Annals of Oncology Advance Access originally published online on January 14, 2005
Annals of Oncology 2005 16(3):430-436; doi:10.1093/annonc/mdi081
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2005 European Society for Medical Oncology
Phase I–II study of amrubicin and cisplatin in previously untreated patients with extensive-stage small-cell lung cancer
1 Department of Internal Medicine, National Cancer Center Hospital, Tokyo; 2 Department of Clinical Oncology, Osaka City General Hospital, Osaka; 3 Department of Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino, Osaka; 4 Department of Medical Oncology, Kinki University School of Medicine, Osakasayama, Osaka; 5 Department of Internal Medicine, Aichi Cancer Center Hospital, Nagoya, Aichi, 6 Department of Radiology, Hyogo Medical Center for Adults, Akashi, Hyogo; 7 Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba; 8 Department of Internal Medicine, National Hospital Organization Toneyama National Hospital, Toyonaka, Osaka; 9 Department of Internal Medicine, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai, Osaka; 10 Aichi Prefectural Hospital, Okazaki, Aichi, Japan
* Correspondence to: Dr Y. Ohe, Department of Internal Medicine, National Cancer Center Hospital 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Tel: +81-3-3542-2511; Fax: +81-3-3542-7006; Email: yohe{at}ncc.go.jp
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and methodsResultsDiscussionReferences |
|---|
Background: 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).
Patients and methods: 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.
Results: Four patients were enrolled at dose level 1 (amrubicin 40 mg/m2/day and cisplatin 60 mg/m2) and three patients at level 2 (amrubicin 45 mg/m2/day and cisplatin 60 mg/m2). 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.
Conclusions: The combination of amrubicin and cisplatin has demonstrated an impressive response rate and MST in patients with previously untreated ED-SCLC.
Key words: anthracycline, cisplatin, phase I–II, small-cell lung cancer
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Small-cell lung cancer (SCLC) is one of the most chemosensitive solid tumors, and the outcome of SCLC patients is slowly but surely improving. Combination chemotherapy consisting of cisplatin plus etoposide and concurrent twice-daily thoracic radiotherapy has yielded a 26% 5-year survival rate in limited-stage (LD) patients [1
]. Despite the high response rate to combination chemotherapy, however, local and distant failure is very common, especially in extensive-stage (ED) patients. Moreover, resistance to chemotherapeutic agents develops easily after failure of initial treatment. Thus, long-term survivors are still very rare among patients with ED-SCLC. To improve the outcome of SCLC patients, several strategies, such as high-dose chemotherapy, dose-intensive chemotherapy, alternating chemotherapy and introduction of new drugs, have been investigated [2–6]. However, only the introduction of new agents has improved the outcome of SCLC patients. Combination chemotherapy with etoposide plus cisplatin or etoposide plus cisplatin alternating cyclophosphamide, doxorubicin and vincristine had been mainly used for SCLC in North America. Recently, a Japanese trial [Japan Clinical Oncology Group (JCOG) 9511] demonstrated the superiority of the combination of irinotecan and cisplatin for ED-SCLC patients over the combination of etoposide and cisplatin [6]. The development of more active chemotherapy, and especially the introduction of effective new drugs, is therefore essential to improve the survival of SCLC patients.
Amrubicin (SM-5887) is a totally synthetic anthracycline and a potent topoisomerase II inhibitor [7–14]. It has antitumor activity, and is more potent than doxorubicin against various mouse experimental tumors and human tumor xenografts. Amrubicin and its 13-hydroxy metabolite, amrubicinol, inhibit purified human DNA topoisomerase II [11]. Amrubicinol is 10–100 times more cytotoxic than amrubicin [9]. The potent therapeutic activity of amrubicin is caused by the selective distribution of its highly active metabolite, amrubicinol, in tumors [9]. In an experimental animal model, amrubicin did not exhibit any chronic cardiotoxicity potential, and no deleterious effects on doxorubicin-induced cardiotoxicity in dogs was observed [14]. In a phase II study of amrubicin using a schedule of 45 mg/m2 on days 1–3 every 3 weeks, in 33 previously untreated ED-SCLC patients, an overall response rate of 76% and a complete response (CR) rate of 9% were reported [15]. Moreover, median survival time (MST) was 11.7 months in the single-agent phase II study of amrubicin. Amrubicin is one of the most active new agents for SCLC. Thus, we conducted a phase I/II study of amrubicin plus cisplatin for untreated ED-SCLC, because cisplatin is considered as one of the most important drugs in the treatment of SCLC. The aims of this trial were to determine the maximum-tolerated doses (MTD) of combination therapy of amrubicin with cisplatin, to assess the efficacy and safety for ED-SCLC at their recommended doses (RD), and to examine the pharmacokinetics of the drug combination.
