A single centre analysis of outcomes and patterns of failure in head and neck cancer patients treated with single modality transoral robotic surgery

Introduction

Head and neck cancer is the seventh most common cancer worldwide with an ongoing predicted rise driven by emerging oropharyngeal squamous cell carcinoma (OPSCC) (1). Evolving etiology of OPSCC has been described with the decline in smoking, and a significant rise in human papillomavirus (HPV) positive oropharyngeal cancer in Western countries (1-3). HPV has been attributed to 70% of all new oropharyngeal cancer diagnosis in Western Europe and North America (4). Patients with HPV-associated oropharyngeal cancer tend to be younger (4,5), have a favorable prognosis with better survival rate compared to patients with HPV-negative oropharyngeal cancer (6,7).

Transoral robotic surgery (TORS) was first introduced in 2007, as a minimally invasive surgical technique to address OPSCC (8,9). Improved transoral visual and instrument access with Da Vinci™ robot has allowed the resection of oropharyngeal cancer with minimal surgical morbidity (8,9). TORS has been shown to have better functional results, and no significant difference in oncological outcomes when compared to open mandibulotomy (10,11). Its efficacy and safety has been reported in a number of observational studies and systematic reviews. It has become the gold standard treatment for transoral access to head and neck cancers (10,12).

Traditionally, head and neck cancer were treated with surgery +/− chemoradiation or definitive chemoradiation based on multidisciplinary team (MDT) meeting recommendations, considering pathology findings and patient characteristics. Treatment with radiation/chemoradiation is associated with long-term side effects including xerostomia, mucositis, progressive dysphagia, and mandibular osteoradionecrosis (13,14). Moreover, definitive chemoradiation as primary treatment limits options for future chemoradiotherapy in the same field in cases of recurrence. With the emerging HPV-positive OPSCC in younger population, patients are more likely to live longer to experience the long-term toxicities from non-surgical management (15). Therefore, there is a need to make careful clinical assessment and case selection with the aim of achieving single modality treatment, where possible, thus minimizing long-term toxicities and optimizing functional outcomes.

There has been a trend in de-escalation in management of early oropharyngeal cancer patients with the introduction of recent trials, including ECOG 3311 (15) and PATHOS (16). Adjuvant therapy, therefore, should be considered carefully, being mindful of the long-term toxicities of radiotherapy and chemotherapy mentioned above.

The aim of this study was to report oncological outcomes, patterns of recurrence and overall survival in head and neck cancer patients treated with TORS +/− neck dissection (ND) as single modality treatment, without the use of adjuvant radiotherapy and/or chemotherapy. We present this article in accordance with the STROBE reporting checklist (available at https://www.theajo.com/article/view/10.21037/ajo-23-54/rc).

Methods

Study design

Retrospective review of prospectively collected data from Royal Adelaide Hospital TORS registry. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Central Adelaide Local Health Network Human Research Ethics Committee (Ref. No 14278). Because of the retrospective nature of research, the requirement of informed consent was waived.

Participants

All patients were discussed at a MDT team meeting. Adult patients with head and neck cancer who underwent curative intent single modality TORS +/− ND in Adelaide from 2013 to 2021 were included in the study. Patients with benign pathology, patients with negative mucosectomy, patients who received palliative intent treatment and patients lost to follow-up were excluded. Patients were also excluded if they received adjuvant chemotherapy and/or radiotherapy. Postoperatively patients were followed up at the head and neck cancer clinic, primarily at the Royal Adelaide Hospital.

Data collection & variables

Information was extracted from patient file notes acquired from medical records and electronic notes at the Royal Adelaide Hospital. Data were extracted to an anonymized excel spreadsheet.

Patient demographics including age, gender, comorbidities, alcohol intake and smoking status were obtained. Smoking status was calculated in pack-years and categorized into more than 10, 10 or less, or non-smoker, guided by Ang et al., who reported >10 pack year history as a major determinant for overall survival (17). For patients with previous head and neck cancer, the type of cancer and treatment modality was recorded. Pathological outcomes including tumor characteristics were determined using the TNM8 staging (18). Histological features including tumor grade, P16 status, extracapsular spread (ECS), margin status, perineural invasion (PNI) or lymphovascular invasion (LVI) were also recorded. Margin status was defined as clear for the closest margin 2 mm or greater, close for 1 to 1.9 mm and involved if less than 1 mm, as per our local MDT agreement. Postoperative 30-day mortality and surgical complications were recorded and classified according to the Clavien-Dindo classification system of surgical complications (19).

