So what about concomitant chemo-radiotherapy? We mentioned that toxicities are higher with concomitant therapies. So in the head and neck that’s mucositis, and soft tissue. And you can observe patients for that. In the lung it’s esophagitis which is very unpleasant and hard to monitor. And it can be radiation pneumonitis and radiation pneumonitis can be fatal. So that concomitant approaches to the lung have been tested with a great deal of caution, historically. The majority of trials therefore looked at single agents including some inactive agents. Now that didn’t make a whole lot of sense, but cisplatin in four trials and cisplatin is – we know from stage IV disease – a 12% active drug. Three of these trials showed no benefit and one showed a little bit of benefit, and I want to show it to you because it is frequently cited. It’s by Shaka-Koenig, New England Journal 1992 and it looked at radiation therapy given for two weeks at slightly larger fractions of free gray and then a four week break, and then another two weeks of treatment. So this is not an orthodox control arm because it’s larger fractions but low total dose of 55 gray given over a prolonged course of time. To this they then added – either weekly or daily – cisplatin. In both cases it amounted to the same total dose of 30 mg per meter square per week, or 6 daily times 5. So there is some beauty in this in terms of its design. It would be great to do in, say, animals. But in humans this was compromised by the fact that this is unorthodox radiation and really very low dose cisplatin. Four times 30 is 120, that’s just a little bit more than you would give as one single modality administration. Now this trial is cited as positive because of long term benefit here for the two platinum arms, and maybe short term benefit with the daily cisplatin, but I’m not sure it is. Because the other three cisplatin trials were negative and the control arm did exceedingly poor, and I just explained to you why; because it wasn’t standard radiation.

Now concomitant chemo-radiotherapy looks more promising when multi-agent drugs have been used. Where you can still get that sensitization or better local control, but you also add at least the potential for some systemic activity. SWOG has been the ones who have done the most trials of this in the United States, looking at platinum VP-16 and concurrent radiation. Recently there are Japanese data that I’ll show you that have looked at the MVP regimen, of mitomycin, Velban platinum with either concurrent or sequential radiation. So here’s the SWOG experience. Platinum, etoposide for two cycles with radiation and then two additional cycles in the adjuvant setting. The white curve here are patients with un-resectable disease. The yellow curve are patients who had resectable disease but got a little bit of this treatment before resection. You look at the three year survival – it’s over 20% – suggesting that this is an active principle, to give concurrent multi-agent drugs with radiation therapy. This is unpublished information that Dave Kandara gave me.

RTOG has looked at this a little bit further, in terms of; if concomitant treatment is good and induction chemotherapy is good, can you say is one better than the other? So the control arm here is induction chemotherapy followed by radiation versus concomitant chemo-radiation, and the third arm of cisplatin and oral etoposide with hyperfractionated radiation. So this is a trial that doesn’t look at new drugs necessarily, but tries to optimize how do we give combined modality therapy. You can see that there are positive data for either one of these, induction or concomitant, but the trial tries to establish which is the best way to do this. It’s completed and probably will have some data on this next year.
Cancer information
Now the Japanese have already established such a trial and that was published in JCO last month, or two months ago, and it looked at un-resectable disease. And either gave MVP concurrent with radiation or for two cycles as induction and then radiation alone. So it looked at multi-agent chemotherapy, induction versus concomitant and this is the outcome. Three year survival, 14% versus 22%, or median survival 13 versus 16 months. Clearly suggesting that induction chemotherapy here is as good as it was in the North American trials – median survival of 13 to 14 months – and concomitant, when using multi-agents, may be a little bit better. This is the survival showing this, 13 versus 16 months median survival. Long term follow-up and the curves do not come back together.