Two studies presented at the 2024 Multidisciplinary Head and Neck Cancers Symposium added support for the deintensification of radiotherapy in early-stage oropharyngeal squamous cell cancers associated with the human papillomavirus (HPV), a subtype typically more responsive to therapy compared to tumors not related to HPV. The nonrandomized studies showed the toxicity commonly associated with standard radiotherapy may be ameliorated by lower radiation doses without compromising oncologic outcomes.
Investigators from Washington University School of Medicine, St. Louis, showed that de-escalated postoperative adjuvant therapy (radiotherapy alone or with chemotherapy) for patients with HPV-associated squamous cell oropharyngeal cancer deemed not at high risk led to significantly less weight loss than conventional treatment and resulted in a 4-year progression-free survival rate of 90%.1 The long-term efficacy results of the nonrandomized phase II MINT trial were presented at the meeting by Wade L. Thorstad, MD, Professor of Radiation Oncology and Chief, Head and Neck Cancer Service, Washington University School of Medicine, St. Louis.1
“We are looking at a future trial to increase the confidence with the arm 1 [de-escalated chemoradiotherapy approach] and perhaps at randomly assigning patients from arm 2 to an even lower radiotherapy dose.”— Wade L. Thorstad, MD
Tweet this quote
In the second nonrandomized study, investigators from the University of Michigan, Ann Arbor, used a risk-based strategy to deintensify radiotherapy from 70 Gy to 54 Gy in patients who had an early response to chemoradiotherapy, based on midtreatment assessment by fluorodeoxyglucose/positron-emission tomography (FDG-PET). These phase II results were presented by Samuel N. Regan, MD, a resident in radiation oncology at the University of Michigan, Ann Arbor.2
About the MINT Study
The MINT trial enrolled 58 patients with clinical stage I–III, HPV-positive oropharyngeal squamous cell carcinoma (or with a positive neck node with an unknown primary) who underwent surgery and selective neck dissection. Then, 54 patients were then stratified by pathologic risk into one of the following three treatment arms based on pathology:
- Arm 1: high-risk pathology (extranodal extension and/or positive margins): De-escalated postoperative adjuvant chemoradiotherapy with cisplatin at 100 mg/m2 for one dose plus 42 Gy of radiotherapy over 21 fractions (n = 20)
- Arm 2: intermediate-risk pathology (lymphovascular invasion, perineural invasion, at least two positive nodes, at least one positive node → 3 mm, T3 or N2 disease): De-escalated postoperative adjuvant radiotherapy with 42 Gy over 21 fractions (n = 30)
- Arm 3: highest-risk pathology (cT3–pT4): Standard-of-care treatment with cisplatin at 100 mg/m2 for three doses plus 60 Gy of radiotherapy delivered concurrently (n = 4).
Dr. Thorstad reported the results of the two experimental arms involving de-escalated chemoradiotherapy (arm 1) and de-escalated radiotherapy (arm 2). The primary hypothesis was that de-escalated treatment would result in less weight loss, which is a quantitative surrogate of the severity of mucositis. Recurrence rate, progression-free survival, and overall survival were also endpoints. The recurrence rate was deemed acceptable if the 95% upper limit of the confidence interval (CI) was ≤ 20%.
Results With De-escalation
The mean percent weight loss during de-escalated postoperative adjuvant chemoradiotherapy was significantly less than in a similar historical cohort treated conventionally: 4.9% vs 7.4% (P = .0003). The mean percent weight loss during de-escalated radiotherapy was 3.18%, Dr. Thorstad reported.
At a median follow-up of 50 months, there were 2 recurrences (distant alone) in the 20 patients in arm 1 (de-escalated chemoradiotherapy) at 12 and 19 months after treatment. There was one recurrence (both regional and distant) in the 30 patients in arm 2 (de-escalated radiotherapy) at 22 months. The one death in arm 2 was a patient known to be disease-free 3 months earlier, he added.
Samuel N. Regan, MD
These events amounted to recurrence rates of 10% in arm 1 (95% CI = 1.2%–31.7%) and 3.3% in arm 2 (95% CI = 0.1%–17.2%). At 4 years, 90.0% and 90.1%, respectively, were progression-free, and 100% and 94%, respectively, were alive. “Note the 95% confidence interval in arm 2 was < 20% as an upper limit [for significance], but we did not achieve that in arm 1, possibly because of the low patient numbers,” Dr. Thorstad commented. “We are looking at a future trial to increase the confidence with the arm 1 [approach] and perhaps at randomly assigning patients from arm 2 to an even lower radiotherapy dose.”
FDG-PET–Guided Deintensification of Radiotherapy
“FDG-PET may be a reliable predictive biomarker to selectively de-escalate the radiation dose in early-stage HPV-positive disease…. There were few locoregional recurrences,” Dr. Regan said.
The study enrolled 89 patients with stage I–II HPV-associated tumors with known avidity on FDG-PET imaging. All patients had a radiation plan for 70 Gy to gross disease and 56 Gy to elective nodal regions, to be given concurrently with carboplatin and paclitaxel. A mid-treatment PET was planned to assess response, which determined additional treatment. Those patients with at least a 50% reduction in metabolic tumor volume stopped treatment at 54 Gy to gross disease, whereas the others completed the entire course of 70 Gy. The primary endpoint was noninferiority of 2-year locoregional recurrence in the entire cohort, compared with an institutional historical control.
Primary Endpoint Met
Of the 84 patients who underwent mid-treatment evaluation, 48 continued to standard therapy, and 36 met criteria for de-escalation. At a median follow-up of 32 months, the study met its primary endpoint, demonstrating a 2-year locoregional recurrence rate of 6.8% for the entire population. By cohort, the 2-year locoregional recurrence rates were 4.6% for patients treated throughout with 70 Gy and 9.4% for those de-escalated to 54 Gy. “Of note, these rates represent only two and three locoregional failures each, respectively. The broad, overlapping confidence intervals preclude any definitive comparison of these two different cohorts,” Dr. Regan said.
