Classical risk factors, but not HPV status, predict survival after chemoradiotherapy in advanced head and neck cancer patients

Head and neck squamous cell carcinoma (HNSCC) represents the fifth most common malignancy diagnosed worldwide. In 2012, HNSCCs accounted for approximately 59.000 new cases in the USA and more than 77.000 in Western and Eastern Europe (Globocan, 2012). These cancers form a group of heterogeneous tumors presenting distinct etiology, histology, risk factors and treatment approaches. Over the last twenty years, a clear increase in the incidence of oropharyngeal and oral cavity carcinomas has been observed, particularly in young adults in both the US and Europe, whereas the incidence of laryngeal carcinomas tended to remain stable or decrease slightly (D’Souza et al. 2007; Sturgis and Cinciripini 2007).

The advent of concomitant chemoradiotherapy (CCRT) in the early 2000s occurred in the phase III trial of Forastière et al’s study (Forastiere et al. 2003), who reported that the use of high-dose cisplatin and radiotherapy resulted in a considerable improvement in the survival of patients with laryngeal cancer. In addition, reduced mortality and improved locoregional control were observed upon treatment with both cetuximab and radiotherapy (Bonner et al. 2006). Currently, CCRT remains the gold standard to treat primary locally advanced head and neck cancer patients, especially those with stage III and IV disease (Forastiere et al. 2003; Bonner et al. 2006; Rosenthal et al. 2015). However, these aggressive treatments are characterized by tissue sequela (i.e., dry mucosa, muscle atrophy, and fibrosis leading to acute and chronic toxicities), morbidity (10 % of tracheotomy cases), and mortality (Trotti et al. 2003; Lazarus 2009; Hu et al. 2012; Hutcheson and Lewin 2012). It is therefore crucial to predict which patients will benefit from CCRT by investigating the impact of risk factors on the response to treatment.

Patients with HNSCCs often present a long history of tobacco and alcohol use. Recently, human papillomavirus (HPV) infection has emerged as an additional risk factor and could be involved in increased worldwide incidence of a subset of HNSCCs, especially oropharyngeal cancers (Fakhry and Gillison 2006; Sturgis and Cinciripini 2007; Fakhry et al. 2014). The development of cancers related to HPV infections has significantly complicated the profile of head and neck cancer patients, notably in terms of prognosis and response to treatment. The management of such patients is particularly complex in Europe, where many individuals are heavy smokers and/or drinkers (Duray et al. 2012; Duray et al. 2013). Indeed, while non-smoking and nondrinking oropharyngeal patients exhibit an improved response to therapy and a better outcome, tobacco and alcohol consumers with non-oropharyngeal cancers are associated with a heterogeneous prognosis (Ang et al. 2010; Isayeva et al. 2012). In this context, controversy exists regarding the prognosis of HPV+ patients treated by CCRT. Whereas several studies have reported that HPV infection is associated with a good prognosis (Kumar et al. 2007; Fakhry et al. 2008; Ang et al. 2010; Rischin et al. 2010; Hong et al. 2010; Nygård et al. 2012), other groups have reported opposing findings (Rosenquist et al. 2007; Lee et al. 2012; Duray et al. 2012). Thus, studies investigating the HPV status of HNSCC patients must be interpreted with caution because many are small clinical series without information regarding the alcohol consumption and smoking status of the patients.

The present study aims to determine the influence of HPV status on the response to CCRT and to estimate the impact of HPV infection as well as tobacco and alcohol consumption on recurrence and survival in a retrospective and prospective analysis of 218 head and neck cancer patients.

Locally advanced HPV+ HNSCCs represent a challenge for clinicians in terms of treatment strategy. This group of patients raises many therapeutic questions, including the choice of optimal treatment modality and the implications of HPV infection on the prognosis and response to CCRT. In our large population-based study, we demonstrated that the HPV status was neither associated with the response to CCRT nor the survival of HNSCC patients. We therefore reviewed previous studies examining HPV infection, response to CCRT and survival (Table 3). We noticed that very few studies have investigated correlations between such parameters and that they found a significant impact of HPV on the response to CCRT and an association with a better prognosis, unlike the findings reported in the current study (Kumar et al. 2007; Chung et al. 2009; Nichols et al. 2009; Fallai et al. 2009; de Jong et al. 2010; Ang et al. 2010; Rischin et al. 2010; Hong et al. 2010; Lill et al. 2011; Flavill et al. 2014; Hasegawa et al. 2014). This discrepancy with our findings can be explained by inclusion of smoker and/or drinker patients in our cohort and by the tumor location, which was not exclusively oropharyngeal. Moreover, smoking and drinking status was mostly imprecise or absent in previous studies, despite the fact that HPV+ tumors linked to tobacco and alcohol consumption represent a distinct biological and clinical entity. Indeed, Gillison and colleagues recently demonstrated that the outcome of treatment was compromised for p16+ and p16− patients who smoked during radiotherapy (Gillison et al. 2012). Unfortunately, HPV+ patients were rarely characterized according to the active nature of the infection, and even though an algorithm has been described that reliably identifies transcriptionally active HPV infection versus non-active infection in HNSCCs (Smeets et al. 2007). This distinction leads to a combination of p16 immunostaining followed by GP5 +/GP6 + PCR with 100 % specificity and sensibility. To our knowledge, ours is the first study to examine the implication of an active HPV infection in a large population of smoker/drinker HNSCCs and to reject the use of HPV as a predictive marker of response to treatment in this context.

