De-escalated adjuvant radiotherapy appears to be safe in patients with surgically resectable, human papillomavirus (HPV)--positive oropharyngeal cancers, particularly in patients without extranodal extension or pN2 disease by American Joint Committee on Cancer (AJCC) 8th edition. These findings from the phase III MC1675 trial were presented at the 2021 American Society for Radiation Oncology (ASTRO) Annual Meeting.1
“De-escalated adjuvant radiation therapy led to less toxicity, improved swallowing function, and quality of life when compared with the standard of care,” stated Daniel J. Ma, MD, of the Mayo Clinic, Alix School of Medicine, Rochester, Minnesota, and winner of the 2021 Steven A. Leibel Memorial Award. “De-
Daniel J. Ma, MD
escalated adjuvant radiation therapy also led to excellent local control, progression-free survival, and overall survival, particularly in the cohort without extranodal extension. The results of the phase III MC1675 randomized trial, however, suggest that caution is advised in de-escalation for patients with pathologic N2 disease. Future studies will define risk groups that may not require adjuvant care as well as the role of systemic intensification for groups at risk for distant disease.”
Although cure rates for HPV-positive oropharyngeal cancers are high, standard radiation therapy can have significant life-altering side effects, including dry mouth, taste alterations, difficulty swallowing, neck stiffness, and mandible problems.
“Some patients [treated with standard radiation therapy] require on average 14 weeks after radiation therapy before returning to work. Radiation therapy can have an impact on patients’ mental and financial well-being. Because of these toxicities, we seek to de-escalate radiation therapy,” Dr. Ma explained.
Phase II Trial of Shorter Schedule of Radiation Therapy
A previously reported phase II trial by Dr. Ma and his colleagues at the Mayo Clinic focused on a shorter radiation schedule in patients with surgically resectable, HPV-positive oropharyngeal cancers with negative margins (MC1273 trial).2 Patients received 30 to 36 Gy of adjuvant radiation therapy delivered over 2 weeks. Cohort A included intermediate-risk patients who were treated with 30 Gy in 1.5 Gy twice-daily fractionation delivered over 2 weeks plus docetaxel at 15 mg/m2 weekly. Cohort B, which included high-risk patients with extranodal extension, received the same radiation course and docetaxel as cohort A plus a radiation boost to the nodal area containing extranodal extension. Patients were observed for 5 years.
The 2-year overall survival was 98.7%, the 2-year locoregional control was 96.2%, and the 2-year progression-free survival was 91.1%. “Based upon these findings, we embarked on MC1675 to compare the shorter course of radiation therapy vs the standard 6-week course,” he said.
MC1675 Trial Details
The MC1675 trial enrolled 194 patients with oropharyngeal HPV-positive squamous cell cancer. The design was similar to that of MC1273, except patients were excluded if they had pathologic T4 disease or required more than two excisions to clear a margin edge. Smoking was a stratification factor.
Cohort A included 79 intermediate-risk patients randomly assigned 2:1 to receive adjuvant de-escalated adjuvant radiation therapy vs the standard of care. Cohort B included 115 high-risk patients with extranodal extension randomly assigned 2:1 to receive adjuvant de-escalated adjuvant radiation therapy vs the standard of care.
The primary endpoint was grade 3 or higher adverse events 3 months or more after radiation therapy. Swallow evaluation was done before radiation therapy and at 1 month and 1 year after radiation therapy. Quality of life was evaluated using the Functional Assessment of Cancer Therapy–Head and Neck (FACT-HN), EORTC Quality-of-Life H&N35, and the -University of Michigan Xerostomia Quality-of-Life Scale before radiation therapy as well as 1, 3, 12, and 24 months after radiation therapy.
Patients were accrued between 2016 and 2020. Median patient age was 59.4 years, and 89% were male, which Dr. Ma said was “congruent with typical patients who have HPV-positive oropharyngeal cancer.” A total of 72% were non-smokers. Median follow-up was 25.3 months. One patient was lost to follow-up.
Regarding disease characteristics, most patients (88.5%) had T1 or T2 disease; 11.9% had T3 disease discovered at surgery. Most patients (84.5%) had N1 disease; 12.9% had N2 disease.
“No discussion can go forward without discussing possible toxicities associated with surgery plus radiation therapy. Some data suggest excess mortality with a surgically oriented de-escalation strategy. This has not been our experience at the Mayo Clinic,” Dr. Ma noted.
