Management of radiation-induced oral mucositis in head and neck cancer patients: a real-life survey among 25 Italian radiation oncology centers

In 2021, a total of 1554 patients with HNC were treated in the 25 centers participating (median 54, IQR: 20–70). The majority (median 91%) of the treatments had a curative intent (36% of them postoperative), while the others were administered for palliative intent. In most cases (mean 84%), patients underwent intensity-modulated RT (IMRT) technique. One center used a 3D RT technique for all patients, while the remaining 24 centers applied this technique on a median of 17% of patients.

Platinum-based chemotherapy was the most (71% of patients) frequently concurrent treatment, with a median of 43% and 29% of patients treated using a weekly and 3-weekly schedule, respectively. Cetuximab was used in 17 centers to treat a mean of 10% of patients.

The median value of median overall treatment time was 41 days (IQR: 35–45). The mean percentage of patients who interrupted treatment due to RT-related toxicity was 14.5% (data available for 19 centers). A median of 6% (IQR: 3.5–15) of patients required enteral nutrition.

In almost all centers (96%), HNC patients are visited at least once a week during the RT course. Quality of life questionnaires were distributed to the patients in 16% of centers and the collection of pain data on a quantitative scale is provided in 80% of cases. In-treatment toxicity is collected systematically at least once a week (84% of facilities), using the CTCAE scale (38%), the RTOG scale (19%), or both (43%). In the case of concurrent chemotherapy, enteral nutrition is proposed only to patients with significant weight loss during the RT course and to all fragile patients in 48% and 20% of cases, respectively (20% in both situations). All but three centers (which never use parenteral nutrition) used similar criteria to select patients candidates for parenteral nutrition.

The majority of the centers (80%) provide patients with written oral cavity hygiene recommendations. Among 17 centers (data not available for three centers), accurate daily oral cavity cleaning (52%), use of mucosal barrier agents (47%), and pre-treatment dentistry evaluation (35%) were the most frequent recommendations.

About half of the centers (52%) use internal guidelines for RIOM prevention, and 15 centers referred to literature evidence and/or expert recommendations (60% of recommendations provided by the Associazione Italiana di Radioterapia ed Oncologia Clinica — AIRO). Eighteen (72%) centers provided written general recommendations for RIOM prevention. Data from 14 centers (data not available for four centers) accurate oral cavity cleaning (60%), oral mouthwashes with bicarbonate (47%), and pre-treatment dentistry evaluation (40%) were the most frequent pieces of advice.

All but four centers also suggest the use of topic and/or systemic agents to prevent RIOM (Fig. 1).

Six centers produce galenic products (a mixture of different agents) produced by their pharmacy.

The radiation oncologist manages the acute RIOM toxicity in all but one center: medical oncologists and pain specialists also support patient care in 12 (48%) and eight centers, respectively. In 16 (64%) centers, hospitalization for supportive care is allowed. Moreover, different services contribute to taking care of patients during the radiation treatment course: 13 (52%) centers have a nurse dedicated to HNC patients, 18 (72%) centers have a supportive therapy service for pain management, 22 (88%) centers have nutritional consultants, 14 (56%) centers have a speech therapy service for the management of mechanical dysphagia while 18 (72%) have a psycho-oncology service as well.

Fourteen (56%) centers base treatments of RIOM on literature evidence, while internal guidelines are present in 13 centers (44%). Eight centers (32%) did not follow either internal guidelines or literature data. Galenic agents were produced by pharmacies of seven institutions.

The frequency of topic and systemic agents used to treat RIOM is reported in Figs. 2 and 3, respectively.

The frequency of topic and systemic agents used to treat RIOM according to the increasing grade of mucositis (from G1 to G3) is reported in Fig. 4 and Fig. 5, respectively.

To investigate the impact of the “volume of patients” (number of patients treated per year) on the management of RIOM, we classified centers as “low-volume” (< 50 patients/years) and “high-volume” (> 50 patients/years). Twelve and 13 centers gathered low- and high-volume cohorts, respectively. The mean number of patients treated in each group was 21 (IQR: 10–25) and 96 (IQR: 66–136) for low- and high-volume centers, respectively.

