10.14639/0392-100X-N0870
Background. The rates of laryngeal preservation according to therapeutic modality in pa- tients with initial laryngeal squamous cell carcinoma (LSCC) are still controversial. This study evaluated the rates of laryngeal preservation in patients who underwent treatment with surgery or radiotherapy.Methods. This retrospective cohort study evaluated 151 patients with stage I or II LSCC. Ninety-six patients were matched using a propensity-score and outcomes were compared within this group.Results. Regarding overall, cancer-specific survival and larynx preservation, no differences were observed according to the therapeutic modalities, but patients who underwent radio- therapy had a higher rate of local recurrence than those who underwent surgery. Patients classified as ASA 3 or 4 and treated with radiotherapy showed a tendency of higher risk of larynx loss.Conclusions. Patients with stage I or II laryngeal tumours can be submitted to surgery or&nbsp;radiotherapy with similar rates of laryngeal preservation.
text/xml
1827-675X
870
en
Luiz Paulo Kowalski
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
organ preservation
Organ preservation and oncological outcomes in early laryngeal cancer: a propensity score-based study
Text.Serial.Journal
https://www.actaitalica.it/
41
Laryngology
2021-09-14
2020-05-19
2021-09-15
2021-09-15
317-326
1
Luiz Paulo Kowalski
2021/09/14
10.14639/0392-100X-N0870
317
Head and Neck Surgery and Otorhinolaryngology Department, A. C. Camargo Cancer Center, São Paulo, Brazil; Head and Neck Surgery Department and LIM 28, University of Sao Paulo Medical School, Sao Paulo, Brazil
1827-675X
organ preservation
en
326
Organ preservation and oncological outcomes in early laryngeal cancer: a propensity score-based study
https://www.actaitalica.it/article/download/870/651
41
ACTA OTORHINOLARYNGOLOGICA ITALICA 2021;41:317-326; doi: 10.14639/0392-100X-N0870




Laryngology


Organ preservation and oncological outcomes in early
laryngeal cancer: a propensity score-based study
Preservazione d’organo ed esiti oncologici nel carcinoma laringeo in stadio iniziale:
uno studio basato sul punteggio di propensione
Genival Barbosa de Carvalho1, Hugo Fontan Kohler1, Julia Bette Homem de Mello1,3, Renan Bezerra Lira1,
Antonio Cássio de Assis Pellizzon2, José Guilherme Vartanian1, Luiz Paulo Kowalski1,4
1
 Head and Neck Surgery and Otorhinolaryngology Department, A. C. Camargo Cancer Center, São Paulo, Brazil; 2 Radiation
Oncology Department, A. C. Camargo Cancer Center, São Paulo, Brazil; 3 Carcinogenesis Molecular Program, National Institute
of Cancer - INCA, Rio de Janeiro, RJ, Brazil; 4 Head and Neck Surgery Department and LIM 28, University of Sao Paulo Medical
School, Sao Paulo, Brazil


SUMMARY
Background. The rates of laryngeal preservation according to therapeutic modality in pa-
tients with initial laryngeal squamous cell carcinoma (LSCC) are still controversial. This
study evaluated the rates of laryngeal preservation in patients who underwent treatment
with surgery or radiotherapy.
Methods. This retrospective cohort study evaluated 151 patients with stage I or II LSCC.
Ninety-six patients were matched using a propensity-score and outcomes were compared
within this group.                                                                              Received: May 19, 2020
Results. Regarding overall, cancer-specific survival and larynx preservation, no differences    Accepted: October 13, 2020
were observed according to the therapeutic modalities, but patients who underwent radio-
therapy had a higher rate of local recurrence than those who underwent surgery. Patients        Correspondence
classified as ASA 3 or 4 and treated with radiotherapy showed a tendency of higher risk of      Genival Barbosa de Carvalho
larynx loss.                                                                                    Head and Neck Surgery and Otorhinolaryngology
Conclusions. Patients with stage I or II laryngeal tumours can be submitted to surgery or       Department, A.C. Camargo Cancer Center
radiotherapy with similar rates of laryngeal preservation.                                      Rua Professor Antonio Prudente, 211, Liberdade
                                                                                                01509-900, São Paulo, Brazil
KEY WORDS: laryngeal neoplasms, laryngeal surgery, laryngeal radiotherapy, organ                Fax +55 11 3277 6789
preservation                                                                                    E-mail: genibarbo@gmail.com

                                                                                                Funding
RIASSUNTO
                                                                                                None.
Background. Le percentuali di conservazione della laringe nei diversi trattamenti dei pa-
zienti affetti da carcinoma a cellule squamose della laringe iniziale (LSCC) sono ancora
                                                                                                Conflict of interest
controversi. Questo studio ha valutato i tassi di preservazione laringea nei pazienti sotto-
                                                                                                The Authors declare no conflict of interest.
posti a trattamento chirurgico o radioterapia.
Metodi. Questo studio di coorte retrospettivo ha valutato 151 pazienti con LSCC, stadio
I o II. Novantasei pazienti sono stati abbinati utilizzando un punteggio di propensione e i       How to cite this article: de Carvalho GB, Kohler
risultati sono stati confrontati all’interno di questo gruppo.                                    HF, de Mello JBH, et al. Organ preservation and
Risultati. Per quanto riguarda la sopravvivenza globale, cancro-specifica e la conservazio-       oncological outcomes in early laryngeal cancer:
ne della laringe, non sono state osservate differenze in base alle modalità terapeutiche, ma      a propensity score-based study. Acta Otorhi-
                                                                                                  nolaryngol Ital 2021;41:317-326. https://doi.
i pazienti sottoposti a radioterapia avevano un tasso di recidiva locale più elevato rispetto
                                                                                                  org/10.14639/0392-100X-N0870
a quelli sottoposti a intervento chirurgico. Inoltre, i pazienti classificati come ASA 3 o 4
e trattati con radioterapia hanno mostrato una tendenza a un rischio maggiore di perdita
                                                                                                © Società Italiana di Otorinolaringoiatria
della laringe.                                                                                  e Chirurgia Cervico-Facciale
Conclusioni. I pazienti con tumori laringei in stadio I o II possono essere sottoposti a chi-
rurgia o radioterapia con tassi di conservazione laringea simili.                                              OPEN ACCESS
PAROLE CHIAVE: neoplasie laringee, chirurgia laringea, radioterapia laringea,                   This is an open access article distributed in accordance with
preservazione d’organo                                                                          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




