermatologic toxicities are
1
Department of Dermatology, Memorial Sloan-Kettering discussed herein, as well as strategies aimed at reducing
Cancer Center, New York, NY, USA
the burden placed on patients and improving their quality
2
Institut Universitaire du Cancer Toulouse – Oncopole, 1 of life (QoL).
avenue Irène Joliot‑Curie, 31059 TOULOUSE Cedex 9, France

Vol.:(0123456789)
S32 M. Lacouture, V. Sibaud

2 Skin Toxicities

Cutaneous toxicities of targeted therapies and immunother-

apies profoundly diminish patient QoL, and impairment
appears to be unexpectedly more severe in patients treated
with a targeted therapy than with chemotherapy (total score
41.7 vs. 32.8; p = 0.02) [1]. The emotional component is the
most significantly affected domain (50.0 vs. 38.1; p = 0.02),
followed by symptoms and pain, indicating that patients
experience a sense of loss of privacy due to their inability
to hide their cancer.
The management of skin toxicities is therefore critical
to improving cancer patient outcomes. However, compared
with dermatologists, oncologists more often overestimate
Fig. 1  Clinical presentation of grade 3 acneiform rash on the trunk of
the severity of dermatologic adverse events (dAEs) [2] and a patient treated with the epidermal growth factor receptor inhibitor
are more prone to discontinuing cancer therapy as a result cetuximab
of skin toxicities, hence reducing patient access to a poten-
tial life-saving treatment. An interdisciplinary collaborative
approach between dermatologists and oncologists is there- Staphylococcus aureus colony formation by the supernatant
fore essential to caring for patients receiving anticancer from EGFRI-treated epidermal keratinocytes was markedly
therapies. decreased [8]. Furthermore, clinical studies with EGFRIs
have reported cutaneous inflammation, and altered immu-
nosuppression, as well as neutrophil accumulation, epider-
2.1 Epidermal Growth Factor Receptor Inhibitor‑ mal keratinocyte proliferation, and erosion of the stratum
and Mitogen‑Activated Protein Kinase Kinase corneum [9, 10]. Those observations, together with the fact
Inhibitor‑Induced Toxicities that about a third of patients develop secondary dermato-
logical infections at the site of toxicities during EGFR- or
2.1.1 Acneiform Rash MEK-targeted therapy in the form of impetigo, cellulitis, or
erysipelas [11], suggest a key role played by inflammation,
Acneiform rash has been instrumental in drawing attention immunosuppression, and superinfection in the pathophysiol-
to cancer therapy-associated skin toxicities in the oncology ogy of EGFRI-induced acneiform rash.
community. This dAE develops in the majority of patients Consequently, the prophylactic use of antibiotics and
treated with inhibitors of epidermal growth factor receptor topical corticosteroids to reduce the incidence of dermato-
inhibitor (EGFRI) and mitogen-activated protein (MAP) logical toxicities was evaluated in phase II studies. Results
kinase kinase inhibitor (MEKI) signaling pathways, while from one of these studies showed a profound reduction in
xerosis and pruritus are less frequently observed [3]. the incidence of grade ≥ 2 dAEs in patients given the EGFRI
In patients on EGFRIs, rash was described with inci- panitumumab who received a 6-week prophylactic treatment
dences ranging from 25 to 85% for all-grade toxicities and with the oral antibiotic doxycycline, topical corticosteroids,
from 1 to 10% for grade 3 [4–6]. Skin rash typically appears sunscreen, and moisturizers versus a curative treatment after
within 2–4 weeks and is characterized by papules and pus- development of skin toxicities (29% vs. 62%, odds ratio
tules, extreme itchiness, and severe pain, with spontane- [OR] = 0.3 [95% confidence limit 0.1–0.6]), with a five-fold
ous bleeding of the lesions therefore profoundly impairing decreased incidence of pruritus and pustular rash, and even
patients’ QoL (Fig. 1). a completely abolished paronychia [10]. Similar results were
Acneiform rash induced by MEKIs presents with a dis- observed in dacomitinib-treated patients given oral doxycy-
tinguishable rash characterized by papules and pustules on cline [12]. Prophylaxis with topical dapsone gel also seems
the face, chest, upper back, and scalp. A higher incidence to be a promising treatment [13]. Prescription of antibiot-
of rash was shown on trametinib than chemotherapy (57% ics upon initiation of EGFRIs or MEKIs should be recom-
vs. 10%) [7]. mended in cancer patients as well as the bacterial culture
The pathophysiology of EGFRI- and MEKI-induced being performed when secondary infection is suspected to
rash remains poorly understood. Experimental and immu- determine the strain involved.
nohistological findings showed that epidermal keratinocytes Finally, two phase III studies suggested that, contrary to
were able to produce chemokines CCL2, CCL5, CCL27, what might be expected, combination therapies such as those
and CXCL14 in response to EGFRIs and that inhibition of with a MEKI and a BRAF inhibitor (BRAFI) [14, 15] may
Skin, Oral Mucosal, Hair, and Nail Toxicities of Targeted Therapies and Immunotherapies S33

improve patient survival without necessarily increasing the spread, and upregulated cyclin D1 expression indicative of
incidence of MEKI-induced dAEs. increased cell proliferation than control nevi [24].

