Next Article in Journal
Death Anxiety in Caregivers of Chronic Patients
Previous Article in Journal
Information and Communication Technology-Based Application for Cognitive Behavioral Therapy among Community-Dwelling Older Adults with Insomnia: Development and Validation Study
Previous Article in Special Issue
Quality of Reporting Randomized Controlled Trials Published in Three of the Most Citable Periodontal Journals from 2018 to 2022
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Healthcare
Volume 12
Issue 1
10.3390/healthcare12010105
healthcare-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Oral Adverse Events Associated with BRAF and MEK Inhibitors in Melanoma Treatment: A Narrative Literature Review

by
Michele Basilicata
1,2,†,
Vincenzo Terrano
3,
Alessandro D'Aurelio
1,
Giovanni Bruno
4,5,*,†,
Teresa Troiani
3,
Patrizio Bollero
1 and
Stefania Napolitano
3
1
UOSD Special Care Dentistry, Department of Experimental Medicine and Surgery, University of Roma Tor Vergata, 00133 Rome, Italy
2
UniCamillus-Saint Camillus, International University of Health Sciences, 00131 Rome, Italy
3
Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Napoli, Italy
4
Department of Neuroscience, University of Padua, 35121 Padova, Italy
5
Department of Industrial Engineering, University of Tor Vergata, 00133 Rome, Italy
*
Author to whom correspondence should be addressed.
†
Second affiliation added after peer-review for a new academic enrolment.
Healthcare 2024, 12(1), 105; https://doi.org/10.3390/healthcare12010105
Submission received: 7 November 2023 / Revised: 21 December 2023 / Accepted: 27 December 2023 / Published: 2 January 2024
(This article belongs to the Special Issue Oral Healthcare: Diagnosis, Prevention and Treatment)
Versions Notes

Abstract

:
Background: Melanoma cancer represents the most lethal type of skin cancer originating from the malignant transformation of melanocyte cells. Almost 50% of melanomas show the activation of BRAF mutations. The identification and characterization of BRAF mutations led to the development of specific drugs that radically changed the therapeutic approach to melanoma. Methods: We conducted a narrative review of the literature according to a written protocol before conducting the study. This article is based on previously conducted studies. We identified articles by searching electronic databases (Medline, Google Scholar and PubMed). We used a combination of “melanoma”, “Braf-Mek inhibitors”, “ targeted therapy” and “oral side effects”. Results: Eighteen studies were reported in this article showing the relationship between the use of targeted therapy in melanoma cancer and the development of oral side effects, such as mucositis, hyperkeratosis and cellular proliferation. Conclusion: Targeted therapy plays an important role in the treatment of melanoma cancer, showing a notable increase in response rate, prolonged progression-free survival and overall survival in BRAF-mutated melanoma patients. Oral side effects represent a common finding over the course of treatment. However, these adverse effects can be easily managed in a multidisciplinary approach involving collaboration between medical oncologists and dental doctors.

1. Introduction

1.1. Melanoma Cancer

Melanoma is the deadliest form of skin cancer and is caused by the malignant transformation of melanocytes [1]. The incidence of melanoma is around 1.7% of all newly diagnosed primary malignant cancers, and its mortality rate is around 0.7% of all cancer mortality. Looking at the incidence and mortality of melanoma in different countries, the rate in Australia, New Zealand, Europe and North America is relatively high, while the rate in Africa is relatively low [2]. The age-standardized incidence rate is 3.8/100,000 for males and 3.0/100,000 for females, with cumulative lifetime risks of 0.42% and 0.33%, respectively [3].
Recent advances in drug development have improved the survival of patients affected by melanoma cancer. BRAF/MEK gene inhibitors and anti-PD1 antibodies, in particular, have totally revolutionized the management of this disease [2]. Activated BRAF mutation occurs in approximately 50% of cutaneous melanoma [4,5]. Actually, almost 300 BRAF mutations have been discovered, the most common being the V600E (valine to glutamic acid; 70–88%) [6,7,8]. The identification and characterization of BRAF mutations led to the development of specific drugs that radically changed the therapeutic approach to melanoma. These results led to the approval of BRAF plus MEK inhibitors for high risk resected (stage III) and advanced melanoma patients [9,10], underlining the importance of the early molecular characterization of high-risk stages II, III and IV melanoma patients, which is actually mandatory according to the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines [11] and represents a fundamental step for tailored therapy. However, despite their important efficacies, primary and acquired resistance during treatment with BRAF plus MEK inhibitors still remain a significant challenge. In addition, targeted agents have shown several adverse events that may delay treatment and limit its effectiveness. The nature and incidence of BRAF and MEK inhibitor adverse oral events is actually not completely described; however, these complications may affect a patient’s quality of life or may require temporary or permanent cancer therapy termination. With this review, we set out to clarify the type, incidence and relative risk of adverse oral events in melanoma patients treated with the combination of BRAF and MEK inhibitors.
These adverse events should be carefully approached in a multidisciplinary team for an optimal treatment of patients with melanoma.

1.2. MAPK Pathway

Several mutated genes were identified as therapeutic targets and were involved in different molecular signaling pathways that are thought to be responsible for the carcinogenic process in melanoma cancer and its development, including the protein kinase B (AKT) pathway, mitogen-activated protein kinase (MAPK) pathway, cell-cycle regulation pathway, pigmentation-related pathway, p53 pathway, epigenetic factors and some others [12]. Mutations in the key signal components, including BRAF, NRAS, NF1 and KIT, are considered responsible for the hyper-activation of the MAPK pathway in melanoma cancer [13]. BRAF is a serine/threonine protein kinase, encoded on chromosome 7q34, that activates the MAP kinase/ERK signaling pathway. It is the family member most easily activated by Ras [14]. Almost 50% of melanomas show the activation of BRAF mutations. Among BRAF mutations in melanoma cancer, about 90% are sited at codon 600, and among these, over 90% are a single nucleotide mutation that results in the substitution of glutamic acid for valine (BRAFV600E: nucleotide 1799 T > A; codon GTG > GAG) [15]. The activation the of RAF protein inducts the phosphorylation of MAPK receptor kinase (MEK), which in turn phosphorylates extracellular signal-regulated kinase (ERK). The activation of the ERK protein activates cellular proliferation and mitochondrial proteins, which stimulate cell growth and inhibit cell apoptosis [16,17,18].

