Patients often ask me, "Why are we only doing four cycles of chemotherapy for my lung cancer?" This is a great question and one for which the answer is a moving target, based on recent data incorporating maintenance therapies. A recently published meta-analysis took another look at this question in NSCLC. The study authors searched the literature and clinical trial registries to identify randomized, controlled trials of front-line chemotherapy regimens in patients with wet IIIB or stage IV. Trials included compared A) fixed number of cycles of chemo versus continuing chemo until progression, B) shorter versus longer number of cycles (but with a predefined limit rather than continuing until progression) or B) initial chemo versus same initial chemo followed by additional cycles of a different chemo. A total of 13 trials were included, with over 3,000 patients total. None of the included trials incorporated targeted therapies approved for use in NSCLC (Avastin, Tarceva, Iressa or Erbitux).

The investigators found that extending chemo was associated with a statistically significant 8% reduction in death compared with standard duration of chemotherapy. Individually, none of the trials comparing shorter versus longer duration of platinum-based doublets was positive for an overall survival benefit.

Additionally, extending chemotherapy yielded a 25% in the risk of progression compared with standard duration chemotherapy (also statistically significant).

The authors acknowledge that it was difficult to compare quality of life and even adverse events because trials measured these outcomes in very different ways. Only 7 of the 13 trials reported on quality of life. Of those, 5 found no difference between standard versus extended therapy in QoL while 2 found that extended therapy was associated with inferior QoL. Extended chemotherapy was generally associated with more adverse side effects.

Interestingly, the improved overall survival seen for extended therapy was only statistically significant with the inclusion of the recent large trial of maintenance Alimta. Many of the trials included used regimens that we would not use any longer in the frontline treatment of NSCLC. One of the seminal trials included compared 4 versus 6 cycles of modern platinum-based therapy (cisplatin plus either docetaxel, paclitaxel or gemcitabine) and is pretty representative. Although patients who received 6 cycles had longer time to progression, there was no benefit in terms of survival. The patients who received 4 cycles were more likely to receive second-line therapy than those who received 6 cycles and they had less toxicity and returned to baseline functional status more quickly. It's important to note that the patients enrolled on this trial were only those who had not progressed after the first 2 cycles of platinum-based therapy (those expected to do the best).

Would I recommend prolonged platinum-based doublets on the basis of these findings? No. While I do sometimes extend platinum based doublets beyond 4-6 cycles in individual patients (ongoing shrinkage of tumor, good tolerance), this is definitely not common in my practice. I am especially reluctant to do this now that we have less toxic but still efficacious maintenance optionsl. The fact is that even in clinical trials that aimed for longer duration of platinum-based therapy, the usual number of cycles administered is 4 because patients have difficulty tolerating more than this. The new data demonstrating improved overall survival with maintenance Alimta or Tarceva after 4 cycles of platinum-based therapy would give me real pause about continuing platinum-based therapy much beyond 4 cycles. For instance, if a patient gets very sick from ongoing platinum-based therapy, they may miss the opportunity to benefit from a less toxic effective second-line or maintenance therapy. The fact that extended therapy only became positive for an overall survival benefit with the addition on the Alimta maintenance trial (which only gave 4 cycles of a platinum doublet) really argues against older strategies of given more platinum-based doublets.

As Dr. West has pointed out previously, exposure to effective agents rather than duration or timing of therapy may be the driving force behind the improved outcomes seen with patients on extended therapy. Both the Alimta maintenance trial and the Taxotere maintenance trial demonstrated that a substantial proportion of patients in the placebo arm never received additional therapy. We can't really say that giving treatment sooner rather than later is better if many of the laters get...nothing. The other confounding factor is frequency of follow-up. If I have a patient on maintenance therapy, most physicians will see them with each chemotherapy visit. When patients are not on therapy, they are generally seen less frequently and there are really no guidelines and lots of variability in how patients are followed. Patients who are not followed as closely might experience a more substantial decline and thus have less likelihood of being able to receive second- or third-line therapy.