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Annals of Oncology : Official Journal... Apr 2010Amrubicin, a new anthracycline agent, has shown high activity for small-cell lung cancer (SCLC) in previous studies. However, a combination regimen with amrubicin and...
BACKGROUND
Amrubicin, a new anthracycline agent, has shown high activity for small-cell lung cancer (SCLC) in previous studies. However, a combination regimen with amrubicin and platinum has been investigated little. On the basis of previous phase I study, we conducted this study to evaluate the efficacy and the safety of amrubicin and carboplatin for elderly patients with SCLC.
METHODS
Chemotherapy-naive elderly patients with SCLC received amrubicin (35 mg/m(2), days 1-3) and carboplatin [area under the curve (AUC) 4.0, day1] every 3 weeks. The primary end point was overall response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival and toxicity profile.
RESULTS
From January 2005 to November 2007, 36 patients were enrolled [median age 76 (range 70-83); ECOG performance status of zero and one in 17 and 19 patients, respectively]. One complete response and 31 partial responses were observed (ORR 89%). Median PFS was 5.8 months and median survival time was 18.6 months. Grade 3-4 neutropenia was observed in 97% of the patients and six patients (17%) suffered from grade 3-4 febrile neutropenia. Other toxic effects were moderate and treatment-related death was not observed.
CONCLUSIONS
Amrubicin combined with carboplatin is quite effective for SCLC with acceptable toxic effects even for the elderly population. Further evaluation of this regimen is warranted.
Topics: Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Female; Humans; Japan; Lung Neoplasms; Male; Small Cell Lung Carcinoma; Societies, Medical; Survival Analysis; Treatment Outcome
PubMed: 19825887
DOI: 10.1093/annonc/mdp384 -
Biological & Pharmaceutical Bulletin 2010The aim of this study was to elucidate the efficacy of combination therapy with irinotecan and amrubicin for lung cancer and the influence of administration schedule in...
The aim of this study was to elucidate the efficacy of combination therapy with irinotecan and amrubicin for lung cancer and the influence of administration schedule in a xenograft mouse model and human cancer cell culture. We investigated the antitumor activity of irinotecan and amrubicin on human small cell lung cancer cell line LX-1 inoculated in mice in vivo and the cytotoxic effect of SN-38 and amrubicinol on human lung cancer cell lines A549 and PC-6 in vitro. Combined administration of irinotecan and amrubicin in divided doses inhibited tumor growth by approximately 90%, with complete recovery observed in one case. Furthermore, combined administration in divided doses induced little loss of body weight. Combination index analysis revealed that the cell growth inhibitory effect of SN-38 combined with amrubicinol was additive, regardless of schedule or cell line. The effect of combination treatment with SN-38 and amrubicinol on cell cycle was investigated. Cell cycle showed arrest at both the S and G2/M phases. The results indicate that combination therapy with irinotecan and amrubicin can be expected to yield improved outcomes, including less toxicity, especially with divided administration.
Topics: Animals; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cell Line, Tumor; Flow Cytometry; Humans; Irinotecan; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Transplantation, Heterologous
PubMed: 20606311
DOI: 10.1248/bpb.33.1183 -
Investigational New Drugs Jun 2017Anthracycline antibiotics (ANT), such as doxorubicin or daunorubicin, are a class of anticancer drugs that are widely used in oncology. Although highly effective in... (Review)
Review
Metabolic carbonyl reduction of anthracyclines - role in cardiotoxicity and cancer resistance. Reducing enzymes as putative targets for novel cardioprotective and chemosensitizing agents.
Anthracycline antibiotics (ANT), such as doxorubicin or daunorubicin, are a class of anticancer drugs that are widely used in oncology. Although highly effective in cancer therapy, their usefulness is greatly limited by their cardiotoxicity. Possible mechanisms of ANT cardiotoxicity include their conversion to secondary alcohol metabolites (i.e. doxorubicinol, daunorubicinol) catalyzed by carbonyl reductases (CBR) and aldo-keto reductases (AKR). These metabolites are suspected to be more cardiotoxic than their parent compounds. Moreover, overexpression of ANT-reducing enzymes (CBR and AKR) are found in many ANT-resistant cancers. The secondary metabolites show decreased cytotoxic properties and are more susceptible to ABC-mediated efflux than their parent compounds; thus, metabolite formation is considered one of the mechanisms of cancer resistance. Inhibitors of CBR and AKR were found to reduce the cardiotoxicity of ANT and the resistance of cancer cells, and therefore are being investigated as prospective cardioprotective and chemosensitizing drug candidates. In this review, the significance of a two-electron reduction of ANT, including daunorubicin, epirubicin, idarubicin, valrubicin, amrubicin, aclarubicin, and especially doxorubicin, is described with respect to toxicity and efficacy of therapy. Additionally, CBR and AKR inhibitors, including monoHER, curcumin, (-)-epigallocatechin gallate, resveratrol, berberine or pixantrone, and their modulating effect on the activity of ANT is characterized and discussed as potential mechanism of action for novel therapeutics in cancer treatment.
