Lam Andrew C L, Hueniken Katrina, Pienkowski Martha, Lee John J W, Dong Mei, Diergaarde Brenda, Olshan Andrew F, Brennan Paul, Virani Shama, Saunders Deborah, Santi Stacey A, Conlon Michael S C, Waterboer Tim, Hayes D Neil, Pring Miranda, Macfarlane Gary J, Lagiou Pagona, Lagiou Areti, Polesel Jerry, Agudo Antonio, Alemany Laia, Ahrens Wolfgang, Healy Claire M, Conway David I, Nygard Mari, Canova Cristina, Hornakova Anna, Richiardi Lorenzo, Znaor Ariana, Hung Rayjean J, Xu Wei, Liu Geoffrey
Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
JAMA Otolaryngol Head Neck Surg. 2025 Apr 1;151(4):360-370. doi: 10.1001/jamaoto.2024.5392.
Cigarette smoking is a strong risk factor for mortality in patients diagnosed with head and neck squamous cell carcinoma (HNSCC). However, little evidence supports which smoking metric best models the association between smoking and survival in HNSCC.
To determine which smoking metric best models a linear association between smoking exposure and overall survival (OS) in patients with HNSCC.
DESIGN, SETTING, AND PARTICIPANTS: A retrospective multicenter cohort study of 6 clinical epidemiological studies was performed. Five were part of the Human Papillomavirus, Oral and Oropharyngeal Cancer Genomic Research (VOYAGER) consortium. Participants included patients 18 years and older with pathologically confirmed HNSCC. Data were collected from January 2002 to December 2019, and data were analyzed between January 2022 to November 2024.
The primary outcome was OS. The performance of 8 smoking metrics, including pack-years, duration, and log cig-years (calculated as log10[cigarettes smoked per day + 1] × number of years smoked) for modeling OS were compared. Metric performance was measured by the strength of association in Cox proportional hazard models, linearity based on P for linear trend, Akaike information criterion (AIC; lower value indicates better model fit), and visual assessment of spline curves. Secondary outcomes included modeling OS in clinicodemographic subgroups and HNSCC anatomic subsites. Exploratory outcomes included cancer-specific survival and noncancer survival.
In total, 8875 patients with HNSCC (2114 [24%] female; median [IQR] age, 61 [54-69] years) were included. Of 8 smoking metrics evaluated, smoking duration (adjusted hazard ratio [aHR], 1.11 [95% CI, 1.03-1.19]) and log cig-years (aHR, 1.11 [95% CI, 1.04-1.18]) had the highest aHRs; both had a statistically significant linear association with OS. Log cig-years had the lowest AIC linear value and the most visually linear spline curve when modeling OS. Duration and log cig-years outperformed pack-years for modeling OS regardless of age, smoking status, and cancer stage. Both performed well in lip and oral cavity, laryngeal (only duration was significant), and human papillomavirus-negative oropharyngeal subsites. In an exploratory analysis, duration had the highest aHR (1.15 [95% CI, 1.02-1.29]), and log cig-years had the lowest AIC linear value when modeling noncancer survival.
In this cohort study, smoking duration and log cig-years best modeled a linear relationship with OS for patients with HNSCC. Both metrics maintained robust performance within specific clinicodemographic subgroups and anatomic subsites. Although most HNSCC survival models control for smoking exposure using smoking status or pack-years, duration and log cig-years may be superior metrics to account for the effects of smoking on survival.
吸烟是头颈部鳞状细胞癌（HNSCC）患者死亡的一个重要危险因素。然而，几乎没有证据支持哪种吸烟指标能最好地模拟吸烟与HNSCC患者生存之间的关联。
确定哪种吸烟指标能最好地模拟HNSCC患者吸烟暴露与总生存期（OS）之间的线性关联。
设计、设置和参与者：对6项临床流行病学研究进行了一项回顾性多中心队列研究。其中5项是人类乳头瘤病毒、口腔和口咽癌基因组研究（VOYAGER）联盟的一部分。参与者包括18岁及以上经病理证实为HNSCC的患者。数据收集时间为2002年1月至2019年12月，数据分析时间为2022年1月至2024年11月。
主要结局为OS。比较了8种吸烟指标（包括吸烟包年数、吸烟持续时间和对数香烟年数[计算为log10（每天吸烟支数+1）×吸烟年数]）对OS进行建模的性能。指标性能通过Cox比例风险模型中的关联强度、基于线性趋势P值的线性度、赤池信息准则（AIC；值越低表明模型拟合越好）以及样条曲线的视觉评估来衡量。次要结局包括在临床人口统计学亚组和HNSCC解剖亚部位对OS进行建模。探索性结局包括癌症特异性生存期和非癌症生存期。
共纳入8875例HNSCC患者（2114例[24%]为女性；年龄中位数[四分位间距]为61[54 - 69]岁）。在评估的8种吸烟指标中，吸烟持续时间（调整后风险比[aHR]，1.11[95%置信区间，1.03 - 1.19]）和对数香烟年数（aHR，1.11[95%置信区间，1.04 - 1.18]）的aHR最高；两者与OS均具有统计学显著的线性关联。在对OS进行建模时，对数香烟年数的AIC线性值最低，样条曲线视觉上最线性。无论年龄、吸烟状态和癌症分期如何，在对OS进行建模时，持续时间和对数香烟年数均优于吸烟包年数。两者在唇部和口腔、喉部（仅持续时间有显著性）以及人类乳头瘤病毒阴性口咽亚部位均表现良好。在一项探索性分析中，在对非癌症生存期进行建模时，持续时间的aHR最高（1.15[95%置信区间，1.02 - 1.29]），对数香烟年数的AIC线性值最低。
在这项队列研究中，吸烟持续时间和对数香烟年数最能模拟HNSCC患者OS的线性关系。这两个指标在特定的临床人口统计学亚组和解剖亚部位均保持稳健性能。尽管大多数HNSCC生存模型使用吸烟状态或吸烟包年数来控制吸烟暴露，但持续时间和对数香烟年数可能是解释吸烟对生存影响的更优指标。
