Authors: B. O'Sullivan, S. Huang, B. Perez-Ordonez, F. Liu, C. Massey, I. Weinreb, E. Chen, B. Cummings, J. Kim, J. Waldron Affiliations: Princess Margaret Hospital / University of Toronto, Toronto, ON, Canada
There is a growing body of evidence that Human Papillomavirus (HPV) infection plays an important role in the pathogenesis of a subset of head and neck squamous cell carcinomas (SCC).
HPV-related tumors are characterized by the presence of HPV DNA within the tumor and are predominantly observed in younger patients with cancers of the oropharynx (Gillison et al. JNCI, 2000).
Ang et al. (NEJM, 2010) published an analysis of 720 patients enrolled in the RTOG 0129 trial, demonstrating that patient HPV status and tobacco pack years are independent predictors of overall survival (OS) and progression free survival (PFS) in patients treated with concurrent chemoradiation.
Given the excellent clinical outcomes observed in patients with HPV + SCC, de-intensification of treatment is a reasonable consideration.
The purpose of this study was to evaluate and compare outcomes of HPV+ vs. HPV- oropharyngeal squamous cell cancer (OPC) treated with radiotherapy alone (RT) or concurrent chemo-radiotherapy (CRT) and to identify subgroups of HPV+ patients suitable for less intensive treatment strategies.
This was a retrospective analysis of a prospective correlative science database (PMH Head and Neck Bioclinical Anthology) built to examine clinical outcomes of patients with OPC treated at Princess Margaret Hospital/ University of Toronto.
The study included OPC patients treated between 7/1/2003 - 12/31/2007.
Actuarial estimates of 3-year overall survival (OS), disease free survival (DFS), and local (LC), regional (RC) and distant (DC) control were calculated and compared.
CRT most commonly consisted of 70 Gy in 35 fractions with concurrent bolus cisplatin (100 mg/m2every 3 weeks).
RT when given alone generally employed altered fractionation and was based on patient/physician choice, RT trials, or CRT tolerance.
HPV status was assessed by p16 immunostaining.
Multiple imputation for missing HPV-status was performed to classify and evaluate concordance within the entire cohort.
94 patients from the RT group (I: 4; II-III: 34; IV: 56)
71 patients from the CRT group (III: 1; IV: 70).
HPV+ patients (n=117) were more likely to have positive nodes and stage IV disease compared to HPV- patients (n = 48) [88% vs. 73% and 82% vs. 63% respectively (p < 0.01)].
Patients receiving RT alone were more likely to be node negative, elderly, or frail. Otherwise the CRT group and RT alone group were well balanced with respect to gender, subsite of disease, and T-stage.
The median follow-up was 4.4 years.
HPV + patients receiving RT alone were found to have significantly better OS, DFS, LC, and RC compared to HPV – patients treated with RT alone, while DC was similar between the two groups.
HPV + treated with RT Alone
HPV – treated with RT alone
p < 0.01
p < 0.01
p < 0.01
p = 0.04
p = 0.68
Among patients with Stage II-III disease, HPV + patients again had improved OS (83 vs. 38%), DFS (78 vs. 31%), and LC (100 vs. 81%) (All p < 0.01), but similar RC (94 vs. 88%, p = 0.49) and DC (both 94%).
HPV+ patients receiving CRT also had improved survival OS, DFS, and LC compared to HPV – patients receiving CRT. There was no significant difference in either RC or DC.
HPV + treated with CRT
HPV – treated with CRT
p < 0.01
p < 0.01
p = 0.04
p = 0.90
p = 0.57
CRT (n= 70) and RT (n = 56) could only be compared in Stage IV patients because from the known HPV cohort, only one CRT case was not Stage IV.
Treatment with CRT was associated with improved OS, and DFS compared receipt of RT alone but only trends in RC, and LC. DC was identical.
Patients receiving CRT
Patients receiving RT alone
p < 0.01
p = 0.02
p = 0.33
p = 0.10
Of note, there were no significant effects found in the HPV + cohort for CRT compared to RT (all p= 0.1).
HPV+ non-smokers showed only trends for improved LC (100 vs. 90%) and RC (100 vs. 83%) with RT but no difference in survival and no influence of CRT.
Results with and without imputation were concordant for all outcomes.
Patients with HPV+ OPC have superior clinical outcomes with both RT and CRT compared to HPV – patients.
Treatment CRT was associated with enhanced survival, LC and RC in HPV- patients compared to RT alone. However, CRT was not associated with a significant benefit in patients with HPV+ Stage IV OPC.
For Stage II-III HPV+ OPC patients, RT alone provides 90% LC and RC and 80% OS and DFS suggesting that RT alone may be suitable for this subgroup and these patients may be candidates for de-intensification trials.
This study is a retrospective analysis of prospectively collected data that examines clinical outcomes associated with CRT and RT alone for patients with OPC, particularly those patients with HPV+ disease.
The authors found no significant benefit associated with combined modality therapy compared to RT alone for patients with HPV + Stage IV OPC.
Observed outcomes in patients with Stage II-III HPV + OPC treated with RT alone are quite good.
These findings suggest that such patients may not require more intense combined modality therapy and may be adequately treated with RT alone.
Limitations of this study include;
The study is a retrospective analysis with a modest sample size
HPV status was not available for a significant number of patients and multiple imputation was required in order perform the comparative analyses between patients receiving CRT vs. RT alone. While multiple imputation is an established statistical technique to compensate for missing data, the possibility remains that the estimation provided may be inaccurate. The authors are continuing to analyze HPV status in the other patients.
The study cohorts were found to be imbalanced. Patients receiving RT alone were more likely to be node negative, elderly and frail compared to those receiving CRT. HPV + patients were more likely to be node positive and to have stage IV disease compared to HPV – patients. These imbalances must be considered when interpreting this data.
While this study has several limitations, it does provide useful data regarding expected clinical outcomes for patients with HPV + OPC receiving RT alone. Such patients may be suitable candidates for treatment de-intensification avoiding the additional toxicities associated with combined modality therapy.
Ultimately, this question should be evaluated through a prospective randomized controlled trial.
Oct 5, 2011 - Diagnostic tests for human papillomavirus-16 in oropharyngeal squamous cell carcinoma differ in accuracy and prognostic value, with a combination of p16 immunohistochemistry and DNA quantitative polymerase chain reaction proving to be the best discriminator of favorable outcome, according to a study published in the Oct. 1 issue of Clinical Cancer Research.