                                                                                                                                                        317
G.B. de Carvalho et al.




Introduction                                                      formation relevant to the study or a follow-up time less of
                                                                  than 6 months.
The treatment of patients with early-stage (stages I and
                                                                  All patients were offered both therapeutic modalities. How-
II) laryngeal squamous cell carcinoma (LSCC) is usually
                                                                  ever, no resources for transoral laser surgery were avail-
based on a single modality, such as surgery or radiotherapy,
                                                                  able at our facility until 2014 and many patients refused
with similar overall survival rates 1-5. Studies evaluating or-
                                                                  conventional partial laryngectomy, due to nasoenteral tube,
gan preservation for these patients have reported controver-
                                                                  or tracheostomy. Therefore, most were treated with radio-
sial results. The systematic review by Warner et al. (2014)
                                                                  therapy. Patients were followed every 1 to 3 months in the
documented only one prospective, randomised study com-
                                                                  first year, every 2 to 4 months in the second year, every 6
paring surgery and radiotherapy in 234 patients with early-
                                                                  months from 3 to 5 years and thereafter every 12 months.
stage disease (all glottic tumours). They demonstrated that
                                                                  Follow-up was performed with videonasolaryngoscopy or
patients submitted to radiotherapy showed higher rates of
                                                                  laryngoscopy and computed tomography (CT) or magnetic
local recurrences than those submitted to surgery. However,
                                                                  resonance imaging (MRI) of the neck.
no information about organ preservation rates was avail-
                                                                  Clinical and pathological data were obtained from medical
able for either group, and no significant differences were
observed in overall and cancer-specific survival rates 6.         charts. A review of data from clinical locoregional physical
Some meta-analyses and systematic reviews including               examination, video laryngoscopy and direct laryngoscopy data
patients with glottic tumours at clinical stages Tis/T1/T2        was carried out to characterise tumour staging. All participants
and N0 have reported that laryngeal preservation rates are        were submitted to MRI or CT of the neck no more than six
higher in patients who underwent transoral laser surgery          weeks before initiation of treatment. In addition, participants
than in patients submitted to radiotherapy 7-9. However, the      were submitted to a simple chest X-ray or CT scan for de-
study by Jones et al. (2004) on 488 larynx cancer patients        tection of distant metastases or lung cancer. All patients were
at clinical stages I and II did not demonstrate a significant     re-staged in accordance with the Classification of Malignant
difference between overall and cancer-specific survival and       Tumours of the UICC (8th Edition) 10. Patients with permanent
local recurrence rates between treatments. The authors also       tracheostomy, recurrent aspiration pneumonia in the last year
described higher rates of regional recurrence and worse vo-       of follow-up, percutaneous gastrostomy, or nasoenteral tube
cal outcomes for patients submitted to surgery than those         were considered with loss of laryngeal function.
submitted to radiotherapy; however, they did not evaluate         To reduce selection bias from non-random allocation to dif-
the organ preservation rates of these patients 3. Most of         ferent treatments, we used propensity-score matching. The
these studies have some limitations, such as the heteroge-        variable used for propensity-score calculation was clinical
neity of treatments, follow-up time, and selection bias due       stage and treatment. Patients were matched according to
to patient or medical decisions.                                  the nearest-neighbor algorithm with a 0.02 caliper. The p-
Considering these controversial results, the present study        value for statistical significance was 5%. Survival curves
evaluated laryngeal preservation rates and survival in pa-        and laryngo-oesophageal dysfunction were analysed using
tients with laryngeal epidermoid carcinoma at stage I or II       the Kaplan Meier method, assessing statistical significance
treated with surgery (transoral or conventional) or radio-        between groups with the log-rank test. Cox regression was
therapy. A propensity score (PS) analysis was performed to        used to estimate the risk factors for clinical outcomes, with
reduce the influence of selection bias in outcome analysis.       its influence evaluated by hazard ratio (HR) and 95% con-
                                                                  fidence intervals. Statistical analysis was performed using
                                                                  SPSS software (v. 21.0; SPSS, Chicago, IL, USA).
Materials and methods
                                                                  Results
Patients, clinical and histopathological characterisation
This is a retrospective cohort study and included 151
patients with cT1N0 or cT2N0 LSCC treated with cura-              Clinical data
tive intent from January 1995 to December 2014 at A.C.            According to inclusion and exclusion criteria, 151 patients
Camargo Cancer Center (Brazil). The study was approved            were included in the study. Among these, 124 patients were
by the ethics committee (2118/15). Inclusion criteria in-         men (82%) and the median age was 61 years (range 22-77
cluded previously untreated LSCC at clinical stages I or II       years). The majority of the patients (n = 135; 89%) had
and treated with curative intent. Exclusion criteria included     previous tobacco exposure and 92 (58.5%) were consumers
patients with other synchronous, prior malignancies in the        of alcoholic beverages. Sixty-six patients (45.2%) had co-
head and neck and those whose medical records lacked in-          morbidities at diagnosis, with hypertension (n = 14; 9.2%)



