Redefining “High Risk” for Patients With Cutaneous Squamous Cell Carcinoma of the Head and Neck
Emma Connolly, MB, BCh, BAO, St Luke’s Radiation Oncology Centre, St James’s Hospital, Dublin, Ireland, discusses an analysis that better defined the high-risk features among patients with cutaneous squamous cell carcinoma (cSCC) of the head and neck. When defined by extranodal involvement and nodal burden, this high-risk subgroup had an inferior disease-free survival (DFS) following postoperative radiotherapy with or without concurrent chemotherapy.
Dr Connolly concluded, “Recognizing this group will be critical in shaping the future adjuvant strategies for cutaneous squamous cell carcinoma of the head and neck.”
Transcript:
Hello. My name is Dr Emma Connolly. I'm a consultant radiation oncologist at St. Luke's Network in Dublin, and a former clinical research fellow at Peter McCallum Cancer Center at Melbourne, Australia. Today, I'm going to be presenting some of our recent work from Australia published in JAMA Otolaryngology Head and Neck Surgery, as well as being presented at this year's ESTRO Conference, titled, Prognostic Subgroups for Disease-Free Survival in Cutaneous Squamous Cell Carcinoma of the Head and Neck: A secondary analysis of the TROG 05.01 trial.
As we know, cutaneous squamous cell carcinoma is one of the most common skin cancers we have, and although most cases are cured with surgery alone, approximately 5% will present with high-risk features that require adjuvant therapies. The TROG 05.01 trial, more commonly known to us as the POST trial, was a landmark phase 3 study that demonstrated adding chemotherapy to postoperative radiotherapy did not improve outcomes in high-risk cases defined at the time. In this trial, the disease-free survival at 3 years of 74%. This was a little higher than expected across both groups, suggesting that the defined risk features in the study, based on the available evidence at the time, may not have truly identified a very high-risk population.
The primary purpose of this TROG-approved secondary analysis was to identify a subgroup who demonstrated an inferior disease-free survival despite postoperative radiotherapy with or without concurrent chemo. The original trial enrolled 321 patients with advanced cutaneous squamous cell carcinoma of the head and neck across multiple sites in Australia. To carry out the secondary analysis and to identify these prognostic subgroups, we used a statistical method called recursive partitioning analysis. This method that essentially just tests all the ways to split patients based on clinical and pathological factors and selects the split that best separates patient outcomes. The process repeats until no better split is possible, or the groups just become too small. We first built a full decision tree using a complexity parameter of 0.005, meaning the split had to improve our model by at least 0.5% to be accepted. To prevent the tree from becoming too complex and overfitting the data, we pruned it using cross-validation. We used this data to identify our high-risk features and to estimate the disease-free survival and overall survival outcomes for each group, using a Cox model and Kaplan-Meier analysis.
The analysis revealed a clearly defined high-risk subgroup. Patients with extranodal extension and at least one node greater or equal to 22 mm in size were found to represent a truly high-risk subgroup for inferior disease-free survival. The high-risk group, which was made up of 88 patients, had significantly worse outcomes: their 5-year disease-free survival at 56% compared to 75% in the non–high-risk group. Again, their overall survival was similarly poor, 59% versus 85% in the non–high-risk group. Looking at the hazard ratios that compare the two, the high-risk patients were found to have twice the risk of recurrence and more than triple the risk of death compared to the others.
The findings have a direct clinical implication and suggest that risk stratification really should go beyond broad high-risk definitions. Instead, we can really refine our selection criteria to identify those patients who are most likely to benefit from treatment intensification. These results helped to define the eligibility criteria for the recently published phase 3 C-POST trial, which evaluated of adjuvant immunotherapy in this setting. This work really ensures that future trials are focused on those patients who benefit from further therapy the most.
In summary, this secondary analysis of the TROG 05.01 trial demonstrates that extranodal extension and a nodal size of greater or equal to 22 mm truly identify a subgroup of patients who have particularly poor outcomes, despite standard therapies. Recognizing this group will be critical in shaping the future adjuvant strategies for cutaneous squamous cell carcinoma of the head and neck. Thank you for your attention.
Source:
Porceddu SV, Connolly E, Bressel M, et al. Prognostic subgroups for disease-free survival with cutaneous squamous cell carcinoma of the head and neck: A secondary analysis of a randomized clinical trial. JAMA Otolaryngol Head Neck Surg. Published on August 28, 2025. doi: 10.1001/jamaoto.2025.2110
