Pemetrexed for Previously Treated Patients with Non-Small Cell Lung Cancer and Differences in Efficacy according to Thymidylate Synthase Expression

Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Japan.
Chemotherapy (Impact Factor: 1.29). 11/2012; 58(4):313-320. DOI: 10.1159/000343048
Source: PubMed


The purpose of this study was to evaluate the efficacy of pemetrexed monotherapy in previously treated patients with advanced non-small cell lung cancer (NSCLC) including salvage treatment, and to evaluate whether thymidylate synthase (TS) expression is a predictor for pemetrexed efficacy. Hundred and four previously treated patients with advanced NSCLC who received pemetrexed monotherapy were retrospectively evaluated for clinical efficacy and toxicity. If available, tissue specimens of patients were also analyzed immunohistochemically for TS expression. The patients' median age was 65 years (range: 43-82). An overall response rate of 9.6% and a median progression-free survival (PFS) time of 3.4 months were achieved. The response rates for the second-line, third-line, fourth-line or further treatments were 9.1, 9.3 and 10.2% (p = 0.33); the median PFS were 3.3, 3.2 and 3.8 months (p = 0.21). The median follow-up duration was 14.9 months; the median overall survival (OS) was 11.9 months. The median PFS and OS were significantly longer in the TS-negative group than in the TS-positive group (5.8 months vs. 1.6 months; p = 0.03, and 14.7 months vs. 8.6 months; p = 0.04, respectively). Pemetrexed monotherapy could be considered as an option in the fourth or later lines of treatment of previously treated patients with advanced NSCLC as well as a second- or third-line treatment, and TS expression may be a potentially predictive factor for pemetrexed efficacy in NSCLC patients.