Topics: Aldo-Keto Reductases; Animals; Anthracyclines; Antibiotics, Antineoplastic; Carbonyl Reductase (NADPH); Cardiotonic Agents; Cardiotoxicity; Drug Resistance, Neoplasm; Humans
PubMed: 28283780
DOI: 10.1007/s10637-017-0443-2 -
Annals of Translational Medicine Apr 2013Small cell lung cancer (SCLC) represents the 15% of the totally of lung cancer. The percentage of cases in women is arising due to the differences in smoking patterns;... (Review)
Review
Small cell lung cancer (SCLC) represents the 15% of the totally of lung cancer. The percentage of cases in women is arising due to the differences in smoking patterns; it occurs almost exclusively in smokers and appears to be most common in heavy smokers. The stage of disease at presentation is the most important prognostic factor in patients with SCLC; for patients with extended stage disease, the median survival is around 10 months, and the five-year survival rate is 1 to 2 percent. The standard regimen for patients with extensive disease is cisplatin based chemotherapy. Second line chemotherapy is generally less effective than the initial treatment but it can provide significant palliation for many patients. We make a review here of the different options of second line chemotherapy and the role of anthracyclines in it.
PubMed: 25332950
DOI: 10.3978/j.issn.2305-5839.2013.01.05 -
OncoTargets and Therapy 2019Extensive-disease small-cell lung cancer (ED-SCLC) has been known to be rapid progression and relapse, despite highly sensitive to chemotherapy. Amrubicin (AMR), a...
Extensive-disease small-cell lung cancer (ED-SCLC) has been known to be rapid progression and relapse, despite highly sensitive to chemotherapy. Amrubicin (AMR), a third-generation synthetic anthracycline, was accepted as a feasible alternative compared with the standard first-line chemotherapy for previously untreated ED-SCLC. While, the efficacies of these amrubicin-based regimens are unsatisfactory. Our meta-analysis was performed to assess the efficacy and toxicity of first-line therapy comparing AMR and chemotherapy in patients with ED-SCLC. Electronic databases were searched for eligible trials updated on November 2018. Randomized-controlled trials assessing the efficacy and safety of AMR in ED-SCLC were included, of which the interested results were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). A total of 6 randomized controlled trials were included in this analysis. There are no significant differences in OS (OR=1.03, 95% CI=0.66-1.60, =0.91), PFS (OR=1.2, 95% CI=10.77-1.88, =0.41) or ORR (OR=1.31, 95% CI=0.90-1.92, =0.16) with AMR (OR=0.90, 95% CI=0.76-1.05, =0.17). The most common treatment-related AEs in the AMR group are leukopenia (OR=3.13, 95% CI=1.22-7.99, =0.02) and neutropenia (OR=3.25, 95% CI=1.38-7.65, =0.007). Fatigue, anemia, nausea, vomiting, diarrhea the difference between the two groups had no statistical significance. The results of our analysis indicated that AMR therapy demonstrated non-inferiority to the standard first-line chemotherapy for previously untreated ED-SCLC. Whether it can be accepted as an alternative regimen to the standard first-line chemotherapy is still warranted.
PubMed: 31303766
DOI: 10.2147/OTT.S200601 -
Current Oncology (Toronto, Ont.) Feb 2021Improving therapeutic strategies for extensive-stage small cell lung cancer (ES-SCLC) remains a challenge. To date, no reports have directly compared the efficacy and... (Meta-Analysis)
Meta-Analysis Review
Comparative Efficacy and Safety of Immunotherapeutic Regimens with PD-1/PD-L1 Inhibitors for Previously Untreated Extensive-Stage Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis.
