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Oral Mucosal Injury Caused by Targeted Cancer Therapies

Oral Mucosal Injury Caused by Targeted Cancer Therapies Abstract Targeted cancer therapies have fundamentally transformed the treatment of many types of cancers over the past decade, including breast, colorectal, lung, and pancreatic cancers, as well as lymphoma, leukemia, and multiple myeloma. The unique mechanisms of action of these agents have resulted in many patients experiencing enhanced tumor response together with a reduced adverse event profile as well. Toxicities do continue to occur, however, and in selected cases can be clinically challenging to manage. Of particular importance in the context of this monograph is that the pathobiology for oral mucosal lesions caused by targeted cancer therapies has only been preliminarily investigated. There is distinct need for novel basic, translational, and clinical research strategies to enhance design of preventive and therapeutic approaches for patients at risk for development of these lesions. The research modeling can be conceptually enhanced by extrapolating “lessons learned” from selected oral mucosal conditions in patients without cancer as well. This approach may permit determination of the extent to which pathobiology and clinical management are either similar to or uniquely distinct from oral mucosal lesions caused by targeted cancer therapies. Modeling associated with oral mucosal disease in non-oncology patients is thus presented in this context as well. This article addresses this emerging paradigm, with emphasis on current mechanistic modeling and clinical treatment. This approach is in turn designed to foster delineation of new research strategies, with the goal of enhancing cancer patient treatment in the future. Targeted cancer therapies have substantially changed the treatment of cancer over the past 10 years. Use of targeted therapy has considerably improved clinical outcomes for many common malignancies, including breast, colorectal, head and neck, lung, and pancreatic cancers, as well as lymphoma, leukemia, and multiple myeloma. Imatinib has had a dramatic effect on chronic myeloid leukemia (1,2), and rituximab, sunitinib, and trastuzumab have revolutionized the treatment of non-Hodgkin’s lymphoma (3,4), renal cell carcinoma (5,6), and breast cancer (7,8), respectively. Relative to other cancers, however, the degree of clinical benefit has been more modest. For example, in patients with advanced pancreatic cancer, adding erlotinib to standard chemotherapy increases the 1-year survival rate from 17% to 23%, which correlates to an increase in median survival from only 24 to 27 weeks (9). In addition to prolonging survival in patients with selected types of cancers, targeted therapies provide treatment options for some patients who may not otherwise be candidates for conventional cancer therapy. For instance, non-small cell lung cancer and non-Hodgkin’s lymphoma primarily affect elderly patients, many of whom have medical comorbidities that limit the use of standard chemotherapy. Targeted therapies such as erlotinib, rituximab, or everolimus often lead to less severe adverse events (AEs) and are better tolerated than traditional chemotherapy, offering these patients additional treatment options. Similarly, immuno-oncology has substantially improved the prognosis for patients with advanced melanoma and squamous non-small cell lung carcinoma following platinum-based chemotherapy. This technology is likely to improve treatment of advanced disease in a number of other malignancies. Despite this collective strategic positive clinical impact, these agents are also associated with a unique constellation of inflammatory conditions of the skin and mucosa (10). These AEs include oral mucosal lesions that are phenotypically distinct from oral mucosal injury caused by conventional high-dose cancer therapy (Figure 1). In addition, AEs other than oral mucosal and dermal lesions, including cardiac dysfunction, thrombosis, hypertension, and proteinuria, can be caused by targeted cancer therapies as well. Figure 1. View largeDownload slide Mammalian target of rapamycin inhibitor-associated stomatitis. A) Tongue, after patient received three 21-day cycles (63 days) of ridaforolimus. B) Inner lip, as positioned by the patient’s fingers, in patient who developed mTOR inhibitor-associated stomatitis within 10 days of initiating treatment with everolimus (10 mg once daily) in combination with figitumumab. Reprinted with permission from Pilotte AP et al. (11). Figure 1. View largeDownload slide Mammalian target of rapamycin inhibitor-associated stomatitis. A) Tongue, after patient received three 21-day cycles (63 days) of ridaforolimus. B) Inner lip, as positioned by the patient’s fingers, in patient who developed mTOR inhibitor-associated stomatitis within 10 days of initiating treatment with everolimus (10 mg once daily) in combination with figitumumab. Reprinted with permission from Pilotte AP et al. (11). Utilization of targeted cancer therapies in oncology practice has thus provided a strategic new opportunity for tailoring cancer treatment to an individual patient’s tumor. Administration of these agents to patients has also resulted in the need to prevent or treat the associated AEs as well as address health-care costs related to their use. An increasing number of individuals will be diagnosed with cancer in the future, with associated expanded use of targeted cancer therapies that in turn results in patients living longer as well. The interprofessional healthcare team will thus need to be positioned to provide care for the increased number of patients who are treated with these agents. Targeted Therapies Unlike conventional cancer therapies, targeted cancer therapies are designed to interfere with tumor cell-specific molecular pathways essential for tumor growth and progression. As such, the ultimate goal of targeted therapies is to eliminate the patient’s cancer with increased precision and fewer AEs than with chemotherapy and/or radiotherapy. Examples of Targeted Cancer Therapies Therapeutic monoclonal antibodies target specific antigens located on the cell surface, such as transmembrane receptors (eg, panitumumab [Vectibix)]) (12) or extracellular growth factors (eg, bevacizumab [Avastin]) (13). In some cases, monoclonal antibodies are conjugated to radio-isotopes or toxins to allow specific delivery of these cytotoxic agents to the intended cancer cell target. Signal transduction inhibitors block signals transmitted from one molecule to another inside the cell. Blocking these signals can affect multiple cellular functions, including cell division and cell death. Examples of this class of agents include cetuximab (Erbitux) (14), everolimus (Afinitor) (15), and imatinib (Glivec) (16). Angiogenesis inhibitors block growth of neovascularization of tumors. Selected angiogenesis inhibitors (eg, bevacizumab [Avastin]) (13) interfere with vascular endothelial growth factor (VEGF), whereas others [eg, combrestatin (Zybrestat) (17)] bind to the β-subunit of tubulin and cause vascular disruption. Apoptosis-inducing drugs cause cancer cells to undergo controlled cell death. However, most of the cytotoxic anticancer drugs in current use have some ability to induce apoptosis. One example of a class of drugs with specific apoptosis-inducing effect is tumor necrosis factor-related apoptosis inducing ligand (Apo2L/TRAIL), expressed on immune cells such as natural killer cells. This moiety binds to several receptors, including death receptor-4 and -5 (DR5), and ultimately leads to an apoptotic cascade. Several monoclonal agonist antibodies have been investigated as cancer therapies; most are directed to DR5. Examples of these agents are lexatumumab (18) and conatumumab (19). As of February 5, 2019 both studies were in either phase I or II clinical trials (20). Gene-expression modulators modify the function of proteins that play a role in controlling gene expression. One of the most well-known classes of drugs are the histone deacetylase inhibitors such as vorinostat (Zolinza) (21) that modulate a broad spectrum of epigenetic activities. Hormone therapies can be considered for treatment of hormone-sensitive malignancies such as prostate cancer and breast cancer. The action of these agents is directed to either suppression of hormone production per se or by interfering with the molecular action of the hormone once bound to the tumor cell. Immunotherapies are currently utilized to treat many different types of cancer. These agents trigger the immune system to recognize and eliminate the cancer cells. Selected biologics are considered targeted therapies as well because they interfere with the growth of specific cancer cells. The main types of immunotherapy currently being used to treat cancer include the following technologies: Monoclonal antibodies that recognize specific molecules on the surface of cancer cells. Binding of the monoclonal antibody to the target molecule results in the immune destruction of cells that express the target molecule. Other monoclonal antibodies bind to certain immune cells to enhance the targeting of these cells against the tumor. Examples of monoclonal antibodies are alemtuzumab (Campath) (22), trastuzumab (Herceptin) (23), ibritumomab tiuxetan (Zevalin) (24), brentuximab vedotin (Adcetris) (25), ado-trastuzumab emtansine (Kadcyla, also called TDM-1) (26), denileukin diftitox (Ontak) (27), and blinatumomab (Blincyto) (28). Checkpoint inhibitors. These agents are immunomodulatory antibodies that include programmed cell death-1 (PD-1) receptor inhibitors. Multiple antibodies against PD-1 and its ligand (eg, pembrolizumab (Keytruda) (29), nivolumab (Opdivo) (30), and the cytotoxic T-lymphocyte-associated antigen 4 ipilimumab (Yervoy) (31) are available. Therapeutic vaccines, including sipuleucel-T (Provenge) (32). Peripheral blood mononuclear cells are obtained by leukapheresis and cultured with recombinant human prostatic acid phosphatase linked to granulocyte-macrophage colony-stimulating factor. Activated cells are injected into the patient to boost the immune response against the tumor. Cytokines (eg, interleukin-2 [Aldesleukin]) (33) and interferon α (IntronA) (34).    These agents are utilized alone or in combination to stimulate the immune system, especially killer T cells, to target cancer cells. Cytokines were commonly used in metastatic malignant melanoma, metastatic renal cell carcinoma, and certain types of leukemia. Their use has, however, declined following the clinical introduction of checkpoint inhibitors. Chimeric antigen receptor (CAR) T-cell therapy.This technology redirects patients’ T cells to specifically target tumor cells and cause tumor cell cytolysis. In 2017, the US Food and Drug Administration approved the first anti-CD19 CAR T-cell therapies for relapsed or refractory B-cell precursor acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Dosing and Effectiveness Targeted therapies inclusive of immunotherapy have introduced several new issues for the oncology team. Determining optimal dosing is one challenge. Clinical trials of traditional chemotherapeutic drugs generally utilize degree of myelosuppression as a pivotal determinant of toxicity. Targeted therapies, however, often do not cause clinically significant hematologic reactions. Mucocutaneous AEs are the most common AEs associated with epidermal growth factor receptor inhibitors, whereas immunotherapies are more likely to cause immuno-related pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, and endocrinopathies. Assessment of treatment effectiveness also may require a paradigm shift. When traditional chemotherapy is effective, reduction in tumor volume is anticipated on serial radiographic studies. In contrast, some targeted therapies may impart a clinical benefit by stabilizing tumors rather than reducing tumor volume, especially in the first cycles of treatment. To determine the dosing and effectiveness of targeted therapies, cancer researchers increasingly are turning to pharmacodynamic endpoints, such as tumor metabolic activity on positron emission tomography scans, levels of circulating tumor and endothelial cells, and serial levels of target molecules in tumor tissue (35–38). Although these studies may initially increase the time and expense of therapy, they may improve its long-term cost-effectiveness by identifying the subset of patients most likely to benefit from specific precision medicine technology. Targeted Cancer Therapy-Associated Oral Injury Clinically important AEs that disrupt normal oral function have been described in recent years related to use of targeted therapies such as tyrosine-kinase inhibitors (39). The oral reactions include oral mucosal ulceration, dysgeusia, oral sensitivity and pain without presence of clinical oral lesions, and xerostomia. Of particular note are the unique oral mucosal lesions that have been reported in patients who received targeted therapies (40,41). Elting et al. determined via meta-analysis with selected targeted agents that oral mucosal injury was most frequent among patients treated with bevacizumab, erlotinib, sorafenib, or sunitinib, although this difference was confined to low-grade mucosal injury (42). Selected immunotherapies have been reported to cause oral reactions as well, including but not limited to oral mucosal lesions (9,10,40). Stomatitis and dry mouth, for instance, appear to be more frequent with PD-1 receptor checkpoint inhibitors than with cytotoxic T-lymphocyte-associated antigen 4 blockade. In a dose-escalation, cohort expansion study of nivolumab for treatment of advanced melanoma, for example, dry mouth was observed in 6.5% of patients, including one case with at least grade 3 severity (43). Oral candidiasis also remains an important consideration in the differential diagnosis of oral mucosal lesions, particularly if a patient has been on corticosteroids for management of other immunotherapy-related AEs and/or is experiencing salivary hypofunction. It is important to consider the terminology of “stomatitis” and “mucositis” relative to AE reporting and targeted therapies as described above. “Stomatitis” is a general, descriptive term that refers to any inflammatory condition of oral tissues including but not limited to oral mucosal erosion or ulceration. In contrast, “mucositis” has emerged in the literature over the past 20 years as the preferred term for oral mucosal injury due to conventional cytotoxic chemotherapy and radiation. Both words are searchable MeSH terms. Regarding mucosal injury induced by the specific class of mammalian target of rapamycin (mTOR) inhibitors, Sonis et al. in 2010 proposed the term “mTOR inhibitor-associated stomatitis” (mIAS) to provide clarity and delineation from oral mucositis due to conventional cytotoxic chemotherapy and radiation (44). There is consensus among oral medicine specialists managing patients with oral mucosal lesions associated with mTOR inhibitors that the term mIAS is preferable to the term “oral mucositis” as described in the literature (45). Mechanistic Modeling of Oral Mucosal Injury Secondary to Targeted Therapies Oral mucositis is a well-known AE that is caused by high-dose ionizing head and neck radiation to the oral cavity or selected chemotherapeutic drugs such as carboplatin, capecitabine, or paclitaxel (46–50). Historically, oral mucositis had been primarily linked to destruction of rapidly dividing clonogenic cells in the basal layer of the epithelium. However, studies in recent years have continued to demonstrate that the mucosal injury is associated with a complex pathobiology (51). The currently accepted five but not functionally separated phases are (1) cellular damage and formation of reactive oxygen species; (2) upregulation of mediators of inflammation and activation of a number of transcription factors, such as NF-κB, Wnt, and p53; (3) upregulation of pro-inflammatory cytokines like TNF; (4) ulceration with or without infection; and (5) healing. This modeling is reviewed in detail in the Monograph chapter “Oral Mucositis Due to High-Dose Chemotherapy and/or Head and Neck Radiation Therapy.” The pathobiology leading to mucosal damage on exposure to targeted drugs is likely also complex. Although not well elucidated, the mechanistic modeling can be categorized by some of the main classes of targeted drugs like inhibition of the EGFR-RAF-MEK pathway, PI3K-AKT-mTOR pathway inhibition, and inhibition of angiogenesis and v-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) (35). The role of genetic polymorphisms in causation, although not well delineated for oral mucosal lesions caused by targeted therapies, has been increasingly demonstrated to contribute in part but not exclusively to risk for development of oral mucositis caused by high-dose cancer therapy (52,53). Examples of drugs intervening with the EGFR-RAF-MEK pathways are cetuximab, erlotinib, and trametinib. For monoclonal antibodies and partly also small molecule EGFR inhibitors, the main event would be an inhibition of cell proliferation via deregulation of the G1 cell cycle checkpoint and subsequently inhibition of EGFR-driven repair of DNA damage. The latter is partly related to increased sequestration of DNA protein kinase due to enucleated EGFR being bound to monoclonal EGFR inhibitors. Consequently, these actions result in increased apoptosis and cell loss (54,55). Also, reduced levels of VEGF followed by reduced capacity for angiogenesis have been suggested as a result of EGFR inhibition. This might also play an important role in the pathobiology of mucositis when EGFR inhibitors are combined with radiotherapy (56–58), because this can influence the vascular density. Overall, these events are related to the first two phases of development of oral mucositis as proposed by Sonis and colleagues (59,60), and cell loss leads to ulceration that subsequently can be colonized by Candida and other fungi or oral bacteria (52). In addition to potential systemic dissemination, bacteria, for example, are active contributors to the mucositis process by simulating the secretion of pro-inflammatory cytokines. It is currently unknown how the contemporary mucositis mechanistic model with the described EGFR- driven processes of inhibition of cell proliferation and DNA repair may integrate into this modeling. The healing and ulceration phases are likely comparable regardless of being induced by chemotherapy, ionizing radiation, or inhibitors of the EGFR-RAF-MEK pathway. Oral ulcerations are common dose-limiting AEs associated with PI3K-AKT-mTOR pathway inhibition (44,61,62). The mIAS presents as multiple or single ulcerations that are usually small and generally less than 0.5 cm in diameter, resembling aphthous stomatitis (63). Although the mechanism of inducing mIAS is not clear, mTOR inhibitors may bind directly to tissue proteins evoking an autoimmune-like inflammatory response (64) and can also inhibit VEGF and nitric oxide, which have been shown to be mediators of angiogenesis, inflammation, and immune function in skin wounds (65). Sirolimus has been specifically shown to disrupt T-cell proliferation, migration, and production of growth factors (66). These changes in nitric oxide and T-cell immune defense may also play an important role in recurrent aphthous stomatitis (67), suggesting that recurrent aphthous stomatitis and mIAS share common pathobiological pathways. However, data are conflicting and selected in vitro studies suggest that mTOR inhibitors increase stimulation of regulatory T-cells leading to increased peripheral tolerance, but mechanisms of action of mTOR inhibitors are likely multifaceted and can exert both immunosuppressive as well as immunostimulatory effects (68). Oral AEs due to antiangiogenic agents are most frequently seen with VEGFR-directed multi-target tyrosine kinase inhibitors such as sunitinib, sorafenib and cabozantinib. Approximately 25% of patients treated with these agents develop some type of stomatitis (10). The oral mucosal ulcerations that develop, although similar phenotypically to the oral aphthous-like lesions caused by mTOR inhibitors, are typically of low-grade severity. By comparison, these patients more typically report nonspecific mucosal inflammatory symptoms including mucosal hypersensitivity or dysesthesia and dysgeusia. These drugs block targets including c-Raf and b-Raf kinases as well as VEGFR-2, VEGFR-3, Flt-3, c-Kit, and the PDGF receptor. As such, they affect a range of cellular processes including tumor growth, tumor progression, angiogenesis, and metastasis. Having said this, knowledge of the underlining pathobiology of the oral AEs is limited. BRAF inhibitors (vemurafenib, dabrafenib) can cause oral hyperkeratotic lesions and gingival hyperplasia (69–72). A case of oral squamous cell carcinoma has also been reported to occur in association with a BRAF inhibitor (71). Notably, similar lesions are commonly caused by BRAF inhibitors on the skin, and they are thought to be due to the proliferation of BRAF wild-type keratinocytes (KCs) induced by paradoxical activation of the mitogen-activated protein kinase pathway in the presence or absence of recurrent aphthous stomatitis (RAS) mutations (71). By comparison, checkpoint inhibitors such as nivolumab have been reported to trigger severe erythema multiforme (EM)-like eruption with erosive oral mucosal involvement (16,17). The majority of these targeted therapeutics in clinical use are administered in combination with other systemic therapies or radiotherapy, making it even more difficult to elucidate the mechanisms and interactions in vivo. Although most of the targeted therapies are well investigated for their anticancer effects, the oral AEs are less frequently systematically characterized. Progress in unraveling the molecular pathways and developing new specific treatments directed to the oral injury thus requires a more appropriate registration and description of the pathology of targeted therapy-induced stomatitis. Do Nontargeted and Targeted Anticancer Agents Cause Different Oral Manifestations? Although designed to be more “precise” than traditional chemotherapies, targeted therapies frequently induce AEs, including in the oral cavity. Targeted drugs known to cause oral AEs include epidermal growth factor receptor inhibitors such as cetuximab, tyrosine kinase inhibitors (axitinib), selective and nonselective antiangiogenic agents (bevacizumab, sunitinib, and sorafenib), mTOR (temsirolimus, everolimus, and ridaforolimus), and BRAF inhibitors (vemurafenib, dabrafenib) (61,73). The oral AEs range from stomatitis to dysgeusia and osteonecrosis of the jaws, oral white patches, and gingival overgrowth. However, the evidence regarding oral cavity injury caused by targeted therapy is relatively limited in quality and quantity (74). The most extensively studied oral AEs to date are those associated with mIAS. With mIAS, the ulcers observed clinically in patients receiving targeted anticancer agents are often described as aphthous-like. However and when the clinical phenotype has been described, the lesions on occasion seem larger and deeper than traditional aphthae (44,75). The ulcers also exhibit a tendency to coalesce and involve sites such as dorsal tongue or attached gingiva, which are usually spared by typical aphthous ulcers (76–78). Infectious causes, for example due to herpesviruses, have not always been properly excluded in the majority of cases. This has been the historical context, even though a number of early studies regarding mTOR inhibitors utilized to prevent graft rejection in solid organ transplantation highlighted the possible herpetic etiology of the oral ulcers (76). A recent structured review regarding risk of oral AEs with mTOR inhibitor stated that stomatitis was different from that seen during traditional radiotherapy and chemotherapy, and when described it resembled either aphthous or herpetic stomatitis (79). However, only 38.6% of the original studies described in detail the oral manifestations and only two, both employing temsirolimus (80,81), of 44 cited aphthous-like ulcers. Selected trials reported various terminology such as mouth sores (82,83), ulcerative mucositis, and aphthous-like ulcers (81). The majority of the studies included grade 3–4 oral AEs, but severe oral lesions were not always and consistently related to increased dosage (84–87). mTOR inhibitor mucositis-related dose reduction and even discontinuation were reported but only by a minority of studies, whereas most did not specify this information (79). A 2015 meta-analysis on stomatitis with mTOR inhibitors in cancer patients reported an incidence of all-grade and high-grade stomatitis of 33.5% and 4.1%, respectively (88). However, in this study incidence of high-grade stomatitis varied statistically significantly with tumor type and mTOR inhibitors. The authors noted that the lack of uniform measurement scales and terminology for stomatitis secondary to mTOR inhibitors may have led to underestimation of stomatitis across the studies. The majority of studies published to date regarding mTOR inhibitors did not apparently include an oral examination performed by trained oral specialists, and the usual way to collect AEs is the National Cancer Institute Common Criteria for Adverse Events reporting, which often relies on spontaneous patient report, leading to possible under- and misreporting (61,74). In addition, measurement scales and terminology differ among studies, which in turn further complicates insight into the prevalence of these AEs (61). The evidence is even more sparse when oral lesions caused by targeted therapeutics other than mTOR are reported (73). In conclusion, although it is likely that targeted cancer therapies cause unique oral AEs, further studies are needed to better characterize, minimize, and manage these lesions. Even if these drugs are causing moderate stomatitis, dose reduction and also cessation of therapy has been reported due to pain with potential deleterious outcomes for tumor response. Prospective studies incorporating patient-reported outcomes using validated instruments together with specific clinical evaluation of the oral cavity are warranted in this context. Comparison With State of the Science of Immunologically Mediated Oral Disease Given the current gaps in understanding of pathobiology of oral mucosal injury caused by targeted cancer agents, review of the state of the science regarding naturally occurring immunologically mediated oral disease (IMOD) may provide key foundational insights into new research directions that could be applied to study the oral mucosal lesions caused by the targeted cancer therapeutics. Elements of the molecular modeling as described below are included in Figures 2 and 3 as well. Figure 2. View largeDownload slide Immunopathogenesis of recurrent aphthous stomatitis. In genetically predisposed patients, an increase of epithelial permeability and dysfunction or regulatory T cells (Treg) enables epithelial cells to begin an inflammatory response triggered by several different factors. The result is an increase of apoptosis and accumulation of antigen presenting cells, cytotoxic T cells, and Th1 cytokines that in turn cause necrosis of keratinocytes and ulceration and further increase of Th1 cytokine release. APC = ; IL = ; PAMP = : ROS = ; Th = ; TLR = . Figure 2. View largeDownload slide Immunopathogenesis of recurrent aphthous stomatitis. In genetically predisposed patients, an increase of epithelial permeability and dysfunction or regulatory T cells (Treg) enables epithelial cells to begin an inflammatory response triggered by several different factors. The result is an increase of apoptosis and accumulation of antigen presenting cells, cytotoxic T cells, and Th1 cytokines that in turn cause necrosis of keratinocytes and ulceration and further increase of Th1 cytokine release. APC = ; IL = ; PAMP = : ROS = ; Th = ; TLR = . Figure 3. View largeDownload slide Immunopathogenesis of pemphigus vulgaris. In genetically predisposed patients, a loss of self-tolerance against Desmoglein 3 (Dsg 3) and potentially other antigens in both T and B lymphocytes can enable different etiologic factors to begin production of IgG autoantibodies. Binding of pathogenic (either anti-Dsg and non‐Dsg) antibodies to keratinocytes causes activation of Src, EGFRK, p38 MAPK, and mammalian target of rapamycin and elevation of intracellular Ca2+, altogether, initiate cell death enzymatic cascades. Suprabasal acantholysis starts when basal cells shrink. Acantholysis advances and stimulates production of secondary (scavenging) antibodies. Rounding up and death of acantholytic cells in the lower epidermal compartment follow irreversible damage of mitochondrial and nuclear proteins. Figure 3. View largeDownload slide Immunopathogenesis of pemphigus vulgaris. In genetically predisposed patients, a loss of self-tolerance against Desmoglein 3 (Dsg 3) and potentially other antigens in both T and B lymphocytes can enable different etiologic factors to begin production of IgG autoantibodies. Binding of pathogenic (either anti-Dsg and non‐Dsg) antibodies to keratinocytes causes activation of Src, EGFRK, p38 MAPK, and mammalian target of rapamycin and elevation of intracellular Ca2+, altogether, initiate cell death enzymatic cascades. Suprabasal acantholysis starts when basal cells shrink. Acantholysis advances and stimulates production of secondary (scavenging) antibodies. Rounding up and death of acantholytic cells in the lower epidermal compartment follow irreversible damage of mitochondrial and nuclear proteins. Text in this section summarizes current knowledge regarding IMOD pathobiology. Potential applicability of this science in nononcology modeling to new research directions regarding oral mucosal lesions caused by targeted cancer therapies is then summarized in the next section of this publication beginning on page 37, titled “What Lessons Can Be Learned From Immunologically Mediated Oral Injury?” There are three main clinical and pathologic inflammatory pathways occurring in the oral cavity: aphthous, lichenoid, and bullous or blistering. RAS, EM, and pemphigus vulgaris (PV) represent prototypic examples of these patterns of inflammation. Oral manifestations of these disorders can mimic stomatitis caused by anticancer targeted drugs, and, remarkably, all these diseases can only affect the mouth. Similar to stomatitis, RAS and EM are principally acute and self-resolving, whereas PV in many but not all the instances is a chronic condition. Interestingly, either EM or PV can be elicited by radiotherapy, whereas drugs can be a potential cause of all three manifestations (89–91). At least for EM there is strong evidence that targeted and nontargeted chemotherapeutic drugs can also cause the injury (92). Moreover, fludarabine, a synthetic nucleoside analogue, has been associated with the onset of paraneoplastic pemphigus (93), an aggressive variety of pemphigus commonly affecting the oral cavity. As previously noted, targeted anticancer therapies, particularly mTOR inhibitors, are considered a cause of oral aphthous-like ulcers based on clinical phenotype. Recurrent Aphthous Stomatitis RAS is a common condition characterized by multiple recurrent small, round, or ovoid ulcers with erythematous haloes almost exclusively affecting nonkeratinized mucosa in otherwise healthy individuals. The etiopathogenesis of RAS is not fully understood; triggering factors potentially include mechanical trauma, microbial factors, vitamin and microelement deficiencies, drugs, foods, hormonal imbalances, and anxiety (94). Systemic diseases such as Behcet’s syndrome are also characterized by aphthous-like ulcers that histologically mimic classic aphthae. There is likely a genetic predisposition, although studies of human leukocyte antigen (HLA) have been inconsistent in this context (94). An association with functional polymorphisms of interleukins (IL)-1β, IL-6, and IL-10 leading to increased