1.3. Current Standard of Care for Melanoma Cancer

Despite advances in melanoma treatment, the 5-year survival rate for patients with advanced melanoma remains poor.
The treatment of melanoma patients has been revolutionized by the introduction of targeted therapy and immunotherapy. Recently, these therapies have become standard care in the adjuvant and metastatic settings. Adjuvant therapy has been approved for stage III melanoma patients. Immunotherapy involves the administration of monoclonal antibodies, T-cells or immuno-stimulatory cytokines focused on priming the immune system and activating immune responses against tumor cells. In 1998, the first approved immunomodulatory for the treatment of advanced melanoma was IL-2; subsequently, interferon-α (IFN-α) has been the only approved agent for the treatment of high-risk cutaneous melanoma. This agent showed such a high rate of side effects that only 50% of patients were able to complete the entire year of therapy [19]. Ipilimumab approval was subsequently expanded for use in the adjuvant setting in 2015 after the phase III international EORTC 18071 trial comparing adjuvant high dose ipilimumab to a placebo in patients with completely resected stage III melanoma [20]. Despite these improvements in relapse-free survival (RFS) and overall survival (OS), ipilimumab has been shown to be associated with a high incidence of adverse events. However, given its toxicity and the introduction of new agents, adjuvant ipilimumab is no longer actually administered. Pembrolizumab and nivolumab are two antibodies that target the PD-1 checkpoint inhibitor. Both antibodies have demonstrated an increase in RFS in stage III melanoma patients [21,22]. Immune-related adverse events of anti-PD1 inhibitors include diarrhea, fatigue, anemia, nausea and decreased appetite with a grade 3–4 incidence of approximately 14% [23]. Recently, adjuvant pembrolizumab also improved RFS in high-risk stage II melanoma patients [24]. Based on these data, the European Medicines Agency (EMA) and Food and Drug Administration (FDA) approved pembrolizumab as an adjuvant treatment for stage II B or II C melanoma patients following complete resection.
Regarding target therapy, the treatment of melanoma was revolutionized with the discovery of the BRAF mutation in 2002. Vemurafenib was the first BRAF inhibitor approved by the FDA in 2011. Since then, the combination of BRAF and MEK inhibitors has been proven to be superior to single-agent BRAF inhibitors. In particular, the combination of the BRAF–MEK inhibitors dabrafenib and trametinib received regulatory approval after demonstrating significant improvements in RFS in stage III melanoma patients with BRAF V600E or V600K mutations [25]. In the current period of effective systemic therapies, the role of radiation therapy (RT) remains controversial [26]. RT looks promising and should be considered after regional lymph node dissection of macroscopic lymph node disease in patients with extracapsular extension; lymph node diameter >3 cm (neck or maxilla); or 4 cm (groin); or at least one involved lymph node in the parotid lymph node region, two in the neck and maxillary region or three in the groin region [27]. Radiation therapy can also be considered after the failure of previous regional lymph node dissection and after the resection of desmoplastic or other melanoma subtypes that show neurotropism. Moreover, patients with resectable metastases melanoma can be candidates to neoadjuvant treatment. Recently, several clinical trials have assessed the superiority of neoadjuvant approaches over standard surgery and subsequent adjuvant treatment [28,29,30,31].
The treatment of metastatic melanoma treatment should be discussed in interdisciplinary tumor boards with representation from multiple medical specialties. Anti PD-1 antibodies, either as monotherapy or in combination with anti-CTLA-4 ones, should be considered first-line treatment for all patients with unresectable metastatic melanoma and independent of tumor BRAF mutational status [32,33,34]. The association of nivolumab and ipilimumab has been shown to be superior in terms of progression-free survival (PFS) with ipilimumab or nivolumab as single agent drugs and is actually approved by the FDA and EMA [35,36,37]. In addition, in the presence of BRAFV600E/K mutation, combinations of BRAF and MEK inhibitors were able to show a significantly increased objective response rate, PFS and OS [38,39,40,41]. In the metastatic setting, there are now three combinations approved: vemurafenib and cobimetinib (V + C), dabrafenib and trametinib (D + T) and encorafenib and binimetinib (E + C) [26]. All these combination regimens showed long-term benefits as first-line treatment in patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation [42,43,44]. Direct head-to-head comparison of the available regimens is unlikely to be performed, but indirect side-by-side analysis of data from V + C, D + T and E + B compared to vemurafenib monotherapy [45] revealed comparable PFS and OS data. The availability of three approved BRAF-MEK inhibitor regimens gives multiple options of treatment for patients with stage IV BRAF-V600E/K mutant melanoma [46]. Finally, a small proportion of melanomas arising in sun-protected sites show mutations in cKIT. KIT inhibitors, most notably imatinib, have shown promising clinical activity in this subtype [47].

1.4. BRAF and MEK Inhibitors Adverse Events: Focus on Oral Side Effects

BRAF and MEK inhibitors are well tolerated, but some adverse events can occur because of paradoxical reactivation of MAPK signaling [48]. Inhibition of the MAPK pathway in keratinocytes can lead to inflammation, decreased keratinocyte cell migration and keratinocyte cell death, resulting in dermatologic side effects [49]. Skin toxicities are the most common adverse events associated with BRAF inhibitor, occurring in up to 57% of patients. Photosensitivity, rash, pruritis, dry skin, papilloma, alopecia, keratoacanthoma and squamocellular carcinoma (SCC) are the most common in BRAF inhibitor monotherapy, with photosensitivity resulting as primarily associated with vemurafenib [50]. Other adverse events that occur more frequently with combination therapy are fever (51%), chills (30%), fatigue (35%), diarrhea (24%), hypertension (22%) and vomiting (20%) [51].
Despite the efficacy of these drugs in the treatment of melanoma, one particular focus that can often be underestimated and that compromises the patient’s quality of life is the cutaneous and oral side effects of these drugs. Adverse reactions can vary from subject to subject and can have varying levels of severity, so a multidisciplinary approach is essential to prevent and manage possible complications, which are often responsible for lower adherence to therapy.
These drugs are endowed with specificity, acting on specific targets expressed exclusively by tumor cells and reducing the damage caused to healthy cells; the cells constituting the oral mucosa, however, having a high cell turnover, are, for this reason, more receptive to the action of these pharmacological agents and, therefore, are associated with a higher incidence of oral adverse effects. The latter are responsible for decreased quality of life and discomfort in terms of nutrition and less adherence to the therapy itself.
Associated with target therapy, one of the most adverse reactions found in the oral district is gingival hyperplasia, which is characterized by the presence of benign hyperkeratotic lesions with a warty appearance, and frequently finding localization at the level of the gingival mucosa, free gingiva and lips [52]. Although rare, a biopsy examination of the hyperkeratotic lesion is still indicated for doubtful cases of squamous cell carcinoma (SCC) associated with target therapy [53].
Other lesions, as described in the study conducted by Gençler et al. [54], can be squamo-proliferative: administration of vemurafenib as monotherapy has been observed to cause activation of the RAS pathway resulting in cutaneous and oral lesions such as squamous cell carcinoma, Keratoacanthoma and Acanthopapillomas.
Often associated with the administration of MEK inhibitors is Cheilitis Angularis, and it tends to occur six months after the start of therapy. It is a fissured lesion involving the corners of the mouth that become reddened and very painful, especially following lip movements, and it presents small cuts and abrasions until it ulcerates causing burning, dryness and suppuration [55].
Oral lichenoid reactions occur most frequently after the administration of multikinase inhibitors. They are closely related to the dose of the drug, and their treatment involves the use of corticosteroids and antihistamines [56].
Ulcerated, painful and atrophic lesions represent a clinical aspect of Mucositis, characterized by erythematous and reddened areas of the oral mucosa; often, the lesions have no dysplasia, only an infiltrate of inflammatory cells.
As outlined by Lueken et al. [57], pigmented lesions are associated with a melanocyte proliferation called Melanocytic Hyperplasia, found at the palatal level, mainly linked with tyrosine kinase inhibitors.
The relationship between concomitant BRAFi intake and periodontal disease is noteworthy; this condition is a chronic inflammatory process of the dental support tissues (periodontal ligament, gingiva, alveolar bone and radicular cementum) that results in the formation of periodontal pockets and resorption of bone support to the point of element loss. In this regard, treatment of periodontal disease with professional hygiene sessions, scaling, root planing and elimination of the inflammatory process will facilitate the healing process of these oral adverse events [58].

