Abstract
Background/Aim: Locally advanced squamous cell carcinoma of the head and neck (L/A SCCHN) is typically treated with surgery or chemoradiation therapy (CRT), whereas salvage surgery is considered for residual disease post-CRT. However, salvage surgery after radiation therapy presents challenges due to tissue fibrosis. Planned neck dissection (ND) combined with CRT, as well as positron emission tomography after CRT, have been proposed strategies, but no definitive consensus has been reached. Therefore, this study aimed to investigate the utility of “upfront ND” performed prior to CRT to enhance local control and reduce complications. Patients and Methods: We retrospectively reviewed 121 patients who underwent primary CRT for oropharyngeal, hypopharyngeal, or laryngeal cancer at Tokyo Medical University Hospital from January 2015 to September 2021. Patients without cervical lymph node metastasis or with unresectable nodes were excluded. All patients underwent pre-treatment imaging and staging. CRT consisted of intensity-modulated radiation therapy (IMRT) and cisplatin-based chemotherapy. Selective ND or modified radical neck dissection was performed based on lymph node involvement. Results: Overall, 35 patients underwent upfront ND, whereas 54 did not. The upfront ND group exhibited significantly better 2-year locoregional recurrence-free survival than the group without upfront ND (93.7% vs. 71.0%). No significant differences were noted in adverse events between groups. Conclusion: The findings highlight upfront ND before CRT as a viable option for locally advanced head and neck cancer, particularly beneficial in cases with extranodal extension. This approach enhances local control and may reduce the need for salvage surgery, thus improving patient outcomes.
Surgery or chemoradiation therapy (CRT) stands as the gold standard for managing locally advanced squamous cell carcinoma of the head and neck (L/A SCCHN) (1-3). CRT emerges as the preferred treatment modality for patients encountering challenges in resection or desiring to preserve essential functions like speech and swallowing. Despite the efficacy of CRT, salvage surgery becomes necessary for individuals with residual disease post-radiation therapy; however, it is associated with a high complication rate due to tissue fibrosis (4). In cases wherein cervical lymph nodes persist, neck dissection (ND) is performed (5), but this can be challenging due to difficulty in dissecting away from vital organs such as the common carotid artery and internal jugular vein.
As a strategic response to the complexities associated with salvage surgery following CRT, the concept of “planned ND” has been introduced, entailing the integration of CRT with ND in advance. This approach targets advanced cervical cases where residual cervical remnants are anticipated post-CRT. However, the presence of false-positive lesions in post-CRT lymphadenopathy raises concerns regarding the necessity of planned ND, potentially leading to unnecessary surgical interventions (6-9). In contrast, positron emission tomography (PET) has been proposed 12 weeks after CRT, with surgery only being considered in positive cases, or in cases of N2c and N3, in which cervical remnants are expected to be highly likely; however, no definitive consensus has been reached to date (10-13).
Against this background, we employ the “upfront ND” technique in cases wherein ND is performed prior to CRT. This approach involves treating L/A SCCHN with cervical lymph node metastases by initially performing ND, followed by CRT as curative therapy. After ND, if the postoperative pathology reveals extranodal extension (ENE), CRT becomes imperative as postoperative therapy (14), including the remaining primary tumor. The advantage of this approach is that surgery is performed without tissue scarring resulting from radiotherapy, thus reducing the risk of complications compared with that noted with salvage surgery after CRT. This approach also allows for removal of lesions that may have otherwise been unresectable following radiotherapy. This approach holds promise for long-term local control and potential life expectancy extension.
Therefore, this retrospective study aimed to review the usefulness of upfront ND for L/A SCCHN as performed within our department.