2.2 BRAF Inhibitor‑Induced Toxicities

2.2.3 Hand–Foot Syndrome (Hyperkeratotic Lesions)
2.2.1 Squamous Cell Carcinomas
Benign hyperkeratotic, thick, occasionally painful lesions
Approved for the treatment of advanced metastatic mela- can be observed on the palms and soles of patients treated
noma [16], BRAFIs can reversibly bind to the mutant with dabrafenib, potentially impacting their QoL and ability
BRAFV600E to inhibit the downstream extracellular signal- to walk [25]. The incidence rate of about 30% with vemu-
regulated kinase (ERK) signaling. However, in wild-type rafenib or dabrafenib is decreased to 6–10% upon addition
cells or cells with UV-induced mutant RAS, binding of of a MEKI [25, 26]. Preventive and supportive care entails
BRAFIs results in heterodimerization of BRAF kinases, the use of keratolytic agents (salicylic acid, urea) or topic
which activates the downstream signaling and thus induces lidocaine for grade ≥ 2 toxicity and, in some cases, man-
opposite effects [17, 18]. As a consequence of this paradoxi- ual paring performed by a podiatrist. Other hyperkeratotic
cal activation, approximately 20% of patients treated with lesions, including verrucal keratoses, keratosis–pilaris rash
BRAFI monotherapy will develop secondary skin tumors or contact hyperkeratosis, may also occur with BRAFI when
and other hyperproliferative lesions, such as squamous cell used as monotherapy.
carcinoma (SCC) and keratoacanthomas (KA) [14, 16, 18].
Metastatic spread has not been reported from those second-
ary cancers and there is usually no need for dose modifi- 2.2.4 Maculopapular ‘Hypersensitivity‑Like’ Rash
cation or treatment interruption [19]. The vast majority of
newly appearing proliferative lesions are benign [20], except A very severe grade 3 maculopapular or morbilliform hyper-
those harboring RAS mutations, especially HRAS, which sensitivity-like rash has been documented in patients with
have a malignant phenotype [21]. Patients with a family his- advanced melanoma treated with vemurafenib who received
tory of skin cancer treated with vemurafenib or melanoma prior immunotherapy with ipilimumab [27] or nivolumab, as
have a higher risk of developing SCC or KA [20]. Inter- activation of the immune system and inflammation persist
estingly, concomitant treatment with MEKIs decreases the even after treatment completion [28]. This rash is likely to
incidence of skin toxicities compared with a BRAFI alone be a non-allergic, non-specific inflammatory reaction, as no
by blocking the MAP kinase pathway downstream [14, 15]. drug-specific T cells were found in patients with this dAE
[29]. Therefore, when the switch to another BRAFI at the
2.2.2 Changes in Melanocytic Lesions first warning signs of hypersensitivity reaction is impos-
sible, an alternative option may be to discontinue therapy
Modifications in pre-existing pigmented lesions, with changes and prescribe oral corticosteroids until resolution. Further
in color and number of globules, have also been reported early reinstatement of the treatment will not always trigger the
after vemurafenib treatment initiation in about 50% of melano- same reaction.
cytic lesions, but their incidence is lower than that of SCC under
vemurafenib [22, 23]. Although alarming at first, biopsies per- 2.3 Immune Checkpoint Inhibitor‑Induced Skin
formed on lesions found suspicious after evaluation by dermos- Toxicities
copy revealed that the incidence of subsequent primary mela-
noma after vemurafenib treatment (about 1.2% of the modified Immune checkpoints have a critical role in maintaining nor-
melanocytic lesions) was what we would expect in any patient mal immunologic homeostasis by downregulating T cell
following a first primary melanoma not treated with a BRAFI. activation. Therapeutic blockade of cytotoxic T lymphocyte-
Therefore, the occurrence of secondary vemurafenib-associ- associated antigen 4 (CTLA-4)/programmed death-1 (PD-
ated melanoma should not cause a great deal of concern, but 1) receptors or PD-ligand 1 (PD-L1) leads to constitutive
requires close clinical monitoring [22]. Interestingly, the addi- CD4 +/CD8 + T cell activation, shifting the immune system
tion of a MEKI to vemurafenib treatment resulted in marked toward antitumor activity [30]. Because of this unique mech-
depigmentation and complete regression of suspicious lesions anism of action, ICIs have a specific safety profile referred
after 3 months of combined therapy [23] and, typically, most to as immune-related adverse events (irAEs) which affect
of these BRAF-induced hyperproliferative melanocytic lesions virtually all organs in the body [31].
are non-malignant. Such pigmented lesions are more frequent in Cutaneous toxicities are the most frequent irAEs, affecting
the extremities and in patients with a history of melanoma, but 40% of patients [32]; they occur within the first 4–8 weeks
also had a higher degree of atypia, hyperpigmentation, pagetoid and can be long-lasting. A non-specific maculopapular rash
S34 M. Lacouture, V. Sibaud

