Abstract
Background/Aim: Accelerated hyperfractionation (AHF) is used in head and neck cancer to improve the local control (LC) rate, but reports of outcomes for early-stage GC are limited. The outcomes of radiotherapy (RT) for stage 1 glottic carcinoma (GC) were retrospectively analyzed, comparing AHF and once-daily fractionation (ODF) using 2.0-2.4 Gy. Patients and Methods: A total of 102 patients with stage 1 GC underwent RT alone between 2007 and 2021, with 43 in the AHF group and 59 in the ODF group. A p-value less than 0.05 was considered to indicate a significant difference. Results: The 5-year LC rate was 98% in the AHF group and 91% in the ODF group (p=0.19). During RT, significantly more patients in the AHF group required opioids due to mucositis than in the ODF group (74% vs. 25%, p<0.001), and the rate of aspiration pneumonia tended to be higher in the AHF group than in the ODF group (7% vs. 0%, p=0.072). Conclusion: There was no difference in the LC rate between AHF and ODF for stage 1 GC. Moreover, the AHF group required opioids at a higher rate and tended to have a higher risk of developing aspiration pneumonia.
Radiotherapy (RT) is the standard treatment for early-stage glottic carcinoma (GC). RT has good outcomes for early-stage GC and preserves the larynx and voice quality, contributing to the maintenance of patients’ quality of life (1). Since lymph node metastasis is extremely rare in early-stage GC, it is important for RT to further improve the local control (LC) rate (2). An important finding in RT for head and neck squamous cell carcinoma (HNSCC) is that a longer overall administration time (OAT) leads to poorer LC of the tumor (3). Consistent with this finding, the previous meta-analyses showed that altered fractionation with shortening of OAT improves LC over standard fractionation delivering 2 Gy once daily, 5 times a week, for a total dose of approximately 66-70 Gy over 7 weeks (4). Accelerated hyperfractionation (AHF) is one of several RT techniques that aim to shorten OAT by irradiating at least twice a day. We previously reported the outcomes of 101 patients with GC and showed that AHF shortened OAT and improved LC rates compared to once-daily fractionation (ODF) using 1.8-2.3 Gy per fraction (5).
However, AHF has the disadvantage of relatively severe acute toxicity, such as mucositis (6, 7). Though several reports have suggested the benefit of AHF for early-stage GC (8, 9), few have described the clinical course of patients exposed to severe acute toxicity. Indeed, the review by Trotti et al. also mentioned that data insufficiency or heterogeneity prohibited analysis of mucositis severity and other associated outcomes, such as opioid use (10). Therefore, a retrospective study of stage 1 GC was designed to compare treatment outcomes, acute toxicity, opioid use, and other adverse events between the AHF group and the ODF group.
Patients and Methods
A total of 106 patients with stage 1 GC who underwent definitive RT in our department between 2007 and 2021 were retrospectively reviewed. Most patients had Eastern Cooperative Oncology Group performance status 0-1. The pre-treatment evaluations included physical examination, laryngoscopy, computed tomography, and magnetic resonance imaging. All patients were diagnosed with SCC. The stage was determined according to the 8th edition of the Union for International Cancer Control. This study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Jichi Medical University (22-068, October 4, 2022).
To ensure that subjects had the opportunity to refuse to participate in the study, the study was posted on the website and at the facilities where the study was conducted (opt-out system) (11). Written, informed consent was obtained from all patients in the pretreatment period regarding the possibility of using their medical records for the study.
Evaluation. The reviewed patients were categorized by fractionation into the AHF and ODF groups for analysis. In the AHF group, most patients were irradiated once on the first day and twice a day starting on the second day, five days a week. The interfraction interval ranged from 4.5-6 hours. In the ODF group, all patients were irradiated once daily, for five days a week. All patients in both groups were treated with 4-MV or 6-MV photons using opposing or oblique bilateral fields. Acute and late adverse events were assessed in each group using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 5.0. In addition, the number of patients who required opioid administration due to acute pharyngeal mucositis was evaluated.
Statistical analyses. The Kaplan-Meier method was used to analyze overall survival (OS), LC, and laryngeal preservation (LP) rates. LP was defined as a condition in which total laryngectomy was not performed and included conditions in which partial laryngectomy was performed. The prognostic relevance of variables was assessed using the log-rank test. The associations between fractionation and clinical characteristics were evaluated using Fisher’s exact test. A p-value less than 0.05 was considered significant. All data were analyzed using R statistical software (version 4.1.3) using Rstudio (RStudio PBC, Boston, MA, USA) with the aid of the libraries survival, survminer, and gtsummary.