2. Materials and Methods

2.1. Design

This literature review follows the “Preferred Reporting Items for Systematic reviews and Meta-analyses” (PRISMA) checklist from 2009, a methodology including studies with qualitative, quantitative and mixed method designs to capture a greater latitude of the field.

2.2. Search Strategy

Literature searches were conducted by using four databases: Medline, Google Scholar, Embase and PubMed. Other relevant studies were identified from reference lists of systematic reviews and meta-analyses. Databases were used according to the inclusion criteria using filters to limit results to “full text” journal articles that were available at a price or free of cost, involving studies conducted in human participants aged at least 18 years old and being melanoma-specific. We did not apply any language restrictions in the searches. Retrospective, prospective and RCT research articles using a combination for “melanoma”, “Braf-Mek inhibitors”, “Targeted therapy” and “oral adverse events” were included. The first research was performed in April 2022, and no time limit was set. Because this is an emerging field of research, electronic searches were performed in all fields of the article. Two researchers (T.V., D.A.A.) executed 100% double title and abstract screening separately with inter-reviewer agreement. Studies that did not follow the inclusion criteria were excluded from full text review, and disagreement between researchers was resolved through discussion. Studies were subjected to full text review by two researchers independently (T.V., D.A.A.).

3. Results

3.1. Screening and Data Extraction

The first evaluation of the manually selected papers showed the necessity to establish some exclusion criteria because several articles were not focus-related to our matter of interest. A total of 30 studies were evaluated for title and abstract screening, and after removing duplicates, a total of 18 studies were judged to be eligible for full text review.

3.2. Data Synthesis

A descriptive and meta-analytical approach to data was considered appropriate to show our findings.
Among the most widely recognized side effects, we can mention SCARs (severe adverse skin reactions), which include the Stevens–Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), drug rash with eosinophilia and systemic syndrome (DRESS), Acute Generalized Exanthematous Pustulosis (AGEP) and Generalized Bullous Fixed Eruption (GBFE) [59,60]; these occur in 20–30% of cases [61].
Torres-Navarro et al., in their study, analyzed the effects produced by some of these drugs; for example, encorafenib, binimetinib, dabrafenib, trametinib, vemurafenib and cobimetinib.
No skin reactions were found for cobimetinib as a monotherapy; instead, trametinib, encorafenib or binimetinib (alone or associated with dabrafenib), were associated in two cases of DRESS [62,63].
Most of the side effects are from the treatment with vemurafenib in association with cobimetinib, but the association in cases of health-threatening SCARs has been confirmed to be between dabrafenib and trametinib [25,64] instead; in contrast, SCARs are less frequent for the encorafenib–binimetinib association [39].
Fractures and osteopenia are serious complications found in two patients treated for a long time with MEKi. In the research of Dumas et al. [65], especially, the first patient with melanoma and under treatment with “pimesertib” for 6 years developed a clinical picture characterized by osteopenia, sacrum fracture, increased alkaline phosphatase levels and vitamin D deficiency.
In the second melanoma patient treated for about 6 months with BRAFi/MEKi combination, a pelvic bone fracture was found at the level of the left acetabulum [66].
Among the adverse effects of these drugs are oral adverse events. In this regard, the study by Dika et al. evaluated these effects in patients affected by melanoma under treatment with BRAFi/MEKi and tyrosine kinase inhibitors and in patients treated with CTLA and PD1 inhibitors [67].
The first group of patients had a clinical picture characterized by gingival hyperplasia (multiple hyperkeratotic lesions at palatal, gingival, tongue and lip levels) [68,69], blue-brown-black pigmentations at the palatal level [70,71] and proliferative lesions such as keratoacanthoma (KA) and squamous cell carcinoma (SCC) [72,73,74].
In contrast, in the second group, the adverse effects are lichenoid reactions with possible risk of neoplastic evolution [75,76], bullous pemphigoid and erythema multiforme [67] and xerostomia with subsequent dysgeusia.
Additional adverse reactions, such as hypertension, diarrhea, fever, skin rash, hemorrhage, mucositis and oral ulceration [71], were relevant from the research of Lyne et al., who studied the adverse effects of the drug Apatinib in refractory or relapsed melanomas.
In addition to these adverse reactions, there is also a case of Actinomycosis revealed by ulcerations of the palate and gingiva; in fact, the study by Dessirier et al. examined a case of melanoma treated with BRAFi, which presented itself with oral, bleeding and hyperalgesic ulcerations.
The histologic examination showed the presence of a filamentous appearance typical of Actinomycosis, thus requiring treatment with an antibiotic (penicillin G) [77].
Hyperkeratosis, hyperplasia, inflammation and gingival ulceration, on the other side, represent the toxicity profile of a melanoma case, undergoing treatment with vemurafenib for the duration of 2 years [58].
The patient, subjected to a treatment plan based on scaling, root planing, periodontal tooth extractions and preservation of a high level of oral hygiene resulted in resolution of gingival abnormalities.
Damsin’s study found endobuccal toxicities in a patient with colorectal adenocarcinoma treated with target therapy; these include aphthoid lesions that tend towards confluence and mucositis.
The main problem is related to overinfection and nutritional disorders of the patient; oral hygiene, rinses with antiseptic mouthwashes and specific nystatin–hydrocortisone–lidocaine solutions are essential [78].
Hyperkeratotic lesions are the most prevalent side effects for vemurafenib and dabrafenib when used in monotherapy. These include keratosis-like rashes, warty papillomas, and tumor-like lesions, such as keratoacanthoma or squamous cell carcinoma.
Oral toxicities have also been described, such as hyperkeratotic lesions on the marginal gingiva, palate, tongue and labial mucosa and vemurafenib-induced Gingival Hyperplasia.
A case of squamous cell carcinoma on vemurafenib-induced lesions on the labial mucosa has also been reported [79,80]. Table 1 reports a resume of the findings.

