Mucositis is a common and clinically significant side effect of both anticancer chemotherapy (CT) and radiation therapy (RT) that can affect any portion of the gastrointestinal (GI) tract. Not only it is associated with an adverse symptom profile, but also it may limit patients’ ability to tolerate treatment if not adequately prevented and managed. Moreover, it may be associated with secondary local and systemic infection and poor health outcomes, and generates additional use of healthcare resources resulting in additional costs (Villa and Sonis, 2015).

Historically, mucositis has been described by its anatomical distribution: oral mucositis (OM) for involvement of the tissues of the upper aerodigestive tract, gastrointestinal mucositis (GIM) for lesions dominantly in the small intestine, and proctitis for injury of the rectal mucosa. The incidence and course of mucositis is site-dependent and related to the cancer treatment regimen.

OM has been the most studied, probably as a consequence of its frequency, ease of access and its course and symptom impact (Sonis et al., 2004). Nonetheless, all forms of mucositis (as well as other epithelially based toxicities) share common features in a complex scheme of pathogenesis. While the historical paradigm suggested that mucosal injury was solely the consequence of damaging effects of CT or RT on rapidly dividing normal cells of the GI tract, more current research has demonstrated that tissue damage occurs as a manifestation of a sequence of biological events that ultimately target epithelial stem cells. Experimental evidence has accumulated to validate mucositis’ pathogenesis as a multi-stage process (Sonis, 1998, 2004).

Like most other toxicities, the incidence of mucositis is likely to be under-reported by clinicians. The incidence of clinically significant mucositis has been reported to range from 15% among patients receiving low-risk treatments up to 60–100% among patients being treated with high-dose CT, radiotherapy and bone marrow transplantation. Nonetheless, this percentage is estimated to be about 40% in patients undergoing standard dose, cycled CT (Kwon, 2016). The incidence range of oral and non-oral mucositis at fixed doses of CT ranges from the single digits to well over 50% (i.e., TPF induction regimens for the treatment of HN cancer). Antimetabolites, anthracyclines, and taxanes are chemotherapeutic drugs frequently associated with the development of mucositis (Pico et al., 1998).

Chemotherapy-induced diarrhea, the key clinical sign of GIM, was reported to occur in 89% of patients treated with FOLFIRI and 50% of patients treated with FOLFOX for colorectal cancer (Keefe et al., 2014). Concomitant use of total body RT in hematopoietic stem cell transplant (HSCT) conditioning regimens markedly increased mucositis throughout the GI tract. RT-induced diarrhea in patients being treated for HN or lung cancers was noted in 29% of patients treated with radiation alone and 42% of patients treated with concomitant CT-RT.

Overall, almost a half million patients will suffer from mucositis this year in the U.S. with a likely similar number in Europe (Sonis et al., 2015).

Both OM and GIM can adversely impact on patients’ quality of life and may cause treatment delays, unplanned interruptions or even premature discontinuation of anticancer therapies, resulting in prolonged hospital stays, increased re-admission rates, more complications and economic burden. It has been reported an estimated incremental cost of hospitalization that may exceed 3,500 USD per cycle with mucositis (Elting et al., 2003) and an incremental cost of about 18,000 USD in HN cancer patients undergoing CT-RT (Nonzee et al., 2008).

The pathogenesis of mucositis is multifaceted and involves not only the epithelium, but also the cells and tissues within the submucosa (Figure 1). Signaling from damaged endothelium, fibroblasts and infiltrating leukocyte cells contributes to apoptosis, loss of renewal, atrophy and ulceration. Whereas these changes occur more slowly in stratified mucosa, they are abrupt in the single layers of the small intestine (Chaveli-López, 2014; Villa and Sonis, 2015).

A five-phase sequence has been used to describe the biological phases of mucositis: initiation, up-regulation and activation leading to generation of messengers, signal amplification, ulceration with inflammation, and healing. For the most part, this order is independent of the insult (RT and CT) or the target tissue involved. Importantly, the elements driving each phase represent potential interventional targets (Sonis et al., 2004).

The initiation of mucositis is triggered by oxidative stress and the generation of reactive oxygen species (ROS), direct DNA and non-DNA damage, and activation of the innate immune response. These events follow the release of endogenous damage-associated molecular pattern molecules from injured cells of the basal epithelial layers, submucosa, and endothelium. Based on the trajectory of gene activation and pathway analysis, it is clear that the initiating biological cascade happens within seconds of the stimulating insult.

