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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 6/2012

01-06-2012 | Original Article

Phase I trial of irinotecan and amrubicin with granulocyte colony-stimulating factor support in extensive-stage small-cell lung cancer

Authors: Maiko Asakuma, Michiko Yamamoto, Mayuko Wada, Shinichiro Ryuge, Ken Katono, Masanori Yokoba, Tomoya Fukui, Akira Takakura, Sakiko Otani, Sachiyo Maki, Satoshi Igawa, Tomoko Yanaihara, Hisashi Mitsufuji, Masaru Kubota, Masato Katagiri, Jiichiro Sasaki, Noriyuki Masuda

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2012

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Abstract

Purpose

We conducted a phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with amrubicin, a topoisomerase II inhibitor, with recombinant human granulocyte colony-stimulating factor (rhG-CSF) support to overcome the neutropenia associated with this particular combination. The aim was to determine the maximum tolerated dose (MTD) of amrubicin combined with a fixed dose of CPT-11 and the dose-limiting toxicities (DLTs) of this combination in extensive-stage small-cell lung cancer (ED-SCLC) patients.

Methods

Fifteen patients with ED-SCLC were treated at 3-week intervals with amrubicin on days 1–3 plus 60 mg/m2 CPT-11 on days 1 and 8. In addition, prophylactic rhG-CSF (50 μg/m2) was given from day 4 to day 21, except on the day of CPT-11 administration. Amrubicin was started at 30 mg/m2 and then escalated in 5 mg/m2 increments until MTD was reached.

Results

The MTD of amrubicin was 35 mg/m2, since 2 of 4 patients experienced DLTs during the first cycle of treatment at the 40 mg/m2 dose level. Neutropenia, neutropenic fever, ileus, and diarrhea were the DLTs. There were 13 partial responses among the 13 assessable patients, yielding an overall response rate of 100 %. Median progression-free survival and overall survival were 7.4 months and 13.4 months, respectively.

