10.14639/0392-100X-N1917
Objective. Patients with early glottic cancer sometimes exhibit new glottic cancer events after 5 years. This study aimed to analyse the patterns and risk factors of new glottic cancer events in patients with early glottic cancer 5 years after initial treatment.Methods. In total, 209 patients were included in this study. Age, sex, T stage, anterior commissure involvement, smoking pattern and treatment modality were retrospectively analysed.Results. The median follow-up was 91 (range, 60-266) months. The median time for the occurrence of new glottic cancer events was 97 (range, 61-199) months. New glottic cancer events occurred 5 years after initial treatment in 16 (7.6%) patients, among whom 12 (75.0%) had new glottic cancer event lesions overlapping with initial lesions. Smoking cessation after treatment was significantly correlated with fewer new glottic cancer events after 5 years. Conclusions. New glottic cancer events occurring 5 years after initial treatment in patients with early glottic cancer are not negligible. In particular, if smoking is continued after treatment, these patients can experience new glottic cancer events even after 5 years.
text/xml
1827-675X
1917
en
Tack-Kyun  Kwon
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
smoking cessation
Long-term impact of smoking cessation on new glottic cancer events in patients with early glottic cancer
Text.Serial.Journal
https://www.actaitalica.it/
42
Laryngology
2022-12-29
2021-12-16
2022-12-29
2023-01-16
525-530
1
Tack-Kyun  Kwon
2022/12/29
10.14639/0392-100X-N1917
525
Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
1827-675X
smoking cessation
en
530
Long-term impact of smoking cessation on new glottic cancer events in patients with early glottic cancer
https://www.actaitalica.it/article/download/1917/891
42
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42:525-530; doi: 10.14639/0392-100X-N1917




Laryngology


Long-term impact of smoking cessation on new
glottic cancer events in patients with early glottic
cancer
Effetti a lungo termine dell’abolizione del fumo di sigaretta sull’insorgenza di nuovi
eventi oncologici laringei, in pazienti trattati per tumori glottici in stadio iniziale
Min-Su Kim1, Hong-Gyun Wu2, Myung-Whun Sung3, Tack-Kyun Kwon3
1
 Department of Otorhinolaryngology-Head and Neck Surgery, CHA Bundang Medical Center, CHA University School of Medicine,
Seongnam, Gyeonggi-do, Republic of Korea; 2 Department of Radiation Oncology, Seoul National University College of Medicine,
Seoul, Republic of Korea; 3 Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of
Medicine, Seoul, Republic of Korea


