The impact of tobacco smoking on survival of patients with oral squamous cell carcinoma: a population-based retrospective study

Figures & data

Figure 1. Flowchart illustrating the selection process of patients from the Copenhagen Oral Cavity Squamous Cell Carcinoma (COrCa) database included in analyses of this study, and reasons for exclusions. ATE: accumulated tobacco exposure.

Table 1. Baseline characteristics of the included patients (study population 1) with oral squamous cell carcinoma (OSCC) from the COrCa database diagnosed between 2000–2019 stratified by smoking status: never-, current and former smokers.

Variable	All patients	Never-smokers	Former smokers	Current smokers	p
n	1717	240	339	1138
(%)	100	14.0	19.7	66.3
Median age at diagnosis (IQR)	63.7 (56.5–71.3)	70.3 (59.2–79.7)	68.0 (61.1–74.6)	61.6 (55.5–68.1)	<0.01
Median age category	60–65	70–75	65–70	60–65	<0.01
Median year of diagnosis (IQR)	2012 (2007–2016)	2013 (2010–2016)	2014 (2010–2017)	2012 (2006–2015)	<0.01
Male sex (%)	1078 (62.8%)	104 (43.3%)	218 (64.3%)	756 (66.4%)	<0.01
Packyears
Non-smokers (0)	240 (14.0%)	240 (100%)	NA	NA	<0.01
0$<$x $\le$ 30	386 (22.5%)	NA	132 (38.9%)	254 (22.3%)
30$<$x $\le$ 60	639 (37.2%)	NA	93 (27.4%)	545 (47.9%)
$\hspace{1em}>$60	172 (10.0%)	NA	24 (7.1%)	148 (13.0%)
Unknown packyears	280 (16.3%)	0 (0%)	90 (26.5%)	191 (16.8%)
Median number of pack-years among smokers (range)	37.5 (0–183)	0 (0–0)	30 (0.5–156)	42.8 (0.5–183)	<0.01
Alcohol consumption:
Never EAC	770 (44.8%)	204 (85.0%)	192 (56.6%)	374 (32.9%)	<0.01
Ever EAC	884 (51.5%)	28 (11.7%)	138 (40.7%)	718 (63.1%)
Unkn. alcohol consumption	63 (3.7%)	8 (3.3%)	9 (2.7%)	46 (4.0%)
Tumor subsite
Floor of mouth (FOM)	619 (40.2%)	19 (7.9%)	105 (31.0%)	567 (49.8%)	<0.01
Oral tongue	609 (35.5%)	129 (53.8%)	129 (38.1%)	351 (30.8%)
Gingiva	195 (11.4%)	51 (21.3%)	50 (14.7%)	94 (8.3%)
Other	208 (12.1%)	38 (15.8%)	53 (15.6%)	117 (10.3%)
Unknown subsite	14 (0.8%)	3 (1.3%)	2 (0.5%)	9 (0.8%)
T-stage
T1	579 (33.7%)	83 (34.6%)	127 (37.5%)	369 (32.4%)	0.29
T2	446 (26.0%)	65 (27.1%)	87 (25.7%)	294 (25.8%)
T3	152 (8.9%)	15 (6.3%)	36 (10.6%)	101 (8.9%)
T4	285 (16.6%)	40 (16.7%)	46 (13.6%)	199 (17.5%)
Unknown T-stage	255 (14.9%)	37 (15.4%)	43 (12.7%)	175 (15.4%)
N-stage
N0	1047 (61.0%)	157 (65.4%)	218 (64.3%)	672 (59.1%)	0.32
N1	237 (13.8%)	33 (13.8%)	50 (14.7%)	154 (13.5%)
N2	115 (6.7%)	10 (4.2%)	18 (5.3%)	87 (7.6%)
N3	147 (8.6%)	22 (9.2%)	26 (7.7%)	99 (8.7%)
Unknown N-stage	171 (10.0%)	18 (7.5%)	27 (8.0%)	126 (11.1%)
UICC7 stage
I	459 (26.7%)	71 (29.6%)	99 (29.2%)	289 (25.4%)	0.29
II	309 (18.0%)	50 (20.8%)	66 (19.5%)	193 (17.0%)
III	271 (15.8%)	32 (13.3%)	61 (18.0%)	178 (15.6%)
IV	432 (25.2%)	58 (24.2%)	75 (22.1%)	299 (26.3%)
Unkonwn UICC7 stage	246 (14.3%)	29 (12.1%)	38 (11.2%)	179 (15.7%)
Treatment method
Surgery (S)	910 (53.0%)	150 (62.5%)	199 (58.7%)	561 (49.3%)	<0.01
Surgery with adjuvant radiotherapy (SR)	536 (31.2%)	66 (27.5%)	102 (30.0%)	368 (32.3%)
Primary radiotherapy (R)	271 (15.8%)	24 (10.0%)	38 (11.2%)	209 (18.4%)
Continued smoking after diagnosis
Yes	633 (36.8%)	0 (0%)	17 (5.0%)	616 (54.1%)	<0.01
No	781 (45.5%)	226 (94.2%)	288 (85.0%)	267 (23.5%)
Unknown	303 (17.6%)	13 (5.4%)	34 (10.0%)	255 (%)

p-Value: the likelihood of a significant difference in the distribution of the given variable between the three groups (never, former and current smokers). EAC: excessive alcohol consumption; IQR: interquartile range; NA: not available.

