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International Journal of Gynecological... 2007Recurrent and advanced cervical cancers are associated with high mortality and a lack of effective treatment options, especially for women who are poor candidates for... (Review)
Review
Recurrent and advanced cervical cancers are associated with high mortality and a lack of effective treatment options, especially for women who are poor candidates for surgery or radiation therapy. The broad clinical effectiveness and manageable toxicity of topotecan in other human malignancies as well as promising recent study results suggest that it is highly effective in treating cervical tumors. We therefore conducted a systematic review on the studies using topotecan in cervical cancer. Seven phase I-III clinical trials using topotecan, both as a single agent and in combination with cisplatin or paclitaxel, in patients with recurrent or advanced carcinoma of the cervix were reviewed. Data from two studies in which topotecan was used in combination with radiotherapy for induction therapy were also evaluated. Although single-agent cisplatin-based chemoradiotherapy is the standard of care for high-risk or locally advanced cervical cancer, topotecan, when used concurrently with cisplatin and/or radiation therapy, produces high objective response rates and prolonged survival. Gynecologic Oncology Group (GOG) Protocol 179 for the first time showed significantly improved overall survival and progression-free survival in a combination therapy for advanced cervical cancer compared to cisplatin alone. Recent data suggest that topotecan, when used concurrently with cisplatin, may be the new standard of care for the management of recurrent or advanced cervical cancer. Ongoing phase III studies (GOG-204, AGO-Zervix-1) will compare this combination with other cisplatin-containing and cisplatin-free combinations. Moreover, further evaluation of topotecan appears to be warranted in conjunction with radiotherapy and in the neoadjuvant setting as well as in combination with novel biologic agents.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Clinical Trials as Topic; Drug Evaluation, Preclinical; Female; Humans; Neoadjuvant Therapy; Paclitaxel; Radiotherapy, Adjuvant; Topotecan; Uterine Cervical Neoplasms
PubMed: 17997795
DOI: 10.1111/j.1525-1438.2007.01003.x -
Critical Reviews in Therapeutic Drug... 2016Topotecan (TPT), a potent anticancer camptothecin analog, is well described for the treatment of ovarian cancer, but has also anticancer activity against small-cell and... (Review)
Review
Topotecan (TPT), a potent anticancer camptothecin analog, is well described for the treatment of ovarian cancer, but has also anticancer activity against small-cell and non-small-cell lung cancer, breast cancer, and acute leukemia. Various nanocarriers, including liposomes, have been exploited for targeted delivery of TPT. However, there are a number of challenges with TPT delivery using TPT liposomes (TLs), such as low encapsulation efficiency, physiological pH labile E ring (hydrolysis), accelerated blood clearance, multidrug resistance, and cancer metastases. This review discusses these problems and the means to overcome them, including modification of TLs using zwitterionic poly(carboxybetaine), prolongation in dosing interval (long-term therapy), and modified liposomal encapsulation techniques including active loading methods. We also explore engineered TLs (surface and integral modifications) such as PEGylated TLs, ligand-anchored TLs, and stimuli-sensitive TLs. Further, potential applications, manifestations at the molecular level, patents granted, and preclinical and clinical outlook for TLs are discussed.
Topics: Chemistry, Pharmaceutical; Drug Carriers; Drug Compounding; Drug Delivery Systems; Humans; Liposomes; Models, Biological; Neoplasms; Patents as Topic; Topotecan
PubMed: 27910741
DOI: 10.1615/CritRevTherDrugCarrierSyst.2016015926 -
Expert Opinion on Pharmacotherapy Feb 2007Topotecan, a semisynthetic camptothecin, exerts its cytotoxic effect through inhibition of DNA topoisomerase I. Single-agent topotecan has demonstrated activity against... (Review)
Review
Topotecan, a semisynthetic camptothecin, exerts its cytotoxic effect through inhibition of DNA topoisomerase I. Single-agent topotecan has demonstrated activity against persistent, metastatic and recurrent cancer of the uterine cervix. When combined with cisplatin in Phase II trials, further improved response rates have been reported. The cisplatin/topotecan doublet subsequently proved to be the first regimen in a series of multiple Phase III studies to demonstrate improved disease-free and overall survival in this setting compared with cisplatin alone, thus leading to its third indication by both the US FDA and the European Medicines Agency in 2006. This survival advantage was achieved at the expense of an increase in grade 3-4 hematologic toxicity; however, there was no difference in patient-reported quality of life between the cisplatin/topotecan doublet and single-agent cisplatin. This article reviews the pharmacology of topotecan and its evolution as an active agent in advanced and metastatic cervical cancer that is not amenable to cure with surgery or radiotherapy.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Resistance, Neoplasm; Female; Humans; Topotecan; Uterine Cervical Neoplasms
