Rationale and Objectives
The aim of this study was to compare tumor changes in patients with hepatocellular carcinoma receiving sorafenib using evaluation criteria of the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) as opposed to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Materials and Methods
Twenty-five patients with inoperable hepatocellular carcinoma receiving oral sorafenib underwent magnetic resonance imaging at baseline and follow-up every 8 weeks (range, 2–19 weeks; mean, 7.6 weeks). Data were evaluated retrospectively. Survey time until progression ranged from 5 to 102 weeks (mean, 25.6 weeks), with a total of 54 target lesions being monitored. Additionally, evaluation of serum α-fetoprotein was performed at follow-up.
Results
The best response at follow-up using RECIST resulted in rates of 4% objective response (complete remission or partial remission), 24% (progressive disease), and 72% (stable disease). In contrast, AASLD and EASL criteria identified objective responses in 28% and 48%. Twenty percent of all patients classified as having progressive disease by RECIST were identified as having “pseudo”-progression due to extensive necrosis. Eleven percent of patients classified as having stable disease by RECIST were disclosed as essentially progressive. AASLD area and AASLD diameter disclosed 36% and 40% of patients as having partial remission, respectively, whereas EASL criteria discovered only 24%. There was no significant correlation between serum α-fetoprotein progression and AASLD, EASL, or RECIST evaluation criteria.
Conclusions
Response monitoring via functional criteria such as AASLD or EASL criteria is likely to more accurately reflect vital tumor burden in hepatocellular carcinoma compared to RECIST.
For patients with advanced hepatocellular carcinoma (HCC), the oral multikinase inhibitor sorafenib is the first and so far only drug enabling an improved survival being demonstrated in a phase III study . In this clinical trial, sorafenib demonstrated a cytostatic, disease-stabilizing activity that prolonged the time to radiologic progression from 2.8 months (placebo group) to 5.5 months and the median survival time from 7.9 months (placebo group) to 10.7 months. With respect to molecular targets, sorafenib simultaneously inhibits kinases and growth factor receptors, thereby reducing tumor growth and abrogating neoangiogenesis . Recently, we reported that sorafenib induces early intralesional necrosis in hepatic tumors with profound changes in T1-weighted, T2-weighted, and diffusion-weighted magnetic resonance imaging (MRI) signal intensities .
However, this progress in the systemic therapy of HCC is not yet accompanied by the application of simple and practical radiologic response criteria that allow reliable monitoring of this new and expensive treatment approach in day-to-day practice. As in the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial , the evaluation of response to therapy is still based mainly on the use of unidimensional tumor measurements according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines . At the same time, there is growing evidence that evaluation by RECIST may not be the method of choice in monitoring treatment response or progression of HCC , which is a heterogeneous and often multifocal tumor. It is known that even within the same tumor nodule, varying degrees of differentiation exist. Growth rates may vary among lesions, which makes macroscopic growth patterns hard to interpret, underlining the importance of functional imaging . RECIST version 1.1 relies on the measurement of a maximum of five target lesions, not exceeding two per organ; subsequently, the sum of the greatest diameters is recorded followed by a final classification . Therefore, RECIST, per definition, is not capable of assessing therapy-induced intratumor changes in response to either local or targeted systemic therapy (eg, sorafenib), because it does not consider therapy-induced tissue necrosis .
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Materials and methods
Patient Demographics and Treatment Plan
Get Radiology Tree app to read full this article<
Inclusion Criteria
Get Radiology Tree app to read full this article<
MRI Evaluation
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Response Assessment by MRI
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Table 1
Patient Demographics
Variable Value Age (years) 65 (42–75) Men/women 23/2 Etiology of HCC HCV 3 HBV 3 Ethanol 8 Hemochromatosis 2 Others 9 Child-Pugh class A 92% B 8% Basal AFP (ng/mL) 59 (2–432,451) <10 22% 10–100 35% >100 43% Histologic differentiation High 33 Moderate 50 Poor 17 ECOG performance status 0 (fully active) 24% 1 or 2 (restricted in physical activity) 76% >2 0% Liver tumor burden T0 or T1 1 T2 12 T3 12 T4 0
AFP, α-fetoprotein; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus.
