ABSTRACT
Background
Post‐diagnosis smoking remains prevalent among head and neck squamous cell carcinoma (HNSCC) patients. Smoking cessation may improve patient outcomes.
Methods
A prospective longitudinal cohort study (2008–2014) included 835 newly diagnosed HNSCC patients and followed up for 7 years. Participants were categorized by smoking behavior (never smokers, former smokers, quitters, continuing smokers, and intermittent smokers). The primary outcomes were overall survival (OS) and recurrence‐free survival (RFS).
Results
Smoking cessation after diagnosis was associated with significantly improved OS. Quitters had a 61% reduction in mortality risk compared to continuing smokers (HR: 0.39, 95% CI: 0.22, 0.69), with the greatest benefit in oral cavity cancer patients (HR: 0.28, 95% CI: 0.12, 0.65). Intermittent smokers also showed improved survival (HR: 0.50, 95% CI: 0.31, 0.79). RFS did not significantly differ based on smoking behavior.
Conclusions
Smoking cessation post‐diagnosis improves OS, particularly in oral cavity cancer patients, highlighting the importance of targeted smoking cessation interventions in HNSCC care.
Keywords: head and neck neoplasms, mouth neoplasms, recurrence, smoking cessation, survival analysis
1. Introduction
Head and neck squamous cell carcinoma (HNSCC) typically encompasses mucosal squamous cell carcinomas found in the lip and oral cavity, pharynx, and larynx. HNSCC is the seventh most common cancer worldwide, with 947 211 new cases and 482 428 deaths in 202 [1]. HNSCC accounts annually for more than 71 000 new cancer cases and leads to approximately 16 100 cancer‐related deaths in the United States [2]. After diagnosis, a minimum of one‐third of patients with head and neck cancer continue smoking [3, 4, 5, 6]. Some studies have demonstrated that stopping smoking significantly improved the overall survival of HNSCC patients (~20% better survival than those continuing smoking after diagnosis) [7, 8]. Continuing smoking not only causes clinical/physical complications but also triggers the manifestation of depressive symptoms, ultimately resulting in a poorer quality of life [9].
As cancer survival rates rise, it becomes more crucial to identify and explore the long‐term lifestyle factors linked to survivorship. This elevates their susceptibility to morbidities, second primary malignancies associated with smoking, cancer recurrence, tumor progression, less response to treatments, treatment‐related toxicity, and increasing risk of mortality [10, 11, 12, 13, 14, 15, 16]. In 2022, the US National Cancer Institute reported that 11% of patients diagnosed within 5 years and 12% diagnosed in six or more years have been current cigarette smokers [17, 18]. Although the prevalence of smoking among cancer survivors has decreased from 19.5% in 1992 to 11.4% in 2022, there is still a need for more effective smoking cessation interventions to reach a larger proportion of cancer patient survivors [18]. To extend the lifespan of cancer patients and survivors and enhance their quality of life, it is imperative to identify these individuals and support them in quitting smoking, and provide evidence‐based tobacco use treatment, ensuring they become and/or remain tobacco‐free post‐diagnosis.
Apart from the general health advantages of quitting smoking permanently, cessation can offer specific benefits for cancer patients. Numerous studies have highlighted improvement in cancer prognosis after smoking cessation [13, 19, 20]. Abstaining from smoking post‐diagnosis correlates with reduced pain levels, improved quality of life, and better performance status [21]. Continuing smoking elevates the risk of disease recurrence, and second primary tumors increase the likelihood of other smoking‐related diseases and reduce treatment efficacy. Additionally, it heightens toxicity and side effects from radiotherapy and adversely impacts overall survival. Among locally advanced HNSCC patients, quitting smoking has been linked to a doubling in complete response rates to radiation therapy [19].
The principal aim of this analysis was to examine the impact of smoking cessation after the diagnosis of HNSCC on the overall survival (OS) rate and recurrence‐free survival (RFS) rate.
