amrubicin and Carcinoma--Small-Cell

Topics: Anthracyclines; Antineoplastic Agents; Carcinoma, Small Cell; Humans; Lung Neoplasms; Neoplasm Recurrence, Local

Despite a decreasing incidence in the United States, small-cell lung cancer (SCLC) remains a major clinical problem, with approximately 30,000 new cases each year. The diagnosis of SCLC is usually not difficult. The Veterans Administration Lung Study Group (VALSG) staging system is less accurate than the American Joint Committee of Cancer tumor-node-metastasis (TNM) system (7th edition) at predicting survival in SCLC, especially in lower stage disease. Surgery has not played a major part in the management of SCLC, but emerging data suggest that resection may have a role in earlier stage disease. While the frontline treatment of SCLC has not changed significantly in the past decade, newer agents that are currently being investigated provide hope for better treatment of relapsed/refractory disease for the future.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Humans; Lung Neoplasms; Neoplasm Staging; Taxoids; Topoisomerase I Inhibitors

Although the advancement of the chemotherapy of non-small cell lung cancer and small cell lung cancer is remarkable in recent years, it is still unsatisfactory. Therefore, some new agents or a new treatment strategy for lung cancer is required. Amrubicin is a totally synthetic anthracycline anticancer drug that acts as a potent topoisomerase II inhibitor. Recently, amrubicin has been approved in Japan for the treatment of small- and non-small cell lung cancers and some clinical trials about amrubicin were conducted in Japan, and promising results have been reported for the treatment of small cell lung cancer in particular. The preclinical, pharmacology and clinical data of amrubicin for the treatment of advanced lung cancer are reviewed.

Topics: Animals; Anthracyclines; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Clinical Trials as Topic; Drug Approval; Drug Evaluation, Preclinical; Humans; Japan; Lung Neoplasms; Topoisomerase II Inhibitors

Amrubicin is a synthetic 9-aminoanthracycline that has significant antitumor activity in Japanese patients with extensive stage small cell lung cancer (SCLC). Clinical trials ongoing in the United States and Europe will determine whether amrubicin will be effective in other ethnic groups (whites) or whether this will be an example of geographic and/or genetic variation. Genetic polymorphisms in the UGT1A1 gene have been identified as one of the causes of the increased diarrhea seen in white patients treated with irinotecan when compared with Japanese patients. Nicotinamide adenine dinucleotide phosphate, reduced form-quinone oxidoreductase (NQ01) is an enzyme that participates in the metabolism of amrubicin and polymorphisms of the enzyme, known to occur in the Asian population, might explain the effectiveness of the drug in Japanese patients with small cell lung cancer. Studies to evaluate the drug in US and European patients with extensive stage small cell lung cancer are ongoing. Levels of NQ01 will also be determined in these studies.

Topics: Anthracyclines; Antineoplastic Agents; Carcinoma, Small Cell; Cisplatin; Europe; Humans; Japan; Lung Neoplasms; Topotecan; United States

Amrubicin is a totally synthetic anthracycline anticancer drug and a potent topoisomerase II inhibitor. Recently, amrubicin was approved in Japan for the treatment of small- and non-small-cell lung cancers (SCLC and NSCLC). Here, we review the efficacy and toxicities of amrubicin monotherapy and amrubicin in combination with cisplatin for extensive-disease SCLC (ED-SCLC), and of amrubicin monotherapy for advanced NSCLC, as observed in the clinical trials. Recommended dosage for previously untreated advanced NCSLC was 45 mg/m2/day by intravenous administration for 3 days. Dose-limiting toxicities were leucopenia, thrombocytopenia, and gastrointestinal disturbance. Response rate was 27.9% for advanced NSCLC, and 75.8% for ED-SCLC with a median survival time (MST) of 11.7 months. Recommended dosage of amrubicin was 40 mg/m2/day in combination with cisplatin at 60 mg/m2/day, with MST of 13.6 months and 1-year survival rate of 56.1%. In sensitive or refractory relapsed SCLC, response rate was 52 and 50%, progression-free survival was 4.2 and 2.6 months, overall survival was 11.6 and 10.3 months, and 1-year survival rate was 46 and 40%, respectively. These results are promising for the treatment of both NSCLC and SCLC. Further clinical trials will clarify the status of amrubicin in the treatment of lung cancer.

Topics: Anthracyclines; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Clinical Trials as Topic; Humans; Neoplasm Recurrence, Local

Among patients with lung cancer, approximately 15% have small-cell lung cancer (SCLC). Although, without therapy, untreated SCLC is a rapidly proliferating tumor with a poor prognosis, response rates to chemotherapy and radiotherapy are high. SCLC is usually staged as either limited disease or extensive disease. Extensive disease is treated primarily with chemotherapy. A recent Japanese randomized trial compared IP (irinotecan [Camptosar]/cisplatin [Platinol]) with EP (etoposide/cisplatin). Patients in the IP arm had significantly better outcomes than patients in the EP arm. In the IP arm, the response rate was 84%, and the median overall survival period was 12.8 months. Limited disease is usually treated with concurrent chemotherapy and accelerated radiation therapy, and approximately 20% of patients are cured. Further investigations to improve local control and inhibit distant metastasis are clearly warranted. The dose-rate escalation in radiotherapy (administered concurrently with chemotherapy) is important in improving local control, and the introduction of molecular-targeting agents is necessary to inhibit distant metastasis.

Topics: Adult; Age Factors; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Small Cell; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Etoposide; Humans; Irinotecan; Lung Neoplasms; Middle Aged; Neoplasm Staging; Prognosis

The treatment of choice for limited small-cell lung cancer (SCLC) is platinum-based chemotherapy combined with early, concurrent thoracic radiotherapy with a hyperfractionated regimen. The standard chemotherapy for extensive SCLC in Japan is the combination of irinotecan and cisplatin. There are expectations for new and effective molecular-target-based drugs for SCLC.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Small Cell; Cisplatin; Combined Modality Therapy; Dose Fractionation, Radiation; Drug Administration Schedule; Etoposide; Humans; Irinotecan; Lung Neoplasms; Survival Analysis

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Humans; Lung Neoplasms; Treatment Outcome

Topics: Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Camptothecin; Carcinoma, Small Cell; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Etoposide; Humans; Imatinib Mesylate; Irinotecan; Lung Neoplasms; Piperazines; Pyrimidines; Vincristine

Small-cell lung cancer(SCLC) represents 15 to 20% of all lung cancers. Since patients with SCLC usually present with disseminated disease, treatment strategies have focused on systemic therapy. Despite advances in the treatment of SCLC during the 1970s with the use of combination chemotherapy, and in the 1980s with the combination of etoposide and cisplatin plus concurrent radiotherapy, there have been no major advances in therapy in the last decade. There is no proven role for dose escalation, alternating chemotherapy, weekly chemotherapy, or maintenance therapy. The recent advent of new active agents, including irinotecan, provides hope for more effective therapies in the 2000s. This review outlines the current treatment strategies including new agents, thoracic radiotherapy, surgical resection, and prophylactic cranial irradiation.