Results
Patient characteristics. Of the 106 reviewed patients, four were excluded from the analysis because two were started with once-daily irradiation, which was changed to twice-daily during the course, one was treated with prophylactic neck irradiation, and one was treated with concomitant chemotherapy (docetaxel). The remaining 102 patients, who completed the planned treatment, with the irradiation field including only the glottis, and with RT alone, were analyzed. The median age of the patients was 71 years (range=42-89 years). The median follow-up time was 57.6 months (range=3.0-166.7 months) from the start of RT. There were 43 cases in the AHF group and 59 cases in the ODF group.
Radiotherapy. Most patients in the AHF group received 2 Gy once on the first day only and then twice daily thereafter. The median dose for the AHF group was 62 Gy (range=61.5-65.5 Gy), and the median dose per dose was 1.5 Gy (range=1.4-1.5 Gy). All patients in the ODF group received RT once daily. The median dose for the ODF group was 60 Gy (range=60-66 Gy), and the median dose per dose was 2.4 Gy (range=2.0-2.4). The median OAT was 5 weeks (range=5-6 weeks) in the AHF group and 6 weeks (range=5-8 weeks) in the ODF group. The median irradiation field size was 6.0 cm (range=5.0-7.3 cm) in width and 5.5 (range=4.8-7.0 cm) in length in the AHF group and 6.0 cm (range=5.0-7.0 cm) in width and 5.2 cm (range=4.8-6.5 cm) in length in the ODF group. Table I shows the characteristics of patients and their RT in the AHF and ODF groups.
Patient characteristics.
Overall survival. Of the 102 reviewed patients, five died of other diseases, whereas none died of GC in the follow-up period. The 5-year OS rates in the AHF and ODF groups were 93% and 98%, respectively (p=0.75, Figure 1). In the AHF group, one patient developed local recurrence, underwent total laryngectomy, and was salvaged from the disease. In the ODF group, four patients developed local recurrence, two of whom were salvaged by total laryngectomy and two by partial resection. The 5-year LC rate was 98% in the AHF group and 91% in the ODF group (p=0.19, Figure 2). The 5-year LP rate was 95% in the AHF group and 96% in the ODF group (p=0.90, Figure 3).
Kaplan-Meier plots of overall survival rates. The solid line indicates accelerated hyperfractionation (AHF), and the dashed line indicates once-daily fractionation (ODF).
Kaplan-Meier plots of local control rates. The solid line indicates accelerated hyperfractionation (AHF), and the dashed line indicates once-daily fractionation (ODF).
Kaplan-Meier plots of laryngeal preservation rates. Laryngeal preservation is defined as the condition in which a total laryngectomy is not performed and includes a condition in which a partial laryngectomy is performed. The solid line indicates accelerated hyperfractionation (AHF), and the dashed line indicates once-daily fractionation (ODF).
Adverse events. Table II shows mucositis, opioid use due to mucositis, dermatitis, and other adverse events during RT. The incidence of grade 2-3 radiation mucositis was relatively common, at 82%, and grade 2 radiation dermatitis occurred in 40% of the patients. No patient developed grade ≥3 dermatitis. The AHF group had a significantly higher incidence of grade ≥2 mucositis than the ODF group (93% vs. 75%, p=0.012). Moreover, opioid use for mucositis pain was significantly higher in the AHF group than in the ODF group (74% vs. 25%, p<0.001). In contrast, the AHF group had a significantly lower incidence of grade 2 dermatitis than the ODF group (23% vs. 53%, p=0.004). In terms of acute adverse events other than dermatitis and mucositis, three patients in the AHF group developed aspiration pneumonia, whereas no patient in the ODF group developed aspiration pneumonia. All three patients diagnosed with aspiration pneumonia had fever with a temperature ≥38°C. Two were diagnosed based on chest radiographs and one based on clinical findings suggestive of aspiration. The incidence of aspiration pneumonia tended to be higher in the AHF group (7% vs. 0%, p=0.072). These acute adverse events were appropriately treated and did not remain after the RT period. Regarding late adverse events, one patient in the AHF group developed grade 4 laryngeal stenosis requiring total laryngectomy, whereas none in the ODF group had severe events related to RT.