2. Materials and Methods
2.1. Study Design and Recruitment
The University of Michigan (UM) Head and Neck Specialized Program of Research Excellence (HN‐SPORE) conducted a prospective longitudinal cohort study involving newly diagnosed head and neck cancer patients prior to treatment initiation. This cohort comprised individuals diagnosed with tumors in the oral cavity, oropharynx, hypopharynx, or larynx. Recruitment occurred between November 2008 and October 2014 within the UM Hospital System, excluding individuals under 18, pregnant, non‐English speakers, those with mental health concerns, other non‐upper aerodigestive tract tumors, or additional primary HNSCC diagnoses in the last 5 years. Baseline and annual medical record reviews tracked clinical factors, including tumor site, stage, treatment history, comorbidities, survival, and recurrence. Initial (pre‐treatment) assessments included dietary records and survey data on health behaviors and epidemiological factors. All procedures adhered to Institutional Review Board standards and Helsinki Declaration guidelines, with written consent obtained for data acquisition and analysis under UM HN‐SPORE.
2.2. Exposures and Covariates
The participants were interviewed using a structured questionnaire that covered detailed questions on demographics, behavioral factors, various exposures, and health conditions. They provided a comprehensive smoking history, including the duration and intensity of tobacco use, as well as the average number of tobacco products smoked daily. The pack‐years of tobacco smoking were then calculated based on this information. All current smokers were offered optional referral to a smoking cessation clinic. Based on the information provided by the patients, they were categorized into four groups according to their smoking history. Never smokers are individuals who have never smoked in their lifetime. Former smokers are those who quit smoking more than 1 year before diagnosis, while quitters are those who stopped smoking within a year prior to diagnosis. Continuing smokers are individuals who continued smoking after diagnosis, and intermittent smokers are those who quit smoking more than a year before diagnosis but resumed smoking at least once after diagnosis.
Some confounders that we considered in our models were also collected, including alcohol consumption data, which was gathered in the same manner as tobacco smoking information. The diagnosis date was established as the day the patient received a biopsy‐confirmed diagnosis of squamous cell carcinoma at the University of Michigan. Comorbidities were assessed at the time of diagnosis using the Adult Comorbidity Evaluation‐27 (ACE‐27), a validated tool for evaluating comorbidity severity in cancer patients. For this study, HNSCC was classified as a new diagnosis if no prior primary tumor in the head and neck region had been identified within the previous 5 years. A team of local experts reviewed all relevant medical documents and completed a questionnaire that included information on the clinical and histopathologic features of the tumor and any existing illnesses. Further treatment recommendations were discussed and standardized by our multidisciplinary expert tumor board. There were no significant changes in diagnostic or treatment options during the study period. Tumor staging was classified using medical documents from the time of diagnosis, prior to any treatment, based on the 7th edition of the TNM classification system proposed by the American Joint Committee on Cancer.
2.3. Follow‐Up Data
Participants were followed annually to monitor changes in their smoking behavior. At each follow‐up, participants or their families were contacted either by mail or during their clinic visits to complete the same questionnaires that were used at the time of recruitment. Participants were classified as quitters if they reported cessation during the follow‐up period; otherwise, they were categorized as continued smokers.
The primary outcomes, recurrence and mortality, were evaluated as time‐to‐event variables using data from medical chart reviews and other sources. Death status was determined through various means, including the Social Security Death Index, LexisNexis, updates to medical and survey data, and notifications from family or other physicians. Recurrence‐free and survival times were calculated from the date of diagnosis, with survival time censored at MM DD, 2014, and recurrence‐free time censored at the date of the last known medical record review. Participants lost to follow‐up were censored at their last reported status date.
2.4. Statistical Analysis
Kaplan–Meier survival analysis was performed to plot the unadjusted survival curves for different smoking patterns after HNSCC diagnosis. The log‐rank test was applied to compare the survival curves among subgroups. A multivariable Cox proportional hazards model was used to evaluate the effect of continuing smoking, adjusting for other relevant variables, including age, gender, cancer stage, BMI, overall comorbidity score, and alcohol drinking status at the time of diagnosis. All variables were included in the multivariable model, which was stratified by HNSCC sub‐sites to account for location‐based differences. All analyses were conducted using SAS 9.4.
3. Results
A cohort of 835 HNSCC patients was followed for 8 years. The majority were men (73.17%) aged 24 to 95, and the vast majority were non‐Hispanic White (95.33%). The cohort included 368 patients with pharyngeal cancer (44.07%), 316 with oral cavity cancer (37.84%), and 151 with laryngeal cancer (18.08%) (Table 1). Based on their tobacco smoking history and follow‐up data, the patients were categorized into five subgroups: 194 were never smokers, 208 continued smoking after diagnosis, 192 quit smoking after diagnosis, 101 remained former smokers, and 140 were intermittent smokers after diagnosis (Table 2).
