While post-operative chemotherapy for early stage NSCLC is a well-established standard for relatively healthy patients with stage II or higher resected cancers, the question of whether adjuvant chemotherapy is more likely to help or hurt a patient remains more a matter of debate.  Much of the debate has focused on a threshold of tumor size, with 4 cm emerging as a cutoff, above which chemotherapy appears more likely to be helpful and is often recommended.  The general concept is that adjuvant chemotherapy confers a benefit that is proportional to the risk of the cancer recurring -- a higher risk cancer is more likely to have the risk reduced by chemo more than enough to counterbalance the acute and chronic side effects of adjuvant chemo.  But while tumor size is certainly one of the more readily identifiable factors associated with risk of recurrence and death, it's not the only relevant factor. The National Comprehensive Cancer Network (NCCN) also includes several other factors in its guidelines for consideration of adjuvant chemotherapy, even for smaller tumors, so let's review those.  

I covered the issues of tumor histology and pleural invasion in a prior post.  In addition, vascular invasion, or tumor cells invading into blood vessels, is associated with increased risk. In fact, as shown in the figure to the left, T1 (smaller) cancers with vascular invasion have a worse outcome than T2 (larger) cancers that don't have vascular invasion.

Another important factor related to the biology of the cancer is the tumor grade -- how well or poorly the tumor cells resemble the normal cells they are derived from.  I discussed this issue years ago, highlighting work that shows that patients with poorly differentiated cancers have a worse survival overall than those with better differentiated cancers.  But if we look at the results just in patients with resected stage I NSCLC (on the left), we also see that patients with poorly differentated tumors do worse, leading to the hypothesis that such patients might be well served by consideration of adjuvant chemotherapy.

 All of these factors are related to the cancer, but other important issues are related to the surgery.  One, as shown on the left, is whether a wedge resection was done, as a smaller surgery is associated with a higher risk of recurrence than a lobectomy.  The other, as described in a prior post, is the association of worse outcome with few nodes being removed at the time of surgery.  This is particularly true in cases where no lymph nodes were removed at the time of surgery, as shown in the figure on the right.  

There are a few reasons why these surgery issues may be important.  First, the surgery itself could be the leading factor: patients who can't tolerate a lobectomy may do worse not because the surgery was inferior, but rather because they aren't well enough to tolerate a lobectomy.  The few randomized trials have suggested that in patients who can tolerate either surgery, a surgery that is less than a lobectomy appears inferior -- though this doesn't necessarily apply to elderly patients or to patients with very small (<2 cm) tumors, perhaps especially bronchioloalveolar carcinomas (BACs).  

With regard to the yield of lymph nodes at surgery, there isn't a defined standard of a threshold number of lymph nodes a surgeon should remove, but it's more than 0.  In general, the surgical literature shows an association of better survival in patients who have many lymph nodes removed.  This may be because removing more lymph nodes provides a more accurate staging, or it may be because there is a direct beneficial effect of removing cancerous nodes, or it may be because the surgeons who remove more lymph nodes are better surgeons who do a more meticulous job.  I suspect that all of these issues are factors, but above all, I would submit that if no lymph nodes have been removed, you can't say someone has a node-negative cancer: that's the "don't ask, don't tell" school of staging (or, if you prefer, fall to the aphorism from the classic humorous medical book The House of God that "you can't find a fever if you don't take a temperature").  

The NCCN, recognizing that all of these factors, along with the size of the cancer, are associated with a higher risk of cancer recurrence in patients with stage I NSCLC after surgery, therefore offers a recommendation for consideration of chemotherapy in people with any or several of these higher risk features.  I personally have generally followed a cut-off of 4 cm as the leading criterion for consideration of adjuvant chemotherapy, and fortunately I have the luxury of working with surgeons who do a great job on surgery and accurate staging.  However, the more I review the evidence on other high risk features of the cancer, the more I recognize that if the goal is to identify people with a risk of recurrence that justifies the challenge of adjuvant chemotherapy, the more I step back and consider that these decisions, like so many others in cancer care, need to be individualized based on many factors, rather than based on a narrow set of rules.