A phase II multicenter study of combined topotecan and gemcitabine as first line chemotherapy for advanced non-small cell lung cancer

Joppert, M.; Garfield, David H.; Gregurich, Mary Ann; Nemunaitis, John; Marsland, Thomas; Khandelwal, Pankaj; Asmar, Lina

doi:10.1016/s0169-5002(02)00502-0

Cited by 16 publications

(4 citation statements)

References 13 publications

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“…18–20 These studies had in common a relatively low planned dose-intensity of gemcitabine (267–500 mg/m 2 /wk) and grade ≥3 thrombocytopenia and granulocytopenia rates of 10–57% and 34–53%, respectively. No promising efficacy signal was observed so as to justify the investigation of this relatively toxic combination in phase III trials.…”

Section: Discussionmentioning

confidence: 99%

Phase I Trial of Weekly Topotecan and Gemcitabine in Patients With Solid Tumors

William

Lee

Shin

et al. 2009

American Journal of Clinical Oncology

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Objective This phase I trial was designed to determine the maximal tolerated dose (MTD) of the combination of topotecan and gemcitabine given in a weekly schedule. Materials and Methods In this single-arm, open label, dose-escalation study, we administered topotecan (0.75–1.5 mg/m2) and gemcitabine (1000 mg/m2) on days 1, 8, and 15 every 4 weeks to 25 patients with advanced solid tumors. Results The topotecan MTD, when combined with gemcitabine, was 1.25 mg/m2/wk. Dose-limiting toxicities consisted of febrile granulocytopenia in 2 patients at the highest dose level. At the MTD, no episodes of granulocytopenia were observed, whereas 2/9 patients exhibited grade 3 thrombocytopenia. Other common grades 3–4 adverse events across all cohorts included non-neutropenic infections, fatigue, skin reactions, vomiting, and fever. One partial response and 2 stable diseases were observed in patients with nasopharyngeal carcinoma. Disease stabilization was also observed in patients with squamous cell carcinoma of the head and neck (3), nonsmall cell lung cancer (1), and thymoma (1). Conclusions Topotecan and gemcitabine combined in a weekly schedule exhibit a favorable toxicity profile. Efficacy results support the further evaluation of this regimen in patients with head and neck cancer (particularly nasopharyngeal carcinoma).

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Section: Discussionmentioning

confidence: 99%

Phase I Trial of Weekly Topotecan and Gemcitabine in Patients With Solid Tumors

William

Lee

Shin

et al. 2009

American Journal of Clinical Oncology

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“…Joppert et al [ 22 ] performed a phase II trial to determine the 1-year survival rate, efficacy and safety, produced by TPT and gemcitabine as first-line chemotherapy in advanced NSCLC. Grade 3 and 4 toxicities included neutropenia (53%), anemia (18%), thrombocytopenia (12%), asthenia (8%) and gastrointestinal disorders (8%); three patients (6%) experienced neutropenic fever.…”

Section: Phase II Clinical Trials Of Tpt As Combination Therapymentioning

confidence: 99%

“…In summary, phase II clinical trials done on TPT as combination therapy at the above mentioned doses had shown good antitumor activity in combination with gemcitabine, paclitaxel and bevacizumab with acceptable toxicity in previously untreated patients [ 22 , 24 , 26 ]. However, it has no benefit when combined with etoposide and ifosfamide [ 21 , 23 ].…”

Section: Phase II Clinical Trials Of Tpt As Combination Therapymentioning

confidence: 99%

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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“…In another phase I/II trial, based on preclinical data showing synergism against A549 cells, the combination of topotecan and gemcitabine was administered to 24 patients with previously untreated metastatic or unresectable NSCLC, and seemed to be active, with 21% partial responses and acceptable haematologic toxicity (Dabrow et al, 2003). Finally, a phase II multicentre study of combined topotecan and gemcitabine as first-line chemotherapy in 51 patients with advanced NSCLC showed a 1-year survival (39%) similar to platinum-based regimens, with 17% partial responses, a high percentage of patients achieving stable disease (23%) and no significant toxicities (Joppert et al, 2003).…”

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confidence: 99%

Interaction between gemcitabine and topotecan in human non-small-cell lung cancer cells: effects on cell survival, cell cycle and pharmacogenetic profile

et al. 2005

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The pyrimidine analogue gemcitabine is an established effective agent in the treatment of non-small-cell lung cancer (NSCLC). The present study investigates whether gemcitabine would be synergistic with the topoisomerase I inhibitor topotecan against the NSCLC A549 and Calu-6 cells. Cells were treated with gemcitabine and topotecan for 1 h and the type of drug interaction was assessed using the combination index (CI). Cell cycle alterations were analysed by flow cytometry, while apoptosis was examined by the occurrence of DNA internucleosomal fragmentation, nuclear condensation and caspase-3 activation. Moreover, the possible involvement of the PI3K-Akt signalling pathway was investigated by the measurement of Akt phosphorylation. Finally, quantitative, real-time PCR (QRT-PCR) was used to study modulation of the gemcitabine-activating enzyme deoxycytidine kinase (dCK) and the cellular target enzyme ribonucleotide reductase (RR). In results, it was found that simultaneous and sequential topotecan-gemcitabine treatments were synergistic, while the reverse sequence was antagonistic in both cell lines. DNA fragmentation, nuclear condensation and enhanced caspase-3 activity demonstrated that the drug combination markedly increased apoptosis in comparison with either single agent, while cell cycle analysis showed that topotecan increased cells in S phase. Furthermore, topotecan treatment significantly decreased the amount of the activated form of Akt, and enhanced the expression of dCK ( þ 155.0 and þ 115.3% in A549 and Calu-6 cells, respectively), potentially facilitating gemcitabine activity. In conclusion, these results indicate that the combination of gemcitabine and topotecan displays schedule-dependent activity in vitro against NSCLC cells. The gemcitabine-topotecan sequence is antagonistic while drug synergism is obtained with the simultaneous and the sequential topotecan-gemcitabine combinations, which are associated with induction of decreased Akt phosphorylation and increased dCK expression.

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A phase II multicenter study of combined topotecan and gemcitabine as first line chemotherapy for advanced non-small cell lung cancer

Cited by 16 publications

References 13 publications

Phase I Trial of Weekly Topotecan and Gemcitabine in Patients With Solid Tumors

Phase I Trial of Weekly Topotecan and Gemcitabine in Patients With Solid Tumors

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

Interaction between gemcitabine and topotecan in human non-small-cell lung cancer cells: effects on cell survival, cell cycle and pharmacogenetic profile

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