ABSTRACT
Background
The standard‐of‐care for advanced periauricular cutaneous squamous cell carcinoma (pCSCC) is surgery and adjuvant radiation therapy. Neoadjuvant immunotherapy recently demonstrated high pathologic response rates in patients with resectable pCSCC.
Methods
This retrospective review was conducted at a tertiary cancer center and included patients with pathologically confirmed pCSCC within the periauricular area treated with curative‐intent surgery with or without neoadjuvant immunotherapy from 2005 to 2025. Patients who received neoadjuvant immunotherapy followed by surgery were age‐ and stage‐matched to those who underwent upfront surgery. The primary outcomes were event‐free survival (EFS) and overall survival (OS), estimated using the Kaplan–Meier method.
Results
The study included 85 patients. Twenty‐four (28.2%) of whom received neoadjuvant immunotherapy and 61 (71.7%) underwent upfront surgery. The two cohorts had no differences in staging or disease burden at presentation. Forty‐eight patients presented with recurrent disease, equally distributed among the groups (57% vs. 54%, p > 0.05). Patients receiving neoadjuvant immunotherapy had longer median EFS than those undergoing upfront surgery (5.9 vs. 3.4 years; hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.13–0.84; p = 0.02). Specifically, EFS at 2 years was 87% in the neoadjuvant group compared with 55% in the upfront surgery group (p < 0.05). Median OS was also longer in the neoadjuvant group (not met vs. 4.4 years; HR, 0.32; 95% CI, 0.11–0.90; p = 0.031).
Conclusions
Neoadjuvant immunotherapy improved survival outcomes in patients with advanced resectable pCSCC. These findings underscore the importance of including this patient population in upcoming randomized trials.
Keywords: immunotherapy, neoadjuvant, squamous cell carcinoma, survival analysis
1. Introduction
Periauricular skin cancers are rare and difficult to manage. Patients often do not present with specific and localized complaints, and diagnosis is delayed until after the cancer has become advanced [1, 2, 3]. Periauricular skin cancers are traditionally managed through surgical resection of the primary site and nodal basins followed by adjuvant radiation and possibly chemotherapy [1, 2, 3, 4]. However, complete surgical clearance of these cancers is difficult because of the periauricular anatomy, leading to high rates of recurrent disease and an increased risk of morbidity. The most common of these cancers is periauricular cutaneous squamous cell carcinoma (pCSCC) [1, 2, 3]. pCSCC tends to invade the ear canal and surrounding structures such as the facial nerve, parotid gland, and temporomandibular joint [5]. Lateral temporal bone resection is required when the disease invades the ear canal, but such surgery requires extensive rehabilitation of hearing. In a cohort of 25 patients treated with lateral temporal bone resection for pCSCC, 12 patients (48%) developed recurrent disease, the overall survival (OS) rate was 78.4% at year 1 [6]. Risk factors associated with worse outcomes in pCSCC include advanced disease stage, nodal metastasis, lymphovascular invasion, and facial nerve dysfunction [6].
The treatment of advanced CSCC has improved over the last half‐decade owing to the increasing implementation of immunotherapy for advanced disease. Cemiplimab, a monoclonal antibody that targets programmed cell death protein 1, is approved by the Food and Drug Association for advanced, unresectable or metastatic CSCC and has remarkably improved clinical outcomes and quality of life [7]. Adjuvant immunotherapy was recently shown to improve outcomes after surgery in patients with high‐risk pathologic features [8]. A prior Phase 2 trial of neoadjuvant immunotherapy showed 51% of patients with advanced CSCC had a pathologic complete response to treatment [9]. Neoadjuvant immunotherapy is currently being tested in a randomized Phase 3 trial (Clinical Trial NCT06568172). Neoadjuvant immunotherapy may have a role in the treatment of patients with pCSCC, in whom the failure to achieve clear surgical margins is associated with high rates of local recurrence, morbidity, and mortality.
The objective of this study was to retrospectively determine whether the addition of neoadjuvant immunotherapy to upfront surgery improves the survival outcomes of patients with advanced pCSCC.
2. Materials and Methods
2.1. Study Design
This study was a single‐institution retrospective cohort study. Patients with advanced pCSCC treated with neoadjuvant immunotherapy (PD‐1 inhibitors) followed by surgery were compared with patients treated with upfront surgery. These patients were identified from a prospective database of otologic‐neurotologic patients. Institutional review board approval was obtained (PA19‐0106).