4. Discussion

The nature and incidence of adverse oral events associated with BRAF and MEK inhibitor therapy are incompletely described. However, these complications may affect a patient’s quality of life or may require temporary or permanent cancer therapy termination. With this review, we set out to clarify the type, incidence and relative risk of adverse oral events in patients with melanoma who are being treated with a combination of BRAF and MEK inhibitors.
These adverse events should be carefully approached in a multidisciplinary team for an optimal treatment of patients with melanoma.
Fundamental is the interdisciplinary approach to treating the patient from every point of view, based on dialogue and collaboration among the various specialists.
This makes it possible to improve the response to the treatments performed, allowing for the effective management of the eventual response of the disease, giving the possibility to take action during all stages of the pathology and taking into account histological and clinical factors.
It is also important to plan adequate monitoring of the efficiency of the professional team, to define the responsibilities of the different clinicians and to use a set of indicators of effectiveness.
The collaboration of oncologists, dermatologists, anatomo-pathologists, nuclear physicians, radiologists, plastic surgeons, dentists, psychologists and the nursing staff allows for framing the patient at the center of a path of care, support and rehabilitation.
To optimize patient management, Claveau et al. emphasize the implementation of a regional multidisciplinary team in order to identify, in the same region, specialists, means of communication of team members, possible obstacles and treatment strategies [81].
The importance of the multidisciplinary team approach (MDT) in the management of the melanoma patient has been reviewed by the study by Cornelius Lynn et al.; the team allows for optimization of care, improved diagnostic accuracy and timely management of side effects [84].
The perspective of the dermatologist who is part of the MDT is to be an active participant in every phase of patient management; the role of the surgeon who is responsible for evaluating and choosing the most appropriate surgical technique is also important.
Instead, it is the responsibility of the oncologist to review the exact clinical and histologic staging of the tumor, discuss treatment options and provide the patient’s educational materials [82].
A Diagnostic Therapeutic Care Pathway (PDTA) has been formalized for melanoma; it provides for cancer patient care, improved care and reduced time for diagnosis, treatment, staging and follow-up.
This pathway provides a reduction in the economic impact on patient management, a prolongation of the survival rate, a high standard of the quality of medical and surgical treatment, an appropriate and efficient treatment according to the individuality of each patient and, lastly, it promotes access to advanced therapies provided by national and international trials in order to limit the movement of patients to other centers in the nation.
Treatment with BRAFi/MEKi for a melanoma is not exempt from side effects, and we may experience adverse reactions especially in the oral cavity. These adverse effects affect patients’ lives by causing functional, aesthetic and masticatory alteration of the stomatognathic apparatus.
In this regard, it is of paramount importance to establish an excellent dentist–patient relationship in order to tailor a treatment plan according to the type and severity of side effects [83].
Dental management will therefore be based on accurate medical history; identifying hereditary conditions; personal physiological for assessing habits, allergies, socio–economic factors, medications taken, alcohol use, smoking and lifestyle; and personal pathological for assessing all past medical interventions, any complications and current issues related to BRAFi/MEKi intake.
The next step will be the objective examination, both extraoral and intraoral, that allows us to examine the current status of mucous membranes; changes in color, shape, texture, function of oral structures; evaluation of signs; and symptoms pathognomonic of pathological processes.
To complete the diagnostic process, the realization of the Clinical and Periodontal Record will be required; then, it will be necessary to evaluate Radiographic Examinations based on Rx Orthopantomography, Rx Endoral and ConeBeamCT to assess radiopacity and radiotransparencies to expand the objective examination. Lastly, laboratory tests will be conducted to allow for the evaluation of blood parameters, such as blood count, leukocyte formula, blood glucose, glycosylated hemoglobin and indices of systemic inflammation.
The aforementioned requirements will enable the creation of the treatment plan that will provide for the resolution of oral problems; it will be based on professional oral hygiene, treatment of incongruous fillings, devitalization of non-viable dental elements, remedies to prevent systemic contamination, prosthetic restorations and the use of devices for controlled release of topical antibiotics or chlorhexidine solutions.
It is crucial to recognize the first symptoms of chemotherapy-induced mucositis in order to avoid further complications. The inflammatory process in the mucous membranes causes a loss of mucosal function with the risk of overinfection.
Currently, there are no guidelines for the treatment of chemotherapy-induced mucositis; the choice falls between pharmacological and non-pharmacological therapies. There is plenty of scientific evidence affirming the efficacy of compounds, such as the hydroglyceric extract of propolis and grapefruit and another active ingredient, ectoin.
The latter has the function of moisturizing the mucous membranes, providing immediate relief and promoting mucosal healing.

5. Conclusions

This review addresses melanoma and its therapy, with a focus on targeted BRAFi/MEKi treatment. Patient involvement and multidisciplinary management are essential for effective treatment. Collaboration between oncologists and dentists is crucial for early diagnosis, investigations and regular check-ups to prevent and treat oral complications, thus improving patients’ quality of life and adherence to treatment.

Author Contributions

Conceptualization, M.B., S.N., A.D., V.T. and P.B.; Methodology, M.B., S.N., T.T. and P.B.; Investigation, M.B., S.N. and P.B.; Data Curation, M.B., S.N. and P.B.; Writing—Original Draft Preparation, M.B., S.N., A.D. and G.B; Writing—Review and Editing, M.B., S.N. and G.B.; Supervision, M.B., S.N., A.D., V.T. and P.B. All authors have read and agreed to the published version of the manuscript.

Funding

This review received no external funding.

