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CHICAGO -- Lower-dose radiotherapy plus concurrent chemotherapy bested radiotherapy alone in the HN002 trial, which tested two treatment de-escalation strategies for low-risk human papillomavirus (HPV)-positive head and neck cancer.

Among 306 patients in the phase II study who were mostly non-smokers, those assigned to lower-dose intensity-modulated radiotherapy (IMRT) plus weekly cisplatin had a 2-year progression-free survival (PFS) of 90.5%, as compared with 87.6% in the group treated with IMRT alone, reported Sue Yom, MD, PhD, of the University of California San Francisco.

For swallowing-related quality of life on the 100-point MD Anderson Dysphagia Inventory (MDADI) scale, both arms surpassed the investigators' prespecified threshold, with scores of 85.3 (5.6-point decline from baseline) in the combined modality arm and 81.8 (6.2-point decline) in the radiation-alone arm.

"The IMRT with weekly cisplatin arm met the acceptability criteria for both the PFS -- 2-year progression-free survival -- and 1-year MDADI co-primary endpoints. The accelerated IMRT arm did not meet the PFS acceptability criterion," Yom said during the plenary session here at the American Society for Radiation Oncology (ASTRO) meeting.

"It was fundamentally a study of de-escalation versus de-escalation ... and de-escalation won," said ASTRO discussant Beth Beadle, MD, of Stanford University Medical Center in California. "These patients are doing exceedingly well, with overall survivals exceeding 96%-97%, low rates of locoregional failure, and impressive toxicity scores."

At 2 years, local recurrence rates were 3.3% in the concurrent chemoradiation group and 9.5% with radiation alone. Distant metastasis rates were 4.0% and 2.1%, respectively. Both arms received radiation at a dose of 60 Gy -- current standard of care is 70 Gy with concurrent cisplatin.

Beadle highlighted how for the past 20 years its been known that HPV-positive oropharyngeal cancer patients have far superior outcomes. But as these patients will live longer, attempts have been made to reduce long-term adverse effects of treatment effects -- either by reducing the chemotherapy or radiation dose, or by reducing both -- while maintaining optimal outcomes.

"There have been a lot of approaches to de-escalation," she said, and pointed in particular to the recent RTOG 1016 findings. At last year's ASTRO meeting, the phase III study showed that a de-escalation attempt of using cetuximab (Erbitux) in place of cisplatin failed to reduce toxicity and led to worse PFS and overall survival in a broader group of HPV-positive oropharynx patients (namely it included patients with a smoking history).

"So what is the best treatment for patients with low-risk oropharynx cancer?" Beadle asked. "Standard of care is standard of care, we do not have phase III data supporting de-escalation off protocol."

"We always get these questions from people, whether they should be de-escalating treatment for their head and neck cancer patients who have HPV-positive oropharynx cancer, and the answer is no, you shouldn't," Nikhil Joshi, MD, of the Cleveland Clinic, told 木瓜直播. "Certainly accrue on institutional protocols or accrue to national studies -- that's the way we will answer these questions definitively in the most scientific manner."

from the American Society of Clinical Oncology has also cautioned that de-intensification should only be undertaken in a clinical trial setting.

"You have to be very careful when you're de-escalating therapy," said Joshi. "You don't want to compromise the oncologic cure."

Beadle pointed out that ahead of their treatment, the top priority for patients with head and neck cancer is cure. And this remains their top goal even when enduring acute treatment-related toxicities, but a tipping point occurs years later where decisional regret becomes proportional to a patient's level of long-term side effects.

"But I would like to caution that our first chance to cure these patients is our best chance," she said. "While cure rates and toxicity are things we need to balance at initial diagnosis, those rates pale in comparison to the rates that we have at recurrence."

De-intensification will march on in the phase II/III HN005 trial, which will compare standard of care against two investigational strategies -- IMRT at 60 Gy plus cisplatin, or IMRT plus the immunotherapy nivolumab (Opdivo).

In a slight shift from the winning arm of the current trial, which tested weekly cisplatin, HN005 will use standard every-3-week cisplatin at 100 mg/m² for the first of its de-escalation arms. "We kept parallelism of the chemotherapy from RTOG 1016," Yom told 木瓜直播. "It is more appropriate since we are using that study as the control arm, and we want to isolate one variable."

HN002 randomized 306 oropharyngeal squamous cell carcinoma patients with T1-T3 disease to either weekly 40 mg/m² cisplatin plus IMRT at 60 Gy over 6 weeks, or to IMRT alone. In the chemotherapy arm, 73% of patients were able to reach a total dose of cisplatin of 200 mg/m². Patients enrolled all had smoking histories of ≤10 pack-years (70% were non-smokers).

Acute grade 3/4 events were less frequent in the IMRT alone arm (52% vs 80% in the combined modality arm) while late grade 3/4 events were similar (18.1% vs 21.3%). Need for feeding tubes spiked toward the end of radiotherapy and declined to less than 5% at 6 months post-treatment. The combined arm had lower feeding tube rates at study end.

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