2.2. Patient Selection
Patients with pathologically confirmed resectable pCSCC involving the ear canal, middle ear, temporal bone, or periauricular skin without evidence of distant metastasis, who were treated with curative‐intent neoadjuvant immunotherapy with expectant surgery or upfront surgical controls from 2005 to 2025, and who were 18 years or older were eligible for inclusion. Patients who underwent neoadjuvant immunotherapy but ultimately did not undergo surgery because of personal preference or clinical improvement and/or did not complete their treatment cycles were included (n = 1). Demographic, tumor, survival, and treatment variables were extracted from the electronic medical record in addition to treatment discontinuation rates and major side effects within this database.
2.3. Treatment
Immunotherapy was prescribed at the discretion of the treating medical oncologist, including preferred agent and number of cycles of treatment. Radiation therapy was recommended to patients according to current NCCN guidelines. Adjuvant treatment including chemotherapy, radiation therapy, or immunotherapy was offered at the discretion of the treatment team. The non‐standardized approach to treatment allows for real‐world analysis of the analysis.
2.4. Statistical Analysis
All data were entered into REDCap (Research Electronic Data Capture, version 15.2.0) and analyzed using Microsoft Excel and R (version 4.4.1). The primary outcomes were EFS and OS. Survival probabilities were estimated using the Kaplan–Meier method. Differences in survival between groups were determined using the log‐rank test. Frequencies were compared using the Fisher exact test. Student t tests were used for comparative analysis for demographic data. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using the cox regression model. A p value of 0.05 was considered significant.
3. Results
3.1. Patient Population
The study included 85 patients with pCSCC treated from 2005 to 2025. For all patients, the median age was 70.3 years (42.8–89.8). The characteristics of the 24 patients treated with neoadjuvant immunotherapy and the 61 patients treated with upfront surgery are provided in Table 1. Patients treated with upfront surgery had a longer mean follow‐up period than those treated with neoadjuvant immunotherapy, albeit not statistically significant (4.7 vs. 3.5 years; p = 0.07). Notably, there was a higher proportion of male patients in the upfront surgery cohort compared to the neoadjuvant cohort (93% vs. 66%, p = 0.003). The proportion of patients in either group who presented with recurrent disease did not differ significantly (Table 1). T and N stages also did not significantly differ between groups (Table 1). No patients had evidence of distant metastasis upon initial presentation. Most patients who underwent neoadjuvant treatment received cemiplimab (n = 21, 88%) with two patients receiving pembrolizumab and one patient receiving a combination of cobimetinib and atezolizumab. The average number of cycles of immunotherapy was 4.6 (median: 2.5; range 1–32, Table 2). One patient who received neoadjuvant immunotherapy declined to pursue surgery after having a complete radiologic response. This patient remains alive and disease free at last follow‐up. Also within the neoadjuvant immunotherapy cohort was one patient who had progression of disease prior to surgery who notably had a history of lymphoma.
TABLE 1.
Patient characteristics according to treatment group.
| Characteristic | All patients (n = 85) | Upfront surgery (n = 61) | Neoadjuvant immunotherapy (n = 24) | p |
|---|---|---|---|---|
| Mean age, years, (SD) | 70.3 (9.5) | 70.7 (8.8) | 68.1 (12.1) | 0.34 |
| Male sex, no. (%) | 72 (85%) | 57 (93%) | 16 (66%) | 0.003 |
| T stage | 0.75 | |||
| Tx a (%) | 4 (4.7) | 3 (4.9) | 1 (4.2) | |
| T1–T2 (%) | 26 (30.6) | 20 (32.8) | 6 (25) | |
| T3–T4 (%) | 55 (64.7) | 38 (62.3) | 17 (70.8) | |
| N stage | 0.57 | |||
| N0 (%) | 47 (55.3) | 36 (59) | 11 (45.8) | |
| N1 (%) | 8 (9.4) | 6 (9.8) | 2 (8.3) | |
| N2 (%) | 24 (28.2) | 16 (26.2) | 8 (33.3) | |
| N3 (%) | 6 (7.1) | 3 (4.9) | 3 (12.5) | |
| Median follow‐up, years | 3.7 | 3.7 | 3.8 | 0.99 |
| Mean follow‐up, years | 4.4 | 4.7 | 3.5 | 0.07 |
| Recurrent disease | 47 (55.3) | 34 (55.7) | 13 (54.2) | 0.99 |
Note: All values are n (%) unless otherwise indicated.
Abbreviation: SD, standard deviation.
Tx indicates an unknown/un‐categorized amount of primary tumor burden upon initial evaluation at our institution.
