Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Topotecan, a novel topoisomerase I inhibitor, is an established treatment for patients with recurrent small-cell lung cancer (SCLC), with antitumor response rates of approximately 20% and median survival of approximately 32 weeks in patients with extensive-stage disease. Topotecan's comparable activity relative to other agents used in SCLC and its novel mechanism of action, noncumulative toxicity, and in vitro synergy with other active agents have provided the rationale for investigating topotecan in first-line therapy. Furthermore, topotecan penetrates the blood-brain barrier and is potentially useful for the relatively large subset of patients with SCLC and brain metastases. In early studies of topotecan in brain metastases, encouraging antitumor activity has been observed. In several feasibility and phase II studies of topotecan as single-agent therapy in patients with extensive- and limited-stage tumors and as part of novel first-line combination regimens, overall response rates have ranged from 42% to 100%. Complete responses of 3%-67% and partial responses of 33%-80% have been observed in first-line therapy. Furthermore, the median overall survival in patients receiving topotecan in first-line therapy has ranged from approximately 8 months (extensive-stage disease) to 20 months (limited-stage disease). The most frequent adverse events associated with topotecan-based regimens include grade 3/4 neutropenia and thrombocytopenia that often require the incorporation of growth factor support into the treatment regimen. Nonhematologic adverse events associated with topotecan-based combination regimens have been mild or primarily attributed to other agents in the combination. Alternative doses and schedules (3 consecutive days and weekly) are being explored because they appear to be associated with considerably less myelosuppression. Although several trials have established the feasibility and activity of topotecan in first-line therapy of patients with SCLC, randomized phase III studies with comparison to standard therapy will be required to confirm a potential role for this active agent and to determine the optimal dosing regimen.
Clin Lung Cancer 2003 Mar
PMID:Emerging role of topotecan in first-line therapy of small-cell lung cancer. 1460 45

An early phase II study of topotecan produced favorable results in a small number of untreated and previously treated patients with small-cell lung cancer (SCLC). This multicenter study was conducted in patients with relapsed SCLC at 19 medical institutions in Japan. Topotecan 1.0 mg/m2/day was administered for 5 consecutive days every 3 weeks. Fifty-three patients were enrolled in the study. One patient was withdrawn before the commencement of study treatment, and 2 patients were unable to continue study treatment due to an interruption in the supply of study medication. The response rate was 26.0% in 13 of the 50 evaluable patients who were eligible and completed protocol-specified treatment and procedures. The median time to progression and overall survival were 133 days and 262 days, respectively. The most frequently reported toxicity was reversible myelosuppression, such as leukopenia, neutropenia, anemia (decreased hemoglobin), and thrombocytopenia. Nonhematological toxicity was also reported but the incidence of grade 3/4 symptoms was low. The results of this study indicate that topotecan is effective against relapsed SCLC with good tolerability.
Clin Lung Cancer 2003 Jan
PMID:A phase II study of topotecan in patients with relapsed small-cell lung cancer. 1462 11

Chemotherapy for extensive-stage small-cell lung cancer (E-SCLC) produces high response rates and improved survival but few cures. We tested three new regimens for E-SCLC that might merit further investigation in a subsequent phase III trial. Cancer and Leukemia Group B 9430 was a randomized phase II study evaluating 4 treatment arms in 57 evaluable, previously untreated E-SCLC patients. Each arm consisted of the following: Arm 1: cisplatin plus topotecan; Arm 2: cisplatin plus paclitaxel; Arm 3: paclitaxel 230 mg/m2 plus topotecan; and Arm 4: paclitaxel 175 mg/m2 plus topotecan. Because of an accrual time difference, Arm 2 will not be discussed in this manuscript. Arm 1 (12 patients) produced 1 complete response (CR, 8%) and an overall response rate (ORR) of 42%. Toxicity was excessive, with 3 deaths (25%). Arm 3 (13 patients) produced no CRs, 7 partial responses (PRs, 54%), median survival of 13.8 months, and failure-free survival (FFS) of 7.41 months, with 3 toxic deaths (25%). Among 32 evaluable patients on Arm 4, there were 2 CRs (6%) and 20 PRs (63%) for an ORR of 69%, median survival of 9.9 months, FFS of 5.21 months, and 1-year survival of 40%. There was 1 possible treatment-related death (3%). Topotecan plus cisplatin, in the doses and schedule employed, produced excessive toxicity and modest efficacy in E-SCLC patients. Paclitaxel (230 mg/m2 on day 1) plus topotecan (1 mg/m2 on days 1-5) produced excessive toxicity that was ameliorated with an attenuated paclitaxel dose (175 mg/m2). With the latter regimen (Arm 4) in patients with a performance status of 0/1, CR rates, FFS, overall survival, and 1-year survival were similar to standard etoposide plus cisplatin chemotherapy. Further exploration of topoisomerase inhibitors and taxanes in SCLC patients is warranted.
Clin Lung Cancer 2002 Feb
PMID:Novel doublets in extensive-stage small-cell lung cancer: a randomized phase II study of topotecan plus cisplatin or paclitaxel (CALGB 9430). 1466 44

