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Phase II Trial of Amrubicin for Treatment of Refractory or Relapsed Small-Cell Lung Cancer: Thoracic Oncology Research Group Study 0301

Sayaka Onoda, Noriyuki Masuda, Takashi Seto, Kenji Eguchi, Yuichi Takiguchi, Hiroshi Isobe, Hiroaki Okamoto, Takashi Ogura, Akira Yokoyama, Nobuhiko Seki, Yoshiko Asaka-Amano, Masao Harada, Akihiro Tagawa, Hiroshi Kunikane, Masanori Yokoba, Kazutsugu Uematsu, Takayuki Kuriyama, Yumi Kuroiwa, Koshiro Watanabe

From the Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa; Department of Respirology, Tokai University School of Medicine, Isehara; Department of Respirology, Graduate School of Medicine, Chiba University, Chiba; Department of Pulmonary Disease, National Hospital Hokkaido Cancer Center, Sapporo; Department of Respirology, Yokohama Municipal Citizen's Hospital; Department of Respiratory Medicine, Kanagawa Cardiovascular & Respiratory Center, Yokohama; and Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan

Address reprint requests to Noriyuki Masuda, MD, PhD, Department of Respiratory Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-0022, Japan; e-mail: masuda{at}med.kitasato-u.ac.jp

	ABSTRACT

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PURPOSE: This multicenter, phase II study was conducted to evaluate the activity of amrubicin, a topoisomerase II inhibitor, against refractory or relapsed small-cell lung cancer (SCLC).

PATIENTS AND METHODS: SCLC patients with measurable disease who had been treated previously with at least one platinum-based chemotherapy regimen and had an Eastern Cooperative Oncology Group performance status of 0 to 2 were eligible. Two groups of patients were selected: patients who experienced first-line treatment failure less than 60 days from treatment discontinuation (refractory group), and patients who responded to first-line treatment and experienced disease progression 60 days after treatment discontinuation (sensitive group). Amrubicin was administered as a 5-minute daily intravenous injection at a dose of 40 mg/m² for 3 consecutive days, every 3 weeks.

RESULTS: Between June 2003 and December 2004, 60 patients (16 refractory and 44 sensitive) were enrolled. The median number of treatment cycles was four (range, one to eight). Grade 3 or 4 hematologic toxicities comprised neutropenia (83%), thrombocytopenia (20%), and anemia (33%). Febrile neutropenia was observed in three patients (5%). Nonhematologic toxicities were mild. No treatment-related death was observed. The overall response rates were 50% (95% CI, 25% to 75%) in the refractory group, and 52% (95% CI, 37% to 68%) in the sensitive group. The progression-free survival, overall survival, and 1-year survival in the refractory group and the sensitive group were 2.6 and 4.2 months, 10.3 and 11.6 months, and 40% and 46%, respectively.

CONCLUSION: Amrubicin exhibits significant activity against SCLC, with predictable and manageable toxicities; this agent deserves to be studied more extensively in additional trials.

	INTRODUCTION

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Approximately 15% of all patients with lung cancer are diagnosed with small-cell lung cancer (SCLC). Unlike other types of lung cancer, SCLC is sensitive to chemotherapy or radiation therapy.¹ Nonetheless, after experiencing an apparently successful induction therapy, most patients experience relapse within 2 years because of the emergence of drug-resistant cancer cells during the induction therapy or the existence of such cells before chemotherapy. Therefore, long-term survival is quite uncommon, with less than 25% of patients with limited-stage, and 1% to 2% of patients with extensive-stage disease remaining alive at 5 years.^2-4 Furthermore, the results of second-line chemotherapy against SCLC are disappointing, with relatively low response rates, brief remissions, and a short survival time.^1,5 In particular, little progress has been made in the re-treatment of patients who experienced progression during first-line therapy or who failed to achieve a progression-free survival of more than 60 to 90 days. As a result, to control SCLC more efficiently, new drugs that are effective for patients who have failed to respond to standard treatment, and who may have multidrug-resistant tumors, are urgently needed.

Amrubicin, a totally synthetic 9-aminoanthracycline, is converted to an active metabolite, amrubicinol, through the reduction of its C-13 ketone group to a hydroxy group.⁶ Despite the similarity of its chemical structure to that of a representative anthracycline, doxorubicin, the mode of action of amrubicin differs from that of doxorubicin.⁷ Amrubicin and amrubicinol are inhibitors of DNA topoisomerase II, which exert cytotoxic effects by stabilizing a topoisomerase II-mediated cleavable complex, and are approximately 1/10 weaker than doxorubicin as a DNA intercalator. The in vitro cytotoxic activity of amrubicinol was 18 to 220 times more potent than that of its parent compound, amrubicin.⁸ In preclinical studies, amrubicin showed a more potent antitumor activity than doxorubicin in several human tumor xenografts implanted in nude mice,⁹ and caused almost no cardiotoxicity.^9,10 The response rates to amrubicin at a dose of 45 mg/m² on days 1 to 3 in chemotherapy-naive patients with stage III or IV non-SCLC and extensive-stage SCLC were 25% and 79% on an intent-to-treat analysis, respectively.^11,12 The major grade 3 or 4 toxicities were neutropenia (72.1%), leukopenia (52.5%), anemia (23.0%), thrombocytopenia (14.8%), anorexia (4.9%), and nausea/vomiting (4.9%) in a phase II trial.¹³

The high activity of amrubicin as a single agent in untreated patients with extensive disease (ED) SCLC led us to carry out this phase II trial, which was designed to determine the antitumor activity and toxicity of amrubicin in previously treated patients with SCLC.

	PATIENTS AND METHODS

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Patient Selection
Before participation in the present study, each patient was examined to ensure he or she met the following criteria: histologic or cytologic proof of SCLC; recurrent or refractory disease after one or two previous chemotherapy regimens (at least one platinum-containing regimen); measurable disease; no chemotherapy or chest radiotherapy within 4 weeks before entry (measurable disease outside the radiation field); life expectancy of at least 8 weeks; performance status of 2 or better according to the Eastern Cooperative Oncology Group scale; age 20 years; adequate bone marrow function (leukocyte count 4,000/µL, absolute neutrophil count [ANC] 2,000/µL, platelet count 100,000/µL, and hemoglobin 9.0 g/dL) and hepatic function (AST and ALT 100 U/L, or 200 U/L in the presence of liver metastases; bilirubin level 1.5 mg/dL); ECG findings within the normal range, and a left ventricular ejection fraction 50%; arterial oxygen partial pressure 60 torr; and the written informed consent of the patient. Patients were ineligible if they had serious infectious diseases or other severe complications (heart disease, pulmonary fibrosis/interstitial pneumonia, or uncontrollable diabetes); had massive pleural or pericardial effusion, or ascitic fluid; had symptomatic brain metastases; had active concurrent malignancies; were lactating or pregnant women or hoped to become pregnant; had a history of a drug allergy; or had other medical problems severe enough to prevent compliance with the protocol. Prior amrubicin chemotherapy was not allowed. Trial document approval was obtained in advance from the ethics committee or institutional review board of each hospital.

Treatment Schedule
Amrubicin was dissolved in 20 mL of normal saline, and administered intravenously as a 5-minute infusion at a dose of 40 mg/m²/d on days 1 to 3 every 3 weeks. Patients with evidence of disease progression or who experienced intolerable toxicity, such as grade 2 or worse pneumonitis, were removed from the study. Before the next course could be started, the patient's ANC had to be 1,500/µL, his or her platelet count had to be 100,000/µL, and any nonhematologic toxicities should have been downgraded to at least grade 1. If more than 6 weeks passed from the time of the last treatment before these criteria were satisfied, the patient was removed from the study.

Granulocyte colony-stimulating factor (G-CSF) was permitted as a therapeutic intervention but was not mandatory as a prophylactic agent against neutropenia for hematologic toxicity.

Subsequent doses were modified based on hematologic and nonhematologic toxicities. If the leukocyte count was less than 1,000/µL for 4 days or longer, the ANC was less than 500/µL for 4 days or longer, the platelet count nadir was less than 20 x 10³/µL, or grade 3 or worse nonhematologic toxicity was observed, the dose of amrubicin was reduced to 35 mg/m²/d. The dose of amrubicin also was reduced to 35 mg/m²/d in patients who developed grade 3 febrile neutropenia.

Evaluation
Patients were evaluated to determine the stage of disease at the time of disease progression or at the time of relapse by taking a complete medical history and performing a physical examination, chest radiograph, computed tomography of the chest and abdomen, and other staging procedures as indicated, including computed tomography of the head and a bone scintiscan. Limited disease (LD) was defined as that confined to one hemithorax, including bilateral mediastinal and bilateral supraclavicular nodes: any involvement beyond these confines was defined as ED. Primary refractory disease (refractory group) was defined as relapse during the first-line chemotherapy regimen or less than 60 days after completing the initial chemotherapy regimen, and sensitive disease (sensitive group) was defined as relapse 60 days after completion of the first-line chemotherapy. Before the first course, each patient was assessed using a CBC, including a differential count and a platelet count, and serum chemistry tests for renal and hepatic functions as well as electrolytes. The CBC and biochemistry tests were repeated at least once a week after this initial evaluation, whereas the other investigations were repeated at least every 6 weeks to evaluate the target lesions.

Adverse events were recorded and graded using the National Cancer Institute Common Toxicity Criteria, Version 2.0 grading system. After completing the chemotherapy regimen, each patient was restaged using all of the tests used during the initial work-up. The tumor response was classified in accordance with the Response Evaluation Criteria in Solid Tumors.¹⁴ The duration of the response was defined as the number of days from the documentation of the response to the detection of disease progression. The eligibility, evaluability, and response of each patient were assessed by extramural reviewers. The duration of survival, determined as the number of days between the enrollment of protocol therapy and death, was censored at the time last known alive for patients who had not died.

Statistical Methods
Kaplan-Meier survival estimates were used to summarize the time-to-event variables.¹⁵ These included time to response, response duration, progression-free survival, and survival. Time-to-event outcomes were compared using the log-rank test. Other statistical analyses were performed using the ² test or Fisher's exact test, and P < .05 was considered to indicate statistical significance. The primary end point was the response rate, which determined the sample size. We chose a 40% response rate as a desirable target level and a 20% response rate as uninteresting in the sensitive group, with a power in excess of 80% and less than 2.5% type I error. For the refractory group, the sample size was planned using an adequate power to demonstrate that the overall response rate was greater than 5%. If the true overall response rate were assumed to be 25%, a sample size of 16 assessable patients would have a power of 80% based on a 5% level (one-sided test) and an exact binomial distribution.

	RESULTS

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Between June 2003 and December 2004, 60 patients were enrolled onto this multicenter trial. Sixteen and 44 patients in the refractory and sensitive groups were eligible for the study, and assessable for toxicity, response, and survival. The characteristics of the 60 patients treated during this trial are listed in Table 1. Fourteen patients were women and 46 were men, and their median age was 67 years (range, 52 to 79 years). Eleven patients (18%) exhibited LD and 49 patients (82%) exhibited ED at the time of enrollment onto this study. All 60 patients had been pretreated using some form of topoisomerase inhibitor–based chemotherapeutic regimens: 24 patients had received prior topoisomerase I inhibitor (irinotecan or topotecan) –containing chemotherapy, 20 had had prior etoposide-containing chemotherapy, and 16 had received both topoisomerase I and II regimens (Table 2). Nineteen of these patients had received thoracic irradiation after or simultaneously with chemotherapy.

Of the 60 patients, 19 patients (32%) were still alive as of April 26, 2006. The median survival time from the enrollment of the protocol treatment for all patients was 11.2 months (sensitive group, 11.6 months; refractory group, 10.3 months; Fig 1). The 1-year actuarial survival rate in patients with sensitive disease was 45.5%, compared with 40.3% in the patients with refractory disease. The 1-year survival rate for all patients was 44.1% (95% CI, 30.6% to 56.8%).

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Median survival times in all patients with refractory or relapsed small-cell lung cancer were 10.3 months in the refractory group (n = 16) and 11.6 months in the sensitive group (n = 44), respectively (P = .974; log-rank test). The 1-year actuarial survival rate in patients with refractory disease was 40.3%, compared with 45.5% in the patients with sensitive relapse.

The most frequent toxicity was myelosuppression, which affected leukocytes primarily: grade 3 or 4 neutropenia was seen in 28% and 55% of patients, respectively (Table 3). G-CSF was administered in 134 (60%) of the 224 cycles that were administered; 42 patients (70%) received G-CSF. However, only three episodes of fever were observed during the period of neutropenia. Thrombocytopenia was relatively infrequent throughout the study: grade 3 and 4 toxicity occurred in 20% and 0% of the patients, respectively. Grade 3 or 4 anemia was reported in 20 patients (33%). Nonhematologic toxicity was generally mild. The most frequent grade 3 or 4 nonhematologic toxicities included anorexia (15%), asthenia (15%), hyponatremia (8%), and nausea (5%). No cardiotoxicity, except for one transient atrial fibrillation, was observed during this trial.

	DISCUSSION

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Treatment options for patients who experience relapse remain limited. Recently, a multicenter randomized trial demonstrated that single-agent topotecan was at least as efficacious as the three-drug combination of cyclophosphamide, doxorubicin, and vincristine for the treatment of patients with sensitive disease.¹⁶ Topotecan showed a response rate of 24% v 18% for cyclophosphamide, doxorubicin, and vincristine (P = .28), with improved symptom control. The median survivals were superimposable between two treatments (25 v 24.7 weeks). The results of the phase III trial have made topotecan the only drug approved by the US Food and Drug Administration for the single-agent management of patients with relapsed SCLC.

Several reports on single-agent activity for newer chemotherapeutic agents, including topoisomerase I inhibitors,^17-21 taxanes,²² gemcitabine,²³ and vinorelbine,^24,25 in the second-line setting have been made. However, few single agents are capable of producing a high incidence of response among patients with early relapse or disease progression during treatment. Smit et al²⁶ reported the results of phase II trial for paclitaxel given as a 3-hour infusion at a dose of 175 mg/m² every 3 weeks in patients refractory to cyclophosphamide, doxorubicin, and etoposide. Although the response rate of 29% was at the upper level of activity for any single agent in this setting, two early deaths and two toxicity-related deaths occurred in the trial, and the median survival time was a disappointingly short 100 days.

This phase II study demonstrated that amrubicin monotherapy is active against refractory or relapsed SCLC, as shown by the overall response rate of 52% (95% CI, 38% to 65%) in 60 patients (Table 2). Although the activity of second-line treatments usually depends on tumor responsiveness to first-line treatment, we could not find any difference in response rates between the two groups (the response rate of 50% [95% CI, 25% to 75%] for refractory disease, and 52% [95% CI, 37% to 68%] for sensitive relapse). This high response rate in chemotherapy-resistant patients is encouraging given the fact that response rates of less than 10% are usually attained for single-agent chemotherapy in patients with this disease category.²⁷ Furthermore, a promising similar survival outcome was obtained in the two groups (10.3 v 11.6 months in refractory and sensitive group, respectively; Fig 1). These results suggest that amrubicin may be a useful new addition to treatment strategies for chemotherapy-resistant patients. Obviously, however, more SCLC patients with refractory disease treated with amrubicin will be needed to determine the true response rate in this population, given that the number of patients in this study is too small to draw any valid conclusion about the ultimate clinical activity of this regimen.

DNA topoisomerase I and II are functionally related and are believed to act in concert in a variety of genetic processes.²⁸ Preclinical studies have demonstrated that resistance to camptothecin, a topoisomerase I inhibitor, is often accompanied by the upregulation of topoisomerase II, causing hypersensitivity to agents that target topoisomerase II.²⁹ This enhanced sensitivity (collateral sensitivity) may explain, in part, the high response rate observed in our patients, given that most of the patients had been heavily pretreated during topoisomerase I inhibitor (irinotecan or topotecan) –containing regimens. Furthermore, objective responses were documented in 19 of 36 patients who had been treated with etoposide, a potent topoisomerase II inhibitor, which suggests that there is some degree of non–cross resistance between amrubicin and etoposide.

The toxicity profile noted in this trial was predictable from that described previously for the phase I and II trials^12,13,30; myelosuppression was the major toxic effect. All adverse effects were manageable. Because grade 3 or 4 neutropenia occurred in 85% of patients with no prior chemotherapy who were treated using the Japanese Ministry of Labor, Health and Welfare–approved dose level of 45 mg/m² per day for 3 days in a previous phase II trial,¹² a reduced dose of 40 mg/m² per day for 3 days was chosen in this trial in view of the chemotherapeutic and radiotherapeutic pretreatment. The low incidence of severe and clinically relevant bone marrow toxicity in our trial may be due to the use of this lower dose of amrubicin (Table 3). The incidence of a decrease in the left ventricular ejection fraction attributable to amrubicin was null, and this effect was never the cause of treatment discontinuation. The incorporation of amrubicin instead of doxorubicin in anthracycline-containing regimens might decrease the incidence of cardiotoxicity, thereby improving the therapeutic index of doxorubicin-containing regimens in future trials.

In conclusion, amrubicin is an active agent for the treatment of refractory or relapsed SCLC. The overall response rate of 50% and the overall survival time of 10.3 months in patients with refractory disease are noteworthy. Given the greater activity of single-agent amrubicin, additional studies in previously treated patients with SCLC are warranted, especially for the patients who are refractory to previous therapy, either as a single agent or in combination with cytotoxic agents or target-based agents.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Noriyuki Masuda, Koshiro Watanabe Provision of study materials or patients: Sayaka Onoda, Noriyuki Masuda, Takashi Seto, Kenji Eguchi, Yuichi Takiguchi, Hiroshi Isobe, Hiroaki Okamoto, Takashi Ogura, Akira Yokoyama, Nobuhiko Seki, Yoshiko Asaka-Amano, Masao Harada, Akihiro Tagawa, Hiroshi Kunikane, Masanori Yokoba, Kazutsugu Uematsu, Takayuki Kuriyama, Yumi Kuroiwa Collection and assembly of data: Sayaka Onoda, Noriyuki Masuda, Takashi Seto, Kenji Eguchi, Yuichi Takiguchi, Hiroshi Isobe, Hiroaki Okamoto, Takashi Ogura, Akira Yokoyama, Nobuhiko Seki, Yoshiko Asaka-Amano, Masao Harada, Akihiro Tagawa, Hiroshi Kunikane, Masanori Yokoba, Kazutsugu Uematsu, Takayuki Kuriyama, Yumi Kuroiwa Data analysis and interpretation: Sayaka Onoda, Noriyuki Masuda, Takashi Seto, Koshiro Watanabe Manuscript writing: Noriyuki Masuda Final approval of manuscript: Noriyuki Masuda, Koshiro Watanabe

 

	ACKNOWLEDGMENTS

 
We thank K. Ogawa, T. Okuda, M. Tomita, M. Matsushita, and K. Fujimaru for their help in data collection and statistical analysis; and K. Minato, MD, S. Tsuchiya, MD, and A. Yoshimura, MD, for an extramural review of this study.

	NOTES

 
Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted July 26, 2006; accepted September 28, 2006.

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