10.5826/dpc.1301a64
Introduction Nail toxicity represents one of the most common cutaneous adverse effects of both classic chemotherapeutic agents and new oncologic drugs, including targeted treatments and immunotherapy. 
Objectives We aimed to provide a comprehensive literature review of nail toxicities derived from conventional chemotherapeutic agents, targeted therapies (EGFR inhibitors, multikinase inhibitors, BRAF and MEK inhibitors) and immune checkpoint inhibitors (ICIs), including clinical presentation, implicated drugs and approaches for prevention and management.
Methods Retrieved literature from PubMed registry database was reviewed to include all articles published up to May 2021 relevant to the clinical presentation, diagnosis, incidence, prevention, and treatment of oncologic treatment-induced nail toxicity. The was searched for relevant studies. 
Results A wide spectrum of nail toxicities is associated with both, conventional and newer anticancer agents. The frequency of nail involvement, especially with immunotherapy and new targeted agents remains unknown and patients with different cancer types receiving different regimens may develop the same nail disorder, whereas patients with the same type of cancer under the same chemotherapeutic treatment may develop different types of nail alterations. The underlying mechanisms of the varying individual susceptibility and the diverse nail responses to various anticancer treatments need further investigation.
Conclusion Early recognition and treatment of nail toxicities can minimize their impact, allowing better adherence to conventional and newer oncologic treatments. Dermatologists, oncologists and other implicated physicians should be aware of these burdensome adverse effects in order to guide management and prevent impairment of patients’ quality of life.
text/xml
2160-9381
2653
en
Myrto Trakatelli
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
immune checkpoint inhibitors
Narrative Review of Drug-Associated Nail Toxicities in Oncologic Patients
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2023-01-31
2022-06-13
2023-01-31
2023-02-27
e2023064
Dermatol Pract Concept
Introduction Nail toxicity represents one of the most common cutaneous adverse effects of both classic chemotherapeutic agents and new oncologic drugs, including targeted treatments and immunotherapy. 
Objectives We aimed to provide a comprehensive literature review of nail toxicities derived from conventional chemotherapeutic agents, targeted therapies (EGFR inhibitors, multikinase inhibitors, BRAF and MEK inhibitors) and immune checkpoint inhibitors (ICIs), including clinical presentation, implicated drugs and approaches for prevention and management.
Methods Retrieved literature from PubMed registry database was reviewed to include all articles published up to May 2021 relevant to the clinical presentation, diagnosis, incidence, prevention, and treatment of oncologic treatment-induced nail toxicity. The was searched for relevant studies. 
Results A wide spectrum of nail toxicities is associated with both, conventional and newer anticancer agents. The frequency of nail involvement, especially with immunotherapy and new targeted agents remains unknown and patients with different cancer types receiving different regimens may develop the same nail disorder, whereas patients with the same type of cancer under the same chemotherapeutic treatment may develop different types of nail alterations. The underlying mechanisms of the varying individual susceptibility and the diverse nail responses to various anticancer treatments need further investigation.
Conclusion Early recognition and treatment of nail toxicities can minimize their impact, allowing better adherence to conventional and newer oncologic treatments. Dermatologists, oncologists and other implicated physicians should be aware of these burdensome adverse effects in order to guide management and prevent impairment of patients’ quality of life.
Myrto Trakatelli
2023/01/31
10.5826/dpc.1301a64
e2023064
Second Department of Dermatology, Aristotle University of Thessaloniki, “Papageorgiou” General Hospital, Thessaloniki, Greece
2160-9381
immune checkpoint inhibitors
en
e2023064
Wollina U, Abdel-Naser MB. Drug reactions affecting hair and nails. Clin Dermatol [Internet]. 2020;38(6):693–701. Available from: https://doi.org/10.1016/j.clindermatol.2020.06.009
Narrative Review of Drug-Associated Nail Toxicities in Oncologic Patients
https://dpcj.org/index.php/dpc/article/download/2653/1963
Narrative Review of Drug-Associated Nail Toxicities
               in Oncologic Patients
           Anastasia Emvalomati1, Valentina Oflidou1, Chryssoula Papageorgiou1,
 Christina Kemanetzi1, Maria Giannouli1, Evangelia Kalloniati1, Konstantinos Efthymiadis2,
   Chrysanthi Koukoutzeli2, Eleni Timotheadou2, Anastasia Trigoni1, Aikaterini Patsatsi1,
                    Elizabeth Lazaridou1, Zoe Apalla1, MyrtoTrakatelli1


1 Second Department of Dermatology, Aristotle University of Thessaloniki, “Papageorgiou” General Hospital, Thessaloniki, Greece
2 Department of Medical Oncology, Aristotle University of Thessaloniki, “Papageorgiou” General Hospital, Thessaloniki, Greece



Key words: nail toxicity, nail changes, chemotherapy, targeted treatment, immune checkpoint inhibitors
Citation: Emvalomati A, Oflidou V, Papageorgiou C, et al. Narrative Review of Drug-Associated Nail Toxicities in Oncologic Patients.
Dermatol Pract Concept. 2023;13(1):e2023064. DOI: https://doi.org/10.5826/dpc.1301a64
Accepted: August 23, 2022; Published: January 2023
Copyright: ©2023 Emvalomati et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing Interests: None.
Authorship: Z. Apalla and M. Trakatelli equally contributed as senior authors.
Corresponding Author: Myrto Trakatelli, PhD, Second Dermatology Department, Aristotle University, 76 Agiou Pavlou, Pavlos Melas,
564 29, Thessaloniki, Greece. Tel. +302313323873, Fax: +302310991473 E-mail: mtrakatelli@hotmail.com




  ABSTRACT             Introduction: Nail toxicity represents one of the most common cutaneous adverse effects of both classic
                       chemotherapeutic agents and new oncologic drugs, including targeted treatments and immunotherapy.
                       Objectives: We aimed to provide a comprehensive literature review of nail toxicities derived from
                       conventional chemotherapeutic agents, targeted therapies (EGFR inhibitors, multikinase inhibitors,
                       BRAF and MEK inhibitors) and immune checkpoint inhibitors (ICIs), including clinical presentation,
                       implicated drugs and approaches for prevention and management.
                       Methods: Retrieved literature from PubMed registry database was reviewed to include all articles
                       published up to May 2021 relevant to the clinical presentation, diagnosis, incidence, prevention, and
                       treatment of oncologic treatment-induced nail toxicity. The internet was searched for relevant studies.
                       Results: A wide spectrum of nail toxicities is associated with both, conventional and newer anticancer
                       agents. The frequency of nail involvement, especially with immunotherapy and new targeted agents re-
                       mains unknown and patients with different cancer types receiving different regimens may develop the
                       same nail disorder, whereas patients with the same type of cancer under the same chemotherapeutic treat-
                       ment may develop different types of nail alterations. The underlying mechanisms of the varying individu-
                       al susceptibility and the diverse nail responses to various anticancer treatments need further investigation.
                       Conclusion: Early recognition and treatment of nail toxicities can minimize their impact, allowing
                       better adherence to conventional and newer oncologic treatments. Dermatologists, oncologists and
                       other implicated physicians should be aware of these burdensome adverse effects in order to guide
                       management and prevent impairment of patients’ quality of life.