|
Patients and methods |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Patient selection
Patients with histologically and/or cytologically documented SCLC were eligible for this study. Each patient was required to meet the following criteria: extensive-stage disease [16
]; no prior therapy for primary lesion; measurable lesion; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–2; expected survival time >2 months; age 20–74 years; adequate hematological function [white blood cell (WBC) count 4000–12 000/mm3, neutrophils 
2000/mm3, platelets 100 000/mm3, hemoglobin 10 g/dl]; adequate hepatic function [total bilirubin within 1.5x the upper limit of normal; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) within 2.5x the upper limit of normal]; adequate renal function (creatinine within the upper limit of normal); partial pressure of arterial oxygen 60 torr; no abnormality requiring treatment on electrocardiogram; left ventricle ejection fraction >60%; written informed consent. Patients with symptomatic brain metastasis, pleural effusion that required drainage, non-steroidal anti-inflammatory drug or glucocorticoid use for >50 days, pericarditis carcinomatous, active infection, varicella, superior vena cava syndrome, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), gastric and/or duodenal ulcer, severe heart disease, severe renal disease, active concomitant malignancy, symptomatic pneumonitis and/or pulmonary fibrosis and pregnant/nursing women were excluded. This study was approved by the Institutional Review Board at each hospital.
Patient evaluation
Pretreatment evaluation consisted of complete blood cell counts, differential, routine chemistry measurements, progastrin-releasing peptide (ProGRP), neuron-specific enolase, electrocardiogram, echocardiography, chest radiograph, chest and abdominal computed tomography (CT) scan, whole-brain magnetic resonance imaging (MRI) or CT scan, and isotope bone scan. Complete blood cell counts, differential and routine chemistry measurements were performed at least once a week during the chemotherapy.
Treatment schedule
At level 1, chemotherapy consisted of cisplatin 60 mg/m2 on day 1 and amrubicin 40 mg/m2 on days 1–3. Amrubicin was administered as an intravenous injection over 5 min and cisplatin was administered as a drip infusion over 60–120 min with adequate hydration. At level 2 the dose of amrubicin was increased to 45 mg/m2 on days 1–3. Level 3 was planned with cisplatin 80 mg/m2 on day 1 and amrubicin 45 mg/m2 on days 1–3. The chemotherapy was repeated every 3 weeks for four to six courses. Intrapatient dose escalation was not allowed. Administration of granulocyte colony-stimulating factor (G-CSF) was permitted prophylactically for patients expected to experience grade 3 neutropenia during the first course. Prophylactic administration of G-CSF was only permitted at second or later courses.
The administrations of both cisplatin and amrubicin were postponed if patients met the following criteria: WBC <3000/mm3; neutrophils <1500/mm3; platelets <100 000/mm3; AST and ALT >5x the upper limit of normal; total bilirubin >1.5x the upper limit of normal; creatinine >1.3x the upper limit of normal; ECOG PS 3 or 4; active infection; grade 2 or worse non-hematological toxicity, except for alopecia, anorexia, nausea, vomiting or fatigue.
The administrations of both cisplatin and amrubicin were withdrawn if patients met the following criteria: tumor regression <15% after first course or <30% after second course; WBC <3000/mm3; neutrophils <1500/mm3; platelets <100 000/mm3; no recovery from grade 3 or 4 non-hematological toxicity at 6 weeks after the start of previous chemotherapy; abnormality of electrocardiogram requiring treatment for more than 6 weeks; left ventricle ejection fraction <48%; treatment delay of >4 weeks.
The dose of amrubicin was decreased 5 mg/m2/day if patients met the following criteria: grade 4 leukopenia or neutropenia for 4 days; grade 3 neutropenia with fever; platelets <20 000/mm3 during the previous course. The dose of cisplatin was decreased to 75% if creatinine increased to >1.5x the upper limit of normal during the previous course.
The dose-limiting toxicity (DLT) was defined as follows: grade 4 leukopenia or neutropenia for 4 days; grade 3 febrile neutropenia; platelets <20 000/mm3; grade 3 or worse non-hematological toxicity except for nausea, vomiting, anorexia, fatigue, hyponatremia and infection. Initially, three patients were treated at each dose level. If DLT was not observed in any of the three patients, dose escalation was carried out. If DLT was observed in one of three patients, an additional three patients were entered at the same dose level. If DLT was observed in three or more of six patients, or two or three of the initial three patients, we considered that dose to be the MTD. If DLT was observed in one or two of six patients, dose escalation was also carried out. Dose escalation was determined based only on the data from the first course of chemotherapy.