Wide geographic variation has been reported regarding tobacco and alcohol consumption in Europe. Indeed, in western and eastern countries, the vast majority of patients are avid consumers, whereas a greater decline in smoking habits was observed among Norwegian, Finnish, and Dutch populations (Giskes et al. 2005; Tinhofer et al. 2015). In this context, there remains a lack of studies assessing tobacco and alcohol exposure in HPV-driven versus tobacco- and alcohol-associated HNSCCs. Thus, considering our smoker/drinker population, we tried to clarify the impact of HPV infection on patient prognosis as well as that of classical risk factors. The major findings of our population-based study are that smoking and drinking significantly increased the rate of death within 5 years after diagnosis in head and neck cancer patients, and that the prognostic behavior of former smokers is similar to that of non-smokers, while that of former drinkers remains relatively poor, such as current drinkers. Our statistic-based observations are fully supported by clinical data reporting that clinical benefits are rapidly observed following the cessation of tobacco, whereas the adverse effects of alcohol impact the health over a longer term and are less easily reversible (Doll et al. 2004). Studies conducted in consumer patients with HNSCCs have already demonstrated the negative impact of smoking tobacco and drinking alcohol on treatment response and OS. Twenty years ago, Browman et al. first reported that patients who continue to smoke during radiation therapy have lower rates of response and survival than patients who do not smoke during radiation therapy (Browman et al. 1993). These results were consistent across many studies that have found that smoking and drinking behavior can predict the clinical outcome of HNSCC patients (Dikshit et al. 2005; Park et al. 2006; Hilgert et al. 2009; Duffy et al. 2009; Chen et al. 2011; Hoff et al. 2012; Sharp et al. 2014). Indeed, through a large meta-analysis, Bagnardi et al. recently confirmed the higher risk of oral and pharyngeal cancer development for heavy drinkers compared to nondrinkers: Alcohol consumers have a 5.13 times higher relative risk of developing this type of tumor (Bagnardi et al. 2015).

The effect of tobacco use on disease recurrence was also examined among patients with HPV-positive oropharyngeal carcinomas. The typically good prognosis of HPV+ oropharyngeal carcinomas was not observed in our at-risk population. In fact, the HPV+ smoker group exhibited an increased risk of recurrence and distant metastases as well as reduced survival compared with the HPV+ non-smoker group (Maxwell et al. 2010). Many additional studies have found that HPV+ smokers exhibit reduced survival compared with HPV+ non-smokers, given the increased risk of both local recurrence and distant metastases in HPV+ smokers (Hafkamp et al. 2008; Kumar et al. 2008; Tribius et al. 2012; Lin et al. 2013).

Moreover, there is increasing support that HPV has developed several mechanisms to escape from immune surveillance and to maintain infection. Additionally, the tobacco use is known to suppress immune function, thereby facilitating persistent infection. Thus, the immunosuppressive mechanisms of smoking may prevent the patient from activating immunologic responses to eradicate the viral infection (Arnson et al. 2010). In this context, we speculate that there is an additive effect of smoking/drinking habits and HPV infection that leads to poorer outcomes in HNSCC patients, possibly due to DNA breaks resulting from tobacco usage in human cells during the process of HPV genome integration, which occurs at fragile sites or “hot spots” of DNA breakage. This mechanism thereby increases the carcinogenic potential of HPV (Hu et al. 2015). These observations suggest that smoking/drinking behavior and an immunosuppressive status promote HPV infection and persistence, leading to poor patient prognosis. These findings highlight the need to evaluate the role of tobacco and alcohol in the natural history of oral HPV infection and the progression to malignancy.

At this time, our data have demonstrated that active HPV infection cannot be used as a prognostic tool in non-oropharyngeal cancer patients. Our analysis is subject to limitations related to the low available number of HPV+/p16+ specimens as supported by a recent meta-analysis demonstrating that transcriptionally active infection rates are generally low for oral cavity and larynx cancer with 16.3 and 8.6 %, respectively (Gama et al. 2016). Nevertheless, our data clearly underscore that smoking and drinking during therapy significantly worsens patient prognosis and increases the risk of recurrence. As previously recommended (Gritz et al. 2005), all future clinical trials should measure tobacco and alcohol exposure to evaluate their effects on disease control alongside determining HPV status. Moreover, our data suggest that heavy tobacco and alcohol consumers who respond to CCRT should remain under close clinical and radiological follow-up at the end of treatment for the early detection of recurrences independent of HPV status and that clinicians should warn patients and encourage them to halt their consumption to better manage this high-risk subpopulation.