To Node or Not to Node: The Paradigm Is Shifting in Early Stage Lung Cancer

Stage IA non-small cell lung cancer (NSCLC) with no evidence of nodal disease is generally perceived to have a favorable prognosis.

While current guidelines from the National Comprehensive Cancer Network (NCCN) recommend invasive nodal staging (INS) in stages IB–IIIA NSCLC, it is not universally required for stage 1A disease given the low likelihood of positive mediastinal nodes with peripheral tumors ≤3 cm and node-negative fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) or CT scans.

However, occult nodal metastasis may be more common than previously believed, raising concerns regarding the adequacy of current staging practices. While this research suggests that preoperative lymph node staging may be an attractive option for patients with early stage disease, cancer outcomes are influenced by competing factors such as timeliness to surgery.

This article reviews current practice patterns and nuances of nodal staging for early stage lung cancers (see Figure 1).

Lessons Learned about Nodal Staging

Peripheral lung cancers with clinical node-negative disease may have higher rates of occult nodal disease, which is different than what was previously understood.¹

A review of 58 patients with small (≤2 cm) clinical T1ab, N0, M0 NSCLC from the Cancer and Leukemia Group B (CALGB) 140503 trial found that 14% had occult N1 metastasis and 3% had occult N2 metastasis after hilar and mediastinal lymph node dissection. Upstaging was primarily detected in peripheral interlobar, lobar, or segmental stations (stations 11-13), with no differences in PET uptake or CT tumor diameter between upstaged and non-upstaged patients.

These findings from the Memorial Sloan Kettering Cancer Center study team may not be entirely surprising as evidence has suggested that nodal status historically was underassessed, and the prevalence of occult disease may be higher than previously reported. Concordantly, the rates of upstaging are similar to the rates of false-negative nodal disease on FDG PET/CT for lung cancer staging.²

While INS by either endobronchial ultrasound (EBUS) or mediastinoscopy has greater sensitivity to detect nodal disease compared to standard cross-sectional imaging alone, these techniques are not perfect. It may be tempting to forego intraoperative surgical nodal staging in early stage cancers with both negative PET/CT and preoperative INS. However, despite its increased sensitivity, INS does not eliminate missed nodal metastasis. In fact, some estimates show that INS may miss up to 19% of nodal disease.³

More specifically, an analysis of The Society of Thoracic Surgeons (STS) General Thoracic Surgery Database (GTSD) of more than 6,600 patients who had both a preoperative CT and PET, found that patients who underwent EBUS and mediastinoscopy had 20% and 18% of missed nodal disease, respectively.³ Despite the advantage of EBUS having the ability to evaluate both hilar and mediastinal nodes, this staging modality was not shown to have superior detection rates compared to mediastinoscopy.

Recognizing that smaller tumors may have a lower risk of nodal metastasis, the subgroup of patients with tumors ≤2 cm still found a rate of missed nodal disease in 16% of EBUS patients and 14% of mediastinoscopy patients. It is likely that the true rate of nodal microinvasion is even higher, as not all surgeons in that cohort performed a complete nodal dissection and, even among those who did, homogeny lacked on which stations were sampled.

Having negative cross-sectional imaging and INS preoperatively does not negate the need for a comprehensive surgical lymph node evaluation as patients with early stage disease may still have nodal disease, undetectable by current techniques.

Several reasons may explain these high rates of missed nodal disease, including high rates of user variability. For example, there are no currently established minimal standard requirements for EBUS-guided mediastinal nodal staging. While some providers may do a comprehensive sampling of each visible node with at least four to six passes per node, others may only perform selective sampling of suspicious nodes >5 mm or even abstain from sampling at all.

Currently, the STS GTSD does not consider EBUS-guided mediastinal nodal staging adequate without nodal biopsies, further invalidating a significant proportion of EBUS procedures performed in current practice. Missed nodal metastasis due to inherent technological limitations, coupled with significant practice variations make INS an imperfect mechanism in which the false-negative rate may be higher than generally realized. While INS may more frequently rule in nodal disease, negative cross-sectional imaging coupled with INS certainly does not exclude lymph node metastasis.

Differences in Outcomes

A key question to consider is whether preoperative INS in early stage lung cancers meaningfully alters the treatment course. Our recently published results examining close to 3,000 surgical patients with node-negative stage I-II NSCLC found that only 18.7% underwent invasive nodal staging and of those patients, only 0.4% were upstaged to stage IIIA or greater in which clinical management and order of sequence may significantly change.⁴ There was no association between upstaging and lack of preoperative invasive nodal staging, challenging the notion that preoperative nodal staging is routinely necessary in all early stage lung cancers.

For patients with micrometastases undetectable by imaging and INS, differences in outcome or survival would support the need for more clear preoperative staging and biopsy.

However, a recent study published in The Lancet found that, when matched for factors such as performance status, centrality, tumor size, and FDG avidity, there were no differences in both 5-year overall survival nor recurrence-free survival between those who did and did not have INS.⁵ Patients with INS had a 5-year overall survival of 74% and 5-year recurrence-free survival of 65%, while patients without INS had a survival of 72% and 68%, respectively.

Not surprisingly, most of the missed nodal metastasis were micrometastases with a maximal diameter of 5 mm, which is difficult to detect with current INS techniques. If the detection of micrometastatic disease significantly alters disease treatment or long-term outcomes (>5 years) for which we currently have minimal data, more widespread use in N0 cancers would be warranted.

With the rise of novel immunotherapies, it remains to be seen whether neoadjuvant immunotherapy for early stage, N1-positive cancers would offer better long-term outcomes and disease-free survival. Cost burden, complications, and delays in definitive treatment must be weighed against comprehensive INS in early cancers.

