Phase II study of amrubicin in previously untreated patients with extensive-disease small cell lung cancer: West Japan Thoracic Oncology Group (WJTOG) study

Yana, Takashi; Negoro, Shunichi; Takada, Minoru; Yokota, Soichiro; Takada, Yoshiki; Sugiura, Takahiko; Yamamoto, Hidehiko; Sawa, Toshiyuki; Kawahara, Mutsuto; Katakami, Nobuyuki; Ariyoshi, Y; Fukuoka, Masahiro

doi:10.1007/s10637-006-9012-9

Cited by 102 publications

(84 citation statements)

References 17 publications

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“…In a phase I/II study of patients with non-small-cell lung cancer, the recommended dose was determined to be 45 mg/ m 2 /day for 3 consecutive days every 3 weeks (5). In a phase II study of SCLC, 35 patients with extensive disease (ED) were treated at the recommended dose, and a response rate of 75.8% and median survival time (MST) of 11.7 months were reported (6).…”

Section: Introductionmentioning

confidence: 99%

Retrospective analysis of Japanese patients with relapse or refractory small-cell lung cancer treated with amrubicin hydrochloride

Kim¹,

Mio²,

Masago³

et al. 2010

Oncology Letters

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Abstract. Amrubicin (AMR) is one of the most active chemotherapeutic agents for small-cell lung cancer (SCLC). Previous phase II studies reported on its effectiveness and severe hematological toxicities. However, AMR has yet to be approved outside Japan. Subsequently, no extensive evidence of its effects exist. Between January 2004 and October 2009, 69 patients received AMR for relapsed SCLC at our hospital. We reviewed these patients, and analyzed the efficacy and hematological toxicities of AMR. There were 27 sensitive relapses (S) and 42 refractory relapses (R). Patients received platinum agents, and 43 and 71% of the patients received etoposide and irinotecan, respectively. The median number of treatment cycles was 3 (range 1-14), and the response rate was 51% (70% in the S and 38% in the R cases, respectively). In patients administered with AMR as second-line therapy, the response rate was 55% and as third-line therapy, 39%. Median progression-free survival time was 3.2 months in the S and 1.9 months in the R patients (p=0.1071). Median survival time from the start of AMR was 6.2 months in the S and 4.8 months in the R cases (p=0.0045). The frequency of grade ≥3 hematological toxicities was leukopenia (41%), neutropenia (51%), anemia (14%), thrombocytopenia (17%) and febrile neutropenia (12%). No treatment-related death was observed. Although hematological toxicities, particularly neutropenia, were severe, AMR showed excellent anti-tumor activity, not only in the S, but also in the R cases, as shown in previous phase II studies. These results warrant further evaluation of AMR in the second-line setting, and also in the first-line setting in both limited-and extensivestage disease. We conducted a phase II study to assess the efficacy of consolidation chemotherapy with AMR after standard chemoradiation in limited-stage SCLC. IntroductionSmall-cell lung cancer (SCLC) accounts for approximately 15% of all types of lung cancer (1). Despite the high sensitivity to chemotherapy, the majority of patients develop relapse. Second-line chemotherapy is considered for cases of relapsed SCLC; however, the prognosis of such patients is usually poor. Topotecan has shown a survival benefit against best supportive care and also a comparable response rate and survival with combination chemotherapy of cyclophosphamide, doxorubicin and vincristine (CAV) in relapsed SCLC (2,3). Currently, topotecan is the only drug approved by the US Food and Drug Administration for relapsed SCLC.Amrubicin (AMR), a totally synthetic 9-aminoanthracycline, is converted to an active metabolite, amrubicinol, by reduction of its C-13 ketone group to a hydroxyl group (4). In a phase I/II study of patients with non-small-cell lung cancer, the recommended dose was determined to be 45 mg/ m 2 /day for 3 consecutive days every 3 weeks (5). In a phase II study of SCLC, 35 patients with extensive disease (ED) were treated at the recommended dose, and a response rate of 75.8% and median survival time (MST) of 11.7 months were reported (6).In a phase II study...

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Section: Introductionmentioning

confidence: 99%

Retrospective analysis of Japanese patients with relapse or refractory small-cell lung cancer treated with amrubicin hydrochloride

Kim¹,

Mio²,

Masago³

et al. 2010

Oncology Letters

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“…However, our observation suggests the possibility that AMR is optimal as a chemotherapeutic agent combined with STI571 in the treatment of SCLC. AMR, a totally synthetic 9-aminoanthracycline, demonstrated excellent anti-tumor activity as a single-agent or combination therapy for ED-SCLC (6,21). Therefore, given that SCF/c-kit-mediated autocrine signal activates Akt in SCLC in vivo, the combination of STI571 and AMR may be promising in the treatment of SCLC.…”

Section: Discussionmentioning

confidence: 99%

Imatinib mesylate (STI571) enhances amrubicin-induced cytotoxic activity through inhibition of the phosphatidylinositol 3-kinase/Akt pathway in small cell lung cancer cells