Following initiation, ROS and the innate immune response further damage cell membranes, stimulate macrophages and activate several transcription factors of which nuclear factor NF-κB plays a prominent role. Once activated, NF-κB-mediated gene expression results in a surge of many pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β and cyclooxygenase-2 (COX-2). The up-regulation of other genes causes the expression of adhesion molecules and angiogenesis (Sonis, 2002; Rm et al., 2007).

More in depth, TNF-α up-regulation may activate caspase pathways and generate a feedback on NF-κB to amplify its response and initiate mitogen-activated protein kinase (MAPK) pathway, leading to activation of c-Jun N-terminal kinase (JNK) signaling; fibronectin breakdown leads to macrophage activation. NF-κB independent pathways such as ceramide pathway may also play a role, resulting in apoptosis of submucosal and basal epithelial cells leading to mucosal ulceration (ulcerative phase) and atrophic changes. Recent studies confirmed the involvement of deregulated expression of metalloproteinases (MMPs) in the pathobiology of mucositis (Al-Dasooqi et al., 2010).

The first three phases rapidly lead to apoptosis of epithelial stem cells. In the case of stratified epithelium (i.e., the upper aerodigestive tract and rectal mucosa), loss of renewal leads to atrophy and then ulceration. From the clinical point of view, the overlying mucosa appears initially normal despite the biological havoc taking placing beneath it. In the case of bolus CT, the time between initial basal cell injury and clinical notable mucosal changes (erythema and thinning) takes about 4 days with ulceration occurring shortly thereafter. In contrast, the consequences of cellular damage in the intestinal villi are almost immediate with clinical evidence of enteritis becoming apparent within 24–48 h of CT.

Bacterial colonization of non-intestinal lesions lags slightly behind ulcer development. However, at that time, a large increase in the bacterial load is seen. In the case of patients receiving CT, this occurs at the time that the patient is least capable of dealing with potential infection as it roughly inversely parallels the course of the leukopenia. Ulcer colonization also results in the release of bacterial cell wall products and cytokine production. Healing generally occurs spontaneously and is characterized by epithelial proliferation, migration, and differentiation stimulated by the extracellular matrix (Blijlevens and Sonis, 2007; Al-Ansari et al., 2015). After the healing phase, the oral mucosa returns normal, although the patient have an increased risk of future episodes of mucositis due to residual angiogenesis.

It is clear to anyone treating cancer patients that the risk of any toxicity, including mucositis, is not consistent. While some patients sail through treatment, others suffer immensely, despite having similar tumors and equivalent treatment. Given the imperatives of the Precision Medicine Initiative and the Cancer Moon Shot, prospective identification of patients at risk for mucositis is an important ongoing research objective. Understanding the mechanisms and incidence rates of GIM is essential to set an effective treatment avoiding treatment discontinuation that could negatively influence patients’ outcome. In general, risk factors may be associated with the treatment regimen and/or the patient (Villa and Sonis, 2015).

Gastrointestinal mucositis can affect any site of the alimentary tract and it may present with a large spectrum of clinical manifestations according to the involved area (Al-Dasooqi et al., 2013).

The first clinical manifestation of OM is erythema of one or more sites of the movable mucosa (i.e., buccal or labial mucosa, ventral tongue, floor of the mouth or soft palate). Lesions typically progress to form painful ulcerations often covered by a pseudomembrane and accompanied by odynophagia, dysphagia, malnutrition, and weight loss (Peterson et al., 2012; Chaveli-López and Bagán-Sebastián, 2016). Disruption of the intact mucosa may be associated with microbial colonization that may remain localized or become disseminated, especially in patients with severe neutropenia (Chaveli-López, 2014; Chaveli-López and Bagán-Sebastián, 2016). OM is usually self-limiting and its course depends on the anticancer treatment. Among patients receiving CT, first signs appear shortly after administration and usually peak at about days 7–14 to completely recover within the following week (Al-Ansari et al., 2015; Villa and Sonis, 2015). On the other hand, RT-induced mucositis usually develops during the second or third week of treatment and often persist until 2–4 weeks after the last dose (Villa and Sonis, 2015).

Little data exist to accurately characterize the course of esophageal or gastric mucositis. Consequently, symptoms such as pain, dysphagia, dyspepsia, nausea, and vomiting are often attributed to gastroesophageal reflux or candidosis, leading to underestimate mucositis in this tract (Squier and Kremer, 2001; Aprile et al., 2015).