Review | Dermatol Pract Concept. 2023;13(1):e2023064                                                                                   1
Introduction                                                        Discussion
Nail toxicity represents one of the most common cutaneous           Conventional Chemotherapeutic Drugs (Figure 1)
adverse effects of both classic chemotherapeutic agents and         Cancer therapy has always been a challenging area in clin-
new oncologic drugs, including targeted treatments and im-          ical medicine and research. Traditionally, chemotherapeutic
munotherapy [1]. While drug-associated nail toxicity is al-         drugs work by disrupting specific phases of the cell cycle in
most never life-threatening, it significantly impairs patients’     actively dividing cancer cells (Table 2). Conventional chemo-
quality of life, often restricting their daily life and self-care   therapeutic drugs continue to be an important part of cancer
activities.                                                         management but may cause various cutaneous and append-
    Dermatologists, oncologists and other implicated physi-         ageal reactions including nail toxicity. Nail involvement in
cians should be aware of these burdensome adverse effects           cancer therapy is reported in fragmented literature from all
in order to guide management and prevent impairment of              over the world. Although it is mostly of cosmetic concern, at
patients’ quality of life. Early recognition and treatment can      times it may require alteration or modification of the ther-
minimize the impact of these toxicities, allowing better ad-        apy, especially if very painful or functionally debilitating
herence to conventional and newer oncologic treatments.             nail toxic effects are present. Pain and associated discomfort
The aim of this article is to provide a comprehensive liter-        impair patients’ quality of life, commonly resulting in the
ature review of nail toxicities derived from conventional           inability to perform daily activities [2].
chemotherapeutic agents, targeted therapies (EGFR inhibi-              The nail apparatus is characterized by the presence of con-
tors, multikinase inhibitors, BRAF and MEK inhibitors) and          tinuously dividing nail matrix cells, thus making it an easy
immune checkpoint inhibitors (ICIs), including clinical pre-        target of the antimitotic activity of chemotherapeutics [3].
sentation, implicated drugs and approaches for prevention           Nail changes in the context of chemotherapy involve multiple
and management.                                                     or even all 20 nails and usually appear in a temporal rela-
                                                                    tion with the drug intake, due to an acute insult of the nail
Materials and Methods                                               matrix epithelium. Effects mostly subside upon withdrawal of
                                                                    the responsible chemotherapeutic agent, but occasionally may
Search Strategy and Study Selection                                 persist. Because of the specific kinetics of nail formation and
The retrieved literature was reviewed to include all articles       growth, it is important to note that the occurrence of these nail
relevant to the clinical presentation, diagnosis, incidence,        toxic effects is often delayed relative to treatment initiation.
prevention, and treatment of oncologic treatment-induced               Clinical presentation varies, depending on the nail struc-
nail toxicity. The PubMed registry database was searched for        ture affected and the severity of the insult [4]. In terms of to-
relevant studies published up to May 2021. The literature ev-       pography, when the nail bed is affected, onycholysis, apparent
idence predominantly comprises case reports, case series and        leukonychia and splinter haemorrhages may be observed.
systematic reviews. The following Medical Subject Headings          Toxicity targeting the nail matrix may result in the appearance
search terms were used: nails, nail changes, nail toxicity; che-    of Beau’s lines, onychomadesis, true leukonychia, slower nail
motherapy, chemotherapeutic drugs/agents, antineoplastic            growth, nail thinning, brittle nails and melanonychia. Finally,
agents. The “related articles” function in PubMed was used          adverse effects involving the perionychium may result in par-
to broaden the search, and all retrieved abstracts, studies and     onychia and pyogenic granuloma [5, 6]. A combination of the
citations were reviewed. In addition, we identified other rel-      aforementioned nail changes is frequent. The most common
evant studies by searching the reference lists of the relevant      nail changes reported in the literature include leukonychia,
articles and by contacting known experts in the field. No           Beau’s lines, brittle thin nails, and nail hyperpigmentation,
language restrictions were applied.                                 which may be diffuse or horizontal [7- 10]. Taxanes and an-
                                                                    thracyclines are the antineoplastic regimens mostly associated
Data Extraction                                                     with nail changes. However, considering that a majority of the
Two reviewers independently assessed all relevant stud-             reported patients were on multiple chemotherapeutic agents,
ies and specifically extracted data regarding study design,         pinpointing the offensive drug was not always feasible. There-
study population characteristics, inclusion and exclusion           fore, a combination of agents was implicated in most cases.
criteria, nail toxicity parameters, class of chemotherapeu-
tic drugs and their mechanism of action. The individually           Alkylating Agents
recorded decisions of both reviewers were compared and              Classical Alkylating: Cyclophosphamide
any disagreements were resolved by the other reviewers.             Classical alkylating agents attach an alkyl group to the
Study authors were contacted for additional information             guanine base of DNA and are used to treat leukaemia, lym-
when necessary.                                                     phoma, Hodgkin disease, multiple myeloma, sarcoma, and



2                                                                               Review | Dermatol Pract Concept. 2023;13(1):e2023064
Figure 1. Nail toxicities due to conventional chemotherapeutic drugs. A. Muehrcke’s lines due to treatment with cisplatin: Transversal white
lines with healthy nail bed between them. B. Dermosopic examination of the same patient with clear visualization of the leukonychia in the
form of Muehrcke’s lines. C. Red-brown discoloration of the nails associated with painful subungual hematomas and onycholysis following
treatment with taxol. D. Dermoscopic image of the chemotherapy-induced central subungual hematoma that differs from traumatic subungal
hematoma: note the bright red color with an orange/brown halo (in trauma: dark violet with globular pattern accompanied by transversal
whitish line). E. Longitudinal melanonychia following cyclophosphamide treatment. F. Dermoscopy image of the cyclophosphamide-induced
melanonychia with a homogenous brown band with absence of Hutchinson or micro-Hutcinson’s sign. Borders appear blurry but this may
happen in the great toenail due to thickness of the nail plate. This is a false positive sign that should be interpreted together with the clinical
history of the patient.



                Table 1. Proposed management algorithm for taxane-related onycholysis [38].
Grade 0*                    • Preventive nail care instructions given
                            • Frozen gloves should be considered
Grade 1*               • Continue drug at current dose and monitor for change in severity
Asymptomatic           • Obtain bacterial/fungal cultures if infection is suspected; apply topical antibiotics or fungal agent
separation of the nail • Reassess after 2/3 weeks. If reaction worsens proceed to next step
bed from the nail
plate or nail loss
Grade 2*                    •   Continue drug at current dose and monitor for change in severity
Symptomatic                 •   Obtain bacterial/fungal cultures if infection is suspected
separation of the nail      •   If infection, begin oral antibiotics with anti –Staphylococcus aureus and gram-positive coverage
bed from the nail           •   If painful hematoma or subungual abscess is suspected, partial or total nail avulsion is required
plate or nail loss;         •   Pain control
Limiting instrumental       •   Reassess after 2 weeks; if reactions worsen or do not improve interrupt treatment until severity
activities of daily             decreases to Grade 0-1
living
Grade 3*                    Interrupt treatment until severity decreases to Grade 0-1, obtain bacterial/fungal cultures if
Severe pain and/or          infection is suspected and continue treatment of nail reaction with the following:
superinfection;             • If infection, begin oral antibiotics with anti –Staphylococcus aureus and gram-positive coverage
Limiting self-care          • If painful hematoma or subungual abscess is suspected, partial or total nail avulsion is required
activities of daily         • Pain control
living                      • Reassess after 2 weeks; if reactions worsen or do not improve, consider dose interruption or
                              discontinuation per protocol and switch to another antineoplastic agent

*From nail loss clinical grading, Common Terminology Criteria for Adverse Events (CTCAE), V4.02



Review | Dermatol Pract Concept. 2023;13(1):e2023064                                                                                             3
    Table 2. Conventional chemotherapeutic drugs, mechanism of action and associated nail toxicity.
                         Chemotherapeutic
       Drug Class            Drugs              Mechanism Of Action                       Nail Disorders
Alkylating agents       Cyclophosphamide    Crosslink with DNA molecules Diffuse hyperpigmentation
Classical alkylating    Cisplatin           and damage cells in all phases Longitudinal melanonychia
Platinum agents         Carboplatin         of the cell cycle              Beau’s lines
                        Oxaliplatin                                        Onychomadesis
                                                                           Mees’ lines
                                                                           Muehrcke’s lines
                                                                           Onycholysis
                                                                           Beau’s lines
                                                                           Hyperpigmentation
                                                                           Muehrcke’s lines
                                                                           Diffuse hyperpigmentation
                                                                           Muehrcke’s lines
Antimetabolites         Pemetrexed          Substitute building blocks of       Melanonychia
Analogs                 5-Fluorouracil      DNA and RNA and damage              Onycholysis
Fluorouracil            Capecitabine        cells in the S phase                Beau’s lines
                        Tegafur                                                 Muehrcke’s lines
                                                                                Paronychia
                                                                                Subungual hyperkeratosis
                                                                                Hyperpigmentation
                                                                                Half and half nails
                                                                                Onycholysis
                                                                                Onychomadesis
                                                                                Onycholysis
                                                                                Hyperpigmentation
                                                                                Longitudinal melanonychia
Antitumor antibiotics   Doxorubicin         Intercalate with DNA base           Diffuse hyperpigmentation
Anthracyclines          Daunorubicin        pairs and interfere with            Beau’s lines
Bleomycin               Epirubicin          topoisomerase II in all cell        Mees’ lines
                                            cycle phases                        Muehrcke’s lines
                                            Induce DNA strand breaks at         Diffuse hyperpigmentation
                                            G2 phase                            Mees’ lines
                                                                                Beau’s lines
                                                                                Diffuse hyperpigmentation
                                                                                Longitudinal melanonychia
                                                                                Beau’s lines
Mitotic inhibitors      Docetaxel           Prevent the formation of            Diffuse hyperpigmentation
Taxanes                 Paclitaxel          spindles or microtubules            Beau’s lines
Vinca alkaloids         Vincristine         during the M phase                  Onychomadesis
                                                                                Mees’ lines
                                                                                Paronychia
                                                                                Subungual hyperkeratosis
                                                                                Pyogenic granuloma
                                                                                Subungual & splinter hemorrhage
                                                                                Onycholysis/Exudative Onycholysis
                                                                                Brittle nails
                                                                                Onychorrhexis
                                                                                Koilonychia
                                                                                Diffusehyperpigmentation
                                                                                Longitudinal melanonychia
                                                                                Beau’s lines
                                                                                Onychomadesis
                                                                                Mees’ lines
                                                                                Muehrcke’s lines
Topoisomerase           Etoposide           Interfere with topoisomerase I      Paronychia
inhibitors                                  or II during DNA replication
Topoisomerase II                            in all cells in the S or G2 phase