Topics: Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Small Cell; Combined Modality Therapy; Humans; Irinotecan; Lung Neoplasms; Topoisomerase I Inhibitors

Doxorubicin is one of the most potent drugs for the treatment of small cell lung cancer (SCLC), but less potent for non-small eell lung cancer (NSCLC). The prevalent use of doxorubicin is limited by the development of cardiomyopathy. Therefore, TUT-7 SM-5887, and ME2303 have been under the clinical studies to find new anthracyclines with less cardiotoxicity and higher therapeutic indices not only for SCLC but also for NSCLC. The dose-limiting factor of these drugs determined in phase I studies was leukocytopenia. Phase II studies which are currently under way have indicated that SM-5887 is possibly most potent for the treatment of NSCLC, and that these drugs have less cardiotoxicity compared to the mother compound, doxorubicin.

Topics: Anthracyclines; Antibiotics, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Doxorubicin; Female; Humans; Lung Neoplasms; Male; Menogaril

This study reports the findings of a Phase I/II, cohort, dose-escalation trial of amrubicin and irinotecan with the support of granulocyte colony-stimulation factor. This study aimed to determine the dose-limiting toxicity of the combination and to define the maximum-tolerated dose, as a recommended dose for Phase II trials. We also sought to obtain preliminary data on the efficacy of this combination as a frontline therapy for extensive-disease small-cell lung cancer.. We included 23 chemo-naïve patients with extensive-disease small-cell lung cancer in the trial. The amrubicin dose was escalated from 35 to 40 mg/m(2) (Levels 1 and 2, respectively) to determine the dose-limiting toxicity, with an unchanged dose of irinotecan at 50 mg/m(2).. Of nine patients, three experienced dose-limiting toxicities at Level 1 of prolonged Grade 4 neutropenia, Grade 3 febrile neutropenia and Grade 3 febrile neutropenia with Grade 3 diarrhea. At Level 2, two patients experienced dose-limiting toxicities of Grade 4 neutropenia and Grade 3 neutropenia with Grade 4 diarrhea. The maximum-tolerated doses and recommended doses for amrubicin and irinotecan were therefore determined to be 35 and 50 mg/m(2), respectively. The Level 1 trial was then expanded to 21 patients, 14 (70%) of whom showed partial responses to the recommended dose. The median progression-free and overall survival times were 6.37 and 15.21 months, respectively.. The combination of amrubicin and irinotecan with the support of granulocyte colony-stimulation factor produced a potent effect in chemo-naïve extensive-disease small-cell lung cancer patients. The use of biomarkers for this regimen may identify patients who are likely to suffer from treatment-ending severe adverse effects.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Small Cell; Diarrhea; Disease-Free Survival; Drug Administration Schedule; Febrile Neutropenia; Female; Granulocyte Colony-Stimulating Factor; Humans; Irinotecan; Kaplan-Meier Estimate; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neutropenia; Protective Agents; Treatment Outcome

To evaluate the safety and tolerability of amrubicin (AMR), determine its maximum tolerated dose (MTD), its dose-limiting toxicities (DLTs), and its recommended dose (RD), and to conduct a pharmacokinetic study of weekly AMR administrations in patients with chemotherapy-refractory or recurrent small cell or non-small cell lung cancer.. Patients with refractory or relapsed non-small cell and small cell lung cancer after 1 or 2 regimens of chemotherapy were eligible. AMR was initiated at 45 mg/m(2) weekly (repetition of dose on 1st and 8th day with a rest on day 15). The dose level was increased by 5 mg/m(2) by modified Fibonacci dose escalation scheme.. Seven patients had small cell lung cancer and 9 had non-small cell lung cancer. Fifty-four courses (median: 3, range: 1-6) were administered at 5 dose levels. At 65 mg/m(2), 3 patients had DLTs as follows: 1 was grade 3 (CTCAE v3.0) in AST/ALT, 1 was grade 3 febrile neutropenia, and 1 was grade 4 neutropenia. Leukocytopenia and neutropenia were correlated with amrubicinol (AMR-OH) C (max) (P = 0.042, P = 0.047, respectively). The AUC (area under the curve of plasma concentration versus time extrapolated to concentration zero) of AMR and AMR-OH did not depend on the dose levels.. In the present phase I study of AMR administered weekly to previously treated lung cancer patients, the maximum tolerated dose and RD were 65 and 60 mg/m(2), respectively. The best response rate was 15.4%, and adverse events with this schedule were tolerable.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Area Under Curve; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local

We conducted a phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with amrubicin, a topoisomerase II inhibitor, with recombinant human granulocyte colony-stimulating factor (rhG-CSF) support to overcome the neutropenia associated with this particular combination. The aim was to determine the maximum tolerated dose (MTD) of amrubicin combined with a fixed dose of CPT-11 and the dose-limiting toxicities (DLTs) of this combination in extensive-stage small-cell lung cancer (ED-SCLC) patients.. Fifteen patients with ED-SCLC were treated at 3-week intervals with amrubicin on days 1-3 plus 60 mg/m(2) CPT-11 on days 1 and 8. In addition, prophylactic rhG-CSF (50 μg/m(2)) was given from day 4 to day 21, except on the day of CPT-11 administration. Amrubicin was started at 30 mg/m(2) and then escalated in 5 mg/m(2) increments until MTD was reached.. The MTD of amrubicin was 35 mg/m(2), since 2 of 4 patients experienced DLTs during the first cycle of treatment at the 40 mg/m(2) dose level. Neutropenia, neutropenic fever, ileus, and diarrhea were the DLTs. There were 13 partial responses among the 13 assessable patients, yielding an overall response rate of 100 %. Median progression-free survival and overall survival were 7.4 months and 13.4 months, respectively.. The combination of amrubicin and CPT-11 showed high activity against ED-SCLC with acceptable toxicity. Use of rhG-CSF allowed the dose of amrubicin to be raised 40 % above that in the original regimen (60 mg/m(2) CPT-11 and 25 mg/m(2) amrubicin).

Topics: Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Small Cell; Female; Granulocyte Colony-Stimulating Factor; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Recombinant Proteins

Amrubicinol (AMR-OH) is an active metabolite of amrubicin (AMR), a novel synthetic 9-aminoanthracycline derivative. The time-concentration profile of AMR-OH exhibits a continuous long plateau slope in the terminal phase. To determine the relationships between the steady-state plasma concentration of AMR-OH and treatment effects and toxicities associated with AMR therapy, we carried out a pharmacokinetic/pharmacodynamic study in patients treated with AMR alone or the combination of AMR+cisplatin (CDDP). AMR was given at a dose of 30 or 40 mg/m(2) on days 1-3. Plasma samples were collected 24 h after the third injection (day 4). Plasma concentrations of AMR-OH or total CDDP were determined by a high-performance liquid chromatography or an atomic absorption spectrometry. Percent change in neutrophil count (dANC) and the plasma concentration of AMR-OH were evaluated using a sigmoid E(max) model. A total of 35 patients were enrolled. Significant relationships were observed between AMR-OH on day 4 and the toxicity grades of leukopenia, neutropenia, and anemia (P=0.018, P=0.012, and P=0.025, respectively). Thrombocytopenia grade exhibited a tendency toward relationship with AMR-OH on day 4 (P=0.081). The plasma concentration of AMR-OH on day 4 was positively correlated with dANC in the group of all patients, as well as in patients treated with AMR alone and in patients coadministered with CDDP. In conclusion, the plasma concentration of AMR-OH on day 4 was correlated with hematological toxicities in patients treated with AMR. The assessment of plasma concentration of AMR-OH at one timepoint might enable the prediction of hematological toxicities.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Drug Administration Schedule; Female; Hematologic Diseases; Humans; Leukopenia; Lung Neoplasms; Male; Middle Aged; Neutropenia; Treatment Outcome

