Top

Published in:

01-11-2019 | Kidney Cancer | Original Article

Optimal dose of sunitinib for long-term treatment in Japanese patients with renal cell carcinoma

Authors: Yuto Yamada, Yuta Ohno, Yu Kato, Ryo Kobayashi, Hideki Hayashi, Shiho Miyahara, Keita Nakane, Kosuke Mizutani, Shigeaki Yokoi, Hironori Fujii, Hirotoshi Iihara, Takuma Ishihara, Takashi Deguchi, Tadashi Sugiyama, Akio Suzuki

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2019

Abstract

Background/aim

Sunitinib is used for the treatment of metastatic renal cell carcinoma (mRCC). Asian patients, including Japanese, tend not to tolerate long-term sunitinib therapy of 50 mg p.o. once daily for 4 weeks, followed by 2 week off treatment due to severe adverse events at this dosage level. The aim of this retrospective study was to investigate the optimal dose of sunitinib for long-term continuation in Asian patients with mRCC.

Patients and methods

The study cases were 50 patients with mRCC who were treated with sunitinib between June 2008 and December 2017. Risk analysis for “unacceptable” adverse events (depending on the physician, ranging from grade 2 to ≥ grade 3) leading to discontinuation of sunitinib was determined by time-dependent Cox proportional hazard regression analysis.

Results

A total of 54 unacceptable adverse events leading to discontinuation occurred. Multivariable analysis indicated that a sunitinib dose of ≤ 37.5 mg/day significantly reduced the risk of discontinuation due to adverse events in comparison with 50 mg/day [hazard ratio (HR) 0.08, 95% confidence interval (CI) 0.03–0.21, p < 0.001). The progression-free survival (PFS) with a sunitinib dose ≤ 37.5 mg/day was longer than that associated with a dose of 50 mg/day, albeit not to a statistically significant degree (120 days for ≤ 37.5 mg/day vs 41 days for 50 mg/day, HR 0.39, 95% CI 0.10–1.44, p = 0.157).

Conclusion

Our findings suggest that the optimal dose of sunitinib for Asian, including Japanese, patients with mRCC is ≤ 37.5 mg/day.

Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9:327–337PubMed

Miyake H, Miyazaki A, Harada K, Fujisawa M (2014) Assessment of efficacy, safety and quality of life of 110 patients treated with sunitinib as first-line therapy for metastatic renal cell carcinoma: experience in real-world clinical practice in Japan. Med Oncol 31:978CrossRefPubMed

Cella D, Cappelleri JC, Bushmakin A, Charbonneau C, Li JZ, Kim ST, Chen I, Michaelson MD, Motzer RJ (2009) Quality of life predicts progression-free survival in patients with metastatic renal cell carcinoma treated with sunitinib versus interferon alfa. J Oncol Pract 5:66–70CrossRefPubMedPubMedCentral

Powers SW, Coffey CS, Chamberlin LA, Ecklund DJ, Klingner EA, Yankey JW, Korbee LL, Porter LL, Hershey AD, Investigators CHAMP (2017) Trial of amitriptyline, topiramate, and placebo for pediatric migraine. N Engl J Med 376:115–124CrossRefPubMed

Liu X, Fiocco M, Swen JJ, Guchelaar HJ (2017) Assessment of ethnic differences in sunitinib outcome between Caucasian and Asian patients with metastatic renal cell carcinoma: a meta-analysis. Acta Oncol 56:582–589CrossRefPubMed

Uemura H, Shinohara N, Yuasa T, Tomita Y, Fujimoto H, Niwakawa M, Mugiya S, Miki T, Nonomura N, Takahashi M, Hasegawa Y, Agata N, Houk B, Naito S, Akaza H (2010) A Phase II study of sunitinib in japanese patients with metastatic renal cell carcinoma: insights into the treatment, efficacy and safety. Jpn J Clin Oncol 40:194–202CrossRefPubMed

