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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Topotecan is a topoisomerase I inhibitor and an analogue of camptothecin with demonstrated activity in small-cell lung cancer. However, less is known about the potential role of topotecan in advanced non-small-cell lung cancer (NSCLC). Platinum-based combination therapy is currently recommended in NSCLC patients presenting with good performance status. Because topotecan demonstrates a novel mechanism of action, its investigation in platinum combinations is warranted. In phase I/II trials of topotecan given as part of a cisplatin-based regimen, significant antitumor activity has been observed, providing the rationale for conducting further studies aimed at assessing survival benefit. However, this combination exhibits sequence dependence, with increasing hematologic toxicity observed when cisplatin is administered on day 1 of a 5-day topotecan course. Cisplatin has been associated with dose-limiting nonhematologic toxicities. Carboplatin exhibits a different toxicity profile compared with cisplatin, which makes it an attractive agent to study in combination. A hypothesis can be made that carboplatin in combination with newer agents such as topotecan might compare favorably with classic cisplatin-based regimens, particularly with respect to efficacy:toxicity ratio. Therefore, a phase II study was initiated to determine the efficacy, toxicity, and safety of carboplatin-topotecan combination in advanced NSCLC. Preliminary results reported here show that topotecan with carboplatin is generally well tolerated with manageable hematologic toxicity. Indirect comparison with cisplatin-topotecan combination suggests a lower incidence of dose-limiting nonhematologic toxicity. Whether or not the carboplatin-topotecan regimen is able to offer tumor response and survival benefit comparable to those observed with cisplatin-based combinations remains to be established.
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PMID:Preliminary results of combined therapy with topotecan and carboplatin in advanced non-small-cell lung cancer. 1159 15

Topotecan (HYCAMTIN; GlaxoSmithKline, Brentford, Middlesex, UK) is a novel topoisomerase I inhibitor with potentially broad applicability in the treatment of solid and hematologic malignancies. In addition to its use in relapsed small-cell lung cancer (SCLC), topotecan is under investigation in numerous studies for first-line therapy in SCLC and for first- and second-line treatment of non-small-cell lung cancer (NSCLC). Preliminary evidence presented in this supplement demonstrates that single-agent topotecan and topotecan-based combination regimens are active in these settings. In addition to its potential use in SCLC and NSCLC, the feasibility and antitumor activity of topotecan as single-agent therapy and in combination therapy are under active investigation in a variety of other solid and hematologic tumors. Other important avenues of investigation include the feasibility and tumor activity of a more convenient oral formulation, as well as the investigation of alternate regimens (e.g., 3-day, weekly), with high priority given to regimen toxicity, patient convenience, and quality of life. Preliminary results of some of these trials are presented in this summary. The results of other clinical experience trials are eagerly anticipated.
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PMID:Future role of topotecan in the treatment of lung cancer. 1159 16

Topotecan (Hycamtin, SmithKline Beecham, Philadelphia, PA) was approved by the U.S. Food and Drug Administration in 1996 for use in relapsed ovarian cancer and in 1999 for platinum-sensitive small-cell lung cancer. Hematologic toxicity has been the predominant side effect associated with its use. Patients who have had extensive platinum-based therapy have exhibited increased degrees of thrombocytopenia and more severe neutropenia. These adverse events can be managed by identifying high-risk patients (i.e., those with more than six cycles of chemotherapy containing an alkylating agent or radiation to more than 25% of marrow-bearing bones, patients with a history of myelosuppression or renal impairment) and by recommending appropriate dose modifications based on the creatinine clearance measurement. By reducing the topotecan dose, myelosuppressive effects, as evidenced by neutropenia and thrombocytopenia, may be lessened or prevented without reducing the antitumor response.
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PMID:Nursing considerations for managing topotecan-related hematologic side effects. 1189 7

Despite the high response rates to chemotherapy, small-cell lung cancer (SCLC) is among the most lethal malignancies. Long-term survival is anecdotal for patients with extensive disease; 5-years survival is < or =5% for those with limited disease. All patients with extensive disease and most patients with limited disease will experience disease progression and become candidates for second-line therapy. Although a number of agents have demonstrated antitumor activity in relapsed SCLC, including paclitaxel, docetaxel, etoposide, cisplatin, and carboplatin, topotecan is the only single agent currently approved in the United States for the treatment of recurrent disease. Topotecan is a novel topoisomerase I inhibitor with established antitumor activity in recurrent SCLC and has a predictable, noncumulative toxicity profile. Furthermore, topotecan has been shown to provide symptom improvement in this predominantly palliative setting. Evidence also suggests that topotecan readily penetrates the blood-brain barrier and might be active in the relatively large subset of SCLC patients who experience brain metastases. This article reviews the clinical utility of topotecan in recurrent SCLC, including its efficacy, tolerability, and quality-of-life effect, when used as monotherapy and in novel combination regimens.
Lung Cancer 2003 Jun
PMID:Treatment of relapsed small-cell lung cancer--a focus on the evolving role of topotecan. 1278 21

