Tobacco exposure as a major modifier of oncologic outcomes in Human PapillomaVirus (HPV) associated oropharyngeal squamous cell carcinoma

doi:10.21203/rs.2.22588/v1

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Research article

Tobacco exposure as a major modifier of oncologic outcomes in Human PapillomaVirus (HPV) associated oropharyngeal squamous cell carcinoma

https://doi.org/10.21203/rs.2.22588/v1

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published 23 Sep, 2020

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Background

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) in the US is rapidly increasing, driven largely by the epidemic of human papillomavirus (HPV)-mediated OPSCC. Although survival for patients with HPV mediated OPSCC (HPV+ OPSCC) is generally better than that of patients with non-viral HPV+ OPSCC, the improvement is not uniform. We hypothesized that tobacco exposure remains a critical modifier of survival for HPV+ OPSCC patients.

Methods

We conducted a retrospective analysis of 611 OPSCC patients with concordant p16 and HPV testing treated at a single institute (2002-2013). Survival analysis was performed using Kaplan-Meier analysis and Cox regression. Recursive partitioning analysis (RPA) was used to define tobacco exposure associated with survival (p<0.05).

Results

Tobacco exposure impacted overall survival (OS) for HPV+ patients on univariate and multivariate analysis (p=0.002, p=0.003 respectively). RPA identified 30 pack-years (PY) as a threshold at which survival became significantly worse in HPV+ patients. OS and disease-free survival (DFS) for HPV+ >30 PY patients didn’t differ significantly from HPV- group (p= 0.72, p= 0.27, respectively). HPV+ >30 PY patients had substantially lower 5-year OS when compared to their ≤30 PYs counterparts: 78.4% vs 91.6%; p= 0.03, 76% vs 88.3%; p= 0.07, and 52.3% vs 74%; p= 0.05, for stages I, II, and III (AJCC 8th Edition Manual), respectively.

Conclusions

Tobacco exposure can eliminate the survival benefit associated with HPV+ status in OPSCC patients. Until this effect can be clearly quantified using prospective datasets, de-escalation of treatment for HPV+OPSCC smokers should be avoided.

Cancer Biology

Oncology

oropharyngeal carcinoma

radiotherapy

tobacco

human papillomavirus

The human papillomavirus (HPV) has transformed the landscape of cancer diagnosis and treatment across multiple solid tumor sites. Oropharyngeal squamous cell carcinoma (OPSCC), a disease traditionally associated with tobacco and alcohol exposure, has now become overwhelmingly a disease associated with HPV.^1–4For many OPSCC patients, this change in the epidemiology of the disease has resulted in dramatic improvements in treatment efficacy, disease specific survival, and overall survival.^1–6 The 8^th Edition of the American Joint Committee on Cancer (AJCC) Staging Manual dramatically downstages HPV mediated (HPV+) OPSCC tumors relative to the prior staging rubric.⁷ Overall, a significant fraction of OPSCC tumors previously staged as stage III-IV has now been down-staged to stage I-II, consistent with the dramatically improved survival for HPV+ OPSCC patients compared to their HPV negative (HPV-) OPSCC counterparts.⁷

In 2010, Ang et al. identified an interaction between HPV status and tobacco exposure in OPSCC patients and defined “low-risk” and “intermediate-risk” tumors based on differential survival.¹ The principle distinction between the 2 risk categories was a poorer survival in patients who were cigarette smokers. The interaction between HPV and cigarette smoking is poorly characterized both from a biological perspective and with respect to clinical outcomes.⁸

Tobacco exposure is generally expressed as a function of volume and time (1 pack-year (PY) = 1 pack of cigarettes per day for 1 year). Ang et al. set a threshold of 10 PY to define a “smoker”.¹ Although sufficient to impact survival, this threshold has not been fully validated in the context of HPV+ OPSCC. For certain patient populations a threshold of 10 PY results in defining nearly 90% of the patient population as smokers.⁸ Data from veterans with HPV+ OPSCC has identified tobacco exposure as high as 150 PY.⁸ Although smoking rates have decreased over the last 2 decades, evidence suggests that tobacco exposure remains a significant consideration for OPSCC patients throughout the United States and varies widely based on race/ethnicity and socioeconomic strata.^{3, 9}

The recent changes to the AJCC staging system for OPSCC make urgent the need to better define the potential impact of tobacco exposure on clinical outcomes for HPV+ OPSCC patients to appropriately counsel patients. Furthermore, given continued efforts at treatment de-escalation for HPV+ OPSCC tumors, it is critical to determine whether a subset of patients may be at risk for inappropriate de-escalation. To this end, we hypothesized that tobacco exposure has a significant negative impact on HPV+ OPSCC patient survival and, sought to test this hypothesis in this large single institution cohort of HPV+ OPSCC patients.

Patients

Following approval by the University of Texas MD Anderson Cancer Center institutional review board, we reviewed 1171 patients with a primary diagnosis of oropharyngeal squamous cell carcinoma (OPSCC) who underwent definitive non-surgical treatment between 2002 and 2013. This end date was chosen to allow for a minimum follow up period of 5 years. Patients with recurrent disease, previous oncologic treatment, and/or lost to follow-up were excluded from the analysis. Demographics, tobacco usage, and clinical-pathologic history were comprehensively reviewed through the institutional electronic medical record. Cancer staging was conducted according to the American Joint Commission on Cancer Staging Manual (both 7^thand 8^th Editions). Tobacco exposure was obtained from the medical record in the form of PY defined as: 1 PY = 1 pack of cigarettes/day for 1 year. Supplementary Figure 1 represents a CONSORT flow diagram showing inclusion and exclusion criteria for the study patients.