Data are expressed as median (range), numbers, or percentages.
Get Radiology Tree app to read full this article<
Response Assessment by AFP Measurement
Get Radiology Tree app to read full this article<
Statistical Analysis
Get Radiology Tree app to read full this article<
Results
Evaluation of Tumor Responses
Get Radiology Tree app to read full this article<
Table 2
Evaluation Criteria Used in the Assessment of Tumor Response
RECIST Version 1.1 AASLD d EASL AASLD a CR No target lesions No viable lesions No viable lesions No viable lesions PR ≥30% decrease (vs baseline sum diameters) ≥30% decrease (vs baseline sum viable diameters) ≥50% decrease (vs baseline sum viable areas) ≥30% decrease (vs baseline sum viable areas) PD ≥20% increase (vs smallest sum on study) or new lesions ≥20% increase (vs smallest sum on study) or new lesions ≥25% increase (vs smallest sum on study) or new lesions ≥20% increase (vs smallest sum on study) or new lesions SD Neither sufficient ↓ for PR nor sufficient ↑ for PD Neither sufficient ↓ for PR nor sufficient ↑ for PD Neither sufficient ↓ for PR nor sufficient ↑ for PD Neither sufficient ↓ for PR nor sufficient ↑ for PD
AASLD a , American Association for the Study of Liver Diseases area; AASLD d , American Association for the Study of Liver Diseases diameter; CR, complete remission; EASL, European Association for the Study of the Liver; PD, progressive disease; PR, partial remission; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; ↑, growth; ↓, shrinkage.
Table 3
Best Response Assessment
Patient AFP RECIST AASLD a EASL AASLD d Overall Survival (Months) 1 PD SD SD SD PR 5, 62PRSDPRPRPR6 3 PR SD SD SD SD 9, 6 4 PD SD SD SD SD 25 † 5 NA SD SD SD PR 29 † 6 PD SD SD SD SD 30 † 7 PD PD PD PD SD 5, 18PRPD ¶ PRPRPR6, 79PRSDPRPRPR11, 1 10 ‡ SD SD SD ∗ SD ∗ PR 12, 1 11 § PR SD ∗ PR SD ∗ SD ∗ 3, 6 12 PR CR CR CR CR 24 † 13 PD SD ∗ SD ∗ SD ∗ SD ∗ 14 14 PR SD PR SD PR 12, 415 ‖ PRSDPRPRPR10, 416NAPD ¶ PRPRPR7, 5 17 SD PD PD PD PD 1, 918SDSDPRPRPR5, 4 19 SD SD PD SD SD 20 † 20 SD SD SD SD SD 19 † 21 NA PD PD PD PD 10 † 22 NA PD PD PD PD 11 † 23 PR SD SD SD PR 8 † 24NASDPDPDPD7 † 25 NA SD PR SD SD 8 †
AASLD a , American Association for the Study of Liver Diseases area; AASLD d , American Association for the Study of Liver Diseases diameter; AFP, α-fetoprotein; CR, complete remission; EASL, European Association for the Study of the Liver; NA, not assessed; PD, progressive disease; PR, partial remission; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.
In addition to imaging evaluations, the best AFP response is displayed. Concerning AFP evaluation, we considered a >20% decrease of AFP levels as PR and a >30% increase as PD; SD was considered as values between PR and PD. In patients with baseline AFP values < 20 g/L, the best AFP response was NA. Boldface type highlights all patients in whom all three diagnostic criteria that consider necrotic areas in a functional assessment indicated different interpretations than the evaluation according to RECIST.
