Portal de Periódicos da CAPES

Sorafenib may induce hypophosphatemia through a fibroblast growth factor-23 (FGF23)-independent mechanism

2011; Elsevier BV; Volume: 22; Issue: 4 Linguagem: Inglês

10.1093/annonc/mdr010

1569-8041

Elisa Bellini, A. Pia, Maria Pia Brizzi, Marco Tampellini, M. Torta, Massimo Terzolo, Luigi Dogliotti, Alfredo Berruti,

Heterotopic Ossification and Related Conditions

Sorafenib, a drug approved for the treatment of advanced renal cancer, inhibits RAF/MAPK pathway, vascular endothelial receptor-2 and -3, platelet-derived growth factor receptor-2 and -3, and c-Kit [1.Wilhelm S.M. Adnane L. Newell P. et al.Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling.Mol Cancer Ther. 2008; 7: 3129-3140Crossref PubMed Scopus (1108) Google Scholar].Hypophosphatemia is a common side-effect, occurring in ∼45% of patients [2.Escudier B. Eisen T. Stadler W.M. et al.Sorafenib in advanced clear-cell carcinoma.N Engl J Med. 2007; 356: 125-134Crossref PubMed Scopus (4311) Google Scholar]. This metabolic derangement is mostly asymptomatic, but the mechanisms involved are unclear [2.Escudier B. Eisen T. Stadler W.M. et al.Sorafenib in advanced clear-cell carcinoma.N Engl J Med. 2007; 356: 125-134Crossref PubMed Scopus (4311) Google Scholar].The physiological balance of phosphate is maintained by the coordinated interactions of the small intestine, bone, parathyroid gland and kidneys [3.Berndt T. Kumar R. Phosphatonins and the regulation of phosphate homeostasis.Annu Rev Physiol. 2007; 69: 341-359Crossref PubMed Scopus (192) Google Scholar] (Figure 1).A major breakthrough in understanding the regulation of phosphate homeostasis was accomplished by the identification of serum fibroblast growth factor-23 (FGF23), a bone-derived hormone able to cause hypophosphatemia by increasing the urinary excretion and decreasing the intestinal absorption of phosphates [4.Razzasque M.S. The FGF23-Klotho axis: endocrine regulation of phosphate homeostasis.Nat Rev Endocrinol. 2009; 5: 611-619Crossref PubMed Scopus (312) Google Scholar].A 64-year-old male with metastatic kidney cancer received sorafenib (400 mg b.i.d. orally) till progression for a total of 11 months. No major toxic effects were recorded and particularly no diarrhea or mucositis was observed. Serum FGF23 together with serum calcium, phosphorus, parathyroid hormone (PTH), 1,25(OH)2 vitamin D, alkaline phosphatase, C-telopeptide of type I collagen (CTX), urinary calcium and phosphorus were measured at baseline condition and every month during the first 5 months. Renal and hepatic functions were within normality throughout the study. The patient who had normal baseline serum phosphorus levels developed hypophosphatemia after 1 month that persisted for two additional months and was associated with a decrease in serum calcium, urinary calcium and phosphate (Table 1). Serum PTH increased, while serum 1,25(OH)2 vitamin D and serum FGF23 decreased. Serum CTX also decreased, but serum alkaline phosphatase did not change (Table 1).Table 1Variation in time of phosphate regulation hormones during Sorafenib administrationFGF23aFGF23 normal values are not available, so only the trend of this hormone serum levels can be considered., pg/mlVitamin D, ng/mlbNormal vitamin D ≥30 ng/ml; insufficiency 10–29 ng/ml; deficiency <10 ng/ml.CTX, ng/l (0.0–1)ALP, U/l (30–120)PTH, pg/ml (10–65)Ca, mmol/lcAlbumin-corrected serum calcium. (2.1–2.55)Ca tot U 24 H, mmol/24 h (2.5–7.5)P, mg/dl (2.5–4.8)Phosph U 24 H, mg/24 h (400–1300)Baseline4.9220.4965302.671.254.1977First month4.5190.26901042.40.222.7787Second month3.815881102.30.22.5738Third month3.1130.17921622.30.22.6642Vitamin D administrationFourth month7.75210.2581812.430.53.0797Fifth month10.2230.4296572.530.93.4853Reference range enclosed in parenthesis.FGF23, serum fibroblast growth factor-23; CTX, C-telopeptide of type I collagen; ALP, serum alkaline phosphatase; PTH, serum parathyroid hormone; Ca, serum calcium; Ca tot U 24 H, 24-h urinary calcium; P, serum phosphate; Phosph U 24 H, 24-h urinary phosphate.a FGF23 normal values are not available, so only the trend of this hormone serum levels can be considered.b Normal vitamin D ≥30 ng/ml; insufficiency 10–29 ng/ml; deficiency <10 ng/ml.c Albumin-corrected serum calcium. Open table in a new tab Due to the severe hypovitaminosis D attained in the first 3 months, a single i.m. dose of cholecalciferol (300 000 U) was administered. In the subsequent 2 months, serum phosphate returned to normal, calcium and vitamin D slightly increased, PTH consistently decreased and FGF23 increased. Also, serum CTX levels increased, while serum alkaline phosphatase did not change (Table 1).The decrease in urinary phosphate and calcium levels over time and the decreasing trend of FGF23 levels suggest that drug-induced hypophosphatemia in this patient was sustained by a low intestinal phosphate absorption and/or low bone phosphate release, while FGF23 was not contributory. Sorafenib inhibited the osteoclast activity as documented by the decrease of serum CTX. The reduction in serum vitamin D levels and the normalization of phosphate levels after vitamin D supplementation suggest a predominant role of this hormone in this metabolic disorder. The mechanism by which sorafenib can cause hypovitaminosis D is unclear and deserves to be confirmed in a prospective study. Concomitant malabsorption can be conceivably excluded since no diarrhea was recorded.Prolonged hypovitaminosis D and hyperparathyroidism lead to osteomalacia, astenia, and increased risk for cardiovascular disease [5.Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10457) Google Scholar]. These effects could negatively impact on long-term sorafenib tolerability. Moreover, since vitamin D has antiproliferative activities, hypovitaminosis D can also potentially influence the drug efficacy [5.Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10457) Google Scholar]. Further studies are warranted to confirm the results of this paper, assess the prognostic significance of hypophosphatemia and define its appropriate treatment.fundingBayer to A.B.disclosureAB has received research funds from Bayer. All other authors declare no conflict of interest. Sorafenib, a drug approved for the treatment of advanced renal cancer, inhibits RAF/MAPK pathway, vascular endothelial receptor-2 and -3, platelet-derived growth factor receptor-2 and -3, and c-Kit [1.Wilhelm S.M. Adnane L. Newell P. et al.Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling.Mol Cancer Ther. 2008; 7: 3129-3140Crossref PubMed Scopus (1108) Google Scholar]. Hypophosphatemia is a common side-effect, occurring in ∼45% of patients [2.Escudier B. Eisen T. Stadler W.M. et al.Sorafenib in advanced clear-cell carcinoma.N Engl J Med. 2007; 356: 125-134Crossref PubMed Scopus (4311) Google Scholar]. This metabolic derangement is mostly asymptomatic, but the mechanisms involved are unclear [2.Escudier B. Eisen T. Stadler W.M. et al.Sorafenib in advanced clear-cell carcinoma.N Engl J Med. 2007; 356: 125-134Crossref PubMed Scopus (4311) Google Scholar]. The physiological balance of phosphate is maintained by the coordinated interactions of the small intestine, bone, parathyroid gland and kidneys [3.Berndt T. Kumar R. Phosphatonins and the regulation of phosphate homeostasis.Annu Rev Physiol. 2007; 69: 341-359Crossref PubMed Scopus (192) Google Scholar] (Figure 1). A major breakthrough in understanding the regulation of phosphate homeostasis was accomplished by the identification of serum fibroblast growth factor-23 (FGF23), a bone-derived hormone able to cause hypophosphatemia by increasing the urinary excretion and decreasing the intestinal absorption of phosphates [4.Razzasque M.S. The FGF23-Klotho axis: endocrine regulation of phosphate homeostasis.Nat Rev Endocrinol. 2009; 5: 611-619Crossref PubMed Scopus (312) Google Scholar]. A 64-year-old male with metastatic kidney cancer received sorafenib (400 mg b.i.d. orally) till progression for a total of 11 months. No major toxic effects were recorded and particularly no diarrhea or mucositis was observed. Serum FGF23 together with serum calcium, phosphorus, parathyroid hormone (PTH), 1,25(OH)2 vitamin D, alkaline phosphatase, C-telopeptide of type I collagen (CTX), urinary calcium and phosphorus were measured at baseline condition and every month during the first 5 months. Renal and hepatic functions were within normality throughout the study. The patient who had normal baseline serum phosphorus levels developed hypophosphatemia after 1 month that persisted for two additional months and was associated with a decrease in serum calcium, urinary calcium and phosphate (Table 1). Serum PTH increased, while serum 1,25(OH)2 vitamin D and serum FGF23 decreased. Serum CTX also decreased, but serum alkaline phosphatase did not change (Table 1). Reference range enclosed in parenthesis. FGF23, serum fibroblast growth factor-23; CTX, C-telopeptide of type I collagen; ALP, serum alkaline phosphatase; PTH, serum parathyroid hormone; Ca, serum calcium; Ca tot U 24 H, 24-h urinary calcium; P, serum phosphate; Phosph U 24 H, 24-h urinary phosphate. Due to the severe hypovitaminosis D attained in the first 3 months, a single i.m. dose of cholecalciferol (300 000 U) was administered. In the subsequent 2 months, serum phosphate returned to normal, calcium and vitamin D slightly increased, PTH consistently decreased and FGF23 increased. Also, serum CTX levels increased, while serum alkaline phosphatase did not change (Table 1). The decrease in urinary phosphate and calcium levels over time and the decreasing trend of FGF23 levels suggest that drug-induced hypophosphatemia in this patient was sustained by a low intestinal phosphate absorption and/or low bone phosphate release, while FGF23 was not contributory. Sorafenib inhibited the osteoclast activity as documented by the decrease of serum CTX. The reduction in serum vitamin D levels and the normalization of phosphate levels after vitamin D supplementation suggest a predominant role of this hormone in this metabolic disorder. The mechanism by which sorafenib can cause hypovitaminosis D is unclear and deserves to be confirmed in a prospective study. Concomitant malabsorption can be conceivably excluded since no diarrhea was recorded. Prolonged hypovitaminosis D and hyperparathyroidism lead to osteomalacia, astenia, and increased risk for cardiovascular disease [5.Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10457) Google Scholar]. These effects could negatively impact on long-term sorafenib tolerability. Moreover, since vitamin D has antiproliferative activities, hypovitaminosis D can also potentially influence the drug efficacy [5.Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10457) Google Scholar]. Further studies are warranted to confirm the results of this paper, assess the prognostic significance of hypophosphatemia and define its appropriate treatment. fundingBayer to A.B. Bayer to A.B.