Assessment of treatment response for Hepatocellular Carcinoma (HCC)

Assessment of treatment response for Hepatocellular Carcinoma (HCC)

Guidelines for evaluating response to treatment in solid tumours have evolved WHO RECIST mRECIST for HCC Handbook for reporting results of cancer treatment1 Response Evaluation Criteria In Solid Tumors4 Proposed modifications to RECISTv1.1 for assessing response in HCC6,7 1979 1992 2000 2001 2008 2009 2010 2012 mWHO EASL criteria RECIST v1.1 mRECIST Conclusions from the Barcelona 2000 EASL conference5 Revised RECIST guidelines8 Modified WHO criteria2,3 EASL-EORTC HCC guideline9 EASL, European Association for the Study of the Liver; HCC, hepatocellular carcinoma; RECIST, Response Evaluation Criteria In Solid Tumors; WHO, World Health Organisation. 1. WHO 1979. Available at: http://whqlibdoc.who.int/offset/WHO_OFFSET_48.pdf; 2. Green S, et al. Invest New Drugs 1992;10:239-53; 3. P. Therasse Ann Oncol (2002) 13(suppl 4): 127-129 ; 4. Therasse P, et al. J Natl Cancer Inst 2000;92:205-16; 5. Bruix J, et al. J Hepatol 2001;35:421-30; 6. Llovet JM, et al. J Natl Cancer Inst 2008;100:698-791; 7. Lencioni R, et al. Semin Liver Dis 2010;30:52-60; 8. Eisenhauer EA, et al. Eur J Cancer 2009;45:228-47; 9. EASL-EORTC Guidelines. J Hepatology 2012;56:908-43

Designed primarily for evaluating cytotoxic drugs1 Molecular-targeted or loco-regional therapies can be effective by causing tumour necrosis2 Measure of antitumour activity based on tumour shrinkage alone1 Changes in tumour vasculature, metabolism or diffusion characteristics not assessed3 Tumour necrosis, however, does not always lead to reductions in lesion size1,2,4-6 RECISTcriteriakeylimitations Assessment of efficacy of molecular-targeted or loco-regional therapies based solely on changes in tumour size can be misleading1 1. Llovet JM, et al. J Natl Cancer Inst 2008;100:698-791; 2. Lencioni R, et al. Semin Liver Dis 2010;30:52-60; 3. van Persijn van Meerten EL, et al. Eur Radiol 2010;20:1456-67; 4. Abou Alfa G, et al. J Clin Oncol 2006;24:4293-300; 5. Choi H, et al. J Clin Oncol 2007;25:1753-9; 6. Bruix J, et al. J Hepatol 2001;35:421-30

RECIST criteriakeylimitations In 2000, a panel of experts on HCC of the European Association for the study of the Liver (EASL) amended RECIST criteria. According to the amended criteria the optimal method to assess treatment response is to estimate reduction in viable tumor area using contrast-enhanced radiologic imaging. AASLD practice guideline on the management of HCC (2005): treatment response evaluation should take into account the induction of intratumoral necrotic areas in estimating the decrease in tumor load, and not just a reduction in overall tumor size. Lencioni R et al. Seminars in liver disease 2010; 30 (1): 52-60

Many targeted agents improve survival, but are associated with low response rates according to RECIST NSCLC, non-small cell lung cancer; HCC, hepatocellular carcinoma; RCC, renal cell carcinoma; CRC, colorectal cancer.1. Shepherd FA, et al. N Engl J Med 2005;353:123-132; 2. Llovet J, et al. New Engl J Med 2008; 3. Hudes G, et al. N Engl J Med 2007;356:2271-81.

