Purpose: Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non–small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting.Patients and Methods: This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m²on day 1 and gemcitabine 1,250 mg/m²on days 1 and 8 (n = 863) or cisplatin 75 mg/m²and pemetrexed 500 mg/m²on day 1 (n = 862) every 3 weeks for up to six cycles.Results: Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.Conclusion: In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

PURPOSE: To evaluate whether two commonly used newer platinum-based regimens offer any advantage over vinorelbine-cisplatin (reference regimen) in response rate for patients with advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients were randomized to receive gemcitabine 1,250 mg/m² days 1 and 8 plus cisplatin 75 mg/m² day 2 every 21 days (GC arm), or paclitaxel 225 mg/m² (3-hour infusion) then carboplatin (area under the concentration-time curve of 6 mg/mL·min), both on day 1 every 21 days (PCb arm), or vinorelbine 25 mg/m²/wk for 12 weeks then every other week plus cisplatin 100 mg/m² day 1 every 28 days (VC arm). RESULTS: Six hundred twelve patients were randomized to treatment (205 GC, 204 PCb, and 203 VC). Overall response rates for the GC (30%) and PCb (32%) arms were not significantly different from that of the VC arm (30%). There were no differences in overall survival, time to disease progression, or time to treatment failure. Median survival for the GC, PCb, and VC groups was 9.8, 9.9, and 9.5 months, respectively. Neutropenia was significantly higher on the VC arm (GC 17% or PCb 35% v VC 43% of cycles, P < .001), as was thrombocytopenia on the GC arm (GC 16% v VC 0.1% of cycles, P < .001). Alopecia and peripheral neurotoxicity were most common on the PCb arm, as was nausea/vomiting on the VC arm (P < .05). CONCLUSION: Efficacy end points were not significantly different between experimental and reference arms, although toxicities showed differences. These findings suggest that chemotherapy in NSCLC has reached a therapeutic plateau.

Background.Recent studies of pemetrexed have identified a predictive role for non-small cell lung cancer (NSCLC) histology. We further reviewed the differential efficacy of pemetrexed according to histology in two large, phase III NSCLC trials. Methods.One study tested pemetrexed versus docetaxel in previously treated patients (n = 571) and the other tested cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemotherapy-naive patients (n = 1,725) with advanced NSCLC. Cox proportional hazard models were used to test for covariate-adjusted treatment-by-histology interactions (THIs) for overall survival (OS) and progression-free survival (PFS). For each histologic subgroup, the Kaplan–Meier method was used to estimate unadjusted within-arm medians, and Cox models were used to estimate covariate-adjusted between-arm hazard ratios (HRs). Results.In both studies, treatment arms were well balanced for histology. THIs were statistically significant (p < .005) for both OS and PFS. Nonsquamous patients treated with pemetrexed-based therapy experienced longer survival than the comparators (HR, 0.78 and 0.84, respectively), whereas squamous patients had shorter survival (HR, 1.56 and 1.23, respectively). Whereas the efficacy of pemetrexed regimens differed according to histology, it did not differ for docetaxel or for cisplatin plus gemcitabine. Pemetrexed was well tolerated across histologic groups. Conclusions.The consistency of these results across studies confirms the predictive effect of histology for pemetrexed and the survival advantage for pemetrexed in patients with nonsquamous histology. These analyses suggest pemetrexed should not be recommended for the treatment of squamous cell carcinoma, but, because of efficacy and safety advantages, pemetrexed may be preferable to other agents for treatment of patients with nonsquamous NSCLC.

Background: Surgery is the primary treatment for patients with stage I, II, or IIIA non–small-cell lung cancer (NSCLC). However, long-term survival of NSCLC patients after surgery alone is largely unsatisfactory, and the role of adjuvant chemotherapy in patient survival has not yet been established. Methods: Between January 1994 and January 1999, 1209 patients with stage I, II, or IIIA NSCLC were randomly assigned to receive mitomycin C (8 mg/m² on day 1), vindesine (3 mg/m² on days 1 and 8), and cisplatin (100 mg/m² on day 1) every 3 weeks for three cycles (MVP group; n = 606) or no treatment (control group; n = 603) after complete resection. Randomization was stratified by investigational center, tumor size, lymph-node involvement, and the intention to perform radiotherapy. The primary endpoint was overall survival and secondary endpoints were progression-free survival and toxicity associated with adjuvant treatment. Survival curves were analyzed using the log-rank test. All statistical tests were two-sided. Results: After a median follow-up time of 64.5 months, there was no statistically significant difference between the two patient groups in overall survival (hazard ratio = 0.96, 95% confidence interval = 0.81 to 1.13; P = .589) or progression-free survival (hazard ratio = 0.89, 95% confidence interval = 0.76 to 1.03; P = .128). Only 69% of patients received the three planned cycles of MVP. Grades 3 and 4 neutropenia occurred in 16% and 12%, respectively, of patients in the MVP arm. Radiotherapy was completed by 65% of patients in the MVP arm and by 82% of patients in the control group. In the multivariable analysis, only disease stage and sex were associated with survival. Conclusion: This randomized trial failed to prospectively confirm a statistically significant role for adjuvant chemotherapy in completely resected NSCLC. Given the poor compliance with the MVP regimen used in this study, future studies should explore more effective treatments.

