ORIGINAL PAPER
Nagoya J. Med. Sci. 83. 811–825, 2021
doi:10.18999/nagjms.83.4.811

Poor local control of ulcerative T1 glottic cancer treated with
2.25-Gy per fraction radiotherapy
Yumi Oie1,9, Yoshiyuki Itoh1,11, Mariko Kawamura1, Yuuki Takase1,2,
Takayuki Murao3, Shunichi Ishihara4, Yoshihito Nomoto5,
Naoki Hirasawa6, Akiko Asano7, Kouji Yamakawa8, Junji Ito1,10,
Fumie Kinoshita12 and Shinji Naganawa1
1
Department of Radiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Department of Radiation Oncology, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Japan3
Department of Radiation Oncology, Ichinomiya Municipal Hospital, Ichinomiya, Japan
4
Department of Radiology, Toyohashi Municipal Hospital, Toyohashi, Japan
5
Department of Radiology, Mie University Graduate School of Medicine, Tsu, Japan
6
Department of Radiology, Komaki City Hospital, Komaki, Japan
7
Department of Radiation Oncology, Gifu Prefectural Tajimi Hospital, Tajimi, Japan
8
Department of Radiology, Tosei General Hospital, Seto, Japan
9
Department of Radiology, Chubu Rosai Hospital, Nagoya, Japan10
Department of Radiation Oncology, Nakatsugawa Municipal General Hospital, Nakatsugawa, Japan
11
Department of Radiology, Nishio Municipal Hospital, Nishio, Japan
12
Statistical Analysis Section, Data Coordinating Center, Department of Advanced Medicine,
Nagoya University Hospital, Nagoya, Japan
2

ABSTRACTThe Tokai Study Group for Therapeutic Radiology and Oncology (TOSTRO) started managing T1 glottic
cancer using 2.25 Gy/fraction radiotherapy in 2011. The aim was to evaluate the local control (LC) rate
and toxicity with 2.25-Gy radiotherapy in clinical practice and identify prognostic factors.The eligibility
criteria were T1 glottic squamous cell carcinoma patients with age ≥20 years, treated with 2.25 Gy/fraction
without chemotherapy between 2011 and 2017. LC rates were evaluated based on age, performance status,
sex, T-category, tumor type (ulcerative or non-ulcerative), presence of anterior commissure invasion, tumor
size, X-ray beam energy, and overall treatment time. Acute and late adverse events were evaluated using
CTCAE version 4.0. A total of 202 patients were enrolled. The median follow-up period was 34.2 months.
The 2- and 4-year LC rates were 93.8% and 93.1%, respectively. There was a significant difference in the
LC rate between non-ulcerative type and ulcerative type (95.2% vs. 74.1% at 2 years, 94.4% vs. 74.1%
at 4 years; p = 0.01). On univariate analysis, only tumor type was significantly correlated with a poor
LC rate (hazard ratio 4.3; 95% confidence interval 1.2–15.4; p = 0.03). Acute grade 3 adverse eventsoccurred in 17 patients. However, no late adverse events of grade 3 or higher have occurred to date. T1glottic cancer treatment outcomes using hypofractionated radiotherapy with 2.25 Gy/fraction in clinicalpractice were comparable to previously reported results. However, ulcerative type tumor was associatedwith a poor LC rate.
Keywords: T1 glottic cancer, hypofractionated radiotherapy, 2.25 Gy, ulcerative tumor type

Received: March 9, 2021; accepted: May 7, 2021
Corresponding Author: Yumi Oie, MD, PhD
Depatrment of Radiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku,
Nagoya 466-8550, Japan
Tel: +81-52-744-2328, Fax: +81-52-744-2335, E-mail: yumi-oie@med.nagoya-u.ac.jp
811

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Yumi Oie et al

Abbreviations:
LC: local control
TOSTRO: Tokai Study Group for Therapeutic Radiology and Oncology
ACE: anterior commissure extension
PS: performance status
CR: complete clinical response
HR: hazard ratio
CI: confidence intervalThis is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
License. To view the details of this license, please visit (http://creativecommons.org/licenses/by-nc-nd/4.0/).