4                                                                   Review | Dermatol Pract Concept. 2023;13(1):e2023064
cancers of the lung, breast and ovary [11]. All can be ad-        and are used to treat various hematologic malignancies and
ministered intravenously, though cyclophosphamide can be          solid tumors. Their main adverse effect is cardiotoxicity,
also taken orally [12]. Cyclophosphamide may cause diffuse        which is limited in the liposomal pegylated or encapsulated
hyperpigmentation, longitudinal melanonychia, Beau’s lines,       form of anthracyclines used for non-Hodgkin lymphoma,
onychomadesis, Mees’ lines, Muehrcke’s lines and onycholy-        multiple myeloma, NSCLC, AIDS-related Kaposi sarcoma,
sis (Table 2).                                                    and refractory ovarian cancer. Both drugs are administered
                                                                  intravenously [12]. Doxorubicin may cause diffuse hyper-
Platinum Agents: Cisplatin, Carboplatin,
                                                                  pigmentation, Beau’s lines, Mees’ lines or Muehrcke’s lines.
and Oxaliplatin
                                                                  Daunorubicin may also cause diffuse hyperpigmentation or
Platinum agents form reactive platinum complexes that
                                                                  Mees’ lines (Table 2).
crosslink with DNA molecules, inhibiting DNA synthesis
and repair, and are given intravenously. Cisplatin is an older    Bleomycin
drug that causes many side effects (eg, ototoxicity, neurotox-
                                                                  Bleomycin is a glycopeptide produced by the bacterium
icity, nephrotoxicity, and emetogenicity) and is used to treat
                                                                  Streptomyces verticillus and is used for the treatment of
a wide variety of solid tumors. Cisplatin may cause Beau’s
                                                                  squamous cell carcinoma, lymphoma, testicular carcinoma,
lines, hyperpigmentation or Muehrcke’s lines. Carboplatin
                                                                  and malignant pleural effusion. It can be administered intra-
and oxaliplatin are newer-generation platinum agents with
                                                                  venously, intramuscularly, intraperitoneally, intrapleurally,
less toxicity [13]. These chemotherapeutic agents may cause
                                                                  or given as an intralesional injection in recalcitrant warts,
diffuse hyperpigmentation or Muehrcke’s lines (Table 2).
                                                                  keloids, and scars [17]. Toxicity to bleomycin occurs in the

Antimetabolites                                                   lungs and skin because these organs lack bleomycin hydro-

Analogs: Pemetrexed                                               lase, an inactivating enzyme [18]. Pulmonary fibrosis is a
                                                                  serious complication of high doses (>400 units), while cuta-
Pemetrexed is an intravenously administered folate analogue
                                                                  neous reactions usually occur between 200 to 300 units [17].
that interferes with enzymes required for pyrimidine and pu-
                                                                     Bleomycin may cause nail dystrophy, and horizontal or
rine synthesis, and is used for the treatment of mesothelioma,
                                                                  vertical nail pigmentation [17] (Table 2).
non-small cell lung carcinoma (NSCLC), and breast, head, and
neck carcinoma. Uncommon reported nail reactions to peme-
                                                                  Mitotic/Spindle Inhibitors
trexed include melanonychia and onycholysis [14] (Table 2).
                                                                  Taxanes: Paclitaxel and Docetaxel
Fluorouracil: 5-Fluorouracil,                                     Taxanes are among the most commonly prescribed antican-
Capecitabine and Tegafur                                          cer drugs and were initially derived from yew trees. Pacli-
5-Fluorouracil (5-FU) is a pyrimidine analog that inhibits the    taxel is a natural extract derived from the bark of the pacific
enzyme thymidylate synthase, thereby interrupting thymi-          yew tree (Taxus brevifolia) that became commercially avail-
dine synthesis required for DNA replication, and can cause        able in 1992. On the other hand, docetaxel is a semisyn-
myelosuppression, diarrhea, mucositis, and dermatitis [12].       thetic analogue of paclitaxel synthesized from the needles
   Capecitabine and Tegafur are orally administered pro-          of the European yew tree (Taxus baccata). Both drugs act
drugs especially used for colon and gastrointestinal neo-         as antimicrotubule agents by promoting the polymerisation
plasms. They are designed to be well absorbed from the            of tubulin into highly stable intracellular microtubules, thus
gastrointestinal tract and converted to 5-FU in the liver or      disrupting mitosis and normal cell division, and eventually
within the tumor at lower concentrations than 5-FU intrave-       leading to cell death [19- 21]. Because of their highly hydro-
nous dosages, thereby minimizing toxicity [15].                   phobic properties, they require the use of solvents (non-ionic
   In the nails, 5-FU may cause diffuse melanonychia, trans-      polyoxyethylated castor oil -Cremophor EL®- for pacli-
verse bands, or half and half-like nails (Lindsay nails), while   taxel; non-ionic surfactant polysorbate 80 for docetaxel) to
there have also been reports of onycholysis, paronychia, and      facilitate parenteral administration. The drugs are approved
thickening of the nail with its use [16]. Capecitabine and        for a number of indications in the US and Europe. Paclitaxel
tegafur also cause longitudinal melanonychia [16]; however,       was the first taxane discovered, is generally administered by
onycholysis and onychomadesis have only been seen with            weekly infusion (80 mg/m2) and is currently approved by
capecitabine [12] (Table 2).                                      the US Food and Drug Administration for the treatment of
                                                                  breast cancer, NSCLC, AIDS-related Kaposi sarcoma, and
Antitumor antibiotics                                             ovarian cancer.
Anthracyclines: Doxorubicin and Daunorubicin                         Docetaxel, developed later, is infused (100 mg/m2) every
The anthracyclines doxorubicin and daunorubicin are de-           three weeks and is used for the management of advanced
rived from the bacterium Streptomyces peucetius var. caesius      breast, gastric, NSCLCs, hormone-refractory prostate



