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The head and neck cancer community has been working to de-escalate treatment for human papillomavirus (HPV)–associated oropharynx squamous cell carcinomas for several years in hopes of preserving oncologic outcomes while reducing treatment toxicity.

There have been numerous investigations into the issue, but they have mostly been small, single-center studies, and agreement has yet to emerge on the best approaches.

Three small studies were presented at the recent American Society for Radiation Oncology (ASTRO) Head and Neck Cancer Symposium showing promising results for reducing radiation doses, limiting radiation field sizes, and using PET imaging to guide de-escalation.

"I believe that everybody here is interested in de-escalation of adjuvant therapy" for HPV-associated oropharynx squamous cell carcinomas, said Wade Thorstad, MD, a radiation oncologist at Washington University in St. Louis, St. Louis, Missouri.

Ideally, practice would be guided by multi-institutional phase III trials, but as data accumulate from these smaller studies, it's possible that "oncologically sound thresholds for de-intensification may converge into consensus," said Philip Schaner, MD, PhD, a radiation oncologist at Dartmouth College in Lebanon, New Hampshire, commenting on the radiation dose reduction study in an ASTRO news brief.

He noted, however, that "the optimal combination of de-intensification of radiation dose with or without systemic therapy, and the extent to which treatment attenuation can be safely diminished for different pathologic risk factors, remains unclear."

Fludeoxyglucose-18 (FDG)-PET to Guide De-escalation

As work on de-escalation continues, it's important to emphasize that it "does not compromise the high chance of curing these patients," Samuel Regan, MD, radiation oncology resident at the University of Michigan, Ann Arbor, Michigan, told Medscape Medical News.

Regan was the lead investigator on a PET imaging study at the University of Michigan, which included 84 patients with stage I/II p16 or HPV-positive oropharynx squamous cell carcinoma treated upfront with radiation and weekly concurrent carboplatin/paclitaxel.

"As many of us know, using only clinical factors to select patients for de-escalation of definitive chemoradiation may be insufficient," he told the ASTRO audience. "However, we currently have no well-validated biomarkers for radiation response in this patient population."

To fill the gap, he and his team turned to FDG-PET scans.

The 36 patients in the study  whose metabolic tumor volumes shrunk 50% or more from baseline on repeat FDG-PET after 8-12 doses of radiation stopped treatment early at 54 Gy to gross disease and 43.2 Gy to elective nodal volumes over 27 fractions.

The 48 subjects who did not hit the 50% mark continued to complete Michigan's usual course of radiation, 70 Gy to gross disease and 56 Gy to lymph nodes over 35 fractions.

The estimated 2-year locoregional recurrence rate was 4.6% in the 70 Gy group and 9.4% in the 54 Gy arm. However, the numbers represent only two 70 Gy failures and three 54 Gy failures, precluding definitive comparisons, Regan said.

Meanwhile, toxicity was substantially lower in the 54 Gy group. Patients reported better short-term outcomes, particularly less pain at 1 month, and lower overall symptom burdens. Three months after radiation, patients in this group had lost a median of 6% of their body weight vs 12.6% in the higher dose group; they also required less use of feeding tubes. There was a grade 4 carotid artery injury with 70 Gy but no grade 4 injuries with 54 Gy.

Although promising, patient selection for the approach needs work, Regan said. For instance, one of the recurrences in the 54 Gy group was in a patient who developed cutaneous squamous cell carcinoma of the head and neck alongside oropharynx squamous cell carcinoma recurrence after an earlier bone marrow transplant.

This suggests "some patients are not well suited to de-escalation," he explained.

On the other hand, smoking histories did not seem to have a strong effect on the risk for recurrence, suggesting perhaps that smoking histories are not a reason to exclude patients from de-escalation, he said.

The approach is not being used off-trial, said Regan, adding that it will be key to incorporate additional biomarkers, "such as circulating tumor DNA or maybe MRI metrics," to help make de-escalation decisions.

Smaller Radiation Fields in the Contralateral Neck

Investigators at the University of Maryland, Baltimore, Maryland, took a different approach: Shrinking radiation field sizes.

Most patients with p16-positive oropharynx squamous cell carcinomas receive radiation to the contralateral neck to wipe out undetected microscopic lymph node metastases, but the side effects from irradiating both sides of the neck can be severe.

To counter the problem, investigators at the university irradiated a smaller area of the contralateral neck than usual.

Dubbing the technique Selective Avoidance of Nodal Volumes at Minimal Risk (SAVER), the researchers limited contralateral nodal radiation to regions of the upper and middle neck.

Lead investigator Jason Molitoris, MD, PhD, from the University of Maryland, Baltimore, Maryland, reported outcomes in 52 patients with T 1-4 disease treated with radiation plus/minus chemotherapy, 36 in the upfront setting and 16 after transoral robotic surgery. Doses to the contralateral neck were approximately 50 Gy.

The goal was to test the approach in as broad a range of patients as possible.

The main exclusion criterion was simply known disease in the contralateral lymph nodes.

So far, there has not been a single contralateral nodal failure across a median follow-up of 19 months. The smaller radiation fields also translated to lower radiation doses to the contralateral parotid gland.

Of the three deaths in the study, two were unrelated and the third was from local recurrence following upfront chemoradiation.

Given the results, the approach has become our institutional standard for contralateral neck irradiation, said Molitoris.

SAVER is used regardless of the extent of "ipsilateral disease; whether treatment is in the definitive or adjuvant setting; whether it is delivered with protons or photons, or where it is delivered within our community of treatment sites," he explained.

De-escalation Based on Surgical Pathology

Thorstad presented a study of 50 T 1-3 patients who had trans-oral robotic or laser surgery with selective neck dissection.

Instead of the university's usual 60 Gy of radiation and three cycles of cisplatin after surgery, 20 high-risk patients — meaning they had extranodal extension or positive surgical margins — were treated with 42 Gy radiation in 21 fractions and one cycle of cisplatin (100 mg/m²).

Thirty patients without high-risk features received just the 42 Gy radiation. Estimated 4-year progression-free survival was 90% in both arms.

Overall survival was 100% in the high-risk group and 94% in the intermediate risk arm; the cause of the one death in the intermediate-risk group is unknown, but the patient was disease free 3 months earlier.

Meanwhile, de-escalated treatment led to fewer swallowing problems and other issues, which translated to a significant difference in weight loss: A mean of 3.18% in the radiation alone group and 4.9% in the chemoradiation arm compared with 7.4% in historical controls treated with the usual approach.

Thorstad said the results are excellent and warrant further investigation, but for now, he and his colleagues plan to stick mostly to 60 Gy radiation outside of clinical trials.

Additional work is needed to shore up the findings in high-risk patients, he said, but he and his fellow researchers are thinking about trying an even lower radiation dose in the intermediate-risk group.

The FDG-PET investigation was funded by the National Institutes of Health; no funding source was reported for the other studies. Schaner, Regan, and Thorstad had no disclosures. Molitoris reported consulting for Sensius Healthcare.

M. Alexander Otto is a physician assistant with a master's degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com