INTRODUCTION
The goal of treatment for early glottic cancer is complete cure with laryngeal preservation.
Therefore, definitive radiotherapy and endoscopic laser excision are generally selected as atreatment plan.
The 5-year local control (LC) rates for T1 glottic cancer treated with conventional radiotherapy
have been reported to range from 73.6% to 94%.1-12 At 10 institutions in the Tokai District,Japan, the 5-year LC rates for T1 glottic cancer treated with conventional radiotherapy alone
between 2000 and 2005 were reported to be 86.5% for T1a cancer and 83.6% for T1b cancer.8
These results are comparable to other reports.1,7,9-11
In 2006, a single-institution, phase III trial performed in Japan reported that hypofractionated radiotherapy using 2.25 Gy per fraction yielded a higher LC rate than did conventional
radiotherapy using 2 Gy per fraction in patients with T1 glottic cancer.9 Moreover, National
Comprehensive Cancer Network clinical practice guidelines recommend either conventionallyfractionated radiotherapy (66 Gy/33 fractions) or hypofractionated radiotherapy (63 Gy/28 fr) forthe management of T1 glottic cancer.13
We, the Tokai Study Group for Therapeutic Radiology and Oncology (TOSTRO), started using
definitive radiotherapy for T1 glottic cancer with 2.25 Gy per fraction in 2011 in our clinicalpractice, and the first report of our initial 5-year experience was published in 2016.14
The aim of this study was to evaluate the clinical outcomes and toxicity rates of T1 glottic
cancer treated with 2.25 Gy per fraction in our clinical practice and identify the prognostic
factors.

MATERIALS AND METHODSThis study was approved by the Institutional Review Board of the Nagoya University Hospital(research representative facility approval: 2013-0074) and all participating institutions. Afterapproval of the ethics committee of each participating institution, information about this study
was released to the public.
Patients’ characteristics
Patients treated in the TOSTRO group from January 2011 to December 2017 were collected.
As the TOSTRO group, we decided to start using definitive radiotherapy for T1 glottic cancer
with 2.25 Gy per fraction in 2011. Between January 2011 and November 2013, the informationin Supplemental Table 114 was acquired from medical records retrospectively. However, after
December 2013, when the ethics committees of all participating institutions approved the collection of the information shown in Supplemental Table 1, all cases were enrolled at the start813
Ulcerative T1 GC treated with 2.25Gy RT

Fig. 1 Representative pictures of the following tumor types
Fig. 1A: Exophytic type.
Fig. 1B: Superficial type.
Fig. 1C: Ulcerative type, invasive lesion with erosion or ulcer on surface.

of treatment, and the information was updated annually. Eligibility criteria were age ≥20 years,
T1 glottic squamous cell carcinoma patients, no chemotherapy, and treated with radiotherapy at
2.25 Gy per fraction for a total dose of approximately 63 Gy. The Eastern Cooperative Oncology
Group scale was used to evaluate performance status (PS). T-category was determined according
to the Union for International Cancer Control TNM classification 7th edition. The presence ofanterior commissure extension (ACE) was assessed by endoscopy. Tumor type was classified
by several radiation oncologists into three types, exophytic type (tumors with exophytic growth
beyond the normal mucosal surface); superficial type (tumors with slight changes in mucosal
surface); ulcerative type (ulcerative tumors that invades below the normal mucosal surface).
Representative pictures of the three tumor types are shown in Figure 1. Localized tumor size
was defined as tumor with a length <2/3 of the vocal cord, and extended tumor size was definedas tumor with a length ≥ 2/3 of the vocal cord.