Review | Dermatol Pract Concept. 2023;13(1):e2023064                                                                           5
cancer, and advanced head and neck squamous cancer [22].           II inhibitors frequently induce rearrangements of the mixed
Docetaxel appears to have recently become most specifically        lineage leukemia gene and can cause a secondary leukemia
associated with nail toxicity, occurring in up to 30 – 40% of      side effect [36]. Etoposide has been approved by the US Food
patients [6, 23].                                                  and Drug Administration to be used in combination with
    Nail changes with taxanes are very common with some            other medications to treat small cell lung cancer and testicu-
series reporting rates as high as 89% after three treatment        lar cancer. It is a derivative of podophyllotoxin. It is typically
cycles [24- 29]. These chemotherapeutic agents may cause           taken orally, but can also be administered intravenously,
diffuse hyperpigmentation, Beau’s lines, onychomadesis,            though care must be used to prevent extravasation because
Mees’ lines, paronychia, subungual hyperkeratosis, pyogenic        it is an irritant and can cause tissue damage. Nail toxic side
granuloma, subungual & splinter hemorrhage, onycholysis/           effect caused by etoposide is paronychia [12] (Table 2).
exudative onycholysis, brittle nails, onychorrhexis or koilon-
ychia (Table 2).                                                   Targeted Biologic Drugs (Figure 2)
    Nab-paclitaxel is a novel, solvent-free, albumin-bound,        Targeted cancer therapies are drugs that selectively block
colloidal suspension (with a size of 130 nm) of paclitaxel         specific parts of cancer cells, such as proteins or genes, that
that has led to a significant improvement in progression-free      help cancers grow and spread. Targeted biologic therapies
survival, median overall survival, and overall response rates      are well-known causing factors of cutaneous adverse effects,
in patients with metastatic breast and pancreatic cancers          including changes in the nail apparatus [37, 38].
[21, 30]. It has received FDA and EMA approvals for the               Cutaneous and nail reactions may be attributed to the
treatment of certain forms of both cancers [30]. It is also        mode of action of these regimens that target specific mol-
approved in the US for metastatic non-small cell lung can-         ecules that are also expressed in the skin and appendageal
cer and is still under evaluation for several other indications,   epithelium.
such as metastatic urothelial tumors [31, 32]. Nab-pacli-
taxel was developed to circumvent the highly hydrophobic           EGFR-Inhibitors
properties of taxanes and to improve intratumoral paclitaxel       Epidermal growth factor receptor inhibitors (gefitinib, erlo-
penetration [30, 33]. Since it is devoid of Cremophor EL®          tinib, cetuximab, panitumumab) block the signal transduc-
(the solvent for paclitaxel), several significant adverse events   tion pathway, needed for cell proliferation, migration and
such as hypersensitivity reactions are less likely to develop      angiogenesis of tumor cells [37- 40].
[30]. Nail toxicity has only been sporadically reported with          Gefitinib and erlotinib are orally administered EGFR
nab-paclitaxel, especially onycholysis, and is easily manage-      tyrosine kinase inhibitors, whilst cetuximab and panitu-
able [34]. The overall incidence of all-grade nail toxic effects   mumab are humanized monoclonal antibodies that are
with nab-paclitaxel is significantly lower in comparison with      given intravenously. These regimens are used for colorectal
paclitaxel or docetaxel (19.4%) (95% CI: 11.8-30.3%) [35].         cancer, breast cancer, non-small cell lung cancer (NSCLC),
                                                                   pancreatic cancer, and head and neck squamous cell carci-
Vinca Alkaloids: Vincristine                                       noma (SCC) [38- 40]. A common nail reaction in the context
Vinca alkaloids were historically extracted from the leaves        of EGFR inhibition is paronychia, representing the second
of the Madagascar periwinkle (Catharanthus roseus). Vin-           most frequent skin toxicity induced by EGFR after papulo-
cristine has been approved for intravenous use in the United       pustular eruption [41]. It involves the nails and the digits,
States and is often used in combination chemotherapy regi-         with the first digit being the site most commonly affected.
mens because of its lack of myelosuppression. Vincristine is       Other ungual adverse reactions include discoloration, pit-
commonly used to treat acute lymphocytic leukemia, multi-          ting, nail thinning/fragility (inhibition of nail matrix kera-
ple myeloma, chronic lymphocytic leukemia, lymphoblastic           tinocytes), periungual pyogenic granuloma (an overgrowth
crisis of chronic myelogenous anemia, sarcomas, and small          of granulation tissue and a formation of painful, bleeding
cell lung cancer with distant metastases [12]. Vincristine may     nodule), cracked and swollen nail folds and cuticles, par-
cause diffuse hyperpigmentation, longitudinal melanony-            tial or complete loss of nails and ingrowth of nails [37,
chia, Beau’s lines, onychomadesis, Mees’ lines or Muehrcke’s       38] (Table 3). The aforementioned alterations may appear
lines (Table 2).                                                   1 to 2 months after treatment initiation and affect about
                                                                   15% of patients [38]. Secondary infection is not unusual
Topoisomerase Inhibitors                                           and in this scenario, a culture swab is recommended. In pa-
Topoisomerase II: Etoposide                                        tients treated with Cetuximab that developed paronychia,
Etoposide is an inhibitor of the enzyme topoisomerase II,          Staphylococcus aureus was found in 23%, while 31% had
which relieves the helical strain during DNA replication by        coagulase-negative, Gram (+) bacteria (nosocomial coloni-
cutting both strands of DNA simultaneously. Topoisomerase          zation) [37, 38]. Prevention of superinfection was achieved



6                                                                              Review | Dermatol Pract Concept. 2023;13(1):e2023064
Figure 2. Nail toxicities due to targeted biologic drugs. A. Paronychia due to treatment with EGFR tyrosine kinase inhibitor (panitumumab)
for colorectal cancer: proximal nail fold is painful, erythematous and swollen with presence of oozing and crusting, B. Same patient as a.:
close-up to a pyogenic granuloma that frequently accompanies paronychia due to EGFR inhibitors. C and D. Clinical and dermoscopy image
of brittle nails during EGFR inhibitor therapy for lung cancer. The nail plate is fragile and the surface of the nail presents longitudinal fine
fissures while the distal edge of the plate appears to crumble and is not sharply delineated. In dermoscopy presence of splinter hemorrhages
can also be detected. E and F. Acute photo-onycholysis in a melanoma patient treated with BRAF inhibitors: clinical and dermoscopic image.
The nails were extremely painful with almost total detachment of the nail plate and presence of oozing and subungual hematoma.




with antibacterial soaks (chlorhexidine or vinegar in water)              Bruton’s Tyrosine Kinase (BTK) Inhibitors
[38]. Warm compresses, silver nitrate, topical corticosteroids            Bruton’s tyrosine kinase inhibitor, ibrutinib, is a small
and systemic tetracyclines are recommended in order to re-                molecule that binds to a protein, important in B-cells. It is
duce periungual inflammation, depending on the grade of                   used for the treatment of chronic lymphocytic leukemia,
the toxicity.                                                             Waldenström’s macroglobulinemia, refractory and relapsed
                                                                          mantle-cell lymphoma. Brittle nails are the most common
Angiogenesis-Inducing Inhibitors
                                                                          nail change, seen in about 2/3 of treated patients, followed
Sorafenib and sunitinib are multikinase inhibitors that spe-
                                                                          by onychoschizia, onychorrhexis and mild onycholysis [38]
cifically target tumor cell angiogenesis and proliferation
                                                                          (Table 3).
via VEGFR (vascular endothelial growth factor), PDGRF
(platelet-derived growth factor receptor) and other kinases               Anti-HER2/Anti-HER
[38]. Sorafenib is indicated in renal cell carcinoma, non-                Anti-human epidermal growth factor receptor 2 (Anti-HER2)
small cell lung cancer, hepatocellular carcinoma, melanoma,               is a class of medicines used to treat all stages of HER2-pos-
pancreatic and colon cancers, whilst sunitinib is prescribed              itive breast cancer, from early-stage to metastatic disease.
for renal cell carcinoma, breast cancer, colon cancer and gas-            Trastuzumab was shown to cause thin nails [37, 38]. lapati-
trointestinal stromal tumor. Both are orally administered.                nib (breast cancer and solid tumors), afatinib (NSCLC) and
Studies report that during the first 2 months of therapy, 70%             dacomitinib (NSCLC), besides thin nails, may induce nail
and 25% of patients taking sorafenib and sunitinib, respec-               reactions such as paronychia, pyogenic granuloma, slower
tively, developed fingernail subungual splinter hemorrhages               growth rate and mild onycholysis [37, 38] (Table 3).
[41] (Table 3). The latter resolved spontaneously without
treatment. This may be linked to the role VEGFR play in                   Anti-MEK
the renewal of capillaries and their sustain despite frequent             Mitogen-activated protein kinase enzymes MEK1 and/
injuries at the distal fingers, which is now inhibited due to             or MEK2, trametinib (metastatic melanoma), cobimetinib
sorafenib and sunitinib intake [38, 41].                                  (melanoma) and selumetinib (Neurofibromatosis type I