TABLE 2.
Treatment characteristics for patients who underwent neoadjuvant immunotherapy.
| Characteristic | Neoadjuvant immunotherapy (n = 24) |
|---|---|
| Prior chemotherapy (%) | 5 (21) |
| Prior radiation (%) | 7 (29) |
| Prior surgery (%) | 13 (54.2) |
| Neoadjuvant agent | |
| Cemiplimab (%) | 21 (87.5) |
| Pembrolizumab (%) | 2 (8.3) |
| Cobimetinib/Atezolizumab (%) | 1 (4.2) |
| Median number of cycles | 2 |
| Adjuvant therapies a | |
| Radiation (%) | 19 (79) |
| Chemotherapy (%) | 10 (41.7) |
Note: All values are n (%) unless otherwise indicated.
Abbreviation: SD, standard deviation.
Adjuvant medications given only after the initial surgery.
3.2. Survival Analysis
For all patients, the median OS duration was 6 years (95% CI 4.3 years—not met). The neoadjuvant immunotherapy group had improved 2‐year EFS (87%) compared to upfront surgery (55%) and improved survival (5.9 vs. 3.4 years; HR, 0.33; 95% CI, 0.13–0.84; p = 0.02, Figure 1). The neoadjuvant immunotherapy group also had a longer OS duration than the upfront surgery group (not met vs. 4.4 years; HR 0.32, 95% CI 0.11–0.90; p = 0.031, Figure 2). The 5‐year OS rate was 73% for those who underwent neoadjuvant immunotherapy compared to 46% for those who underwent upfront surgery. Patients who presented with recurrent disease had a shorter 2‐year EFS% (59% vs. 70%) and a shorter overall median EFS duration than those who did not present with recurrent disease (3.4 vs. 11.0 years; HR, 1.86, 95% CI, 1.01–3.42; p = 0.045). Importantly, within the cohort of patients who presented with recurrent disease, those who underwent neoadjuvant immunotherapy (n = 13) had an improved 2‐year EFS% (84% vs. 49%) compared to surgical controls (n = 34) and trended toward an overall improved EFS compared to upfront surgical controls (1.9 vs. 5.9 years; HR, 0.35, 95% CI, 0.12–1.01; p = 0.052, log rank p‐value = 0.045, Figure 3). A controlled cox proportional hazard model was also created to analyze the impact on gender, recurrent disease at presentation, and adjuvant radiation on EFS. While controlling for these variables, patients treated with neoadjuvant immunotherapy still had improved EFS compared to those who underwent upfront surgery (HR, 0.37, 95% CI, 0.14–0.95, p‐value = 0.04). Notably, none of the other variables (gender, recurrent at presentation or adjuvant radiation) were significant within the controlled cox proportional hazard model (all p > 0.05).
FIGURE 1.
Kaplan–Meier curve depicting the event‐free survival of patients who underwent neoadjuvant immunotherapy versus upfront surgery with associated risk table. p‐value determined from log‐rank test.
FIGURE 2.
Kaplan–Meier curve depicting the overall survival of patients who underwent neoadjuvant immunotherapy versus upfront surgery with associated risk table. p‐value determined from log‐rank test.
FIGURE 3.
Kaplan–Meier curve depicting the event free survival of patients who presented with recurrent disease and those who underwent neoadjuvant immunotherapy versus upfront surgery with associated risk table. p‐value determined from log‐rank test.
4. Discussion
This study demonstrates that patients with pCSCC treated with neoadjuvant immunotherapy experienced improved oncologic outcomes compared with those undergoing upfront surgery. pCSCC can be challenging to achieve negative surgical margins depending on the extent of disease, and adjuvant therapies can be associated with significant morbidity [2, 5, 10, 11, 12, 13, 14]. Given pCSCC's high rate of perineural invasion and proximity to bony anatomy and important vascular structures, complete excision and clear margins can be difficult to obtain [5, 10, 13, 14]. As such, pCSCC can have a remarkably difficult‐to‐treat presentation and may benefit from neoadjuvant immunotherapy. There is significant evidence to support the efficacy and safety of anti‐PDL1 immunotherapy in the treatment of CSCC and there is emerging evidence of its successful utilization in real‐world situations [15, 16, 17].