318
                                                                                              Organ preservation in early laryngeal cancer




and type II diabetes (n = 7; 4.2%) being the most frequent.    treatment, the overall survival rates of patients submitted to
Thirty-five patients (41.2%) were in the normal weight         surgery and radiotherapy were 70.4% and 77.6%, respec-
range considering body mass index (BMI) and most were          tively (p = 0.43) (Fig. 1).
classified as ASA 2 (n = 72; 76.6%). The follow-up pe-         Cancer-specific survival (CSS) rates at 5 and 10 years were
riod ranged from 6 to 276 months (median of 55 months).        89.7% and 83.2%, respectively. The CSS rate at 5 years
Twenty-three (15.2%) patients were lost to follow up, with     was 85.9% for patients with glottic tumours and 87.6% for
a median time of 34 months (ranging from 18 days to 97         patients with other tumour locations (p = 0.61); 87.1% for
months). There were no significant differences between pa-     patients with clinical stage I and 88.2% for patients with
tients lost to follow-up according to treatment.               clinical stage II (p = 0.47); 87.3% for tumors with staging
Among these patients, 96 were matched after PS analysis.
                                                               cT1a, 70% cT1b and 88.2% cT2 (p = 0.64). In relation to
These groups were used to evaluate the association of treat-
                                                               treatment, the CSS rates in patients submitted to surgery
ment modality with clinical outcomes and functional lar-
                                                               and radiotherapy were 89.2% and 86.7%, respectively
ynx preservation rates.
Of the 48 patients submitted to surgery, 37 (77,1%) un-        (p = 0.78) (Fig. 2). Table II shows the estimates of the pa-
derwent a conventional partial laryngectomy, 12 (25%)
underwent frontolateral partial laryngectomy, 11 (22.9%)
transoral endoscopic surgery resection and 39 (81,2)%)
had resection with free margins. After pathological analy-
sis, three of 18 cT1a patients were upstaged to pT2. From
28 tumours staged as cT2, six (21.4%) were staged as pT1
and six (21.4%) as pT3 due to paraglottic space invasion.
No patient with a transglottic tumour was submitted to sur-
gery. Among these patients, eight (16.6%) underwent post-
operative adjuvant radiotherapy by positive margins.
In patients submitted to radiotherapy, the final dose ranged
from 51.7 to 70.4 Gy (median, 66 Gy) for cT1a patients,
50.5 to 70 Gy (median, 64.2 Gy) for cT1b patients and 54
to 74.4 Gy (median, 69.7 Gy) in cT2 patients. Radiotherapy
treatment time was 51 days, ranging from 26 to 85 days.
Most patients presented acute side effects (n = 45; 95.8%),
with radiodermatitis grades 1 or 2 being the most frequent,
but only four (3.9%) patients discontinued the treatment       Figure 1. Overall survival by treatment.
due to complications.
Table I depicts the characteristics of all patients and the
study sample after selection, with higher prevalence of
smokers, alcohol consumers and supraglottic tumors in the
group submitted to surgery, and more glottic tumours in the
group submitted to radiotherapy. Tumour extension to the
anterior commissure was more prevalent in the radiother-
apy group. No other significant differences were observed
between groups.

Overall survival and cancer-specific survival
The overall survival rate was 78.6% at 5 years, and 64.2%
at 10 years. No significant difference in overall survival
was observed between groups. The overall survival rate at 5
years was 78.9% for patients with glottic tumors and 67.9%
for patients with other tumour locations (p = 0.59); 80.9%
for patients with clinical stage I and 70.4% for clinical
stage II (p = 0.61); it was 79.4% for tumours with staging
cT1a, 87.5% cT1b and 73% cT2 (p = 0.72). In relation to        Figure 2. Cancer-specific survival by treatment.



                                                                                                                                    319
G.B. de Carvalho et al.




Table I. Demographic variables related to the patient and tumour extension by categories and frequencies according to the treatment performed before and after
the propensity score.
 Variables               Categories                         Before propensity score                                   After propensity score
                                                            Surgery                Radiotherapy                p*             Surgery      Radiotherapy    p
                                                            Freq. (%)                Freq. (%)                                Freq. (%)      Freq. (%)
    Gender                         Female                    5 (10.4%)               22 (21.4%)             0.160              5 (10.4%)    11 (22.9%)    0.170
                                     Male                   43 (89.6%)               81 (78.6%)                               43 (89.6%)     37 (77.1)
    Age (years)                      ≤ 70                   39 (81.3%)               73 (70.9%)             0.247             39 (81.3%)    39 (81.3%)     1
                                     > 70                    9 (18.8%)               30 (29.1%)                                9 (18.8%)     9 (18.8%)
    Education level            No graduation                32 (82.1%)               61 (75.4%)             0.140             32 (82.1%)    27 (72.9%)    0.198
                             Graduation or more              7 (17.9%)               21 (25.6%)                                7 (17.9%)   10 (27.10%)
    Race                            White                   43 (89.6%)               97 (94.2%)             0.512             43 (89.6%)   46 (95.8%)     0.488
                                   No white                  5 (10.4%)                 6 (5.8%)                                 3 (6.3%)     1 (2.1%)
    Smoking                           No                      0 (0.0%)               16 (16.3%)             0.003               0 (0.0%)    7 (15.2%)     0.006
                                     Yes                    36 (75.0%)               50 (51.0%)                               36 (75.0%)   23 (50.0%)
                                 Ex-smoker                  12 (25.0%)               32 (32.7%)                               12 (21.2%)   16 (34.8%)
    Alcohol use                       No                    12 (25.0%)               47 (50.0%)             0.005             12 (25.0%)   21 (47.7%)     0.021
                                     Yes                    29 (60.4%)               43 (45.7%)                               29 (60.4%)   22 (50.0%)
                                  Ex-drinker                 7 (14.6%)                 4 (4.3%)                                7 (14.6%)     1 (2.3%)
    Comorbidities                     No                    20 (42.6%)               60 (60.6%)             0.062             20 (42.6%)   28 (59.6%)     0.074
                                     Yes                    27 (57.4%)               39 (39.4%)                               27 (57.4%)   19 (40.4%)
    BMI**                       Underweight                   1 (3.2%)                1 ( 1.9%)             0.612               1 (3.2%)     1 (4.5%)     0.609
                                    Heathy                  15 (48.4%)               20 (37.0%)                               15 (48.4%)    7 (31.8%)
                             Excess body weight             11 (35.5%)               27 (50.0%)                               11 (35.5%)   12 (54.5%)
                                    Obese                    4 (12.9%)                6 (11.2%)                                4 (12.9%)     2 (9.1%)
    ASA***                             1                      1 (2.4%)                4 ( 7.5%)             0.622               1 (2.4%)    2 (10.0%)     0.409
                                       2                    34 (82.9%)              38t (71.7%)                               34 (82.9%)   14 (70.0%)
                                       3                     5 (12.2%)                9 (17.0%)                                5 (12.2%)    4 (20.0%)
                                       4                     1 ( 2.4%)                2 ( 3.8%)                                 1 (2.4%)     0 (0.0%)
    Tumour site                     Glottic                 22 (45.8%)               90 (87.4%)            < 0.001            22 (45.8%)   39 (81.3%)     0.03
                                Supraglottic                26 (54.2%)               11 (10.7%)                               26 (54.2%)    7 (14.6%)
                                 Transglottic                0 (0.0%)                 2 (1.9%)                                  0 (0.0%)     2 (4.2%)
    Clinical tumour                  T1a                    18 (37.0%)               49 (47.6%)             0.001              18 (37.%)   14 (29.2%)     0.287
    stage                            T1b                     2 (4.2%)                23 (22.3%)                                2 (4.2%)     6 (12.5%)
                                      T2                    28 (58.3%)               31 (30.1%)                               28 (58.3%)   28 (58.3%)
    Anterior                          No                    45 (93.8%)               75 (72.8%)             0.006             45 (93.8%)   37 (77.1%)     0.04
    commissure                       Yes                     3 (6.3%)                28 (27.2%)                                3 (6.3%)    11 (22.9%)
    Clinical stage                      I                   20 (41.7%)               72 (69.9%)             0.002             20 (41.7%)   20 (41.7%)     0.999
                                       II                  28 (58.3%)               31 (30.1%)                                28 (58.3%)   28 (58.3%)
    Previous                          No                   48 (100.0%)              101 (98.1%)              1.00             48 (100%)    46 (95.8%)     0.247
    tracheostomy                     Yes                       0 (0%)                2 (1.19%)                                 0 (0.0%)      2 (4.2%)
*
    Chi-square test. ** Body mass index *** Physical Status Classification System of American Society of Anesthesiologists.




