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Phase II trial of amrubicin and carboplatin in patients with sensitive or refractory relapsed small-cell lung cancer
Lung Cancer 73 (2011) 345–350
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Phase II trial of amrubicin and carboplatin in patients with sensitive or refractory relapsed small-cell lung cancer Takashi Hirose a,∗ , Masanao Nakashima a , Takao Shirai a , Sojiro Kusumoto a , Tomohide Sugiyama a , Toshimitsu Yamaoka a , Kentaro Okuda a , Tsukasa Ohnishi a , Tohru Ohmori b , Mitsuru Adachi a a b
Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8666, Japan Institute of Molecular Oncology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8666, Japan
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Article history: Received 9 August 2010 Received in revised form 25 September 2010 Accepted 25 December 2010 Keywords: Amrubicin Carboplatin Phase II trial Refractory relapsed Sensitive relapsed Small-cell lung cancer
a b s t r a c t Amrubicin is a novel, totally synthesized anthracycline derivative, and has antitumor activity against several human tumor xenografts. The combination of amrubicin with platinum derivative showed additive effect against a human small-cell lung cancer (SCLC) cell line. Until now, the combination of amrubicin plus carboplatin has not been studied in patients with previously treated SCLC. Therefore, we examined the safety and efficacy of the combination of amrubicin plus carboplatin in patients with sensitive or refractory relapsed SCLC. Patients with previously treated SCLC were eligible if they had a performance status of 2 or less, were 75 years or younger, and had adequate organ function. Twenty-five patients were enrolled (21 men and 4 women; median age, 65 years; age range 55–73 years). Patients received the combination of amrubicin (30 mg/m2 on days 1–3) plus carboplatin (with a target area under the concentration-versus-time curve of 4 mg min/ml using the Calvert formula on day 1) every 3 weeks. The overall response rate was 36.0% (95% confidence interval [CI], 18.0–57.5%). Response rates differed significantly between patients with sensitive relapse (58.3%; 95% CI, 27.7–84.8%) and those with refractory relapse (15.4%; 95% CI, 1.9–15.4%; p = 0.03). The median survival time (MST) from the start of this treatment was 7 months (range: 1–42 months); the MST of patients with sensitive relapse (10 months) was significantly longer than that of patients with refractory relapse (5 months: p = 0.004). The median progression-free survival (PFS) time was 3 months (range: 1–14 months): the median PFS time of patients with sensitive relapse (5 months) was significantly longer than that of patients with refractory relapse (2 months; p = 0.01). The most frequent grade 3–4 toxicity was myelosuppression, especially neutropenia, which developed in 88% of patients. Grade 3–4 thrombocytopenia developed in 44% of patients, and anemia developed in 56%. Nonhematologic toxicities were generally mild to moderately severe and temporary. None of the patients had cardiotoxicity. In conclusion, this therapy is effective and well tolerated for previously treated SCLC. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Most patients with small-cell lung cancer (SCLC) show favorable responses to first-line chemotherapy. However, SCLC often recurs during the subsequent 2 years: the 2-year cumulative relapse rate is 75% in patients with limited disease (LD) and nearly 100% in patients with extensive disease (ED) [1]. The prognosis of patients who have relapsed SCLC and do not receive additional therapy is extremely poor: expected survival is 2–4 months [2]. On the other hand, some patients are still good candidates for second-line chemotherapy, because they maintain a good performance status (PS) and have adequate organ function despite relapse.
∗ Corresponding author. Tel.: +81 3 3784 8532; fax: +81 3 3784 8742. E-mail address: [email protected] (T. Hirose). 0169-5002/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2010.12.015
In a phase III trial for patients with SCLC that relapsed more than 60 days after completion of first-line chemotherapy, i.e. sensitive relapse, topotecan achieved an equivalent response rate (24% versus 18%) and median survival time (MST) after relapse (25.0 weeks versus 24.7 weeks) to those of the 3-drug combination of cyclophosphamide, doxorubicin, and vincristine and also achieved higher quality of life scores and better symptom control [3]. As a result of this phase III trial, topotecan has been approved by the United States Food and Drug Administration for patients with relapsed SCLC. However, the efficacy of topotecan has not been satisfactory. Therefore, a more effective chemotherapy regimen is urgently needed for relapsed SCLC. Amrubicin is a novel, totally synthesized anthracycline derivative that is structurally distinguishable from doxorubicin due to an amino group at position 9 and its unique sugar moiety [4]. The potent therapeutic activity of amrubicin is attributed to the selective distribution of its highly active 13-hydroxy metabolite,
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amrubicinol, in tumors [5]. The catatonic activity of amrubicinol in vitro is 18–220 times as great as that of its parent compound amrubicin [5]. The inhibitory effects of amrubicin and amrubicinol on cell growth appear to be primarily related to the inhibition of DNA topoisomerase II, although anthracyclines have been reported to have diverse molecular effects, such as DNA intercalation, inhibition of topoisomerase II, and stabilization of topoisomerase II alpha cleavable complexes [6]. Amrubicin has greater antitumor activity than does doxorubicin against several human tumor xenografts implanted in nude mice [7]. In addition, amrubicin does not induce cardiotoxicity or exacerbate doxorubicin-induced cardiotoxicity in dogs or rabbits [8,9]. In two phase II trials of 40 mg/m2 of amrubicin alone on days 1–3 in patients with sensitive or refractory relapsed SCLC, overall response rates were 38% and 52% and MSTs were 8.1 months and 11.2 months [10,11]. The combination of amrubicin with cisplatin showed additive effect against a human SCLC cell line [12]. In a phase II study of amrubicin plus cisplatin for untreated ED-SCLC, the response rate was 87.8%, the MST was 13.6 months, and the 1-year survival rate was 56.1% at the recommended dose (RD) of 40 mg/m2 of amrubicin on days 1–3 and 60 mg/m2 of cisplatin on day 1 [13]. On the other hand, in a phase I study of amrubicin plus carboplatin for patients 70 year or older with previously untreated SCLC, the RD of amrubicin and carboplatin were determined to be 35 mg/m2 and the target area under the concentration versus time curve (AUC) of 4 mg min/ml [14]. To the best of our knowledge, the combination of amrubicin plus carboplatin has not been studied in patients with sensitive or refractory relapsed SCLC. Therefore, we performed a phase II study to