Radiotherapy
All patients were placed in the supine position, immobilized with a thermoplastic mask, andtreated based on three-dimensional treatment planning. The clinical target volume included the
vocal cords, and the planning target volume included the clinical target volume with a sufficientmargin of 5–10 mm to cover laryngeal motion (field size, approximately 5 × 5 cm). The planningtarget volume needed to be covered by at least 95% of the prescribed dose. A linear accelerator
was used to deliver 4- or 6-MV photon beams. A standard radiation schedule was administereddaily (2.25 Gy per day for a total dose of 63 Gy), five days a week. The majority of treatments
were delivered using laterally opposed fields, and weighted beams and wedges were used as
appropriate to improve dose homogeneity.

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Yumi Oie et al

Outcomes
The primary response and the LC rate were diagnosed by endoscopy, and regional lymph
node metastases and distant metastases were diagnosed by computed tomography and/or magnetic
resonance imaging. The LC rate and overall survival were updated annually. The acute andlate adverse events were evaluated using the Common Terminology Criteria for Adverse Events
version 4.0. Specifically, dermatitis, laryngeal mucositis, laryngeal edema, laryngeal hemorrhage,pharyngolaryngeal pain, laryngeal necrosis, and hoarseness were evaluated.
Statistical analysis
The radiotherapy start date was the basis for determining the duration of observations. LC rates
were estimated using the Kaplan-Meier method, and the log-rank test was used to assess differences in LC rates based on the following prognostic factors: age, PS, sex, T-category, tumor type,
ACE, tumor size, X-ray beam energy, and overall treatment time. A Cox proportional hazards
model was used for univariate analysis to determine the significance of potential risk factors
for LC. Hazard ratios (HRs), 95% confidence intervals (95% CIs), and p-values were generated
from a univariate Cox proportional hazards model. Results were considered significant at thelevel of p < 0.05, and tests were based on a two-sided significance level. Statistical computations
were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan).

RESULTS
Included in this study were 202 patients from 11 institutions participating in TOSTRO. Of the
202 patients, 49 were treated between January 2011 and November 2013, and 153 were treatedbetween December 2013 and December 2017. The patients’ characteristics are summarized inTable 1. The median follow-up period was 34.2 (range 2.4–79.1) months. The total dose range
was 56.25–67.5 Gy, and 189 patients (93.6%) received a radiotherapy dose of 63 Gy. The median
duration of radiotherapy was 41 (range 33–53) days. Disease outcomes are summarized in Table
2. A complete clinical response (CR) as the primary response to treatment was observed in
201 patients (99.5%). One patient with partial response as the primary response was followed
without additional treatment and is alive without evidence of recurrence. Fourteen patients (7.0%)
showed local glottic recurrence during follow-up. The median time to local glottic recurrence was
14.5 (5–55) months. Eleven of these 14 patients who received salvage surgery are disease-free
and alive. Three patients with recurrence did not undergo surgical salvage because of patient
non-consent, old age, and complications, respectively. Twelve of the patients who showed norecurrence died of another comorbidity. There were no cases of lymph node recurrence or distantmetastasis.

Table 1

Patients’ characteristics (n = 202)

Characteristic
Age (years), median (range)Value
72 (44–92)

Sex, n (%)
Male

184 (91.1)

Female18 (8.9)

Performance status, n (%)
0131 (64.9)

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Ulcerative T1 GC treated with 2.25Gy RT

1

63 (31.2)

2

7 (3.5)3

1 (0.5)T-category, n (%)
T1a

146 (72.3)

T1b

56 (27.7)

Anterior commissure extension, n (%)
No

146 (72.3)

Yes

56 (27.7)

Tumor type, n (%)
Exophytic

71 (35.1)

Superficial

119 (58.9)

Ulcerative

12 (5.9)

Tumor size, n (%)
Localized

124 (61.4)

Extended78 (38.6)

Energy, n (%)
4 MV

137 (67.8)

6 MV

65(32.2)

Dose/fractions, n (%)
56.25 Gy/25 fr

5 (2.5)58.50 Gy/26 fr

1 (0.5)60.75 Gy/27 fr

1 (0.5)63.00 Gy/28 fr

189 (93.6)

67.50 Gy/30 fr

6 (3.0)

Table 2Disease outcomes (n = 202)

Outcomen (%)