activities of those cytokines has been suggested (95) and confirmed in different populations by meta-analyses (96–98). Moreover, increased production of IL-1 has been shown in RAS patients (99). Notably, the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (the so-called PFAPA syndrome) is a disorder of innate immunity and Th1 activation characterized by increased level of complement and IL-1β/-18 during flares (100). Similarly, there is an increase production of Th1 cytokines in RAS. It remains unclear if RAS is caused by a T-cell–mediated immune reaction (type IV reaction according to Gell-Coombs) (101), or if it rather represents an antibody-dependent cell-mediated cytotoxicity (type II) (94). Circulating CD4+ T cells are reduced whereas CD8+ and γδ T cells are increased (102,103). In the pre-ulcerative phase of RAS, there is a local mononuclear infiltrate consisting initially of CD4+T cells (104), whereas the ulcerative phase is associated with the appearance of CD8+ lymphocytes (105) and increased number of antigen-presenting cells. In vitro studies have indicated that peripheral blood leucocytes of patients with RAS may demonstrate increased cytotoxicity towards oral mucosal epithelium expressing class I and II MHC antigens (106–111). It is thus possible that RAS may represent an antibody-dependent cell-mediated cytotoxicity-type reaction to the oral mucosa. Other studies, however, suggest that RAS could be a T-cell–mediated response. For example, antigens of Streptococcus sanguis may cross-react with mitochondrial heat shock proteins and induce oral mucosal damage (112). Notably, a quantitative and functional dysfunction of regulatory T cells (Treg) cells in RAS patients has been suggested (113). Treg cells are critical in the maintenance of peripheral self-tolerance and controlling the immune responses against microbes. There is an increasing body of evidence suggesting that perturbations of mucosal microbiota, called microbial dysbiosis, can modulate innate and adaptive immune responses (114). This evidence suggests that mucosal microbiome changes in patients with idiopathic RAS may contribute to ulcer pathogenesis. Interestingly and in contrast to healthy mucosa, in RAS patients the normal polarity of Toll-like receptor (TLR) architecture is lost and most of TLRs extend to the epithelial cell surface, ultimately causing increased epithelial permeability and enabling those epithelial cells to start an inflammatory response to well-conserved pathogen associated molecular patterns (115). Oral epithelial cells in RAS are indeed not only passive targets of immune-inflammation but represent a potentially very important inflammatory cell pool that can produce IL-17C (116). RAS can be initiated by sudden and severe apoptosis of the oral epithelial cells (117). Because of a lack of scavenging anti-inflammatory macrophages, apoptotic cells likely undergo secondary necrosis and thus release pro-inflammatory signals such as self-DNA. This outcome may in turn contribute to the peripheral inflammatory halo (117) and further increase Th1 cytokine release. Erythema Multiforme EM is a muco-cutaneous disorder belonging to the lichenoid tissue reaction-interface dermatitis group (118). These disorders share a pattern of common histopathological elements including liquefative or vacuolar degeneration of basal KCs, a band-like array of mononuclear cells in the dermis including activated T cells, macrophages, and dendritic cells (119). EM is an example of low-density inflammatory infiltrate in the lichenoid tissue reaction-interface dermatitis group. Clinically, EM can occur independently or in combination in the mouth and other mucous membrane and skin. However, isolated oral lesions are commonly misdiagnosed as fixed drug eruption (120), unspecified oral ulcerations (121), or atypical erosive oral lichen planus (122). Typical EM oral lesions are ulcerative in nature and are often widespread and predominantly involving the anterior part of the oral cavity with frequent crusting and ulceration of the lips. EM, particularly the severe variant called EM major, is strictly related to potentially fatal Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) and is considered part of the same spectrum (123). The characteristic histolopathologic pattern of SJS and TEN, for example, presents with necrotic KCs in either wide dissemination or full-thickness necrosis of the epidermis (123). EM and SJS or TEN are currently considered as cell-mediated reactions aimed at the destruction of KCs and /or mucosal KCs expressing herpes- or drug-related antigens (124); however, the pattern and distribution of individual cutaneous lesions can be different (125). Oral ulcerations can be seen in the majority of severe EM and SJS or TEN. Both nontargeted (alkylating agents, purines, mitotic inhibitors) and targeted (nonreceptor tyrosine kinase inhibitors, hormone antagonists, checkpoint inhibitors) drugs can trigger EM (92). EM is a type IV reaction according to the Gell-Coombs system classification (101). A possible pathogenetic role of autoantibodies against desmoplakin I and II has been suggested in EM (126). However, desmoplakin-positive patients might simply represent a subset of PV patients with an unusual phenotype of EM (127). Generation of auto-reactive T cells that target the epidermis plays an important role in the pathogenesis of EM (125,128). Studies have shown that sparse distribution of Tregs might be involved in the onset of severe muco-cutaneous adverse drug reactions and that Treg migration toward epithelial cells can be influenced by medication such as allopurinol, commonly causing severe EM. These auto-reactive T cells release inflammatory cytokines, such as interferon-γ and tumor necrosis factor (TNF)-α (128), which can induce apoptosis and related changes in epidermal KCs. Various mediators have been suggested to stimulate apoptosis, including TNF-α-related apoptosis inducing ligand, perforin/grazyme, Fas-ligand, CD40/CD40 ligand system and granulysin (129). The peptide antigens (either viral or drug) have to be bound to MHC protein in the intracellular environment and expressed on the surface of antigen presenting cells to stimulate T-cell activation. Models explaining how small-molecule pharmaceutical compound might interact with MHC include the hapten-prohapten model, the p-i model, and the altered peptide reporter model. EM appears to be associated with selected HLA loci, mainly with HLA-B15 (B62), HLA- B35, HLA-A33, HLADR53, and HLA-DQB1*0301. The latter has been strongly associated with herpes simplex virus-associated EM (130). Notably, several associations between adverse drug reactions and HLA class I and/or class II alleles are characterized by a high predictive value, which makes it possible to use those associations to screen patients and prevent the risk. This strategy has been applied in clinical settings in Chinese patients carrying the HLA-B*15:02 allele who have a substantial risk of SJS or TEN and in various populations in whom allopurinol intake has been associated with similar risk of SJN or TEN when positive for the HLA-B*58:01 allele (131,132). It is still unknown what factors, in addition to HLA risk allele carriage, are required to trigger a T-cell–mediated drug hypersensitivity reaction and what might account for the differences among clinical phenotype of different reactions (133). Because cellular immunity requires plasticity, it might be that heterologous immunity, namely the concept of a single T cell receptor recognizing peptides derived from more than one source (either viral or drug related), is involved. Notably, several viruses have been seen to influence allergic reactions to drugs including EM. These viruses mainly belong to the human herpesvirus family and encompass human herpes virus 6, cytomegalovirus, and Epstein-Barr virus (134–136). Pemphigus Vulgaris PV is a potentially lethal muco-cutaneous blistering disease characterized by IgG autoantibodies (PVIgG) binding to KCs (137). This is a type II reaction according to the Gell-Coombs system classification (101). PV patients develop cell-cell detachment (acantholysis), blisters, and nonhealing erosions due to suprabasal split within the epidermis. Little is known about how intercellular autoantibodies arise. In most individuals, the disease is idiopathic. However, in some patients it is triggered by an external cause, such as drugs, particularly those having a thiol (a sulfhydryl radical) group in their molecule [eg, penicillamine, captopril, bucillamine, and thiopronine (91)], and ionizing radiation (89). Other putative inducing factors can be pesticides, dietary factors (particularly garlic, leeks, and onion) and emotional stress (138). PV can be also aggravated by radiotherapy (139). The mechanisms through which drugs and ionizing radiation can elicit or facilitate autoantibody production is still unclear, but thiol acantholysis is probably both biochemical and immunologic (138). Notably, discontinuation of the putative culprit drug causes spontaneous recovery in the majority of the patients. PV typically initially presents in the mouth and remains limited to the oral cavity. The onset can be subtle and mimic recurrent aphthous stomatitis (140) or even factitious or traumatic lesions, but established lesions are wide ulcerations and can occur on any oral mucosal tissue. The main target of PVIgG appears to be the extracellular domains of desmosomal cadherins called desmoglein 1 and 3 (Dsg1 and Dsg3) (141,142). The fact that Dsg3 is prevalently expressed in the oral cavity may explain the predominant prevalence of oral lesions at onset (142). Passive transfer of the monoclonal antibody AK23 against Dsg3 in mice results in the development of PV lesions (143–146). Besides Dsg3 and Dsg1, several other non-Dsg autoantibodies have been linked to tissue damage and acantholysis in PV (147). PV has a strong genetic predisposition and was consistently found to be associated with the alleles HLA-DRB1*0402 and DRB1*1404 and DQB1*0302 and 0503 (148). The DRB*1404 is mainly associated with patients of South Asian origin, whereas the DRB1*0402 is prevalent in white Europeans and Ashkenazian Jews (149–151). Interestingly, most functional studies have shown that Dsg3-specific T-cell lines were restricted to DR (152). However, emerging data questioned the monopathogenic PV theory that suggests that antibody-dependent disabling of the Dsg 1- and/or Dsg 3-mediated cell-cell attachments of KCs is sufficient to disrupt epidermal integrity and cause blistering (153). For example, recent proteomic analyses of large cohorts of pemphigus and normal control sera revealed reactivities with desmocollin 1 and 3, several muscarinic and nicotinic acetylcholine receptor subtypes (154–156). Selected non-Dsg autoantibodies have been demonstrated to be pathogenic based on animal models. Conversely, the multipathogenic theory of PV pathophysiology explains intraepidermal blistering through the “multiple hit” hypothesis (153). According to this hypothesis, a simultaneous and synchronized inactivation of the physiological mechanisms regulating and/or mediating intercellular adhesion of KCs is necessary to disrupt epidermal integrity. Among these phenomena, increasing importance has been placed upon apoptotic mechanisms, and the concept of apoptolysis has been proposed (137). Epidemiologic studies revealed the population-specific association between PV and a polymorphic variant of the ST18 gene encoding a proapoptotic molecule (98). Moreover, proapoptotic mediators such as Fas-ligand and p38 MAPK are clearly activated on PV (157). It thus may be postulated that predisposed individual cell detachment and death in PV develop through binding of pathogenic antibodies to KCs, leading to activation of Src, EGFRK, p38MAPK, and mTOR and other signaling that together with elevation of intracellular calcium initiate cell death. Suprabasal acantholysis begins when basal cells shrink, followed by destruction of desmosomes and subsequent production of scavenging (secondary) autoantibodies targeted primarily to adhesion molecules that have been sloughed. The final phase is the rounding up and death of acantholytic cells in the lower epidermal compartment (157). What Lessons Can Be Learned From Immunologically Mediated Oral Injury? As noted in the previous section, knowledge regarding oral mucosal diseases in non-oncology modeling may help delineate new research directions involving oral mucosal lesions caused by targeted cancer therapies. The following five “lessons learned” are thus presented in this context. The first lesson is that AEs caused by targeted anticancer drugs must be better characterized and constantly and consistently reported in a standardized way. Although mIAS is commonly described as similar to aphthous ulcers, the lesions appear sometimes EM-like or even PV-like if not clearly viral. When atypical presentations are seen, further investigation such as viral or immunological tests could be considered. The involvement of oral medicine specialists in future trials is likely crucial to improve the recognition and management of oral AEs. Oral medicine experts are now indeed available in many countries (158). A second lesson is that despite the sometimes clinical similarity of mIAS with RAS, the outcome of the two conditions seems to be very different. Many mIAS cases improve or resolve spontaneously despite continuation of the treatment (61), whereas previous attacks of RAS do not confer protection or alleviation against future episodes (115). The same can be said for recurrent EM and PV. However, when a medication is the culprit, withdrawal of the causative drug can cause remission of the IMOD. Conversely, it seems that in mIAS in several instances, the body is able to reestablish a homeostasis and possibly tolerance. Study of TLR and Treg cells in these patients could be highly relevant in this context. A third lesson is that many, if not all, IMODs are associated with genetic predisposition that can in some instances help in predicting who is going to develop the manifestation. However, it is clear that the etiology of these disorders is multifactorial and likely involve multiple genes as shown in preliminary genome-wide studies (159). It is of note that, in mucositis caused by conventional cancer therapies, there has been some activity in identifying differences in the expression of genes that affect drug metabolism as an approach to predict AE risk among patients being treated with chemotherapy (160–162). Analysis of gene polymorphisms can be of value in the design of tailored cancer therapy (163). The future is likely the establishment of a hierarchy of multiple genes that help in stratifying the risk of patients to develop oral AEs of targeted therapies. A fourth lesson is that it is now evident that oral KCs not only function as passive targets but in IMOD can serve as immune-cells and eventually amplify the epithelial damage induced by several type of injuries. It thus becomes important to direct additional research attention to the role of oral epithelial cells in this modeling. The fifth lesson is that some targeted cancer strategies can also be used for IMOD, and the information gathered can feed future therapeutic developments. For example, a recent study showed CAR T-cell efficacy in targeting pathogenic B cells in PV, opening exciting avenues for CAR-T therapy in dermato-oncology (164). As with IMOD research in the past, previous research regarding oral mucosal injury caused by conventional high-dose cancer therapy was limited by an outdated, simplistic pathobiological paradigm. Modern mechanistic IMOD concepts might be utilized as an inspiration to broaden the research regarding mucosal injury caused by targeted therapies, particularly via identification of biological pathways that lead to clinical development of the lesions in cancer patients. Selected pathways (eg, apoptosis) are clearly involved in most if not all IMODs as well as with oral mucositis caused by cancer therapy. In this context, the lessons learned as delineated above are designed to inform future research with both categories of diseases. Clinical Assessment and Treatment of Oral Mucosal Injury Caused by Targeted Agents As noted previously, the oral mucosa may become directly injured by targeted cancer therapies. Conversely, oral mucosal lesions may be present before initiation of the therapy or develop due to nontargeted therapy causes during active cancer treatment. It is thus important to perform a baseline oral mucosal assessment before initiation of the targeted cancer therapy and implement management of preexisting oral mucosal conditions in addition to monitoring oral mucosal status during targeted cancer treatment. Assessment of oral mucosal injury caused by targeted cancer therapies includes investigating the constellation of symptoms and signs as well as their impact on the patient’s health-related quality of life. These evaluations and associated treatments should be performed in the context of standardized, literature-based approaches for oral mucosal lesions as well as concurrent oral AEs, as described previously. Accurate early assessment of oral mucosal lesions and their associated sequalae enhances the opportunity for their effective early treatment, thereby often mitigating the need for targeted therapy dose reduction or discontinuation that could otherwise negatively affect treatment outcomes for the patient. Assessment of AEs, including oral mucositis in oncology patients, has historically been based on validated grading schema as exemplified by the National Cancer Institute Common Criteria for Adverse Events (165) and the World Health Organization (166). Moderate to severe symptoms have typically driven clinical intervention. By comparison, multiple mild or early moderate symptoms, although individually not having statistically significant negative impact on quality of life, may nonetheless collectively represent a burden of illness that is clinically relevant and warrant treatment as well. Despite the value of these and related oral mucositis scales, however, they have not been specifically designed to grade oral mucosal lesions caused by targeted cancer therapies. As such, the scales may underestimate the morbidity of mIAS, because even small localized ulcerations can be extremely painful and affect compliance. A mIAS scale has thus been specifically developed for assessing mIAS (167). This mIAS scale includes a subjective component measuring pain and an objective component measuring duration of lesions. It is suggested that dose modification be considered only when both subjective and objective grades are severe, representing persistent lesions with substantial pain despite the use of analgesics or other supportive care interventions (61). An additional grading tool, the MASCC EGFR Inhibitor Skin Toxicity Tool, has been developed specifically for the assessment of dermal and related AEs caused by EGFR inhibitors (168,169). In this scale, oral mucosal injury is reported as “mucositis–oral” and is classified across a range of grade 1 (mild erythema or edema, and asymptomatic) to grade 4 (erythema and ulceration, cannot tolerate oral intake; requires tube feeding or hospitalization). The scale thus has utility for management of patients receiving EGFR inhibitors. In the context of these grading scales, recording of specific additional characteristics of the aphthous-like mIAS lesions can be of value as well. These characteristics include date of onset, location, size, number (single or multiple), severity, duration, and signs such as color and border texture. Stimuli associated with triggering of oral pain, such as eating selected foods, oral hygiene practices, and/or oral medication dosing, can also delineate important features of the lesion. These collective characteristics provide additional precision for lesion assessment and subsequent treatment. Patient Education Regarding Oral Mucosal Injury Secondary to Targeted Cancer Therapies Overall Context The patient and family and/or caregivers should be educated regarding management of oral mucosal injury caused by targeted cancer therapies. They should be advised that treatment with targeted therapy agents is a primary cause for developing the oral lesions and that treatment options exist for their clinical management. They should also be advised that other factors may contribute to oral AEs as well, including age, impaired nutritional status, mucosal infections, dental pathology, defective restorations/fillings and prosthesis, and compromised oral hygiene. The goal of this phase of patient education is to provide a patient-based context for prevention and treatment of oral mucosal injury in the targeted cancer therapy setting, as described below. Prevention Patients should be instructed regarding the value of an oral care protocol (170). The protocol typically includes the systematic (eg, q.i.d.) use of nonmedicated saline and/or sodium bicarbonate mouth rinses that are in turn designed to enhance oral mucosal hydration as well as oral mucosal cleansing. Relative to mIAS, there is currently no systemically derived evidence for this approach. However, and because targeted agents are associated with inflammation and localized and systemic infections, the mucosal hygiene approach described above could be recommended to the patient until a more comprehensive, evidence-based approach has been developed based on future research (45). Treatment Comprehensive oral assessment is warranted when oral mucosal injury develops. Based on this assessment, treatment of concurrent oral AEs as described in Tables 1–6 may be clinically indicated as well. Table 1. Basic mouthcare interventions for the oncology patient* Subtype Intervention All types Oral care protocols: Expert opinion suggests that basic oral care protocols be used to prevent stomatitis in all cancer groups and across all targeted therapy modalities. Effective oral hygiene in line with mucositis directive; to prevent inflammation and infection remains the most important measure. All types Sodium bicarbonate-containing mouthwash: Expert opinion suggests that patients should rinse their mouths with a bland, nonalcoholic, sodium bicarbonate-containing mouthwash 4–6 times per day to prevent oral injury. Frequency of the mouthwash may be increased, if necessary, up to each hour. If oral hygiene is compromised due to oral pain Chlorhexidine: Expert opinion suggests use of 0.12% or 0.2% chlorhexidine digluconate oral rinse BID. Subtype Intervention All types Oral care protocols: Expert opinion suggests that basic oral care protocols be used to prevent stomatitis in all cancer groups and across all targeted therapy modalities. Effective oral hygiene in line with mucositis directive; to prevent inflammation and infection remains the most important measure. All types Sodium bicarbonate-containing mouthwash: Expert opinion suggests that patients should rinse their mouths with a bland, nonalcoholic, sodium bicarbonate-containing mouthwash 4–6 times per day to prevent oral injury. Frequency of the mouthwash may be increased, if necessary, up to each hour. If oral hygiene is compromised due to oral pain Chlorhexidine: Expert opinion suggests use of 0.12% or 0.2% chlorhexidine digluconate oral rinse BID. * Adapted from (48) and (170). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. View Large Table 1. Basic mouthcare interventions for the oncology patient* Subtype Intervention All types Oral care protocols: Expert opinion suggests that basic oral care protocols be used to prevent stomatitis in all cancer groups and across all targeted therapy modalities. Effective oral hygiene in line with mucositis directive; to prevent inflammation and infection remains the most important measure. All types Sodium bicarbonate-containing mouthwash: Expert opinion suggests that patients should rinse their mouths with a bland, nonalcoholic, sodium bicarbonate-containing mouthwash 4–6 times per day to prevent oral injury. Frequency of the mouthwash may be increased, if necessary, up to each hour. If oral hygiene is compromised due to oral pain Chlorhexidine: Expert opinion suggests use of 0.12% or 0.2% chlorhexidine digluconate oral rinse BID. Subtype Intervention All types Oral care protocols: Expert opinion suggests that basic oral care protocols be used to prevent stomatitis in all cancer groups and across all targeted therapy modalities. Effective oral hygiene in line with mucositis directive; to prevent inflammation and infection remains the most important measure. All types Sodium bicarbonate-containing mouthwash: Expert opinion suggests that patients should rinse their mouths with a bland, nonalcoholic, sodium bicarbonate-containing mouthwash 4–6 times per day to prevent oral injury. Frequency of the mouthwash may be increased, if necessary, up to each hour. If oral hygiene is compromised due to oral pain Chlorhexidine: Expert opinion suggests use of 0.12% or 0.2% chlorhexidine digluconate oral rinse BID. * Adapted from (48) and (170). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. View Large Table 2. General treatment suggestions for oral injury* Subtype Intervention Stomatitis Sodium bicarbonate-containing mouthwash: Expert opinion suggests that frequency of bland, nonalcoholic, sodium bicarbonate-containing oral rinse be increased, if necessary, up to each hour as needed Stomatitis not responsive to sodium bicarbonate-containing mouthwash Other treatments: Expert opinion suggests that other treatments, such as coating agents, topical analgesic or anti-inflammatory agents, topical anesthetics, and alternative mouthwashes may be considered. Subtype Intervention Stomatitis Sodium bicarbonate-containing mouthwash: Expert opinion suggests that frequency of bland, nonalcoholic, sodium bicarbonate-containing oral rinse be increased, if necessary, up to each hour as needed Stomatitis not responsive to sodium bicarbonate-containing mouthwash Other treatments: Expert opinion suggests that other treatments, such as coating agents, topical analgesic or anti-inflammatory agents, topical anesthetics, and alternative mouthwashes may be considered. * Adapted from (170). These expert opinion suggestions for management targeted therapy-associated stomatitis are for cancers of any kind, across all targeted therapy modalities. The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. View Large Table 2. General treatment suggestions for oral injury* Subtype Intervention Stomatitis Sodium bicarbonate-containing mouthwash: Expert opinion suggests that frequency of bland, nonalcoholic, sodium bicarbonate-containing oral rinse be increased, if necessary, up to each hour as needed Stomatitis not responsive to sodium bicarbonate-containing mouthwash Other treatments: Expert opinion suggests that other treatments, such as coating agents, topical analgesic or anti-inflammatory agents, topical anesthetics, and alternative mouthwashes may be considered. Subtype Intervention Stomatitis Sodium bicarbonate-containing mouthwash: Expert opinion suggests that frequency of bland, nonalcoholic, sodium bicarbonate-containing oral rinse be increased, if necessary, up to each hour as needed Stomatitis not responsive to sodium bicarbonate-containing mouthwash Other treatments: Expert opinion suggests that other treatments, such as coating agents, topical analgesic or anti-inflammatory agents, topical anesthetics, and alternative mouthwashes may be considered. * Adapted from (170). These expert opinion suggestions for management targeted therapy-associated stomatitis are for cancers of any kind, across all targeted therapy modalities. The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. View Large Table 3. Treatment suggestions for oral dryness* Subtype Intervention All subtypes Sugarless chewing gum, candy, salivary substitutes or sialogogues: Expert opinion suggests that sugarless chewing gum or candy, salivary substitutes, or sialogogues in patients experiencing oral dryness should be considered to promote salivary flow. Symptom of oral dryness (xerostomia) Mouth wetting agents: Expert opinion suggests mouth wetting agents (eg, saliva substitutes or a spray with plain water) to relieve the patient’s perception of oral dryness. Stimulation of residual saliva gland function stimulation Sialogogues: Expert opinion suggests sialogogues if residual saliva gland function is present. Lip dryness Lip lubrication: Expert opinion suggests lubrication of lips with lip balm or lip cream. Petrolatum jelly should not be used chronically on the lips. The product promotes mucosal cell dehydration and is occlusive, leading to potential risk of secondary mucosal infection. Subtype Intervention All subtypes Sugarless chewing gum, candy, salivary substitutes or sialogogues: Expert opinion suggests that sugarless chewing gum or candy, salivary substitutes, or sialogogues in patients experiencing oral dryness should be considered to promote salivary flow. Symptom of oral dryness (xerostomia) Mouth wetting agents: Expert opinion suggests mouth wetting agents (eg, saliva substitutes or a spray with plain water) to relieve the patient’s perception of oral dryness. Stimulation of residual saliva gland function stimulation Sialogogues: Expert opinion suggests sialogogues if residual saliva gland function is present. Lip dryness Lip lubrication: Expert opinion suggests lubrication of lips with lip balm or lip cream. Petrolatum jelly should not be used chronically on the lips. The product promotes mucosal cell dehydration and is occlusive, leading to potential risk of secondary mucosal infection. * Adapted from (170). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. View Large Table 3. Treatment suggestions for oral dryness* Subtype Intervention All subtypes Sugarless chewing gum, candy, salivary substitutes or sialogogues: Expert opinion suggests that sugarless chewing gum or candy, salivary substitutes, or sialogogues in patients experiencing oral dryness should be considered to promote salivary flow. Symptom of oral dryness (xerostomia) Mouth wetting agents: Expert opinion suggests mouth wetting agents (eg, saliva substitutes or a spray with plain water) to relieve the patient’s perception of oral dryness. Stimulation of residual saliva gland function stimulation Sialogogues: Expert opinion suggests sialogogues if residual saliva gland function is present. Lip dryness Lip lubrication: Expert opinion suggests lubrication of lips with lip balm or lip cream. Petrolatum jelly should not be used chronically on the lips. The product promotes mucosal cell dehydration and is occlusive, leading to potential risk of secondary mucosal infection. Subtype Intervention All subtypes Sugarless chewing gum, candy, salivary substitutes or sialogogues: Expert opinion suggests that sugarless chewing gum or candy, salivary substitutes, or sialogogues in patients experiencing oral dryness should be considered to promote salivary flow. Symptom of oral dryness (xerostomia) Mouth wetting agents: Expert opinion suggests mouth wetting agents (eg, saliva substitutes or a spray with plain water) to relieve the patient’s perception of oral dryness. Stimulation of residual saliva gland function stimulation Sialogogues: Expert opinion suggests sialogogues if residual saliva gland function is present. Lip dryness Lip lubrication: Expert opinion suggests lubrication of lips with lip balm or lip cream. Petrolatum jelly should not be used chronically on the lips. The product promotes mucosal cell dehydration and is occlusive, leading to potential risk of secondary mucosal infection. * Adapted from (170). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. View Large Table 4. Treatment suggestions for oral pain* Subtype Intervention Mild-moderate oral pain Analgesics; mouthwashes: Expert opinion suggests that adequate pain management, eg, anesthetic mouthwashes (doxepin rinse 0.5% or viscous lidocaine 2%), coating agents, may be provided as required. If patients find mouthwash painful, they should be advised to use pain medication beforehand in accordance with the WHO pain management ladder. Moderate oral pain on local sites Analgesics; topical: Expert opinion suggests that with moderate oral pain, morphine and doxepin as per MASCC/ISOO guidelines, mucous membrane spray, gel or liquid or a topical NSAID (eg, benzydamine or amlexanox 5% (Aphthasol, Miraftil) oral paste; 0.5 cm of oral paste directly on each ulcer; QID may be considered to treat moderate oral pain. Topical anesthetics can cause burning or stinging on application, compromise taste, have short duration of effect, and lead to altered swallowing sensation. They are therefore not the first choice for oral mucosal pain management. Moderate oral pain Analgesics; systemic: systemic analgesic pain (eg, acetaminophen [paracetamol] or NSAIDs), per WHO pain management ladder may be provided to treat oral pain. Severe oral pain or when NSAIDs not tolerated Analgesics; systemic: With more severe oral pain or when NSAIDs are not tolerated, consider acetaminophen (paracetamol) as maintenance therapy in combination with an immediate-release oral opioid or fast-acting fentanyl preparation (eg, fast-acting fentanyl nasal spray 50 µg) to relieve pain on short-term basis. Fast-acting fentanyl preparations, based on registration for use in patients currently being treated with opioids for other clinical indications, may be considered in this population in context of short-term pain relief. Persistent severe oral pain Analgesics; opioid: Expert opinion suggests that with persistent severe oral pain, more aggressive pain management (eg, orally administered opioid) may be considered. Because oral mucosal injury can complicate administration of drugs by mouth, one should also consider other routes of administration such as transdermal or intranasal (eg, fast-acting fentanyl nasal spray 50 µg). Subtype Intervention Mild-moderate oral pain Analgesics; mouthwashes: Expert opinion suggests that adequate pain management, eg, anesthetic mouthwashes (doxepin rinse 0.5% or viscous lidocaine 2%), coating agents, may be provided as required. If patients find mouthwash painful, they should be advised to use pain medication beforehand in accordance with the WHO pain management ladder. Moderate oral pain on local sites Analgesics; topical: Expert opinion suggests that with moderate oral pain, morphine and doxepin as per MASCC/ISOO guidelines, mucous membrane spray, gel or liquid or a topical NSAID (eg, benzydamine or amlexanox 5% (Aphthasol, Miraftil) oral paste; 0.5 cm of oral paste directly on each ulcer; QID may be considered to treat moderate oral pain. Topical anesthetics can cause burning or stinging on application, compromise taste, have short duration of effect, and lead to altered swallowing sensation. They are therefore not the first choice for oral mucosal pain management. Moderate oral pain Analgesics; systemic: systemic analgesic pain (eg, acetaminophen [paracetamol] or NSAIDs), per WHO pain management ladder may be provided to treat oral pain. Severe oral pain or when NSAIDs not tolerated Analgesics; systemic: With more severe oral pain or when NSAIDs are not tolerated, consider acetaminophen (paracetamol) as maintenance therapy in combination with an immediate-release oral opioid or fast-acting fentanyl preparation (eg, fast-acting fentanyl nasal spray 50 µg) to relieve pain on short-term basis. Fast-acting fentanyl preparations, based on registration for use in patients currently being treated with opioids for other clinical indications, may be considered in this population in context of short-term pain relief. Persistent severe oral pain Analgesics; opioid: Expert opinion suggests that with persistent severe oral pain, more aggressive pain management (eg, orally administered opioid) may be considered. Because oral mucosal injury can complicate administration of drugs by mouth, one should also consider other routes of administration such as transdermal or intranasal (eg, fast-acting fentanyl nasal spray 50 µg). * Adapted from (170). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. NSAID = nonsteroidal anti-inflammatory drug. View Large Table 4. Treatment suggestions for oral pain* Subtype Intervention Mild-moderate oral pain Analgesics; mouthwashes: Expert opinion suggests that adequate pain management, eg, anesthetic mouthwashes (doxepin rinse 0.5% or viscous lidocaine 2%), coating agents, may be provided as required. If patients find mouthwash painful, they should be advised to use pain medication beforehand in accordance with the WHO pain management ladder. Moderate oral pain on local sites Analgesics; topical: Expert opinion suggests that with moderate oral pain, morphine and doxepin as per MASCC/ISOO guidelines, mucous membrane spray, gel or liquid or a topical NSAID (eg, benzydamine or amlexanox 5% (Aphthasol, Miraftil) oral paste; 0.5 cm of oral paste directly on each ulcer; QID may be considered to treat moderate oral pain. Topical anesthetics can cause burning or stinging on application, compromise taste, have short duration of effect, and lead to altered swallowing sensation. They are therefore not the first choice for oral mucosal pain management. Moderate oral pain Analgesics; systemic: systemic analgesic pain (eg, acetaminophen [paracetamol] or NSAIDs), per WHO pain management ladder may be provided to treat oral pain. Severe oral pain or when NSAIDs not tolerated Analgesics; systemic: With more severe oral pain or when NSAIDs are not tolerated, consider acetaminophen (paracetamol) as maintenance therapy in combination with an immediate-release oral opioid or fast-acting fentanyl preparation (eg, fast-acting fentanyl nasal spray 50 µg) to relieve pain on short-term basis. Fast-acting fentanyl preparations, based on registration for use in patients currently being treated with opioids for other clinical indications, may be considered in this population in context of short-term pain relief. Persistent severe oral pain Analgesics; opioid: Expert opinion suggests that with persistent severe oral pain, more aggressive pain management (eg, orally administered opioid) may be considered. Because oral mucosal injury can complicate administration of drugs by mouth, one should also consider other routes of administration such as transdermal or intranasal (eg, fast-acting fentanyl nasal spray 50 µg). Subtype Intervention Mild-moderate oral pain Analgesics; mouthwashes: Expert opinion suggests that adequate pain management, eg, anesthetic mouthwashes (doxepin rinse 0.5% or viscous lidocaine 2%), coating agents, may be provided as required. If patients find mouthwash painful, they should be advised to use pain medication beforehand in accordance with the WHO pain management ladder. Moderate oral pain on local sites Analgesics; topical: Expert opinion suggests that with moderate oral pain, morphine and doxepin as per MASCC/ISOO guidelines, mucous membrane spray, gel or liquid or a topical NSAID (eg, benzydamine or amlexanox 5% (Aphthasol, Miraftil) oral paste; 0.5 cm of oral paste directly on each ulcer; QID may be considered to treat moderate oral pain. Topical anesthetics can cause burning or stinging on application, compromise taste, have short duration of effect, and lead to altered swallowing sensation. They are therefore not the first choice for oral mucosal pain management. Moderate oral pain Analgesics; systemic: systemic analgesic pain (eg, acetaminophen [paracetamol] or NSAIDs), per WHO pain management ladder may be provided to treat oral pain. Severe oral pain or when NSAIDs not tolerated Analgesics; systemic: With more severe oral pain or when NSAIDs are not tolerated, consider acetaminophen (paracetamol) as maintenance therapy in combination with an immediate-release oral opioid or fast-acting fentanyl preparation (eg, fast-acting fentanyl nasal spray 50 µg) to relieve pain on short-term basis. Fast-acting fentanyl preparations, based on registration for use in patients currently being treated with opioids for other clinical indications, may be considered in this population in context of short-term pain relief. Persistent severe oral pain Analgesics; opioid: Expert opinion suggests that with persistent severe oral pain, more aggressive pain management (eg, orally administered opioid) may be considered. Because oral mucosal injury can complicate administration of drugs by mouth, one should also consider other routes of administration such as transdermal or intranasal (eg, fast-acting fentanyl nasal spray 50 µg). * Adapted from (170). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. NSAID = nonsteroidal anti-inflammatory drug. View Large Table 5. Treatment suggestions for oral infections* Infection Treatment suggestions All types Antimicrobials: Expert opinion suggests that all types of infection should be treated based per confirmed infection. Treatment should be continued for at least 1 week after symptoms have resolved. Bacterial Antibacterials: Expert opinion suggests that if clinically urgent to initiate treatment of bacterial infection, institute metronidazole (Flagyl) 1.5 g/d for 1 week or until antibiogram data are available, whichever comes first. Fungal Antifungals: Expert opinion suggests treatment with miconazole (Daktarin) oral gel QID 20 mg/kg/d administered in 4 divided doses on denture surface and lip commissures. Daily dose should not exceed 250 mg (10 mL oral gel). The gel should not be swallowed immediately but held in the mouth as long as possible. If the above product is not available, miconazole mucoadhesive tablet (Oravig/Loramyc) can be used. Alternatively, nystatin 100 000 μ/mLas mouthwash (4×/d) or fluconazole oral suspension 50 mg/5 mL (3×/d) can be administered. Viral (eg, herpesvirus) Antivirals: Expert opinion suggests treatment with valacyclovir 1 g/d for 1 week. Acute periodontal Expert opinion suggests that treatment with local therapy (eg, 0.12% or 0.2% chlorhexidine gluconate oral rinse) plus systemic antibiotic. Infection Treatment suggestions All types Antimicrobials: Expert opinion suggests that all types of infection should be treated based per confirmed infection. Treatment should be continued for at least 1 week after symptoms have resolved. Bacterial Antibacterials: Expert opinion suggests that if clinically urgent to initiate treatment of bacterial infection, institute metronidazole (Flagyl) 1.5 g/d for 1 week or until antibiogram data are available, whichever comes first. Fungal Antifungals: Expert opinion suggests treatment with miconazole (Daktarin) oral gel QID 20 mg/kg/d administered in 4 divided doses on denture surface and lip commissures. Daily dose should not exceed 250 mg (10 mL oral gel). The gel should not be swallowed immediately but held in the mouth as long as possible. If the above product is not available, miconazole mucoadhesive tablet (Oravig/Loramyc) can be used. Alternatively, nystatin 100 000 μ/mLas mouthwash (4×/d) or fluconazole oral suspension 50 mg/5 mL (3×/d) can be administered. Viral (eg, herpesvirus) Antivirals: Expert opinion suggests treatment with valacyclovir 1 g/d for 1 week. Acute periodontal Expert opinion suggests that treatment with local therapy (eg, 0.12% or 0.2% chlorhexidine gluconate oral rinse) plus systemic antibiotic. * Adapted from (170). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. View Large Table 5. Treatment suggestions for oral infections* Infection Treatment suggestions All types Antimicrobials: Expert opinion suggests that all types of infection should be treated based per confirmed infection. Treatment should be continued for at least 1 week after symptoms have resolved. Bacterial Antibacterials: Expert opinion suggests that if clinically urgent to initiate treatment of bacterial infection, institute metronidazole (Flagyl) 1.5 g/d for 1 week or until antibiogram data are available, whichever comes first. Fungal Antifungals: Expert opinion suggests treatment with miconazole (Daktarin) oral gel QID 20 mg/kg/d administered in 4 divided doses on denture surface and lip commissures. Daily dose should not exceed 250 mg (10 mL oral gel). The gel should not be swallowed immediately but held in the mouth as long as possible. If the above product is not available, miconazole mucoadhesive tablet (Oravig/Loramyc) can be used. Alternatively, nystatin 100 000 μ/mLas mouthwash (4×/d) or fluconazole oral suspension 50 mg/5 mL (3×/d) can be administered. Viral (eg, herpesvirus) Antivirals: Expert opinion suggests treatment with valacyclovir 1 g/d for 1 week. Acute periodontal Expert opinion suggests that treatment with local therapy (eg, 0.12% or 0.2% chlorhexidine gluconate oral rinse) plus systemic antibiotic. Infection Treatment suggestions All types Antimicrobials: Expert opinion suggests that all types of infection should be treated based per confirmed infection. Treatment should be continued for at least 1 week after symptoms have resolved. Bacterial Antibacterials: Expert opinion suggests that if clinically urgent to initiate treatment of bacterial infection, institute metronidazole (Flagyl) 1.5 g/d for 1 week or until antibiogram data are available, whichever comes first. Fungal Antifungals: Expert opinion suggests treatment with miconazole (Daktarin) oral gel QID 20 mg/kg/d administered in 4 divided doses on denture surface and lip commissures. Daily dose should not exceed 250 mg (10 mL oral gel). The gel should not be swallowed immediately but held in the mouth as long as possible. If the above product is not available, miconazole mucoadhesive tablet (Oravig/Loramyc) can be used. Alternatively, nystatin 100 000 μ/mLas mouthwash (4×/d) or fluconazole oral suspension 50 mg/5 mL (3×/d) can be administered. Viral (eg, herpesvirus) Antivirals: Expert opinion suggests treatment with valacyclovir 1 g/d for 1 week. Acute periodontal Expert opinion suggests that treatment with local therapy (eg, 0.12% or 0.2% chlorhexidine gluconate oral rinse) plus systemic antibiotic. * Adapted from (170). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. View Large Table 6. Treatment suggestions for oral ulcerations caused by targeted cancer therapies* Subtype Treatment suggestions Limited and easily accessed ulcers Steroids; topical: Expert opinion suggests that for limited locations and easy to access ulcers, topical high-potency corticosteroids should be considered first: clobetasol gel or ointment (0.05% QD-BID) with or without adhesive bases such as carboximethyl or hydroxyethyl-cellulose. Limited and easily accessed ulcers Topical NSAID: Expert opinion suggests that for limited locations and easy to access ulcers amlexanox (Aphthasol, Miraftil), 5% oral paste (0.5 cm of oral paste directly on each ulcer; QID) or benzydamine 0.15% mouthwash or spray (4–8×/d) may be considered. Widespread or difficult to access ulcers Steroids; topical: Expert opinion suggests that if several locations of the oral cavity are involved or difficult to access ulcers, topical high-potency corticosteroids should be considered first: (eg, dexamethasone mouth rinse (0.1 mg/mL) or clobetasol propionate 0.05% in aqueous solution, 3×/d). Widespread or difficult to access ulcers Compounded rinse: Expert opinion suggests that if several sites of oral cavity are involved or difficult to access, budesonide rinse 0.5% may be considered. Highly symptomatic ulcers, recurrent ulcers, or esophageal ulcers Steroids; systemic: Expert opinion suggests that for highly symptomatic ulcers and recurrent ulcers or esophageal lesions, systemic corticosteroids be utilized as initial therapy to control symptoms (high-dose pulse 30–60 mg or 1 mg/kg) oral prednisone/prednisolone for 1 week followed by dose tapering over second week should be considered to treat mIAS. Without ulcer resolution Steroid; intralesional injection: Expert opinion suggests that with no ulcer resolution, intralesional steroid injection (triamcinolone weekly; total dose 28 mg) in conjunction with oral expert AND topical clobetasol gel or ointment (0.05%) with or without adhesive bases such as carboxymethyl or hydroxyethyl-cellulose should be considered to treat mIAS. Subtype Treatment suggestions Limited and easily accessed ulcers Steroids; topical: Expert opinion suggests that for limited locations and easy to access ulcers, topical high-potency corticosteroids should be considered first: clobetasol gel or ointment (0.05% QD-BID) with or without adhesive bases such as carboximethyl or hydroxyethyl-cellulose. Limited and easily accessed ulcers Topical NSAID: Expert opinion suggests that for limited locations and easy to access ulcers amlexanox (Aphthasol, Miraftil), 5% oral paste (0.5 cm of oral paste directly on each ulcer; QID) or benzydamine 0.15% mouthwash or spray (4–8×/d) may be considered. Widespread or difficult to access ulcers Steroids; topical: Expert opinion suggests that if several locations of the oral cavity are involved or difficult to access ulcers, topical high-potency corticosteroids should be considered first: (eg, dexamethasone mouth rinse (0.1 mg/mL) or clobetasol propionate 0.05% in aqueous solution, 3×/d). Widespread or difficult to access ulcers Compounded rinse: Expert opinion suggests that if several sites of oral cavity are involved or difficult to access, budesonide rinse 0.5% may be considered. Highly symptomatic ulcers, recurrent ulcers, or esophageal ulcers Steroids; systemic: Expert opinion suggests that for highly symptomatic ulcers and recurrent ulcers or esophageal lesions, systemic corticosteroids be utilized as initial therapy to control symptoms (high-dose pulse 30–60 mg or 1 mg/kg) oral prednisone/prednisolone for 1 week followed by dose tapering over second week should be considered to treat mIAS. Without ulcer resolution Steroid; intralesional injection: Expert opinion suggests that with no ulcer resolution, intralesional steroid injection (triamcinolone weekly; total dose 28 mg) in conjunction with oral expert AND topical clobetasol gel or ointment (0.05%) with or without adhesive bases such as carboxymethyl or hydroxyethyl-cellulose should be considered to treat mIAS. * Adapted from (11,45,61,75). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. NSAID = nonsteroidal anti-inflammatory drug. View Large Table 6. Treatment suggestions for oral ulcerations caused by targeted cancer therapies* Subtype Treatment suggestions Limited and easily accessed ulcers Steroids; topical: Expert opinion suggests that for limited locations and easy to access ulcers, topical high-potency corticosteroids should be considered first: clobetasol gel or ointment (0.05% QD-BID) with or without adhesive bases such as carboximethyl or hydroxyethyl-cellulose. Limited and easily accessed ulcers Topical NSAID: Expert opinion suggests that for limited locations and easy to access ulcers amlexanox (Aphthasol, Miraftil), 5% oral paste (0.5 cm of oral paste directly on each ulcer; QID) or benzydamine 0.15% mouthwash or spray (4–8×/d) may be considered. Widespread or difficult to access ulcers Steroids; topical: Expert opinion suggests that if several locations of the oral cavity are involved or difficult to access ulcers, topical high-potency corticosteroids should be considered first: (eg, dexamethasone mouth rinse (0.1 mg/mL) or clobetasol propionate 0.05% in aqueous solution, 3×/d). Widespread or difficult to access ulcers Compounded rinse: Expert opinion suggests that if several sites of oral cavity are involved or difficult to access, budesonide rinse 0.5% may be considered. Highly symptomatic ulcers, recurrent ulcers, or esophageal ulcers Steroids; systemic: Expert opinion suggests that for highly symptomatic ulcers and recurrent ulcers or esophageal lesions, systemic corticosteroids be utilized as initial therapy to control symptoms (high-dose pulse 30–60 mg or 1 mg/kg) oral prednisone/prednisolone for 1 week followed by dose tapering over second week should be considered to treat mIAS. Without ulcer resolution Steroid; intralesional injection: Expert opinion suggests that with no ulcer resolution, intralesional steroid injection (triamcinolone weekly; total dose 28 mg) in conjunction with oral expert AND topical clobetasol gel or ointment (0.05%) with or without adhesive bases such as carboxymethyl or hydroxyethyl-cellulose should be considered to treat mIAS. Subtype Treatment suggestions Limited and easily accessed ulcers Steroids; topical: Expert opinion suggests that for limited locations and easy to access ulcers, topical high-potency corticosteroids should be considered first: clobetasol gel or ointment (0.05% QD-BID) with or without adhesive bases such as carboximethyl or hydroxyethyl-cellulose. Limited and easily accessed ulcers Topical NSAID: Expert opinion suggests that for limited locations and easy to access ulcers amlexanox (Aphthasol, Miraftil), 5% oral paste (0.5 cm of oral paste directly on each ulcer; QID) or benzydamine 0.15% mouthwash or spray (4–8×/d) may be considered. Widespread or difficult to access ulcers Steroids; topical: Expert opinion suggests that if several locations of the oral cavity are involved or difficult to access ulcers, topical high-potency corticosteroids should be considered first: (eg, dexamethasone mouth rinse (0.1 mg/mL) or clobetasol propionate 0.05% in aqueous solution, 3×/d). Widespread or difficult to access ulcers Compounded rinse: Expert opinion suggests that if several sites of oral cavity are involved or difficult to access, budesonide rinse 0.5% may be considered. Highly symptomatic ulcers, recurrent ulcers, or esophageal ulcers Steroids; systemic: Expert opinion suggests that for highly symptomatic ulcers and recurrent ulcers or esophageal lesions, systemic corticosteroids be utilized as initial therapy to control symptoms (high-dose pulse 30–60 mg or 1 mg/kg) oral prednisone/prednisolone for 1 week followed by dose tapering over second week should be considered to treat mIAS. Without ulcer resolution Steroid; intralesional injection: Expert opinion suggests that with no ulcer resolution, intralesional steroid injection (triamcinolone weekly; total dose 28 mg) in conjunction with oral expert AND topical clobetasol gel or ointment (0.05%) with or without adhesive bases such as carboxymethyl or hydroxyethyl-cellulose should be considered to treat mIAS. * Adapted from (11,45,61,75). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. NSAID = nonsteroidal anti-inflammatory drug. View Large Successful management should include treatment directed at all components of the oral lesion. Short-term high-potent topical or systemic corticosteroids can lead to effective response when utilized for an inflammatory-driven reaction such as mIAS but will not relieve dry mouth, oral infection, and/or dysgeusia. Similarly, analgesics will relieve selected types of oral pain but not pain associated with an oral burning sensation. It thus becomes essential to specifically define the constellation of oral AEs in a given patient in order to optimally manage the oral mucosal injury and related oral AEs. This comprehensive approach can mitigate the necessity of dose reduction or discontinuation of the targeted cancer therapy. Key Research Questions The following key research questions derive from the state of the science of oral mucosal disease as presented in this chapter: What key genetic and/or molecular factors are principally responsible for causing oral mucosal lesions associated with targeted cancer therapies? Despite fundamentally different modes of actions across the classes of targeted cancer therapies, why is there, in many cases, consistent conservation of the clinical phenotype of the oral mucosal injury among patients receiving different targeted therapies? Why is the clinical phenotype of oral mucosal injury secondary to targeted agents often similar to recurrent aphthous stomatitis, and different from oral mucositis secondary to conventional chemotherapy? Is the genetic governance of oral pain concordant between oral mucositis caused by conventional cancer therapies in relation to oral mucosal injury caused by targeted cancer agents? How could answers to the above research questions be applied to the development of novel preventive and therapeutic interventions? Notes Affiliations of authors: Center for Oral Health Research, Oral Medicine Department, School of Dental Sciences, Newcastle University, UK (MC); Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark (JGE); Institut Niçois de Cancérologie (INC), Centre de Haute Energie, Nice, France (RJB); CancerMed, Department of Medical Strategy, Wormer, The Netherlands (CBBD); Impaqtt Foundation, Department of Adverse Event Research & Valorisation, Wormer, The Netherlands (CBBD); Section of Oral Medicine, Department of Oral Health & Diagnostic Sciences, School of Dental Medicine, UConn Health, Farmington, CT (RVL); Section of Oral Medicine, Department of Oral Health & Diagnostic Sciences, School of Dental Medicine & Neag Comprehensive Cancer Center, UConn Health, Farmington, CT (DEP). M. Carrozzo, J. Grau Eriksen, and R.-.J Bensadoun declare no conflicts of interest. C. Boers-Doets has received grants for education and travel funded by the following pharmaceutical companies that have a targeted therapy in their respective portfolio: Amgen, Bayer, EUSA Pharma, GSK Netherlands (now part of Novartis), Merck, Novartis, Pfizer, and Roche; consulting fees funded by the following pharmaceutical companies that have a targeted therapy in their respective portfolio: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Ipsen, Lilly, Merck, MSD (Merck Sharp & Dohme), Novartis, Pfizer, and Roche. R. Lalla has received grants from Oragenics and Vigilant Biosciences and is a consultant for Alira Health, Biotechspert, Colgate Oral Pharmaceuticals, Eagle Pharma, Galera Therapeutics, Ingalfarma, Leerink, Metlife, Monopar Therapeutics, and SAI Med and has stock in Logic Biosciences. None of the preceding disclosures is related to the content of this manuscript. D. Peterson has received consulting fees from Amgen Inc., Optum Epidemiology, PSI CRO, SAI MedPartner LLC, and AEC Partners. He also receives consulting fees from and holds equity ownership in Applied Glycan Technologies, Inc. None of this consulting activity is related to the content of this manuscript. For support see Funding Acknowledgement section of Monograph. References 1 Subramanian J , Vlahiotis A , Frazee S , et al. . Real-world utilization of targeted therapy in cancer treatment . J Clin Oncol . 2011 ; 29 (suppl; abstr e16618). WorldCat 2 Claudiani S , Apperley JF. The argument for using imatinib in CML . Hematology Am Soc Hematol Educ Program . 2018 ; 2018 1 : 161 – 167 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Hornberger JC , Friedmann M , Han L , et al. . Economic impact of rituximab as maintenance therapy in previously treated follicular non-Hodgkin lymphoma . J Clin Oncol. 2011 ; 29 (suppl 15; abstract e18544). WorldCat 4 Heyman B , Yang Y. New developments in immunotherapy for lymphoma . Cancer Biol Med. 2018 ; 15 3 : 189 – 209 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Bajic P , Flanigan RC , Joyce CJ , et al. . Sunitinib and cytoreductive nephrectomy for metastatic renal cell carcinoma . J Urol. 2019 ; 201 3 : 453 – 454 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Motzer RJ , Hutson TE , Tomczak P , et al. . Sunitinib versus interferon alfa in metastatic renal-cell carcinoma . N Engl J Med. 2007 ; 356 2 : 115 – 124 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Romond EH , Perez EA , Bryant J , et al. . Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer . N Engl J Med. 2005 ; 353 16 : 1673 – 1684 . Google Scholar Crossref Search ADS PubMed WorldCat 8 Hayes DF. Further progress for patients with breast cancer . N Engl J Med. 2019 ; 380 7 : 676 – 677 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Moore MJ , Goldstein D , Hamm J , et al. . Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group . J Clin Oncol. 2007 ; 25 15 : 1960 – 1966 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Lacouture M , Sibaud V. Toxic side effects of targeted therapies and immunotherapies affecting the skin, oral mucosa, hair, and nails . Am J Clin Dermatol. 2018 ; 19(Suppl 1) : 31 – 39 . Google Scholar Crossref Search ADS WorldCat 11 Pilotte AP , Hohos MB , Polson KM , et al. . Managing stomatitis in patients treated with Mammalian target of rapamycin inhibitors . Clin J Oncol Nurs. 2011 ; 15 5 : E83 – E89 . Google Scholar Crossref Search ADS PubMed WorldCat 12 Van Cutsem E , Peeters M , Siena S , et al. . Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer . J Clin Oncol. 2007 ; 25 13 : 1658 – 1664 . Google Scholar Crossref Search ADS PubMed WorldCat 13 Hurwitz H , Fehrenbacher L , Novotny W , et al. . Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer . N Engl J Med. 2004 ; 350 23 : 2335 – 2342 . Google Scholar Crossref Search ADS PubMed WorldCat 14 Bonner JA , Harari PM , Giralt J , et al. . Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck . N Engl J Med. 2006 ; 354 6 : 567 – 578 . Google Scholar Crossref Search ADS PubMed WorldCat 15 Motzer RJ , Escudier B , Oudard S , et al. . Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial . Lancet. 2008 ; 372 9637 : 449 – 456 . Google Scholar Crossref Search ADS PubMed WorldCat 16 O'Brien SG , Guilhot F , Larson RA , et al. . Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia . N Engl J Med. 2003 ; 348 11 : 994 – 1004 . Google Scholar Crossref Search ADS PubMed WorldCat 17 Zweifel M , Jayson GC , Reed NS , et al. . Phase II trial of combretastatin A4 phosphate, carboplatin, and paclitaxel in patients with platinum-resistant ovarian cancer . Ann Oncol. 2011 ; 22 9 : 2036 – 2041 . Google Scholar Crossref Search ADS PubMed WorldCat 18 Plummer R , Attard G , Pacey S , et al. . Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers . Clin Cancer Res. 2007 ; 13 20 : 6187 – 6194 . Google Scholar Crossref Search ADS PubMed WorldCat 19 Kindler HL , Richards DA , Garbo LE , et al. . A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer . Ann Oncol. 2012 ; 23 11 : 2834 – 2842 . Google Scholar Crossref Search ADS PubMed WorldCat 20 Clinical Trials.gov. clinicaltrials.gov. Accessed February 5, 2019. 21 Dimopoulos M , Siegel DS , Lonial S , et al. . Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study . Lancet Oncol. 2013 ; 14 11 : 1129 – 1140 . Google Scholar Crossref Search ADS PubMed WorldCat 22 Wendtner CM , Ritgen M , Schweighofer CD , et al. . Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission—experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG) . Leukemia. 2004 ; 18 6 : 1093 – 1101 . Google Scholar Crossref Search ADS PubMed WorldCat 23 Eiermann W , International Herceptin Study Group . Trastuzumab combined with chemotherapy for the treatment of HER2-positive metastatic breast cancer: pivotal trial data . Ann Oncol . 2001 ; 12(Suppl 1) : S57 – S62 . Google Scholar Crossref Search ADS PubMed WorldCat 24 Wiseman GA , White CA , Sparks RB , et al. . Biodistribution and dosimetry results from a phase III prospectively randomized controlled trial of Zevalin radioimmunotherapy for low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma . Crit Rev Oncol Hematol. 2001 ; 39 ( 1–2 ): 181 – 194 . Google Scholar Crossref Search ADS PubMed WorldCat 25 Moskowitz CH , Nademanee A , Masszi T , et al. . Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial . Lancet. 2015 ; 385 9980 : 1853 – 1862 . Google Scholar Crossref Search ADS PubMed WorldCat 26 Verma S , Miles D , Gianni L , et al. . Trastuzumab emtansine for HER2-positive advanced breast cancer . N Engl J Med. 2012 ; 367 19 : 1783 – 1791 . Google Scholar Crossref Search ADS PubMed WorldCat 27 Prince HM , Duvic M , Martin A , et al. . Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma . J Clin Oncol. 2010 ; 28 11 : 1870 – 1877 . Google Scholar Crossref Search ADS PubMed WorldCat 28 Topp MS , Kufer P , Gökbuget N , et al. . Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival . J Clin Oncol. 