CTRI

Background & Rationale:

Head and neck squamous cell carcinoma is the sixth most common cancer worldwide and fifth most common cancer in Southeast Asia region. [1] The incidence varies widely around the world and within populations. Oral and oropharyngeal cancer constitutes 3 to 5 percent of the malignancies in Europe, while in parts of Southeast Asia and India, it reaches up to 40 to 50 percent [2-4]. About 40,000 pharyngeal cancers occur in India every year. [5]

Incidence of oropharyngeal squamous cell carcinoma (OPSCC) is rising in contrast to decreasing incidence of carcinomas in other subsites of head and neck, in spite of reduced prevalence of smoking. Human papilloma virus or HPV, in particular HPV-16, is recognized to be responsible, with different epidemiological, clinical, anatomical, radiological, behavioural, biological, and prognostic characteristics from HPV negative OPSCC. [6,7] The only head and neck site with a definite etiological association between persistent high-risk, HR HPV infection and development of SCC is the oropharynx. The Agency for Research on Cancer (IARC) now recognizes HPV as a risk factor for oropharyngeal cancer, and accumulating molecular and epidemiological data now show that high-risk types of HPV are responsible for a subset of oropharyngeal cancer. These trends have been associated with a shift in demographics to a younger, high-functioning population with lower rates of co-morbid illness, minimal or no history of tobacco use, better response to treatment, outcome, and survival benefit. [8-10]

Treatment selection in these patients is now becoming a critical issue and current strategies may represent an over treatment. Due to the functional morbidity and complications of open surgical approaches, organ-sparing protocols, have become the standard of care. [11-13] All treatment modalities have similar oncological outcomes [13], but functional outcomes have critical consideration. Minimally-invasive approaches, especially transoral robotic surgery or TORS, have revolutionized the treatment of OPSCC by achieving satisfactory oncological outcomes without compromising functional outcomes. [14] TORS, not only improves oncologic results but also decreases toxicities caused by chemoradiation and is crucial in these typically younger patients.

Strategy

The proposed study aims to detect the HPV status in the Indian population and stratify the patients based on tumour biomarkers towards optimal treatment and follow up protocols. This is especially important considering long-term outcomes of these patients, since they are at risk of a lifetime of compromised quality of life due to toxicities of chemoradiation.

Rationale

Till date, no consensus has been reached on the optimal way to identify HPV-associated SCC, and ancillary studies in the distinction between HPV-positive and -negative SCC have utilized many methods. All the methods aim to give information about the presence of High-Risk HPV in biological samples, either directly within the tumour or otherwise in the patient. The common methodologies include HPV polymerase chain reaction (PCR) testing, HPV in situ hybridization (ISH) analysis, immunohistochemical (IHC) staining for p16. Each test possesses its own strength and weakness and, at the present time, IHC staining for p16 and PCR for HPV appear to be the most sensitive markers of HPV, while ISH confers the greatest specificity. Current techniques for assessing the HPV-16 status in HNSCC include the detection of HPV-16 DNA and p16INK4a expression in tumour tissues. When tumours originate from hidden anatomical sites, this method can be challenging.

A non-invasive and cost-effective alternative to biopsy is therefore desirable for HPV-16 detection especially within a community setting to screen at-risk individuals. The over-expression of HPV-16 early genes (E6 and E7) is crucial in tumour initiation and progression. Therefore, PCR methods targeting HPV-specific transcripts in serum and saliva samples may provide evidence of clinically relevant infection and/or persistent infection. Tumour p16INK4a is an indirect marker for HPV status which is widely used by clinical pathology laboratories around the world due to its low technical costs compared to ISH and PCR based tests. Therefore, there is a strong need for the correct diagnosis or detection of HPV-16 in OPSCC patients, which may enable risk stratification, patient counselling and potential de-escalation of chemo- and radio-therapy.

Â· Advantages of HPV DNA/RNA detection in body fluids

1. Non-invasive and cost-effective diagnostic method

2. May prove to be an alternative to biopsy for HPV detection in oral oropharyngeal cancers for HPV detection

3. Ideal method for community and high-risk screening

4. Assessing response to treatment and early detection of recurrence by positive post-treatment serum and saliva HPV biomarker status

5. Determination of prognosis and overall survival

References:

1. M. L. Gillison, â€œHuman papillomavirus-associated head and neck cancer is a distinct epidemiologic, clinical, and molecular entity,â€ Seminars in Oncology, vol. 31, no. 6, pp. 744â€“754, 2004.

2. F. Bray, R. Sankila, J. Ferlay, and D. M. Parkin, â€œEstimates of cancer incidence and mortality in Europe in 1995,â€ European Journal of Cancer, vol. 38, no. 1, pp. 99â€“166, 2002.

3. D. M. Parkin, F. Bray, J. Ferlay, and P. Pisani, â€œGlobal cancer statistics, 2002,â€ Ca-A Cancer Journal for Clinicians, vol. 55, no. 2, pp. 74â€“108, 2005.

4. J. J. Pindborg, K. H. Zheng, C. R. Kong, and F. X. Lin, â€œPilot survey of oral mucosa in areca (betel) nut chewers on Hainan Island of the Peopleâ€™s Republic of China,â€ Community Dentistry and Oral Epidemiology, vol. 12, no. 3, pp. 195â€“196, 1984.

5. GLOBOCAN Estimated Cancer Incidence, Mortality and Prevalence Worldwide in; 2012

6. C Fakhry, ML Gillison: Clinical implications of human papillomavirus in head and neck cancers J Clin Oncol 24: 2606â€“ 2611, 2006.

7. S Marur, G Dâ€™Souza, WH Westra, etal: HPV-associated head and neck cancer: A virus-related cancer epidemic Lancet Oncol 11: 781â€“ 789, 2010.

8. L Licitra, F Perrone, P Bossi, etal: High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma J Clin Oncol 24: 5630â€“ 5636, 2006.

9. KK Ang, J Harris, R Wheeler, etal: Human papillomavirus and survival of patients with oropharyngeal cancer N Engl J Med 363: 24â€“ 35, 2010.

10. C Fakhry, WH Westra, S Li, etal: Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial J Natl Cancer Inst 100: 261â€“ 269, 2008.

11. Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst. 1999;91: 2081â€“2086.

12. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010; 363:24â€“35.

13. Pignon JP, le Maitre A, Maillard E, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009; 92:4â€“14.

14. Dowthwaite SA, Franklin JH, Palma DA, et al. The role of transoral robotic surgery in the management of oropharyngeal cancer: a review of the literature. ISRN Oncol. 2012; 2012:945 162â€“945162.