assess the antitumor activity and toxicity of the combination of amrubicin plus carboplatin in patients with sensitive or refractory relapsed SCLC. 2. Patients and methods 2.1. Eligibility criteria Patients with previously treated SCLC were enrolled. The criteria for study entry were as follows: (1) histologically or cytologically confirmed SCLC; (2) age 75 years or less; (3) Eastern Cooperative Oncology Group PS of 2 or less; (4) measurable or assessable lesions; (5) life expectancy of at least 8 weeks; (6) adequate bone marrow function (white blood cell [WBC] count from 4000/ul or more, neutrophil count of 2000/ul or more, platelet count of 100,000/ul or more, and hemoglobin level of 9 g/dl or more), hepatic function (total serum bilirubin level less than the upper limit of the normal range, levels of aspartate aminotransferase and alanine aminotransferase less than or equal to twice the upper limits of the normal ranges), and renal function (serum creatinine level less than 1.5 mg/dl, creatinine clearance rate of 50 ml/min or more), and arterial oxygen pressure of 60 mmHg or more. Patients were excluded if they had prior amrubicin treatment, pulmonary fibrosis, uncontrolled diabetes mellitus, severe heart disease, active infection, symptomatic brain metastasis, or active second malignancy. The study protocol was approved by the institutional review board of the Showa University School of Medicine, and all patients provided written informed consent. 2.2. Treatment schedule Carboplatin (target AUC, 4 mg min/ml) was diluted in 500 ml of normal saline and given over 30 min as an intravenous drip infusion after the amrubicin infusion on day 1. The carboplatin dose was calculated with Calvert’s formula and the 24-hour creatinine clearance rate. Amrubicin was diluted in 20 ml normal saline and given
intravenously as a 5-min infusion on days 1–3. This chemotherapy regimen was repeated every 3 weeks for maximum of 4 courses. Prophylactic antiemetic treatment with ondansetron and dexamethasone were routinely given to all patients before carboplatin. Palliative radiotherapy was permitted to control persistent pain associated with bone metastasis. The first 4 patients were treated every 3 weeks with carboplatin (target AUC, 4 mg min/ml on day 1) plus amrubicin (35 mg/m2 on days 1–3) according to the above phase I study [14]. However, the amrubicin dosage had to be reduced in all 4 patients who were treated with this dosage because of grade 4 neutropenia lasting 3 days or longer in 4 patients and grade 4 thrombocytopenia in 3 patients. Thus, we decreased the amrubicin dosage from 35 to 30 mg/m2 . Chemotherapy was discontinued for grade 3 or higher nonhematologoic toxicity, except for nausea/vomiting, anorexia, constipation, alopecia, and fatigue at any time, or if the treatment outcome was progressive disease at any time. If 2 or more weeks had passed after the scheduled start of the next course until these criteria were satisfied, the patient left the study at that time but was still included in the analysis. The next course of treatment was started when the neutrophil count returned to 1500/l, the platelet count returned to 75,000/l, and nonhematologoic toxicity decreased to grade 2 or less. The amrubicin dosage was reduced by 5 mg/m2 if the patient had grade 4 leukopenia or neutropenia lasting 3 days or longer, grade 4 thrombocytopenia or had received a platelet transfusion for grade 3 thrombocytopenia, or if day 2 or 3 of the previous course had been omitted because of severe toxicity. The carboplatin dosage was reduced by 1 mg min/ml if the patient had grade 4 thrombocytopenia or had received a platelet transfusion for grade 3 thrombocytopenia. If the leukopenia or neutropenia had developed grade 3 or 4 after chemotherapy, granulocyte colony-stimulating factor (G-CSF) was administered until the WBC and the neutrophil count recovered, according to the guideline of the Japanese Ministry of Health, Labour and Welfare.
2.3. Evaluation Evaluation before treatment included a baseline history and physical examination, complete blood count with differential, routine chemistry profiles, chest radiography, computed tomography (CT) of the chest and abdomen, magnetic resonance (MR) or CT of the brain, and radionucleotide bone scan. Complete blood counts with differential and routine chemistry profiles were determined at least once a week during chemotherapy. Chest radiography was performed once per week during chemotherapy. Electrocardiograms were obtained before and after chemotherapy. The disease was categorized according to the response to firstline therapy as sensitive relapse or refractory relapse. A refractory relapse was defined as radiographically documented progression as best response to first-line chemotherapy, radiographically documented response or stable disease with subsequent progression during continued chemotherapy, or relapse within 3 months after the completion of first-line chemotherapy. A sensitive relapse was diagnosed when the SCLC relapsed more than 3 months after the completion of first-line chemotherapy. Tumor response was classified according to Response Evaluation Criteria in Solid Tumors (RECIST) Guideline version 1.0 [15]. Toxicities were assessed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. All patients who had received at least 1 cycle of chemotherapy were assessable for response, toxicity, and survival.
T. Hirose et al. / Lung Cancer 73 (2011) 345–350 Table 1 Patient characteristics. Total number of patients Sex (M/F) Age, years (range) Performance status at relapse (0/1/2) Stage at diagnosis (LD/ED) Status at relpase Sensitive Refractory Number of previous chemotherapy regimens (1/2/3) Previous chemotherapy Cisplatin + etoposide Cisplatin + irinotecan Carboplatin + etoposide Carboplatin + irinotecan Response to previous chemotherapy Complete response Partial response Stable disease Progressive disease
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Table 2 Response rate. 25 21/4 65 (55–73) 3/16/6 7/18 12 13 22/2/1 8 5 2 10 5 14 1 5
2.4. Statistical methods The trial was designed as a phase II study, with response rate as the main endpoint. According to the Simons minimax design, our study, with a sample size of 22, had 90% power to accept the hypothesis that the true response rate was greater than 60% and had 5% significance to reject the hypothesis that the true response rate was less than 30%. Progression free survival (PFS) was defined as the period from the start of this treatment to the identifiable time for the first progression or death from any cause. Survival time was measured from the start of the present treatment until death or last follow-up. The Kaplan–Meier method was used to construct survival curves. Survival differences between subgroups were compared by means of the log-rank test. The chi-square test was used to determine the significance of differences between means. Differences with a p-value < 0.05 were considered statistically significant.
