The Clinical Significance of Erythrocytic Macrocytosis in Metastatic Renal Cell Cancer and Sarcoma Patients Treated with Pazopanib

Abstract

Objective: Pazopanib is a multi-kinase inhibitor used in metastatic renal cell carcinoma or sarcomas (mRCC or mSTS). We aimed to investigate the relationship between pazopanib and macrocytosis and evaluate the clinical significant of this effect in mRCC or mSTS. Methods: Patients diagnosed with mRCC and mSTS and have been treated with pazopanib were included. Drug-induced macrocytosis was defined as MCV >100 fL during any mount of treatment. ΔMCV was defined as difference between MCV during pazopanib treatment and baseline MCV. Data was collected retrospectively. Results: 50 patients were included the study. During the pazopanib treatment, significant increase in MCV levels was observed and the mean MCV at the 0, 1, 3, 6, and 9 months were found as 86.7±7.6 fL, 87.8 ± 7.5, 92.4 ± 8.9, 94.8 ± 11.1 and 99.0 ± 10.7 fL, retrospectively (p<0.001). In the group with ΔMCV3 ≥ 5fL, median PFS was found 48.0 months (95% CI, 26.3-69.9); in the group with ΔMCV3 <5, it was 25 months (95% CI, 14.6-35.4) (p:0.036). Median PFS was 21.0 months (%95 CI, 0-46.3) for macrocytic patients compared to 4.0 months (%95 CI, 2.0-5.9) in normocytic patients (p:0.023).There was no statistically significant difference between the groups for overall survival. Conclusion: A significant increases in MCV values or the development of macrocytosis during the pazopanib treatment in mRCC and mSTS, can be used as an important biomarker for progression-free survival.

Keywords

• Mean Corpuscular Volume (MCV)
• Macrocytosis
• Pazopanib
• Progression-free Survival

Metastatik Renal Hücreli Kanser ve Metastatik Sarkom Tedavisi Sırasında Gelişen Pazopanib İlişkili Makrositoz’un Klinik Önemi

Öz

Amaç: Pazopanib, metastatik renal hücreli karsinom (mRHK) ve metastatik yumuşak doku kanserlerinde (mYDK) kullanılan multi-kinaz inhibitörüdür. Çalışmamızda pazopanib tedavisinin ortalama eritrosit hacmi (MCV) üzerine etkisinin ve progresyonsuz sağkalım süresi (PSS) ve genel sağkalım süresi (GSS) üzerine etkilerinin incelenmesi amaçlanmıştır. Yöntem: Çalışmamız tek merkezli, retrospektif olarak planlandı ve mRHK veya mYDK tanılı ve pazopanib kullanan hastalar dahil edilmiştir. ΔMCV, tedavinin belli bir ayındaki MCV ile başlangıç MCV arasındaki fark; makrositoz ise tedavinin herhangi bir ayında MCV >100 fL olarak tanımlanmıştır. MCV artışı ve makrositoz ile sağkalım ilişkisi istatiksel olarak analiz edilmiştir. Bulgular: Hasta sayısı 50 idi. Pazopanib ile 0.ay, 1.ay, 3.ay, 6.ay ve 9.ay ortalama MCV değerleri sırasıyla 86,7 ± 7,6, 87,8 ± 7,5, 92,4 ± 8,9, 94,8 ± 11,1 ve 99,0 ± 10,7 fL olarak hesaplandı (p<0,001). Yirmi iki hastanın (%44) üçüncü MCV’si 5 fL ve üzeri artmış olarak bulundu. Hastaların 14’ ünde (%28) makrositoz gelişti. Üçüncü ayda ΔMCV 5 fL ve üstü olanların mPSS 48.0 ay (%95 CI, 26.3-69.9) iken; 5’in altı olanlarda mPSS 25 ay (%95 CI, 14.6-35.4) olarak bulundu (p:0.036). Makrositoz olmayan hastalarda mPSS 4.0 ay iken (%95 CI, 2.0-5.9); makrositoz gelişen hastalarda mPSS 21.0 ay (%95 CI, 0-46.3) olarak bulundu (p: 0.023). ΔMCV ve makrositoz gelişimi ile GSS arasında istatiksel anlamlı bir fark bulunmadı. Sonuç: Pazopanib ile tedavi edilen mRHK ve mYDK’ de, MCV değerlerindeki anlamlı artışın veya makrositoz gelişiminin, prospektif çalışmalar ile valide edildiği takdirde önemli bir gösterge olabileceğini düşünmekteyiz.