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Table 4
Percentage of Patients: Best Overall Response
Evaluation Criteria CR PR SD PD RECIST version 1.1 4% (1/25) 0% (0/25) 72% (18/25) 24% (6/25) AASLD a 4% (1/25) 36% (9/25) 36% (9/25) 24% (6/25) AASLD d 4% (1/25) 44% (11/25) 36% (9/25) 16% (4/25) EASL 4% (1/25) 24% (6/25) 52% (13/25) 20% (5/25)
AASLD a , American Association for the Study of Liver Diseases area; AASLD d , American Association for the Study of Liver Diseases diameter; CR, complete remission; EASL, European Association for the Study of the Liver; PD, progressive disease; PR, partial remission; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Table 5
BR Assessment: Mean Tumor Size Measurements
RECIST (cm) EASL/AASLD a (cm 2 ) AASLD d (cm) Patient BL BR (Time of BR ∗ ) BL BR (Time of BR ∗ ) BL BR (Time of BR ∗ ) 1 3.5 3.9 (4) 7.1 5.0 (4) 1.5 0.9 (1.2)22524 ( 1.9)551.0 ( 1.9)3.60.1 ( 1.9) 3 24 25 (2.1) 193 181 (2.1) 19 16 (2.1) 4 † 11 11 (24) 41 35 (21) 5.9 6.3 (21) 5 † 2.9 3.3 (7.2) 6.1 5.9 (3.2) 1.6 1.0 (11) 6 † 8.3 9.5 (7.9) 20 19 (7.9) 4.6 5.4 (4) 7 8.6 11.8 (1.8) 13 23 (1.8) 2.3 2.1 (1.8)8 ¶ 6.88.2 ( 0.5)184.6 ( 1.5)3.52.1 ( 0.5)92829 ( 8.8)11475 ( 3.2)209.9 ( 2) 10 ‡ 8.3 8.3 (4.2) 32 28 (1.2) 8.3 5.7 (1.2) 11 § 17 17 (1.6) 62 34 (0.7) 4.6 3.3 (1.6) 12 † 4.4 NM (14) 9.1 NM (14) 2.3 NM (14) 13 9.4 9.7 (0.8) 14 16 (0.8) 5.4 5.1 (0.8) 14 5.9 4.3 (5.8) 13 6.7 (2.2) 2.5 1.0 (2.2)15 ‖ 1615 ( 3.7)6935 ( 0.7)8.95.3 ( 0.7)16 ¶ 9.411.4 ( 1.2)2510.6 ( 1.2)4.01.2 ( 1.2) 17 11.8 13.2 (2) 32.5 52.0 (2) 7.9 10.4 (2)182225 ( 3.3)10752 ( 1.4)6.74.3 ( 1.4) 19 † 11 11 (1.9) 37 45 (1.9) 3.7 4.2 (1.9) 20 † 2.9 2.7 (5.8) 2.5 2.7 (5.8) 1.5 1.5 (5.8) 21 † 8.5 10.1 (2.8) 9.7 16.6 (2.8) 2.0 3.4 (2.8) 22 † 6.2 6.7 (4.9) 13 12 (4.9) 2.6 2.3 (4.9) 23 † 5.8 5.5 (6.2) 12 9.2(6.2) 3.4 2.1 (4.9)24 † 3.33.6 ( 6.2)3.95.1 ( 3.0)2.02.6 ( 3.0) 25 † 6.5 7.0 (4.8) 13 8.9 (1.7) 2.7 2.1(4.8)
AASLD a , American Association for the Study of Liver Diseases area; AASLD d , American Association for the Study of Liver Diseases diameter; BL, baseline; BR, best response; EASL, European Association for the Study of the Liver; NM, not measurable; RECIST, Response Evaluation Criteria in Solid Tumors.
Boldface type highlights all patients in whom all three diagnostic criteria that consider necrotic areas in a functional assessment indicated different interpretations than the evaluation according to RECIST.
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Discussion
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Conclusions
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
References
1. Llovet J.M., Ricci S., Mazzaferro V., et. al.: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: pp. 378-390.
2. Wilhelm S.M., Carter C., Tang L., et. al.: BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 64: pp. 7099-7109.
3. Horger M., Lauer U.M., Schraml C., et. al.: Early MRI response monitoring of patients with advanced hepatocellular carcinoma under treatment with the multikinase inhibitor sorafenib. BMC Cancer 2009; 9: pp. 208.
4. Schraml C., Schwenzer N.F., Martirosian P., et. al.: Diffusion-weighted MRI of advanced hepatocellular carcinoma during sorafenib treatment: initial results. AJR Am J Roentgenol 2009; 193: pp. W301-W307.
5. Eisenhauer E.A., Therasse P., Bogaerts J., et. al.: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: pp. 228-247.
