The efficacy of pemetrexed as a third- or fourth-line therapy and the significance of thymidylate synthase expression in patients with advanced non-small cell lung cancer

Chang, Myung Hee; Ahn, Jin Seok; Lee, Jeeyun; Kim, Kyoung Ha; Park, Yeon Hee; Han, Joungho; Ahn, Myung‐Ju; Park, Keunchil

doi:10.1016/j.lungcan.2009.12.002

Cited by 52 publications

(46 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…22,23 Selection of chemotherapeutic agents is also targeted, and pemetrexed has been shown to be more effective in adenocarcinomas than squamous cell carcinomas, and it is believed that this is dependent on the levels of thymidylate synthase expression. [16][17][18] Unfortunately, although more options now exist for patients with non-small cell lung cancer, mixed histology tumors such as adenosquamous carcinomas have not yet been extensively studied, and no clear treatment protocols exist. This is especially disconcerting, as adenosquamous carcinomas have been shown to have poorer prognosis than adenocarcinomas and squamous cell carcinomas in many studies, 4,5 including Takamori et al 24 of 56 adenosquamous carcinomas, 1 of the largest adenosquamous series, in which they compared Kaplan-Meier survival curves of these three different types of non-small cell lung cancer.…”

Section: Discussionmentioning

confidence: 99%

“…14 Squamous cell carcinomas are known to have higher levels of thymidylate synthase expression than adenocarcinomas, 15 and it is speculated that the efficacy of pemetrexed partially depends upon the level of thymidylate synthase expression. [16][17][18] Accordingly, pemetrexed is approved solely for the treatment of patients with non-squamous tumors for whom it is viewed as a superior drug as compared with taxanes or gemcitabine based on the above data.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Thymidylate synthase expression and molecular alterations in adenosquamous carcinoma of the lung

et al. 2013

View full text Add to dashboard Cite

Thymidylate synthase expression is known to be higher in squamous cell carcinoma than in adenocarcinoma of the lung. It is thought that this is the reason for the poor efficacy of pemetrexed in squamous cell carcinoma. However, there is limited data on thymidylate synthase expression in adenosquamous carcinoma, a distinct subtype of lung cancer containing both squamous and glandular differentiation. Furthermore, molecular alterations like epidermal growth factor receptor and Kirsten rat sarcoma 2 viral oncogene homolog mutations, which are seen in adenocarcinomas, are not well understood in mixed histology tumors such as adenosquamous carcinoma. In our study, we sought to better characterize adenosquamous tumors of the lung. Using immunohistochemistry to evaluate thymidylate synthase protein levels, we found that the expression of thymidylate synthase in these mixed tumors roughly parallel that of squamous cell carcinoma, instead of falling in between squamous cell and adenocarcinoma. Of note, in adenosquamous samples, the expression of thymidylate synthase was more closely correlated within the two components than would be expected by random chance alone. Also, we had a relatively high rate of epidermal growth factor receptor (11%) and Kirsten rat sarcoma 2 viral oncogene homolog (33%) mutations in these specimens, with the mutations showing convergence in both the glandular and squamous components upon microdissection. Our results indicate that adenosquamous carcinomas are not simple mixtures of their two histological components; they rather behave as their own entity, and it is important to further understand their behavior. Given the similarity of thymidylate synthase expression between squamous cell and adenosquamous carcinoma, and that thymidylate synthase is the main target of pemetrexed, we extrapolate that pemetrexed may also have inferior clinical activity in adenosquamous carcinoma.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Thymidylate synthase expression and molecular alterations in adenosquamous carcinoma of the lung

et al. 2013

View full text Add to dashboard Cite

show abstract

“…After completing the selection process, data from a total of eight studies involving 526 patients ( Figure 1) systematically was analyzed. All of them studied the association between TS expression and response to pemetrexedcontaining chemotherapy [6,[22][23][24][25][26][27][28][29][30][31].…”

Section: Selection Of Studiesmentioning

confidence: 99%

“…This scale has been adopted in other nonrandomized studies [28,32,33]. Studies which met five or more of the eight criteria were given higher quality scores.…”

Section: Selection Of Studiesmentioning

confidence: 99%

The Pemetrexed-Containing Treatments in the Non-small Cell Lung Cancer, Is -/Low Thymidylate Synthase Expression Better than +/High Thymidylate Synthase Expression? A Meta-analysis

Wang

Pan

et al. 2014

Chest

View full text Add to dashboard Cite

Background: The predictive value of thymidylate synthase (TS) for clinical sensitivity to pemetrexed-containing chemotherapy in patients with non-small cell lung cancer (NSCLC) remains controversial. This meta-analysis is performed to provide an assessment of whether expression variations of TS are associated with objective response in patients with NSCLC treated with pemetrexed-containing chemotherapy. Methods: An electronic search was conducted using the databases MEDLINE, EMBASE and CNKI, from inception to June 10 th , 2013. A systemic review of the studies on the association between TS expression in NSCLC and objective response of pemetrexed-containing regimen was performed. Pooled odds ratios (OR) for the response rate were calculated using the software Revman 5.0.Results: There were a total of 526 patients in the eight studies that met our criteria for evaluation. +/high expression of TS was found in 269 patients (51.1%), and -/low expression for this gene was found in 257 (48.9%) patients. The objective response rate for pemetrexed-containing chemotherapy was significantly higher in patients with -/low expression TS expression (OR = 0.45; 95% CI, 0.29-0.70; p = 0.0004). Although patients with -/low expression of TS have a longer median overall survival time and progression free survival time than those with +/high expression of TS, the difference was not statistically significant.Conclusions: −/low expression of TS was associated with higher objective response in NSCLC patients treated with pemetrexed-containing chemotherapy. TS may be a suitable marker of sensitivity to pemetrexed-based chemotherapy in patients with NSCLC.

show abstract

“…Previous studies showed that higher tumor tissue TS levels in NSCLC patients were associated with a poor prognosis [8,9,10], and that they could be used as a predictor of a response to TS inhibitors [11]. With regard to the correlation between the efficacy of pemetrexed and TS expression, a recent study reported that there were no significant differences in progression-free survival (PFS) or overall survival (OS) as a function of TS expression levels [12]. On the other hand, another recent study reported that significantly higher response rates and a longer PFS were associated with TS negativity compared with TS positivity [13].…”

Section: Introductionmentioning

confidence: 99%

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

Igawa

Ryuge²,

Wada³

et al. 2012

Chemotherapy

View full text Add to dashboard Cite

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.

show abstract

The efficacy of pemetrexed as a third- or fourth-line therapy and the significance of thymidylate synthase expression in patients with advanced non-small cell lung cancer

Cited by 52 publications

References 24 publications

Thymidylate synthase expression and molecular alterations in adenosquamous carcinoma of the lung

Thymidylate synthase expression and molecular alterations in adenosquamous carcinoma of the lung

The Pemetrexed-Containing Treatments in the Non-small Cell Lung Cancer, Is -/Low Thymidylate Synthase Expression Better than +/High Thymidylate Synthase Expression? A Meta-analysis

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

Contact Info

Product

Resources

About