Although I've previously written about the question about optimal duration of therapy for first-line chemotherapy in advanced NSCLC (post here), these conclusions have been based on a limited number of trials. One study randomized patients to three or six cycles of rather old chemo and found no significant differences (abstract here). Another more recent study randomized patients to four cycles of carbo/taxol compared with treatment until progression or prohibitive toxicity, with some patients going for more than 12 cycles, also demonstrating no significant differences in survival (abstract here). Based on the rather modest data, the current guidelines of the American Society for Clinical Oncology (ASCO) are to treat for no more than four cycles in non-responders, and no more than six cycles in patients who demonstrate a response to first-line treatment.

Most US-based oncologists follow a practice of treating up to either four or six cycles, although a reasonable minoriity in the US, and a higher proportion in other parts of the world, still treat beyond six cycles and up to the time of progression. Our current clinical trials, developed to include current best treatment practices, incorporate either four or six cycles of chemotherapy, with no consensus. The ECOG 4599 trial that established the role of avastin with carbo/taxol gave six cycles of chemo and avastin together, followed by maintenance avastin (abstract here). On the other hand, multiple trials that have focused on the maintenance portion or timing of second-line therapy have stopped at four cycles (see prior post here). What's really the best approach?

A trial by Park and colleagues from Korea that was just reported in the Journal of Clinical Oncology tried to address this question (abstract here). As shown in the schema below, 452 patients with previously untreated advanced NSCLC were treated first with two cycles of cisplatin-based chemo, and then responses were measured. One third who showed progression or toxicity problems came off the trial, leaving 314 who experienced stable disease or a response to be randomized to either four more cycles (total of 6) or two more cycles (total of 4) cycles of the same chemotherapy:

(Click on image to enlarge)

Patients were then followed, received a CT every three months after chemo ended, and in most cases received subsequent chemo (off protocol) at that point.

The results demonstrated that the patients who received a total of six cycles had a significantly longer progression-free survival, but both groups had the same overall survival, as shown here:

Differences in side effects weren't very different between the two arms, with a little more toxicity in the patients who received more chemo, as you'd expect. Quality of life was also measured, and while there were no overall clear differences, a few parameters favored the shorter treatment arm, and none favored the longer treatment arm.

The results are noteworthy for a number of reasons. The authors make the point that the survival is quite favorable, and if the numbers you see look especially good, that is largely because the numbers reflect survival of a group of patients who remained after the third who had progressed or otherwise done poorly came off the study -- the only ones randomized were those with stable disease or better after two initial chemo cycles. Second, more than half of the patients on the trial received iressa, and we know that Asian patients are more likely to do particularly well with EGFR inhibitors. At the same time, however, some trials that compare results in Japanese vs. North American trials that used the exact same chemo in the same setting produced more favorable results in the Japanese population. It is possible that patients in Japan do better because something about the supportive care is better, they have more responsive disease, or some combination of factors.

I don't get a clear answer to the question of whether four cycles or six cycles is a better choice, and frankly I don't think it matters much. I think that if patients tolerate chemo well and are still demonstrating stable disease, it's perfectly great to continue to six cycles, but four is going to get people to pretty much the same place. I think the main reason for this is that there's a dilution of any differences with second line and often third line treatments. An advantage of stopping after four cycles is that it may deliver more patients to later therapies with a good performance status and "bone marrow reserve" -- the capacity to have the bone marrow make more blood cells quickly after subsequent chemo. Overall, I wouldn't have any hesitation about participating in a trial that includes four cycles, nor would going to six cycles be a problem, as long as a patient continues to feel OK on chemo. With several later treatment options available now, and a real possibility (and I'd even say probability) of more new treatments emerging as 2nd, 3rd, or even 4th line options for advanced NSCLC, subtle differences in what happens in first line treatment are increasingly likely to get washed out over time.