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Table of Contents
CASE REPORT
Year : 2019  |  Volume : 2  |  Issue : 1  |  Page : 26-28

Escalating erythrocytosis after start of pazopanib-treatment in metastatic renal cell carcinoma


Department of Internal Medicine, Medical Centre Leeuwarden (MCL), Leeuwarden, The Netherlands

Date of Web Publication26-Jun-2019

Correspondence Address:
Drs. Pepijn M Langbroek
Department of Internal Medicine, Polikliniek Interne Geneeskunde, Treant Zorggroep Ziekenhuislocatie Scheper, Postbus 30002, 7800 RA Emmen
The Netherlands
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCO.JCO_24_18

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  Abstract 

Renal cell carcinoma accounts for 2% of adult malignancies in the Netherlands. Metastatic disease is often treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors, such as pazopanib. This treatment is known to cause a slight increase in hemoglobin level during treatment. We present a patient who was diagnosed with metastatic renal cell carcinoma during analyses for erythrocytosis and who developed a further rise in hemoglobin level to 13.2 mmol/L 2 weeks after starting pazopanib treatment. Multiple phlebotomies were necessary before symptoms improved. Preexistent erythrocytosis should be considered as a risk factor for symptomatic erythrocytosis during pazopanib treatment and warrants timely laboratory follow-up and phlebotomies if indicated.

Keywords: Erythrocytosis, pazopanib, phlebotomies, renal cell carcinoma


How to cite this article:
Langbroek PM, Polée MB, de Graaf H. Escalating erythrocytosis after start of pazopanib-treatment in metastatic renal cell carcinoma. J Curr Oncol 2019;2:26-8

How to cite this URL:
Langbroek PM, Polée MB, de Graaf H. Escalating erythrocytosis after start of pazopanib-treatment in metastatic renal cell carcinoma. J Curr Oncol [serial online] 2019 [cited 2019 Oct 18];2:26-8. Available from: http://www.journalofcurrentoncology.org/text.asp?2019/2/1/26/261473




  Introduction Top


Renal cell carcinoma (RCC) accounts for 2% of adult malignancies in the Netherlands. Clear cell type RCC (ccRCC) is the most common subtype and is known for its paraneoplastic syndromes. One of these syndromes, erythrocytosis, is thought to be caused by an overproduction of erythropoietin (EPO) and vascular endothelial growth factor (VEGF).[1] Therapy for incurable RCC is largely based on targeting VEGF with VEGF receptor tyrosine kinase inhibitors (TKIs) such as sunitinib and pazopanib. TKIs can lead to a diversity of adverse effects, ranging from hypertension to hepatotoxicity. A rise in hemoglobin level caused by TKIs has been reported previously, but has required therapy in only a few of described cases.[2],[3],[4],[5],[6],[7] We describe a patient who developed a symptomatic polycythemia concurrent with hepatic toxicity shortly after starting pazopanib treatment for recently diagnosed metastatic ccRCC.


  Case History Top


A 71-year-old woman was referred to our hospital after being diagnosed with a T2bNxM1 Motzer score 2 ccRCC with pulmonary, retroperitoneal, and suspected pancreatic metastases. The tumor was discovered during analysis for a hemoglobin level of 11.9 mmol/L (n = 7.5–10 mmol/L). She was a nonsmoker and was hypertensive. Further background was unremarkable. Screening for JAK2 mutation was negative. Treatment with pazopanib 400mg once daily was started after confirmation of diagnosis on renal biopsy. Two weeks after pazopanib treatment was started, the treatment was postponed due to the occurrence of nausea, vomiting, and drowsiness. She was admitted to our hospital for further analysis. Laboratory tests revealed a rise in hemoglobin level to 13.3 mmol/L. EPO concentration was 46.0 U/L (n = 4.5–19.6 U/L). Brain imaging was normal. We suspected hepatic encephalopathy due to disorders in liver biochemical tests up to aspartate transaminase 256 U/L (n = <40 U/L), alanine transaminase 162 U/L (n = <45 U/L), alkaline phosphatase 294 U/L (n = <120 U/L), gamma glutamyl transpeptidase 108 U/L (n = <40 U/L), albumin 18g/L (n = 35–50g/L), and ammonia 51 μmol/L (n = <30 μmol/L). Lactulose and fluid therapy were started. However, symptoms persisted and hemoglobin level remained stable. After consulting a hematologist, we started treatment with phlebotomies. Over the course of 2 weeks, 2750mL of blood was drained. Sensorium improved shortly after initiation of phlebotomies. After 2 weeks, our patient was sufficiently recovered and was discharged. Several months after discharge, hemoglobin level had remained stable and EPO level had not relevantly changed [Table 1], [Figure 1]. Computed tomography imaging was repeated and showed stable disease.
Table 1: Laboratory test results during follow-up

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Figure 1: Hemoglobin concentration and hematocrit

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  Discussion Top


We report a patient who developed a further rise of an already high hemoglobin level within 2 weeks after starting pazopanib treatment for recently diagnosed metastatic ccRCC. Erythrocytosis was diagnosed simultaneously with diagnosis of acute liver failure with hepatic encephalopathy, a known complication of pazopanib treatment.

