Dataset Information

Incidence and relative risk of hepatic toxicity in patients treated with anti-angiogenic tyrosine kinase inhibitors for malignancy.

ABSTRACT:

Aim

The aim of this study is to investigate the incidence and risk of hepatic toxicity in patients receiving tyrosine kinase inhibitors (TKIs) through a large up-to-date meta-analysis of available clinical trials.

Methods

PubMed was reviewed for phase III randomized trials with axitinib, pazopanib, sorafenib, sunitinib, regorafenib or vandetanib. The characteristics of each study and incidence of all and high grades of ALT, AST and total bilirubin increase were collected.

Results

A total of 3691 patients was available for meta-analysis, 1170 had metastatic renal cell carcinoma; 950 had advanced non-small cell lung carcinoma, 454 had hepatocarcinoma, 753 had metastatic colorectal cancer and 362 had metastatic soft-tissue sarcoma. The incidence of ALT, AST and bilirubin increase of any grade in patients treated with TKIs was 34.0% (95% CI 31.6, 36.3), 39.2% (95% CI 36.7, 41.6) and 21.8% (95% CI 19.9, 23.7), respectively. The incidence of the high grade increase was 5.2% (95% CI 4.2, 6.4), 5.0% (95% CI, 3.8, 6.2) and 1.7% (95% CI 1.1, 2.4), respectively. The relative risk of ALT, AST and total bilirubin increase was 1.85, 2.19 and 1.79 for any grade and 2.75, 2.39 and 1.65 for high grade, respectively.

Conclusions

Hepatotoxicity is a relative common event occurring in 23-40% of patients treated with TKIs. Despite this, only 5% of patients have had high grade of toxicity. A better knowledge of this phenomenon may prevent high grade toxicity and reduce treatment discontinuation due to this adverse event.

SUBMITTER: Iacovelli R

PROVIDER: S-EPMC4093918 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundIncreasing studies implicate cancer stem cells (CSCs) as the source of resistance and relapse following conventional cytotoxic therapies. Few studies have examined the response of CSCs to targeted therapies, such as tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs would have differential effects on CSC populations depending on their mechanism of action (anti-proliferative vs. anti-angiogenic).MethodsWe exposed human sarcoma cell lines to sorafenib, regorafenib, and pazopanib and assessed cell viability and expression of CSC markers (ALDH, CD24, CD44, and CD133). We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy. We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.ResultsAfter functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P < 0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P < 0.05). In contrast, we observed negligible effects on viability and CSC sub-populations with pazopanib. At low doses, there was progressive CSC enrichment in vitro after longer term exposure to sorafenib although the anti-proliferative effects were attenuated. In vivo, sorafenib improved median survival by 11 days (P < 0.05), but enriched ALDHbright cells 2.5 - 2.8 fold (P < 0.05). Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells (P < 0.05). Again, negligible effects from pazopanib were observed. TMA analysis of archived specimens from sarcoma patients treated with sorafenib demonstrated significant enrichment for ALDHbright cells in the post-treatment resection specimen (P < 0.05), whereas clinical specimens obtained longitudinally from a patient treated with pazopanib showed no enrichment for ALDHbright cells (P > 0.05).ConclusionsAnti-proliferative TKIs appear to enrich for sarcoma CSCs while anti-angiogenic TKIs do not. The rational selection of targeted therapies for sarcoma patients may benefit from an awareness of the differential impact of TKIs on CSC populations.