PubMed: 17257092
DOI: 10.1517/14656566.8.2.227 -
Drugs Sep 1999Topotecan, a water soluble semisynthetic derivative of camptothecin, has demonstrated antineoplastic activity in a wide range of cell culture and xenograft systems and... (Comparative Study)
Comparative Study Review
UNLABELLED
Topotecan, a water soluble semisynthetic derivative of camptothecin, has demonstrated antineoplastic activity in a wide range of cell culture and xenograft systems and is currently approved for second-line therapy in ovarian and small cell lung cancer (SCLC). The drug inhibits replication of rapidly dividing cells by disrupting the normal function of the nuclear enzyme topoisomerase I. The efficacy of topotecan is related to exposure time and the recommended regimen is 1.5 mg/m2 as a 30-minute intravenous infusion, daily for 5 days, repeated every 21 days. In phase II trials of topotecan in SCLC (usually with the 1.5mg/m2, 5 day regimen) the overall response rate in refractory patients (those who had relapsed < or =90 days after first-line therapy) was low at 2 to 11%, whereas in sensitive patients (those relapsing > or =90 days after first-line therapy) the overall response rate was 14 to 37%. Topotecan was compared with combined cyclophosphamide/doxorubicin(adriamycin)/vincristine (CAV) therapy in patients with relapsed, sensitive (relapsed > or =60 days after first-line therapy) SCLC. The response rates were 24.3% and 18.3% and, respectively, for the topotecan- and CAV-treated groups, and no significant differences were detected when primary efficacy endpoints (response rates and duration) were compared. However, the results of a symptom-specific questionnaire for SCLC did suggest that topotecan offered superior control of some symptoms. SCLC is usually treated with combinations of cytotoxic drugs, and topotecan is showing promise when partnered with paclitaxel and platinum compounds. The efficacy of an oral formulation of topotecan is also being investigated; preliminary results are encouraging and suggest similar efficacy to intravenous formulations, but with less frequent neutropenia. The tolerability and compliance advantages of oral topotecan may make this the route of choice in the future. Noncumulative anaemia, neutropenia and thrombocytopenia are the dose-limiting adverse effects associated with topotecan. CAV and topotecan therapy had similar suppressive effects on neutrophils in patients with SCLC, but the incidences of grade 3 or 4 anaemia and grade 4 thrombocytopenia were significantly higher in topotecan-treated patients. Non-haematological adverse events in SCLC patients treated with topotecan or CAV were similar and most were grade 1 or 2. Gastrointestinal disturbances were common in both groups, as were alopecia and fatigue.
CONCLUSIONS
In a large randomised comparative study, topotecan was as effective as CAV in treating relapsed SCLC. The response rate was modest and further comparative and drug-combination studies are required to accurately position topotecan within the schedule of available drugs used to treat SCLC, particularly in relation to first-line therapy. However, recurrent SCLC is extremely intractable to therapy and topotecan is a valuable extension to the limited range of treatment options for SCLC.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; In Vitro Techniques; Lung Neoplasms; Topotecan
PubMed: 10493279
DOI: 10.2165/00003495-199958030-00020 -
Cancer Treatment Reviews May 2011Topotecan is a relatively new drug for use as a second-line treatment in patients with relapsed small cell lung cancer (SCLC). We performed a systematic review and... (Review)
Review
BACKGROUND
Topotecan is a relatively new drug for use as a second-line treatment in patients with relapsed small cell lung cancer (SCLC). We performed a systematic review and economic evaluation of topotecan, and consider it here in relation to the NICE end of life criteria.
METHODS
Seventeen bibliographic databases (including Cochrane library, Medline and Embase) were searched from 1990 to February 2009, and experts and manufacturers were consulted, to identify relevant randomised controlled trials (RCTs) which were selected according to prospectively defined criteria. An economic evaluation was undertaken to assess cost effectiveness compared with best supportive care (BSC) in the UK.
RESULTS
Five RCTs were included. The clinical evidence indicates a statistically significant benefit of oral topotecan plus BSC compared to BSC alone for overall survival. Intravenous topotecan was similar in efficacy to both oral topotecan and CAV (cyclophosphamide, doxorubicin and vincristine). In the survival model, oral topotecan plus BSC was associated with an average gain in life expectancy of approximately 4 months, resulting in a gain of 0.183 quality-adjusted life years (QALYs). At an incremental cost of approximately £6200 the incremental cost effectiveness ratio (ICER) is £33,851 per QALY gained.
CONCLUSIONS
Compared with BSC alone, oral topotecan for patients with relapsed SCLC was associated with improved health outcomes but at increased cost. The ICER is at the upper extreme of the range conventionally regarded as cost effective from an NHS decision making perspective. However, this treatment may fall under supplementary guidance for life extending, end of life treatments.