Differences in terms of RT technique, concurrent systemic agents, center supportive network, and prevention/treatment strategies between high- and low-volume centers are reported in Table 1.

The mean value of the overall treatment time resulted to be 42 (IQR: 38–45) and 40 (IQR: 30–45) days in low- and high-volume centers, respectively. The percentage of patients who interrupted the RT treatment according to low- and high-volume classification was 16% and 13%, respectively.

Results of MASCC/ISOO, ESMO, and AIRO recommendations on the prevention of RIOM are summarized in Table 2.

Although supported by low-level evidence of literature, pre-treatment dental evaluation, accurate oral hygiene, and sodium bicarbonate were recommended as standard of care for all adult patients candidates to RT for HNC [15‐17]. Among the participating centers, two centers do not provide any recommendations to prevent RIOM. Of the remaining 19 (four centers used internal guidelines and details were not provided), sodium bicarbonate was the most frequently used agent (70% of the centers). Data on the use of saline solution were more controversial and were not considered robust enough by the ESMO panelists. In the present survey, only one center advised patients to use saline solution mouthwashes to prevent RIOM.

Benzydamine and low-energy laser (LEL) were recommended for the prevention of RIOM both in patients treated with RT alone and in those treated with chemoradiation [15]. Benzydamine is a non-steroidal anti-inflammatory drug with anesthetic, analgesic, and antiseptic properties. A randomized multicentric randomized double-blind placebo-controlled trial demonstrated the efficacy of benzydamine for RIOM prevention [23]. A total of 172 subjects (84 treated with benzydamine and 88 with placebo) were enrolled in 16 North American centers. Benzydamine oral rinse (1.5 mg/ml) or placebo was administered before, during RT, and for 2 weeks from the end of treatment. Results showed that benzydamine produced a 26.3% reduction of mucositis in area under curve compared to placebo (p = 0.009). In particular, benzydamine produces a statistically significant benefit at high RT doses (range 25–37.5 Gy, p < 0.001, and range 37.5–50 Gy, p = 0.006) while it was not effective in patients treated with a slight hypofractionated schedule (>2.2 Gy/fraction). Moreover, 33% of patients treated with benzydamine remained free from ulcers compared to 18% of the placebo group (p = 0.037). Subsequently, four more prospective studies confirmed the efficacy of benzydamine in preventing and reducing the severity of oral mucositis in patients treated with RT [24‐27]. Despite literature evidence and recommendations, only three (12%) centers participating in the present survey stated to have benzydamine in their armamentarium to prevent RIOM.

LEL stimulates the biological responses to repair injuries in healthy tissues and is therefore included among the photobiomodulation therapies. A double-blind randomized trial (low-energy He-Ne laser vs placebo-light treatment) has been published in 1999 by Bensadoun et al. [28]. Thirty patients were enrolled and received a daily application with laser/placebo during the whole course of RT. Results showed that the mean grade of mucositis was significantly lower in patients treated with LEL compared to the control group (grade 1.7 ± 0.26 vs 2.1 ± 0.26, respectively, p = 0.01) with the highest differences observed during the last weeks (from 4th to 7th) of treatment. Moreover, the preventive use of the laser also allowed a significant reduction in oral pain (p = 0.025). Subsequent studies confirmed the efficacy and safety of LEL in adult patients with HNC treated with RT [29‐31]. A recent position paper published by the World Association of photobiomoduLation Therapy stated that literature evidence is robust enough for the clinical application of LEL to prevent oral mucositis as well as in other settings of treatment-induced toxicities [32]. The reported data led to the inclusion of LEL in all published recommendations and guidelines. Despite this, only one center involved in the present survey uses LEL in its clinical practice. On the contrary, some other products like mucoadhesive agents, chlorhexidine, and sucralfate are used by 10, 1, and 3 centers respectively although not supported by robust data. Of note, oral mucosa barrier and hyaluronic acid-based agents are routinely used by 43 and 26% of centers, respectively, despite not being mentioned within the above-cited published recommendations.