is most commonly reported (Fig. 2), with a frequency rang- develop; these warrant prompt recognition, discontinuation
ing from 14 to 40% depending on the drug and whether it is of treatment, and aggressive management [40]. Vitiligo is
used in combination or alone [33]. Subsets of patients also also commonly described in patients treated for melanoma
present eczema-like or psoriatic lesions [34] while others [41, 42]. Patients are usually not bothered by the disease as
develop lichenoid dermatitis [35, 36] in response to PD-1 its impact on their social life is minor. Interestingly, how-
and PD-L1 inhibitors. Lichenoid rash in patients treated with ever, patients who develop cutaneous reactions in response
ICIs is very similar to idiopathic lichen planus, except for a to pembrolizumab [43, 44] or rash or vitiligo when treated
slightly increased abundance of CD163-positive cells indi- with nivolumab [45] have an overall increased survival and
cating a macrophage–monocyte lineage [36]. better outcomes than those who do not, suggesting a better
Other bothersome irAEs include xerosis and pruritus response to immunotherapy. ICI-treated patients must there-
with secondary excoriations, which may be associated with fore receive proper counselling as part of a supportive care
a rash. Although all-grade pruritus is frequent (10–30% of regimen to help them cope with dermatological toxicities
patients) [33, 37], it remains underreported and underdi- and ensure that QoL is maintained.
agnosed. As this irAE has a profound negative impact on
patients’ QoL, it is currently the focus of intense investi-
gation. Treatment includes high-potency corticosteroids or
γ-aminobutyric acid (GABA) agonists along with antihista- 3 Oral Mucosal Toxicities
mines for grade ≥ 2 toxicities.
Other clinical presentations of irAEs include autoimmune 3.1 Oral Mucosal Toxicities of Targeted Therapies
bullous disorders such as BP180/230-positive bullous pem-
phigoid (BP) [38] in < 1% of patients, as well as worsening 3.1.1 Mammalian Target of Rapamycin (mTOR)
or de novo appearance of autoimmune dermatosis such as Inhibitor‑Associated Stomatitis
psoriasis [39]. Rarely, life-threatening conditions such as
grade 4 Stevens-Johnson syndrome (SJS)-like eruptions may Oral mucositis is the most frequent dose-limiting toxicity
observed with mammalian target of rapamycin (mTOR) inhibi-
tors (everolimus, temsirolimus, and sirolimus). It is character-
ized by aphthous-like lesions which are very different from
the ones induced by chemo- and radiotherapy. These single or
multiple well-circumscribed, round, superficial, painful ulcers
are solely localized in the non-keratinized mucosa and occa-
sionally surrounded by an erythematous halo. mTOR inhibitor-
associated stomatitis occurs in about 30% of patients treated
with monotherapy, mostly within the first 8 weeks of treatment;
5% are grade ≥ 3 toxicities [46]. In addition, although usually
self-limited, lesions can be very painful [47].
Early patient education is critical to prevent repeated
trauma and avoid aggressive treatment modalities to the oral
mucosa [47, 48]. Close follow-up by an odontologist is also
essential. Early management consists of the promotion of
good oral hygiene, including mouth washing with normal
saline, sterile water, or sodium bicarbonate. A wide range
of treatments can also be used, including low-level laser
therapy, also known as soft laser therapy, pain management,
and morphine mouthwash, but the first line of therapy should
include topical corticosteroids [47, 48]. The SWISH trial
demonstrated the efficacy of topical corticosteroids in post-
menopausal women treated with everolimus and exemestane
who prophylactically used dexamethasone-based mouthwash
starting on the first day of treatment [49]. After 8 weeks,
the incidence of grade ≥ 2 stomatitis was only 2% compared
with 33% in the historical BOLERO-2 (Breast Cancer Trials
Fig. 2  Clinical presentation of grade 2/3 non-specific maculopapu-
lar rash on the trunk of a patient treated with a programmed death– of Oral Everolimus-2) study (p < 0.0001), with no grade 3
ligand 1 (PD-L1) inhibitor toxicity.
Skin, Oral Mucosal, Hair, and Nail Toxicities of Targeted Therapies and Immunotherapies S35

3.1.2 Multikinase Angiogenesis and HER

Inhibitor‑Associated Stomatitis

About 25% and 15% of patients treated with multikinase

angiogenesis inhibitors (sorafenib, sunitinib, cabozantinib,
pazopanib, etc.) and EGFRIs (erlotinib, gefitinib) develop
stomatitis, respectively. However, the all-grade incidence
appears to be significantly higher with the newly developed
pan-HER inhibitors (dacomitinib, afatinib) [47].
Similar well-demarcated ulcerations on non-kerati-
nized mucosa may also occur, which are roughly similar
to aphthous-like lesions induced by mTOR inhibitors [47].
However, they are most often limited and of low grade, and
patients generally report non-specific stomatitis with diffuse
mucosal hypersensitivity/dysesthesia and dysgeusia, some- Fig. 3  Oral lichenoid reaction induced by immune checkpoint inhibi-
tor anti-programmed death-1 (PD-1) nivolumab
times associated with erythema or painful burning mouth
(mucosa inflammation). Rapid development after treatment
initiation and gradual disappearance is noted. ICIs targeting PD-1/PD-L1, with reticulated white streaks
and papular, plaque-like, ulcerative, or atrophic/erythematous
lesions (Fig. 3). Patients usually remain asymptomatic [35,
3.1.3 Other Oral Toxicities with Targeted Therapies 55]. These lesions are reversible and can be treated with topical
corticosteroids while maintaining immunotherapy at the same
Geographic tongue has been described in association with dose [55]. Histological analysis shows patchy and/or florid
bevacizumab or multikinase angiogenesis inhibitors [50]. lichenoid interface dermatitis in the upper lamina propria and
Although geographic tongue does not require any treatment, predominantly CD4/CD8-positive band-like T cell infiltrate.
it is essential to reassure the patient, and clinicians should Xerostomia, the second most common oral toxicity
avoid prescribing ineffective antifungal agents. induced by ICIs (6% of patients) is occasionally associated
As described in Sect. 2.2.3, reactional hyperkeratotic with dysgeusia and occasionally can be very severe [47].
lesions are also observed in both keratinized and non-kerati- The occurrence of Sjögren’s syndrome has been seldom
nized areas, as well as occasional SCC occurring in patients reported. Xerostomia may represent the most burdensome
treated with BRAFIs as monotherapy [51]. Vemurafenib or adverse effect induced by immunotherapy and patients with
dabrafenib in monotherapy results in oral mucosal hyperker- xerostomia need to be managed properly. Xerostomia has
atosis within the first weeks of treatment, which noticeably also been described with chemotherapy and radiotherapy,
regresses upon addition of MEKIs (cobimetinib, trametinib), as well as targeted therapies with human epidermal growth
as shown for skin toxicities [52]. factor receptor (HER) TKIs, multi-targeted angiogenesis
Oral lichenoid reactions are frequently observed in inhibitors (4–12%), mTOR inhibitors (6%), and new selec-
patients treated with the first-generation BCR-ABL tyrosine tive fibroblast growth factor receptor (FGFR) inhibitors [47].
kinase inhibitor (TKI) imatinib and are characterized by a
combination of reticular striae with symptomatic ulcerative,
erosive, or atrophic lesions [53]. Often underestimated, these 4 Hair Toxicities
lesions can be isolated or associated with nail or skin reac-
tions and regular follow-up is recommended. Of note, these Hair toxicities caused by systemic therapies are rapidly
lesions have not been described with the new-generation growing in importance as patients survive longer and QoL
BCR-ABL TKIs nilotinib, dasatinib, and bosutinib. Finally, is becoming a key component of cancer treatment.
blue–gray–black asymptomatic hyperpigmentation of the
hard palate has sometimes been reported in response to 4.1 Targeted Therapy and Immune Checkpoint
imatinib, similar to that induced by antimalarial agents [54]. Inhibitor‑Induced Alopecia