Topics: Antineoplastic Agents; Cost-Benefit Analysis; Humans; Lung Neoplasms; Neoplasm Recurrence, Local; Randomized Controlled Trials as Topic; Small Cell Lung Carcinoma; Topotecan
PubMed: 20709456
DOI: 10.1016/j.ctrv.2010.07.005 -
Clinical Cancer Research : An Official... Jan 1999
Review
Topics: Antineoplastic Agents; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Administration Schedule; Humans; Topotecan
PubMed: 9918195
DOI: No ID Found -
The Oncologist 2004Topotecan dosing considerations and alternative dosing schedules to reduce and manage myelosuppression during the treatment of relapsed ovarian cancer were reviewed. The... (Review)
Review
Topotecan dosing considerations and alternative dosing schedules to reduce and manage myelosuppression during the treatment of relapsed ovarian cancer were reviewed. The myelosuppression patterns from phase I, II, and III clinical trials were analyzed to evaluate the degree of hematologic toxicity and to determine risk factors predictive of myelosuppression. Additionally, recent publications of alternative topotecan doses and schedules were examined. Extent of prior therapy, prior platinum therapy (particularly carboplatin), advanced age, impaired renal function, and prior radiation therapy were identified as potential risk factors for greater hematologic toxicity after topotecan therapy. Reducing the starting topotecan dose to 1.0 or 1.25 mg/m2/day is recommended to reduce the incidence of severe myelosuppression in high-risk individuals receiving topotecan for 5 consecutive days. Hematopoietic growth factors, transfusion therapy, and schedule adjustments may also help manage myelosuppression. Alternative schedules of 3-day or weekly dosing appear to have less myelotoxicity and are currently under evaluation. The clinical aspects of topotecan-related myelosuppression and results from clinical trials indicate that the dose, and possibly the dosing schedule, of topotecan can be modified to reduce hematologic toxicity and improve tolerance without compromising efficacy. Prospective individualization of topotecan dosing may prevent or minimize dose-limiting myelosuppression and allow patients to achieve the maximum topotecan benefit by improving their ability to complete therapy with fewer treatment delays. Ongoing clinical trials evaluating alternative dosing schedules with superior hematologic tolerability may facilitate the inclusion of topotecan in combination regimens for patients with ovarian cancer. Proposed topotecan dosing guidelines to reduce and manage myelosuppression are outlined.
Topics: Antineoplastic Agents; Drug Administration Schedule; Female; Hematologic Diseases; Humans; Incidence; Ovarian Neoplasms; Practice Guidelines as Topic; Receptors, Colony-Stimulating Factor; Recurrence; Risk Factors; Topotecan
PubMed: 14755013
DOI: 10.1634/theoncologist.9-1-33 -
Oncology 1999Topotecan, a water-soluble analogue of camptothecin, is a newly available cytotoxic agent which acts as an inhibitor of topoisomerase I, an enzyme necessary for DNA... (Review)
Review
Topotecan, a water-soluble analogue of camptothecin, is a newly available cytotoxic agent which acts as an inhibitor of topoisomerase I, an enzyme necessary for DNA replication. Topotecan is a semisynthetic product derived from camptothecin, which was discovered during a National Cancer Institute cytotoxic drug screening program almost 30 years ago. It acts by forming a stable covalent complex with the DNA/topoisomerase I aggregate, the so-called 'cleavable complex'. This process leads to breaks in the DNA strand resulting in apoptosis and cell death. Topotecan possesses a serum half-life of approximately 3 h, a high volume of distribution with high tissue uptake and a low protein binding. The chemical structure is based on a lactone ring. Topotecan undergoes reversible hydrolysis from its biologically active lactone form to the open ring inactive carboxylate form. It is also able to penetrate the intact blood-brain barrier. Since most of the agent is excreted by the kidneys, dose adjustment is necessary when renal function is impaired. In contrast, pharmacokinetic behavior is unchanged in patients with limited hepatic function. The principal toxicity of topotecan when administered at standard doses is neutropenia, but thrombocytopenia and anemia occur as well, while the nonhematological toxicities are usually mild. Alopecia is frequently observed and some patients may suffer from pronounced fatigue. Most clinical data available are based on the following schedule: 1.5 mg/m2 topotecan given as a 30-min infusion, days 1-5. There are currently only minimal data available regarding a dose-antitumor activity relationship. Other topotecan administration schedules are currently being investigated. Preclinical data suggest that continuous-infusion schedules may be a better application form in terms of both, toxicity and antitumor activity. However, clinical trials could not confirm these results to date. Results of phase II studies suggest considerable antitumor activity of single agent topotecan in small cell lung cancer and ovarian cancer patients. A randomized phase III trial of topotecan versus paclitaxel in ovarian cancer patients pretreated with cisplatin/cyclophosphamide has demonstrated that topotecan is as effective as paclitaxel in the second-line treatment of these patients. Activity of topotecan was also observed in non-small-cell lung cancer, refractory leukemias/myelodysplastic syndromes and in childhood sarcomas. Due to its unique mechanism of action and lack of cross-resistance, cisplatin, etoposide, cytarabine and paclitaxel are potential interacting partners for combination chemotherapy regimens. However, the best combination regimen as well as the optimal combination schedule have yet to be conclusively determined. The potential of topotecan in a variety of solid tumors, as well as its use in combination regimens for ovarian and small cell lung cancer is currently being investigated.