Outcomes

The primary outcome measures were overall survival and disease-free survival. The secondary outcome of interest was patterns of recurrence and complications. Estimated 2- and 3-year disease-free survival, and overall survival were measured as outcomes of interest. Patients with cancer recurrence, the timing of recurrence, pattern of recurrence, and subsequent treatment modality were recorded.

Statistics

Patient characteristics and follow-up were reported as medians and interquartile ranges (IQR). Statistical analysis was conducted by University of Adelaide statistician. Kaplan-Meier survival plots were used to predict 2-, and 3-year disease-free survival, and overall survival. Cox proportional hazard model tests were run on various predictors including age, ECS, margin status, P16 status, PNI, and LVI. P value of 0.05 was determined as threshold for significance. All statistical analysis was performed using R V4.20 (R core team, 2022).

Results

A total of 309 patients who underwent TORS +/− ND between 2013 and 2021 at the Royal Adelaide Hospital were considered for inclusion. Of those, 254 patients were excluded—49 patients had benign pathology, 192 received adjuvant radiotherapy or chemoradiotherapy, 6 had negative mucosectomy, 3 received palliative intent TORS, and 4 were lost to follow-up. A total of 55 patients with a median (IQR) age of 59.0 (54.0–66.5) years were included. Patients were followed up for a median (IQR) of 34.0 (18.0–47.5) months after primary treatment. Patient demographic data and baseline characteristics are summarized in Table 1.

Pathological characteristics & MDT recommendations

Pathological characteristics are summarized in Table 2. All patients had squamous cell carcinoma. The primary site was tonsil, tongue base and other in 67.3%, 25.5% and 7.2% respectively; 60.0% of patients had cervical nodal metastasis and no patients had distant metastatic disease; 78.2% of patients had clear surgical margins, while four patients had involved margins. Among these cases, one patient was advised to undergo adjuvant chemoradiation (CRT), however declined, subsequently re-presenting with recurrence. For the remaining three patients, two underwent re-resection with TORS with no residual cancer, while MDT opted for surveillance in one case due to the well-circumscribed nature of tumour. P16 status and proportion of patients with LVI, PNI and ECS is summarized in Table 2.

Following MDT discussion, adjuvant radiotherapy was recommended to 19 patients who declined; and therefore, were eligible for inclusion in this study. There were three patients not eligible for adjuvant radiotherapy due to previous cancer with treatment within the same radiotherapy field.

Overall and disease-free survival

Survival estimates using the Kaplan-Meier survival analysis (Figure 1) demonstrated 2-year overall survival of 98.2%, and disease-free survival of 91.6%. Estimated 3-year oncological outcomes were 93.4% overall survival, and 87.8% disease-free survival. In this small cohort of patients, there was no significant difference in oncological outcomes between P16 positive and negative patients (Figure 2).

Figure 1 Kaplan-Meier curve for survival estimates.

Figure 2 P16 positive and negative patients log rank test.

Cox proportional hazard analysis was performed on several predictors. ECS (P=0.001), and LVI (P=0.042) were identified as significant risk factors affecting disease-free survival, however, not overall survival, acknowledging the small number of ECS patients. PNI, and margin status showed no statistically significant correlation in disease-free survival or disease-specific survival. Those with smoking history or alcohol history did not have significant reduction in disease-free survival, or overall survival. History of previous head and neck cancer showed significant association with overall [hazard ratio (HR) 22, P=0.011] and disease-specific survival (HR 18, P=0.0167).

Cox proportional HR was used to compare the outcomes of 27 patients aged 60 and over, and 28 patients under 60 years old at the time of the operation. This did not show any significant difference in survival outcomes.

In total, 6 (10.9%) patients died during the study period. The median time of death was 35 months after the operation (IQR, 26.9–41.5 months). There were three cancer-related deaths. Other causes of death included second primary cancer, pulmonary nocardia and hepatic encephalopathy with alcoholic cirrhosis. Recurrence occurred in six patients (10.9%), mostly locoregional with a median time of 16.5 months after primary treatment (IQR, 12.8–30.8 months). There were ten recurrences, as three had more than one recurrence. A summary of patterns of recurrence are presented in Table 3. Radical chemoradiation was used in three, radical radiotherapy in one, wide local excision in one, and palliative therapy in five.