3.1.4 Oral Mucosal Toxicities of Immune Checkpoint Alopecia is commonly reported in patients treated with
Inhibitors BRAFIs (23.7% and 18.9% of patients treated with
vemurafenib and dabrafenib, respectively) and MEKIs
Besides skin reactions, ICIs may also induce oral mucosal (trametinib, 13.3%), with a decreased incidence with com-
injuries. Oral lichenoid reactions are typically described with bined BRAFI/MEKI therapy (vemurafenib/cobimetinib, 13%
S36 M. Lacouture, V. Sibaud

and dabrafenib/trametinib, 6%) [56, 57]. Management of this chemotherapy-induced lesions (Fig. 4a, b) that are mostly
type of alopecia may involve use of minoxidil. Furthermore, observed in the nail plate or the nail matrix. As some patients
evidence shows that PD-L1 is expressed on the hair follicle may receive both treatment types combined, clinicians must
dermal sheath cup cells [58]. Therefore, an estimated 1–2% be fully informed of differences between chemotherapy and
of patients treated with ICIs develop either alopecia areata targeted therapy-associated nail toxicities. Paronychia and
(spot baldness) or alopecia universalis with CD4 and scant periungual granulomas are mostly reported in response to
CD8-positive T cells [59]. EGFRIs, with a 17.2% all-grade toxicity incidence [63], as
well as MEKIs and mTOR inhibitors to a lesser extent [64].
4.2 Endocrine Therapy and Alopecia Typical lesions, which mostly affect toenails or thumbs,
develop slowly after several weeks or months of treatment.
While more than half of women with breast cancer report Damage typically starts with the development of periungual
alopecia as the most traumatic adverse event during treat- inflammatory paronychia and can evolve into overgrowing
ment, hormone therapy-induced alopecia (HTIA) is still of friable granulation tissue on lateral and/or proximal nail
largely underreported, with only 6% of studies of tamox- folds, mimicking ingrown nails. Although usually not severe,
ifen reporting it [60]. In a meta-analysis of 35 studies such lesions can still be very debilitating for the patient,
(n = 13,415 patients) the incidence of all-grade HTIA especially when they persist for a long time. Therefore,
ranged from 0% with anti-androgen therapies to 25% with aggressive strategies must be implemented to help patients
selective estrogen receptor modulators (SERMs), corre- cope with these adverse effects. The standard of care for
sponding to an overall incidence of 4.4% [60]. In a ret- pyogenic granuloma is surgery with partial removal of the
rospective study of the data for 112 patients treated with nail plate and matrix and physical destruction of the granula-
SERMs/aromatase inhibitors, HTIA was most often (92%) tion tissue and phenolization [65]. In patients with multiple
characterized by an androgenic alopecia pattern and low concomitant lesions, conservative treatment should be prior-
severity grade [61]. Tamoxifen-induced alopecia is char- itized, with supportive oncodermatology while maintaining
acterized by a reduction in the number of hair follicles targeted therapy. In close collaboration with a podiatrist,
[62]. Microscopically, hair looks more brittle and breaks nail curvature can be corrected if needed. Stretchable tape,
more easily due to estrogen production inhibition. Topical liquid nitrogen, a combination of topical corticosteroids and
minoxidil may provide moderate to significant improve- antibiotics, antiseptic soaks, and silver nitrate can also be
ment in most patients (80%) [61]. used [66]. Topical timolol can also be helpful for periungual
pyogenic granuloma [67].
Patients treated with MEKIs, EGFRIs, and mTOR
5 Nail Toxicities inhibitors can also develop mild to moderate changes
of the nail bed and matrix. These lesions are character-
5.1 Nail Toxicities of Targeted Therapies ized by mild onycholysis, brittle nails, and a slower nail
growth rate [68].
Targeted therapies may cause damage to nail folds, with par- Selective pan-FGFR 1–4 inhibitors are a new class of
onychia and periungual pyogenic granuloma distinct from targeted therapy drugs currently under development for

