The debate between investigators striving to de-intensify treatment for low-risk HPV-positive oropharynx (OPC) cancer and decrease long-term treatment-related toxicities has been present for some time. On one end of the spectrum, some experts called for treating patients on innovative but aggressive clinical trials investigating treatment de-escalation while others criticized aggressive investigational efforts as pre-emptive and risky.

The issues underlying this debate are real and evolving, and were recently highlighted at the recent Multidisciplinary Head and Neck Cancer Symposium in Scottsdale, AZ (Feb. 15–17). For investigators who have witnessed the morbidities associated with decades of treatment intensification, the desire to spare patients such effects feels particularly urgent in a cohort of patients (HPV-related non-smokers) where the likelihood of successful treatment is high. Other investigators advocated for a centrally administered, step-wise approach towards de-escalation. For everyone in the field of head and neck oncology, we are watching the HPV epidemic unfold before our eyes and experiencing first-hand the difficulty in trying to define new standards of care in real-time through the necessary mechanism of clinical trials.

Three abstracts presented at the conference discussed ongoing de-escalation strategies. Dr. Bhisham Chera from the University of North Carolina presented data from their de-escalation trial that treated patients with low-risk HPV-positive OPC (T1 or T2, N1-N2b, <10 pack-year smoking) with reduced doses of definitive chemoradiation (total radiation dose 60 Gy) with very encouraging survival outcomes (2 year OS 95%).

Dr. Tanguy Seiwert from the University of Chicago presented a different strategy using induction chemotherapy to determine which patients could receive response-stratified dose de-escalation (radiation doses ranging from 45 Gy to 75 Gy), citing the choice of intensive up-front chemotherapy in order to prevent distant failures, which has emerged as the predominant type of failure for HPV-related OPC.

Finally, Dr. Katharine Price from the Mayo Clinic presented toxicity, swallowing, and quality of life (QOL) data from the Mayo group’s de-escalation trial of treating post-operative patients with HPV-OPC with significantly reduced adjuvant radiation doses and weekly docetaxel (30–36 Gy for 2 weeks). Their data showed very low rates of toxicity (total grade 3–4 toxicity 5%, long-term grade 2 toxicity 8%) and exceptional swallow outcomes while maintaining a 2 year overall OS of 98%.

One of the criticisms of these abstracts was the lack of uniformity in study design — complicating the best path forward for future de-escalation strategies. This also raises critical questions regarding the treatment of patients with HPV-positive OPC. Should there be one de-escalation strategy for all patients, or should de-escalation strategies be individualized? In commentary, we feel that a broad gamut of de-escalation strategies helps inform the scientific community on the future possibilities for dose de-escalation — strategies that can subsequently be refined over time as we learn more about the biology of the disease.

The number of patients with HPV-positive OPC is growing exponentially and we should not take decades to determine the best response to this epidemic. We need all efforts — bold and incremental- to advance the science and to treat as many patients as possible on clinical trial, where such efforts at de-escalation should be concentrated. All investigators agreed that dose de-escalation was investigational and should not be performed outside the context of a clinical trial.

Finally, one topic that was notably absent from discussion was that of vaccination. The United States has shockingly low rates of vaccination for HPV. We all need to come together as a community to advocate for better HPV vaccination coverage for all boys and girls as, ultimately, the best de-escalation strategy is one of prevention.

Katharine A. R. Price, M.D., Division of Medical Oncology, Mayo Clinic, Rochester, MN

Daniel Ma, M.D., Department of Radiation Oncology, Mayo Clinic, Rochester, MN