Response
Complete

201 (99.5)

Partial

1 (0.5)

Regional lymph node metastasis
No

201 (99.5)

Yes

1 (0.5)Distant metastasis
No

202 (100)Yes

0 (0.0)StatusAlive

187 (92.6)

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Yumi Oie et al

Dead

15 (7.4)

Local glottic recurrenceNo

188 (93.1)

Yes

14 (6.9)

The 2- and 4-year LC rates for all patients were 93.8% and 93.1%, respectively (Figure2A). The log-rank test results for prognostic factors affecting the LC rate are shown in Table
3. There was a sigificant difference in the LC rate between non-ulcerative type and ulcerative
type (95.2% vs. 74.1% at 2 years, 94.4% vs. 74.1% at 4 years; p = 0.01) (Figure 2B). On
univariate analysis, only tumor type correlated significantly with a poor LC rate (HR 4.3; 95%
CI 1.2–15.4; p = 0.03). Acute grade 3 adverse events were observed in 17 patients (8.4%).
Acute grade 3 dermatitis occurred in 13 patients (6.4%), acute grade 3 mucositis occurred in six
patients (3.0%), and acute grade 3 pain occurred in one patient (0.5%). No late adverse eventsof grade 3 or higher have occurred to date.

Fig. 2 Kaplan-Meier curves of local control (LC) rates
Fig. 2A: Kaplan-Meier curve of the LC rate for all patients.
Fig. 2B: Kaplan-Meier curves of LC rates for non-ulcerative type and ulcerative type.

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Ulcerative T1 GC treated with 2.25Gy RT

Table 3

Variable

Prognostic factors and the LC rate

2-year LC rate

4-year LC rate

<72

94.8%

94.8%

≥72

93.2%

91.7%

0, 1

93.6%

92.8%

≥2

100%

100%

Male

93.3%

92.5%

Female

100%

100%

T1a

93.6%

92.6%

T1b

94.5%

94.5%

Ulcerative

74.1%

74.1%

Non-ulcerative

95.2%

94.4%

Yes

94.6%

94.6%

No

93.7%

92.7%

Localized

94.5%

93.3%

Extended

92.8%

92.8%

4

93.5%

92.4%

6

94.8%

94.8%

<44

95.4%

94.6%

≥44

85.2%

85.2%

P value (log-rank)

Age, years
0.13

Performance status
0.41

Sex
0.28

T-category
0.79

Tumor type
0.01

Anterior commissure extension
0.71

Tumor size
0.75

X-ray beam energy, MV
0.85

Overall treatment time, days
0.12

LC: local control

DISCUSSION
Several studies have reported that the risk factors for radiation failure in early glottic cancers
include sex, pretreatment hemoglobin level, tobacco use, T-category, tumor size, and ACE.15-17
However, the present analysis did not show significant differences in sex, tumor size, or ACE.
Lucas et al published a systematic review and meta-analysis to assess the benefit of alteredfractionation radiotherapy in early-stage glottic cancer and reported that the benefit persisted
for ACE in patients with T1 glottic cancer.18 In addition, Tong et al reported that the negative
impact of ACE could be diminished by delivering a higher tumor biological effective dose with

