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.

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.

So where is the field going? This is an important trial by ECOG that looks at several of these drugs as cisplatin-based doublets, versus carboplatin and paclitaxel. This will establish the relative contributions or the sameness of these relative contributions, but maybe alter differing toxicity profiles for these four treatment arms. The trial is completed but not yet evaluated or analyzed. SWOG, we mentioned, completed a trial of cis, vinorelbine versus carbo, paclitaxel. They then decided to look at a phase II trial, looking at gem, carbo followed by a single agent, versus cis, vinorelbine followed by docetaxel. This is not yet active, I think, but it’s a concept. EURTC in Europe is looking at cis, paclitaxel as their standard now versus cis, gemcitabine. And then interesting, in a regimen that no longer contains either cis or carboplatin, in this case. Just simply looking at these two together, Taxol, gemcitabine. CALGB finally is looking at what’s the minimum amount of therapy one can get away with. Do patients really need a doublet such as carbo, Taxol or could the single agent be just as good and as end points of survival and response, quality of life and economics. So you see that this group of drugs, these five drugs, that have come in – with the exception currently of CPT-11 – are really quite established, that they are a little bit better than the regimens of the 1980’s in terms of improving the quality of life and survival a little bit more, and that at this time we are just sort of looking at the fringes of what other kinds of combinations might there be and how can be improve survival a little bit more using these tools. But really looking forward. What’s going to be necessary from here on, are new active principles and therapies and that means another generation of new drugs.

So that is for stage IV disease. Chemotherapy is accepted and if you want to have a standard regimen, I think it could be cis or carbo and Taxol. It could be cis with vinorelbine, cis with gemcitabine and Taxotere maybe, although the definitive randomized trials are not out there yet. The same would be true for CPT-11.

So let’s move on then to the other common stage. Stage IV is about 50% of patients. Stage IIIb is defined as either very large primaries or contralateral mediastinal nodes, or supraclavicular nodes. So look at this picture and you will see, because it is M0, that this can be treated with curative intent because you can still slap a radiotherapy field over all known disease. So you have a modality that can address all macroscopic disease. But it is no longer feasible to do surgery, not curative surgery on this kind of picture. If you treat this IIIb disease with radiation therapy alone, what is regionally apparently confined, two things happen. Patients fail at a rate of over 90%, either in the ipsilateral chest that’s within that very irradiated volume, or systemically because even though we don’t detect it, the majority of these patients actually do have micro-metastatic disease. This has been looked at. This is the French group. Arm A is radiotherapy only. Look at the failure at five years. Distant failure is 70% – that’s probably an underestimate – and local failure, 90%. So this should let us think about how good is radiation to the chest, because it can shrink tumors but it usually does not eradicate macroscopic disease. Out of this then is our charge. We know from head and neck cancer that this is going to lead to multi-modality therapy. Our charge in doing so is to improve both distant and local tumor control.

So we have the same models that we had in head and neck cancer, so let’s look at induction chemotherapy first. Remember, induction chemotherapy primarily targets micro-metastatic disease because it is early chemotherapy, systemically active. It may down-stage or shrink the local tumor, but what it may do best really is eradication of micro-metastatic systemic disease. Here’s a summary in non-small cell lung cancer, what induction chemotherapy does. It increases median survival so it is a standard treatment; from 10-14 months. It may increase long term survival. This is less firm, and it does eradicate micro-metastatic systemic diseases. Does not improve local control. I’ll show you an example of this. This is the classic trial. Dillman et al in the New England Journal, updated in national JMCI in 2006. This is the design; radiation alone, 60 gray – these days you’d give a bit more than that – versus two cycles only of platinum Velban followed by that same radiation therapy. These were unresectable stage III or IIIb disease but good performance status and limited pre-treatment weight loss. So it’s a selected group of patients that’s in this trial. This is the long term outcome, and it establishes two principles. One is, an increase in median survival by about four months, 10-14, and more importantly, at least the possibility of long term benefit. You look at five years, 7% with radiation alone, 17% with chemotherapy followed by radiation. Of course, somewhat flattened curves in both arms after 2-3 years. So patients fail early with lung cancer and then after that actually may live for quite some time.

Now have any of these new regimens been compared amongst themselves? This is a SWOG trial that was presented at ASCO this year, looking at cisplatin, vinorelbine versus carbo and Taxol in this case. And what it showed is that response rates were similar at 28% and 25%. This is cisplatin, vinorelbine. Carboplatin, Taxol one year survival 36% and quality of life improved or stable also in about 60%. So this established, as some of us have felt for awhile, that several of these new regimens are probably going to emerge as of equal efficacy. So cisplatin, vinorelbine, carbo, Taxol, cis, Taxol is shown here, but they differ a little bit in their toxicity spectrum. If you look at neutropenia, that was more common with cisplatin, vinorelbine than with carbo, Taxol. If you look at neuropathy, then that was a little more common with carbo and Taxol. So that can guide you sometimes maybe to the choice of regimen.

