small cell lung cancer ( sclc ) accounts for approximately 15% of all lung cancer cases , with two - thirds of patients presenting with extensive disease ( ed ) . without treatment , however , the disease shows a high response rate to chemotherapy and radiotherapy , except in a low percentage of patients . a randomized trial demonstrated that single - agent topotecan was at least as efficacious as the three - drug combination of cyclophosphamide - doxorubicin - vincristine for the treatment of patients with sensitive relapsed cases.1 response rates and median survival times were 24% and 25.0 weeks for topotecan , and 18% and 24.7 weeks for cyclophosphamide - doxorubicin - vincristine , respectively . in previously untreated ed - sclc , amrubicin yielded an extremely high response rate of 79% and a median survival time of 11 months , which was comparable with the results achieved with platinum.2,3 recently , clinical studies have demonstrated the efficacy of amrubicin in patients with relapsed sclc . this review presents the results of clinical studies showing the efficacy and safety of amrubicin for the treatment of relapsed sclc . amrubicin hydrochloride is a synthetic anthracycline agent , with a similar structure to doxorubicin , in which the hydroxyl group at position 9 group in amrubicin is replaced by an amino group to enhance efficacy ( see figure 1 ) . amrubicin is converted to an active metabolite , amrubicinol , which is 554 times more active than amrubicin , through reduction of its c-13 ketone group to a hydroxyl group by carbonyl reductase.4 other enzymes metabolizing amrubicin and amrubicinol are nicotinamide adenine dinucleotide phosphate ( nadph)-dependent p450 reductase and nad[p]h - dependent quinone oxidoreductase . doxorubicin , amrubicin , and amrubicinol are inhibitors of dna topoisomerase ii , exerting their cytotoxic effects by stabilizing a topoisomerase ii - mediated cleavable complex.5 in addition , they are more or less only one - tenth as potent as doxorubicin in producing dna intercalation . antitumor activity and toxicologic aspects were first reported for amrubicin by morisada et al.6 they evaluated this agent in six murine systems and nine human tumor - nude mouse systems , and found that the antitumor activity of amrubicin was superior to adriamycin in human tumor xenografts , and almost equal against murine experimental tumors . the acute toxic signs were body weight decrease , ataxia , hair loss , and myelosuppression , and these toxicities were qualitatively comparable with those induced by adriamycin . the maximum tolerated dose was estimated to be 25 mg / kg in four mouse strains , and the drug had anticancer activity against human lung cancer xenografts in vivo.7 cardiomyopathy is a burdensome toxicity with the anthracyclines . suzuki et al evaluated the degree of cardiotoxicity of amrubicin compared with that of adriamycin in rabbits.8 the drugs were intravenously administered three times a week for eight weeks . in this study , prolongation of the qtc interval and stt changes were observed in rabbits administered amrubicin and adriamycin . morphologic studies showed that myocardial tissue damage in animals administered amrubicin was comparable with that seen in controls . considering the results of the antitumor efficacy studies comparing amrubicin with adriamycin , they concluded that the cardiotoxicity of amrubicin was very slight . long - term survival is quite uncommon in refractory sclc patients , with less than 25% of patients with limited - stage disease and 1%2% of patients with extensive - stage disease remaining alive at five years . a phase ii study was conducted in patients with relapsed disease who had previously received one or two regimens , including at least one regimen of platinum - based chemotherapy9 ( table 1 ) . the disease progressed within 60 days after the final dose of previous chemotherapy in 16 and 44 refractory patients , respectively . the sensitive groups , in which complete response ( cr ) or partial response ( pr ) was observed with previous chemotherapy and the disease progressed or relapsed within 60 days of the final dose of previous chemotherapy , were eligible for the study , and were assessable for toxicity , response , and survival . amrubicin was administered intravenously at a dose of 40 mg / m on days 13 every three weeks . there were no differences in the response rate , ie , 50% ( 95% ci 25%75% ) for refractory disease and 52% [ 95% ci 37%68% ] for sensitive disease . the median survival times were 10.3 months in the refractory group and 11.6 months in the sensitive group , respectively ( p = 0.0974 , log rank test ) . common adverse events were hematologic toxicities , including grade 34 neutropenia ( 83% ) , leucopenia ( 70% ) , anemia ( 33% ) , thrombocytopenia ( 20% ) , and febrile neutropenia ( 5% ) . nonhematologic adverse events included grade 34 anorexia ( 15% ) , asthenia ( 15% ) , hyponatremia ( 8% ) , and nausea ( 5% ) . another phase ii study of amrubicin in patients with previously treated sclc was conducted by kaira et al10 ( table 2 ) . twenty - nine patients with relapsed sclc who had previously received platinum - based chemotherapy were enrolled in the trial , including 10 patients with sensitive relapse and 19 patients with refractory relapse . amrubicin was administered intravenously at a dose of 35 mg / m on days 13 every three weeks . the