Post-operative complications were categorized with the Clavien-Dindo classification system (19), and 12.7% of patients had severe (Clavien-Dindo III–IV) complications post-operatively, including 4 (7.3%) patients with secondary hemorrhage requiring a return to theatre. There was no 30-day post-operative mortality (Figure 3).

Figure 3 Clavien-Dindo post-operative complications.

Discussion

With the increase in a younger population presenting with HPV positive OPSCC, treatment protocols to reduce long-term toxicities and complications of chemoradiotherapy are being investigated (20). The trend towards de-escalation in adjuvant treatment has been supported by randomized controlled trials such as ECOG 3311 (15), and is being validated by currently recruiting randomized controlled trials, including PATHOS (16). Given the favorable quality of life and functional outcome of avoiding adjuvant chemo/radiotherapy (12,15,21), examining the recurrence and survival rates of single modality TORS treatment is of great interest. To our knowledge, our study represents the largest retrospective cohort study in Australia, investigating oncological outcomes of patients undergoing single modality TORS+/− ND. Our results support the oncological safety of including single modality TORS as part of randomized controlled trials with favorable disease-free survival, and overall survival. Lack of 30-day post-operative mortality, and 7.3% postoperative hemorrhage rate, supports the surgical safety of TORS in our institution.

Prior studies have investigated the oncological and functional outcomes of single-modality TORS for OPSCC (12,15,22-24). In a randomized controlled trial, ECOG 3311 (15) reported 96.9% 2-year progression-free survival in low-risk patients treated with TORS alone, whilst demonstrating better swallowing, and quality of life compared to intermediate/high-risk patients who received adjuvant radiotherapy/chemoradiotherapy. This was further supported by prospective (25,26) and retrospective (21) cohort studies showing improved outcome in swallowing and quality of life with avoidance of radiotherapy/chemoradiotherapy. One study by Fradet et al. (12), comparing (I) TORS single modality, (II) adjuvant radiotherapy to neck alone, and (III) adjuvant radiotherapy to neck and primary site showed better swallowing outcomes in (I) TORS single modality and (II) adjuvant radiotherapy to neck alone group compared to (III) adjuvant therapy to primary site group. However, the regional control was significantly lower in the TORS single modality group compared to the other two groups (90% vs. 100%), potentially signifying the importance of risk stratification and case selection in treatment de-escalation. Similarly, a study based in Pennsylvania (27), reported higher locoregional recurrence rates in TORS only patients compared to those who received adjuvant therapy, albeit locoregional control did not make any difference in overall or disease-free survival. There is varying international consensus on the margin status for TORS. Conventionally, minimum of 5 mm margin was well accepted without good evidence (28). ECOG 3311 (15) defined clear margin as 3 mm, other studies, such as Fradet et al. (12) and Carey et al. (27) used 2 mm as cut off. Other retrospective studies (28,29) have identified 1.0–1.1 mm margin as the most discriminating cut off point for local control. This study defined clear margin as 2 mm or greater and included twelve patients with close/involved margin (<2 mm), who underwent re-resection, observed, or offered adjuvant therapy and declined. Our data with 2 mm margin cut off achieved comparable results, possibly due to our rigorous policy working in close collaboration with pathologists, inking of false margins, to facilitate exact orientation of extra margins on main specimen. Another factor for consideration is our primary site. Majority of our primary pathology was tonsil, followed by tongue base, which may indicate tonsil primaries present with more favorable disease or is easier to achieve clear margins.

In our study we examined several predictive factors of recurrence following single modality TORS. Results show that LVI and ECS are negative predictors for disease-free survival, however not overall survival. The study did not demonstrate any significant impact of survival in patients who were older (>60 years) or patients with PNI.

Overall, patients with HPV-associated OPSCC tend to exhibit superior survival outcomes compared to those with HPV-negative OPSCC. However, our study findings revealed no significant difference in survival between patients with P16-positive and P16-negative OPSCC. This may be attributed to the tendency of patients undergoing unimodality treatment with TORS to predominantly consist of lower stage cases. This demonstrates the feasibility of lower stage P16-negative cancers being safety treated with unimodality surgery, with comparable outcome to the P16 positive cohort.