Complete response Partial response Stable disease Progressive disease
Sensitive relapse (n = 12)
Refractory relapse (n = 13)
Total
Number
%
Number
%
Number
%
2 5 2 3
16.7 41.7 16.7 25.0
0 2 1 10
0.0 15.4 7.7 76.9
2 7 3 13
8.0 28.0 12.0 52.0
3.2. Treatment response and survival The overall response rate was 36.0% (95% confidence interval [CI], 18.0–57.5%; Table 2). Response rates differed significantly between patients with sensitive relapse (58.3%; 95% CI, 27.7–84.8%) and patients with refractory relapse (15.4%; 95% CI, 1.9–15.4%; p = 0.03). Response rates did not differ significantly between patients who had received a previous regimen including carboplatin or etoposide, which is topoisomerase II inhibitor, and those who had not. The disease control rate was 48.0% (95% CI, 27.8–68.7%; Table 2). Disease control rates differed significantly between patients with sensitive relapse (75.0%; 95% CI l, 42.8–94.5%) and patients with refractory relapse (23.1%; 95% CI, 5.0–53.8%; p = 0.01). Survival analysis was performed when the median follow-up time from the start of this treatment in all evaluable patients was 7 months. At the time of analysis, 2 patients (8%) are alive, and no patient has been lost to follow-up. The overall MST from the start of this treatment was 7 months (range 1–42 months, Fig. 1); the MST of patients with sensitive relapse (10 months) was significantly longer than that of patients with refractory relapse (5 months: p = 0.004). The overall median PFS from the start of this treatment was 3 months (range 1–14 months, Fig. 2): the median PFS of patients with sensitive relapse (5 months) was significantly longer than that of patients with refractory relapse (2 months; p = 0.01). 3.3. Toxicity
3. Results 3.1. Patients characteristics From July 2005 through April 2009, 29 patients were enrolled, but the first 4 patients who were treated with the dosage of 35 mg/m2 of amrubicin on days 1–3 and an AUC of 4 mg min/ml of carboplatin on day 1 were excluded from analysis. Response, toxicity, and survival could be assessed in remaining 25 enrolled patients (Table 1). Of the 25 patients, 6 (24%) had a PS of 2 at relapse. Three patients (12%) had LD, and 22 patients (88%) had ED at relapse. Twelve patients (48%) had sensitive relapse, and 13 patients (52%) had refractory relapse. All 3 patients who received more than 1 prior therapy had refractory relapse. Ten patients (40%) had received thoracic irradiation with previous chemotherapy. The median time off chemotherapy to the present treatment was 3 month (range 0.5–27 months). After the protocol treatment, 15 (60%) patients received subsequent chemotherapy: 8 patients received 1 regimen, 5 patients received 2 regimens, 1 patient received 3 regimens, and 1 patient received 4 regimens. Regimens used in subsequent chemotherapy were as follows: carboplatin plus irinotecan (5 patients), carboplatin plus etoposide (5 patients), etoposide alone (3 patients), cisplatin plus irinotecan (2 patients), cisplatin plus etoposide (2 patients), irinotecan alone (2 patients), topotecan alone (2 patients), amrubicin alone (1 patient), carboplatin plus topotecan (1 patient), and carboplatin plus paclitaxel (1 patient).
A total of 75 courses of chemotherapy were given. The median number of courses given per patients was 3.5 (range 1–4). Table 3 lists the maximum toxicities experienced during treatment. The most frequent grade 3–4 toxicity was myelosuppression, especially neutropenia, which developed in 88% of patients. However, the median duration of grade 4 neutropenia was only 4 days (range 2–9 days). Additionally, the incidence of grade 3 or 4 infection was only
Fig. 1. Overall survival from the start of this treatment estimated with the Kaplan–Meier method. The median survival time was 7 months (range 1–42 months).
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4. Discussion
Fig. 2. Progression-free survival from the start of this treatment estimated with the Kaplan–Meier method. The median length of progression-free survival was 3 months (range 1–14 months).
8% or 0%: 1 patient (4%) had febrile neutropenia and 1 patient (4%) had pneumonia without neutropenia. No patient had sepsis. G-CSF support was given during 68% of the 75 courses (median duration of administration, 4 days; range 1–13 days). Grade 3–4 thrombocytopenia developed in 44% of patients, and anemia developed in 56%. Seven patients received platelet transfusions, and 6 patients received erythrocyte transfusions. However, no patients had severe bleeding episodes or anemia-related episodes. Additionally, thrombocytopenia and anemia resolved quickly after transfusions. Nonhematologic toxicities were generally mild to moderately severe and temporary. No patients had grade 3–4 nausea and vomiting or diarrhea. None of the patients had cardiotoxicity. There were no treatment-related deaths. 3.4. Dose intensity Owing to toxicity, doses of both amrubicin and carboplatin were reduced in 4 patients: because of grade 4 thrombocytopenia in 2 patients and platelet transfusions for grade 3 thrombocytopenia in 2 patients. In addition, the doses of amrubicin alone were reduced in 6 patients: because of grade 4 neutropenia lasting 3 days or longer in 5 patients and because of grade 3 infection in 1 patient. A total of 16 courses were delayed, mostly because of neutropenia or thrombocytopenia. The mean individual doses of amrubicin and carboplatin actually delivered were 26.9 mg/m2 (89.7% of planned) and 3.64 mg min/ml (91.0% of planned), respectively. Table 3 Toxicity. National Cancer Institute-Common Terminology Criteria grade Toxicity Leukopenia Neutropenia Thrombocytopenia Anemia Nausea Vomiting Anorexia Stomatitis Diarrhea Constipation Infection Elevation of serum creatinine Elevation of aminotransferases Abnormality of potassium Hyponatremia Fatigue or asthenia
1 0 2 1 1 5 3 8 2 2 10 3 5 8 8 12 10
2 2 0 9 10 1 1 4 0 1 3 2 1 4 2 0 0
3 12 4 3 9 0 0 1 2 0 1 2 0 1 1 2 0
4 11 18 8 5 0 0 0 0 0 0 0 0 0 0 1 0
3/4 (%) 92 88 44 56 0 0 4 8 0 4 8 0 4 4 12 0