TABLE 1.
Demographic characteristics of a cohort of 835 head and neck cancer patients.
| Demographic characteristics | Total (N = 835) |
|---|---|
| Sex | No. (%) |
| Men | 611 (73.17) |
| Women | 224 (26.83) |
| Age (range 24–95) [Mean ± SD] | 60.68 ± 11.49 |
| BMI | |
| Under weight | 27 (3.23) |
| Normal weight | 262 (31.38) |
| Overweight | 310 (37.13) |
| Obese | 236 (28.26) |
| Overall comorbidity score | |
| None | 207 (24.79) |
| Mild | 406 (48.62) |
| Moderate | 160 (19.16) |
| Severe | 62 (7.43) |
| Race | |
| White | 796 (95.33) |
| Other | 39 (4.67) |
| Tumor topography | |
| Oral cavity | 316 (37.84) |
| Pharynx | 368 (44.07) |
| Larynx | 151 (18.08) |
| Stage | |
| In situ | 16 (1.92) |
| I | 126 (15.09) |
| II | 109 (13.05) |
| III | 112 (13.41) |
| IV | 472 (56.53) |
| Treatment | |
| Only radiation therapy | 69 (8.26) |
| Only surgery | 218 (26.11) |
| Chemoradiation therapy | 352 (42.16) |
| Surgery + Adjuvant chemoradiation therapy | 85 (10.18) |
| Surgery + Adjuvant radiation therapy | 111 (13.29) |
| Pack‐years | 36.68 ± 65.38 |
| Alcohol drinking | |
| Never drinker | 75 (8.98) |
| Current drinker | 470 (56.29) |
| Former drinker | 290 (34.73) |
| Smoking Status | |
| Never smoker | 194 (23.23) |
| Continuing smoking | 208 (24.91) |
| Quit smoking | 192 (22.99) |
| Remained former | 101 (12.10) |
| Intermittent smoking | 140 (16.77) |
TABLE 2.
Demographic and clinical characteristics 835 head and neck cancer patients by post‐diagnosis smoking behavior.
| Smoking behavior after diagnosis | Never smoker (194) | Former smoker (101) | Continuing smoking (208) | Quit smoking (192) | Intermittent smoking (140) | p |
|---|---|---|---|---|---|---|
| Sex | ||||||
| Men | 133 (68.56) | 75 (74.26) | 148 (71.15) | 143 (74.48) | 112 (80) | 0.192 |
| Women | 61 (31.44) | 26 (25.74) | 60 (28.85) | 49 (25.52) | 28 (20) | |
| Age (Mean ± SD) | 59.68 ± 12.47 | 66.35 ± 11.94 | 59.07 ± 10.95 | 57.72 ± 9.93 | 64.42 ± 10.24 | < 0.0001 |
| BMI | ||||||
| Under weight | 1 (0.52) | 1 (0.99) | 12 (5.77) | 11 (5.73) | 2 (1.43) | < 0.0001 |
| Normal weight | 45 (23.20) | 27 (26.73) | 84 (40.38) | 65 (33.85) | 41 (29.29) | |
| Overweight | 75 (38.66) | 37 (36.63) | 69 (33.17) | 66 (34.38) | 63 (45) | |
| Obese | 73 (37.63) | 36 (35.64) | 43 (20.67) | 50 (26.04) | 34 (24.29) | |
| Overall comorbidity score | ||||||
| None | 62 (31.96) | 19 (18.81) | 46 (22.12) | 49 (25.52) | 31 (22.14) | 0.206 |
| Mild | 92 (47.42) | 51 (50.50) | 98 (47.12) | 88 (45.83) | 77 (55) | |
| Moderate | 30 (1546) | 20 (19.80) | 45 (21.63) | 42 (21.88) | 23 (16.43) | |
| Severe | 10 (5.15) | 11 (10.89) | 19 (9.13) | 13 (6.77) | 9 (6.43) | |
| Race | ||||||
| White | 185 (95.36) | 94 (93.07) | 196 (94.23) | 182 (94.79) | 139 (99.29) | 0.148 |
| Other | 9 (4.64) | 7 (6.93) | 12 (5.77) | 10 (5.21) | 1 (0.71) | |
| Tumor topography | ||||||
| Oral cavity | 74 (38.14) | 41 (40.59) | 87 (41.83) | 73 (38.02) | 41 (29.29) | < 0.0001 |
| Pharynx | 110 (56.70) | 44 (43.56) | 71 (34.13) | 67 (34.90) | 76 (54.29) | |
| Larynx | 10 (5.15) | 16 (15.84) | 50 (24.04) | 52 (16.43) | 23 (16.43) | |
| Stage | ||||||