This study contains some limitations. Firstly, this study stems from a single center experience, which affects the external validity and generalization of its outcome. However, patients were operated by the same surgical team based at the Royal Adelaide Hospital who achieved comparable margin status (Table 1). Secondly, the current study focused on oncological outcomes of single modality patients. Long-term functional outcomes were beyond the scope of this study. Due to the small number of recurrences, it is difficult to reliably analyze the variables as risk factors for recurrence and mortality.

Conclusions

Our outcomes show that single modality TORS treatment is safe and efficacious in patients with small volume head and neck cancer with low-risk histological features. Careful consideration should be given in case selection for post-operative adjuvant therapy to prevent long-term toxicities from chemoradiation.

There is emerging evidence of lesser margin being acceptable in retrospective data and this study supports it. Large sample randomized controlled trials in the future to compare outcome of single modality TORS treatment to TORS with chemoradiotherapy or radiotherapy is necessary.

Acknowledgments

The authors would like to thank George Bouras from University of Adelaide for his contribution in statistics, Leanne Scott, from Krishnan Medical Centre, Lee Jill Suen, Tse Xu Mark Leonard Chee from University of Adelaide for their contribution in data collection. The abstract in this article has been presented at ASOHNS ASM 2022, taking place in Adelaide.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://www.theajo.com/article/view/10.21037/ajo-23-54/rc

Data Sharing Statement: Available at https://www.theajo.com/article/view/10.21037/ajo-23-54/dss