320
                                                                                                                                     Organ preservation in early laryngeal cancer




Table II. Estimates of the parameters of the Cox regression model for the outcome of overall and cancer-specific survival.
 Variables          Categories              Overall survival                                             Cancer-specific
                                               No event              Event               HR              p            No event              Event
                                               (n = 70)             (n = 26)                                          (n = 84)             (n = 12)        HR            p
    Gender                   Female           13 (18.6%)           3 (11.5%)            Ref                          15 (17.9%)           1 (8.3%)         Ref         0.385
                              Male            57 (81.4%)          23 (88.5%)           1.712          0.381          69 (82.1%)          11 (91.7%)       2.478
    Age (years)               ≤ 70             56 (80%)           22 (84.6%)            Ref                          67 (79.8%)          11 (91.7%)        Ref         0.377
                              > 70             14 (20%)           4 (15.4%)            0.784          0.655          17 (20.2%)           1 (8.3%)        0.398
    Race                      White           65 (92.9%)          24 (92.3%)            Ref                          53 (80.3%)          6 (60.0%)         Ref         0.152
                            No white           5 (7.1%)            2 (7.7%)            2.359          0.250          13 (19.7%)          4 (40.0%)        2.550
    Education                  No             44 (78.6%)           15 (75%)             Ref                          77 (91.7%)          12 (100%)
    degree level           graduation
                          Graduation or       12 (21.4%)            5 (25%)            1.247          0.670           7 (8.3%)            0 (0.0%)         NE*
                              more
    Smoking                     No              6 (8.8%)            1 (3.8%)            Ref                            7 (8.5%)            0 (0.0%)        NE*
                               Yes            41 (60.3%)          18 (69.2%)           2.495          0.374          50 (61.0%)           9 (75.0%)        NE*
                           Ex-smoker          21 (30.9%)           7 (26.9%)           2.128          0.480          25 (30.5%)           3 (25.0%)        NE*
    Alcohol use                 No            24 (36.4%)           9 (34.6%)            Ref                          28 (35.0%)           5 (41.7%)        NE*
                               Yes            38 (57.6%)           13 (50%)            1.071          0.874          44 (55.0%)           7 (58.3%)        NE*
                           Ex-drinker           4 (6.1%)           4 (15.4%)           3.041          0.066           8 (10.0%)            0 (0.0%)        NE*
    Comorbidities               No            35 (51.5%)           13 (50%)             Ref                          42 (51.2%)           6 (50.0%)        Ref         0.688
                               Yes            33 (48.5%)           13 (50%)            0.792          0.553          40 (48.8%)           6 (50.0%)       0.793
    BMI**                  No heathy          24 (57.1%)           7 (63.6%)            Ref                          28 (58.3%)           3 (60.0%)                    0.933
                             Heathy           18 (42.9%)           4 (36.4%)           0.993          0.992          20 (41.7%)           2 (40.0%)       1.081
    ASA***                    1 or 2          39 (84.8%)           12 (80%)             Ref                          45 (83.3%)           6 (85.7%)        Ref         0.979
                              3 or 4           7 (15.2%)            3 (20%)            1.386          0.617           9 (16.7%)           1 (14.3%)       0.972
    Tumour site             No glottic        23 (32.9%)          12 (46.2%)            Ref                          31 (36.9%)           4 (33.3%)        Ref         0.616
                              Glottic         47 (67.1%)          14 (53.8%)           0.808          0.588          53 (63.1%)           8 (66.7%)       1.359
    Clinical tumour             1a            26 (37.1%)           6 (23.1%)            Ref                          28 (33.3%)           4 (33.3%)        Ref         0.586
    stage                       1b              5 (7.1%)           3 (11.5%)           1.599          0.507           6 (7.1%)            2 (16.7%)       1.604        0.669
                                2             39 (55.7%)          17 (65.4%)           1.412          0.468          50 (59.5%)           6 (50.0%)       0.759
    Clinical stage                I           31 (44.3%)           9 (34.6%)            Ref                          34 (40.5%)           6 (50.0%)        Ref         0.478
                                 II           39 (55.7%)          17 (65.4%)           1.236          0.608          50 (59.5%)           6 (50.0%)       0.664
    Anterior                   No             61 (87.1%)          21 (80.8%)            Ref                          72 (85.7%)          10 (83.3%)        Ref         0.934
    commissure                 Yes             9 (12.9%)           5 (19.2%)           1.298          0.601          12 (14.3%)          2 (16.7%)        1.066
    Treatment                Surgery          34 (48.6%)          14 (53.8%)            Ref                          42 (50.0%)          6 (50.0%)         Ref         0.784
                          Radiotherapy        36 (51.4%)          12 (46.2%)           0.736          0.436          42 (50.0%)          6 (50.0%)        0.854
*
    There are no numbers to evaluate ** Body mass index. *** Physical Status Classification System of American Society of Anesthesiologists.



