Different studies have been conducted to evaluate the frequency and possible risk factors of concurrent chemoradiotherapy (CTRT) induced oral mucositis. However, the details of the mechanism of oral mucositis development are completely unknown, and its control during CTRT remains challenging . To the best of our knowledge, this is the first longitudinal study to investigate the association between oral mucositis and different risk factors during CTRT. The overall incidence of mucositis in our patients was 96.9% (508/524) and grade 3 and above were seen in 61.3% (321/524) patients. The overall incidence of oral mucositis was similar in both the arms (p value = 0.58); however, that of grade 3–5 was more in the NCRT arm (p value = 0.01). We also found that the rate of hospitalization increased with increasing severity of mucositis and 25.5% (82) patients with grade 3 or more mucositis required indoor care.
In the landmark studies by Bernier et al. and Cooper et al., they noted that cumulative grade 3 or above mucosal adverse events were more in the CCRT arm (cisplatin 100 mg/m2, 3-weekly) in comparison to the radiation alone arm that is 41% vs. 21%; p = 0.001 and 44.5% vs. 21.3%, p < 0.001, respectively [9, 10]. Many studies like these in the literature have described and reported the occurrence of acute oral mucositis with 3-weekly cisplatin, but there only a handful of them studying the same with the weekly cisplatin regime. Tsan et al. compared weekly and 3-weekly cisplatin regimes in a small cohort of 55 patients and found that 22 (91.7%) patients in the former group (n = 24) had grade 3 and above oral mucositis . Noronha et al., in a randomized phase III controlled trial from India, found a similar rate of severe acute oral mucositis (grade 3 or above) in once weekly and once 3-weekly cisplatin regimens (17.3% vs 18.1%, p value = 0.9) . Further, a systematic review of literature and meta-analysis by Szturz et al. showed that patients in the weekly cisplatin arm experienced a higher rate of grade 3 or above acute oral mucositis (75% vs 40%, p = .0202) . Similarly, the prevalence and severity of acute oral mucositis in our study were high (61.3%).
Radiotherapy induced mucositis begins in the 2nd or 3rd week of treatment and reaches its peak at around 5th to 6th week . Similarly, in our study the median time to oral mucositis was 3 weeks and it peaked at 7th week.
Along with the type of chemoradiotherapy, a variety of factors including age, nutritional status, type of malignancy, pretreatment oral condition, oral care during treatment, and pretreatment neutrophil counts are proposed to be associated with the development of acute oral mucositis in patients with HNSCC . In an Indian study by Suresh et al. age > 40 years, ECOG PS > 2, total leucocyte count < 3000/μL, elevated erythrocyte sedimentation rate, serum albumin < 3 gm/dL, a primary tumor of stage 3 or more, comorbid conditions, nutritional status, oral hygiene, and tobacco use were taken as the risk factors. They used these risk factors to calculate a score. The higher the score, the more is the chance of developing acute oral mucositis . Out of all risk factors listed in our study, we found that the addition of nimotuzumab was significantly linked with the development of grade 3 and above acute oral mucositis (p value = 0.01).
In a systematic review of literature, which included 33 studies to see the incidence, severity, and outcomes of oral mucositis, oral pain, weight loss, dysphagia, dehydration, and use of analgesics/opioid were reported as the important symptoms of oral mucositis . Out of these, weight loss was the most common symptom seen in 10/33 studies. Notably, the rates of hospitalization due to acute oral mucositis were higher in patients in the chemoradiotherapy group than those who received radiotherapy alone (6% vs. 2% group) . One needs to pay attention that severe oral mucositis is significantly associated with more total parenteral nutrition support and parenteral narcotic therapy. Also, there is a higher chance of infection which may further increase the duration of hospital stay and cost of inpatient supportive care . In our patients, 21.8% and 25.5% patients with any grade and grade 3 and above oral mucositis required inpatient care, which was high but the actual number of patients who were admitted because of oral mucositis per se was not captured and this remains one of the limitations of our study.
It should be noted that oral mucositis can lead to treatment delay and treatment (chemotherapy and radiotherapy dose) modification. However, in both the CCRT and NCRT arms of our study, no difference in delay of chemotherapy and radiotherapy delivery was seen and cumulative doses of chemotherapy and radiotherapy were similar as well. In various studies, planned or unplanned treatment modifications have been reported frequently, but the extent or link to mucositis is rarely noted by the authors .
To our knowledge, this study represents the largest and most comprehensive report of acute oral mucositis and its outcomes in patients with LA-HNSCC treated with radiotherapy and concurrent chemotherapy. Overall, the current data indicates that patients continue to require supportive care for a range of treatment-related toxicities, including acute oral mucositis, particularly beginning in the first 3–4 weeks, until the final weeks of treatment with symptoms improving thereafter.