ORIGINAL PAPER
Nagoya J. Med. Sci. 85. 241–254, 2023
doi:10.18999/nagjms.85.2.241

Optimized radiotherapy treatment strategy forearly glottic carcinoma
Tamami Ono1, Yoshiyuki Itoh2, Shunichi Ishihara1, Mariko Kawamura1,
Yumi Oie1, Yuuki Takase1, Masayuki Okumura1, Hidekazu Oyoshi3,
Naoya Nagai1 and Shinji Naganawa1
Department of Radiology, Nagoya University Graduate School of Medicine, Nagoya, Japan2
Department of Radiology, Anjyo Kosei Hospital, Anjyo, Japan
Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Japan1
3

ABSTRACTThe local control rates of T1 bulky and T2 glottic carcinoma treated via radiation therapy alone areunsatisfactory; thus, we aimed to evaluate the efficacy and safety of our treatment protocol for early glottic
carcinoma. Patients with early glottic squamous cell carcinoma treated via radiation therapy from January
2007 to November 2019 were reviewed. Patients were treated with: 63–67.5 Gy/28–30 fractions of radiation
therapy alone for T1 non-bulky; concurrent chemoradiotherapy with S-1 and 60 Gy/30 fractions for T1
bulky and T2 favorable; and concurrent chemoradiotherapy with high-dose cisplatin and 66–70 Gy/33–35
fractions for T2 unfavorable glottic carcinoma. Local failure rates were estimated using the cumulative
incidence function, overall and disease specific survival rates were estimated using Kaplan-Meier analysis,
and adverse events were evaluated. Eighty patients were analyzed; the median age was 69.5 (range, 26–90)
years, the median follow-up time for survivors was 40.1 (range, 1.9–128.4) months, and the 3-year local
failure, disease specific survival, and overall survival rates were 5.8%, 98.3%, and 94.4%, respectively. In
T1 bulky and T2 cases, the local failure rate was significantly lower in the concurrent chemoradiotherapy
than in the radiation therapy alone group. Grade 3 acute dermatitis and mucositis were noted in nineand four patients, respectively. There were no acute adverse events of Grade 4 or higher, or late adverse
events of Grade 2 or higher. The treatment protocol was effective and well-tolerated; thus, the efficacy of
concurrent chemoradiotherapy was suggested in T1 bulky and T2 cases.
Keywords: early glottic carcinoma, radiation therapy, chemoradiotherapy
Abbreviations:
GC: glottic carcinoma
RT: radiation therapy
LC: local control
CCRT: concurrent chemoradiotherapy
CDDP: cisplatin
LF: local failure
OS: overall survival
DSS: disease specific survival
AEs: adverse events

Received: March 30, 2022; accepted: May 27, 2022
Corresponding Author: Tamami Ono, MD
Department 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: tamami.ono@med.nagoya-u.ac.jp241