Adverse events.
Discussion
In the present study, there were two important clinical findings. First, patients in the AHF group had a significantly higher rate of requiring opioids for severe mucositis. Second, the AHF group tended to have a higher risk of developing aspiration pneumonia during RT. Although AHF is known to be more toxic in the acute phase than ODF, few reports have examined the clinical effects of AHF toxicity on patients.
First, the AHF group had a significantly higher rate of requiring opioids for severe mucositis. As shown in a phase 3 trial conducted by the Radiation Therapy Oncology Group, AHF is associated with a high rate of severe acute mucositis (12). Although the severe acute toxicity of AHF is generally well known, there is a reason why AHF is used in HNSCC. One of the important problems in HNSCC is that a prolonged RT results in tumor resistance to treatment. After a certain period of RT, the number of cancer stem cells increases at an accelerated rate. This is called proliferation promotion (or repopulation) and is recognized as a mechanism of resistance to irradiation (13). This phenomenon also has clinical significance since Fowler et al. reported a 3-25% decrease in the LC rate with a 1-week prolongation of OAT (14). Based on these characteristics of tumors, AHF is considered one of the regimens that shorten OAT and improve LC rates. The meta-analyses of early-stage GC showed that AHF and hypofractionation improved LC (15). Both regimens shorten OAT compared to standard fractionation, consistent with the fact that OAT is directly associated with LC rates. Although several other reports have been published suggesting the feasibility of AHF for early-stage GC, few reports have evaluated the actual clinical impact on patients due to mucosal toxicity. In the present study, opioid use was significantly higher in the AHF group. Opioids are widely used drugs in cancer care, including treatment for acute toxicity of RT, and many patients could tolerate opioids. However, as with most drug therapies, opioid use is also associated with several side effects and complications (e.g., constipation, nausea and vomiting, respiratory depression, hyperalgesia, immunosuppression, decreased hormone levels, bladder disorder, etc.). There has been a previous warning that these serious adverse events tended to increase (16). As a result of the accumulation of these findings, it has been reported that opioid prescription rates have been declining worldwide over the last decade (17). Opioids are cornerstones of pain management for many cancer patients and should be used appropriately. Thus, it should be recognized that AHF has a higher rate of opioid use than ODF.
Second, the AHF group tended to have a higher risk of developing aspiration pneumonia. There are two possible reasons why the AHF group tended to develop aspiration pneumonia. First, in RT for head and neck cancer, severe mucositis may be associated with the risk of aspiration pneumonia. Kawashita et al. recently reported that acute grade 3 oral mucositis is a risk factor for developing aspiration pneumonia during RT (18). In Stage 1 GC, the oral cavity is rarely included in the irradiation field, and pharyngeal mucositis seems to be the main acute toxicity. To the best of our knowledge, few reports have examined the severity of pharyngeal mucositis and the risk of aspiration pneumonia, but based on their report, severe mucositis in RT for HNSCC should be considered a risk factor for aspiration pneumonia. Another reason is that taking opioids may also have led to aspiration pneumonia. Historically, opioid use has been associated with respiratory depression, which increases the risk of aspiration (19). The population-based, case-control study conducted by Dublin et al. found that opioid use in the elderly was associated with pneumonia risk (20). The authors also noted that the risk of pneumonia is significantly increased immediately after the start of opioid administration, whereas no increased risk was observed with benzodiazepine use. In another study, Wiese et al. reported that opioid use was associated with an increased risk of pneumococcal pneumonia, which they defined as non-aspiration pneumonia (21). The immunosuppressive effects of certain opioid analgesics have been discussed above, and both reports noted that such effects increase the risk of pneumonia not due to respiratory depression. All three patients who developed aspiration pneumonia in the present study were taking opioids, and combined with exposure to the strong mucosal toxicity of AHF, their risk of developing aspiration pneumonia seemed very high.