| In situ | 2 (1.03) | 1 (0.99) | 6 (2.88) | 3 (1.56) | 4 (2.86) | 0.333 |
| I | 33 (17.01) | 15 (14.85) | 28 (13.46) | 27 (14.06) | 23 (16.43) | |
| II | 23 (11.86) | 15 (14.85) | 25 (12.02) | 34 (17.71) | 12 (8.57) | |
| III | 18 (9.28) | 14 (13.86) | 38 (18.27) | 23 (11.98) | 19 (13.57) | |
| IV | 118 (60.82) | 56 (55.45) | 111 (53.37) | 105 (54.69) | 82 (58.57) | |
| Treatment | ||||||
| Only radiation therapy | 10 (5.15) | 11 (10.89) | 19 (9.13) | 20 (10.42) | 9 (6.43) | 0.164 |
| Only surgery | 51 (26.29) | 30 (29.70) | 52 (25) | 47 (24.48) | 38 (27.14) | |
| Chemoradiation therapy | 94 (48.45) | 38 (37.62) | 82 (39.42) | 70 (36.46) | 68 (48.57) | |
| Surgery + Adjuvant chemoradiation therapy | 14 (7.22) | 7 (6.93) | 24 (11.54) | 25 (13.02) | 15 (10.71) | |
| Surgery + Adjuvant radiation therapy | 25 (12.89) | 15 (14.85) | 31 (14.90) | 30 (15.63) | 10 (7.14) | |
| Pack‐year | 35.45 ± 81.37 | 39.32 ± 29.31 | 43.06 ± 87.71 | 34.16 ± 54.90 | 0.616 | |
| Alcohol drinking | ||||||
| Never drinker | 31 (15.98) | 5 (4.95) | 23 (11.06) | 9 (4.69) | 7 (5) | < 0.0001 |
| Current drinker | 118 (60.82) | 52 (51.49) | 118 (56.73) | 96 (50) | 86 (61.43) | |
| Former drinker | 45 (23.20) | 44 (43.56) | 67 (32.21) | 87 (45.31) | 47 (33.57) | |
| Vital status | ||||||
| Number of death | 26 (13.40) | 34 (33.66) | 68 (32.69) | 44 (22.92) | 27 (19.29) | < 0.0001 |
| Number of alive | 168 (86.60) | 67 (66.34) | 140 (67.31) | 148 (77.08) | 113 (80.71) | |
| Recurrence status | ||||||
| Recurred | 35 (18.04) | 23 (22.77) | 40 (19.23) | 35 (18.23) | 28 (20) | 0.883 |
| Non‐recurred | 159 (81.96) | 78 (77.23) | 168 (80.77) | 157 (81.77) | 112 (80) | |
Those who quit smoking after diagnosis were the youngest on average (57.72 ± 9.93). Although the overall comorbidity score did not differ significantly among the subgroups (p = 0.206), severe comorbidities were more prevalent in the continuing smokers (9.13%). The highest incidence of laryngeal cancer was observed in the continuing smoking group (24.04%) (Table 2).
3.1. OS and RFS by Post‐Diagnosis Smoking
The adjusted hazard ratio (HR) for OS in HNSCC patients‐combined subsites‐was significantly better among those who quit smoking after diagnosis compared to those who continued smoking at the end of the second year of follow‐up, 0.39 (95% CI: 0.22, 0.69) and the fifth year 0.68 (95% CI: 0.45, 1.00); however, the HR was not statistically significant at the seventh year, 0.73 (95% CI: 0.50, 1.07) (Table 3). Quitting smoking after diagnosis significantly improved OS for oral cavity cancer in the second year, with a HR of 0.28 (95% CI: 0.12, 0.65) and in the 5th year 0.54 (95% CI: 0.29, 0.99). However, for pharyngeal cancer, quitting smoking did not significantly improve OS at any time point: Similarly, for laryngeal cancer, the benefit in OS was not observed at any time points. For OS, there were no statistically significant differences in risk among continuing, quitting, or intermittent smokers with more than 30 pack‐years (PKY) compared to those with less. However, former smokers with > 30 PKY had a significantly higher risk of death [HR = 3.45; 95% CI: 1.70, 7.01] (Table 3).
