- Top of page
- MATERIALS AND METHODS
- FUNDING SUPPORT
- CONFLICT OF INTEREST DISCLOSURES
Despite decreases in per capita smoking prevalence and alcohol consumption in the United States over the past several decades, the incidence of oropharyngeal squamous cell carcinomas (OSCC) has steadily increased.[1-3] The increasing incidence in OSCC is attributed to a growing number of cancers caused by the human papillomavirus (HPV).[3, 4] Indeed, recent research has indicated that HPV-associated OSCC (HPV-OSCC) is a distinct etiologic entity, and this subset of head and neck cancers is associated with an improved prognosis compared with HPV-negative head and neck cancers.[5-13] Although the improved survival rates of patients with HPV-OSCC have been well established, clinically, there is a patient subset that still experiences poor outcomes.
A recent survival analysis demonstrated important prognostic differences between HPV-positive and HPV-negative OSCC. However, prognostic factors for patients with HPV-OSCC are less clear but of significant interest given the consideration of de-escalation treatment strategies for this patient population. Therefore, we analyzed predictors of survival in a series of patients with HPV-OSCC who were treated at a single academic institution.
- Top of page
- MATERIALS AND METHODS
- FUNDING SUPPORT
- CONFLICT OF INTEREST DISCLOSURES
Although patients who have HPV-OSCC have an improved prognosis compared with patients who have HPV-negative OSCC, there is a subset of patients with HPV-OSCC who experience a poor clinical outcome. Identification of the risk factors for a poor outcome among patients with HPV-OSCC is of particular interest, because it would facilitate the stratification of those patients who may benefit from more aggressive intervention or, conversely, those who may benefit from de-escalation treatment approaches.
To identify risk factors for poor outcome in patients with HPV-OSCC, we retrospectively analyzed OS and RFS rates in 157 patients with HPV-OSCC who received treatment at the Johns Hopkins Hospital. To date, this is one of the largest studies evaluating predictors of survival among HPV-positive patients, some of whom have been followed for more than 10 years after definitive treatment. We demonstrated a 5-year OS rate of 89%, which was reduced in older patients, those with advanced clinical T-classification, and current tobacco users, and an RFS of rate 86%, which was reduced in patients with advanced clinical T-classification, current/former alcohol users, and unmarried patients.
Maxwell et al reported that tobacco use in patients with HPV-OSCC was associated with a higher risk of disease recurrence compared with never-users of tobacco. Our study provides further evidence that current tobacco use increases the risk of poor OS for patients with HPV-OSCC. It is unclear whether there is a true interaction between tobacco use and HPV. It has been hypothesized that the direct effect of tobacco on the pathogenesis of cancer is secondary to the carcinogenic properties of tobacco smoke, which can increase the risk of developing genetic alterations. Tobacco is also considered immunosuppressive; and, in the setting of a virus-related cancer, tobacco may inhibit the body's natural ability to mount effective immunologic responses to eradicate the virus and any virus-related cancer cells.
Advanced clinical T-classification has been reported as a significant risk factor for recurrence and death in patients with OSCC. Studies among patients with OSCC who received concurrent chemoradiation or underwent transoral laser microsurgery demonstrated poorer survival for those who had T3/T4 tumors versus those who had T1/T2 tumors, similar to what we observed in the current study. We also observed that lower clinical N stage was a poor prognostic factor, which may be explained in part by the clinical characteristics of the HPV-OSCC patient population. Patients with HPV-OSCC often have cystic cervical lymph nodes, which can result in a higher clinical N stage. In our study, the HPV-positive patients were diagnosed with a more advanced N stage compared with HPV-negative patients (77.1% vs 22.9%; P = .007); and, among the patients with a higher N stage, 89% had a lower T-classification (Tx, T1-T2). Given the association of higher N stage with lower T-classification in our study group, the prognostic effect of T-classification and N stage may have been confounded. Additional studies will be required to evaluate the prognostic effect of N stage in patients with HPV-OSCC.