Anahtar Kelimeler

• Ortalama eritrosit hacmi (MCV)
• Makrositoz
• Pazopanib
• Progresyonsuz Sağkalım

References

1. REFERENCES 1. Shingo Miyamoto, Shigenori Kakutani, Yujiro Sato, Akira Hanashi, Yoshitaka Kinoshita, Akira Ishikawa, Drug review: Pazopanib, Jpn J Clin Oncol 2018; 48(6):503-13.
2. 2. Schallier D, Trullemans F, Fontaine C, Decoster L, De Greve J. Tyrosine Kinase Inhibitor-induced Macrocytosis, Anticancer Research 2009; 29 (12): 5225-28.
3. 3. Jain L, Sissung TM, Danesi R, Kohn EC, Dahut WL, Kummar S, Venzon D, Liewehr D, English BC, Baum CE, Yarchoan R, Giaccone G, Venitz J, Price DK, Figg WD. Hypertension and hand-foot skin reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib. J Exp Clin Cancer Res. 2010;29:95.
4. 4. Poprach A, Pavlik T, Melichar B, Puzanov I, Dusek L, Bortlicek Z, Vyzula R, Abrahamova J, Buchler T; Czech Renal Cancer Cooperative Group. Skin toxicity and efficacy of sunitinib and sorafenib in metastatic renal cell carcinoma: a national registry-based study. Ann Oncol. 2012;23(12):3137-43.
5. 5. Huang PW, Chou WC, Shen WC, Hung CY, Huang KG, Su YL, Lu CH, Liu CT, Chang YS, Liau CT. Hand-foot skin reaction predicts treatment outcome of pazopanib in patients with metastatic soft tissue sarcoma: A multicenter study in the Asian population. Asia Pac J Clin Oncol. 2018;14(4):353-60.
6. 6. Kaferle J, Strzoda CE. Evaluation of macrocytosis. Am Fam Physician. 2009;79(3):203-8.
7. 7. Kloth JSL, Hamberg P, Mendelaar PAJ, Dulfer RR, van der Holt B, Eechoute K, Wiemer EAC, Kruit WHJ, Sleijfer S, Mathijssen RHJ. Macrocytosis as a potential parameter associated with survival after tyrosine kinase inhibitor treatment. Eur J Cancer. 2016;56:101-6.
8. 8. Burns ER, Reed LJ, Wenz B. Volumetric erythrocyte macrocytosis induced by hydroxyurea. AmJ Clin Pathol 1986;85(3):337-41.

9. 9. Karvellas CJ, Sawyer M, Hamilton M, Mackey JR. Effect of capecitabine on mean corpuscular volume in patients with metastatic breast cancer. Am J Clin Oncol 2004;27(4):364-8.
10. 10. Weinblatt ME, Fraser P. Elevated mean corpuscular volume as a predictor of hematologic toxicity due to methotrexate therapy. Arthritis Rheum 1989;32(12):1592-6.
11. 11. Bourlon MT, Gao D, Trigero S, Clemons JE, Breaker K, Lam ET, Flaig TW. Clinical significance of sunitinib-associated macrocytosis in metastatic renal cell carcinoma. Cancer Med. 2016;5(12):3386-93.
12. 12. Kumar A, Burton JK, Suman VJ , Qin R, Erlichman C, Harris HPPJ , Bible KC. Effects of pazopanib therapy on mean corpuscular volume in patients enrolled in MC1112: Analysis of correlation with time to disease progression in solid tumors. 2015 ASCO Annual Meeting I. jco.2015.33.15_suppl.e13596 Journal of Clinical Oncology 33, no. 15_suppl.
13. 13. Billemont B, Izzedine H, Rixe O. Macrocytosis due to treatment with sunitinib. N Engl J Med 2007;27;357(13):1351-2.
14. 14. Price J, Shaarbaf R, Wood L. Sunitinib causes macrocytosis in patients with advanced renal cell carcinoma. Curr Oncol 2010 Apr;17(2):30-3.
15. 15. Kucharz J, Giza A, Dumnicka P, Kuzniewski M, Kusnierz-Cabala B, Bryniarski P, Herman R, Zygulska AL, Krzemieniecki K. Macrocytosis during sunitinib treatment predicts progression-free survival in patients with metastatic renal cell carcinoma. Med Oncol 2016 Aug; 33(10):109.