Clinical significance of sunitinib-associated macrocytosis in metastatic renal cell carcinoma

Cancer Med. 2016 Dec;5(12):3386-3393. doi: 10.1002/cam4.919. Epub 2016 Oct 19.


Increases in the mean corpuscular volume (MCV) have been observed in patients with metastatic renal cell carcinoma (mRCC) on tyrosine kinase inhibitor (TKI) treatment; however, its association with progression-free-survival (PFS) is unknown. We aimed to characterize TKI-associated macrocytosis in mRCC and its relationship with PFS. Retrospective review of data on macrocytosis and thyroid dysfunction on mRCC patients treated with sunitinib and/or sorafenib. These results are evaluated in the context of our previous report on the association of hypothyroidism in this setting. We assessed PFS as clinically defined by the treating physician. Seventy-four patients, 29 of whom received both drugs, were included. A treatment period was defined as time from initiation to discontinuation of either sunitinib or sorafenib; 103 treatment periods [sorafenib (47), sunitinib (56)] were analyzed. Macrocytosis was found in 55 and 8% of sunitinib- and sorafenib-treated patients, respectively, P < 0.001. The median time to developing macrocytosis was 3 months (m, range 1-7). Median PFS in sunitinib-treated patients was 11 m (95% CI: 6-19). Median PFS was higher among those with macrocytosis compared to normocytosis (21 m [95% CI: 11-25] vs. 4 m [95% CI: 3-8] P = 0.0001). Macrocytosis and hypothyroidism were two significant predictors of PFS. The greatest difference in PFS among all patients was observed in patients with both macrocytosis and hypothyroidism (25 m), compared to the normocytic and euthyroid patients (5 m) (P < 0.0001). Sunitinib-related macrocytosis was associated with prolonged PFS, and concurrent development of hypothyroidism and macrocytosis further prolonged PFS. Increased MCV may have a role as a predictive biomarker for sunitinib. Prospective studies accounting for other known prognostic factors are needed to confirm this finding.

Keywords: Clinical biomarker; macrocytosis; mean corpuscular volume; progression-free survival; renal cell carcinoma; sorafenib; sunitinib; tyrosine kinase inhibitors.

MeSH terms

  • Angiogenesis Inhibitors / adverse effects
  • Angiogenesis Inhibitors / therapeutic use
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Renal Cell / complications*
  • Carcinoma, Renal Cell / drug therapy
  • Carcinoma, Renal Cell / mortality
  • Carcinoma, Renal Cell / pathology
  • Erythrocyte Indices
  • Erythrocytes, Abnormal*
  • Female
  • Hematologic Diseases / diagnosis*
  • Hematologic Diseases / etiology*
  • Hematologic Diseases / mortality
  • Humans
  • Indoles / adverse effects*
  • Indoles / therapeutic use
  • Kaplan-Meier Estimate
  • Kidney Neoplasms / complications*
  • Kidney Neoplasms / drug therapy
  • Kidney Neoplasms / mortality
  • Kidney Neoplasms / pathology
  • Male
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Niacinamide / adverse effects
  • Niacinamide / analogs & derivatives
  • Niacinamide / therapeutic use
  • Phenylurea Compounds / adverse effects
  • Phenylurea Compounds / therapeutic use
  • Pyrroles / adverse effects*
  • Pyrroles / therapeutic use
  • Sorafenib
  • Sunitinib
  • Treatment Outcome


  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Indoles
  • Phenylurea Compounds
  • Pyrroles
  • Niacinamide
  • Sorafenib
  • Sunitinib