HPV determination

All tumors were tested via evaluating the presence of HPV16 DNA by use of the in-situ hybridization (ISH)-catalyzed signal amplification method for biotinylated probes and/or the expression status of p16 via immunohistochemistry (IHC). For the purposes of this analysis, only patients who underwent both p16 and HPV testing and with concordant results were included.^{1, 8}

Treatment

The overall treatment strategy was determined through a multidisciplinary team decision following case discussion. Surgically treated patients were excluded from this analysis. All patients were treated using intensity-modulated radiotherapy (IMRT) using previously described protocols.^{10, 11} Generally, we treat the primary tumor and the upper neck nodal disease using a split-ﬁeld technique matching with a lower anterior neck ﬁeld with a larynx midline block. Whole-ﬁeld IMRT was used for junctional tumors to avoid under-dosing. Small volume primary tumors were usually prescribed up to 66 Gy, while more advanced tumors were prescribed up to 70–72 Gy. Radiation was delivered using 6-MV photons linear accelerators. Decisions of systemic therapy addition to IMRT were individualized based on the disease burden as well as associated medical comorbidities and performance status. Concurrent chemo/IMRT was prescribed to patients with advanced primary tumor and/or bulky lymph node metastasis, while induction chemotherapy was assigned for patients with high risk of distant recurrence (e.g. advanced N-stage).¹²

Study endpoints and statistical analysis

The outcomes of interest –all reported in months- included: 'Loco-regional control (LRC)' defined as time from date of completion of treatment to date of diagnosis of local and/or regional recurrence; 'Freedom from distant metastasis (FDM)' defined as time from date of completion of treatment to date of diagnosis of malignant metastasis to distant body organ; ‘Disease-free survival (DFS)' defined as time from date of completion of treatment to date of diagnosis of loco-regional and/or distant recurrence (i.e. whichever occurred initially); and ‘Overall survival (OS)' defined as time from date of completion of treatment till death or last recorded follow-up. Chi-square test was used to compare the categorical variables (e.g. sex, race, T-category, N-category, etc.) among p16+/HPV+ (or shortly HPV+) versus p16-/HPV- (or shortly HPV-) groups. Survival analysis was performed using Kaplan‐Meier analysis (log-rank test). Uni- and multi-variable survival analyses were performed using Cox regression; and hazard ratios (HR) and 95% confidence intervals (CI) were calculated. Recursive partitioning analysis (RPA) was used to quantify a threshold for tobacco exposure significantly associated with overall survival (p<0.05). For multivariable analysis, we tested the prognostic impact of the AJCC staging system and tobacco exposure in HPV+ patients compared with a baseline model of standard clinical variables. The baseline model included age, sex, AJCC 7^th edition, chemotherapy sequence, and total external beam radiotherapy (EBRT) dose. We then compared the alternative models using Bayesian information criteria¹³ (BIC). A lower BIC indicates improved model performance and parsimony, using the BIC evidence grades presented by Raftery¹⁴ with the posterior probability of superiority of a lower BIC model, where a BIC decrease of <2 is considered “Weak” (representing a 50–75% posterior probability of being superior model), 2–6 denoted “Positive” (posterior probability of 75–95%), 6–10 as “Strong” (posterior probability of >95%), and >10, “Very strong” (posterior probability >99%). Furthermore, we analyzed the competing risk of failure and death using Weibull parametric fitting of cause of failure and death, respectively, as a competing risk variable for uncensored data. Statistical analysis was performed using JMP Pro statistical software (version 11.2.0; SAS Institute Inc, Cary, NC).

Patients

A total of 611 patients were included in the analysis. The majority (89%) were HPV+ and half of these patients reported 0 PY history of tobacco exposure whereas only 20% of the HPV- patients were non-smokers. Approximately one-third of the smokers in the HPV+ cohort reported heavy exposure (i.e. >30 PY history) compared with approximately half of the smokers in the HPV- cohort. The details of tobacco exposure in PY for both cohorts are shown in Supplementary Figure 2. The HPV+ group contained more males than the HPV- group (87% vs 68%, p<0.0001). The pattern of disease subsites was equivalent in both cohorts, with approximately even distribution of base of tongue and tonsillar primaries. The majority of patients in both cohorts had earlier T-category (i.e. T1–2) while N-category significantly varied using different editions of the AJCC staging system with the most frequent N-category shifting from N2 per 7^th edition to N1 per 8^th edition for the HPV+ group as detailed in Table 1. The regimen of treatment did not vary significantly among both cohorts.

HPV status impacts OPSCC patient survival

The 5‐year actuarial LRC, FDM, DFS, and OS rates for the entire cohort were 88.9%, 91.3%, 83.3%, and 84.3% respectively. The 5-year outcomes for HPV+ group were significantly more favorable compared with HPV- group for all studied endpoints except FDM. Overall survival was 85.8% vs 71.2%; p = 0.0009, in HPV+ versus HPV- groups, DFS was 84.7% vs 70.2%; p = 0.004 (Figure 1). In addition, LRC was 89.8 % vs 81.2%; p = 0.04, and FDM was 91.7% vs 88.3%; p = 0.44, in HPV+ versus HPV- groups respectively. Corresponding Kaplan-Meier survival plots for the LRC and FDM are depicted in Supplementary Figure 3.

