One of the core ideas in the management of stage III, or locally advanced, NSCLC is that unresectable disease that is being treated with curative intent is most effectively treated with a combination of concurrent systemic (“whole body”) therapy and chest radiation to all of the visible cancer. The systemic therapy, which has been conventional chemotherapy, is given to both make the radiation work better and to treat potential micrometastatic disease, cancer cells in the bloodstream that can’t be reached by radiation but could potentially be killed off by a treatment that goes throughout the bloodstream.
The challenge, though, is that concurrent chemo and radiation is hard on people, with a rate of treatment-related deaths of about 5-7% of people even on clinical trials (which often select for a fitter population than are seen in the “real world” of many ineligible patients). So we reach a point where the aggressiveness of the treatment can be associated with problems that are as threatening or worse than the underlying disease. And this is a particular problem for older and/or frailer patients, which happens to cover a significant proportion of people with lung cancer.
Part of the promise of targeted therapies all along has been that they could potentially substitute for standard chemotherapy as a systemic therapy that is perhaps as effective as chemo but with fewer side effects. Most of our work with these agents has been to just add them to our current standards, but it still makes sense to consider using them as a substitute in patients for whom conventional chemo is really at the upper limits of what is tolerable. And it’s clear that doing chemo concurrent with radiation is overall more effective than doing them sequentially, but perhaps we could get the tolerability of a sequential approach with the efficacy of concurrent therapy by doing a program of targeted therapy (and no chemo) concurrent with chest radiation.
In fact, erbitux has been FDA approved for treating head and neck cancer as an alternative to standard chemo, given with radiation. While some patients are treated with chemo and concurrent radiation for head and neck cancer, this is a very, very hard treatment for patients. A trial published in the New England Journal of Medicine (abstract here) showed that weekly erbitux with radiation gave a significant survival benefit compared with radiation alone. It’s not clear whether it gives the same benefit as chemo, because there hasn’t been a trial that has really compared erbitux/RT to chemo/RT. Of course, oncologists have tried to give chemo and erbitux and RT in head and neck cancer (again, we love to ADD), and that work was stopped early because of excessive side effects and patient deaths.
In a prior post I had described one of the early experiences of using targeted therapy instead of chemo for stage III NSCLC, in which the CALGB studied iressa concurrent with radiation. In fact, they gave iressa concurrent with chemo and radiation for healthier patients and gave iressa and no chemo with radiation to marginal performance status patients. It was the more frail patients who did better, and I think that a large part of this may be because chemo and iressa were antagonistic with each other (as I’ve alleged previously).
Another approach is the one that SWOG is pursuing, which is giving a light weekly chemo. This trial, known as SWOG 0429, targets a population who are considered to be less than ideal candidates for the most aggressive chemo and radiation approaches: those with a marginal performance status, compromised lung function, and/or low serum protein levels (actually, the albumin level, which is being used as a surrogate for nutritional status). Patients start with a “loading dose” of erbitux (a higher dose than the regular maintenance one, to get up to target blood levels quickly — this is the standard way erbitux is given), then a week later the patient starts weekly low-dose taxotere and erbitux with radiation to 61 Gray (full dose), and then maintenance erbitux until progression:
Note that this proposes to give weekly therapy until progression to people who may be cured, so you could have people going on for more than a year. I don’t know how feasible it would really be to have people continue maintenance weekly therapy indefinitely.
For anyone who is interested, details about this ongoing trial are available here.