In contrast to the latest NCCN guidelines which suggest adjuvant radiotherapy for patients with pN1 disease, our results demonstrated that postoperative radiotherapy was effective only in those without good-quality neck dissection (LN yield < 18).14,15 The protective effect of adjuvant radiotherapy failed to reach statistical significance for those with LN yield > 18. Because of the protective role of postoperative radiotherapy in oral and oropharyngeal cancer patients with pT1-2N1M0 disease without good-quality neck dissection, the NCCN guidelines for adjuvant radiotherapy in pN1 disease without adverse features may need to be modified according to the quality of retrieved LNs.
Several studies have demonstrated that pN1 may itself be an indication for postoperative radiotherapy after resection of oral cavity primary tumors.4,16 Chen et al. reported an association of postoperative radiotherapy with improved OS for 1,467 patients from the National Cancer Database with oral (HR, 0.76; 95% CI, 0.63–0.92) and oropharyngeal cancer (HR, 0.62; 95% CI, 0.41–0.92) with pN1 disease without adverse feature, especially in those younger than 70 years or those with pT2 disease. Shrime et al., in an analysis of 1,539 patients with T-21N1 oral cancer, found that 78.6% had postoperative radiotherapy, which was associated with better 5-year OS (54.2% vs 41.4%, P < 0.001).17 However, from the same SEER database, Kao et al. found no significant difference in 5-year OS between patients with N1 oral cancer with and without postoperative radiotherapy (38.7% vs 36.0%, P = 0.23).18 One explanation for these different results may be that inadequate LN harvests could lead to stage migration and subsequent underestimation of disease severity, especially in those with pN1disease.5 To our knowledge, our study is the first to evaluate the benefit of postoperative radiotherapy by quality of neck dissection in patients with pN1 involvement and no risk factors. Moreover, our large cohort (n = 1,765) indicates that the effect of operative radiotherapy on survival could assist clinicians in their therapeutic planning for these patients.
Because cervical LN metastasis significantly worsens the prognosis of patients with primary head and neck cancer by 50%, in general, the status of LN metastasis must be known for proper treatment.1 Many studies have used LN count as a prognostic factor in head and neck cancer patients and also as a potential quality metric for neck dissection.6,8 Divi et. al examined these associations in a large cohort from the U.S. National Cancer Database.19 They found an independent and significant association between examining < 18 LNs and increased risk of death (hazard ratio [HR] 1.18; 95% CI, 1.13–1.22). When patients were stratified by clinical nodal stage, the hazard of death was increased in both node negative and node positive groups (HR, 1.24; 95% CI, 1.17–1.32; HR, 1.12; 95% CI, 1.05–1.19, respectively). The study found a significant overall survival advantage when > 18 LNs are examined after neck dissection, concluding that 18 LNs is an effective cutoff for improved survival.
Although several studies have outlined the importance of LN yield on head and neck cancer, few have discussed the association of postoperative adjuvant radiotherapy with the quality of neck dissection.20,21 According to the latest NCCN guidelines, postoperative adjuvant radiotherapy may be considered in those with pN1 disease without other risk features.14 Our study explored the impact of postoperative radiotherapy in patients with pT1-2N1M0 without extranodal extension stratified by the number of retrieved LNs. For patients without good-quality neck dissection (LN yield < 18), postoperative adjuvant therapy could reduce the mortality rate 40%. However, patients with good-quality neck dissection (LN yield > 18) did not have a statistically significant reduction in 5-year OS or DSS (Tables 3 and 4). To spare them the potential side effects of pain, dry mouth, swallowing dysfunction, and neck fibrosis, postoperative radiotherapy could be omitted in such patients.
At present, treatment protocols for head and neck cancer, such NCCN guidelines, incorporate the TNM stage, surgical margin, pathological adverse features, and response to chemotherapy or radiotherapy.14 Margin status could be regarded as a proxy of surgery quality for primary tumor resection, although compartment surgery more than wide resection had better outcomes.22 However, neck dissection quality is not included in the treatment guidelines, even though retrieving more than 10 LNs in elective neck dissection and more than 15 in radical neck dissection has been suggested in order to prevent stage migration.10 For head and neck patients with pN1 disease, reports of the association between disease outcomes and adjuvant radiotherapy are conflicting.23,24 The confusion may stem in part from the heterogenous pattern of pN1 disease (which ranges from microscopic disease to 3 cm LNs), the extent of extracapsular spread, the various cancer subsites, and the quality of the neck dissection. In 2019, an expert panel suggested adjuvant radiotherapy in oral cancer patients with pN1 disease without good-quality neck dissection (< 18 LNs) and recommended the conduct of further prospective clinical trials.25 Our report provides evidence for the therapeutic effect of adjuvant radiotherapy for patients with pT1-2N1M0 oral cancer. Among patients without good-quality neck dissection, adjuvant radiotherapy could reduce the mortality rate up to 40% (aHR, 0.61; 95% CI, 0.48–0.78). Radiotherapy appears to offset the negative effect of poor-quality neck dissection and its therapeutic effect decreased as the number of retrieved LNs increased (Fig. 2).
There are several limitations in our series. First, the radiation field was not clearly described in the database. The radiation field might include the primary tumor, regional neck area, or both. These data could be not be extracted from the SEER database. Second, we tried to explore the effect of postoperative radiotherapy in pT1-2N1M0 patients and assumed that the radiotherapy was probably directed to the neck region for pN1 status. However, postoperative radiotherapy could be applied to the primary site due to the pathological features of the primary tumor. The positive margin has been reported to be around 1.6% in early stage oral cancer surgery.26 In T1-2 oral cancer patients, the rate of lymphovascluar permeation or perineural invasion is 13.3%.26 In sensitivity testing in our study, the effect of postoperative radiotherapy remained robust among patients without good-quality neck dissection, when the association of margin status, lymphovascluar permeation, or perineural invasion in the primary tumor were considered. Third, the study included only pT1-2N1M0 patients. Generalization of these results to other oral cancer patients, such as those with T3-4N1M0, will require additional studies.