Time to Surgery as a New Quality Metric

Time to surgery has recently emerged as an important predictor of outcome (see Figure 2). In more than 2,500 patients with clinical stages I-II NSCLC, our group concluded that delays in surgery of more than 8 weeks was shown to increase 5-year risk of mortality (hazard ratio 1.19) and 1-year risk of recurrence (hazard ratio 1.25).⁶

In certain cases, upfront surgery may be preferable in early cancers rather than delay for more precise preoperative staging. The complexity of cancer care continues to grow, and additional diagnostic tests have inevitably lengthened the time from diagnosis to treatment.

Patients within a comprehensive healthcare system may experience minimal impact while underserved, low health literacy populations may face the most significant delays in care, especially when navigating fragmented care across multiple health systems. Access to healthcare even for those with adequate insurance may become more challenging as the population ages and the physician shortage continues to grow.

Many projections estimate that in the next 2 decades, the US could face a shortage of more than 100,000 physicians. The ability to schedule a timely appointment with a provider may become increasingly problematic, especially as new technologies allow for the earlier detection of disease. As the burden of disease and patient demand increases, the ability for medicine as a whole to meet that demand will be more difficult.

In select cases of early stage lung cancers with a negative PET/CT scan, upfront surgery with a comprehensive intraoperative mediastinal, and hilar lymph node dissection may lead to better outcomes. In fact, an STS clinical practice guideline strongly recommends definitive surgical resection with curative intent within 8-12 weeks from the time of diagnosis for patients with screening-detected suspicious lesions or patients with clinical stage 1 NSCLC who are good operative candidates.

Importance of Intraoperative Nodal Sampling

With the limitations surrounding preoperative lymph node staging described in this article, comprehensive intraoperative nodal evaluations are becoming increasingly important. Prior research has shown that a lack of lymph node examination leads to worse survival for patients.

Five-year survival rates of patients in the Surveillance, Epidemiology, and End Results Program who had no lymph nodes examined during definitive surgery (47%) were similar to those with N1 disease (45%), contrasted to patients with no disease (67%).⁷ Similarly, median duration of survival in patients with no nodes examined (3 years) was also similar to those with N1 disease (2.8 years), markedly lower than patients with N0 cancer (6.4 years).

Even after exclusion of patients who had a sublobar resection, a proportion of the population that may have confounded the results due to increased frailty and overall mortality, survival results in patients without lymph node examination remained similar to those with N1 disease. In fact, overall survival in those with six or more lymph nodes examined was higher when compared to those with one to five lymph nodes.

To address this variability in cancer surgery, over the last decade, the ACS has published a series of manuals, known as the Operative Standards for Cancer Surgery, defining key surgical techniques to achieve optimal surgical outcomes. In 2021, the ACS Commission on Cancer (CoC) adopted six operative standards as part of its national accreditation program across 1,400 hospitals nationwide.

Among these standards is Standard 5.8, requiring examination of one hilar lymph node (stations 10-14) and three mediastinal lymph nodes from three distinct stations (stations 2-9) for all lung cancer surgery with curative intent (see Figure 3). Standard 5.8 applies to all surgical patients with NSCLC, small cell lung cancer, and carcinoid tumors of the lung, regardless of type of surgical resection or operative approach (see Figure 4).

Currently, CoC Standard 5.8 is still in its initial implementation period, with limited published data on national hospital compliance. However, in our examination within an integrated healthcare system, significant heterogeneity exists with substantial room for improvement. In a sample of lung surgeries performed between 2009 and 2019, only 44% of patients had surgical nodes sampled meeting the Standard 5.8 criteria, a rate that was significantly higher than prior national averages.⁴

Although cancer care has improved dramatically within the last 2 decades, clinicians still face the ever-present variability in outcomes in a portion of patients.

Despite patients having similar cancer staging, patient characteristics, and treatment, recurrence and overall survival may still vary drastically in a subset. Part of this incongruity may be due to differences in surgical practice. Lack of proper intraoperative surgical examination of lymph nodes will inevitably lead to the underdiagnosis of patients who would otherwise be upstaged and benefit from adjuvant therapy.

Investigations regarding the implementation and effectiveness of the CoC operative standards are underway, including the Assessing the Effectiveness and Significance of the Operative Standards Program (also known as AESOP) study, supported by a federally funded research grant led by investigators at the University of Michigan in Ann Arbor and Yale University in New Haven, Connecticut, in collaboration with the ACS.

Accurate lymph node staging is essential for diagnosis, staging, and guiding treatment decisions for NSCLC. Invasive nodal staging has an important role in ruling in nodal disease and ruling out false positives such as in granulomatous nodes. However, in the subset of patients with early stage NSCLC with no suspicious lymph nodes on imaging, the utility of preoperative invasive nodal staging must be balanced with the potential delays they introduce.

Until recently, time from diagnosis to surgery has not played a large role in the overall management of NSCLC but new data have emerged showing that this metric may be more important than previously realized. In certain cases of node negative, early stage cancers—forgoing preoperative invasive nodal staging for upfront surgery with intraoperative nodal sampling—may be preferred, particularly if preoperative invasive staging risks delaying care. Vital to this approach, though, is a comprehensive, intraoperative lymph node dissection.

As treatment strategies continue to evolve, striking the right balance between accurate staging and timely intervention will remain essential for optimizing patient outcomes.

Dr. Michael Ou is a general surgery resident at UCSF.

Dr. Alison Baskin is a general surgery resident at UCSF.

Dr. Jeffrey Velotta is a thoracic surgeon, clinical professor at the Kaiser Permanente Bernard J. Tyson School of Medicine in Pasadena, CA, and clinical assistant professor at UCSF.

References

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