And you see there are at least four, all asking basically the same thing and all coming to the same conclusion. This is the best one, British Medical Journal, 1995. Median survival six months with supportive care, eight months with chemotherapy. One year survival, 16% versus 26%. All four concluded that chemotherapy improved survival by a little. This is a more recent example. MIC, standing for mitomycin, ifosfamide, cisplatin; the British trial, published this month in JCO. And here four cycles of MIC versus best supportive care: median survival, five versus seven months, statistically significant. I show this trial and the data are in the Journal because they looked at quality of life and it was improved with chemotherapy over best supportive care. This had also been addressed in previous trials, but addresses this issue where frequently it was meant that yeah, you only improve survival a little and are patients really benefiting from it? Well, they do.

What about elderly? This is a disease that frequently occurs in the elderly. So patients 70-years-old, or in the past it would be argued, “Well, let’s not treat that patient anymore. It’s too old.” Well, 191 patients were randomized to either vinorelbine single agent or best supportive care. Median survival with chemo: 27 weeks versus 21 weeks. Sort of showing the same thing in this group of patients. Six months survival: 54% versus 39%, statistically significant. One year: 27% versus 5%. Quality life here too was analyzed – this was published in JMCI last year, or early this year rather – improved with chemotherapy. Finally, cost-effectiveness has been looked at, particularly with one of these trials, the so-called Canadian trial. And to not go into great detail, just to make the case, that even though the chemotherapy costs some money they felt that this was well within the range of any other interventions and that cost or cost-effectiveness should not be a barrier to offering chemotherapy. So looking at this information, you can summarize that chemotherapy is an active modality in stage IV disease, that it prolongs survival by a little, that it improves quality of life – and it does so at acceptable cost – and as a consequence should be offered to these patients. The debate is done. That’s the literature of the 80’s.

So what we want to move onto then is in the 90’s, not much any more do we want to use chemotherapy but can we identify better chemotherapy? I mentioned that there were five drugs that came out during this decade. They have now been somewhat evaluated and let’s go over that a little bit, in sequence at least. The first two trials will focus on vinorelbine. That was the first drug that came out. It’s a Vinca alkaloid. This is the definitive trial done by SWOG, Tony Wosniak published in JCO. Cisplatin alone is the control arm, cisplatin, vinorelbine was the experimental arm. Median age 63 years as a standard. Most patients male, as is the case, and most had stage IV disease. So this is a poor prognostic group of patients. Some other trials have more patients with stage IIIb disease in there. You can look at response. So what’s the single agent response rate to cisplatin? It’s 12% and to cisplatin and vinorelbine it’s 26%. Here’s the overall survival: median survival six months with cisplatin alone and about eight months with cisplatin and vinorelbine and statistically significantly improved. So this is the trial, or one of them, that got vinorelbine approved by the FDA for non-small cell lung cancer, and cisplatin, vinorelbine then as a possible standard regimen.

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.
Cancer
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.

Lung cancer is smoking-related. This is a totally preventable disease if patients do not smoke. And all of what we talked about wouldn’t be necessary if not for cigarettes. So it is the second most common malignancy in both sexes. Head and neck cancer was 40,000, this is 172,000 cases per year and it’s the most common cause of death in either sex. Meaning that in males it is a more common cause of death than prostate cancer, and in females more common a cause of death than breast cancer. Eighty percent of cases at least attributed to smoking. There may be some other risk factors and a genetic predisposition – largely, we think, because there is no familial clustering outside of smoking – in terms of how individual patients metabolize or otherwise handle the carcinogens contained in the smoking.

Let’s look at some of the incidence figures. These are incidence, cancer rates. This is prostate cancer shooting up when PSA becomes available then down. This is lung cancer in terms of incidence, slightly going down in males for the last 20 years or so. This is incidence rates for females and you see it’s still rising, as far as lung cancer is concerned. This is breast cancer – more common. Now let’s look at the death rates. These are the death rates in males. This is lung cancer. Exceeding everything else by far with somewhat of a reverse trend in the last few years. And this is the same in women, exceeding everything else with what still appears to be a rising incidence of lung cancer deaths in women. So that is where smoking prevention is more important than anything we can talk about in this kind of lecture. This is way too late and conceptually of course, not in an epidemiological sense, the primary thing to do.
Pharmacy
Now what about the histologic types? Seventy-five percent are non-small cell, that’s what we will cover here. The others are small cell and non-small cell, divided up into these cancers: in the United States now adenocarcinoma is the most common, squamous carcinoma is next. This used to be different 20 years ago but now adenocarcinomas are the common ones and we are not sure why that is. Then this is stage-specific survival. Stage I is a confined disease. These patients are treated with curative intent by resection. Stage II is very similar, with at most, hilar lymphadenopathy. Many patients can be cured although you are down now to about 30%. Stage III, we will talk about a bit more in detail, includes regionally advanced disease. So that is disease in the chest involving large primaries or lymph nodes, mediastinal lymph nodes or supraclavicular lymph nodes, but no distant metastases. Then stage IV is distant metastases. We can also look at this is a sense of how far along can we use surgery. For metastatic disease we wouldn’t, and for stage I or II we would. Because these patients can be cured surgically, at least in some cases. Then stage III is split. Where usually IIIa is, at least in theory, resectable whereas IIIb is considered un-resectable. So that is the split from a surgical point of view.