2011 ; 29 18 : 2493 – 2498 . Google Scholar Crossref Search ADS PubMed WorldCat 29 Robert C , Schachter J , Long GV , et al. . Pembrolizumab versus Ipilimumab in Advanced Melanoma . N Engl J Med. 2015 ; 372 26 : 2521 – 2532 . Google Scholar Crossref Search ADS PubMed WorldCat 30 Weber JS , D'Angelo SP , Minor 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 4 : 375 – 384 . Google Scholar Crossref Search ADS PubMed WorldCat 31 Hodi FS , O'Day SJ , McDermott DF , et al. . Improved survival with ipilimumab in patients with metastatic melanoma . N Engl J Med. 2010 ; 363 8 : 711 – 723 . Google Scholar Crossref Search ADS PubMed WorldCat 32 Sheikh NA , Petrylak D , Kantoff PW , et al. . Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer . Cancer Immunol Immunother. 2013 ; 62 1 : 137 – 147 . Google Scholar Crossref Search ADS PubMed WorldCat 33 Agarwala SS , Glaspy J , O'Day SJ , et al. . Results from a randomized phase III study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus interleukin-2 alone in patients with metastatic melanoma . J Clin Oncol. 2002 ; 20 1 : 125 – 133 . Google Scholar Crossref Search ADS PubMed WorldCat 34 Solal-Celigny P , Lepage E , Brousse N , et al. . Recombinant interferon alfa-2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. Groupe d'Etude des Lymphomes de l'Adulte . N Engl J Med. 1993 ; 329 22 : 1608 – 1614 . Google Scholar Crossref Search ADS PubMed WorldCat 35 Park JW , Kerbel RS , Kelloff GJ , et al. . Rationale for biomarkers and surrogate end points in mechanism-driven oncology drug development . Clin Cancer Res. 2004 ; 10 11 : 3885 – 3896 . Google Scholar Crossref Search ADS PubMed WorldCat 36 Figg WD , Newell DR. Pharmacologic biomarkers in the development of stratified cancer medicine . Clin Cancer Res. 2014 ; 20 10 : 2525 – 2529 . Google Scholar Crossref Search ADS PubMed WorldCat 37 Sperger JM , Strotman LN , Welsh A , et al. . Integrated analysis of multiple biomarkers from circulating tumor cells enabled by exclusion-based analyte isolation . Clin Cancer Res. 2017 ; 23 3 : 746 – 756 . Google Scholar Crossref Search ADS PubMed WorldCat 38 Parchment RE , Doroshow JH. Pharmacodynamic endpoints as clinical trial objectives to answer important questions in oncology drug development . Semin Oncol. 2016 ; 43 4 : 514 – 525 . Google Scholar Crossref Search ADS PubMed WorldCat 39 Yuan A , Kurtz SL , Barysauskas CM , et al. . Oral adverse events in cancer patients treated with VEGFR-directed multitargeted tyrosine kinase inhibitors . Oral Oncol. 2015 ; 51 11 : 1026 – 1033 . Google Scholar Crossref Search ADS PubMed WorldCat 40 Vigarios E , Epstein JB , Sibaud V. Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors . Support Care Cancer. 2017 ; 25 5 : 1713 – 1739 . Google Scholar Crossref Search ADS PubMed WorldCat 41 Sibaud V , Eid C , Belum VR , et al. . Oral lichenoid reactions associated with anti-PD-1/PD-L1 therapies: clinicopathological findings . J Eur Acad Dermatol Venereol. 2017 ; 31 10 : e464 – e469 . Google Scholar Crossref Search ADS PubMed WorldCat 42 Elting LS , Chang YC , Parelkar P , et al. . Risk of oral and gastrointestinal mucosal injury among patients receiving selected targeted agents: a meta-analysis . Support Care Cancer. 2013 ; 21 11 : 3243 – 3254 . Google Scholar Crossref Search ADS PubMed WorldCat 43 Topalian SL , Sznol M , McDermott DF , et al. . Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab . J Clin Oncol. 2014 ; 32 10 : 1020 – 1030 . Google Scholar Crossref Search ADS PubMed WorldCat 44 Sonis S , Treister N , Chawla S , et al. . Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients . Cancer. 2010 ; 116 1 : 210 – 215 . Google Scholar PubMed WorldCat 45 Peterson DE , Boers-Doets CB , Bensadoun RJ , et al. . Management of oral and gastrointestinal mucosal injury: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up . Ann Oncol. 2015 ; 26(Suppl 5) : v139 – v151 . Google Scholar Crossref Search ADS PubMed WorldCat 46 Sonis ST , Elting LS , Keefe D , et al. . Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients . Cancer . 2004 ; 100(9 Suppl) : 1995 – 2025 . Google Scholar Crossref Search ADS WorldCat 47 Keefe DM , Schubert MM , Elting LS , et al. . Updated clinical practice guidelines for the prevention and treatment of mucositis . Cancer. 2007 ; 109 5 : 820 – 831 . Google Scholar Crossref Search ADS PubMed WorldCat 48 Lalla RV , Bowen J , Barasch A , et al. . MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy . Cancer. 2014 ; 120 10 : 1453 – 1461 . Google Scholar Crossref Search ADS PubMed WorldCat 49 Lalla RV , Gordon GB , Schubert M , et al. . A randomized, double-blind, placebo-controlled trial of misoprostol for oral mucositis secondary to high-dose chemotherapy . Support Care Cancer. 2012 ; 20 8 : 1797 – 1804 . Google Scholar Crossref Search ADS PubMed WorldCat 50 Jensen SB , Peterson DE. Oral mucosal injury caused by cancer therapies: current management and new frontiers in research . J Oral Pathol Med. 2014 ; 43 2 : 81 – 90 . Google Scholar Crossref Search ADS PubMed WorldCat 51 Villa A , Sonis ST. Pharmacotherapy for the management of cancer regimen-related oral mucositis . Expert Opin Pharmacother. 2016 ; 17 13 : 1801 – 1807 . Google Scholar Crossref Search ADS PubMed WorldCat 52 Peterson DE , Keefe DM , Sonis ST. New frontiers in mucositis. In: Govindan R , ed. American Society of Clinical Oncology Educational Book . 2012 : 545 – 551 . Google Preview WorldCat COPAC 53 Bachour PC , Sonis ST. Predicting mucositis risk associated with cytotoxic cancer treatment regimens: rationale, complexity, and challenges . Curr Opin Support Palliat Care . 2018 ; 12 2 : 198 – 210 . Google Scholar PubMed WorldCat 54 Partridge AH , Avorn J , Wang PS , et al. . Adherence to therapy with oral antineoplastic agents . J Natl Cancer Inst. 2002 ; 94 9 : 652 – 661 . Google Scholar Crossref Search ADS PubMed WorldCat 55 Cunningham D , Humblet Y , Siena S , et al. . Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer . N Engl J Med. 2004 ; 351 4 : 337 – 345 . Google Scholar Crossref Search ADS PubMed WorldCat 56 Epstein JB , Gorsky M , Guglietta A , et al. . The correlation between epidermal growth factor levels in saliva and the severity of oral mucositis during oropharyngeal radiation therapy . Cancer . 2000 ; 89 11 : 2258 – 2265 . Google Scholar Crossref Search ADS PubMed WorldCat 57 Al-Ansari S , Zecha JA , Barasch A , et al. . Oral mucositis induced by anticancer therapies . Curr Oral Health Rep. 2015 ; 2 4 : 202 – 211 . Google Scholar Crossref Search ADS PubMed WorldCat 58 Sonis ST. Mucositis: the impact, biology and therapeutic opportunities of oral mucositis . Oral Oncol. 2009 ; 45 12 : 1015 – 1020 . Google Scholar Crossref Search ADS PubMed WorldCat 59 Sonis ST. Oral mucositis in head and neck cancer: risk, biology, and management . Am Soc Clin Oncol Educ Book . 2013 . doi:10.1200/EdBook_AM.2013.33.e236. WorldCat 60 Al-Dasooqi N , Sonis ST , Bowen JM , et al. . Emerging evidence on the pathobiology of mucositis . Support Care Cancer. 2013 ; 21 7 : 2075 – 2083 . Google Scholar Crossref Search ADS PubMed WorldCat 61 Boers-Doets CB , Raber-Durlacher JE , Treister NS , et al. . Mammalian target of rapamycin inhibitor-associated stomatitis . Future Oncol. 2013 ; 9 12 : 1883 – 1892 . Google Scholar Crossref Search ADS PubMed WorldCat 62 Peterson DE , O'Shaughnessy JA , Rugo HS , et al. . Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice . Cancer Med . 2016 ; 5 8 : 1897 – 1907 . Google Scholar Crossref Search ADS PubMed WorldCat 63 Scully C. Clinical practice. Aphthous ulceration . N Engl J Med . 2006 ; 355 2 : 165 – 172 . Google Scholar Crossref Search ADS PubMed WorldCat 64 Morelon E , Stern M , Israel-Biet D , et al. . Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients . Transplantation. 2001 ; 72 5 : 787 – 790 . Google Scholar Crossref Search ADS PubMed WorldCat 65 Tiong HY , Flechner SM , Zhou L , et al. . A systematic approach to minimizing wound problems for de novo sirolimus-treated kidney transplant recipients . Transplantation. 2009 ; 87 2 : 296 – 302 . Google Scholar Crossref Search ADS PubMed WorldCat 66 Mills RE , Taylor KR , Podshivalova K , et al. . Defects in skin gamma delta T cell function contribute to delayed wound repair in rapamycin-treated mice . J Immunol. 2008 ; 181 6 : 3974 – 3983 . Google Scholar Crossref Search ADS PubMed WorldCat 67 Avci E , Akarslan ZZ , Erten H , et al. . Oxidative stress and cellular immunity in patients with recurrent aphthous ulcers . Braz J Med Biol Res. 2014 ; 47 5 : 355 – 360 . Google Scholar Crossref Search ADS PubMed WorldCat 68 Weichhart T , Säemann MD. The multiple facets of mTOR in immunity . Trends Immunol. 2009 ; 30 5 : 218 – 226 . Google Scholar Crossref Search ADS PubMed WorldCat 69 Boussemart L , Routier E , Mateus C , et al. . Prospective study of cutaneous side-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients . Ann Oncol. 2013 ; 24 6 : 1691 – 1697 . Google Scholar Crossref Search ADS PubMed WorldCat 70 Mangold AR , Bryce A , Sekulic A. Vemurafenib-associated gingival hyperplasia in patient with metastatic melanoma . J Am Acad Dermatol. 2014 ; 71 5 : e205 – e206 . Google Scholar Crossref Search ADS PubMed WorldCat 71 Vigarios E , Lamant L , Delord JP , et al. . Oral squamous cell carcinoma and hyperkeratotic lesions with BRAF inhibitors . Br J Dermatol. 2015 ; 172 6 : 1680 – 1682 . Google Scholar Crossref Search ADS PubMed WorldCat 72 Lloyd-Lavery A , Hodgson T , Coupe N , et al. . Delayed oral toxicity from long term Vemurafenib therapy (letter to editor) . Br J Dermatol. 2016 ; 174( 5 ): 1159 – 1160 . Google Scholar Crossref Search ADS PubMed WorldCat 73 Dietrich E , Antoniades K. Molecularly targeted drugs for the treatment of cancer: oral complications and pathophysiology . Hippokratia. 2012 ; 16 3 : 196 – 199 . Google Scholar PubMed WorldCat 74 Watters AL , Epstein JB , Agulnik M. Oral complications of targeted cancer therapies: a narrative literature review . Oral Oncol. 2011 ; 47 6 : 441 – 448 . Google Scholar Crossref Search ADS PubMed WorldCat 75 de Oliveira MA , Martins EMF , Wang Q , et al. . Clinical presentation and management of mTOR inhibitor-associated stomatitis . Oral Oncol. 2011 ; 47 10 : 998 – 1003 . Google Scholar Crossref Search ADS PubMed WorldCat 76 van Gelder T , ter Meulen CG , Hené R , et al. . Oral ulcers in kidney transplant recipients treated with sirolimus and mycophenolate mofetil . Transplantation. 2003 ; 75 6 : 788 – 791 . Google Scholar Crossref Search ADS PubMed WorldCat 77 Campistol JM , de Fijter JW , Flechner SM , et al. . mTOR inhibitor-associated dermatologic and mucosal problems . Clin Transplant. 2010 ; 24 2 : 149 – 156 . Google Scholar Crossref Search ADS PubMed WorldCat 78 Gomez-Fernandez C , Garden BC , Wu S , et al. . The risk of skin rash and stomatitis with the mammalian target of rapamycin inhibitor temsirolimus: a systematic review of the literature and meta-analysis . Eur J Cancer. 2012 ; 48 3 : 340 – 346 . Google Scholar Crossref Search ADS PubMed WorldCat 79 Martins F , de Oliveira MA , Wang Q , et al. . A review of oral toxicity associated with mTOR inhibitor therapy in cancer patients . Oral Oncol. 2013 ; 49 4 : 293 – 298 . Google Scholar Crossref Search ADS PubMed WorldCat 80 Raymond E , Alexandre J , Faivre S , et al. . Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer . J Clin Oncol. 2004 ; 22 12 : 2336 – 2347 . Google Scholar Crossref Search ADS PubMed WorldCat 81 Buckner JC , Forouzesh B , Erlichman C , et al. . Phase I, pharmacokinetic study of temsirolimus administered orally to patients with advanced cancer . Invest New Drugs. 2010 ; 28 3 : 334 – 342 . Google Scholar Crossref Search ADS PubMed WorldCat 82 Sessa C , Tosi D , Viganò L , et al. . Phase Ib study of weekly mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) with weekly paclitaxel . Ann Oncol. 2010 ; 21 6 : 1315 – 1322 . Google Scholar Crossref Search ADS PubMed WorldCat 83 Mita MM , Mita AC , Chu QS , et al. . Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies . J Clin Oncol. 2008 ; 26 3 : 361 – 367 . Google Scholar Crossref Search ADS PubMed WorldCat 84 Jerusalem G , Fasolo A , Dieras V , et al. . Phase I trial of oral mTOR inhibitor everolimus in combination with trastuzumab and vinorelbine in pre-treated patients with HER2-overexpressing metastatic breast cancer . Breast Cancer Res Treat. 2011 ; 125 2 : 447 – 455 . Google Scholar Crossref Search ADS PubMed WorldCat 85 Tabernero J , Rojo F , Calvo E , et al. . Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors . J Clin Oncol. 2008 ; 26 10 : 1603 – 1610 . Google Scholar Crossref Search ADS PubMed WorldCat 86 Perotti A , Locatelli A , Sessa C , et al. . Phase IB study of the mTOR inhibitor ridaforolimus with capecitabine . J Clin Oncol. 2010 ; 28 30 : 4554 – 4561 . Google Scholar Crossref Search ADS PubMed WorldCat 87 Hartford CM , Desai AA , Janisch L , et al. . A phase I trial to determine the safety, tolerability, and maximum tolerated dose of deforolimus in patients with advanced malignancies . Clin Cancer Res. 2009 ; 15 4 : 1428 – 1434 . Google Scholar Crossref Search ADS PubMed WorldCat 88 Shameem R , Lacouture M , Wu S. Incidence and risk of high-grade stomatitis with mTOR inhibitors in cancer patients . Cancer Invest. 2015 ; 33 3 : 70 – 77 . Google Scholar Crossref Search ADS PubMed WorldCat 89 Badri T , Hammami H , Lachkham A , et al. . Radiotherapy-induced pemphigus vulgaris with autoantibodies targeting a 110 kDa epidermal antigen . Int J Dermatol. 2011 ; 50 12 : 1475 – 1479 . Google Scholar Crossref Search ADS PubMed WorldCat 90 Vern-Gross TZ , Kowal-Vern A. Erythema multiforme, Stevens Johnson syndrome, and toxic epidermal necrolysis syndrome in patients undergoing radiation therapy: a literature review . Am J Clin Oncol. 2014 ; 37 5 : 506 – 513 . Google Scholar Crossref Search ADS PubMed WorldCat 91 Brenner S , Bialy-Golan A , Ruocco V. Drug-induced pemphigus . Clin Dermatol. 1998 ; 16 3 : 393 – 397 . Google Scholar Crossref Search ADS PubMed WorldCat 92 Baldo BA , Pham NH. Adverse reactions to targeted and non-targeted chemotherapeutic drugs with emphasis on hypersensitivity responses and the invasive metastatic switch . Cancer Metastasis Rev. 2013 ; 32 ( 3–4 ): 723 – 761 . Google Scholar Crossref Search ADS PubMed WorldCat 93 Yildiz O , Ozguroglu M , Yanmaz MT , et al. . Paraneoplastic pemphigus associated with fludarabine use . Med Oncol. 2007 ; 24 1 : 115 – 118 . Google Scholar Crossref Search ADS PubMed WorldCat 94 Jurge S , Kuffer R , Scully C , Porter SR. Mucosal disease series. Number VI. Recurrent aphthous stomatitis . Oral Dis . 2006 ; 12 1 : 1 – 21 . Google Scholar Crossref Search ADS PubMed WorldCat 95 Bazrafshani MR , Hajeer AH , Ollier WE , et al. . IL-1B and IL-6 gene polymorphisms encode significant risk for the development of recurrent aphthous stomatitis (RAS) . Genes Immun. 2002 ; 3 5 : 302 – 305 . Google Scholar Crossref Search ADS PubMed WorldCat 96 Najafi S , Yousefi H , Mohammadzadeh M , et al. . Association study of interleukin-1 family and interleukin-6 gene single nucleotide polymorphisms in recurrent aphthous stomatitis . Int J Immunogenet. 2015 ; 42 6 : 428 – 431 . Google Scholar Crossref Search ADS PubMed WorldCat 97 Guimarães AL , Correia-Silva Jde F , Sá AR , et al. . Investigation of functional gene polymorphisms IL-1beta, IL-6, IL-10 and TNF-alpha in individuals with recurrent aphthous stomatitis . Arch Oral Biol. 2007 ; 52 3 : 268 – 272 . Google Scholar Crossref Search ADS PubMed WorldCat 98 Karakus N , Yigit S , Rustemoglu A , et al. . Effects of interleukin (IL)-6 gene polymorphisms on recurrent aphthous stomatitis . Arch Dermatol Res. 2014 ; 306 2 : 173 – 180 . Google Scholar Crossref Search ADS PubMed WorldCat 99 Ozyurt K , Celik A , Sayarlioglu M , et al. . Serum Th1, Th2 and Th17 cytokine profiles and alpha-enolase levels in recurrent aphthous stomatitis . J Oral Pathol Med. 2014 ; 43 9 : 691 – 695 . Google Scholar Crossref Search ADS PubMed WorldCat 100 Stojanov S , Lapidus S , Chitkara P , et al. . Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade . Proc Natl Acad Sci U S A. 2011 ; 108 17 : 7148 – 7153 . Google Scholar Crossref Search ADS PubMed WorldCat 101 Gell PGH , Coombs RRA , eds. The Classification of Allergic Reactions Underlying Disease . Blackwell Sciences ; 1963 . Google Preview WorldCat COPAC 102 Pedersen A , Klausen B , Hougen HP , et al. . T-lymphocyte subsets in recurrent aphthous ulceration . J Oral Pathol Med. 1989 ; 18 1 : 59 – 60 . Google Scholar Crossref Search ADS PubMed WorldCat 103 Pedersen A , Ryder LP. Gamma delta T-cell fraction of peripheral blood is increased in recurrent aphthous ulceration . Clin Immunol Immunopathol. 1994 ; 72 1 : 98 – 104 . Google Scholar Crossref Search ADS PubMed WorldCat 104 Hayrinen-Immonen R , Nordstrom D , Malmstrom M , et al. . Immune-inflammatory cells in recurrent oral ulcers (ROU ). Scand J Dent Res . 1991 ; 99 6 : 510 – 518 . Google Scholar PubMed WorldCat 105 Savage NW , Seymour GJ , Kruger BJ. T-lymphocyte subset changes in recurrent aphthous stomatitis . Oral Surg Oral Med Oral Pathol. 1985 ; 60 2 : 175 – 181 . Google Scholar Crossref Search ADS PubMed WorldCat 106 Lehner T. Stimulation of lymphocyte transformation by tissue homogenates in recurrent oral ulceration . Immunology. 1967 ; 13 2 : 159 – 166 . Google Scholar PubMed WorldCat 107 Dolby AE. Recurrent aphthous ulceration. Effect of sera and peripheral blood lymphocytes upon oral epithelial tissue culture cells . Immunology. 1969 ; 17 5 : 709 – 714 . Google Scholar PubMed WorldCat 108 Rogers RS 3rd , Sams WM Jr , Shorter RG. Lymphocytotoxicity in recurrent aphthous stomatitis. Lymphocytotoxicity for oral epithelial cells in recurrent aphthous stomatitis and Bechet syndrome . Arch Dermatol. 1974 ; 109 3 : 361 – 363 . Google Scholar Crossref Search ADS PubMed WorldCat 109 Rogers RS 3rd , Movius DL , Pierre RV. Lymphocyte-epithelial cell interactions in oral mucosal inflammatory diseases . J Invest Dermatol. 1976 ; 67 5 : 599 – 602 . Google Scholar Crossref Search ADS PubMed WorldCat 110 Greenspan JS , Gadol N , Olson JA , et al. . Antibody-dependent cellular cytotoxicity in recurrent aphthous ulceration . Clin Exp Immunol. 1981 ; 44 3 : 603 – 610 . Google Scholar PubMed WorldCat 111 Burnett PR , Wray D. Lytic effects of serum and mononuclear leukocytes on oral epithelial cells in recurrent aphthous stomatitis . Clin Immunol Immunopathol. 1985 ; 34 2 : 197 – 204 . Google Scholar Crossref Search ADS PubMed WorldCat 112 Hasan A , Childerstone A , Pervin K , et al. . Recognition of a unique peptide epitope of the mycobacterial and human heat shock protein 65–60 antigen by T cells of patients with recurrent oral ulcers . Clin Exp Immunol. 1995 ; 99 3 : 392 – 397 . Google Scholar Crossref Search ADS PubMed WorldCat 113 Lewkowicz N , Lewkowicz P , Dzitko K , et al. . Dysfunction of CD4+CD25high T regulatory cells in patients with recurrent aphthous stomatitis . J Oral Pathol Med. 2008 ; 37 8 : 454 – 461 . Google Scholar Crossref Search ADS PubMed WorldCat 114 Hijazi K , Lowe T , Meharg C , et al. . Mucosal microbiome in patients with recurrent aphthous stomatitis . J Dent Res. 2015 ; 94(3 Suppl) : 87S – 94S . Google Scholar Crossref Search ADS WorldCat 115 Hietanen J , Häyrinen-Immonen R , Al-Samadi A , et al. . Recurrent aphthous ulcers--a toll-like receptor-mediated disease? J Oral Pathol Med. 2012 ; 41 2 : 158 – 164 . Google Scholar Crossref Search ADS PubMed WorldCat 116 Al-Samadi A , Kouri VP , Salem A , et al. . IL-17C and its receptor IL-17RA/IL-17RE identify human oral epithelial cell as an inflammatory cell in recurrent aphthous ulcer . J Oral Pathol Med. 2014 ; 43 2 : 117 – 124 . Google Scholar Crossref Search ADS PubMed WorldCat 117 Al-Samadi A , Drozd A , Salem A , et al. . Epithelial cell apoptosis in recurrent aphthous ulcers . J Dent Res. 2015 ; 94 7 : 928 – 935 . Google Scholar Crossref Search ADS PubMed WorldCat 118 Khudhur AS , Di Zenzo G , Carrozzo M. Oral lichenoid tissue reactions: diagnosis and classification . Expert Rev Mol Diagn. 2014 ; 14 2 : 169 – 184 . Google Scholar Crossref Search ADS PubMed WorldCat 119 Sontheimer RD. Lichenoid tissue reaction/interface dermatitis: clinical and histological perspectives . J Invest Dermatol. 2009 ; 129 5 : 1088 – 1099 . Google Scholar Crossref Search ADS PubMed WorldCat 120 Ozkaya E. Oral mucosal fixed drug eruption: characteristics and differential diagnosis . J Am Acad Dermatol . 2013 ; 69 2 : e51 – e58 . Google Scholar Crossref Search ADS PubMed WorldCat 121 Webster K , Godbold P. Nicorandil induced oral ulceration . Br Dent J. 2005 ; 198 10 : 619 – 621 . Google Scholar Crossref Search ADS PubMed WorldCat 122 Oyama N , Setterfield JF , Gratian MJ , et al. . Oral and genital lichenoid reactions associated with circulating autoantibodies to desmoplakins I and II: a novel target antigen or example of epitope spreading? J Am Acad Dermatol. 2003 ; 48 3 : 433 – 438 . Google Scholar Crossref Search ADS PubMed WorldCat 123 Mockenhaupt M. The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis . Expert Rev Clin Immunol. 2011 ; 7 6 : 803 – 813 ; quiz 14–15. Google Scholar Crossref Search ADS PubMed WorldCat 124 Caproni M , Torchia D , Schincaglia E , et al. . The CD40/CD40 ligand system is expressed in the cutaneous lesions of erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum . Br J Dermatol. 2006 ; 154 2 : 319 – 324 . Google Scholar Crossref Search ADS PubMed WorldCat 125 Heng YK , Lee HY , Roujeau JC. Epidermal necrolysis: 60 years of errors and advances . Br J Dermatol. 2015 ; 173 5 : 1250 – 1254 . Google Scholar Crossref Search ADS PubMed WorldCat 126 Foedinger D , Anhalt GJ , Boecskoer B , et al. . Autoantibodies to desmoplakin I and II in patients with erythema multiforme . J Exp Med. 1995 ; 181 1 : 169 – 179 . Google Scholar Crossref Search ADS PubMed WorldCat 127 Cozzani E , Di Zenzo G , Calabresi V , et al. . Anti-desmoplakin antibodies in erythema multiforme and Stevens-Johnson syndrome sera: pathogenic or epiphenomenon? Eur J Dermatol. 2011 ; 21 1 : 32 – 36 . Google Scholar PubMed WorldCat 128 Kokuba H , Aurelian L , Burnett J. Herpes simplex virus associated erythema multiforme (HAEM) is mechanistically distinct from drug-induced erythema multiforme: interferon-gamma is expressed in HAEM lesions and tumor necrosis factor-alpha in drug-induced erythema multiforme lesions . J Invest Dermatol. 1999 ; 113 5 : 808 – 815 . Google Scholar Crossref Search ADS PubMed WorldCat 129 Chung WH , Hung SI , Yang JY , et al. . Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis . Nat Med. 2008 ; 14 12 : 1343 – 1350 . Google Scholar Crossref Search ADS PubMed WorldCat 130 Khalil I , Lepage V , Douay C , et al. . HLA DQB1*0301 allele is involved in the susceptibility to erythema multiforme . J Invest Dermatol. 1991 ; 97 4 : 697 – 700 . Google Scholar Crossref Search ADS PubMed WorldCat 131 Tassaneeyakul W , Tiamkao S , Jantararoungtong T , et al. . Association between HLA-B*1502 and carbamazepine-induced severe cutaneous adverse drug reactions in a Thai population . Epilepsia . 2010 ; 51 5 : 926 – 930 . Google Scholar Crossref Search ADS PubMed WorldCat 132 Somkrua R , Eickman EE , Saokaew S , et al. . Association of HLA-B*5801 allele and allopurinol-induced Stevens Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis . BMC Med Genet . 2011 ; 12 : 118 . Google Scholar Crossref Search ADS PubMed WorldCat 133 White KD , Chung WH , Hung SI , et al. . Evolving models of the immunopathogenesis of T cell-mediated drug allergy: the role of host, pathogens, and drug response . J Allergy Clin Immunol. 2015 ; 136 2 : 219 – 234 ; quiz 35. Google Scholar Crossref Search ADS PubMed WorldCat 134 Hashimoto K , Yasukawa M , Tohyama M. Human herpesvirus 6 and drug allergy . Curr Opin Allergy Clin Immunol. 2003 ; 3 4 : 255 – 260 . Google Scholar Crossref Search ADS PubMed WorldCat 135 Descamps V , Mahe E , Houhou N , et al. . Drug-induced hypersensitivity syndrome associated with Epstein-Barr virus infection . Br J Dermatol. 2003 ; 148 5 : 1032 – 1034 . Google Scholar Crossref Search ADS PubMed WorldCat 136 González-Delgado P , Blanes M , Soriano V , et al. . Erythema multiforme to amoxicillin with concurrent infection by Epstein-Barr virus . Allergol Immunopathol (Madr) . 2006 ; 34 2 : 76 – 78 . Google Scholar Crossref Search ADS PubMed WorldCat 137 Cirillo N , Cozzani E , Carrozzo M , et al. . Urban legends: pemphigus vulgaris . Oral Dis. 2012 ; 18 5 : 442 – 458 . Google Scholar Crossref Search ADS PubMed WorldCat 138 Ruocco V , Ruocco E , Lo Schiavo A , et al. . Pemphigus: etiology, pathogenesis, and inducing or triggering factors: facts and controversies . Clin Dermatol. 2013 ; 31 4 : 374 – 381 . Google Scholar Crossref Search ADS PubMed WorldCat 139 Orion E , Matz H , Wolf R. Pemphigus vulgaris induced by radiotherapy . J Eur Acad Dermatol Venereol. 2004 ; 18 4 : 508 – 509 . Google Scholar Crossref Search ADS PubMed WorldCat 140 Daneshpazhooh M , Chams-Davatchi C , Ramezani A , et al. . Abortive aphthous-like oral lesions: an underreported initial presentation of pemphigus vulgaris . J Eur Acad Dermatol Venereol. 2009 ; 23 2 : 157 – 159 . Google Scholar Crossref Search ADS PubMed WorldCat 141 Amagai M , Klaus-Kovtun V , Stanley JR. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion . Cell. 1991 ; 67 5 : 869 – 877 . Google Scholar Crossref Search ADS PubMed WorldCat 142 Amagai M , Tsunoda K , Zillikens D , et al. . The clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile . J Am Acad Dermatol. 1999 ; 40(2 Pt 1) : 167 – 170 . Google Scholar Crossref Search ADS WorldCat 143 Tsunoda K , Ota T , Aoki M , et al. . Induction of pemphigus phenotype by a mouse monoclonal antibody against the amino-terminal adhesive interface of desmoglein 3 . J Immunol. 2003 ; 170 4 : 2170 – 2178 . Google Scholar Crossref Search ADS PubMed WorldCat 144 Payne AS , Ishii K , Kacir S , et al. . Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display . J Clin Invest. 2005 ; 115 4 : 888 – 899 . Google Scholar Crossref Search ADS PubMed WorldCat 145 Schulze K , Galichet A , Sayar BS , et al. . An adult passive transfer mouse model to study desmoglein 3 signaling in pemphigus vulgaris . J Invest Dermatol. 2012 ; 132 2 : 346 – 355 . Google Scholar Crossref Search ADS PubMed WorldCat 146 Spindler V , Rotzer V , Dehner C , et al. . Peptide-mediated desmoglein 3 crosslinking prevents pemphigus vulgaris autoantibody-induced skin blistering . J Clin Invest . 2013 ; 123 2 : 800 – 811 . Google Scholar PubMed WorldCat 147 Di Zenzo G , Amber KT , Sayar BS , et al. . Immune response in pemphigus and beyond: progresses and emerging concepts . Semin Immunopathol. 2016 ; 38 1 : 57 – 74 . Google Scholar Crossref Search ADS PubMed WorldCat 148 Tron F , Gilbert D , Joly P , et al. . Immunogenetics of pemphigus: an update . Autoimmunity. 2006 ; 39 7 : 531 – 539 . Google Scholar Crossref Search ADS PubMed WorldCat 149 Ahmed AR , Yunis EJ , Khatri K , et al. . Major histocompatibility complex haplotype studies in Ashkenazi Jewish patients with pemphigus vulgaris . Proc Natl Acad Sci U S A. 1990 ; 87 19 : 7658 – 7662 . Google Scholar Crossref Search ADS PubMed WorldCat 150 Miyagawa S , Higashimine I , Iida T , et al. . HLA-DRB1*04 and DRB1*14 alleles are associated with susceptibility to pemphigus among Japanese . J Invest Dermatol. 1997 ; 109 5 : 615 – 618 . Google Scholar Crossref Search ADS PubMed WorldCat 151 Lombardi ML , Mercuro O , Ruocco V , et al. . Common human leukocyte antigen alleles in pemphigus vulgaris and pemphigus foliaceus Italian patients . J Invest Dermatol. 1999 ; 113 1 : 107 – 110 . Google Scholar Crossref Search ADS PubMed WorldCat 152 Riechers R , Grötzinger J , Hertl M. HLA class II restriction of autoreactive T cell responses in pemphigus vulgaris: review of the literature and potential applications for the development of a specific immunotherapy . Autoimmunity. 1999 ; 30 3 : 183 – 196 . Google Scholar Crossref Search ADS PubMed WorldCat 153 Ahmed AR , Carrozzo M , Caux F , et al. . Monopathogenic vs multipathogenic explanations of pemphigus pathophysiology . Exp Dermatol. 2016 ; 25 11 : 839 – 846 . Google Scholar Crossref Search ADS PubMed WorldCat 154 Kalantari-Dehaghi M , Anhalt GJ , Camilleri MJ , et al. . Pemphigus vulgaris autoantibody profiling by proteomic technique . PLoS One. 2013 ; 8 3 : e57587 . Google Scholar Crossref Search ADS PubMed WorldCat 155 Sajda T , Hazelton J , Patel M , et al. . Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus . Proc Natl Acad Sci U S A. 2016 ; 113 7 : 1859 – 1864 . Google Scholar Crossref Search ADS PubMed WorldCat 156 Chernyavsky A , Amber KT , Agnoletti AF , et al. . Synergy among non-desmoglein antibodies contributes to the immunopathology of desmoglein antibody-negative pemphigus vulgaris . J Biol Chem 2019 ; 294 12 : 4520 – 4528 . Google Scholar Crossref Search ADS PubMed WorldCat 157 Grando SA. Pemphigus autoimmunity: hypotheses and realities . Autoimmunity. 2012 ; 45 1 : 7 – 35 . Google Scholar Crossref Search ADS PubMed WorldCat 158 Scully C , Miller CS , Aguirre Urizar JM , et al. . Oral medicine (stomatology) across the globe: birth, growth, and future . Oral Surg Oral Med Oral Pathol Oral Radiol. 2016 ; 121 2 : 149 – 157.e5 . Google Scholar Crossref Search ADS PubMed WorldCat 159 Dey-Rao R , Seiffert-Sinha K , Sinha AA. Genome-wide expression analysis suggests unique disease-promoting and disease-preventing signatures in Pemphigus vulgaris . Genes Immun. 2013 ; 14 8 : 487 – 499 . Google Scholar Crossref Search ADS PubMed WorldCat 160 Pullarkat ST , Stoehlmacher J , Ghaderi V , et al. . Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy . Pharmacogenomics J. 2001 ; 1 1 : 65 – 70 . Google Scholar Crossref Search ADS PubMed WorldCat 161 Lecomte T , Ferraz JM , Zinzindohoué F , et al. . Thymidylate synthase gene polymorphism predicts toxicity in colorectal cancer patients receiving 5-fluorouracil-based chemotherapy . Clin Cancer Res. 2004 ; 10 17 : 5880 – 5888 . Google Scholar Crossref Search ADS PubMed WorldCat 162 Schwab M , Zanger UM , Marx C , et al. . Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group . J Clin Oncol. 2008 ; 26 13 : 2131 – 2138 . Google Scholar Crossref Search ADS PubMed WorldCat 163 Sonis ST. New thoughts on the initiation of mucositis . Oral Dis. 2010 ; 16 7 : 597 – 600 . Google Scholar Crossref Search ADS PubMed WorldCat 164 Ellebrecht CT , Bhoj VG , Nace A , et al. . Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease . Science. 2016 ; 353 6295 : 179 – 184 . Google Scholar Crossref Search ADS PubMed WorldCat 165 U.S. Department of Health and Human Services. Common Terninology Criteria for Adverse Events (CTCAE) Version 5 (27 Nov 2017). https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf. Accessed March 14, 2019. 166 National Institute for Health and Care Excellence . Interventional Procedures Progamme. https://www.nice.org.uk/guidance/ipg615/documents/overview. Accessed March 14, 2019. 167 Boers-Doets CB , Nicolatou-Gailitis O , Lalla RV. The mIAS Scale: a scale to measure mTOR inhibitor-associated stomatitis . Support Care Cancer . 2013 ; 21 ( S1 ): S140 . WorldCat 168 Lacouture ME , Maitland ML , Segaert S , et al. . A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCC skin toxicity study group . Support Care Cancer. 2010 ; 18 4 : 509 – 522 . Google Scholar Crossref Search ADS PubMed WorldCat 169 Chan A , Tan EH. How well does the MESTT correlate with CTCAE scale for the grading of dermatological toxicities associated with oral tyrosine kinase inhibitors? Support Care Cancer. 2011 ; 19 10 : 1667 – 1674 . Google Scholar Crossref Search ADS PubMed WorldCat 170 National Cancer Institute . Oral Complications of Chemotherapy and Head/Neck Radiation (PDQ)-Healt Professional version. 2019 . https://www.cancer.gov/about-cancer/treatment/side-effects/mouth-throat/oral-complications-hp-pdq. Accessed March 14, 2019. © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Monographs Oxford University Press

Oral Mucosal Injury Caused by Targeted Cancer Therapies

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Oxford University Press
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© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