Review | Dermatol Pract Concept. 2023;13(1):e2023064                                                                                          7
                  Table 3. Main nail toxicities induced by targeted anticancer therapies [38].
      Drug Class                  Target             Chemotherapeutic Drugs                        Nail Disorders
 Anti-EGFR                EGFR (HER1 or ErbB1)      Cetuximab                        Paronychia
                                                    Panitumumab,                     Pyogenic granuloma Slower growth rate
                                                    Erlotinib                        Mild onycholysis
                                                    Gefitinib                        Thin nails
                                                    Necitumumab                      Brittle nails
 Anti-HER2                HER2                      Trastuzumab                      Thin nails
 Anti-HER                 HER1-4 (ErbB1-4)          Lapatinib                        Paronychia
                                                    Afatinib                         Pyogenic granuloma
                                                    Dacomitinib                      Slower growth rate
                                                                                     Mild onycholysis
                                                                                     Thin nails
                                                                                     Brittle nails
 Anti-MEK                 MEK 1/2                   Trametinib                       Paronychia
                                                    Cobimetinib                      Pyogenic granuloma
                                                    Selumetinib                      Slower growth rate
                                                                                     Mild onycholysis
                                                                                     Brittle nails
 mTOR inhibitors          mTOR                      Everolimus                       Paronychia
                                                    Temsirolimus                     Pyogenic granuloma
                                                                                     Yellow nail discoloration Slower growth
                                                                                     rate-thin nails
                                                                                     Mild onycholysis
                                                                                     Brittle nails
 Angiogenesis             VEGRF 1-3                 Sunitinib                        Splinter subungual hemorrhage
 multikinase inhibitors   PDGFR α/β and other       Sorafenib                        Brittle nails
                          molecular targets         Cabozantinib
                                                    Axitinib
                                                    Pazotinib
                                                    Regorafenib
 RET inhibitor            EGFR                      Vandetanib                       Paronychia
                          VEGFR 2/3                                                  Pyogenic granuloma
                          RET                                                        Photoonycholysis
                                                                                     Splinter subungual hemorrhage
 BCR-ABL inhibitor        BCR-ABL                   Imatinib                         Melanonychia
                          c-KIT                                                      Lichenoid reactions
                          PDGFR
 Bruton inhibitors        Bruton tyrosine kinase    Ibrutinib                        Brittle nails
                                                                                     Onychoschizia
                                                                                     Onychorrhexis
                                                                                     Mild onycholysis




treatment) have been associated with paronychia, pyogenic        complex, certain types of seizures in adults and children and
granuloma, slower growth rate, mild onycholysis and brittle      prevention of transplant rejection), as well as temsirolimus
nails [38, 41].                                                  (indicated in renal cell carcinoma), may cause yellow nail dis-
                                                                 coloration, paronychia, pyogenic granuloma, slower growth
M-TOR Inhibitors                                                 rate-thin nails, mild onycholysis and brittle nails [38] (Table 3).
The mammalian target of rapamycin regulates cellular
­metabolism, growth and proliferation by forming and signal-     RET Inhibitor
ling through two protein complexes, mTORC1 and mTORC2            RET inhibitors are targeted therapies used on tumors charac-
[38]. Everolimus (indicated in advanced renal cell carcinoma,    terized by activated alterations in the RET proto-oncogene.
advanced breast cancer, pancreas, stomach, intestines, lungs,    These include non-small cell lung cancer (NSCLC), medul-
subependymal giant cell astrocytoma, tuberous sclerosis          lary thyroid cancer and papillary thyroid cancer.



8                                                                            Review | Dermatol Pract Concept. 2023;13(1):e2023064
    Vandetanib is an oral multikinase inhibitor which targets              very rare but may provoke a destruction of the matrix and a
the RET, proto-oncogene, EGF and VEGF receptors. The                       subsequent scar formation.
most prevalent nail adverse event associated with Vande-
tanib therapy is subungual hemorrhage (due to VEGFR inhi-                  Immunotherapy (Figure 3)
bition), paronychia/pyogenic granuloma (EGFR inhibition)                   The immune system, as part of its normal function, detects
and a painful type 1 photo-onycholysis [38] (Table 3). Pa-                 and destroys abnormal cells and prevents or suppresses can-
tients should be informed about UVA/UVB photo-protection.                  cer growth. Despite that, cancer cells have ways to evade
                                                                           the immune system. They may present genetic changes that
BCR-ABL Inhibitors                                                         make them less visible to the immune system, have proteins
BCR-ABL is a gene produced by the BCR gene and the C-ABL                   on their surface that turn off immune cells or affect the nor-
proto-oncogene and is considered to be the main cause of                   mal cells surrounding a tumor in a way that they interfere
chronic myelogenous leukemia (CML), acute lymphocytic                      with the immune response to cancer cells.
leukemia (ALL) that are Philadelphia chromosome-positive,                      The most prevalent immune-related dermatologic ad-
certain types of gastrointestinal stromal tumors, hypereosin-              verse events (irAE) are triggered by immune checkpoint in-
ophilic syndrome, chronic eosinophilic leukemia, systemic                  hibitors (CPIs).
mastocytosis and myelodysplastic syndrome [38]. Imatinib                       Immune Checkpoint Inhibitors (CPIs) are targeted
is an oral medication of this group that may induce mela-                  molecules that modulate the immune system, assist with
nonychia and lichenoid reactions (Table 3). Melanonychia                   self-tolerance, and minimize collateral tissue damage when
appears 1-2 months after treatment initiation. It results from             immune responses are activated. These checkpoints are a nor-
the direct toxic action of the regimen on the melanocytes of               mal part of the immune system and keep immune responses
the nail matrix, with secondary melanin production. Mela-                  from being too strong. By blocking them, these drugs allow
nonychia striate, as well as total melanonychia do not require             immune cells to respond more efficiently to cancer. This
any treatment. They regress spontaneously several months                   blockade has been associated with autoimmune-like toxic-
after treatment discontinuation [38]. Lichenoid reactions are              ities, named immune-related adverse events (irAE) [24, 43].




Figure 3. Nail toxicities due to immunotherapy. A. Psoriatic changes in nails following treatment with immune checkpoint inhibitor
(­pembrolizumab): presence of subtle pitting, onycholysis and paronychia with scaling of the skin. B. Same patient as a, dermoscopic image:
Remark the presence of splinter hemorrhages as well as the yellow discoloration of the onycholysis suggestive of psoriatic disease. C, D.
Lichenoid-like reactions in a melanoma patient treated with nivolumab: Onychorhexis visualized both clinically and with dermoscopy. In the
dermoscopic image the presence of dust in the nail fissures gives the characteristic image of “dirty nail” that is a common finding in lichen-like
reactions of the nail plate. E, F: Same patient as c, d different nails, dermoscopic images. Characteristic presence of erythema in the lunula
seen in patients treated with nivolumab.



Review | Dermatol Pract Concept. 2023;13(1):e2023064                                                                                            9
     Immune checkpoints include cytotoxic T-lymphocyte an-             First-line treatment for these nail changes is topical ther-
tigen 4 (CTLA-4), programmed cell death 1 (PD-1) and pro-          apy. If topicals fail and there is also skin involvement, sys-
grammed cell death ligand 1 (PD-L1). The CTLA-4, PD-1,             temic therapy should be considered [43, 45].
and PD-L1 pathways mediate immune responses at different               Pathogenesis of certain nail changes and potentially re-
levels. CTLA-4 controls the amplitude of immunologic re-           sponsible anticancer drugs. Table 4 highlights the diagnostic
sponse at early stages of T-cell activation, whereas PD-1 and      challenges related to drug-induced nail toxicities.
PD-L1 pathways act at later stages, limiting T- cell activity in
the peripheral tissues. By activating cytotoxic CD4+/CD8+          Melanonychia
T cells, immune checkpoint blockade therapy shifts the im-         Melanonychia represents one of the most common adverse
mune system towards anti-tumor activity [42- 44].                  effects of chemotherapeutic agents. Saraswat et al. [4] and
     The etiopathogenetic mechanism seems to be con-               Pavey et al. [1] found nail hyperpigmentation as the most
nected to the T-cell activation, mediated by the blockade of       common nail toxicity of chemotherapeutic drugs. This pig-
PD-1/PD-L1 and CTLA-4 receptors.                                   mentation develops after 1–2 months of treatment and is
     CPIs include anti-PD-1 (nivolumab and pembrolizumab)          proposed to be the outcome of matrix melanocyte activation,
and anti-CTLA-4 (ipilimumab, tremelimumab) agents, as              which usually affects several nail plates. Nail melanocytes
well as the newly developed anti-PD-L1 agents (atezoli-            are quiescent and generally do not produce melanin. Mela-
zumab, durvalumab, avelumab) [42- 44].                             nonychia results from the direct toxic action of chemother-
     ICIs nail alterations have not been systemically investi-     apy on the melanocytes of the nail matrix, with secondary
gated and are considered uncommon. Nail toxicity presents          melanin production analogous to that of post-inflammatory
late in time, with an onset extended up to several months          hyperpigmentation seen in the skin [46- 49].
from ICI initiation [42, 43].                                          The activation of a subgroup of melanocytes produces a
     Persistence of the nail change after ICI discontinuation      single or several longitudinal pigmented bands (melanony-
has been also reported.                                            chia striata) whereas diffuse activation of melanocytes gives
     Diverse nail changes have been reported in relationship       rise to diffuse nail pigmentation (total melanonychia). Trans-
to ICIs, including onycholysis, onychomadesis, longitudinal        verse melanonychia may also be observed [2]. Skin or muco-
fissures, onychorrhexis, layered splitting of the nail plate,      sal pigmentary changes are frequently associated.
lunular erythema, thinning of the nail plate and fragility.            Nail hyperpigmentation is more often reported with che-
Commonly, more than one finger- or toenails are involved.          motherapeutic agents like cyclophosphamide, cisplatin, fluo-
Nail psoriasis is the most common immunotherapy-related            rouracil and its prodrug capecitabine, taxanes, doxorubicin,
toxicity [42, 45].                                                 bleomycin and Imatinib [16, 38, 50- 54] (Table 5).
     Since the majority of nail alterations appear in conjunc-         Chemo-induced hyperpigmentation does not require any
tion with psoriasiform or lichenoid rashes, they are most          treatment and progressively regresses several months after treat-
probably of the same nature. In line with this theory are the      ment discontinuation. For patients who would like to conceal
histopathologic alterations found in two patients exhibiting       this melanonychia, dark-colored nail polish may be proposed.
onycholysis that were consistent with lichenoid reaction.
This develops either as a deterioration of pre-existing nail       Beau’s Lines
psoriasis, or as a de-novo appearance. Histopathologically         Beau’s lines correspond to the formation of transverse lin-
confirmed psoriasis of the nail has been described in associa-     ear depressions in the dorsum of the nail plate and result
tion with nivolumab, clinically characterized by nail thicken-     from a transitory decrease in mitotic activity of the proximal
ing combined with periungual erythema [43, 45].                    nail matrix keratinocytes. The depth of the groove is strictly