Institutional Review Board Statement

This is a review; therefore, no ethnical approval is required.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Lo, J.A.; Fisher, D.E. The melanoma revolution: From UV carcinogenesis to a new era in therapeutics. Science 2014, 346, 945–949. [Google Scholar] [CrossRef] [PubMed]
  2. Ferlay, J.; Colombet, M.; Soerjomataram, I.; Parkin, D.M.; Piñeros, M.; Znaor, A.; Bray, F. Cancer statistics for the year 2020: An overview. Int. J. Cancer 2021, 149, 778–789. [Google Scholar] [CrossRef] [PubMed]
  3. Guo, W.; Wang, H.; Li, C. Signal pathways of melanoma and targeted therapy. Signal Transduct. Target. Ther. 2021, 6, 424. [Google Scholar] [CrossRef] [PubMed]
  4. The Cancer Genome Atlas Network. Genomic Classification of Cutaneous Melanoma. Cell 2015, 161, 1681–1696. [Google Scholar] [CrossRef] [PubMed]
  5. Sanchez-Vega, F.; Mina, M.; Armenia, J.; Chatila, W.K.; Luna, A.; La, K.C.; Dimitriadoy, S.; Liu, D.L.; Kantheti, H.S.; Saghafinia, S.; et al. Oncogenic Signaling Pathways in The Cancer Genome Atlas. Cell 2018, 173, 321–337.e10. [Google Scholar] [CrossRef] [PubMed]
  6. Rubinstein, J.C.; Sznol, M.; Pavlick, A.C.; Ariyan, S.; Cheng, E.; Bacchiocchi, A.; Kluger, H.M.; Narayan, D.; Halaban, R. Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J. Transl. Med. 2010, 8, 67. [Google Scholar] [CrossRef]
  7. Lovly, C.M.; Dahlman, K.B.; Fohn, L.E.; Su, Z.; Dias-Santagata, D.; Hicks, D.J.; Hucks, D.; Berry, E.; Terry, C.; Duke, M.; et al. Routine Multiplex Mutational Profiling of Melanomas Enables Enrollment in Genotype-Driven Therapeutic Trials. PLoS ONE 2012, 7, e35309. [Google Scholar] [CrossRef]
  8. Menzies, A.M.; Haydu, L.E.; Visintin, L.; Carlino, M.S.; Howle, J.R.; Thompson, J.F.; Kefford, R.F.; Scolyer, R.A.; Long, G.V. Distinguishing clinicopatho-logic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res. 2012, 18, 3242–3249. [Google Scholar] [CrossRef]
  9. Long, G.V.; Flaherty, K.T.; Stroyakovskiy, D.; Gogas, H.; Levchenko, E.; De Braud, F.; Larkin, J.; Garbe, C.; Jouary, T.; Hauschild, A.; et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: Long-term survival and safety analysis of a phase 3 study. Ann. Oncol. 2017, 28, 1631–1639. [Google Scholar] [CrossRef]
  10. Queirolo, P.; Boutros, A.; Tanda, E.; Spagnolo, F.; Quaglino, P. Immune-checkpoint inhibitors for the treatment of metastatic melanoma: A model of cancer immunotherapy. Semin. Cancer Biol. 2019, 59, 290–297. [Google Scholar] [CrossRef]
  11. Michielin, O.; Van Akkooi, A.C.J.; Ascierto, P.A.; Dummer, R.; Keilholz, U.; ESMO Guidelines Committee. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2019, 30, 1884–1901. [Google Scholar] [CrossRef] [PubMed]
  12. Davies, H.; Bignell, G.R.; Cox, C.; Stephens, P.; Edkins, S.; Clegg, S.; Teague, J.; Woffendin, H.; Garnett, M.J.; Bottomley, W.; et al. Mutations of the BRAF gene in human cancer. Nature 2002, 417, 949–954. [Google Scholar] [CrossRef] [PubMed]
  13. Ascierto, P.A.; Kirkwood, J.M.; Grob, J.-J.; Simeone, E.; Grimaldi, A.M.; Maio, M.; Palmieri, G.; Testori, A.; Marincola, F.M.; Mozzillo, N. The role of BRAF V600 mutation in melanoma. J. Transl. Med. 2012, 10, 85. [Google Scholar] [CrossRef] [PubMed]
  14. Catalogue of Somatic Mutations in Cancer [COSMIC]. Available online: http://www.sanger.ac.uk/cosmic (accessed on 6 November 2023).
  15. Nikolaou, V.A.; Stratigos, A.J.; Flaherty, K.T.; Tsao, H. Melanoma: New Insights and New Therapies. J. Investig. Dermatol. 2012, 132, 854–863. [Google Scholar] [CrossRef] [PubMed]
  16. Sullivan, R.J.; Flaherty, K.T. Resistance to BRAF-targeted therapy in melanoma. Eur. J. Cancer 2013, 49, 1297–1304. [Google Scholar] [CrossRef] [PubMed]
  17. Song, Y.; Bi, Z.; Liu, Y.; Qin, F.; Wei, Y.; Wei, X. Targeting RAS–RAF–MEK–ERK signaling pathway in human cancer: Current status in clinical trials. Genes Dis. 2023, 10, 76–88. [Google Scholar] [CrossRef]
  18. Faries, M.B.; Thompson, J.F.; Cochran, A.J.; Andtbacka, R.H.; Mozzillo, N.; Zager, J.S.; Jahkola, T.; Bowles, T.L.; Testori, A.; Beitsch, P.D.; et al. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N. Engl. J. Med. 2017, 376, 2211–2222. [Google Scholar] [CrossRef]
  19. Eggermont, A.M.; Chiarion-Sileni, V.; Grob, J.J.; Dummer, R.; Wolchok, J.D.; Schmidt, H.; Hamid, O.; Robert, C.; Ascierto, P.A.; Richards, J.M.; et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): A randomised, double-blind, phase 3 trial. Lancet Oncol. 2015, 16, 522–530. [Google Scholar] [CrossRef]
  20. Weber, J.S.; D’Angelo, S.P.; Minor, D.; Hodi, F.S.; Gutzmer, R.; Neyns, B.; Hoeller, C.; Khushalani, N.I.; Miller, W.H., Jr.; Lao, C.D.; et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015, 16, 375–384. [Google Scholar] [CrossRef]
  21. Eggermont, A.M.; Blank, C.U.; Mandala, M.; Long, G.V.; Atkinson, V.; Dalle, S.; Haydon, A.; Lichinitser, M.; Khattak, A.; Carlino, M.S.; et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N. Engl. J. Med. 2018, 378, 1789–1801. [Google Scholar] [CrossRef]
  22. Weber, J.; Mandala, M.; Del Vecchio, M.; Gogas, H.J.; Arance, A.M.; Cowey, C.L.; Dalle, S.; Schenker, M.; Chiarion-Sileni, V.; Marquez-Rodas, I.; et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N. Engl. J. Med. 2017, 377, 1824–1835. [Google Scholar] [CrossRef] [PubMed]
  23. Postow, M.A.; Chesney, J.; Pavlick, A.C.; Robert, C.; Grossmann, K.; McDermott, D.; Linette, G.P.; Meyer, N.; Giguere, J.K.; Agarwala, S.S.; et al. Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma. N. Engl. J. Med. 2015, 372, 2006–2017. [Google Scholar] [CrossRef] [PubMed]
  24. Luke, J.J.; Rutkowski, P.; Queirolo, P.; Del Vecchio, M.; Mackiewicz, J.; Chiarion-Sileni, V.; Merino, L.D.l.C.; Khattak, M.A.; Schadendorf, D.; Long, G.V.; et al. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): A randomised, double-blind, phase 3 trial. Lancet 2022, 399, 1718–1729. [Google Scholar] [CrossRef] [PubMed]
  25. Long, G.V.; Hauschild, A.; Santinami, M.; Atkinson, V.; Mandalà, M.; Chiarion-Sileni, V.; Larkin, J.; Nyakas, M.; Dutriaux, C.; Haydon, A.; et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N. Engl. J. Med. 2017, 377, 1813–1823. [Google Scholar] [CrossRef] [PubMed]
  26. Henderson, M.A.; Burmeister, B.H.; Ainslie, J.; Fisher, R.; Di Iulio, J.; Smithers, B.M.; Hong, A.; Shannon, K.; Scolyer, R.A.; Carruthers, S.; et al. Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial. Lancet Oncol. 2015, 16, 1049–1060. [Google Scholar] [CrossRef] [PubMed]