818
Yumi Oie et ala fraction size > 2 Gy.19 The present result showing no significant difference in the LC rate for
ACE appears consistent with their report.
The main finding of the present study is that the ulcerative type of tumor was associatedwith a poor LC rate, which, to the best of the authors’ knowledge, has never been reported
previously. Although patients treated before December 2013 were collected retrospectively, 153
patients, accounting for approximately 3/4 of all patients, were treated from December 2013,
meaning that 3/4 of all patients’ tumor types were registered at the start of treatment. In addition,a subset analysis of 153 patients treated from December 2013 was performed and is shown in
Supplementary Tables 2 to 4. In brief, the characteristics and disease outcomes were similar, andthe LC rate of non-ulcerative type was significantly better than that of ulcerative type (94.3% vs.
64.8% at 2 years, 93.1% vs. 64.8% at 4 years; p < 0.01). Furthermore, on univariate analysis,
ulcerative tumor type correlated significantly with a poor LC rate (HR 6.2; 95% CI 1.6–23.4; p< 0.01). Thus, selection bias appears to have been minimal.
Wu et al compared the surface morphology of glottic cancer with the histopathologicalcharacteristics.20 They classified surface morphology as “pushing carcinoma” and “infiltrating
carcinoma”, where the morphology of infiltrating carcinoma was close to that of ulcerative
type in the present analysis. They reported that infiltrating carcinoma, ulcerative type in thepresent classification, presented as multiple tumor nests that were often surrounded by fibrosis
histopathologically. Interestingly, some authors have reported that the histological characteristics
of recurrent glottic cancer after radiotherapy and primary glottic cancer are different, and mostrecurrent cancers present with multiple tumor nests.21,22 The histopathology of ulcerative tumor
types may be related to radiotherapy resistance, which may result in a low LC rate. Therefore,
further investigation using surface morphology is desirable.
Although there have been several reports of randomized controlled trials with promising results
using hypofractionation in the treatment of glottic cancer,9,11 questions remain with respect toclinical practice. Patients with a poor PS or who are very old, and/or those with a comorbidity
are often excluded from clinical trials, which may lead to different results in “real-world” practice.
In the present study, there were 35 patients (17.3%) older than 80 years of age, 8 (4.0%) withPS ≥2, and 28 patients (13.9%) with a history of other malignant diseases, but they tolerated thehypofractionated treatment, and the LC rate and the adverse effects were comparable to the resultsfrom previous studies (Table 4,3,4,8-11 Supplementary Tables 5 and 64,11,23,24). Because the present
study was based on clinical practice, the total dose could be increased or decreased from 63 Gy
at the discretion of the clinician, considering patient age, PS, or adverse effects, and 7 patientswere treated with total doses less than 63 Gy. Five patients treated with 25 fractions came fromthe same institution. Of the 7 patients who were treated with less than 63 Gy, all achieved CR
as the primary response. One had local relapse at follow-up, but it was not ulcerative type. Six
patients treated with more than 63 Gy have achieved CR to date; none had ulcerative type, andonly one had acute grade 3 dermatitis. There were no grade 2 or greater late adverse events todate among patients treated with more than 63 Gy.
There are several limitations to the present study. First, the number of patients with ulcerative
type was very small. Because there have been very few reports classifying tumors morphologically, the ulcerative type may be very rare. A previous study by Yamazaki et al also reported avery small number of cases of ulcerative type (2/180).9 Therefore, additional multicenter studies
are warranted. Second, the median follow-up period was relatively short to evaluate LC rates
and late toxicities. However, the median time to recurrence in reported series was mostly within
30 months, and the present report was similar.2,3,6,10-12,17,23 Late adverse events were no worse
than those reported for comparable median follow-up periods.23 Third, the pathological resultsof patients with local recurrence and salvage surgery were not investigated.

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Ulcerative T1 GC treated with 2.25Gy RT

Table 4Five-year LC rates from studies using hypofractionated radiotherapy with 2.25 Gy
for T1 glottic cancer

Author

Dose/fractions

Fractionsize (Gy)Current study(TOSTRO Study)

63 Gy/28 fr (6% of series 2.25
included other schedules)

Hirasawa et al8(TOSTRO Study)

60–74 Gy/30–37 fr(9% of series included
other schedules)

2

Yamazaki et al9(RCT)56.25–63 Gy/25–28 fr,
60–66 Gy/30–33 fr

2.25,
2

Moon et al11(RCT)

63 Gy/28 fr,
66 Gy/33 fr

2.25,
2

Kim et al3

67.5 Gy/30 fr,
70 Gy/35 fr

2.25,
2

Chera et al1063 Gy/28 fr(39% of series included
other schedules)

