Toxicity Reduction in the Treatment of HPV Positive Oropharyngeal Cancer: Emerging Combined Modality Approaches

Abstract

Human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) is a distinct clinical entity within the head and neck cancers, with a unique epidemiology and, in general, a favorable prognosis. Because of this favorable prognosis, researchers have considered de-intensifying the current standard treatment of HPV+ OPC in order to reduce acute and late treatment related toxicity without compromising outcome. Current ongoing trials can be divided in three main categories: de-intensification of the chemotherapy by replacing concomitant platinum-based chemotherapy with the EGFR-inhibitor cetuximab, or de-intensification of the radiation dose of either the primary radiotherapy of selected, good-responding patients after induction chemotherapy or of the adjuvant radiotherapy based on pathology features after primary surgery. Despite the good prognosis of the majority of HPV+ OPC patients, a proportion of them still have poor prognosis. This unmet need has led clinical research on new treatment strategies focused on influencing the unique micro-environment of HPV+ OPC with for example immunotherapy. This article summarizes the current understanding regarding the optimal treatment of non-metastatic HPV+ OPC. Ongoing and published clinical trials regarding de-intensification strategies, immunotherapy and proton therapy are described focusing on the rationale and underlying evidence of these emerging treatment strategies. Nevertheless, until the results of the ongoing trials are known, the treatment of HPV+ OPC in clinical practice should remain identical to the treatment of HPV negative OPC.

Modern treatment outcomes for early T-stage oropharyngeal cancer treated with intensity-modulated radiation therapy at a tertiary care institution

“…However, due to short- and long-term toxicities, and due to the fact that HPV-associated OPSCC is more sensitive to chemotherapy and radiation than HPV-negative OPSCC, there has been much interest in treatment de-escalation [ 23 , 24 ]. Some current strategies under investigation include weekly cisplatin instead of high-dose cisplatin, lower radiation dose, or decreased adjuvant radiation and/or chemotherapy after surgery [ 25 – 27 ]. Other strategies, such as using the epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab, have conclusively been shown to provide inferior survival without meaningfully improving quality of life which only further highlights the importance of balancing toxicity with survival [ 28 , 29 ].…”

Postoperative Radiation Therapy Refusal in Human Papillomavirus‐Associated Oropharyngeal Squamous Cell Carcinoma

“…9 HPV-associated disease represents the majority of OPSCC 10 and is associated with improved overall survival and disease-free survival compared to non-HPVassociated OPSCCs. 11,12 Due to the improved prognosis, there is interest in de-intensification of therapy for HPVpositive OPSCC, particularly to mitigate treatmentrelated toxicities, 13,14 including xerostomia, impaired wound healing, dysphagia, or radionecrosis, [15][16][17] which can severely impact quality of life, particularly in underserved populations. 18,19 The rate of PORT refusal, its oncologic impact, and associated clinical or demographic factors have not been studied in HPV-associated OPSCC.…”

Randomized clinical trial on reduction of radiotherapy dose to the elective neck in head and neck squamous cell carcinoma; update of the long-term tumor outcome

“…In general, these tumors are more radiosensitive, have a better prognosis and patients live longer with long term treatment-related toxicity [26]. Therefore, not only the optimal RT dose on the elective nodal neck but also on the macroscopic tumor and the need for systemic treatment are under investigation [27][28][29]. At Memorial Sloan Kettering Cancer Center, patients with HPV positive OPC treated with CRT are included in an ENI low dose program in which the ENI is irradiated up to an EQD2 of 30 Gy [30].…”