What about gemcitabine, then? Gemcitabine is also a new active drug. This is the definitive trial for gemcitabine that got that drug approved for non-small cell lung cancer. I failed to mention, Taxol-2 is approved. A large multi-center randomized trial of single agent cisplatin versus cisplatin plus gemcitabine. Not fully published yet but this is data from the abstract, looking at grade II or IV neutropenia, more common with the combination. Same for thrombocytopenia. Response rate was 31% versus 9%, and median survival 8.7 versus 7.6 months with a statistical trend. This has not yet been fully published.

So what about docetaxel then? Docetaxel; there are no completed randomized trials yet as a first line agent but what’s interesting about docetaxel is that it has been evaluated as a second line treatment agent, which is quite unique for non-small cell lung cancer. Remember, we just established that chemotherapy is worth doing first line. Well, second line; it’s been evaluated in a number of phase II trials where response rates were seen as high as about 17%. A multi-center phase II was done and presented at ASCO in 2006 by Dave Kendara, and the response rate there was 15% in patients who had been previously treated, usually with cisplatin-based therapy. So there are now two randomized trials, second line therapy randomized trials that have been presented. They are not fully published yet. This was shown by Dr. Pasella at ASCO this year and they looked at either docetaxel at two doses, high and less high, versus either vinorelbine or ifosfamide and the choice here had to do with prior chemotherapy in that specific patient. When you look at the one year survival, then the low dose Taxol, Taxotere, was superior to the other two arms. That suggests that if you too toxic that can be detrimental but certainly if you look at response rate at 1%, vinorelbine or ifosfamide, docetaxel seemed to be the more promising approach. There is a second trial, docetaxel versus best supportive care in previously treated patients, because we now feel that most patients should get chemotherapy up front. But second line best supportive care trials are probably okay to do. You look at median survival time; 7 months with Taxotere versus 4.7 months with best supportive care. Quality of life – in particular, pain and fatigue – better. So here Francis Shepard who presented this recommended that second line therapy could be given, but again, at the lower Taxotere dose of 75 mg per meter squared. So this is an emerging approach. It is still hard to make generalizations because the prior therapy for many of these patients was not yet what frequently would now include actually a taxane as first line therapy. So if you have it first line, would you use it second line? Probably not.

This is the second trial, a French study. Control arm here was cisplatin with vindesine, an 80’s type of platinum Vinca, versus cisplatin, Navelbine versus Navelbine alone. And this is the outcome: median survival 40 weeks with cisplatin, vinorelbine versus 30 weeks with cisplatin, vindesine. And of note, vinorelbine as a single agent very similar. Of course, vinorelbine as a single agent, I just mentioned in the elderly, coming to similar outcome of about 27 weeks median survival. So this is the second trial that established cisplatin and vinorelbine as a possible standard regimen, slightly better than those of the 1980’s.

There is a third trial that did not show that difference but it really didn’t have a control arm. The only control arm with this one was vinorelbine versus cisplatin, vinorelbine and it showed a median survival for both of about 33 weeks.

So let’s move on to Taxol then. This is probably the best of the U.S. trials. This was an ECOG trial early on. The control arm was cisplatin, etoposide. It was compared with cisplatin, Taxol low dose versus cisplatin, Taxol high dose with GCSF. Of note, and I think this is the only such trial, the Taxol here was given as a 24 hour infusion. Not as we would do now, one or three hours. Median survival: 7.6 months with cisplatin, etoposide and close to 10 months with the two Taxol arms, and there was no dose response curve. Meaning that there is probably a threshold value for this drug but not a dose response curve. So this is a trial that suggested that cisplatin, Taxol could also be a standard regimen. This trial has not yet been published, even though it is a few years old. But supposedly it is going to come up pretty soon.
Cancer
This is a European trial, cisplatin, Taxol versus cisplatin, VM-26. This is a drug that is not available in the United States, teniposide, but these two are also a standard doublet. Published in JCO by _ in 2006. It’s a large study. You see the doses here; cisplatin 80 plus either teniposide or paclitaxel as a three hour infusion. Look at response rate; 28% versus 40% with paclitaxel. And median survival not different but very good on both arms at almost 10 months. One year survival of 41% and 43%. So this trial was actually not positive for survival, although encouraging on both arms, and here the Taxol was chosen as the future arm because it was felt to be less toxic and provide better quality of life, but had some late neuropathy. This is the outcome. You see no difference between the two but somewhat better median survival.