Locally advanced, or stage III, NSCLC, can potentially include patients for whom surgery is an option, but for many patients with stage IIIA and a majority of those with stage IIIB NSCLC, a non-surgical approach is the best treatment recommendation. It's important to keep in mind that the goal of treatment for patients with locally advanced NSCLC but who don't have a malignant pleural effusion (fluid inside the chest but outside of the lung, with cancer cells in it) can potentially be cured. The risk of doing poorly are from both local growth and distant micrometastatic spread (living cancer cells traveling elsewhere in the body through the bloodstream).

The old standard in the 1980s was radiation alone. An important clinical trial the "Dillman Trial" then compared the old standard of just radiation alone to chemo with a two drug combination of "cisplatin-based" chemo for two cycles followed by the same radiation plan. The cure rate was significantly better, although unfortunately we were still curing these patients far too rarely. However, it changed the standard of care from radiation alone to a combination of chemo and radiation together.

Over the last decade, the more timely question has been how best to combine chemo and radiation. Multiple trials from different countries have tested chemo and radiation given one at a time ("sequential chemoradiation", as was done in the Dillman trial) to chemo and radiation given together ("concurrent chemoradation"). The vast majority of these studies have shown that concurrent chemo and radiation is associated with better chances for cure, at a cost of greater short-term toxicity during and shortly after treatment. The leading side effect problems with this approach are severe esophagitis, or burning/irritation of the esophagus that can make it very painful to swallow, and pneumonitis, which is inflammation of the lung tissue.

Patients with significant medical problems, particularly very compromised lung function, as well as patients with large tumors that would require very large radiation fields, are potentially not well served by this approach and may do better to receive sequential therapy, or possibly chemo alone to shrink the cancer somewhat so that the radiation field may be smaller. In general, stage III NSCLC is an area where the toxicity of treatment, and even the potential for dying from the challenging treatment, can limit the feasibility and potential benefit of a very aggressive approach.

Some physicians and centers routinely chemo and radiation together, followed by additional and often different chemo alone (generally docetaxel, or Taxotere). This is based on very encouraging early work by the Southwest Oncology Group (SWOG) that showed remarkably good results from a cisplatin-based doublet chemo (cisplatin/etoposide) with radiation followed by three cycles of taxotere. This is still controversial, since it can be very challenging to get patients through this approach safely, and the patients enrolled on this trial were unusually fit, not representative of a more general population of patients with marginal lung function and significant other medical problems. We still await further trials to clarify whether this approach is ideal. Other doctors commonly give carboplatin-based chemo on a weekly basis with radiation, but I don't favor this approach as much, since our results tend to be a bit better with cisplatin than with carboplatin, and we don't have as much evidence as we would like that carboplatin gives as good results. And the stakes are high, so we don't want to cut the chances of cure even slightly if we don't have to. We just need to balance that against the very real safety risks.

Current trials are focusing on newer chemo in this mix, adding targeted therapies to potentially improve cure, and adding prophylactic brain radiation after everything else. The last is an important ongoing question because we see a distressingly high rate of relapses in the brain first or brain only after all of the other treatment, presumably because the central nervous system acts as a "sanctuary site" where chemo cannot easily penetrate and fight micrometastatic disease. However, we still don't know that brain radiation is appropriate here, so I don't recommend it in this setting outside of a clinical trial. Together, the improvements in our treatment plans have led to significant gains in our cure rate for stage III NSCLC over the past 20 years, but we still need to build on this momentum.