response rate was 44.8% ( 95% ci 26%64% ) , being 60% for sensitive cases and no significant difference in the response rate was observed between sensitive cases and relapsed cases ( p = 0.233 , log rank test ) . the median progression - free survival and median survival times were 4.0 months ( sensitive relapse , 4.0 months ; refractory relapse , 4.0 months ) and 12.0 months ( sensitive relapse , 12.0 months ; refractory relapse , 11.0 months ) , respectively . there was no difference in median progression - free survival and median survival time between sensitive relapse and refractory relapse . grade 3 or 4 neutropenia and febrile neutropenia were observed in 42% and 3% of patients , respectively . however , this study involved only japanese patients , so it would be necessary to conduct clinical studies in non - japanese patients to confirm efficacy . a randomized phase ii trial of amrubicin versus topotecan as second - line treatment for sensitive ed - sclc was therefore conducted11 ( table 3 ) . seventy - six patients who had previously received platinum - based firstline chemotherapy were enrolled . all were sensitive cases , in which cr or pr had been observed with previous chemotherapy and the disease had then progressed or relapsed within at least 90 days of the final dose . amrubicin was administered intravenously at a dose of 40 mg / m on days 13 every three weeks . topotecan was administered intravenously at a dose of 1.5 mg / m on days 15 every three weeks . the response rate for amrubicin was 34% ( 95% ci 22%48% ) , and for topotecan was 4% ( 95% ci 1%19% ) . there was a trend towards a longer progression - free survival time in the amrubicin group ( 4.6 months , 95% ci 64187 ) than in the topotecan group ( 3.5 months , 95% ci 75177 ) . this study showed that amrubicin is also active in non - japanese patients and is well tolerated , with myelotoxicity being the main dose - limiting toxicity . inoue et al conducted a randomized phase ii trial comparing amrubicin with topotecan in not only sensitive relapsed but also refractory cases12 ( table 4 ) . sensitive cases were defined as cr or pr being achieved with the previous chemotherapy , after which the disease progressed or relapsed at least 90 days after the final dose . fifty - nine patients were randomized in a 1:1 ratio to receive either amrubicin or topotecan . amrubicin was administered intravenously at a dose of 40 mg / m on days 13 every three weeks . topotecan was administered intravenously at a dose of 1.0 mg / the response rate for amrubicin was 38% ( 95% ci 60%92% ) and for topotecan was 13% ( 95% ci 4%31% ) . in sensitive relapsed cases , the response rate for amrubicin was 53% ( 95% ci 28%77% ) , and for topotecan was 21% ( 95% ci 6%46% ) . in refractory relapsed cases , the response rate for amrubicin was 17% ( 95% ci 2%48% ) , and for topotecan was 0% ( 95% ci 0%28% ) . the median progression - free survival time with amrubicin was 3.5 months and with topotecan was 2.2 months . the median overall survival time with amrubicin was 8.1 months and with topotecan was 8.4 months . there was no difference in the frequency of hematologic toxicity more than grade 3 between amrubicin and topotecan . these studies show that amrubicin monotherapy is an encouraging regimen for second - line treatment of sclc . clinical investigation of the novel anticancer agent , amrubicin , has increased quickly , and there are high expectations for this agent in trials to improve the outcome for relapsed sclc patients . amrubicin is an active agent for the treatment of relapsed sclc , but because it is strongly myelotoxic , particular care should be taken with its use .
long - term survival is quite uncommon in refractory small cell lung cancer ( sclc ) patients , with less than 25% of patients with limited - stage disease and 1%2% of patients with extensive - stage disease remaining alive at five years . 
 recent clinical studies have demonstrated the promising efficacy of amrubicin for patients with relapsed sclc . 
 this review presents the results of clinical studies showing the efficacy and safety of amrubicin for the treatment of relapsed sclc . 
 amrubicin is a synthetic anthracycline agent with a similar structure to doxorubicin , in which the hydroxyl group at position 9 in amrubicin is replaced by an amino group to enhance efficacy . 
 it is converted to an active metabolite , amrubicinol , which is 554 times more active than amrubicin . 
 amrubicin and amrubicinol are inhibitors of dna topoisomerase ii , exerting their cytotoxic effects by stabilizing a topoisomerase ii - mediated cleavable complex . 
 the toxicity of amrubicin is similar to that of doxorubicin , although amrubicin shows almost no cardiotoxicity . in the relevant trials 
 , amrubicin was administered intravenously at a dose of 3540 mg / m2 on days 13 every three weeks . 
 the response rate was 34%52% and median survival times were 8.112.0 months . 
 common hematologic toxicities included neutropenia , leucopenia , anemia , thrombocytopenia , and febrile neutropenia . 
 nonhematologic adverse events included grade 34 anorexia , asthenia , hyponatremia , and nausea . 
 the results of the studies which demonstrated the efficacy of monotherapy for relapsed sclc involved mainly japanese patients . 
 therefore , it is necessary to conduct more clinical studies in non - japanese patients to confirm the efficacy of amrubicin .