Results of MASCC/ISOO, ESMO, and AIRO recommendations on the treatment of RIOM are summarized in Table 3.

With regard to strategies aiming to treat RIOM, only topical morphine resulted to be indicated to reduce oral pain. Its use is suggested by either MASCC/ISOO or ESMO recommendations. In a double-blind study, Sarvizadeh et al. randomized 30 patients to treat grade 3 mucositis with topical morphine or a magic mouthwash (magnesium aluminum, hydroxide, lidocaine, and diphenhydramine) for a period of 6 days. On the last day of treatment, mucositis resulted significantly lower in the study group compared to the control cohort (p = 0.045) [33]. Similar results were obtained in a group of 26 patients randomly assigned to receive topical morphine or magic mouthwashes [34]. The duration of severe pain as well as pain intensity resulted lower in patients who received morphine compared to the control group. In the present survey, only one center prescribes topical morphine to treat any grade of mucositis, while other agents like mucoadhesive solution and chlorhexidine are more frequently used.

Hyaluronic acid-based agents are the most frequent products administered by respondents to the survey. A recent meta-analysis showed that it was beneficial for both cutaneous and mucosal radiation-induced side effects (RR: 0.14, 95% CI: 0.04 to 0.45) [35].

The occurrence of RIOM causes pain and dysphagia which produce patients’ weight loss and worsening of overall treatment compliance. This aspect may lead to interruptions of the RT course due to uncontrolled side effects. Worsening of oncological outcomes occurs in patients who did not complete the RT treatment course within the planned time. González Ferreira et al. [7] carried out a literature review and showed that delays in RT could produce an average loss of locoregional control ranging from 1.2% per day to 12–14% per week of interruption [7]. Moreover, it has been estimated that a daily dose increase of about 0.6–0.8 Gy would be required to compensate for each day of overall treatment time prolongation. The median value of the overall treatment time (considering both curative and postoperative treatments) reported by centers participating in the present survey resulted to be quite low (41 days, IQR: 35–45). Based on this finding, two main considerations can be done: (1) despite the wide variety of approaches both in preventing and treating RIOM, their impact on the overall treatment course seems to be low and (2) a network of supportive care services (including management of pain, nutrition, and psychological support as well as hospitalization if required) is provided by the majority of RT facilities and this aspect could have done a positive impact on patients’ compliance.

The definition of “high” and “low” volume centers (in terms of hospital volume and/or professional experience) has not been established yet. Nevertheless, it has been demonstrated that the higher the number of patients treated, the better the oncological outcomes. Eskander et al. performed a systematic review of the literature and showed that high-volume hospitals (HR 0.886, 95% CI 0.820–0.956) achieved better results in terms of patients’ long-term survival [36]. In order to quantify the impact of the centers’ experience on the management of RIOM, we performed a subgroup analysis according to the number of treated patients/year using an arbitrary cut-off of 50 patients. Results showed that in high-volume centers, modern RT (namely IMRT) and standard high-dose chemotherapy (3-weekly CDDP) are more frequently used compared to low-volume centers. Similarly, the overall use of published RIOM-related recommendations and availability of supportive care services are slightly higher in high-volume centers for the majority of the considered parameters. Nevertheless, the mean overall treatment time resulted similar between the two groups as well as the number of patients who required a treatment interruption due to RIOM-related toxicity.

Several criticisms burdened the present study. Centers participating in the present survey represent only 15% of Italian RT facilities [37]. Nevertheless, the spread of geographical distribution among south (28%), center (20%), and northern Italy (52%), as well as the variability of treated patients/year number (centers at high and low volume), ensure that reported results could be considered representative of how RIOM is nowadays managed among Italian centers in the daily clinical practice. Moreover, several other drugs and agents reported in the literature (i.e., anti-oxidant or immunonutrition) have not been considered in the present analysis. Finally, other factors than mucositis (such as patient’s age, comorbidities, treatment characteristics, and dysgeusia) could impact the patient’s compliance with the radiation treatment.