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4L lymph node dissection may improve lung cancer survival

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September 11, 2018

Patients with primary left lung cancer who underwent 4L lymph node dissection had more favorable survival outcomes than those who did not receive 4L dissection, according a single-center, retrospective study.

“The standard treatment procedure for resectable non-small cell lung cancer involves lobectomy with systemic mediastinal lymph node dissection,” Ya-Nan Wang, PhD, of Tianjin Medical

University Cancer Institute, and colleagues wrote. “However, the degree to which the mediastinal lymph nodes should be exposed and the extent of their excision is still under debate.

“Station 4L LN dissection for left lung cancer is more difficult than that for right lung cancer because of anatomic limitations caused by the aortic arch, left recurrent laryngeal nerve and thoracic duct,” Wang and colleagues added. “Therefore, superior mediastinal lymph node metastasis of left lung cancer is rarely studied.”

However, the International Association for the Study of Lung Cancer (IASLC) suggests that systematic nodal dissection involves the minimal excision of at least three mediastinal nodal stations without requiring 4L lymph nodes among patients with left-sided tumors.

To evaluate the clinical significance of 4L lymph node dissection, Wang and colleagues collected data from 657 patients with primary left lung cancer who underwent surgical pulmonary resection, 139 of whom received 4L lymph node dissection.

Researchers used the lymph node map proposed by IASLC to classify lymph node stations, with the goal of removing station 1 to station 12.

DFS and OS served as the primary endpoints.

Researchers found that 20.9% of patients who underwent 4L lymph node dissection had 4L involvement, which appeared significantly higher than the metastasis rate of station 7 (14%; P = .048) and station 9 (9.8%; P < .001) lymph nodes.

Univariate analysis suggested station 4L metastasis correlated with metastasis in most other lymph node stations except for station 8. However, multivariate analysis showed only station 10 lymph node metastasis served as an independent risk factor for 4L lymph node metastasis (OR = 0.25; 95% CI, 0.1-0.58).

Researchers observed improved 5-year DFS (54.8% vs. 42.7%; P = .0376) and 5-year OS (58.9% vs. 47.2%; P = .02) among patients who underwent 4L lymph node dissection compared with those who did not.

In a multivariate analysis with adjustment for potential confounders, 4L lymph node dissection had an independent benefit on DFS (HR = 1.5; 95% CI, 1.15-1.94) and OS (HR = 1.58; 95% CI, 1.22-2.05).

Propensity score weighting further confirmed patients who underwent 4L lymph node dissection had improved DFS (P = .0014) and OS (P < .001).

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The limitations of the study included its retrospective study design, possible selection bias and patients lost to follow-up.

“Consequently, long-term effects remain to be fully confirmed and should be studied further with a larger sample size and a multicenter randomized clinical trial,” the researchers wrote.

In an accompanying editorial, Dirk K.M. De Ruysscher, MD, of the MAASTRO Clinic in the Netherlands and Herbert Decaluwé, MD, of the University Hospitals Leuven in Belgium, agreed a survival benefit is difficult to prove without a randomized controlled trial.

“The findings in the Wang et al study, that surgical removal of station 4L might improve OS, should therefore be viewed as hypothesis generating only,” they wrote. “As the authors note, their study is retrospective with significant known imbalances in the prognostic factors between the group treated with 4L dissection and the other group. Propensity techniques are an attempt to deal with the imbalance of confounders, but they are by no means as strong as randomization.” – by Cassie Homer

Disclosures: The authors report no relevant financial diclosures. De Ruysscher reports institutional consultant/advisory roles with AstraZeneca, Bristol-Myers Squibb, Celgene, Genentech and Merck Serono, and institutional research funding from Bristol-Myers Squibb and Boehringer Ingelheim. Decaluwé reports no relevant financial disclosures.

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For resectable NSCLC, most experts recommend a systematic nodal dissection that includes a minimum of three N2 lymph node stations. In this thoughtful retrospective analysis, Wang and colleagues report a prognostic benefit of including 4L within N2 lymph node dissection. The analysis included 657 patients with primary left lung cancer who were divided into two groups, those who underwent 4L dissection (n = 139) and those who did not (n = 518). Benefits occurred for both 5-year DFS (54.8% vs. 42.7%; P = .04) and OS (58.9% vs. 47.2%; P = .02) in 4L dissection group. Interestingly, metastasis in station 10 was independently associated with 4L metastasis.

Pneumonectomy for lung cancer was first reported by Graham and colleagues in 1933. Later, Cahan and colleagues reported successful cases of lobectomy with regional lymph node dissection. Video assistance provided the next improvement in intrathoracotomy hilar and mediastinal lymph node evaluations, demonstrating OS benefit of systematic lymph node dissection.

For left-sided tumors, it is common practice in United States to dissect only stations 5, 6, 7 and 10L (often excluding 4L). This is largely based on ACOSOG Z0030 trial in which 4L dissection was optional. In this trial, researchers prospectively randomized 1,111 patients 1:1 to complete mediastinal lymph node dissection or sampling. No OS benefit occurred at 8.5 years (50.9% vs. 52.4%; P = 0.5). Moreover, dissection of 4L is challenging as it sits above 10L and is fraught with injury to thoracic duct, recurrent nerve and aortic arch, as indicated by Wang and colleagues. Thus, 4L dissection is rarely R0 and mostly R1/R2. 

Although this study is important to complete and publish, the mentioned limitations should be considered when interpreting the results:

  • More patients in group that did not undergo 4L dissection were smokers, they had more comorbidities and they demonstrated 10-fold higher lost-to-follow-up rate, possibly contributing to decreased survival in this group;
  • Authors used propensity score weighing, eliminating known — but not unknown — sources of bias; and
  • The report provided limited information on presurgical clinical staging (ie, PET/CT, EBUS) or pre/postsurgical therapy. For example, in those 20.9% patients who underwent 4L dissection who were upstaged to pN2, did this alter adjuvant recommendations? And did those recommendations result in outcome differences? Was it the physical node removal or the adjuvant therapy that resulted in better OS? The authors report a group of patients (41%) who had pN2 disease with an unusually high 5-year OS of 60%.

What do we do with this information provided by Wang and colleagues? With its inherent limitations as described above and lack of survival benefit from prospective randomized controlled trials, it is difficult to accept this study’s conclusion of OS benefit from 4L dissection. However, the authors’ conclusion that 4L is not rare, especially when 10L is involved, is hypothesis generating. One application could be to obtain an intraoperative frozen section of 10L lymph node and, if positive, then assume additional risk by completing the 4L dissection.

Finally, this study is a reminder of the prognostic impact of lymph node evaluations in malignancies. Established surgical standards exist for colon (minimum 12 LNs) and gastric (D2 resection) cancers, predicting survival benefit. In lung cancer, recent WHO data demonstrated the importance of identifying the “number” of involved lymph nodes. This study should be considered in future investigations to improve lung cancer lymph node dissection standards.

Mufti Naeem Ahmad, MD

Kathryn Finch Mileham, MD, FACP

Levine Cancer Institute

Atrium Health

Disclosure: Ahmad and Mileham report no relevant financial disclosures.