Incidence and risk of regorafenib-induced hepatotoxicity

Abstract

Regorafenib, an oral multi-kinase inhibitor, has been approved for the treatments of several malignancies. Unlike traditional cytotoxic chemotherapeutic agents, regorafenib therapy often induces a distinct profile of adverse events (AEs) including hepatotoxicity. Here we conducted an up-to-date meta-analysis to assess the incidence and risk of regorafenib related hepatic toxicities. PubMed and Embase database were reviewed from inception to June 2017 for relevant trials. Eligible studies include subjects with solid tumors treated with 160 mg of regorafenib daily during the first three week of each four-week cycle, and adequate safety data reporting the elevation of aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and bilirubin. Statistical analyses were conducted to calculate the summary incidence and relative risk (RR). A total of 2,213 subjects from 14 trials were included. The incidences of regorafenib-associated all-grade and high-grade hepatotoxicity were: bilirubin elevation: 23% and 5%; AST elevation: 32% and 6%; ALT elevation: 27% and 5%; ALP elevation: 31% and 2%. Regorafenib-treated subjects had a significant increased risk of all-grade (RR = 3.10; 95% CI, 2.22–4.34) and high-grade (RR = 1.74; 95% CI, 1.09–2.80) bilirubin elevation; all-grade (RR = 1.51; 95% CI, 1.13–2.00) and high-grade (RR = 1.79; 95% CI, 1.00–3.22) AST elevation; all-grade (RR = 1.82; 95% CI, 1.25–2.64) and high-grade (RR = 3.07; 95% CI, 1.30–7.22) ALT elevation; and all-grade (RR = 2.11; 95% CI, 1.01–4.40) ALP elevation. Our results suggest that regorafenib is associated with an increased risk of hepatic toxicities. Hepatotoxicity examination at regular intervals should be advised to clinicians.

Modeling Hepatocellular Carcinoma Cells Dynamics by Serological and Imaging Biomarkers to Explain the Different Responses to Sorafenib and Regorafenib

“…The increase may have a temporal delay and kinetics different from those of cancer cells. In addition, these drugs can also exert anti-vascular toxic effects on non-tumor liver cells [ 18 , 19 ]; the hypothetical amount of PIVKA-II produced in this way, expressed by the term Tox(t), was computed according to the equation Tox(t) = π4 × F(t) × t π5 , where the coefficient π4 is the parameter that accounts for the dose dependent effect (no toxicity in Case-2 = 0; in Case-3 = 15), and the exponent π5 accounts for the time dependent effect (in Case-3 = 1.52). In this patient, the fluctuations observed after 3 months of therapy are due to the PIVKA-II Tox(t) component, and reflect the dose of active drug F(t) which fluctuates because of the treatment schedule adopted with regorafenib, given every day for 3 weeks followed by one week off ( Figure 6 ).…”

“…In Case-3, however, the increase of PIVKA-II was slower and prolonged for 3 months, then followed by rapid fluctuations strongly correlated with the schedule of regorafenib dosing, that is administered consecutively for 3 weeks followed by one week off treatment. Since hypoxia is a condition frequently found within the cores of tumors [ 28 ] but also in chronic liver diseases of different etiologies, in particular when cirrhosis is present [ 29 ], we hypothesize that regorafenib could have exerted its anti-vascular toxic effects on non-tumor liver cells also [ 19 , 20 ]. In fact, best fitting of PIVKA-II levels in Case-3 ( Figure 6 ) was obtained assuming that a mechanism similar to that causing the increase of PIVKA-II production by cancer cells can also affect non-neoplastic hepatocytes with different dose and time dependent relationships.…”

“…The increase may have a temporal delay and kinetics different from those of cancer cells. In addition, these drugs can also exert anti-vascular toxic effects on non-tumor liver cells [18,19]; the hypothetical amount of PIVKA-II produced in this way, expressed by the term Tox(t), was computed according to the equation Tox Briefly, the reduction of PIVKA-II plasma levels during effective TKI therapy can be preceded by a transient increase, attributed to the ischemia of cancer cells [15]. The amount of PIVKA-II produced in the spike was computed assuming that it is proportional to PIVKA-II value at the beginning of therapy P(0) and to the density (R) of the cancer cells in the tumor mass.…”

Maximising clinical benefit with adequate patient management beyond the second line in mCRC

“…Grade ≥3 hepatic-related/liver-related adverse events such as increases in alanine aminotransferase, aspartate aminotransferase and total bilirubin were greater with regorafenib (5.5%, 5.9% and 12.4%, respectively) compared with trifluridine/tipiracil (2%, 4% and 9%, respectively) 11 12. As regorafenib is metabolised via the liver, its use in patients with liver dysfunction remains a challenge, and it is important to ensure that a patient has proficient liver function prior to administration 29. For observed elevations of alanine aminotransferase and/or aspartate aminotransferase >5 times the upper limit of normal (ULN) but ≤20 times the ULN, treatment with regorafenib should be interrupted and its use reassessed 30.…”

Further Therapeutic Options in Heavily Pretreated Colorectal Cancer Patients

“…Treatment with regorafenib may also contribute to all-grade hepatotoxicity (bilirubin, AST, ALT, and ALP elevation), an AE observed in approximately one-third of patients treated with this anticancer agent [14].…”