TABLE 3.
Overall survival and recurrence‐free survival of head and neck cancer by subsites.
| Adjusted hazard ratio of overall survival a | Adjusted hazard ratio of recurrence‐free survival a | |||||
|---|---|---|---|---|---|---|
| HNSCC combined | 2‐year | 5‐year | 7‐year | 6‐month | 1‐year | 2‐year |
| Continued smoking | 1 | 1 | 1 | 1 | 1 | 1 |
| Quit smoking | 0.39 (0.22, 0.69) | 0.68 (0.45, 1.00) | 0.73 (0.50, 1.07) | 1.75 (0.29, 10.62) | 0.68 (0.34, 1.33) | 0.91 (0.55, 1.51) |
| Former smoker | 0.95 (0.56, 1.62) | 1.05 (0.67, 1.63) | 1.05 (0.68, 1.63) | 4.83 (0.93, 25.17) | 1.56 (0.80, 3.05) | 1.36 (0.77, 2.39) |
| Intermittent smoking | 0.32 (0.16, 0.62) | 0.49 (0.30, 0.79) | 0.50 (0.31, 0.79) | 1.33 (0.18, 9.65) | 0.69 (0.33, 1.46) | 0.97 (0.57, 1.67) |
| Never smoking | 0.37 (0.21, 0.67) | 0.44 (0.27, 0.71) | 0.46 (0.28, 0.73) | 2.53 (0.48, 13.14) | 1.00 (0.54, 1.88) | 1.01 (0.61, 1.67) |
| Oral cavity | ||||||
| Continued smoking | 1 | 1 | 1 | 1 | 1 | 1 |
| Quit smoking | 0.28 (0.12, 0.65) | 0.54 (0.29, 0.99) | 0.58 (0.32, 1.04) | — | 0.43 (0.13, 1.38) | 0.53 (0.23, 1.19) |
| Former smoker | 1.23 (0.63, 2.41) | 1.26 (0.70, 2.28) | 1.23 (0.68, 2.23) | 3.79 (0.64, 22.39) | 1.85 (0.70, 4.90) | 1.28 (0.57, 2.86) |
| Intermittent smoking | 0.34 (0.12, 0.92) | 0.59 (0.28, 1.23) | 0.64 (0.31, 1.31) | — | 0.70 (0.21, 2.32) | 0.91 (0.39, 2.08) |
| Never smoking | 0.49 (0.24, 1.00) | 0.52 (0.27, 0.99) | 0.52 (0.27, 0.99) | 2.28 (0.42, 12.18) | 1.28 (0.53, 3.07) | 1.10 (0.56, 2.17) |
| Pharynx | ||||||
| Continued smoking | 1 | 1 | 1 | 1 | 1 | 1 |
| Quit smoking | 0.45 (0.17, 1.20) | 0.73 (0.37, 1.44) | 0.77 (0.40, 1.49) | — | 0.81 (0.28, 2.36) | 1.39 (0.59, 3.25) |
| Former smoker | 0.67 (0.24, 1.82) | 0.71 (0.33, 1.55) | 0.77 (0.36, 1.63) | — | 1.94 (0.70, 5.34) | 1.70 (0.69, 4.20) |
| Intermittent smoking | 0.26 (0.09, 0.75) | 0.33 (0.15, 0.71) | 0.35 (0.16, 0.73) | — | 0.54 (0.17, 1.70) | 0.56 (0.21, 1.51) |
| Never smoking | 0.19 (0.06, 0.61) | 0.30 (0.14, 0.67) | 0.30 (0.13, 0.66) | — | 0.68 (0.25, 1.85) | 0.71 (0.30, 1.70) |
| Larynx | ||||||
| Continued smoking | 1 | 1 | 1 | 1 | 1 | 1 |
| Quit smoking | 1.02 (0.27, 3.89) | 1.22 (0.50, 2.96) | 1.08 (0.48, 2.42) | — | 1.16 (0.28, 4.80) | 1.47 (0.46, 4.69) |
| Former smoker | 0.99 (0.09, 9.98) | 1.36 (0.33, 5.60) | 1.17 (0.29, 4.70) | — | — | 0.72 (0.07, 6.68) |
| Intermittent smoking | 0.22 (0.02, 2.09) | 0.55 (0.17, 1.75) | 0.46 (0.15, 1.45) | — | 0.65 (0.10, 3.99) | 2.77 (0.83, 9.26) |
| Never smoking | — | 0.56 (0.06, 4.71) | 0.99 (0.20, 4.83) | — | — | 0.96 (0.10, 8.89) |
Hazard ratio (95% CI) adjusted for age, gender, BMI, alcohol drinking, overall comorbidity score, cancer site (only for combined HNSCC).
