Oral Oncology 127 (2022) 105782

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Oral Oncology
journal homepage: www.elsevier.com/locate/oraloncology

Single vocal cord irradiation for early-stage glottic cancer: Excellent local
control and favorable toxicity profile
Lisa Tans a, *, Abrahim Al-Mamgani b, Stefan L.S. Kwa a, Jos B.W. Elbers a,
Fatma Keskin-Cambay a, Aniel Sewnaik c, Maarten Dorr c, Remi Nout a, Wilma Heemsbergen a
a
Department of Radiotherapy, Erasmus MC Cancer Institute, University Medical Center Rotterdam, The Netherlands
b
Department of Radiation Oncology, Netherlands Cancer Institute/Antoni van Leeuwenhoek, Amsterdam, the Netherlands
c
Department of Otolaryngology and Head and Neck Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

A R T I C L E I N F O A B S T R A C T

Keywords: Objective: To validate the earlier reported promising oncologic outcomes and favorable toxicity profile following
Laryngeal cancer single vocal cord irradiation (SVCI) in an expanded cohort of patients with early-stage glottic cancer treated at
Single vocal cord irradiation our institute with longer follow-up time.
IMRT
Materials and methods: Between February 2011 and January 2020, 111 consecutive patients with early-stage
Toxicity
glottic cancer were treated with SVCI to the whole involved vocal cord (58.08 Gy, given in 16 fractions of
Voice handicap index
3.63 Gy). Setup verification was done using cone-beam CT, prior to each fraction. The endpoints were local
control (LC), overall survival (OS), grade ≥ 3 toxicity and voice quality assessment using voice-handicap index
(VHI) questionnaires.
Results: Median follow-up was 41 months (range; 8–84). Two patients developed in-field local failure (LF). The 3-
and 5-year LC rates were 99.1% and 97.1%, respectively. As both patients with LF were successfully salvaged
with total laryngectomy, the 5-year ultimate LC-rates was 99%. The 5-years OS was 80.6%. All patients finished
treatment without any interruption. No patients developed acute grade ≥ 3 toxicity. Late grade 3 toxicity was
reported in 7 patients (6.5%) out of 108 patients evaluable for late toxicity; 2 because of severe hoarseness and 5
because of laryngeal radionecrosis (4.5%). The 5-years laryngectomy-free survival was 98.1%. The VHI-scores
improved over time, only 22% of patients had VHI > 30 at 3-years post-radiotherapy, compared to 38% at
baseline.
Conclusions: Local control rate and laryngectomy-free survival of SVCI are excellent with favorable toxicity
profile and good VHI-score. These results validate our early results.

Introduction neck surgeon and patient. Radiotherapy could be a better treatment

option to preserve voice quality in patients with involvement of the
Laryngeal cancer is a common head and neck cancer with about 700 anterior commissure and in case there is a (relative) contraindication to
new cases yearly in the Netherlands [1]. Approximately 80% of all anesthesia. On the other hand, a one-step treatment such as MLS might
laryngeal tumors present with an early-stage disease (T1-2) because be more an attractive in older patients because of the limited number of
hoarseness of the voice is the first clinical symptom. The treatment of hospital visits.
early-stage laryngeal cancer is either surgical by means of trans-oral Historically, the standard radiation treatment for early-stage glottic
laser microsurgery (MLS) or radiotherapy, with similar oncologic out­ cancer (ESGC) (T1-2) is irradiation to the entire larynx, in 25 to 33
comes [2–5]. The choice for one of these options will be done based on fractions over 5 to 7 weeks up to a total dose of 60–66 Gy using either 3-
tumor- and patient-related factors and increasingly done in a shared- D conformal radiotherapy (3DCRT) or intensity-modulated radio­
decision making session with the radiation oncologist, the head and therapy (IMRT) [3,6]. In our institute, a novel IMRT technique was