The combination of amrubicin (Am) and irinotecan (CPT) shows appreciable activity against small-cell lung cancer (SCLC) in vitro.. We conducted a dose escalation study of Am in combination with CPT to determine the qualitative and quantitative toxicities and efficacy against extensive (ED) SCLC.. Thirteen previously untreated patients with ED-SCLC were treated with CPT at 60 mg/m(2) on day 1 and dose-escalated Am on days 1-3 with prophylactic granulocyte colony-stimulating factor subcutaneously on days 5-9 every 2-3 weeks. At level 3 (40 mg/m(2)/day Am), 3 of 4 registered patients experienced dose-limiting toxicity such as grade 4 neutropenic fever, and therefore, this was defined as the maximum tolerated dose. A total of 31 courses was administered at dose level 2 (35 mg/m(2)/day) in 6 patients, and grade 4 neutropenia was observed during 5 courses (16.1%). Non-hematological toxicities, except 1 course of grade 3 transfusion of red blood cells and 1 course of grade 3 transaminase elevation, were mild. Thus, dose level 2 of Am was recommended for further study. One patient achieved complete remission and 12 achieved partial remission, and the overall response rate was 100%. The median survival time was 17.4 months, and the 1-year survival rate was 76.9%.. CPT at 60 mg/m(2) on day 1 and Am at 35 mg/m(2)/day on days 1-3 with granulocyte colony-stimulating factor support every 3 weeks is recommended for Japanese patients with ED-SCLC.

Topics: Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Small Cell; Dose-Response Relationship, Drug; Female; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged; Survival Analysis; Treatment Outcome

Amrubicin, a new anthracycline agent, and topotecan are both active for previously treated small-cell lung cancer (SCLC). No comparative study of these agents has been reported. This randomized phase II study was conducted to select amrubicin or topotecan for future evaluation.. Patients with SCLC previously treated with platinum-containing chemotherapy were randomly assigned to receive amrubicin (40 mg/m(2) on days 1 through 3) or topotecan (1.0 mg/m(2) on days 1 through 5). Patients were stratified by Eastern Cooperative Oncology Group performance status (0, 1, or 2) and type of relapse (chemotherapy sensitive or refractory). The primary end point was overall response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival, and toxicity profile.. From February 2004 to July 2007, 60 patients were enrolled, and 59 patients (36 patients with sensitive and 23 patients with refractory relapse) were assessable for efficacy and safety evaluation. Neutropenia was severe, and one treatment-related death owing to infection was observed in the amrubicin arm. ORRs were 38% (95% CI, 20% to 56%) for the amrubicin arm and 13% (95% CI, 1% to 25%) for the topotecan arm. In sensitive relapse, ORRs were 53% for the amrubicin arm and 21% for the topotecan arm. In refractory relapse, ORRs were 17% for the amrubicin arm and 0% for the topotecan arm. Median PFS was 3.5 months for patients in the amrubicin arm and 2.2 months for patients in the topotecan arm. Multivariate analysis revealed that amrubicin has more influence than topotecan on overall survival.. Amrubicin may be superior to topotecan with acceptable toxicity for previously treated patients with SCLC. Further evaluation of amrubicin for relapsed SCLC is warranted.

Topics: Aged; Anthracyclines; Carcinoma, Small Cell; Disease Progression; Disease-Free Survival; Female; Humans; Lung Neoplasms; Male; Middle Aged; Survival Rate; Topotecan

To evaluate the efficacy and safety of amrubicin, (+)-(7S, 9S)-9-acetyl-9-amino-7-[(2-deoxy-beta-D-erythro-pentopyranosyl )oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-naphthacenedione hydrochloride, in previously untreated patients with extensive-disease small cell lung cancer (SCLC).. A total of 35 previously untreated patients with extensive-disease SCLC were entered into the study. Amrubicin was given by daily intravenous infusion at 45 mg/m(2)/day for 3 consecutive days, every 3 weeks. Unless there was tumor regression of 25% or greater after the first cycle, or 50% or greater after the second cycle, treatment was switched to salvage chemotherapy in combination with etoposide (100 mg/m(2), days 1, 2, and 3) and cisplatin (80 mg/m(2), day 1).. Of the 35 patients entered, 33 were eligible and assessable for efficacy and toxicity. Of the 33 patients, 3 (9.1%) had a complete response (95% confidence interval [CI], 1.9-24.3%) and 22 had a partial response, for an overall response rate of 75.8% (95% CI, 57.7-88.9%). Median survival time was 11.7 months (95% CI, 9.9-15.3 months), and 1-year and 2-year survival rates were 48.5% and 20.2%, respectively. The most common toxicity was hematologic. Non-hematologic toxicity of grade 3 or 4 was only seen in 3 patients with anorexia (9.1%) and 1 patient with alopecia (3.0%). Salvage chemotherapy was administered to only 6 patients.. Amrubicin was active for extensive-disease SCLC with acceptable toxicity. Further studies in combination with other agents for SCLC are warranted.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cisplatin; Drug Administration Schedule; Etoposide; Female; Humans; Infusions, Intravenous; Japan; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Salvage Therapy; Time Factors; Treatment Outcome

This study was conducted to evaluate the recommended dose and activity of amrubicin (AMR) as second- or third-line chemotherapy for small-cell lung cancer (SCLC).. Small-cell lung cancer patients with measurable disease who had previously been treated with at least one platinum-based chemotherapy regimen and had an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. Two groups of patients were selected: (1) a group to be treated with second-line chemotherapy and (2) a group to be treated with third-line chemotherapy. AMR was administered to both groups as a 5-minute daily intravenous injection at a dose of 40 or 35 mg/m2 for three consecutive days every 3 weeks.. Between March 2003 and June 2006, 27 patients (second-line, 40 mg/m2: 13 patients; third-line, 40 mg/m2: seven patients; and 35 mg/m2: seven patients) were enrolled. Although the 40-mg/m2 dose of AMR was feasible (one of 13 patients developed febrile neutropenia and four of 13 patients had grade 4 neutropenia) and effective (six of 13 patients had a partial response) in the second-line group, it produced unacceptable toxicity in a third-line setting (three of seven patients with grade 3 nonhematologic toxicities [febrile neutropenia in two patients and fatigue in one patient] and four of seven patients with grade 4 neutropenia). The 35-mg/m2 dose of AMR had acceptable toxicity in the third-line group (one of seven patients with febrile neutropenia and one of seven had grade 4 neutropenia) and moderate efficacy (one of seven patients had a partial response and two of seven had stable disease).. AMR exhibits significant activity as second-line or third-line chemotherapy for small-cell lung cancer. The recommended dose is 40 mg/m2 in a second-line setting and 35 mg/m2 in a third-line setting.

Topics: Aged; Anthracyclines; Antineoplastic Agents; Carcinoma, Small Cell; Female; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Palliative Care; Salvage Therapy; Survival Rate; Treatment Outcome

Amrubicin is a novel synthetic 9-aminoanthracycline derivative and is converted enzymatically to its C-13 hydroxy metabolite, amrubicinol, whose cytotoxic activity is 10-100 times that of amrubicin. We aimed to determine the maximum tolerated dose (MTD) of amrubicin and to characterize the pharmacokinetics of amrubicin and amrubicinol in previously treated patients with refractory or relapsed lung cancer. The 15 patients were treated with amrubicin intravenously at doses of 30, 35, or 40 mg/m(2) on three consecutive days every 3 weeks for a total of 43 courses. Neutropenia was the major toxicity (grade 4, 67%). The MTD was 40 mg/m(2), with the specific dose-limiting toxicities being grade 4 neutropenia persisting for >4 days, febrile neutropenia, or grade 3 arrhythmia in the three patients treated at this dose. A patient with non-small-cell lung cancer showed a partial response, and ten individuals experienced a stable disease. The area under the plasma concentration versus time curve (AUC) for amrubicin and that for amrubicinol increased with amrubicin dose. The amrubicin AUC was significantly correlated with the amrubicinol AUC. The recommended phase II dose of amrubicin for patients with lung cancer refractory to standard chemotherapy is thus 35 mg/m(2) once a day for three consecutive days every 3 weeks.

Topics: Aged; Anthracyclines; Antineoplastic Agents; Area Under Curve; Atrial Fibrillation; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Chromatography, High Pressure Liquid; Disopyramide; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyspnea; Female; Half-Life; Humans; Hypoxia; Infusions, Intravenous; Leukopenia; Male; Middle Aged; Neoplasm Recurrence, Local; Neutropenia; Platelet Transfusion; Pneumonia; Steroids; Thrombocytopenia

Amrubicin, a synthetic 9-aminoanthracycline agent, was recently approved in Japan for treatment of small-cell lung cancer and non-small-cell lung cancer. Amrubicin is converted enzymatically to the C-13 hydroxy metabolite amrubicinol, which is active and possesses a cytotoxicity 10 to 100 times that of the parent drug. The purpose of this study was to characterize the pharmacokinetics of amrubicin and its active metabolite amrubicinol. Amrubicin was administered on days 1-3 in 16 patients with advanced lung cancer. The pharmacokinetics analysis of amrubicin and amrubicinol was performed by high-performance liquid chromatography. When 45 mg/m amrubicin was administered in a bolus injection once every 24 hours for 3 consecutive days, the areas under the curves (0 to 72 hours) for amrubicin and amrubicinol were 13,490 and 2585 ng . h/mL, respectively. The apparent total clearance (CLapp) of amrubicin was 15.4 L/h. The area-under-the-curve ratio of amrubicinol to amrubicin was 15.1 +/- 4.6% (mean +/- SD) at doses ranging from 30 to 45 mg/m. Interindividual variability in the enzymatic conversion of amrubicin to amrubicinol was small. In contrast, a large interindividual variability in the CLapp of amrubicin was observed (CV = 49.8%). The areas under the curves of amrubicin and amrubicinol seemed to be associated with the severity of hematologic toxicities. There is a possibility that monitoring of the plasma concentrations of amrubicin and amrubicinol may provide an efficient tool for establishing the optimal dosage of amrubicin in each patient.

Topics: Aged; Anthracyclines; Area Under Curve; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Chromatography, High Pressure Liquid; Female; Humans; Leukopenia; Lung Neoplasms; Male; Middle Aged; Thrombocytopenia

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.

Topics: Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Biomarkers; Carcinoma, Small Cell; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Female; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Topotecan; Treatment Outcome

This multicenter, phase II study was conducted to evaluate the activity of amrubicin, a topoisomerase II inhibitor, against refractory or relapsed small-cell lung cancer (SCLC).. SCLC patients with measurable disease who had been treated previously with at least one platinum-based chemotherapy regimen and had an Eastern Cooperative Oncology Group performance status of 0 to 2 were eligible. Two groups of patients were selected: patients who experienced first-line treatment failure less than 60 days from treatment discontinuation (refractory group), and patients who responded to first-line treatment and experienced disease progression > or = 60 days after treatment discontinuation (sensitive group). Amrubicin was administered as a 5-minute daily intravenous injection at a dose of 40 mg/m2 for 3 consecutive days, every 3 weeks.. Between June 2003 and December 2004, 60 patients (16 refractory and 44 sensitive) were enrolled. The median number of treatment cycles was four (range, one to eight). Grade 3 or 4 hematologic toxicities comprised neutropenia (83%), thrombocytopenia (20%), and anemia (33%). Febrile neutropenia was observed in three patients (5%). Nonhematologic toxicities were mild. No treatment-related death was observed. The overall response rates were 50% (95% CI, 25% to 75%) in the refractory group, and 52% (95% CI, 37% to 68%) in the sensitive group. The progression-free survival, overall survival, and 1-year survival in the refractory group and the sensitive group were 2.6 and 4.2 months, 10.3 and 11.6 months, and 40% and 46%, respectively.. Amrubicin exhibits significant activity against SCLC, with predictable and manageable toxicities; this agent deserves to be studied more extensively in additional trials.

Topics: Aged; Anthracyclines; Antineoplastic Agents; Carcinoma, Small Cell; Drug Resistance, Neoplasm; Female; Hematologic Diseases; Humans; Infusions, Intravenous; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Palliative Care; Quality of Life; Survival Rate; Treatment Outcome

Amrubicin, a new anthracycline agent, has shown high activity for small-cell lung cancer (SCLC) with acceptable toxicities in previous studies. However, a combination regimen of platinum and amrubicin for elderly patients has not been reported. In this phase I study, the dose-limiting toxicity (DLT), the maximal tolerable dose (MTD), and the antitumor activity of a combination of amrubicin and carboplatin in elderly patients with SCLC were evaluated.. Previously untreated elderly patients (> or =70 years old) with SCLC were enrolled in this study. Amrubicin was administered from day 1 to day 3, and carboplatin was administered on day 1 intravenously. The treatment was repeated every 3 weeks. Three escalating dose levels of amrubicin (mg/m)/carboplatin (area under the curve; AUC) (40/4.0, 40/5.0, and 45/5.0) were initially planned.. Twelve patients were enrolled. At level 1 (amrubicin 40 mg/m and carboplatin AUC 4.0), all three patients experienced DLTs (grade 4 neutropenia > or =4 days, thrombocytopenia <20,000/mm, or grade 3 diarrhea), and this dose level was determined to be the MTD. At the reduced dose of level 0 (amrubicin 35 mg/m and carboplatin AUC 4.0), although DLTs were observed in three of the nine patients, they were considered to be clinically not severe and could be managed. Non-hematological toxicities were mild or moderate and reversible. The objective response rate was 83%, and the median survival time was 12.7 months.. The MTD of this combination was amrubicin 40 mg/m and carboplatin AUC 4.0, and the recommended dose for a phase II trial is a combination of amrubicin 35 mg/m and carboplatin AUC 4.0. We are now conducting a multicenter phase II trial of this regimen to determine the activity of this combination for elderly patients with SCLC.

Topics: Age Factors; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Small Cell; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Japan; Lung Neoplasms; Male; Maximum Tolerated Dose; Neoplasm Staging; Patient Selection; Prognosis; Risk Factors; Survival Analysis; Treatment Outcome

Amrubicin, a totally synthetic 9-amino-anthracycline, demonstrated excellent single-agent activity for extensive-stage small-cell lung cancer (ED-SCLC). The aims of this trial were to determine the maximum-tolerated doses (MTD) of combination therapy with amrubicin and cisplatin, and to assess the efficacy and safety at their recommended doses (RD).. Eligibility criteria were patients having histologically or cytologically proven measurable ED-SCLC, no previous systemic therapy, an Eastern Cooperative Oncology Group performance status of 0-2 and adequate organ function. Amrubicin was administered on days 1-3 and cisplatin on day 1, every 3 weeks.. Four patients were enrolled at dose level 1 (amrubicin 40 mg/m(2)/day and cisplatin 60 mg/m(2)) and three patients at level 2 (amrubicin 45 mg/m(2)/day and cisplatin 60 mg/m(2)). Consequently, the MTD and RD were determined to be at level 2 and level 1, respectively. The response rate at the RD was 87.8% (36/41). The median survival time (MST) was 13.6 months and the 1-year survival rate was 56.1%. Grade 3/4 neutropenia and leukopenia occurred in 95.1% and 65.9% of patients, respectively.. The combination of amrubicin and cisplatin has demonstrated an impressive response rate and MST in patients with previously untreated ED-SCLC.

Topics: Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cisplatin; Female; Humans; Infusions, Intravenous; Injections, Intravenous; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged

Topics: Aged; Anthracyclines; Antineoplastic Agents; Carcinoma, Small Cell; Drug Resistance, Neoplasm; Humans; Male; Middle Aged; Platinum; Prognosis; Prostatic Neoplasms

A 68-year-old man was diagnosed with prostate cancer (initial serum prostate specific antigen [PSA] 389 ng/ml, stage cT4N1M1c, Gleason score 5+4), and androgen deprivation therapy was initiated. Despite the low serum PSA level, he developed postrenal acute kidney failure 4 years later, with progression of prostate cancer and liver and lung metastases. Serum levels of neuron-specific enolase and pro-gastrinreleasing peptide (tumor markers) were elevated. He underwent re-biopsy of the prostate, and histopathological examination revealed small cell carcinoma. He was initially treated with carboplatin and etoposide therapy. Liver metastases showed partial remission, and serum tumor marker levels were temporarily reduced. However, disease progression was observed after 4 chemotherapy cycles, and he was then treated with an 8-cycle course of amrubicin. Metastases showed shrinkage, and serum tumor marker levels were reduced after 2 chemotherapy cycles. Tumor enlargement recurred after 8 cycles, and the patient is being treated with palliative therapy. Amrubicin therapy may be effective in the treatment of small cell carcinoma of the prostate.

Topics: Aged; Androgen Antagonists; Anthracyclines; Carcinoma, Small Cell; Humans; Male; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatic Neoplasms

We report a 59-year-old male patient with metastatic small cell carcinoma of the bladder treated with systemic chemotherapy including an amrubicin. The patient was referred to our hospital complaining of macrohematuria. A cytoscopy revealed a non-papillary, broad-based tumor extending from the right to the posterior wall of the bladder. A computed tomography showed bilateral hydronephrosis caused by the bladder tumor and multiple metastases to the para-aortic and common iliac lymph nodes. The histopathological findings following a transurethral resection of the bladder tumor revealed a T2N3M1, LYM, stage IV small cell carcinoma. We administered two courses of systemic chemotherapy consisting of cisplatin (CDDP) plus an etoposide (VP-16), a first-line treatment usually administered to patients with small cell carcinoma of the lung. We then administered second-line chemotherapy consisting of CDDP plus an irinotecan. When the first and second-line therapies failed to halt progression of the disease, we decided to use amrubicin as the third-line therapy concomitant with radiotherapy for local control. Although the NSE (neuron-specific enolase) value decreased, the patient died 11 months after the initial examination. To our knowledge, this is the first case in which small cell carcinoma of the bladder was treated with amrubicin.

Topics: Anthracyclines; Antineoplastic Agents; Carcinoma, Small Cell; Chemoradiotherapy, Adjuvant; Combined Modality Therapy; Fatal Outcome; Humans; Lymphatic Metastasis; Male; Middle Aged; Nephrectomy; Urinary Bladder Neoplasms

Small cell carcinoma of the prostate (SCCP) is rare, and no standard treatment regimen has yet been established. The overall prognosis remains poor. We experienced a case who obtained relative long-term survival with two types of chemotherapy treatments. A 69-year-old man underwent combined androgen blockade (CAB) with a diagnosis of prostate adenocarcinoma (Gleason score = 5 + 3) that was staged T3bN1M1b (initial PSA = 352 ng/ml). Twenty-five months after hormonal therapy, the level of serum PSA had elapsed remain low, however, FDG-PET/CT revealed high value at the lymph node of para-aortic and pelvic lesion. The levels of serum NSE and Pro-GRP elevated, and a prostate re-biopsy revealed a small cell carcinoma. Therefore, he was treated with 12-cycles of combination chemotherapy consisting of etoposide and carboplatin. Then, disease has progressed, so he was changed to second line chemotherapy with amrubicin. He underwent 12-cycles chemotherapy with amrubicin, but he died of cancer 39 months after the initial treatment of SCCP.

Topics: Aged; Anthracyclines; Antineoplastic Agents; Carboplatin; Carcinoma, Small Cell; Etoposide; Fatal Outcome; Humans; Lymphatic Metastasis; Male; Multimodal Imaging; Positron-Emission Tomography; Prostatic Neoplasms; Time Factors; Tomography, X-Ray Computed

Thymic carcinoma is a rare mediastinal neoplasm, and the prognosis of patients with advanced thymic carcinoma is poor. No standard chemotherapeutic regimen has yet been established for the disease. This is the first report to evaluate the role of amrubicin, a novel anthracycline anticancer drug, in second-line and beyond treatment for patients with platinum-refractory advanced thymic carcinoma.. This study was a review of thymic carcinoma patients who had received amrubicin monotherapy between June 2003 and December 2011 for the progression of disease previously treated with platinum-based chemotherapy. Amrubicin was administered at 35 or 40 mg/m(2) for three consecutive days every 3 weeks, until progression.. Nine patients with recurrent thymic carcinoma were registered. Their median age was 61 years (range 45-72), and the patients included five males and four females. All nine patients had Masaoka's Stage IVb disease. There were three squamous cell carcinomas, one adenocarcinoma, one small-cell carcinoma and two other histological types. The mean number of chemotherapy cycles was five (range 2-13). Grade 3 or higher toxicities included mainly neutropenia (55.5%), anemia (25.0%) and febrile neutropenia (11.1%). No treatment-related deaths were observed. The response rate was 44.4% (95% confidence interval: 19-73). The median progression-free survival after the amrubicin monotherapy was 4.9 months, while the median overall survival was 6.4 months.. Single-agent amrubicin was found to be potentially useful as second-line and beyond chemotherapy for patients with advanced thymic carcinoma. Further multi-institutional prospective studies are warranted.

Topics: Adenocarcinoma; Aged; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Agents; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Disease-Free Survival; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Staging; Platinum Compounds; Retrospective Studies; Thymoma; Thymus Neoplasms; Treatment Outcome

Small cell carcinoma of the esophagus (SmCCE) is a rare and aggressive disease known to have a poor prognosis. SmCCE patients are generally treated with a chemotherapeutic regimen for small cell lung cancer. Salvage therapy for patients with relapsed or refractory tumors has not yet been established. A 63-year-old man with extensive SmCCE was treated with chemotherapy consisting of cisplatin (CDDP) and irinotecan (CPT-11). After the second course of CPT-11/CDDP, the celiac lymph node increased in size. Amrubicin (AMR) as second-line chemotherapy was started. The patient had a complete response after the fifth course of AMR, resulting in an 8-month progression-free survival after initial administration. This case suggests that, as in small cell lung cancer, AMR is effective for SmCCE.

Topics: Anthracyclines; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Small Cell; Disease-Free Survival; Esophageal Neoplasms; Fatal Outcome; Humans; Male; Middle Aged

Amrubicin is an active agent for the treatment of small-cell lung cancer (SCLC). However, there have been no reports of long-term amrubicin use.. Twelve patients with SCLC who were treated with eight or more cycles of amrubicin chemotherapy were retrospectively reviewed.. The median number of cycles of amrubicin chemotherapy received by the patients was 12 (range=8-20), and the median cumulative dose of amrubicin was 2076 mg (range=1200-2856 mg). The median survival time of the study patients was 1104 days (range=459-1997 days). The main adverse events observed during amrubicin chemotherapy were leukopenia and neutropenia. The cardiothoracic ratio (CTR), expressed as the mean (standard deviation) of the values measured at the initiation and termination of amrubicin chemotherapy was 46.2 (4.0), and 46.1 (5.1), respectively. The change in CTR did not reach statistical significance (p=0.92).. Long-term amrubicin chemotherapy is a safe and effective treatment that is associated with a good survival prognosis in properly selected patients.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Carcinoma, Small Cell; Female; Humans; Lung Neoplasms; Male; Middle Aged

Recent reports have suggested the efficacy of amrubicin (AMR) for relapsed small-cell lung cancer (SCLC). However, doses of AMR in these reports were 40 mg/m(2) or 45 mg/m(2), and severe and frequent myelosuppression were observed. Such side effects are occasionally intolerable, as serious myelosuppression may induce fatal infections. To overcome this clinical problem, we investigated whether 35 mg/m(2) of AMR administration with routine prophylactic use of granulocyte-colony stimulating factor (G-CSF) can reduce myelosuppression, while maintaining efficacy.. Between July 2003 and November 2008, 30 relapsed SCLC patients receiving 35 mg/m(2)/day of AMR were evaluated. Amrubicin was administered on days 1-3 every 3 or 4 weeks. Routine prophylactic use of G-CSF was performed beginning on day 8 and continuing for at least 5 consecutive days or until neutrophils recovered to the normal level.. The median number of treatment cycles was four (range 1-9). No complete responses and 13 partial responses were observed, with response rates of: overall 43% (95% confidence interval [CI]: 26-63%); sensitive cases 33% (95% CI: 10-65%); and refractory cases 50% (95% CI: 26-74%) (p=0.4651). The disease control rate (partial response and stable disease) was 80% (95% CI: 61-92%). The progression-free survival times were: overall 4.2 months (95% CI: 3.2-5.2 months); sensitive cases 4.7 months (95% CI: 2.6-5.4 months); and refractory cases 3.5 months (95% CI: 2.6-5.2 months) (p=0.7124). The median OS times were: overall 9.6 months (95% CI: 7.2-12.5 months); sensitive cases 8.4 months (95% CI: 4.6-13.4 months); and refractory cases 11.0 months (95% CI: 6.5-12.6 months) (p=0.9315). The 1-year survival rate was 33%. Regarding grade 3/4 hematological toxicities: leukopenia (47%); neutropenia (50%); anemia (30%); and thrombocytopenia (33%) were observed. Febrile neutropenia occurred in three patients (10%). Transfusions of red blood cells and platelets were performed for eight (27%) and one (3%) patients, respectively. Treatment-related deaths and grade 3/4 non-hematological toxicities were not observed at all.. Considering both safety and efficacy, AMR at a dose of 35 mg/m(2) with routine prophylactic use of G-CSF may be more desirable for the treatment of relapsed SCLC in clinical practice.

Topics: Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cell Count; Clinical Protocols; Disease-Free Survival; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukopenia; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neutropenia; Neutrophils; Recombinant Proteins; Survival Analysis

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.. 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.. 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.. 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

Small cell lung cancer (SCLC) is one of the intractable malignancies. The goal of this study was to clarify whether Akt activity is involved with chemo-resistance and to improve the sensitivity of SCLC cells to the current standard chemotherapeutic drugs with agents that are expected to suppress Akt activity through tyrosine kinase inhibition. Although Akt activity seemed to be involved with the sensitivity of SCLC cells to chemotherapeutic agents (cisplatin, etoposide, SN38 and amrubicin), in Akt-activated N417 cells, only amrubicin exerted synergistic cell growth inhibition when combined with an Akt inhibitor, LY294002. A non-specific tyrosine kinase inhibitor, genistein, suppressed Akt and showed synergistic interaction in combination with amrubicin in N417 cells. Among tyrosine kinases (insulin-like growth factor I receptor, c-Kit and c-Src), only c-Src was activated in N417 cells compared with Akt-inactive H209 cells. A c-Src-specific inhibitor, PP2, and a clinically available multi-tyrosine kinase inhibitor, dasatinib, suppressed Akt activity in parallel with c-Src inhibition. Both PP2 and dasatinib exerted synergistic growth inhibition of N417 cells in the combination with amrubicin. In immunohistochemical analysis, c-Src was expressed in 17 of 19 of the SCLC tumor tissues. These observations suggested that Akt suppression enhances the cytotoxicity of amrubicin, and for the purpose of Akt suppression, c-Src is a promising target in SCLC.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cell Growth Processes; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Synergism; Growth Inhibitors; Humans; Immunohistochemistry; Lung Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-akt; src-Family Kinases

Topics: Anthracyclines; Antineoplastic Agents; Carcinoma, Small Cell; Humans; Lung Neoplasms; Male; Middle Aged; Pleural Neoplasms; Salvage Therapy; Thymus Neoplasms

A 64-year old man first visited our clinic approximately 10 years ago because of diabetic nephropathy that had developed into chronic renal failure. He was hospitalized to examine a left S10 tumor shadow. Based on the results of these examinations, a primary left S10 T2N0M1, ED small cell lung cancer, was diagnosed. During his outpatient visits nephropathy was found. Following admission, he began dialysis (HD). During the detailed examinations, chemotherapy with amrubicin (AMR)was performed and the blood concentration of the drug was measured. The results showed no significant variations in blood concentration before and after the dialysis. While PR was achieved in this patient, a reduction in grade 4 eosinophils was observed as an adverse reaction.

Topics: Anthracyclines; Carcinoma, Small Cell; Humans; Kidney Failure, Chronic; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Tomography, X-Ray Computed

We retrospectively investigated monotherapy of amrubicin hydrochloride in patients with extensive-disease small cell lung cancer (ED-SCLC) and assessed its efficacy and safety. Twenty-two patients were enrolled. The response rate of total, previously untreated, sensitive relapsed, and refractory relapsed cases were 59%, 50%, 100% and 46%, respectively. As for the dose of amrubicin, the response rates of 30 mg/m(2), 35 mg/m(2), 40 mg/m(2), and 45 mg/m(2) were 50%, 33%, 69% and 100%, respectively. Severe myelosuppression was frequently observed as the adverse event, but significant differences among several dosages were not recognized. Median survival time was 230 days in relapsed cases. Monotherapy of amrubicin might be effective in ED-SCLC not only as first-line but also as second-line treatment in relapsed cases. The recommended dose was above 40 mg/m(2) because of its higher response rate.

Topics: Age Distribution; Aged; Aged, 80 and over; Anthracyclines; Carcinoma, Small Cell; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Retrospective Studies; Survival Rate

The patients were a 59-year-old man and 68-year-old man with previously-treated small cell lung cancer (extensive disease). Amrubicin (40 mg/m(2) and 45 mg/m(2)) was administered for 3 days after brain irradiation. Severe neutropenia continued for nine days from day 8 following administration. Although both patients had an infection, it improved by granulocyte-colony stimulating factor (G-CSF), and antibiotics, plus a blood transfusion. Particular attention for severe myelosuppression should be given to amrubicin therapy with previously-treated small cell lung cancer. However, a detailed blood test in course 1 and early administration of drugs such as G-CSF make this therapy feasible. In addition, to control the condition of patients, repeated administration of amrubicin with dose reduction is recommended.

Topics: Aged; Anthracyclines; Carcinoma, Small Cell; Humans; Lung Neoplasms; Male; Middle Aged; Neutropenia; Time Factors

We describe the use of amrubicin hydrochloride to treat small cell carcinoma of the prostate in a 23-year-old man. Initial radiological examinations of the patient revealed a pelvic tumor associated with bilateral hydronephrosis, pelvic lymph node swelling, and lumbar vertebral bone metastases. The pathological diagnosis was small cell carcinoma originating in the prostate, based on positive immunohistochemical staining for neuron-specific enolase, synaptophysin, and myoglobulin; and negative staining for CD3e, CD20, leukocyte common antigen, and CD99. The clinical stage was T4N1M1. A bilateral nephrostomy was performed to improve renal function, and an ileostomy was established to prevent ileus. The first induction chemotherapy consisted of amrubicin 35 mg/m(2) (days 1, 2, 3, monthly). The amrubicin regimen caused a dramatic reduction in tumor size, but could not be continued, because of the occurrence of grade 4 diarrhea. A different regimen was then administered, consisting of one cycle of a 50% dose and a second cycle of a 75% dose of etoposide (100 mg/m(2) days 1, 2, 3), coadministered with carboplatin (AUC 5, plasma concentration curve). Five months after the induction of chemotherapy, the patient suffered respiratory arrest and died.

Topics: Adult; Anthracyclines; Antineoplastic Agents; Bone Neoplasms; Carcinoma, Small Cell; Humans; Hydronephrosis; Male; Pelvic Neoplasms; Prostatic Neoplasms

Amrubicin, a completely synthetic 9-aminoanthracycline derivative, is an active agent in the treatment of untreated extensive disease-small-cell lung cancer and advanced non-small-cell lung cancer. Amrubicin administered intravenously at 25 mg/kg substantially prevented the growth of five of six human lung cancer xenografts established in athymic nude mice, confirming that amrubicin as a single agent was active in human lung tumors. To survey which antitumor agent available for clinical use produces a synergistic interaction with amrubicin, we examined the effects in combinations with amrubicinol, an active metabolite of amrubicin, of several chemotherapeutic agents in vitro using five human cancer cell lines using the combination index (CI) method of Chou and Talalay. Synergistic effects were obtained on the simultaneous use of amrubicinol with cisplatin, irinotecan, gefitinib and trastuzumab, with CI values after 3 days of exposure being <1. Additive effect was observed with the combination containing vinorelbine with CI values indistinguishable from 1, while the combination of amrubicinol with gemcitabine was antagonistic. All combinations tested in vivo were well tolerated. The combinations of cisplatin, irinotecan, vinorelbine, trastuzumab, tegafur/uracil, and to a lesser extent, gemcitabine with amrubicin caused significant growth inhibition of human tumor xenografts without pronouncedly enhancing body weight loss, compared with treatment using amrubicin alone at the maximum tolerated dose. Growth inhibition of tumors by gefitinib was not antagonized by amrubicin. These results suggest that amrubicin appears to be a possible candidate for combined use with cisplatin, irinotecan, vinorelbine, gemcitabine, tegafur/uracil or trastuzumab.

Topics: Animals; Anthracyclines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Camptothecin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cell Line, Tumor; Cisplatin; Deoxycytidine; Drug Synergism; Female; Gefitinib; Gemcitabine; Humans; In Vitro Techniques; Irinotecan; Lung Neoplasms; Mice; Mice, Nude; Quinazolines; Random Allocation; Stomach Neoplasms; Tegafur; Trastuzumab; Uracil; Vinblastine; Vinorelbine; Xenograft Model Antitumor Assays

Topics: Anthracyclines; Antineoplastic Agents; Carcinoma, Small Cell; Humans; Lung Neoplasms

We reported a case of small cell lung cancer treated with amrubicin while receiving hemodialysis. An 83-year-old man with chronic renal failure being treated by hemodialysis was admitted because of a left hilar mass. Small cell lung cancer with liver metastasis (cT2NOM1) was diagnosed. Two courses of chemotherapy with amrubicin resulted in partial response. Toxicity was relatively mild. We measured blood concentration of amrubicin during the first course of chemotherapy. There was no significant difference in blood cell and plasma concentration of amrubicin hydrochloride and amrubicinol between days when he received hemodialysis and when he did not receive hemodialysis. Thus, we considered that amrubicin hydrochloride may be a good candidate for the treatment of small cell lung cancer patients with chronic renal failure under hemodialysis.

Topics: Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Carcinoma, Small Cell; Drug Administration Schedule; Humans; Kidney Failure, Chronic; Liver Neoplasms; Lung Neoplasms; Male; Renal Dialysis

Although amrubicin hydrochloride (AMR) has promising activity against pretreated lung cancer, there are few reports on the adverse events of this agent in a clinical practice setting. We analyzed the adverse events experienced in 27 hospitalized patients who had received AMR monotherapy by collecting data from the pharmaceutical management records. Neutropenia was the main hematological toxicity, and 77.8% of patients developed grade 3/4 neutropenia. Neutrophil counts reached the nadir in 9 to 21 (median 14) days and recovered to normal in 14 to 27 (median 20) days. Seven cases experienced febrile neutropenia without any serious sequelae. Grade 2 or worse non-hematological toxicities were fatigue, constipation, nausea, vomiting, anorexia, and pneumonitis. In comparison with the data of pre-marketing clinical trials, constipation was more commonly observed, while nausea/vomiting was less frequent probably due to appropriate preventive antiemetics. Based on these findings, we have created a novel drug information chart for patients and utilized it in pharmaceutical care in our hospital.

Topics: Aged; Aged, 80 and over; Anorexia; Anthracyclines; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Drug Administration Schedule; Fatigue; Female; Humans; Leukopenia; Lung Neoplasms; Male; Middle Aged; Nausea; Neutropenia; Vomiting, Anticipatory

Cardiotoxicity is a known adverse reaction of high cumulative doses of anthracycline drugs. We encountered a case successfully treated without myocardial disorder. A 54-year-old man who had been given a diagnosis of small-cell lung cancer (SCLC) (extensive disease) was treated with cisplatin (CDDP) plus irinotecan (CPT-11) as first-line chemotherapy, followed by amrubicin (AMR) (30 mg/m2) for 3 consecutive days against the relapsed SCLC. The cumulative dose reached 1110 mg/m2. This case report suggests that repeated treatment with AMR may be effective for relapsed SCLC.

Topics: Anthracyclines; Antineoplastic Agents; Carcinoma, Small Cell; Humans; Lung Neoplasms; Male; Middle Aged

We previously demonstrated the doxorubicin-induced expression of urokinase-type plasminogen activator (uPA), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha in human RC-K8 lymphoma cells and NCI-H69 small cell lung carcinoma cells in which reactive oxygen species might be involved. Amurubicin hydrochloride (AMR), a novel derivative drug of doxorubicin, was recently introduced to clinical practice for treatment of lung cancer in Japan. Therefore, we investigated the effects of AMR on the expression of uPA and chemokines in NCI-H69 cells. AMR and its active form, amurubicinol hydrochloride (AMROH), both induced the expression of uPA, IL-8 and MCP-1 in H69 cells in a dose-dependent manner. When the cultured supernatant obtained from AMR-treated H69 cells was subcutaneously injected into rabbits, migration of a significant number of eosinophils was observed around the injected site. Antigen levels of eotaxin-3, a major migration-factor of eosinophils, were increased in AMROH-treated cells in parallel with the mRNA levels. The induction was observed below the clinically achievable concentration of AMR or AMROH. Thus, the simultaneous induction of uPA, IL-8, MCP-1 and eotaxin-3 may play a role in the pharmacological action of AMR through induction of the interaction between proinflammatory cells and lung carcinoma cells.

Topics: Animals; Anthracyclines; Blotting, Northern; Carcinoma, Small Cell; Cell Line, Tumor; Cell Movement; Chemokine CCL2; Chemokine CCL26; Chemokines, CC; Culture Media, Conditioned; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Eosinophils; Gene Expression Regulation, Neoplastic; Humans; Injections, Subcutaneous; Interleukin-8; Lung Neoplasms; Rabbits; RNA, Messenger; Urokinase-Type Plasminogen Activator

The single agent of amrubicin is active in untreated small-cell lung cancer (SCLC). Cytotoxicity of amrubicinol, the active form of amrubicin, was evaluated in a parent SCLC cell line (SBC-3); an active metabolite of irinotecan, 7-ethyl-10-hydroxy-camptothecin (SN-38)-resistant subline (SBC-3/SN-38); and cisplatin-resistant subline (SBC-3/CDDP) using AlamarBlue assay. Interaction of the combined drugs was evaluated by median-effect plot analysis, and the fraction of apoptotic cells was determined using flow cytometry. SBC-3/SN-38 was 34-fold more resistant to SN-38 and SBC-3/CDDP was 7.2-fold more resistant to cisplatin than parental SBC-3. However, these resistant sublines retained sensitivity to amrubicinol (1.8- and 1.7-fold, respectively). Simultaneous exposure of SBC-3/SN-38 cells to amrubicinol and cisplatin showed a synergistic effect. Simultaneous exposure of SBC-3/CDDP cells to amrubicinol and SN-38 displayed synergistic or additive effects. The two-drug combination produced an increase of apoptotic cells compared to each single agent alone in both resistant cells. These findings suggest that amrubicin alone and in combination with cisplatin or irinotecan is effective against SCLC refractory to irinotecan and/or cisplatin.

Topics: Anthracyclines; Antineoplastic Agents; Apoptosis; Camptothecin; Carcinoma, Small Cell; Cell Cycle; Cell Line, Tumor; Cell Survival; Cisplatin; Drug Resistance, Neoplasm; Drug Synergism; Humans; Inhibitory Concentration 50; Irinotecan; Lung Neoplasms

The patient was a 62-year-old man with small-cell lung cancer (limited disease). He was treated with cisplatin (CDDP) plus etoposide(ETP) and concurrent radiotherapy as first-line treatment. Although a complete response was achieved, his pro-GRP elevated 10 months later. He was treated with several anticancer agents including, CDDP plus irinotecan (CPT-11), CPT-11, paclitaxel and amrubicin (AMR). Although, as a monotherapy, the administration of AMR (30 mg/m(2)) for 3 consecutive days (3-day schedule) seemed to be most effective, severe myelosuppression was observed, and this treatment was discontinued. We changed the treatment schedule to biweekly administration of AMR (30 mg/m(2)). The level of pro-GRP decreased, and it was maintained at a similar level for 7 months. No severe toxicity was observed during this period. This case suggests that the bi-weekly administration of AMR may be a useful option for the treatment of small-cell lung cancer when a 3-day AMR schedule is highly myelosuppressive.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Camptothecin; Carcinoma, Small Cell; Cisplatin; Drug Administration Schedule; Etoposide; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged

Amrubicin is a completely synthetic anthracycline derivative. In contrast, however, the anthracyclines used clinically thus far have been produced by fermentation or semisynthesis. Amrubicin is structurally distinguishable from other anthracyclines by the amino group at the 9-position and its unique sugar moiety. Amrubicinol, the C-13 hydroxy- metabolite of amrubicin, is associated with a 5 to 200 times greater cytotoxicity than amrubicin. Amrubicin exhibited superior in vivo antitumor activity to doxorubicin in the human tumor xenograft model. Using this model, the level of amrubicinol (active metabolite) was shown to be higher than that of doxorubicin in tumor tissues, but lower in normal tissues. These results suggest potent therapeutic activity for amrubicin because of the selective distribution of its highly active metabolite, amrubicinol, in tumors. These anti-tumor effects of amrubicin are considered to be induced by DNA topoisomeraseII inhibition. In clinical studies, amrubicin has demonstrated potent single agent activity as compared to a standard regimen in untreated patients with extensive small cell lung cancer. Its major toxicity was myelosuppression (especially neutropenia).

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Carcinoma, Small Cell; Cell Division; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Depression, Chemical; DNA, Neoplasm; Humans; Lung Neoplasms; Mice; Neutropenia; Topoisomerase II Inhibitors; Tumor Cells, Cultured