We had a mixed population of patients treated with various modalities. Fifty-one percent of patients underwent open surgeries, and 49% received treatment with nonsurgical approaches. Postoperative adjuvant concurrent chemoradiation therapy is often administered based on aggressive pathologic features, including extracapsular extension (ECE). Although ECE was not evaluated specifically in our study, of the 80 surgical patients who were included, 50% received adjuvant concurrent chemoradiation therapy, and 48.8% received adjuvant radiation therapy alone. On the basis of previously published studies, ECE in head and neck squamous cell cancer usually predicts worse outcomes. However, in the era of HPV-OSCC, this is an area of controversy. A recent study evaluated 101 cases of OSCC in which 90% of the cancers were p16-positive. ECE, defined as extension into soft tissue, was not significantly associated with poorer OS (P = .14), disease-free survival (P = .2), or disease-specific survival (P = .09) in multivariate analysis. Those authors concluded that the impact of ECE in lymph node metastases was limited in OSCC. Thus, ECE may not be an applicable prognostic factor for HPV-OSCC. These results are intriguing, and ECE, as well as other traditionally aggressive pathologic features, in HPV-OSCC needs to be evaluated in future studies.
Head and neck squamous cell cancer is traditionally associated with recurrence rates of 50%, and approximately 80% to 90% of tumors recur within the first 2 to 4 years after definitive therapy.[24-31] These rates of recurrence have changed in the era of HPV-OSCC. In the HPV-OSCC patient population, it has been documented that recurrences occur at approximately 13.6% of local sites and 8.7% of distant sites within 3 years after the completion of definitive treatment. One study reported on the risk factors for distant metastasis in HPV-OSCC and observed that patients with N2c disease had reduced distant control if they received radiotherapy alone, suggesting that these patients may not be candidates for deintensification strategies that do not include chemotherapy. In our study, we reported a cumulative incidence of recurrence in HPV-OSCC of 14% after 5 years; and, in those patients who were recurrence-free for 5 years, the cumulative risk of recurrence at 10 years was 8.6%. This finding may provide us with further observational insight into the pathophysiology and natural course of this disease process. The indolent growth of these tumors may explain the increased number of recurrences 10 years post-treatment compared with HPV-negative head and neck squamous cell cancer. Nonetheless, these observations need to be further confirmed in additional studies to determine whether extended cancer surveillance is warranted in this cancer population.
Prior studies suggested that marital status had prognostic significance in patients with head and neck cancer, with partnered patients experiencing lower rates of recurrence and better OS compared with unpartnered patients.[33-35] We observed a similar trend toward poorer OS and significant recurrence rates in unmarried patients versus married patients diagnosed with HPV-OSCC. These findings highlight the finding that social support continues to be an important consideration in caring for head and neck cancers patients, independent of HPV status.
Differences in survival according to sex have been difficult to study, because men have a higher incidence of HPV-OSCC than women.[4, 13] Our study is one of the largest series to date comparing the survival of women and men with HPV-OSCC, and the survival of women did not differ statistically from that of men, suggesting that HPV-OSCC is a distinct clinical and pathologic entity driven predominantly by tumor biology rather than differences in sex.
Our institution is a large referral base that treats patients from diverse geographic and demographic backgrounds. Having all patients treated at a single institution has the inherent advantage that all patients are treated and clinically monitored for recurrence in a uniform manner. An additional strength of the study is that all of these tumors were tested for HPV status. Overall, our findings suggest that demographic and clinical features like advanced patient age, tobacco and alcohol use, advanced clinical T-classification, and unmarried status, which have been reported as poor prognostic factors for patients with head and neck cancer, continue to be applicable prognostic markers in patients with HPV-associated OSCC, independent of treatment modality. It is noteworthy that we observed a trend toward an increased risk of recurrence after the conventional 5-year cancer surveillance period subsequent to definitive therapy, and this trend needs to be investigated further to determine whether extended cancer surveillance is warranted in this cancer population.