Tamami Ono et al

This 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 goals of treatment for early glottic carcinoma (GC) are tumor eradication and preservationof larynx functions, including speaking and swallowing. The recommended treatment strategy
for early GC is partial laryngectomy, including endoscopic and open resection, and definitive
radiation therapy (RT); generally, the efficacies of resection and RT are comparable.1,2 Previous
studies have shown that the local control (LC) rate of early stage GC varies widely, while thatof RT alone for T2 GC is unsatisfactory, ranging from 65% to 80%.3-5 Reddy et al6 reported thattumor size is an important prognostic factor for the LC rate in T1 GC, and that the LC rate islower in T1 bulky tumors. Several studies have subclassified T2 GC into T2a and T2b, reporting
lower LC rates in T2b.7-9 In this study, we subclassified T1 and T2 GCs into T1 nonbulky, T1bulky, T2 favorable, and T2 unfavorable, following previous reports.
We first designed a concurrent chemoradiotherapy (CCRT) protocol using S-1 (tegafur, gimeracil, and oteracil) for T1 bulky and T2 favorable GCs with the aim of improving the LC rate;
the efficacy and safety of this protocol was demonstrated in our previous phase I/II study.10,11
S-1 is an orally administered antineoplastic agent shown to be effective against a variety of solid
tumors including head and neck cancer. Due to the inadequate results observed in our previous
experiments regarding CCRT with low-dose cisplatin (CDDP)/5-fluorouracil for T2 GC,12,13 wewere concerned that CCRT with S-1 may be inadequate in patients with T2 unfavorable GC;
thus, CCRT with high-dose CDDP was selected. Furthermore, we changed the RT dose from
2.0 Gy/fraction to 2.25 Gy/fraction, thereby reducing the number of fractions from 35 to 28
for patients with T1 nonbulky GC. This was based on reports, from Japan as well as overseas,that the LC rates for T1 tumors were higher than 90% when using 2.25 Gy/fraction.14,15 Our
research group also reported comparable efficacy and acceptable safety of the 2.25 Gy/fraction
method, compared with the conventional 2.0 Gy/fraction method, in a multicenter survey of theTokai Study Group for Therapeutic Radiology and Oncology conducted in Japan from 2011 to2015.16 A recent meta-analysis by Benson et al,17 including several randomized controlled trials,
also reported that hypofractionation for early GC is effective for improving LC rates.
The overall results of our optimized treatment strategy were reported in 2017, demonstratingthat our protocol, which has been used in our institution since 2007,18 was both effective andwell tolerated.19 The purpose of this study was to evaluate the clinical efficacy of our optimized
treatment strategy in early GC in a larger cohort.

MATERIALS AND METHODSPatients
This study was approved by the Institutional Review Board of Nagoya University Hospital(reference number: 2020-0018) and conducted in accordance with the 1964 Declaration of
Helsinki and subsequent amendments. Informed consent was obtained from all study participantsprior to initial treatment.
Patients with T1 or T2N0M0 (stage I–II) glottic squamous cell carcinoma—treated via definitive RT at Nagoya University Hospital between January 2007 and November 2019—were includedin the study. The histological diagnoses were confirmed by biopsy, and all tumors were staged
according to the eighth edition of the Union for International Cancer Control staging classification
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Optimized treatment of glottic carcinoma

system.20 In addition, T1 and T2 GC were substaged. T1 bulky tumors were defined as tumors
extending over the entire true vocal fold, and/or horseshoe-shaped tumors extending over theanterior commissure and one-third of both true vocal folds; T1 nonbulky tumors were defined astumors that did not extend over these boundaries, based on the report by Reddy et al6 T2 favorable tumors were defined as tumors with normal vocal fold mobility; T2 unfavorable tumors were
defined as tumors with impaired vocal fold mobility, based on previous studies.7-9 The treatment
policy for each patient was established in a conference attended by both otolaryngologists andradiation oncologists, and the final treatment modality was selected based on the patient’s wishes.
Treatment
Figure 1 shows the details of the treatment protocol for early GC at our institution; RT was
performed for all patients once a day on weekdays, ie, five times a week, with no irradiation
on holidays. Patients with T1 nonbulky lesions were treated with 28–30 fractions of RT alone at
2.25 Gy/fraction per day. Patients with T1 bulky or T2 favorable GC were treated with CCRT
using S-1. S-1 was taken once daily, 3–6 h prior to RT; RT was initiated on the same day as
S-1 administration, and the patients were treated with 30 fractions at 2.0 Gy/fraction per day. S-1
was not administered on days when RT was not performed; the dose of S-1 was 55.3 mg/m2 perday, the recommended dose determined in our phase I/II study.10,11 Patients with T2 unfavorable
lesions were treated with CCRT using high-dose CDDP. CDDP was administered intravenously
at 80mg/m2 tri-weekly concurrently with RT for three courses. Patients were treated with 33–35
fractions of RT at 2.0 Gy/fraction per day, initiated on the same day as CDDP administration.
Patients who were not eligible for CCRT due to advanced age or renal dysfunction were treatedwith 28–30 fractions of RT alone at 2.25 Gy/fraction per day.
All patients were immobilized in the supine position wearing a thermoplastic mask andunderwent computed tomography (CT) simulation without contrast enhancement. RT was delivered