SUMMARY
Objective. Patients with early glottic cancer sometimes exhibit new glottic cancer events
after 5 years. This study aimed to analyse the patterns and risk factors of new glottic cancer
events in patients with early glottic cancer 5 years after initial treatment.
Methods. In total, 209 patients were included in this study. Age, sex, T stage, anterior
commissure involvement, smoking pattern and treatment modality were retrospectively
analysed.
Results. The median follow-up was 91 (range, 60-266) months. The median time for the
occurrence of new glottic cancer events was 97 (range, 61-199) months. New glottic can-
cer events occurred 5 years after initial treatment in 16 (7.6%) patients, among whom 12
(75.0%) had new glottic cancer event lesions overlapping with initial lesions. Smoking
cessation after treatment was significantly correlated with fewer new glottic cancer events         Received: December 18, 2021
after 5 years.                                                                                      Accepted: June 13, 2022
Conclusions. New glottic cancer events occurring 5 years after initial treatment in patients
with early glottic cancer are not negligible. In particular, if smoking is continued after treat-   Correspondence
ment, these patients can experience new glottic cancer events even after 5 years.                   Tack-Kyun Kwon
                                                                                                    Department of Otorhinolaryngology-Head-and-
KEY WORDS: laryngeal neoplasms, glottis, recurrence, smoking cessation                              Neck Surgery, Seoul National University College
                                                                                                    of Medicine, Boramae Medical Center, Room No
                                                                                                    11221, 11th floor, Hangbok Building, Boramae
RIASSUNTO
                                                                                                    Medical Center 20, Boramae-ro 5-gil, Dongjak-gu,
Obiettivo. I pazienti con cancro glottico a basso stadio talvolta presentano nuovi tumori           Seoul 07061, Republic of Korea
glottici dopo 5 anni. Questo studio ha lo scopo di analizzare i pattern e i fattori di rischio      E-mail: kwontk@snu.ac.kr
correlati con l’insorgenza di nuovi tumori glottici dopo 5 anni dal trattamento iniziale.
Metodi. In totale, 209 pazienti sono stati inclusi nello studio. L’età, il genere, lo stadio di
T, il coinvolgimento della commissura anteriore, il fumo, e la modalità di trattamento sono           How to cite this article: Kim M-S, Wu
stati analizzati retrospettivamente.                                                                  H-G, Sung M-W, et al. Long-term impact
                                                                                                      of smoking cessation on new glottic cancer
Risultati. Il follow-up mediano è stato di 91 mesi (range, 60-266). Il tempo medio di insor-
                                                                                                      events in patients with early glottic cancer. Acta
genza di un nuovo cancro glottico è stato di 97 mesi (range, 61-199). I nuovi cancri della            Otorhinolaryngol Ital 2022;42:525-530. https://
glottide si sono manifestati 5 anni dopo il trattamento iniziale in 16 (7,6%) pazienti; 12            doi.org/10.14639/0392-100X-N1917
(75,0%) tra questi presentavano lesioni sovrapponibili a quelle iniziali. La sospensione del
fumo si è rivelata essere correlata in maniera statisticamente significativa con un minor           © Società Italiana di Otorinolaringoiatria
rischio di nuovi tumori.                                                                            e Chirurgia Cervico-Facciale
Conclusioni. La frequenza di nuovi tumori glottici a distanza di almeno 5 anni dal tratta-
mento iniziale non è trascurabile. In particolare, se l’abitudine del fumo è continuata dopo                       OPEN ACCESS
il trattamento, questi pazienti possono mostrare nuovi tumori glottici anche dopo 5 anni.
                                                                                                    This is an open access article distributed in accordance with
PAROLE CHIAVE: neoplasie laringee, glottide, recidiva, cessazione del fumo                          the CC-BY-NC-ND (Creative Commons Attribution-Non-
                                                                                                    Commercial-NoDerivatives 4.0 International) license. The
                                                                                                    article can be used by giving appropriate credit and mentio-
                                                                                                    ning the license, but only for non-commercial purposes and
                                                                                                    only in the original version. For further information: https://
                                                                                                    creativecommons.org/licenses/by-nc-nd/4.0/deed.en




