Discussion

To the best of our knowledge, this is the largest meta-analysis (including subgroup analyses by follow-up period) to compare sentinel node biopsy with elective neck dissection for early-stage oral cavity SCC patients with clinically N₀ necks (no metastases). We found no significant difference in overall survival (hazard ratio = 1.12), disease-free survival (hazard ratio = 0.96), or disease-specific survival (hazard ratio = 1.08). Ding et al. reported similar five-year disease-free survival and overall survival in sentinel node biopsy and elective neck dissection groups in their review article.^{Reference Ding, Xiao, Huang, Yuan, Ye and Xuan9} However, they included only six prospective studies and did not discuss disease-specific survival. Saleem et al. found no significant difference in disease-free survival or overall survival between patients who underwent sentinel node biopsy and elective neck dissection.^{Reference Saleem, Peng, Zhu, Wong, Pereira and Tham37} However, unlike our study, their disease-free survival data were heterogeneous. Saleem et al.^{Reference Saleem, Peng, Zhu, Wong, Pereira and Tham37} included 10 studies in a meta-analysis, but one of those studies (Hiraki et al.^{Reference Hiraki, Fukuma, Nagata, Shiraishi, Kawahara and Matsuoka38}) compared sentinel node biopsy and no neck dissection groups. Recently, Gupta et al. found no significant difference in overall survival between sentinel node biopsy and elective neck dissection groups.^{Reference Gupta, Maheshwari, Kannan, Nair, Chaturvedi and Agarwal39} Isolated neck nodal and locoregional recurrences were compared, and there was no significant difference; however, only three studies were included.

Five of the studies included in our meta-analysis had high weights because of their large sample sizes.^{Reference Fan, Zeng, Peng, Guo, Wang and Zhang20,Reference Cramer, Sridharan, Ferris, Duvvuri and Samant24,Reference den Toom, Boeve, Lobeek, Bloemena, Donswijk and de Keizer27–Reference Hasegawa, Tsukahara, Yoshimoto, Miura, Yokoyama and Hirano29} However, subgroup analyses showed minimal heterogeneity. Thus, although the studies varied somewhat in terms of design and quality, the variations did not affect the results, and the survival outcomes of sentinel node biopsy and elective neck dissection were similar. In contrast to Saleem et al., we found no significant difference in overall survival, disease-free survival or disease-specific survival between sentinel node biopsy and elective neck dissection in any study (Figure 2), possibly because our subgroups were defined by follow-up period (3, 5 and 10 years).^{Reference Ding, Xiao, Huang, Yuan, Ye and Xuan9,Reference Saleem, Peng, Zhu, Wong, Pereira and Tham37,Reference Gupta, Maheshwari, Kannan, Nair, Chaturvedi and Agarwal39,Reference Crocetta, Botti, Pernice, Murri, Castellucci and Menichetti40} Earlier meta-analyses did not perform subgroup analyses by follow-up period. In our analyses, the outcomes of sentinel node biopsy and elective neck dissection were similar. Also, we included three more papers than the largest previous meta-analysis.^{Reference Saleem, Peng, Zhu, Wong, Pereira and Tham37}

Sentinel node biopsy shows if there is a need for neck dissection; patients without neck node metastases can thus avoid unnecessary dissection. Elective neck dissection is associated with minimal complications.^{Reference Hernando, Villarreal, Alvarez-Marcos, Gallego, García-Consuegra and Junquera41} The sensitivity of sentinel node biopsy for head and neck cancer was reported as 92 per cent^{Reference Pitman, Johnson, Brown and Myers42}; in another study, it was 82.7 per cent, and the specificity was 98.1 per cent.^{Reference Kim, Kim, Kim and Hwang15,Reference Yang, Zhou and Wu16,Reference Schilling, Stoeckli, Haerle, Broglie, Huber and Sorensen43} The Sentinel European Node Trial recommended sentinel node biopsy for patients with clinical N₀ oral cavity SCC.^{Reference Schilling, Stoeckli, Haerle, Broglie, Huber and Sorensen43} Sentinel node biopsy is also recommended by the National Comprehensive Cancer Network.^{Reference Network44} Sentinel node biopsy is also effective in patients with other cancers and is widely used to evaluate breast cancer patients without metastases.^{Reference Glechner, Wöckel, Gartlehner, Thaler, Strobelberger and Griebler12} However, sentinel node biopsy has certain disadvantages. The node closest to the injection site may be too bright, which can lead to error.^{Reference Mahieu, de Maar, Nieuwenhuis, Deckers, Moonen and Alic45} Also, radiotracers may reduce sentinel node biopsy effectiveness. In patients with other cancers, the use of methylene blue dye was associated with high false-negative rates. When methylene blue was combined with indocyanine green or a technetium-based radiotracer, sentinel nodes were effectively detected.^{Reference Kim, Ku, Yang and Byeon46} Sentinel node biopsy accuracy was enhanced by dynamic lymphoscintigraphy and the use of a same-day protocol.^{Reference Tartaglione, Vigili, Rahimi, Celebrini, Pagan and Lauro47,Reference Nieuwenhuis, Pijpers, Castelijns and Snow48} Sentinel node biopsy tracers require further study.

The main strength of our meta-analysis is that it included 12 studies with 10 583 patients and showed publication bias in terms of overall survival or disease-specific survival (Figure 3). Some bias in terms of the disease-free survival for sentinel node biopsy was initially suggested, but the Duval and Tweedie trim and fill method indicated otherwise. Therefore, we concluded that the studies were not biased and the data are thus clinically relevant.

Our meta-analysis had some limitations. First, most of the included studies were non-randomised, so patient characteristics and tumour subsites may have differed among the groups, which would have slightly affected the results. However, few survival studies are randomised.^{Reference Djurisic, Rath, Gaber, Garattini, Bertele and Ngwabyt49} Garrel et al. included mainly early stage oral cavity SCC patients with no clinical lymph node metastases, but also a small number of oropharyngeal cancer patients (less than 13 per cent).^{Reference Garrel, Poissonnet, Moyà Plana, Fakhry, Dolivet and Lallemant28} Patients with human papillomavirus-positive oropharyngeal cancer have good prognoses and should be analysed separately.^{Reference Mallen-St Clair, Alani, Wang and Srivatsan50} Sundaram and Subramanyam included mainly T₁ and T₂ patients but also a small number of T₃ patients (less than 13 per cent).^{Reference Sundaram and Subramanyam26} Second, the tracers differed among the included studies. Several studies used tracers detectable by single-photon emission computed tomography–computed tomography,^{Reference Carvalho GMd, Kohler, Guimarães and Crespo22,Reference Moya-Plana, Aupérin, Guerlain, Gorphe, Casiraghi and Mamelle25,Reference den Toom, Boeve, Lobeek, Bloemena, Donswijk and de Keizer27,Reference Seferin, Pinto, Lin, Leite, Gimenes and Dedivitis31} but Hasegawa et al. used a tracer evident on single-photon emission–computed tomography.^{Reference Hasegawa, Tsukahara, Yoshimoto, Miura, Yokoyama and Hirano29} Third, we lacked data on smoking history and co-morbidities, which may affect survival.