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Treatment outcomes in current smokers versus former smokers undergoing concurrent chemoradiotherapy for head and neck cancer
For correspondence: Dr Samreen Zaheer, Department of Radiotherapy, Jawaharlal Nehru Medical College and Hospital, Aligarh Muslim University, Aligarh 202 001, Uttar Pradesh, India e-mail: samreenzaheer@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Zaheer S, Agrawal A, P A, Akram M. Treatment outcomes in current smokers versus former smokers undergoing concurrent chemoradiotherapy for head and neck cancer. Indian J Med Res. 2026;163:415-9. doi: 10.25259/IJMR_1931_2025.
Abstract
Background and objectives
Head and neck cancers are aggressive tumours with a multidisciplinary treatment strategy. Concurrent chemoradiotherapy is recommended for locally advanced cases. The carboxyhaemoglobin level is higher in smokers, resulting in a hypoxic environment and radio resistance, which affect treatment outcomes. Data for effect of continued smoking is not available in the Indian setting. This study aims to compare treatment response, failure rate, patterns, and progression-free survival in current smokers vs. former smokers receiving definitive concurrent chemoradiotherapy for head and neck cancer.
Methods
We conducted this retrospective observational study in patients receiving definitive chemoradiotherapy for head and neck cancer with two groups: current smokers and former smokers. Both arms received weekly 40 mg/m2 cisplatin along with radiotherapy. Endpoints included treatment response, progression-free survival, and failure patterns.
Results
There were fewer complete treatment responses and more failures in current smokers receiving CRT, with a significant difference in progression-free survival.
Interpretation & conclusions
Continued smoking during definitive chemoradiotherapy for head and neck cancers resulted in poorer treatment outcomes. Integrating tobacco cessation in oncological care should be a standard of care in managing head and neck cancers.
Keywords
Current smokers
Definitive concurrent chemoradiotherapy
Head and neck cancer
Progression-free survival
Treatment outcomes
Squamous cell carcinomas of the head and neck are highly aggressive malignancies. The major risk factors are alcohol, smoking, and viral infection (human papillomavirus).1,2 The treatment modalities for the disease include surgery, chemotherapy, radiotherapy, or a combination of these modalities.3
Approximately one-third of the diagnosed patients continue smoking during treatment.4 Smoking results in the formation of carboxyhaemoglobin because haemoglobin has a higher affinity for carbon monoxide than for oxygen. Carboxyhaemoglobin levels in smokers can reach 15-20%, compared to 1-2% in non-smokers.5 The carboxyhaemoglobin results in inadequate oxygen delivery to the tissues as a result of the left shift of the haemoglobin-oxygen dissociation curve. This causes an increased fraction of hypoxic cells.6 Thus, active smoking during treatment may compromise the treatment outcomes due to chronic hypoxia,7 because it is one of the major factors associated with radioresistance.8
This study aims to compare the treatment response, failure rate, patterns, and progression-free survival in current smokers vs. former smokers receiving definitive chemoradiotherapy for head and neck cancers.
Methods
This is a retrospective observational, single-centre study undertaken by the department of Radiotherapy, Jawaharlal Nehru Medical College and Hospital, Aligarh Muslim University, Aligarh, Uttar Pradesh, India. We included patients with histologically proven, inoperable squamous cell carcinoma of the head and neck cancer.
Patients with a past history of chemotherapy, radiotherapy, or any malignancy were excluded. The baseline workup of the patients included clinical history, haematological, and biochemical parameters. Contrast-enhanced computerized tomography (CECT) or magnetic resonance imaging of the head and neck, and chest X-ray were done to assess the local extent of disease and to rule out any distant metastasis.
Patient Recruitment and Stratification
Patients were categorised into two arms based on their smoking status, i.e., current smokers (Arm A), who continued smoking during chemoradiotherapy versus former smokers (Arm B). Former smokers consisted of the subset of patients who quit smoking after the diagnosis and were not currently smoking but had smoked at least 100 cigarettes in their lives. Never smokers were not included in this study. Smoking status was defined according to the definitions given by the National Health Interview Survey (NHIS).9 Patients in both the arms received definitive concurrent chemoradiotherapy in a dose of 70Gy/35# at 2Gy per fraction with concurrent weekly 40 mg/m2 cisplatin.