Patients and Methods
Participants. From January 2015 to September 2021, 121 patients underwent CRT as primary treatment for oropharyngeal, hypopharyngeal, or laryngeal cancer at Tokyo Medical University Hospital. Patients without cervical lymph node metastasis, those with unresectable cervical lymph nodes due to carotid perineural invasion, and those with distant metastasis were excluded (Figure 1). As a rule, all patients underwent computed tomography (CT), magnetic resonance imaging (MRI), and PET prior to treatment, and staging was performed by a head and neck surgeon and a head and neck radiologist. TNM classification was performed using the Union for International Cancer Control version 7 criteria (15). The presence of ENE was determined radiographically.
Flowchart outlining the selection of study participants.
Written informed consent for publication of this study was obtained from all patients. This retrospective study was approved by the Institutional Review Board of Tokyo Medical University Hospital (approval number T2021-0306) and conducted in accordance with the Declaration of Helsinki.
Treatment. Concurrent chemoradiotherapy. CRT was performed on all patients. Intensity-modulated radiation therapy (IMRT) was used to reduce toxicity, with radiation dose of 2 Gy/day and expected total dose of 70 Gy. In principle, cisplatin is used in combination as a chemotherapeutic component. In this study, chemotherapy was performed with cisplatin at a dose of 80 mg/m2 every three weeks (days 1, 22, and 43). The dose was reduced to 80% of the cisplatin dose (64 mg/m2) when hematologic toxicity (leukopenia, neutropenia, anemia, and thrombocytopenia) was Grade 3 or higher. Similarly, 80% dose was administered when the estimated glomerular filtration rate (eGFR) was 40-60 ml/min/1.73 m2 and was discontinued when eGFR was <40 ml/min/1.73 m2. Notably, only one patient received 1.8 Gy/day due to concurrent treatment for esophageal cancer. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (16).
Neck dissection. As a rule, selective ND was performed to preserve the internal jugular vein, accessory nerves, and sternocleidomastoid muscle in level II-IV dissection. Depending on the location of the enlarged lymph node, dissection was extended to level I or level V, as appropriate. In cases with clear invasion of important vessels, cranial nerves, or skin, modified radical ND was performed, in which only the invaded structures were excised in combined resection. In cases with skin resection, reconstruction was performed with a pectoralis major skin valve. ND levels were classified based on guidelines of the American Head and Neck Society (AHNS) and the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) (17). Perioperative complications were assessed using the Clavien-Dindo classification, with complications defined as Grade II or higher (18).
Follow-up. The first post-treatment CT was performed approximately 2 months following completion of CRT. CT was performed every 3 months for 1 year and every 3-6 months from the second year to the fifth year. The pharynx and larynx were observed endoscopically, as appropriate.
Endpoint. The study endpoints were locoregional recurrence-free survival (LRFS), relapse-free survival (RFS), and overall survival (OS). In addition, those with ENE-positive pre-treatment imaging studies were extracted and compared by dividing into two groups based on the presence or absence of ND. LRFS was defined as the time from treatment initiation to local recurrence or death. RFS was defined as the time from treatment initiation to recurrence or death. OS was defined as the time from start of treatment to death.
Statistical analysis. Survival analyses for LRFS, RFS, and OS were performed using the Kaplan-Meier method, and between-group comparisons were tested using the log-rank test. Multivariate analysis was performed using the COX hazard model. Patient background, ND status, and prognosis were analyzed using Fisher’s exact test. A p-value of <0.05 was considered to be statistically significant. All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) (19). More precisely, it is a modified version of R commander designed to add statistical functions frequently used in biostatistics.
Results
Patients and treatment. Patient demographic data are presented in Table I. The upfront ND group had 35 patients, whereas the without upfront ND group had 54 patients. The median age of all patients was 63 years, 84 (94%) were men, and 78 (88%) had Eastern Cooperative Oncology Group Performance Status (ECOG PS) of PS 0. The primary site was the mid-pharynx in 45 patients (51%), the hypopharynx in 37 patients (42%), and the larynx in seven patients (8%). Radiographically, preoperative ENE was positive in 40 patients (45%). Regarding upfront ND cases, the median time from ND to CRT initiation was 29 (range=19-77 days).
Patient clinical characteristics.