Fig. 4  a Painful onycholysis with docetaxel. b Diffuse paronychia secondary to anti-epidermal growth factor receptor therapy
Skin, Oral Mucosal, Hair, and Nail Toxicities of Targeted Therapies and Immunotherapies S37

a large range of solid tumors. More than 35% of patients presenting at the Entretiens d’Avène Americas conference. MEL is
receiving these drugs experience very severe nail tox- funded in part through the NIH/NCI Cancer Center Support Grant
P30 CA008748.
icities 1–2 months after starting the treatment, with
onycholysis, onychomadesis, and nail bed superinfection
Conflict of interest Vincent Sibaud declares he received fees from Lab-
occurring [69]. These dose-dependent adverse events oratoires dermatologiques Avène, Roche, Novartis, Bayer, Pierre Fabre
are similar to taxane-related nail changes. Ibrutinib is a and BMS. Mario Lacouture declares he has received consulting/advi-
first-in-class, oral covalent inhibitor of Bruton’s tyrosine sory fees from Merck Sharp & Dohme Corporation, Galderma, Jans-
kinase that is now approved in chronic lymphocytic leu- sen Research & Development, LLC, Abbvie, Inc., Helsinn Healthcare
SA, Novocure Inc., Boehringer Ingelheim Pharma GMBH & Co.KG,
kemia and cell mantle lymphoma. Nail changes including F. Hoffmann-La Roche AG, Allergan Inc., Amgen Inc., E.R. Squibb
brittle nails (23–67% of patients), onychoschizia, onych- & Sons, L.L.C., Novartis Pharmaceuticals Corporation, EMD Serono,
orrhexis, and onycholysis have been described. These nail Inc., Astrazeneca Pharmaceuticals LP, Genentech, Inc, Leo Pharma
changes become apparent after several months of treat- Inc, Seattle Genetics, Debiopharm, Lindi, Bayer, Manner SAS, Menlo
Ther, Celldex, Lutris, Pierre Fabre, Legacy Healthcare, Roche, Amryt
ment (median 6–9 months) and are commonly associated Pharma, Johnson & Johnson, Paxman Coolers, Adjucare, Dignitana,
with hair changes [70]. Biotechspert, Parexel, Adgero, Veloce, Berg, US Biotest and research
funding from Veloce, Berg, US Biotest, BMS.

Disclosure statement This article is published as part of a journal sup-

5.2 Preventive Strategies for Targeted plement wholly funded by Laboratoires dermatologiques Avène.
Therapy‑Induced Nail Toxicities
Open Access This article is distributed under the terms of the Crea-
To prevent nail adverse effects of targeted therapies, it is tive Commons Attribution-NonCommercial 4.0 International License
recommended that patients be counselled and properly (http://creativecommons.org/licenses/by-nc/4.0/), which permits any
educated with clear and detailed information, and offered noncommercial use, distribution, and reproduction in any medium,
appropriate preventive strategies (avoid repeated trauma provided you give appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons license, and indicate
or friction and pressure on nails and nail beds; use pro- if changes were made.
tective gloves; avoid prolonged contact with water; do
not use nail polish removers and hardeners; trim nails
regularly; apply topical emollients daily and US Food and References
Drug Administration [FDA]-approved nail lacquers; wear
comfortable, wide-fitting footwear and cotton socks) upon 1. Rosen AC, Case EC, Dusza SW, Balagula Y, Gordon J, West DP,
initiation of the treatment, particularly for patients treated et al. Impact of dermatologic adverse events on quality of life in
283 cancer patients: a questionnaire study in a dermatology refer-
with EGFRIs [64]. Clinicians should be proactive and ral clinic. Am J Clin Dermatol. 2013;14(4):327–33.
aggressive when addressing very severe toxicities such 2. Hassel JC, Kripp M, Al-Batran S, Hofheinz RD. Treatment of
as painful onycholysis or pyogenic granuloma. epidermal growth factor receptor antagonist-induced skin rash:
results of a survey among German oncologists. Onkologie.
2010;33(3):94–8.
3. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR
6 Conclusion inhibitors. Nat Rev Cancer. 2006;6(10):803–12.
4. Drucker AM, Wu S, Dang CT, Lacouture ME. Risk of rash with
Dermatologic toxicities involving the skin, mucosa, hair, the anti-HER2 dimerization antibody pertuzumab: a meta-analy-
sis. Breast Cancer Res Treat. 2012;135(2):347–54.
and nails are very common and varied in patients treated 5. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V,
with targeted therapies and ICIs. These toxicities profoundly Thongprasert S, et al. Erlotinib in previously treated non-small-
diminish patients’ QoL, which impacts their adherence to cell lung cancer. N Engl J Med. 2005;353(2):123–32.
the treatment, jeopardizing its success and thus patients’ 6. Rosen AC, Wu S, Damse A, Sherman E, Lacouture ME. Risk of
rash in cancer patients treated with vandetanib: systematic review
progression-free survival. Closer collaboration between and meta-analysis. J Clin Endocrinol Metab. 2012;97(4):1125–33.
dermatologists and oncologists is therefore essential. 7. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M,
et al. Improved survival with MEK inhibition in BRAF-mutated
Acknowledgements The authors thank Marianne Pons, PhD and Mari- melanoma. N Engl J Med. 2012;367(2):107–14.
elle Romet, PhD (Synergy Pharm) who provided medical writing assis- 8. Lichtenberger BM, Gerber PA, Holcmann M, Buhren BA,
tance funded by Laboratoires dermatologiques Avène. Amberg N, Smolle V, et al. Epidermal EGFR controls cutane-
ous host defense and prevents inflammation. Sci Transl Med.
2013;5(199):199ra11.
Compliance with Ethical Standards 9. Nardone B, Nicholson K, Newman M, Guitart J, Gerami P, Talar-
ico N, et al. Histopathologic and immunohistochemical charac-
Funding Medical writing assistance was funded by Laboratoires der- terization of rash to human epidermal growth factor receptor 1
matologiques Avène. Mario Lacouture and Vincent Sibaud received (HER1) and HER1/2 inhibitors in cancer patients. Clin Cancer
funds from Laboratoires dermatologiques Avène for traveling to and Res. 2010;16(17):4452–60.
S38 M. Lacouture, V. Sibaud