There were no grade 5 postoperative events. Postoperative bleeding occurred in 3.2%, most of which was venous bleeding stopped by cautery. “In context, this is a lower bleeding rate than after common pediatric tonsillectomy, where the bleeding rate is 3.5%,” mentioned Dr. Ma.
Radiation-related side effects were more common with the standard of care; 1.6% of the de-escalated adjuvant radiation therapy group vs 27.4% of those given the standard of care required a feeding tube (P < .0001). The rates of grade 3 or higher adverse events at 6 months were 1.6% with de-escalated adjuvant radiation therapy and 7.1% with the standard of care (P = .058).
Formal swallowing function after radiation therapy was superior in the arm given de-escalated adjuvant radiation therapy. Patients had higher quality-of-life scores, less pain, and less xerostomia with de-escalated adjuvant radiation therapy. De-escalated adjuvant radiation therapy was significantly superior to the standard of care on the scores of the following instruments: FACT-HN: 5.1 vs 3.2 (P = .0007); EORTC Quality of Life H&N35: 8.6 vs 2.5 (P = .0009); Xerostomia Quality-of-Life Scale: 2.9 vs 11.7 (P = .0001).
Overall survival was 96.1% for patients given de-escalated adjuvant radiation therapy and 97% for those given the standard of care. When broken down by cohorts A and B, it was apparent that patients without extranodal extension reaped a greater benefit from de-escalated adjuvant radiation therapy than did patients with extranodal extension. The 2-year overall survival was 100% with de-escalated adjuvant radiation therapy and 90.9% with the standard of care for patients without extranodal extension and 93.4% vs 100%, respectively, for patients with extranodal extension.
Regarding locoregional control, the 2-year recurrence-free survival rates were 95.5% with de-escalated adjuvant radiation therapy and 97.9% with the standard of care. By cohort, in patients without extranodal extension, the rate was 100% vs 93.3%, respectively; for patients with extranodal extension, the rate was 92.2% vs 100%, respectively.
Progression-free survival was 86.5% with de-escalated adjuvant radiation therapy and 95.1% with the standard of care. By cohort, the 2-year progression-free survival rates were 97.6% with de-escalated adjuvant radiation therapy and 95.3% with the standard of care in patients without extranodal extension. For patients with extranodal extension, the 2-year progression-free survival rates were 78.9% with de-escalated adjuvant radiation therapy and 96.2% with the standard of care.
Digging deeper into the data, “extranodal extension positivity does not tell the entire story [of progression-free survival],” Dr. Ma told listeners. “Extranodal extension and one outlier contributed to the progression-free survival events.”
For more on the comparison of longer and shorter courses of radiotherapy for HPV-associated oropharyngeal carcinoma, see an interview with Daniel J. Ma, MD, on The ASCO Post Newsreels at ascopost.com/videos.
The outlier was AJCC 8 stage pN2 disease. Patients with extranodal extension who had N2 tumors had a 2-year progression-free survival of 42.9% with de-escalated adjuvant radiation therapy. “The majority of events were distant metastases, although there was also some associated with locoregional failure,” he stated.
Based on the results of this phase III trial, the Mayo Clinic has adopted de-escalated adjuvant radiation therapy as a standard of care for well-selected patients. However, ongoing questions include the durability of these results and whether they are generalizable outside of the Mayo Clinic.
“Another question is can we tailor a de-escalation strategy based more on biologic factors. The follow-up clinical trial is in development,” Dr. Ma stated.
DISCLOSURE: Dr. Ma reported no conflicts of interest.
1. Ma DJ, Price K, Moore EJ, et al: MC1675, a phase III evaluation of de-escalated adjuvant radiation therapy (DART) vs standard adjuvant treatment for human papillomavirus associated oropharyngeal squamous cell carcinoma. 2021 ASTRO Annual Meeting. Abstract LBA-1. Presented October 25, 2021.
2. Ma DJ, Price K, Moore EJ, et al: Two-year results for MC1273, a phase 2 evaluation of aggressive dose de-escalation for adjuvant chemoradiation in HPV+ oropharynx squamous cell carcinoma. Int J Radiat Oncol Biol Phys 99:P1320, 2017.
“MC1675 is an important and exciting trial,” stated invited discussant Farzan Siddiqui, MD, PhD, of the Henry Ford Cancer Institute, Detroit. “Congratulations to the authors and to Dr. Ma for his award.”
Farzan Siddiqui, MD, PhD
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