Clinical Relevance of Occult Metastases in Lymph Nodes

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Clinical Relevance of Occult Metastases in Lymph Nodes from Resected Early Stage NSCLC

http://blog.lungevity.org/2011/10/20/z0 ... rly-nsclc/

October 20th, 2011 - by Dr. Jack West

Though we know that nodal involvement by a lung cancer is well correlated with prognosis, that refers to clear evidence of involvement by pathology review under a microscopy. But another way to assess them is to check for the presence of occult (and microscopic) metastases (OMs) in bone marrow or lymph nodes with very detailed examination. The American College of Surgeons Oncology Group (ACOSOG) just published their results on a trial known as Z0040, which was developed to look for OMS in washings of the pleural space at the time of surgery, from bone marrow collected from a rib, and from lymph nodes that appeared to be negative for cancer involvement by standard pathology review. These were the central questions posed by the study:

1) How commonly will we see OMs in the pleural space, bone marrow, and “negative” lymph nodes?

2) Do patients who have evidence of OMs have a worse prognosis than patients who don’t have them?

To test this question, ACOSOG enrolled 1047 patients with resectable stage I-III NSCLC between 1999 and 2004. Among them, 50% had an adenocarcinoma, 66% stage I, they were nearly 50/50 split by patient sex, and the median age was 67. These patients underwent surgery that included “pleural lavage”: sterile fluid was put into to the cavity outside of the lung, aspirated back up, and then a pathologist searched for cancer cells in the fluid, using immunihistochemistry (IHC), a special staining technique that can identify cells that have proteins consistent with cancer. These surgical patients also had a 3-4 cm piece of rib sent off for bone marrow to be extracted, looking for cancer cells using IHC; finally, all lymph nodes that were reviewed and found to be negative for cancer involvement by standard evaluation were also reviewed in detail using IHC staining techniques. All tests were conducted at a single lab at the University of Southern California (USC). Following surgery, patients were followed for at least five years to assess their cancer status and survival.

The investigators found that OMs in the pleural space or bone marrow were actually quite uncommon (3% and 8%, respectively). While the low frequency of OMs in the pleural space made it difficult to say anything meaningful about these patients, for those with OMs in the bone marrow, they showed the same frequency of involvement from stage Ia to IIIB (there were very few patients with stage IIIB NSCLC who underwent surgery, as you would expect) and didn’t show evidence of doing worse than those who didn’t have OMs in their bone marrow.

We saw a different and very important result from the patients with OMs in their lymph nodes that were considered negative. OMs were detected in lymph nodes from 22.4% of patients who underwent surgery, more commonly in higher stage patients, as you would expect – though they were still seen in about 17% of patients with a smaller, otherwise node-negative cancer. Most importantly, the investigators found that nodal OMs were associated with an approproximately 60% higher risk of developing cancer recurrence and also dying at any given time point over the next 5 years following resection, compared with those who didn’t have nodal OMs. This result is illustrated below (top is disease-free survival, and bottom is overall survival):

(Click on the blog link above for the image)

So, what do we do with these results? The authors note that these results are directly relevant to clinical practice, and I agree. Today, we struggle in the post-operative setting with who is best served by adjuvant chemotherapy, which is given to eradicate micrometastatic disease, and who can safely forgo it. While it is standard to recommend it to people with clearly node-positive disease, the question of which patients with node-negative disease to suggest chemotherapy for remains an open question. Because it can cause serious side effects, giving chemotherapy to people who have a low enough risk of recurrence that they aren’t likely to benefit may be worse than just observing them. But we might well imagine that the people with microscopic OMs in their lymph nodes and no other evidence of nodal involvement, who this study shows are at significant risk of recurrence and death from lung cancer, are the very patients who might be most likely to benefit from adjuvant chemotherapy. For now, that’s just a hypothesis, but the authors note that these IHC and close examination techniques are available through pathology labs everywhere, even if they require a certain level of time and skill to do.

My interpretation is that these results are important enough for me to want to discuss them with my own multidisciplinary lung cancer team at my own institution, with a suggestion that we should consider changing own practices to follow this lead. My hope is that this could lead to better recommendations of which patients are more likely to benefit from adjuvant chemotherapy and which we can have some confidence would do better holding off.