The majority of patients receiving chemoradiotherapy develop oral mucositis (OM), with reports demonstrating grade 3 or higher OM in over 40% of patients despite modern radiotherapy techniques (1-3). OM has several distinct phases of evolution that can result in severe pain (4). Subsequently, OM may cause dysphagia, an increase in aspiration risk, weight loss leading to feeding tube placement, and a decrease in quality of life (QOL), culminating in the potential for an increase in treatment breaks, hospitalizations, and medical care costs (5-13).
As reviewed in Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO), multi-agent combination oral care protocols have been shown to have efficacy for the prevention of OM during head and neck radiation therapy (14). However, these interventions largely focused on patients treated with radiation alone (15,16). Overall, several interventions for the prevention and treatment of OM, including professional oral care, multi-agent combination oral care protocols, and various rinses have been described (17).
Despite these overarching reviews, practical guidance on either the particular agent(s) to deploy or when to deploy them during the course of mucositis remains elusive (14,17). Furthermore, several additional treatments for OM during chemoradiation for head and neck cancer, including GC4419 (18), doxepin mouthwash (19), diphenhydramine-lidocaine-antacid (DLA) mouthwash (19), gabapentin (20), and methadone (20), have been published since the MASCC/ISOO review.
We performed this review to evaluate treatment with these newer agents and offer practical guidance on how and when to deploy a therapy. We present the following article in accordance with the Narrative Review reporting checklist (available at http://dx.doi.org/10.21037/atm-20-3931).
In April 2020, the PubMed database was searched for articles detailing the clinical management of OM in head and neck cancer published after July 1 2016, as prior to that Hong et al. detailed interventions for OM. The goal of this search was to identify studies in which OM prevention and/or treatment was a primary or secondary endpoint in head and neck cancer. Author LJ was responsible for the initial search, exclusion, and final assembly of included articles. Keywords utilized for search were “mucositis”, “head and neck neoplasms”, with the search query defined as ((((“mucositis”[MeSH Terms]) OR “mucositis”[Title/Abstract])) AND (((“head and neck neoplasms”[MeSH Terms])) OR (“head and neck”[Title/Abstract]))) AND (“2016/07/01”[Date - Publication]: “3000”[Date - Publication]), which returned 522 results.
The above search criterion identified 522 studies, of which 94 were human studies (Figure 1). In addition, we identified 9 clinical trials from the personal reference library of AS. The results from these databases were combined and 3 duplicates were removed for a total of 100 clinical trials. Of these studies, 51 were excluded because either (I) OM treatment or prevention was not a primary or secondary endpoint, (II) Head and neck cancer was not the primary population studied, or (III) Study was otherwise not relevant to OM. Upon further examination of the full text, 14 additional trials were excluded as ultimately the study was not relevant or there was incomplete data for this review. Ultimately, a total of 35 clinical trials were included in this review.
This review summarizes the literature since 2016 for the management of OM in head and neck cancer patients. Moreover, we synthesize the literature into a practical guideline of how to integrate various clinically available therapies to mitigate OM during chemoradiation therapy for head and neck cancer.
A multi-agent approach, in agreement with previous recommendations (14), remains necessary. The rational combination of agents should be designed to optimize both short- and long-term pain relief (Figure 2). This is illustrated and explained as a 1-page hand out in Appendix 1.
We recommend initiating home humidification, oral rinses and gabapentin at the beginning of treatment. Macann et al. treated patients used humidifiers overnight with additional use throughout the day from the first day of RT for 12 weeks (21). Humidification was found to result in a decrease in the development of functional mucositis. Additionally, treated patients had lower feeding tube use, and a lower risk of being admitted to the hospital. However, patient compliance was an issue. Many patients already have treatment for sleep apnea and their positive pressure devices may achieve some of this effect. Anecdotally, patients also report some benefit with a cool mist humidifier placed by the bed.