3.2. OS and RFS by Post‐Diagnosis Smoking, Stratified by HPV, Gender, and Comorbidity Score
Stratifying oropharyngeal cancer patients by HPV status showed no differences in OS or RFS based on smoking patterns after diagnosis (Table 4). Gender‐wise, quitting smoking within the first 2 years after diagnosis improved OS by up to 64% among men, with HR of 0.36 (95% CI: 0.19, 0.69). For men, both intermittent smokers and never‐smokers had higher OS compared to those who continued smoking after diagnosis at all time points. Specifically, in the 7th year, the HR for intermittent smokers was 0.47 (95% CI: 0.27, 0.79), and for never‐smokers was 0.29 (95% CI: 0.15, 0.56). Additionally, RFS was significantly better for intermittent and never smokers within the first 6 months after diagnosis, with HRs of 0.47 (95% CI: 0.27, 0.79) and 0.29 (95% CI: 0.15, 0.56), respectively. Unfortunately, no significant impact on OS and RFS was observed in women at any of the assessed time points.
TABLE 4.
Overall survival and recurrence‐free survival of oropharyngeal cancer patients by Human Papillomavirus (HPV) Infection status.
| Oropharyngeal cancer | Adjusted hazard ratio of overall survival a | Adjusted hazard ratio of recurrence‐free survival a | ||||
|---|---|---|---|---|---|---|
| HPV positive | 2‐year | 5‐year | 7‐year | 6‐month | 1‐year | 2‐year |
| Continued smoking | 1 | 1 | 1 | 1 | 1 | 1 |
| Quit smoking | 0.97 (0.13, 3.70) | 1.30 (0.43, 3.91) | 1.28 (0.42, 3.86) | — | — | 1.07 (0.26, 4.37) |
| Former smoker | 0.61 (0.05, 7.06) | 0.55 (0.10, 2.77) | 0.53 (0.10, 2.68) | — | 0.81 (0.07, 9.12) | 0.38 (0.04, 3.43) |
| Intermittent smoking | 1.84 (0.34, 9.73) | 0.87 (0.29, 2.66) | 0.97 (0.33, 2.87) | — | 2.24 (0.42, 11.92) | 1.32 (0.36, 4.85) |
| Never smoking | 0.62 (0.10, 3.70) | 0.43 (0.13, 1.40) | 0.42 (0.13, 1.36) | — | 1.35 (0.26, 6.94) | 0.95 (0.28, 3.18) |
| HPV negative | ||||||
| Continued smoking | 1 | 1 | 1 | 1 | 1 | 1 |
| Quit smoking | 0.36 (0.02, 4.80) | 0.18 (0.01, 1.93) | 0.35 (0.05, 2.38) | — | 1.08 (0.20, 5.66) | 0.78 (0.14, 4.45) |
| Former smoker | 1.60 (0.10, 5.67) | 1.34 (0.15, 1.54) | 2.09 (0.23, 18.39) | — | 3.54 (0.33, 37.36) | 1.40 (0.18, 10.78) |
| Intermittent smoking | — | — | — | — | — | — |
| Never smoking | — | 0.39 (0.04, 3.89) | 0.42 (0.04, 4.07) | — | — | — |
Hazard ratio (95% CI) adjusted for age, gender, BMI, alcohol drinking, overall comorbidity score.
Regarding overall comorbidity score, never and intermittent smokers with mild comorbidities had significantly better survival than continued smokers, particularly at year 2. This benefit lessened with higher comorbidity, and former smokers showed no consistent survival advantage across time points (eTable 1).
3.3. OS and RFS by Post‐Diagnosis Smoking Stratified by Stage
Analysis by disease stage indicated that OS among late‐stage HNSCC patients significantly differed by post‐diagnosis smoking status after 40 months of follow‐up (p < 0.0361) (Figure 1). Subsite‐specific analysis revealed that OS was significantly improved in the late‐stage oral cavity patients who quit smoking after diagnosis (p = 0.015) (Figure 2). RFS did not significantly differ in either early‐stage (p = 0.988) or late‐stage (p = 0.685) HNSCC combined patients. RFS among late‐stage oral cavity cancer patients was notably better in those who quit smoking compared to those who continued smoking (p = 0.041) (Figure 2).