Several authors have reported the occurrence of erythrocytosis during treatment with TKIs, sometimes requiring treatment with phlebotomies [Table 2].[2],[3],[4],[5],[6],[7] Van der Veldt et al.[2] found the rise in hemoglobin level to reoccur in subsequent treatment cycles, confirming causal relationship. Various explanations for the rise in hemoglobin level due to VEGF TKIs have been proposed. Several authors speculate an enhanced EPO production is responsible, possibly in response to stringent VEGF receptor blockage.[3],[4],[5] This lead to the hypothesis that the development of erythrocytosis might be a favorable prognostic clinical marker for response to treatment.[5] However, Tripathi et al.[6] found the degree of hemoglobin increase to be correlated with a worse progression-free survival. Not all authors found an increased EPO level in their patients.[7] Therefore, EPO-independent mechanisms might also exist. Alexandrescu et al.[7] speculates a sensitization to the effects of EPO through TKI inhibition is possible. According to van der Veldt et al.[2] a reduction in plasma volume caused by VEGF receptor 2 blockage might be responsible, as hemoglobin level decreased rapidly after discontinuation of therapy in their patients. EPO level in our patient was high on admission, but did not relevantly change after discontinuation of pazopanib therapy. It, therefore, seems unlikely that pazopanib caused a rise in EPO level in our patient. As the rise in hemoglobin level occurred shortly after start of pazopanib treatment and erythrocytosis did not reoccur after cessation of pazopanib treatment, a relation between pazopanib treatment and the increase of hemoglobin level in our patient does seem probable (Naranjo Causality Scale, score: 6).[8] We speculate pazopanib might have stimulated erythropoiesis through EPO-independent mechanisms. Dehydration might also have been a factor in our patient.
Table 2: Overview of hemoglobin rise and number of patients treated with phlebotomies in earlier studies

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Secondary erythrocytosis does not always require treatment. In polycythemia vera, phlebotomies and aspirin are the mainstay of therapy, preventing thrombosis and treating symptoms. In a case series regarding secondary erythrocytosis due to VEGF TKIs, treatment with phlebotomies was initiated in all cases due to symptoms such as headaches, hypertension, and weakness.[6] None of the authors mention prophylactic antithrombotic therapy or secondary thrombotic complications. Braekkan et al.[9] published a prospective cohort study describing the incidence of venous thromboembolism (VTE) in 26,108 subjects in a general population. A 5% increase in hematocrit was associated with an age-adjusted hazard ratio for VTE of 1.35. Randi et al.[10] reported thrombotic events in 14% of patients with idiopathic erythrocytosis, compared to 40% of patients with polycythemia vera. Thus, secondary erythrocytosis is a risk factor for thrombotic events, however, not to the same degree as is the case in polycythemia vera. We suggest prophylactic antithrombotic treatment should only be considered when other risk factors for thrombosis are present. We would advise treatment with phlebotomies if clinical symptoms are present or when hemoglobin level is extremely high.

In conclusion, preexistent paraneoplastic erythrocytosis should be considered as a risk factor for further elevation of hemoglobin level during VEGF-targeted therapy and should warrant timely laboratory follow-up. Phlebotomies can be considered when symptoms of erythrocytosis occur.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Ding GX, Feng CC, Song NH, Fang ZJ, Xia GW, Jiang HW, et al. Paraneoplastic symptoms: cachexia, polycythemia, and hypercalcemia are, respectively, related to vascular endothelial growth factor (VEGF) expression in renal clear cell carcinoma. Urol Oncol 2013;31:1820-5.  Back to cited text no. 1
    
2.
van der Veldt AA, Boven E, Vroling L, Broxterman HJ, van den Eertwegh AJ, Haanen JG. Sunitinib-induced hemoglobin changes are related to the dosing schedule. J Clin Oncol 2009;27: 1339-40; author reply 1340-2.  Back to cited text no. 2
    
3.
Alexandre I, Billemont B, Meric JB, Richard S, Rixe O. Axitinib induces paradoxical erythropoietin synthesis in metastatic renal cell carcinoma. J Clin Oncol 2009;27:472-3; author reply 473-4.  Back to cited text no. 3
    
4.
Wang W, Cheng J, Mallon C, Al-Marrawi MY, Holder S, Joshi M, et al. Symptomatic secondary polycythemia induced by anti-VEGF therapy for the treatment of metastatic renal cell carcinoma: a case series and review. Clin Genitourin Cancer 2015;13:e391-5.  Back to cited text no. 4
    
5.
Bukhari N, Winquist E. Case: secondary polycythemia due to pazopanib in patients with metastatic renal cell carcinoma. Can Urol Assoc J 2017;11:E449-50.  Back to cited text no. 5
    
6.
Tripathi A, Jacobus S, Feldman H, Choueiri TK, Harshman LC. Prognostic significance of increases in hemoglobin in renal cell carcinoma patients during treatment with VEGF-directed therapy. Clin Genitourin Cancer 2017;15:396-402.  Back to cited text no. 6
    
7.
Alexandrescu DT, McClure R, Farzanmehr H, Dasanu CA. Secondary erythrocytosis produced by the tyrosine kinase inhibitors sunitinib and sorafenib. J Clin Oncol 2008;26:4047-8.  Back to cited text no. 7
    
8.
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 8
    
9.
Braekkan SK, Mathiesen EB, Njølstad I, Wilsgaard T, Hansen JB. Hematocrit and risk of venous thromboembolism in a general population. The Tromso study. Haematologica 2010;95:270-5.  Back to cited text no. 9
    
10.
Randi ML, Bertozzi I, Cosi E, Santarossa C, Peroni E, Fabris F. Idiopathic erythrocytosis: a study of a large cohort with a long follow-up. Ann Hematol 2016;95:233-7.  Back to cited text no. 10
    


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