Fig. 1
RT: radiation therapy
fr: fraction
CCRT: concurrent chemoradiotherapy
CDDP: cisplatin
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Tamami Ono et alusing a 4 MV photon beam with 3D-CT-based technology. Two parallel-opposed lateral fields
were used to set up a rectangular irradiation field of 6 × 6 cm in most cases, and a pair of 15°
or 30° wedge filters were used to optimize the dose distribution. In patients with T2 GC, we firstused a slightly larger field size for irradiation upto 40 Gy than in T1 GC patients; thereafter,
the field size was reduced depending on the reduction in tumor size.
Outcome measures
The outcomes of this study were the evaluations of efficacy and safety of our optimized
treatment protocol in early GC; this included the assessment of clinical response, local failure(LF) rate, overall survival (OS) rate, disease specific survival (DSS) rate, and adverse events(AEs) in all patients. One to two months after completing RT or CCRT, the clinical response ofeach patient was evaluated by combining the fiberscopic, CT, and magnetic resonance imaging
findings. A clinical response was defined as the complete disappearance of all measurable lesions(determined by the otolaryngologist via fiberscopy), as well as no evidence of progression or
lymph node metastases (determined by the radiologist via CT or magnetic resonance imaging).
LF was defined as including both local recurrence alone and local recurrence with regional lymph
node recurrence. Patients were monitored for AEs at 1-week intervals during treatment, 1-monthintervals during the first year, 2-month intervals during the second year, every 3 months during
the third year, every 4 months during the fourth year, and every 6 months thereafter. AEs wereclassified according to the Common Terminology Criteria for Adverse Events Version 4.0.
Statistical analysis
OS, DSS and LC rates were analyzed using the Kaplan-Meier method with the log-rank
test. The LF curves were estimated using the cumulative incidence function—considering thecompeting risk of death without LF—and compared using Gray’s test. All statistical analyses
were performed using EZR (The R Foundation for Statistical Computing, Vienna, Austria), agraphical user interface for R.21

RESULTSA total of 80 patients were analyzed. The median follow-up time for survivors was 40.1
(range, 1.9–128.4) months, the median duration of RT treatment was 42 (range, 37–66) days, andthe median number of days off irradiation was 2 (range, 0–21) days. There were two patients
who discontinued irradiation during the treatment period: one patient had a 21-day irradiation
pause due to the onset of unstable angina during RT, the other had a 9-day irradiation pause
due to fever caused by side effects of chemotherapy. Patient characteristics are shown in Table
1; the median age was 69.5 (range, 26–90) years, 77 (96%) patients were male, and 14 (18%)
had another primary cancer prior to or concurrent with RT. Anterior and posterior commissure
invasion occurred in 38 (48%) and 10 (13%) patients, respectively.
Details of the treatment are shown in Table 2; 51 (64%) patients were treated via RT alone
through 28–30 fractions of 2.25 Gy/fraction per day. Exceptionally, one patient was treated with
35 fractions of RT alone at 2.0 Gy/fraction per day, as a subglottic skip lesion was suspected
via fiberscopy; although deemed pathologically negative, the irradiation area was prophylactically
expanded. Twenty-nine patients were treated with chemotherapy, receiving 30–35 fractions of RT
at 2.0 Gy/fraction per day; 22 (76%) patients received S-1, six (21%) received CDDP, and one(3%) received UFT which components are tegafur and uracil. Patients treated with UFT received
sequential chemotherapy before and after RT at other hospitals. One patient who received S-1 was
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Table 1

