Cisplatin-topotecan-paclitaxel weekly administration with G-CSF support for ovarian and small-cell lung cancer patients: A dose-finding study

Frasci, G.; Panza, N.; Comella, Pasquale; Cartenì, Giacomo; Guida, T.G.; Nicolella, Gianpaolo; Natale, Michele; Lombardi, Rosa; Apicella, Anna; Pacilio, Carmen; Gravina, Adriano; Lapenta, Liliana; Comella, G.

doi:10.1023/a:1008301222560

Cited by 36 publications

(16 citation statements)

References 8 publications

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“…The haematologic data of the present study confirms the findings of our previous phase I trial testing this new weekly combination (Frasci et al, 1999). Indeed, the occurrence of severe neutropenia or thrombocytopenia was negligible with this combination, while anaemia, although more frequent, actually cannot be considered as a life-threatening toxicity.…”

Section: Discussionsupporting

confidence: 89%

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A weekly regimen of cisplatin, paclitaxel and topotecan with granulocyte-colony stimulating factor support for patients with extensive disease small cell lung cancer: a phase II study

Frasci¹,

Nicolella²,

Comella³

et al. 2001

Br J Cancer

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The present study was aimed at defining the antitumour activity of the cisplatin-paclitaxel-topotecan (CPT) weekly administration with G-CSF support in chemo-naive SCLC patients with extensive disease (ED-SCLC). Chemonaive ED-SCLC patients received cisplatin 40 mg/m 2 , paclitaxel 85 mg/m 2 , and topotecan 2.25 mg/m 2 weekly, with G-CSF (5 μg/kg days 3–5) support, for a maximum of 12 weeks. 37 patients were treated, for a total of 348 cycles delivered. 8 complete responses (22%) and 22 partial responses (59%) were recorded, giving an 81% [95% CI = 65–92%] ORR. At a 13-month (range, 4–26) median follow-up, median progression-free and overall survival were 8 months and 12.5 months, with 1-year and 2-year projected survivals of 55% and 21%, respectively. No toxic deaths occurred. Grade 4 neutropenia and thrombocytopenia occurred in 6 and 3 patients, respectively. Only one case of neutropenic sepsis was recorded, while haemorrhagic thrombocytopenia was never observed. Diarrhoea, paraesthesias and fatigue were the main nonhaematologic toxicities being severe in 6, 2 and 10 patients, respectively. The weekly CPT combination with G-CSF support represents a well tolerated therapeutic approach in chemo-naive ED-SCLC patients. The activity rate seems at least similar to that achievable with the standard front-line approaches. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Section: Discussionsupporting

confidence: 89%

“…In the presence of G-CSF support from days 3 to 5 of each week, doses of cisplatin 40 mg/m 2 , paclitaxel 85 mg/m 2 and topotecan 2.25 mg/ m 2 were given weekly at a price of mild haematologic and nonhaematologic toxicity (Frasci et al, 1999).…”

mentioning

confidence: 99%

A weekly regimen of cisplatin, paclitaxel and topotecan with granulocyte-colony stimulating factor support for patients with extensive disease small cell lung cancer: a phase II study

Frasci¹,

Nicolella²,

Comella³

et al. 2001

Br J Cancer

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“…As summarized in Table 2, clinical investigations have recently evaluated the antitumor activity and tolerability of topotecan administered as part of a triplet regimen with paclitaxel and platinum ( [32][33][34] and Engelholm and Scarfone, personal communications).…”

Section: Triplet Regimenmentioning

confidence: 99%

“…Frasci and colleagues [32] conducted a phase I study to determine the MTD of topotecan given weekly over 30 minutes in combination with cisplatin and paclitaxel, with G-CSF support. Nineteen ovarian cancer patients, 11 of whom were chemotherapy naïve, received a combination of cisplatin, 40 mg/m 2 , paclitaxel, 85 mg/m 2 (1-hour infusion), and escalating doses of topotecan (beginning at 0.75 mg/m 2 over 30 minutes) weekly.…”