  27. Frakes, J.M.; Figura, N.B.; Ahmed, K.A.; Juan, T.H.; Patel, N.; Latifi, K.; Sarangkasiri, S.; Strom, T.J.; Chinnaiyan, P.; Rao, N.G.; et al. Potential role for LINAC-based stereotactic radiosurgery for the treatment of 5 or more radioresistant melanoma brain metastases. J. Neurosurg. 2015, 123, 1261–1267. [Google Scholar] [CrossRef] [PubMed]
  28. Rozeman, E.A.; Menzies, A.M.; van Akkooi, A.C.; Adhikari, C.; Bierman, C.; van de Wiel, B.A.; Scolyer, R.A.; Krijgsman, O.; Sikorska, K.; Eriksson, H.; et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): A multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 2019, 20, 948–960. [Google Scholar] [CrossRef]
  29. Amaria, R.N.; Postow, M.; Burton, E.M.; Tetzlaff, M.T.; Ross, M.I.; Torres-Cabala, C.; Glitza, I.C.; Duan, F.; Milton, D.R.; Busam, K.; et al. Neoadjuvant relatlimab and nivolumab in resectable melanoma. Nature 2022, 611, 155–160. [Google Scholar] [CrossRef]
  30. Reijers, I.L.; Menzies, A.M.; Van Akkooi, A.C.; Versluis, J.M.; Van Den Heuvel, N.M.; Saw, R.P.; Pennington, T.E.; Kapiteijn, E.; Van Der Veldt, A.A.; Suijkerbuijk, K.P.; et al. Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: The PRADO trial. Nat Med. 2022, 28, 1178–1188. [Google Scholar] [CrossRef]
  31. Patel, S.P.; Othus, M.; Chen, Y.; Wright Jr, G.P.; Yost, K.J.; Hyngstrom, J.R.; Hu-Lieskovan, S.; Lao, C.D.; Fecher, L.A.; Truong, T.G.; et al. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N. Engl. J. Med. 2023, 388, 813–823. [Google Scholar] [CrossRef]
  32. Robert, C.; Long, G.V.; Brady, B.; Dutriaux, C.; Maio, M.; Mortier, L.; Hassel, J.C.; Rutkowski, P.; McNeil, C.; Kalinka-Warzocha, E.; et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 2015, 372, 320–330. [Google Scholar] [CrossRef] [PubMed]
  33. Robert, C.; Schachter, J.; Long, G.V.; Arance, A.; Grob, J.J.; Mortier, L.; Daud, A.; Carlino, M.S.; McNeil, C.; Lotem, M.; et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N. Engl. J. Med. 2015, 372, 2521–2532. [Google Scholar] [CrossRef] [PubMed]
  34. Larkin, J.; Chiarion-Sileni, V.; Gonzalez, R.; Grob, J.J.; Cowey, C.L.; Lao, C.D.; Schadendorf, D.; Dummer, R.; Smylie, M.; Rutkowski, P.; et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N. Engl. J. Med. 2015, 373, 23–34. [Google Scholar] [CrossRef] [PubMed]
  35. Tawbi, H.A.; Forsyth, P.A.; Algazi, A.; Hamid, O.; Hodi, F.S.; Moschos, S.J.; Khushalani, N.I.; Lewis, K.; Lao, C.D.; Postow, M.A.; et al. Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. N. Engl. J. Med. 2018, 379, 722–730. [Google Scholar] [CrossRef] [PubMed]
  36. Wolchok, J.D.; Chiarion-Sileni, V.; Gonzalez, R.; Grob, J.J.; Rutkowski, P.; Lao, C.D.; Cowey, C.L.; Schadendorf, D.; Wagstaff, J.; Dummer, R.; et al. Long-Term Outcomes with Nivolumab Plus Ipilimumab or Nivolumab Alone versus Ipilimumab in Patients with Advanced Melanoma. J. Clin. Oncol. 2022, 40, 127–137. [Google Scholar] [CrossRef] [PubMed]
  37. Tawbi, H.A.; Schadendorf, D.; Lipson, E.J.; Ascierto, P.A.; Matamala, L.; Gutiérrez, E.C.; Rutkowski, P.; Gogas, H.J.; Lao, C.D.; De Menezes, J.J.; et al. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N. Engl. J. Med. 2022, 386, 24–34. [Google Scholar] [CrossRef] [PubMed]
  38. Larkin, J.; Ascierto, P.A.; Dréno, B.; Atkinson, V.; Liszkay, G.; Maio, M.; Mandalà, M.; Demidov, L.; Stroyakovskiy, D.; Thomas, L.; et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N. Engl. J. Med. 2014, 371, 1867–1876. [Google Scholar] [CrossRef]
  39. Robert, C.; Karaszewska, B.; Schachter, J.; Rutkowski, P.; Mackiewicz, A.; Stroiakovski, D.; Lichinitser, M.; Dummer, R.; Grange, F.; Mortier, L.; et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl. J. Med. 2015, 372, 30–39. [Google Scholar] [CrossRef]
  40. Long, G.V.; Stroyakovskiy, D.; Gogas, H.; Levchenko, E.; de Braud, F.; Larkin, J.; Garbe, C.; Jouary, T.; Hauschild, A.; Grob, J.-J.; et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: A multicentre, double-blind, phase 3 randomised controlled trial. Lancet 2015, 386, 444–451. [Google Scholar] [CrossRef]
  41. Dummer, R.; Ascierto, P.A.; Gogas, H.J.; Arance, A.; Mandala, M.; Liszkay, G.; Garbe, C.; Schadendorf, D.; Krajsova, I.; Gutzmer, R.; et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018, 19, 603–615. [Google Scholar] [CrossRef]
  42. Ascierto, P.A.; Dréno, B.; Larkin, J.; Ribas, A.; Liszkay, G.; Maio, M.; Mandalà, M.; Demidov, L.; Stroyakovskiy, D.; Thomas, L.; et al. 5-Year Outcomes with Cobimetinib plus Vemurafenib in BRAFV600 Mutation-Positive Advanced Melanoma: Extended Follow-Up of the coBRIM Study. Clin. Cancer Res. 2021, 27, 5225–5235. [Google Scholar] [CrossRef] [PubMed]
  43. Robert, C.; Grob, J.J.; Stroyakovskiy, D.; Karaszewska, B.; Hauschild, A.; Levchenko, E.; Chiarion Sileni, V.; Schachter, J.; Garbe, C.; Bondarenko, I.; et al. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. N. Engl. J. Med. 2019, 381, 626–636. [Google Scholar] [CrossRef] [PubMed]
  44. Dummer, R.; Flaherty, K.T.; Robert, C.; Arance, A.; de Groot, J.W.B.; Garbe, C.; Gogas, H.J.; Gutzmer, R.; Krajsová, I.; Liszkay, G.; et al. COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients with BRAF V600-Mutant Melanoma. J. Clin. Oncol. 2022, 40, 4178–4188. [Google Scholar] [CrossRef] [PubMed]
  45. Hamid, O.; Cowey, C.L.; Offner, M.; Faries, M.; Carvajal, R.D. Efficacy, Safety, and Tolerability of Approved Combination BRAF and MEK Inhibitor Regimens for BRAF-Mutant Melanoma. Cancers 2019, 11, 1642. [Google Scholar] [CrossRef]
  46. Chapman, P.B.; Hauschild, A.; Robert, C.; Haanen, J.B.; Ascierto, P.; Larkin, J.; Dummer, R.; Garbe, C.; Testori, A.; Maio, M.; et al. BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 2011, 364, 2507–2516. [Google Scholar] [CrossRef] [PubMed]
  47. Ny, L.; Hernberg, M.; Nyakas, M.; Koivunen, J.; Oddershede, L.; Yoon, M.; Wang, X.; Guyot, P.; Geisler, J. BRAF mutational status as a prognostic marker for survival in malignant melanoma: A systematic review and meta-analysis. Acta Oncol. 2020, 59, 833–844. [Google Scholar] [CrossRef] [PubMed]
  48. Manousaridis, I.; Mavridou, S.; Goerdt, S.; Leverkus, M.; Utikal, J. Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management. J. Eur. Acad. Dermatol. Venereol. 2013, 27, 11–18. [Google Scholar] [CrossRef]
  49. Sinha, R.; Edmonds, K.; Newton-Bishop, J.A.; Gore, M.E.; Larkin, J.; Fearfield, L. Cutaneous adverse events associated with vemurafenib in patients with metastatic melanoma: Practical advice on diagnosis, prevention and management of the main treatment-related skin toxicities. Br. J. Dermatol. 2012, 167, 987–994. [Google Scholar] [CrossRef]
