A Randomized Phase II Trial of Oral Topotecan Versus Docetaxel in the Second-Line Treatment of Non–Small-Cell Lung Cancer

Jones, Suzanne F.; Thompson, Dana S.; Barton, John H.; Patton, Jeffrey; Shipley, Dianna; Greco, F. Anthony; Spigel, David R.; Infante, J.; Burris, Howard A.

doi:10.3816/clc.2008.n.023

Cited by 8 publications

(8 citation statements)

References 12 publications

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“…TPT is FDA approved as a second-line drug for the treatment of advanced ovarian, cervical, and small cell lung cancers (McGuire et al, 2000; Monk et al, 2009; O'Brien et al, 2007). The limited number of clinical trials using TPT as a single agent for NSCLC have demonstrated response rates (RR) and median OS ranging from 0 – 25% and 40 – 74 weeks as first-line and 2.8 – 8% and 10 – 34 weeks in second-line settings, respectively (Gonzalez et al, 2010; Jones et al, 2008). Two recent phase II and phase III clinical trials, demonstrated that oral TPT in unselected NSCLC patients is as effective as docetaxel, the FDA approved second-line drug for NSCLC (Gonzalez et al, 2010; Jones et al, 2008; Ramlau et al, 2006; Weitz et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…The limited number of clinical trials using TPT as a single agent for NSCLC have demonstrated response rates (RR) and median OS ranging from 0 – 25% and 40 – 74 weeks as first-line and 2.8 – 8% and 10 – 34 weeks in second-line settings, respectively (Gonzalez et al, 2010; Jones et al, 2008). Two recent phase II and phase III clinical trials, demonstrated that oral TPT in unselected NSCLC patients is as effective as docetaxel, the FDA approved second-line drug for NSCLC (Gonzalez et al, 2010; Jones et al, 2008; Ramlau et al, 2006; Weitz et al, 2000). Large intra-study differences in OS ranging from 4 – 59 and 2 – 46 weeks were also seen when TPT was used as a first- or second-line therapy for NSCLC patients, respectively (Gonzalez et al, 2010; White et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

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SULF2 methylation is prognostic for lung cancer survival and increases sensitivity to topoisomerase-I inhibitors via induction of ISG15

et al. 2011

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The heparan sulfate 6-O-endosulfatase (SULF2) promotes growth and metastasis of solid tumors. We recently identified that cytosine methylation of the SULF2 promoter is associated with better survival of resected lung adenocarcinoma patients and now also demonstrate a marginal improvement in survival of advanced non-small cell lung cancer (NSCLC) patients receiving standard chemotherapy (HR = 0.63, p = 0.07). Subsequent studies focused on investigating the effect of methylation on SULF2 expression and its genome-wide impact. The genes and pathways modulated by epigenetic inactivation of SULF2 and the effects on sensitivity to chemotherapy were characterized in vitro and in vivo. Silencing SULF2 through siRNA or methylation primarily increased expression of interferon-inducible genes including ISG15, a marker for increased sensitivity to topoisomerase-1 inhibitors such as camptothecin. NSCLC cell lines with methylated SULF2 (SULF2M) express 60-fold higher ISG15 compared to SULF2 unmethylated (SULF2U) NSCLC cell lines and normal human bronchial epithelial cells. In vitro, SULF2M and high ISG15 (ISG15H) expressing NSCLC cell lines were 134-fold more sensitive to camptothecin than SULF2U and low ISG15 (ISG15L) expressing cell lines. Topotecan, a soluble analogue of camptothecin and FDA approved anti-cancer drug, dramatically arrested the growth of SULF2M-ISG15H, but not SULF2U-ISG15L lung tumors in nude mice (p < 0.002). Similarly, high ISG15 expression that is comparable to the topotecan sensitive NSCLC cell lines was found in tumors from 25% of NSCLC patients compared to normal lung indicating a potential to identify and target the most sensitive NSCLC subpopulation for personalized topotecan therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

SULF2 methylation is prognostic for lung cancer survival and increases sensitivity to topoisomerase-I inhibitors via induction of ISG15

et al. 2011

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“…In summary, single-agent oral TPT at a dose of 2.3 mg/m 2 /day for 5 days every 21 days can be used as a second-line agent in patients with relapsed advanced NSCLC who desire oral therapy and where palliation of symptoms is desired. This is proven based on the trials done by Ramlau et al [ 12 ], Jones et al [ 25 ] and White et al [ 11 ].…”

Section: Phase III Clinical Trials Of Tptmentioning

confidence: 92%

“…Jones et al [ 25 ] performed a randomized phase II trial to evaluate the efficacy of oral TPT compared with IV docetaxel in the second-line treatment of patients with NSCLC. Thirty-nine patients received 138 cycles of TPT.…”

Section: Phase II Clinical Trials Of Tpt As Combination Therapymentioning

confidence: 99%

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Role of Topotecan in Non-Small Cell Lung Cancer: A Review of Literature

2015

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Topotecan (TPT), a chemotherapeutic agent, is a topoisomerase-I inhibitor. Topoisomerase-I is a nuclear enzyme that relieves torsion strain in DNA by opening single strand breaks which helps in DNA replication. TPT inhibits this enzyme, thus preventing DNA replication and causes cell death. TPT has demonstrated to have broad spectrum of antitumor activity in tumors like cervical, ovarian, endometrial and small cell lung cancers (SCLCs). The intravenous (IV) formulation of the drug is currently approved by the US Food and Drug Administration for the treatment of patients with SCLC and ovarian cancer at a dose of 1.5 mg/m2 administered daily for five consecutive days, with treatment cycles repeated every 3 weeks. TPT has shown some promising activity in the treatment of non-small cell lung cancer (NSCLC) with favorable side effect profile. Several clinical trials have been conducted with TPT in either IV or oral formulation for the treatment of NSCLC as a first or second-line treatment. Here we reviewed all the clinical trials done with TPT to date in the treatment of NSCLC both as a single-agent and combination therapy.

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Phase II study of S-1 and docetaxel for previously treated patients with locally advanced or metastatic non-small cell lung cancer

Yanagihara

Yoshimura

Niimi

et al. 2010

Cancer Chemother Pharmacol

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A Randomized Phase II Trial of Oral Topotecan Versus Docetaxel in the Second-Line Treatment of Non–Small-Cell Lung Cancer

Cited by 8 publications

References 12 publications

SULF2 methylation is prognostic for lung cancer survival and increases sensitivity to topoisomerase-I inhibitors via induction of ISG15

SULF2 methylation is prognostic for lung cancer survival and increases sensitivity to topoisomerase-I inhibitors via induction of ISG15

Role of Topotecan in Non-Small Cell Lung Cancer: A Review of Literature

Phase II study of S-1 and docetaxel for previously treated patients with locally advanced or metastatic non-small cell lung cancer

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