Section: Triplet Regimenmentioning

confidence: 99%

Emerging Role of Topotecan in Front-Line Treatment of Carcinoma of the Ovary

Coleman¹

2002

The Oncologist

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The conventional front-line chemotherapy strategy for advanced epithelial ovarian carcinoma has become adjuvant administration of platinum (carboplatin and cisplatin), either alone or, most often, in combination with a taxane. However, a number of active agents have been identified in phase II/III trials of second-line and salvage ovarian cancer patients that may augment this front-line strategy. One agent, topotecan, has antitumor activity comparable with paclitaxel in patients with recurrent ovarian cancer and is an established treatment in secondline or salvage settings. Additionally, its mechanism of action is different from paclitaxel and is nonoverlapping. These properties, coupled with the in vitro synergy observed in tumor models among topotecan, paclitaxel, and platinum, have provided the rationale for investigators to examine topotecan in front-line ovarian cancer therapy. A number of strategies for incorporating topotecan into front-line therapy are under active investigation, including the replacement of paclitaxel with topotecan, a triplet regimen with cisplatin or carboplatin and paclitaxel, a consolidation regimen consisting of several courses of a platinum agent and paclitaxel followed by several courses of topotecan, and a sequential doublet regimen in which patients receive platinum in every course as part of a doublet with alternating or sequential topotecan and paclitaxel. Preliminary data from ongoing clinical trials of these new regimens show favorable response rates and generally manageable toxicity profiles. This review summarizes the preliminary clinical findings associated with the four strategies and outlines ongoing and future randomized studies of topotecan in front-line ovarian cancer. The Oncologist 2002;7(suppl 5):46-55 The Oncologist 2002;7(suppl 5):46-55 www.TheOncologist.com

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“…The predictable toxicity profile of topotecan makes it feasible to combine topotecan with other agents with nonoverlapping toxicities. Topotecan has been investigated in doublet and triplet combinations with several agents, including cisplatin, paclitaxel, and etoposide (Ardizzoni et al, 1999;Frasci et al, 1999;Hainsworth et al, 1999;Jacobs et al, 1999;O'Neill et al, 2001;Fiorica et al, 2002). Randomised trials are underway in several diseases to evaluate the efficacy of topotecan in combination with other agents.…”

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confidence: 99%

Ex vivo analysis of topotecan: advancing the application of laboratory-based clinical therapeutics

et al. 2003

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Topotecan is currently approved for relapsed small-cell lung cancer and ovarian cancer. Topotecan's efficacy in the second-line setting and novel mechanism of action suggest broad antitumour activity. We utilised a clinically validated, cell-death, ex vivo assay in human tumour explants to examine the activity profile of topotecan alone and in combination with other antitumour agents. Serial dilutions of topotecan alone and in combination with other cytotoxic agents were applied to biopsy specimens of non-small-cell lung cancer (NSCLC) and breast, colon, and prostate cancers. Dose -response curves were interpolated to provide 50% lethal concentrations (LC 50 ). The degree of synergy (by median effect) and normalised Z-scores (raw scores converted to relative activity distributed around the mean) were then computed. Single-agent activity was observed for topotecan in all four tumour types. In 57 chemotherapy-naive specimens, NSCLC revealed the highest activity, demonstrated by the lowest LC 50 value (0.2670.06 mg ml À1 ; P ¼ 0.002). Overall, previously treated and chemotherapy-naive specimens revealed no significant differences in mean LC 50 's. Synergy was observed for several combinations, including topotecan plus cisplatin in prostate and for topotecan plus 5-fluorouracil in breast cancers. The Z-score analyses conducted suggest activity for previously unexplored drug regimens, including topotecan plus 5-fluorouracil, vinorelbine, and mitomycin-C in NSCLC and breast cancer. Phase II studies are underway to determine the degree to which these ex vivo findings will translate into improved clinical results. Topotecan, a semisynthetic, water-soluble derivative of camptothecin, is an inhibitor of topoisomerase I (Kingsbury et al, 1991). This derivative is more stable, has increased solubility, a shorter half-life, and decreased toxicity compared with its parent compound (Verweij et al, 1993;Burke and Mi, 1994;Rothenberg, 1997). Topoisomerase I is a nuclear enzyme that relieves torsional strain on supercoiled DNA and creates single-strand breaks during DNA replication. Topotecan prevents topoisomerase I from repairing the cleaved DNA, which results in double-stranded DNA breaks and eventually apoptosis. The unique mechanism of action of topotecan and lack of clinical crossresistance with other antineoplastic compounds suggest that topotecan has the potential for broad antitumour activity.The activity of topotecan has been demonstrated in several open-label, randomised phase II and III trials. Currently, topotecan is approved for the treatment of relapsed small-cell lung cancer (SCLC) (Eckardt et

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Cisplatin-topotecan-paclitaxel weekly administration with G-CSF support for ovarian and small-cell lung cancer patients: A dose-finding study

Abstract: The CDDP/TPT/PTX weekly administration with filgrastim support represents a well-tolerated and active therapeutic approach in both chemo-naïve and pretreated OC and SCLC patients. A weekly dose of TPT of 2.25 mg/m2 is recommended for the phase II study.

Cited by 36 publications

References 8 publications

A weekly regimen of cisplatin, paclitaxel and topotecan with granulocyte-colony stimulating factor support for patients with extensive disease small cell lung cancer: a phase II study

A weekly regimen of cisplatin, paclitaxel and topotecan with granulocyte-colony stimulating factor support for patients with extensive disease small cell lung cancer: a phase II study

Emerging Role of Topotecan in Front-Line Treatment of Carcinoma of the Ovary

Ex vivo analysis of topotecan: advancing the application of laboratory-based clinical therapeutics

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