De-escalation of Adjuvant Radiation for Low-Risk HPV Oropharyngeal Cancers

HPV+ oropharyngeal carcinoma can be treated with either definitive radiotherapy or transoral surgery (TOS, using a predominantly robotic or laser approach), with equivalent oncologic results.23 The proportion of patients who receive definitive radiotherapy or TOS followed by adjuvant radiotherapy (in over 80% of patients) has roughly reached parity. At large academic centers with significant head and neck cancer expertise, the decision to treat with either definitive radiation or TOS followed by adjuvant radiotherapy is driven by non-oncologic considerations most often dictated by anatomic factors such as the presence of a retropharyngeal internal carotid artery, proximity of nodal disease to the carotid artery, involvement of the soft palate, or patient ability to tolerate resection. None of these factors would be expected to affect the probability of oncologic outcomes.

In addition to definitive radiation, the introduction of improved surgical techniques has allowed select patients with oropharyngeal cancer to undergo resection of the primary disease as well as dissection of neck disease as part of their treatment regimen. The utilization of TOS with neck dissection is followed by observation, radiation or chemoradiation based on standard pathologic risk factors such as the presence of perineural invasion, lymphovascular space invasion, close or involved margins, T3-T4 disease, or the presence of multiple involved lymph nodes .24 25 Since over 50% of patients who are treated with TOS are treated with adjuvant radiation utilizing concurrent chemotherapy based on pathologic factors, and over 80% of patients treated with primary TOS are treated with adjuvant radiation of some form, it is important to consider deintensifying treatment for patients with good prognosis cancers.

The most commonly utilized dose in this clinical situation is 60Gy in 30 fractions; however, this is based on literature from smoking-related cancers that suggest that 57.6Gy in 32 fractions would be an acceptable dose for patients with high-risk disease (Peters et al,).

Treatment with adjuvant therapy for TOS patients has involved several deintensification approaches, depending on pathologic factors. Approaches for de-escalation can include decreasing the treatment volume, decreasing radiation dose, or excluding chemotherapy in patients with extracapsular extension.

The Eastern Cooperative Oncology Group ECOG 3311 trial, a phase II randomized study of TOS patients with HPV(+) oropharyngeal cancers is studying dose de-escalation from 60Gy to 50Gy in intermediate-risk patients receiving adjuvant IMRT radiation, but has not yet reported its results. Another approach in the postoperative setting has been using chemotherapy to decrease the dose of radiation used; the Mayo Clinic in Minnesota has reported the use of docetaxel and cisplatin chemotherapy with low-dose radiation (twice daily radiation to 30-36Gy in 20 fractions) without any unexpected recurrences in 80 patients, with locoregional control of 95% and distant control of 94%.

For patients with extracapsular extension (ECE), the addition of concurrent chemotherapy to adjuvant radiation has not shown a benefit in a retrospective series of 152 patients.28 In fact, the aforementioned ECOG 3311 phase II trial of radiotherapy dose de-escalation for adjuvant patients excludes chemotherapy for all these patients, and is de-escalating radiation dose down to 50Gy in this population. A similar approach in patient with ECE ≤1mm is being taken in the SIRS trial from Mt. Sinai with an expected enrollment of 200 patients, which entails de-escalating radiation dose to 50Gy without chemotherapy. The PATHOS trial from the UK will be doing a direct comparison of patients with ECE >1mm, looking at whether chemotherapy can be omitted from this population of higher-risk patients who have predominantly more extensive ECE.

There is no study which we are currently aware that combines the concept of omission of the primary site from the radiation therapy field with dose de-escalation to the nodal bed at risk. A study that combines these concepts found in the literature as well as current clinical trials would therefore be novel and could have a significant of quality-of-life benefit for patients if found to be effective.

A prospective phase II trial at the University of Pennsylvania of 60 patients omitting the primary resection bed while treating the nodal basin with standard doses of adjuvant radiation has demonstrated excellent control rates.33 With 2-year mean follow-up, local control was 98%, regional control 100%, and distant control was 97% Patients were treated to a standard dose of 60-63 Gy. Excluding the primary site led to 1 recurrence in the 60 patients, which was successfully salvaged via surgical resection. There was a 2% gastrostomy dependence rate in this population.

Radiation will involve with a lower than standard radiation dose (50Gy in 25 fractions, with either IMRT or proton beam therapy) and to a smaller than standard radiation field (to the neck only, excluding the original site of tumor in the oropharynx).