Response and toxicity evaluation
Response was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) and tumor markers were excluded from the criteria [17]. CR was defined as the complete disappearance of all clinically detectable tumors for at least 4 weeks and no new lesions. Partial response (PR) was defined as at least a 30% decrease in the sum of the longest diameters of target lesion, taking as reference the baseline sum longest diameter, the required non-progression in non-target lesions and no new lesions for at least 4 weeks. Stable disease (SD) included: regression of target lesions insufficient to meet the criteria for PR, a <20% increase in the sum of the longest diameter of target lesion, taking as reference the smallest sum longest diameters recorded since the treatment started, the required non-progression in non-target lesions and no new lesions for at least 6 weeks. Progressive disease (PD) indicated a >20% increase in the sum of the longest diameters of target lesion, taking as reference the smallest sum longest diameter recorded since the treatment started and/or unequivocal progression of existing non-target lesions and/or appearance of new lesions. The evaluation of objective tumor response for all patients was performed by an external review committee.
Toxicity grading criteria of the National Cancer Institute Common Toxicity Criteria (version 2.0) was used for evaluation of toxicity.
Statistical analysis
This study was designed to reject response rates of 70% (P0) at a significance level of 0.05 (one-tailed) with a statistical power of 80% to assess the activity of the regimen as a 85% response rate (P1) at the recommended dose. The upper limit of rejection was 29 responses (CR + PR) among 37 evaluable patients. Overall survival was defined as the interval between the first administration of the drugs in this study and death or the last follow-up visit. Median overall survival was estimated using the Kaplan–Meier method [18].
Pharmacokinetic analysis
Pharmocokinetic analysis was performed in patients entering the phase I section of this study. One milliliter of the blood was taken from the patients before administration of amrubicin, and at 0 min, 15 min, 1, 2, 3, 4, 8 and 24 h after administration on days 1 and 3 in the first course of chemotherapy. Concentrations of amrubicin and its active metabolite, amrubicinol, in plasma and red blood cells were measured as reported elsewhere [9].
|
Results |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Patient characteristics
Between April 2001 and December 2002, 45 patients with ED-SCLC were enrolled and 44 were treated in this study (Table 1). One patient did not receive the protocol treatment because atrial fibrillation was observed just before administration on day 1 of the first course. All treated patients were assessed for response, survival and toxicity. The median age of the treated patients was 64.5 years (range 50–74). There were 36 males and eight females. Five patients had an ECOG PS 0 and 39 patients had PS 1. Only one patient received surgery for brain metastasis as a prior therapy.
|
MTD and DLT in the phase I study
Four patients were enrolled at dose level 1 (amrubicin 40 mg/m2 on days 1–3 and cisplatin 60 mg/m2 on day 1) and three patients at level 2 (amrubicin 45 mg/m2 on days 1–3 and cisplatin 60 mg/m2 on day 1). Toxicities in the phase I study are listed in Table 2. No DLT were observed during the first course of level 1. At level 2, grade 4 neutropenia for
4 days and febrile neutropenia occurred in one patient, and febrile neutropenia and grade 3 constipation occurred in another patient. Consequently, the MTD and RD were determined to be level 2 and level 1, respectively.
|
Pharmacokinetics of amrubicin and its active metabolite, amrubicinol
Pharmacokinetic parameters of amrubicin in plasma were almost identical on days 1 and 3 at the two dose levels (Table 3). No clear dose relationship in the area under the concentration–time curve (AUC) of amrubicin in the plasma was observed. The AUC of amrubicinol in red blood cells tended to increase on day 3 at both doses (Table 4). No clear dose relationship in the AUC of amrubicinol in red blood cells was observed. Combination with cisplatin did not alter the pharmacokinetics of amrubicin and amrubicinol (data not shown).
|
|
Treatment received in patients treated at the RD
Forty-one patients were treated at the RD: amrubicin 40 mg/m2 on days 1–3 and cisplatin 60 mg/m2 on day 1. Of 41 patients, 32 (78%) patients received more than three courses of chemotherapy, and 10 (31%) of these 32 patients needed dose reduction of amrubicin at the fourth course (Table 5). Of 41 patients, 22 (54%) patients completed four courses of chemotherapy without dose modification. The main cause of dose reduction was myelosuppression, especially leukopenia and neutropenia.