Tobacco exposure impacts OPSCC patient survival

Univariable analysis demonstrated that tobacco exposure (quantified in PY) was significantly associated with OS in both HPV+ and HPV- groups (p = 0.002 and 0.0006, respectively). Subsequent RPA identified 30 PY as the cut-off threshold for differential OS risk; and the resulting binary risk groups (PY ≤30 and PY >30) were then integrated into the final analysis. Smokers >30 PY were shown to have more than double the hazard of death for both HPV+ (HR = 2.6, 95%CI = 1.5–4.2, p = 0.0006) and HPV- (HR = 2.7, 95%CI = 1.1–7.5, p = 0.03) groups as compared to ≤30 PY smokers. In addition, the following clinical variables were also significantly associated with OS in the HPV+ group: T-category; AJCC stage (8^th edition); chemotherapy sequence; and total EBRT dose. However, for the HPV- group, T-category was the only additional clinical variable with significant association with OS (Supplementary Table 1)..

Patients in the HPV+ group with tobacco exposure of >30 PY had decreased 5-year OS (72.1% vs 88.3%; p = 0.0001) and 5-year DFS (76.9% vs 86.1%; p = 0.07) as compared to those with lower tobacco ≤30 PY (Figure 1).. While 5-year LRC was worse in HPV+ >30 PY subset (81.7% vs 91.2%; p = 0.02), 5-year FDM did not show significant differences between the two subsets (91.2% vs 91.8%; p = 0.39) (Supplementary Figure 4)..

Overall survival and DFS Kaplan-Meier survival probability estimates at 5 years did not statistically differ for HPV+ >30 PY and HPV- subsets: 72.1% vs 71.2%; p = 0.72, and 76.9% vs 70.2%; p = 0.27, respectively. Moreover, smoking status at diagnosis didn’t significantly correlate to OS or DFS in HPV+ patients on univariable analysis. When patients in the HPV+ group with tobacco exposure >30 PY, were stratified into current and former smokers (n = 43; each), OS and DFS Kaplan-Meier survival probability estimates at 5 years still did not statistically differ between the two subgroups.

We stratified each of the three AJCC (8^th edition) HPV+ patient clusters into low (≤30 PY) and high (>30 PY) tobacco exposure, and plotted KM OS curves accordingly (Figure 2).. Patients with higher tobacco exposure in each stage showed worse 5-year OS compared to their counterparts within the same stage category as shown in Figure 2. The 5-year OS for HPV+ patients with >30 vs ≤30 PY was 78.4% vs 91.6%; p = 0.03, 76% vs 88.3%; p = 0.07, and 52.3% vs 74%; p = 0.05, for stages I, II, and III, respectively.

In multivariable analysis, AJCC 8^th edition markedly improved the OS model performance over the baseline model when added instead of the 7^th edition (i.e. BIC decreased by 11). Further addition of the tobacco risk grouping achieved the best OS model performance (BIC decreased by 13 over the baseline and 2 over the AJCC 8^thmodels,respectively). Uni- and multi-variable analysis for DFS showed no correlation between tobacco exposure and DFS in both HPV+ and HPV- groups. While chemotherapy sequence, total EBRT dose, T- and N-categories, and AJCC stage (8^th edition) were associated with DFS in the HPV+ cohort on univariable analysis, only AJCC stage (8^th edition) retained significant association with DFS, when combined into a multivariable model. On the other hand, DFS in HPV- OPSCC subset was significantly associated with age at diagnosis and T-category (on univariable analysis), and total EBRT dose (on both analyses) (Supplementary Table 2)..

Competing risk analysis

Supplementary Table 3 and 4 depict causes of death and failure, respectively, in HPV+OPC stratified by our proposed cutoff of 30 PY. Afterwards, a competing risk analysis of causes of death stratified by p16/HPV status and tobacco exposure demonstrated that index cancer-specific deaths were the predominant cause of death in HPV- group independent of the tobacco exposure status and in HPV+ subset with lower (≤30 PY) tobacco exposure, as shown in Figures (3A), (3B), and (3C), respectively. However, the HPV+ subgroup with higher (>30 PY) tobacco exposure had a relatively higher risk of non-cancer deaths compared to other three subgroups (Figure 3D). Furthermore, competing risk of the mode of failure in all the four OPSCC patients subsets revealed a much higher probability of loco-regional failure in patients with high (>30 PY) tobacco exposure as compared to the lower tobacco exposure subgroups, regardless of the p16/HPV status. Compared to failures attributed to distant metastases, patients with high tobacco exposure have double the probability of developing loco-regional failure at 5-years (Figure 4).

OPSCC incidence is rising at an alarming rate in the United States.^{2, 3, 15, 16} The most recent analysis completed in 2018 demonstrated a persistently low rate of HPV preventive vaccination among the US population.¹⁷ It is, therefore, reasonable to expect that the current increase in OPSCC incidence secondary to HPV is likely to continue for at least the next few decades, especially in North and South America, Central, Eastern, and Northern Europe.¹⁸ As the OPSCC patient population is expected to increase, it is critical to improve our understanding of how disease biology interacts with and/or determines treatment response.^{2, 3, 8, 15, 16} This requires not only an improved understanding of HPV-mediated effects on tumorigenesis and treatment response, but also a better understanding of the interaction between HPV exposure and other OPSCC risk factors such as tobacco exposure.