Characteristics of the patients

Total no. of patients
Age, median (range), y
69.5 (26-90)
GenderMale
FemalePerformance status (ECOG)01
2
T stage
T1a
Nonbulky
Bulky
T1b
Nonbulky
Bulky
T2
Favorable
Unfavorable
A-com involvement
Yes
No
P-com involvement
Yes
No
Macroscopic classification of tumor
Superficial
Exophytic
Unclassified
Another primary cancer prior to or concurrent with RT
YesNo
Smoking
Yes
No
Alcohol
Yes
No

n
80

Percent (%)
100

77
3

96
4

41
37
2

51
46
3

27
22
5
13
9
4
40
33
7

34
28
6
16
11
5
50
41
9

38
42

48
52

10
70

13
87

36
41
3

45
51
4

14
66

18
82

73
7

91
9

66
14

83
17

ECOG: Eastern Cooperative Oncology Group
A-com: anterior commissure
P-com: posterior commissure
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Table 2Treatment details

Number of patients (%)(n = 80)

Radiation [1 dose/ fr]

Total dose/ fr[2.25Gy/ fr]

67.5Gy/ 30fr (RT alone)

14 (18)63Gy/ 28fr (RT alone)

36 (45)[2Gy/ fr]

Chemotherapy

56.25Gy/ 25fr (CCRT with S-1)

1 (1)60Gy/ 30fr (CCRT with S-1)

21 (26)

66Gy/ 33fr (CCRT with CDDP)

3 (4)70Gy/ 35fr (CCRT with CDDP or RT alone)

5 (6)Types of chemotherapy

Number of patients (%)(n = 29)S-1

22 (76)CDDP

6 (21)

UFT

1 (3)fr: fraction
RT: radiation therapy
CCRT: concurrent chemoradiotherapy
CDDP: cisplatin
UFT: tegafur and uracil

treated with 25 fractions of 2.25 Gy/fraction per day; this was performed according to our new
CCRT protocol22 aimed at shortening the treatment time. The remaining patients who received
S-1 or CDDP were treated according to the study protocol. The initial response to treatment
was complete response in all cases, except for one patient who was transferred to the hospital
before assessment.
Overall outcomes are shown in Figure 2. Among all patients, the 3-year LF rate was 5.8%
(95% CI, 1.8–13.1); the 3-year OS and DSS rates were 94.4% (95% CI, 83.4–98.2) and 98.0%(95% CI, 86.6–99.7), respectively. In the univariate analysis, the LF, OS and DSS rates did notshow any statistically significant association with either clinical or tumor characteristics. Recurrence and death occurred in five patients each. All five recurrent patients were treated with RT
alone: one was a T1 nonbulky case and four were T2 cases; of these, three patients developed
only local recurrence, one developed only regional lymph node recurrence, and one developed
both local recurrence and regional lymph node recurrence. All patients underwent either salvage
surgery, salvage radiotherapy, or both. Four recurrent patients achieved progression-free survival,and one patient died of aspiration pneumonia after salvage surgery; the remaining four of fivepatients died from secondary primary cancers.
The cumulative incidence curves of LF by tumor classification are shown in Figure 3. The
3-year LF rates in the T1 and T2 groups were 2.9% (95% CI, 0.2–13.2) and 8.1% (95% CI,
2.0–19.8), respectively (p=0.39). The 3-year LF rates in the T1 nonbulky, T1 bulky, T2 favorable,
and T2 unfavorable groups were 3.7% (95% CI, 0.3–16.2), 0% (95% CI, 0–0), 6.8% (95% CI,
1.2–19.8), and 14.3% (95% CI, 0.5–49.1), respectively.
We subcategorized T1 bulky and T2 patients into the CCRT and RT alone groups to evaluate
the efficacy of CCRT; four patients who discontinued chemotherapy due to AEs, and one patient
who received sequential UFT chemotherapy, were excluded. Finally, there were 24 patients in the
CCRT group and 20 patients in the RT alone group. The cumulative incidence curves for LF in
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A

