Do patients with cN0 oral squamous cell carcinoma benefit from elective neck dissection? A large-scale population-based study

According to the GLOBOCAN 2020 database, there were 377,713 new cases (2.0% of the total) of lip and oral cavity cancer and 177,757 new deaths (1.8% of the total) from this condition in 2020, the majority of which were oral squamous cell carcinoma (OSCC) [1]. Surgical excision of the primary tumor is the major treatment for patients with OSCC according to the NCCN Clinical Practice Guidelines in Oncology for Head and Neck Cancers, combined with radiation therapy, chemotherapy and the newly introduced immunotherapy [2].

One of the defining features of OSCC is lymph node metastasis, which can be occult and dramatically affect the survival and prognosis of patients [3]. Although imaging technologies have evolved in decades, it is still impossible to detect all occult metastases in the cervical lymph nodes [4]. The best approach to neck management has not reached a consensus, especially for clinical-nodal negative (cN0) OSCC patients [5].

Elective neck dissection (END) and observation are the two main strategies for neck management, which are chosen mostly based on the judgments of surgeons [5]. Whether to perform END or just wait and observe has been debated for a long time but still remains controversial [6]. Many researchers found that END could significantly prolong the survival time and decrease regional recurrences in patients with tongue, floor of mouth, buccal mucosa or other sites of squamous cell carcinoma, advocating that END should be the upfront treatment to remove any occult metastasis [7, 8]. In contrast, other studies showed that the performance of END was not associated with improved rates of overall or disease-specific survival, especially in cT1-2 OSCC, and it was associated with higher rates of complications, including shoulder dysfunction, pain, and contour changes [9‐11]. The conflict between these two decisions may be due to the lack of sufficient samples and multidimensional analysis of different kinds of patients with OSCC.

The Surveillance, Epidemiology, and End Results (SEER) database provides an appropriate opportunity to survey the necessity and benefit of END in patients with cN0 OSCC because of its large sample size and relatively comprehensive clinical records [12]. Based on the large-scale population of these patients, we thoroughly investigated the potential factors that modulate the benefit of END on patient survival and identified the optimal candidates who could gain maximum benefit from END with multiple subgroup analyses. To our knowledge, this retrospective study was conducted with the most updated data from the SEER database and the largest possible sample size. We sought to provide objective evidence for the management of the cN0 neck in patients with OSCC.

Based on the large-population survival analysis of patients with cN0 OSCC acquired from the SEER database, we found that END was an independent prognostic factor. Surprisingly, in the subgroup analysis, END did not affect survival in patients who underwent primary site surgery. After excluding the influence of radiation or chemotherapy on survival, we found that not all patients with cN0 OSCC could definitely benefit from END. Further analysis showed that patients with TSCC, even those with early-stage tumors, could benefit from END, but END did not lead to significantly better survival results for tumors arising from other sites.

In recent decades, researchers around the world have continuously focused on END in OSCC patients, especially those with early-stage tumors. Before 2010, four randomized controlled trials (RCTs) were carried out with small samples (only 67–71), three of which did not find differences in survival between END or observation [14‐17]. A surgical team from Brazil found that patients treated with elective supraomohyoid neck dissection had a significant benefit in terms of disease-free survival (DFS) only in those whose tumor thickness was > 4 mm and a later stage, leaving the question unanswered [16]. In 2015, D’Cruz AK and his team performed the largest single-center RCT, the Mumbai trial [18], comparing END and therapeutic node dissection (watchful waiting followed by neck dissection for nodal relapse). Their results showed an improved rate of overall survival (80.0% vs. 67.5%, P = 0.01) and disease-free survival with END relative to those in the therapeutic surgery group (69.5% vs. 45.9%, P < 0.001), with similar complication rates (6.6% vs. 3.6%). Nevertheless, these studies could not provide conclusive evidence because of the low quality of the trials [19]. Later, the high-quality SEND study [19] in 2019 with 27 hospitals in the UK and 250 randomized patients indicated that those who underwent END had a lower risk of death or local recurrence, even with small tumors. However, the lack of enough samples from extensive areas still limits the generalization of END in cN0 OSCC patients.

Many researchers have conducted meta-analyses to summarize the effect of END from a larger cohort [20, 21], but the inherent heterogeneity among different studies, especially between RCTs and retrospective studies, makes it difficult to provide convincing conclusions [22]. Three meta-analyses, which included only the RCTs mentioned above, were conducted in 2011 [23], 2015 [24] and 2019 [25]. Their results revealed that END significantly reduced the risk of regional recurrences and the risk of disease-specific death and revealed a longer OS and DFS compared to observation. These studies, however, included low-quality RCTs, leading to their inferior reliability.

The SEER Program of the National Cancer Institute is a relatively comprehensive source of information on cancer incidence and survival in the United States, covering 48% of the U.S. population currently [25]. Several studies have investigated cN0 OSCC patients within this database [26]. Alimujiang et al. performed two SEER-based analyses comparing END and observation in cT1N0 or T2N0 OSCC patients separately [13, 27]. Through survival analysis and the Cox regression model, they showed that END was an independent prognostic indicator, improving both DSS and OS. These results are in accordance with our findings, but in our study, we further explored the potential factors that affect the survival of END-treated patients and the actual characteristics that predict a benefit from END.

To our knowledge, our study is the first to evaluate the effect of END in cN0 OSCC with multidimensional subgroup analysis. However, there are still several shortcomings of this study. An analysis of pathological grade was not included because the records of pathological grade were missing in most cases, and those with this record were censored at 2 years. Another disadvantage lies in the missing data of the actual affected lymph node distribution in different areas of the neck in those who underwent END, making it impossible to elucidate which district should be surgically excised among the different sites [28].

To conclude, primary tumor site and T stage are the essential factors that influence the benefit of END on patient survival, and END is recommended in patients with cN0 TSCC, especially those with early-stage tumors. In the future, the potential immunological or molecular mechanism of END should be clarified, and large-scale multicenter RCTs investigating new surgical methods, such as sentinel lymph node dissection (SLND), are urgently needed [29].