                                                                                                                                                            525
M.-S. Kim et al.




Introduction                                                       Of the 330 patients, 121 were excluded – 48 reported recur-
                                                                   rences within 5 years after the initial treatment, 51 were
Laryngeal cancer is one of the most common head and
                                                                   lost to follow-up over 5 years after the initial treatment, and
neck cancers. An estimated 13,560 new laryngeal cancer
                                                                   22 received RT after TLM because of close resection mar-
cases occurred in the United States in 2015, accounting for
                                                                   gins. Finally, 209 patients with early glottic cancer without
3,640 deaths 1. Among laryngeal cancers, glottic cancer re-
                                                                   recurrence within 5 years were enrolled. Follow-up was
fers to a malignancy of the true vocal cords and is the most
                                                                   regularly performed – 1 month after treatment completion,
common laryngeal cancer. Stage I (T1N0M0) and stage II
                                                                   every 2 months in the first year and every 6 months for
(T2N0M0) glottic cancers are typically grouped together
                                                                   5 years using laryngoscopy at every visit. Neck computed
as early glottic cancer and are mostly treated as a single
                                                                   tomography was performed annually. Thereafter, follow-up
entity 2. Standard treatments for early glottic cancer in-
                                                                   was performed annually using only laryngoscopy at every
clude transoral laser microsurgery (TLM) and radiotherapy
                                                                   visit. New glottic cancer events were recorded during fol-
(RT), both resulting in favourable oncologic outcomes 3.
                                                                   low-up visits.
The 5-year local control rates following TLM are report-
                                                                   Various clinical factors, including age, sex, T stage, ante-
edly 85-95% and 65-85% for patients with Stage I and II
glottic cancers, respectively. Similarly, 5-year local control     rior commissure involvement, smoking history and treat-
rates following RT are reportedly 85-95% and 60-80% for            ment modality, were analysed. The 8th edition of the Ameri-
patients with Stage I and II glottic cancers, respectively 4.      can Joint Committee on Cancer staging manual was used
Local control failure occurs mostly within 5 years of initial      for staging 22. This manual defines T1 tumours as tumours
treatment in patients with early glottic cancer, regardless        confined to a unilateral vocal fold (T1a) or bilateral vocal
of whether they have undergone RT or TLM 5-8. Therefore,           folds (T1b) and T2 tumours as tumours extending to the
clinical follow-up for these patients has been traditionally       supraglottis or subglottis with or without impaired vocal
performed for 5 years after initial treatment.                     fold mobility. We also defined stage I (T1N0M0) and stage
Although most studies have examined 5-year local con-              II (T2N0M0) glottic cancers as early glottic cancer.
trol rates 9-16, some new glottic cancer events have been
observed after more than 5 years following initial treat-          Statistical analysis
ment in patients with early glottic cancer without recur-          The clinical data were summarised as means for continu-
rence during the first 5 years. Some studies have examined         ous variables and numbers for categorical variables. Con-
such cases, but have only described the overall long-term          tinuous variables were compared using independent t-test.
rates and showed decreasing Kaplan-Meier curves without            Nominal and ordinal categorical variables were compared
focusing on lesions occurring beyond 5 years after initial         using chi-square test, Fisher’s exact test, and linear-by-lin-
treatment 17-19. New cancer lesions occurring after 5 years        ear association. The cumulative probability of new glottic
are considered secondary primary cancers rather than re-           cancer events was calculated using Kaplan-Meier analysis
currences. Therefore, studies on secondary primary can-            and compared using log-rank test. Univariable analysis of
cers after glottic cancer usually include oral, pharyngeal,        new glottic cancer events was performed using Cox regres-
oesophageal and lung cancers 20,21. However, we have re-           sion. For all analyses, P-values of < 0.05 were considered
cently encountered new glottic cancer events around the            to indicate significance. SPSS software (ver. 22.0; SPSS,
initial glottic cancer lesions 5 years after the initial treat-    Chicago, IL, USA) was used for statistical analyses.
ment of early glottic cancer. To the best of our knowledge,
new glottic cancer events after 5 years of initial treatment       Results
in patients with early glottic cancer have not been suffi-
ciently researched. Therefore, this study aimed to analyse         The following patient characteristics were analysed: age,
the prognostic factors and patterns of new glottic cancer          sex, T stage, anterior commissure involvement, smoking his-
events at 5 years after initial treatment in patients with early   tory and treatment modality (Tab. I). The median follow-up
glottic cancer without recurrence during the first 5 years.        period was 91 (range, 60-266) months. However, the follow-
                                                                   up periods were not sufficient for many patients (166/209,
                                                                   79.4%) at the time of analysis. Of the 124 patients in the
Materials and methods                                              smoking cessation success group, 101 were not continuously
Patients                                                           followed. Among the 85 patients in the smoking cessation
We included 330 patients diagnosed with early glottic can-         failure group, 65 were not continuously followed.
cer who had undergone single treatment modality (TLM or            Of the 209 patients, 16 experienced new glottic cancer
RT) at our hospital between January 1994 and May 2014.             events at more than 5 years after the initial treatment. The



526
                                                                                   Long-term results (beyond 5 years) in patients with early glottic cancer