rameters of the Cox regression model for the outcome of                                         tumours who underwent radiotherapy had a higher risk of
overall and cancer-specific survival and Figure 2 shows                                         local recurrences. Conversely, no significance differences
CSS by treatment.                                                                               were seen for gender, tobacco and alcohol exposure, patho-
                                                                                                logical classification and tumour extension for anterior
                                                                                                commissure. The LRFS rate was 76.5% for patients with
Local recurrence-free survival
                                                                                                glottic tumours and 83.7% for patients with tumours at
The local recurrence-free survival (LRFS) rate was 76.5%                                        other locations (p = 0.048); 79.3% for patients with clinical
at 5 years, and 67.6% at 10 years. The recurrence rate                                          stage I disease and 79.3% for patients with clinical stage
was 12.5% after surgery and 37.5% after radiotherapy                                            II (p = 0.53); and 79.2% for tumours staged cT1a, 74.3%
(p = 0.021). Patients classified as ASA 3 or 4 with glottic                                     cT1b and 79.2% cT2 (p = 0.73). With respect to treatment,



                                                                                                                                                                             321
G.B. de Carvalho et al.




Figure 3. Local recurrence-free survival by treatment.         Figure 4. Laryngo-oesophageal dysfunction free survival by treatment.


LRFS rates of patients submitted to surgery and radiothera-    ryngeal preservation and Figure 4 shows laryngo-oesopha-
py were 84.3% and 63.6%, respectively (p = 0.016) (Fig. 3,     geal dysfunction-free survival curves.
Tab. III).
Among patients who underwent surgery, six had local re-        Discussion
currence, with one frontolateral partial laryngectomy and
three total laryngectomies with neck dissection and adju-      The treatment of patients with LSCC at clinical stages
vant radiotherapy as salvage procedures. Chemoradiother-       cT1N0 or cT2N0 depends on various factors such as avail-
apy as an organ preservation strategy after local recurrence   ability of infrastructure for each treatment modality, the
was performed in two patients. In patients treated with ra-    patient’s physical condition, multidisciplinary team prefer-
diotherapy, 18 presented local recurrence, 14 were submit-     ences and patient choice, especially regarding voice pres-
ted to total laryngectomy with neck dissection, two to fron-   ervation together with characteristics of the tumours, and
tolateral laryngectomy, one supracricoid laryngectomy and      especially its primary location. Thus, random prospective
one to endoscopic transoral surgery. Local recurrence rates    studies for this group of patients have not been developed,
were higher in patients with supraglottic tumours staged by    with the exception of Ogol’tsova et al. (1990) cited by
cT2 and treated with radiotherapy (Tab. IV).                   Warner et al. (2014), which has some methodological is-
                                                               sues.
Laryngeal preservation                                         Data from the literature and previous analysis of this study
The laryngeal preservation rate was 78.2%. No correlation      showed a trend towards the use of radiotherapy in patients
was found between the probability of laryngeal preserva-       with glottic tumours and the use of surgery in patients with
tion and the variables analysed, although patients with        supraglottic tumours or stage cT2N0. Thus, the propen-
ASA classification 3 or 4 who underwent radiotherapy pre-      sity score was used to reduce the impact of selection bias
sented a tendency towards higher risk of laryngeal loss, but   in outcomes. This methodology has been largely used in
without statistical significance. Among the 48 patients who    medicine and is considered a good option for randomised
underwent surgery, seven had a non-functional larynx at        prospective clinical studies 11.
the end of follow-up: three were submitted to salvage total    OS and CSS had no significant association with clinical
laryngectomy, two presented chronic aspiration and had a       variables. Although Guimarães et al. (2018) described a
percutaneous gastrostomy and two had permanent trache-         higher OS and CSS rates for patients with glottic tumours
ostomy due to laryngeal stenosis. In the patients treated by   cTis/cT1a treated with surgery compared to those treated
radiotherapy, except for 14 who underwent salvage total        with radiotherapy. Similar results were found in the study
laryngectomy, the remaining had a functioning larynx at        by Vaculik et al. (2019) on patients with cT1 stage glottic
the time of assessment. Table V shows the estimates of the     tumours. In contrast, the systematic reviews by Yoo et al.
parameters of the simple logistic regression model for la-     (2014) and Warner et al. (2014) found no significant differ-



322
                                                                                                                            Organ preservation in early laryngeal cancer




