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
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Abstract |
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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 02 and adequate organ function. Amrubicin was administered on days 13 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 III, small-cell lung cancer
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Introduction |
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Amrubicin (SM-5887) is a totally synthetic anthracycline and a potent topoisomerase II inhibitor [714
]. 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 10100 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 13 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.
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Patients and methods |
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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 13. Amrubicin was administered as an intravenous injection over 5 min and cisplatin was administered as a drip infusion over 60120 min with adequate hydration. At level 2 the dose of amrubicin was increased to 45 mg/m2 on days 13. Level 3 was planned with cisplatin 80 mg/m2 on day 1 and amrubicin 45 mg/m2 on days 13. 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 KaplanMeier 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].
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Results |
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Discussion |
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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 13 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 III 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 24, due to relatively severe myelotoxicity. We considered that amrubicin <35 mg/m2 on days 24 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 13 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.
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Acknowledgements |
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Received for publication September 2, 2004. Revision received October 14, 2004. Accepted for publication October 22, 2004.
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