New Treatments for Non-Small Cell Lung Cancer

There are some other pretreatment prognostic factors, and most of these are established in patients with stage IV disease, so those are treated with chemotherapy. There are some large trials that have looked at retrospective evaluation of large numbers. There are newer references for this but they all show the same. Stage is the predominant clinical pretreatment prognostic factor. Performance status is a very strong next, pretreatment weight loss and then adverse effects of male gender and age. For patients with stage IV disease in particular, the number of metastatic sites matters and the use of chemotherapy, in particular cisplatin-based chemotherapy. Now in earlier stage disease, those who have surgery we can also look at molecular abnormalities. These are the two that over the years have been established as negative prognostic factors. That’s the K-ras mutation that’s frequently seen in adenocarcinomas, and absence of blood group antigen A which probably correlates with something else missing. It’s not the absence of the antigen that is harmful to the patient, but there may be loss of a tumor suppresser gene associated with that.

So let’s focus then, for non-small cell lung cancer, on therapy and since most of you are medical oncologists that’s what we want to focus on. About 50% of patients present with stage IV disease. They are treated for palliation, and as I will show you, chemotherapy improves survival and quality of life at acceptable cost. It is now accepted therapy for stage IV disease. If you look back to the 1980’s, then the platinum and Vinca regimens have all similar activity, and the same is true for cisplatin and carboplatin which have similar single agent activity. So this is a disease where either one could be used. The current dogma is that doublets are as good as anything. Adding a third or fourth drug has not been shown to be beneficial. There may be exceptions but that’s the rule. There is probably no dose response curve for survival but there may be threshold doses and that’s coming out particularly with the novel agents that you need to get to a certain dose, but from then on there is no further benefit. That is, of course, softer knowledge but nevertheless it looks like that, particularly for the taxines. Activity for single agent therapy in non-small cell lung cancer has been defined historically as 15% or more. Well, it isn’t always even 15%. Some of these are more like 10%.

There are two groups. These are the older drugs that were available a decade ago and typical regimens then consisted of cisplatin in combination with vinblastine or cisplatin in combination with etoposide. There was also a so-called MVP regimen of cisplatin, mitomycin and vinblastine. That was a triplet. Since 1990 we have at least five new drugs with significant single agent activity, and I will focus on some of that: vinorelbine, Taxol, paclitaxel, docetaxel, gemcitabine and CPT-11 or irinotecan.
So let’s look at the literature of the 1980’s first because what was established during that decade is that chemotherapy is useful for non-small cell lung cancer. Response rates were around 20-30% with most regimens, median survival times around eight months, so how good really was chemotherapy? What was done then is combine, do a randomized trial, comparing chemo alone versus no chemo. Just supportive care. A large number of trials but usually few patients and if you looked at outcome, only three were statistically positive supporting the use of chemotherapy. You can, however, look into this column and what you’ll see – this is median survival in weeks – is usually 25 to the low 30’s and if you look at best supportive care you usually see 15-17. So that’s a poor-mans metaanalysis. Right out of this you could make some conclusions and then have three trials that have statistically positive results and all the others showing the same thing. So metaanalyses were of course done then.

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