10. Lacouture ME, Mitchell EP, Piperdi B, Pillai MV, Shearer H, Ian- 26. Ascierto PA, McArthur GA, Dreno B, Atkinson V, Liszkay
notti N, et al. Skin toxicity evaluation protocol with panitumumab G, Di Giacomo AM, et al. Cobimetinib combined with vemu-
(STEPP), a phase II, open-label, randomized trial evaluating the rafenib in advanced BRAF(V600)-mutant melanoma (coBRIM):
impact of a pre-Emptive Skin treatment regimen on skin toxicities updated efficacy results from a randomised, double-blind, phase
and quality of life in patients with metastatic colorectal cancer. J 3 trial. Lancet Oncol. 2016;17(9):1248–60.
Clin Oncol. 2010;28(8):1351–7. 27. Harding JJ, Pulitzer M, Chapman PB. Vemurafenib sen-
11. Eilers RE Jr, Gandhi M, Patel JD, Mulcahy MF, Agulnik M, Hens- sitivity skin reaction after ipilimumab. N Engl J Med.
ing T, et al. Dermatologic infections in cancer patients treated 2012;366(9):866–8.
with epidermal growth factor receptor inhibitor therapy. J Natl 28. Imafuku K, Yoshino K, Ymaguchi K, Tsuboi S, Ohara K,
Cancer Inst. 2010;102(1):47–53. Hata H. Nivolumab therapy before vemurafenib administra-
12. Lacouture ME, Keefe DM, Sonis S, Jatoi A, Gernhardt D, Wang T, tion induces a severe skin rash. J Eur Acad Dermatol Venereol.
et al. A phase II study (ARCHER 1042) to evaluate prophylactic 2017;31(3):e169–71.
treatment of dacomitinib-induced dermatologic and gastrointes- 29. Klossowski N, Kislat A, Homey B, Gerber PA, Meller S. Suc-
tinal adverse events in advanced non-small-cell lung cancer. Ann cessful drug desensitization after vemurafenib-induced rash [in
Oncol. 2016;27(9):1712–8. German]. Hautarzt. 2015;66(4):221–3.
13. Belum VR, Marchetti MA, Dusza SW, Cercek A, Kemeny NE, 30. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade:
Lacouture ME. A prospective, randomized, double-blinded, split- new immunotherapeutic modalities with durable clinical benefit
face/chest study of prophylactic topical dapsone 5% gel versus in melanoma patients. Clin Cancer Res. 2013;19(19):5300–9.
moisturizer for the prevention of cetuximab-induced acneiform 31. Champiat S, Lambotte O, Barreau E, Belkhir R, Berdelou A,
rash. J Am Acad Dermatol. 2017;77(3):577–9. Carbonnel F, et al. Management of immune checkpoint block-
14. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, ade dysimmune toxicities: a collaborative position paper. Ann
Sosman J, et al. Combined BRAF and MEK inhibition in Oncol. 2016;27(4):559–74.
melanoma with BRAF V600 mutations. N Engl J Med. 32. Sibaud V, Meyer N, Lamant L, Vigarios E, Mazieres J, Delord
2012;367(18):1694–703. JP. Dermatologic complications of anti-PD-1/PD-L1 immune
15. Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M, checkpoint antibodies. Curr Opin Oncol. 2016;28(4):254–63.
et al. Combined vemurafenib and cobimetinib in BRAF-mutated 33. Belum VR, Benhuri B, Postow MA, Hellmann MD, Lesokhin
melanoma. N Engl J Med. 2014;371(20):1867–76. AM, Segal NH, et al. Characterisation and management of der-
16. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto matologic adverse events to agents targeting the PD-1 receptor.
P, Larkin J, et al. Improved survival with vemurafenib in Eur J Cancer. 2016;60:12–25.
melanoma with BRAF V600E mutation. N Engl J Med. 34. Kaunitz GJ, Loss M, Rizvi H, Ravi S, Cuda JD, Bleich KB, et al.
2011;364(26):2507–16. Cutaneous eruptions in patients receiving immune checkpoint
17. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson blockade: clinicopathologic analysis of the nonlichenoid histo-
DJ, Alvarado R, et al. RAF inhibitors prime wild-type RAF logic pattern. Am J Surg Pathol. 2017;41(10):1381–9.
to activate the MAPK pathway and enhance growth. Nature. 35. Shi VJ, Rodic N, Gettinger S, Leventhal JS, Neckman JP,