B

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C

Fig. 2 Overall outcomesFig. 2A: Cumulative incidence curves of local failure among all patients.
Fig. 2B: Kaplan–Meier curves of overall survival among all patients.
Fig. 2C: Kaplan–Meier curves of disease specific survival among all patients.
RT: radiation therapy

the two groups are shown in Figure 4. The 3-year LF rate was significantly lower in the CCRT
than the RT alone group (0% [95% CI, 0–0] vs 19.9% [95% CI, 4.4–43.3]; p=0.025). The patientstreated via RT alone who could not receive CCRT had a single or multiple reasons for deviatingfrom our protocol, including advanced age; underlying diseases, such as renal dysfunction orheart failure; treatment strategy considering secondary primary cancers; and patient convenience.
Two patients discontinued chemotherapy due to renal failure, one due to laryngeal bleeding,and one due to fever as a side effect. The patient with fever discontinued S-1 on day 29; only
RT was restarted on day 34, administered to 70 Gy. The other three patients who discontinued
chemotherapy continued RT as per our protocol.
Table 3 shows the AEs. Grade 3 acute AEs were noted in 10 patients overall: three patients(30%) treated with CCRT, and seven (70%) treated with RT alone. Grade 3 dermatitis was notedin nine patients (11%), and mucositis in four patients (5%). There were no acute AEs of grade
4 or higher, or late AEs of grade 2 or higher.

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A

B

Fig. 3 Cumulative incidence curves
Fig. 3A:	Cumulative incidence curves of local failure in the T1 (black) and T2 (red) groups.
Fig. 3B:	Cumulative incidence curves of local failure in the T1 bulky (black), T1 nonbulky (red), T2 favorable(green), T2 unfavorable (blue) groups.
RT: radiation therapy
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Fig. 4 T1 bulky/T2 cases
Cumulative incidence curves of local failure in the RT alone (black) and CCRT (red) groups.
RT: radiation therapy
CCRT: concurrent chemoradiotherapy

Table 3 AEs (CTCAE v4.0)

Acute
Dermatitis
Mucositis
Laryngeal edema
Laryngeal hemorrhage
Laryngeal pain
Late
HoarsenessSoft tissue necrosis
Laryngeal edema
Laryngeal hemorrhage
Laryngeal pain

Grade (n = 80)
Number of patients (%)
no AEsgrade 1

grade 2

grade 3

1 (1)
5 (6)
32 (40)74 (93)7 (9)31 (39)49 (61)48 (60)6 (7)68 (85)39 (49)22 (28)
0 (0)
0 (0)
5 (6)

9 (11)
4 (5)
0 (0)
0 (0)
0 (0)

50 (63)80 (100)79 (99)80 (100)75 (94)30 (37)
0 (0)
1 (1)
0 (0)
5 (6)

0 (0)
0 (0)
0 (0)
0 (0)
0 (0)

0 (0)
0 (0)
0 (0)
0 (0)
0 (0)