Tomita Y, Shinohara N, Yuasa T, Fujimoto H, Niwakawa M, Mugiya S, Miki T, Uemura H, Nonomura N, Takahashi M, Hasegawa Y, Agata N, Houk B, Naito S, Akaza H (2010) Overall survival and updated results from a phase II study of sunitinib in Japanese patients with metastatic renal cell carcinoma. Jpn J Clin Oncol 40:1166–1172CrossRefPubMed

US Department of Health and Human Services. National Institutes of Health National Cancer Institute (2009) Common terminology criteria for adverse events (CTCAE) Version 4.0. https://www.eortc.be/services/doc/ctc/; Accessed 24 March 2019

Akaza H, Naito S, Ueno N, Aoki K, Houzawa H, Pitman Lowenthal S, Lee SY (2015) Real-world use of sunitinib in Japanese patients with advanced renal cell carcinoma: efficacy, safety and biomarker analyses in 1689 consecutive patients. Jpn J Clin Oncol 45:576–583CrossRefPubMedPubMedCentral

10.

Kawashima A, Tsujimura A, Takayama H, Arai Y, Nin M, Tanigawa G, Yasunaga Y, Mukai M, Uemura M, Nakai Y, Nishimura K, Nonomura N, Osaka Renal Cell Carcinoma Clinical Study Collaboration (2012) Importance of continuing therapy and maintaining one-month relative dose intensity in sunitinib therapy for metastatic renal cell carcinoma. Importance of continuing therapy and maintaining one-month relative dose intensity in sunitinib therapy for metastatic renal cell carcinoma. Med Oncol 29:3298–3305CrossRefPubMed

11.

Nagata M, Ishiwata Y, Takahashi Y, Takahashi H, Saito K, Fujii Y, Kihara K, Yasuhara M (2015) Pharmacokinetic-pharmacodynamic analysis of sunitinib-induced thrombocytopenia in Japanese patients with renal cell carcinoma. Biol Pharm Bull 38:402–410CrossRefPubMed

12.

Teo YL, Chue XP, Chau NM, Tan MH, Kanesvaran R, Wee HL, Ho HK, Chan A (2015) Association of drug exposure with toxicity and clinical response in metastatic renal cell carcinoma patients receiving an attenuated dosing regimen of sunitinib. Target Oncol 10:429–437CrossRefPubMed

13.

Mizuno M, Iizuka K, Ishihara T, Fukaya S, Yoshida S, Takeda J (2019) High dose prednisolone lowers plasma glycated albumin levels compared to actual glycemic control: a retrospective observational study. Diabetes Ther 10:269–276CrossRefPubMed

14.

Simon R, Makuch RW (1984) A non-parametric graphical representation of the relationship between survival and the occurrence of an event: application to responder versus nonresponder bias. Stat Med 3:35–44CrossRefPubMed

15.

Noda S, Otsuji T, Baba M, Yoshida T, Kageyama S, Okamoto K, Okada Y, Kawauchi A, Onishi H, Hira D, Morita SY, Terada T (2015) Assessment of sunitinib-induced toxicities and clinical outcomes based on therapeutic drug monitoring of sunitinib for patients with renal cell carcinoma. Clin Genitourin Cancer 13:350–358CrossRefPubMed

16.

Takasaki S, Kawasaki Y, Kikuchi M, Tanaka M, Suzuka M, Noda A, Sato Y, Yamashita S, Mitsuzuka K, Saito H, Ito A, Yamaguchi H, Arai Y, Mano N (2018) Relationships between sunitinib plasma concentration and clinical outcomes in Japanese patients with metastatic renal cell carcinoma. Int J Clin Oncol 23:936–943CrossRefPubMed

17.

Ruiz-Morales JM, Swierkowski M, Wells JC, Fraccon AP, Pasini F, Donskov F, Bjarnason GA, Lee JL, Sim HW, Sliwczynsk A, Ptak-Chmielewska A, Teter Z, Beuselinck B, Wood LA, Yuasa T, Pezaro C, Rini BI, Szczylik C, Choueiri TK, Heng DY (2016) First-line sunitinib versus pazopanib in metastatic renal cell carcinoma: results from the international metastatic renal cell carcinoma database consortium. Eur J Cancer 65:102–108CrossRefPubMed

18.