Peer Review File: Available at https://www.theajo.com/article/view/10.21037/ajo-23-54/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://www.theajo.com/article/view/10.21037/ajo-23-54/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Adelaide Local Health Network Human Research Ethics Committee (Ref. No 14278). Because of the retrospective nature of the research, the requirement for informed consent was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Gormley M, Creaney G, Schache A, et al. Reviewing the epidemiology of head and neck cancer: definitions, trends and risk factors. Br Dent J 2022;233:780-6. [Crossref] [PubMed]
2. Lassen P, Lacas B, Pignon JP, et al. Prognostic impact of HPV-associated p16-expression and smoking status on outcomes following radiotherapy for oropharyngeal cancer: The MARCH-HPV project. Radiother Oncol 2018;126:107-15. [Crossref] [PubMed]
3. Aupérin A. Epidemiology of head and neck cancers: an update. Curr Opin Oncol 2020;32:178-86. [Crossref] [PubMed]
4. Gooi Z, Chan JY, Fakhry C. The epidemiology of the human papillomavirus related to oropharyngeal head and neck cancer. Laryngoscope 2016;126:894-900. [Crossref] [PubMed]
5. Lechner M, Liu J, Masterson L, et al. HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management. Nat Rev Clin Oncol 2022;19:306-27. [Crossref] [PubMed]
6. Guo K, Xiao W, Chen X, et al. Epidemiological Trends of Head and Neck Cancer: A Population-Based Study. Biomed Res Int 2021;2021:1738932. [PubMed]
7. Gordis TM, Cagle JL, Nguyen SA, et al. Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis of Clinical Trial Demographics. Cancers (Basel) 2022;14:4061. [Crossref] [PubMed]
8. Paleri V, Fox H, Winter S. Transoral Robotic Surgery for Oropharyngeal Cancer. ORL J Otorhinolaryngol Relat Spec 2018;80:156-70. [Crossref] [PubMed]
9. Weinstein GS, O'Malley BW Jr, Snyder W, et al. Transoral robotic surgery: radical tonsillectomy. Arch Otolaryngol Head Neck Surg 2007;133:1220-6. [Crossref] [PubMed]
10. Roselló À, Albuquerque R, Roselló-Llabrés X, et al. Transoral robotic surgery vs open surgery in head and neck cancer. A systematic review of the literature. Med Oral Patol Oral Cir Bucal 2020;25:e599-607. [Crossref] [PubMed]
11. Haigentz M Jr, Silver CE, Corry J, et al. Current trends in initial management of oropharyngeal cancer: the declining use of open surgery. Eur Arch Otorhinolaryngol 2009;266:1845-55. [Crossref] [PubMed]
12. Fradet L, Charters E, Gao K, et al. Avoidance of primary site adjuvant radiotherapy following transoral robotic surgery: a cohort study. ANZ J Surg 2022;92:511-7. [Crossref] [PubMed]
13. Strojan P, Hutcheson KA, Eisbruch A, et al. Treatment of late sequelae after radiotherapy for head and neck cancer. Cancer Treat Rev 2017;59:79-92. [Crossref] [PubMed]
14. Lalla RV, Brennan MT, Gordon SM, et al. Oral Mucositis Due to High-Dose Chemotherapy and/or Head and Neck Radiation Therapy. J Natl Cancer Inst Monogr 2019;2019:lgz011. [PubMed]
15. Ferris RL, Flamand Y, Weinstein GS, et al. Phase II Randomized Trial of Transoral Surgery and Low-Dose Intensity Modulated Radiation Therapy in Resectable p16+ Locally Advanced Oropharynx Cancer: An ECOG-ACRIN Cancer Research Group Trial (E3311). J Clin Oncol 2022;40:138-49. [Crossref] [PubMed]
16. Owadally W, Hurt C, Timmins H, et al. PATHOS: a phase II/III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery for Human papillomavirus (HPV) positive oropharyngeal cancer. BMC Cancer 2015;15:602. [Crossref] [PubMed]
17. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:24-35. [Crossref] [PubMed]
18. Huang SH, O'Sullivan B. Overview of the 8th Edition TNM Classification for Head and Neck Cancer. Curr Treat Options Oncol 2017;18:40.
19. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205-13. [Crossref] [PubMed]
20. Hargreaves S, Beasley M, Hurt C, et al. Deintensification of Adjuvant Treatment After Transoral Surgery in Patients With Human Papillomavirus-Positive Oropharyngeal Cancer: The Conception of the PATHOS Study and Its Development. Front Oncol 2019;9:936. [Crossref] [PubMed]
21. Xu MJ, Plonowska KA, Gurman ZR, et al. Treatment modality impact on quality of life for human papillomavirus-associated oropharynx cancer. Laryngoscope 2020;130:E48-56. [Crossref] [PubMed]
22. Dhere VR, Escott CE, Tian S, et al. The omission of intentional primary site radiation following transoral robotic surgery in 59 patients: No local-regional failures. Head Neck 2022;44:382-90. [Crossref] [PubMed]
23. O'Hara J, Warner L, Fox H, et al. Primary transoral robotic surgery +/- adjuvant therapy for oropharyngeal squamous cell carcinoma-A large observational single-centre series from the United Kingdom. Clin Otolaryngol 2021;46:1005-12. [Crossref] [PubMed]
24. Parhar HS, Shimunov D, Newman JG, et al. Oncologic Outcomes Following Transoral Robotic Surgery for Human Papillomavirus-Associated Oropharyngeal Carcinoma in Older Patients. JAMA Otolaryngol Head Neck Surg 2020;146:1167-75. [Crossref] [PubMed]
25. Achim V, Bolognone RK, Palmer AD, et al. Long-term Functional and Quality-of-Life Outcomes After Transoral Robotic Surgery in Patients With Oropharyngeal Cancer. JAMA Otolaryngol Head Neck Surg 2018;144:18-27. [PubMed]
26. Dziegielewski PT, Teknos TN, Durmus K, et al. Transoral robotic surgery for oropharyngeal cancer: long-term quality of life and functional outcomes. JAMA Otolaryngol Head Neck Surg 2013;139:1099-108. [Crossref] [PubMed]
27. Carey RM, Brody RM, Shimunov D, et al. Locoregional Recurrence in p16-Positive Oropharyngeal Squamous Cell Carcinoma After TORS. Laryngoscope 2021;131:E2865-73. [Crossref] [PubMed]
28. Warner L, O'Hara JT, Lin DJ, et al. Transoral robotic surgery and neck dissection alone for head and neck squamous cell carcinoma: Influence of resection margins on oncological outcomes. Oral Oncol 2022;130:105909. [Crossref] [PubMed]
29. Hardman JC, Holsinger FC, Brady GC, et al. Transoral Robotic Surgery for Recurrent Tumors of the Upper Aerodigestive Tract (RECUT): An International Cohort Study. J Natl Cancer Inst 2022;114:1400-9. [Crossref] [PubMed]