Before new drugs, such as topotecan and amrubicin, were introduced, second-line chemotherapy usually did not prolong survival in patients with SCLC: MSTs after relapse were only 2.5–3.9 months [2]. Huisman et al. [16] have summarized 21 phase II studies and 3 randomized trials reported from 1989 through 1999 of second-line chemotherapy in patients with SCLC. They found cumulative response rates of 21% (range 4.5–88.2%) for multidrug regimens and 19% (range 2.4–47%) for single agents. Topotecan or re-treatment with the same regimen used for first-line chemotherapy is a standard treatment for patients with sensitive relapsed SCLC. However, the efficacy has not been satisfactory. Additionally, because the combination of irinotecan and cisplatin is one of the standard regimens for patients with previously untreated ED-SCLC, especially in Japan [17], second-line treatment with topotecan might be inappropriate for many patients with ED-SCLC because both topotecan and irinotecan are camptothecin analog. Moreover, there are no standard treatments for refractory relapsed SCLC. Furthermore, there is no clinical evidence to suggest that combination chemotherapy regimens are superior to single-agent regimens for relapsed SCLC. Therefore, further research should focus on the development of regimens that are more effective against sensitive or refractory relapsed SCLC. The function of the kidneys or other organs decreases in previously treated patients. These decreases in function directly affect the tolerability of systemic chemotherapy for previously treated patients. Carboplatin has less renal, neurologic, and gastrointestinal toxicity and is easier to administer than cisplatin [18]. Additionally, carboplatin is one of the most active drugs against SCLC, and as a single agent, has achieved a 56% overall response rate in previously untreated patients [19]. In a phase III study in patients with previously untreated SCLC, the combination of carboplatin plus etoposide achieved response and survival rates similar to those of cisplatin plus etoposide but was significantly less toxic [20]. Thus, we believe carboplatin is more appropriate than cisplatin for previously treated patients who had several organs with lower functional reserve. In a phase I study of amrubicin plus carboplatin for patients with previously untreated SCLC who were 75 years or younger and had a PS of 0 or 1, the RD of amrubicin was determined to be 35 mg/m2 on days 1–3, and the AUC of carboplatin was 5 mg min/ml on day 1 [21]. On the other hand, in a phase I study of amrubicin plus carboplatin for patients with previously untreated SCLC who were 70 years or older and had a PS of 0 or 1, the RD of amrubicin was determined to be 35 mg/m2 on days 1–3 and the AUC of carboplatin was 4 mg min/ml on day 1 [14]. Because both elderly patients and previously treated patients have lower reserves of organ function than do younger and previously untreated patients, we chose the dosage of 35 mg/m2 of amrubicin on days 1–3 and an AUC of 4 mg min/ml of carboplatin on day 1. However, the amrubicin dosage had to be reduced in all 4 patients who were treated with this dosage because of grade 4 neutropenia lasting 3 days or longer in 4 patients and grade 4 thrombocytopenia in 3 patients. We considered this dosage to be too toxic for previously treated patients. Thus, we decreased the amrubicin dosage from 35 to 30 mg/m2 . Okamoto et al. have recommended an amrubicin dosage of 35 mg/m2 on days 1–3 as a single agent for patients with previously treated lung cancer [22]. Therefore, we believe our decision to decrease the amrubicin dosage was appropriate. In several recent trials of second-line chemotherapy in patients with SCLC, the overall response rates have ranged from 7% to 73%, disease control rates have ranged from 29% to 79%, and MSTs after relapse have ranged from 6.1 to 11.7 months [3,10,11,23–26]. In the present study, the overall response rate was 36%, the disease
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control rate was 48%, and the MST after relapse was 7 months. Our results compare favorably with those of recent trials in patients with sensitive or refractory relapsed SCLC. However, response rates and survival times after relapse in the present study were less than [10] or equivalent to [11] those in previous studies of amrubicin used as a single agent. These differences may be due to differences in patient characteristics or other confounding variables. The outcome of second-line treatment in SCLC depends on several factors, including whether the relapse is sensitive or refractory, the interval since the completion of previous chemotherapy, the cytotoxic drugs used for previous therapy, the extent of disease at relapse, and the PS [2,16]. In the present study, 24% of patients had a PS of 2 at relapse, and the median time off chemotherapy before this treatment was only 3 months. In our patients with sensitive relapse, the response rate of 58.3%, the disease control rate of 75%, and the MST after relapse of 10 months were equivalent to those in previous studies: response rates have ranged from 18% to 77%, disease control rates have ranged from 29% to 88%, and MSTs after relapse have ranged from 6 to 11.7 months [3,10,11,23–26]. Additionally, in our patients with refractory relapse the response rate of 15.4%, the disease control rate of 23.1%, and the MST after relapse of 5 months were also equivalent to those in previous studies: response rates have ranged from 0% to 70%, disease control rates have ranged from 18% to 68%, and MSTs after relapse have ranged from 5.3 to 10.3 months [3,10,11,23–27]. Moreover, because few single agents have consistently achieved response rates greater than 10% in patients with refractory relapse [28], our regimen could be an attractive option. In the present study the most frequent toxicity was myelosuppression, especially neutropenia. Grade 3–4 hematologic toxicities included neutropenia in 88% of patients, thrombocytopenia in 44%, and anemia in 56%. Previous studies have also found that the principle toxicity of amrubicin, alone, or in combination with platinum derivatives, is myelosuppression [10,11,13,21,22,27,29]. In phase II studies of amrubicin alone in patients with previously treated SCLC, rates of grade 3–4 neutropenia, thrombocytopenia, and anemia were 67–93%, 20–41%, and 21–33% of patients, respectively [10,11,27]. In addition, in a phase II study of amrubicin plus carboplatin for elderly patients with previously untreated SCLC, grade 3–4 neutropenia, thrombocytopenia, and anemia developed in 97%, 28%, and 28% of patients, respectively [29]. However, in our study, all cases of myelosuppression were manageable, and the incidence of grade 3 or 4 infection was only 8% or 0%, respectively. Additionally, these rates of toxicity compare favorably with those in most recent trials in patients with previously treated SCLC. Rates of grade 3–4 neutropenia, thrombocytopenia, and anemia in recent trials were 48.8–93%, 14.9–57.6%, and 5.9–42.3%, respectively [3,23–26]. Nonhematologic toxicities in the present study were generally mild to moderately severe. Moreover, cardiotoxicity was not observed, which is consistent with results of previous clinical trials and postmarketing surveillance. Furthermore, the delivered dose intensities for amrubicin and carboplatin were 89.7% and 91.0%, respectively. When we consider the lower bone marrow reserves in previously treated patients, the dose intensities in our study do not seem too low. In conclusion, to the best of our knowledge, the present phase II study is the first to examine the combination of amrubicin plus carboplatin for sensitive or refractory relapsed SCLC. This regimen is a safe and effective treatment for patients with previously treated SCLC, especially those who have had sensitive relapse. Therefore, this treatment could be an acceptable option in patients with previously treated SCLC. However, our results were not superior to those of the studies of amrubicin used as a single agent for previously treated SCLC. In the future, the search for more active regimens should be continued.