                       Table 4. Challenges in the diagnosis of drug-induced nail toxicity.
       Several factors may pose diagnostic difficulties in the scenario of drug-induced nail toxicity [2, 3, 7, 81]
 1. Nail changes may appear several weeks after drug intake, due to the kinetics of nail formation and the slow growth
    rate of the nail plate
 2. Patients are often on multiple potentially causative medications
 3. Symptoms often improve or resolve without drug withdrawal
 4. Rechallenge is commonly uneventful
 5. Non-drug causes may be involved
 6. Abnormalities do not necessarily involve all nails
 7. Poor understanding of the pathogenesis of nail damage.



10                                                                             Review | Dermatol Pract Concept. 2023;13(1):e2023064
 Table 5. Nail changes presented in association with the potentially responsible anticancer regimen.
    Nail Changes            Conventional Chemotherapeutic Drugs                  Targeted Chemotherapeutic Drugs
 Diffuse                Cyclophosphamide, vincristine, cisplatin,           Imatinib
 hyper-pigmentation     carboplatin, oxaliplatin, 5-fluorouracil,
                        capecitabine, doxorubicin, daunorubicin,
                        bleomycin, hydroxyurea, busulfan, docetaxel,
                        paclitaxel, pemetrexed, etoposide
                        combination of cyclophosphamide/adriamycin/
                        vincristine/cyclophosphamide/adriamycin/
                        docetaxel
 Longitudinal           Cyclophosphamide, vincristine, bleomycin,           Imatinib
 melanonychia           tegafur, combination of cyclophosphamide/
                        adriamycin/vincristine
 Beau’s lines           Docetaxel, paclitaxel, cisplatin, doxorubicin,
                        bleomycin, combination of epirubicin/
                        vincristine/cyclophosphamide
                        cyclophosphamide/doxorubicin/fluorouracil
 Onychomadesis          Paclitaxel, docetaxel, capecitabine, combination
                        of cyclophosphamide/vincristine/procarbazine/
                        prednisolone
 Mees’ lines            Cyclophosphamide, doxorubicin, vincristine,
                        docetaxel, paclitaxel, combination of cytarabine/
                        daunorubicin
                        cyclophosphamide/doxorubicin/vincristine/
                        prednisolone (CHOP)
 Muehrcke’s lines       Combination of cyclophosphamide/
                        doxorubicin/5-fluorouracil
                        vincristine/doxorubicin/dexamethasone
                        cisplatin, oxaliplatin
 Half and half nails    5-Fluorouracil
 (Lindsay’s nails)
 Onycholysis            Docetaxel, paclitaxel, cyclophosphamide,            Cetuximab, panitumumab,erlotinib, gefitinib,
                        pemetrexed, 5-fluorouracil, capecitabine            necituumab, lapatinib, afatinib, dacomitinib,
                                                                            trametinib, cobimetinib, selumetinib, everolimus,
                                                                            temsirolimus, ibrutinib, vandetanib
 Paronychia             Fluorouracil, docetaxel, paclitaxel, etoposide      Cetuximab, panitumumab,erlotinib, gefitinib,
                                                                            necituumab, lapatinib, afatinib, dacomitinib,
                                                                            trametinib, cobimetinib, selumetinib, everolimus,
                                                                            temsirolimus, vandetanib
 Subungual              Docetaxel, paclitaxel, fluorouracil
 hyperkeratosis
 Pyogenic               Docetaxel, paclitaxel                               Cetuximab, panitumumab,erlotinib
 granuloma                                                                  gefitinib, necituumab, lapatinib, afatinib,
                                                                            dacomitinib, trametinib, cobimetinib,
                                                                            selumetinib, everolimus, temsirolimus,
                                                                            vandetanib
 Subungual &         Docetaxel, paclitaxel                                  Vandetanib, sunitinib, sorafenib, cabozantinib,
 splinter hemorrhage                                                        axitinib, pazotinib, regorafenib
 Brittle nails          Docetaxel, paclitaxel                               Cetuximab, panitumumab,erlotinib, gefitinib,
                                                                            necituumab, lapatinib, afatinib, dacomitinib,
                                                                            trametinib, cobimetinib, selumetinib, everolimus
                                                                            temsirolimus, ibrutinib, sunitinib, sorafenib,
                                                                            cabozantinib, axitinib, pazotinib, regorafenib
 Onychorrhexis          Docetaxel, paclitaxel                               Ibrutinib
 Koilonychia            Docetaxel, paclitaxel