|
Objective tumor response and overall survival
The objective tumor responses are given in Table 6. Four CRs and 32 PRs occurred, for an objective response rate of 87.8% [95% confidence interval (CI) 73.8% to 95.9%] in 41 patients treated at the RD. The objective response rate for all 44 patients was 88.6% (95% CI 75.4% to 96.2%). The overall survival times of the 41 patients treated at the RD are shown in Figure 1. The MST of the 41 patients was 13.6 months (95% CI 11.1–16.6), with a median follow-up time for eight censored patients of 16.4 months (95% CI 14.2–18.8). The 1- and 2-year survival rates were 56.1% and 17.6%, respectively. The MST of all 44 patients was 13.8 months (95% CI 11.1–16.6). The 1- and 2-year survival rates of all 44 patients were 56.8% and 21.4%, respectively.
|
|
Toxicity in patients treated at the RD
The worst grades of hematological and non-hematological toxicities experienced by each patient are listed in Table 7. Hematological toxicity, especially leukopenia and neutropenia, was common and relatively severe. Grade 3 or worse leukopenia and neutropenia occurred in 65.9% and 95.1% of patients, respectively. Febrile neutropenia was observed in two patients at level 2. Grade 3 or worse anemia and thrombocytopenia occurred in 53.7% and 24.4% of patients, respectively. Four patients received platelet transfusions. Common non-hematological toxicities were gastrointestinal toxicity, such as anorexia, nausea, vomiting, constipation, diarrhea and stomatitis. Gastric ulcers developed in three patients. Hepatic and renal toxicity were not common in this study. Grade 3 or worse hyponatremia and hypokalemia occurred in 22% and 9.8% of patients, respectively. One patient developed myocardial infarction; however, cardiac toxicity was not common. No treatment-related deaths were observed.
|
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Doxorubicin and epirubicin are classified as active agents for SCLC, for which single-agent activity is a >20% response rate [19
]. Doxorubicin has been used as a constituent of combination therapy for SCLC in the CAV (cyclophospamide, doxorubicin and vincristine) and CAP (cyclophosphamide, doxorubicin and cisplatin) regimens. Epirubicin has shown 50% and 48% response rates in two clinical studies in 41 and 80 previously untreated patients, respectively, with ED-SCLC [20, 21]. However, currently, combination modalities containing doxorubicin or epirubicin are not being used in the therapy of SCLC, in preference to combination therapy with cisplatin and etoposide. Since amrubicin has shown excellent single-agent activity [15], it can be expected to be superior to other anthracyclines in the treatment of SCLC. Additionally, the present results of combination therapy with cisplatin support the view that amrubicin may be a promising agent that overcomes the therapeutic plateau of SCLC.
Amrubicin is one of the most promising new agents for the treatment of SCLC. In a previous phase II study of amrubicin 45 mg/m2 on days 1–3 every 3 weeks as a monotherapy for chemonaive ED-SCLC, a 76% overall response rate and 11.7 month MST were observed [15]. The overall response rate and MST were comparable to those achieved with standard combination chemotherapy, such as etoposide plus cisplatin [5, 6]. Moreover, only a few patients treated in the phase II study received salvage chemotherapy consisting of cisplatin and etoposide [15]. The major toxicity of amrubicin as a monotherapy was hematological toxicity: grade 4 leukopenia and neutropenia were seen in 12.1% and 39.4% of patients, respectively, and thrombocytopenia and anemia of grade 3 or worse in 21.2%. Hepatic, renal and cardiac toxicities with amrubicin were not common. Cisplatin is a key drug for the treatment of SCLC and its hematological toxicity, such as leukopenia and neutropenia, is not severe. Thus, we conducted a phase I–II study of amrubicin and cisplatin treatment for chemonaive ED-SCLC to determine the MTD of this combination therapy, to assess the efficacy and safety of the drugs delivered at their RD in chemonaive ED-SCLC, and to examine pharmacokinetics.
