Radiation Therapy for HPV-Related Oropharyngeal Squamous Cell Carcinoma: Prospects and Controversies

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In the treatment of patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma, neither cancer outcomes nor measurable quality of life have yet been shown to differ between surgery- and radiotherapy-based approaches, according to Sue S. Yom, MD, PhD, FASTRO, Professor of Radiation Oncology and Otolaryngology Head and Neck Surgery at the University of California, San Francisco. The difference may come down to the specific eligibility criteria and outcome variables being measured. Dr. Yom discussed this topic during the 2021 Winship Cancer Institute of Emory University Symposium: Updates in the Management of Head and Neck Cancer.1

“The MDADI is well validated, has a physical correlate (modified barium swallow), and is highly accepted in the surgical as well as radiation communities.”
— Sue S. Yom, MD, PhD, FASTRO

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According to Dr. Yom, in the definitive setting of radiation-based therapy, cetuximab is not equivalent to every-3-week or every-1-week concurrent cisplatin. In the setting of induction chemotherapy, cetuximab-based induction and concurrent cetuximab with reduced radiation may be acceptable in good-prognosis patients. In the transoral surgery–based setting, postoperative radiation to 50 Gy may be acceptable after surgery, and surgical monotherapy may be an option for very low–risk patients.

“There are a lot of ‘maybes’ and not a lot of definitives here,” Dr. Yom noted. “Because we still don’t have much randomized phase III data in this space at the national or international level.”

Dr. Yom focused solely on multi-institutional and national studies during her presentation (as they are more generalizable and most likely to change practice soon). She cautioned that cross-trial comparisons, particularly of phase II data, can be fraught with inaccuracies.

Radiation-Based Approaches

The phase III RTOG 1016 trial randomly assigned patients with HPV-positive oropharyngeal cancer, smokers and non-smokers, to accelerated intensity-modulated radiation therapy with high-dose cisplatin or weekly cetuximab.2 Results showed that cetuximab was not equivalent to cisplatin in terms of locoregional control or overall survival. Similar results were confirmed for low-risk HPV oropharyngeal cancer in further studies ( identifier NCT01855451).3

The NRG HN002 trial focused on de-intensification of radiation therapy for very good–risk patients.4 Patients in this trial received 60 Gy of radiation, either mildly accelerated or in combination with weekly cisplatin.

Both arms satisfied the swallowing-related quality of life (MD Anderson Dysphagia Inventory [MDADI]) acceptability endpoint set in the trial. However, only the combination of cisplatin and radiation satisfied the 2-year progression-free survival acceptability; the latter approach was selected to go forward into the NRG HN005 trial (NCT03952585). This trial will directly compare 70 Gy of radiation with high-dose cisplatin with a first experimental arm of 60 Gy with the same chemotherapy and a second experimental arm of accelerated radiation and nivolumab.

“The standard arm, as well as one or two of the experimental arms, if they can meet the progression-free survival and MDADI thresholds for accessibility, will go forward into a randomized phase III trial,” explained Dr. Yom. “We are hoping to see some impact on the radiation-based standard of care if this large-scale randomized phase III trial finishes with that finding.” She noted that these studies are some of the first to use quality of life as a major co-primary endpoint along with progression-free survival, due to the unique nature and concerns of this head and neck cancer population.

“MDADI has become a very important measure in these studies, because it quantifies swallowing quality of life,” said Dr. Yom. “MDADI is popular because it is well validated, has a physical correlate (modified barium swallow), and is highly accepted in the surgical as well as radiation communities.” In addition, she considered the MDADI score of 85 in the combined-modality arm of the HN002 trial to be a “very good” 1-year MDADI score.

Transoral Surgery–Based Approaches

The phase II ECOG 3311 trial looked at transoral endoscopic surgery in patients with HPV-positive oropharyngeal squamous cell carcinoma (NCT01898494). Of 359 evaluable patients, 11% were classified as low risk and underwent observation alone; 31% had high-risk features and received triple-modality therapy with 66 Gy of radiation and concurrent cisplatin; and 58% were intermediate risk and were randomly assigned to either 60 Gy or 50 Gy of postoperative radiation.

The 2-year progression-free survival was more than 90% in all three groups, Dr. Yom reported. Grade 3 and higher bleeding was 6%, but the trial had just one fatality. “This study was important for setting up surgical quality assurance procedures and processes,” she said.


  • In HPV-related disease, neither surgery nor radiation therapy has been set as the standard of care for treatment.
  • Radiation dose and/or volume reduction comprise a complex set of variables, and the metric of “prescribed dose” of radiation has its limitations.
  • Developing concepts, such as patient-reported outcomes as well as genomic and circulating tumor DNA biomarkers, should continue to inform more nuanced selection of patients for de-intensification.