Review | Dermatol Pract Concept. 2023;13(1):e2023064                                                                          11
correlated to the extent of nail matrix damage. The width is          True Leukonychia (white opaque coloration - total or
proportional to the duration of the insult. Beau’s lines have     transverse: Mees’ lines) results from altered keratinization
been described with nearly all chemotherapeutic agents,           of the distal nail matrix. Parakeratotic nuclei are retained
especially when used in combination or with a high-dose           in the nail plate and thus the nail appears opaque and white
regimen. They are probably the most frequent nail changes         in color owing to the diffraction of light by parakeratotic
noted in patients exposed to chemotherapy [46- 48]. Beau’s        cells. True leukonychia does not disappear with pressure
lines often affect all nails but are more frequent in finger-     and moves distally as the nail grows. Mees’ lines are trans-
nails and appear after a few weeks of chemotherapy [4, 55].       verse white, non-blanching parallel lines to the lunula across
After repeated courses of chemotherapy, several depressions       the entire nail bed and have no palpable ridges [63, 64]. In
can be noted in the same nail. They move distally with nail       chemotherapy-induced true transverse leukonychia, the ses-
growth. The presence of regular transverse Beau’s lines in the    sions of transverse white bands and the distance between
nail plate reflects the temporary cessation of matrix prolif-     them seemed to coincide with the number and duration of
eration during each chemotherapy cycle. Chemotherapeutic          chemotherapy cycles, respectively.
agents such as docetaxel, paclitaxel, a combination of epiru-         Apparent Leukonychia (white transparent coloration)
bicin/vincristine/cyclophosphamide, and cyclophosphamide/         is observed because of changes in the nail bed vasculature
doxorubicin/fluorouracil are associated with Beau’s lines         on pressure, visible through the translucent nail plate. True
[4, 56, 57] (Table 5).                                            and apparent leukonychia may be differentiated clinically
                                                                  by diascopy. The whitish discoloration disappears (or fades)
Onychomadesis                                                     with digital compression and is not modified by nail growth.
Onychomadesis is a spontaneous separation of the nail plate       Apparent leukonychia can present as three different clinical
from the nail bed in its proximal portion. It implies a limited   types: Muehrcke’s lines (the most frequent form in associ-
lesion affecting the proximal part of the matrix. It results      ation with chemotherapy), Half and half nails (Lindsay’s
from temporary cessation of nail growth lasting for more          nails), or Terry’s nails.
than 2 weeks. Initially, a small cleavage appears under the
proximal portion of the nail. This forms a shallow ulcer that     a. Muehrcke’s Lines (the most frequent form in associa-
does not involve the deeper layers. When the injury is healed,        tion with chemotherapy) are present as multiple, paired,
the nail regrows over again distally. In latent onychomadesis,        transverse, whitish bands, parallel to the lunula. Chen
the nail plate demonstrates transverse split because of com-          et al. [6] found Muehrcke’s lines as the most common
plete inhibition of nail growth for 1–2 weeks. Beau’s lines           nail toxicity of chemotherapeutic drugs in children. This
may evolve into the formation of onychomadesis, which                 change is commonly seen after chemotherapy and in
essentially corresponds to the extreme form of Beau’s lines.          chronic hypoalbuminemia of less than 2 mg/dl (seen in
The nail plate is then divided into two parts by a transverse         nephrotic syndrome, glomerulonephritis, liver disease,
thick groove, which remains latent for a long period before           and malnutrition), and is commonly found on the sec-
the nail plate ultimately sheds [58]. Onychomadesis induced           ond, third, and fourth fingernails. Thumbnail involve-
by chemotherapeutic agents is thought to be the result of             ment is rare. The lines tend to resolve with correction of
arrested mitotic activity in the nail matrix resulting in nail        hypoalbuminemia. The exact pathogenesis is unknown,
separation and shedding [59, 60].                                     but the suggested reasons are edema of the nail bed,
     Onychomadesis induced by chemotherapeutic agents                 which occurs due to hypoalbuminemia, and an alteration
was originally described by Kochupillai et al [61]. Since then        of nail plate attachment to the nail bed, which occurs
only five cases have been reported in the literature. In Saras-       due to vascular compromise following chemotherapy [6].
wat et al. the drugs associated with the development of on-       b. Half and Half Nails (Lindsay’s nails) where there is a
ychomadesis were imatinib, paclitaxel, capecitabine, and a            definite border between the proximal area (opaque
combination of cyclophosphamide/vincristine/procarbazine/             white) and the distal area (pink or reddish brown) occu-
prednisolone (Table 5).                                               pying 20%–60% of the nail bed. Distal red-brown pig-
                                                                      mentation does not fade with pressure.
Leukonychia                                                       c. Terry’s Nails, where the whole nail appears white, ex-
Leukonychia is characterized by white discoloration of                cept a 1–2 mm pink-to-brown distal band, and the lunula
a part of the nail plate or the complete nail plate, and              may or may not be visible.
can be divided into true leukonychia and apparent leu-
konychia. Leukonychia induced by chemotherapeutic                     In most cases, leukonychia involves all fingernails and
agents usually occurs in the form of apparent leukonychia         may coexist with melanonychia. It has been described in
[10, 46- 48, 62].                                                 association with numerous chemotherapeutic agents but



12                                                                            Review | Dermatol Pract Concept. 2023;13(1):e2023064
generally develops when chemotherapy is used in combina-             cycles given and the cumulative dose of taxanes [29, 46, 47,
tion. Systematic screening for associated hypoalbuminemia            59]. Although it is more common in patients receiving the
should be performed in this context.                                 once-weekly regimen, it can also be observed with the every
   Mees’ lines are usually observed with the use of docetaxel        3-week regimen [29, 46].
and a combination of cytarabine/daunorubicin and cyclo-                 The onycholytic portion of the nail plate becomes
phosphamide/doxorubicin/vincristine/prednisolone [65- 67]            opaque, loses its translucency, and can take on a white,
(Table 5).                                                           black, or brown-red color, depending on the type of lesion
   Muehrcke’s lines have been reported with cispla-                  [57, 59, 60]. The fingernails are more often involved than
tin, oxaliplatin and a combination of cyclophosphamide/              toenails and the number of digits affected varies, although
doxorubicin/5-fluorouracil      and    vincristine/doxorubicin/      involvement may also be diffuse [29, 59, 69- 72]. Onycholy-
dexamethasone [68] (Table 5).                                        sis is initially asymptomatic; however, pain may occur due
   Nail growth is faster in children and adolescents, and            to acute trauma, progression of the detachment, or devel-
is estimated to be at a rate of 0.12 mm/day [23]. However,           opment of subungual hemorrhagic blisters or abscesses with
chemotherapy-induced nail changes in children, in compari-           purulent malodorous discharge (exudative onycholysis) [22,
son to adult cases, are less well characterized in the literature.   26, 48, 60, 71]. Secondary bacterial or fungal infections may
Reviewing the limited case reports, transverse leukonychia           also develop because of the debris collected in the ventral
seems to be the most frequently described nail change in             part of the detached plate. Cosmetic and functional impacts
children receiving chemotherapy, with doxorubicin/dauno-             depend on the number of nails involved, the severity of the
rubicin, vincristine and cyclophosphamide being the main             detachment, and the extent of pain [29].
causative agents [23, 66].                                              Taxane-related onycholysis is sometimes associated with
                                                                     inflammatory erythema of dorsal hands or the perimalleolar
Onycholysis                                                          and Achille’s areas (PATEO syndrome: periarticular thenar
Onycholysis is defined by the separation of the nail plate           erythema with onycholysis) [22, 24].
from the underlying nail bed [48]. It usually starts from the           The changes may affect both the nail matrix (melanon-
distal portion of the nail bed, progresses proximally, and can       ychia, true leukonychia, Beau’s lines and onychomadesis,
involve the entire nail with the formation of a space. This may      brittle nails with ridging and thinning, onychorrhexis, koil-
result in the formation of painful subungual abscesses and           onychias), the nail bed (onycholysis and apparent leukon-
hemorrhages and finally loss of the nail plate. It is notewor-       ychia) or the periungual tissue (paronychia or pyogenic
thy that the chemotherapeutic agents that most frequently            granuloma), may also be affected at the same time with tax-
induce nail changes are taxanes: docetaxel and paclitaxel,           ane chemotherapy [22, 24, 26, 47].
resulting from a direct toxic effect [22, 25, 26, 46, 59].              The pathophysiological origin of taxane-induced on-
   However, mild to moderate onycholysis may also be                 ycholysis is not clearly established. It may be the result of
noted with other chemotherapeutic agents as well (capecit-           direct cytotoxic damage to the nail matrix and epithelial
abine, etoposide, cytarabine, cyclophosphamide, doxoru-              cells of the nail bed with epidermolysis and the secondary
bicin, or combination therapy) [24, 46, 48]. The targeted            loss of adhesion of the nail plate to the nail bed [24, 47].
chemotherapeutic agents, which may cause onycholysis are             An intrinsic antiangiogenic activity of taxanes has also been
cetuximab, panitumumab, erlotinib, gefitinib, necitumumab,           postulated [22]. Similarly, a phototoxic mechanism for pho-
lapatinib, afatinib, dacomitinib, trametinib, cobimetinib,           to-onycholysis has been advanced by some authors but re-
selumetinib, everolimus, temsirolimus, ibrutinib and vande-          mains to be confirmed [59]. Lastly, unilateral onycholysis has
tanib [38] (Table 5).                                                been reported in patients suffering from contralateral periph-
   Onycholysis is one of the most prevalent adverse events           eral palsy, suggesting a taxane-induced neurotropic effect
induced by docetaxel or paclitaxel [22]. Recently, the over-         (neurogenic or prostaglandin-mediated inflammation) [73].
all incidence of taxane-induced nail toxicity has been sys-             More recently, Schepisi et al. [34] hypothesized that
tematically investigated [35]; all-grade incidence was 43.7%         paclitaxel-related onycholysis may be directly correlated to
with paclitaxel (95% CI: 18.0-73.3%) and 34.9% (95% CI:              the duration of the infusion. Indeed, onycholysis may de-
29.9-40.2%) with docetaxel. For the latter, the relative risk        velop more frequently with a shorter infusion (1 hour) than
was 77.74 (95% CI: 41.88-144.32; p<0.001) as compared                with a prolonged infusion, because of increased systemic ex-
to controls [22].                                                    posure to the Cremophor vehicle (paclitaxel solvent). That
   Nail changes are evident after several weeks of treat-            may explain, at least in part, the higher incidence seen in
ment because of the slow growth rate of the nail plate [29].         patients receiving the weekly paclitaxel regimen (1-hour
The development of nail changes is strongly associated               infusion) in comparison with the every 3-week regimen
with weekly administration, the number of chemotherapy               (3-hour infusion).