Response assessment
Response was assessed after 6 weeks of treatment completion using response evaluation criteria in solid tumours (RECIST version 1.1) in terms of complete response, partial response, and overall response rate. Treatment failure was assessed at two time points, initially at 6 wk for no response (stable disease or progressive disease) and subsequently during follow-up for any disease recurrence. Progression-free survival was defined as the time from completion of concurrent chemoradiotherapy to the date of first documented disease progression or recurrence, or last disease evaluation for patients without progression.
Statistical analysis
For sample size calculation, we assumed a 30% higher complete response in former smokers based on the results of Browman et al.10 The minimum sample size was calculated to be 44 patients per arm for 80% power at α=0.05. Statistical analysis was performed using Statistical Package for Social Sciences (SPSS) software, IBM manufacturer, Chicago, USA, ver 25.0. Descriptive analysis was done using mean, frequency, and percentage. Quantitative variables were compared using Mann Whitney U test, and categorical variables were compared by Chi-square test. Multivariate analysis was done to account for confounding factors. The procedures followed were in accordance with the ethical standards of the institution.
Results
One hundred patients with histologically proven, inoperable squamous cell carcinoma of the head and neck were selected for this study. Of these, 91 patients with inoperable squamous cell carcinoma of the head and neck were finally evaluated. In Arm A, one patient was ineligible due to loss to follow up. In Arm B, 8 patients were ineligible due to loss to follow up (n=6) or died due to a non-oncological cause (n=2).
Demographics
All the patients included in the study had non-metastatic head and neck carcinoma with squamous cell histology. The demographic characteristics and clinical features are shown in Table I. The median age of the participants was 50 yr (IQR=19 for Arm A, IQR=16 for Arm B). Both groups had a significant history of smoking before diagnosis, with an average smoking duration of 25 yr in Arm A and 24 yr in Arm B, and mean pack-years of 22 ± 15 and 20 ± 12, respectively. In Arm B (former smokers), the interval between smoking cessation and the start of chemoradiotherapy was relatively short – on average about 4 weeks (mean ∼30 days, range 7–60 days) – since these patients quit upon diagnosis.
| Variables | Current smokers (Arm A), n (%) | Former smokers (Arm B), n (%) |
|---|---|---|
| Gender | ||
| Male | 48 (97.96) | 30 (71.43) |
| Female | 1 (2.04) | 12 (28.57) |
| Age | ||
| Mean (SD) | 48.22 (11.39) | 49.10 (10.28) |
| Median (range) | 50.00 (34-76) | 50.00 (35-73) |
| Tumour site | ||
| Oral cavity | 13 (26.53) | 22 (52.38) |
| Oropharynx | 24 (48.97) | 14 (33.33) |
| Larynx | 12 (24.4) | 4 (9.52) |
| Others | 0 | 2 (4.76) |
| AJCC Clinical Stage, (as per 8th edition) | ||
| Stage III | 15 (30.61) | 10 (23.80) |
| Stage IV | 34 (69.38) | 32 (76.19) |
| Smoking exposure | ||
| Mean pack yr ± SD | 22±15 | 20±12 |
| Median pack yr (range) | 20 (5-50) | 18(5-60) |
| Tobacco chewer | 19 (38.8) | 24 (57.1) |
Treatment Response
At 6 weeks post chemotherapy, former smokers showed a higher overall response rate (ORR) as compared to current smokers (P=0.03) (Table II).
| Treatment response | Current smokers, n (%) | Former smokers, n (%) | P value |
|---|---|---|---|
| Complete response | 8 (16.3) | 12 (28.6) | 0.16 |
| Partial response | 20 (40.8) | 21(50.0) | 0.31 |
| Overall response | 28 (57.1) | 33 (78.6) | 0.03 |
| Progressive disease | 7 (14.3) | 2 (4.8) | 0.19 |
| Stable disease | 14 (28.6) | 7 (16.7) | 0.17 |
Failure patterns
Treatment failure included stable disease, progressive disease, or any recurrence during follow-up. It was assessed at two points: (i) Initial failure–lack of tumour response (stable disease or progressive disease) on the first post-treatment evaluation at 6 weeks after completion of chemoradiotherapy, and (ii) Recurrence–any disease progression during follow-up after an initial response. When compared by RECIST criteria,11 current smokers showed a greater number of failures as compared to former smokers (P< 0.05). In Arm A, n=14 (28.6%) patients showed no response to treatment, i.e., had stable disease, n=7 (14.28%) had progressive disease, and n=11 (22.45%) presented with disease recurrence within 6 months of completion of radiation therapy. A total of n=32 (65.3%) current smokers failed treatment, as against n=17 (40.5%) in former smokers. All the recurrences noted in our study were loco-regional, and none of the patients developed distant metastasis.
