HPV-related OPSCC is known for its different etiology and therapeutic response from HPV-unrelated OPSCC (1, 2). HPV-related OPSCC is caused by infection of the high risk HPV and responds well to the therapeutic interventions with a favorable prognosis in comparison to the HPV-unrelated OPSCC. TNM-8 classifies HPV-related OPSCC and HPV-unrelated OPSCC separately, taking the etiological and prognostic differences of them into consideration. TNM-8 uses p16 positivity as a surrogate of HPV infection similar to this study. Although some have reported better differentiation of OS according to stages by TNM-8 than by 7th edition TNM classification (7–9), there are also reports indicating that prognoses according to the stages are inadequately differentiated, especially between stage II and III by using TNM-8 for p16-positive OPSCC (10–12). Current study showed the stages defined by TNM-8 were inadequate in differentiating OS and DSS. Additionally more than 60% of HPV-related OPSCC patients were classified into stage I in this study, and further classification of stage I patients should be considered to improve differentiation of prognosis and to allocate equal number of patients to each stage (10).
While HPV-unrelated OPSCC is caused mainly by tobacco smoking and alcoholic consumption, the relationship of HPV-related OPSCC and tobacco smoking has been variously reported (2, 3, 13–23). Most notably Ang et al. demonstrated that amount of tobacco smoking expressed by PY > 10 and PY ≤ 10 had an influence upon OS and progression-free survival (PFS) in HPV-related OPSCC treated by chemoradiation and they proposed a risk classification of OPSCC according to p16 status, smoking habit, and tumor and nodal stages (2, 12). Although many studies have shown a statistically significant influence of tobacco smoking on OS (4, 17, 19, 22, 23), controversial results have been reported concerning the effect of tobacco smoking on DSS and locoregional control (15) (4) (21). While most studies have studied the patients with HPV-related OPSCC treated by radiotherapy with or without chemotherapy (16, 22, 23), there is a report refusing the influence of tobacco smoking on OS and DSS in the patients with HPV-related OPSCC treated by transoral robotic surgery (13). In contrary, the study from Canada, where the patients undergoing surgical treatment as well as radiation therapy were reported together, revealed that tobacco smoking has more unfavorable effect upon PFS in the patients treated surgically than in the patients treated by radiation therapy (21). Therefore, the impact of tobacco smoking might be different in various treatment modalities.
This study demonstrated that the patients managed by the treatment including radiation therapy showed no statistically significant difference in DSS by smoking represented by PY > 30 or PY < 30. In contrast, the patients treated by chemotherapy and surgery showed statistically significant differences in DSS by smoking. Also in Cox multivariate analysis employing smoking and the presence of secondary cancer as covariates, smoking lost a statistically significant impact in DSS in the patients treated by radiation therapy. Radiation therapy seems to reduce the influence of tobacco smoking, although the impact of tobacco smoking continues to exist in the patients undergoing surgery. These findings suggests that the influence of tobacco smoking upon DSS seems to be different according to therapeutic strategy.
In this study, tobacco smoking represented by PY ≥ 30 vs. < 30 was used to show the influence of tobacco smoking upon prognosis. We also analyzed the prognosis of never-smokers and searched for multiple dichotomized points of PY and dichotomy at PY = 30 was found to influence both OS and DSS of HPV-related OPSCC with the smallest p-values. Also time interval between cessation of smoking and treatment initiation of OPSCC was examined, but no statistically significant influence upon prognosis was observed.
As a retrospective study, this study has some limitations. Deviation of prognostic factor like the presence of secondary cancer was seen between the patients with PY ≥ 30 and < 30. Secondary cancers were more frequently seen in the patients with PY ≥ 30. However, multivariate analysis revealed the presence of secondary cancer lost a statistical significance in DSS. Additionally because of the favorable prognosis of HPV-related OPSCC total number of events in DSS is only 10 and it was difficult to show statistical significances in some analyses. In future, the prospective trial is necessary to elucidate the different impact of smoking upon various treatment modalities. Because many different metrics of tobacco smoking, such as number of PY, never vs. ever smokers, current vs. former smokers, and cessation length of tobacco smoking, were used, common language of expression of tobacco smoking should be defined beforehand (20).