The onset of CT-associated intestinal mucositis (enteritis) tends to be acute (usually within 24–48 h after treatment) and may present with diarrhea, constipation, abdominal pain, nausea, vomiting, and anorexia. In some cases malnutrition, dehydration, infections, and sepsis may also occur (Al-Dasooqi et al., 2013; Ribeiro et al., 2016). Typhlitis, otherwise known as neutropenic enterocolitis, is a mucositis of ileo-cecal region with high mortality risk, typically affecting patients with neutropenic fever. Its clinical manifestation ranges from abdominal pain, bloating and diarrhea to acute abdomen (Davila, 2006). This severe form of enteritis may complicate treatments for hematologic tumors but it is observed also in patients undergoing cytotoxic drugs for solid malignancies (Sachak et al., 2015).

Proctitis usually occurs in patients undergoing chemoradiation for rectal, prostate or other pelvic cancers; symptoms include painful tenesmus with mucus discharge and rectal bleeding. Onset may be acute and/or not develop until several weeks after starting treatment. While these conditions are usually transient and resolve within a few weeks following the completion of RT, chronicity is not rare.

Moreover, both OM and GIM may cause systemic clinical manifestation such as anorexia, malabsorption, weight loss, anemia, fatigue, and sepsis (Al-Dasooqi et al., 2013).

In this landscape, targeted therapies-induced mucositis, such as mIAS, deserves a special mention and represents an emerging issue with different characteristics (Peterson et al., 2015; Kwon, 2016). According to ESMO guidelines (Peterson et al., 2015), the term stomatitis is more appropriate and should be used to indicate the mucosal inflammation related to these novel drugs.

Assessment scales provide the basis of objective comparisons of regimen-related toxicities or efficacy of toxicity treatment intervention. Currently, there is not a single instrument which is used universally. Rather, a range of scoring instruments are used with each depending on somewhat different subjective and/or objective criteria to define the severity of GIM (Villa and Sonis, 2016). One of the most commonly used is the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, most recent version 4.03), which grades mucositis severity 0–5, based primarily upon symptom severity, functional alteration and intervention requirements. NCI-CTC criteria for mucositis vary by anatomic site. The changing nature of NCI-CTC benchmarks, which has been a feature of each new iteration of the scale, has hindered longitudinal regimen-related toxicity comparisons (United States Department of Health and Human Services, 2010; Peterson et al., 2015). The World Health Organization (WHO) scale is widely used for grading OM and incorporates both objective and functional (ability to eat) assessments (Peterson et al., 2015; Villa and Sonis, 2015). Independently, the Radiation Therapy Oncology Group (RTOG) has developed Cooperative Group Common Toxicity Criteria which are, in some ways, a hybrid of those described by the NCI-CTC and WHO scores (Sonis, 2011).

Over the years, other scales designed primarily for use in clinical trials have been developed, such as the Oral Mucositis Assessment Scale (OMAS) (Sonis et al., 1999). However, measures developed for CT or RT-induced mucositis may not apply to patients treated with targeted agents. Thus, ad hoc scales have been designed for this population, such as the mIAS scale to assess mIAS (Boers-Doets and Lalla, 2013). Moreover, the integration with patient-reported outcome (PRO) becomes critical to improving the accuracy of clinical evaluation (Sonis, 2010; Bossi et al., 2015). Indeed, clinicians may underestimate the real burden of mucositis. Furthermore, the inter-observer variability can lead to discrepant scoring. Examples of PRO instruments are represented by the Oral Mucositis Daily Questionnaire (OMDQ) (Stiff et al., 2006b), the abovementioned OMAS and the Patient-Reported Oral Mucositis Symptom (PROMS) scale (Kushner et al., 2008).

It would be worthy to have a single standardized scale that incorporated clinicians and patients’ measures to describe GIM severity and to compare different prevention modalities and treatment regimens.

Although the quality of evidence derived from clinical studies is somewhat limited (Worthington et al., 2011), MASCC and ESMO have developed guidelines which offer potential strategies for managing mucositis (Lalla et al., 2014). It should be noted that the guidelines themselves are not definitive and represent the synthesis of a consensus of opinions of their authors. The guidelines should be viewed as fluid and will likely undergo changes as higher levels of evidence which support or refute treatment develop.

Notably, given the relatively recent development of new drugs, only expert opinions on the management of targeted therapies-induced mucositis are available (Peterson et al., 2015).

Prevention and treatment strategies for OM and GIM are listed in Tables 1, 2, respectively.

