What is happening for at least N2 IIIa disease right now is a very important trial that accepts concomitant chemo-radiotherapy – that’s the SWOG regimen, platinum, etoposide, radiation – and then asks, “Do these patients really need surgery? Do they benefit from that or is chemo-radiotherapy just as good?” So they randomized on the standard arm to receive 45 gray of radiation with two cycles of platinum, etoposide and then surgery versus that same initial chemo-radiotherapy and then a chemo-radiotherapy boost. This trial is in progress and hopefully will complete in the very near future.

What about classical adjuvant chemotherapy for earlier stage disease, stage I or stage II? This is a very typical design. You would look at surgery and radiation, in some cases surgery alone, versus surgery, radiation and chemo. Well, to make it brief, to date there is no proven role for adjuvant chemotherapy. I’m showing you this trial as the most recent example of a negative trial. This was a large U.S. intergroup trial, designed just as this: surgery, radiation, surgery, radiation with platinum, etoposide. Two cycles concurrent and two cycles adjuvant afterwards. Preliminary analysis shown at ASCO this year, long term follow-up already. Median 41 months and median survival identical, 38 months on both arms. The only thing that is encouraging about this is that the median survival was really high on both arms. Surprisingly so, maybe, and the five year survival rate particularly encouraging at 39% and 33%. But this does not support a role for adjuvant chemotherapy, not yet.

This is a positive trial, a European trial, that actually suggests that induction chemotherapy may be of benefit in stage Ib to IIIa where patients had either surgery or MIP, mitomycin ifosfamide, platinum, and then surgery. And radiation was given to some patients according to individual preference. In this trial, if you look at the two and three year survival, there is a suggestion of benefit. But it’s confounded by a number of things. The number of patients getting radiation on the surgical arm is much higher and paradoxically we now think that adjuvant radiation for at least some of these patients actually decreases their chances of survival or cure rather than increasing it. That’s again fairly recent literature looking at the role of radiation. So I’m showing you this to say that not all data are negative, but it’s certainly not yet conclusively supporting induction chemotherapy.

Now finally then, looking at current affairs here, here in early stage disease – much like in the advanced stages – we are looking at the newer regimens and what is called the bi-modality lung oncology trial, or BLOT. Bi-modality because it is chemo and surgery, looks at induction chemotherapy with carboplatin and paclitaxel in stage Ib through IIIa disease. This has been piloted in 94 patients with an objective response rate of the chemotherapy of 54%, which is not bad, and based on this the phase III trial has been activated where patients received either surgery or induction, not adjuvant, carbo and paclitaxel for three cycles.

So you can summarize then that induction chemotherapy is established, that concomitant chemo-radiotherapy is probably also established and may be even a little bit better, but we don’t know yet. I think the RTOG trial is important for that. And that we now need to integrate the new drugs and maybe find out; is induction better than concomitant, but should maybe both be given? This is the first such trial that tried to evaluate should both be given, giving induction and then radiation versus radiation with weekly carbo at low doses. So this is going back to the single agent concept. And you see no difference. That’s actually consistent with cisplatin literature, that single agent radiation sensitization is simply not enough to make a difference. Median survival, 13 months in both arms as you would expect in an induction chemotherapy trial.

In CLGB we’ve now looked at giving induction and concomitant but multi-agent therapies. And several other groups are looking at this and then adding the new drugs into this menu. We have some preliminary data that suggests that this can be done. We’ve looked at gemcitabine in this setting, paclitaxel and vinorelbine. All three are feasible but how good they are and what kind of long term survival rates we get, we are not sure of yet. So this was a randomized phase II trial, about 60 patients per arm, and we do now that all three arms are feasible and that these new drugs may have a role in stage III disease, much as they do in stage IV disease.

So in the last few minutes then, let’s move down to the earlier stage disease settings. If chemotherapy has a role in stage IV for palliation and in stage IIIb to increase survival, then moving to the earlier stages you have fewer patients to evaluate, you bring in surgery as a third modality, randomized trials are very few and the conclusions are much less clear. So I just want to leave you with a few impressions. This is stage IIIa disease where again you have large primary lymph nodal disease but usually the surgeon has an option of at least attempting a curative intent resection. There have been two very small trials that are frequently cited that have looked at induction chemotherapy for stage IIIa disease and in this case surgery versus chemotherapy, followed by surgery. If you look at the three year survival there was a large difference favoring induction chemotherapy. A very similar trial from Spain, published in the New England Journal 1994, again about 30 patients – these are much harder to do these trials than stage IV or IIIb – surgery followed by radiation, versus chemotherapy followed by surgery and radiation. You look at the median survival, eight versus 26 months, and again a suggestion also of long term benefit. But both are very small trials and I could show you similar small trials that did not show that benefit. So for IIIa disease, induction chemotherapy, we’re really not sure yet.

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.