Table I. General characteristics of participants (n = 209).
 Variable                                                  Total (n = 209)   New glottic cancer (-)      New glottic cancer (+)                P
                                                                                  (n = 193)                    (n = 16)
 Age (mean ± SD, years)                                    60.51 ± 7.94          60.24 ± 8.03                 62.88 ± 6.93                  0.210
 Sex
    Male                                                   201 (96.2%)            185 (92.0%)                   16 (8.0%)                   1.000
    Female                                                   8 (3.8%)              8 (100%)                      0 (0%)
 T stage                                                                                                                                    0.538
    T1a                                                     93 (44.5%)            86 (92.5%)                    7 (7.5%)
    T1b                                                     73 (34.9%)            69 (94.5%)                    4 (5.5%)
    T2                                                      43 (20.6%)            38 (88.4%)                    5 (11.6%)
 AC involvement                                                                                                                             0.089
    Yes                                                    92 (38.9%)             88 (95.7%)                     4 (4.3%)
    No                                                     117 (61.1%)            105 (89.7%)                   12 (10.3%)
 Smoking cessation after treatment                                                                                                          0.003
    Success                                                124 (37.8%)            124 (100%)                     0 (0.0%)
    Failure                                                 85 (62.2%)            69 (81.2%)                    16 (18.8%)
 Treatment                                                                                                                                  0.670
    Transoral laser microsurgery                           81 (38.8%)             74 (91.4%)                     7 (8.6%)
    Radiotherapy                                           128 (61.2%)            119 (92.9%)                    9 (7.1%)
*SD: standard deviation; AC: anterior commissure.



10-year disease-free survival rate was 90.7%. The median
time for occurrence of new glottic cancer events was 97
(range, 61-199) months (Fig. 1). The disease-free survival
rate was significantly higher in the smoking cessation suc-
cess group after treatment than in the smoking cessation
failure group (Fig. 2). Smoking cessation failure after treat-
ment was significantly associated with the risk of new glot-
tic cancer events at more than 5 years after initial treatment
(Tab. II). No significant differences in second extra-glottic
cancers [success, 4.1% (5/124) vs. failure, 8.2% (7/85);




                                                                             Figure 2. Kaplan-Meier curve of new glottic cancer events according to
                                                                             smoking cessation.


                                                                             P = 0.19] or Charlson comorbidity index scores (success,
                                                                             1.3 vs failure, 1.9; P = 0.31] were observed between the
                                                                             smoking cessation success and failure groups.
                                                                             Of the 16 patients with new glottic cancer events, 10 were
                                                                             diagnosed based on changes in voice and 6 were diagnosed
                                                                             via follow-up laryngoscopy without definite symptoms. If
                                                                             the glottic anatomic extent of the initial and new glottic
                                                                             lesions overlapped, the cases were considered to be over-
Figure 1. Kaplan-Meier curve of new glottic cancer events.                   lapping, otherwise the cases were considered to be non-



                                                                                                                                                     527
M.-S. Kim et al.




Table II. Univariate Cox regression model for new glottic cancer events occurring after 5 years in patients with early glottic cancer.
 Variable                                                                                                                  Univariate analysis
                                                                                                                                HR      95% CI       P
 Age (< 65 yr/ ≥ 65 yr)                                                                                                        2.39    0.88-6.49   0.187
 Sex (male/female)                                                                                                             0.04    0.43-9.35   0.575
 T stage (T1/T2)                                                                                                               1.47    0.50-4.24   0.477
 AC involvement (yes/no)                                                                                                       1.96    0.63-6.09   0.245
 Smoking cessation after treatment (success/failure)                                                                           4.31    1.58-7.53   0.047
 Treatment (RT/TLM)                                                                                                            1.91    0.69-5.31   0.214
*HR: hazard ratio; CI: confidence interval; yr: years; AC: anterior commissure; RT: radiotherapy; TLM: transoral laser microsurgery.



overlapping. Further, 12 (75.0%) overlapping cases and 4                                       out follow-up beyond 5 years after the initial treatment.
(25.0%) non-overlapping cases of new glottic cancer were                                       Therefore, accurate comparisons between the results of this
observed. Among the overlapping cases, 5 (41.7%) were                                          study and those of the previous studies may be difficult.
previously treated with TLM and 7 (58.3%) were previ-                                          To the best of our knowledge, this is the first report dem-
ously treated with RT. Among the non-overlapping cases,                                        onstrating that continued smoking is related to new glottic
2 each (50%) were previously treated with TLM and RT.                                          cancer events at more than 5 years after the initial treatment
No significant differences in overlapping lesions were ob-                                     for early glottic cancer. Smoking is the main risk factor for
served between the TLM and RT groups (P = 0.77).                                               head and neck cancer development. However, smoking ces-
                                                                                               sation is a difficult process for patients with this disease.
Discussion                                                                                     Chan et al. reported that 45% of patients with head and
                                                                                               neck cancer continue to smoke after cancer diagnosis, and
Among the 209 patients included in this study, 16 experi-                                      patients willing to quit smoking after disease onset often
enced new glottic cancer events at 5 years after initial treat-                                fail to do so 23. A systematic review revealed that smoking
ment for early glottic cancer without recurrence within the                                    cessation in patients with head and neck cancer is associ-
first 5 years. Moreover, the glottic anatomic extent of the                                    ated with improved overall survival, recurrence rates and
initial and new glottic lesions overlapped in many cases.                                      second primary tumours 24. However, it is somewhat sur-
Smoking cessation failure after treatment was a significant                                    prising that patients who continue smoking develop new
risk factor related to new glottic cancer events occurring                                     glottic cancer events even 5 years after the treatment of
beyond 5 years.                                                                                early glottic cancer, which usually shows relatively good
Some studies have investigated new glottic cancer events                                       prognosis. This suggests that even patients with early glot-
beyond 5 years in patients with early glottic cancer; how-                                     tic cancer require continual education about smoking ces-
ever, these studies have not specifically reported the num-                                    sation during follow-up.
ber of new glottic cancer events occurring beyond 5 years.                                     We believe that some new glottic cancer events may be sec-
These studies have only described the overall long-term                                        ondary primary malignancies or late recurrences. The clas-
rate and showed decreasing Kaplan-Meier curves after 5                                         sic criteria for defining second primary malignancy pro-
years during follow-up. Moreover, they have analysed pa-                                       posed by Warren and Gates are as follows: 1) histological
tients with early glottic cancer treated with only TLM 17,18.                                  confirmation of malignancy in both the index and second-
Our data showed that treatment modality was not an inde-                                       ary tumours; 2) anatomical separation of the two malignan-
pendent predictor of new glottic cancer events occurring 5                                     cies by normal mucosa; and 3) exclusion of the possibil-
years after the initial treatment. This result was similar to                                  ity of the second primary malignancy being a metastasis
that of previous studies indicating that TLM and RT are                                        from the index tumour 25. Some new glottic cancer events
equally effective for treatment of early glottic cancer 6,9. In                                were somewhat inconsistent with the second criterion. The
contrast to previous studies 1,2,14,15,18,19, T stage and anterior                             glottic anatomic extent of the initial and new glottic le-
commissure involvement were not found to be significant                                        sions overlapped in many new glottic cancer events (12/16,
prognostic factors for new glottic cancer events occurring                                     75.0%). The concept of late recurrence has often been used
5 years after the initial treatment in the present study. This                                 in breast cancer and typically refers to those events occur-
difference may be attributed to our study design, which was                                    ring ≥ 5 years after diagnosis 26. However, confirmation of
aimed to reduce bias; we excluded patients with recurrence                                     late recurrence requires molecular analysis, which was not
within 5 years after the initial treatment and patients with-                                  performed in this study. If the molecular patterns of initial



528
                                                                         Long-term results (beyond 5 years) in patients with early glottic cancer




and new glottic lesions are identical, it may suggest late        review board (SNUH IRB No.1509-044-702). The need for
recurrences 27,28.                                                informed consent was waived because of the retrospective
One of the strengths of this study was the substantially long     nature of this analysis.
follow-up of our patients, with the longest being 266 months.     The research was conducted ethically, with all study pro-
Most studies on early glottic cancer only report 5-year fol-      cedures being performed in accordance with the require-
low-up. Therefore, our study offers a new perspective. Nev-       ments of the World Medical Association’s Declaration of
ertheless, there are limitations to this study that must be ac-   Helsinki.
knowledged. The retrospective nature of this single-centre
study might limit the generalisability of our findings. In ad-
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