2.25

Salas et al4

63.8–63 Gy/22–29 fr,
70 Gy/35 fr

2.2–2.25,
2

LC rate,T1a

LC rate,T1b

LC rate,all T1

92.6%(4-yearLC rate)94.5%(4-yearLC rate)93.1%(4-yearLC rate)

86.5%

83.8%

92%,
77%
93.0%,
76.7%

83.2%,
87.6%

90.1%,
80.3%
95%,
83%

94%

93%

83.7%,
86.2%

RCT: randomized, controlled trial
LC: local control

CONCLUSIONTOSTRO’s LC rates for T1 glottic cancer treated using 2.25 Gy per fraction in practice were
better than those using 2 Gy per fraction from 2000 to 2005.8 However, the ulcerative type oftumor was associated with a poor LC rate; thus, further investigation of this tumor subtype iswarranted.

CONFLICT OF INTERESTNone.

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Appendix.
Supplementary Table 1

Questionnaire summary14

Questionnaire items
1. Age, sex, performance status (Eastern Cooperative Oncology Group)
2. T- category: T1a/T1b
3. Tumor type: exophytic/superficial/ulcerative
4. Anterior commissure extension
5. Tumor size: localized (<2/3 of the vocal cord) / extended (≥2/3 of the vocal cord)
6. Radiation starting date, ending date, break period
7. X-ray beam energy, dose fractionation, total radiation dose
8. Primary response, local control
9. Regional lymph node metastases, distal metastases
10. Life and death, date last verified
11. Acute and late adverse events (Common Terminology Criteria for Adverse Events version 4.0)

Supplementary Table 2 Patients’ characteristics (n = 153)

Characteristic

Value

Age (years), median (range)

72 (44–92)

Sex, n (%)
Male137 (89.5)

Female16 (10.5)

Performance status, n (%)
0104 (68.0)

1

45 (29.4)

23 (2.0)3

1 (0.7)

T-category, n (%)
T1a

107 (69.9)

T1b

46 (30.1)

Anterior commissure extension, n (%)
No

106 (69.3)

Yes

47 (30.7)

Tumor type, n (%)
Exophytic

88 (57.5)

Superficial

56 (36.6)

Ulcerative

9 (5.9)Tumor size, n (%)
Localized

95 (62.1)

822
Yumi Oie et al

Extended58 (37.9)

Energy, n (%)
4 MV

106 (69.3)

6 MV

47 (30.7)

Dose/fractions, n (%)
56.25 Gy/25 fr

3 (2.0)58.50 Gy/26 fr

1 (0.7)60.75 Gy/27 fr

1 (0.7)63.00 Gy/28 fr

142 (92.8)

67.50 Gy/30 fr

6 (3.9)Supplementary Table 3 Disease outcomes (n = 153)

Outcomen (%)

Response
Complete

153 (100)

Partial0 (0)Regional lymph node metastasis
No

153 (100)

Yes

0 (0)

Distant metastasis
No

153 (100)

Yes

0 (0)

StatusAlive

146 (95.4)

Dead

7 (4.6)

Local glottic recurrenceNo

142 (92.8)

Yes

11 (7.2)

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Ulcerative T1 GC treated with 2.25Gy RT

Supplementary Table 4 Prognostic factors and the LC rate (n = 153)

Variable

2-year LC rate

4-year LC rate

<72

94.4%

94.4%

≥72

91.0%

88.7%

0, 1

92.2%

91.0%

≥2

100%

100%

Male

91.6%

90.4%

Female

100%

100%

T1a

92.1%

90.5%

T1b

93.2%

93.2%

Ulcerative

64.8%

64.8%

Non-ulcerative

94.3%

93.1%

Yes

93.5%

93.5%

No

92.1%

90.6%

Localized

93.9%

92.1%

Extended

90.0%

90%

4

91.3%

89.8%

6

95.6%

95.6%

<44

93.6%

92.3%

≥44

86.5%

86.5%

P value (log-rank)