However, MDADI scores in patients who underwent surgery followed by radiation or chemoradiation were noticeably impacted in the first year, with scores being in the high 70s (although they did improve slightly at 2 years). “These numbers are lower than what we saw in HN002, so I think the impact of surgery and radiation together does need to be explored,” she said. “But, of note, the patients who could have surgery alone in the low-risk observation arm had excellent MDADI scores at 1 and 2 years.”

Optimizing the Surgery-Based Approach

Two randomized phase III studies in Europe are focused on optimizing the surgery-based approach. The EORTC “Best Of” study is randomly assigning low-risk patients to intensity-modulated radiation therapy of 70 Gy against transoral surgery alone, with a primary endpoint of quality of life (NCT02984410).

The PATHOS trial takes a similar approach to ECOG 3311 with low-, intermediate-, and high-risk patients (NCT02215265). High-risk patients are randomly assigned to 60 Gy of radiation, with or without cisplatin, with an endpoint of overall survival. According to Dr. Yom, the PATHOS study “will answer some important questions regarding whether or not high-risk patients should undergo de-escalation.”

Optimizing the Radiation Therapy Platform

The recently activated HN009 trial will set out to answer the “age-old question” of weekly cisplatin vs high-dose cisplatin in HPV-positive higher-risk cohorts and HPV-negative cohorts (NCT05050162). “Both regimens were used in HN002 and HN005, because there is not a very clear standard right now,” Dr. Yom explained. “Once we have these data, they will optimize the platform going forward in future studies, not only in HPV-positive but also HPV-negative patients.”

Dr. Yom pointed out the limitations of a “prescribed dose” of radiation, explaining that radiation dose and/or volume reduction comprise a complex set of variables. “The maximum prescribed dose doesn’t capture what’s happening in the volume of radiation that’s being delivered to a patient’s body,” she said. “So, dose is not the only question.”

“The dose doesn’t capture what’s happening in the volume of radiation that’s being delivered to a patient’s body. So, dose is not the only question.”
— Sue S. Yom, MD, PhD, FASTRO

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In the phase II EVADER study, the Canadian Clinical Trials Group will explore treating low-risk patients with 70 Gy of radiation and standard cisplatin, focusing on limited volume as opposed to looking at dose alone (NCT03822897).

“Likewise, I would say chemotherapy choices and dosing are complex, and there are also costs and toxicities to induction chemotherapy, as well as with upfront surgery,” Dr. Yom added.

Evolving Principles of Treatment Selection

According to Dr. Yom, quality of life will continue to play a major role in optimizing treatment selection going forward. Researchers on the ORATOR trial reported that the spectrum of toxicities at 1 year was significantly different between the radiation and surgery arms.5 For example, MDADI scores favored radiation therapy, whereas surgery resulted in less tinnitus and hearing loss.

“As head and neck practitioners, I think we all know that the spectrum of effects could evolve with longer-term follow-up,” she shared. “So, what more sophisticated quality-of-life measurements could we use in the future, and how do we integrate patient priorities within that to make them more meaningful? I think it’s going to go way past MDADI at some point.”

An approach brought forward by researchers at Duke University suggests that early PET-CT response during radiation therapy may predict disease recurrence.6 Another approach uses circulating tumor HPV DNA in the plasma to predict recurrence.7 According to Dr. Yom, these evolving concepts may serve to inform more nuanced or dynamic selection of patients for de-intensification in the future. 

DISCLOSURE: Dr. Yom has received research funding from Genentech, Merck, Bristol Myers Squibb, and BioMimetix; grants from NRG Oncology and the National Institutes of Health; and honoraria from the American Society for Radiation Oncology and the National Cancer Institute.


1. Yom S: Radiation in HPV-related oropharyngeal SCC: Prospects and controversies. 2021 Updates in the Management of Head and Neck Cancer. Presented November 6, 2021.

2. Gillison ML, Trotti AM, Harris J, et al: Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): A randomised, multicentre, non-inferiority trial. Lancet 393:40-50, 2019.

3. Mehanna H, Robinson M, Hartley A, et al: Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): An open-label randomised controlled phase 3 trial. Lancet 393:51-60, 2019.

4. Yom SS, Saavedra-Torres P, Caudell JJ, et al: Reduced-dose radiation therapy for HPV-associated oropharyngeal carcinoma (NRG Oncology HN002). J Clin Oncol 39:956-965, 2021.

5. Nichols AC, Theurer J, Prisman E, et al: Radiotherapy versus transoral robotic surgery and neck dissection for oropharyngeal squamous cell carcinoma (ORATOR): An open-label, phase 2, randomised trial. Lancet Oncol 20:1349-1359, 2019.

6. Mowery YM, Vergalasova I, Rushing CN, et al: Early18F-FDG-PET response during radiation therapy for HPV-related oropharyngeal cancer may predict disease recurrence. Int J Radiat Oncol Biol Phys 108:969-976, 2020.

7. Chera BS, Kumar S, Shen C, et al: Plasma circulating tumor HPV DNA for the surveillance of cancer recurrence in HPV-associated oropharyngeal cancer. J Clin Oncol 38:1050-1058, 2020.

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