A randomized two-stage, phase II study was conducted to assess the antitumor activity of two different schedules of topotecan in the treatment of extensive-stage small-cell lung cancer (SCLC) in chemotherapy-naive patients. A total of 40 eligible patients were randomized to receive either the daily schedule, with topotecan being administered intravenously at 1.5 mg/m2 daily for 5 days every 3 weeks, or the continuous-infusion schedule, with topotecan administered intravenously at a dosage of 1.3 mg/m2 per day over 72 hours every 4 weeks. Randomization to the continuous-infusion schedule was discontinued due to inactivity, and an additional 20 patients were treated on the daily schedule. Patients received an average of 5 courses (range: 1-13) of the daily schedule compared to an average of 2 courses (range: 1-7) of the continuous-infusion schedule (p < 0.01). Confirmed response rates for the daily and continuous-infusion schedules are 62.5% (90% CI: 49-75%) and 15% (90% CI: 1-29%), respectively. Toxicity was predominantly hematologic with 92% (55/60) having greater than or equal to grade III neutropenia and 58% (35/60) reporting greater than or equal to grade III leukopenia for both IV schedules. Nonhematologic toxicity was very mild, with only 10% (6/60) patients experiencing grade IV toxicities. One patient died of infection on the continuous-infusion arm. Median times to progression for the daily and continuous-infusion schedules are 5 months (90% CI: 4.4-7.2) and 2 months (90% CI: 1.1-2.1), respectively. Estimated 1-year survival rates for patients receiving daily and continuous-infusion schedules are 63% (90% CI: 51-76%) and 55% (90% CI: 39-77%), respectively. Fifty percent (30/60) of patients received second-line therapy with etoposide and cisplatin. Forty-three percent (13/30) of patients who received second-line therapy achieved a confirmed response. Topotecan showed significant activity in the treatment of extensive stage SCLC when administered as a brief daily IV repeated every 3 weeks.
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PMID:Randomized phase II study of daily versus continuous-infusion schedules of topotecan in the treatment of extensive-stage small cell lung cancers. 1279 91

Small-cell lung cancer (SCLC) is highly chemosensitive but up to 70% of patients with limited disease and more than 90% of patients with extensive disease will relapse after first-line treatment. There are several standard chemotherapy regimens used for second-line treatment yet the prognosis for patients requiring this treatment remains poor. The topoisomerase-I inhibitor, topotecan, has achieved response rates of up to 22% in previously treated patients with SCLC and survival almost double that achieved with other single agents. Compared with cyclophosphamide/doxorubicin/vincristine (CAV), single-agent topotecan achieved a higher response rate, longer survival and statistically significant improvements in dyspnea, hoarseness, fatigue, anorexia and interference with daily activities. Brain metastases are common in SCLC. Topotecan crosses the blood-brain barrier and shows promise for the management of brain metastases.
Lung Cancer 2003 Aug
PMID:The role of topotecan in treating small cell lung cancer: second-line treatment. 1456 8

Although current treatments for small-cell lung cancer (SCLC) yield objective response rates exceeding 50%, most patients relapse. Hence, research into the identification of novel agents and combinations that may improve therapy is ongoing. Topotecan, an established treatment for patients with recurrent SCLC, is being investigated as first-line therapy for SCLC because of its novel mechanism of action, non-cumulative toxicity and in vitro synergy with other active agents. Several phase II studies of doublet and triplet combination therapy with other agents, including paclitaxel, cisplatin, carboplatin and etoposide, have reported promising results for first-line treatment of SCLC. For example, in combination with paclitaxel, complete and overall responses were 3-67% and 45-100%, respectively, in extensive-stage disease. Furthermore, two studies of the triplet combination of topotecan with paclitaxel plus carboplatin yielded impressive complete response rates of 37-51% in limited-stage SCLC. The most frequent adverse events associated with topotecan-based regimens have been reported as neutropenia and thrombocytopenia so growth factor support is often incorporated into treatments. Several ongoing phase III studies will help to clarify the role of topotecan in the first-line treatment of SCLC.
Lung Cancer 2003 Aug
PMID:Topotecan as first-line therapy for small cell lung cancer. 1456 9

Patients with non-small cell lung cancer (NSCLC) typically receive platinum-based combination chemotherapy. In spite of improvements in symptoms and survival, response rates remain low and newer agents are being investigated. The newer agents may offer increased efficacy and reduced toxicity compared with established agents and regimens. The topoisomerase-I inhibitor, topotecan, achieves single-agent response rates of 4-25% in NSCLC. Topotecan has also been studied in combinations: a combination of topotecan, administered using the standard 5-day schedule, with cisplatin was effective but was associated with myelosuppression. The combination of topotecan plus carboplatin may be better tolerated and warrants further investigation. Topotecan was also combined with newer agents (gemcitabine, vinorelbine, docetaxel, paclitaxel) using a range of different administration schedules of topotecan. Response rates of up to 30% were achieved. A weekly schedule of topotecan was effective and well tolerated and was also convenient for healthcare professionals and patients.
Lung Cancer 2003 Aug
PMID:Combination chemotherapy with topotecan for non-small cell lung cancer. 1456 11

Chemotherapy agents require a range of administration schedules, including 3-weekly, 4-weekly and daily administration. Some agents, for example gemcitabine and vinorelbine, have been developed for use in a weekly regimen. The possibility of administering other agents using a weekly schedule is being investigated. Weekly schedules offer practical benefits in terms of convenience to patients and allow drugs to be combined more easily. In addition, toxicity may be reduced. The standard 5-day schedule of topotecan has demonstrated effectiveness and patient benefits. Topotecan at this dose is generally well tolerated, with dose-limiting myelosuppression. Preclinical data supported intermittent dosing with topotecan and clinical studies with weekly dosing in ovarian cancer have indicated reduced myelosuppression compared with the 5-day regimen. Several studies in non-small cell lung cancer investigated topotecan combined with cisplatin or gemcitabine and confirmed these findings. However, further studies are needed to confirm that efficacy of topotecan (response and survival) is maintained with the altered regimen.
Lung Cancer 2003 Aug
PMID:Weekly topotecan in the management of lung cancer. 1456 12

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 (0.26+/-0.06 microg ml(-1); P=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.
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PMID:Ex vivo analysis of topotecan: advancing the application of laboratory-based clinical therapeutics. 1458 85


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