Conclusion

The combination of amrubicin and CPT-11 showed high activity against ED-SCLC with acceptable toxicity. Use of rhG-CSF allowed the dose of amrubicin to be raised 40 % above that in the original regimen (60 mg/m2 CPT-11 and 25 mg/m2 amrubicin).
Literature
1.
Azoulay E, Attalah H, Harf A, Schlemmer B, Delclaux C (2001) Granulocyte colony-stimulating factor or neutrophil-induced pulmonary toxicity: myth or reality? Systematic review of clinical case reports and experimental data. Chest 120:1695–1701PubMedCrossRef
2.
Bugat R (2003) Irinotecan in the treatment of gastric cancer. Ann Oncol 14(Suppl 2):ii37–ii40PubMed
3.
Calhoun EA, Schumock GT, McKoy JM, Pickard S, Fitzner KA, Heckinger EA, Powell EF, McCaffrey KR, Bennett CL (2005) Granulocyte colony–stimulating factor for chemotherapy-induced neutropenia in patients with small cell lung cancer: the 40% rule revisited. Pharmacoeconomics 23:767–775PubMedCrossRef
4.
Ceppi P, Papotti M, Scagliotti G (2010) New strategies for targeting the therapy of NSCLC: the role of ERCC1 and TS. Adv Med Sci 55:22–25PubMedCrossRef
5.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247PubMedCrossRef
6.
Friedman HS, Keir ST, Houghton PJ (2003) The emerging role of irinotecan (CPT-11) in the treatment of malignant glioma in brain tumors. Cancer 97:2359–2362PubMedCrossRef
7.
Fujita K, Ando Y, Nagashima F, Yamamoto W, Eodo H, Araki K, Kodama K, Miya T, Narabayashi M, Sasaki Y (2007) Genetic linkage of UGT1A7 and UGT1A9 polymorphisms to UGT1A1*6 is associated with reduced activity for SN-38 in Japanese patients with cancer. Cancer Chemother Pharmacol 60:515–522PubMedCrossRef
8.
Ganti AK, Huang CH, Klein MA, Keefe S, Kelley MJ (2011) Lung cancer management in 2010. Oncology (Williston Park) 25:64–73
9.
Ganti AK, West WW, Lackner RP, Kessinger A (2010) Current concepts in the diagnosis and management of small-cell lung cancer. Oncology (Williston Park) 24:1034–1039
10.
Gertz MA, Lacy MQ, Bjornsson J, Litzow MR (2000) Fatal pulmonary toxicity related to the administration of granulocyte colony-stimulating factor in amyloidosis: a report and review of growth factor-induced pulmonary toxicity. J Hematother Stem Cell Res 9:635–643PubMedCrossRef
11.
Ishizumi K, Ohashi N, Tanno N et al (1987) Stereospecific total synthesis of 9-aminoanthracyclines: (+)-9-amino-9-deoxydaunomycin and related compounds. J Org Chem 52:4477–4485CrossRef
12.
Katoh M, Shikoshi K, Takada M, Umeda M, Tsukahara T, Kitagawa S, Shirai T (1993) Development of interstitial pneumonitis during treatment with granulocyte colony-stimulating factor. Ann Hematol 67:201–202PubMedCrossRef
13.
Kimura I, Ohonoshi T, Okabe T, Takaku F, Nishiwaki H, Saijo N, Ikegami H, Fukuoka M, Furuse K (1990) [Clinical trial of KRN 8601 in patients with neutropenia induced by chemotherapy for lung cancer]. Gan to kagaku ryoho. Cancer chemother 17:999–1003
14.
Kudoh S, Kato H, Nishiwaki Y, Fukuoka M, Nakata K, Ichinose Y, Tsuboi M, Yokota S, Nakagawa K, Suga M, Jiang H, Itoh Y, Armour A, Watkins C, Higenbottam T, Nyberg F (2008) Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study. Am J Respir Crit Care Med 177:1348–1357PubMedCrossRef
15.
Langer CJ (2003) The global role of irinotecan in the treatment of lung cancer: 2003 update. Oncology (Huntingt) 17:30–40
16.
Martin LP, Hamilton TC, Schilder RJ (2008) Platinum resistance: the role of DNA repair pathways. Clin Cancer Res 14:1291–1295PubMedCrossRef
17.
Masuda N, Fukuoka M, Fujita A, Kurita Y, Tsuchiya S, Nagao K, Negoro S, Nishikawa H, Katakami N, Nakagawa K, Niitani H (1998) A phase II trial of combination of CPT-11 and cisplatin for advanced non-small-cell lung cancer. CPT-11 Lung Cancer Study Group. Br J Cancer 78:251–256PubMedCrossRef
18.
Masuda N, Fukuoka M, Kudoh S, Matsui K, Kusunoki Y, Takada M, Nakagawa K, Hirashima T, Tsukada H, Yana T et al (1994) Phase I and pharmacologic study of irinotecan and etoposide with recombinant human granulocyte colony-stimulating factor support for advanced lung cancer. J Clin Oncol 12:1833–1841PubMed
19.