In contrast to these adverse effects, the occurrence of grade 2 dermatitis was significantly lower in the AHF group than in the ODF group. Based on a meta-analysis of radiotherapy in HN cancers, limited data show that altered fractionation increases the incidence of grade ≥3 dermatitis more than standard fractionation (22). However, few reports have evaluated the development of grade 2 dermatitis in early-stage GC, and even fewer have compared AHF and ODF. Tamaki et al. analyzed the outcome of AHF for stage 1 GC and reported that grade 2 dermatitis occurred in 29.3% (23). According to several reports related to ODF for early-stage GC using 2-2.25 Gy per fraction, the incidence of grade ≥2 dermatitis was 19-50% (24-26). Although the results of the present study do not differ significantly from these reports, there are no reports comparing AHF with ODF, and it is not clear from the present results that AHF has lower dermal toxicity than ODF. In locoregional advanced HN cancer, however, Narvaez et al. recently compared the outcomes of AHF and ODF for stage 4 HN cancer and reported a significantly lower occurrence of grade ≥2 dermatitis in the AHF group than in the standard fractionation group (27). They used an AHF technique called “concomitant boost” or “late-course AHF”, which irradiates once-daily up to week 3 and twice-daily from week 4. Since the energy and technique were not mentioned in their report, it is unclear whether it was actually the result of fractionation. However, based on the results of Narvaez et al. and the present study, AHF may have low dermal toxicity. Further data analysis is needed.
In the present study, the LC rates of AHF and ODF were comparable. Recently, hypofractionation has emerged as an RT regimen to shorten the OAT of HNSCC by increasing the dose per fraction (>2 Gy) and reducing the total number of fractions. A phase 3 trial was conducted by the Japanese Society of Clinical Oncology Radiotherapy Research Group from 2007 to 2013 (JCOG0701) (28). The trial compared the outcomes of 2.4 Gy per fraction and 2 Gy per fraction for early-stage GC. The results showed that 2.4 Gy per fraction has comparable efficacy and toxicity to 2 Gy per fraction, suggesting that hypofractionation could be a treatment option for early-stage GC. Furthermore, the shortening of OAT by hypofractionation has also been shown to reduce RT costs (29), which is an advantage that AHF cannot provide. In recent years, we have treated almost all cases of early-stage GC with the hypofractionation regimen using 2.4 Gy per fraction. Since recent reports in early-stage GC with RT showed a very good 5-year OS rate of 80.6-97.2% and a 5-year LC rate of 85.0-97.8% (2, 30, 31), it is more important to provide minimally invasive, low-cost treatment for early-stage GC patients. In advanced HNSCC, an updated meta-analysis has shown that the results of RT alone with altered fractionation including AHF are inferior to those of concurrent chemoradiotherapy with standard fractionation (22). However, clinicians occasionally encounter patients with advanced HNSCC who cannot tolerate chemotherapy. The meta-analysis also showed that AHF seems to improve locoregional control over standard fractionation. There is still a considerable need for research on fractionation for patients who cannot be treated with chemotherapy.
The present study has a few limitations. First, it was a retrospective study that included a small number of patients from a single center. Because of the very good outcomes of RT for stage 1 GC, the number of cases would be insufficient to investigate significant differences in OS, LC, and LP rates. In addition, the assignment of AHF and ODF was not random. Before we started to mainly use hypofractionation, AHF was generally applied, and patients were admitted for RT; ODF was used for patients who wanted RT as an outpatient. Second, the observation period was long. RT regimens for GC have changed significantly over the past few years, and the total dose and the dose per fraction used in this study varied widely. In particular, the ODF group included standard fractionation and hypofractionation with various doses.
Conclusion
In conclusion, there was no difference in treatment outcomes between AHF and ODF for stage 1 GC. Acute mucositis was more severe and required opioids at a higher rate in the AHF group, which also tended to have a higher risk of developing aspiration pneumonia during the treatment period.
Acknowledgements
The Authors would like to thank Forte Science Communications (www.forte-science.co.jp) for their English language editing services.
Footnotes
Authors’ Contributions
Endo M worked on the conceptualization, data curation, formal analysis, and drafting of the manuscript. RO, TN, and HN worked on the investigation and data curation. Fukuda Y, Okada K, Ogawa K, Takahashi S, Murakami E, and Shibayama C worked on the formal analysis. Kawahara M and Akahane K reviewed and edited the manuscript. Nishino H, Kanazawa T, Mori H, and Shirai K supervised the study. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors declared no potential conflicts of interest concerning this research, authorship, and/or publication.
- Received June 11, 2023.
- Revision received July 15, 2023.
- Accepted July 17, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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