One of the issues we struggle the most with, as oncologists, patients, and families, is how to choose a therapy that won’t make someone feel worse. There are so many things to factor into these decisions: what is the baseline function of the person, what comorbidities (other chronic illnesses) might interact or interfere, what side effects are acceptable or worth the risk, to what degree is the cancer interfering with their functioning and can this be reversed with chemo, and of course what does any individual patient want and expect from chemo? Not to mention the choices between a few different agents or combinations of agents!

The issue of “performance status” (PS) is fundamentally important in lung cancer, especially in non-small cell lung cancer (NSCLC). There are different scales we use to measure this, which have been posted and discussed previously. Most publications use the Eastern Cooperative Oncology Group (ECOG) scale – partly because it’s rated 0 – 4 which is easy to remember. Zero is normal, and 4 is very debilitated, essentially bed-bound. Perhaps it is somewhat surprising that despite all of the fancy molecular markers and blood tests we have, a person’s functional impairment of PS is one of the most important predictors of how “bad” a cancer is. The other two factors are stage (how much cancer is there?) and degree of weight loss. It is well described, and there are other posts on the site elaborating on this, that if someone is very sick either from the cancer or from other concurrent illnesses, standard chemotherapy will only make things worse. But there's an "in between" group, with a performance status of 2, who may not be as well served by the more aggressive standard approaches but still may benefit from cancer treatment.

The great hope of the next generation of “targeted” therapy is that oncologists will be able to more accurately predict who will benefit from which drug and that the newer drugs will be less toxic and thus perhaps even better for people who are too sick to tolerate our current forms of chemotherapy.

So – it was with considerable surprise, quite frankly, when the results of Dr. Rogerio Lilenbaum’s phase II study of the epidermal growth factor receptor (EGFR) inhibitor tarceva versus he standard chemo combination carboplatin-taxol in people with a poor PS, was presented at ASCO last year and it was found that the erlotinib arm did considerably worse. The full and peer-reviewed results were recently published in the Journal of Clinical Oncology (abstract here) thus prompting me to write this post.

The study design was very straightforward: 103 patients with advanced NSCLC and ECOG PS of 2 were randomly assigned to tarceva 150 mg orally daily until progression or to carboplatin and taxol IV every three weeks (standard doses) for up to four cycles. Patients who experienced progression or did not tolerate or refused further chemotherapy were allowed to cross over to erlotinib (29 patients, 57% did cross over). Of note, PS 2 basically means that people are up and about for more than 50% of their waking hours and able to look after themselves but are unable to work.

Between 2002 – 2004, the enrolled patients were put on the study at 14 different centers. There were no major clinical differences between the 2 arms (chemo or tarceva). A summary of the results demonstrates that cancers were more likely to shrink by 50% or more with carbo-taxol (though not much more likely: 12% versus 4%) and both treatments were associated with stable disease in about 40%. The toxicities were what you might expect from each type of treatment. What was somewhat surprising was that the progression free survival (the time it takes for a cancer to grow from the start of treatment) was longer in the carbo-taxol arm: 3.5 months versus 1.9 months. And the median survival was also better in the carbo-taxol arm: 9.5 months with chemo versus 6.6 months with tarceva, a pretty big difference:

(Click on image to enlarge)

In addition, although there were some chemo-related toxicities like numbness/tingling with the taxol – the quality of life scores filled out by the patients were about the same if not slightly better on the carbo-taxol arm.

So – what is my take on this? I think that there are some things we have to be careful of with this study and things that I learned from it. First, it was not statistically powered to really compare the arms to each other; it is more of a “pick the winner in a race” design. But of course we all tend to compare them. Perhaps the newer generation of chemotherapies like tarceva and others are less toxic but if they don’t “work” as well, then the quality of life on carbo-taxol might be better or at least the same, i.e. maybe chemo isn’t so bad after all. This reinforces the previous finding that if you start out with a poor PS, it doesn’t bode well for the disease -- so don’t delay too long if you are going to try chemotherapy. And finally – these new drugs need to be given to more selected patient population, and we’re going to need to do more research to find out who these people are. Until then, just because it’s less toxic doesn’t mean it’s better.