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Phase II trial of amrubicin and carboplatin in patients with sensitive or refractory relapsed small-cell lung cancer Takashi Hirose a,∗ , Masanao Nakashima a , Takao Shirai a , Sojiro Kusumoto a , Tomohide Sugiyama a , Toshimitsu Yamaoka a , Kentaro Okuda a , Tsukasa Ohnishi a , Tohru Ohmori b , Mitsuru Adachi a a b
Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8666, Japan Institute of Molecular Oncology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8666, Japan
a r t i c l e
i n f o
Article history: Received 9 August 2010 Received in revised form 25 September 2010 Accepted 25 December 2010 Keywords: Amrubicin Carboplatin Phase II trial Refractory relapsed Sensitive relapsed Small-cell lung cancer
a b s t r a c t Amrubicin is a novel, totally synthesized anthracycline derivative, and has antitumor activity against several human tumor xenografts. The combination of amrubicin with platinum derivative showed additive effect against a human small-cell lung cancer (SCLC) cell line. Until now, the combination of amrubicin plus carboplatin has not been studied in patients with previously treated SCLC. Therefore, we examined the safety and efficacy of the combination of amrubicin plus carboplatin in patients with sensitive or refractory relapsed SCLC. Patients with previously treated SCLC were eligible if they had a performance status of 2 or less, were 75 years or younger, and had adequate organ function. Twenty-five patients were enrolled (21 men and 4 women; median age, 65 years; age range 55–73 years). Patients received the combination of amrubicin (30 mg/m2 on days 1–3) plus carboplatin (with a target area under the concentration-versus-time curve of 4 mg min/ml using the Calvert formula on day 1) every 3 weeks. The overall response rate was 36.0% (95% confidence interval [CI], 18.0–57.5%). Response rates differed significantly between patients with sensitive relapse (58.3%; 95% CI, 27.7–84.8%) and those with refractory relapse (15.4%; 95% CI, 1.9–15.4%; p = 0.03). The median survival time (MST) from the start of this treatment was 7 months (range: 1–42 months); the MST of patients with sensitive relapse (10 months) was significantly longer than that of patients with refractory relapse (5 months: p = 0.004). The median progression-free survival (PFS) time was 3 months (range: 1–14 months): the median PFS time of patients with sensitive relapse (5 months) was significantly longer than that of patients with refractory relapse (2 months; p = 0.01). The most frequent grade 3–4 toxicity was myelosuppression, especially neutropenia, which developed in 88% of patients. Grade 3–4 thrombocytopenia developed in 44% of patients, and anemia developed in 56%. Nonhematologic toxicities were generally mild to moderately severe and temporary. None of the patients had cardiotoxicity. In conclusion, this therapy is effective and well tolerated for previously treated SCLC. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Most patients with small-cell lung cancer (SCLC) show favorable responses to first-line chemotherapy. However, SCLC often recurs during the subsequent 2 years: the 2-year cumulative relapse rate is 75% in patients with limited disease (LD) and nearly 100% in patients with extensive disease (ED) [1]. The prognosis of patients who have relapsed SCLC and do not receive additional therapy is extremely poor: expected survival is 2–4 months [2]. On the other hand, some patients are still good candidates for second-line chemotherapy, because they maintain a good performance status (PS) and have adequate organ function despite relapse.
∗ Corresponding author. Tel.: +81 3 3784 8532; fax: +81 3 3784 8742. E-mail address: [email protected] (T. Hirose). 0169-5002/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2010.12.015
In a phase III trial for patients with SCLC that relapsed more than 60 days after completion of first-line chemotherapy, i.e. sensitive relapse, topotecan achieved an equivalent response rate (24% versus 18%) and median survival time (MST) after relapse (25.0 weeks versus 24.7 weeks) to those of the 3-drug combination of cyclophosphamide, doxorubicin, and vincristine and also achieved higher quality of life scores and better symptom control [3]. As a result of this phase III trial, topotecan has been approved by the United States Food and Drug Administration for patients with relapsed SCLC. However, the efficacy of topotecan has not been satisfactory. Therefore, a more effective chemotherapy regimen is urgently needed for relapsed SCLC. Amrubicin is a novel, totally synthesized anthracycline derivative that is structurally distinguishable from doxorubicin due to an amino group at position 9 and its unique sugar moiety [4]. The potent therapeutic activity of amrubicin is attributed to the selective distribution of its highly active 13-hydroxy metabolite,
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amrubicinol, in tumors [5]. The catatonic activity of amrubicinol in vitro is 18–220 times as great as that of its parent compound amrubicin [5]. The inhibitory effects of amrubicin and amrubicinol on cell growth appear to be primarily related to the inhibition of DNA topoisomerase II, although anthracyclines have been reported to have diverse molecular effects, such as DNA intercalation, inhibition of topoisomerase II, and stabilization of topoisomerase II alpha cleavable complexes [6]. Amrubicin has greater antitumor activity than does doxorubicin against several human tumor xenografts implanted in nude mice [7]. In addition, amrubicin does not induce cardiotoxicity or exacerbate doxorubicin-induced cardiotoxicity in dogs or rabbits [8,9]. In two phase II trials of 40 mg/m2 of amrubicin alone on days 1–3 in patients with sensitive or refractory relapsed SCLC, overall response rates were 38% and 52% and MSTs were 8.1 months and 11.2 months [10,11]. The combination of amrubicin with cisplatin showed additive effect against a human SCLC cell line [12]. In a phase II study of amrubicin plus cisplatin for untreated ED-SCLC, the response rate was 87.8%, the MST was 13.6 months, and the 1-year survival rate was 56.1% at the recommended dose (RD) of 40 mg/m2 of amrubicin on days 1–3 and 60 mg/m2 of cisplatin on day 1 [13]. On the other hand, in a phase I study of amrubicin plus carboplatin for patients 70 year or older with previously untreated SCLC, the RD of amrubicin and carboplatin were determined to be 35 mg/m2 and the target area under the concentration versus time curve (AUC) of 4 mg min/ml [14]. To the best of our knowledge, the combination of amrubicin plus carboplatin has not been studied in patients with sensitive or refractory relapsed SCLC. Therefore, we performed a phase II study to assess the antitumor activity and toxicity of the combination of amrubicin plus carboplatin in patients with sensitive