The topoisomerase I inhibitor, irinotecan, is also very effective for SCLC [6]. Combinations of topoisomerase I and topoisomerase II inhibitors, such as irinotecan plus etoposide, have been reported as active combination chemotherapy for SCLC [22]. Thus, combination of irinotecan and amrubicin is another candidate for new combination chemotherapy for SCLC. A phase I study of irinotecan and amrubicin for chemonaive non-SCLC was performed in National Cancer Center Hospital (unpublished data). However, the MTD was less than irinotecan 60 mg/m2 on days 1 and 8 and amrubicin 35 mg/m2 on days 2–4, due to relatively severe myelotoxicity. We considered that amrubicin <35 mg/m2 on days 2–4 with irinotecan 60 mg/m2 on days 1 and 8 was insufficient to treat SCLC.
In this study, we determined the RD to be amrubicin 40 mg/m2 on days 1–3 and cisplatin 60 mg/m2 on day 1 every 3 weeks, and 41 patients were treated at the RD. Main toxicities of this combination chemotherapy were myelosuppression, especially leukopenia and neutropenia, and gastrointestinal toxicities including anorexia, nausea, vomiting, constipation, diarrhea, stomatitis and gastric ulcer. Of 41 patients, 32 (78%) patients received four or more courses of chemotherapy, and 22 (54%) patients completed four courses of chemotherapy without dose modification. One patient developed myocardial infarction; however, other cardiac toxicity, including decrease in left ventricle ejection fraction, was not observed in up to six courses of chemotherapy. The total dose of amrubicin was 720 mg/m2. Grade 3 or 4 hyponatremia occurred in nine (22%) patients; however, most of the patients were asymptomatic. No unexpected toxicities and no treatment-related deaths were observed in this study. Toxicities observed in this study were manageable.
Four CRs and 32 PRs occurred, for an objective response rate of 87.8% (95% CI 73.8% to 95.9%) in 41 patients treated at the RD. In most patients, ProGRP levels changed in parallel with tumor responses. The MST of the 41 patients was 13.6 months, and the 1-year survival rate was 56.1%. These results were better than recently reported results for irinotecan and cisplatin in chemonaive ED-SCLC: an objective response rate of 84% and MST of 12.8 months [6]. The combination of amrubicin and cisplatin has demonstrated an impressive response rate and MST in patients with previously untreated ED-SCLC. A possible reason for the better results is overselection of patients, because we used unusual exclusion criteria such as non-steroidal anti-inflammatory drug or adrenal cortical steroid use for >50 days, and gastric and/or duodenal ulcer. However, in a phase II study, this kind of bias is not uncommon.
Combination chemotherapy with etoposide plus cisplatin or etoposide plus cisplatin, alternating with cyclophosphamide, doxorubicin and vincristine, had been considered as standard chemotherapy for SCLC in North America and Japan. A Japanese phase III trial (JCOG 9511) demonstrated that treatment with four cycles of irinotecan plus cisplatin every 4 weeks yielded a highly significant improvement in survival in ED-SCLC patients over standard etoposide plus cisplatin, with less myelosuppression [6]. Based on the results of the JCOG 9511 trial, irinotecan plus cisplatin is considered to be the reference chemotherapy arm for ED-SCLC in future trials in Japan [23]. The JCOG are preparing a phase III clinical trial of amrubicin and cisplatin for previously untreated ED-SCLC to compare combination therapy of irinotecan with cisplatin.
|
Acknowledgements |
|---|
This study was supported by Sumitomo Pharmaceuticals Co., Ltd., Osaka, Japan. Previously presented in part at the Annual Meetings of the American Society of Clinical Oncology, Chicago, IL, 31 May to 3 June 2003 and New Orleans, LA, 5–8 June 2004.
Received for publication September 2, 2004. Revision received October 14, 2004. Accepted for publication October 22, 2004.
|
References |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
1. Turrisi A, Kim K, Blum R et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999; 340: 265–271.
2. Armitage JO. Bone marrow transplantation. N Engl J Med 1994; 330: 827–838.
3. Furuse K, Fukuoka M, Nishiwaki Y et al. Phase III study of intensive weekly chemotherapy with recombinant human granulocyte colony-stimulating factor versus standard chemotherapy in extensive-disease small-cell lung cancer. J Clin Oncol 1998; 16: 2126–2132.[Abstract]
4. Murray N, Livingston RB, Shepherd FA et al. Randomized study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: an Intergroup Study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group. J Clin Oncol 1999; 17: 2300–2308.
5. Fukuoka M, Furuse K, Saijo N et al. Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer. J Natl Cancer Inst 1991; 83: 855–861.
6. Noda K, Nishiwaki Y, Kawahara M et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 2002; 346: 85–91.
7. Ohe Y, Nakagawa K, Fujiwara Y et al. In vitro evaluation of the new anticancer agents KT6149, MX-2, SM5887, menogaril, and liblomycin using cisplatin- or adriamycin-resistant human cancer cell lines. Cancer Res 1949; 49: 4098–4102.
