Randomized phase II study comparing topotecan/cisplatin administration for 5 days versus 3 days in the treatment of extensive stage small cell lung cancer (SCLC)

Seifart, Ulf; Jensen, Katrin; Ukena, Julia; Mueller, C.; Schröder, M.; Fuhr, H. G.; Keppler, U.; Neubauer, Andreas; Staab, Hans-Jürgen; Wolf, M.

doi:10.1016/j.lungcan.2004.12.003

Cited by 19 publications

(9 citation statements)

References 19 publications

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“…Indeed the response of SCLC to systemic CHT has already been demonstrated in several studies, even using cytostatics unable to penetrate the intact BBB [30][31][32][33][34][35][36]. Possible explanation is that brain metastases cause a disruption of the BBB, rendering it permeable for agents unable to penetrate it under physiological circumstances [13,24,27,[31][32][33][34][35][36][37][38]. Interestingly, adding BBB-penetrating drugs such as procarbazine, nitrosoureas and high-dose methotrexate to a standard combination regimen against SCLC did not improve the CNS relapse frequency [39].…”

Section: Discussionmentioning

confidence: 95%

“…Clinical synergism is better observed when etoposide follows platinum in SCLC [12]. In a randomized phase II study of cisplatin and topotecan, the 3-day treatment was not inferior to the standard 5-day treatment [13]. On the other hand adding a blood-brain barrier (BBB)-penetrating drug, with the initial cycle, such as topotecan having an activity against SCLC may possibly result in a more effective treatment and prevention of CNS relapse [14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 97%

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Topotecan–carboplatin–etoposide combination as 1st line treatment in patients with small cell lung cancer

et al. 2009

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 97%

Topotecan–carboplatin–etoposide combination as 1st line treatment in patients with small cell lung cancer

et al. 2009

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“…The incidence of sepsis was 0% with topotecan plus cisplatin versus 9.8% with topotecan plus etoposide. Secondary to the significant myelosuppression of the topotecan-cisplatin combination, investigators have studied shorter schedules of topotecan in combination with cisplatin [7,16,17], including a 3-day administration schedule of topotecan that appears to be comparable with the standard 5-day schedule [7]. A randomized phase II study in 86 patients with ED-SCLC compared a 1.0-mg/m 2 dose of topotecan on days 1-5 with a 1.5-mg/m 2 dose on days 1-3, each with cisplatin (75 mg/m 2 ) on the last day of topotecan treatment.…”

Section: IV Topotecan For Untreated Sclcmentioning

confidence: 99%

“…infusion, daily for five consecutive days, every 21 days. However, multiple trials have evaluated alternative doses and schedules, including lower starting doses of 1.25 or 1.0 mg/m 2 given for 5 days, 3-day schedules, and weekly bolus schedules [7][8][9]. i.v.…”

Section: Introductionmentioning

confidence: 99%

Recent Advances with Topotecan in the Treatment of Lung Cancer

O’Brien

Eckardt²,

Ramlau

2007

The Oncologist

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After completing this course, the reader will be able to:1. Describe phase I studies evaluating the pharmacokinetics and early safety data of single-agent oral topotecan. Discuss the results and implications of clinical trials evaluating oral topotecan for small cell lung cancer (SCLC)and non-small cell lung cancer (NSCLC).3. Explain why topotecan is a good candidate for combination with other novel anticancer agents.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME Further, an oral formulation of topotecan is currently under investigation and may provide added convenience for patients. Oral topotecan has been studied in the first-and second-line settings for both SCLC and non-small cell lung cancer (NSCLC). Three recent phase III trials have demonstrated the activity of oral topotecan. In the first study of chemotherapy-naïve patients with extensivedisease SCLC, oral topotecan plus cisplatin provided efficacy and safety similar to those of etoposide plus cisplatin. In a second study of patients with relapsed SCLC, treatment with oral topotecan showed a statistically significant and clinically meaningful longer overall survival time and improvement in dyspnea and quality of life compared with best supportive care alone in all prognostic groups. Finally, in previously treated patients with NSCLC, single-agent oral topotecan was shown to be noninferior in 1-year survival rate relative to the current standard of i.v. docetaxel. In future studies, oral topotecan will represent a good candidate for combination therapy with other i.v. or oral chemotherapy agents, monoclonal antibodies, and small molecule tyrosine kinase inhibitors. ABSTRACT