FIGURE 1.
Kaplan–Meier (K‐M) survival curves comparing overall survival (OS) and recurrence‐free survival (RFS) among early‐ and late‐stage head and neck squamous cell carcinoma (HNSCC) patients, stratified by smoking status (quit vs. continued smoking). (A) OS curves for early‐stage HNSCC patients, showing no significant difference in OS between those who quit smoking and those who continued (p = 0.8379). (B) OS curves for late‐stage HNSCC patients, demonstrating a significantly better survival among patients who quit smoking compared to those who continued (p = 0.0361). (C) RFS curves for early‐stage HNSCC patients, showing no significant difference in time to recurrence between quitters and those who continued smoking (p = 0.9888). (D) RFS curves for late‐stage HNSCC patients, reflecting no significant difference of recurrence rates based on smoking status (p = 0.6852). [Color figure can be viewed at wileyonlinelibrary.com]
FIGURE 2.
Kaplan–Meier (K‐M) survival curves showing overall survival (OS) and recurrence‐free survival (RFS) in late‐stage head and neck cancer patients, stratified by tumor subsite (larynx, pharynx, and oral cavity) and smoking status (quit vs. continued smoking). (A) OS curves for late‐stage laryngeal cancer patients, showing no differences in survival between those who quit smoking and those who continued (p = 0.8760). (B) OS curves for late‐stage pharyngeal cancer patients, comparing survival trajectories between quitters and continued smokers (p = 0.3188). (C) OS curves for late‐stage oral cavity cancer patients, illustrating significant OS probability over time by smoking status (p = 0.0154). (D) RFS curves for late‐stage laryngeal cancer patients, comparing time to recurrence based on smoking behavior (p = 0.3296). (E) RFS curves for late‐stage pharyngeal cancer patients, showing similar recurrence patterns in quitters versus continued smokers (p = 0.5136). (F) RFS curves for late‐stage oral cavity cancer patients, illustrating a statistically significant difference in recurrence‐free survival by smoking status, with lower recurrence observed among patients who quit smoking after diagnosis compared to those who continued (p = 0.0413). [Color figure can be viewed at wileyonlinelibrary.com]
3.4. OS and RFS by Smoking Across Treatment Modalities
Our findings suggested that quitting smoking may have a borderline impact on overall survival across different treatment modalities. An analysis of HNSCC subsites by treatment modality revealed that being an intermittent smoker was beneficial for oral cavity cancer patients. Intermittent smokers had a 73% better OS, and never smokers had a 75% better survival. Additionally, chemoradiation therapy was significantly beneficial for pharyngeal cancer patients who were either intermittent smokers [HR = 0.28, 95% CI: 0.12, 0.67] or never smokers [HR = 0.25, 95% CI: 0.10, 0.59] (eTable 2). Neither treatment modality nor specific HNSCC subsites significantly influenced RFS (eTable 3).
4. Discussion
This prospective cohort study of 835 HNSCC patients followed for about 8 years indicates quitting smoking after diagnosis was associated with improved OS compared to continued smoking. At 2 years of follow‐up, HNSCC combined patients who quit smoking after diagnosis had a 61% reduced risk of OS compared to those who continued smoking. By 5 years of follow‐up, this risk reduction decreased to 32%. The reduction in mortality risk was predominantly observed among oral cavity cancer patients, with those who quit smoking having a 72% lower risk of death at 2 years of follow‐up, which decreased to 46% by 5 years. However, RFS was not generally affected by post‐diagnosis smoking patterns.
Although some studies report conflicting evidence [22, 23, 24], the prevailing consensus in the scientific community is that smoking substantially diminishes survival outcomes for HNSCC patients [25, 26]. This negative association between smoking and survival has been supported by multiple studies highlighting the detrimental effects of tobacco use on disease progression, treatment response, and overall prognosis of HNSCC. A meta‐analysis of 16 studies, comprising approximately 2300 patients with HNSCC, revealed that quitting smoking at or around the time of diagnosis led to a significant 20% improvement in OS (HR = 0.80, 95% CI: 0.70–0.93) [27]. Our study further supports these findings, showing an even more significant impact with a 32% death risk reduction among those who quit smoking after diagnosis. However, only a few studies included in the meta‐analysis were prospective; they assessed smoking status after the time of diagnosis [28, 29, 30], while the majority were retrospective and lacked a precise definition of smoking cessation and suffered from information bias. Despite the limitations, the consistency across multiple studies highlights the critical importance of smoking cessation for improving long‐term survival in HNSCC patients.