Improving therapeutic strategies for extensive-stage small cell lung cancer (ES-SCLC) remains a challenge. To date, no reports have directly compared the efficacy and safety of immune checkpoint inhibitors plus platinum-etoposide (ICIs+EP) with platinum-irinotecan (IP) or directly compared different ICIs+EP for previously untreated ES-SCLC. This study used a Bayesian approach for network meta-analysis to compare efficacy and safety between ICIs+EP and IP and between each pair of three ICIs+EP. The six treatment arms were: pembrolizumab plus platinum-etoposide (Pem+EP), durvalumab plus platinum-etoposide (Dur+EP), atezolizumab plus platinum-etoposide (Atz+EP), platinum-amrubicin (AP), IP, and platinum-etoposide (EP). No significant differences in overall survival were observed between ICIs+EP and IP and between each pair of three ICIs+EP. The incidence of ≥grade 3 adverse events (G3-AEs) was significantly higher in ICIs+EP than IP, whereas no significant difference was found in G3-AEs between each pair of three ICIs+EP. The incidence of ≥grade 3 neutropenia and thrombocytopenia was significantly higher in ICIs+EP than IP, whereas the incidence of ≥grade 3 diarrhea was significantly lower in ICIs+EP than IP. These findings will help clinicians better select treatment strategies for ES-SCLC.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Lung Neoplasms; Network Meta-Analysis; Programmed Cell Death 1 Receptor; Small Cell Lung Carcinoma
PubMed: 33673470
DOI: 10.3390/curroncol28020106 -
Internal Medicine (Tokyo, Japan) 2010The novel anthracycline agent amrubicin, has been approved in Japan to treat small and non-small cell lung cancers (SCLC and NSCLC). The present study evaluates the...
OBJECTIVE
The novel anthracycline agent amrubicin, has been approved in Japan to treat small and non-small cell lung cancers (SCLC and NSCLC). The present study evaluates the toxicity and effect of amrubicin especially in elderly patients with previously treated lung cancer.
PATIENTS AND METHODS
This retrospective study analyzed data from 51 patients (<70 years of age, n=29; > oor =70 years of age, n=22) with lung cancer (NSCLC, n=21; SCLC, n=30) who were treated with amrubicin at our hospital, between July 2003 and October 2009. All patients had recurrent or refractory lung cancer after one or more chemotherapy regimens. We compared the outcomes of patients younger and older than 70 years of age. Amrubicin (30-40 mg/m(2)/day) was infused depending on patient performance status and laboratory data over a period of 5 minutes on days 1-3, with courses repeated at intervals of at least 3 weeks. The dose was modified according to myelosuppression.
RESULTS
The mean number of treatment cycles, mean dose and mean interval of amrubicin administration did not significantly differ between patients aged <70 and > or =70 years. The rate of hematological toxicities (> or = Grade 3) also did not significantly differ between the two age groups (leukopenia, 48.3% and 59.1% for age <70 and > or =70 years, p=0.573; neutropenia, 65.5% vs. 77.3%, p=0.536; anemia, 20.7% vs. 22.7%, p=1.000; thrombocytopenia, 13.8% vs. 31.8%, p=0.173). The incidence of grade 2-4 non-hematological toxicities also did not significantly differ between the groups. The response rate of SCLC and disease control rate of NSCLC were similar in the younger and older groups.
CONCLUSION
Amrubicin monotherapy might be equally tolerated by elderly and younger patients. Further studies are needed to investigate the benefit of amrubicin monotherapy among elderly patients with previously treated lung cancer.
Topics: Age Factors; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Lung Neoplasms; Male; Middle Aged; Recurrence; Retrospective Studies; Salvage Therapy; Topoisomerase II Inhibitors; Treatment Outcome
PubMed: 20823645
DOI: 10.2169/internalmedicine.49.3606 -
Journal of Thoracic Oncology : Official... Jun 2009Amrubicin and cisplatin are active in the treatment of small cell lung cancer (SCLC), and carboplatin is an analogue of cisplatin with less nonhematological toxicity....
BACKGROUND
Amrubicin and cisplatin are active in the treatment of small cell lung cancer (SCLC), and carboplatin is an analogue of cisplatin with less nonhematological toxicity. The appropriate dose of amrubicin and carboplatin combination chemotherapy for previously untreated patients with extensive-disease (ED) SCLC has not been established.
PURPOSE
To determine the maximum-tolerated dose and dose-limiting toxicity (DLT) of amrubicin and carboplatin in ED-SCLC.
PATIENTS AND METHODS
Eligibility criteria were chemotherapy-naive ED-SCLC patients, performance status 0-1, age < or =75, and adequate hematological, hepatic, and renal function. Patients received escalating amrubicin doses under a fixed target area under the curve (AUC) 5 of carboplatin (Chatelut formula). Amrubicin and carboplatin were administered by intravenous (IV) infusion on days 1, 2, and 3, and day 1, respectively. The initial dose of amrubicin was 30 mg/m(2), and the dose was escalated to 35 and 40 mg/m(2).
RESULTS
Sixteen patients were enrolled and 15 eligible patients were evaluated. One of six patients in level 1, one of six in level 2, and three of three in level 3 experienced DLTs. The presentation of DLTs included neutropenia, leukopenia, thrombocytopenia, febrile neutropenia, and liver dysfunction. Evaluation of responses were two complete response, nine partial response, three stable disease, and one progressive disease (response rate 73%), and the median survival time was 13.6 months. The maximum-tolerated doses of amrubicin and carboplatin were determined as 40 mg/m(2) and AUC 5. A dose of 35 mg/m(2) amrubicin and carboplatin AUC 5 was recommended in this regimen.