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“…TPT has demonstrated moderate (∼10−38% response rates) activity as second-line therapy in patients with metastatic ovarian carcinoma, small cell lung cancer, and other tumors [16][17][18][19][40][41][42][43][44][45][46][47][48][49]. Intravenous TPT treatment can give only 35 −38% response rates in recurrent ovarian carcinoma [40] and ∼10% in breast cancer [22].…”

Section: Introductionmentioning

confidence: 99%

Topotecan Is a Substrate for Multidrug Resistance Associated Protein 4

Tian

Zhang²,

Chan³

et al. 2006

CDM

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Topotecan (TPT) is a semisynthetic water-soluble derivative of camptothecin (CPT) used as second-line therapy in patients with metastatic ovarian carcinoma, small cell lung cancer, and other malignancies. However, both dose-limiting toxicity and tumor resistance hinder the clinical use of TPT. The mechanisms for resistance to TPT are not fully defined, but increased efflux of the drug by multiple drug transporters including P-glycoprotein (PgP), multidrug resistance associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) from tumor cells has been highly implicated. This study aimed to investigate whether overexpression of human MRP4 rendered resistance to TPT by examining the cytotoxicity profiles using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide (MTT) assay and cellular accumulation of TPT in HepG2 cells stably overexpressing MRP4. Two kinds of cell lines, HepG2 with insertion of an empty vector plasmid (V/HepG2), HepG2 cells stably expressing MRP4 (MRP4/HepG2), were exposed to TPT for 4 or 48 hr in the absence or presence of various MRP4 inhibitors including DL-buthionine-(S,R)-sulphoximine (BSO), diclofenac, celecoxib, or MK-571. The intracellular accumulation of TPT and paclitaxel (a PgP substrate) by V/HepG2 and MRP4/HepG2 cells was determined by incubation of TPT with the cells and the amounts of the drug in cells were determined by validated HPLC methods. The study demonstrated that MRP4 conferred a 12.03- and 6.86-fold resistance to TPT in the 4- and 48-hr drug-exposure MTT assay, respectively. BSO, MK-571, celecoxib, or diclofenac sensitised MRP4/HepG2 cells to TPT cytotoxicity and partially reversed MRP4-mediated resistance to TPT. In addition, the accumulation of TPT was significantly reduced in MRP4/HepG2 cells compared to V/HepG2 cells, and one-binding site model was found the best fit for the MRP4-mediated efflux of TPT, with an estimated K(m) of 1.66 microM and V(max) of 0.341 ng/min/106 cells. Preincubation of MRP4/HepG2 cells with BSO (200 microM) for 24 hr, celecoxib (50 microM), or MK-571 (100 microM) for 2 hr significantly increased the accumulation of TPT over 10 min in MRP4/HepG2 cells by 28.0%, 37.3% and 32.5% (P < 0.05), respectively. By contrast, there was no significant difference in intracellular accumulation of paclitaxel in V/HepG2 and MRP4/HepG2 cells over 120 min. MRP4 also rendered resistance to adefovir dipivoxil (bis-POM-PMEA) and methotrexate, two reported MRP4 substrates. MRP4 did not exhibit any significant resistance to other model drugs including vinblastine, vincristine, etoposide, carboplatin, cyclosporine and paclitaxel in both long (48 hr) and short (4 hr) drug-exposure MTT assays. These findings indicate that MRP4 confers resistance to TPT and TPT is the substrate for MRP4. Further studies are needed to explore the role of MRP4 in resistance to, toxicity and pharmacokinetics of TPT in cancer patients.

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Randomized phase II study comparing topotecan/cisplatin administration for 5 days versus 3 days in the treatment of extensive stage small cell lung cancer (SCLC)

Cited by 19 publications

References 19 publications

Topotecan–carboplatin–etoposide combination as 1st line treatment in patients with small cell lung cancer

Topotecan–carboplatin–etoposide combination as 1st line treatment in patients with small cell lung cancer

Recent Advances with Topotecan in the Treatment of Lung Cancer

Topotecan Is a Substrate for Multidrug Resistance Associated Protein 4

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