Adjuvant chemo has become increasingly established as having a survival advantage, at least for the general population of stage II and IIIA patients, and potentially for some with earlier stage disease (see adjuvant chemo post). However, post-operative radiation therapy, or PORT, does not have an established role. While historically there has not a clear advantage from PORT for patients with N1 nodal disease, for those with N2 nodes there has been a consistent improvement at least in local control and now emerging evidence of an survival benefit from PORT (see PORT post).

So for patients who undergo resection and had N2 nodes, there may be a benefit from both chemotherapy and radiation. One way to treat patients with N2 disease, if we know from a mediastinoscopy or another method that someone has N2 nodes involved prior to surgery, induction chemotherapy, or chemotherapy and radiation, are commonly used. In those cases, sometimes additional chemo is recommended after surgery, but not typically more radiation if it was given before surgery.

But there are also plenty of patients who either had unsuspected N2 disease until after surgery, or who undergo upfront surgery despite pre-operative staging showing N2 disease. Such patients were included on many of the trials testing the value of adjuvant chemo.

The problem of administering chemo and radiation after surgery is that it's hard enough to take chemo after surgery, and adding another modality can escalate the challenge significantly. In the many clinical trials with cisplatin-based chemo after surgery, only approximately 70% of patients are able to get though the majority of planned chemo (carboplatin-based chemo is more feasible, with 85% of patients on the CALGB 9633 trial (initial positive 2004 abstract here, updated and now negative 2006 abstract here).

So when adding radiation to chemo, we need to balance the effectiveness with the safety and feasibility of what is now a tri-modality approach (surgery + chemo + radiation). In the ANITA trial that allowed radiation while testing the value of adjuvant chemo (abstract here), the patients who received both chemo and radiation did not receive them concurrently, but rather received chemo followed by radiation. Our experience with patients receiving chemo and radiation together for unresectable NSCLC has consistently demonstrated that concurrent chemoradiation is associated with a much higher likelihood of serious esophagitis, inflammation of the esophagus, that can limit the ability to eat and drink and make it very hard to continue treatment to completion.

One trial that is instructive about the challenges of administering chemo and concurrent radiation is the ECOG 3590 trial by Keller and colleagues (abstract here). In this trial designed to test the value of adjuvant chemotherapy for resected stage II and IIIA NSCLC, the investigators compromised by offering both arms PORT, and just one arm concurrent chemo with PORT, fearing that the arm not getting chemo would unwilling to be randomized to no treatment after surgery, so both arms received PORT, despite the fact that there was no established role for PORT. The schema is as shown:

(click to enlarge)

In that trial, similar to the results on ANITA with N1 nodal disease, the combination of both modalities together did not provide any added benefit compared with one post-operative approach alone. Specifically, the results were essentially superimposable, and slightly better for radiation alone (median survival 39 months for PORT arm, 38 months for PORT/Chemo arm):

Only 65% of patients were able to even start all four of their intended chemo cycles -- many patients found this aggressive approach too much to tolerate, even if they didn't technically have enough side effects to be forced to stop (many patients refused to continue). There were considerably greater side effects with the combination, and a 1.6% risk of dying on treatment (1.2% with PORT alone).

So we have some evidence that chemo after surgery for N2 nodal disease is beneficial, and radiation after surgery for N2 nodal disease is also beneficial. The ANITA-1 trial suggests that both chemo and radiation given in a sequential way can provided greater benefits than just chemo. While the results of non-surgical stage III NSCLC show that concurrent chemo and radiation is generally more effective than sequential chemo and radiation, despite higher toxicity, but the older Keller trial suggests that giving chemo and radiation together after a very major lung surgery can be just too much for people to tolerate.

We don't have a clear answer to the best way to combine all of these treatments for patients with resected N2 disease. SWOG is developing a trial now that will directly compare a concurrent approach (cisplatin/etoposide/RT to 50 Gy) followed by more chemo (taxotere) to a sequential post-op approach of chemo (4 cycles of cisplatin/taxotere) followed by PORT to 50 Gy.

This trial will plan to enroll approximately 120 patients over 1-2 years, and from there we can see if there is a clear winner. It will look at safety/feasibility as the primary endpoint, but it will obviously also be looking at survival as well.

Outside of a protocol, I and many of my colleagues tend to recommend sequential treatment in this setting after surgery, with N2 nodes involved. Specifically, with a more consistent survival benefit seen with adjuvant chemo, I generally recommend starting with chemo x 3-4 cycles, and then would recommend PORT if a patient is still up for more treatment that may add benefit -- this is just what was done on the ANITA trial. But doing both together may be like juggling too many balls in the air at once, leading you to drop everything and not be able to complete planned chemo or radiation, and therefore potentially get less treatment benefit than just concentrating on one approach at a time. We need to balance the aggressiveness of these approaches against the feasibility of just getting through it all.