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1052-6773
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1745-6614
DOI
10.1093/jncimonographs/lgz012
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Abstract

Abstract Targeted cancer therapies have fundamentally transformed the treatment of many types of cancers over the past decade, including breast, colorectal, lung, and pancreatic cancers, as well as lymphoma, leukemia, and multiple myeloma. The unique mechanisms of action of these agents have resulted in many patients experiencing enhanced tumor response together with a reduced adverse event profile as well. Toxicities do continue to occur, however, and in selected cases can be clinically challenging to manage. Of particular importance in the context of this monograph is that the pathobiology for oral mucosal lesions caused by targeted cancer therapies has only been preliminarily investigated. There is distinct need for novel basic, translational, and clinical research strategies to enhance design of preventive and therapeutic approaches for patients at risk for development of these lesions. The research modeling can be conceptually enhanced by extrapolating “lessons learned” from selected oral mucosal conditions in patients without cancer as well. This approach may permit determination of the extent to which pathobiology and clinical management are either similar to or uniquely distinct from oral mucosal lesions caused by targeted cancer therapies. Modeling associated with oral mucosal disease in non-oncology patients is thus presented in this context as well. This article addresses this emerging paradigm, with emphasis on current mechanistic modeling and clinical treatment. This approach is in turn designed to foster delineation of new research strategies, with the goal of enhancing cancer patient treatment in the future. Targeted cancer therapies have substantially changed the treatment of cancer over the past 10 years. Use of targeted therapy has considerably improved clinical outcomes for many common malignancies, including breast, colorectal, head and neck, lung, and pancreatic cancers, as well as lymphoma, leukemia, and multiple myeloma. Imatinib has had a dramatic effect on chronic myeloid leukemia (1,2), and rituximab, sunitinib, and trastuzumab have revolutionized the treatment of non-Hodgkin’s lymphoma (3,4), renal cell carcinoma (5,6), and breast cancer (7,8), respectively. Relative to other cancers, however, the degree of clinical benefit has been more modest. For example, in patients with advanced pancreatic cancer, adding erlotinib to standard chemotherapy increases the 1-year survival rate from 17% to 23%, which correlates to an increase in median survival from only 24 to 27 weeks (9). In addition to prolonging survival in patients with selected types of cancers, targeted therapies provide treatment options for some patients who may not otherwise be candidates for conventional cancer therapy. For instance, non-small cell lung cancer and non-Hodgkin’s lymphoma primarily affect elderly patients, many of whom have medical comorbidities that limit the use of standard chemotherapy. Targeted therapies such as erlotinib, rituximab, or everolimus often lead to less severe adverse events (AEs) and are better tolerated than traditional chemotherapy, offering these patients additional treatment options. Similarly, immuno-oncology has substantially improved the prognosis for patients with advanced melanoma and squamous non-small cell lung carcinoma following platinum-based chemotherapy. This technology is likely to improve treatment of advanced disease in a number of other malignancies. Despite this collective strategic positive clinical impact, these agents are also associated with a unique constellation of inflammatory conditions of the skin and mucosa (10). These AEs include oral mucosal lesions that are phenotypically distinct from oral mucosal injury caused by conventional high-dose cancer therapy (Figure 1). In addition, AEs other than oral mucosal and dermal lesions, including cardiac dysfunction, thrombosis, hypertension, and proteinuria, can be caused by targeted cancer therapies as well. Figure 1. View largeDownload slide Mammalian target of rapamycin inhibitor-associated stomatitis. A) Tongue, after patient received three 21-day cycles (63 days) of ridaforolimus. B) Inner lip, as positioned by the patient’s fingers, in patient who developed mTOR inhibitor-associated stomatitis within 10 days of initiating treatment with everolimus (10 mg once daily) in combination with figitumumab. Reprinted with permission from Pilotte AP et al. (11). Figure 1. View largeDownload slide Mammalian target of rapamycin inhibitor-associated stomatitis. A) Tongue, after patient received three 21-day cycles (63 days) of ridaforolimus. B) Inner lip, as positioned by the patient’s fingers, in patient who developed mTOR inhibitor-associated stomatitis within 10 days of initiating treatment with everolimus (10 mg once daily) in combination with figitumumab. Reprinted with permission from Pilotte AP et al. (11). Utilization of targeted cancer therapies in oncology practice has thus provided a strategic new opportunity for tailoring cancer treatment to an individual patient’s tumor. Administration of these agents to patients has also resulted in the need to prevent or treat the associated AEs as well as address health-care costs related to their use. An increasing number of individuals will be diagnosed with cancer in the future, with associated expanded use of targeted cancer therapies that in turn results in patients living longer as well. The interprofessional healthcare team will thus need to be positioned to provide care for the increased number of patients who are treated with these agents. Targeted Therapies Unlike conventional cancer therapies, targeted cancer therapies are designed to interfere with tumor cell-specific molecular pathways essential for tumor growth and progression. As such, the ultimate goal of targeted therapies is to eliminate the patient’s cancer with increased precision and fewer AEs than with chemotherapy and/or radiotherapy. Examples of Targeted Cancer Therapies Therapeutic monoclonal antibodies target specific antigens located on the cell surface, such as transmembrane receptors (eg, panitumumab [Vectibix)]) (12) or extracellular growth factors (eg, bevacizumab [Avastin]) (13). In some cases, monoclonal antibodies are conjugated to radio-isotopes or toxins to allow specific delivery of these cytotoxic agents to the intended cancer cell target. Signal transduction inhibitors block signals transmitted from one molecule to another inside the cell. Blocking these signals can affect multiple cellular functions, including cell division and cell death. Examples of this class of agents include cetuximab (Erbitux) (14), everolimus (Afinitor) (15), and imatinib (Glivec) (16). Angiogenesis inhibitors block growth of neovascularization of tumors. Selected angiogenesis inhibitors (eg, bevacizumab [Avastin]) (13) interfere with vascular endothelial growth factor (VEGF), whereas others [eg, combrestatin (Zybrestat) (17)] bind to the β-subunit of tubulin and cause vascular disruption. Apoptosis-inducing drugs cause cancer cells to undergo controlled cell death. However, most of the cytotoxic anticancer drugs in current use have some ability to induce apoptosis. One example of a class of drugs with specific apoptosis-inducing effect is tumor necrosis factor-related apoptosis inducing ligand (Apo2L/TRAIL), expressed on immune cells such as natural killer cells. This moiety binds to several receptors, including death receptor-4 and -5 (DR5), and ultimately leads to an apoptotic cascade. Several monoclonal agonist antibodies have been investigated as cancer therapies; most are directed to DR5. Examples of these agents are lexatumumab (18) and conatumumab (19). As of February 5, 2019 both studies were in either phase I or II clinical trials (20). Gene-expression modulators modify the function of proteins that play a role in controlling gene expression. One of the most well-known classes of drugs are the histone deacetylase inhibitors such as vorinostat (Zolinza) (21) that modulate a broad spectrum of epigenetic activities. Hormone therapies can be considered for treatment of hormone-sensitive malignancies such as prostate cancer and breast cancer. The action of these agents is directed to either suppression of hormone production per se or by interfering with the molecular action of the hormone once bound to the tumor cell. Immunotherapies are currently utilized to treat many different types of cancer. These agents trigger the immune system to recognize and eliminate the cancer cells. Selected biologics are considered targeted therapies as well because they interfere with the growth of specific cancer cells. The main types of immunotherapy currently being used to treat cancer include the following technologies: Monoclonal antibodies that recognize specific molecules on the surface of cancer cells. Binding of the monoclonal antibody to the target molecule results in the immune destruction of cells that express the target molecule. Other monoclonal antibodies bind to certain immune cells to enhance the targeting of these cells against the tumor. Examples of monoclonal antibodies are alemtuzumab (Campath) (22), trastuzumab (Herceptin) (23), ibritumomab tiuxetan (Zevalin) (24), brentuximab vedotin (Adcetris) (25), ado-trastuzumab emtansine (Kadcyla, also called TDM-1) (26), denileukin diftitox (Ontak) (27), and blinatumomab (Blincyto) (28). Checkpoint inhibitors. These agents are immunomodulatory antibodies that include programmed cell death-1 (PD-1) receptor inhibitors. Multiple antibodies against PD-1 and its ligand (eg, pembrolizumab (Keytruda) (29), nivolumab (Opdivo) (30), and the cytotoxic T-lymphocyte-associated antigen 4 ipilimumab (Yervoy) (31) are available. Therapeutic vaccines, including sipuleucel-T (Provenge) (32). Peripheral blood mononuclear cells are obtained by leukapheresis and cultured with recombinant human prostatic acid phosphatase linked to granulocyte-macrophage colony-stimulating factor. Activated cells are injected into the patient to boost the immune response against the tumor. Cytokines (eg, interleukin-2 [Aldesleukin]) (33) and interferon α (IntronA) (34).    These agents are utilized alone or in combination to stimulate the immune system, especially killer T cells, to target cancer cells. Cytokines were commonly used in metastatic malignant melanoma, metastatic renal cell carcinoma, and certain types of leukemia. Their use has, however, declined following the clinical introduction of checkpoint inhibitors. Chimeric antigen receptor (CAR) T-cell therapy.This technology redirects patients’ T cells to specifically target tumor cells and cause tumor cell cytolysis. In 2017, the US Food and Drug Administration approved the first anti-CD19 CAR T-cell therapies for relapsed or refractory B-cell precursor acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Dosing and Effectiveness Targeted therapies inclusive of immunotherapy have introduced several new issues for the oncology team. Determining optimal dosing is one challenge. Clinical trials of traditional chemotherapeutic drugs generally utilize degree of myelosuppression as a pivotal determinant of toxicity. Targeted therapies, however, often do not cause clinically significant hematologic reactions. Mucocutaneous AEs are the most common AEs associated with epidermal growth factor receptor inhibitors, whereas immunotherapies are more likely to cause immuno-related pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, and endocrinopathies. Assessment of treatment effectiveness also may require a paradigm shift. When traditional chemotherapy is effective, reduction in tumor volume is anticipated on serial radiographic studies. In contrast, some targeted therapies may impart a clinical benefit by stabilizing tumors rather than reducing tumor volume, especially in the first cycles of treatment. To determine the dosing and effectiveness of targeted therapies, cancer researchers increasingly are turning to pharmacodynamic endpoints, such as tumor metabolic activity on positron emission tomography scans, levels of circulating tumor and endothelial cells, and serial levels of target molecules in tumor tissue (35–38). Although these studies may initially increase the time and expense of therapy, they may improve its long-term cost-effectiveness by identifying the subset of patients most likely to benefit from specific precision medicine technology. Targeted Cancer Therapy-Associated Oral Injury Clinically important AEs that disrupt normal oral function have been described in recent years related to use of targeted therapies such as tyrosine-kinase inhibitors (39). The oral reactions include oral mucosal ulceration, dysgeusia, oral sensitivity and pain without presence of clinical oral lesions, and xerostomia. Of particular note are the unique oral mucosal lesions that have been reported in patients who received targeted therapies (40,41). Elting et al. determined via meta-analysis with selected targeted agents that oral mucosal injury was most frequent among patients treated with bevacizumab, erlotinib, sorafenib, or sunitinib, although this difference was confined to low-grade mucosal injury (42). Selected immunotherapies have been reported to cause oral reactions as well, including but not limited to oral mucosal lesions (9,10,40). Stomatitis and dry mouth, for instance, appear to be more frequent with PD-1 receptor checkpoint inhibitors than with cytotoxic T-lymphocyte-associated antigen 4 blockade. In a dose-escalation, cohort expansion study of nivolumab for treatment of advanced melanoma, for example, dry mouth was observed in 6.5% of patients, including one case with at least grade 3 severity (43). Oral candidiasis also remains an important consideration in the differential diagnosis of oral mucosal lesions, particularly if a patient has been on corticosteroids for management of other immunotherapy-related AEs and/or is experiencing salivary hypofunction. It is important to consider the terminology of “stomatitis” and “mucositis” relative to AE reporting and targeted therapies as described above. “Stomatitis” is a general, descriptive term that refers to any inflammatory condition of oral tissues including but not limited to oral mucosal erosion or ulceration. In contrast, “mucositis” has emerged in the literature over the past 20 years as the preferred term for oral mucosal injury due to conventional cytotoxic chemotherapy and radiation. Both words are searchable MeSH terms. Regarding mucosal injury induced by the specific class of mammalian target of rapamycin (mTOR) inhibitors, Sonis et al. in 2010 proposed the term “mTOR inhibitor-associated stomatitis” (mIAS) to provide clarity and delineation from oral mucositis due to conventional cytotoxic chemotherapy and radiation (44). There is consensus among oral medicine specialists managing patients with oral mucosal lesions associated with mTOR inhibitors that the term mIAS is preferable to the term “oral mucositis” as described in the literature (45). Mechanistic Modeling of Oral Mucosal Injury Secondary to Targeted Therapies Oral mucositis is a well-known AE that is caused by high-dose ionizing head and neck radiation to the oral cavity or selected chemotherapeutic drugs such as carboplatin, capecitabine, or paclitaxel (46–50). Historically, oral mucositis had been primarily linked to destruction of rapidly dividing clonogenic cells in the basal layer of the epithelium. However, studies in recent years have continued to demonstrate that the mucosal injury is associated with a complex pathobiology (51). The currently accepted five but not functionally separated phases are (1) cellular damage and formation of reactive oxygen species; (2) upregulation of mediators of inflammation and activation of a number of transcription factors, such as NF-κB, Wnt, and p53; (3) upregulation of pro-inflammatory cytokines like TNF; (4) ulceration with or without infection; and (5) healing. This modeling is reviewed in detail in the Monograph chapter “Oral Mucositis Due to High-Dose Chemotherapy and/or Head and Neck Radiation Therapy.” The pathobiology leading to mucosal damage on exposure to targeted drugs is likely also complex. Although not well elucidated, the mechanistic modeling can be categorized by some of the main classes of targeted drugs like inhibition of the EGFR-RAF-MEK pathway, PI3K-AKT-mTOR pathway inhibition, and inhibition of angiogenesis and v-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) (35). The role of genetic polymorphisms in causation, although not well delineated for oral mucosal lesions caused by targeted therapies, has been increasingly demonstrated to contribute in part but not exclusively to risk for development of oral mucositis caused by high-dose cancer therapy (52,53). Examples of drugs intervening with the EGFR-RAF-MEK pathways are cetuximab, erlotinib, and trametinib. For monoclonal antibodies and partly also small molecule EGFR inhibitors, the main event would be an inhibition of cell proliferation via deregulation of the G1 cell cycle checkpoint and subsequently inhibition of EGFR-driven repair of DNA damage. The latter is partly related to increased sequestration of DNA protein kinase due to enucleated EGFR being bound to monoclonal EGFR inhibitors. Consequently, these actions result in increased apoptosis and cell loss (54,55). Also, reduced levels of VEGF followed by reduced capacity for angiogenesis have been suggested as a result of EGFR inhibition. This might also play an important role in the pathobiology of mucositis when EGFR inhibitors are combined with radiotherapy (56–58), because this can influence the vascular density. Overall, these events are related to the first two phases of development of oral mucositis as proposed by Sonis and colleagues (59,60), and cell loss leads to ulceration that subsequently can be colonized by Candida and other fungi or oral bacteria (52). In addition to potential systemic dissemination, bacteria, for example, are active contributors to the mucositis process by simulating the secretion of pro-inflammatory cytokines. It is currently unknown how the contemporary mucositis mechanistic model with the described EGFR- driven processes of inhibition of cell proliferation and DNA repair may integrate into this modeling. The healing and ulceration phases are likely comparable regardless of being induced by chemotherapy, ionizing radiation, or inhibitors of the EGFR-RAF-MEK pathway. Oral ulcerations are common dose-limiting AEs associated with PI3K-AKT-mTOR pathway inhibition (44,61,62). The mIAS presents as multiple or single ulcerations that are usually small and generally less than 0.5 cm in diameter, resembling aphthous stomatitis (63). Although the mechanism of inducing mIAS is not clear, mTOR inhibitors may bind directly to tissue proteins evoking an autoimmune-like inflammatory response (64) and can also inhibit VEGF and nitric oxide, which have been shown to be mediators of angiogenesis, inflammation, and immune function in skin wounds (65). Sirolimus has been specifically shown to disrupt T-cell proliferation, migration, and production of growth factors (66). These changes in nitric oxide and T-cell immune defense may also play an important role in recurrent aphthous stomatitis (67), suggesting that recurrent aphthous stomatitis and mIAS share common pathobiological pathways. However, data are conflicting and selected in vitro studies suggest that mTOR inhibitors increase stimulation of regulatory T-cells leading to increased peripheral tolerance, but mechanisms of action of mTOR inhibitors are likely multifaceted and can exert both immunosuppressive as well as immunostimulatory effects (68). Oral AEs due to antiangiogenic agents are most frequently seen with VEGFR-directed multi-target tyrosine kinase inhibitors such as sunitinib, sorafenib and cabozantinib. Approximately 25% of patients treated with these agents develop some type of stomatitis (10). The oral mucosal ulcerations that develop, although similar phenotypically to the oral aphthous-like lesions caused by mTOR inhibitors, are typically of low-grade severity. By comparison, these patients more typically report nonspecific mucosal inflammatory symptoms including mucosal hypersensitivity or dysesthesia and dysgeusia. These drugs block targets including c-Raf and b-Raf kinases as well as VEGFR-2, VEGFR-3, Flt-3, c-Kit, and the PDGF receptor. As such, they affect a range of cellular processes including tumor growth, tumor progression, angiogenesis, and metastasis. Having said this, knowledge of the underlining pathobiology of the oral AEs is limited. BRAF inhibitors (vemurafenib, dabrafenib) can cause oral hyperkeratotic lesions and gingival hyperplasia (69–72). A case of oral squamous cell carcinoma has also been reported to occur in association with a BRAF inhibitor (71). Notably, similar lesions are commonly caused by BRAF inhibitors on the skin, and they are thought to be due to the proliferation of BRAF wild-type keratinocytes (KCs) induced by paradoxical activation of the mitogen-activated protein kinase pathway in the presence or absence of recurrent aphthous stomatitis (RAS) mutations (71). By comparison, checkpoint inhibitors such as nivolumab have been reported to trigger severe erythema multiforme (EM)-like eruption with erosive oral mucosal involvement (16,17). The majority of these targeted therapeutics in clinical use are administered in combination with other systemic therapies or radiotherapy, making it even more difficult to elucidate the mechanisms and interactions in vivo. Although most of the targeted therapies are well investigated for their anticancer effects, the oral AEs are less frequently systematically characterized. Progress in unraveling the molecular pathways and developing new specific treatments directed to the oral injury thus requires a more appropriate registration and description of the pathology of targeted therapy-induced stomatitis. Do Nontargeted and Targeted Anticancer Agents Cause Different Oral Manifestations? Although designed to be more “precise” than traditional chemotherapies, targeted therapies frequently induce AEs, including in the oral cavity. Targeted drugs known to cause oral AEs include epidermal growth factor receptor inhibitors such as cetuximab, tyrosine kinase inhibitors (axitinib), selective and nonselective antiangiogenic agents (bevacizumab, sunitinib, and sorafenib), mTOR (temsirolimus, everolimus, and ridaforolimus), and BRAF inhibitors (vemurafenib, dabrafenib) (61,73). The oral AEs range from stomatitis to dysgeusia and osteonecrosis of the jaws, oral white patches, and gingival overgrowth. However, the evidence regarding oral cavity injury caused by targeted therapy is relatively limited in quality and quantity (74). The most extensively studied oral AEs to date are those associated with mIAS. With mIAS, the ulcers observed clinically in patients receiving targeted anticancer agents are often described as aphthous-like. However and when the clinical phenotype has been described, the lesions on occasion seem larger and deeper than traditional aphthae (44,75). The ulcers also exhibit a tendency to coalesce and involve sites such as dorsal tongue or attached gingiva, which are usually spared by typical aphthous ulcers (76–78). Infectious causes, for example due to herpesviruses, have not always been properly excluded in the majority of cases. This has been the historical context, even though a number of early studies regarding mTOR inhibitors utilized to prevent graft rejection in solid organ transplantation highlighted the possible herpetic etiology of the oral ulcers (76). A recent structured review regarding risk of oral AEs with mTOR inhibitor stated that stomatitis was different from that seen during traditional radiotherapy and chemotherapy, and when described it resembled either aphthous or herpetic stomatitis (79). However, only 38.6% of the original studies described in detail the oral manifestations and only two, both employing temsirolimus (80,81), of 44 cited aphthous-like ulcers. Selected trials reported various terminology such as mouth sores (82,83), ulcerative mucositis, and aphthous-like ulcers (81). The majority of the studies included grade 3–4 oral AEs, but severe oral lesions were not always and consistently related to increased dosage (84–87). mTOR inhibitor mucositis-related dose reduction and even discontinuation were reported but only by a minority of studies, whereas most did not specify this information (79). A 2015 meta-analysis on stomatitis with mTOR inhibitors in cancer patients reported an incidence of all-grade and high-grade stomatitis of 33.5% and 4.1%, respectively (88). However, in this study incidence of high-grade stomatitis varied statistically significantly with tumor type and mTOR inhibitors. The authors noted that the lack of uniform measurement scales and terminology for stomatitis secondary to mTOR inhibitors may have led to underestimation of stomatitis across the studies. The majority of studies published to date regarding mTOR inhibitors did not apparently include an oral examination performed by trained oral specialists, and the usual way to collect AEs is the National Cancer Institute Common Criteria for Adverse Events reporting, which often relies on spontaneous patient report, leading to possible under- and misreporting (61,74). In addition, measurement scales and terminology differ among studies, which in turn further complicates insight into the prevalence of these AEs (61). The evidence is even more sparse when oral lesions caused by targeted therapeutics other than mTOR are reported (73). In conclusion, although it is likely that targeted cancer therapies cause unique oral AEs, further studies are needed to better characterize, minimize, and manage these lesions. Even if these drugs are causing moderate stomatitis, dose reduction and also cessation of therapy has been reported due to pain with potential deleterious outcomes for tumor response. Prospective studies incorporating patient-reported outcomes using validated instruments together with specific clinical evaluation of the oral cavity are warranted in this context. Comparison With State of the Science of Immunologically Mediated Oral Disease Given the current gaps in understanding of pathobiology of oral mucosal injury caused by targeted cancer agents, review of the state of the science regarding naturally occurring immunologically mediated oral disease (IMOD) may provide key foundational insights into new research directions that could be applied to study the oral mucosal lesions caused by the targeted cancer therapeutics. Elements of the molecular modeling as described below are included in Figures 2 and 3 as well. Figure 2. View largeDownload slide Immunopathogenesis of recurrent aphthous stomatitis. In genetically predisposed patients, an increase of epithelial permeability and dysfunction or regulatory T cells (Treg) enables epithelial cells to begin an inflammatory response triggered by several different factors. The result is an increase of apoptosis and accumulation of antigen presenting cells, cytotoxic T cells, and Th1 cytokines that in turn cause necrosis of keratinocytes and ulceration and further increase of Th1 cytokine release. APC = ; IL = ; PAMP = : ROS = ; Th = ; TLR = . Figure 2. View largeDownload slide Immunopathogenesis of recurrent aphthous stomatitis. In genetically predisposed patients, an increase of epithelial permeability and dysfunction or regulatory T cells (Treg) enables epithelial cells to begin an inflammatory response triggered by several different factors. The result is an increase of apoptosis and accumulation of antigen presenting cells, cytotoxic T cells, and Th1 cytokines that in turn cause necrosis of keratinocytes and ulceration and further increase of Th1 cytokine release. APC = ; IL = ; PAMP = : ROS = ; Th = ; TLR = . Figure 3. View largeDownload slide Immunopathogenesis of pemphigus vulgaris. In genetically predisposed patients, a loss of self-tolerance against Desmoglein 3 (Dsg 3) and potentially other antigens in both T and B lymphocytes can enable different etiologic factors to begin production of IgG autoantibodies. Binding of pathogenic (either anti-Dsg and non‐Dsg) antibodies to keratinocytes causes activation of Src, EGFRK, p38 MAPK, and mammalian target of rapamycin and elevation of intracellular Ca2+, altogether, initiate cell death enzymatic cascades. Suprabasal acantholysis starts when basal cells shrink. Acantholysis advances and stimulates production of secondary (scavenging) antibodies. Rounding up and death of acantholytic cells in the lower epidermal compartment follow irreversible damage of mitochondrial and nuclear proteins. Figure 3. View largeDownload slide Immunopathogenesis of pemphigus vulgaris. In genetically predisposed patients, a loss of self-tolerance against Desmoglein 3 (Dsg 3) and potentially other antigens in both T and B lymphocytes can enable different etiologic factors to begin production of IgG autoantibodies. Binding of pathogenic (either anti-Dsg and non‐Dsg) antibodies to keratinocytes causes activation of Src, EGFRK, p38 MAPK, and mammalian target of rapamycin and elevation of intracellular Ca2+, altogether, initiate cell death enzymatic cascades. Suprabasal acantholysis starts when basal cells shrink. Acantholysis advances and stimulates production of secondary (scavenging) antibodies. Rounding up and death of acantholytic cells in the lower epidermal compartment follow irreversible damage of mitochondrial and nuclear proteins. Text in this section summarizes current knowledge regarding IMOD pathobiology. Potential applicability of this science in nononcology modeling to new research directions regarding oral mucosal lesions caused by targeted cancer therapies is then summarized in the next section of this publication beginning on page 37, titled “What Lessons Can Be Learned From Immunologically Mediated Oral Injury?” There are three main clinical and pathologic inflammatory pathways occurring in the oral cavity: aphthous, lichenoid, and bullous or blistering. RAS, EM, and pemphigus vulgaris (PV) represent prototypic examples of these patterns of inflammation. Oral manifestations of these disorders can mimic stomatitis caused by anticancer targeted drugs, and, remarkably, all these diseases can only affect the mouth. Similar to stomatitis, RAS and EM are principally acute and self-resolving, whereas PV in many but not all the instances is a chronic condition. Interestingly, either EM or PV can be elicited by radiotherapy, whereas drugs can be a potential cause of all three manifestations (89–91). At least for EM there is strong evidence that targeted and nontargeted chemotherapeutic drugs can also cause the injury (92). Moreover, fludarabine, a synthetic nucleoside analogue, has been associated with the onset of paraneoplastic pemphigus (93), an aggressive variety of pemphigus commonly affecting the oral cavity. As previously noted, targeted anticancer therapies, particularly mTOR inhibitors, are considered a cause of oral aphthous-like ulcers based on clinical phenotype. Recurrent Aphthous Stomatitis RAS is a common condition characterized by multiple recurrent small, round, or ovoid ulcers with erythematous haloes almost exclusively affecting nonkeratinized mucosa in otherwise healthy individuals. The etiopathogenesis of RAS is not fully understood; triggering factors potentially include mechanical trauma, microbial factors, vitamin and microelement deficiencies, drugs, foods, hormonal imbalances, and anxiety (94). Systemic diseases such as Behcet’s syndrome are also characterized by aphthous-like ulcers that histologically mimic classic aphthae. There is likely a genetic predisposition, although studies of human leukocyte antigen (HLA) have been inconsistent in this context (94). An association with functional polymorphisms of interleukins (IL)-1β, IL-6, and IL-10 leading to increased activities of those cytokines has been suggested (95) and confirmed in different populations by meta-analyses (96–98). Moreover, increased production of IL-1 has been shown in RAS patients (99). Notably, the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (the so-called PFAPA syndrome) is a disorder of innate immunity and Th1 activation characterized by increased level of complement and IL-1β/-18 during flares (100). Similarly, there is an increase production of Th1 cytokines in RAS. It remains unclear if RAS is caused by a T-cell–mediated immune reaction (type IV reaction according to Gell-Coombs) (101), or if it rather represents an antibody-dependent cell-mediated cytotoxicity (type II) (94). Circulating CD4+ T cells are reduced whereas CD8+ and γδ T cells are increased (102,103). In the pre-ulcerative phase of RAS, there is a local mononuclear infiltrate consisting initially of CD4+T cells (104), whereas the ulcerative phase is associated with the appearance of CD8+ lymphocytes (105) and increased number of antigen-presenting cells. In vitro studies have indicated that peripheral blood leucocytes of patients with RAS may demonstrate increased cytotoxicity towards oral mucosal epithelium expressing class I and II MHC antigens (106–111). It is thus possible that RAS may represent an antibody-dependent cell-mediated cytotoxicity-type reaction to the oral mucosa. Other studies, however, suggest that RAS could be a T-cell–mediated response. For example, antigens of Streptococcus sanguis may cross-react with mitochondrial heat shock proteins and induce oral mucosal damage (112). Notably, a quantitative and functional dysfunction of regulatory T cells (Treg) cells in RAS patients has been suggested (113). Treg cells are critical in the maintenance of peripheral self-tolerance and controlling the immune responses against microbes. There is an increasing body of evidence suggesting that perturbations of mucosal microbiota, called microbial dysbiosis, can modulate innate and adaptive immune responses (114). This evidence suggests that mucosal microbiome changes in patients with idiopathic RAS may contribute to ulcer pathogenesis. Interestingly and in contrast to healthy mucosa, in RAS patients the normal polarity of Toll-like receptor (TLR) architecture is lost and most of TLRs extend to the epithelial cell surface, ultimately causing increased epithelial permeability and enabling those epithelial cells to start an inflammatory response to well-conserved pathogen associated molecular patterns (115). Oral epithelial cells in RAS are indeed not only passive targets of immune-inflammation but represent a potentially very important inflammatory cell pool that can produce IL-17C (116). RAS can be initiated by sudden and severe apoptosis of the oral epithelial cells (117). Because of a lack of scavenging anti-inflammatory macrophages, apoptotic cells likely undergo secondary necrosis and thus release pro-inflammatory signals such as self-DNA. This outcome may in turn contribute to the peripheral inflammatory halo (117) and further increase Th1 cytokine release. Erythema Multiforme EM is a muco-cutaneous disorder belonging to the lichenoid tissue reaction-interface dermatitis group (118). These disorders share a pattern of common histopathological elements including liquefative or vacuolar degeneration of basal KCs, a band-like array of mononuclear cells in the dermis including activated T cells, macrophages, and dendritic cells (119). EM is an example of low-density inflammatory infiltrate in the lichenoid tissue reaction-interface dermatitis group. Clinically, EM can occur independently or in combination in the mouth and other mucous membrane and skin. However, isolated oral lesions are commonly misdiagnosed as fixed drug eruption (120), unspecified oral ulcerations (121), or atypical erosive oral lichen planus (122). Typical EM oral lesions are ulcerative in nature and are often widespread and predominantly involving the anterior part of the oral cavity with frequent crusting and ulceration of the lips. EM, particularly the severe variant called EM major, is strictly related to potentially fatal Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) and is considered part of the same spectrum (123). The characteristic histolopathologic pattern of SJS and TEN, for example, presents with necrotic KCs in either wide dissemination or full-thickness necrosis of the epidermis (123). EM and SJS or TEN are currently considered as cell-mediated reactions aimed at the destruction of KCs and /or mucosal KCs expressing herpes- or drug-related antigens (124); however, the pattern and distribution of individual cutaneous lesions can be different (125). Oral ulcerations can be seen in the majority of severe EM and SJS or TEN. Both nontargeted (alkylating agents, purines, mitotic inhibitors) and targeted (nonreceptor tyrosine kinase inhibitors, hormone antagonists, checkpoint inhibitors) drugs can trigger EM (92). EM is a type IV reaction according to the Gell-Coombs system classification (101). A possible pathogenetic role of autoantibodies against desmoplakin I and II has been suggested in EM (126). However, desmoplakin-positive patients might simply represent a subset of PV patients with an unusual phenotype of EM (127). Generation of auto-reactive T cells that target the epidermis plays an important role in the pathogenesis of EM (125,128). Studies have shown that sparse distribution of Tregs might be involved in the onset of severe muco-cutaneous adverse drug reactions and that Treg migration toward epithelial cells can be influenced by medication such as allopurinol, commonly causing severe EM. These auto-reactive T cells release inflammatory cytokines, such as interferon-γ and tumor necrosis factor (TNF)-α (128), which can induce apoptosis and related changes in epidermal KCs. Various mediators have been suggested to stimulate apoptosis, including TNF-α-related apoptosis inducing ligand, perforin/grazyme, Fas-ligand, CD40/CD40 ligand system and granulysin (129). The peptide antigens (either viral or drug) have to be bound to MHC protein in the intracellular environment and expressed on the surface of antigen presenting cells to stimulate T-cell activation. Models explaining how small-molecule pharmaceutical compound might interact with MHC include the hapten-prohapten model, the p-i model, and the altered peptide reporter model. EM appears to be associated with selected HLA loci, mainly with HLA-B15 (B62), HLA- B35, HLA-A33, HLADR53, and HLA-DQB1*0301. The latter has been strongly associated with herpes simplex virus-associated EM (130). Notably, several associations between adverse drug reactions and HLA class I and/or class II alleles are characterized by a high predictive value, which makes it possible to use those associations to screen patients and prevent the risk. This strategy has been applied in clinical settings in Chinese patients carrying the HLA-B*15:02 allele who have a substantial risk of SJS or TEN and in various populations in whom allopurinol intake has been associated with similar risk of SJN or TEN when positive for the HLA-B*58:01 allele (131,132). It is still unknown what factors, in addition to HLA risk allele carriage, are required to trigger a T-cell–mediated drug hypersensitivity reaction and what might account for the differences among clinical phenotype of different reactions (133). Because cellular immunity requires plasticity, it might be that heterologous immunity, namely the concept of a single T cell receptor recognizing peptides derived from more than one source (either viral or drug related), is involved. Notably, several viruses have been seen to influence allergic reactions to drugs including EM. These viruses mainly belong to the human herpesvirus family and encompass human herpes virus 6, cytomegalovirus, and Epstein-Barr virus (134–136). Pemphigus Vulgaris PV is a potentially lethal muco-cutaneous blistering disease characterized by IgG autoantibodies (PVIgG) binding to KCs (137). This is a type II reaction according to the Gell-Coombs system classification (101). PV patients develop cell-cell detachment (acantholysis), blisters, and nonhealing erosions due to suprabasal split within the epidermis. Little is known about how intercellular autoantibodies arise. In most individuals, the disease is idiopathic. However, in some patients it is triggered by an external cause, such as drugs, particularly those having a thiol (a sulfhydryl radical) group in their molecule [eg, penicillamine, captopril, bucillamine, and thiopronine (91)], and ionizing radiation (89). Other putative inducing factors can be pesticides, dietary factors (particularly garlic, leeks, and onion) and emotional stress (138). PV can be also aggravated by radiotherapy (139). The mechanisms through which drugs and ionizing radiation can elicit or facilitate autoantibody production is still unclear, but thiol acantholysis is probably both biochemical and immunologic (138). Notably, discontinuation of the putative culprit drug causes spontaneous recovery in the majority of the patients. PV typically initially presents in the mouth and remains limited to the oral cavity. The onset can be subtle and mimic recurrent aphthous stomatitis (140) or even factitious or traumatic lesions, but established lesions are wide ulcerations and can occur on any oral mucosal tissue. The main target of PVIgG appears to be the extracellular domains of desmosomal cadherins called desmoglein 1 and 3 (Dsg1 and Dsg3) (141,142). The fact that Dsg3 is prevalently expressed in the oral cavity may explain the predominant prevalence of oral lesions at onset (142). Passive transfer of the monoclonal antibody AK23 against Dsg3 in mice results in the development of PV lesions (143–146). Besides Dsg3 and Dsg1, several other non-Dsg autoantibodies have been linked to tissue damage and acantholysis in PV (147). PV has a strong genetic predisposition and was consistently found to be associated with the alleles HLA-DRB1*0402 and DRB1*1404 and DQB1*0302 and 0503 (148). The DRB*1404 is mainly associated with patients of South Asian origin, whereas the DRB1*0402 is prevalent in white Europeans and Ashkenazian Jews (149–151). Interestingly, most functional studies have shown that Dsg3-specific T-cell lines were restricted to DR (152). However, emerging data questioned the monopathogenic PV theory that suggests that antibody-dependent disabling of the Dsg 1- and/or Dsg 3-mediated cell-cell attachments of KCs is sufficient to disrupt epidermal integrity and cause blistering (153). For example, recent proteomic analyses of large cohorts of pemphigus and normal control sera revealed reactivities with desmocollin 1 and 3, several muscarinic and nicotinic acetylcholine receptor subtypes (154–156). Selected non-Dsg autoantibodies have been demonstrated to be pathogenic based on animal models. Conversely, the multipathogenic theory of PV pathophysiology explains intraepidermal blistering through the “multiple hit” hypothesis (153). According to this hypothesis, a simultaneous and synchronized inactivation of the physiological mechanisms regulating and/or mediating intercellular adhesion of KCs is necessary to disrupt epidermal integrity. Among these phenomena, increasing importance has been placed upon apoptotic mechanisms, and the concept of apoptolysis has been proposed (137). Epidemiologic studies revealed the population-specific association between PV and a polymorphic variant of the ST18 gene encoding a proapoptotic molecule (98). Moreover, proapoptotic mediators such as Fas-ligand and p38 MAPK are clearly activated on PV (157). It thus may be postulated that predisposed individual cell detachment and death in PV develop through binding of pathogenic antibodies to KCs, leading to activation of Src, EGFRK, p38MAPK, and mTOR and other signaling that together with elevation of intracellular calcium initiate cell death. Suprabasal acantholysis begins when basal cells shrink, followed by destruction of desmosomes and subsequent production of scavenging (secondary) autoantibodies targeted primarily to adhesion molecules that have been sloughed. The final phase is the rounding up and death of acantholytic cells in the lower epidermal compartment (157). What Lessons Can Be Learned From Immunologically Mediated Oral Injury? As noted in the previous section, knowledge regarding oral mucosal diseases in non-oncology modeling may help delineate new research directions involving oral mucosal lesions caused by targeted cancer therapies. The following five “lessons learned” are thus presented in this context. The first lesson is that AEs caused by targeted anticancer drugs must be better characterized and constantly and consistently reported in a standardized way. Although mIAS is commonly described as similar to aphthous ulcers, the lesions appear sometimes EM-like or even PV-like if not clearly viral. When atypical presentations are seen, further investigation such as viral or immunological tests could be considered. The involvement of oral medicine specialists in future trials is likely crucial to improve the recognition and management of oral AEs. Oral medicine experts are now indeed available in many countries (158). A second lesson is that despite the sometimes clinical similarity of mIAS with RAS, the outcome of the two conditions seems to be very different. Many mIAS cases improve or resolve spontaneously despite continuation of the treatment (61), whereas previous attacks of RAS do not confer protection or alleviation against future episodes (115). The same can be said for recurrent EM and PV. However, when a medication is the culprit, withdrawal of the causative drug can cause remission of the IMOD. Conversely, it seems that in mIAS in several instances, the body is able to reestablish a homeostasis and possibly tolerance. Study of TLR and Treg cells in these patients could be highly relevant in this context. A third lesson is that many, if not all, IMODs are associated with genetic predisposition that can in some instances help in predicting who is going to develop the manifestation. However, it is clear that the etiology of these disorders is multifactorial and likely involve multiple genes as shown in preliminary genome-wide studies (159). It is of note that, in mucositis caused by conventional cancer therapies, there has been some activity in identifying differences in the expression of genes that affect drug metabolism as an approach to predict AE risk among patients being treated with chemotherapy (160–162). Analysis of gene polymorphisms can be of value in the design of tailored cancer therapy (163). The future is likely the establishment of a hierarchy of multiple genes that help in stratifying the risk of patients to develop oral AEs of targeted therapies. A fourth lesson is that it is now evident that oral KCs not only function as passive targets but in IMOD can serve as immune-cells and eventually amplify the epithelial damage induced by several type of injuries. It thus becomes important to direct additional research attention to the role of oral epithelial cells in this modeling. The fifth lesson is that some targeted cancer strategies can also be used for IMOD, and the information gathered can feed future therapeutic developments. For example, a recent study showed CAR T-cell efficacy in targeting pathogenic B cells in PV, opening exciting avenues for CAR-T therapy in dermato-oncology (164). As with IMOD research in the past, previous research regarding oral mucosal injury caused by conventional high-dose cancer therapy was limited by an outdated, simplistic pathobiological paradigm. Modern mechanistic IMOD concepts might be utilized as an inspiration to broaden the research regarding mucosal injury caused by targeted therapies, particularly via identification of biological pathways that lead to clinical development of the lesions in cancer patients. Selected pathways (eg, apoptosis) are clearly involved in most if not all IMODs as well as with oral mucositis caused by cancer therapy. In this context, the lessons learned as delineated above are designed to inform future research with both categories of diseases. Clinical Assessment and Treatment of Oral Mucosal Injury Caused by Targeted Agents As noted previously, the oral mucosa may become directly injured by targeted cancer therapies. Conversely, oral mucosal lesions may be present before initiation of the therapy or develop due to nontargeted therapy causes during active cancer treatment. It is thus important to perform a baseline oral mucosal assessment before initiation of the targeted cancer therapy and implement management of preexisting oral mucosal conditions in addition to monitoring oral mucosal status during targeted cancer treatment. Assessment of oral mucosal injury caused by targeted cancer therapies includes investigating the constellation of symptoms and signs as well as their impact on the patient’s health-related quality of life. These evaluations and associated treatments should be performed in the context of standardized, literature-based approaches for oral mucosal lesions as well as concurrent oral AEs, as described previously. Accurate early assessment of oral mucosal lesions and their associated sequalae enhances the opportunity for their effective early treatment, thereby often mitigating the need for targeted therapy dose reduction or discontinuation that could otherwise negatively affect treatment outcomes for the patient. Assessment of AEs, including oral mucositis in oncology patients, has historically been based on validated grading schema as exemplified by the National Cancer Institute Common Criteria for Adverse Events (165) and the World Health Organization (166). Moderate to severe symptoms have typically driven clinical intervention. By comparison, multiple mild or early moderate symptoms, although individually not having statistically significant negative impact on quality of life, may nonetheless collectively represent a burden of illness that is clinically relevant and warrant treatment as well. Despite the value of these and related oral mucositis scales, however, they have not been specifically designed to grade oral mucosal lesions caused by targeted cancer therapies. As such, the scales may underestimate the morbidity of mIAS, because even small localized ulcerations can be extremely painful and affect compliance. A mIAS scale has thus been specifically developed for assessing mIAS (167). This mIAS scale includes a subjective component measuring pain and an objective component measuring duration of lesions. It is suggested that dose modification be considered only when both subjective and objective grades are severe, representing persistent lesions with substantial pain despite the use of analgesics or other supportive care interventions (61). An additional grading tool, the MASCC EGFR Inhibitor Skin Toxicity Tool, has been developed specifically for the assessment of dermal and related AEs caused by EGFR inhibitors (168,169). In this scale, oral mucosal injury is reported as “mucositis–oral” and is classified across a range of grade 1 (mild erythema or edema, and asymptomatic) to grade 4 (erythema and ulceration, cannot tolerate oral intake; requires tube feeding or hospitalization). The scale thus has utility for management of patients receiving EGFR inhibitors. In the context of these grading scales, recording of specific additional characteristics of the aphthous-like mIAS lesions can be of value as well. These characteristics include date of onset, location, size, number (single or multiple), severity, duration, and signs such as color and border texture. Stimuli associated with triggering of oral pain, such as eating selected foods, oral hygiene practices, and/or oral medication dosing, can also delineate important features of the lesion. These collective characteristics provide additional precision for lesion assessment and subsequent treatment. Patient Education Regarding Oral Mucosal Injury Secondary to Targeted Cancer Therapies Overall Context The patient and family and/or caregivers should be educated regarding management of oral mucosal injury caused by targeted cancer therapies. They should be advised that treatment with targeted therapy agents is a primary cause for developing the oral lesions and that treatment options exist for their clinical management. They should also be advised that other factors may contribute to oral AEs as well, including age, impaired nutritional status, mucosal infections, dental pathology, defective restorations/fillings and prosthesis, and compromised oral hygiene. The goal of this phase of patient education is to provide a patient-based context for prevention and treatment of oral mucosal injury in the targeted cancer therapy setting, as described below. Prevention Patients should be instructed regarding the value of an oral care protocol (170). The protocol typically includes the systematic (eg, q.i.d.) use of nonmedicated saline and/or sodium bicarbonate mouth rinses that are in turn designed to enhance oral mucosal hydration as well as oral mucosal cleansing. Relative to mIAS, there is currently no systemically derived evidence for this approach. However, and because targeted agents are associated with inflammation and localized and systemic infections, the mucosal hygiene approach described above could be recommended to the patient until a more comprehensive, evidence-based approach has been developed based on future research (45). Treatment Comprehensive oral assessment is warranted when oral mucosal injury develops. Based on this assessment, treatment of concurrent oral AEs as described in Tables 1–6 may be clinically indicated as well. Table 1. Basic mouthcare interventions for the oncology patient* Subtype Intervention All types Oral care protocols: Expert opinion suggests that basic oral care protocols be used to prevent stomatitis in all cancer groups and across all targeted therapy modalities. Effective oral hygiene in line with mucositis directive; to prevent inflammation and infection remains the most important measure. All types Sodium bicarbonate-containing mouthwash: Expert opinion suggests that patients should rinse their mouths with a bland, nonalcoholic, sodium bicarbonate-containing mouthwash 4–6 times per day to prevent oral injury. Frequency of the mouthwash may be increased, if necessary, up to each hour. If oral hygiene is compromised due to oral pain Chlorhexidine: Expert opinion suggests use of 0.12% or 0.2% chlorhexidine digluconate oral rinse BID. Subtype Intervention All types Oral care protocols: Expert opinion suggests that basic oral care protocols be used to prevent stomatitis in all cancer groups and across all targeted therapy modalities. Effective oral hygiene in line with mucositis directive; to prevent inflammation and infection remains the most important measure. All types Sodium bicarbonate-containing mouthwash: Expert opinion suggests that patients should rinse their mouths with a bland, nonalcoholic, sodium bicarbonate-containing mouthwash 4–6 times per day to prevent oral injury. Frequency of the mouthwash may be increased, if necessary, up to each hour. If oral hygiene is compromised due to oral pain Chlorhexidine: Expert opinion suggests use of 0.12% or 0.2% chlorhexidine digluconate oral rinse BID. * Adapted from (48) and (170). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. View Large Table 1. Basic mouthcare interventions for the oncology patient* Subtype Intervention All types Oral care protocols: Expert opinion suggests that basic oral care protocols be used to prevent stomatitis in all cancer groups and across all targeted therapy modalities. Effective oral hygiene in line with mucositis directive; to prevent inflammation and infection remains the most important measure. All types Sodium bicarbonate-containing mouthwash: Expert opinion suggests that patients should rinse their mouths with a bland, nonalcoholic, sodium bicarbonate-containing mouthwash 4–6 times per day to prevent oral injury. Frequency of the mouthwash may be increased, if necessary, up to each hour. If oral hygiene is compromised due to oral pain Chlorhexidine: Expert opinion suggests use of 0.12% or 0.2% chlorhexidine digluconate oral rinse BID. Subtype Intervention All types Oral care protocols: Expert opinion suggests that basic oral care protocols be used to prevent stomatitis in all cancer groups and across all targeted therapy modalities. Effective oral hygiene in line with mucositis directive; to prevent inflammation and infection remains the most important measure. All types Sodium bicarbonate-containing mouthwash: Expert opinion suggests that patients should rinse their mouths with a bland, nonalcoholic, sodium bicarbonate-containing mouthwash 4–6 times per day to prevent oral injury. Frequency of the mouthwash may be increased, if necessary, up to each hour. If oral hygiene is compromised due to oral pain Chlorhexidine: Expert opinion suggests use of 0.12% or 0.2% chlorhexidine digluconate oral rinse BID. * Adapted from (48) and (170). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. View Large Table 2. General treatment suggestions for oral injury* Subtype Intervention Stomatitis Sodium bicarbonate-containing mouthwash: Expert opinion suggests that frequency of bland, nonalcoholic, sodium bicarbonate-containing oral rinse be increased, if necessary, up to each hour as needed Stomatitis not responsive to sodium bicarbonate-containing mouthwash Other treatments: Expert opinion suggests that other treatments, such as coating agents, topical analgesic or anti-inflammatory agents, topical anesthetics, and alternative mouthwashes may be considered. Subtype Intervention Stomatitis Sodium bicarbonate-containing mouthwash: Expert opinion suggests that frequency of bland, nonalcoholic, sodium bicarbonate-containing oral rinse be increased, if necessary, up to each hour as needed Stomatitis not responsive to sodium bicarbonate-containing mouthwash Other treatments: Expert opinion suggests that other treatments, such as coating agents, topical analgesic or anti-inflammatory agents, topical anesthetics, and alternative mouthwashes may be considered. * Adapted from (170). These expert opinion suggestions for management targeted therapy-associated stomatitis are for cancers of any kind, across all targeted therapy modalities. The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. View Large Table 2. General treatment suggestions for oral injury* Subtype Intervention Stomatitis Sodium bicarbonate-containing mouthwash: Expert opinion suggests that frequency of bland, nonalcoholic, sodium bicarbonate-containing oral rinse be increased, if necessary, up to each hour as needed Stomatitis not responsive to sodium bicarbonate-containing mouthwash Other treatments: Expert opinion suggests that other treatments, such as coating agents, topical analgesic or anti-inflammatory agents, topical anesthetics, and alternative mouthwashes may be considered. Subtype Intervention Stomatitis Sodium bicarbonate-containing mouthwash: Expert opinion suggests that frequency of bland, nonalcoholic, sodium bicarbonate-containing oral rinse be increased, if necessary, up to each hour as needed Stomatitis not responsive to sodium bicarbonate-containing mouthwash Other treatments: Expert opinion suggests that other treatments, such as coating agents, topical analgesic or anti-inflammatory agents, topical anesthetics, and alternative mouthwashes may be considered. * Adapted from (170). These expert opinion suggestions for management targeted therapy-associated stomatitis are for cancers of any kind, across all targeted therapy modalities. The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. View Large Table 3. Treatment suggestions for oral dryness* Subtype Intervention All subtypes Sugarless chewing gum, candy, salivary substitutes or sialogogues: Expert opinion suggests that sugarless chewing gum or candy, salivary substitutes, or sialogogues in patients experiencing oral dryness should be considered to promote salivary flow. Symptom of oral dryness (xerostomia) Mouth wetting agents: Expert opinion suggests mouth wetting agents (eg, saliva substitutes or a spray with plain water) to relieve the patient’s perception of oral dryness. Stimulation of residual saliva gland function stimulation Sialogogues: Expert opinion suggests sialogogues if residual saliva gland function is present. Lip dryness Lip lubrication: Expert opinion suggests lubrication of lips with lip balm or lip cream. Petrolatum jelly should not be used chronically on the lips. The product promotes mucosal cell dehydration and is occlusive, leading to potential risk of secondary mucosal infection. Subtype Intervention All subtypes Sugarless chewing gum, candy, salivary substitutes or sialogogues: Expert opinion suggests that sugarless chewing gum or candy, salivary substitutes, or sialogogues in patients experiencing oral dryness should be considered to promote salivary flow. Symptom of oral dryness (xerostomia) Mouth wetting agents: Expert opinion suggests mouth wetting agents (eg, saliva substitutes or a spray with plain water) to relieve the patient’s perception of oral dryness. Stimulation of residual saliva gland function stimulation Sialogogues: Expert opinion suggests sialogogues if residual saliva gland function is present. Lip dryness Lip lubrication: Expert opinion suggests lubrication of lips with lip balm or lip cream. Petrolatum jelly should not be used chronically on the lips. The product promotes mucosal cell dehydration and is occlusive, leading to potential risk of secondary mucosal infection. * Adapted from (170). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. View Large Table 3. Treatment suggestions for oral dryness* Subtype Intervention All subtypes Sugarless chewing gum, candy, salivary substitutes or sialogogues: Expert opinion suggests that sugarless chewing gum or candy, salivary substitutes, or sialogogues in patients experiencing oral dryness should be considered to promote salivary flow. Symptom of oral dryness (xerostomia) Mouth wetting agents: Expert opinion suggests mouth wetting agents (eg, saliva substitutes or a spray with plain water) to relieve the patient’s perception of oral dryness. Stimulation of residual saliva gland function stimulation Sialogogues: Expert opinion suggests sialogogues if residual saliva gland function is present. Lip dryness Lip lubrication: Expert opinion suggests lubrication of lips with lip balm or lip cream. Petrolatum jelly should not be used chronically on the lips. The product promotes mucosal cell dehydration and is occlusive, leading to potential risk of secondary mucosal infection. Subtype Intervention All subtypes Sugarless chewing gum, candy, salivary substitutes or sialogogues: Expert opinion suggests that sugarless chewing gum or candy, salivary substitutes, or sialogogues in patients experiencing oral dryness should be considered to promote salivary flow. Symptom of oral dryness (xerostomia) Mouth wetting agents: Expert opinion suggests mouth wetting agents (eg, saliva substitutes or a spray with plain water) to relieve the patient’s perception of oral dryness. Stimulation of residual saliva gland function stimulation Sialogogues: Expert opinion suggests sialogogues if residual saliva gland function is present. Lip dryness Lip lubrication: Expert opinion suggests lubrication of lips with lip balm or lip cream. Petrolatum jelly should not be used chronically on the lips. The product promotes mucosal cell dehydration and is occlusive, leading to potential risk of secondary mucosal infection. * Adapted from (170). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. View Large Table 4. Treatment suggestions for oral pain* Subtype Intervention Mild-moderate oral pain Analgesics; mouthwashes: Expert opinion suggests that adequate pain management, eg, anesthetic mouthwashes (doxepin rinse 0.5% or viscous lidocaine 2%), coating agents, may be provided as required. If patients find mouthwash painful, they should be advised to use pain medication beforehand in accordance with the WHO pain management ladder. Moderate oral pain on local sites Analgesics; topical: Expert opinion suggests that with moderate oral pain, morphine and doxepin as per MASCC/ISOO guidelines, mucous membrane spray, gel or liquid or a topical NSAID (eg, benzydamine or amlexanox 5% (Aphthasol, Miraftil) oral paste; 0.5 cm of oral paste directly on each ulcer; QID may be considered to treat moderate oral pain. Topical anesthetics can cause burning or stinging on application, compromise taste, have short duration of effect, and lead to altered swallowing sensation. They are therefore not the first choice for oral mucosal pain management. Moderate oral pain Analgesics; systemic: systemic analgesic pain (eg, acetaminophen [paracetamol] or NSAIDs), per WHO pain management ladder may be provided to treat oral pain. Severe oral pain or when NSAIDs not tolerated Analgesics; systemic: With more severe oral pain or when NSAIDs are not tolerated, consider acetaminophen (paracetamol) as maintenance therapy in combination with an immediate-release oral opioid or fast-acting fentanyl preparation (eg, fast-acting fentanyl nasal spray 50 µg) to relieve pain on short-term basis. Fast-acting fentanyl preparations, based on registration for use in patients currently being treated with opioids for other clinical indications, may be considered in this population in context of short-term pain relief. Persistent severe oral pain Analgesics; opioid: Expert opinion suggests that with persistent severe oral pain, more aggressive pain management (eg, orally administered opioid) may be considered. Because oral mucosal injury can complicate administration of drugs by mouth, one should also consider other routes of administration such as transdermal or intranasal (eg, fast-acting fentanyl nasal spray 50 µg). Subtype Intervention Mild-moderate oral pain Analgesics; mouthwashes: Expert opinion suggests that adequate pain management, eg, anesthetic mouthwashes (doxepin rinse 0.5% or viscous lidocaine 2%), coating agents, may be provided as required. If patients find mouthwash painful, they should be advised to use pain medication beforehand in accordance with the WHO pain management ladder. Moderate oral pain on local sites Analgesics; topical: Expert opinion suggests that with moderate oral pain, morphine and doxepin as per MASCC/ISOO guidelines, mucous membrane spray, gel or liquid or a topical NSAID (eg, benzydamine or amlexanox 5% (Aphthasol, Miraftil) oral paste; 0.5 cm of oral paste directly on each ulcer; QID may be considered to treat moderate oral pain. Topical anesthetics can cause burning or stinging on application, compromise taste, have short duration of effect, and lead to altered swallowing sensation. They are therefore not the first choice for oral mucosal pain management. Moderate oral pain Analgesics; systemic: systemic analgesic pain (eg, acetaminophen [paracetamol] or NSAIDs), per WHO pain management ladder may be provided to treat oral pain. Severe oral pain or when NSAIDs not tolerated Analgesics; systemic: With more severe oral pain or when NSAIDs are not tolerated, consider acetaminophen (paracetamol) as maintenance therapy in combination with an immediate-release oral opioid or fast-acting fentanyl preparation (eg, fast-acting fentanyl nasal spray 50 µg) to relieve pain on short-term basis. Fast-acting fentanyl preparations, based on registration for use in patients currently being treated with opioids for other clinical indications, may be considered in this population in context of short-term pain relief. Persistent severe oral pain Analgesics; opioid: Expert opinion suggests that with persistent severe oral pain, more aggressive pain management (eg, orally administered opioid) may be considered. Because oral mucosal injury can complicate administration of drugs by mouth, one should also consider other routes of administration such as transdermal or intranasal (eg, fast-acting fentanyl nasal spray 50 µg). * Adapted from (170). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. NSAID = nonsteroidal anti-inflammatory drug. View Large Table 4. Treatment suggestions for oral pain* Subtype Intervention Mild-moderate oral pain Analgesics; mouthwashes: Expert opinion suggests that adequate pain management, eg, anesthetic mouthwashes (doxepin rinse 0.5% or viscous lidocaine 2%), coating agents, may be provided as required. If patients find mouthwash painful, they should be advised to use pain medication beforehand in accordance with the WHO pain management ladder. Moderate oral pain on local sites Analgesics; topical: Expert opinion suggests that with moderate oral pain, morphine and doxepin as per MASCC/ISOO guidelines, mucous membrane spray, gel or liquid or a topical NSAID (eg, benzydamine or amlexanox 5% (Aphthasol, Miraftil) oral paste; 0.5 cm of oral paste directly on each ulcer; QID may be considered to treat moderate oral pain. Topical anesthetics can cause burning or stinging on application, compromise taste, have short duration of effect, and lead to altered swallowing sensation. They are therefore not the first choice for oral mucosal pain management. Moderate oral pain Analgesics; systemic: systemic analgesic pain (eg, acetaminophen [paracetamol] or NSAIDs), per WHO pain management ladder may be provided to treat oral pain. Severe oral pain or when NSAIDs not tolerated Analgesics; systemic: With more severe oral pain or when NSAIDs are not tolerated, consider acetaminophen (paracetamol) as maintenance therapy in combination with an immediate-release oral opioid or fast-acting fentanyl preparation (eg, fast-acting fentanyl nasal spray 50 µg) to relieve pain on short-term basis. Fast-acting fentanyl preparations, based on registration for use in patients currently being treated with opioids for other clinical indications, may be considered in this population in context of short-term pain relief. Persistent severe oral pain Analgesics; opioid: Expert opinion suggests that with persistent severe oral pain, more aggressive pain management (eg, orally administered opioid) may be considered. Because oral mucosal injury can complicate administration of drugs by mouth, one should also consider other routes of administration such as transdermal or intranasal (eg, fast-acting fentanyl nasal spray 50 µg). Subtype Intervention Mild-moderate oral pain Analgesics; mouthwashes: Expert opinion suggests that adequate pain management, eg, anesthetic mouthwashes (doxepin rinse 0.5% or viscous lidocaine 2%), coating agents, may be provided as required. If patients find mouthwash painful, they should be advised to use pain medication beforehand in accordance with the WHO pain management ladder. Moderate oral pain on local sites Analgesics; topical: Expert opinion suggests that with moderate oral pain, morphine and doxepin as per MASCC/ISOO guidelines, mucous membrane spray, gel or liquid or a topical NSAID (eg, benzydamine or amlexanox 5% (Aphthasol, Miraftil) oral paste; 0.5 cm of oral paste directly on each ulcer; QID may be considered to treat moderate oral pain. Topical anesthetics can cause burning or stinging on application, compromise taste, have short duration of effect, and lead to altered swallowing sensation. They are therefore not the first choice for oral mucosal pain management. Moderate oral pain Analgesics; systemic: systemic analgesic pain (eg, acetaminophen [paracetamol] or NSAIDs), per WHO pain management ladder may be provided to treat oral pain. Severe oral pain or when NSAIDs not tolerated Analgesics; systemic: With more severe oral pain or when NSAIDs are not tolerated, consider acetaminophen (paracetamol) as maintenance therapy in combination with an immediate-release oral opioid or fast-acting fentanyl preparation (eg, fast-acting fentanyl nasal spray 50 µg) to relieve pain on short-term basis. Fast-acting fentanyl preparations, based on registration for use in patients currently being treated with opioids for other clinical indications, may be considered in this population in context of short-term pain relief. Persistent severe oral pain Analgesics; opioid: Expert opinion suggests that with persistent severe oral pain, more aggressive pain management (eg, orally administered opioid) may be considered. Because oral mucosal injury can complicate administration of drugs by mouth, one should also consider other routes of administration such as transdermal or intranasal (eg, fast-acting fentanyl nasal spray 50 µg). * Adapted from (170). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. NSAID = nonsteroidal anti-inflammatory drug. View Large Table 5. Treatment suggestions for oral infections* Infection Treatment suggestions All types Antimicrobials: Expert opinion suggests that all types of infection should be treated based per confirmed infection. Treatment should be continued for at least 1 week after symptoms have resolved. Bacterial Antibacterials: Expert opinion suggests that if clinically urgent to initiate treatment of bacterial infection, institute metronidazole (Flagyl) 1.5 g/d for 1 week or until antibiogram data are available, whichever comes first. Fungal Antifungals: Expert opinion suggests treatment with miconazole (Daktarin) oral gel QID 20 mg/kg/d administered in 4 divided doses on denture surface and lip commissures. Daily dose should not exceed 250 mg (10 mL oral gel). The gel should not be swallowed immediately but held in the mouth as long as possible. If the above product is not available, miconazole mucoadhesive tablet (Oravig/Loramyc) can be used. Alternatively, nystatin 100 000 μ/mLas mouthwash (4×/d) or fluconazole oral suspension 50 mg/5 mL (3×/d) can be administered. Viral (eg, herpesvirus) Antivirals: Expert opinion suggests treatment with valacyclovir 1 g/d for 1 week. Acute periodontal Expert opinion suggests that treatment with local therapy (eg, 0.12% or 0.2% chlorhexidine gluconate oral rinse) plus systemic antibiotic. Infection Treatment suggestions All types Antimicrobials: Expert opinion suggests that all types of infection should be treated based per confirmed infection. Treatment should be continued for at least 1 week after symptoms have resolved. Bacterial Antibacterials: Expert opinion suggests that if clinically urgent to initiate treatment of bacterial infection, institute metronidazole (Flagyl) 1.5 g/d for 1 week or until antibiogram data are available, whichever comes first. Fungal Antifungals: Expert opinion suggests treatment with miconazole (Daktarin) oral gel QID 20 mg/kg/d administered in 4 divided doses on denture surface and lip commissures. Daily dose should not exceed 250 mg (10 mL oral gel). The gel should not be swallowed immediately but held in the mouth as long as possible. If the above product is not available, miconazole mucoadhesive tablet (Oravig/Loramyc) can be used. Alternatively, nystatin 100 000 μ/mLas mouthwash (4×/d) or fluconazole oral suspension 50 mg/5 mL (3×/d) can be administered. Viral (eg, herpesvirus) Antivirals: Expert opinion suggests treatment with valacyclovir 1 g/d for 1 week. Acute periodontal Expert opinion suggests that treatment with local therapy (eg, 0.12% or 0.2% chlorhexidine gluconate oral rinse) plus systemic antibiotic. * Adapted from (170). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. View Large Table 5. Treatment suggestions for oral infections* Infection Treatment suggestions All types Antimicrobials: Expert opinion suggests that all types of infection should be treated based per confirmed infection. Treatment should be continued for at least 1 week after symptoms have resolved. Bacterial Antibacterials: Expert opinion suggests that if clinically urgent to initiate treatment of bacterial infection, institute metronidazole (Flagyl) 1.5 g/d for 1 week or until antibiogram data are available, whichever comes first. Fungal Antifungals: Expert opinion suggests treatment with miconazole (Daktarin) oral gel QID 20 mg/kg/d administered in 4 divided doses on denture surface and lip commissures. Daily dose should not exceed 250 mg (10 mL oral gel). The gel should not be swallowed immediately but held in the mouth as long as possible. If the above product is not available, miconazole mucoadhesive tablet (Oravig/Loramyc) can be used. Alternatively, nystatin 100 000 μ/mLas mouthwash (4×/d) or fluconazole oral suspension 50 mg/5 mL (3×/d) can be administered. Viral (eg, herpesvirus) Antivirals: Expert opinion suggests treatment with valacyclovir 1 g/d for 1 week. Acute periodontal Expert opinion suggests that treatment with local therapy (eg, 0.12% or 0.2% chlorhexidine gluconate oral rinse) plus systemic antibiotic. Infection Treatment suggestions All types Antimicrobials: Expert opinion suggests that all types of infection should be treated based per confirmed infection. Treatment should be continued for at least 1 week after symptoms have resolved. Bacterial Antibacterials: Expert opinion suggests that if clinically urgent to initiate treatment of bacterial infection, institute metronidazole (Flagyl) 1.5 g/d for 1 week or until antibiogram data are available, whichever comes first. Fungal Antifungals: Expert opinion suggests treatment with miconazole (Daktarin) oral gel QID 20 mg/kg/d administered in 4 divided doses on denture surface and lip commissures. Daily dose should not exceed 250 mg (10 mL oral gel). The gel should not be swallowed immediately but held in the mouth as long as possible. If the above product is not available, miconazole mucoadhesive tablet (Oravig/Loramyc) can be used. Alternatively, nystatin 100 000 μ/mLas mouthwash (4×/d) or fluconazole oral suspension 50 mg/5 mL (3×/d) can be administered. Viral (eg, herpesvirus) Antivirals: Expert opinion suggests treatment with valacyclovir 1 g/d for 1 week. Acute periodontal Expert opinion suggests that treatment with local therapy (eg, 0.12% or 0.2% chlorhexidine gluconate oral rinse) plus systemic antibiotic. * Adapted from (170). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. View Large Table 6. Treatment suggestions for oral ulcerations caused by targeted cancer therapies* Subtype Treatment suggestions Limited and easily accessed ulcers Steroids; topical: Expert opinion suggests that for limited locations and easy to access ulcers, topical high-potency corticosteroids should be considered first: clobetasol gel or ointment (0.05% QD-BID) with or without adhesive bases such as carboximethyl or hydroxyethyl-cellulose. Limited and easily accessed ulcers Topical NSAID: Expert opinion suggests that for limited locations and easy to access ulcers amlexanox (Aphthasol, Miraftil), 5% oral paste (0.5 cm of oral paste directly on each ulcer; QID) or benzydamine 0.15% mouthwash or spray (4–8×/d) may be considered. Widespread or difficult to access ulcers Steroids; topical: Expert opinion suggests that if several locations of the oral cavity are involved or difficult to access ulcers, topical high-potency corticosteroids should be considered first: (eg, dexamethasone mouth rinse (0.1 mg/mL) or clobetasol propionate 0.05% in aqueous solution, 3×/d). Widespread or difficult to access ulcers Compounded rinse: Expert opinion suggests that if several sites of oral cavity are involved or difficult to access, budesonide rinse 0.5% may be considered. Highly symptomatic ulcers, recurrent ulcers, or esophageal ulcers Steroids; systemic: Expert opinion suggests that for highly symptomatic ulcers and recurrent ulcers or esophageal lesions, systemic corticosteroids be utilized as initial therapy to control symptoms (high-dose pulse 30–60 mg or 1 mg/kg) oral prednisone/prednisolone for 1 week followed by dose tapering over second week should be considered to treat mIAS. Without ulcer resolution Steroid; intralesional injection: Expert opinion suggests that with no ulcer resolution, intralesional steroid injection (triamcinolone weekly; total dose 28 mg) in conjunction with oral expert AND topical clobetasol gel or ointment (0.05%) with or without adhesive bases such as carboxymethyl or hydroxyethyl-cellulose should be considered to treat mIAS. Subtype Treatment suggestions Limited and easily accessed ulcers Steroids; topical: Expert opinion suggests that for limited locations and easy to access ulcers, topical high-potency corticosteroids should be considered first: clobetasol gel or ointment (0.05% QD-BID) with or without adhesive bases such as carboximethyl or hydroxyethyl-cellulose. Limited and easily accessed ulcers Topical NSAID: Expert opinion suggests that for limited locations and easy to access ulcers amlexanox (Aphthasol, Miraftil), 5% oral paste (0.5 cm of oral paste directly on each ulcer; QID) or benzydamine 0.15% mouthwash or spray (4–8×/d) may be considered. Widespread or difficult to access ulcers Steroids; topical: Expert opinion suggests that if several locations of the oral cavity are involved or difficult to access ulcers, topical high-potency corticosteroids should be considered first: (eg, dexamethasone mouth rinse (0.1 mg/mL) or clobetasol propionate 0.05% in aqueous solution, 3×/d). Widespread or difficult to access ulcers Compounded rinse: Expert opinion suggests that if several sites of oral cavity are involved or difficult to access, budesonide rinse 0.5% may be considered. Highly symptomatic ulcers, recurrent ulcers, or esophageal ulcers Steroids; systemic: Expert opinion suggests that for highly symptomatic ulcers and recurrent ulcers or esophageal lesions, systemic corticosteroids be utilized as initial therapy to control symptoms (high-dose pulse 30–60 mg or 1 mg/kg) oral prednisone/prednisolone for 1 week followed by dose tapering over second week should be considered to treat mIAS. Without ulcer resolution Steroid; intralesional injection: Expert opinion suggests that with no ulcer resolution, intralesional steroid injection (triamcinolone weekly; total dose 28 mg) in conjunction with oral expert AND topical clobetasol gel or ointment (0.05%) with or without adhesive bases such as carboxymethyl or hydroxyethyl-cellulose should be considered to treat mIAS. * Adapted from (11,45,61,75). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. NSAID = nonsteroidal anti-inflammatory drug. View Large Table 6. Treatment suggestions for oral ulcerations caused by targeted cancer therapies* Subtype Treatment suggestions Limited and easily accessed ulcers Steroids; topical: Expert opinion suggests that for limited locations and easy to access ulcers, topical high-potency corticosteroids should be considered first: clobetasol gel or ointment (0.05% QD-BID) with or without adhesive bases such as carboximethyl or hydroxyethyl-cellulose. Limited and easily accessed ulcers Topical NSAID: Expert opinion suggests that for limited locations and easy to access ulcers amlexanox (Aphthasol, Miraftil), 5% oral paste (0.5 cm of oral paste directly on each ulcer; QID) or benzydamine 0.15% mouthwash or spray (4–8×/d) may be considered. Widespread or difficult to access ulcers Steroids; topical: Expert opinion suggests that if several locations of the oral cavity are involved or difficult to access ulcers, topical high-potency corticosteroids should be considered first: (eg, dexamethasone mouth rinse (0.1 mg/mL) or clobetasol propionate 0.05% in aqueous solution, 3×/d). Widespread or difficult to access ulcers Compounded rinse: Expert opinion suggests that if several sites of oral cavity are involved or difficult to access, budesonide rinse 0.5% may be considered. Highly symptomatic ulcers, recurrent ulcers, or esophageal ulcers Steroids; systemic: Expert opinion suggests that for highly symptomatic ulcers and recurrent ulcers or esophageal lesions, systemic corticosteroids be utilized as initial therapy to control symptoms (high-dose pulse 30–60 mg or 1 mg/kg) oral prednisone/prednisolone for 1 week followed by dose tapering over second week should be considered to treat mIAS. Without ulcer resolution Steroid; intralesional injection: Expert opinion suggests that with no ulcer resolution, intralesional steroid injection (triamcinolone weekly; total dose 28 mg) in conjunction with oral expert AND topical clobetasol gel or ointment (0.05%) with or without adhesive bases such as carboxymethyl or hydroxyethyl-cellulose should be considered to treat mIAS. Subtype Treatment suggestions Limited and easily accessed ulcers Steroids; topical: Expert opinion suggests that for limited locations and easy to access ulcers, topical high-potency corticosteroids should be considered first: clobetasol gel or ointment (0.05% QD-BID) with or without adhesive bases such as carboximethyl or hydroxyethyl-cellulose. Limited and easily accessed ulcers Topical NSAID: Expert opinion suggests that for limited locations and easy to access ulcers amlexanox (Aphthasol, Miraftil), 5% oral paste (0.5 cm of oral paste directly on each ulcer; QID) or benzydamine 0.15% mouthwash or spray (4–8×/d) may be considered. Widespread or difficult to access ulcers Steroids; topical: Expert opinion suggests that if several locations of the oral cavity are involved or difficult to access ulcers, topical high-potency corticosteroids should be considered first: (eg, dexamethasone mouth rinse (0.1 mg/mL) or clobetasol propionate 0.05% in aqueous solution, 3×/d). Widespread or difficult to access ulcers Compounded rinse: Expert opinion suggests that if several sites of oral cavity are involved or difficult to access, budesonide rinse 0.5% may be considered. Highly symptomatic ulcers, recurrent ulcers, or esophageal ulcers Steroids; systemic: Expert opinion suggests that for highly symptomatic ulcers and recurrent ulcers or esophageal lesions, systemic corticosteroids be utilized as initial therapy to control symptoms (high-dose pulse 30–60 mg or 1 mg/kg) oral prednisone/prednisolone for 1 week followed by dose tapering over second week should be considered to treat mIAS. Without ulcer resolution Steroid; intralesional injection: Expert opinion suggests that with no ulcer resolution, intralesional steroid injection (triamcinolone weekly; total dose 28 mg) in conjunction with oral expert AND topical clobetasol gel or ointment (0.05%) with or without adhesive bases such as carboxymethyl or hydroxyethyl-cellulose should be considered to treat mIAS. * Adapted from (11,45,61,75). The suggestions are provided as examples. Clinical decision-making specific to each patient’s status should be customized as needed. NSAID = nonsteroidal anti-inflammatory drug. View Large Successful management should include treatment directed at all components of the oral lesion. Short-term high-potent topical or systemic corticosteroids can lead to effective response when utilized for an inflammatory-driven reaction such as mIAS but will not relieve dry mouth, oral infection, and/or dysgeusia. Similarly, analgesics will relieve selected types of oral pain but not pain associated with an oral burning sensation. It thus becomes essential to specifically define the constellation of oral AEs in a given patient in order to optimally manage the oral mucosal injury and related oral AEs. This comprehensive approach can mitigate the necessity of dose reduction or discontinuation of the targeted cancer therapy. Key Research Questions The following key research questions derive from the state of the science of oral mucosal disease as presented in this chapter: What key genetic and/or molecular factors are principally responsible for causing oral mucosal lesions associated with targeted cancer therapies? Despite fundamentally different modes of actions across the classes of targeted cancer therapies, why is there, in many cases, consistent conservation of the clinical phenotype of the oral mucosal injury among patients receiving different targeted therapies? Why is the clinical phenotype of oral mucosal injury secondary to targeted agents often similar to recurrent aphthous stomatitis, and different from oral mucositis secondary to conventional chemotherapy? Is the genetic governance of oral pain concordant between oral mucositis caused by conventional cancer therapies in relation to oral mucosal injury caused by targeted cancer agents? How could answers to the above research questions be applied to the development of novel preventive and therapeutic interventions? Notes Affiliations of authors: Center for Oral Health Research, Oral Medicine Department, School of Dental Sciences, Newcastle University, UK (MC); Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark (JGE); Institut Niçois de Cancérologie (INC), Centre de Haute Energie, Nice, France (RJB); CancerMed, Department of Medical Strategy, Wormer, The Netherlands (CBBD); Impaqtt Foundation, Department of Adverse Event Research & Valorisation, Wormer, The Netherlands (CBBD); Section of Oral Medicine, Department of Oral Health & Diagnostic Sciences, School of Dental Medicine, UConn Health, Farmington, CT (RVL); Section of Oral Medicine, Department of Oral Health & Diagnostic Sciences, School of Dental Medicine & Neag Comprehensive Cancer Center, UConn Health, Farmington, CT (DEP). M. Carrozzo, J. Grau Eriksen, and R.-.J Bensadoun declare no conflicts of interest. C. Boers-Doets has received grants for education and travel funded by the following pharmaceutical companies that have a targeted therapy in their respective portfolio: Amgen, Bayer, EUSA Pharma, GSK Netherlands (now part of Novartis), Merck, Novartis, Pfizer, and Roche; consulting fees funded by the following pharmaceutical companies that have a targeted therapy in their respective portfolio: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Ipsen, Lilly, Merck, MSD (Merck Sharp & Dohme), Novartis, Pfizer, and Roche. R. Lalla has received grants from Oragenics and Vigilant Biosciences and is a consultant for Alira Health, Biotechspert, Colgate Oral Pharmaceuticals, Eagle Pharma, Galera Therapeutics, Ingalfarma, Leerink, Metlife, Monopar Therapeutics, and SAI Med and has stock in Logic Biosciences. None of the preceding disclosures is related to the content of this manuscript. D. Peterson has received consulting fees from Amgen Inc., Optum Epidemiology, PSI CRO, SAI MedPartner LLC, and AEC Partners. He also receives consulting fees from and holds equity ownership in Applied Glycan Technologies, Inc. None of this consulting activity is related to the content of this manuscript. For support see Funding Acknowledgement section of Monograph. References 1 Subramanian J , Vlahiotis A , Frazee S , et al. . Real-world utilization of targeted therapy in cancer treatment . J Clin Oncol . 2011 ; 29 (suppl; abstr e16618). WorldCat 2 Claudiani S , Apperley JF. The argument for using imatinib in CML . Hematology Am Soc Hematol Educ Program . 2018 ; 2018 1 : 161 – 167 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Hornberger JC , Friedmann M , Han L , et al. . Economic impact of rituximab as maintenance therapy in previously treated follicular non-Hodgkin lymphoma . J Clin Oncol. 2011 ; 29 (suppl 15; abstract e18544). WorldCat 4 Heyman B , Yang Y. New developments in immunotherapy for lymphoma . Cancer Biol Med. 2018 ; 15 3 : 189 – 209 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Bajic P , Flanigan RC , Joyce CJ , et al. . Sunitinib and cytoreductive nephrectomy for metastatic renal cell carcinoma . J Urol. 2019 ; 201 3 : 453 – 454 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Motzer RJ , Hutson TE , Tomczak P , et al. . Sunitinib versus interferon alfa in metastatic renal-cell carcinoma . N Engl J Med. 2007 ; 356 2 : 115 – 124 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Romond EH , Perez EA , Bryant J , et al. . Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer . N Engl J Med. 2005 ; 353 16 : 1673 – 1684 . Google Scholar Crossref Search ADS PubMed WorldCat 8 Hayes DF. Further progress for patients with breast cancer . N Engl J Med. 2019 ; 380 7 : 676 – 677 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Moore MJ , Goldstein D , Hamm J , et al. . Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group . J Clin Oncol. 2007 ; 25 15 : 1960 – 1966 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Lacouture M , Sibaud V. Toxic side effects of targeted therapies and immunotherapies affecting the skin, oral mucosa, hair, and nails . Am J Clin Dermatol. 2018 ; 19(Suppl 1) : 31 – 39 . Google Scholar Crossref Search ADS WorldCat 11 Pilotte AP , Hohos MB , Polson KM , et al. . Managing stomatitis in patients treated with Mammalian target of rapamycin inhibitors . Clin J Oncol Nurs. 2011 ; 15 5 : E83 – E89 . Google Scholar Crossref Search ADS PubMed WorldCat 12 Van Cutsem E , Peeters M , Siena S , et al. . Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer . J Clin Oncol. 2007 ; 25 13 : 1658 – 1664 . Google Scholar Crossref Search ADS PubMed WorldCat 13 Hurwitz H , Fehrenbacher L , Novotny W , et al. . Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer . N Engl J Med. 2004 ; 350 23 : 2335 – 2342 . Google Scholar Crossref Search ADS PubMed WorldCat 14 Bonner JA , Harari PM , Giralt J , et al. . Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck . N Engl J Med. 2006 ; 354 6 : 567 – 578 . Google Scholar Crossref Search ADS PubMed WorldCat 15 Motzer RJ , Escudier B , Oudard S , et al. . Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial . Lancet. 2008 ; 372 9637 : 449 – 456 . Google Scholar Crossref Search ADS PubMed WorldCat 16 O'Brien SG , Guilhot F , Larson RA , et al. . Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia . N Engl J Med. 2003 ; 348 11 : 994 – 1004 . Google Scholar Crossref Search ADS PubMed WorldCat 17 Zweifel M , Jayson GC , Reed NS , et al. . Phase II trial of combretastatin A4 phosphate, carboplatin, and paclitaxel in patients with platinum-resistant ovarian cancer . Ann Oncol. 2011 ; 22 9 : 2036 – 2041 . Google Scholar Crossref Search ADS PubMed WorldCat 18 Plummer R , Attard G , Pacey S , et al. . Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers . Clin Cancer Res. 2007 ; 13 20 : 6187 – 6194 . Google Scholar Crossref Search ADS PubMed WorldCat 19 Kindler HL , Richards DA , Garbo LE , et al. . A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer . Ann Oncol. 2012 ; 23 11 : 2834 – 2842 . Google Scholar Crossref Search ADS PubMed WorldCat 20 Clinical Trials.gov. clinicaltrials.gov. Accessed February 5, 2019. 21 Dimopoulos M , Siegel DS , Lonial S , et al. . Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study . Lancet Oncol. 2013 ; 14 11 : 1129 – 1140 . Google Scholar Crossref Search ADS PubMed WorldCat 22 Wendtner CM , Ritgen M , Schweighofer CD , et al. . Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission—experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG) . Leukemia. 2004 ; 18 6 : 1093 – 1101 . Google Scholar Crossref Search ADS PubMed WorldCat 23 Eiermann W , International Herceptin Study Group . Trastuzumab combined with chemotherapy for the treatment of HER2-positive metastatic breast cancer: pivotal trial data . Ann Oncol . 2001 ; 12(Suppl 1) : S57 – S62 . Google Scholar Crossref Search ADS PubMed WorldCat 24 Wiseman GA , White CA , Sparks RB , et al. . Biodistribution and dosimetry results from a phase III prospectively randomized controlled trial of Zevalin radioimmunotherapy for low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma . Crit Rev Oncol Hematol. 2001 ; 39 ( 1–2 ): 181 – 194 . Google Scholar Crossref Search ADS PubMed WorldCat 25 Moskowitz CH , Nademanee A , Masszi T , et al. . Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial . Lancet. 2015 ; 385 9980 : 1853 – 1862 . Google Scholar Crossref Search ADS PubMed WorldCat 26 Verma S , Miles D , Gianni L , et al. . Trastuzumab emtansine for HER2-positive advanced breast cancer . N Engl J Med. 2012 ; 367 19 : 1783 – 1791 . Google Scholar Crossref Search ADS PubMed WorldCat 27 Prince HM , Duvic M , Martin A , et al. . Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma . J Clin Oncol. 2010 ; 28 11 : 1870 – 1877 . Google Scholar Crossref Search ADS PubMed WorldCat 28 Topp MS , Kufer P , Gökbuget N , et al. . Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival . J Clin Oncol. 