Moving from conventional to adaptive risk stratification for oropharyngeal cancer

Abstract

Oropharyngeal cancer (OPC) poses a complex therapeutic dilemma for patients and oncologists alike, made worse by the epidemic increase in new cases associated with the oncogenic human papillomavirus (HPV). In a counterintuitive manner, the very thing which gives patients hope, the high response rate of HPV-associated OPC to conventional chemo-radiation strategies, has become one of the biggest challenges for the field as a whole. It has now become clear that for ~30-40% of patients, treatment intensity could be reduced without losing therapeutic efficacy, yet substantially diminishing the acute and lifelong morbidity resulting from conventional chemotherapy and radiation. At the same time, conventional approaches to de-escalation at a population (selected or unselected) level are hampered by a simple fact: we lack patient-specific information from individual tumors that can predict responsiveness. This results in a problematic tradeoff between the deleterious impact of de-escalation on patients with aggressive, treatment-refractory disease and the beneficial reduction in treatment-related morbidity for patients with treatment-responsive disease. True precision oncology approaches require a constant, iterative interrogation of solid tumors prior to and especially during cancer treatment in order to tailor treatment intensity to tumor biology. Whereas this approach can be deployed in hematologic diseases with some success, our ability to extend it to solid cancers with regional metastasis has been extremely limited in the curative intent setting. New developments in metabolic imaging and quantitative interrogation of circulating DNA, tumor exosomes and whole circulating tumor cells, however, provide renewed opportunities to adapt and individualize even conventional chemo-radiation strategies to diseases with highly variable biology such as OPC. In this review, we discuss opportunities to deploy developing technologies in the context of institutional and cooperative group clinical trials over the coming decade.

Keywords: cell free DNA; circulating tumor cells; hyperpolarized MRI; oropharynx; radiation; smoking.

Figure 1

Dynamic Adaptive Risk Stratification. Treatment decisions for our patients balance maximizing disease response and minimizing treatment-related toxicity. There is currently a scarcity of clear biologically consistent drivers of response to therapy which can be used to mechanistically inform modulation of therapy, especially de-escalation strategies. Dynamic assessment of treatment response may allow therapeutic modification to balance disease control with toxicity. Tumor shedding creates a multitude of circulating biomarkers (e.g., viral DNA, tumor exosomes, viable circulating tumor cells) that provide high biological resolution regarding response to therapy, while imaging-based parameters may afford high spatiotemporal resolution reflective of tumor heterogeneity in response to treatment.