In the past couple of posts we’ve seen that based on evidence from Japan and Rome, number of lymph nodes resected and also the absolute number of positive nodes and/or proportion of positive nodes may be important prognostic variable. A third abstract I reviewed on the same subject came from Peoria, IL, and illustrated a key reason why using these variables may not be as consistently useful as we’d like, at least in many parts of the world. In the study from Japan I discussed in a recent prior post, the investigators evaluated records from 574 patients and excluded the 27 (5%) of cases in which fewer than 10 nodes were removed at surgery, because they considered this to be a suboptimal resection. Meanwhile, the study from Italy that I reviewed in my last post wasn’t as stringent but also identified 10 lymph notes as an important separation point for better vs. worse survival.

So how do we do in the US? Peoria is a town in Illinois that is considered to be so representative of Anytown, USA (at least any small to medium-sized town) that the phrase, “But how does it play in Peoria?” is a common way of asking whether something is representative of a broader American experience. As it happens, the last presentation I reviewed tells us something about these surgical questions in Peoria, because it reviewed the experience of 98 patients who underwent surgery for stage IA NSCLC at a hospital in Peoria, IL over a 7-year period (abstract here). Stage I NSCLC is defined by an absence of any lymph node involvement, so the investigators excluded the patients who didn’t have even a single lymph node removed at surgery (not exactly a high bar compared with the experience in Japan, where they excluded the 5% of cases where fewer than 10 nodes were removed! (And we don’t even know how many cases in Peoria missed that rather non-ambitious cutoff...) They found that, as in the Italian study, prognosis was better in the patients in whom more lymph nodes were removed, as shown here:

There are several points to take from this. First, in this study only 13% of patients had more than 9 lymph nodes removed, while a full third of patients had just 1-3 lymph nodes removed, while another third had 4-6 nodes removed. So 87% of the surgeries from Peoria didn’t meet the standard that the Japanese investigators considered to be desirable for an optimal NSCLC surgery. While the patients who had the most nodes removed here did quite well, the results in the groups with few nodes removed is very, very poor, especially in the group that had just 1-3 nodes removed. This group did so poorly, it’s as if they weren’t really stage IA patients.

And that brings up a key problem with this line of research. One issue that is very well established for patients with early stage NSCLC is that there is a big difference between clinical staging and pathologic staging. Clinical staging is based on scans, while pathologic staging is based on an actual surgery to clarify what areas are involved with cancer and what are not. As you can see from the table below, the prognosis of a patient with any stage of potentially resectable NSCLC is notably higher for those patients who undergo pathologic staging compared with those who are considered to be the same stage but assessed only by scans.

Why? Because actually looking in the chest and removing many lymph nodes that can be examined under a microscope provides a significant opportunity to find cancer involvement in unsuspected places. You can’t find a fever if you don’t take a temperature, and you can’t find that non-enlarged lymph nodes are positive for cancer spread unless you get them and look. So a large proportion of patients who don’t have surgery are understaged and actually would have been found to have stage II or III or even stage IV NSCLC if someone had gone searching better. And I would argue that removing just 1-3 lymph nodes at surgery is not much better than clinical staging. I suspect that a large proportion of the patients staged as IA in Peoria had higher stage disease but didn’t get adequately evaluated.

In fact, studies have shown that the more you look, the more you find. For instance, one study conducted in France and Russia (publication here) that started with mediastinal lymph node sampling (just checking suspicious nodes) and then did a complete mediastinal dissection (surgery to remove all accessible nodes) found that 20% of the patients who underwent just sampling had a higher stage of disease detected by the more extensive surgery. Clearly, one major factor in comparing surgical studies in different places is how “pure” the staging is. Better staging leads to better results, in some part simply because stage I patients who have had 20 nodes removed have been proven to actually have stage I disease despite thorough testing to check if they actually have higher stage disease. The patients called stage I but who only have 3 lymph nodes removed at surgery may very well have had cancer in the 4th or 10th lymph node, for instance, but that node is still sitting in the patient. So less well staged patients are really a mix of lower stage and higher stage patients, and of course they do less well as a group. It’s the “don’t ask, don’t tell” staging policy.

This idea of stage migration is also likely to be a part of why PET has helped us appear to do better. Prior to PET scans, small liver or adrenal lesions, for instance, often went undetected, and patients went on to a “futile surgery” because they actually had metastatic disease for which surgery wouldn’t help. When you remove the patients with a tiny amount of metastatic cancer from a surgical group and then add them to a group with metastatic disease, both groups appear to do better, because you’ve made the surgical group purer and diluted the metastatic group with patients who have a very low tumor burden and are likely to do better than the patients with very extensive and bulky metastatic disease. This is the so-called “Will Rogers Phenomenon”, referring to the entertainer’s famous quip that when the Okies left Oklahoma in the Depression and moved to California, they raised the intelligence of both states.

There are also a few other reasons why looking at the number of lymph nodes resected may be problematic for assessing prognosis. First, at the time of surgery, nodes are often removed in pieces, so a pathologist looking at the whole collection of material often can’t tell what’s a node vs. a fragment (similar to counting the number of beans in a cup of navy bean soup, I suppose). Second, node numbers also depend on how meticulous and skilled the pathologist is in teasing apart nodes from fat and other tissues. A very diligent pathologist can find more nodes than a mediocre one, and in situations where surgeons or medical oncologists tell the pathologist that they need to go back to find more (decisions about chemo in colon cancer, for instance, depend on examining a certain number of nodes), they almost always seem to find exactly the number needed. Finally, number of nodes may also be a more general reflection of surgical skill and the overall quality of medical care a patient receives.

In case you think I’m picking on Peoria by singling out this town, the available evidence suggests that their results represent the real-world experience in much of the US. I’ll finish this long string of related posts on surgical issues in early stage NSCLC with one last one soon that covers the evidence using surgical findings in a broader American experience.