Over the last several years, chemotherapy after surgery has become the standard strategy for improving survival compared to surgery alone, at least for stage II and IIIA patients who don't have mediastinal (N2) lymph nodes involved, and it's often used also for patients with stage IB NSCLC (no lymph nodes, but a larger tumor or tumor involvement with the pleural lining around the lung). However, another approach that has been studied, albeit less so than adjuvant (post-operative) chemotherapy is neoadjuvant (pre-operative, also known as induction) chemotherapy. This strategy has several potential advantages over administering chemo after surgery. First, when we're trying to improve survival with chemo by treating potential micrometastases, neoadjuvant chemotherapy has the potential to start treating these micrometastases at the earliest possible time. In addition, chemotherapy before surgery can allow us to assess how responsive the cancer is to treatment, in a way that post-operative chemo cannot. We can see how much the tumor shrank on repeat CT scans (+/- PET scans), and we can look at changes in the tumor itself after it has been removed at surgery. Perhaps more importantly, there is the potential that in patients who have a tumor that may require a more extensive surgery such as a bilobectomy (lwo right-sided lobes) or pneumonectomy (full lung resected), it may be possible to shrink the tumor enough before surgery to do a lobectomy (in fact, people still debate whether you should do the surgery that was needed before the induction therapy, or whether you can do surgery and just remove the area that it shrunk to. This is really a question of whether there are residual "islands" of viable tumor outside of the newly shrunken borders of a tumor after treatment). It is also possible to identify a small minority of patinets who progress immediately, despite treatment, which happens perhaps 5-10% of the time. In those patients who develop progression with metastases before getting to surgery, you could consider them as having lost the chance for cure with surgery, but we really think these are the patients who would have shown progression immediately after surgery if they had gone straight to the operating room, so they have probably been spared a surgery that would not have helped them.

But the leading reason that we would consider pre-operative chemotherapy to be potentially more helpful than post-operative chemo is that we think you can get it in more reliably. One of the biggest problems with adjuvant chemo is that patients are just recovering from a MAJOR surgery, and many have recently lost a bunch of weight, they're in pain, they're constipated because of their pain meds, or any of many other problems people can have after major surgery. They may not be able to get through a challenging plan for 3-4 cycles of chemo, since chemo isn't exactly a cake walk even for people who didn't just have major surgery. The trials of adjuvant chemo, which only included the patients motivated and fit enough after surgery to consider chemo (which definitely isn't every patient), have consistently shown that only about two thirds can get through the majority of planned treatment:

(click to enlarge)

An early trial called the BLOT trial (for Bimodality Lung Cancer Oncology Team, bimodality being chemo and surgery)(abstract here) gave chemotherapy with carboplatin and paclitaxel to early stage NSCLC patients before and after surgery. The trial was originally designed to give two cycles of chemo before surgery and three after surgery, but the investigators found it so challenging to get the post-operative chemo into patients that they switched the design during the trial to give three cycles pre-operatively and two after. The basics of the trial are shown here:

Although you can't draw firm conclusions from a single-arm trial (everyone gets the same treatment) with 94 patients, several points were striking. First, the response rate after induction therapy was 56%, much higher than you tend to see in more advanced disease. Only 3 patients (3%) experienced progression during pre-operatively therapy. Although 96% of patients received all of their pre-operative chemotherapy as planned, less than half of the patients received all of their planned post-operative chemotherapy, and 46% received no chemotherapy after surgery at all, for a variety of reasons. It's clearly something that can't be taken for granted. This study showed a very encouraging survival, with better results than would be expected historically: one year overall survival was 85%, and 5-year survival was 42% (updated survival results in abstract here).

