Deintensified treatment involving a lower radiation dose and immunotherapy in place of chemotherapy may not perform as well as a more rigorous chemoradiation treatment approach in patients with early-stage human papillomavirus (HPV)-associated oropharyngeal cancer, according to new findings presented by Yom et al at the 2024 American Society for Radiation Oncology (ASTRO) Annual Meeting (Abstract LBA03) and simultaneously published in the International Journal of Radiation Oncology • Biology • Physics.
Background
In the United States, an estimated 70% or more of newly diagnosed cases of oropharyngeal cancer are caused by HPV, and incidence rates of HPV-associated disease are currently increasing in most developed nations, including the United States. HPV-associated oropharyngeal cancer is the most common HPV-related cancer among men and the second most common among women following cervical cancer.
Patients diagnosed with HPV-associated oropharyngeal cancers tend to be younger, with an average age of 55 years at diagnosis in the United States, and typically have better outcomes compared with those diagnosed with tobacco- or alcohol use–associated throat cancer.
Radiation therapy is an especially effective treatment option for tumors caused by HPV, which are more radiosensitive. This type of therapy can be administered as stand-alone treatment or in combination with systemic therapy and/or surgery; however, many patients experience severe side effects during treatment, and some also experience long-term side effects from chronic inflammation and tissue damage that can arise up to 2 decades later, including difficulty swallowing or recurring infections of the soft tissue in the mouth and throat.
Sue S. Yom, MD, PhD, FASTRO
“Now that our chemoradiation treatments have improved to this point, we have a substantial number of patients surviving for longer durations, and we are starting to understand their experiences at very late follow-up,” explained lead study author Sue S. Yom, MD, PhD, FASTRO, the Irwin Mark Jacobs and Joan Klein Jacobs Distinguished Professor in Head and Neck Cancer Radiation Oncology at the University of California, San Francisco. “The new challenge when treating these patients is how to keep them healthy and well for 25 or 35 years. We know that there is a minority of these patients who will have negative effects many years later,” she added.
Study Methods and Results
In the phase II/III NRG Oncology HN005 trial, researchers randomly assigned 382 patients with HPV-associated locoregionally advanced oropharyngeal squamous cell carcinomas to one of three treatment arms: usual radiation dosing at 70 Gy total mildly accelerated over 6 weeks combined with cisplatin chemotherapy, reduced radiation dosing at 60 Gy total over 6 weeks combined with cisplatin chemotherapy, or reduced radiation dosing at 60 Gy total mildly accelerated over 5 weeks combined with the immunotherapy agent nivolumab in place of chemotherapy. All of the patients received intensity-modulated radiation therapy, 90.6% of them were male, 87.5% of them were White, and 79.4% of them were never-smokers.
“In very rigorous testing, those experimental arms did not produce equivalent results to the control arm. The experimental arms were close to meeting their expected goals, but the patients treated [in] the control arm had such incredible results that we had an ethical responsibility to halt the study. I believe we have to take stock of this new benchmark and that new trial designs for this disease will need to account for this result,” Dr. Yom emphasized.
The trial was designed to trigger a futility analysis for each experimental arm after a predetermined number of patients experienced disease progression. These tests showed that neither de-intensified treatment approach met the threshold for noninferiority compared with the standard treatment. After a median follow-up of 2.2 years, the researchers found that the patients in the control arm reached a 2-year progression-free survival rate of 98.1% compared with 88.6% among the patients in the reduced radiation with chemotherapy arm and 90.3% among the patients in the reduced radiation with immunotherapy arm. The 2-year overall survival rates were 99%, 98% and 96.1%, respectively. As a result, the trial was closed early.
“In cancer treatment, 98% progression-free survival at 2 years is a number you just don’t see. It’s the highest that has ever been published in the literature for head and neck cancer, and in and of itself, it is strong evidence that modern chemoradiation therapy is highly effective for these patients. Deintensification of chemoradiation treatments for HPV-associated oropharyngeal cancers is of very high interest to patients and researchers, but our study makes clear that these approaches should remain very experimental. Further work needs to be done to find ways that we can reduce side effects while maintaining these extremely high cure rates,” Dr. Yom suggested.
Conclusions
“I think this study is a good reminder that patients with this disease have really outstanding cure rates after we treat them with contemporary chemoradiation. At this point, neither of the deintensification options we tested would be appropriate for standard of care use because you would actually be changing some patients’ chance for a cure,” Dr. Yom underscored. “This remains a work in progress, however. Most patients diagnosed with HPV-positive oropharyngeal cancer have a very long life trajectory ahead of them. As researchers, our focus now should be on identifying which patients can benefit from these newer paradigms and then finding a more personalized therapy that works for each of these different groups of patients. The future goal would be that each patient gets what they need, but no more than what they need,” she concluded.
Disclosure: The research in this study was supported by funding from the National Cancer Institute and Bristol Myers Squibb. For full disclosures of the study authors, visit astro2024.eventscribe.net and redjournal.org.
