NEOADJUVANT CHEMOTHERAPY FOR STAGE IIIA NSCLC

Recently I attended a meeting of the European lung cancer community in Geneva, Switzerland. I attended a session^[1] led by Dr. Dingemans from The Netherlands and Dr. Pless from Switzerland, who discussed the management of patients with stage IIIa disease and whether to use neoadjuvant therapy or chemoradiotherapy.

Although both approaches are clearly equivalent in terms of improving outcomes, it is also clear that there are several advantages to using induction therapy. If there was one agreement at that meeting, it is that we need to do better in this area. The cure rate for these patients is still hovering around 20%, and we need to do better than that.

How can we move forward? These specialists first discussed a way in which we should not move forward: We should not use concurrent chemotherapy and radiation preoperatively. Intuitively, we know you could have definitive local therapy with surgery. Radiation does not make sense. Clinical trials have shown no advantage in terms of improving survival by adding radiation before surgery. If anything, radiation increases complications and difficulties with surgery.

I believe that there is a clear role for radiation in patients with stage IIIa disease, but I would recommend that every patient be seen by a radiation oncologist and radiation be given afterinduction chemotherapy and surgery.

Three Strategies to Move Forward

So, how can we move forward? I want to suggest a couple of ideas.

The first is to use neoadjuvant therapy, which is clearly equivalent and has several great advantages. If it is not working it can be stopped; and now that we have more drugs available to treat people with advanced lung cancer, if we stop a less effective therapy, we can substitute another that is potentially more effective.

Second, assessing pathologic complete response with chemotherapy at the time of surgery is a potent predictor of overall outcome. Using the pathologic complete response is a good strategy for those of us developing new therapies or those of us trying to find those patients who are high risk, so that we can focus our efforts to lower their risk. There are trials now in the adjuvant setting, but we're talking about a 10-year timeline. That is really too long for this disease, with so many people at risk. We need to find shorter timelines when designing these trials and using the pathologic complete response at the time of surgery; assessing this after neoadjuvant therapy is one way to do that.

Finally, we should consider using molecularly targeted therapies for patients for whom a driver oncogene is discovered. Emerging evidence shows that those patients who have an oncogenic driver, particularly epidermal growth factor receptor (EGFR) mutant lung cancers, will probably benefit from an EGFR tyrosine kinase inhibitor. The data from gastrointestinal stromal (GIST) tumors is extremely compelling and extremely parallel and comforting, and the emerging data in lung cancer patients in particular shows that in a mutated cohort -- not an unselected cohort, a mutated cohort -- these agents can be helpful, clearly for EGFR and probably for ALK mutations as well.

Randomized trials are being planned, but they are still in the planning stages. They will take a decade to read out, and I think now individual doctors have to make a decision for patients -- whether or not it makes sense to go ahead with a tyrosine kinase inhibitor now, knowing the high risk for these stage IIIa patients.

I urge you to consider neoadjuvant therapy, to use the results of neoadjuvant therapy to help guide future treatment, and to think about adding a tyrosine kinase inhibitor in these patients. We have to do a better job, and we have some ways that I think we can do that. Thank you.