One of the more common approaches to treating stage IIIA NSCLC with N2 lymph nodes (mediastinal, or mid-chest, on the same side as the primary tumor) is chemotherapy or chemoradiation before surgery. For those who recommend induction therapy (treatment before planned resection), there is a pretty even split between those who recommend chemotherapy alone and those who recommend chemo with concurrent radiation. So how do knowledgeable people come to different conclusions, and who is right?

Pursuing at least chemotherapy before surgery, rather than just surgery alone, for stage IIIA N2 NSCLC, has been pretty well established for more than a decade. In 1994, two small trials were reported that had randomized patients to either surgery alone or chemotherapy before surgery. One study, conducted by Rafael Rosell and the Spanish Lung Cancer Group (abstract here), stopping after a preliminary analysis with the first 60 patients showed a dramatic benefit in favor of the recipients of chemotherapy. While limited because of the small size, a second trial done in the US by Jack Roth and colleagues from MD Anderson Cancer Center (abstract here) also randomized patients to up front surgery or chemo followed by surgery, and this study also was stopped after 60 patients were enrolled after 60 patients were enrolled because of very significant benefits in favor of the patients who received chemo before surgery. This trial was published just months after the Spanish trial, and alhough there were issues with some of the specifics of the trials, and they only enrolled 120 patients between them, the benefits were so striking that it made pre-operative therapy with chemotherapy a standard approach. The results of these trials are summarized in the following slide/figure:

(click to enlarge)

Other studies showed encouraging results with an approach of chemo and radiation together before surgery. In the SWOG 8805 trial(abstract here), 126 patients with stage IIIA or IIIB NSCLC (the IIIB patients mostly having advanced primary tumors rather than N3 nodal disease, which is lymph node involvement in the side of the mid-chest opposite the primary tumor) received two cycles of cisplatin/etoposide along with radiation to an induction dose of 45 Gray (just under 3/4 the "full dose" used when radiation is given as a curative therapy). This trial produced quite encouraging results, particularly in the patients in whom mediastinal nodes were sterilized (no evidence of disease after induction therapy), as shown here:

A subsequent trial (descibed in a prior post) randomized patients to chemo and radiation as induction therapy before surgery or chemo and a higher dose of radiation without surgery, the overall survival was not significantly different but trended toward higher long-term survival with surgery. However, the patients who underwent surgery were more likely to die from fatal side effects of treatment. In other words, an approach of chemo and radiation followed by surgery reached a point where the benefits of aggressive treatment were counteracted, at least partly, by people dying from the aggressiveness of the treatment. So if chemo alone before surgery is also an option, could that be a less toxic but equally effective option than chemoradiation before surgery. What is radiation adding to the picture?

That's not an easy answer. The evidence suggests that patients who receive radiation with chemo before surgery are more likely to have no evidence of any tumor remaining at the time of surgery than patients who received chemo alone (a "pathologic complete response"). On the other hand, we don't have evidence that the higher rate of radiation induced complete responses translates to better long term survival. There have really been no good studies of this question, but the small exploratory trials that compared induction chemo to chemo and radiation before surgery have showed no survival benefit despite a higher response rate, both on scans and under a microscope. The results from a French trial of 92 patients (abstract here), showed that the response rate was higher for chemoradiation than chemo (86 vs 55%), as was the rate of pathologic downstaging (58% vs. 50%), but the 3 year survival was actually better for chemotherapy alone (40% vs. 33%) for the stage IIIA patients, and the same trends were seen for the stage IIIB patients they included. The few other small trials also suggest that chemoradiation is not associated with a higher survival, even if it does possibly produce better responses and local responses. This may be because survival in this setting may be driven more by control of distant disease, which is presumably mediated more by chemotherapy than radiation, but nothing definitive is known.

The question of whether patients with resectable, non-bulky stage IIIA NSCLC should receive chemotherapy or chemoradiation as induction therapy was considered such a relevant "next question" for the field that two different cancer cooperative groups decided that this was worth conducting as a national trial. The RTOG and SWOG ended up writing and starting this trial together, planning to enroll 574 patients over several years, with a plan to treat patients with cisplatin and taxotere with or without radiation before surgery, which would then be followed by taxotere alone for three cycles:

Unfortunately, after years of developing the trial (I was one of the leaders), the enrollment was too slow, and it closed down last year. We may never get an answer, so we are left with either chemo or chemo and radiation as a very reasonable option before surgery. And neither can be said to be the best choice.