Our study underscores the beneficial effects of smoking cessation, especially for patients undergoing surgery for HNSCC. Research examining smoking habits both before and after treatment consistently showed better outcomes for those who quit smoking [31, 32]. For patients having surgery, stopping smoking at diagnosis is linked to improved wound healing, fewer complications such as pneumonia, and a lower risk of developing secondary cancers [33]. Our findings indicated that smoking cessation lowered mortality risk by up to 59% in patients treated with surgery alone, although the reduction in death risk was borderline significant. These results highlight the importance of incorporating smoking cessation efforts into the surgical care plan for HNSCC patients.
The impact of smoking on chemoradiotherapy (CRT) outcomes has been widely documented. Continued smoking during CRT significantly increases the risks of treatment‐related toxicities and tumor progression, lower tumor response rates, and poorer survival in HNSCC patients [19]. In this study, no significant benefits of smoking cessation were observed among laryngeal cancer patients. This might be because only 18% of the tumors studied were laryngeal cancer, with approximately 35% of them receiving CRT, compared to about 78% of pharyngeal cancer patients who underwent CRT. However, our patients identified as intermittent smokers showed that even reducing smoking levels after diagnosis and during CRT could lower the risk of death by up to 60%.
Moreover, post‐diagnosis smoking is also connected to peritumoral hypoxia, which can result in an incomplete response to radiotherapy and diminished effectiveness of platinum‐based chemotherapy [34]. In addition to the impact of smoking on treatment outcomes and side effects, smoking cessation may also reduce the costs and adverse effects associated with immunotherapy, specifically PD‐1 checkpoint inhibitors [35].
Many cancer patients who smoke may not realize that quitting remains beneficial even post‐diagnosis, and some are not advised by their physicians to stop, despite the clear advantages [36, 37, 38, 39]. Assessing smoking behavior after diagnosis allows clinicians to personalize care, while integrating cessation programs into cancer treatment can improve survival and disease management outcomes. However, there is limited research addressing the gap between the high participation of cancer survivors in smoking cessation programs and their notably low cessation success rates. While 69% of smokers aim to quit within a year, less than 10% are ready to try within 30 days [40, 41]. There is little data on the readiness of cancer survivors to quit smoking. Unfortunately, our prospective study did not document participation or success of our voluntary smoking cessation program.
As an observational study, it is prone to biases and confounding. Some information was obtained from active and passive follow‐up, which could lead to variability in accuracy. Misclassification is also a concern, particularly with self‐reported smoking status, which could result in overreporting cessation and potentially bias the findings. The small sample size in some subgroup analyses limits the power of these results, requiring careful interpretation. Furthermore, although the long follow‐up period provided valuable data on the effects of smoking cessation, it also introduced challenges, such as potential loss to follow‐up.
This prospective cohort study of HNSCC patients found that quitting smoking after diagnosis significantly improved OS compared to continued smoking. The benefits of smoking cessation were most notable in the early years of follow‐up, particularly among oral cavity cancer patients. For future studies, it would be beneficial to explore the long‐term effects of smoking cessation beyond 5 years and investigate the biological mechanisms underlying the varying impact of quitting smoking across different HNSCC subtypes. Additionally, studies could focus on interventions that support sustained smoking cessation to maximize survival benefits.
Supporting information
Data S1. Supplementary Information.
Acknowledgments
We acknowledge the support of the NIH/NCI (Grant number 2P50CA097248‐06A1) for funding this study.
Mohebbi E., Guthrie G., Patil S., et al., “Postdiagnosis Smoking Cessation and Survival Outcomes of Head and Neck Cancer Patients,” Head & Neck 47, no. 10 (2025): 2725–2734, 10.1002/hed.28182.
Funding: This work was supported by NIH/NCI (2P50CA097248‐06A1).
Data Availability Statement
Research data are not shared.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1. Supplementary Information.
Data Availability Statement
Research data are not shared.