Suyama

Igishi²,

Ueda³

et al. 2009

Oncol Rep

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Abstract. Small cell lung cancer (SCLC) is characterized by autocrine mechanisms. Stem cell factor (SCF) and its receptor c-kit can activate Akt and extracellular signal-regulated kinase (Erk) pathways. Imatinib mesylate (STI571) can inhibit c-kit tyrosine kinase activity, but clinical trials have resulted in failure. We investigated the possibility of SCF/c-kit-targeted therapy against SCLC. Using c-kit-positive SCLC cells (H209 and H69 cells) and SCF as a model of the autocrine mechanisms, the effects of SCF, LY294002, PD98059 or STI571 on Akt and Erk were assessed by Western blot analysis. The cell growth inhibitions of cisplatin, etoposide irinotecan and amrubicin (AMR) with or without SCF, LY294002, PD98059 or STI571 were evaluated by MTT assay. Treatment with SCF activated Akt and Erk and the activations were inhibited by STI571 in H209 but not in H69 cells. LY294002 and PD98059 inhibited SCF-induced Akt and Erk activation in H209 cells, respectively. STI571 alone did not exert growth inhibition in the SCF-treated cells. In H209 cells, SCF decreased the cytotoxicity of AMR, but not of other drugs. In H69 cells, SCF did not affect sensitivity to any drugs. LY294002 but not PD98059 restored or enhanced AMR-sensitivity in SCF-treated H209 or untreated H69 cells, respectively. STI571 restored the AMR-sensitivity of SCF-treated H209 cells to the basal level. If the SCF/c-kit contributes to Akt activation in vivo, the combination of STI571 and AMR may be effective against SCLC. Additionally, using a combination of AKT inhibitors and AMR may be a promising treatment in the future. IntroductionSmall cell lung cancer (SCLC) is a highly aggressive neoplasm characterized by a high growth fraction, short doubling time and high rate of metastasis (1), but is sensitive to chemotherapy (2). Systemic chemotherapy prolongs the survival of SCLC patients (3), and cisplatin (CDDP), etoposide (VP-16), topoisomerase I inhibitors [irinotecan (CPT-11) and topotecan] (4,5) and amrubicin (AMR) (6) (a totally synthetic 9-aminoanthracycline) are used in regular clinical practice in Japan. Among these chemotherapeutic agents, the combination chemotherapy of CDDP and VP-16 is considered the standard first line chemotherapeutic regimen worldwide (7). Despite high response rates with these first line CDDP-based chemotherapies, most patients eventually experience disease progression. Accordingly, novel chemotherapeutic regimens based on new conceptions are needed for treating SCLC patients.SCLC is, per se, characterized by several autocrine growth mechanisms including stem cell factor (SCF) and its receptor c-kit, and c-kit overexpression is found in up to 70% of SCLC (8). In view of c-kit signal transduction, an SCF/c-kit can activate several intracellular pathways including phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/Erk) pathways (9).Imatinib mesylate (STI571) was developed as a Bcr-Abl inhibitor and has become a standard therapeutic drug for chronic my...

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“…Although 57.6% of patients experienced nausea and vomiting during the phase II clinical trial (WJTOG study) that was conducted in Japan, grade 3 or higher nausea and vomiting were not observed during this trial [7]. However, since the WJTOG study sample size was small, the prophylactic antiemetic therapy during the observational period could not be clarified.…”

Section: Ivyspring International Publishermentioning

confidence: 93%

Antiemetic Effects of Granisetron or Metoclopramide Administered Prior to Amrubicin Monotherapy

Aoyama¹,

Suzuki²,

Tanaka³

et al. 2017

Oncomedicine

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Purpose: Amrubicin (AMR) is an anthracycline antitumor agent that has little cardiotoxicity and exhibits promising activity for small cell lung cancer (SCLC). Although AMR monotherapy is primarily used as a second-line treatment for SCLC in Japan, AMR-induced nausea and vomiting have not been definitively evaluated, and antiemetic therapy for AMR has yet to be established. This study retrospectively evaluated the antiemetic effects of granisetron or metoclopramide during AMR monotherapy. Methods: We reviewed the medical records of SCLC patients who received AMR monotherapy at our hospital. Incidence of nausea and vomiting and the complete response (CR) of the anti-emesis, which was defined as the absence of any emetic episode or the use of any rescue medication, were evaluated. Results: A total of 63 SCLC patients were treated with AMR monotherapy between April 2009 and November 2014. Antiemetic therapy was administered on days 1-3, with 33 patients receiving 3 mg of granisetron (Group G) and 30 patients receiving 20 mg of metoclopramide (Group M). Nausea and vomiting were observed in 30.3% of Group G and 30.0% of Group M patients. The CR rate observed was 78.7% in Group G and 73.3% in Group M. There were no significant differences between Groups G and M. Conclusion: Both granisetron and metoclopramide were successfully used for anti-emesis during AMR monotherapy.

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Phase II study of amrubicin in previously untreated patients with extensive-disease small cell lung cancer: West Japan Thoracic Oncology Group (WJTOG) study

Abstract: Amrubicin was active for extensive-disease SCLC with acceptable toxicity. Further studies in combination with other agents for SCLC are warranted.

Cited by 102 publications

References 17 publications

Retrospective analysis of Japanese patients with relapse or refractory small-cell lung cancer treated with amrubicin hydrochloride

Retrospective analysis of Japanese patients with relapse or refractory small-cell lung cancer treated with amrubicin hydrochloride

Imatinib mesylate (STI571) enhances amrubicin-induced cytotoxic activity through inhibition of the phosphatidylinositol 3-kinase/Akt pathway in small cell lung cancer cells

Antiemetic Effects of Granisetron or Metoclopramide Administered Prior to Amrubicin Monotherapy

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