CRT data are shown in Table II. The cisplatin dose was not significantly different (p=0.19) between the without upfront ND group [mean, 180 mg (range=80-240 mg)] and with upfront ND group [mean, 212 mg (range=80-240 mg)]. Radiation doses were not significantly different between the two groups (p>0.99), with a mean of 69 Gy (range=42-70 Gy) in the without upfront ND group and 69 Gy (range=54-70 Gy) in the with upfront ND group. CRT adverse events are shown in Table III and Table IV. There were no Grade 5 events. Grade 3-4 adverse events were not significantly different between the with upfront ND and without upfront ND groups.
Summary of chemoradiation therapy.
Summary of adverse events of chemoradiation therapy.
Comparison of Grade 3-4 adverse events between with upfront neck dissection and without upfront neck dissection.
Regarding ND, Grade I was noted in five (14%) cases, whereas no Grade II or higher cases were observed, according to the Clavien-Dindo classification. Perioperative complications were not observed, and no patients developed complications in their postoperative course. The median time from surgery to discharge was eight days (range=3-22 days). The patient with the longest hospital stay (22 days) had a complicated skin excision and pectoralis major valve reconstruction due to cutaneous involvement of the cervical lymph nodes.
Efficacy. The median follow-up duration was 25.2 months (range=3.1-79.8 months) for surviving patients. The 2-year LRFS was 71.0% [95% confidence interval (CI)=56.3-81.5] in the without upfront ND group and 93.7% (95%CI=77.2-98.4) in the with upfront ND group, a statistically significant difference [hazard ratio (HR)=0.27; 95%CI=0.08-0.93, p=0.04; Figure 2A]. The 2-year RFS was 56.6% (95%CI=41.5-69.2) in the without upfront ND group and 69.0% (95%CI=49.9-82.1) in the with upfront ND group (HR=0.56; 95%CI=0.27-1.14, p=0.08; Figure 2B). The 2-year OS was 84.2% (95%CI=69.3-92.3) in the without upfront ND group and 83.8% (95%CI=65.1-93.0) in the with upfront ND group, with no statistically significant difference (HR=0.69; 95%CI=0.25-1.87, p=0.46, Figure 2C).
Kaplan-Meier plots showing (A) locoregional recurrence-free survival (LRFS), (B) relapse-free survival (RFS), and (C) overall survival (OS) with/without upfront neck dissection (ND) for all patients.
For patients with radiographically positive preoperative ENE (40 cases), the 2-year LRFS was 57.1% (95%CI=28.9-77.7) in the without upfront ND group and 95.0% (95%CI=69.5-99.3) in the with upfront ND group, a statistically significant difference (HR=0.19; 95%CI=0.04-0.92, p=0.04; Figure 3A). The 2-year RFS was 47.6% (95%CI=22.8-68.9) in the without upfront ND group and 59.9% (95%CI=35.4-77.7) in the with upfront ND group, showing no statistically significant difference, but a trend toward superiority in the with upfront ND group (HR=0.46; 95%CI=0.18-1.18, p=0.11; Figure 3B). The 2-year OS was 63.3% (95%CI=31.7-83.3) in the without upfront ND group and 80.1% (95%CI=55.2-92.1) in the with upfront ND group, with no statistically significant difference (HR=0.52; 95%CI=0.16-1.73, p=0.28; Figure 3C).
Kaplan-Meier plots showing (A) locoregional recurrence-free survival (LRFS), (B) relapse-free survival (RFS), and (C) overall survival (OS) with/without upfront neck dissection (ND) for patients with extranodal extension.
Discussion
In this study, we explored the utility of “upfront ND” performed prior to CRT for enhancing local control and reducing complications. The with upfront ND group had a significantly better 2-year LRFS than the without upfront ND group. Further, although not statistically significant, the RFS tended to be superior in the with upfront ND group. No perioperative complications requiring treatment with upfront ND were noted, with no prolonged hospital stay, indicating the safety of this upfront ND.