Despite continued decrease over the last half century, tobacco use remains associated with 4 out of 5 leading causes of death in the US.¹⁹ The interplay among smoking, HPV infection, other risk factors, and carcinogenesis is complex and multifactorial.²⁰ Increasing tobacco exposure has been linked to greater hazard of contracting and persisting oral HPV infection in healthy individuals, displaying a prominent dose-response fashion.^21–23 The interaction between tobacco exposure and HPV infection in OPSCC carcinogenesis and whether the risk of HPV-mediated OPSCC is higher or lower among smokers have been a matter of ongoing debate.^24–26 Our data in the US veteran population indicates that tobacco exposure is nearly ubiquitous and that approximately 75% of new HPV+ OPSCC diagnoses occur in patients with >10 pack-year history of tobacco exposure.⁸ Similar data have been reported for other patient populations including the indigent, uninsured and underinsured patients.^{27, 28}

The 8^th Edition of the AJCC staging manual recognized the more favorable prognosis in patients with HPV-mediated OPSCC. As such, the current staging has downstaged patients with what was historically regarded as locally advanced disease and assigned high stage designation. However, while recognizing that patients with HPV-mediated disease have better prognoses, it has also been recognized that current and former smokers tend to have worse survival rates than non-smokers.⁷ The AJCC was challenged with incorporating smoking into the staging, which was later described in the manual as follows: “the role of tobacco as a negative prognostic factor is well established. However, exactly how this could be codified in the staging system is less clear”.²⁹ Even prior to the AJCC 8^th edition era, similar challenges were reported when smoking was introduced to prognostic framework like in the study by Huang et al. where the model appeared robust for Stages I and II (by criteria used for 8th edition) at a threshold of 20 PY but did not hold in Stage III. That was attributed to the detrimental influence of age in the model, potentially related to inability to tolerate intensive treatment for these anatomically more extensive HPV+ lesions (T4 and N3).³⁰ Our data strongly suggest that, although survival is greatly impacted by HPV status, tobacco exposure also plays a very important role. This has been strikingly demonstrated by a poorer survival in both HPV+ and HPV- heavy smokers (i.e. more than double the hazard of death) compared to <30 PY smokers. This suggests that not all HPV+ OPSCC tumors should be expected to demonstrate the same excellent outcomes we have come to expect. Perhaps most concerning is the significant survival decrease in patients with heavy tobacco exposure. For overall survival, tobacco exposure erases the favorable survival impact of HPV positivity, generating an absolute survival decrement of approximately 16%. As a point of reference, the absolute survival benefit for the addition of chemotherapy to radiation was only ~8%, based on the most recent MACH-NC meta-analysis.³¹ We recently updated survival for patients with oral cavity SCC, and identified the relative effect size for nodal metastasis at ~15% and extra-nodal extension at ~20%.³² These data place the impact of tobacco exposure within the range of other treatment modifying clinical-pathologic parameters.

Furthermore, our results showed that the impact of heavy tobacco exposure is alarmingly impacting the outcomes of even early stage disease as defined by the newest edition of the AJCC staging system. Our results showed that our proposed tobacco exposure cutoff of 30 py clearly stratified patients at each AJCC (8^thedition) stage in terms of overall survival outcomes. However, statistical significance was only reached in stage I, probably because of smaller numbers of patients with more advanced disease, i.e. ~60% of the whole cohort was categorized as stage I. Nonetheless, heavy smokers with stage I or II disease had 5-year outcomes that were approximating or -in some cases- even worse than outcomes of patients with lower smoking index and more advanced disease stage. This observation must be considered in the inclusion criteria for future dose de-escalation studies in early stage HPV+ OPSCC. In agreement with these results, a recent study by Vawda et al.³³ has demonstrated that higher intensity of smoking exposure was associated with poorer outcomes in a cohort of exclusively HPV+ oropharyngeal cancer patients treated with primary radiation or surgery. The study, however, lacked the comparison with an HPV- cohort. As a result, the relative effect size of tobacco exposure in the HPV+ OPSCC population remains only partially contextualized. Our findings track closely with those of this recently published data. Moreover, our data indicate that HPV+ patients with smoking index above 30 have surprisingly comparable outcomes to HPV- patients, highlighting the importance of considering this very important risk factor in the treatment decision making process.

In the meantime, the putative impact of smoking on cancer-specific mortality in HPV+ OPSCC subpopulation cannot be interpreted barring the known adverse effects of smoking on general co-morbidity and death, including cardio-vascular, cerebrovascular, pulmonary, other cancers, and co-existing risk factors (e.g. alcoholism), among others.^{34, 35} Our competing risk analysis indicated that the worse survival outcomes of HPV+ heavy smokers were attributable to two main factors; the increased risk of locoregional failure that leads to more cancer related deaths as well as the overall increased risk of non-cancer related deaths compared with smokers below the identified threshold. (Figures 3 and 4) That’s to say HPV+ heavy smokers who don’t die of smoking-related comorbidities (the dominant detrimental effect of smoking per Figure 3D) will more probably die of loco-regional failure (Figure 4D).

Although large this is a single institution patient cohort and as such our findings must be validated in additional patient cohorts. It is also important to note, that our outcomes for HPV- patients in this series are dramatically better than historical data even from our institution.^{1, 2, 6} This, combined with the relative small size of the HPV- cohort may confound the comparison between the 3 groups outlined in Figure 1. Moreover, chemotherapy, despite being associated by multiple randomized controlled trials with better treatment outcomes, was not shown to be an independent prognostic factor even in HPV- subpopulation where more benefit from chemotherapy would be expected.³⁶ This can be attributed in part to the retrospective nature of the study where treatment decisions followed the institutional multidisciplinary protocol. That’s to say, patients with early OPC, with more favorable prognosis, received no chemotherapy in contrast to the more advanced HPV-OPC patients who still showed worse outcomes despite receiving chemotherapy.

