Effect of CTCAE v4 grading of hypertension on reported toxicity in advanced cancer patients receiving vascular endothelial growth factor (VEGF)-targeting agents.

Abstract

e15600 Background: The NCI Common Terminology Criteria for Adverse Events (CTCAE) system changed to version 4 in 2009, and several AE categories underwent changes in grading (Gr), including HTN. As many anti-neoplastic agents, particularly those targeting VEGF are associated with HTN, changing in the grading system may result in changes to maximum tolerated or recommended phase II doses in early dose-escalation studies or overall HTN AE reporting across all studies. Methods: We initially reviewed individual patient data of a multicenter phase I/II trial of sorafenib plus gemcitabine and capecitabine for advanced renal cell carcinoma (RCC), which graded AE’s using CTCAE v3. Individual patient (pt) data was reviewed and HTN AE’s were re-graded using CTCAE v4 criteria for up to 12 cycles of therapy on study. A separate (confirmatory) data set in pts with metastatic colorectal cancer (CRC) treated on a phase IIIb study of regorafenib was subsequently analyzed. Results: In the RCC study, only 1 of 23 pts with complete source documents available had stable highest HTN Gr across both CTCAE versions. In the CRC study, 0 of 8 pts had stable Gr. Table 1 compares each individual’s highest CTCAE v3 versus v4 grading of HTN in each study. Across both studies, all pts had HTN AE’s using CTCAE v4. Only 1 pt maintained grading using both versions (Gr 3), with 30 (96.8%) changing grades. Four (12.9%) moved from Gr 0 to Gr 1, fifteen (48.4%) from Gr 0 to Gr 2, five (16.1%) from Gr 1 to Gr 2, one from Gr 1 to Gr 3, and six (19.4%) from Gr 2 to Gr 3. Conclusions: Re-classification of grading in this study demonstrates that only 3.2% maintained stable grading of HTN across systems, with 51.6% increasing by 2 grades. The change in AE reporting criteria has the potential to significantly impact results of clinical trials. This may be particularly important with VEGF-targeted agents, with emerging data pointing towards HTN as a pharmacodynamic marker in pts with RCC, and may affect dosing and AE reporting of other drugs with blood pressure effects. Clinical trial information: NCT00121251, NCT01538680. [Table: see text]