8. Noguchi T, Ichii S, Morisada S et al. In vivo efficacy and tumor-selective metabolism of amrubicin to its active metabolite. Jpn J Cancer Res 1998; 89: 1055–1060.[CrossRef][ISI][Medline]
9. Noguchi T, Ichii S, Morisada S et al. Tumor-selective distribution of an active metabolite of the 9-aminoanthracycline amrubicin. Jpn J Cancer Res 1998; 89: 1061–1066.[CrossRef][ISI][Medline]
10. Yamaoka T, Hanada M, Ichii S et al. Cytotoxicity of amrubicin, a novel 9-aminoanthracycline, and its active metabolite amrubicinol on human tumor cells. Jpn J Cancer Res 1998; 89: 1067–1073.[CrossRef][ISI][Medline]
11. Hanada M, Mizuno S, Fukushima A et al. A new antitumor agent amrubicin induces cell growth inhibition by stabilizing topoisomerase II-DNA complex. Jpn J Cancer Res 1998; 89: 1229–1238.[CrossRef][ISI][Medline]
12. Yamaoka T, Hanada M, Ichii S et al. Uptake and intracellular distribution of amrubicin, a novel 9-amino-anthracycline, and its active metabolite amrubicinol in P388 murine leukemia cells. Jpn J Cancer Res 1999; 90: 685–690.[CrossRef][ISI][Medline]
13. Obara N, Imagawa S, Nakano Y et al. Hematological aspects of a novel 9-aminoanthracycline, amrubicin. Cancer Sci 2003; 94: 1104–1106.[CrossRef][Medline]
14. Noda T, Watanabe T, Kohda A et al. Chronic effect of a novel synthetic anthracycline derivative (SM-5887) on normal heart and doxorubicin-induced cardiomyopathy in beagle dogs. Invest New Drugs 1998; 16: 121–128.[CrossRef][ISI][Medline]
15. Yana T, Negoro S, Takada Y et al. Phase II study of amrubicin (SM-5887), a 9-amino-anthracycline, in previously untreated patients with extensive stage small-cell lung cancer (ES-SCLC): a West Japan Lung Cancer Group trial. Proc Am Soc Clin Oncol 1998; 17: 450a.
16. Stahel RA, Ginsberg R, Havemann K et al. Staging and prognostic factors in small cell lung cancer: a consensus report. Lung Cancer 1989; 5: 119–126.[CrossRef]
17. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 200; 92: 205–216.
18. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.[CrossRef][ISI]
19. Grant SC, Gralla RJ, Kris MG et al. Single-agent chemotherapy trials in small-cell lung cancer, 1970 to 1990: the case for studies in previously treated patients. J Clin Oncol 1992; 10: 484–494.
20. Blackstein M, Eisenhauer EA, Weirzbicki R et al. Epirubicin in extensive small-cell lung cancer: a phase II study in previously untreated patients: A National Cancer Institute of Canada Clinical Trials Group study. J Clin Oncol 1990; 8: 385–389.[Abstract]
21. Eckhardt S, Kolaric K, Vukas D et al. Phase II study of 4'-epi-doxorubicin in patients with untreated, extensive small cell lung cancer. Med Oncol Tumor Pharmacother 1990; 7: 19–23.[ISI][Medline]
22. Masuda N, Matsui K, Negoro S et al. Combination of irinotecan and etoposide for treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 1998; 16: 3329–3334.[Abstract]
23. Ohe Y, Saijo N. Results of recent Japanese clinical trials in lung cancer. Clin Lung Cancer 2002; 3: 243–248.[Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Onoda, N. Masuda, T. Seto, K. Eguchi, Y. Takiguchi, H. Isobe, H. Okamoto, T. Ogura, A. Yokoyama, N. Seki, et al. Phase II Trial of Amrubicin for Treatment of Refractory or Relapsed Small-Cell Lung Cancer: Thoracic Oncology Research Group Study 0301 J. Clin. Oncol., December 1, 2006; 24(34): 5448 - 5453. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Ikeda, R. Maruyama, T. Okamoto, F. Shoji, H. Wataya, and Y. Ichinose Phase I Study of Amrubicin Hydrochloride and Cisplatin in Patients Previously Treated for Advanced Non-small Cell Lung Cancer Jpn. J. Clin. Oncol., January 1, 2006; 36(1): 12 - 16. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||