Topics: Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Administration Schedule; Enzyme Inhibitors; Humans; Topoisomerase I Inhibitors; Topotecan; Treatment Outcome
PubMed: 9885371
DOI: 10.1159/000011923 -
Retina (Philadelphia, Pa.) Sep 2014To review the ocular pharmacology and antitumor activity of topotecan for the treatment of retinoblastoma by an evaluation of different routes of administration. (Review)
Review
PURPOSE
To review the ocular pharmacology and antitumor activity of topotecan for the treatment of retinoblastoma by an evaluation of different routes of administration.
METHODS
Systematic review of studies available at PubMed using the keywords retinoblastoma, topotecan, and camptothecins, including preclinical data such as cell lines and animal models, as well as clinical studies in patients with retinoblastoma.
RESULTS
Forty-two available studies were reviewed. Evidence of antitumor activity against retinoblastoma as a single agent is based on data on cell lines and a limited number of affected patients with intraocular and extraocular disease when given in a protracted schedule. Evidence of additive or synergistic activity in combination with other agents such as carboplatin, melphalan, and vincristine was reported in preclinical and clinical models. In animal models, pharmacokinetic evaluation of topotecan administered by the periocular route shows that most of the drug reaches the vitreous through the systemic circulation. Topotecan administered by intravitreal injection shows high and sustained vitreal concentrations with limited systemic exposure and lack of retinal toxicity at a dose of up to 5 μg. Topotecan administered intraophthalmic artery shows higher passage to the vitreous compared with periocular administration in a swine model.
CONCLUSION
Topotecan alone or in combination is active against retinoblastoma. It shows a favorable passage to the vitreous when given intravenously and intraarterially, and ocular toxicity is minimal by all routes of administration. However, its clinical role, optimal dose, and route of administration for the treatment of retinoblastoma are to be determined.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Routes; Humans; Intravitreal Injections; Retinal Neoplasms; Retinoblastoma; Tissue Distribution; Topoisomerase I Inhibitors; Topotecan; Tumor Cells, Cultured; Vitreous Body
PubMed: 25099219
DOI: 10.1097/IAE.0000000000000253 -
The Oncologist 2004Small cell lung cancer (SCLC) is an aggressive malignancy with a high propensity for early regional and distant metastasis. Response rates to first-line chemotherapy are... (Review)
Review
Small cell lung cancer (SCLC) is an aggressive malignancy with a high propensity for early regional and distant metastasis. Response rates to first-line chemotherapy are typically high, but short lived. The outlook for patients with recurrent SCLC is poor. A variety of single- and multi-agent chemotherapy regimens have met with limited success in patients with recurrent SCLC, and survival is generally measured in weeks. Until recently, further chemotherapy was not widely considered appropriate for patients with relapsed SCLC. The choice of chemotherapy at relapse is dependent on many factors, including type of and response to first-line therapy, the treatment-free interval, and the patient's performance status. Intravenous topotecan (Hycamtin; GlaxoSmithKline; Philadelphia, PA) has provided oncologists and patients in many countries with an effective and tolerable therapeutic option for recurrent SCLC. The clinical profile of topotecan was established in several phase II studies and confirmed in a randomized, phase III trial versus cyclophosphamide, doxorubicin (Adriamycin; Bedford Laboratories; Bedford, OH), and vincristine (Oncovin; Eli Lilly and Company; Indianapolis, IN)--CAV. In those studies, topotecan exhibited antitumor activity in both chemosensitive and refractory disease. Further, topotecan therapy is associated with significant symptom palliation in this patient population. Because the toxicity profile of topotecan is predictable, generally manageable, and noncumulative, the agent also has potential utility in patients with a poor prognosis and/or a poor performance status. Alternative dosing regimens (lower dose, weekly) and the introduction of an oral formulation may expand the use of topotecan as a single agent and in combination therapy in the second- and first-line treatment of this disease.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Humans; Lung Neoplasms; Neoplasm Recurrence, Local; Topotecan
PubMed: 15616145
DOI: 10.1634/theoncologist.9-90006-4