* Corresponding author at: Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
E-mail addresses: l.tans@erasmusmc.nl (L. Tans), a.almamgani@nki.nl (A. Al-Mamgani), s.kwa@erasmusmc.nl (S.L.S. Kwa), j.elbers@erasmusmc.nl
(J.B.W. Elbers), f.cambay@erasmusmc.nl (F. Keskin-Cambay), a.sewnaik@erasmusmc.nl (A. Sewnaik), m.dorr@erasmusmc.nl (M. Dorr), r.nout@erasmusmc.nl
(R. Nout), w.heemsbergen@erasmusmc.nl (W. Heemsbergen).

https://doi.org/10.1016/j.oraloncology.2022.105782
Received 11 October 2021; Received in revised form 27 January 2022; Accepted 14 February 2022
Available online 8 March 2022
1368-8375/© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
L. Tans et al. Oral Oncology 127 (2022) 105782

developed in 2011 [7–9], the Single Vocal Cord Irradiation (SVCI). Late toxicity (>90 days after treatment) was scored according to the
Selected patients with T1a laryngeal cancer were treated with a mild CTCAEv5. The voice quality was determined from a validated voice-
hypofractionated scheme with limited volumes and with highly specific questionnaire, the VHI [12]. Patients with VHI score below 10
conformal target coverage. This resulted in significant reduction of the was scored as normal, score between 10 and 30 was considered to be
radiation dose to the adjacent organs at risk without compromising the “minimal voice handicap”, score between 31 and 60 as “moderate”, and
oncologic outcomes [8–10]. scores between 61 and 120 as “serious handicap”. Voice quality
The aim of the current study is to validate the earlier reported assessment was done at baseline, at the end of treatment, and at 4, 6, and
promising oncologic outcomes and favorable toxicity profile after SVCI 12 weeks and 6, 12, 18, and 36 months after treatment
in an expanded cohort of patients (n = 111) with T1a or very limited T2
glottic cancer that were treated at our institute and for whom longer Statistical analysis
follow-up time is currently available.
Follow-up time was calculated from start of radiotherapy. Kaplan-
Patients and methods Meier method was used to estimate the actuarial rates of LC, OS, and
laryngectomy-free survival. For the statistical analyses SPSS software
Between February 2011 and January 2020, 111 consecutive patients was used (version 25, IBM Corporation, Armonk, NY). We considered p-
with previously untreated ESGC, who were not suitable for laser surgery, values < 0.05 as statistically significant. Toxicity was evaluated upon
were treated with SVCI in our institute. All patients had a histologically last follow-up visit, death, tumor progression, or diagnosis of a new
proven squamous cell carcinoma (T1a) or severe dysplasia limited to one primary tumor, whichever came first. Baseline risk factors for devel­
vocal cord. Patients with minimal invasion to the ipsilateral supraglottic oping toxicity were evaluated using Cox regression.
region (very limited T2) were also eligible. Permission for retrospective
anonymized data collection for the current study was obtained after Results
protocol review by the Medical Ethical Committee of the Erasmus
Medical Center (reference number MEC-2020-0234). Median follow-up was 41 months for patients alive (range 8–84).
Seven patients were lost to follow-up within 36 months (range 7–30),
Treatment and follow-up mainly because of comorbidity or preference for follow-up at their own
regional hospital. From the total population of 111 patients, 108 (97%)
At baseline, all patient were examined by the head and neck surgeon had at least 6 months of follow-up and were evaluable for late toxicity.
and radiation oncologist using flexible naso-endoscopy. Chest X-ray was Patients, tumor and treatment characteristics are shown in Table 1. The
done in all patients and when indicated neck ultrasonography or CT scan majority of the patients were male (92%), and most tumors (97%) were
of the larynx. SVCI was offered to patients who were not suitable for staged T1a. The median PTV volume was 12.5 cc.
laser surgery because of wide involvement of the anterior commissure,
inadequate exposition, patient’s refusal, and/or contraindication for
anesthesia. This decision was made at the regular meetings of the
multidisciplinary head and neck tumor board.
Table 1
The entire vocal cord was encompassed within the clinical target Patients, tumor, and treatment characteristics.
volume (CTV). The planning target volume (PTV) was automatically
Age; mean in years 68.7
generated in the planning system by addition of a margin to the CTV.
Age; range in years 49–88
This was 3, 5, and 3 mm for the left–right, cranial-caudal, and anterior- Follow-up; median in months 41
posterior directions, respectively. Dose prescription was set to 16x3.63 Follow-up; range in months 8–84
Gy (total dose 58.08 Gy), using 5 to 9 IMRT beams. Applied dose con­
straints for organs at risk were Dmean for the contralateral vocal cord and Numbers %
the contralateral arytenoid lower than 50 Gy and 35 Gy, respectively.
Gender
The maximal Dmean for the contralateral and the ipsilateral carotid ar­ Male 102 92
teries were 15 Gy and 20 Gy, respectively. Setup verification was done Female 9 8
by online correction protocol using cone beam-computed tomography, T stage
performed prior to each radiation fraction. Further treatment details are T1a 108 97
T2a 3 3
thoroughly described previously [8–10] Histology
Patients were followed up every 2 months for the first year, every 3 Squamous cell carcinoma 76 68
months for the second and third year, and after this period every 6 Dysplasia 35 32
months. Flexible naso-laryngoscopy was performed at each visit. Involvement of anterior commissure
Yes 44 40
No 67 60
Study endpoints Smoking
Stopped before SVCI 83 75
Primary endpoints were local tumor control (LC), patient-reported Continued smoking during SVCI 22 20
Voice Handicap Index (VHI) score, and late grade ≥ 3 toxicity accord­ Unknown 6 5
PTV volume; median in cc 12.5
ing the Common Terminology of Adverse Events (CTCAEv5) [11]. The PTV volume; range in cc 7.8–23.9
following Grade ≥ 3 toxicity endpoints were evaluated: cough, hoarse­ Radiation dose to the contralateral vocal cord
ness, voice alteration, dysphagia, xerostomia, larynx radionecrosis, Median in Gy 45
larynx edema, lymph edema, soft tissue ulcer, weight loss, and hypo­ Range in Gy 26.2–54.3
Radiation dose to the contralateral arytenoid cartilage
thyroidism. Secondary endpoints were regional failure, distant metas­
Median in Gy 28
tasis, overall survival (OS), acute grade ≥ 3 toxicity (mucositis, Range in Gy 20–47
dysphagia), and laryngectomy-free survival. Additional survival data Radiation dose to the supraglottic region
was obtained from the national database on municipal death/emigra­ Median in Gy 21
tion records for patients with no recent visit to the outpatient clinic. Range in Gy 12.8–50