The importance of mucosal hydration in ameliorating toxicity is consistent with data showing that in the middle of radiation therapy, patients with worse mucositis pain also have worse dehydration (22). Intravenous fluids during this period can significantly and immediately reduce this pain (Rivers et al., manuscript submitted).
Saline oral rinses in our case are composed of tap water, sodium chloride, and sodium bicarbonate with recommended daily rinses of at least 20 times a day (Appendix 1). Oral care is commonly recommended to reduce the incidence of OM, however this is not based on strong evidence (14). However, they are commonly used, helpful for oral hygiene, and appear to be otherwise harmless. Clinically, while we are quite vigilant about the use of prescription medications, we understand the weakness of the oral care data and only adamantly require its’ use in those patients with a large increase in mucus.
Gabapentin, originally developed as an anti-convulsant agent, has been shown to have efficacy in the treatment of neuropathic pain (23). Sharp et al. found that gabapentin reduced mucosal neuropathy in two patients who had a received a trial of gefitinib and paclitaxel (24). Gabapentin should be slowly escalated from 300 daily to 1,200 mg three times per day. The use of high dose gabapentin is based on the experience of our on-going current study and Hermann et al. who found that high dose gabapentin resulted in a significantly greater percentage of patients never requiring opioids (42% vs. 7%, P=0.002) (20) (ClinicalTrials.gov identifier NCT 03547492). Several prospective trials demonstrated that gabapentin can reduce the need for enteric feeding tubes and narcotics, as well as improve QoL despite no significant impact on OM incidence or severity (20,25-27). While gabapentin does require an initial dose escalation, overall it has a favorable side-effect profile. As such, we recommend the use of prophylactic gabapentin in this setting. Gabapentin is renally excreted and the total dose should be limited in those with a baseline creatinine clearance below 60 milliliters/minute. In practice we have not had any toxicities in those patients taking 3,600 mg daily who were later found to have asymptomatic cisplatin induced acute renal failure; this was treated with intravenous hydration and monitoring without change in the gabapentin dose.
At the development of symptomatic OM, we recommend initiating either doxepin or DLA mouthwash. DLA can be used as a mouth and/or throat wash, or used to treat select sore areas via a sponge stick. Sio et al. evaluated the use of doxepin or DLA mouthwashes for the reduction of OM related pain (19). Both interventions were successful at reducing pain at 4 hours without significantly impacting median overall pain scores. The study was not designed to make comparisons between each agent, therefore we recommend either doxepin or DLA mouthwashes for short-term OM-related pain.
When pain is no longer adequately controlled via this regimen, we recommend introducing alternating doses of ibuprofen and acetaminophen. Patients are instructed to start Ibuprofen 400 mg and 4 hours later, take Acetaminophen 1,000 mg. This can be repeated every 6–8 hours however maximum recommended daily dose of Acetaminophen is 3,000 mg. There is no current guideline regarding the use of over-the-counter analgesics such as ibuprofen or acetaminophen (14). These medications have a well-established role for pain-relief however the role in the treatment of OM is unclear. Nevertheless, given the favorable side-effect profile and potential to relief OM-related pain, it is reasonable to utilize these medications in this setting.
In the last weeks of treatment, many patients have difficulty achieving adequate pain relief and require narcotics. We recommend methadone 2 mg three times a day to supplement the above regimen. In our experience it is rare to require more than 5 mg of methadone three times per day and we have never escalated a patient beyond 10 mg three times per day. Methadone may be more effective for neuropathic pain and unlike other opiates, methadone has a long half-life, therefore providing prolonged pain relief (28). Methadone, when used in conjunction with gabapentin, improves pain control and several QoL/function metrics (20,29). While it is unclear whether high dose gabapentin adds additional benefit to methadone, we recommend the use of methadone for pain relief in patients not well controlled on high dose gabapentin and over-counter-analgesics. Additionally, in order to reduce opioid-constipation, we recommend a stool softener with laxatives as needed to be taken in conjunction with methadone.
