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Dr. Jack West is a medical oncologist and thoracic oncology specialist who is the Founder and previously served as President & CEO, currently a member of the Board of Directors of the Global Resource for Advancing Cancer Education (GRACE)


Can We Define "Best Treatment" for Stage IIIA NSCLC?
Howard (Jack) West, MD

Stage IIIA NSCLC, particularly with N2 lymph node involvement, is probably the NSCLC treatment setting that is most controversial. While it is the latest stage that we routinely consider surgery for, it is actively debated whether patients with stage IIIA NSCLC should have surgery or be treated with a combination of chemo and radiation without surgery.

For the patients who undergo surgery, most patients receive preoperative therapy before resection. This standard was established from a series of small randomized trials published more than a decade ago that demonstrated striking improvements in survival in the group of patients that received chemotherapy prior to surgery. Despite the clear conclusion that pre-op chemo improves survival, these trials were all very small (primarily because they were stopped early when the huge benefit of pre-operative treatment became apparent), the patients one the surgery arm of one key trial did much worse than expected, and there were problems with some prognostic factors not being well balanced between the two groups in one trial. Regardless, the benefits in the patients who received chemo before surgery were so great that this became a preferred approach, but there is no standard approach that has emerged as a best choice.

Pre-operative radiation is often given in combination with chemotherapy, based largely on very promising results from this approach followed by surgery to treat locally advanced NSCLC in some prominent research done through the Southwest Oncology Group. In this trial, as well as many others since then, the patients who had no evidence of cancer in their lymph nodes in the middle of the chest (the mediastinum) after their pre-operative therapy was completed did remarkably better than the people who had residual active cancer in these nodes. So patients were already destined to do well or poorly BEFORE they went to surgery, raising the question of whether the chemo and radiation were doing the key work and surgery was potentially adding more risk than benefit.

This led to a trial done across North America (abstract here), known as Intergroup 0139 (multiple cancer groups joined together to do an Inter-group trial). This complicated trial tested chemo (cisplatin and etoposide) and full dose radiation without surgery for half of the patients, compared to the same chemo with less radiation, all followed by surgery and, if patients could do it, more chemo after surgery (about half of the patients couldn't do post-op chemo). The schema is shown here:

Int 0139 schema (click to enlarge)

While patients who received trimodality therapy (chemo and radiation and surgery) were less likely have their cancer return, there was not a significant improvement in survival for the patients who had surgery because they had more complications and even deaths from the aggressive treatment.

INT 0139 results curves INT 0139 trial results numbers

So this stage of NSCLC is one where it becomes very important to balance the aggressiveness of treatment against cancer vs. the danger of the treatment.

Some interpret this trial as showing that since patients who didn't do surgery did essentially as well as those who did, this stage of NSCLC shouldn't be treated with surgery, but rather with chemo and radiation together. I don't believe it is that simple. The fact is that some patients on the trial had a very bulky, huge amount of cancer involving the mediastinal (mid-chest, between the lungs) lymph nodes, but others had just a little bit. And some patients were very healthy, while others were in very marginal health. So I individualize my recommendations for this treatment stage, considering the chemoradiation followed by surgery to be the best option for healthier patients with little tumor bulk, while somewhat sicker patients and/or those with bulky lymph node disease may be better served by chemo and radiation without surgery. It's also worth considering the particular strengths of the center. One of my friends who is a national lung cancer expert is at a center with a particular expertise in aggressive radiation, and probably largely because of that they strongly favor a chemoradiation without surgery approach there.

Overall, it's fair to say that this is an area where there is no clear best treatment plan in stage IIIA NSCLC, an area where even the world experts have plenty of room to debate each other.

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