In addition, the tobacco exposure range for the HPV+ cohort is substantially skewed toward the lower range of exposure (Supplementary Figure 2), likely limiting our ability to generate a more granular, dose-dependent effect for tobacco exposure on survival. Moreover, data suggests that current smoking status adversely affects LRC and OS in patients with HNSCC.^{37, 38} This is further exacerbated by the smoking-induced reduction of radiation-induced tumor killing with subsequent worsening of locoregional control.^{39, 40} The unavailability of smoking status for patients while on-treatment –as is the case with our study- might raise a question on the weight that should be assigned to the carcinogenic effect of smoking compared to its antagonistic impact on radiotherapy efficacy. Nonetheless, our results showed no differential disease control or overall survival between current and former smokers, even in the heavy smoker subset (PY >30). We acknowledge that our study lacks a detailed categorization of history of tobacco exposure per the International Classification of Diseases, Tenth Revision (ICD–10) diagnosis code, as a result of inherent flaws of retrospective data collection.⁴¹ However, it is still intuitive to extricate from our results the useful public health message relating to advice concerning smoking cessation, especially during radiotherapy course.⁴² Benefits can include limiting radiotherapy/chemotherapy treatment prolongation or interruption and associated heavy symptom burden during and following treatment, in addition to the rapid return of carboxyhemoglobin levels in patients who quit to that of light /never smokers.^{43, 44}

Conversely, by limiting our analysis to only those patients with concordant p16 and HPV testing data, we can feel very confident that however limited the data, it is in fact reflective of the underlying tumor biology and not simply a testing artifact. The data generated here conform to what we have come to expect from OPSCC defined by conventional risk factor exposure (i.e. tobacco exposure), namely decreased treatment response and a high rate of loco-regional failure. We previously showed that >90% of recurrence/progression occurs loco-regionally in a patient cohort with significant tobacco exposure.⁸ The fact that tobacco exposure is a distinct competing risk for loco-regional failure not only suggests an impact on treatment effectiveness, but is particularly concerning when considering current efforts to de-escalate treatment for HPV+ OPSCC patients.

Tobacco remains a critical driver of survival and treatment response in HPV+ OPSCC. Based on this dataset, we strongly recommend development of a multi-institutional cooperative group focused on characterizing and quantifying the relative impact of tobacco exposure on HPV+OPSCC clinical outcomes. Until such time that definitive national datasets can be generated, we recommend strong consideration of tobacco exposure in the context of ongoing institutional and cooperative group trials aimed at de-escalation regimens for HPV+ OPSCC along the same lines as the phase II/III PATHOS and the recently completed NRG HN002 randomized controlled trials.^{45, 46} Furthermore, we recommend a dedicated multi-institutional effort aimed at validating the current dataset and developing additional guidance for consideration of tobacco exposure in the context of the AJCC 8^th Edition Staging Manual.

AJCC: American Joint Committee on Cancer

BIC: Bayesian information criteria

CI: Confidence interval

DFS: Disease-free survival

EBRT: External beam radiotherapy

FDM: Freedom from distant metastasis

HPV: Human papillomavirus

HR: Hazard ratio

ICD–10: International Classification of Diseases, Tenth Revision

IHC: Immunohistochemistry

IMRT: Intensity-modulated radiotherapy

ISH: in situ hybridization

LRC: Loco-regional control

MACH-NC: Meta-analysis of Chemotherapy in Head and Neck Cancer

NRG: An organization that brings together the National Surgical Adjuvant Breast and Bowel Project (NSABP), the Radiation Therapy Oncology Group (RTOG), and the Gynecologic Oncology Group (GOG)

OPSCC: Oropharyngeal squamous cell carcinoma

OS: Overall survival

PY: Pack-years

RPA: Recursive partitioning analysis

US: United States

Ethics approval and consent to participate

This study was approval by the University of Texas MD Anderson Cancer Center institutional review board (RCR–03–800)

Consent for publication

Not applicable

Availability of data and materials

Clinical dataset is not available as it includes personal health identifiers (PHI)

Competing interests

The authors have no competing interests to report.

Funding

The acknowledged funders/supporters played no role in the study design, collection, analysis, interpretation of data, manuscript writing, or decision to submit the report for publication.

Authors’ contributions

All listed co-authors performed the following:

Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work;
Drafting the work or revising it critically for important intellectual content
Final approval of the version to be published
Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Specific additional individual cooperative effort contributions to study/manuscript design/execution/interpretation, in addition to all criteria above are listed as follows:

Hesham Elhalawani: Conceptualization, data curation, formal analysis, methodology, visualization, writing-original draft, and writing-review and editing. Abdallah S. R. Mohamed: Conceptualization, data curation, formal analysis, methodology, visualization, writing-original draft, and writing-review and editing. Baher Elgohari: data curation and writing-review and editing. Timothy A. Lin: data curation and writing-review and editing. Andrew G. Sikora: Conceptualization, methodology, and writing-review and editing. Stephen Y. Lai: Conceptualization, methodology, and writing-review and editing. Jack Phan: Conceptualization, methodology, and writing-review and editing. William H. Morrison: Conceptualization, methodology, and writing-review and editing. G. Brandon Gunn: Conceptualization, methodology, and writing-review and editing. David I. Rosenthal: Conceptualization, methodology, and writing-review and editing Adam S. Garden: Conceptualization, methodology, writing-original, and writing-review and editing. Clifton D. Fuller: Conceptualization, formal analysis, methodology, writing-original, and writing-review and editing. Vlad C. Sandulache: Conceptualization, formal analysis, methodology, visualization, writing-original draft, and writing-review and editing.

