Evolution of a Paradigm Switch in Diagnosis and Treatment of HPV-Driven Head and Neck Cancer-Striking the Balance Between Toxicity and Cure

Abstract

More than a decade after the discovery of p16 immunohistochemistry (IHC) as a surrogate for human papilloma virus (HPV)-driven head and neck squamous cell carcinoma (HNSCC), p16-IHC has become a routinely evaluated biomarker to stratify oropharyngeal squamous cell carcinoma (OPSCC) into a molecularly distinct subtype with favorable clinical prognosis. Clinical trials of treatment de-escalation frequently use combinations of biomarkers (p16-IHC, HPV-RNA in situ hybridization, and amplification of HPV-DNA by PCR) to further improve molecular stratification. Implementation of these methods into clinical routine may be limited in the case of RNA by the low RNA quality of formalin-fixed paraffin-embedded tissue blocks (FFPE) or in the case of DNA by cross contamination with HPV-DNA and false PCR amplification errors. Advanced technological developments such as investigation of tumor mutational landscape (NGS), liquid-biopsies (LBx and cell-free cfDNA), and other blood-based HPV immunity surrogates (antibodies in serum) may provide novel venues to further improve diagnostic uncertainties. Moreover, the value of HPV/p16-IHC outside the oropharynx in HNSCC patients needs to be clarified. With regards to therapy, postoperative (adjuvant) or definitive (primary) radiochemotherapy constitutes cornerstones for curative treatment of HNSCC. Side effects of chemotherapy such as bone-marrow suppression could lead to radiotherapy interruption and may compromise the therapy outcome. Therefore, reduction of chemotherapy or its replacement with targeted anticancer agents holds the promise to further optimize the toxicity profile of systemic treatment. Modern radiotherapy gradually adapts the dose. Higher doses are administered to the visible tumor bulk and positive lymph nodes, while a lower dose is prescribed to locoregional volumes empirically suspected to be invaded by tumor cells. Further attempts for radiotherapy de-escalation may improve acute toxicities, for example, the rates for dysphagia and feeding tube requirement, or ameliorate late toxicities like tissue scars (fibrosis) or dry mouth. The main objective of current de-intensification trials is therefore to reduce acute and/or late treatment-associated toxicity while preserving the favorable clinical outcomes. Deep molecular characterization of HPV-driven HNSCC and radiotherapy interactions with the tumor immune microenvironment may be instructive for the development of next-generation de-escalation strategies.

Keywords: de-intensification trials; head and neck (H&N) cancer; human papilloma virus—HPV; oropharyngeal cancer (OPC); patient stratification strategy; precision medicine; radiotherapy.

FIGURE 1

(A) Acute and late toxicity profile of local and systemic chemotherapy. (i) Sagittal view of a CT-scan shows the patient’s tumor (in blue). Local therapy (surgery and radiotherapy) and systemic treatment can result in acute side effects (occurring within the first 90 days of treatment) or chronic side effects (lasting beyond 90 days). Local side effects include dermatitis, mucositis, xerostomia (dry mouth), dysphagia (difficulty swallowing), bleeding, wound healing swelling, and fibrosis. (ii) Systemic side effects are related to the cytotoxic properties of chemotherapy. Increased rates of adverse events (occurring synergistically due to the combination of radiotherapy/chemotherapy) may lead to treatment interruptions, jeopardizing patient outcomes. (B) Kinetics of adverse events over time. The aim of de-escalation trials is to flatten the curve of adverse effects [whether acute (in red) or chronic (in blue)], thereby improving the quality of life of patients with HNSCC and cancer survivors.

FIGURE 2

Current principles, de-escalation strategies, and clinical endpoints for therapy de-intensification in HPV-driven OPSCC. The motivation for therapy de-intensification is to decrease toxicity of treatment without compromising patient outcomes. (A) In the setting of primary CRT, current strategies focus on dose modification or omission of chemotherapy, substitution of cisplatin (with targeted agents or immunoncology), reduction of radiotherapy dose, or modification of CRT dose based on response to induction chemotherapy. Similar strategies are also employed in the postsurgical adjuvant setting. (B) Survey of primary clinical endpoints under investigation in de-escalation trials. Not all trials are powered to investigate changes in the clinical outcome. (DLT, dose-liming toxicity; RR, response rate.)