Purpose: This phase III, multicenter, randomized, placebo-controlled trial assessed the efficacy and safety of sorafenib, an oral multikinase inhibitor, in combination with carboplatin and paclitaxel in chemotherapy-naïve patients with unresectable stage IIIB or IV non–small-cell lung cancer (NSCLC). Patients and Methods: Nine hundred twenty-six patients were randomly assigned to receive up to six 21-day cycles of carboplatin area under the curve 6 and paclitaxel 200 mg/m² (CP) on day 1, followed by either sorafenib 400 mg twice a day (n = 464, arm A) or placebo (n = 462, arm B) on days 2 to 19. The maintenance phase after CP consisted of sorafenib 400 mg or placebo twice a day. The primary end point was overall survival (OS); secondary end points included progression-free survival and tumor response. Results: Overall demographics were balanced between arms; 223 patients (24%) had squamous cell histology. On the basis of a planned interim analysis, median OS was 10.7 months in arm A and 10.6 months in arm B (hazard ratio [HR] = 1.15; 95% CI, 0.94 to 1.41; P = .915). The study was terminated after the interim analysis concluded that the study was highly unlikely to meet its primary end point. A prespecified exploratory analysis revealed that patients with squamous cell histology had greater mortality in arm A than in arm B (HR = 1.85; 95% CI, 1.22 to 2.81). Main grade 3 or 4 sorafenib-related toxicities included rash (8.4%), hand-foot skin reaction (7.8%), and diarrhea (3.5%). Conclusion: No clinical benefit was observed from adding sorafenib to CP chemotherapy as first-line treatment for NSCLC.

BACKGROUND.: In patients with cancer, one of the main mechanism of resistance to antimetabolite drugs is related to higher levels of thymidylate synthase (TS) activity.METHODS.: To investigate the association between TS expression and histopathologic data, 56 resection specimens from patients with nonsmall cell lung carcinoma (NSCLC) were collected consecutively. TS messenger RNA (mRNA) was evaluated in tumor specimens by using real‐time polymerase chain reaction (PCR) analysis; protein expression was evaluated by using immunohistochemistry (IHC) in formalin‐fixed, paraffin‐embedded (FFPE) specimens; and the analysis of TS transcriptional regulation activity was performed by using real‐time PCR analysis in snap‐frozen normal and tumor specimens.RESULTS.: The amplification of the TS gene from FFPE tissues was obtained from all samples, with a median level (unit‐less ratio) of 1.45 (range, 0.34–5.24); whereas positive TS status at IHC (>10% positive cells) was detected in 56% of samples. It is noteworthy that TS expression was significantly higher in squamous cell carcinoma compared with adenocarcinoma when both mRNA levels (2.17 vs. 1.16; P < .0001) and protein levels (P = .0269) were considered in FFPE specimens, and a strong association was observed between mRNA and protein expression (P = .00017). Moreover, higher TS levels were observed in high‐grade tumors (P = .0389 and P = .0068 for mRNA and protein quantification, respectively). The analysis in snap‐frozen samples revealed that the TS gene was up‐regulated strongly in tumors (P = 3.8 × 10⁻¹²), and an 8‐fold increase (as a cut‐off value) in the TS mRNA ratio between tumor and corresponding normal tissue was detected in 32 of 56 patients (57%) bearing preferentially squamous cell tumors (P = .0022) and high‐grade tumors (P < .001).CONCLUSIONS.: Data from the current study consistently indicated higher TS expression levels in squamous cell and in high‐grade carcinomas. This information may be useful in selecting which patients with NSCLC should receive treatment with TS‐inhibiting agents. Cancer 2006. © 2006 American Cancer Society.