  50. Kudchadkar, R.R.; Smalley, K.S.; Glass, L.F.; Trimble, J.S.; Sondak, V.K. Targeted therapy in melanoma. Clin. Dermatol. 2013, 31, 200–208. [Google Scholar] [CrossRef]
  51. Roujeau, J.C.; Stern, R.S. Severe Adverse Cutaneous Reactions to Drugs. N. Engl. J. Med. 1994, 331, 1272–1285. [Google Scholar] [CrossRef]
  52. Mangold, A.R.; Bryce, A.; Sekulic, A. Vemurafenib-associated gingival hyperplasia in patient with metastatic melanoma. J. Am. Acad. Dermatol. 2014, 71, e205–e206. [Google Scholar] [CrossRef] [PubMed]
  53. Flaherty, K.T.; Infante, J.R.; Daud, A.; Gonzalez, R.; Kefford, R.F.; Sosman, J.; Hamid, O.; Schuchter, L.; Cebon, J.; Ibrahim, N.; et al. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. N. Engl. J. Med. 2012, 367, 1694–1703. [Google Scholar] [CrossRef] [PubMed]
  54. Gençler, B.; Gönül, M. Cutaneous Side Effects of BRAF Inhibitors in Advanced Melanoma: Review of the Literature. Dermatol. Res. Pract. 2016, 2016, 5361569. [Google Scholar] [CrossRef] [PubMed]
  55. Balagula, Y.; Barth Huston, K.; Busam, K.J.; Lacouture, M.E.; Chapman, P.B.; Myskowski, P.L. Dermatologic side effects associated with the MEK 1/2 88. inhibitor selumetinib (AZD6244, ARRY-142886). Investig. New Drugs 2011, 29, 1114–1121. [Google Scholar] [CrossRef] [PubMed]
  56. Livingstone, E.; Zimmer, L.; Vaubel, J.; Schadendorf, D. BRAF, MEK and KIT inhibitors for melanoma: Adverse events and their management. Chin. Clin. Oncol. 2014, 3, 29. [Google Scholar] [PubMed]
  57. Lueken, N.; Kaune, K.M.; Zutt, M. A Large Gray-Blue Macule on the Hard Palate as an Adverse Effect of Imatinib. Dtsch. Ärzteblatt Int. 2019, 116, 95. [Google Scholar]
  58. Shephard, M.K.; Lloyd-Lavery, A. Resolution of severe oral mucosal changes related to vemurafenib therapy with intensive periodontal treatment. Br. J. Dermatol. 2019, 181, 639–640. [Google Scholar] [CrossRef]
  59. Duong, T.A.; Valeyrie-Allanore, L.; Wolkenstein, P.; Chosidow, O. Severe cutaneous adverse reactions to drugs. Lancet 2017, 390, 1996–2011. [Google Scholar] [CrossRef]
  60. Grávalos, C.; Sanmartín, O.; Gúrpide, A.; España, A.; Majem, M.; Suh Oh, H.J.; Aragón, I.; Segura, S.; Beato, C.; Botella, R. Clinical management of cutaneous adverse events in patients on targeted anticancer therapies and immunotherapies: A national consensus statement by the Spanish Academy of Dermatology and Venereology and the Spanish Society of Medical Oncology. Clin. Transl. Oncol. 2019, 21, 556–571. [Google Scholar] [CrossRef]
  61. Lamiaux, M.; Scalbert, C.; Lepesant, P.; Desmedt, E.; Templier, C.; Dziwniel, V.; Staumont-Sallé, D.; Mortier, L. Severe skin toxicity with organ damage under the combination of targeted therapy following immunotherapy in metastatic melanoma. Melanoma Res. 2018, 28, 451–457. [Google Scholar] [CrossRef]
  62. Luherne, C.; Darrigade, A.S.; Dutriaux, C.; Prey, S.; Milpied, B. Reintroduction of dabrafenib after previous vemurafenib-induced DRESS: Not always safe! JAAD Case Rep. 2019, 5, 422–423. [Google Scholar] [CrossRef] [PubMed]
  63. Testori, A.A.E.; Ribero, S.; Indini, A.; Mandalà, M. Adjuvant Treatment of Melanoma: Recent Developments and Future Perspectives. Am. J. Clin. Dermatol. 2019, 20, 817–827. [Google Scholar] [CrossRef]
  64. Dummer, R.; Ascierto, P.A.; Gogas, H.J.; Arance, A.; Mandala, M.; Liszkay, G.; Garbe, C.; Schadendorf, D.; Krajsova, I.; Gutzmer, R.; et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018, 19, 1315–1327. [Google Scholar] [CrossRef] [PubMed]
  65. Dumas, M.; Laly, P.; Gottlieb, J.; Vercellino, L.; Paycha, F.; Bagot, M.; Baroudjian, B.; Madelaine, I.; Basset-Seguin, N.; Eftekhari, P.; et al. Osteopenia and fractures associated with long-term therapy with MEK inhibitors. Melanoma Res. 2018, 28, 641–644. [Google Scholar] [CrossRef] [PubMed]
  66. Kanis, J.A.; Johnell, O.; Oden, A.; Johansson, H.; McCloskey, E. FRAX™ and the assessment of fracture probability in men and women from the UK. Osteoporos. Int. 2008, 19, 385–397. [Google Scholar] [CrossRef] [PubMed]
  67. Dika, E.; Lambertini, M.; Gouveia, B.; Mussi, M.; Marcelli, E.; Campione, E.; Gurioli, C.; Melotti, B.; Alessandrini, A.; Ribero, S. Oral Manifestations in Melanoma Patients Treated with Target or Immunomodulatory Therapies. J. Clin. Med. 2021, 10, 1283. [Google Scholar] [CrossRef]
  68. Spain, L.; Larkin, J.; Turajlic, S. New survival standards for advanced melanoma. Br. J. Cancer 2020, 122, 1275–1276. [Google Scholar] [CrossRef]
  69. Dummer, R.; Hauschild, A.; Santinami, M.; Atkinson, V.; Mandalà, M.; Kirkwood, J.M.; Sileni, V.C.; Larkin, J.; Nyakas, M.; Dutriaux, C.; et al. Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. N. Engl. J. Med. 2020, 383, 1139–1148. [Google Scholar] [CrossRef]
  70. Schadendorf, D.; Hauschild, A.; Santinami, M.; Atkinson, V.; Mandalà, M.; Chiarion-Sileni, V.; Larkin, J.; Nyakas, M.; Dutriaux, C.; Haydon, A.; et al. Patient-reported outcomes in patients with resected, high-risk melanoma with BRAFV600E or BRAFV600K mutations treated with adjuvant dabrafenib plus trametinib (COMBI-AD): A randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019, 20, 701–710. [Google Scholar] [CrossRef]
  71. Lyne, A.; Creedon, A.; Bailey, B.M.W. Mucosal pigmentation of the hard palate in a patient taking imatinib. BMJ Case Rep. 2015, 2015, bcr2015209335. [Google Scholar] [CrossRef]
  72. Su, F.; Viros, A.; Milagre, C.; Trunzer, K.; Bollag, G.; Spleiss, O.; Reis-Filho, J.S.; Kong, X.; Koya, R.C.; Flaherty, K.T.; et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N. Engl. J. Med. 2012, 366, 207–215. [Google Scholar] [CrossRef] [PubMed]
  73. Dika, E.; Patrizi, A.; Venturoli, S.; Fanti, P.A.; Barbieri, D.; Strammiello, R.; Melotti, B.; La Placa, M. Human papillomavirus evaluation of vemurafenib-induced skin epithelial tumors: A case series. Br. J. Dermatol. 2015, 172, 540–542. [Google Scholar] [CrossRef] [PubMed]
  74. Vigarios, E.; Lamant, L.; Delord, J.; Fricain, J.; Chevreau, C.; Barrés, B.; Gomez-Roca, C.; Boulanger, M.; Sibaud, V. Oral squamous cell carcinoma and hyperkeratotic lesions with BRAF inhibitors. Br. J. Dermatol. 2015, 172, 1680–1682. [Google Scholar] [CrossRef] [PubMed]
  75. Carrozzo, M.; Porter, S.; Mercadante, V.; Fedele, S. Oral lichen planus: A disease or a spectrum of tissue reactions? Types, causes, diagnostic algorhythms, prognosis, management strategies. Periodontol. 2000 2019, 80, 105–125. [Google Scholar] [CrossRef]