2010;464(7287):431–5. Girardi M, et al. Clinical and histologic features of lichenoid
18. Lacouture ME, O’Reilly K, Rosen N, Solit DB. Induction of cuta- mucocutaneous eruptions due to anti-programmed cell death
neous squamous cell carcinomas by RAF inhibitors: cause for 1 and anti-programmed cell death ligand 1 immunotherapy.
concern? J Clin Oncol. 2012;30(3):329–30. JAMA Dermatol. 2016;152(10):1128–36.
19. Lacouture ME, Duvic M, Hauschild A, Prieto VG, Robert C, Scha- 36. Schaberg KB, Novoa RA, Wakelee HA, Kim J, Cheung C, Srini-
dendorf D, et al. Analysis of dermatologic events in vemurafenib- vas S, et al. Immunohistochemical analysis of lichenoid reac-
treated patients with melanoma. Oncologist. 2013;18(3):314–22. tions in patients treated with anti-PD-L1 and anti-PD-1 therapy.
20. Belum VR, Rosen AC, Jaimes N, Dranitsaris G, Pulitzer MP, J Cutan Pathol. 2016;43(4):339–46.
Busam KJ, et al. Clinico-morphological features of BRAF inhibi- 37. Ensslin CJ, Rosen AC, Wu S, Lacouture ME. Pruritus in patients
tion-induced proliferative skin lesions in cancer patients. Cancer. treated with targeted cancer therapies: systematic review and
2015;121(1):60–8. meta-analysis. J Am Acad Dermatol. 2013;69(5):708–20.
21. Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, et al. 38. Naidoo J, Schindler K, Querfeld C, Busam K, Cunningham
RAS mutations in cutaneous squamous-cell carcinomas in patients J, Page DB, et al. Autoimmune Bullous Skin Disorders with
treated with BRAF inhibitors. N Engl J Med. 2012;366(3):207–15. Immune Checkpoint Inhibitors Targeting PD-1 and PD-L1. Can-
22. Perier-Muzet M, Thomas L, Poulalhon N, Debarbieux S, Brin- cer Immunol Res. 2016;4(5):383–9.
guier PP, Duru G, et al. Melanoma patients under vemurafenib: 39. Bonigen J, Raynaud-Donzel C, Hureaux J, Kramkimel N, Blom
prospective follow-up of melanocytic lesions by digital dermos- A, Jeudy G, et al. Anti-PD1-induced psoriasis: a study of 21
copy. J Invest Dermatol. 2014;134(5):1351–8. patients. J Eur Acad Dermatol Venereol. 2017;31(5):e254–7.
23. Perier-Muzet M, Boespflug A, Poulalhon N, Caramel J, Breton 40. Villadolid J, Amin A. Immune checkpoint inhibitors in clinical
AL, Thomas L, et al. Dermoscopic evaluation of melanocytic practice: update on management of immune-related toxicities.
nevi changes with combined mitogen-activated protein kinase Transl Lung Cancer Res. 2015;4(5):560–75.
pathway inhibitors therapy for melanoma. JAMA Dermatol. 41. Hua C, Boussemart L, Mateus C, Routier E, Boutros C, Caze-
2016;152(10):1162–4. nave H, et al. Association of vitiligo with tumor response in
24. Mudaliar K, Tetzlaff MT, Duvic M, Ciurea A, Hymes S, Milton patients with metastatic melanoma treated with pembrolizumab.
DR, et al. BRAF inhibitor therapy-associated melanocytic lesions JAMA Dermatol. 2016;152(1):45–51.
lack the BRAF V600E mutation and show increased levels of 42. Dai J, Belum VR, Wu S, Sibaud V, Lacouture ME. Pigmentary
cyclin D1 expression. Hum Pathol. 2016;50:79–89. changes in patients treated with targeted anticancer agents: a
25. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud systematic review and meta-analysis. J Am Acad Dermatol.
F, Larkin J, et al. Dabrafenib and trametinib versus dabrafenib 2017;77(5):902–10.e2.
and placebo for Val600 BRAF-mutant melanoma: a multicen- 43. Lo JA, Fisher DE, Flaherty KT. Prognostic significance of cuta-
tre, double-blind, phase 3 randomised controlled trial. Lancet. neous adverse events associated with pembrolizumab therapy.
2015;386(9992):444–51. JAMA Oncol. 2015;1(9):1340–1.
Skin, Oral Mucosal, Hair, and Nail Toxicities of Targeted Therapies and Immunotherapies S39

