Low-dose radiation after transoral resection effective in HPV-related oropharynx cancer
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Transoral resection followed by low-dose radiation appeared safe and effective for patients with p16-positive oropharynx cancer, according to results of a randomized phase 2 trial presented during the ASCO20 Virtual Scientific Program.
Two-year PFS appeared favorable without postoperative therapy among patients with low-risk disease, results showed.
Reduced-dose postoperative radiotherapy without chemotherapy appeared sufficient for patients with uninvolved surgical margins, less than five involved nodes and minimal extranodal extension.
Transoral surgery in combination with 50 Gy radiation should be compared with optimal nonsurgical therapy in future phase 3 trials, Robert L. Ferris, MD, PhD, FACS, director of UPMC Hillman Cancer Center, Hillman professor of oncology and associate vice chancellor for cancer research at University of Pittsburgh, and colleagues concluded.
Between December 2013 and July 2017, surgeons performed transoral resection on 519 patients with stage III to stage IV oropharynx cancer without matted neck nodes. They determined postoperative management based on pathologically assessed risk.
Among 353 treated patients eligible for the study, 37 with low-risk disease — defined as clear margins, no more than one involved node and no extranodal extension — underwent observation. The 110 eligible patients with high-risk disease — defined as extranodal extension greater than 1 mm, more than four positive nodes and/or positive margins — received usual radiation therapy (60-66 Gy) with weekly cisplatin dosed at 40 mg/m2.
Ferris and colleagues randomly assigned the 206 eligible patients with intermediate risk — defined as clear/close margins, two to four positive nodes, or extranodal extension of 1 mm or less — to 50 Gy radiation (n = 102) or 60 Gy radiation (n = 104) without chemotherapy.
Researchers stratified intermediate-risk patients by smoking history. They reported the primary endpoint of 2-year PFS for patients randomly assigned to 50 Gy vs. 60 Gy radiation.
Median follow-up was 31.8 months.
Results showed 2-year PFS of 93.9% (90% CI, 87.3-100) for patients in the observation group, 95% (90% CI, 91.4-98.6) in the 50 Gy group, 95.9% (90% CI, 92.6-99.3) in the 60 Gy group and 90.5% (90% CI, 85.9-95.3) in the combination group.
Seven of the 17 progression events that occurred were locoregional. Researchers observed 10 distant recurrences. These included one in the observation group, two in the 50 Gy group, four in the 60 Gy group and three in the combination group.
Two treatment-related deaths occurred — one during surgery and one in the combination group. Additionally, grade 3 treatment-related adverse events occurred among 15% of patients during surgery, 13% of patients in the 50 Gy group and 25% of patients in the 60 Gy group.
Perspective
Back to TopWilliam A. Stokes, MD, and Walter J. Curran Jr., MD
Many patients with newly diagnosed HPV-driven locoregionally advanced oropharyngeal cancer confront a difficult choice: stick with the historical standard of organ preservation via definitive chemoradiotherapy or pursue an upfront surgical approach in the hope of reducing the intensity of adjuvant therapy.
The younger age and favorable prognosis of these patients have motivated efforts to reduce the toxicity of their treatment. Advocates of deintensification will derive new enthusiasm from the ASCO20 Virtual Scientific Program, which included presentation of ECOG-ACRIN E3311, a prospective clinical trial of patients managed with upfront transoral surgery and neck dissection.
Researchers randomly assigned patients with intermediate-risk pathologic factors to either 50 Gy or 60 Gy of adjuvant radiation without systemic therapy. Encouragingly, PFS rates at 2 years from postsurgical registration appeared comparable between these two groups, at 95% and 95.9%.
These are important results for the head and neck oncology community; however, careful consideration of the presented data brings to light some details that warrant further attention.
First, a variety of features qualified patients for randomization. The presence of any of the following six factors could place a patient in the intermediate-risk group:
- close (3 mm or smaller) primary surgical margin;
- perineural invasion;
- lymphovascular invasion;
- any involved lymph node of greater than 3 cm extent;
- two to four involved lymph nodes; or
- minimal (1 mm or smaller) extracapsular extension (ECE).
Given this panoply of qualifying features, it comes as no surprise that over half (58%) of the final cohort was assigned to the intermediate-risk group. Although this allocation produced a sizeable cohort for randomization, the inherent heterogeneity undermines the internal validity of the analysis.
Consider an extreme comparison between a patient with a single intermediate-risk factor and another patient with all six. One would expect the latter to be at higher risk for recurrence; however, the design of this trial would lump both patients into the same intermediate-risk group.
Moreover, the individual contribution of each of the six factors to recurrence risk is unclear in HPV-driven oropharyngeal cancer, and the interplay among their potential combinations further complicates risk assessment.
Ultimately, the effect observed in the overall intermediate-risk group may not represent the effect in the individual patient, especially for those with risk factor profiles poorly represented in the cohort. Some patients with intermediate risk may benefit from treatment intensification, either from higher doses of radiotherapy or from the addition of systemic therapy, whereas others may experience comparable oncologic outcomes despite further reduction or even elimination of adjuvant radiation.
Hopefully, this and other prospective studies of surgical patients will enable us to further refine risk stratification. These insights may allow subclassification of the intermediate-risk group, as used in prostate or endometrial cancer, and permit oncologists to tailor adjuvant therapy accordingly.
Another detail about a different group in this trial warrants special consideration. It is disheartening that nearly one-third (31%) of the final cohort fell into the high-risk group, defined by any single factor among a positive primary surgical margin, more than four involved lymph nodes or greater than 1 mm ECE.
These unfortunate patients, having already received transoral surgery and neck dissection, proceeded to adjuvant chemoradiotherapy of 66 Gy with cisplatin, ultimately receiving trimodality therapy. A growing body of evidence indicates that these patients could expect comparable oncologic outcomes, reduced toxicity and better quality of life with organ preservation. Of course, it is easy to argue with the benefit of hindsight that organ preservation would have been the preferred option for these patients, and preoperative prediction of postoperative pathologic features is fraught with challenges. This conundrum underscores the importance of counseling patients who are considering an upfront surgical approach about their 3-in-10 risk for having indications for treatment intensification. Data from studies such as E3311 may inform the use of clinical features to predict pathologic endpoints and facilitate patient selection.
This brings us to a final detail. While studies such as E3311 explore strategies to deintensify adjuvant therapy, trials are simultaneously evaluating deintensification strategies in organ preservation.
NRG HN005, for example, is currently randomly assigning patients to the current standard of full-dose chemoradiotherapy vs. one of two deintensified strategies with reduced-dose radiation. Other investigators are employing “harm-minimization” techniques, such as highly conformal radiotherapy modalities (including proton therapy) or adaptive treatment based on radiographic or metabolic response. Innovations in adjuvant therapy, therefore, are not taking place in isolation but in parallel with those in organ preservation.
Ultimately, despite the useful information E3311 provides for head and neck oncologists and patients, the choice between upfront surgery and organ preservation remains as difficult as ever. The results of randomized trials comparing deintensified forms of these two approaches, such as ORATOR2 (NCT03210103), are eagerly anticipated.
William A. Stokes, MD
Emory University
Walter J. Curran Jr., MD
Winship Cancer Institute of Emory University
Cancer Woodruff Health Sciences Center
Emory University School of Medicine
HemOnc Today Editorial Board Member
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Ferris RL, et al. Abstract 6500. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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