Progression-free survival
Former smokers showed more years of progression-free survival as compared to current smokers (2.2±2.03 yr vs. 1.25±0.75yr; P=0.012; Figure).
- Kaplan Meier curve for progression free survival in months for Arm A vs. Arm B.
Addiction to tobacco chewing was also noted in the study population, in addition to smoking. In Arm A, 19 (38.8%) patients were tobacco chewers compared to 24 (57.1%) in Arm B. In a binary logistic regression model of complete/partial response adjusting for tumour site, gender, and concurrent tobacco chewing, active smoking during treatment emerged as an independent predictor of poorer response. The adjusted odds ratio for achieving a tumour response (complete or partial remission) in Arm A versus Arm B was 0.22 [95% confidence interval (CI) ∼0.08–0.65, P=0.01], indicating that patients who kept smoking had significantly lower odds of tumour regression even after controlling for other factors. None of the other covariates (site, gender, or chewing) reached statistical significance in this model.
Discussion
Our study demonstrates that head and neck cancer patients who were current smokers during the treatment, despite adequate counselling to quit, had poor treatment outcomes as compared to the patients who were former smokers. Some studies have shown that continuation of smoking during CRT can lead to a higher symptom burden and can lead to treatment interruptions and delays. This compromise in the treatment efficacy may result in lower quality of life and reduced survival rates, significantly impacting the physical, mental, and social well-being of affected individuals.12,13
Both combustible forms of tobacco, like cigarettes, bidi, chuttas, and cigars, as well as smokeless tobacco such as tobacco chewing, snuff, gutkha, and betel quid, are associated with carcinogenesis.14 E-cigarettes or vapes are classified as an electronic nicotine delivery system. In these devices, a liquid containing varying amounts of nicotine, glycerine, and propylene glycols is heated, resulting in the production of an inhalable aerosol.15
A study by Browman et al,10 concluded that active smoking during radiotherapy resulted in lower rates of treatment response and poor survival outcomes in head and neck cancer cases when compared to patients who discontinued smoking during the treatment. Complete remission was achieved in 75% of non-smokers vs. 45% in smokers. Similarly, in our study, ORR was 78.6% vs. 57.1% in former smokers vs. current smokers. Another study by Al-Mamgani et al,16 demonstrated that active smoking during radiotherapy showed significantly poor local control in patients with glottis cancer.
In a study by Chen et al,17 patients who were active smokers had significantly inferior 5-year overall survival (23% in active smokers vs. 55% in non-smokers) and locoregional control (58% in active smokers vs. 69% in non-smokers) compared to the former smokers who had quit smoking before radiation therapy (P<0.05 for all). In our study, the overall response rate was significantly higher in former smokers compared to current smokers, which correlated with the existing studies. Former smokers showed more years of progression-free survival as compared to the current smokers. In a study by Chen et al,18 patients with smoking cessation during treatment had a significantly greater survival of 61% vs. 34% in patients who continued to smoke during the treatment (P=0.03). This finding aligns with our study.
Hoff et al,19 conducted a prospective study, concluding that heavy smokers showed significantly lower disease-specific survival, overall survival, and locoregional control when compared to the patients who did not smoke during the treatment.
Our study shows that continued smoking during treatment was associated with higher rates of both primary treatment failure and subsequent tumour recurrence. Response assessment was done with CECT face and neck at 6 weeks post-CRT, and PET CT was not done, mainly due to affordability issues.
