In non-small cell lung cancer, analysis of the lymph nodes is necessary to determine the appropriate treatment and stage of the cancer, and prognosis is associated with whether metastases are present.1 However, the preferred method for assessing the lymph nodes — complete mediastinal lymph node dissection vs. systematic lymph node sampling — is a topic that has been debated for several decades.2
“There has been a long-standing debate between lymph node dissection and lymph node sampling for lung cancer,” Raja Flores, MD, chief of the division of thoracic surgery at Mount Sinai Hospital and Ames Professor of Cardiothoracic Surgery at Icahn School of Medicine at Mount Sinai, told Healio. “Some believe that a mediastinal nodal dissection is essential to improve the cure rate of lung cancer. Some argue that such dissection just increases the chances of a surgical complication and worsens the outcome of these patients.”
“However, both sides agree that identification of positive lymph nodes, by either dissection or sampling, improves survival by accurately staging patients and providing additional treatment,” Flores continued. “Therefore, it is universally accepted that patients undergo lymph node evaluation by either method. All surgical and medical societies recommend mediastinal nodal evaluation.”
Mokhles and colleagues conducted a systematic review and meta-analysis of five randomized controlled trials comparing the two procedures, and although they found that lymph node dissection was associated with improved long-term survival vs. lymph node sampling, they noted that bias in the trials makes these findings inconclusive.3
In the American College of Surgery Oncology Group Z0030 Trial, Darling and colleagues evaluated whether lymph node dissection improved survival vs. lymph node sampling in patients undergoing resection for N0, or nonhilar N1, T1 or T2 NSCLC.⁴ The study included 1,023 eligible and evaluable patients randomly assigned to lymph node sampling (n = 498) or lymph node dissection (n = 525).
After a median follow-up of 6.5 years, the median survival for lymph node sampling was 8.1 years vs. 8.5 years for lymph node dissection (P = .25).4 In addition, the 5-year disease-free survival was 69% for lymph node sampling vs. 68% for lymph node dissection (P = .92). There was no difference in recurrence rates — local, regional or distant.
“Logic would have it that if there was no difference in outcome, then one should perform the lesser extensive procedure,” Flores said “However, the authors still recommended doing dissection rather than sampling. This emphasizes that surgical trials, even when performed, have small influences on actual practice.”
In another study, Sugi and colleagues evaluated 115 patients with tumors less than 2 cm in diameter who were randomly assigned to lobectomy with lymph node sampling (n = 56) or lobectomy with lymph node dissection (n = 59).⁵ The 5-year survival rate was 81% in the lymph node dissection group and 84% in the lymph node sampling group, with no significant differences in recurrence rate.
Nevertheless, there is still a debate, despite findings that lymph node dissection is associated with prolonged hospitalization and increased mortality, as well as increased operative risks, including increased operative time, blood loss, recurrent laryngeal nerve injury, chylothorax, risk for bronchopleural fistula, large vessel injury and tracheoesophageal fistula.6
Despite the many trials showing no difference in survival benefit between the procedures, some trials have demonstrated different findings, mainly favoring lymph node dissection.
In a systematic review and meta-analysis, Wright and colleagues evaluated 11 randomized controlled trials to compare the efficacy of different surgical procedures and determine whether surgical resection improves disease-specific mortality in patients with NSCLC.7 In a pooled analysis of three trials, they found that the 4-year survival among patients who underwent lymph node dissection was superior compared with lymph node sampling (HR = 0.78; 95% CI, 0.65-0.93).
Wang and colleagues conducted a retrospective study of 712 patients with N0-1 lung cancer to determine if lymph node dissection, performed according to the National Comprehensive Cancer Network’s criteria (3 or more stations of N2 node dissection), improved outcomes.8 They found that performing the procedure compliant with these criteria was a prognostic factor for OS across the entire cohort of patients (HR = 0.598; 95% CI, 0.425-0.841), particularly among the subgroup of patients with pathologic N2 stage disease (HR = 0.559; 95% CI 0.323-0.968).
Shen-Tu and colleagues performed a cohort study to assess long-term survival in patients undergoing lymph node dissection.9 The study included 317 patients with stage I NSCLC who were followed for at least 10 years. Among those, 161 patients underwent lymph node dissection and 156 underwent lymph node sampling.
They found that the lymph node dissection group had a better survival time: 154.67 months vs. 127.67 months among those who underwent lymph node sampling.9 The lymph node sampling group also experienced a higher mortality rate (crude HR =1.32; 95% CI, 0.97-1.78), and association persisted after adjusting for age and sex (P = .047). The researchers found that the increased mortality appeared strongest among patients with tumor sizes between 2 cm and 3 cm (HR = 2.79; 95% CI, 1.45-5.37).
“Each patient needs to be looked at individually,” Flores said. “Some patients may be better off with a sampling, and others with a dissection, depending on the histology of the tumor and findings on the CT and PET scans. This is up to the discretion of the surgeon. But all agree that evaluation of the mediastinal nodes is standard of care.”
In a review published in the European Journal of Cardio-thoracic Surgery, Zhong and colleagues concluded that complete lymph node dissection “is the core component of the lung cancer multidisciplinary therapy.”10 However, they also noted that “with the emergence of various preoperative staging techniques, the advantages of accurate neoplasm staging by [lymph node dissection] could be partially supplanted.”
The increase in use of video-assisted thoracic surgery, for example, may lead some surgeons away from performing lymph node dissection, because this technique makes dissection difficult to perform.10 In addition, the surgical approach will continue to evolve as video-assisted techniques are increasingly used to perform lobectomy, primarily in stage I and stage II cancers.
Su and colleagues performed a substudy of the American College of Surgery Oncology Group Z0030 Trial, evaluating differences in survival between patients who underwent video-assisted thoracoscopic surgery resection vs. open resection by conducting a propensity-score matched analysis. The study included 752 patients, of whom 66 underwent video-assisted thoracoscopic surgery and 686 underwent open surgery. Among the patients, 578 had stage T1 tumors and 440 had stage T2 tumors. They found no difference in OS, disease-free survival or development of new primary tumors.11
The authors noted, however, that “concern has been raised that [video-assisted thoracoscopic surgery] lobectomy for clinical Ta-2 N0 NSCLC may lead to less complete N1 lymph node evaluation and lower rates of N1 upstaging compared with open lobectomy.”11
Saji and colleagues wrote, “the effect of specific number of nodes removed on survival outcome remains controversial. Thus, further extensive prospective clinical studies are needed for lymph nodal assessment.”
They noted that the JCOG1413 trial, being conducted in Japan, is currently enrolling patients. The trial is a randomized phase 3 trial of lobe-specific vs. systematic nodal dissection for patients with stage I or II NSCLC. The endpoint is OS, and the objective is to “validate the non-inferiority of lobe-specific systematic nodal dissection based on lobectomy.”
The study is expected to enroll 1,700 patients.1 – by Emily Shafer, MA, ELS
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