44. Sanlorenzo M, Vujic I, Daud A, Algazi A, Gubens M, Luna 58. Wang X, Marr AK, Breitkopf T, Leung G, Hao J, Wang E, et al.
SA, et al. Pembrolizumab cutaneous adverse events and Hair follicle mesenchyme-associated PD-L1 regulates T-cell
their association with disease progression. JAMA Dermatol. activation induced apoptosis: a potential mechanism of immune
2015;151(11):1206–12. privilege. J Invest Dermatol. 2014;134(3):736–45.
45. Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, 59. Zarbo A, Belum VR, Sibaud V, Oudard S, Postow MA, Hsieh JJ,
Weber JS. Nivolumab in resected and unresectable metastatic et al. Immune-related alopecia (areata and universalis) in cancer
melanoma: characteristics of immune-related adverse events and patients receiving immune checkpoint inhibitors. Br J Dermatol.
association with outcomes. Clin Cancer Res. 2016;22(4):886–94. 2017;176(6):1649–52.
46. Rugo HS, Hortobagyi GN, Yao J, Pavel M, Ravaud A, Franz D, 60. Saggar V, Wu S, Dickler MN, Lacouture ME. Alopecia with
et al. Meta-analysis of stomatitis in clinical studies of everoli- endocrine therapies in patients with cancer. Oncologist.
mus: incidence and relationship with efficacy. Ann Oncol. 2013;18(10):1126–34.
2016;27(3):519–25. 61. Freites-Martinez A, Shapiro J, Chan D, Fornier M, Modi S, Gajria
47. Vigarios E, Epstein JB, Sibaud V. Oral mucosal changes induced D, et al. Endocrine therapy-induced alopecia in patients with
by anticancer targeted therapies and immune checkpoint inhibi- breast cancer. JAMA Dermatol. 2018;154(6):670–5.
tors. Support Care Cancer. 2017;25(5):1713–39. 62. Lindner J, Hillmann K, Blume-Peytavi U, Lademann J, Lux A,
48. Peterson DE, Boers-Doets CB, Bensadoun RJ, Herrstedt J. Man- Stroux A, et al. Hair shaft abnormalities after chemotherapy and
agement of oral and gastrointestinal mucosal injury: ESMO clini- tamoxifen therapy in patients with breast cancer evaluated by opti-
cal practice guidelines for diagnosis, treatment, and follow-up. cal coherence tomography. Br J Dermatol. 2012;167(6):1272–8.
Ann Oncol. 2015;26(Suppl 5):v139–51. 63. Garden BC, Wu S, Lacouture ME. The risk of nail changes
49. Rugo HS, Seneviratne L, Beck JT, Glaspy JA, Peguero JA, Pluard with epidermal growth factor receptor inhibitors: a systematic
TJ, et al. Prevention of everolimus-related stomatitis in women review of the literature and meta-analysis. J Am Acad Dermatol.
with hormone receptor-positive, HER2-negative metastatic breast 2012;67(3):400–8.
cancer using dexamethasone mouthwash (SWISH): a single-arm, 64. Robert C, Sibaud V, Mateus C, Verschoore M, Charles C, Lanoy
phase 2 trial. Lancet Oncol. 2017;18(5):654–62. E, et al. Nail toxicities induced by systemic anticancer treatments.
50. Hubiche T, Valenza B, Chevreau C, Fricain JC, Del Giudice P, Lancet Oncol. 2015;16(4):e181–9.
Sibaud V. Geographic tongue induced by angiogenesis inhibitors. 65. Piraccini BM, Bellavista S, Misciali C, Tosti A, de Berker D,
Oncologist. 2013;18(4):e16–7. Richert B. Periungual and subungual pyogenic granuloma. Br J
51. Vigarios E, Lamant L, Delord JP, Fricain JC, Chevreau C, Barres Dermatol. 2010;163(5):941–53.
B, et al. Oral squamous cell carcinoma and hyperkeratotic lesions 66. Kiyohara Y, Yamazaki N, Kishi A. Erlotinib-related skin toxici-
with BRAF inhibitors. Br J Dermatol. 2015;172(6):1680–2. ties: treatment strategies in patients with metastatic non-small cell
52. Carlos G, Anforth R, Clements A, Menzies AM, Carlino MS, lung cancer. J Am Acad Dermatol. 2013;69(3):463–72.
Chou S, et al. Cutaneous toxic effects of BRAF inhibitors alone 67. Cubiro X, Planas-Ciudad S, Garcia-Muret MP, Puig L. Topical
and in combination with MEK inhibitors for metastatic melanoma. timolol for paronychia and pseudopyogenic granuloma in patients
JAMA Dermatol. 2015;151(10):1103–9. treated with epidermal growth factor receptor inhibitors and
53. Sibaud V, Boralevi F, Vigarios E, Fricain JC. Oral toxicity of capecitabine. JAMA Dermatol. 2018;154(1):99–100.
targeted anticancer therapies [in French]. Ann Dermatol Venereol. 68. Osio A, Mateus C, Soria JC, Massard C, Malka D, Boige V,
2014;141(5):354–63. et al. Cutaneous side-effects in patients on long-term treatment
54. Fricain JC, Sibaud V. Pigmentations of the oral cavity [in French]. with epidermal growth factor receptor inhibitors. Br J Dermatol.
Presse Med. 2017;46(3):303–19. 2009;161(3):515–21.
55. Sibaud V, Eid C, Belum VR, Combemale P, Barres B, Lamant L, 69. Betrian S, Gomez-Roca C, Vigarios E, Delord JP, Sibaud
et al. Oral lichenoid reactions associated with anti-PD-1/PD-L1 V. Severe onycholysis and eyelash trichomegaly following
therapies: clinicopathological findings. J Eur Acad Dermatol use of new selective pan-FGFR inhibitors. JAMA Dermatol.
Venereol. 2017;31(10):e464–9. 2017;153(7):723–5.
56. Belum VR, Marulanda K, Ensslin C, Gorcey L, Parikh T, Wu 70. Bitar C, Farooqui MZ, Valdez J, Saba NS, Soto S, Bray A,
S, et al. Alopecia in patients treated with molecularly targeted et al. Hair and nail changes during long-term therapy with
anticancer therapies. Ann Oncol. 2015;26(12):2496–502. ibrutinib for chronic lymphocytic leukemia. JAMA Dermatol.
57. Piraccini BM, Patrizi A, Fanti PA, Starace M, Bruni F, Melotti B, 2016;152(6):698–701.
et al. RASopathic alopecia: hair changes associated with vemu-
rafenib therapy. J Am Acad Dermatol. 2015;72(4):738–41.