Download full-text


Available from: Yuichi Sato
  • Source
    • "Publication Study design Follow-up Region of Number of Male Median age Histology Stage Method TS high/ TS targeted HR year (months) study patients (%) low drug estimate Chen [20] 2011 Retrospective − Asia 42 57% 61.5 (26–79) AD SCC IIIB IV IHC 20/22 PEM Curve Chang [29] 2010 Retrospective 16.1 (7,30.8) Asia 55 51% 59 (24–84) NSCC SCC − IHC 11/44 PEM Curve Lee [30] 2013 Retrospective − Asia 41 61% 68 (32–79) AD IIIB IV IHC 21/20 PEM Original Duan [31] 2012 Retrospective 19 Asia 30 53% − AD LCC IIIB IV IHC 10/20 PEM Original Igawa [32] 2012 Retrospective 14.9 Asia 54 50% 65 (43,82) AD LCC other IIIB IV IHC 23/31 PEM Curve Gadgeel [42] 2011 Perspective 41 America 16 68% 60 AD SCC IIIAIIIB IHC 7/9 PEM Original Sun [19] 2011 Retrospective − Asia 193 63% − AD LCC other IIIB IV IHC 92/101 PEM Original Takezawa [33] 2011 Retrospective − Asia 24 71% 66 1 (38–85) AD SCC other IIIB IV IHC 12/12 PEM Curve Christoph [21] 2013 Retrospective − Europe 193 54% 59 (23–90) ADLCCSCCother I-IV IHC 83/110 PEM Original Wang [18] 2013 Perspective − Asia 106 59% − AD IIIB-IV IHC 67/39 PEM Original Huang [34] 2 2005 Retrospective 77.0 ± 28.9 Asia 173 67% 67 (35–76) AD SCC LCC I-III IHC 93/80 no Original Nakano [14] 2006 Perspective 65.7 Asia 151 69% 64 (35–76) AD SCC LCC I-III IHC 82/69 UFT Original Wynes [17] 2012 Perspective 63.6(13.2–82.8) Europe 168 78% 63 ADSCCLCCother I-IV IHC 79/89 no Curve Shintani [35] 2003 Perspective 33 (9–42) Asia 70 67% 65.5 1 AD SCC I-II PCR/ IHC 33/37 no Curve Miyoshi [23] 2007 Retrospective − Asia 54 80% 61.7 1 (38–80) ADSCCLCCother I-IV IHC 16/38 UFT Curve Nakagawa [36] 2002 Retrospective − Asia 104 61% − AD p-stage I IHC 75/29 no Original Shimokawa [37] 2011 Perspective 34.2 Asia 183 56% 68.5 1 (23–88) AD I-III IHC 39/144 no Original Kaira [7] 2012 Retrospective 73 (7–102) Asia 160 61% 67 (43–83) AD SCC LCC I-III IHC 74/86 no Curve Zheng [16] 2008 Perspective − America 160 54% − ADSCCLCCBAC I IHC/AQUA 120/40 no Original Yokomise [38] 2013 Retrospective − Asia 45 84% 63.8 (46–76) AD SCC III IHC 20/25 no Original VOLM [40] 1992 Retrospective − Europe 13 − − − − IHC 8/5 no Curve Huang [22] 2000 Retrospective 34.4 ± 21.2 Asia 68 69% − AD SCC LCC I, III IHC 40/28 5-FU/UFT Original Nicolson [41] 2013 Perspective − Europe 60 58% 65.1 (41–78) AD other IIIB-IV IHC 12/48 PEM Original NAKAGAWA [39] 2013 Perspective − Asia 117 78% 65.7 AD SCC LCC I-IV IHC 63/54 no curve 1 mean age; 2 "
    [Show abstract] [Hide abstract]
    ABSTRACT: It remains controversial whether thymidylate synthase (TS) protein expression is associated with survival for patients with non-small cell lung cancer (NSCLC). To evaluate prognostic and predictive significance of tumor TS protein level in NSCLC. Electronic searches were performed for relevant studies in PubMed, EMBASE, Web of Science, and Chinese Biomedical Literature Database. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were pooled for meta-analysis. Subgroup and sensitivity analyses were performed. Publication bias was evaluated by funnel plot and Begg's test. Twenty-four studies, including 2280 patients, were eligible. This analysis showed that patients with low TS expression had statistically significantly longer OS and PFS than those with high TS (HR=0.51 and HR=0.49, respectively). Based on TS-targeted drug use status, TS expression was significantly associated with OS in pemetrexed (HR=0.42) and 5-Fluorouracil subgroups (HR=0.34), but not in no TS-targeted drug subgroup. There were similar results for PFS analyses. Sensitivity analysis indicated that the results were robust. Begg's test did not reveal any publication bias. Low TS protein expression is a favorable predictive factor for better OS/PFS in NSCLC patients treated with TS-targeted drugs. Prognostic value of TS protein expression needs further validation.
    Full-text · Article · Jan 2015 · Cancer biomarkers: section A of Disease markers
  • Source
    • "Six studies (n=483) compared the objective response between TYMS low/negative group with TYMS high/positive group [21–23,29,32,33]. No heterogeneity was found among studies (Chi2=2.59, "
    [Show abstract] [Hide abstract]
    ABSTRACT: The predictive value of thymidylate synthase (TYMS) to sensitivity to pemetrexed-based chemotherapy in advanced non-small cell lung cancer (NSCLC) patients is controversial. We conducted a meta-analysis of all relevant published data to assess the association of TYMS expression with the clinical outcomes of pemetrexed-based regimen in advanced NSCLC. We conducted an electronic search using using PubMed, Embase, OVID and Cochrane Library databases and manual search. Pooled odds ratio (OR) for the response rate and hazard ratio (HR) for the overall survival and progression free survival were calculated using the software Revman 5.0. There were 11 studies (n=798) met our criteria for evaluation. Response rate to pemetrexed-based regimen was significantly higher in patients with low/negative TYMS (OR=2.96, 95%CI [1.81, 4.86] P<0.0001). Patients with low/negative TYMS who were treated with pemetrexed-based regimen had longer progression free survival (HR 0.50, 95%CI [0.41, 0.61] P <0.00001) and overall survival (HR 0.41, 95%CI [0.22, 0.78] P=0.007) than those with high/positive TYMS. Low/negative TYMS expression was significantly associated with higher response rate, longer median survival and longer progression free survival for advanced NSCLC patients receiving pemtrexed-based chemotherapy. Hence, TYMS may be a potential predictor of sensitivity to pemtrexed-based chemotherapy in advanced NSCLC. Large scale prospective clinical trials are still warranted.
    Preview · Article · Sep 2013 · PLoS ONE
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In recent years, major strides in cancer research have made it possible to select personalized chemotherapy recommendations based on an individual patient's tumor biology. The prognostic and/or predictive ability of biomarkers seeks to tailor the use of targeted chemotherapy and can result in improved clinical outcomes with reduced toxicity. A proliferation of new technology and pharmacotherapeutics in the setting of current FDA Clinical Laboratory Improvement Amendment (CLIA) standards has resulted in a recent surge in direct-to-physician biomarker tests. However, in the absence of clinical validation, there is the concern that the biomarkers may be utilized prematurely, resulting in improper chemotherapy selection and patient harm. Thymidylate synthase (TS) has been marketed as a predictive biomarker for the use of pemetrexed in NSCLC. We will examine the evidence behind the use of TS as a predictive biomarker to predict response to pemetrexed in NSCLC. At this time, the evidence does not currently support using TS assays to guide chemotherapy selection outside of a clinical research protocol.
    Full-text · Article · Dec 2013
Show more