AEs: adverse events
CTCAE v4.0: Common Terminology Criteria for Adverse Events version 4.0
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DISCUSSION
We have been treating early GC with our optimized treatment strategy—shown in Figure
1—since 2007; its safety and efficacy were reported in our initial report in 2017.19 In this study,
we increased the number of patients and reevaluated the safety and efficacy of this treatment
strategy. Mostly, the 3-year OS and DSS rates of all patients were similar or slightly better
than observed in our previous report. The 3-year LC of all patients was also good; however,
the occurrence of relapses slightly increased compared with our previous report. Four of the five
relapses were T2 cases where the treatment strategy was changed from CCRT to RT alone; thus,
the strategy deviated from our treatment protocol. The LF rates in this study were generallycomparable to those reported in several randomized controlled trials regarding patients treated
via altered-fractionation radiotherapy,15,17,23,24 whether in the T1-2, T1, or T2 group. AEs weregenerally comparable to our previous report and other randomized controlled trials.17,19,23,24
In this study, we performed sub-analyses to evaluate the efficacy of CCRT in T1 bulky/
T2 cases, finding that the LF rate was significantly lower in the CCRT group than in the RT
alone group. The efficacy of CCRT in T2 laryngeal cancer was previously reported in several
studies.25,26 Overall, the low LF observed in this study may have been due to the use of CCRT
for T1 bulky/T2 cases as risk groups.
The RTOG 91-11 by Forastiere et al27 reported that use of CCRT for advanced laryngeal cancer
increased the mortality rate not attributable to GC or treatments. Among the five patients whodied in our study, one died from relapse, and four from secondary primary cancers; of these four
patients, only one patient was treated with CCRT. There were no late AEs of grade 2 or higher
in the toxicity profile of this study. The CCRT group appears to have attained good long-term
results; however, longer follow-up is needed to verify the long-term effects.
In T1 bulky/T2 cases, patients who could not receive CCRT due to performance status, age,and comorbidities such as renal dysfunction were included in the RT alone group; we therefore
need to explore alternative treatments to improve LC in T1 bulky/T2 patients not eligible fortreatment via CCRT. We recently planned a new protocol for CCRT using S-1 (UMIN000023416)
and have since started a new clinical trial.22 Our new protocol improves the current one by
reducing the S-1 administration period to 5 weeks while maintaining the daily dose, and insteadchanging the RT dose to 2.25 Gy/fraction for a total of 25 fractions. With these improvements,
older patients may be more likely to undergo CCRT because the total S-1 dose is reduced andthe hospital visit duration is shortened. However, even with this new protocol, there still are
patients who are not eligible for treatment via CCRT; therefore, new treatment options need to
be devised.
Twenty-two patients received CCRT with S-1, and six received CCRT with CDDP in thisstudy; neither of these patients experienced a recurrence. Although various CCRT regimens withseveral antineoplastic agents have been adopted to improve the LC rate for T2 GC, their doses
and schedules have not been determined. S-1 and CDDP have been reported to act as antitumor
medication, as well as radiosensitizers.28,29 S-1—an orally available antineoplastic agent—is easy
to use, as patients can receive the S-1 regimen in an outpatient setting. A recent meta-analysis
by Shih et al30 reported that CCRT with S-1 for head and neck squamous cell carcinoma resulted
in a good tumor response, favorable survival rate, and low number of AEs. Considering theinadequate results of our previous CCRT treatment regimen with low-dose CDDP/5-fluorouracil
for T2 GC,12,13 we prescribed high-dose CDDP for T2 unfavorable cases in this study. Forastiere
et al reported the efficacy and safety of CCRT with high-dose CDDP for advanced laryngeal
cancer31; however, the dose used in our regimen (80 mg/m2) was lower than the one they used foradvanced GC (100 mg/m2); nevertheless, the dosing schedule was the same. Our dose reduction
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is expected to be acceptable for early GC and to reduce side effects. However, additional cases
are required to evaluate the efficacy and safety of our CCRT regimen with high-dose CDDP.
Limitations
Due to the retrospective nature of the study, the selection of patients based on age andcomorbidities may have affected the results of the LF rate analysis when comparing the CCRTand RT alone groups. Our results seem to confirm the efficacy and safety of our original
optimized treatment in early GC; however, although the number of patients in this study was
greater than that in our previous report,19 the small sample size remains a limitation of this study.
We therefore need to increase the sample size over a longer duration to further investigate theefficacy and safety of our protocol.

CONCLUSION
Treating early GC according to our optimized protocol resulted in low LF rates, high OS
and DSS rates, and acceptable AEs. Our results also suggest that CCRT is more effective thanRT alone in T1 bulky/T2 cases.

ACKNOWLEDGMENTS
This study was possible thanks to the cooperation among many researchers. We would liketo express our sincere gratitude to each of them.

CONFLICT OF INTEREST
The authors declare that they have no competing interests.

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