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Phase I study of sequential administration of topotecan and 5-fluorouracil in patients with advanced malignancies
Eric I Sbar1, Jamil Khatri, W David Rodman
1Department of Hematology/Oncology, Cooper Hospital/University Medical Center, 3 Cooper Plaza, Suite 211, Camden, NJ 08103, USA.
Abstract:
Topotecan is a topoisomerase-I inhibitor, a drug that stabilizes a covalent complex of enzymes and causes strand cleavage of DNA. 5-Fluorouracil (5FU) is an antimetabolite that interferes with DNA synthesis. Preclinical studies using human cancer cell line models have shown potential therapeutic synergy between these two drugs by showing the maximum cytolytic effect using sequential 5FU followed by topotecan. In the current study, 5FU was used at a fixed dose of 375 mg/m2 given intravenously for five consecutive days on a 28 day cycle. Topotecan was dose-escalated in cohorts of patients from 0.5 to 1.0 mg/m2 given intravenously for 5 days after the 5FU dose. Eleven patients were entered at different dose levels. Both hematological and gastrointestinal toxicity were dose limiting. Diarrhea was the dose-limiting toxicity at the dose of 0.75 mg/m2 of topotecan. Two cases of grade 4 neutropenia were also observed at this dose level. One patient with small cell lung cancer had a complete response, while one patient with metastatic colorectal cancer had a partial remission. Three other patients had stable disease, lasting between 6 and 8 months. Overall, the regimen was well tolerated. A phase II study using a dose of 5FU at 375 mg/m2 followed by topotecan at 0.75 mg/m2 intravenously over 5 days every 28 days is recommended.
Insights
Sequential administration of 5-Fluorouracil (5FU) followed by topotecan demonstrated therapeutic synergy in cancer patients. The recommended Phase II dose is 5FU at 375 mg/m2 with topotecan at 0.75 mg/m2.
Area of Science:
- Oncology
- Pharmacology
- Cancer Therapeutics
Background:
- Topotecan is a topoisomerase-I inhibitor that induces DNA strand cleavage.
- 5-Fluorouracil (5FU) is an antimetabolite that disrupts DNA synthesis.
- Preclinical models suggest synergistic effects of sequential 5FU followed by topotecan.
Purpose of the Study:
- To evaluate the safety and efficacy of escalating doses of topotecan in combination with 5FU.
- To determine the dose-limiting toxicities of the sequential regimen.
- To identify a recommended dose for a Phase II study.
Main Methods:
- A dose-escalation study of topotecan (0.5-1.0 mg/m2) administered after a fixed dose of 5FU (375 mg/m2) over 5 days every 28 days.
- Eleven patients with various cancers were enrolled across different dose levels.
- Toxicity assessments included hematological and gastrointestinal parameters.
Main Results:
- Dose-limiting toxicities included diarrhea and grade 4 neutropenia, observed at topotecan doses of 0.75 mg/m2.
- One complete response in small cell lung cancer and one partial remission in metastatic colorectal cancer were observed.
- Three patients achieved stable disease for 6-8 months.
Conclusions:
- The combination of 5FU and topotecan was generally well-tolerated.
- A recommended Phase II dose of 5FU 375 mg/m2 followed by topotecan 0.75 mg/m2 every 28 days is proposed.
- This regimen shows potential for further investigation in cancer treatment.
