Duration of Chemotherapy for Metastatic Non-Small-Cell Lung Cancer: More May Be Better After All

Non–small-cell lung cancer (NSCLC) is one of the few diseases for which numerous randomized clinical trials have compared best supportive care with chemotherapy. These studies have shown that compared with best supportive care, platin-based chemotherapy improves survival in patients with good performance status. Since these studies were performed, we have seen the impact of systemic therapy on survival, both in second-line (docetaxel, erlotinib, and pemetrexed) and third-line (erlotinib) recurrent disease settings. Despite the survival advantage observed with firstand secondline chemotherapy, most randomized studies to date have failed to show a definitive improvement in survival with the administration of additional first-line chemotherapy, although most have shown an improvement in progression-free survival (PFS), more often than not with a higher incidence of adverse events. As pointed out by Soon et al in this issue of Journal of Clinical Oncology, there are several ways to administer additional chemotherapy to patients who have responded or stabilized after four to six cycles of first-line chemotherapy. These include: first, continuing first-line chemotherapy until disease progression; second, continuing first-line chemotherapy, but limiting it to a specified number of cycles; and third, switching to a different regimen after a defined number of cycles of first-line chemotherapy. Various terms have been used to describe to these different scenarios. Some call the first and second approaches maintenance therapy and the third early second-line therapy, whereas others call the first and second approaches prolonged chemotherapy and the third induction chemotherapy followed by consolidation. Although there is no uniform consensus regarding terminology, early second-line therapy implies interval progression, and maintenance therapy implies continuation of original regimen, whereas consolidation implies switching to a different treatment. We prefer the terminology of maintenance for the first and second approaches and consolidation for the third. Regardless of the terminology, before the administration of additional chemotherapy can be adopted as part of routine practice, it is critically important to show a survival benefit, given the toxicities associated with chemotherapy in diseases with poor prognoses, such as lung cancer. Presumably, an improvement in PFS without an improvement in overall survival suggests that both the first and second regimens are active, and it does not matter when the second regimen is administered—at progression or immediately after the first regimen. Although this question of sequence has only been formally tested in one advanced NSCLC trial, it has been tested extensively in other malignancies, such as colorectal carcinoma and breast cancer. In reports of these studies, it has been argued that if PFS is improved without corresponding improvement in survival, the timing of administration of consolidation or second therapy does not matter; the second regimen could be delayed until progression. Regardless of the underlying mechanism, what is most important is that an approach works (ie, that it improves survival). In the absence of a clearcut survival advantage, it is hard to justify added expense or toxicity. However, several recent studies have suggested that there may be benefit in administering additional chemotherapy after four to six cycles of a front-line regimen. In the clinical trial in advanced NSCLC reported by Fidias et al, patients received gemcitabine and carboplatin as first-line therapy. Those without progression after four cycles of chemotherapy were randomly assigned to immediately receive an additional six cycles of docetaxel or to follow the standard of care, which was defined as no additional therapy until disease progression, at which point they received docetaxel. Median PFS with immediate docetaxel (5.7 months) was significantly longer (P .0001) than that with delayed docetaxel (2.7 months). Although there was a trend toward improved survival with immediate docetaxel (12.3 months) compared with delayed docetaxel (9.7 months), it did not quite reach statistical significance (P .0853). One reason for poorer survival in the delayed arm of the trial reported by Fidias et al may have been because many patients randomly assigned to receive delayed docetaxel at progression never received it. Whereas 145 (95%) of 153 patients randomly assigned to receive immediate docetaxel received at least one cycle of additional chemotherapy, only 98 (63%) of 156 patients randomly assigned to the delayed arm actually went on to receive docetaxel at progression. Thirty of the remaining 58 patients did not receive delayed docetaxel because of disease progression or death. Survival for the 98 patients in the delayed arm who actually received docetaxel was 12.5 months— identical to the 12.5-month survival of the 145 patients in the immediate arm. This discrepancy suggests that the trend toward improved survival in the immediate arm as a whole was simply a result of more patients being able to receive an active drug. Thus, early treatment may be better, not because it does a better job of killing cancer cells in the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 20 JULY 1