or refractory relapsed SCLC. 2. Patients and methods 2.1. Eligibility criteria Patients with previously treated SCLC were enrolled. The criteria for study entry were as follows: (1) histologically or cytologically confirmed SCLC; (2) age 75 years or less; (3) Eastern Cooperative Oncology Group PS of 2 or less; (4) measurable or assessable lesions; (5) life expectancy of at least 8 weeks; (6) adequate bone marrow function (white blood cell [WBC] count from 4000/ul or more, neutrophil count of 2000/ul or more, platelet count of 100,000/ul or more, and hemoglobin level of 9 g/dl or more), hepatic function (total serum bilirubin level less than the upper limit of the normal range, levels of aspartate aminotransferase and alanine aminotransferase less than or equal to twice the upper limits of the normal ranges), and renal function (serum creatinine level less than 1.5 mg/dl, creatinine clearance rate of 50 ml/min or more), and arterial oxygen pressure of 60 mmHg or more. Patients were excluded if they had prior amrubicin treatment, pulmonary fibrosis, uncontrolled diabetes mellitus, severe heart disease, active infection, symptomatic brain metastasis, or active second malignancy. The study protocol was approved by the institutional review board of the Showa University School of Medicine, and all patients provided written informed consent. 2.2. Treatment schedule Carboplatin (target AUC, 4 mg min/ml) was diluted in 500 ml of normal saline and given over 30 min as an intravenous drip infusion after the amrubicin infusion on day 1. The carboplatin dose was calculated with Calvert’s formula and the 24-hour creatinine clearance rate. Amrubicin was diluted in 20 ml normal saline and given
intravenously as a 5-min infusion on days 1–3. This chemotherapy regimen was repeated every 3 weeks for maximum of 4 courses. Prophylactic antiemetic treatment with ondansetron and dexamethasone were routinely given to all patients before carboplatin. Palliative radiotherapy was permitted to control persistent pain associated with bone metastasis. The first 4 patients were treated every 3 weeks with carboplatin (target AUC, 4 mg min/ml on day 1) plus amrubicin (35 mg/m2 on days 1–3) according to the above phase I study [14]. However, the amrubicin dosage had to be reduced in all 4 patients who were treated with this dosage because of grade 4 neutropenia lasting 3 days or longer in 4 patients and grade 4 thrombocytopenia in 3 patients. Thus, we decreased the amrubicin dosage from 35 to 30 mg/m2 . Chemotherapy was discontinued for grade 3 or higher nonhematologoic toxicity, except for nausea/vomiting, anorexia, constipation, alopecia, and fatigue at any time, or if the treatment outcome was progressive disease at any time. If 2 or more weeks had passed after the scheduled start of the next course until these criteria were satisfied, the patient left the study at that time but was still included in the analysis. The next course of treatment was started when the neutrophil count returned to 1500/l, the platelet count returned to 75,000/l, and nonhematologoic toxicity decreased to grade 2 or less. The amrubicin dosage was reduced by 5 mg/m2 if the patient had grade 4 leukopenia or neutropenia lasting 3 days or longer, grade 4 thrombocytopenia or had received a platelet transfusion for grade 3 thrombocytopenia, or if day 2 or 3 of the previous course had been omitted because of severe toxicity. The carboplatin dosage was reduced by 1 mg min/ml if the patient had grade 4 thrombocytopenia or had received a platelet transfusion for grade 3 thrombocytopenia. If the leukopenia or neutropenia had developed grade 3 or 4 after chemotherapy, granulocyte colony-stimulating factor (G-CSF) was administered until the WBC and the neutrophil count recovered, according to the guideline of the Japanese Ministry of Health, Labour and Welfare.
2.3. Evaluation Evaluation before treatment included a baseline history and physical examination, complete blood count with differential, routine chemistry profiles, chest radiography, computed tomography (CT) of the chest and abdomen, magnetic resonance (MR) or CT of the brain, and radionucleotide bone scan. Complete blood counts with differential and routine chemistry profiles were determined at least once a week during chemotherapy. Chest radiography was performed once per week during chemotherapy. Electrocardiograms were obtained before and after chemotherapy. The disease was categorized according to the response to firstline therapy as sensitive relapse or refractory relapse. A refractory relapse was defined as radiographically documented progression as best response to first-line chemotherapy, radiographically documented response or stable disease with subsequent progression during continued chemotherapy, or relapse within 3 months after the completion of first-line chemotherapy. A sensitive relapse was diagnosed when the SCLC relapsed more than 3 months after the completion of first-line chemotherapy. Tumor response was classified according to Response Evaluation Criteria in Solid Tumors (RECIST) Guideline version 1.0 [15]. Toxicities were assessed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. All patients who had received at least 1 cycle of chemotherapy were assessable for response, toxicity, and survival.
T. Hirose et al. / Lung Cancer 73 (2011) 345–350 Table 1 Patient characteristics. Total number of patients Sex (M/F) Age, years (range) Performance status at relapse (0/1/2) Stage at diagnosis (LD/ED) Status at relpase Sensitive Refractory Number of previous chemotherapy regimens (1/2/3) Previous chemotherapy Cisplatin + etoposide Cisplatin + irinotecan Carboplatin + etoposide Carboplatin + irinotecan Response to previous chemotherapy Complete response Partial response Stable disease Progressive disease
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Table 2 Response rate. 25 21/4 65 (55–73) 3/16/6 7/18 12 13 22/2/1 8 5 2 10 5 14 1 5
2.4. Statistical methods The trial was designed as a phase II study, with response rate as the main endpoint. According to the Simons minimax design, our study, with a sample size of 22, had 90% power to accept the hypothesis that the true response rate was greater than 60% and had 5% significance to reject the hypothesis that the true response rate was less than 30%. Progression free survival (PFS) was defined as the period from the start of this treatment to the identifiable time for the first progression or death from any cause. Survival time was measured from the start of the present treatment until death or last follow-up. The Kaplan–Meier method was used to construct survival curves. Survival differences between subgroups were compared by means of the log-rank test. The chi-square test was used to determine the significance of differences between means. Differences with a p-value < 0.05 were considered statistically significant.
Complete response Partial response Stable disease Progressive disease
Sensitive relapse (n = 12)
Refractory relapse (n = 13)
Total
Number
%
Number
%
Number
%
2 5 2 3
16.7 41.7 16.7 25.0
0 2 1 10
0.0 15.4 7.7 76.9
2 7 3 13
8.0 28.0 12.0 52.0
3.2. Treatment response and survival The overall response rate was 36.0% (95% confidence interval [CI], 18.0–57.5%; Table 2). Response rates differed significantly between patients with sensitive relapse (58.3%; 95% CI, 27.7–84.8%) and patients with refractory relapse (15.4%; 95% CI, 1.9–15.4%; p = 0.03). Response rates did not differ significantly between patients who had received a previous regimen including carboplatin or etoposide, which is topoisomerase II inhibitor, and those who had not. The disease control rate was 48.0% (95% CI, 27.8–68.7%; Table 2). Disease control rates differed significantly between patients with sensitive relapse (75.0%; 95% CI l, 42.8–94.5%) and patients with refractory relapse (23.1%; 95% CI, 5.0–53.8%; p = 0.01). Survival analysis was performed when the median follow-up time from the start of this treatment in all evaluable patients was 7 months. At the time of analysis, 2 patients (8%) are alive, and no patient has been lost to follow-up. The overall MST from the start of this treatment was 7 months (range 1–42 months, Fig. 1); the MST of patients with sensitive relapse (10 months) was significantly longer than that of patients with refractory relapse (5 months: p = 0.004). The overall median PFS from the start of this treatment was 3 months (range 1–14 months, Fig. 2): the median PFS of patients with sensitive relapse (5 months) was significantly longer than that of patients with refractory relapse (2 months; p = 0.01). 3.3. Toxicity
3. Results 3.1. Patients characteristics From July 2005 through April 2009, 29 patients were enrolled, but the first 4 patients who were treated with the dosage of 35 mg/m2 of amrubicin on days 1–3 and an AUC of 4 mg min/ml of carboplatin on day 1 were excluded from analysis. Response, toxicity, and survival could be assessed in remaining 25 enrolled patients (Table 1). Of the 25 patients, 6 (24%) had a PS of 2 at relapse. Three patients (12%) had LD, and 22 patients (88%) had ED at relapse. Twelve patients (48%) had sensitive relapse, and 13 patients (52%) had refractory relapse. All 3 patients who received more than 1 prior therapy had refractory relapse. Ten patients (40%) had received thoracic irradiation with previous chemotherapy. The median time off chemotherapy to the present treatment was 3 month (range 0.5–27 months). After the protocol treatment, 15 (60%) patients received subsequent chemotherapy: 8 patients received 1 regimen, 5 patients received 2 regimens, 1 patient received 3 regimens, and 1 patient received 4 regimens. Regimens used in subsequent chemotherapy were as follows: carboplatin plus irinotecan (5 patients), carboplatin plus etoposide (5 patients), etoposide alone (3 patients), cisplatin plus irinotecan (2 patients), cisplatin plus etoposide (2 patients), irinotecan alone (2 patients), topotecan alone (2 patients), amrubicin alone (1 patient), carboplatin plus topotecan (1 patient), and carboplatin plus paclitaxel (1 patient).
A total of 75 courses of chemotherapy were given. The median number of courses given per patients was 3.5 (range 1–4). Table 3 lists the maximum toxicities experienced during treatment. The most frequent grade 3–4 toxicity was myelosuppression, especially neutropenia, which developed in 88% of patients. However, the median duration of grade 4 neutropenia was only 4 days (range 2–9 days). Additionally, the incidence of grade 3 or 4 infection was only
Fig. 1. Overall survival from the start of this treatment estimated with the Kaplan–Meier method. The median survival time was 7 months (range 1–42 months).
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4. Discussion
Fig. 2. Progression-free survival from the start of this treatment estimated with the Kaplan–Meier method. The median length of progression-free survival was 3 months (range 1–14 months).
8% or 0%: 1 patient (4%) had febrile neutropenia and 1 patient (4%) had pneumonia without neutropenia. No patient had sepsis. G-CSF support was given during 68% of the 75 courses (median duration of administration, 4 days; range 1–13 days). Grade 3–4 thrombocytopenia developed in 44% of patients, and anemia developed in 56%. Seven patients received platelet transfusions, and 6 patients received erythrocyte transfusions. However, no patients had severe bleeding episodes or anemia-related episodes. Additionally, thrombocytopenia and anemia resolved quickly after transfusions. Nonhematologic toxicities were generally mild to moderately severe and temporary. No patients had grade 3–4 nausea and vomiting or diarrhea. None of the patients had cardiotoxicity. There were no treatment-related deaths. 3.4. Dose intensity Owing to toxicity, doses of both amrubicin and carboplatin were reduced in 4 patients: because of grade 4 thrombocytopenia in 2 patients and platelet transfusions for grade 3 thrombocytopenia in 2 patients. In addition, the doses of amrubicin alone were reduced in 6 patients: because of grade 4 neutropenia lasting 3 days or longer in 5 patients and because of grade 3 infection in 1 patient. A total of 16 courses were delayed, mostly because of neutropenia or thrombocytopenia. The mean individual doses of amrubicin and carboplatin actually delivered were 26.9 mg/m2 (89.7% of planned) and 3.64 mg min/ml (91.0% of planned), respectively. Table 3 Toxicity. National Cancer Institute-Common Terminology Criteria grade Toxicity Leukopenia Neutropenia Thrombocytopenia Anemia Nausea Vomiting Anorexia Stomatitis Diarrhea Constipation Infection Elevation of serum creatinine Elevation of aminotransferases Abnormality of potassium Hyponatremia Fatigue or asthenia
1 0 2 1 1 5 3 8 2 2 10 3 5 8 8 12 10
2 2 0 9 10 1 1 4 0 1 3 2 1 4 2 0 0
3 12 4 3 9 0 0 1 2 0 1 2 0 1 1 2 0
4 11 18 8 5 0 0 0 0 0 0 0 0 0 0 1 0
3/4 (%) 92 88 44 56 0 0 4 8 0 4 8 0 4 4 12 0
Before new drugs, such as topotecan and amrubicin, were introduced, second-line chemotherapy usually did not prolong survival in patients with SCLC: MSTs after relapse were only 2.5–3.9 months [2]. Huisman et al. [16] have summarized 21 phase II studies and 3 randomized trials reported from 1989 through 1999 of second-line chemotherapy in patients with SCLC. They found cumulative response rates of 21% (range 4.5–88.2%) for multidrug regimens and 19% (range 2.4–47%) for single agents. Topotecan or re-treatment with the same regimen used for first-line chemotherapy is a standard treatment for patients with sensitive relapsed SCLC. However, the efficacy has not been satisfactory. Additionally, because the combination of irinotecan and cisplatin is one of the standard regimens for patients with previously untreated ED-SCLC, especially in Japan [17], second-line treatment with topotecan might be inappropriate for many patients with ED-SCLC because both topotecan and irinotecan are camptothecin analog. Moreover, there are no standard treatments for refractory relapsed