The objective of the current investigation was to assess the impact of neoadjuvant immunotherapy on the survival of patients with advanced resectable pCSCC. We found that patients treated with upfront surgery had longer mean follow‐up periods, which was expected given that immunotherapy has only recently been applied in the neoadjuvant setting. Additionally, we found that neoadjuvant immunotherapy resulted in improved 2‐year EFS (87% vs. 55%). Patients treated with neoadjuvant immunotherapy also having improved 5‐year OS rate (73% vs. 46%, HR 0.37). Notably, even when controlling for gender, recurrent disease, and adjuvant radiation, EFS was still greatly improved in patients who were treated with neoadjuvant intent. Consistent with current NCCN guidelines, our finding supports the utilization of neoadjuvant immunotherapy for advanced pCSCC when the risk of significant functional loss is great with upfront surgery. Importantly, neoadjuvant immunotherapy has been utilized successfully in organ preservation and de‐escalation of surgery, with McLean et al. reporting that 6/7 patients were able to avoid orbital exenteration after neoadjuvant immunotherapy [18].
However, it is critical to recognize that currently neoadjuvant immunotherapy is not FDA approved for this indication. Further, there can be serious side effects from treatment with immunotherapy, even if only a short preoperative course. As such, the decision to offer neoadjuvant immunotherapy for pCSCC should only be made in the multidisciplinary setting with full consideration of all treatment strategies. Additionally, there are significant considerations when treating patients with neoadjuvant immunotherapy. For example, pseudoprogression is not routinely evaluated in patients who undergo treatment and can be missed in these cohorts [19]. This study described herein was not appropriately characterized to evaluate pseudoprogression however it should be noted that one patient in the neoadjuvant immunotherapy cohort did have progression of disease prior to surgery. This same patient did notably have a history of lymphoma and lymphoma treatment.
Overall, our study had several limitations. For example, these cohorts were inherently heterogenous. Patients who underwent upfront surgery had longer follow‐up, which may have influenced our findings. More research is needed to evaluate the optimal follow‐up period for those who undergo immunotherapy [20]. This investigation also had a non‐randomized design and nonstandardized drug cycle and dosing, which both adds to its strength as a real‐world analysis and as a limitation due to the non‐standardization of its approach.
5. Conclusions
To our knowledge, this is the first analysis of the effect of neoadjuvant immunotherapy on survival outcomes in pCSCC. We illustrated that, compared with upfront surgery, neoadjuvant immunotherapy improved median EFS and OS in patients with advanced and/or recurrent pCSCC.
Author Contributions
Concept and design: David Z. Allen, Paul Gidley, and Neil Gross. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: All authors. Critical review of the manuscript for important intellectual content: All authors. Statistical analysis: David Z. Allen. Administrative, technical, or material support: Neil Gross, Nader, Ferrarotto, Moran Amit, Priyadharsini Nagarajan, Paul Gidley. David Z. Allen and Paul Gidley had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Conflicts of Interest
Neil Gross reports institutional research funding from Regeneron Pharmaceuticals; speaker honoraria from AiCME; and advisory board and consulting fees from PDS Biotechnology, Replimmune, Regeneron Pharmaceuticals, and Merck. Marc‐Elie Nader reports stock ownership in 3M, Amgen, Kimberly‐Clark, Johnson & Johnson, Medtronic, Nestle, and Pfizer. Renata Ferrarotto reports personal fees from Regeneron‐Sanofi, Ayala Pharma, Klus Pharma, Medscape, Cellestia Biotech, Carevive, Prelude, and Bicara; grants from AstraZeneca, Merck, Gennentech, Pfizer, Oropharynx Program Stiefel clinical trials, ASCO Career Development Award, and MD Anderson Khalifa Award within the past 2 years. Paul Gidley reports stock ownership in Amgen, Eli Lily, GE Healthcare, Kyndryl, Medtronic, Merck, Novartis, Organon, Pfizer, and Roche. The other authors declare no conflicts of interest.
Acknowledgments
We thank Madison Semro, Associate Scientific Editor, and Joe Munch, Senior Scientific Editor, in the Research Medical Library at The University of Texas MD Anderson Cancer Center for editing this article.
Allen D. Z., Gross N., Nader M.‐E., et al., “Neoadjuvant Immunotherapy for Periauricular Cutaneous Squamous Cell Carcinoma,” Head & Neck 48, no. 3 (2026): 837–842, 10.1002/hed.70080.
Funding: This research was supported by the NIH/NCI under award P30CA016672.
This research was presented at the American Head and Neck Society portion of the Combined Otolaryngology Spring Meetings (COSM) and received a Best Poster award; May 2024; Chicago, Illinois.
Data Availability Statement
Research data are not shared.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Research data are not shared.