Table 2. Multivariable Cox regression analyses adjusted for the below mentioned variables on overall survival (OS) and disease-free survival (DFS) for patients with oral squamous cell carcinoma from the COrCa database.

	Overall survival (OS) HR (95% Cl)	p	Disease-free survival (DFS) HR (95% Cl)	p
With adjustment for EAC:
Smoking-status^α
Never-smokers	1 (Ref)		1 (Ref)
Current smokers	1.83 (1.38−2.42)	<0.01	1.32 (1.04−1.68)	0.02
Former smokers	1.32 (0.98−1.77)	0.07	1.17 (0.90−1.51)	0.24
Ever smokers	1.59 (1.22−2.07)	<0.01	1.26 (1.00−1.58)	0.05
Categorical ATE^α
0	1 (Ref)		1 (Ref)
0$<$x $\le$ 30	1.44 (1.07−1.94)	0.02	1.22 (0.95−1.58)	0.13
30$<$x $\le$ 60	1.68 (1.25−2.26)	<0.01	1.25 (0.97−1.62)	0.09
$\hspace{1em}>$60	2.10 (1.47−2.99)	<0.01	1.49 (1.09−2.04)	0.01
Smoking cessation at diagnosis^β
Yes	1 (Ref)		1 (Ref)
No (<X years after diagnosis)	1.06 (0.77−1.45)	0.73	0.90 (0.68−1.19)	0.47
No (>X years after diagnosis)	2.37 (1.57−3.59)	<0.01	2.27 (1.54−3.35)	<0.01
Without adjustment for EAC:
Smoking-status^γ
Never-smokers	1 (Ref)		1 (Ref)
Current smokers	2.15 (1.65−2.81)	<0.01	1.53 (1.22−1.93)	<0.01
Former smokers	1.46 (1.09−1.95)	0.01	1.27 (0.99−1.64)	0.06
Ever smokers	1.85 (1.43−2.39)	<0.01	1.43 (1.15−1.79)	<0.01
Categorical ATE^γ
0	1 (Ref)		1 (Ref)
0$<$x $\le$ 30	1.58 (1.18−2.11)	<0.01	1.33 (1.03−1.71)	0.03
30$<$x $\le$ 60	1.95 (1.47−2.59)	<0.01	1.43 (1.12−1.83)	<0.01
$\hspace{1em}>$60	2.56 (1.83−3.59)	<0.01	1.78 (1.31−2.40)	<0.01
Smoking cessation at diagnosis^δ
Yes	1 (Ref)		1 (Ref)
No (<X years after diagnosis)	1.12 (0.82−1.53)	0.46	0.96 (0.73−1.27)	0.78
No (>X years after diagnosis)	2.57 (1.70−3.88)	<0.01	2.38 (1.63−3.50)	<0.01

α: Adjusted for sex, age at diagnosis, year of diagnosis, UICC7 stage, tumor subsite, and EAC.

β: Adjusted for sex, age at diagnosis, year of diagnosis, UICC7 stage, tumor subsite, EAC, and categorical ATE.

γ: Adjusted for sex, age at diagnosis, year of diagnosis, UICC7 stage, and tumor subsite.

δ: Adjusted for sex, age at diagnosis, year of diagnosis, UICC7 stage, tumor subsite, and categorical ATE.

Ever smokers were current and former smokers pooled in one group. X being 3.5 years for OS and X being 2.5 years for DFS (time-split analyses to fulfill the proportionality assumption).

HR: Hazard ratio; 95% CI: 95% confidence intervals; EAC: excessive alcohol consumption.

Figure 2. Kaplan–Meier (KM) curves for overall survival (OS) and disease-free survival (DFS). KM-curves for (A) OS and (B) DFS stratified by smoking status, and (C) OS and (D) DFS stratified by categorical ATE. The 2- and 5-year survival probability (in percent) with 95% confidence intervals are tabulated below.

Figure 3. Interaction analyses between smoking history (continuous ATE (i.e. number of PYs) included through a restricted cubic spline model and smoking status (yes/no)) and (A) tumor subsite (FOM, gingiva and oral tongue) and (B) excessive alcohol consumption (ever- and never-EAC) on survival estimates (OS and DFS) adjusted for α: sex, age at diagnosis, year of diagnosis, UICC7 stage, tumor subsite, and alcohol consumption. p-values for heterogeneity between multivariable Cox regression analyses (with and without an interaction term), were placed in the upper left corners of the plots. The patients with 0 Pys are not shown in the histograms. ATE: accumulated tobacco exposure. OS: overall survival; DFS: disease-free survival; FOM: floor of mouth; EAC: excessive alcohol consumption.

Data availability statement

Data are available from the corresponding author upon request, however transfer of data requires specific approval from the Danish authorities.