Unexpected Outcome in Head and Neck Ca Trial

The first randomized clinical trial to compare transoral robotic surgery (TORS) to radiotherapy in patients with oropharyngeal squamous cell carcinoma showed that the ability to swallow, among other outcomes, may in fact be better with the latter.

With a follow-up of about 2 years, the phase II ORATOR study met its primary endpoint, showing a statistically significant improvement in swallowing 1 year after treatment in the radiotherapy group compared with the surgery group, Anthony Nichols, MD, of London Health Sciences Centre (LHSC) in Ontario, Canada, and colleagues reported.

As described in the Lancet Oncology, the nearly 7-point advantage in MD Anderson Dysphagia Inventory (MDADI) scores (86.9 vs 80.1, respectively, P=0.042) suggests that patients in the radiotherapy group may have improved swallowing function -- to be considered "clinically meaningful," the difference had to be at least 10 points.

The findings contradict previous retrospective studies that favored surgery over radiation, and indicate that patients should be informed of both options.

Retrospective studies show they are intrinsically biased, explained Nichols, a head and neck cancer surgeon at LHSC. For example, there tends to be more patients with larger tumors and more bulky spread to the lymph nodes among patients who receive radiotherapy compared with surgery.

"Until you do a randomized trial like this," Nichols told MedPage Today, "you can't remove all of those confounders."

"In the absence of randomized data, the general belief has been that transoral surgery will lead to less morbidity than definitive chemoradiation," Barbara Burtness, MD, a medical oncologist at Yale Cancer Center in New Haven, Connecticut, told MedPage Today. "With much of the data coming from a retrospective series without formal toxicity evaluation, this may have reflected an underestimate of the late effects of transoral surgery."

In addition, Nichols added, retrospective studies may not report all of the complications, such as catastrophic bleeding during surgery. In fact, catastrophic bleeding during surgery led to a patient death in the ORATOR trial.

"In the context of a clinical trial, there's nowhere to hide," he said. "Every single complication is captured."

From 2012 to 2017, the ORATOR trial enrolled 68 patients with oropharyngeal squamous cell carcinoma from six hospitals in Canada and Australia. Only patients with primary tumors staged T1 or T2 and regional lymph node status of N0, N1, or N2 were eligible. Nichols' team assessed swallowing function using MDADI scores -- which range from 20 to 100, with higher scores representing better quality of life.

Patients were first stratified by p16 status and then randomly assigned to receive radiotherapy or TORS with concurrent neck dissection. Patients in the radiotherapy group who had nodal involvement (N1 or N2) also received chemotherapy; patients in the surgery group had the option of adjuvant chemoradiotherapy, depending on pathology.

Six patients in the radiotherapy group experienced dysphagia compared with nine in the TORS group.

"The careful delineation of late dysphagia in this study indicates that further study is required before we can assume that transoral surgery is a de-intensification strategy in oropharyngeal cancer," commented Burtness, who was not involved in the trial.

The study also found that 100% patients in the radiotherapy group could have an oral diet with no restrictions compared with 84% patients in the surgery group (P=0.055).

Authors of a corresponding editorial were particularly critical of the MDADI score as a reflection of swallowing function, however. Vincent Grégoire, MD, PhD, of the Centre Léon Bérard in France, and Piero Nicolai, MD, of the University of Brescia in Italy, described it as a "subjective" evaluation that was "strongly influenced" by anxiety and depression and recommended using objective tests, such as such as fiberoptic endoscopic examination of swallowing and videofluoroscopy.

As for toxicity, the radiotherapy and surgery groups had a similar proportion of treatment-related grade 2 or higher adverse events (91% vs 97%). Any grade hearing loss, neutropenia, constipation, and tinnitus were significantly more common among the radiotherapy group. By comparison, oral bleeding, weakness, and trismus were significantly more common among the surgery group.

No survival differences were observed between treatment groups, but the trial was also not sufficiently powered to detect a survival difference.

Nichols said that to conduct a non-inferiority study powered to evaluate survival would require nearly 1,000 patients, which he said is not feasible due to the already difficult task of accruing patients to a randomized trial that compares surgery and radiation.

"Historically, it's been seen as very difficult to conduct a randomized trial in which the arms are extremely different as [seen] here," said Burtness. "The success of these investigators in conducting such a trial demonstrates that this is possible, and perhaps in the past the barrier has been more among the investigators than among patients."

A larger follow-up trial, ORATOR2, is now underway to evaluate quality of life and survival rates between the two approaches in human papillomavirus (HPV)-associated oropharyngeal cancer.