Lakomy R, Poprach A, Bortlicek Z, Melichar B, Chloupkova R, Vyzula R, Zemanova M, Kopeckova K, Svoboda M, Slaby O, Kiss I, Studentova H, Juracek J, Fiala O, Kopecky J, Finek J, Dusek L, Hejduk K, Buchler T, Lakomy R, Poprach A, Bortlicek Z, Melichar B, Chloupkova R, Vyzula R, Zemanova M, Kopeckova K, Svoboda M, Slaby O, Kiss I, Studentova H, Juracek J, Fiala O, Kopecky J, Finek J, Dusek L, Hejduk K, Buchler T (2017) Utilization and efficacy of second-line targeted therapy in metastatic renal cell carcinoma: data from a national registry. BMC Cancer 17:880CrossRefPubMedPubMedCentral

19.

Takahito N, Kei N, Hidenori I, Nobuki F, Kenichi T, Motonobu N (2018) Efficacy and safety of third- and fourth-line targeted therapy in Japanese patients with metastatic renal cell carcinoma: a retrospective analysis. Indian J Urol 34:127–132CrossRefPubMedPubMedCentral

20.

Mizuno T, Terada T, Kamba T, Fukudo M, Katsura T, Nakamura E, Ogawa O, Inui K (2010) ABCG2 421C > A polymorphism and high exposure of sunitinib in a patient with renal cell carcinoma. Ann Oncol 21:1382–1383CrossRefPubMed

21.

Mizuno T, Fukudo M, Terada T, Kamba T, Nakamura E, Ogawa O, Inui K, Katsura T (2012) Impact of genetic variation in breast cancer resistance protein (BCRP/ABCG2) on sunitinib pharmacokinetics. Drug Metab Pharmacokinet 27:631–639CrossRefPubMed

22.

Mizuno T, Fukudo M, Fukuda T, Terada T, Dong M, Kamba T, Yamasaki T, Ogawa O, Katsura T, Inui K, Vinks AA, Matsubara K (2014) The effect of ABCG2 genotype on the population pharmacokinetics of sunitinib in patients with renal cell carcinoma. Ther Drug Monit 36:310–316CrossRefPubMed

23.

Title: Optimal dose of sunitinib for long-term treatment in Japanese patients with renal cell carcinoma
Authors: Yuto Yamada
Yuta Ohno
Yu Kato
Ryo Kobayashi
Hideki Hayashi
Shiho Miyahara
Keita Nakane
Kosuke Mizutani
Shigeaki Yokoi
Hironori Fujii
Hirotoshi Iihara
Takuma Ishihara
Takashi Deguchi
Tadashi Sugiyama
Akio Suzuki
Publication date: 01-11-2019
Publisher: Springer Berlin Heidelberg
Keywords: Kidney Cancer
Kidney Cancer
Kidney Cancer
Sunitinib
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03935-x

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background/aim

Patients and methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 5/2019

Real-world data on initial treatment strategies for older adult patients with endometrial cancer in Japan

Serum microRNA-21 predicted treatment outcome and survival in HER2-positive breast cancer patients receiving neoadjuvant chemotherapy combined with trastuzumab

Pharmacokinetics and safety of neratinib during co-administration with loperamide in healthy subjects

A phase II trial of induction of erlotinib followed by cytotoxic chemotherapy for EGFR mutation-positive non-squamous non-small cell lung cancer patients

Exposure–response analysis to inform the optimal dose of veliparib in combination with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer patients

Polymorphisms of genes encoding drug transporters or cytochrome P450 enzymes and association with clinical response in cancer patients: a systematic review

Keynote webinar | Spotlight on antibody–drug conjugates in cancer