Studies have highlighted a relatively high incidence of residual cervical lymph nodes after CRT in N2 and N3 cases (20, 21). However, cervical residual lymph nodes are difficult to determine, and the rate of postoperative pathologic lymph node metastasis in planned ND is estimated to be 23%-75%, including false-positive results (6-9). This uncertainty raises concerns about unnecessary surgery if postoperative pathologic lymph nodes in planned ND are negative for metastasis. Moreover, surgery following radiotherapy increases the risk of perioperative complications, potentially necessitating further surgical interventions (22-24). Therefore, we believe that upfront ND followed by CRT is acceptable for advanced N cases, to increase the rate of local control. In the present study, the cases in which upfront ND was performed were significantly more likely to be early T and advanced N cases. We believe that surgeons were proactive in performing upfront ND in such cases. In one patient with cervical lymph node involvement of the skin, local control was achieved by upfront ND, combined skin excision, and pectoralis major skin valve reconstruction followed by CRT. As such, upfront ND was useful even in patients who required an extended resection.
ENE-positive patients have a higher rate of cervical recurrence and distant metastases and a lower survival rate than N0 and ENE-negative patients (25, 26). In addition, if the pathology results after radical surgery are ENE-positive, CRT is recommended because of a high risk for recurrence (14). Therefore, upfront ND should be performed in clinical imaging ENE-positive cases, followed by CRT of the primary tumor and neck. Compared to surgery on the primary tumor and cervical lymph nodes followed by CRT, our procedure may be less invasive and improve the cure rate, as it reduces the need for surgery for the primary tumor. However, cervical lymph node metastasis of p16-positive oropharyngeal carcinoma often results in cystic changes, and conventional imaging criteria are considered unhelpful, and specific findings are not clear (27-29). Therefore, p16-positive oropharyngeal carcinoma may need to be distinguished from p16-negative oropharyngeal carcinoma and other squamous cell carcinomas of the head and neck.
One disadvantage of this approach is that, because both upfront ND and CRT are performed, there is a risk of increased adverse events due to ND compared with that due to CRT alone. In our study, perioperative complications due to ND did not occur, and patients’ course was favorable. Although there is concern that the treatment period may be prolonged, the median time from upfront ND to CRT initiation was 29 days in this study. Additionally, no cases of clinically evident enlargement were observed during this period. Nevertheless, this approach may not be suitable for patients with rapidly growing primary lesions, highlighting the challenge of shortening the time interval between upfront ND and CRT.
Study limitations. First, because this is a single-center, retrospective study, it is subject to some inherent selection bias. In fact, the upfront ND group had a higher proportion of early T cases and fewer early N cases, suggesting a tendency to prioritize ND for large cervical lymph nodes and CRT for large primary tumors. Second, our study did not include cases where ND was performed on residual cervical lymph nodes after CRT, nor did it explore upfront ND in cases of bilateral cervical lymph node metastases. Third, although perioperative complications related to ND were not observed in our study, differences in surgeon skill level and patient backgrounds may have influenced outcomes. Standardizing surgeon expertise and patient characteristics in future studies could address this limitation. Finally, long-term adverse events such as dysphagia were not investigated in our study, highlighting the need for further research in this area.
Conclusion
The study findings reveal that upfront ND is an option for primary treatment of locally advanced head and neck cancer and was particularly useful in ENE-positive cases. Upfront ND should be performed to achieve local control in resectable advanced N cases.
Acknowledgements
The Authors would like to thank Editage (www.editage.com) for English language editing.
Footnotes
Authors’ Contributions
TO and YU contributed to the conception and design of this study. HS, Kunihiko Tokashiki, Takahito Kondo, Takuma Kishida, and TI were responsible for the data collection. UY and IO contributed to data analysis. TO and YU drafted the manuscript. IO and Kiyoaki Tsukahara revised the manuscript critically for important intellectual content. The final version was read and approved by all the Authors.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
- Received August 19, 2024.
- Revision received September 13, 2024.
- Accepted September 16, 2024.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
