HPV-Positive Oropharyngeal Cancers: How Do We De-escalate Treatment?

By Michael Spiotto, MD, PhD

The optimal treatment for patients with human papillomavirus (HPV)-positive head and neck cancers remains unclear.

While these patients with locally advanced disease fare well with concurrent chemoradiation regimens, the current treatments needed to cure these patients may be excessive.

HPV-positive cancers appear more sensitive to chemoradiation as patients with low risk HPV-positive oropharyngeal cancers have almost double the overall survival as patients high risk HPV-negative cancers (3y OS: 93% vs. 46%). (1).

This benefit in HPV-positive patients results from improved locoregional control rather than decreased distant metastasis. Since concurrent chemoradiation at least doubles the rate of acute and long term toxicities, many groups are searching for less intense treatment regimens that maximize cure while decreasing toxicities.

To de-intensify the current standard of care would require reducing the current radiation dose and/or the chemotherapy regimens. To this end, recent ECOG and RTOG trials are addressing these questions.

The ECOG Phase II trial (E1308) tests the efficacy of decreasing the radiation dose.

Patients achieving a complete response to induction chemotherapy were treated with lower dose radiation and cetuximab.

Radiation with cetuximab, or bioradiotherapy, is distinct from chemoradiotherapy because, unlike the chemotherapeutic cisplatin that cross-links DNA, cetuximab is an antibody targeting the cancer cell membrane and is associated with fewer toxicities.

At ASCO 2013, E1308 reported promising preliminary results where patients achieved overall response rates of 86% (2) with decreased toxicity compared to historical outcomes. While results on the progression free survival and overall survival are pending, these responses bode well.

Yet, it remains unclear whether bioradiotherapy provides as good locoregional control as chemoradiotherapy. Retrospective analysis has shown that bioradiotherapy may not be as effective as chemoradiation, especially in patients with HPV-positive cancers (3).

Similarly, a recent trial suggested that bioradiotherapy had more local failures than chemoradiotherapy in patients with laryngeal cancers (4). Nevertheless, the ECOG trial is an important first step forward towards de-intensification of treatments even though there was no direct comparison between bioradiotherapy and chemoradiotherapy.

By contrast, the RTOG1016, which has nearly met its accrual, is directly comparing chemoradiation to bioradiation.

Since HPV-positive patients have improved locoregional control but similar rates of distant metastasis, it will be interesting to see what type of patients accrue to this study.

Recently, O’Sullivan et al. demonstrated that chemoradiation improved distant metastasis but not locoregional control in HPV-positive patients with N2b or greater nodal disease (5).

Unlike chemotherapy that decreases distant metastasis when given prior to or during radiation (6), bioradiotherapy has not been shown to impact distant failure rates (7). Therefore, if RTOG 1016 still demonstrates a benefit for chemoradiation, will it be due to impacting distant metastasis and not locoregional failure?

And, if chemoradiation is not necessary, will this trial have enough power to detect differences in distant metastasis even as an ad hoc analysis?

Over the next few years, we will likely see a shift in the treatment paradigm for HPV-positive oropharyngeal cancers.

At the current time, patients with advanced HPV-positive oropharyngeal cancers likely still need concurrent chemoradiation given the high cure rates for the initial treatment and the poor outcomes associated with salvage therapy.

Furthermore, for the time being, patients treated with de-intensified regimens should remain on clinical protocols.

But the question remains how to de-intensify treatments.

In patients with advanced nodal disease, chemotherapy may still be required to decrease the risk of distant metastasis. Since evidence is mounting that chemoradiation may not improve locoregional control in HPV-positive tumors, one way may be induction chemotherapy followed by radiotherapy alone or bioradiotherapy.

As induction chemotherapy, chemotherapy would still control distant metastasis but cause fewer toxicities than when given concurrently with radiation.

Therefore, as the treatment paradigms for HPV-positive cancers continue to change we must evaluate how different de-escalated treatments distinctly impact locoregional and distant control.

Michael Spiotto, MD, PhD, is an Assistant Professor of Radiation & Cellular Oncology at the University of Chicago Medicine. He specializes in treating patients with head and neck cancer. Whenever possible, he uses image-guided radiation therapy to target a tumor more precisely while reducing damage to surrounding tissue.


1. Ang KK, Harris J, Wheeler R, et al: Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363:24-35

2. Marur S, al. e: E1308: A phase II trial of induction chemotherapy (IC) followed by cetuximab with low dose versus standard dose IMRT in patients with human papilloma virus (HPV) -associated resectable squamous cell carcinoma of the orophayrnx (OPSCC). JCO 2013 ASCO Annual Meeting. 31:Suppl 6005., 2013

3. Koutcher L, Sherman E, Fury M, et al: Concurrent cisplatin and radiation versus cetuximab and radiation for locally advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 81:915-22

4. Lefebvre JL, Pointreau Y, Rolland F, et al: Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study. J Clin Oncol 31:853-9

5. O’Sullivan B, Huang SH, Siu LL, et al: Deintensification candidate subgroups in human papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis. J Clin Oncol 31:543-50

6. Pignon JP, le Maitre A, Maillard E, et al: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 92:4-14, 2009

7. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567-78, 2006

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