Masuda N, Fukuoka M, Takada M, Kusunoki Y, Negoro S, Matsui K, Kudoh S, Takifuji N, Nakagawa K, Kishimoto S (1992) CPT-11 in combination with cisplatin for advanced non-small-cell lung cancer. J Clin Oncol 10:1775–1780PubMed
20.
Masuda N, Kudoh S, Fukuoka M (1996) Irinotecan (CPT-11): pharmacology and clinical applications. Crit Rev Oncol Hematol 24:3–26PubMedCrossRef
21.
Masuda N, Matsui K, Negoro S, Takifuji N, Takeda K, Yana T, Kobayashi M, Hirashima T, Kusunoki Y, Ushijima S, Kawase I, Tada T, Sawaguchi H, Fukuoka M (1998) Combination of irinotecan and etoposide for treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 16:3329–3334PubMed
22.
Negoro S, Fukuoka M, Masuda N, Takada M, Kusunoki Y, Matsui K, Takifuji N, Kudoh S, Niitani H, Taguchi T (1991) Phase I study of weekly intravenous infusions of CPT-11, a new derivative of camptothecin, in the treatment of advanced non-small-cell lung cancer. J Natl Cancer Inst 83:1164–1168PubMedCrossRef
23.
Niitsu N, Iki S, Muroi K, Motomura S, Murakami M, Takeyama H, Ohsaka A, Urabe A (1997) Interstitial pneumonia in patients receiving granulocyte colony-stimulating factor during chemotherapy: survey in Japan 1991–96. Br J Cancer 76:1661–1666PubMedCrossRef
24.
Onoda S, Masuda N, Seto T, Eguchi K, Takiguchi Y, Isobe H, Okamoto H, Ogura T, Yokoyama A, Seki N, Asaka-Amano Y, Harada M, Tagawa A, Kunikane H, Yokoba M, Uematsu K, Kuriyama T, Kuroiwa Y, Watanabe K (2006) Phase II trial of amrubicin for treatment of refractory or relapsed small-cell lung cancer: Thoracic Oncology Research Group Study 0301. J Clin Oncol 24:5448–5453PubMedCrossRef
25.
Rodriguez E, Lilenbaum RC (2010) Small cell lung cancer: past, present, and future. Curr Oncol Rep 12:327–334PubMedCrossRef
26.
Sawa T, Yana T, Takada M, Sugiura T, Kudoh S, Kamei T, Isobe T, Yamamoto H, Yokota S, Katakami N, Tohda Y, Kawakami A, Nakanishi Y, Ariyoshi Y (2006) Multicenter phase II study of amrubicin, 9-amino-anthracycline, in patients with advanced non-small-cell lung cancer (Study 1): West Japan Thoracic Oncology Group (WJTOG) trial. Invest New Drugs 24:151–158PubMedCrossRef
27.
Shishido Y, Furuta T, Matsuzaki T, Nagata H, Hashimoto S (2010) Efficacy of combination treatment and influence of schedule with irinotecan and amrubicin in human lung carcinoma cells in vivo and in vitro. Biol Pharm Bull 33:1183–1191PubMedCrossRef
28.
Vasey PA, Kaye SB (1997) Combined inhibition of topoisomerases I and II–is this a worthwhile/feasible strategy? Br J Cancer 76:1395–1397PubMedCrossRef
29.
Yamamoto M, Takakura A, Masuda N (2009) Next-generation anthracycline for the management of small cell lung cancer: focus on amrubicin. Drug Des Devel Ther 2:189–192PubMed
30.
Yamaoka T, Hanada M, Ichii S, Morisada S, Noguchi T, Yanagi Y (1998) Cytotoxicity of amrubicin, a novel 9-aminoanthracycline, and its active metabolite amrubicinol on human tumor cells. Jpn J Cancer Res 89:1067–1073PubMedCrossRef
31.
Yana T, Negoro S, Takada M, Yokota S, Takada Y, Sugiura T, Yamamoto H, Sawa T, Kawahara M, Katakami N, Ariyoshi Y, Fukuoka M (2007) Phase II study of amrubicin in previously untreated patients with extensive-disease small cell lung cancer: West Japan Thoracic Oncology Group (WJTOG) study. Invest New Drugs 25:253–258PubMedCrossRef
32.
Yanaihara T, Yokoba M, Onoda S, Yamamoto M, Ryuge S, Hagiri S, Katagiri M, Wada M, Mitsufuji H, Kubota M, Arai S, Kobayashi H, Yanase N, Abe T, Masuda N (2007) Phase I and pharmacologic study of irinotecan and amrubicin in advanced non-small cell lung cancer. Cancer Chemother Pharmacol 59:419–427PubMedCrossRef
Metadata
Title
Phase I trial of irinotecan and amrubicin with granulocyte colony-stimulating factor support in extensive-stage small-cell lung cancer
Authors
Maiko Asakuma
Michiko Yamamoto
Mayuko Wada
Shinichiro Ryuge
Ken Katono
Masanori Yokoba
Tomoya Fukui
Akira Takakura
Sakiko Otani
Sachiyo Maki
Satoshi Igawa
Tomoko Yanaihara
Hisashi Mitsufuji
Masaru Kubota
Masato Katagiri
Jiichiro Sasaki
Noriyuki Masuda
Publication date
01-06-2012
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 6/2012
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-012-1858-2

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