So this is the trial that is most suggestive of a benefit for induction chemotherapy. It required confirmation. One trial is usually not enough, so there was a large intergroup trial that repeated that design, radiation alone versus induction, two cycles, followed by radiation. Bill Soss published this in JMCI. It’s been updated since. But because these were primarily radiation oncologists who were conduction this trial, they were interested in also knowing, could more aggressive radiation just by itself – hyperfractionated radiation – cause similar benefit. You look at median survival; well, this trial confirms the benefit of induction chemotherapy and it does not suggest that, at least hyperfractionated radiation, is of benefit. These are updated survival curves from 2006. Here’s the induction chemotherapy and this is hyperfractionated radiation. So there may be some similar long term benefit, but as median survival goes – you saw the numbers – 14, 12 and 11 months, again favoring induction chemotherapy. Now this trial doesn’t have quite the follow-up yet but it does suggest, at least here on, that the long term benefit – what I showed on the Dillman trial for induction chemotherapy – may be less pronounced here than it was in that trial. These curves are all pretty low out there. So induction chemotherapy is an accepted principle and standard therapy for stage IIIb disease.

What about more aggressive radiation? Well, we mentioned that hyperfractionated radiation didn’t do much, but there is a British trial that looked at something called continuous hyperfractionated accelerated radiation therapy, CHART. What that consists of is 1.5 gray, given three times daily for 12 days in a row. Patients sort of lived right next to the hospital in what they called the CHART house, and got 54 gray and after that of course had mucositis. But that didn’t come until the treatment was completed. And compared that to standard fractionation radiation. Now this trial is a little bit different from most others in that it’s a British trial and many patients didn’t have un-resectable disease, be it IIIb or IIIa, but earlier stage disease which in the United States would be treated with surgery. Furthermore, if you look at the histology; squamous cell, well, poorly, moderately or not specified differentiated, but you add all that up and you come to 80% squamous cell. And we mentioned that that’s no longer representative. And squamous cell probably of all histologies tends to spread a little bit later. So if you select for squamous cell carcinoma, as you may have, that histology which is most amenable to better local control with higher and more aggressive radiation. Large cell adeno, 15%. So it’s a somewhat different trial but within those limitations CHART did better than radiation alone, in terms of survival – median and maybe long term. So there may be a role for more aggressive radiation therapy in non-small cell lung cancer.

CHART meant 12 days in a row, so that included weekends and that is not necessarily appealing to radiation oncologists, or for that matter patients. So in the United States the C was dropped. It’s no longer continuous. And what you have then is hyperfractionated accelerated radiation therapy. Given here Monday through Friday on three consecutive weeks, slightly higher dose but still three daily fractions with four hour interval. This was a pilot trial, objective response rate 54%, median survival 13 months. So this may be good, and when something may be good it ought to be examined in a randomized trial. Two cycles of carbo, Taxol, so standard induction chemotherapy but not using an 80’s regimen, using a 90’s regimen, followed by either conventional radiation – so this is the standard arm – versus followed by hyperfractionated accelerated radiation therapy. Now you can see the conceptual beauty of this because we know that induction chemotherapy improves survival by helping with distant disease and that concomitant or very aggressive single modality radiation therapy improves survival by improving local control. So this just might work. And ECOG is currently putting this into randomized clinical trial.