Locally advanced non-small-cell lung cancer represents 30% to 40% of all pulmonary malignancies. Most patients will die of the disease after aggressive contemporary treatments. Therefore, significant improvement in therapeutic methods must be implemented to improve overall survival rates. The arrival of a new generation of chemotherapeutic agents--including the taxanes, gemcitabine (Gemzar), and topoisomerase inhibitors such as irinotecan (Camptosar) and topotecan (Hycamtin)--offers the hope of significant advances in the treatment of lung cancer. Irinotecan and topotecan are camptothecin derivatives that inhibit topoisomerase I enzyme. It is believed that topoisomerase I inhibitors stabilize a DNA/topoisomerase I complex and interact with replication machinery to cause cell death. A significant amount of data demonstrates that these topoisomerase I inhibitors also act as radiosensitizers. With the increasing data that support concurrent chemoradiation treatment for malignancies, including lung cancer and head and neck cancers, there is an impetus to pursue the additional drugs that may potentially improve local control and survival. Irinotecan is undergoing early clinical trials in the combined-modality setting in several different disease sites. This paper will review the data on the role of camptothecin derivatives as a radiosensitizer and as a component of combined-modality therapy for lung cancer. It is hoped that newer treatment strategies, like the combination of radiation and topoisomerase I inhibitors, will have a significant impact on cure rates in the future.
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PMID:Topoisomerase I inhibitors in the combined-modality therapy of lung cancer. 1525 65

Topotecan HCl is an antitumor drug exhibiting topoisomerase 1-inhibitory activity. Topotecan is used in the treatment of metastatic carcinoma of the ovary and as second-line treatment of small-cell lung cancer. Reported dose-limiting adverse reactions to topotecan are primarily hematologic in nature. To date, only one other case of lung toxicity in a patient taking topotecan has been reported. The authors describe the development of obliterative bronchiolitis, as evidenced by radiographic and pulmonary function testing abnormalities, in a 61-year-old woman who presented with dyspnea, and who was receiving topotecan for peritoneal carcinomatosis.
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PMID:Topotecan-induced bronchiolitis. 1530 Nov 30

Key goals in the treatment of lung cancer are to improve both survival and quality of life (QOL). While formal techniques are frequently used to evaluate survival and response, such rigor is used less often in assessing the impact of treatment on quality of life. Many patients with lung cancer are elderly and have complex medical histories and a myriad of comorbidities. In these patients, with limited survival expectations, symptom palliation, quality of life, and convenience of therapy are especially important end points. Indeed, clinical trials are now incorporating symptom scores and QOL outcomes in their designs (now combined as "patient reported outcomes" or PROs). Moreover, symptom palliation correlates well with QOL and survival duration, providing further rationale for therapy selection based on these parameters. The potential palliative and QOL benefits of chemotherapy have been investigated for several agents in lung cancer trials. Of these, topotecan (Hycamtin; GlaxoSmithKline; Philadelphia, PA) is the best characterized in relapsed small cell lung cancer (SCLC). In a phase III trial of topotecan versus cyclophosphamide, doxorubicin (Adriamycin; Bedford Laboratories; Bedford, OH), and vincristine (Oncovin; Eli Lilly and Company; Indianapolis, IN) (CAV) in patients with recurrent SCLC, topotecan was associated with statistically significant (p < 0.05) improvements in general symptoms (e.g., fatigue and interference with daily activity) and disease-specific symptoms (e.g., dyspnea and hoarseness). Moreover, the introduction of oral therapies, such as oral topotecan, may increase the convenience of therapy by reducing the time needed for therapy and the need for frequent venipuncture. This review summarizes the role of chemotherapy in symptom palliation, with an emphasis on the impact of topotecan therapy on symptom parameters in patients with relapsed SCLC and the emerging role of oral therapy in this setting.
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PMID:Quality-of-life considerations in patients with advanced lung cancer: effect of topotecan on symptom palliation and quality of life. 1561 46