Acute toxicity (<90 days after treatment) was evaluated weekly by Abbreviation: SCC: Squamous cell carcinoma; SVCI: single vocal cord irradia­
the radiation oncologist at the outpatients’ clinic during the treatment. tion; PTV: planning target volume.

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L. Tans et al. Oral Oncology 127 (2022) 105782

Oncologic outcomes Correlation of dose-volume histogram parameters with LF and late grade 3
toxicity
Two patients developed in-field LF (one within the CTV, one within
the PTV). This was after 7 and 41 months respectively. The 3- and 5- LF was not correlated with PTV volume. In the 2 patients with LF, the
years actuarial LC rates were 99.1% (0.9 %1SE) and 97.1% (2.1 % PTV volumes were 11 and 12 cc, compared to the mean PTV volume of
1SE), respectively (Fig. 1). Because the two patients with LF were patients without LF of 13.84 (SD 3.96).
salvaged by total laryngectomy (TL), the ultimate local control rate at 5- In patients with late grade 3 toxicity, the mean dose to the contra­
years was 99%. One patient died because of second recurrence after TL. lateral vocal cord, the arytenoid cartilage and the supraglottic region
The 5-years laryngectomy-free rate is 98.1%. None of the patients were 45.82, 29.68, and 25.54 Gy, respectively. These doses were not
developed regional or distant failure. Eighteen patients had died at the significantly higher than in patients without late grade 3 toxicity (44.47,
time of the current analysis. From this group, only one patient died 29.77, and 24.72 Gy , respectively) (p > 0.05, all).
because of the laryngeal cancer and all other patients died because of
intercurrent disease. The actuarial 5-years OS was 80.6% (Fig. 1). Discussion