One study that tested pre-operative chemotherapy against surgery alone was reported by Depierre and colleagues from France in 2002 (abstract here). This study enrolled over 350 patients with stage IB to stage IIIA NSCLC, administering "peri-operative" (both pre- and post-op) chemo to one arm, and just surgery to the other arm, except that patients with stage IIIA NSCLC on either arm received post-operative radiation therapy:

The chemo used was rather old school, a hard regimen with cisplatin as well as ifosfamide and mitomycin C, and it's very rarely used in the US. I guess the French patients are pretty tough, because in this trial there wasn't a major drop-off in delivery of chemo after surgery. As in the BLOT trial, the response rate in this trial was high, at 64%, including 11% with complete responses, after neoadjuvant chemotherapy. Otherwise, although the group receiving peri-operative chemotherapy had a median survival of 37 months, compared with just 26 months for the patients who received surgery alone (or with post-operative radation for stage IIIA), this difference was not quite statistically significant. However, there was a significant improvement in disease-free survival, which was more than doubled in the patients who received chemo: 26.7 vs. 12.9 months. Interestingly, the trial showed a survival benefit for the patients with stage I and II NSCLC, but not an improvement with chemo for the patients with stage IIIA NSCLC (in contrast to a lot of other work):

A few other interesting things were noted from this trial. First, there was a modest but not significant increase in post-operative mortality after chemo (from 4.5% to 6.7%), which has been a lingering question and potential downside of pre-operative treatment. Second, the trial showed that there was a very significant decrease in development of distant metastases in patients who received chemo, exactly what you'd expect chemo to do:

There have been a few other trials of pre-operative chemo. One was done in the US as a follow-up to the BLOT trial, and it was a randomized phase III study designed to enroll 600 patients with early stage NSCLC to receive surgery alone or 3 cycles of carboplatin/paclitaxel before surgery. It was known as SWOG 9900, or affectionally called the BLOT or Not trial (could also be considered BLOT or Knot, for surgical knot). This trial was closed quite early, with just 354 patients, three years ago, because several adjuvant trials showed a benefit of chemo, and it was felt unethical to continue to enroll patients to surgery alone, with no chemo. The design is as shown below:

Dr. Kathy Pisters from MD Anderson Cancer Center presented the very preliminary results at ASCO in 2005 (abstract here), which were inconclusive but somewhat disappointing. The response rate in chemo recipients was 41% (10% with complete responses), but only 77% of patients received all three cycles, which isn't clearly better than what you'd expect for adjuvant chemo (85% of patients received all four cycles of carbo/taxol in the adjuvant chemo trial CALGB 9633 (abstract here)). There were no fewer pneumonectomies performed in the people who had preoperative chemotherapy (17% for both arms). And while there appeared to be a modest improvement in survival with pre-op chemo, it wasn't statistically significant:

Admittedly, this was an early report of the data, and the trial enrolled only about 60% of the planned number of patients, but it was disappointing, and overall it provided no argument to favor pre-operative chemo over the more established adjuvant chemo strategy.

The trials of pre-operative chemo tend to be harder to do because some patients just want to "get it out right now", and many surgeons are reluctant to send a patient who could go to surgery immediately to the oncologist, potentially to have progression or a complication keep that patient from ever getting to surgery a few months later.

The best way to compare pre-operative chemo to post operative chemo is to directly compare them in the same trial. In Spain, Rafael Rosell of the Spanish Lung Cancer Group has enrolled approximately 600 patients to the NATCH trial (Neoadjuvant Adjuvant Taxol Carboplatin Hope), in which there are three arms, one of surgery alone, one of pre-operative carbo/taxol, and one of post-operative carbo/taxol. Another trial, based in the US, was designed to test cisplatin/taxotere as a pre-operative vs. post-operative treatment, but this study unfortunately just closed due to poor accrual. The design of these studies is illustrated here:

We haven't learned the results of the NATCH trial but should soon; the other trial closed far too early to provide information. In the meantime, induction chemotherapy is certainly a reasonable consideration for individual patients, perhaps someone in whom there is a great hope that tumor shrinkage could allow for a less extensive surgery, but at the present time adjuvant chemo remains the standard with considerably stronger data behind it. The exception is stage IIIA, N2 NSCLC that is felt to be resectable, which is usually treated with induction chemo or chemoradiation before surgery. I'll cover the questions about the optimal approach to induction for stage IIIA N2 disease in a separate post soon.