Cisplatin-based chemotherapy is considered to be a standard treatment in patients with relapsed or extensive-disease (ED) small-cell lung cancer (SCLC), the survival benefit remains modest. Relapsed or ED-SCLC patients were enrolled. Topotecan and amrubicin were administered on Days 1-5 and on Days 3-5, respectively. Nine patients received a total of 24 cycles. Since all three patients experienced dose-limiting toxicity (grade 4 neutropenia lasting for more than 4 days, grade 3 febrile neutropenia, and grade 4 thrombocytopenia) at the third dose level (topotecan: 0.75 mg/m2, amrubicin 40 mg/m2), the maximum tolerated dose was determined to be this dose level. Objective response was observed in six patients (67%). The maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) of amrubicin increased in a dose-dependent manner. Amrubicin did not influence the pharmacokinetics of topotecan. The Cmax and AUC of amrubicin were correlated with the duration of grade 4 neutropenia. The mean Cmax of topotecan on day 2 in responders (22.9+/-3.6) was significantly higher than that in non-responders (10.9+/-0.4). This phase I study showed the safety and activity of two-drug combination of amrubicin and topotecan in patients with relapsed or ED-SCLC.
Lung Cancer 2006 Aug
PMID:A phase I and pharmacological study of amrubicin and topotecan in patients of small-cell lung cancer with relapsed or extensive-disease small-cell lung cancer. 1680 73

The topoisomerase I inhibitor, topotecan, is approved for the treatment of recurrent small-cell lung cancer (SCLC) and ovarian cancer (OC). Patients with recurrent SCLC and OC typically experience multiple relapses and receive multiple rounds of chemotherapy. In these settings, disease stabilisation is considered a treatment benefit, and quality-of-life effects and cumulative toxicities of treatments should be considered. Many patients with recurrent cancer may be predisposed to treatment-related adverse events because of advanced age, renal impairment or extensive prior therapy. The standard regimen of topotecan, 1.5 mg/m(2) on days 1-5 of a 21-day cycle, has generally mild nonhaematological toxicity and a well-defined haematological toxicity profile characterised by reversible and noncumulative neutropenia. Alternative regimens may lower the incidence of haematological toxicities and maintain antitumour efficacy. Topotecan may provide physicians with a versatile therapeutic option for the treatment of patients with relapsed SCLC or OC.
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PMID:Safety of topotecan in the treatment of recurrent small-cell lung cancer and ovarian cancer. 1718 52

Lung cancer is the most prevalent and yet the most preventable malignancy worldwide. Owing to the propensity of small-cell lung cancer to early relapse and its relative resistance to subsequent treatment there is a need to improve currently available therapies. Topotecan has provided an efficacious and tolerable therapeutic option for patients with recurrent small-cell lung cancer, and the oral formulation has also been shown to be beneficial, even in elderly patients of poor performance status. Herein we review the role of topotecan in the treatment of small-cell lung cancer.
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PMID:Topotecan for the treatment of small-cell lung cancer. 1755 89

The incidence of lung cancer has been increasing over recent decades. Previous studies show that polymorphisms of the genes involved in carcinogen-detoxication, DNA repair and cell cycle control compose of the risk factors for lung cancer. Recent observations reveal that the components of CAK: Cdk7, MAT1 and cyclin H, may play important roles in cell cycle control, transcriptional control, and DNA repairing process, all of which are important in carcinogenesis. To test whether the genetic variants of CAK genes modify the risk of lung cancer, we compared the manifestation of 25 single nucleotide polymorphisms (SNPs) and the haplotypes of Cdk7, MAT1 and cyclin H between 500 patients with lung cancer and 517 healthy controls. Our results indicated that the genotype frequency of MAT1 79023A/G (p = 0.042) and MAT1 85693C/T (p = 0.005) of cases significantly differed from those of the controls. Further analyses revealed that cyclin H 11817C/T, MAT1 12199A/G, MAT1 70650A/G, MAT1 79023A/G and MAT1 85693C/T significantly influenced the susceptibility of lung cancer in a dominant genetic model while cyclin H 12128A/T and MAT1 42172A/G did in a recessive model. Strongest association between cyclin H alleles and lung cancer patients was found in the non-smoke subpopulation. The haplotype 'TAC' (p = 0.007) increased and the haplotype 'TTC' (p = 0.043) decreased the risk of lung cancer. The potential gene-gene and gene-environmental interactions on lung cancer risk was evaluated using MDR software. A significant interaction between the three CAK component genes was identified and the combination of smoking status and genetic factors barely increased the accuracy. Our results suggested that genetic variants in CAK genes, Cdk7, cyclin H, MAT1, might modulate the risk of lung cancer in a gene-gene interaction mode, which consist to the biochemical interaction of corresponding proteins.
Lung Cancer 2007 Nov
PMID:Polymorphisms of CAK genes and risk for lung cancer: a case-control study in Chinese population. 1770 48


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