The current study validated the previously reported promising re­

Toxicity sults of the SVCI technique developed at our institution in 2011 [10]. In
a larger group of patients with ESGC with longer follow-up, we observed
There were no treatment interruptions. No patients developed acute 5-year LC, OS and laryngectomy-free rates of 97.1%, 80.6%, and 98.1%,
grade ≥ 3 toxicity. One-hundred-and-eight patients were evaluable for respectively. No grade ≥ 3 acute toxicity was reported. Only 6.5% of
late toxicity (≥6 months of follow-up). No grade 4 or 5 toxicity was patients had late grade 3 toxicity, of which 5% experienced laryngeal
reported. Late grade 3 toxicity was reported in 7 patients (6.5%); 2 radionecrosis. For the majority of the patients voice quality showed
because of severe hoarseness/voice alteration, and 5 patient because of normal scores or minimal deterioration 3 years after the SVCI. Only 22%
laryngeal radionecrosis, 5 to 25 months after SVCI. The 3-year cumu­ of patients had moderate and serious voice handicap (score > 30).
lative incidence of laryngeal radionecrosis was 6.6 % (Fig. 2). All pa­ Furthermore, patients who continued smoking during and after SVCI
tients with laryngeal radionecrosis had also G3 hoarseness/voice had more frequently late grade 3 toxicity. These findings were also
alteration and in 2 cases there was also G3 laryngeal edema. Patients observed in patients previously treated with conventional schemes of
with laryngeal radionecrosis (n = 5) were treated by hospitalization, radiotherapy in our institute [3] and emphasizes the importance of
dexamethasone and with hyperbaric oxygen (n = 3). Two patient (1.8%) smoking cessation during and after successful radiotherapy.
were treated with tracheostomy because of stridor and severe laryngeal The results of the current study are favorable in terms of both LC and
edema. Three of 7 patients (43%) with late grade 3 toxicity continued toxicity, compared to patients that were treated with conventional
smoking during and after SVCI, compared to 18% (p = 0.02) of patients schemes [3,6]. Patients with T1a/T1b tumors treated at our institute
without toxicity. There were no cases of the other evaluated grade 3 with conventional scheme of 66 Gy in 33 fractions (5 or 6 times a week)
toxicity endpoints. showed LC rates of 91% at 5 years. The excellent local control rates in
our study can be explained by the high radiobiological equivalent dose
used as a result of high fraction dose and the short overall treatment time
VHI- scores (OTT) (22 days). Different studies have shown that high fraction dose
has a positive impact on LC rates in ESGC [13]. This is because most
The course of the VHI scores over time is summarized in Fig. 3. Voice ESGC are of the well- or moderately-differentiated squamous type. Well-
quality improved over time because only 22% of patients had VHI score differentiated squamous cell carcinoma has a shorter potential doubling
> 30 at 3 years, compared to 38% at baseline (Fig. 2A). With regard to time and a greater propensity for accelerated repopulation [13,14].
the correlation between moderate and serious voice handicap (score > However, it is difficult to point out whether the high fraction size or the
30) and different patient demographics, VHI > 30 at 18 months was short OTT is the reason for improve LC, as hypofractionated schemes are
more frequently reported in patients with any late grade 3 toxicity, usually completed within a short OTT, compared to conventional
compared to those without (60% vs. 22%, P < 0.050) (Fig. 4).

Fig. 1. The Kaplan-Meier curve for local control and overall survival and.

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L. Tans et al. Oral Oncology 127 (2022) 105782

Fig. 2. The cumulative incidence of laryngeal radionecrosis.

Fig. 3. The voice-handicap index scores of the whole group at different

Fig. 4. The proportion of patients with moderate or severe voice-handicap
time points.
index (scores > 30) in correlation with the presence or absence of any grade
≥ 3 late toxicity.
schemes. Le et al. [15], have shown in their consecutive patient series,
that the dose per fraction has a prognostic significance independent of
With respect to late toxicity, the observed incidence of laryngeal
the OTT for T2 lesions, but not for T1 tumors. radionecrosis of 5% is at the upper limit of the range of 1–5% that was
In patients treated at our institute with conventional scheme of 66 Gy
reported in a review of Fernati et al. [21].
in 33 fractions (5 or 6 times a week), 10 % needed tube feeding at the Beside the radiobiological advantages of this short-course of radio­
end of treatment and 10% and 6% of patients had late grade ≥ 2 xero­
therapy, patient comfort and treatment burden are also important, as
stomia and dysphagia, respectively [3]. The favorable acute toxicity patients need to visit the radiation department much less frequently (16
profiles reported in the current study could be explained by the reduced
instead of 33 times in case of conventional radiation schemes).
treated volume and small margins used, as these issues have significant Furthermore, the reduction in the number of fractions allows also more
impact on the toxicity in patients with head and neck cancer treated
efficiency for the radiation departments with helping to reduce waiting
with radiotherapy [16–20], while patients in the 66 Gy group were lists.
irradiated with a larger volume, as the whole larynx was incorporated in
ESGC are usually treated by surgery or radiotherapy. There is no
the CTV. solid evidence that one treatment is better than the other. To the best of

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L. Tans et al. Oral Oncology 127 (2022) 105782

our knowledge, the only randomized trial that investigated the differ­ (6.8%) developed dose-limiting toxicities (grade 3–4 laryngeal necrosis,
ences in outcome of these two modalities was performed in patients edema and dysphagia) and local recurrence was reported in 5 patients
treated in the eighties. Although radiation techniques have been (17%). The authors concluded that such strategy warrants prospective
modernized significantly and the surgical treatment was not the investigation as the treatment was tolerable, the voice quality was
currently used endoscopic technique, this study showed no survival excellent and the preliminary efficacy data was promising. On the other
differences between both treatment modalities. Since then different at­ hand, Knag et al [39] reported on the early closure of a phase I trial for
tempts to perform a randomized trial in order to compare the outcome of ablative SBRT because of an unexpected dose-limiting toxicity in 2 pa­
radiotherapy with endoscopic resection failed because of difficulties in tients (33%) treated with 55 Gy in 11 fraction. This regime, however,
accrual [22–23]. In addition, different systemic reviews and meta-ana­ results in a total radiobiological equivalent dose of 88 Gy compared to
lyses of (mostly) retrospective case series have been published with no 77 Gy for the radiation scheme used in the SVCI in the current study (α/β
statistically significant differences in outcomes [22–27]. Furthermore, ratio = 3 for late toxicity).
different studies have also shown that the LC and laryngectomy-free Furthermore, patients treated within the first study [38] might
survival of both treatments are comparable [28–29], suggesting that develop more severe late toxicity with longer follow up, as the radio­
oncologic and functional outcomes of MLS are comparable with those of biological equivalent dose of 42.5 Gy in 5 fractions is around 98 Gy,
SVCI. Beside MLS, different other organ-sparing surgical techniques are using α/β ratio = 3 for late toxicity. A word of caution should, therefore,
possible for patients with ESGC such as partial laryngectomy and uni­ be made to avoid continuously escalating the fraction dose and the total
lateral hemi-laryngectomy. Thomas et al. [30] reviewed the LC rates of dose, as excellent LC rates can already be achieved using a total
different treatment modalities for ESGC and reported excellent LC rates (equivalent) radiation dose around 66 to 70 Gy (3,6,10,13,14,). In fact,
around 95% in patients treated with organ conservation partial laryn­ better selection criteria need to be considered in order to reduce the
gectomy. Comparable LC rates were also achieved in patients treated incidence of laryngeal osteoradionecrosis, especially in young patients
with unilateral hemi-laryngectomy with good functional outcomes who continued smoking, as the incidence of laryngeal radionecrsosis
[31–34]. The ongoing randomized trial, the VoiceS study (NCT 2–3 folds higher in patients continued smoking during radiotherapy. In
04057209), will investigate the impact of two treatment modalities; the these cases mild hypofractionated or conventional radiation schemes
Transoral CO2-Laser Microsurgical Cordectomy and same scheme of might be advocated, using the same SVCI technique.
SVCI used in the current study, on voice quality, LC, and toxicity. Since all data were extracted retrospectively, the results presented in
Kim et al (33) reviewed the outcome of 14,498 patients with ESGC this study are subject to limitations. In particular toxicity is notoriously
identified in the National Cancer Database. Within the whole group, under-reported in retrospective analysis, type and frequency of toxicity
25% were treated by surgery and 75% by means of radiotherapy; either should be interpreted with caution. We think it is safe to assume that
with conventional or mild hypofractionated schemes. Surgically treated acute toxicity was recorded frequently and quite accurately, as patients
patients had significantly better OS, compared to patients treated by consistently visited the radiation oncologist weekly during SVCI. How­
radiation (HR 0.87, p = 0.0004). However, when the OS of hypo­ ever, for late toxicity, accurate information of grade 1–2 complications is
fractionated radiotherapy was compared with surgery, no statistically not reliable because it was not recorded in a consistent way. Due to the
significant differences were observed (HR 0.94, p = 0.154). In patients sincerity and evident manifestation of grade ≥ 3 toxicity, we believe late
treated with radiotherapy, the OS was significantly better in patients severe toxicities were captured and noted adequately.
treated with hypofractionated schemes, compared to those that were In conclusion, the investigated SVCI of 16 fractions of 3.63 Gy with a
treated with 2 Gy/per fraction to a total dose of 66–70 Gy (HR 1.15, p = median OTT of 22 days showed excellent local control rates in ESGC. We
0.0003). The meta-analyses published by Sapineza et al (34) showed that believe that shorter OTT and large fraction size have resulted in a higher
altered fractionation (both hypo- and hyperfractionation) improved LC, biological effective dose and therefore a high LC. Furthermore toxicity
compared to conventional schemes especially in patients with T1 tumor, profiles were favorable due to the limited irradiated volumes, resulting
and even for tumor involving the anterior commissure. in a good preservation of the functional voice quality. The current results
Involvement of the anterior commissure was shown to be a predic­ validate our early results and compare favorably to those of patients
tive factor for worse LC in different studies [35–37]. Hoffmann et al [35] treated to the whole larynx with a conventional scheme of 66 Gy in 33
reported on the outcome of 96 patients with ESGC with involvement of fractions at our institute.
the anterior commissure. From the group of patients with involvement
of one vocal cord (Tis or T1a) (n = 32), 8 recurrences were observed Declaration of Competing Interest
(24%). Most of patients were treated by second or third laser treatment
resulting in a ultimate LC and laryngeal preservation rates of 94%. In 2 The authors declare that they have no known competing financial
patients, total laryngectomy was necessary to achieve LC. In our study, interests or personal relationships that could have appeared to influence
no patients with involvement of the anterior commissure (n = 44) the work reported in this paper.
developed local recurrence. Considering the excellent oncologic and
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