From the Journals

ORATOR2 mute on best de-escalation therapy for low-risk HPV+ oropharynx cancers



The question of whether primary transoral surgery or radiation is a better treatment deescalation option for patients with low-risk human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCCs) is still unanswered, despite the best efforts of investigators in the randomized phase 2 ORATOR2 trial.

Transoral surgery was associated with an unacceptable risk of grade 5 toxic effects, but patients in both trial arms achieved good swallowing outcomes at 1 year, the study found.

The trial, begun in early 2018, was halted in late 2020 because of safety concerns after 2 of 31 patients randomized to surgery died from treatment-related causes.

But the story doesn’t end there, investigators and observers say.

In both trial arms, patients had good swallowing outcomes and other favorable quality-of-life measures at 1 year, and it’s too early to tell whether the transoral surgery (TOS) was associated with an unacceptable risk of grade 5 toxic effects, but patients in both trial arms achieved good swallowing outcomes at 1 year, wrote investigators Daniel A. Palma, MD, from Western University in London, Ontario, and colleagues in JAMA Oncology.

Nonetheless, “the results of this randomized clinical trial suggest that a primary [surgery] approach was associated with an up-front risk of treatment-related mortality, and caution is warranted with this approach,” the investigators wrote.

Hard to interpret

“It’s challenging to do that study in Canada, frankly, and it’s hard to make much of it, with the trial being terminated early,” said Neil D. Gross, MD, a head and neck cancer surgeon-scientist with MD Anderson Cancer Center, Houston, in an interview.

Dr. Gross and Sewit Teckie, MD, system chief of radiation oncology at NYC Health and Hospitals, cowrote an editorial accompanying the ORATOR2 results that was published in JAMA Oncology.

“There’s a huge difference in the volume of transoral robotic surgery performed in the United States, compared with Canada – it’s night and day, and that’s due to the different kind of healthcare systems that we have,” Dr. Gross said.

As he and Dr. Teckie noted, the combined mortality rate for surgical patients in the multicenter ORATOR2 and the earlier ORATOR trial, which was not limited to patients with HPV-related cancers, was 3.6%.

In contrast, in the ECOG-ACRIN 3311 trial comparing standard radiation with reduced dose radiation following TOS in patients with intermediate-risk HPV-positive oropharynx cancer, there was only one death among 495 patients, for a mortality rate of 0.2%.

“In the United States, mortality after transoral robotic surgery compares favorably with nonsurgical treatment and is lowest at high-volume centers. ORATOR2 also mandated prophylactic tracheostomy, a practice rarely used in contemporary transoral surgery for low-risk HPV-related OPSCC,” the authors wrote.

In defense of surgery

In an interview posted on the JAMA Network website, ORATOR2 co-investigator Anthony C. Nichols, MD, from the department of otolaryngology, head and neck surgery at Western University, London, Ontario, said that despite the findings of ORATOR2, transoral surgery is a good option for patients with low-risk disease and favorable anatomy.

“When you even look at the subset of these early T-stage patients that have anatomy that’s favorable towards transoral surgery, they do better. Their burden of disease is smaller, there’s less extensive neck disease ... so what happens very frequently, including even in the discussion of ECOG-ACRIN 3311, is comparisons to these large cooperative group studies that include T3, T4 tumors that no one on the planet would think about removing transorally,” he said.

“Everyone focuses on the surgical stopping, but what we should also focus on is how outstanding the patients did in the RT arm in both these studies,” he added.

Dr. Nichols also noted that quality-of-life metrics for patients randomized to surgery are comparable with those of patients randomized to radiation and that swallowing outcomes with surgery may be superior.

“In our minds, I think the issue is resolved, and we’re just moving on to the next concept, and the debate will rage on,” he said.


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