  76. Fitzpatrick, S.G.; Hirsch, S.A.; Gordon, S.C. The malignant transformation of oral lichen planus and oral lichenoid lesions: A systematic review. J. Am. Dent. Assoc. 2014, 145, 45–56. [Google Scholar] [CrossRef] [PubMed]
  77. Dessirier, F.; Arnault, J.P.; Denamps, J.; Sevestre, H.; Attencourt, C.; Lok, C. Actinomycose révélée par une ulcération du palais et de la gencive [Actinomycosis revealed by ulceration of the palate and gingiva]. Ann. Dermatol. Venereol. 2018, 145, 173–177. (In French) [Google Scholar] [CrossRef] [PubMed]
  78. Damsin, T.; Collignon, J.; Lebas, E.; Libon, F.; Dezfoulian, B.; Nikkels, A.F. Comment je traite … les toxicités mucocutanées des thérapies ciblées en oncologie [Treatment of mucocutaneous toxicity of target therapy in oncology]. Rev. Med. Liege 2019, 74, 7–14. (In French) [Google Scholar] [PubMed]
  79. Peterson, D.E.; Boers-Doets, C.B.; Bensadoun, R.J.; Herrstedt, J.; on behalf of the ESMO Guidelines Committee. Management of oral and gastrointestinal mucosal injury: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Ann. Oncol. 2015, 26 (Suppl. S5), v139–v151. [Google Scholar] [CrossRef]
  80. Vigarios, E.; Epstein, J.B.; Sibaud, V. Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors. Support. Care Cancer 2017, 25, 1713–1739. [Google Scholar] [CrossRef]
  81. Claveau, J.; Archambault, J.; Ernst, D.S.; Giacomantonio, C.; Limacher, J.J.; Murray, C.; Parent, F.; Zloty, D. Multidisciplinary management of locally advanced and metastatic cutaneous squamous cell carcinoma. Curr. Oncol. 2020, 27, e399–e407. [Google Scholar] [CrossRef]
  82. Horvath, L.E.; Yordan, E.; Malhotra, D.; Leyva, I.; Bortel, K.; Schalk, D.; Mellinger, P.; Huml, M.; Kesslering, C.; Huml, J. Multidisciplinary Care in the Oncology Setting: Historical Perspective and Data From Lung and Gynecology Multidisciplinary Clinics. J. Oncol. Pract. 2010, 6, e21–e26. [Google Scholar] [CrossRef] [PubMed]
  83. Gershenwald, J.E.; Scolyer, R.A.; Hess, K.R.; Sondak, V.K.; Long, G.V.; Ross, M.I.; Lazar, A.J.; Faries, M.B.; Kirkwood, J.M.; McArthur, G.A.; et al. For members of the American Joint Committee on Cancer Melanoma Expert Panel and the International Melanoma Database and Discovery Platform. Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017, 67, 472–492. [Google Scholar] [PubMed]
  84. Cornelius, L.A.; Fields, R.C.; Tarhini, A. Multidisciplinary Care of BRAF-Mutant Stage III Melanoma: A Physicians Perspective Review. Oncologist 2021, 26, e1644–e1651. [Google Scholar] [CrossRef] [PubMed]
Table 1. Resuming table of the result section. NA: not applicable.
Table 1. Resuming table of the result section. NA: not applicable.
AuthorsTarget
Terapy		Number of PatientsToxicityTreatment
Rouleau JC et al. [52]NA50% of hospitalized patientsStevens–Johnson Syndrome (SJS)
(Erosive stomatitis)		Appropriate diet, antibacterial treatment, plasmapheresis
Duong TA et al. [60]NANADrug rash with eosinophilia and systemic syndrome (DRESS)Oral corticosteroids, antipyretics, patch testing at month 6
NAOral mucous membrane
involvement		Topical steroids, antipyretics, patch testing after 6 weeks
Lamiaux et al. [62]Vemurafenib associated
with cobimetinib		one caseStevens–Johnson syndromeCorticotherapy (case by case)
Vemurafenib associated
with cobimetinib		four casesDrug rash with eosinophilia and systemic
symptoms (DRESS)		Corticotherapy (case by case)
G.V. Long et al. [65]Dabrafenib
plus trametinib		438 patientsKeratoacanthoma was reported in eight patientsNA
Dummer R et al. [66]Encorafenib or vemurafenib52 patientsDysgeusiaNA
Robert C. et al. [67]Dabrafenib plus trametinib699 patientsHyperkeratosis in 15 patientsNA
VemurafenibHyperkeratosis in 88 patientsNA
Dumas et al. [68]Dabrafenib with trametinibtwo patientsFractures with osteopeniaCalcium, vitamin D, phosphate supplements or calcitriol
Dika et al. [70]NANAGingival hyperplasiaFollow-up
NivolumabNALichenoid reactionsTopical corticosteroids
Anti-PD-1 treatmentNAImmunobullous ReactionsNA
Nivolumab or pembrolizumabNAXerostomiaAccurate oral hygiene,
dietary advice
ImatinibNAPigmentation disorders of the palateClinical and dermoscopic follow-up
VemurafenibNASquamoproliferative lesionsNA
Bevacizumab,
sorafenib and sunitinib		NABenign migratory glossitisNA
Lyne et al. [74]Imatinibone caseOral mucosal pigmentationNA
Su et al. [75]VemurafenibNAKeratocantomaNA
Dika et al. [76]VemurafenibSeven patientsSquamo-proliferative epithelial neoplasmsNA
Vigarios et al. [77]Vemurafenib,
dabrafenib		NAHyperkeratotic lesions (linea alba, hard palate, gingiva…),
hyperplasia of gum,
secondary squamous cell carcinoma		NA
Carrozzo et al. [78]NANAOral lichen planusNA
Fitzpatrick et al. [79]NANAOral lichen planus
Oral lichenoid lesions		NA
Dessirier et al. [80]Dabrafenibone caseActynomicosisAntibiotics
Shephard et al. [81]Vemurafenibone caseHyperkeratosis, hyper-plasia, ulceration and inflammation of the gingivaePeriodontal treatment
Peterson et al. [82]NANANANA
Vigarios et al. [83]Dabrafenib with vemurafenibNAHyperkeratotic lesionsNA
Mangold et al. [53]Vemurafenibone caseGingival hyperplasiaNA
Gençler et al. [55]Vemurafenib,
dabrafenib		NASquamo-proliferative lesionsNA
Balagula et al. [56]Selumetinib8Cheilitis angularisNA
Livingstone et al. [57]Multikinase inhibitors (imatinib, dasatinib e nilotinib)NAOral lichenoid reactions, mucositis and oral ulcerationsCorticosteroids, antihistamines
Lueken et al. [58]Tyrosine kinase inhibitorsone casePigmented lesionsFollow-up
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Basilicata, M.; Terrano, V.; D'Aurelio, A.; Bruno, G.; Troiani, T.; Bollero, P.; Napolitano, S. Oral Adverse Events Associated with BRAF and MEK Inhibitors in Melanoma Treatment: A Narrative Literature Review. Healthcare 2024, 12, 105. https://doi.org/10.3390/healthcare12010105

AMA Style

Basilicata M, Terrano V, D'Aurelio A, Bruno G, Troiani T, Bollero P, Napolitano S. Oral Adverse Events Associated with BRAF and MEK Inhibitors in Melanoma Treatment: A Narrative Literature Review. Healthcare. 2024; 12(1):105. https://doi.org/10.3390/healthcare12010105

Chicago/Turabian Style

Basilicata, Michele, Vincenzo Terrano, Alessandro D'Aurelio, Giovanni Bruno, Teresa Troiani, Patrizio Bollero, and Stefania Napolitano. 2024. "Oral Adverse Events Associated with BRAF and MEK Inhibitors in Melanoma Treatment: A Narrative Literature Review" Healthcare 12, no. 1: 105. https://doi.org/10.3390/healthcare12010105

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop