amrubicin and Carcinoma--Non-Small-Cell-Lung

There are no standard cytotoxic treatments for non-small-cell lung cancer (NSCLC) patients beyond third-line therapy. The purpose of this study was to evaluate the efficacy and safety of amrubicin in pretreated NSCLC patients.. The records of NSCLC patients who received amrubicin monotherapy as a third or later line of chemotherapy at Shizuoka General Hospital between April 2007 and March 2015 were retrospectively reviewed. Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1. Toxicities were evaluated according to the Common Terminology Criteria for Adverse Events version 3.0.. Overall, 69 patients were enrolled in this study; 16 patients were female and the median age was 67 years. The median number of treatment cycles was 3. The response rate was 7.2%, and the disease control rate was 63.8%. The median progression-free survival was 2.8 months. The median overall survival was 7.7 months. Hematological toxicities of ≥ grade 3 included leukopenia (59.4%) and neutropenia (62.3%). Non-hematological toxicities of ≥ grade 2 included anorexia (27.5%) and fatigue (24.6%).. Although hematological toxicities were severe, these results suggested that amrubicin in NSCLC patients beyond third-line therapy shows sufficient clinical benefit.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Treatment Outcome

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 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

Lung cancer is the leading cause of cancer-related death throughout the world including Japan. During the 1990s, new cytotoxic agents such as irinotecan, paclitaxel, docetaxel, vinorelbine, gemcitabine, and amrubicin showed impressive single-agent activity in patients with lung cancer. To date, clinical research has defined the current standard chemotherapy for advanced non-small cell lung cancer (NSCLC) as modern platinum-based doublets considered more efficacious than any single regimen and with no added benefit to triplet therapies. However, we have reached an efficacy plateau with these agents. Rearrangement of the drug combination or change of the drug doses and schedules will not result in significant further progress. New, less toxic agents that improve survival and quality of life are clearly needed. In the last three decades, we have gained a growing understanding of the molecular biologic changes and the complex series of cellular signals that allow cancer cells to manifest behavior. This provides an opportunity to develop novel therapies aimed at inhibiting some of these changes and signals. Targeted agents, primarily the epidermal growth factor receptor inhibitors, have led to a new era in the treatment of NSCLC. This paper will review the current status of cytotoxic agents and molecular targeted therapy in lung cancer potential useful in the treatment of the patients.

Topics: Anthracyclines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Boronic Acids; Bortezomib; Camptothecin; Carcinoma, Non-Small-Cell Lung; Cetuximab; Clinical Trials as Topic; Deoxycytidine; Drug Combinations; Erlotinib Hydrochloride; Furans; Gefitinib; Gemcitabine; Glutamates; Guanine; Humans; Irinotecan; Lung Neoplasms; Oxonic Acid; Pemetrexed; Pyrazines; Pyridines; Quinazolines; Tegafur; Vinblastine; Vinorelbine

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

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

Amrubicin is approved for treating non-small-cell lung cancer (NSCLC) and small-cell lung cancer. However, no direct comparisons between amrubicin and docetaxel, a standard treatment for NSCLC, have been reported.. We conducted a randomized phase III trial of Japanese NSCLC patients after one or two chemotherapy regimens. Patients were randomized to amrubicin (35 mg/m2 on days 1-3 every 3 weeks) or docetaxel (60 mg/m2 on day 1 every 3 weeks). Outcomes included progression-free survival, overall survival, tumor responses, and safety.. Between October 2010 and June 2012, 202 patients were enrolled across 32 institutions. Median progression-free survival (3.6 versus 3.0 months; P = 0.54) and overall survival (14.6 versus 13.5 months; P = 0.86) were comparable in the amrubicin and docetaxel groups, respectively. The overall response rate was 14.4% (14/97) and 19.6% (19/97) in the amrubicin and docetaxel groups, respectively (P = 0.45). The disease control rate was 55.7% in both groups. Adverse events occurred in all patients, and included grade ≥3 neutropenia occurred in 82.7% and 78.8% of patients in the amrubicin and docetaxel groups, respectively, grade ≥3 leukopenia occurred in 63.3% and 70.7%, and grade ≥3 febrile neutropenia occurred in 13.3% and 18.2% of patients in the amrubicin and docetaxel groups, respectively. Of eight cardiac-related events in the amrubicin group, three were considered related to amrubicin and resolved without treatment discontinuation.. This was the first phase III study to compare amrubicin and docetaxel in patients with pretreated NSCLC. Amrubicin did not significantly improve the primary endpoint of PFS compared with docetaxel.. NCT01207011 (ClinicalTrials.gov).

Topics: Aged; Anthracyclines; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Docetaxel; Drug Resistance, Neoplasm; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Proportional Hazards Models; Small Cell Lung Carcinoma; Taxoids; Treatment Outcome

We conducted a phase I dose escalation study to determine the maximum tolerated dose (MTD), the recommended dose (RD) and the safety profile of amrubicin (AMR) plus paclitaxel (PTX) combination regimen for patients with previously treated non-small cell lung cancer (NSCLC).. PTX was administered at a fixed dose of 150 mg/m(2)/day on day 1 and AMR was intravenously administered at a starting dose of 25 mg/m(2)/day on days 1-3, and this was repeated every 4 weeks. Doses of each drug were planned as follows-level 0, 20/150; level 1, 25/150; level 2, 30/150; level 3, 30/180 AMR mg/m(2) per day/PTX mg/m(2) per day.. Twelve patients were enrolled in this study. The dose-limiting toxicity (DLT) of the regimen was assessed during the first cycle. At level 1, all three patients developed a DLT due to grade 4 neutropenia lasting >4 days, grade 4 thrombocytopenia and grade 3 febrile neutropenia. Therefore, level 1 was considered the MTD and level 0 was selected as the RD. Objective responses were seen in two patients (response rate 16.7 %). Overall disease control rate was 91.7 %.. The combination of AMR and PTX is a feasible and well-tolerated regimen for the treatment of patients with previously treated advanced NSCLC. Although our study included a small number of patients, encouraging disease control and progression-free survival were achieved at the recommended doses. Further clinical trials are warranted.

Topics: Adenocarcinoma; Administration, Intravenous; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Paclitaxel; Prognosis; Salvage Therapy; Survival Rate

We conducted a phase I trial of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, combined with amrubicin, a topoisomerase II inhibitor. The aim was to determine the maximum tolerated dose, the dose-limiting toxicities (DLTs), and the pharmacokinetics of this combination in patients with non-small cell lung cancer who had received previous chemotherapy.. A total of 9 patients with stage IV disease were treated at 3-week intervals with erlotinib once daily on days 1 through 21 plus a 5-minute intravenous injection of amrubicin on days 1 through 3.. The dose levels evaluated were erlotinib (mg/body)/amrubicin (mg/m): 100/30 (n=3), 100/35 (n=3), and 150/30 (n=3). The maximum tolerated dose of erlotinib and amrubicin was 100 mg/body and 35 mg/m because 2 of the 3 patients experienced DLTs during the first cycle of treatment at the third dose level of 150 mg/body and 30 mg/m. Cessation of erlotinib administration for 8 days because of grade 3 leukopenia and grade 3 skin infection (erysipelas) were the DLTs. No drug-drug interactions between erlotinib and amrubicin were observed in this study. The overall response rate was 33%, including 3 partial responses, in the 9 patients. The median progression-free survival for all patients was quite long, 11.3 months, and the median overall survival has not yet been reached.. Combined erlotinib plus amrubicin therapy seems to be highly effective, with acceptable toxicity, against non-small cell lung cancer. The recommended dose for phase II studies was erlotinib 100 mg once daily on days 1 through 21, and amrubicin 35 mg/m on days 1 through 3 administered every 21 days.

Topics: Adenocarcinoma; Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Erlotinib Hydrochloride; Erysipelas; Female; Humans; Leukopenia; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Quinazolines; Treatment Outcome

A phase I/II study of combination chemotherapy with amrubicin and nedaplatin for patients with untreated, advanced, non-small cell lung cancer (NSCLC) was conducted. Amrubicin was given on days 1-3, with nedaplatin given on day 1. The treatment was repeated every 3 weeks. In the phase I trial, the initial amrubicin dose of 25 mg/m(2) was escalated in 5-mg/m(2) increments until the maximum tolerated dose was reached, with the dose of nedaplatin fixed at 100 mg/m(2). In the phase II trial, the primary endpoint was the overall response rate (ORR), assuming 20% for a standard therapy and 40% for a target therapy (α = 0.05 and β = 0.20), and the estimated required total number of patients was 35. In the phase I study, nedaplatin 100 mg/m(2) and amrubicin 25 mg/m(2) was recommended. In the phase II study, 17 out of 35 patients achieved a partial response, and the ORR was 48.6%. Grade 3/4 neutropenia, grade 3 anemia and grade 3/4 thrombocytopenia occurred in 62.9, 11.4 and 11.4% of cycles, respectively. Febrile neutropenia occurred in 5 cycles (3.9%) and all cases were manageable. The recommended dose of this combination is well tolerated and effective in patients with advanced NSCLC.

Topics: Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds

Amrubicin, a third-generation synthetic anthracycline agent, has favorable clinical activity and acceptable toxicity for the treatment of patients with non-small cell lung cancer (NSCLC) and small cell lung cancer. We conducted this study to evaluate the efficacy and safety of amrubicin for advanced NSCLC patients as a third- or fourth-line therapy. Eligible patients had recurrent or refractory advanced NSCLC after second- or third-line therapy. Patients received amrubicin, 35 mg/m(2) i.v. on days 1-3 every 3 weeks. The primary endpoint was the disease control rate (DCR). Secondary endpoints were the overall survival (OS) time, progression-free survival (PFS) time, response rate, and toxicity profile. Of the 41 patients enrolled, 26 received amrubicin as a third-line and 15 received it as a fourth-line therapy. The median number of treatment cycles was two (range, 1-9). Objective responses were complete response (n = 0), partial response (n = 4), stable disease (n = 21), progressive disease (n = 15), and not evaluable (n = 1), resulting in a DCR of 61.0% (95% confidence interval, 46.0%-75.9%). The overall response rate was 9.8% (95% confidence interval, 0.6%-18.8%). The median PFS interval was 3.0 months, median OS time was 12.6 months, and 1-year survival rate was 53.7%. Grade 3 or 4 hematological toxicities were neutropenia (68%), anemia (12%), thrombocytopenia (12%), and febrile neutropenia (17%). Nonhematological toxicities were mild and reversible. No treatment-related deaths were observed. Amrubicin showed significant clinical activity with manageable toxicities as a third- or fourth-line therapy for patients with advanced NSCLC. This study provides relevant data for routine practice and future prospective trials evaluating third- or fourth-line treatment strategies for patients with advanced NSCLC.

Topics: Adult; Aged; Anthracyclines; Carcinoma, Non-Small-Cell Lung; Combined Modality Therapy; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Neoplasm Staging

Both amrubicin (Am) and S-1 are effective against non-small-cell lung cancer (NSCLC), and preclinical studies have demonstrated that the effect of tegafur/uracil, the original compound of S-1, in combination with Am significantly inhibits tumor growth.. We conducted a phase I/II study of Am and S-1 against pretreated NSCLC without EGFR mutation. We fixed the dose of S-1 at 40 mg/m(2) on days 1-14 and escalated the Am dose in increments of 5 mg/m(2) from a starting dose of 30 mg/m(2)/day on days 1-3 and repeated the cycle every 4 weeks.. Twenty-six patients were registered. In phase I, at an Am dose of 35 mg/m(2)/day, three patients experienced grade 2 leukopenia during S-1 administration, and S-1 was withdrawn. Another patient developed grade 2 serum bilirubin in the first cycle. DLTs were observed in four of six patients at this dose level, and therefore, 30 mg/m(2)/day was set as the recommended dose for Am. Twenty patients received this recommended Am dose. Febrile neutropenia was observed in two patients, and one patient developed a grade 4 increase in serum creatinine. Grade 3 vomiting, infection, hypotension, and urinary retention were observed in one patient each, respectively. Other toxicities were mild, and there were no treatment-related deaths. Two patients showed a CR, three showed a PR, and the overall response rate was 25.0%. The median progression-free and the median survival times were 3.8 and 15.6 months, respectively, and the 1-year survival rate was 60%.. Am and S-1 every 4 weeks is an effective combination for pretreated NSCLC without EGFR mutation.

Topics: Adult; Aged; Anthracyclines; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Combinations; ErbB Receptors; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Mutation; Oxonic Acid; Survival Analysis; Tegafur

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

The survival advantage achieved by existing anti-cancer agents as second-line therapy for relapsed non-small cell lung cancer (NSCLC) is modest and further improvement of treatment outcome is desired. Combination chemotherapy with irinotecan and amrubicin for advanced NSCLC has not been fully evaluated.. The primary endpoint of this phase II clinical trial was objective response. Patients with NSCLC who had been treated previously with one or two chemotherapy agents were enrolled. Irinotecan and amrubicin were both administered on Days 1 and 8 of a 21-day cycle, at doses of 100 mg/m(2) and 40 mg/m(2), respectively.. Between 2004 and 2006, 31 patients received a total of 101 courses; the median number of courses administered was three (range, one to six). Objective response was obtained in nine of the 31 patients (29.0% response rate; 95% confidence interval (CI), 12.1-46.0%). With a median follow-up time of 43.9 months, median survival time and the median progression-free survival time were 14.2 and 4.0 months, respectively. Myelosuppression was the most frequently observed adverse event, with grade 3/4 neutropenia in 51% of patients. Febrile neutropenia developed after nine courses (9%) and resulted in one treatment-related death. Cardiac toxicity and diarrhea, possibly specific for both agents, were infrequent and manageable.. Combination chemotherapy with irinotecan and amrubicin is effective in patients with NSCLC but showed moderate toxicities in second- or third-line settings.

Topics: Adenocarcinoma; Adult; Age Factors; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Female; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Salvage Therapy; Survival Rate

The EORTC 08062 phase II randomised trial investigated the activity and safety of single agent amrubicin, cisplatin combined with amrubicin, and cisplatin combined with etoposide as first line treatment in extensive disease (ED) small cell lung cancer (SCLC).. Eligible patients with previously untreated ED-SCLC, WHO performance status (PS) 0-2 and measurable disease were randomised to 3 weekly cycles of either amrubicin alone 45mg/m(2) i.v. day(d) 1-3 (A), cisplatin 60mg/m(2) i.v. d1 and amrubicin 40mg/m(2) i.v. d1-3 (PA), or cisplatin 75mg/m(2) i.v. d1 and etoposide 100mg/m(2) d1, d2-3 i.v./po (PE). The primary end-point was overall response rate (ORR) as assessed by local investigators (RECIST1.0 criteria). Secondary end-points were treatment toxicity, progression-free survival and overall survival.. The number of randomised/eligible patients who started treatment was 33/28 in A, 33/30 in PA and 33/30 in PE, respectively. Grade (G) ⩾3 haematological toxicity in A, PA and PE was neutropenia (73%, 73%, 69%); thrombocytopenia (17%, 15%, 9.4%), anaemia (10%, 15%, 3.1%) and febrile neutropenia (13%, 18%, 6%). Early deaths, including treatment related, occurred in 1, 3 and 3 patients in A, PA and PE arms, respectively. Cardiac toxicity did not differ among the 3 arms. Out of 88 eligible patients who started treatment, ORR was 61%, (90% 1-sided confidence intervals [CI] 47-100%), 77% (CI 64-100%) and 63%, (CI 50-100%) for A, PA and PE respectively.. All regimens were active and PA met the criteria for further investigation, despite slightly higher haematological toxicity.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Disease-Free Survival; Etoposide; Europe; Female; Humans; Lung Neoplasms; Male; Middle Aged; Survival Analysis; Survival Rate; Time Factors; Treatment Outcome

This study was designed to confirm the efficacy and safety of amrubicin, a new anthracycline agent, in patients with previously treated non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).. Eligible patients were required to have recurrent or refractory NSCLC and SCLC after one or two previous chemotherapy regimens. All patients received intravenous amrubicin 35 mg/m(2) on days 1-3 every 3 weeks. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated.. Sixty-six patients (37 NSCLC and 29 SCLC) were assessable for efficacy and safety evaluation. Grade 3 or 4 neutropenia was observed in 39.4% of all patients (NSCLC, 37.8%; SCLC, 41.4%). Nonhematological toxicities were mild. No treatment-related death was observed. The ORRs were 13.5% (95% CI, 4.5-28.8%) in NSCLC and 44.8% (95% CI, 26.4-64.3%) in SCLC. In SCLC, ORRs were 60.0% in the sensitive relapse and 36.8% in the refractory relapse (p=0.2332). In NSCLC, the PFS, OS, and 1-year survival were 3.3 months, 12.0 months, and 35.3%, respectively. In SCLC, the PFS, OS, and 1-year survival were 4.0 months, 12.0 months, and 46.7%, respectively.. Amrubicin is an active and well-tolerated regimen in patients with previously treated lung cancer. Amrubicin 35 mg/m(2) seems to achieve similar efficacy with less toxicity than amrubicin 40 mg/m(2) in this patient population. These results warrant further evaluation in previously treated lung cancer.

Topics: Aged; Anthracyclines; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Female; Humans; Lung Neoplasms; Male; Middle Aged; Small Cell Lung Carcinoma

Amrubicin is a synthetic anthracycline drug that is a potent inhibitor of topoisomerase II. We have performed a multicenter phase II trial to evaluate the efficacy and safety of amrubicin for patients with previously treated non-small cell lung cancer (NSCLC).. Patients with advanced NSCLC who experienced disease recurrence after one platinum-based chemotherapy regimen were eligible for enrollment in the study. Amrubicin was administered by intravenous injection at a dose of 40 mg/m2 on 3 consecutive days every 3 weeks.. Sixty-one enrolled patients received a total of 192 treatment cycles (median, 2; range, 1-15). Response was as follows: complete response, 0; partial response, seven (11.5%); stable disease, 20 (32.8%); and progressive disease, 34 (55.7%). Median progression-free survival was 1.8 months, whereas median overall survival was 8.5 months, and the 1-year survival rate was 32%. Hematologic toxicities of grade 3 or 4 included neutropenia (82.0%), leukopenia (73.8%), thrombocytopenia (24.6%), and anemia (27.9%). Febrile neutropenia occurred in 18 patients (29.5%). One treatment-related death due to infection was observed. Nonhematologic toxicities were mild.. Amrubicin is a possible alternative for second-line treatment of advanced NSCLC, although a relevant hematological toxicity is significant, especially with a febrile neutropenia.

Topics: Adenocarcinoma; Aged; Anthracyclines; Antineoplastic Agents; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Female; Follow-Up Studies; Humans; Japan; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Salvage Therapy; Survival Rate; Treatment Outcome

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

Combination chemotherapy comprising amrubicin and vinorelbine as a second-line therapy for advanced non-small cell lung cancer (NSCLC) has not been fully evaluated. To determine the maximum tolerated dose (MTD) and recommended dose (RD), the present phase I study examined patients with advanced NSCLC.. The subjects were nine patients with histologically confirmed advanced NSCLC, Eastern Cooperative Oncology Group performance status 0-1, prior platinum-based first-line chemotherapy, and measurable or evaluable lesions. Treatment consisted of five dose levels, with amrubicin 35-45 mg/m2 administered as a 5-min intravenous infusion on days 1-3 and vinorelbine 15-25 mg/m2 given as a 1-h intravenous infusion on days 1 and 8, every 3 weeks.. All patients had received carboplatin and paclitaxel as first-line therapy. Dose-limiting toxicity (DLT) was seen in two of six patients (febrile neutropenia and deep vein thrombosis ) at level 1, allowing us to conduct level 2. At level 2, all three patients experienced DLT (leucopenia > or =4 days in one patient; febrile neutropenia in three patients; and infection in two patients), and this level was determined as the MTD. Subsequently, level 1 (amrubicin 35 mg/m2 and vinorelbine 15 mg/m2) was defined as the RD. Responses in the nine patients included a partial response in one patient and stable disease in four patients.. As second-line therapy, the RD of the combination of amrubicin and vinorelbine is 35 mg/m2 and 15 mg/m2, respectively. Further study should proceed to clarify the efficacy of this regimen.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Paclitaxel; Vinblastine; Vinorelbine

We conducted a Phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with amrubicin, a topoisomerase II inhibitor. The aim was to determine the maximum tolerated dose (MTD) of amrubicin combined with a fixed dose of CPT-11 as well as the dose-limiting toxicities (DLT) of this combination in patients with advanced non-small cell lung cancer.. Eleven patients with stage IIIB or IV disease were treated at 3-week intervals with amrubicin (5-min intravenous injection on days 1-3) plus 60 mg/m2 of CPT-11 (90-min intravenous infusion on days 1 and 8). The starting dose of amrubicin was 25 mg/m2, and it was escalated in 5 mg/m2 increments until the maximum tolerated dose was reached.. The 30 mg/m2 of amrubicin dose was one dose level above the MTD, since three of the five patients experienced DLT during the first cycle of treatment at this dose level. Diarrhea and leukopenia were the DLT, while thrombocytopenia was only a moderate problem. Amrubicin did not affect the pharmacokinetics of CPT-11, SN-38 or SN-38 glucuronide. Except for one patient, the biliary index on day-1 correlated well with the percentage decrease of neutrophils in a sigmoid Emax model. There were five partial responses among 11 patients for an overall response rate of 45%.. The combination of amrubicin and CPT-11 seems to be active against non-small cell lung cancer with acceptable toxicity. The recommended dose for Phase II studies is 60 mg/m2 of CPT-11 (days 1 and 8) and 25 mg/m2 of amrubicin (days 1-3) administered every 21 days.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Non-Small-Cell Lung; Female; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged

We conducted a multicenter phase II study of amrubicin, a novel 9-aminoanthracycline, to evaluate its efficacy and safety in patients with non-small-cell lung cancer (NSCLC).. Entry requirements included cytologically or histologically proven measurable NSCLC, stage III or IV, no prior therapy, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and adequate organ function. Amrubicin was given by daily intravenous injection at 45 mg/m2/day for three consecutive days, repeated at 3 week intervals. Each patient received at least three treatment cycles.. Sixty-two patients were enrolled in this study. Of the 62 registered patients, 60 were eligible and assessable for efficacy, and 59 for toxicity. Overall response rate was 18.3% (95% confidence interval [CI], 9.5 to 30.4%) and median survival time was 8.2 months (95% CI, 6.7 to 10.4 months). Major toxicity was myelosuppression, with incidences of grade 3 or 4 toxicity of 78.0% for neutropenia, 54.2% for leukopenia, 30.5% for anemia, and 28.8% for thrombocytopenia. Non-hematological toxicities with a greater than 50% incidence were anorexia (69.5%), nausea/vomiting (55.9%), and alopecia (75.9%), but were relatively mild, with grade 3 toxicities observed in only one patient each (1.7%).. Amrubicin was an active, well-tolerated agent in the treatment of NSCLC.

Topics: Adult; Aged; Anemia; Anthracyclines; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Female; Humans; Japan; Leukopenia; Lung Neoplasms; Male; Middle Aged; Survival Analysis

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

A single-center phase I trial was designed to determine both the dose-limiting toxicities and the maximum tolerated dose (MTD) for amrubicin hydrochloride in combination therapy with cisplatin for advanced non-small cell lung cancer (NSCLC) patients with prior chemotherapy.. Eligible patients received amrubicin and cisplatin on days 1 through 3 every 3 or 4 weeks. Cisplatin was administered at a fixed dosage of 20 mg/m(2) while the administered dose of amrubicin was started at 20 mg/m(2). Each group comprised 3 or 6 patients. When dose limiting toxicities were noted in three or more of six patients at a particular level, that level was estimated to be the MTD.. Fifteen patients were enrolled in this study, including 5 males and 10 females, with a median age of 57. The dose limiting toxicities included grade 4 neutropenia which lasted 4 or more days and febrile neutropenia. The non-hematologic toxicities were well managed and rarely severe. The MTD of amrubicin in this combination regimen was estimated to be 30 mg/m(2).A partial response was observed in 4 of 15 patients (27%).. The recommended dose was thus determined to be 25 mg/m(2) amrubicin with 20 mg/m(2) cisplatin for 3 consecutive days. A phase II study is currently underway.

Topics: Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Drug Administration Schedule; Female; Fever; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Nausea; Neutropenia; Vomiting, Anticipatory

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

Amrubicin is a novel 9-aminoanthracycline. This multicenter phase II study was conducted to evaluate the efficacy and safety of amrubicin in patients with non-small-cell lung cancer (NSCLC).. Sixty-one previously untreated patients with stage III or IV NSCLC were entered this study. The patients were required to have cytologically or histologically proven measurable NSCLC, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and adequate organ function. Amrubicin was administered by daily intravenous injection at 45 mg/m2/day for 3 consecutive days every 3 weeks. At least 3 cycles of treatment were administered to each patient.. All 61 patients registered in this trial were eligible and assessable for efficacy and toxicity. Of them, 17 patients achieved objective responses, consisting of one complete response and 16 partial responses, and the overall response rate was 27.9% (95% confidence interval [CI], 17.1% to 40.8%). The median survival time was 9.8 months (95% CI, 7.7 months to 14.9 months). The major toxicity was myelosuppression. The incidences of grade 3 or 4 toxicity were 72.1% for neutropenia, 52.5% for leukopenia, 23.0% for anemia, and 14.8% for thrombocytopenia. As noticeable toxic events, grade 3 hypotention and alkaline phosphatase elevation were transiently observed in one patient each. In addition, three patients who had had asymptomatic interstitial pneumonitis, identified by diagnostic imaging before treatment, aggravated after amrubicin treatment; two of them died. Other non-hematologic toxicities were relatively mild.. Amrubicin was an active, well-tolerated agent in the treatment of NSCLC.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Administration Schedule; Female; Humans; Japan; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Survival Analysis

Amrubicin is a novel, totally synthetic 9-aminoanthracycline. The present phase I/II study was performed to define its maximum-tolerated dose (MTD), efficacy and toxicity in the treatment of previously untreated patients with advanced non-small-cell lung cancer (NSCLC).. Chemonaive patients were required to have cytologically or histologically proven measurable NSCLC, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, and adequate organ functions. Amrubicin was administered by daily intravenous injection for 3 consecutive days every 3 weeks.. In a phase I study, four patients were enrolled at dose level 1 (40 mg/m(2)/day) and four at dose level 2 (45 mg/m(2)/day). No dose limiting toxicity (DLT), which was defined as toxicity consisting of grade 4 neutropenia and leukopenia lasting four days or more, and grade 3 or 4 toxicity other than neutropenia, leukopenia, anorexia, nausea/vomiting, and alopecia, was observed at these dose levels. Subsequently, at dose level 3 (50 mg/m(2)/day), 3 of 5 patients experienced DLTs (leukopenia, neutropenia, thrombocytopenia, or gastrointestinal complications). The MTD and recommended dose (RD) were determined to be 50 mg/m(2)/day and 45 mg/m(2)/day, respectively. Three partial responses (PRs) were achieved in 13 patients (response rate, 23.1%) in a phase I study. In a phase II study, 15 patients were assessable for efficacy and toxicity at the RD, and four PRs were obtained (response rate, 26.7%). The major toxicities were leukopenia and neutropenia, while non-hematologic toxicities were mild. The overall response rate in the combined patient population of the phase I/II study was 25.0% (7 PRs in 28 patients), with a 95% confidence interval of 10.7% to 44.9%.. Amrubicin exerted promising antitumor activity on NSCLC with acceptable toxicity.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Electrocardiography; Female; Humans; Injections, Intravenous; Leukopenia; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neutropenia; Survival Analysis; Topoisomerase II Inhibitors

The therapeutic efficacy of cytotoxic anticancer drugs has been reported to be enhanced after immune checkpoint inhibitors (ICI) in non-small cell lung cancer; however, it is unclear whether the same is applicable for small cell lung cancer (SCLC). We evaluated the efficacy of second-line amrubicin (AMR) following first-line platinum-based chemotherapy and ICI combination therapy (chemo-ICI) in SCLC.. We retrospectively enrolled consecutive patients with SCLC treated with AMR as a second-line following chemo-ICI as first-line between July 2019 and April 2021 from 16 institutions throughout Japan. We investigated the therapeutic effectiveness, safety, and efficacy-enhancing variables of AMR.. Overall, 89 patients treated with AMR after first-line chemo-ICI were analyzed. The overall response rate (ORR) was 29.2% (95% confidence intervals [CI], 20.1-39.8) and median PFS (m PFS) was 2.99 months (95% CI, 2.27-3.65). Patients who relapsed more than 90 days after receiving first-line platinum combination therapy (sensitive relapse) exhibited greater ORR (58.3% vs. 24.7%, p = 0.035) and m PFS (5.03 vs. 2.56 months, p = 0.019) than patients who relapsed in <90 days (refractory relapse). Grade 3 or higher adverse events were mainly hematological toxicity.. Our study suggested that the therapeutic effect of AMR was not enhanced after ICI on SCLC. However, AMR may be effective in cases of sensitive relapse after chemo-ICI. There was no increase in severe toxicity associated with AMR after ICI.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Humans; Immune Checkpoint Inhibitors; Lung Neoplasms; Neoplasm Recurrence, Local; Recurrence; Retrospective Studies; Small Cell Lung Carcinoma; Treatment Outcome

Amrubicin chemotherapy is a treatment option for patients with non-small cell lung cancer (NSCLC) after third-line treatment in Japan. Although topoisomerase-II (Topo-II), a target of amrubicin, has been reported to be a prognostic or predictive marker for chemosensitivity and clinical outcomes in various types of malignancies, its effects in the Japanese population remain unknown.. Data regarding 44 patients with advanced NSCLC treated with amrubicin between April 2004 and May 2014 were retrospectively analyzed. We evaluated the expression levels of Topo-II by immunohistochemical staining of tumor specimens obtained via biopsy or surgical resection.. The majority of enrolled patients were men (68%) with a median age of 67 (range, 43-78) years. The most common histological type was adenocarcinoma (70%). High Topo-II expression was observed in 13 (30%) of the 44 patients. The median progression-free survival and overall survival (OS) durations were 1.8 and 8.8 months, respectively. While there was no significant association between Topo-II expression and progression-free survival, patients with low Topo-II expression had significantly longer OS than did those with high Topo-II expression. Good performance status and low expression of Topo-II were all significantly associated with a favorable OS.. Low expression of Topo-II was identified as an independent prognostic factor for longer survival in patients with NSCLC receiving amrubicin, a Topo-II inhibitor.. Significant findings of the study The median progression-free survival and overall survival (OS) durations were 1.8 and 8.8 months, respectively. While there was no significant association between Topo-II expression and progression-free survival, patients with low Topo-II expression had significantly longer OS than did those with high Topo-II expression. Good performance status and low expression of Topo-II were all significantly associated with a favorable OS. What this study adds This study is the first to assess the effects of topoisomerase-II (Topo-II), a target of amrubicin, as a prognostic or predictive marker for chemosensitivity and clinical outcomes in the Japanese population.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; DNA Topoisomerases, Type II; Female; Follow-Up Studies; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Male; Middle Aged; Prognosis; Retrospective Studies; Survival Rate

Squamous cell lung carcinoma (SQCLC) is an aggressive type of lung cancer. In contrast with the marked advances that have been achieved in the treatment of lung adenocarcinoma, there are currently no effective targeted therapies for SQCLC, for with cytotoxic drugs are still the main treatment strategy. Therefore, the present study aimed to develop novel combination therapies for SQCLC. The results demonstrated that a combined treatment with the potent histone deacetylase (HDAC) inhibitor OBP‑801 and the third‑generation anthracycline amrubicin synergistically inhibited the viability of SQCLC cell lines by inducing apoptosis signal‑regulating kinase 1 (ASK1)‑dependent, as well as JNK‑ and p38 mitogen‑activated protein kinase (MAPK)‑independent apoptosis. OBP‑801 treatment strongly induced the protein expression levels of thioredoxin‑interacting protein (TXNIP), and amrubicin treatment increased the levels of intracellular reactive oxygen species (ROS), which suggested that this combination oxidized and dissociated thioredoxin 2 (Trx2) from mitochondrial ASK1 and activated ASK1. Moreover, mouse xenograft experiments using human H520 SQCLC cells revealed that the co‑treatment potently suppressed tumor growth in vivo. These results suggested that a combined treatment with OBP‑801 and amrubicin may have potential as a therapeutic strategy for SQCLC.

Topics: Animals; Anthracyclines; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Lung Neoplasms; MAP Kinase Kinase Kinase 5; Mice; Peptides, Cyclic; Xenograft Model Antitumor Assays

The efficacy of the combination of amrubicin and bevacizumab against advanced non small-cell lung cancer (NSCLC), as a second or third-line treatment, was evaluated.. Amrubicin was administered for 3 days to patients with previously treated advanced NSCLC, whereas bevacizumab was administered on day 1 of each cycle; this regimen was repeated every 3 weeks.. Among the 16 patients, an overall response rate of 12.5% (for two patients) was achieved, and the overall disease control rate was 93.7%. Progression free survival and overall survival were 8.5 and 16.6 months, respectively. Grade 3 or 4 haematological toxicities were leukopenia, neutropenia, and febrile neutropenia. Grade 3 proteinuria and infection were the non haematological adverse events.. The combination of amrubicin and bevacizumab is a promising regimen in the second or third-line treatment for advanced non-squamous NSCLC; however, physicians must recognise the risk of proteinuria related with this regimen.

Topics: Aged; Anthracyclines; Antineoplastic Agents; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Feasibility Studies; Female; Humans; Lung Neoplasms; Male; Middle Aged; Prospective Studies

The aim of this study is to examine the efficacy of weekly amrubicin (WA) for treating refractory or relapsed non-small cell lung cancer (RRNSCLC).. The literature search will be performed using the Cochrane Library, MEDLINE, EMBASE, CINAHL, PsycINFO, Scopus, Chinese Biomedical Literature Database, WANGFANG, VIP database, and China National Knowledge Infrastructure from inception onwards up to the March 1, 2020. No language limitation will be implemented. Randomized controlled trials that examined the efficacy and safety of WA for the treatment of RRNSCLC will be included. Literature selection, data extraction, and methodological quality assessment will be handled by 2 independent authors. We will invite a third author to disentangle any divergences between 2 authors. We will carry out statistical analysis using RevMan 5.3 software.. This study will summarize current evidence to assess the efficacy and safety of WA for the treatment of RRNSCLC.. The findings of this study will provide helpful evidence for the clinician, and will promote further studies, as well as clarify the direction of research on WA for the management of RRNSCLC.Study registration number: INPLASY202040168.

Topics: Anthracyclines; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Meta-Analysis as Topic; Neoplasm Recurrence, Local; Systematic Reviews as Topic

The toxic effects of combined cisplatin/docetaxel therapy cycles on erythroid and granulocytic hematopoietic lineages as well as their intercycle recovery were examined in patients with stage III-IV non-small-cell lung carcinoma. Responsiveness of the blood system to this therapy remained at a high level. Combined therapy pronouncedly activated the key elements of the erythroid and granulocytic hematopoietic lineages leading to accumulation of immature and mature myelokaryocytes in the bone marrow, enlargement of the medullary pool of mature neutrophils, and increase in the count of medullary erythroid and granulocytic precursor cells under conditions of their accelerated maturation.

Topics: Anthracyclines; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Differentiation; Cisplatin; Disaccharides; Docetaxel; Doxorubicin; Erythropoiesis; Granulocytes; Hematopoietic Stem Cells; Humans; Lung Neoplasms; Macrolides; Nitrosourea Compounds; Organoplatinum Compounds; Taxoids

The purpose is to examine the synergistic effect of pemetrexed (PEM) and amrubicin (AMR) on the proliferation of lung cancer cell lines. In vitro, dose-dependent synergistic effects of concurrent PEM and AMRol, which is an active metabolite of AMR were observed in A549 and H460 cells. In real-time RT-qPCR analysis and western blotting, expression of the target enzymes of PEM were suppressed in cells treated with amrubicinol alone. In vivo, AMR/PEM treatment also showed synergistic antitumor activity both in A549-bearing and H520-bearing mice. PEM and AMR work synergistically to inhibit the proliferation of several different lung cancer cell lines.

Topics: Animals; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Drug Synergism; Female; Glutamates; Guanine; Humans; Inhibitory Concentration 50; Lung Neoplasms; Mice; Mice, Inbred BALB C; Pemetrexed; Time Factors

Previously we showed that Akt-suppressing agents, combined with amrubicin, synergistically inhibited the growth of small cell lung cancer cells. The combined effects of chemotherapeutic agents and Akt-suppressing agents, including epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, were evaluated in A549 lung adenocarcinoma cells harboring K-ras mutation and wild-type EGFR. Only amrubicin and not other chemotherapeutics (cisplatin, pemetrexed and paclitaxel) synergistically inhibited cell growth when combined with an Akt inhibitor, LY294002. The combination of amrubicin and LY294002 enhanced Annexin V binding to cells. A non-specific tyrosine kinase inhibitor, genistein, suppressed Akt and showed synergistic interaction in combination with amrubicin. Two EGFR tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, suppressed Akt activity at clinically achievable concentrations and demonstrated synergism when combined with amrubicin. The suppression of K-ras expression by siRNA interfered with this synergism and inhibited both EGFR and Akt activity in A549 cells. In Ma10 cells, which harbor wild-type EGFR and K-ras, EGFR-TKIs neither suppressed Akt activity nor exhibited such synergism when combined with amrubicin. We concluded that the synergism by the combination of EGFR-TKI and amrubicin is attributable, at least partially, to K-ras mutation in A549 cells. The combination of EGFR-TKI and amrubicin may be a promising treatment for lung cancer with wild-type EGFR and K-ras mutation.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anthracyclines; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Chromones; Drug Synergism; ErbB Receptors; Genes, ras; Humans; Lung Neoplasms; Morpholines; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt

Currently, there are no standard cytotoxic treatments for non-small-cell lung cancer (NSCLC) patients beyond third-line therapy. The purpose of this study was to evaluate the efficacy of amrubicin monotherapy as a salvage treatment in heavily pretreated NSCLC patients.. The records of NSCLC patients who received amrubicin monotherapy as a third or later line of chemotherapy at a Kitasato University Hospital between January 2009 and December 2012 were retrospectively reviewed. Amrubicin was administered to patients by intravenous injection at a dose of 35 or 40 mg/m(2) daily on 3 consecutive days, and cycles were repeated at 3-week intervals.. There were 36 patients who met the inclusion criteria. Their median number of prior chemotherapy treatments was 4 (range 2-7), and the median number of chemotherapy cycles per patient was 4 (range 1-9). Grade 3 or 4 hematologic toxicities included neutropenia (61.1%), leukopenia (58.3%), thrombocytopenia (22.2%) and anemia (11.1%). Febrile neutropenia occurred in 8 patients (22.2%). Nonhematologic toxicities were mild. The overall response rate, median progression-free survival time and median survival time were 8.3%, 1.7 months, and 6.3 months, respectively. Progression-free survival time was the same, i.e. 1.7 months in both groups i.e. the 35- and the 40-mg/m(2)-dose groups.. Amrubicin exhibits modest activity and acceptable toxicity when used as a third or later line of chemotherapy for advanced NSCLC.

Topics: Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cohort Studies; Disease-Free Survival; Female; Hematologic Diseases; Humans; Injections, Intravenous; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Retrospective Studies; Severity of Illness Index

Cisplatin is a key drug used in the treatment of non-small cell lung cancer (NSCLC), and amrubicin is one of the new active agents for NSCLC. The objective of this study was to determine the recommended dose (RD) of amrubicin in combination with a fixed dose of cisplatin, and to assess the toxicity profile and feasibility of this regimen.. We conducted a dose escalation study of amrubicin and cisplatin in previously untreated patients with stage IIIB or IV NSCLC. Dose level 1 of amrubicin was 30 mg/m on days 1 to 3 and level 2 was 35 mg/m. Cisplatin was administered at a fixed dose of 80 mg/m on day 1. Chemotherapy was given in a 3-week cycle.. Twenty patients were enrolled. Dose-limiting toxicities were neutropenia, febrile neutropenia, thrombocytopenia, and creatinine elevation. Level 1 (30 mg/m) was determined to be the RD, and 35 mg/m exceeded the RD. In 17 patients treated with the RD, the overall response rate was 41.2% (95% confidence interval, 17.7-64.7) and the median survival time was 16.4 months (95% confidence interval, 13.1-19.5).. This amrubicin and cisplatin regimen may be feasible and promising against advanced NSCLC. The efficacy and safety of this regimen should be confirmed in a phase II study.

Topics: Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Dose-Response Relationship, Drug; Feasibility Studies; Female; Humans; Lung Neoplasms; Male; Middle Aged; Survival Rate; Treatment Outcome

The pharmacokinetic (PK)-pharmacodynamic (PD) relationship of amrubicin and its active metabolite, amrubicinol, has only been evaluated using trough levels of these agents since the full PK profiles not yet been clarified so far. This study was performed to analyze the full PK profiles of amrubicin and amrubicinol and to evaluate their toxicity-PK relationships in Japanese patients.. Amrubicin (35-40 mg/m(2)) was administered to 21 lung cancer patients on days 1-3 every 3-4 weeks. Fourteen blood samples were obtained per patient over the course of 3 administration days. The plasma concentrations of amrubicin and amrubicinol were quantitated by HPLC, and the relationships between PK parameters of these compounds and hematological toxicities were evaluated.. The overall PK profiles of amrubicin and amrubicinol were well characterized using a 3-compartment model and a 1-compartment model with a first-order metabolic process, respectively. The major toxicities were hematological. The clearance of amrubicinol was significantly correlated with grade 4 neutropenia (P = 0.01). The percentage decreases in the neutrophil count, hemoglobin level and platelet count were well correlated with the amrubicinol AUC.. The pharmacokinetic profiles of amrubicin and amrubicinol were clarified, and the subsequent PK-PD analyses indicate that the clearance of amrubicinol is the major determinant of neutropenia.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Carcinoma, Non-Small-Cell Lung; Female; Humans; Japan; Lung Neoplasms; Male; Middle Aged; Small Cell Lung Carcinoma

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

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

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