CONCLUSIONS
This regimen is associated with an acceptable tolerability profile, and warrants evaluation in the phase II setting.
Topics: Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Female; Humans; Incidence; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Prognosis; Small Cell Lung Carcinoma; Survival Rate; Treatment Outcome
PubMed: 19404211
DOI: 10.1097/JTO.0b013e3181a52946 -
Lung Cancer (Amsterdam, Netherlands) Oct 2011Chemotherapy is a mainstay in the treatment of extensive-disease small-cell lung cancer (ED-SCLC), although the survival benefit remains modest. We conducted a phase II...
A phase II study of amrubicin and topotecan combination therapy in patients with relapsed or extensive-disease small-cell lung cancer: Okayama Lung Cancer Study Group Trial 0401.
BACKGROUNDS
Chemotherapy is a mainstay in the treatment of extensive-disease small-cell lung cancer (ED-SCLC), although the survival benefit remains modest. We conducted a phase II trial of amrubicin (a topoisomerase II inhibitor) and topotecan (a topoisomerase I inhibitor) in chemotherapy-naïve and relapsed SCLC patients.
METHODS
Amrubicin (35 mg/m(2)) and topotecan (0.75 mg/m(2)) were administered on days 3-5 and 1-5, respectively. The objective response rate (ORR) was set as the primary endpoint, which was assessed separately in chemotherapy-naïve and relapsed cases.
RESULTS
Fifty-nine patients were enrolled (chemotherapy-naïve 31, relapsed 28). The ORRs were 74% and 43% in the chemotherapy-naïve and relapsed cases, respectively. Survival data were also promising, with a median progression-free survival time and median survival time of 5.3 and 14.9 months and 4.7 and 10.2 months in the chemotherapy-naïve and relapsed cases, respectively. Even refractory-relapsed cases responded to the treatment favorably (27% ORR). The primary toxicity was myelosuppression with grades 3 or 4 neutropenia in 97% of the patients, which led to grades 3 or 4 febrile neutropenia in 41% of the patients and two toxic deaths.
CONCLUSION
This phase II study showed the favorable efficacy and moderate safety profiles of a topotecan and amrubicin two-drug combination especially in relapsed patients with ED-SCLC.
Topics: Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Female; Follow-Up Studies; Humans; Japan; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Neutropenia; Recurrence; Small Cell Lung Carcinoma; Survival Analysis; Topotecan; Treatment Outcome
PubMed: 21334093
DOI: 10.1016/j.lungcan.2011.01.018 -
Molecular and Clinical Oncology May 2017There is no standard chemotherapy for pulmonary large-cell neuroendocrine carcinoma (LCNEC) and this type of cancer is difficult to diagnose using biopsy specimens. At...
Amrubicin monotherapy may be an effective second-line treatment for patients with large-cell neuroendocrine carcinoma or high-grade non-small-cell neuroendocrine carcinoma.
There is no standard chemotherapy for pulmonary large-cell neuroendocrine carcinoma (LCNEC) and this type of cancer is difficult to diagnose using biopsy specimens. At the Shizuoka Cancer Center, when small biopsy specimens are used, they are diagnosed as high-grade non-small-cell neuroendocrine carcinoma (HNSCNEC) and the patients are treated according to the small-cell lung cancer (SCLC) guidelines. Amrubicin is an effective second-line treatment for patients with SCLC, although it remains unclear whether amrubicin monotherapy is effective for patients with LCNEC or HNSCNEC. Between September, 2004 and December, 2013, 18 patients with advanced LCNEC or HNSCNEC received amrubicin monotherapy in the second-line setting. The efficacy and toxicity of this treatment were retrospectively assessed. A total of 6 patients had LCNEC and 12 patients had HNSCNEC. The patients included 13 men, and the median age was 66 years (range, 57-82 years). A total of 16 patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. All the patients had received platinum-based chemotherapy as first-line treatment, and the median number of amrubicin cycles per patient was 4 (range, 1-9). The overall response rate was 11.1%. The median progression-free and overall survival were 4.0 and 9.1 months, respectively. Grade 3 or 4 neutropenia was observed in 44% of the patients, and grade 3 febrile neutropenia occurred in 17% of the patients. One patient developed pneumonia and succumbed to the disease. Non-hematological toxicities were generally mild and manageable. Therefore, the efficacy of amrubicin in the second-line setting for patients with LCNEC or HNSCNEC is limited. Development of new drugs and/or treatment strategies is warranted.
PubMed: 28529747
DOI: 10.3892/mco.2017.1198