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.