Table III. Estimates of the parameters of the Cox regression model for the outcome of local recurrence-free survival.
 Variables                 Categories               Local recurrence                 HR                           CI (95%)                                    p
                                                         No event              Event
                                                         (n = 72)             (n = 24)                              Lower              Higher
    Gender                        Female                13 (18.1%)          3 (12.5%)                Ref
                                    Male                59 (81.9%)          21 (87.5%)              1.594           0.475               5.347               0.450
    Age (years)                     ≤70                 55 (76.4%)          23 (95.8%)               Ref
                                    > 70                17 (23.6%)            1 (4.2%)              0.164           0.022               1.217               0.077
    Race                           White                65 (90.3%)          24 (100%)
                                  No white               7 (9.7%)             0 (0.0%)               NA
    Education degree           No graduation            43 (76.8%)           16 (80.%)               Ref
    level                    Graduation or more         13 (23.2%)           4 (20.0%)              0.866           0.289               2.595               0.798
    Smoking                          No                  6 (8.6%)             1 (4.2%)               Ref
                                     Yes                44 (62.9%)          15 (62.5%)              2.012           0.265              15.251               0.499
                                 Ex-smoker              20 (28.6%)           8 (33.3%)              2.233           0.279              17.883               0.449
    Alcohol use                      No                 25 (36.8%)           8 (33.3%)               Ref
                                     Yes                36 (52.9%)          15 (62.5%)              1.406           0.596               3.320               0.436
                                 Ex-drinker              7 (10.3%)            1 (4.2%)              0.734           0.091               5.890               0.771
    Comorbidities                    No                 35 (50.0%)          13 (54.2%)               Ref
                                     Yes                35 (50.0%)          11 (45.8%)              0.663           0.296               1.483               0.317
    BMI*                         No heathy              25 (59.5%)           6 (54.5%)               Ref
                                   Heathy               17 (40.5%)           5 (45.5%)              1.163           0.354               3.821               0.803
    ASA **
                                   1 or 2               42 (89.4%)          9 (64.3%)                Ref
                                   3 or 4               5 (10.6%)           5 (35.7%)               3.092           1.030               9.285               0.044
    Tumour site                  No glottic             30 (41.7%)           5 (20.8%)               Ref
                                   Glottic              42 (58.3%)          19 (79.2%)              2.705           1.008               7.261               0.048
    Clinical tumour                  1a                 23 (31.9%)           9 (37.5%)               Ref
    stage                            1b                  6 (8.3%)             2 (8.3%)              0.695           0.150               3.219               0.642
                                      2                 43 (59.7%)          13 (54.2%)              0.718           0.306               1.681               0.445
    Clinical stage                    I                 29 (40.3%)          11 (45.8%)               Ref
                                      II                43 (59.7%)          13 (54.2%)              0.775           0.347               1.731               0.534
    Anterior                         No                 62 (86.1%)          20 (83.3%)               Ref
    commissure                       Yes                10 (13.9%)           4 (16.7%)              1.021           0.349               2.991               0.969
    Treatment                     Surgery               42 (58.3%)           6 (25.0%)               Ref
                                Radiotherapy            30 (41.7%)          18 (75.0%)              2.967           1.177               7.479               0.016
*
    Body mass index. ** Physical Status Classification System of American Society of Anesthesiologists.



Table IV. Local recurrence-free survival estimates at 5 years by tumour location and staging according to treatment.
 Variables                                    Categories                                                Treatment                                             p
                                                                                                          Surgery               Radiotherapy
    Tumour site/Stage                       Glottic                         T1                             76.5%                    63.2%                   0.949
                                                                            T2                             80.0%                    65.0%                   0.286
                                         Supraglottic                       T1                            100.0%                   100.0%                     1
                                                                            T2                             95.7%                    50.0%                   0.04




                                                                                                                                                                    323
G.B. de Carvalho et al.




Table V. Estimates of parameters of the simple logistic regression model for laryngeal preservation.
 Variables            Categories                Laryngeal preservation                       p                                               95% CI                               p
                                                      No (n = 21)                  Yes (n = 75)                                 OR            Lower           Higher
 Gender                      Female                      2 (9.5%)                   14 (18.7%)              0.510*             Ref
                              Male                     19 (90.5%)                   61 (81.3%)                                0.459           0.096           2.201            0.330
 Age                          ≤ 70                     18 (85.7%)                   60 (80.0%)              0.755              Ref
                              > 70                      3 (14.3%)                   15 (20.0%)                                1.500           0.390           5.768            0.555
 Race                         White                    21 (100%)                    68 (90.7%)              0.341*
                            No White                     0 (0.0%)                    7 (9.3%)                                  NA
 Education                No graduation                15 (78.9%)                   44 (77.2%)              0.999   *
                                                                                                                               Ref
 degree level             Graduation or                 4 (21.1%)                   13 (22.8%)                                1.108           0.313           3.924            0.874
                              more
 Smoking                       No                        0 (0.0%)                     7 (9.6%)             0.334***            NA
                               Yes                     14 (66.7%)                   45 (61.6%)                                 NA
                           Ex-smoker                    7 (33.3%)                   21 (28.8%)                                 NA
 Alcohol use                   No                       8 (38.1%)                   25 (35.2%)             0.765***            Ref
                               Yes                     12 (57.1%)                   39 (54.9%)                                1.040           0.373           2.901            0.940
                           Ex-drinker                   1 (4.8%)                     7 (9.9%)                                 2.240           0.238          21.072            0.481
 Comorbidities                 No                      10 (47.6%)                   38 (52.1%)              0.912**            Ref
                               Yes                     11 (52.4%)                   35 (47.9%)                                0.837           0.317           2.213            0.720
 BMI****                   No heathy                   10 (76.9%)                   21 (52.5%)              0.219**            Ref
                             Heathy                     3 (23.1%)                   19 (47.5%)                                3.016           0.721          12.624            0.131
 ASA   *****
                              1 or 2                   10 (66.7%)                   41 (89.1%)              0.101   *
                                                                                                                               Ref
                              3 or 4                    5 (33.3%)                    5 (10.9%)                                0.244           0.059           1.008            0.051
 Tumour site                No glottic                  5 (23.8%)                   30 (40.0%)              0.269**            Ref
                              Glottic                  16 (76.2%)                   45 (60.0%)                                0.469           0.155           1.416            0.179
 Anterior                      No                      16 (76.2%)                    66 (88%)               0.180*             Ref
 commissure                    Yes                      5 (23.8%)                     9 (12%)                                 0.436           0.129           1.481            0.184
 cT                             1a                      5 (23.8%)                   27 (36.0%)             0.380   ***
                                                                                                                               Ref
                                1b                      3 (14.3%)                     5 (6.7%)                                0.309           0.055           1.724            0.180
                                2                      13 (61.9%)                   43 (57.3%)                                0.613           0.196           1.912            0.399
 Treatment                   Surgery                   7 (33.3%)                    41 (54.7%)              0.139**            Ref
                          Radiotherapy                 14 (66.7%)                   34 (45.3%)                                0.415           0.150           1.144            0.089
NA: Not available due to insufficient number for calculation OR. * Fisher exact test. ** Chi-square test with continuity correction. *** Chi-square test. **** Body mass index. **** Physical
Status Classification System of American Society of Anesthesiologists.



