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Dr. Jack West is a medical oncologist and thoracic oncology specialist who is the Founder and previously served as President & CEO, currently a member of the Board of Directors of the Global Resource for Advancing Cancer Education (GRACE)

 

Long-Term Follow-Up of Pre-Operative Chemotherapy for Early Stage NSCLC
Author
Howard (Jack) West, MD

Here is a continuation of the webinar discussion I did with Dr. Pennell a month ago, in which we discussed some of the most interesting presentations on lung cancer at ASCO 2010. Although the most provocative results were the negative results on the BR.19 trial that suggested a potential detrimental effect of the oral EGFR inhibitor Iressa (gefitinib) after surgery, there was also a trial on early stage NSCLC that was more favorable, even if it didn't reach statistical significance for a survival benefit. This trial focused on pre-operative, or neoadjuvant, chemotherapy. Here's the transcript with associated figures (admittedly similar to a prior post on this subject):

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Dr. West: So, I'm going to turn briefly to an update of a trial that was actually published years ago and this was a study of generally pre-operative therapy with an older regimen called MIP, or MIC, for mitomycin C, ifosfamide, and cisplatin. And most of the people who have been following our discussions of treatment options in non-small cell have little or no familiarity with at least the first two of those agents, because they have beenvery uncommonly used over the last decade or so, having been replaced by newer therapies. Nevertheless, this is an older study and what this study looked at was the long-term, now with more than 10-year follow-up results of pre-operative chemo followed by surgery versus surgery alone.

ifct-neoadj-schema-slide (click on image to enlarge)

Some of the patients, if you had responded to the pre-operative chemo, would get an additional two cycles, and in Europe they still do a fair bit of radiation for locally advanced disease.

This study had been presented and not quite statistically significant years ago. But we have also seen with some of our early stage studies that we can see different results with long follow-up, and this is the now longer term with a median follow-up of almost 14 years results with this pre-operative approach, and what the investigators reported was that there is an approximately 8% difference at 10 years out, and it's really been sustained over time, this gap between the two curves.

ifct-neoadj-os-slide

The P value is 0.12 is not statistically significant, but this is only a little over the threshold of 0.05, in a population of under 400 patients. So it's not an extremely large study, and it's worth noting that our statistically significant trials in the early stage setting for post-operative therapy have been with larger groups of patients.

So in absolute terms and looking at these curves, this separation is really pretty comparable to what we achieve in the post-op setting, yet it is not statistically significant. Here's the disease-free survival, which is really quite robust and even a greater difference, although it's pretty comparable, and so really suggesting that these approaches are pretty similar to a post-op setting and it's a viable consideration.

ifct-neoadj-dfs It is not necessarily inferior in absolute terms, yet post-operative chemotherapy is the better studied standard, and we may or may not ever see another good comparison trying to look at pre-operative versus post-op. Even though there actually has been one study called NATCH that looked at this, it had a lot of limitations.

In a multivariate analysis, they did see that neo-adjuvant chemotherapy, when separating out for differences in stage, and they were more patients with N2 involvement in the chemotherapy arm, there was a significant difference in overall survival, a little over 30% favoring the neo-adjuvant approach.

ifct-neoadj-multivariate-analysis

So even though this is a negative trial, and there was another negative trial, at least statistically, from the Southwest Oncology Group called 9900 that gave three cycles of pre-operative carboplatin and paclitaxel, both of these studies had the same magnitude of benefit that we see in the post-op setting. I would say that it certainly suggestive that if there are circumstances that would make one think about giving pre-op instead of post-op, that is certainly a viable choice that probably produces very comparable results. Nate, did you have any thoughts on that?

Dr. Pennell: I think that this is something that is talked about a lot, and certainly the Europeans, I think, still do a fair amount of induction chemotherapy prior to surgery. There's been a couple of meta-analyses of all of the trials done using the pre-operative chemotherapy approach that have generally concluded that the benefit in survival is almost exactly the same as what you see in the adjuvant setting, in the range of 5%. And so I think this just lends further support that chemotherapy improves survival in the early stage setting that is somewhere in that magnitude, in the single digits --probably less than 10% -- and I would not call this, just because it's negative, a trial that argues against that benefit.

We know that in order to really be able to statistically see a magnitude, a benefit of less than 10%, you have to have a big trial with lots of patients, and this was just not big enough to see it, and it also used an older chemotherapy regimen. So I would consider this to really be a supportive trial for this strategy.

Dr. West: In fact, over the last few years when you've seen some longer follow-up of studies like IALT, that even showed an erosion of the previously significant benefit of post-operative chemotherapy with longer follow-up, it's actually reassuring to see a sustained, really unchanged benefit from 5 to 10-plus years out.

Dr. Pennell: Yeah, absolutely. Luckily, the BR.10 trial did a similar update that also showed a preserved survival benefit, but it's nice to see more trials coming out and showing that the benefit of chemotherapy is preserved further out, because we'd all get pretty depressed if the patients the survival benefit from chemotherapy was actually very transient.

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