Acknowledgements

Multiple funders/agencies contributed to personnel salaries or project support during the manuscript preparation interval. Dr. Elhalawani is supported in part by the philanthropic donations from the Family of Paul W. Beach to Dr. G. Brandon Gunn, MD. Drs. Elhalawani and Fuller received salary support from National Institutes of Health (NIH)/National Cancer Institute (NCI) Head and Neck Specialized Programs of Research Excellence (SPORE) Developmental Research Program Award (P50 CA097007–10). Drs. Fuller and Mohamed receive(d) salary support from NIH, including: National Institute for Dental and Craniofacial Research Award (1R01DE025248–01/R56DE025248–01); NCI Early Phase Clinical Trials in Imaging and Image-Guided Interventions Program (1R01CA218148–01); NCI Big Data to Knowledge (BD2K) Early Stage Development of Technologies in Biomedical Computing, Informatics, and Big Data Science Award (1R01CA214825–01); NCI Cancer Center Support Grant (CCSG) Radiation Oncology and Cancer Imaging Program Pilot Research Program Award (P30CA016672); NCI/National Science Foundation Joint NSF/NIH Initiative on Quantitative Approaches to Biomedical Big Data (QuBBD) award (5R01CA225190–0); and the National Institute of Biomedical Imaging and Bioengineering (NIBIB) Research Education Program (R25EB025787). This research is supported by the Andrew Sabin Family Foundation; Dr. Fuller is a Sabin Family Foundation Fellow. Dr. Fuller has received direct institutional academic/industry grant support from Elekta AB via a Elekta AB/MD Anderson Department of Radiation Oncology Seed Grant. Dr. Fuller has received speaker travel and honoraria from Elekta AB. Dr. Elgohari is funded through joint supervision program by the Egyptian Ministry of Cultural and Higher Education. Dr. Sikora receives funding from the FDA (1R01FD005109–01), NCI and NIDCR (U01DE028233), Veteran’s Administration (1 I01 BX004183), and the Caroline Weiss Law Foundation for Academic Excellence. Dr. Sandulache has received support through the Seed Grant Program of the Michael E. DeBakey Veterans Affairs Medical Center and through institutional seed funds (Baylor College of Medicine). Dr. Sikora has received support from the Department of Veterans Affairs Million Veteran Program (BX004183–01A1).

Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363: 24–35.
Dahlstrom KR, Calzada G, Hanby JD, et al. An evolution in demographics, treatment, and outcomes of oropharyngeal cancer at a major cancer center: a staging system in need of repair. Cancer. 2013;119: 81–89.
Gillison ML, Chaturvedi AK, Anderson WF, Fakhry C. Epidemiology of Human Papillomavirus-Positive Head and Neck Squamous Cell Carcinoma. J Clin Oncol. 2015;33: 3235–3242.
Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92: 709–720.
Cohen MA, Weinstein GS, O’Malley BW, Jr., Feldman M, Quon H. Transoral robotic surgery and human papillomavirus status: Oncologic results. Head Neck. 2011;33: 573–580.
Garden AS, Kies MS, Morrison WH, et al. Outcomes and patterns of care of patients with locally advanced oropharyngeal carcinoma treated in the early 21st century. Radiat Oncol. 2013;8: 21.
Lydiatt WM, Patel SG, O’Sullivan B, et al. Head and Neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67: 122–137.
Sandulache VC, Hamblin J, Lai S, et al. Oropharyngeal squamous cell carcinoma in the veteran population: Association with traditional carcinogen exposure and poor clinical outcomes. Head Neck. 2015;37: 1246–1253.
Centers for Disease Control and Prevention. Current Cigarette Smoking Among Adults—United States, 2016. Morbidity and Mortality Weekly Report 2018;67(2):53–9 [accessed 2019 Jan 29].
Gunn GB, Blanchard P, Garden AS, et al. Clinical Outcomes and Patterns of Disease Recurrence After Intensity Modulated Proton Therapy for Oropharyngeal Squamous Carcinoma. Int J Radiat Oncol Biol Phys. 2016;95: 360–367.
Garden AS, Dong L, Morrison WH, et al. Patterns of Disease Recurrence Following Treatment of Oropharyngeal Cancer With Intensity Modulated Radiation Therapy. International Journal of Radiation Oncology*Biology*Physics. 2013;85: 941–947.
Garden AS, Gunn GB, Hessel A, et al. Management of the lymph node-positive neck in the patient with human papillomavirus-associated oropharyngeal cancer. Cancer. 2014;120: 3082–3088.
Volinsky CT, Raftery AE. Bayesian information criterion for censored survival models. Biometrics. 2000;56: 256–262.
Raftery A. Bayesian Model Selection in Social Research. Sociological Methodology. 1995;25: 111–163.
Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008;26: 612–619.
Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100: 261–269.
Chaturvedi AK, Graubard BI, Broutian T, et al. Effect of Prophylactic Human Papillomavirus (HPV) Vaccination on Oral HPV Infections Among Young Adults in the United States. J Clin Oncol. 2018;36: 262–267.
Castellsagué X, Alemany L, Quer M, et al. HPV Involvement in Head and Neck Cancers: Comprehensive Assessment of Biomarkers in 3680 Patients. JNCI: Journal of the National Cancer Institute. 2016;108.
Centers for Disease Control and Prevention. https://www.cdc.gov/media/releases/2016/p1117-preventable-deaths.html [accessed 2019 Jan 29].
Ducatman BS. The Role of Human Papillomavirus in Oropharyngeal Squamous Cell Carcinoma. Archives of Pathology & Laboratory Medicine. 2018;142: 715–718.
Shigeishi H, Sugiyama M. Risk Factors for Oral Human Papillomavirus Infection in Healthy Individuals: A Systematic Review and Meta-Analysis. Journal of clinical medicine research. 2016;8: 721–729.
Kero K, Rautava J, Syrjanen K, Willberg J, Grenman S, Syrjanen S. Smoking increases oral HPV persistence among men: 7-year follow-up study. Eur J Clin Microbiol Infect Dis. 2014;33: 123–133.
Fakhry C, Gillison ML, D’Souza G. Tobacco Use and Oral HPV–16 InfectionTobacco Use and Oral HPV–16 InfectionLetters. JAMA. 2014;312: 1465–1467.
Herrero R, Castellsague X, Pawlita M, et al. Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. J Natl Cancer Inst. 2003;95: 1772–1783.
Chaturvedi AK, D’Souza G, Gillison ML, Katki HA. Burden of HPV-positive oropharynx cancers among ever and never smokers in the U.S. population. Oral Oncol. 2016;60: 61–67.
Smith EM, Ritchie JM, Summersgill KF, et al. Human papillomavirus in oral exfoliated cells and risk of head and neck cancer. J Natl Cancer Inst. 2004;96: 449–455.
Kwok J, Langevin SM, Argiris A, Grandis JR, Gooding WE, Taioli E. The impact of health insurance status on the survival of patients with head and neck cancer. Cancer. 2010;116: 476–485.
Conway DI, McMahon AD, Smith K, et al. Components of socioeconomic risk associated with head and neck cancer: A population-based case–control study in Scotland. British Journal of Oral and Maxillofacial Surgery. 2010;48: 11–17.
Mahul B. Amin, MD, FCAP, ed. 2017. AJCC Cancer Staging Manual. Springer International Publishing. ISBN–10: 3–319–40617–5, ISBN–13: 978–3–319–40617–6.
Huang SH, Xu W, Waldron J, et al. Refining American Joint Committee on Cancer/Union for International Cancer Control TNM Stage and Prognostic Groups for Human Papillomavirus–Related Oropharyngeal Carcinomas. Journal of Clinical Oncology. 2015;33: 836–845.
Blanchard P, Baujat B, Holostenco V, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother Oncol. 2011;100: 33–40.
Sandulache VC, Michikawa C, Kataria P, et al. High-Risk TP53 Mutations Are Associated with Extranodal Extension in Oral Cavity Squamous Cell Carcinoma. Clin Cancer Res. 2018;24: 1727–1733.
Vawda N, Banerjee RN, Debenham BJ. Impact of Smoking on Outcomes of HPV-related Oropharyngeal Cancer Treated with Primary Radiation or Surgery. Int J Radiat Oncol Biol Phys. 2018.
Maxwell JH, Kumar B, Feng FY, et al. Tobacco use in human papillomavirus-positive advanced oropharynx cancer patients related to increased risk of distant metastases and tumor recurrence. Clinical cancer research: an official journal of the American Association for Cancer Research. 2010;16: 1226–1235.
Roversi S, Fabbri LM, Sin DD, Hawkins NM, Agustí A. Chronic Obstructive Pulmonary Disease and Cardiac Diseases. An Urgent Need for Integrated Care. American Journal of Respiratory and Critical Care Medicine. 2016;194: 1319–1336.
Blanchard P, Hill C, Guihenneuc-Jouyaux C, Baey C, Bourhis J, Pignon JP. Mixed treatment comparison meta-analysis of altered fractionated radiotherapy and chemotherapy in head and neck cancer. Journal of Clinical Epidemiology. 2011;64: 985–992.
Chen AM, Chen LM, Vaughan A, et al. Tobacco Smoking During Radiation Therapy for Head-and-Neck Cancer Is Associated With Unfavorable Outcome. International Journal of Radiation Oncology*Biology*Physics. 2011;79: 414–419.
Smith J, Nastasi D, Tso R, Vangaveti V, Renison B, Chilkuri M. The effects of continued smoking in head and neck cancer patients treated with radiotherapy: A systematic review and meta-analysis. Radiotherapy and Oncology. 2019;135: 51–57.
Browman GP, Wong G, Hodson I, et al. Influence of Cigarette Smoking on the Efficacy of Radiation Therapy in Head and Neck Cancer. New England Journal of Medicine. 1993;328: 159–163.
Gillison ML, Zhang Q, Jordan R, et al. Tobacco Smoking and Increased Risk of Death and Progression for Patients With p16-Positive and p16-Negative Oropharyngeal Cancer. Journal of Clinical Oncology. 2012;30: 2102–2111.
Rubenstein J. ICD–10-CM changes for October 1, 2017. Rev Urol. 2017;19: 129–130.
McCarter K, Martínez Ú, Britton B, et al. Smoking cessation care among patients with head and neck cancer: a systematic review. BMJ Open. 2016;6: e012296.
Peppone LJ, Mustian KM, Morrow GR, et al. The effect of cigarette smoking on cancer treatment-related side effects. Oncologist. 2011;16: 1784–1792.
Hoff CM, Grau C, Overgaard J. Effect of smoking on oxygen delivery and outcome in patients treated with radiotherapy for head and neck squamous cell carcinoma—A prospective study. Radiotherapy and Oncology. 2012;103: 38–44.
Owadally W, Hurt C, Timmins H, et al. PATHOS: a phase II/III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery for Human papillomavirus (HPV) positive oropharyngeal cancer. BMC cancer. 2015;15: 602–602.
Reduced-Dose Intensity-Modulated Radiation Therapy With or Without Cisplatin in Treating Patients With Advanced Oropharyngeal Cancer. Available from URL: https://ClinicalTrials.gov/show/NCT02254278.