ences in OS and CSS between surgery and radiotherapy in                                          The laryngeal preservation rate has been controversially
patients with early laryngeal cancer.                                                            reported in the literature. Some authors demonstrated
The local recurrence-free survival rate was lower in patients                                    higher rates of preservation in patients who underwent
classified as ASA 3 or 4, with glottic tumours, and submit-                                      surgery 8,12-15, whereas others demonstrated that radio-
ted to radiotherapy. These patients were preferably treated                                      therapy shows similar results to surgery with even better
with radiotherapy because of the high risk of surgery and                                        functional results 3,16,17. In the present study, we observed
to improve the quality of voice preservation, respectively.                                      a higher tendency for laryngeal preservation in patients
Kowalski et al. (1993) evaluated 145 patients treated be-                                        who underwent surgery compared with those who under-
tween 1954 and 1990 and described a higher rate of local                                         went radiotherapy, although the difference was not statis-
recurrences in patients undergoing radiotherapy (29.5%)                                          tically significant. Compared with surgery, radiotherapy
compared to those who underwent surgery (10%). Of                                                showed higher rates of local recurrence (12.5 vs 37.5%)
course, differences in technology in diagnosing and treat-                                       and 22% were candidates for salvage partial laryngecto-
ing these tumors has a definite impact on clinical outcomes.                                     my. In this scenario, partial laryngectomy presented high



324
                                                                                                 Organ preservation in early laryngeal cancer




rates of local complications, longer decannulation and          Conclusions
enteral feeding times, and a higher risk of second recur-
                                                                Patients with LSCC at clinical stages I/II treated with sur-
rences. Therefore, patients must be carefully selected for
                                                                gery or radiotherapy at a reference oncology centre with
this treatment modality 18,19.
                                                                multidisciplinary teams and regular post-treatment follow-
Long-term laryngeal preservation in patients who had local
                                                                up seems to have similar overall and cancer-specific sur-
recurrence is dependent on the patient’s physical condition,
                                                                vival. However, even in this scenario, treatment with radio-
the possibility of proper follow up and the experience of
                                                                therapy is associated with a higher risk of local recurrence,
the multidisciplinary team in performing partial salvage
                                                                not only for possible inappropriate clinical staging, but also
laryngectomy 20,21. These factors should also be considered
                                                                due to biological factors related to radiotherapy resistance.
when choosing initial treatment. Furthermore, the initial
                                                                Thus, the appropriate follow-up and expertise of perform-
therapeutic choice should also consider the outcome of the
                                                                ing salvage partial laryngectomy after local recurrence
salvage treatment.
                                                                after radiotherapy is essential to achieve similar laryngeal
In pathological staging, 16.7% of cT1a tumours were re-
                                                                preservation rates.
staged for pT2; of 28 cT2 tumours, 17 (60.7%) had a differ-
ent final pathological staging: six were pT1a (21.4%), six
were pT3 (21.4%) and five changed to pT4a (17.8%) due to        References
laryngeal cartilage in the anterior commissure invasion (not    1
                                                                     Kowalski LP, Batista MB, Santos CR, et al. Prognostic factors in glot-
detected on previous CT for pre-surgery staging). There-             tic carcinoma clinical stage I and II treated by surgery or radiotherapy.
                                                                     Am J Otolaryngol 1993;14:122-127.
fore, the higher incidence of local recurrence in patients
                                                                2
                                                                     Ansarin M, Zabrodsky M, Bianchi L, et al. Endoscopic CO2 laser
who underwent radiotherapy than in those who underwent               surgery for early glottic cancer in patients who are candidates for ra-
surgery could be related not only to biological factors, but         diotherapy: results of a prospective nonrandomized study. Head Neck
also to inappropriate clinical tumour stage. Thus, accurate          2006;28:121-125. https://doi.org/10.1002/hed.20301
clinical staging is essential for adequate treatment, espe-     3
                                                                     Jones DA, Mendenhall CM, Kirwan J, et al. Radiation therapy for man-
                                                                     agement of t1-t2 glottic cancer at a private practice. Am J Clin Oncol
cially in cT2.
                                                                     2010;33:587-590. https://doi.org/10.1097/COC.0b013e3181beaab0
 Regarding the radiotherapy group, the rate of radiotherapy     4
                                                                     Thomas L, Drinnan M, Natesh B, et al. Open conservation partial
interruption was only 3.9%, and patients were treated with           laryngectomy for laryngeal cancer: a systematic review of English
doses of radiation described in the literature: a median of          language literature. Cancer Treat Rev 2012;38:203-211. https://doi.
66 Gy in cT1a tumours, 64.2 Gy in cT1b tumours and 69.7              org/10.1016/j.ctrv.2011.05.010
Gy in cT2 tumours 22,23.
                                                                5
                                                                     O’Hara J, Markey A, Homer JJ. Transoral laser surgery versus ra-
                                                                     diotherapy for tumour stage 1a or 1b glottic squamous cell carci-
Despite the use of the PS method to match patients accord-           noma: systematic review of local control outcomes. J Laryngol Otol
ing to treatment modality, this study has limitations inher-         2013;127:732-738. https://doi.org/10.1017/S0022215113001400
ent to the retrospective cohort design. Unlike randomised       6
                                                                     Warner L, Chudasama J, Kelly CG, et al. Radiotherapy versus open
prospective studies where groups are matched by known                surgery versus endolaryngeal surgery (with or without laser) for
                                                                     early laryngeal squamous cell cancer. Cochrane Database Syst Rev
and unknown variables, the propensity score method does              2014;12:CD002027. https://doi.org/ 10.1002/14651858.CD002027
not allow matching by all characteristics. This study also      7
                                                                     Yoo J, Lacchetti C, Hammond JA, et al. Role of endolaryngeal surgery
demonstrated additional significant differences between              (with or without laser) versus radiotherapy in the management of ear-
the groups even after PS matching. A high prevalence of              ly (T1) glottic cancer: a systematic review. Head Neck 2014;36:1807-
                                                                     1819. https://doi.org/10.1002/hed.23504
alcohol and tobacco consumers and cT2N0 tumours was             8
                                                                     Hendriksma M, Heijnen BJ, Sjögren EV. Oncologic and functional
observed in the surgery group, whereas the group treated             outcomes of patients treated with transoral CO2 laser microsurgery
with radiotherapy had a higher prevalence of cT1aN0 glot-            or radiotherapy for T2 glottic carcinoma: a systematic review of the
tic tumors. These characteristics may indicate a bias in             literature. Curr Opin Otolaryngol Head Neck Surg 2018;26:84-93.
                                                                     https://doi.org/10.1097/MOO.0000000000000438.
group selection. These types of biases have been a limita-
                                                                9
                                                                     Guimarães AV, Dedivitis RA, Matos LL, et al. Comparison be-
tion in a variety of retrospective studies 24 in comparison
                                                                     tween transoral laser surgery and radiotherapy in the treatment of
to randomised prospective trials 25. The presence of miss-           early glottic cancer: a systematic review and meta-analysis. Sci Rep
ing values for some variables is also a limitation, such as          2018;8:11900. https://doi.org/10.1038/s41598-018-30218-x
the possibility of adequate exposure of the larynx in pa-       10
                                                                     Amin MB, Edge SB, Greene FL, et al. AJCC Cancer Staging Manual.
tients who underwent radiotherapy, whether the therapeutic           Eighth edition. New York: Springer; 2017. Larynx; pp. 46-64.
choice was made mainly by the medical team or the patient,
                                                                11
                                                                     Loux TM. Randomization, matching, and propensity scores in the
                                                                     design and analysis of experimental studies with measured base-
lack of information regarding final vocal quality, and treat-        line covariates. Stat Med 2015;34:558-570. https://doi.org/10.1002/
ment costs according to therapeutic modality.                        sim.6361




                                                                                                                                        325
G.B. de Carvalho et al.




12
     Abdurehim Y, Hua Z, Yasin Y, et al. Transoral laser surgery versus            cer. Laryngoscope 2019;129:2328-2333. https://doi.org/10.1002/
     radiotherapy: systematic review and meta-analysis for treatment op-           lary.27702
     tions of T1a glottic cancer. Head Neck 2012;34:23-33. https://doi.       19
                                                                                   Bertolin A, Lionello M, Ghizzo M, et al. Salvage open partial hori-
     org/10.1002/hed.21686                                                         zontal laryngectomy after failed radiotherapy: a multicentric study.
13
     Succo G, Crosetti E, Bertolin A, et al. Benefits and drawbacks of             Laryngoscope 2020;130:431-436. https://doi.org/10.1002/lary.27959
     open partial horizontal laryngectomies. Part A: early-to intermediate-   20
                                                                                   Pontes P, Brasil Ode O, Amorim Filho Fde S, et al. Radiotherapy
     stage glottic carcinoma. Head Neck 2016;38:333-340. https://doi.
                                                                                   for early glottic cancer and salvage surgery after recurrence. Braz
     org/10.1002/hed.23997
                                                                                   J Otorhinolaryngol 2011;77:299-302. https://doi.org/10.1590/
14
     Ansarin M, Cattaneo A, De Benedetto L, et al. Retrospective analysis          s1808-86942011000300005
     of factors influencing oncologic outcome in 590 patients with early-     21
                                                                                   Agra IM, Ferlito A, Takes RP, et al. Diagnosis and treatment of re-
     intermediate glottic cancer treated by transoral laser microsurgery.
     Head Neck 2017;39:71-81. https://doi.org/10.1002/hed.24534                    current laryngeal cancer following initial nonsurgical therapy. Head
                                                                                   Neck 2012;34:727-735. https://doi.org/10.1002/hed.21739
15
     Vaculik MF, MacKay CA, Taylor SM, et al. Systematic review and
     meta-analysis of T1 glottic cancer outcomes comparing CO(2) tran-
                                                                              22
                                                                                   Mendenhall WM, Parsons JT, Stringer SP, et al. Management of Tis, T1,
     soral laser microsurgery and radiotherapy. J Otolaryngol Head Neck            and T2 squamous cell carcinoma of the glottic larynx. Am J Otolaryn-
     Surg 2019;48:44. https://doi.org/10.1186/s40463-019-0367-2                    gol 1994;15:250-257. https://doi.org/10.1016/0196-0709(94)90091-4
16
     Rosier JF, Grégoire V, Counoy H, et al. Comparison of external ra-
                                                                              23
                                                                                   Franchin G, Minatel E, Gobitti C, et al. Radiation treatment of glottic
     diotherapy, laser microsurgery and partial laryngectomy for the               squamous cell carcinoma, stage I and II: analysis of factors affecting
     treatment of T1N0M0 glottic carcinomas: a retrospective evalua-               prognosis. Int J Radiat Oncol Biol Phys 1998;40:541-548. https://doi.
     tion. Radiother Oncol 1998;48:175-183. https://doi.org/10.1016/               org/10.1016/s0360-3016(97)00768-2
     s0167-8140(98)00058-9                                                    24
                                                                                   Enarson DA, Kennedy SM, Miller DL. Choosing a research study
17
     Aaltonen LM, Rautiainen N, Sellman J, et al. Voice quality after              design and selecting a population to study. Int J Tuberc Lung Dis
     treatment of early vocal cord cancer: a randomized trial comparing            2004;8:1151-1156.
     laser surgery with radiation therapy. Int J Radiat Oncol Biol Phys       25
                                                                                   Anglemyer A, Horvath HT, Bero L. Healthcare outcomes assessed
     2014;90:255-260. https://doi.org/10.1016/j.ijrobp.2014.06.032                 with observational study designs compared with those assessed in
18
     Locatello LG, Cannavicci A, Gallo O. Prognostic impact of initial             randomized trials. Cochrane Database Syst Rev 2014;9:MR000034.
     treatment in surgically salvaged recurrences of early glottic can-            https://doi.org/10.1002/14651858.MR000034




326
