Single agent docetaxel, or pemetrexed or EFGR TKIs (erlotinib and gefitinib) represent the standard of care for second-line treatment for NSCLC patients. However, the results observed with second-line treatment are generally poor with response rate of less than 10% and overall survival of 7-8 months [10–14]. One logical approach to improve these results is to evaluate combination regimens. This is the first phase III trial, at least in our knowledge, comparing docetaxel monotherapy with a docetaxel/carboplatin doublet in patients with recurrent or relapsed NSCLC.
The results of the current study demonstrate that second-line combination treatment with docetaxel/carboplatin offers a statistically significant therapeutic benefit compared to docetaxel monotherapy, in terms of PFS in patients with NSCLC who were not previously treated with docetaxel-based chemotherapy. Indeed, PFS was significantly prolonged in the DC arm as compared to D arm (p = 0.012). However, although there was a difference in terms of PFS this could not be translated to a significant difference in terms of OS (p = 0.550). Additionally, no difference was observed in ORR between the two treatment arms (p = 0.764). Taken together, these observations suggest that the higher percentage of patients with stable disease in the DC arm might have played a role in the differences observed in PFS.
Efficacy results in the current trial were obtained with an acceptable toxicity profile. With the exception of thrombocytopenia, the DC arm was not associated with higher toxicity. Indeed, both chemotherapy regimens were well tolerated, with toxicities being relatively infrequent and mild in the vast majority of cases.
The results observed in the single-agent docetaxel arm of the current study are remarkably similar to those observed in the phase III trials that led to registration of docetaxel as second-line treatment in NSCLC [10, 11]. Indeed, OS in these trials was 5.7-7.0 months, median PFS 2.12-2.65 months, and ORR 5.8%-6.7%. The current study reported a median OS of 7.70 months, a median PFS of 2.60 months and an ORR of 7.7%. On the other hand, patients in the docetaxel-carboplatin arm had a longer OS (10.27 months) when compared to historical data [15, 16]. It is noteworthy that the results of the current study are in accordance with the results of a phase III trial  and several randomised phase II trials comparing single-agent versus combination regimens as second-line treatment of NSCLC [25–28]. Although all these trials demonstrated a statistically significant improvement in PFS with chemotherapy combinations, this improvement in PFS was not translated into an OS prolongation. This observation should be attributed to the fact that an important proportion of patients with advanced/metastatic NSCLC have a good performance status and a acceptable expectancy of life making them suitable to receive third-line treatment; in the current study 71 (54%) out of 132 studied patients received third-line chemotherapy or TKIs.
The results of the current study are also in agreement with the results of a recently published meta-analysis based on individual data of 847 patients. Di Maio et al, compared the efficacy of a doublet chemotherapy regimen with single agent treatment as second-line treatment . The conclusion of this meta-analysis was that although combination treatment was associated with significantly higher ORR and significant prolongation of TTP, this difference was not translated into a significant survival benefit . Additionally, patients receiving combination treatment experienced significantly more toxicity. So, based on the lack of a survival benefit and the issue of toxicity, someone could argue against the use of combination regimens in the second-line setting. Furthermore, since patients' quality of life is of particular relevance especially for second-line treatment there is a need for a regimen with a favourable toxicity profile. On that basis we selected the bi-weekly mode of docetaxel administration because it has been reported that it is associated with a marked reduction in haematological toxicity .
Another important issue is the timing of administration of second-line treatment. A recently reported phase III study  demonstrated a statistically significant improvement in PFS and a non-statistically significant increase in OS when docetaxel was administered immediately after front-line gemcitabine/carboplatin doublet compared to its administration at the time of clinical disease progression; in addition, this strategy was not associated with increasing toxicity or decreasing QOL. Practically similar results were obtained with pemetrexed; indeed, in a recent phase III study, patients without disease progression after four cycles of platinum-based front-line treatment who received pemetrexed as maintenance treatment experienced a significantly longer median PFS and OS compared to patients who received placebo . Additionally, erlotinib as maintenance treatment after front-line platinum based chemotherapy resulted in a significant prolongation of PFS .
Another controversial issue is the substitution of carboplatin for cisplatin and it could be argued our decision to use carboplatin instead of cisplatin. It is known that cisplatin-based doublets offer a small survival benefit as front-line treatment, when compared with carboplatin-based doublets . On the other hand, carboplatin has a more favorable toxicity profile when compared with cisplatin . Additionally, the administration of cisplatin requires the need for hydration and it is relatively contraindicated in patients with cardiopulmonary co-morbidities and renal insufficiency. Furthermore, given the practical advantage of carboplatin in terms of ease of administration, it could be argued that the small benefit achieved with cisplatin relative to carboplatin does not justify its use in clinical practice.
Another important issue is whether this study is clinically relevant, since many patients receive platinum-based first-line treatment. However, it should be noted that no phase III trial has clearly demonstrated that platinum-based doublets offer a survival benefit over platinum-free regimens. Furthermore, a recently published meta-analysis failed to show any difference in favor of platinum-based doublets when compared with platinum-free third generation combinations . Thus, a number of NSCLC patients could receive platinum-free regimens as first-line treatment and this trial is relevant for these patients who could receive platinum derivatives as second line.
In conclusion, the combination of docetaxel/carboplatin was well tolerated as second-line treatment for NSCLC patients. Although the primary end-point of the study (prolongation of OS) could not be achieved, the docetaxel/carboplatin combination was associated with a significant clinical benefit in terms of PFS. Based on the results of the current study, docetaxel single-agent should be considered as one of the "standards" options for second-line treatment of advanced/metastatic NSCLC while its combination with carboplatin might be administered in patients with good PS who were not previously treated with a platinum-based doublet or within a well designed clinical trial. Further research is required for the development of more effective chemotherapeutic regimens and for the integration of newer targeted agents into NSCLC treatment.