Therapeutic Outcomes of HPV Positive and HPV Negative Oropharyngeal Squamous Cell Carcinomas

Background & Objectives: HPV associated (HPV+) oropharyngeal cancers, compared with HPV non-associated ones (HPV−) have different characters and significantly better outcomes. HPV and cancer characteristics differ among countries and few data is available in Indian population regarding this issue. Thus, we attempted to determine the treatment response and survival rates between HPV+ versus HPV negative oropharyngeal cancers in Indian population. Methods: This prospective observational study was conducted from December 2016 - October 2018 in patients with stage III/IV oropharyngeal squamous cell carcinomas (SCC) (n = 65). The patients received induction chemotherapy with Docetaxel, Cisplatin, 5-Fluorouracil × 3 cycles, followed by concurrent chemoradiation 66 Gy as 33 fractions along with cisplatin 40 mg/m 2 weekly. The primary outcome was treatment response rate, which was defined as per Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Secondary outcomes were clinico-pathological differences between two groups, overall survival (OS), progression free survival (PFS). Results: Of the 65 patients included in the study, 17 were HPV positive and 48 patients were HPV negative. Median age in HPV positive arm is 48 years and HPV negative arm is 59 years. HPV positive patients presented with differ significantly between HPV positive and HPV negative arms. Conclusion: HPV positive oropharyngeal SCC patients showed significantly better treatment response than HPV negative ones. Progression free survival, overall survival and toxicity profile did not differ significantly between the two groups. Although due to small size, we did not compare data stratified by the cancer characteristics, the data is worthy to further characterize this tumour especially as HPV positive versus HPV negative.


Introduction
Head and neck squamous cell carcinoma is the third most common malignancy in both sexes across the globe. It is the most common malignancy in Indian males [1]. Oropharyngeal cancers account for approximately 10% of the annual worldwide incidence of head and neck squamous cell carcinomas (HNSCC).
Overall incidence of HNSCC has fallen in the last three decades; however, the incidence of oropharyngeal carcinoma, mainly tonsil and base of tongue, has been increasing both in United States and Europe.
The incidence of oropharyngeal cancer differs significantly by geography. In United States of America, the annual incidence of oropharyngeal squamous cell carcinoma is 4.8/100,000. The rate has increased by 28% from 1988 to 2004 largely because of 225% increase in HPV associated oropharyngeal cancer [2] [3] [4].
The rise in developed countries is unique as other mucosal head and neck cancers have decreased over this same time period. The cause of this is the increasing incidence of HPV associated cancers. The incidence in developing countries is lower at approximately 3/100,000.

The Cancer Atlas project by ICMR (Indian Council of Medical Research) has
shown the incidence of various cancers in different parts of India [5]. Kerala has one of the highest incidences of HNSCC which constitutes 30% of all cancers in India. HPV prevalence in India ranges from 33.6% in Eastern region to 67% in South, 15% in western India.
About 15% -20% of all head and neck squamous cell carcinomas are associated with high risk HPV infection. The highest rates of HPV DNA (upto 70%) have been found in oropharyngeal squamous cell carcinomas (OSCC) especially the tonsils followed by base of tongue. HPV 16 is the most common type, detected in 90% -95% of HPV related OSCC.
HPV associated oropharyngeal cancers are more likely to occur among men (80% of whom will not have a smoking history), more common among white individuals, diagnosed in individuals who are 5 to 10 years younger than HPV unassociated oropharyngeal cancers, more common with higher socioeconomic There is growing support for the view that the treatment protocol for oropharyngeal cancer should be modified according to HPV status and that de-escalation of treatment intensity may be a real possibility for patients with HPV positive OPSCC.

Aims and Objectives
Primary Objective To assess the treatment response in HPV positive and HPV negative oropha- The treatment toxicity will be assessed in both groups using CTC version 4.

Results
In this prospective observational study, we have enrolled a total of 65 pathologically proved squamous cell carcinoma of oropharynx who satisfied the selection criteria. Among this, 17 patients were HPV positive and 48 patients were HPV negative.
1) Baseline characteristics of the patients in this study are depicted in Table 1.

6) Treatment response
The response to the planned treatment as per RECIST criteria is shown in Table 5. 7) Time to maximum response-Nearly 90% of the responders in both the arms showed the response to treatment in less than 6 month period ( Table 6).
8) Toxicities-The major toxicities are enlisted as a table below (Table 7).
9) Recurrence pattern-The first failure pattern of the study population during the study period is given in Table 8.

Discussion
The median age in HPV positive arm was 48 years while in HPV negative arm it was 59 years. This is similar to the findings of the study by Chaturvedi et al. in which HPV positive patients tend to be 5 to 10 years younger than HPV negative patients [6]. The male: female ratio in HPV positive arm is less which is corre- that HPV positive tumours present with higher N stage [10].
In both arms the most common histology was moderately differentiated SCC.
In HPV positive patients poorly differentiated histopathology was seen in 23.5% of patients and basaloid SCC in 11.8% while in HPV negative patients, poorly differentiated was only 18.8% and no basaloid SCC. These findings show similar pattern as in the study by Gillison et al. [11], which showed that HPV positive tumours tend to be poorly differentiated and basaloid squamous cell carcinomas.
The incidence of HPV in the cohort is 26%. A study by V Murthy et al. shows an incidence of HPV oropharyngeal cancer in India varies from 20% to 38% [12].
In HPV positive arm, the objective treatment response rate is 82% while in HPV negative arm the response rate is 52%. There was statistically significant difference between two groups in case of treatment response (p value-0.029).
Study by Fakhry et al. the treatment response in HPV positive arm was 84% and in HPV negative arm was 57% [13] [14].
In HPV positive arm the 1 year progression free survival is 76.5% while in HPV negative arm the 1 year progression free survival is 52.1%. But the difference between thetwo groups was not statistically significant (p value-0.08). This may be due to the small sample size of the study.
In HPV positive arm the 1 year overall survival is 82.4% while in HPV negative arm the 1 year overall survival is 70.8%. But the difference between the two arms was not statistically significant (p value-0.353). Nguyen-Tan et al. [15] study showed improved PFS and OS in HPV positive OPSCC. In HPV positive  [16].
The treatment related toxicities were almost similar in both arms. The percentage of grade 3 and 4 mucositis in HPV positive arm is 35.3% and in HPV negative arm was 31.2%.Grade 3 and 4 dermatitis in HPV positive arm is 41.2% and in HPV negative arm is 39.6%. The results of these toxicities correlated with the study by Kanotra et al. [17].

Conclusion
The prevalence of HPV in the present study is 26% and the highest prevalence is noted in the tonsillar subsite of oropharynx. In this prospective observational study, we observed that there is a statistically significant difference in treatment response in HPV positive patients compared to HPV negative patients. Though there was no statistically significant difference between two arms in case of progression free survival and overall survival, there was a trend of better PFS and OS towards HPV positive patients. The limitation of our study is that due to small sample size a sub group analysis cannot be made based on the different characteristics. In view of better prognosis of HPV positive patients, several investigators are trying for de-escalation of treatment for HPV positive patients.
HPV status in future will definitely play role in decision of treatment planning in oropharyngeal squamous cell carcinoma patients.