Dose escalation study of amrubicin and cisplatin with concurrent thoracic radiotherapy for limited-disease small cell lung cancer
Amrubicin and cisplatin is one of the active regimens used to treat patients with extensive-disease (ED)-small cell lung cancer (SCLC), whereas combined therapy involving chemotherapy and concurrent thoracic radiotherapy is the standard treatment for limited-disease (LD)-SCLC.
This study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of amrubicin and cisplatin with concurrent thoracic radiotherapy (TRT) for LD-SCLC.
Patients and methods
Patients that fulfilled the following eligibility criteria were enrolled: being aged ≤ 75 years and chemotherapy-naïve and having a performance status (PS) of 0–1, LD-SCLC, and adequate organ function. The patients received escalating doses of amrubicin on days 1, 2, and 3, and a fixed 60-mg/m2 dose of cisplatin on day 1. Four cycles of chemotherapy were administered, with each cycle lasting 4 weeks. TRT involving 2 Gy/day, once daily, commenced on day 2 of the first cycle of chemotherapy. The initial dose of amrubicin was 20 mg/m2 (level 1), and the dose was escalated to 25 mg/m2 (level 2) and then 30 mg/m2 (level 3).
Eight patients from three institutions were enrolled at three dose levels. The patients’ characteristics were as follows: male/female: 3/5; median age (range): 68.5 (60–73); PS 0/1: 4/4; stage IIIA/IIIB disease: 3/5. Both level 3 patients experienced DLT (grade 4 neutropenia and/or leukopenia lasting > 4 days). Level 3 was defined as the MTD, and level 2 was recommended as the dose for this regimen. Seven patients exhibited partial responses, and 1 displayed progressive disease (response rate: 88%). The median progression-free survival and overall survival periods were 11.1 and 39.5 months, respectively. No treatment-related deaths occurred.
When this regimen was combined with TRT for LD-SCLC, the MTD was 30 mg/m2 for amrubicin and 60 mg/m2 for cisplatin. In addition, neutropenia and leukopenia were DLT, and doses of 25 mg/m2 for amrubicin and 60 mg/m2 for cisplatin are recommended for this regimen.
KeywordsAmrubicin Cisplatin Small cell lung cancer Radiotherapy
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 1.National Cancer Center Japan, Center for Cancer Control and Information Services (2018). Available from http://ganjoho.jp/reg_stat/statistics/stat/short_pred.html. Cited 25 March 2018
- 4.Hanna N, Bunn PA Jr, Langer C, Einhorn L, Guthrie T Jr, Beck T, Ansari R, Ellis P, Byrne M, Morrison M, Hariharan S, Wang B, Sandler A (2006) Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 24:2038–2043CrossRefGoogle Scholar
- 5.Kubota K, Hida T, Ishikura S, Mizusawa J, Nishio M, Kawahara M, Yokoyama A, Imamura F, Takeda K, Negoro S, Harada M, Okamoto H, Yamamoto N, Shinkai T, Sakai H, Matsui K, Nakagawa K, Shibata T, Saijo N, Tamura T, Japan Clinical Oncology Group (2014) Etoposide and cisplatin versus irinotecan and cisplatin in patients with limited-stage small-cell lung cancer treated with etoposide and cisplatin plus concurrent accelerated hyperfractionated thoracic radiotherapy (JCOG0202): a randomized phase 3 study. Lancet Oncol 15:106–113CrossRefGoogle Scholar
- 6.Fukuda M, Nakamura Y, Kinoshita A, Soejima Y, Yamaguchi H, Ikeda T, Izumikawa K, Takatani H, Fukuda M, Soda H, Hayashi N, Tsukamoto K, Oka M, Kohno S (2012) Phase II study of irinotecan and cisplatin with concurrent split-course radiotherapy in limited-disease small cell lung cancer. Cancer Chemother Pharmacol 70:645–651CrossRefGoogle Scholar
- 9.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 25:253–258CrossRefGoogle Scholar
- 11.Noda K, Nishiwaki Y, Kawahara M, Negoro S, Sugiura T, Yokoyama A, Fukuoka M, Mori K, Watanabe K, Tamura T, Yamamoto S, Saijo N, Japan Clinical Oncology Group (2002) Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 346:85–91CrossRefGoogle Scholar
- 12.Satouchi M, Kotani Y, Shibata T, Ando M, Nakagawa K, Yamamoto N, Ichinose Y, Ohe Y, Nishio M, Hida T, Takeda K, Kimura T, Minato K, Yokoyama A, Atagi S, Fukuda H, Tamura T, Saijo N (2014) Phase III study comparing amrubicin plus cisplatin with irinotecan plus cisplatin in the treatment of extensive-disease small-cell lung cancer: JCOG0509. J Clin Oncol 32:1262–1268CrossRefGoogle Scholar
- 13.Sun Y, Cheng Y, Hao X, Wang J, Hu C, Han B, Liu X, Zhang L, Wan H, Xia Z, Liu Y, Li W, Hou M, Zhang H, Xiu Q, Zhu Y, Feng J, Qin S, Luo X (2016) Randomized phase III trial of amrubicin/cisplatin versus etoposide/cisplatin as first-line treatment for extensive small-cell lung cancer. BMC Cancer 16:265–272CrossRefGoogle Scholar
- 15.Ogawara D, Fukuda M, Nakamura Y, Kohno S (2010) Efficacy and safety of amrubicin hydrochloride for treatment of relapsed small cell lung cancer. Cancer Manag Res 2:191–195Google Scholar
- 17.Faivre-Finn C, Snee M, Ashcroft L, Appel W, Barlesi F, Bhatnagar A, Bezjak A, Cardenal F, Fournel P, Harden S, Le Pechoux C, McMenemin R, Mohammed N, O’Brien M, Pantarotto J, Surmont V, Van Meerbeeck JP, Woll PJ, Lorigan P, Blackhall F, CONVERT Study Team (2017) Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomized, superiority trial. Lancet Oncol 18:1116–1125CrossRefGoogle Scholar
- 18.Fukuda M, Soda H, Fukuda M, Kinoshita A, Nakamura Y, Nagashima S, Takatani H, Tsukamoto K, Kohno S, Oka M (2007) Irinotecan and cisplatin with concurrent split-course radiotherapy in locally advanced non-small cell lung cancer: a multiinstitutional phase 2 study. Cancer 110:606–613CrossRefGoogle Scholar