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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

Is lymph node involvement by direct extension more favorable than "separate" nodal involvement?
Sun, 11/14/2010 - 11:22
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

The staging of lung cancer makes the distinction of whether there are any lymph nodes involved with cancer, and if so, whether they are within the lung that houses the primary cancer or outside of it; if the latter, a distinction is made among mid-chest nodes on the same side as the main tumor (N2), mid-chest nodes on the opposite side from the main tumor (N3), or above the collarbone (N3). This staging is described in more detail in a summary chapter in the lung cancer reference library on initial workup and staging of lung cancer.

But there may also be useful distinctions to be made. I've previously described some investigational work suggesting that the number of lymph nodes involved may have prognostic value. Another concept that is commonly accepted is that the risk of recurrence is lower if a patient has a lymph node involved just by direct extension of the cancer into an adjacent lymph node, as opposed to spread to lymph nodes that are some distance away from the primary tumor and therefore presumed to have spread through lymphatic channels. A Japanese study reviewed results in patients with resected early stage NSCLC and N1 nodal disease in order to address this question.

A prior publication by the same group from earlier this year looked at outcomes from just patients with squamous NSCLC who underwent surgery and had N1 disease as their highest stage. Among the 120 patients with N1 nodal disease, the 5-year survival was 67.7% in those with just direct extension, compared with the significantly inferior 5-year survival of 32.4% in those with distant spread, a result that was comparable to that seen in patients with N2 nodal involvement. The current effort looked at a much larger group of 324 consecutive patients with pathologically confirmed N1 nodal involvement, including patients with both squamous and adenocarcinoma histologies. They compared these results to those of 1524 patients with node-negative disease, and 330 others with N2 nodal disease (N3 nodal involvement is generally considered to not be best managed with surgery). The investigators reviewed whether there were differences in the overall NSCLC population and also looking specifically at the histology of the NSCLC tumor, as squamous tumors have a tendency toward more local spread and adenocarcinomas tend toward earlier spread to distant sites, although these are only general tendencies.

First, not surprisingly, patients with N1 disease had a 5-year overall survival (OS) of 51.3%, right between that of patients with N0 (zero) disease (i.e., no nodal involvement) at 77.5% and those with N2 nodal involvement, at 27.9%. And recapitulating the results of the earlier experience with squamous NSCLC on a larger scale, they found that the overall NSCLC patient population with N1 involvement defining their stage only by direct extension had a significantly better survival than those with separate lymph node spread. In fact, those who had only direct extension did worse than those with no nodal disease (also formally designated as N0 ("zero") disease), but better than those with separate N1 disease, who in turn still did better than those with N2 nodal disease confirmed after surgery. These results are shown in the curves below (top curves show pooled OS results for all N1 patients, and lower curves show OS results for N1 patients as broken down by direct extension (pN1 - D) or any separate nodal disease (pN1 - S)

nakao-os-by-lymph-node-details (click on image to enlarge)

The breakdown by NSCLC histology was quite interesting, showing that the differences in behavior based on direct extension vs. separate nodal involvement was especially pronounced in patients with squamous NSCLC and less so for those with an adenocarcinoma.


As shown in the curves above (upper - squamous; lower - adenocarcinoma), those with squamous histology and N1 nodes by direct extension only had a survival that was completely comparable with the outcomes of patients with no nodal involvement, while those with separate N1 nodal involvement tracked with the patients with N2 disease. In contrast, the patients with N1 disease and an adenocarcinoma showed a moderate effect, in which those with adenocarcinoma and N1 nodal involvement by direct extension had a moderately but not quite statistically significantly better 5-year OS than those with an adenocarcinoma and N1 disease in one or more separate and more distant nodes (52.2% vs. 46.2%, p = 0.06).

This large database of outcomes for resected patients also provides an opportunity to assess which other variables are relevant in the outcomes of patients with resected N1 disease. Along with the factor of direct extension vs. separate node involvement, other significant or borderline statistically significant factors included age of younger than 65 or older than that (5-year OS 57% vs. 47%, respectively), central vs. peripheral location (63% vs 43%), tumor size of up to 4 cm vs. larger (56% vs. 45%), absence or presence of lymphatic invasion (58% vs. 47%), and pleural invasion (56% vs. 47%).

Overall, these results are interesting in confirming our general teaching tha N1t nodal involvement by direct extension is more favorable than more distant N1 nodal spread, though very likely this distinction is more pronounced in those with a squamous tumor (presumably, adenocarcinoma histology is somewhat more likely to still have distant spread even if there is just N1 nodal disease by direct extension). The fact is that in many patients, the recommendation for adjuvant chemotherapy is not necessarily definitive, since many patients may not be ideal candidates and/or may question whether the benefit is worth the risk and challenge of several cycles of adjuvant therapy. Results from studies like this one can arguably allow us to offer a more refined recommendation about the anticipated benefits and risks, potentially making a physician and patient more comfortable about not as forcefully recommending adjuvant therapy for someone with a single lymph node involved by direct extension, especially if that person has a smaller squamous cancer (we'd often recommend chemo just on the basis of a tumor measuring 4 cm or larger, regardless of nodal status). And for a wider population, this information can potentially provide a better honed sense of prognosis.

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