KEY POINTS
- De-escalation of radiation has become of great interest in HPV-associated oropharyngeal carcinoma, as many of these patients are frequently overtreated.
- Postoperative adjuvant therapy—both chemoradiotherapy and radiotherapy alone—for HPV-associated squamous cell oropharyngeal cancer may be safely de-escalated using pathology-based risk stratification.
- Mid-treatment response by FDG-PET may be another approach to identifying patients for whom the radiation dose can be reduced.
The 2-year progression-free survival rate was 87% with 70 Gy (four events, one likely treatment-related death) and 84% with 54 Gy (four events). After initial salvage therapy for the eight patients with recurrences (locoregional or distant), three of four treated with 54 Gy have no evidence of disease, and one is still on treatment, whereas with 70 Gy, two of four patients have no evidence of disease, one is on treatment, and one has died.
Weight Loss, Swallowing, and Quality of Life
Median weight loss from baseline to 3 months after radiotherapy was 23 lb in the standard-treatment group and 11 lb in the de-escalated group (P < .001), and the percentages lost were 12.6% and 6.0%, respectively (P < .001). A nasogastric tube was required by 16% and 11%, respectively (P = .5), and there was no appreciable change in the penetration-aspiration scale from baseline in either group.
More Information
For more on the possibility of de-escalating chemo-radiotherapy for HPV-related oropharyngeal cancer, see a joint interview with Samuel N. Regan, MD, and Benjamin Rosen, PhD, on The ASCO Post Newsreels at ascopost.com/videos.
The University of Washington Quality-of-Life Total and Pain Subscale scores as well as the Functional Assessment of Cancer Therapy–Head & Neck Total and Cancer Subscale scores significantly improved at 1 month, above the minimal clinically important difference threshold (0.5 standard deviations), in the de-escalated cohort. Most patients in both cohorts returned to baseline at 1 year.
DISCLOSURE: Dr. Thorstad and Dr. Regan reported no conflicts of interest.
REFERENCES
1. Thorstad WL, Jackson RS, Oppelt P, et al: Long-term efficacy of risk-directed, de-escalated post-operative adjuvant therapy for surgically resected locally advanced, human papillomavirus-positive oropharynx squamous-cell carcinoma: A non-randomized, multi-arm phase 2 trial. 2024 Multidisciplinary Head and Neck Cancers Symposium. Abstract 14. Presented March 1, 2024.
2. Regan SN, Rosen BS, Suresh K, et al: FDG-PET-based selective de-escalation of radiotherapy for HPV-related oropharynx cancer: Results from a phase II trial. 2024 Multidisciplinary Head and Neck Cancers Symposium. Abstract 16. Presented March 1, 2024.
EXPERT POINT OF VIEW
The ASCO Post invited comments on the radiation de-escalation studies from Marshall R. Posner, MD, Director of Head and Neck Medical Oncology and Professor of Medicine, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York. He emphasized that oropharyngeal cancer associated with human papillomavirus (HPV) is highly curable, but current standard-of-care chemoradiotherapy can lead to significant long-term morbidity and late mortality.
Marshall R. Posner, MD
“It’s very clear we are overtreating patients with HPV-positive oropharyngeal carcinoma, and the later consequences of that are extremely concerning. It was heartening to see multiple abstracts at the 2024 Multidisciplinary Head and Neck Cancers Symposium demonstrating growing awareness of the problem. We are beginning to see a broader breadth of studies of different approaches,” commented Dr. Posner.
Among the approaches described at the symposium were less radiation, the use of pathologic features to determine radiation dose, and the use of mid-treatment response by fludeoxyglucose/positron-emission tomography (FDG-PET). Response to induction chemotherapy can also guide [us] to de-escalation, Dr. Posner and his colleagues have reported.1 “I would celebrate all these different ways of looking at response and identifying patients for de-escalation,” he added. “It doesn’t have to be ‘no radiation at all,’ but we can certainly treat patients with significantly less.”
‘Appropriate Level of Treatment’
For HPV-associated tumors, multiple studies affirm that the radiation dose can be lowered in most cases, Dr. Posner emphasized. “What is considered a high-risk factor for someone with a non–HPV-associated tumor is a much lower risk factor for a patient with an HPV-positive tumor,” he noted, adding that in many cases, surgical resection with minimal or no adjuvant therapy will suffice. “I’ve seen many cases in which patients get multimodality therapy when all they need is surgery…. Furthermore, it’s clear from de-escalation studies that we can salvage patients who don’t receive radiation with subsequent chemoradiotherapy and achieve a 95% survival rate…. Once we give radiation, we get long-term consequences and reduce our ability to provide salvage radiation later.”
Dr. Posner also advocated for designing “appropriate studies that directly address the issue of de-escalation and that use treatments with a biological foundation.” He explained: “It’s important to recognize that radiation, chemotherapy, and surgery can be looked at as ‘different drugs,’ just as we use pharmacology in combination chemotherapy, optimizing outcomes and reducing morbidity by combining treatments with nonoverlapping toxicities…. The whole point is to give the appropriate level of treatment.”
DISCLOSURE: Dr. Posner reported no conflicts of interest.
REFERENCE
1. Posner MR, Botzler J, Takahashi M, et al: The Quarterback trials: Phase 2 series of sequential studies of induction chemotherapy and reduced dose chemoradiation for human papillomavirus positive oropharynx cancer. 2023 ASCO Annual Meeting. Abstract 6020. Presented June 5, 2023.