SCLC. Furthermore, there is no clinical evidence to suggest that combination chemotherapy regimens are superior to single-agent regimens for relapsed SCLC. Therefore, further research should focus on the development of regimens that are more effective against sensitive or refractory relapsed SCLC. The function of the kidneys or other organs decreases in previously treated patients. These decreases in function directly affect the tolerability of systemic chemotherapy for previously treated patients. Carboplatin has less renal, neurologic, and gastrointestinal toxicity and is easier to administer than cisplatin [18]. Additionally, carboplatin is one of the most active drugs against SCLC, and as a single agent, has achieved a 56% overall response rate in previously untreated patients [19]. In a phase III study in patients with previously untreated SCLC, the combination of carboplatin plus etoposide achieved response and survival rates similar to those of cisplatin plus etoposide but was significantly less toxic [20]. Thus, we believe carboplatin is more appropriate than cisplatin for previously treated patients who had several organs with lower functional reserve. In a phase I study of amrubicin plus carboplatin for patients with previously untreated SCLC who were 75 years or younger and had a PS of 0 or 1, the RD of amrubicin was determined to be 35 mg/m2 on days 1–3, and the AUC of carboplatin was 5 mg min/ml on day 1 [21]. On the other hand, in a phase I study of amrubicin plus carboplatin for patients with previously untreated SCLC who were 70 years or older and had a PS of 0 or 1, the RD of amrubicin was determined to be 35 mg/m2 on days 1–3 and the AUC of carboplatin was 4 mg min/ml on day 1 [14]. Because both elderly patients and previously treated patients have lower reserves of organ function than do younger and previously untreated patients, we chose the dosage of 35 mg/m2 of amrubicin on days 1–3 and an AUC of 4 mg min/ml of carboplatin on day 1. However, the amrubicin dosage had to be reduced in all 4 patients who were treated with this dosage because of grade 4 neutropenia lasting 3 days or longer in 4 patients and grade 4 thrombocytopenia in 3 patients. We considered this dosage to be too toxic for previously treated patients. Thus, we decreased the amrubicin dosage from 35 to 30 mg/m2 . Okamoto et al. have recommended an amrubicin dosage of 35 mg/m2 on days 1–3 as a single agent for patients with previously treated lung cancer [22]. Therefore, we believe our decision to decrease the amrubicin dosage was appropriate. In several recent trials of second-line chemotherapy in patients with SCLC, the overall response rates have ranged from 7% to 73%, disease control rates have ranged from 29% to 79%, and MSTs after relapse have ranged from 6.1 to 11.7 months [3,10,11,23–26]. In the present study, the overall response rate was 36%, the disease
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control rate was 48%, and the MST after relapse was 7 months. Our results compare favorably with those of recent trials in patients with sensitive or refractory relapsed SCLC. However, response rates and survival times after relapse in the present study were less than [10] or equivalent to [11] those in previous studies of amrubicin used as a single agent. These differences may be due to differences in patient characteristics or other confounding variables. The outcome of second-line treatment in SCLC depends on several factors, including whether the relapse is sensitive or refractory, the interval since the completion of previous chemotherapy, the cytotoxic drugs used for previous therapy, the extent of disease at relapse, and the PS [2,16]. In the present study, 24% of patients had a PS of 2 at relapse, and the median time off chemotherapy before this treatment was only 3 months. In our patients with sensitive relapse, the response rate of 58.3%, the disease control rate of 75%, and the MST after relapse of 10 months were equivalent to those in previous studies: response rates have ranged from 18% to 77%, disease control rates have ranged from 29% to 88%, and MSTs after relapse have ranged from 6 to 11.7 months [3,10,11,23–26]. Additionally, in our patients with refractory relapse the response rate of 15.4%, the disease control rate of 23.1%, and the MST after relapse of 5 months were also equivalent to those in previous studies: response rates have ranged from 0% to 70%, disease control rates have ranged from 18% to 68%, and MSTs after relapse have ranged from 5.3 to 10.3 months [3,10,11,23–27]. Moreover, because few single agents have consistently achieved response rates greater than 10% in patients with refractory relapse [28], our regimen could be an attractive option. In the present study the most frequent toxicity was myelosuppression, especially neutropenia. Grade 3–4 hematologic toxicities included neutropenia in 88% of patients, thrombocytopenia in 44%, and anemia in 56%. Previous studies have also found that the principle toxicity of amrubicin, alone, or in combination with platinum derivatives, is myelosuppression [10,11,13,21,22,27,29]. In phase II studies of amrubicin alone in patients with previously treated SCLC, rates of grade 3–4 neutropenia, thrombocytopenia, and anemia were 67–93%, 20–41%, and 21–33% of patients, respectively [10,11,27]. In addition, in a phase II study of amrubicin plus carboplatin for elderly patients with previously untreated SCLC, grade 3–4 neutropenia, thrombocytopenia, and anemia developed in 97%, 28%, and 28% of patients, respectively [29]. However, in our study, all cases of myelosuppression were manageable, and the incidence of grade 3 or 4 infection was only 8% or 0%, respectively. Additionally, these rates of toxicity compare favorably with those in most recent trials in patients with previously treated SCLC. Rates of grade 3–4 neutropenia, thrombocytopenia, and anemia in recent trials were 48.8–93%, 14.9–57.6%, and 5.9–42.3%, respectively [3,23–26]. Nonhematologic toxicities in the present study were generally mild to moderately severe. Moreover, cardiotoxicity was not observed, which is consistent with results of previous clinical trials and postmarketing surveillance. Furthermore, the delivered dose intensities for amrubicin and carboplatin were 89.7% and 91.0%, respectively. When we consider the lower bone marrow reserves in previously treated patients, the dose intensities in our study do not seem too low. In conclusion, to the best of our knowledge, the present phase II study is the first to examine the combination of amrubicin plus carboplatin for sensitive or refractory relapsed SCLC. This regimen is a safe and effective treatment for patients with previously treated SCLC, especially those who have had sensitive relapse. Therefore, this treatment could be an acceptable option in patients with previously treated SCLC. However, our results were not superior to those of the studies of amrubicin used as a single agent for previously treated SCLC. In the future, the search for more active regimens should be continued.
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