March 28, 2012 4:37 pm
Tumor response assessment to sorafenib in patients with advanced hepatocellular carcinoma: do we need new criteria?
By Dr Mohmed Bouattour
Sorafenib, an oral multi-tyrosine kinase inhibitor, is the first and so far the only drug that has shown overall survival benefit in patients with advanced hepatocellular carcinoma (HCC) in two large multicenter, double-blind, placebo-controlled randomized phase III trials [1-2]. Despite the survival benefit in this population, sorafenib has been infrequently associated with changes in tumors dimensions, challenging standard RECIST criteria [3]. Tumor shrinkage and dimensional change, usually assessed to define tumor response of cytotoxic drugs based on the morphological RECIST criteria, was observed in less than 5% of patients. Furthermore, changes in tumor angiogenesis are observed such as decrease in the number of vessels in tumor masses and the appearance of large areas of intratumor necrosis (Figure 2). This feature is acknowledged to reflect the antitumor activity of antiangiogenic drugs that does not always translate into changes in the diameter of the tumor, making the radiological evaluation of efficacy using standard RECIST criteria often inappropriate [4].
In the phase II study evaluating sorafenib [5], among 11 patients strictly evaluated for intratumor necrosis appearance in addition to RECIST criteria, several tumors had size increasing and as well as increasing tumor necrosis. Before treatment, the mean diameter of these tumors was 6.4 cm (interval 2.5 to 14.2 cm) and the mean proportion of tumor necrosis was 9.8% (interval 0.4% to 33.5%). After treatment, the mean diameter of these tumors was 7.2 cm (interval 1.7 to 16.0 cm) and the mean proportion of tumor necrosis was 27% (interval 0.7 to 75%) [5]. Similar observations were shown with sunitinib [6] and bevacizumab [7].
Given this context, experts have suggested new response criteria based on changes in tumor vascularization and density. The modified RECIST criteria (mRECIST) were an amendment of the RECIST criteria; they take into account dimension changes in the tumor arterial enhancement [8]. Choi criteria [9] where composite criteria, covering tumor size and tumor density in CT scan, have been proposed to evaluate response to sunitinib, another potent antiangiogenic agent, in HCC patients [10].
We recently showed in the American Association for the Study of Liver Disease meeting (AASLD) 2011 at San Francisco, interesting results about the relevance of theses criteria in patients with advanced HCC and treated with sorafenib [11]. In our study, 60 patients were evaluated according to those criteria by CT-scan performed within 3 months of treatment. At the first tumor evaluation,we observed that only 2 patients (3.3%) experienced a decrease ≥ 30% of the largest diameter. The majority of patients (51.6%) had no significant changes in tumor size. This confirms the low response rates by RECIST criteria observed with sorafenib. According to mRECIST, 12 patients (21.4%) were categorized as early responder with 2 complete response (3.3%) and 10 partial response (16.7%). When we apply the Choi criteria, we noticed that 27 patients (45%) were considered as partial responders and 14 patients (23.3%) had tumor stabilization. Interestingly, these new criteria were able to identify responders with better overall survival. In fact, responder patients according to mRECIST had better OS than progressive patients (> 14.4 months vs. 5.8 months, respectively, p = 0.0008). Moreover, Choi criteria can predict overall survival in patients with HCC treated by sorafenib since the median OS in the group of responder patients was > 14.4 months compared to the median OS of 6 months in the group of progressive patients (p= 0.0012) [11]. Our results were comparable to another published study [12] in which the best tumor response rates of 53 patients were assessed by RECIST and mRECIST. In this cohort, the rates of objective response, stable disease were 2% and 79% respectively according to RECIST and 23% and 57% respectively by mRECIST. Similar to our results, response according mRECIST criteria can predict survival, since the median OS in the group of responder patients was 18 months compared to the median OS of 8 months in the group non-responder patients (p= 0.013) [12].
Taken together, those results stress the need to evaluate behind tumor size changes, vascular modification and disturbance observed with sorafenib and other antiangiogenic agents in patients with HCC. Further robust studies should take into account those criteria to validate them clinical practice.
References
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2. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009; 10: 25-34.
3. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, el al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205-16.
4. Bouattour M, Dreyer C, Faivre S, Raymond E. Evaluation of antiangiogenic effects: biomarkers and functional imaging. International Oncology Updates: Present and future for antiangiogenic therapies in cancer. Permalyer Barcelona, 2010: 63-84.
5. Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006; 24: 4293-300.
6. Faivre S, Bouattour M, Dreyer C, Raymond E. Sunitinib in hepatocellular carcinoma: redefining appropriate dosing, schedule, and activity endpoints. J Clin Oncol 2009; 27: 248-50.
7. Siegel AB, Cohen EI, Ocean A, Lehrer D, Goldenberg A, Knox JJ, et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 2008;26:2992-98.
8. Lencioni, R. & Llovet, J. M. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin. Liver Dis. 30, 52–60 (2010).
9. Choi H, Charnsangavej C, Faria SC, Macapinlac HA, Burgess MA, Patel SR, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007 ;25:1753-9.
10. Faivre S, Zappa M, Vilgrain V, Boucher E, Douillard JY, Lim HY, et al. Changes in tumor density in patients with advanced hepatocellular carcinoma treated with sunitinib. Clin. Cancer Res. 2011; 17, 4504–12.
11. Bouattour M, Wassermann J, Bruno O, et al. Blinded independent centralresponse assessment using RECIST, modified RECIST, and Choi criteria in patients treated with sorafenib for advanced advanced hepatocellular carcinoma. Oral communication presented at ILCA 2011 in Hong Kong and at AASLD 2011 in San Francisco. Hepatology; 2011 54(S1) (A 270).
12. Edeline J, Boucher E, Rolland Y, Vauléon E, Pracht M, Perrin C,et al. Comparison of tumor response by Response Evaluation Criteria in Solid Tumors(RECIST) and modified RECIST in patients treated with sorafenib for hepatocellular carcinoma. Cancer. 2012;118(1):147-56.
About the Author
Dr Mohamed Bouattour
Mohmed Bouattour is a Clinical physician in the department of Oncology and Hepatology at Beuajon Hospital in France. Dr. Mohamed Bouattour received his Gastroenterology Hepatology training at the Faculty of medicine of Sfax and Tunis in Tunisia. He completed and achieved his fellow at the department of Hepatology and Oncology in Beaujon Hospital in Paris France. He is currently a practitioner in Beaujon Hospital at these departments.
His interests go toward the field of Hepatology to study liver disease, hepatic malignancies and clinical trials to evaluate new agents in hepatocellular carcinoma.
Dr. Mohamed Bouattour is a peer reviewer for several scientific journals and has authored and co-authored more than 20 publications as well as book chapters. He is an active member of the European Association for the Study of the Liver (EASL), the American Association for the Study of Liver (AASLD) and The American Society of Clinical Oncology (ASCO).
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