Topotecan toxicity

The first clinical trials were performed in the 1970 s using a sodium salt derivative with an open E-ting (Fig. 1). However, the clinical efficacy was limited and severe bladder toxicity led to the termination of the clinical trials. The poor efficacy of the camptothecin sodium salt in those clinical trials was probably due to the fact that the open E-ring form of camptothecin (carboxylate derivative) is inactive as a Topi inhibitor. Following the identification of Topi as a target of camptothecin, water-soluble derivatives were produced by the pharmaceutical industry. Two of these water-soluble derivatives have been approved by the FDA for cancer treatment in the early 2000s topotecan and irinotecan. 

Representatives of another important class of plant-derived semisynthetic compounds are the camptothecin (27) derivatives, irinotecan (28) and topotecan (29). Camptothecin (27) was originally discovered as an antileukemic agent in a mouse model when isolated from Camptotheca acuminata Decne. Compounds (28) and (29) are both employed in cancer chemotherapy. These substances are important mechanistically because of their activity against the enzyme, topoisomerase I. These compounds were designed to address efficacy and toxicity concerns with the parent compound, camptothecin, and its sodium salt. ... 

Combination chemotherapy is the standard approach to stage III and stage IV disease. Randomized clinical studies have shown that the combination of paclitaxel and cisplatin provides survival benefit compared with the previous standard combination of cisplatin plus cyclophosphamide. More recently, several studies have shown that carboplatin and paclitaxel yields clinical results similar to what is achieved with the cisplatin plus paclitaxel combination however, because of reduced toxicity and greater ease of administration, carboplatin plus paclitaxel has now become the treatment of choice. In patients who present with recurrent disease, the topoisomerase I inhibitor topotecan, the alkylating agent altretamine, and liposomal doxorubicin are used as single agent monotherapy. 

A phase III study was conducted to compare PEG-liposomal DXR (50 mg/m2 every 4 weeks) with paclitaxel (175 mg/m2 every 3 weeks) using 214 patients with relapse after first-line platinum-based chemotherapy [420], As previously, the response rates and PFS were not significantly different, but again the liposomal formulation was notably less toxic as fewer patients recorded with grade 4 adverse effects (17% compared to 71% for topotecan) and thus was more tolerable. 

CISPLATIN TOPOTECAN t risk of bone marrow suppression, especially when topotecan is administered in doses >0.75 mg/m2 on days 1-5 and cisplatin in doses >50 mg/m2 on day 1 before topotecan Attributed to cisplatin inducing subclinical renal toxicity, possibly causing 1 clearance of topotecan Administer cisplatin on day 5 after topotecan if dose of topotecan is >0.75 mg/m2 and cisplatin dose is >50 mg/m2 with the use of granulocyte colony-stimulating factors... 

Doxorubicin is a nonspecific inhibitor of topoiso-merase I and II. Topotecan and irinotecan selectively inhibit topoisomerase I, an enzyme required for DNA replication. These agents have clinical efficacy in relapsed ovarian and colorectal cancer, respectively. Dose limiting toxicity is bone marrow depression and, in the case of irinotecan, delayed diarrhoea. Administration of irinotecan may be complicated by an acute cholinergic reaction, reversible by administering atropine s.c. 

The systemic availability of oral topotecan is about 30%. Dose-limiting toxicity was reached at a dose of 0.6 mg/m bd and consisted of diarrhea, which started from day 12 to day 20. Other toxic effects, including leukopenia and thrombocytopenia, were mild. The recommended dose for phase II trials was 0.5 mg/m bd for 21 days (65-67). 

Myelosuppression, neutropenia, and to a lesser extent thrombocytopenia, are dose-limiting toxic effects of topotecan. Reversible non-cumulative neutropenia usually occurs at between days 8 and 15 after an intravenous dosage of 1.5 mg/m on five consecutive days. The nadir of the neutrophil count occurs on day 11, with recovery on day 21. Neutropenia, with cell counts less than 1.5 x lO /l (grade 2) and 0.5 x 10 /1 (grade 4), is observed in 70-97% of patients. In addition, 4-33% of patients treated with conventional dosages of topotecan develop neutropenic fever (97-99). 

Anorexia, nausea and vomiting, and diarrhea are generally mild after the administration of conventional doses of etoposide and teniposide. Stomatitis is uncommon and mucositis starts to be more severe in patients who receive intravenous doses of etoposide up to 1000 mg/m. Gastrointestinal toxicity after topotecan is generally mild to moderate. Under 10% of patients complain of grade 3/4 nausea and vomiting, diarrhea or constipation, abdominal pain, or stomatitis. Mucositis is uncommon and mild after intravenous topotecan. 

A 51-year-old woman is being treated with topotecan for refractory ovarian cancer that failed to respond to initial therapy. She wishes to be as aggressive as possible with her therapy and would like you to explain why the recommended dose of topotecan cannot be exceeded. What is the dose-limiting toxicity of topotecan ... 

The camptothecins were discovered in extracts from the Chinese tree Camptotheca acuminata. Initial studies showed that camptothecins had antitumor activity, but clinical trials demonstrated severe side effects and toxicity. Numerous camptothecin analogues have been synthesized several have received FDA approval (irinotecan and topotecan), whereas others are still in clinical trials. 

Camptothecin, a plant alkaloid derived from Camptotheca acuminata, is a potent inhibitor of DNA topoisomerase I. Clinical trials failed to show expected antitumor activity, and the drug produced severe, unpredictable toxicity. The camptothecin analogs irinotecan and topotecan were synthesized to reduce toxicity and improve therapeutic... 

---