Table 1. Patients, tumor and treatment characteristics. Abbreviations: EBRT= external beam radiation therapy, IC= induction chemotherapy, CEBRT= concurrent chemotherapy + EBRT. * indicates p<0.05 when comparing the HPV+ and HPV- groups.

Variable	p16+/HPV+ N (%)	p16-/HPV- N (%)	p-value
	N=546 (89.4%)	N=65 (10.6%)
Age			p=0.84
<50	86 (15.8)	11 (16.9)
50-<60	231 (42.3)	25 (38.5)
≥60	229 (41.9)	29 (44.6)
Sex			p<0.0001*
Male	473 (86.6)	44 (67.7)
Female	73 (13.4)	21 (32.3)
Race			p=0.08
White	505 (92.5)	56 (86.2)
Non-white	41 (7.5)	9 (13.8)
Cancer subsite of origin			p=0.8
Base of tongue	250 (45.8)	27 (41.5)
Tonsil	252 (46.2)	26 (40)
Other	44 (8)	12 (18.5)
T-category			p=0.09
T1	168 (30.8)	17 (26.2)
T2	211 (38.6)	18 (27.6)
T3	98 (17.9)	15 (23.1)
T4	69 (12.7)	15 (23.1)
N-category (7^th edition)			p=0.26
N0	39 (7.1)	8 (12.3)
N1	65 (11.9)	10 (15.4)
N2	429 (78.6)	45 (69.2)
N3	13 (2.4)	2 (3.1)
N-category (8^th edition)			p<0.0001*
N0	39 (7.1)	8 (12.3)
N1	373 (68.3)	10 (15.4)
N2	121 (22.2)	45 (69.2)
N3	13 (2.4)	2 (3.1)
AJCC (7^th edition)			p=0.11
I	7 (1.3)	1 (1.5)
II	15 (2.7)	4 (6.2)
III	72 (13.2)	13 (20.0)
IV	452 (82.8)	47 (72.3)
AJCC (8^thedition)			p<0.0001*
I	316 (57.9)	1 (1.5)
II	149 (27.3)	4 (6.2)
III	81 (14.8)	13 (20.0)
IV	0	47 (72.3)
Smoking status at diagnosis			<0.0001
Current smoker	101 (18.5)	25 (38.46)
Former smoker	208 (38.1)	28 (43.08)
Never smoker	249 (40.75)	12 (18.46)
Tobacco exposure (PY)			p<0.0001*
0	277 (50.7)	13 (20)
>0-10	87 (15.9)	6 (9.2)
>10-20	50 (9.2)	8 (12.3)
>20-30	46 (8.4)	11 (17)
>30	86 (15.8)	27 (41.5)
Tobacco exposure per AJCC (8^th edition) stage			p<0.0001
I/pack-years <30	263 (48.2)	1 (1.5)
I/pack-years ≥30	53 (9.7)	0
II/pack-years <30	113 (20.7)	1 (1.5)
II/pack-years ≥30	36 (6.6)	3 (4.6)
III/pack-years <30	59 (10.8)	4 (6.2)
III/pack-years ≥30	22 (4)	9 (13.8)
IV/pack-years <30	0	27 (41.6)
IV/pack-years ≥30	0	20 (30.8)
Chemotherapy (Cth) sequence			p=0.94
No Cth	99 (18.1)	12 (18.5)
Induction Cth (IC) only	82 (15.0)	8 (12.2)
Concurrent Cth (CC) only	210 (38.5)	25 (38.5)
IC + CC	155 (28.4)	20 (30.8)

Supplementary Figure 1. CONSORT flow diagram of selection process of patients for this study (OPC: oropharynx cancer; IMRT: intensity-modulated radiotherapy; HPV: human papillomavirus; ISH: in situ hybridization; IHC: immunohistochemistry).

Supplementary Figure 2. Histogram of tobacco exposure in human papillomavirus-mediated (HPV+) and HPV- groups.

Supplementary Figure 3 Parts A-B. Impact of human papillomavirus (HPV) status on survival. Kaplan-Meier plots for clinical outcomes for the entire patient cohort stratified by HPV status: (A) Loco-regional control; and (B) Freedom from distant metastasis.

Supplementary Figure 4 Parts A-B. Impact of tobacco exposure on survival. Kaplan-Meier plots for clinical outcomes for the HPV+ oropharyngeal cancer group stratified by extent of tobacco exposure: (A) Loco-regional control; and (B) Freedom from distant metastasis.

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Tobacco exposure as a major modifier of oncologic outcomes in Human PapillomaVirus (HPV) associated oropharyngeal squamous cell carcinoma

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Background

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HPV determination

Treatment

Study endpoints and statistical analysis

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Patients

HPV status impacts OPSCC patient survival

Tobacco exposure impacts OPSCC patient survival

Competing risk analysis

Discussion

Conclusions

Abbreviations

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Ethics approval and consent to participate

Consent for publication

Availability of data and materials

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