Abstract
HPV infection renders oropharyngeal squamous cell carcinomas more radiosensitive, which results in a favorable prognosis for HPV-positive patients treated with radiation alone or with concurrent platinum-based chemotherapy. The degree of radiosensitivity in fractionated regimens has not yet been fully explored; therefore, in this study, the radiosensitivity of HPV-negative tumors (FaDu) was compared to that of HPV-positive tumors (2A3) subjected to concurrent cisplatin chemotherapy and fractionated versus isoeffective single-dose tumor irradiation in immunodeficient mice. HPV-positive tumors were approximately 5 times more radiosensitive than HPV-negative tumors, irrespective of the irradiation regimen. In both tumor models, concurrent cisplatin chemotherapy and the fractionated regimen induced significant tumor radiosensitization, with a 3- to 4-fold increase in the tumor growth delay compared to that of single-dose irradiation. Furthermore, the degree of radiosensitization induced by cisplatin chemotherapy concurrent with the fractionated irradiation regimen was much higher in HPV-positive tumors, where a synergistic antitumor effect was observed. Specifically, after combined therapy, a 26% higher survival rate was observed in mice with HPV-positive tumors than in mice with HPV-negative tumors. These data suggest that HPV-positive tumors are more radiosensitive to fractionated regimen than to single-dose irradiation with concurrent cisplatin chemotherapy acting synergistically to irradiation.
Highlights
HPV-positive squamous cell carcinoma (SCC) of the oropharynx is an increasingly common disease and is in many ways distinct from its HPV-negative counterpart, which is caused by smoking and excessive alcohol consumption[1]
The current study confirms the previous findings and extends them to a clinically relevant fractionated regimen. These results suggest that HPV-positive tumors respond better to fractionated radiotherapy with or without concurrent cisplatin chemotherapy than HPV-negative tumors
Our data demonstrate a significant increase in G2/M arrest after concurrent cisplatin treatment combined with a single-dose or fractionated irradiation regimen, which is more pronounced in the HPV-positive tumor model than in the HPV-negative model
Summary
HPV-positive squamous cell carcinoma (SCC) of the oropharynx is an increasingly common disease and is in many ways distinct from its HPV-negative counterpart, which is caused by smoking and excessive alcohol consumption[1]. It was observed that HPV-positive oropharyngeal SCC responds better to treatment with radiotherapy and concurrent platinum-based chemotherapy[2,3]. These studies suggested that the reason for the better response of HPV-positive SCC to the treatment may be impaired DNA damage repair in HPV-infected tumor cells[5,6,7]. This impairment is probably caused by HPV-viral proteins, E6 and E7, which interfere with the host cell cycle to promote the reproduction of the virus[11,12,13]. Due to the improved response of HPV-positive oropharyngeal SCC to nonsurgical treatments, several studies evaluating different protocols of treatment de-escalation were initiated in patients with these tumors. The aim of the present study was to compare HPV-positive tumors to HPV-negative tumors in response to concurrent cisplatin chemotherapy and fractionated irradiation in comparison to isoeffective single-dose tumor irradiation
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