2011 ; 29 18 : 2493 – 2498 . Google Scholar Crossref Search ADS PubMed WorldCat 29 Robert C , Schachter J , Long GV , et al. . Pembrolizumab versus Ipilimumab in Advanced Melanoma . N Engl J Med. 2015 ; 372 26 : 2521 – 2532 . Google Scholar Crossref Search ADS PubMed WorldCat 30 Weber JS , D'Angelo SP , Minor 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 4 : 375 – 384 . Google Scholar Crossref Search ADS PubMed WorldCat 31 Hodi FS , O'Day SJ , McDermott DF , et al. . Improved survival with ipilimumab in patients with metastatic melanoma . N Engl J Med. 2010 ; 363 8 : 711 – 723 . Google Scholar Crossref Search ADS PubMed WorldCat 32 Sheikh NA , Petrylak D , Kantoff PW , et al. . Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer . Cancer Immunol Immunother. 2013 ; 62 1 : 137 – 147 . Google Scholar Crossref Search ADS PubMed WorldCat 33 Agarwala SS , Glaspy J , O'Day SJ , et al. . Results from a randomized phase III study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus interleukin-2 alone in patients with metastatic melanoma . J Clin Oncol. 2002 ; 20 1 : 125 – 133 . Google Scholar Crossref Search ADS PubMed WorldCat 34 Solal-Celigny P , Lepage E , Brousse N , et al. . Recombinant interferon alfa-2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. Groupe d'Etude des Lymphomes de l'Adulte . N Engl J Med. 1993 ; 329 22 : 1608 – 1614 . Google Scholar Crossref Search ADS PubMed WorldCat 35 Park JW , Kerbel RS , Kelloff GJ , et al. . Rationale for biomarkers and surrogate end points in mechanism-driven oncology drug development . Clin Cancer Res. 2004 ; 10 11 : 3885 – 3896 . Google Scholar Crossref Search ADS PubMed WorldCat 36 Figg WD , Newell DR. Pharmacologic biomarkers in the development of stratified cancer medicine . Clin Cancer Res. 2014 ; 20 10 : 2525 – 2529 . Google Scholar Crossref Search ADS PubMed WorldCat 37 Sperger JM , Strotman LN , Welsh A , et al. . Integrated analysis of multiple biomarkers from circulating tumor cells enabled by exclusion-based analyte isolation . Clin Cancer Res. 2017 ; 23 3 : 746 – 756 . Google Scholar Crossref Search ADS PubMed WorldCat 38 Parchment RE , Doroshow JH. Pharmacodynamic endpoints as clinical trial objectives to answer important questions in oncology drug development . Semin Oncol. 2016 ; 43 4 : 514 – 525 . Google Scholar Crossref Search ADS PubMed WorldCat 39 Yuan A , Kurtz SL , Barysauskas CM , et al. . Oral adverse events in cancer patients treated with VEGFR-directed multitargeted tyrosine kinase inhibitors . Oral Oncol. 2015 ; 51 11 : 1026 – 1033 . Google Scholar Crossref Search ADS PubMed WorldCat 40 Vigarios E , Epstein JB , Sibaud V. Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors . Support Care Cancer. 2017 ; 25 5 : 1713 – 1739 . Google Scholar Crossref Search ADS PubMed WorldCat 41 Sibaud V , Eid C , Belum VR , et al. . Oral lichenoid reactions associated with anti-PD-1/PD-L1 therapies: clinicopathological findings . J Eur Acad Dermatol Venereol. 2017 ; 31 10 : e464 – e469 . Google Scholar Crossref Search ADS PubMed WorldCat 42 Elting LS , Chang YC , Parelkar P , et al. . Risk of oral and gastrointestinal mucosal injury among patients receiving selected targeted agents: a meta-analysis . Support Care Cancer. 2013 ; 21 11 : 3243 – 3254 . Google Scholar Crossref Search ADS PubMed WorldCat 43 Topalian SL , Sznol M , McDermott DF , et al. . Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab . J Clin Oncol. 2014 ; 32 10 : 1020 – 1030 . Google Scholar Crossref Search ADS PubMed WorldCat 44 Sonis S , Treister N , Chawla S , et al. . Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients . Cancer. 2010 ; 116 1 : 210 – 215 . Google Scholar PubMed WorldCat 45 Peterson DE , Boers-Doets CB , Bensadoun RJ , et al. . Management of oral and gastrointestinal mucosal injury: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up . Ann Oncol. 2015 ; 26(Suppl 5) : v139 – v151 . Google Scholar Crossref Search ADS PubMed WorldCat 46 Sonis ST , Elting LS , Keefe D , et al. . Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients . Cancer . 2004 ; 100(9 Suppl) : 1995 – 2025 . Google Scholar Crossref Search ADS WorldCat 47 Keefe DM , Schubert MM , Elting LS , et al. . Updated clinical practice guidelines for the prevention and treatment of mucositis . Cancer. 2007 ; 109 5 : 820 – 831 . Google Scholar Crossref Search ADS PubMed WorldCat 48 Lalla RV , Bowen J , Barasch A , et al. . MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy . Cancer. 2014 ; 120 10 : 1453 – 1461 . Google Scholar Crossref Search ADS PubMed WorldCat 49 Lalla RV , Gordon GB , Schubert M , et al. . A randomized, double-blind, placebo-controlled trial of misoprostol for oral mucositis secondary to high-dose chemotherapy . Support Care Cancer. 2012 ; 20 8 : 1797 – 1804 . Google Scholar Crossref Search ADS PubMed WorldCat 50 Jensen SB , Peterson DE. Oral mucosal injury caused by cancer therapies: current management and new frontiers in research . J Oral Pathol Med. 2014 ; 43 2 : 81 – 90 . Google Scholar Crossref Search ADS PubMed WorldCat 51 Villa A , Sonis ST. Pharmacotherapy for the management of cancer regimen-related oral mucositis . Expert Opin Pharmacother. 2016 ; 17 13 : 1801 – 1807 . Google Scholar Crossref Search ADS PubMed WorldCat 52 Peterson DE , Keefe DM , Sonis ST. New frontiers in mucositis. In: Govindan R , ed. American Society of Clinical Oncology Educational Book . 2012 : 545 – 551 . Google Preview WorldCat COPAC 53 Bachour PC , Sonis ST. Predicting mucositis risk associated with cytotoxic cancer treatment regimens: rationale, complexity, and challenges . Curr Opin Support Palliat Care . 2018 ; 12 2 : 198 – 210 . Google Scholar PubMed WorldCat 54 Partridge AH , Avorn J , Wang PS , et al. . Adherence to therapy with oral antineoplastic agents . J Natl Cancer Inst. 2002 ; 94 9 : 652 – 661 . Google Scholar Crossref Search ADS PubMed WorldCat 55 Cunningham D , Humblet Y , Siena S , et al. . Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer . N Engl J Med. 2004 ; 351 4 : 337 – 345 . Google Scholar Crossref Search ADS PubMed WorldCat 56 Epstein JB , Gorsky M , Guglietta A , et al. . The correlation between epidermal growth factor levels in saliva and the severity of oral mucositis during oropharyngeal radiation therapy . Cancer . 2000 ; 89 11 : 2258 – 2265 . Google Scholar Crossref Search ADS PubMed WorldCat 57 Al-Ansari S , Zecha JA , Barasch A , et al. . Oral mucositis induced by anticancer therapies . Curr Oral Health Rep. 2015 ; 2 4 : 202 – 211 . Google Scholar Crossref Search ADS PubMed WorldCat 58 Sonis ST. Mucositis: the impact, biology and therapeutic opportunities of oral mucositis . Oral Oncol. 2009 ; 45 12 : 1015 – 1020 . Google Scholar Crossref Search ADS PubMed WorldCat 59 Sonis ST. Oral mucositis in head and neck cancer: risk, biology, and management . Am Soc Clin Oncol Educ Book . 2013 . doi:10.1200/EdBook_AM.2013.33.e236. WorldCat 60 Al-Dasooqi N , Sonis ST , Bowen JM , et al. . Emerging evidence on the pathobiology of mucositis . Support Care Cancer. 2013 ; 21 7 : 2075 – 2083 . Google Scholar Crossref Search ADS PubMed WorldCat 61 Boers-Doets CB , Raber-Durlacher JE , Treister NS , et al. . Mammalian target of rapamycin inhibitor-associated stomatitis . Future Oncol. 2013 ; 9 12 : 1883 – 1892 . Google Scholar Crossref Search ADS PubMed WorldCat 62 Peterson DE , O'Shaughnessy JA , Rugo HS , et al. . Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice . Cancer Med . 2016 ; 5 8 : 1897 – 1907 . Google Scholar Crossref Search ADS PubMed WorldCat 63 Scully C. Clinical practice. Aphthous ulceration . N Engl J Med . 2006 ; 355 2 : 165 – 172 . Google Scholar Crossref Search ADS PubMed WorldCat 64 Morelon E , Stern M , Israel-Biet D , et al. . Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients . Transplantation. 2001 ; 72 5 : 787 – 790 . Google Scholar Crossref Search ADS PubMed WorldCat 65 Tiong HY , Flechner SM , Zhou L , et al. . A systematic approach to minimizing wound problems for de novo sirolimus-treated kidney transplant recipients . Transplantation. 2009 ; 87 2 : 296 – 302 . Google Scholar Crossref Search ADS PubMed WorldCat 66 Mills RE , Taylor KR , Podshivalova K , et al. . Defects in skin gamma delta T cell function contribute to delayed wound repair in rapamycin-treated mice . J Immunol. 2008 ; 181 6 : 3974 – 3983 . Google Scholar Crossref Search ADS PubMed WorldCat 67 Avci E , Akarslan ZZ , Erten H , et al. . Oxidative stress and cellular immunity in patients with recurrent aphthous ulcers . Braz J Med Biol Res. 2014 ; 47 5 : 355 – 360 . Google Scholar Crossref Search ADS PubMed WorldCat 68 Weichhart T , Säemann MD. The multiple facets of mTOR in immunity . Trends Immunol. 2009 ; 30 5 : 218 – 226 . Google Scholar Crossref Search ADS PubMed WorldCat 69 Boussemart L , Routier E , Mateus C , et al. . Prospective study of cutaneous side-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients . Ann Oncol. 2013 ; 24 6 : 1691 – 1697 . Google Scholar Crossref Search ADS PubMed WorldCat 70 Mangold AR , Bryce A , Sekulic A. Vemurafenib-associated gingival hyperplasia in patient with metastatic melanoma . J Am Acad Dermatol. 2014 ; 71 5 : e205 – e206 . Google Scholar Crossref Search ADS PubMed WorldCat 71 Vigarios E , Lamant L , Delord JP , et al. . Oral squamous cell carcinoma and hyperkeratotic lesions with BRAF inhibitors . Br J Dermatol. 2015 ; 172 6 : 1680 – 1682 . Google Scholar Crossref Search ADS PubMed WorldCat 72 Lloyd-Lavery A , Hodgson T , Coupe N , et al. . Delayed oral toxicity from long term Vemurafenib therapy (letter to editor) . Br J Dermatol. 2016 ; 174( 5 ): 1159 – 1160 . Google Scholar Crossref Search ADS PubMed WorldCat 73 Dietrich E , Antoniades K. Molecularly targeted drugs for the treatment of cancer: oral complications and pathophysiology . Hippokratia. 2012 ; 16 3 : 196 – 199 . Google Scholar PubMed WorldCat 74 Watters AL , Epstein JB , Agulnik M. Oral complications of targeted cancer therapies: a narrative literature review . Oral Oncol. 2011 ; 47 6 : 441 – 448 . Google Scholar Crossref Search ADS PubMed WorldCat 75 de Oliveira MA , Martins EMF , Wang Q , et al. . Clinical presentation and management of mTOR inhibitor-associated stomatitis . Oral Oncol. 2011 ; 47 10 : 998 – 1003 . Google Scholar Crossref Search ADS PubMed WorldCat 76 van Gelder T , ter Meulen CG , Hené R , et al. . Oral ulcers in kidney transplant recipients treated with sirolimus and mycophenolate mofetil . Transplantation. 2003 ; 75 6 : 788 – 791 . Google Scholar Crossref Search ADS PubMed WorldCat 77 Campistol JM , de Fijter JW , Flechner SM , et al. . mTOR inhibitor-associated dermatologic and mucosal problems . Clin Transplant. 2010 ; 24 2 : 149 – 156 . Google Scholar Crossref Search ADS PubMed WorldCat 78 Gomez-Fernandez C , Garden BC , Wu S , et al. . The risk of skin rash and stomatitis with the mammalian target of rapamycin inhibitor temsirolimus: a systematic review of the literature and meta-analysis . Eur J Cancer. 2012 ; 48 3 : 340 – 346 . Google Scholar Crossref Search ADS PubMed WorldCat 79 Martins F , de Oliveira MA , Wang Q , et al. . A review of oral toxicity associated with mTOR inhibitor therapy in cancer patients . Oral Oncol. 2013 ; 49 4 : 293 – 298 . Google Scholar Crossref Search ADS PubMed WorldCat 80 Raymond E , Alexandre J , Faivre S , et al. . Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer . J Clin Oncol. 2004 ; 22 12 : 2336 – 2347 . Google Scholar Crossref Search ADS PubMed WorldCat 81 Buckner JC , Forouzesh B , Erlichman C , et al. . Phase I, pharmacokinetic study of temsirolimus administered orally to patients with advanced cancer . Invest New Drugs. 2010 ; 28 3 : 334 – 342 . Google Scholar Crossref Search ADS PubMed WorldCat 82 Sessa C , Tosi D , Viganò L , et al. . Phase Ib study of weekly mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) with weekly paclitaxel . Ann Oncol. 2010 ; 21 6 : 1315 – 1322 . Google Scholar Crossref Search ADS PubMed WorldCat 83 Mita MM , Mita AC , Chu QS , et al. . Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies . J Clin Oncol. 2008 ; 26 3 : 361 – 367 . Google Scholar Crossref Search ADS PubMed WorldCat 84 Jerusalem G , Fasolo A , Dieras V , et al. . Phase I trial of oral mTOR inhibitor everolimus in combination with trastuzumab and vinorelbine in pre-treated patients with HER2-overexpressing metastatic breast cancer . Breast Cancer Res Treat. 2011 ; 125 2 : 447 – 455 . Google Scholar Crossref Search ADS PubMed WorldCat 85 Tabernero J , Rojo F , Calvo E , et al. . Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors . J Clin Oncol. 2008 ; 26 10 : 1603 – 1610 . Google Scholar Crossref Search ADS PubMed WorldCat 86 Perotti A , Locatelli A , Sessa C , et al. . Phase IB study of the mTOR inhibitor ridaforolimus with capecitabine . J Clin Oncol. 2010 ; 28 30 : 4554 – 4561 . Google Scholar Crossref Search ADS PubMed WorldCat 87 Hartford CM , Desai AA , Janisch L , et al. . A phase I trial to determine the safety, tolerability, and maximum tolerated dose of deforolimus in patients with advanced malignancies . Clin Cancer Res. 2009 ; 15 4 : 1428 – 1434 . Google Scholar Crossref Search ADS PubMed WorldCat 88 Shameem R , Lacouture M , Wu S. Incidence and risk of high-grade stomatitis with mTOR inhibitors in cancer patients . Cancer Invest. 2015 ; 33 3 : 70 – 77 . Google Scholar Crossref Search ADS PubMed WorldCat 89 Badri T , Hammami H , Lachkham A , et al. . Radiotherapy-induced pemphigus vulgaris with autoantibodies targeting a 110 kDa epidermal antigen . Int J Dermatol. 2011 ; 50 12 : 1475 – 1479 . Google Scholar Crossref Search ADS PubMed WorldCat 90 Vern-Gross TZ , Kowal-Vern A. Erythema multiforme, Stevens Johnson syndrome, and toxic epidermal necrolysis syndrome in patients undergoing radiation therapy: a literature review . Am J Clin Oncol. 2014 ; 37 5 : 506 – 513 . Google Scholar Crossref Search ADS PubMed WorldCat 91 Brenner S , Bialy-Golan A , Ruocco V. Drug-induced pemphigus . Clin Dermatol. 1998 ; 16 3 : 393 – 397 . Google Scholar Crossref Search ADS PubMed WorldCat 92 Baldo BA , Pham NH. Adverse reactions to targeted and non-targeted chemotherapeutic drugs with emphasis on hypersensitivity responses and the invasive metastatic switch . Cancer Metastasis Rev. 2013 ; 32 ( 3–4 ): 723 – 761 . Google Scholar Crossref Search ADS PubMed WorldCat 93 Yildiz O , Ozguroglu M , Yanmaz MT , et al. . Paraneoplastic pemphigus associated with fludarabine use . Med Oncol. 2007 ; 24 1 : 115 – 118 . Google Scholar Crossref Search ADS PubMed WorldCat 94 Jurge S , Kuffer R , Scully C , Porter SR. Mucosal disease series. Number VI. Recurrent aphthous stomatitis . Oral Dis . 2006 ; 12 1 : 1 – 21 . Google Scholar Crossref Search ADS PubMed WorldCat 95 Bazrafshani MR , Hajeer AH , Ollier WE , et al. . IL-1B and IL-6 gene polymorphisms encode significant risk for the development of recurrent aphthous stomatitis (RAS) . Genes Immun. 2002 ; 3 5 : 302 – 305 . Google Scholar Crossref Search ADS PubMed WorldCat 96 Najafi S , Yousefi H , Mohammadzadeh M , et al. . Association study of interleukin-1 family and interleukin-6 gene single nucleotide polymorphisms in recurrent aphthous stomatitis . Int J Immunogenet. 2015 ; 42 6 : 428 – 431 . Google Scholar Crossref Search ADS PubMed WorldCat 97 Guimarães AL , Correia-Silva Jde F , Sá AR , et al. . Investigation of functional gene polymorphisms IL-1beta, IL-6, IL-10 and TNF-alpha in individuals with recurrent aphthous stomatitis . Arch Oral Biol. 2007 ; 52 3 : 268 – 272 . Google Scholar Crossref Search ADS PubMed WorldCat 98 Karakus N , Yigit S , Rustemoglu A , et al. . Effects of interleukin (IL)-6 gene polymorphisms on recurrent aphthous stomatitis . Arch Dermatol Res. 2014 ; 306 2 : 173 – 180 . Google Scholar Crossref Search ADS PubMed WorldCat 99 Ozyurt K , Celik A , Sayarlioglu M , et al. . Serum Th1, Th2 and Th17 cytokine profiles and alpha-enolase levels in recurrent aphthous stomatitis . J Oral Pathol Med. 2014 ; 43 9 : 691 – 695 . Google Scholar Crossref Search ADS PubMed WorldCat 100 Stojanov S , Lapidus S , Chitkara P , et al. . Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade . Proc Natl Acad Sci U S A. 2011 ; 108 17 : 7148 – 7153 . Google Scholar Crossref Search ADS PubMed WorldCat 101 Gell PGH , Coombs RRA , eds. The Classification of Allergic Reactions Underlying Disease . Blackwell Sciences ; 1963 . Google Preview WorldCat COPAC 102 Pedersen A , Klausen B , Hougen HP , et al. . T-lymphocyte subsets in recurrent aphthous ulceration . J Oral Pathol Med. 1989 ; 18 1 : 59 – 60 . Google Scholar Crossref Search ADS PubMed WorldCat 103 Pedersen A , Ryder LP. Gamma delta T-cell fraction of peripheral blood is increased in recurrent aphthous ulceration . Clin Immunol Immunopathol. 1994 ; 72 1 : 98 – 104 . Google Scholar Crossref Search ADS PubMed WorldCat 104 Hayrinen-Immonen R , Nordstrom D , Malmstrom M , et al. . Immune-inflammatory cells in recurrent oral ulcers (ROU ). Scand J Dent Res . 1991 ; 99 6 : 510 – 518 . Google Scholar PubMed WorldCat 105 Savage NW , Seymour GJ , Kruger BJ. T-lymphocyte subset changes in recurrent aphthous stomatitis . Oral Surg Oral Med Oral Pathol. 1985 ; 60 2 : 175 – 181 . Google Scholar Crossref Search ADS PubMed WorldCat 106 Lehner T. Stimulation of lymphocyte transformation by tissue homogenates in recurrent oral ulceration . Immunology. 1967 ; 13 2 : 159 – 166 . Google Scholar PubMed WorldCat 107 Dolby AE. Recurrent aphthous ulceration. Effect of sera and peripheral blood lymphocytes upon oral epithelial tissue culture cells . Immunology. 1969 ; 17 5 : 709 – 714 . Google Scholar PubMed WorldCat 108 Rogers RS 3rd , Sams WM Jr , Shorter RG. Lymphocytotoxicity in recurrent aphthous stomatitis. Lymphocytotoxicity for oral epithelial cells in recurrent aphthous stomatitis and Bechet syndrome . Arch Dermatol. 1974 ; 109 3 : 361 – 363 . Google Scholar Crossref Search ADS PubMed WorldCat 109 Rogers RS 3rd , Movius DL , Pierre RV. Lymphocyte-epithelial cell interactions in oral mucosal inflammatory diseases . J Invest Dermatol. 1976 ; 67 5 : 599 – 602 . Google Scholar Crossref Search ADS PubMed WorldCat 110 Greenspan JS , Gadol N , Olson JA , et al. . Antibody-dependent cellular cytotoxicity in recurrent aphthous ulceration . Clin Exp Immunol. 1981 ; 44 3 : 603 – 610 . Google Scholar PubMed WorldCat 111 Burnett PR , Wray D. Lytic effects of serum and mononuclear leukocytes on oral epithelial cells in recurrent aphthous stomatitis . Clin Immunol Immunopathol. 1985 ; 34 2 : 197 – 204 . Google Scholar Crossref Search ADS PubMed WorldCat 112 Hasan A , Childerstone A , Pervin K , et al. . Recognition of a unique peptide epitope of the mycobacterial and human heat shock protein 65–60 antigen by T cells of patients with recurrent oral ulcers . Clin Exp Immunol. 1995 ; 99 3 : 392 – 397 . Google Scholar Crossref Search ADS PubMed WorldCat 113 Lewkowicz N , Lewkowicz P , Dzitko K , et al. . Dysfunction of CD4+CD25high T regulatory cells in patients with recurrent aphthous stomatitis . J Oral Pathol Med. 2008 ; 37 8 : 454 – 461 . Google Scholar Crossref Search ADS PubMed WorldCat 114 Hijazi K , Lowe T , Meharg C , et al. . Mucosal microbiome in patients with recurrent aphthous stomatitis . J Dent Res. 2015 ; 94(3 Suppl) : 87S – 94S . Google Scholar Crossref Search ADS WorldCat 115 Hietanen J , Häyrinen-Immonen R , Al-Samadi A , et al. . Recurrent aphthous ulcers--a toll-like receptor-mediated disease? J Oral Pathol Med. 2012 ; 41 2 : 158 – 164 . Google Scholar Crossref Search ADS PubMed WorldCat 116 Al-Samadi A , Kouri VP , Salem A , et al. . IL-17C and its receptor IL-17RA/IL-17RE identify human oral epithelial cell as an inflammatory cell in recurrent aphthous ulcer . J Oral Pathol Med. 2014 ; 43 2 : 117 – 124 . Google Scholar Crossref Search ADS PubMed WorldCat 117 Al-Samadi A , Drozd A , Salem A , et al. . Epithelial cell apoptosis in recurrent aphthous ulcers . J Dent Res. 2015 ; 94 7 : 928 – 935 . Google Scholar Crossref Search ADS PubMed WorldCat 118 Khudhur AS , Di Zenzo G , Carrozzo M. Oral lichenoid tissue reactions: diagnosis and classification . Expert Rev Mol Diagn. 2014 ; 14 2 : 169 – 184 . Google Scholar Crossref Search ADS PubMed WorldCat 119 Sontheimer RD. Lichenoid tissue reaction/interface dermatitis: clinical and histological perspectives . J Invest Dermatol. 2009 ; 129 5 : 1088 – 1099 . Google Scholar Crossref Search ADS PubMed WorldCat 120 Ozkaya E. Oral mucosal fixed drug eruption: characteristics and differential diagnosis . J Am Acad Dermatol . 2013 ; 69 2 : e51 – e58 . Google Scholar Crossref Search ADS PubMed WorldCat 121 Webster K , Godbold P. Nicorandil induced oral ulceration . Br Dent J. 2005 ; 198 10 : 619 – 621 . Google Scholar Crossref Search ADS PubMed WorldCat 122 Oyama N , Setterfield JF , Gratian MJ , et al. . Oral and genital lichenoid reactions associated with circulating autoantibodies to desmoplakins I and II: a novel target antigen or example of epitope spreading? J Am Acad Dermatol. 2003 ; 48 3 : 433 – 438 . Google Scholar Crossref Search ADS PubMed WorldCat 123 Mockenhaupt M. The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis . Expert Rev Clin Immunol. 2011 ; 7 6 : 803 – 813 ; quiz 14–15. Google Scholar Crossref Search ADS PubMed WorldCat 124 Caproni M , Torchia D , Schincaglia E , et al. . The CD40/CD40 ligand system is expressed in the cutaneous lesions of erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum . Br J Dermatol. 2006 ; 154 2 : 319 – 324 . Google Scholar Crossref Search ADS PubMed WorldCat 125 Heng YK , Lee HY , Roujeau JC. Epidermal necrolysis: 60 years of errors and advances . Br J Dermatol. 2015 ; 173 5 : 1250 – 1254 . Google Scholar Crossref Search ADS PubMed WorldCat 126 Foedinger D , Anhalt GJ , Boecskoer B , et al. . Autoantibodies to desmoplakin I and II in patients with erythema multiforme . J Exp Med. 1995 ; 181 1 : 169 – 179 . Google Scholar Crossref Search ADS PubMed WorldCat 127 Cozzani E , Di Zenzo G , Calabresi V , et al. . Anti-desmoplakin antibodies in erythema multiforme and Stevens-Johnson syndrome sera: pathogenic or epiphenomenon? Eur J Dermatol. 2011 ; 21 1 : 32 – 36 . Google Scholar PubMed WorldCat 128 Kokuba H , Aurelian L , Burnett J. Herpes simplex virus associated erythema multiforme (HAEM) is mechanistically distinct from drug-induced erythema multiforme: interferon-gamma is expressed in HAEM lesions and tumor necrosis factor-alpha in drug-induced erythema multiforme lesions . J Invest Dermatol. 1999 ; 113 5 : 808 – 815 . Google Scholar Crossref Search ADS PubMed WorldCat 129 Chung WH , Hung SI , Yang JY , et al. . Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis . Nat Med. 2008 ; 14 12 : 1343 – 1350 . Google Scholar Crossref Search ADS PubMed WorldCat 130 Khalil I , Lepage V , Douay C , et al. . HLA DQB1*0301 allele is involved in the susceptibility to erythema multiforme . J Invest Dermatol. 1991 ; 97 4 : 697 – 700 . Google Scholar Crossref Search ADS PubMed WorldCat 131 Tassaneeyakul W , Tiamkao S , Jantararoungtong T , et al. . Association between HLA-B*1502 and carbamazepine-induced severe cutaneous adverse drug reactions in a Thai population . Epilepsia . 2010 ; 51 5 : 926 – 930 . Google Scholar Crossref Search ADS PubMed WorldCat 132 Somkrua R , Eickman EE , Saokaew S , et al. . Association of HLA-B*5801 allele and allopurinol-induced Stevens Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis . BMC Med Genet . 2011 ; 12 : 118 . Google Scholar Crossref Search ADS PubMed WorldCat 133 White KD , Chung WH , Hung SI , et al. . Evolving models of the immunopathogenesis of T cell-mediated drug allergy: the role of host, pathogens, and drug response . J Allergy Clin Immunol. 2015 ; 136 2 : 219 – 234 ; quiz 35. Google Scholar Crossref Search ADS PubMed WorldCat 134 Hashimoto K , Yasukawa M , Tohyama M. Human herpesvirus 6 and drug allergy . Curr Opin Allergy Clin Immunol. 2003 ; 3 4 : 255 – 260 . Google Scholar Crossref Search ADS PubMed WorldCat 135 Descamps V , Mahe E , Houhou N , et al. . Drug-induced hypersensitivity syndrome associated with Epstein-Barr virus infection . Br J Dermatol. 2003 ; 148 5 : 1032 – 1034 . Google Scholar Crossref Search ADS PubMed WorldCat 136 González-Delgado P , Blanes M , Soriano V , et al. . Erythema multiforme to amoxicillin with concurrent infection by Epstein-Barr virus . Allergol Immunopathol (Madr) . 2006 ; 34 2 : 76 – 78 . Google Scholar Crossref Search ADS PubMed WorldCat 137 Cirillo N , Cozzani E , Carrozzo M , et al. . Urban legends: pemphigus vulgaris . Oral Dis. 2012 ; 18 5 : 442 – 458 . Google Scholar Crossref Search ADS PubMed WorldCat 138 Ruocco V , Ruocco E , Lo Schiavo A , et al. . Pemphigus: etiology, pathogenesis, and inducing or triggering factors: facts and controversies . Clin Dermatol. 2013 ; 31 4 : 374 – 381 . Google Scholar Crossref Search ADS PubMed WorldCat 139 Orion E , Matz H , Wolf R. Pemphigus vulgaris induced by radiotherapy . J Eur Acad Dermatol Venereol. 2004 ; 18 4 : 508 – 509 . Google Scholar Crossref Search ADS PubMed WorldCat 140 Daneshpazhooh M , Chams-Davatchi C , Ramezani A , et al. . Abortive aphthous-like oral lesions: an underreported initial presentation of pemphigus vulgaris . J Eur Acad Dermatol Venereol. 2009 ; 23 2 : 157 – 159 . Google Scholar Crossref Search ADS PubMed WorldCat 141 Amagai M , Klaus-Kovtun V , Stanley JR. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion . Cell. 1991 ; 67 5 : 869 – 877 . Google Scholar Crossref Search ADS PubMed WorldCat 142 Amagai M , Tsunoda K , Zillikens D , et al. . The clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile . J Am Acad Dermatol. 1999 ; 40(2 Pt 1) : 167 – 170 . Google Scholar Crossref Search ADS WorldCat 143 Tsunoda K , Ota T , Aoki M , et al. . Induction of pemphigus phenotype by a mouse monoclonal antibody against the amino-terminal adhesive interface of desmoglein 3 . J Immunol. 2003 ; 170 4 : 2170 – 2178 . Google Scholar Crossref Search ADS PubMed WorldCat 144 Payne AS , Ishii K , Kacir S , et al. . Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display . J Clin Invest. 2005 ; 115 4 : 888 – 899 . Google Scholar Crossref Search ADS PubMed WorldCat 145 Schulze K , Galichet A , Sayar BS , et al. . An adult passive transfer mouse model to study desmoglein 3 signaling in pemphigus vulgaris . J Invest Dermatol. 2012 ; 132 2 : 346 – 355 . Google Scholar Crossref Search ADS PubMed WorldCat 146 Spindler V , Rotzer V , Dehner C , et al. . Peptide-mediated desmoglein 3 crosslinking prevents pemphigus vulgaris autoantibody-induced skin blistering . J Clin Invest . 2013 ; 123 2 : 800 – 811 . Google Scholar PubMed WorldCat 147 Di Zenzo G , Amber KT , Sayar BS , et al. . Immune response in pemphigus and beyond: progresses and emerging concepts . Semin Immunopathol. 2016 ; 38 1 : 57 – 74 . Google Scholar Crossref Search ADS PubMed WorldCat 148 Tron F , Gilbert D , Joly P , et al. . Immunogenetics of pemphigus: an update . Autoimmunity. 2006 ; 39 7 : 531 – 539 . Google Scholar Crossref Search ADS PubMed WorldCat 149 Ahmed AR , Yunis EJ , Khatri K , et al. . Major histocompatibility complex haplotype studies in Ashkenazi Jewish patients with pemphigus vulgaris . Proc Natl Acad Sci U S A. 1990 ; 87 19 : 7658 – 7662 . Google Scholar Crossref Search ADS PubMed WorldCat 150 Miyagawa S , Higashimine I , Iida T , et al. . HLA-DRB1*04 and DRB1*14 alleles are associated with susceptibility to pemphigus among Japanese . J Invest Dermatol. 1997 ; 109 5 : 615 – 618 . Google Scholar Crossref Search ADS PubMed WorldCat 151 Lombardi ML , Mercuro O , Ruocco V , et al. . Common human leukocyte antigen alleles in pemphigus vulgaris and pemphigus foliaceus Italian patients . J Invest Dermatol. 1999 ; 113 1 : 107 – 110 . Google Scholar Crossref Search ADS PubMed WorldCat 152 Riechers R , Grötzinger J , Hertl M. HLA class II restriction of autoreactive T cell responses in pemphigus vulgaris: review of the literature and potential applications for the development of a specific immunotherapy . Autoimmunity. 1999 ; 30 3 : 183 – 196 . Google Scholar Crossref Search ADS PubMed WorldCat 153 Ahmed AR , Carrozzo M , Caux F , et al. . Monopathogenic vs multipathogenic explanations of pemphigus pathophysiology . Exp Dermatol. 2016 ; 25 11 : 839 – 846 . Google Scholar Crossref Search ADS PubMed WorldCat 154 Kalantari-Dehaghi M , Anhalt GJ , Camilleri MJ , et al. . Pemphigus vulgaris autoantibody profiling by proteomic technique . PLoS One. 2013 ; 8 3 : e57587 . Google Scholar Crossref Search ADS PubMed WorldCat 155 Sajda T , Hazelton J , Patel M , et al. . Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus . Proc Natl Acad Sci U S A. 2016 ; 113 7 : 1859 – 1864 . Google Scholar Crossref Search ADS PubMed WorldCat 156 Chernyavsky A , Amber KT , Agnoletti AF , et al. . Synergy among non-desmoglein antibodies contributes to the immunopathology of desmoglein antibody-negative pemphigus vulgaris . J Biol Chem 2019 ; 294 12 : 4520 – 4528 . Google Scholar Crossref Search ADS PubMed WorldCat 157 Grando SA. Pemphigus autoimmunity: hypotheses and realities . Autoimmunity. 2012 ; 45 1 : 7 – 35 . Google Scholar Crossref Search ADS PubMed WorldCat 158 Scully C , Miller CS , Aguirre Urizar JM , et al. . Oral medicine (stomatology) across the globe: birth, growth, and future . Oral Surg Oral Med Oral Pathol Oral Radiol. 2016 ; 121 2 : 149 – 157.e5 . Google Scholar Crossref Search ADS PubMed WorldCat 159 Dey-Rao R , Seiffert-Sinha K , Sinha AA. Genome-wide expression analysis suggests unique disease-promoting and disease-preventing signatures in Pemphigus vulgaris . Genes Immun. 2013 ; 14 8 : 487 – 499 . Google Scholar Crossref Search ADS PubMed WorldCat 160 Pullarkat ST , Stoehlmacher J , Ghaderi V , et al. . Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy . Pharmacogenomics J. 2001 ; 1 1 : 65 – 70 . Google Scholar Crossref Search ADS PubMed WorldCat 161 Lecomte T , Ferraz JM , Zinzindohoué F , et al. . Thymidylate synthase gene polymorphism predicts toxicity in colorectal cancer patients receiving 5-fluorouracil-based chemotherapy . Clin Cancer Res. 2004 ; 10 17 : 5880 – 5888 . Google Scholar Crossref Search ADS PubMed WorldCat 162 Schwab M , Zanger UM , Marx C , et al. . Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group . J Clin Oncol. 2008 ; 26 13 : 2131 – 2138 . Google Scholar Crossref Search ADS PubMed WorldCat 163 Sonis ST. New thoughts on the initiation of mucositis . Oral Dis. 2010 ; 16 7 : 597 – 600 . Google Scholar Crossref Search ADS PubMed WorldCat 164 Ellebrecht CT , Bhoj VG , Nace A , et al. . Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease . Science. 2016 ; 353 6295 : 179 – 184 . Google Scholar Crossref Search ADS PubMed WorldCat 165 U.S. Department of Health and Human Services. Common Terninology Criteria for Adverse Events (CTCAE) Version 5 (27 Nov 2017). https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf. Accessed March 14, 2019. 166 National Institute for Health and Care Excellence . Interventional Procedures Progamme. https://www.nice.org.uk/guidance/ipg615/documents/overview. Accessed March 14, 2019. 167 Boers-Doets CB , Nicolatou-Gailitis O , Lalla RV. The mIAS Scale: a scale to measure mTOR inhibitor-associated stomatitis . Support Care Cancer . 2013 ; 21 ( S1 ): S140 . WorldCat 168 Lacouture ME , Maitland ML , Segaert S , et al. . A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCC skin toxicity study group . Support Care Cancer. 2010 ; 18 4 : 509 – 522 . Google Scholar Crossref Search ADS PubMed WorldCat 169 Chan A , Tan EH. How well does the MESTT correlate with CTCAE scale for the grading of dermatological toxicities associated with oral tyrosine kinase inhibitors? Support Care Cancer. 2011 ; 19 10 : 1667 – 1674 . Google Scholar Crossref Search ADS PubMed WorldCat 170 National Cancer Institute . Oral Complications of Chemotherapy and Head/Neck Radiation (PDQ)-Healt Professional version. 2019 . https://www.cancer.gov/about-cancer/treatment/side-effects/mouth-throat/oral-complications-hp-pdq. Accessed March 14, 2019. © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

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JNCI MonographsOxford University Press

Published: Aug 1, 2019

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