Age, years
0.15

Performance status
0.54

Sex
0.27

T-category
0.88

Tumor type
< 0.01

Anterior commissure extension
0.87

Tumor size
0.62

X-ray beam energy, MV
0.43

Overall treatment time, days

LC: local control

0.34

824
Yumi Oie et al

Supplementary Table 5

Grade ≥3 acute AEs from studies using hypofractionated radiotherapy

Acute AE
Current study
N=202

Moon et al11
(RCT)
CONV,
N=82
HYPO (2.25 Gy),
N=74
Salas et al4
CONV,
N=71
HYPO
(2.2–2.25 Gy),
N=67
Vassikis et al23
HYPO (2.3 Gy),
N=47

CONV, N (%)

HYPO, N (%)

Grade 3

Grade 3

Grade 4

Grade 4

Dermatitis

13 (6.4)0 (0)Laryngeal mucositis

6 (3.0)0 (0)Laryngeal edema

0 (0)

0 (0)

Laryngeal hemorrhage

0 (0)

0 (0)

Pharyngolaryngeal pain

1 (0.5)

0 (0)

0 (0)

0 (0)

Skin

0 (0)

0 (0)

Mucosa

0 (0)

0 (0)

0 (0)

0 (0)

Larynx

0 (0)

0 (0)

0 (0)

0 (0)

Skin

1 (1.4)0 (0)4 (6.0)0 (0)Mucosa5 (7.0)0 (0)4 (6.0)0 (0)Larynx1 (1.4)0 (0)1 (1.5)0 (0)4 (8.5)0 (0)Whispered speech
Throat pain or referred
ear pain requiring narcotic
Confluent fibrinous exudate
Marked arytenoid edema

Kodaira et al24
(RCT)
CONV,
N=177
HYPO (2.4 Gy),
N=183

Skin

18 (10.2)

0 (0)7 (3.8)0 (0)Mucosa

7 (4)

0 (0)

10 (5.5)

0 (0)

Pain

0 (0)

0 (0)

0 (0)

0 (0)

Dysphagia

0 (0)

0 (0)

0 (0)

0 (0)

Voice Change

2 (1.1)0 (0)4 (2.2)0 (0)AE: adverse event
CONV: conventional radiotherapy
HYPO: hypofractionated radiotherapy
RCT: randomized, controlled study

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Ulcerative T1 GC treated with 2.25Gy RT

Supplementary Table 6

Grade ≥3 late AEs from studies using hypofractionated radiotherapy

Late AE
Current study
N=202

Moon et al11
(RCT)
CONV,
N=82
HYPO (2.25 Gy),
N=74

Kodaira et al24
(RCT)
CONV,
N=182
HYPO (2.4 Gy),
N=184

HYPO, N (%)

Grade 3

Grade 3

Grade 4

Grade 4

Hoarseness

0 (0)

0 (0)

Laryngeal necrosis

0 (0)

0 (0)

Laryngeal edema

0 (0)

0 (0)

Laryngeal hemorrhage

0 (0)

0 (0)

Pharyngolaryngeal pain

0 (0)

0 (0)

0 (0)

0 (0)

Skin

0 (0)

0 (0)

Mucosa

0 (0)

0 (0)

0 (0)

0 (0)

Larynx

0 (0)

0 (0)

0 (0)

0 (0)

1 (1.4)0 (0)1 (1.5)

0 (0)

0 (0)

0 (0)

0 (0)

0 (0)

Salas et al4
Larynx
CONV,
N=71
HYPO (2.2–2.25 Gy),
N=67
Vassikis et al23
HYPO (2.3 Gy),
N=47

CONV, N (%)

Laryngeal edema
Chondritis
Laryngeal edema

0 (0)

0 (0)

Pharyngolaryngeal pain

1 (0.5)0 (0)1 (0.5)0 (0)Voice change

0 (0)

0 (0)

0 (0)

0 (0)

Soft tissue necrosis

0 (0)1 (0.6)

1 (0.6)

1 (0.6)

Induration

0 (0

–

0 (0)

0 (0)

AE: adverse event
CONV: conventional radiotherapy
HYPO: hypofractionated radiotherapy
RCT: randomized, controlled study