6. Llovet J.M., Di Bisceglie A.M., Bruix J., et. al.: Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008; 100: pp. 698-711.
7. Forner A., Ayuso C., Varela M., et. al.: Evaluation of tumor response after locoregional therapies in hepatocellular carcinoma: are response evaluation criteria in solid tumors reliable?. Cancer 2009; 115: pp. 616-623.
8. Eisenhauer E.A.: Response evaluation: beyond RECIST. Ann Oncol 2007; 18: pp. ix29-ix32.
9. Michaelis L.C., Ratain M.J.: Measuring response in a post-RECIST world: from black and white to shades of grey. Nat Rev Cancer 2006; 6: pp. 409-414.
10. El-Serag H.B., Rudolph K.L.: Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132: pp. 2557-2576.
11. Abou-Alfa G.K.: Hepatocellular carcinoma: molecular biology and therapy. Semin Oncol 2006; 33: pp. S79-S83.
12. Bruix J., Sherman M., Llovet J.M., et. al.: Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. J Hepatol 2001; 35: pp. 421-430.
13. Yang J.C., Haworth L., Sherry R.M., et. al.: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003; 349: pp. 427-434.
14. Oken M.M., Creech R.H., Tormey D.C., et. al.: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: pp. 649-655.
15. Chan S.L., Mo F.K., Johnson P.J., et. al.: New utility of an old marker: serial alpha-fetoprotein measurement in predicting radiologic response and survival of patients with hepatocellular carcinoma undergoing systemic chemotherapy. J Clin Oncol 2009; 27: pp. 446-452.
16. Efremidis S.C., Hytiroglou P., Matsui O.: Enhancement patterns and signal-intensity characteristics of small hepatocellular carcinoma in cirrhosis: pathologic basis and diagnostic challenges. Eur Radiol 2007; 17: pp. 2969-2982.
17. Stacchiotti S., Collini P., Messina A., et. al.: High-grade soft-tissue sarcomas: tumor response assessment—pilot study to assess the correlation between radiologic and pathologic response by using RECIST and Choi criteria. Radiology 2009; 251: pp. 447-456.
18. Choi H., Charnsangavej C., Faria S.C., 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: pp. 1753-1759.
19. Benjamin R.S., Choi H., Macapinlac H.A., et. al.: We should desist using RECIST, at least in GIST. J Clin Oncol 2007; 25: pp. 1760-1764.
20. Crabb S.J., Patsios D., Sauerbrei E., et. al.: Tumor cavitation: impact on objective response evaluation in trials of angiogenesis inhibitors in non-small-cell lung cancer. J Clin Oncol 2009; 27: pp. 404-410.
21. Liapi E., Geschwind J.F., Vossen J.A., et. al.: Functional MRI evaluation of tumor response in patients with neuroendocrine hepatic metastasis treated with transcatheter arterial chemoembolization. AJR Am J Roentgenol 2008; 190: pp. 67-73.
22. Scher H.I., Morris M.J., Kelly W.K., et. al.: Prostate cancer clinical trial end points: “RECIST”ing a step backwards. Clin Cancer Res 2005; 11: pp. 5223-5232.
23. van Klaveren R.J., Aerts J.G., de Bruin H., et. al.: Inadequacy of the RECIST criteria for response evaluation in patients with malignant pleural mesothelioma. Lung Cancer 2004; 43: pp. 63-69.
24. Byrne M.J., Nowak A.K.: Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol 2004; 15: pp. 257-260.
25. Gopinath G., Ahmed A., Buscombe J.R., et. al.: Prediction of clinical outcome in treated neuroendocrine tumours of carcinoid type using functional volumes on 111In-pentetreotide SPECT imaging. Nucl Med Commun 2004; 25: pp. 253-257.
26. Hurwitz H., Fehrenbacher L., Novotny W., et. al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: pp. 2335-2342.
27. Shepherd F.A., Rodrigues Pereira J., Ciuleanu T., et. al.: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353: pp. 123-132.
28. Hudes G., Carducci M., Tomczak P., et. al.: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007; 356: pp. 2271-2281.
29. Bruix J., Sherman M.: Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology 2005; 42: pp. 1208-1236.