In this JCO Article Insights episode, Dr. Joseph Matthew interviews authors Dr. Yang Zhang and Dr. Haiquan Chen about their recently published JCO article, "Phase III Study of Mediastinal Lymph Node Dissection for Ground Glass Opacity–Dominant Lung Adenocarcinoma"

TRANSCRIPT

Joseph Mathew: Welcome to the Journal of Clinical Oncology Article Insights episode for the August issue of the JCO. This is Joseph Mathew, editorial fellow for JCO, and today, it is my pleasure to have with us Dr. Haiquan Chen and Dr. Yang Zhang, authors of the recently published manuscript, "Phase 3 Study of Mediastinal Lymph Node Dissection for Ground-Glass Opacity-Dominant Lung Adenocarcinoma," which we will be discussing today. Dr. Chen is the Director of the Institute of Thoracic Oncology at Fudan University and the Chief of Thoracic Surgery at Fudan University Shanghai Cancer Center, where he is also the Head of Thoracic Oncology MDT and the Director of the Lung Cancer Center. Dr. Chen is a surgeon-scientist and a pioneer in developing individualized surgical strategies for early-stage non-small cell lung cancer. Dr. Zhang is a surgical oncologist and a member of the team which Dr. Chen leads at the Fudan University Shanghai Cancer Center.

Welcome Dr. Chen and Dr. Zhang. Thank you very much for accepting our invitation and joining us today as part of this podcast episode.

To summarize the salient points, this study presented the interim analysis of a multi-center, open-label, non-inferiority, randomized controlled trial investigating the necessity of systematic mediastinal lymph node dissection at the time of segmentectomy or lobectomy in patients with clinical stage T1N0M0 ground-glass opacity-dominant invasive lung adenocarcinoma, as defined by a consolidation-to-tumor ratio of 0.5 or less on thin-section computed tomography and a maximum tumor diameter of 3 cm or less. Eligible participants with intraoperatively confirmed invasive adenocarcinoma on frozen section analysis were randomized to either the systematic mediastinal lymph node dissection arm or to no mediastinal lymph node dissection. In the latter experimental group, mediastinal lymph nodes comprising the N2 nodal stations were not dissected, and the hilar nodes were variably addressed at the discretion of the operating surgeon.

The primary endpoint of the trial was disease-free survival at 3 years. Secondary endpoints included perioperative outcomes, the status of lymph node metastasis in the systemic lymph node dissection arm, and 3-year overall survival. Before the trial reached its accrual target, a pre-planned interim safety analysis set for the time point when enrollment reached 300 patients was performed. It was noted that while none of the patients in either arm had nodal metastasis on postoperative pathological evaluation, lymph node dissection-related intraoperative and postoperative complications were more commonly observed in the systematic lymph node dissection arm, including one life-threatening episode of massive bleeding. Since this met the predefined criteria for trial termination, and in accordance with the principle of non-maleficence, further recruitment was stopped and the trial terminated.

Although the 3-year disease-free survival and the overall survival for the enrolled patients were comparable, operative outcomes, including the duration of surgery, blood loss, chest tube duration, length of postoperative stay, and the rate of clinically significant complications, were significantly lower in the experimental arm compared with the systematic lymph node dissection group. The authors concluded that for well-selected patients, mediastinal nodal dissection could be omitted without adversely affecting oncological outcomes, representing a significant shift in current surgical practice, given that guidelines the world over recommend systematic lymph node dissection or sampling for all invasive lung cancers.

In summary, this study addressed a clinically relevant question with regard to the extent of nodal dissection, especially in the light of recent evidence recommending less extensive parenchymal dissections for early-stage non-small cell lung cancer, with the findings suggesting that invasive lung adenocarcinoma associated with ground-glass opacities of consolidation-to-tumor ratio up to 0.5 was an excellent predictor of tumor biology, and in clinical T1N0M0 lesions, a reliable predictor of negative mediastinal lymph node involvement.

So Dr. Chen and Dr. Zhang, could you tell us some more about what led you to do this research and the challenges which you faced while recruiting patients for this trial?

Dr. Yang Zhang: Dr. Mathew, thank you for your summary. The current clinical guidelines recommend systematic lymph node dissection or sampling for every patient with early-stage lung cancer, regardless of their lymph node status. And in our clinical practice, we observe that this procedure causes a lot of surgical complications including chylothorax and recurrent laryngeal nerve injury. Furthermore, dissecting the tumor-draining lymph nodes actually may potentially damage the body's anti-tumor immunity. So, Dr. Chen proposed the concept of selective lymph node dissection, which we aimed to dissect the metastatic lymph nodes, while at the same time we try to preserve as many uninvolved lymph nodes as possible.

So previously, we have conducted a series of retrospective studies to identify reliable predictors of nodal negative status in certain mediastinal zones, and we have performed a prospective observational phase 2 clinical trial to validate that the six criteria we proposed are 100% in predicting node-negative status. And this forms the basis for our phase 3 clinical trial.

Dr. Haiquan Chen: This trial is only one of the series of trials. The meaning of this trial you already said. And for a long time, from the surgeon's point of view, we considered minimally invasive surgery. It minimizes the size of the incision and minimizes the number of the holes we made. So, the true and the high-impact of minimally invasive, we make a concept of minimal dissection, that means organ-level minimally invasive. So we proposed the concept of minimally invasive 3.0, that means minimal incision, minimal dissection (that means organ-level minimal), and systemic minimally invasive.

So at first, we judged from the point of minimally invasive surgery. As long as immunotherapy is widely used in the clinical practice, we know immunotherapy, that means you use drugs to stimulate and activate the lymph node site. If we dissect all the metastatic lymph nodes, cut them out, how can we restimulate that lymph node site? So, from minimally invasive trauma and second, from the functional aspect, to try to save as many uninvolved lymph nodes as possible.

Joseph Mathew: Thank you, Dr. Chen. That's a very interesting concept that you alluded to even in the discussion of this paper, as to the potential role of the non-metastatic lymph nodes as immune reservoirs.

So, coming back to this paper, were there any challenges which you faced while recruiting patients for this trial?

Dr. Haiquan Chen: The c