Review | Dermatol Pract Concept. 2023;13(1):e2023064                                                                           13
     The impact of taxane-related onycholysis on the quality            Onychorrhexis is a type of longitudinal groove wherein
of life and daily activities varies; effects depend on the number   a series of shallow and narrow furrows are present running
of digits involved, the degree of detachment, and the extent of     parallel on the nail surface. Docetaxel, paclitaxel and ibruti-
pain and if significant it can result in treatment interruption     nib may cause onychorrhexis (Table 5).
[28, 29]. Therefore, management of onycholysis depends on               Onychoschizia is clinically characterized by the splitting
the clinical grading (i.e., National Cancer Institute, Common       of the nail plate at the free edges in the fingers and toes. It
Terminology Criteria for Adverse Events (CTCAE) v4.02)              may be localized or the full length of the free edge may be
and impact on activities of daily living [38] (Table 1). Ony-       involved. Electron microscopy reveals horizontal separation
cholysis is slowly reversible after treatment, however chronic      of the nail plate, which may, sometimes, extend up to the
onycholysis can lead to nail bed keratinization and persistent      proximal nail fold. It also demonstrates individual cells ly-
subungual hyperkeratosis [22, 74]. Therefore, it is crucial to      ing in the empty spaces. These observations indicate lamellar
promote nail reattachment as early as possible by preventing        splitting in onychoschizia occurs between the cell layers.
further toxicity and treating underlying infections, otherwise
onycholysis may become permanent.                                   Management and Prevention
                                                                    Counselling for the prevention of nail toxic effects is man-
Paronychia                                                          datory. Healthcare professionals should provide patients with
Paronychia is the result of inflammation of proximal/lateral        clear and detailed information. The patients should avoid re-
nail folds with erythema, edema, tenderness or pain of the          peated trauma or pressure on nails and nail beds or irritant
nail folds and impaired activity. It usually develops soon af-      regimen, including manipulation of the cuticles and nail bit-
ter intake of the drug, involves one or several nails and is        ing, use of fingernails as “tools,” prolonged soaking in water,
thought to be the result of the toxic effect of the drug on nail    exposure to solvents or hard chemicals, and application of ar-
epithelium [2, 8]. Paronychia is a frequent but uncommonly          tificial nails. They are encouraged to trim their nails regularly
reported adverse effect of epidermal growth factor inhibitors       and smooth the edges. The nails should be straight/squared
which is the result of aberrant vascular response affecting         and not too short. Prophylactic measures include the use of
nail folds [75, 76]. Except for anti-EGFR targeted therapy,         cotton gloves, comfortable wide-fitting footwear and cotton
RET inhibitor, mTOR inhibitors, anti-MEK, anti-HER,                 socks. Housework should be performed only with glove pro-
5-fluorouracil and docetaxel have been reported to develop          tection. When UV-associated toxicity is related to the drug
paronychia as well [4] (Table 5).                                   regimen patients should be informed and wear gloves when
                                                                    outside. Nail lacquers are recommended to limit water loss
Brittle Nails and Decreased Nail Growth                             from the nail plate (especially for brittle nails). Furthermore,
A decrease in nail plate growth is commonly noted with che-         daily use of topical emollients on the total nail apparatus (cu-
motherapy, although it will usually go unnoticed by patients        ticles, plate, and periungual folds) is a prophylactic manage-
or physicians. The nails are often fragile and thinner, which       ment for chemotherapy-induced nail toxicity [48]. In addition,
can lead to koilonychia, onychorrhexis, or onychoschizia af-        Scotté et al. [25] have demonstrated that the preventive use
ter several cycles of chemotherapy [74]. Chemotherapeutic           of frozen gloves/socks in patients treated with docetaxel al-
agents such as cetuximab, panitumumab, erlotinib, gefitinib,        lowed a significant reduction in changes from 51% to 11%
necitumumab, lapatinib, afatinib, dacomitinib, trametinib,          (p=0.0001) in fingernails, and from 21% to 0% in toenails,
cobimetinib, selumetinib, everolimus, temsirolimus, ibruti-         with a trend towards a prolongation (albeit non-significant) of
nib, sunitinib, sorafenib, cabozantinib, axitinib, pazotinib,       the median time to development of these lesions. Importantly,
regorafenib, docetaxel and paclitaxelare associated with            the Grade 2 or greater nail AEs were reduced from 22% to
brittle nails (Table 5).                                            0% (p=0.0001) [25, 69]. Therefore, the preventive use of fro-
     Koilonychia is a common nail dystrophy in which the            zen gloves/socks should be advised in patients treated with
dorsal surface of the nail plate becomes flat or truly concave.     taxanes [25]. Alternatively, the use of ice packs may be a less
It is derived from the Greek word koilos, meaning hollow.           expensive and effective strategy with similar efficacy [27].
     Pathogenesis of koilonychia is not known but it is sug-        In addition to preventing nail toxicities, frozen gloves or ice
gested that anoxia and atrophy of the distal matrix are con-        packs have been shown to decrease the incidence of peripheral
tributory. Koilonychia is the converse of clubbing and it is        neuropathy, another potentially dose-limiting adverse event. It
more appreciated when viewed from the side. When a drop             is intriguing that despite the simplicity and effectiveness of this
of water is put on the surface, it will not fall off. It should     intervention, it is not universally employed.
be noted that nails in koilonychia are brittle. It is commonly          In case onycholysis develops, excising the nail plate (par-
seen in fingernails rather than toenails. Docetaxel and Pacli-      tially or totally) may be necessary (Figure 4), especially in se-
taxel may cause koilonychia more often (Table 5).                   vere and painful lesions, or when associated with a pressure



14                                                                              Review | Dermatol Pract Concept. 2023;13(1):e2023064
   Figure 4. A. Onycholysis due to taxane treatment. Observe important detachment of plate from bed and presence of purulent
   ­discharge, B. Clipping of the onycholytic part of the nails relieves pain and allows for better hygiene.



hematoma or subungual abscess [7]. The nail bed should be        Cryotherapy’s effect is related to cold-induced vasocon-
cleaned and a sample for culture collected at the same time,     striction, which reduces the quantity of drugs reaching the
and in case of suspected infection should be also promptly       proliferating stem cells. For patients who can afford them,
treated with topical/oral antibiotics antiviral or antifungal    tolerate discomfort and exhibit compliance, these prophy-
therapy [48]. The detached nails should be cut regularly until   lactic managements of taxane-induced nail toxicity can be
the nail plate grows and covers the nail bed. In the setting     suggested as an option to improve patients’ quality of life
of paronychia without infection, potent topical steroids are     and functional statuses. However, future investigations and
recommended.                                                     studies are needed to establish the routine usage protocols,
   Except for the aforementioned traditional management          standard outcome measures, long-term efficacy and safety
modalities, some other clinical methods, such as cryotherapy     for these ­interventions [77].
and nail solution (nail balm), have been reported and pro-
moted. Huang et al. [77] in their meta-analysis revealed that
                                                                 Conclusions
both nail solution-based and cryotherapy-based prophylac-
tic management (frozen gloves, frozen socks and ice packs)       A wide spectrum of nail toxicities has so far been described
were effective for treating taxane-induced nail toxicity. Nail   in association with both, conventional and newer antican-
solution use is known to reduce the levels of substance P,       cer agents; however, less importance has been given to nail
a neurotransmitter that induces inflammation, which ad-          changes as compared to other skin toxicities. Considering
versely affects nails [78]. Moreover, plant-based waxes and      that nail toxicity is indeed almost never life-threatening, dis-
essential oils are naturally rich in phytochemicals, partic-     continuation of oncologic therapy is only rarely necessary.
ularly phenolic polyphenols, which have been reported to         However, drug interruptions or dose modifications may be
exhibit antioxidant, anti-inflammatory, DNA repair-enhanc-       warranted, mostly due to serious impairment of patients’
ing and antimicrobial properties [79, 80]. In addition to        quality of life. Management is primarily directed at symp-
their abilities to moisturize the skin and prevent the drying    tom control and relief of the patient. Nail changes that re-
and splitting of nails, the waxes and essential oils were hy-    sult from matrix interruption of blood flow often induce
pothesized to be sufficiently absorbed into the nail beds to     cosmetic changes (not requiring intervention), with the nail
act as local antidotes to the chemotherapeutic agent, thus       eventually growing out normally after treatment discontin-
preventing damage to the proliferating stem cells, avoiding      uation. On the other hand, nail changes due to disruption
secondary damage from inflammation or secondary infec-           of the nail folds frequently require therapeutic intervention,
tion as well as delaying the time to nail toxicity [79, 80].     and depending on the severity, also dose modifications.



Review | Dermatol Pract Concept. 2023;13(1):e2023064                                                                           15
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