Gastrointestinal mucositis remains a significant, common unmet clinical need in cancer patients. Although frequently reported, the real rate and impact of this worrisome toxicity may be underestimated, and it consistently contributes to burden in terms of negative impact on quality of life, outcome and healthcare costs. The baseline risk-assessment is crucial to identify patients more likely to develop severe GIM in order to provide the best possible preventive and therapeutic approaches, with the aim of preserving optimal treatment intensity and maximize patients’ safety.

To date, most of the literature reports refer to OM, while the management of GIM remains a major challenge. In recent years, the increasing knowledge on the mucositis pathobiology has provided opportunities for the development of new approaches based upon the underlying molecular pathways. Although an increasing number of possible treatments have emerged, no standard measures have been established. A future, biologically based strategy may consist in combining interventions acting on the different phases of mucositis’ pathogenesis.

More research efforts are needed to better understand the underpinning biological processes in order to develop new effective treatments. Investigations should be performed to further characterize the role of the oral environment, including studies on the potential contribution of the oral/periodontal microbiome in the pathobiology of mucositis associated with targeted agents. Similarly, studies on changes in salivary output and proteome induced by anticancer therapies may contribute to a scientific base for OM risk prediction, early diagnosis and interventions (Al-Ansari et al., 2015).

Despite its longstanding recognition, frequency, clinical impact and cost, the treatment options for mucositis are disappointingly sparse. Only one agent, palifermin, has been approved for mitigation of OM in the U.S. – and only for a very limited segment of the at-risk population. GI mucositis suffers a similar fate. Its management is reliant on symptom control.

Next year will mark two decades since the recognition that the biological basis for mucositis’ pathogenesis is far more complex than simply being ascribed solely to non-specific clonogenic cell death of epithelial stem cells. The presentation of that concept and data from the subsequent studies that have followed, provided a plethora of information which have had tremendous potential translational value in identifying druggable targets for the enablement of new drugs and biologicals. Consequently, as discussed above, we are seeing a broad range of mechanistically based compounds in all phases of pre-clinical and clinical development. Preventing or limiting CT- or RT-induced normal tissue injury, while not interfering with a desired anti-tumor effect is not easy. The development of animal models to both study the pathobiology of mucositis and to serve as pre-clinical development platforms has been critical. For the most part, animal models for mucositis have been rodent (mouse, rat, and hamster) based. While no model is perfect, the predictive value of these ones relative to assessing a compounds behavior in humans has been unquestionably valuable. For example, the efficacy outcomes of a number of compounds that were observed in hamster models has been replicated in human studies. Likewise, although accumulating data highlight the differences between normal and tumor cells behavior, assessing that medications for supportive care do nothing to hinder the effectiveness of cancer therapy or induce negative tumor behaviors is critical. Animal models have been conducted for this purpose prior to the start of clinical trials.

However, animal models are characterized by several limitations and some successes which may be present in pre-clinical setting are not always evident in the clinical one. First of all, few animal studies focus on GIM, with most of the evidence deriving from trials on OM (Bowen et al., 2005; Viet et al., 2014). Moreover, in some animal models mucosal ulceration requires mechanical injury (Sonis et al., 1990), while in human patients the development of mucositis is independent of mechanical irritation. Another issue of pre-clinical models is represented by doses and scheduling; indeed, the susceptibility to a particular chemotherapic or radiotherapic regimen may be different between species. In addition, some animal models are characterized by the need of higher doses of CT than humans to induce the same grade of mucositis, due to the different keratinization of the epithelium. Moreover, such models sometimes require a route of drug administration not translatable to human patients. A further issue derives from the use of fully humanized monoclonal antibodies, which may not be active in animal setting (Bowen et al., 2011). Finally, few pre-clinical trials exist in order to investigate the molecular pathways of mucosal pain and most of the evidence is derived from animal models of pain related to oral cavity tumors or temporomandibular disorders (Viet et al., 2014).

Continued development of models and robust analyses of how animal results compare with those in humans will provide the information needed to help optimize the pre-clinical pathway for the development of new therapies.

All of this is taking place in an environment which increasingly recognizes that patients differ in their individual risk for mucositis (and other toxicities) and in how they might respond to one treatment or another. As a result, the literature reflects studies which now embed concepts of precision medicine in clinical trial design for mucositis interventions.

Given the impact of the above on the trajectory and enthusiasm for developing effective preventive and treatment options for mucositis, it is hard not to be optimistic that the current pipeline will result in effective therapies for mucositis in the relatively near future.

Manuscript writing: MC, GA, PE, DB, MV, and SS. Final approval of manuscript: MC, GA, PE, DB, MV, VF, GP, LC, and SS.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.