Methadone is thought to work in minimizing neuropathic pain due to its action on the N-Methyl-D-Aspartate receptor (20). Methadone also has a long half-life, which provides long acting pain relief (28). Haumann et al. ran two RCTs to compare the use of methadone to fentanyl in both nociceptive and neuropathic pain domains in OM. Opioid-naïve patients reported significantly decreased average pain with the use of methadone at 3 weeks of treatment (29). In addition, all measures demonstrated noninferiority of methadone to fentanyl, with no difference in side effect profile. Likewise, in a neuropathic pain focused trial, patients reported significantly decreased average pain with the use of methadone at weeks 1 and 3 of treatment (30). Hermann et al. found that use of methadone lowered total narcotic requirements and significantly improved several QOL domains (20).
In terms of OM prevention, there are no well-validated strategies to significantly reduce the development of OM. While modern techniques for radiation therapy have increased capacity for tissue sparing, often a significant dose to the head and neck mucosa is unavoidable due to its proximity to tumor and electively covered regions (31). Another common approach of radioprotection is to mitigate the radiation-induced damage through reduction and/or quenching of reactive-oxygen species. Initial studies of GC4419 have shown a reduction of incidence, duration, and severity of OM (18,32). Results from a phase 3 study, currently underway, are eagerly anticipated. However, this compound requires daily infusions which may limit its use by some patients or physicians.
Reports examining amino acid & amino acid derivatives for OM are either preliminary or have shown no benefit (33-41). Similarly, no recommendation can be made on the use of alternative therapies. Low-level laser therapy (LLLT) has promising limited data which requires additional study; however, LLLT requires technology which is not widely available (42,43). Similarly, the other positive clinical trials reported in Table 1 merit further consideration and research but are not yet widely clinically applicable.
Additional interventions which are not directly related to OM can still benefit patients. The use of NSAIDs was recently shown to be associated with an improvement in overall survival in head and neck cancer patients (70). As such, we recommend that patients take a low-dose or baby aspirin prior to and indefinitely after therapy. Radiation dermatitis is a distinct entity from OM, however it can contribute to the overall pain profile of a patient. Barrier ointments are frequently used to treat radiation dermatitis (71).
There are limitations to this review. We recognize that some of the interventions, namely humidification, saline rinses, and over the counter analgesics, are not based on rigorous studies. Nevertheless, we feel that these recommendations are reasonable based on clinical experience and the relative benign nature of the treatment.
In conclusion, this review highlights a variety of different clinical interventions aimed at alleviating OM in head and neck cancer, favoring a multi-agent approach to this difficult problem. Non-pharmacologic interventions such as humification and saline rinses can be started immediately which may provide symptom relief without potential harm to the patient. Mitigation of OM-related pain can also begin immediately via a tapered increase of Gabapentin. As an adjunct, medicated mouthwashes such as DLA or doxepin can be used for short-term pain relief to aid in eating and drinking. Other strategies to improve pain control during the course of treatment include over the counter analgesics, followed by methadone if OM-related pain continues to be poorly controlled. Future studies include investigating whether other agents for neuropathic pain, such as the selective norepinephrine uptake inhibitors, can be effective in treating OM-related pain. Currently, we are exploring whether the addition of venlafaxine to the gabapentin regimen improves pain control and reduces opioid use in the treatment of head and neck cancer.
We thank Kelsey Bezon PA for her active management of our patients and contributions to the development of our current institutional guidelines.
Provenance and Peer Review: This article was commissioned by the Guest Editor (Dr. Mukund Seshadri) for the series “Head and Neck Cancers – Disease Biology, Diagnostics, Prevention and Management” published in Annals of Translational Medicine. The article has undergone external peer review.
Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-3931
Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-3931). The series “Head and Neck Cancers – Disease Biology, Diagnostics, Prevention and Management” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work is appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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