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CHICAGO — The idea of de-escalating radiotherapy for patients with oropharyngeal squamous cell carcinoma (OPSCC) that is positive for human papilloma virus (HPV) has been debated for a while. Now results from a phase 3 trial (MC1275) show that de-escalated adjuvant radiation therapy (DART) resulted in robust responses and lower toxicity as compared with standard care radiotherapy.  

Significantly fewer patients who received DART had grade 3 or greater radiation-related adverse events at 3 months vs those receiving standard of care (1.6% vs 7.1%; P = .058).

In addition, only 1.6% of patients in the DART cohort required feeding tubes vs 27.4% in the standard treatment arm (P < .0001).

“DART demonstrated less toxicity, improved swallowing function, and quality of life compared with standard of care, can flagyl cause seizures in dogs ” said lead author Daniel Ma, MD, a head and neck radiation oncologist at the Mayo Clinic in Rochester, Minnesota. “DART also had excellent locoregional control, progression-free survival and overall survival rates, particularly in the extranodal extension (ENE)-negative cohort.”

However, the results for patients with ENE-positive disease were worse with DART than with standard care, so Ma advised “caution” in this patient population.   

The results of the study were presented during the plenary session here at the 2021 American Society for Radiation Oncology annual meeting.

Aiming to Reduce Toxicity

Ma explained that the impetus for de-escalating radiotherapy is to minimize side effects. Standard treatment can have serious and potentially life-altering side effects, he said, and can have significant impact on patient mental and financial well-being. “For example, after treatment about half of head and neck cancer patients experience some sort of depression. And on average they require 14 weeks before they can resume work.”

His group had previously conducted a phase 2 clinical trial (MC1273) that evaluated a de-escalated regimen of 30-36 Gy adjuvant radiation therapy for selected patients with HPV positive OPSCC. The results showed a 2-year overall survival of 98.7%, 2-year locoregional control (LRC) of 96.2%, and 2 year progression-free survival of 91.1%.

Based on these findings, the team then went ahead with the current phase 3 trial, MC1275, which included 194 patients.

The median age within this cohort was 59.4 years, and 59% had ENE-positive disease. All patients underwent transoral robotic surgery (TORS) and neck dissection for a margin-negative resection and were then randomly assigned to either DART or standard of care.

The DART regimen consisted of docetaxel 15 mg/m2 on days 1 and 8, and patients with intermediate-risk disease received 30 Gy/1.5 Gy twice daily, while those with ENE positive disease received 36 Gy/1.8 Gy twice daily.

Standard of care was 60 Gy with or without cisplatin.

As noted above, the DART group had significantly fewer grade 3 or higher adverse events. They also had superior swallowing function (median modified barium swallow impairment score -0.3 vs -2.6, P = .0155) and less pain (EORTC-HN pain score was -8.6 vs 2.5), and also fewer problems with dry mouth (University of Michigan Xerostomia QOL Scale was 2.9 vs 11.7 (P = .0001).

Clinical outcomes were similar in the two groups. The 2-year overall survival for DART was 96.1% vs 97.0% for standard of care. Among patients with ENE-negative disease, the rates were 100% vs 90.9% for standard care, but the rates for patients with ENE-positive disease were 93.4% for DART vs 100% for standard care.

For progression-free survival, the rate at 2 years was 86.5% vs 95.1%, and similar for ENE-negative patients (97.6% vs 93.3%). However, 2-year progression-free survival was only 78.9% in the DART arm for patients in the ENE positive disease group, compared with 96.2% among the group receiving standard of care. The rate in the DART group was largely driven by the pN2 cohort, Ma explained.

Among patients with pN2 disease, progression-free survival was only 42.9% in DART group vs 100% for standard of care patients.

“Caution is advised for de-escalating ENE-positive patients, particularly those with pN2 disease,” Ma said.

Remaining Questions

Ma noted that it was still unclear how durable these results will be. He commented that the 5-year results from the earlier phase 2 trial (MC1273) suggest that “they are durable but only time will tell.”

He also noted that it’s unclear if these results are generalizable outside of the Mayo clinic, where this trial was conducted. “We had no grade 5 bleeds, which is different from other institutions, a 3.2% post-TORS intervention rate, and no trial requirement for tracheostomy,” said Ma. “Whether this is widely applicable, again remains to be seen. However, a private practice group has prospectively investigated the DART regimen and we await those results.”

Another question is whether the de-escalation strategy can be tailored based on biologic factors such as circulating tumor DNA.

“Overall, DART demonstrated less toxicity, improved swallowing function and quality of life when compared to standard of care,” he concluded. “DART also had excellent LRC, profession-free and overall survival rates, particularly in the ENE negative cohort.”

Promise and Peril

These new results illustrate “both the promise and peril of treatment reduction in the management of this disease,” commented Thomas J. Galloway, MD, Chief, Division of Head and Neck Radiation Oncology at Fox Chase Cancer Center, Philadelphia, Pennsylvania. He was not involved in this trial and was approached for comment.

“Patients with intermediate risk disease did well with 30Gy plus docetaxel and presented data confirms that this dose reduction resulted in both patient-reported and objective symptom reduction. This is very promising,” he said. “However patients with high-risk disease, who made up more than half of the cohort, had a significantly worse 2-year progression free survival with 36Gy plus docetaxel secondary to poor outcomes seen in patients with both high metastatic node number and ENE.”

Galloway added that “better mechanisms to predict ENE preoperatively are needed as those patients may not be good candidates for a surgical de-intensification treatment regimen.”

Ma has disclosed no relevant financial relationships. Galloway has served on an advisory board for Naveris.

American Society for Radiation Oncology (ASTRO) 2021 Annual Meeting: Abstract LBA-1. Presented October 25, 2021.

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