There are certain caveats of the current study. This is a retrospective and non-randomised study with its inherent drawbacks. The history of smoking pack-years and time duration from the point of quitting to the treatment initiation ranged considerably. Although the number of tobacco chewers were more in the former smoker arm, tobacco chewing could be one of the confounding factors. Also, we could not stratify the results according to long-term quitters vs. short-term quitters because the smoking cessation interval in former smokers was relatively short. It remains unanswered whether never-smoking status or a longer cessation interval would confer greater advantage than that observed in the current study. Despite these limitations, our study provides important evidence from an Indian tertiary care setting and underscores the importance of smoking cessation as an integral part of comprehensive cancer management. Counselling sessions for smoking cessation during the definitive chemoradiotherapy CRT should be offered to all the patients to improve the efficacy of the treatment.
Authors contributions
SZ: Conceptualization, methodology, validation, formal analysis, data curation, visualization, supervision, manuscript writing; AA: Methodology, formal analysis, data curation, manuscript writing, visualization; AP: Methodology, data curation; MA: Conceptualization, validation, visualization, supervision.
Financial support & sponsorship
None.
Conflicts of Interest
None.
Use of Artificial Intelligence (AI)-Assisted Technology for manuscript preparation
The authors confirm that there was no use of AI-assisted technology for assisting in the writing of the manuscript and no images were manipulated using AI.
References
- Global epidemiology of head and neck cancers: A continuing challenge. Oncology.. 2016;91:13-2.
- [CrossRef] [PubMed] [Google Scholar]
- Head and neck squamous cell carcinoma: Update on epidemiology, diagnosis, and treatment. Mayo Clin Proc.. 2016;91:386-96.
- [CrossRef] [PubMed] [Google Scholar]
- Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol.. 2014;32:2735-43.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- Prevalence and predictors of continued tobacco use after treatment of patients with head and neck cancer. Cancer.. 1995;75:569-76.
- [CrossRef] [PubMed] [Google Scholar]
- Carbon monoxide poisoning. J R Soc Med.. 2001;94:270-2.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- Smoking: The influence of carboxyhemoglobin (HbCO) on tumor oxygenation and response to radiation. Int J Radiat Oncol Biol. 1978;4:657-62.
- [CrossRef] [Google Scholar]
- Impact of tumor hypoxia and anemia on radiation therapy outcomes. Oncologist.. 2002;7:492-508.
- [CrossRef] [PubMed] [Google Scholar]
- Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck--a systematic review and meta-analysis. Radiother Oncol.. 2011;100:22-3.
- [CrossRef] [PubMed] [Google Scholar]
- Health behaviors of adults: United States, 2005-2007. Vital Health Stat 10. 2010:1-132.
- [Google Scholar]
- Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med.. 1993;328:159-63.
- [CrossRef] [PubMed] [Google Scholar]
- New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer.. 2009;45:228-47.
- [CrossRef] [PubMed] [Google Scholar]
- The effect of cigarette smoking on cancer treatment-related side effects. Oncologist.. 2011;16:1784-92.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- Depressive symptoms, smoking, drinking, and quality of life among head and neck cancer patients. Psychosomatics.. 2007;48:142-8.
- [CrossRef] [PubMed] [Google Scholar]
- Tobacco-related carcinogenesis in head and neck cancer. Cancer Metastasis Rev.. 2017;36:411-23.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- E-cigarettes, heat-not-burn and smokeless tobacco products. Breathe (Sheff). 2020;16:161ELF.
- [CrossRef] [PubMed] [Google Scholar]
- Radiotherapy for T1a glottic cancer: The influence of smoking cessation and fractionation schedule of radiotherapy. Eur Arch Otorhinolaryngol.. 2014;271:125-32.
- [CrossRef] [PubMed] [Google Scholar]
- Tobacco smoking during radiation therapy for head-and-neck cancer is associated with unfavorable outcome. Int J Radiat Oncol Biol Phys.. 2011;79:414-9.
- [CrossRef] [PubMed] [Google Scholar]
- Impact of smoking cessation on clinical outcomes in patients with head and neck squamous cell carcinoma receiving curative chemoradiotherapy: A prospective study. Head Neck.. 2019;41:3201-10.
- [CrossRef] [PubMed] [Google Scholar]
- Effect of smoking on oxygen delivery and outcome in patients treated with radiotherapy for head and neck squamous cell carcinoma--a prospective study. Radiother Oncol.. 2012;103:38-44.
- [CrossRef] [PubMed] [Google Scholar]