Targeted agents can induce tumour necrosis, but not necessarily tumour shrinkage Representative CT scanS from a single patient included in a phase II study of 137 patients with inoperable HCC treated with sorafenib Tumour size increase CT, computed tomography1. Abou Alfa G, et al. J ClinOncol 2006;24:4293-300

Treatment efficacyassessment • The endpoint in cancer research is overall survival. • Tumor response and time to progression have been considered pivotal for surrogate assessment of efficacy. • Tumor response was initially measured according to the World Health Organization (WHO) criteria, and afterwards according to the Response Evaluation Criteria in Solid Tumors (RECIST) guideline. • WHO and RECIST define standard measurement methods for converting radiology image observations into a quantitative and statistically tractable framework for measuring the response of tumor size to therapy. • Target lesions are measured using: • the bilinear product approach (WHO) or • single linear summation (RECIST) Lencioni R et al. Seminars in liver disease 2010; 30 (1): 52-60

Taking tumour necrosis into account: EASL criteria 2001 EASL Panel of HCC Experts conclusions:1 Measurement of tumour load by simple bidimensional determinations of diameter is not accurate enough, since tumour necrosis due to treatment is not taken into account Extensive tumour necrosis may not be paralleled by a reduction in diameter of the lesion Estimation of the reduction in viable tumour volume (recognized by non-enhanced areas by spiral CT) should be considered the optimal method to assess the local response to treatment Definition Viable tumor: uptake of contrast agent in the arterial phase of dynamic computed tomography (CT) or magnetic resonance imaging (MRI). 2 1. Bruix J, et al. J Hepatol 2001;35:421-30; 2. Lencioni R, et al. Semin Liver Dis 2010;30:52-60

Taking tumour necrosis into account: EASL criteria • Tumour necrosis previously not considered • Tumour necrosis ≠ reduction in tumour diameter • Spiral CT optimal to assess viable tumour volume EASL criteria [change in enhancement (viable volume)] RECIST criteria (change in size) 1. Bruix J, et al. J Hepatol 2001;35:421-30; 2. Riaz A, et al. J Hepatol 2011; 54: 695–704;

Taking tumour necrosis into account: EASL criteria 1. Bruix J, et al. J Hepatol 2001;35:421-30; 2. Spira D et al. Academic Radiol 2011;18:89-96

EASL criteria better reflect the therapeutic benefit of loco-regional therapy in HCC Comparison of two patient cohorts selected from prospective studies at the same centre assessing DEB-TACE (n=24) or PEI/RFA (n=31)1 Evaluation of response should incorporate reduction in viable tumour burden DEB-TACE, drug-eluting bead transarterial chemoembolization; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation.1 Forner A, et al. Cancer 2009;115:616-23.

Taking tumour necrosis into account:AASLD recommendations • An AASLD expert panel on trial design1 suggested the following changes to those initially proposed by the EASL Panel of HCC Experts:2 • Measurements by change in the sum of diameters of viable target lesions (contrast enhancement in the arterial phase) • Uniform image acquisition parameters, quality control, and independent blinded multi-reader assessment to be used • The 2010 update of the AASLD Practice Guidelines for the management of HCC state:3 • Evaluation of treatment response should take into account intra-tumoural necrotic areas in estimating the decrease in tumour load • For the investigation of small nodules in patients at risk of HCC, a multidetector CT scan for arterial hypervascularity and venous or delayed phase is recommended AASLD, American Association for the Study of Liver Diseases1. Llovet JM, et al. J Natl Cancer Inst 2008;100:698-791; 2. Bruix J, et al. J Hepatol 2001;35:421–30; 3. Bruix J & Shermann M. Hepatology 2010. Available at: http://www.aasld.org/practiceguidelines

Taking tumour necrosis into account:EASL-EORTC recommendations • Assessment of response in HCC should be based on mRECISTcriteria(recommendation 2B) • Use of changes in serum levels of biomarkers such as AFP levels is under investigation • Dynamic CT or MRI are recommended tools to assess response one month after resection, loco-regional or systemic therapies (recommendation 1A) • Follow-up strategies for detection of recurrence include one imaging technique every 3 months to complete at least two years. Afterwards, regular ultrasound is recommended every 6 months. • Assessment of time to progression is recommended with CT and/or MRI every 6-8 weeks based on the modification of the RECIST criteria during the first year, and every six months thereafter EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma J Hepatology 2012;56:908-43 Available on: http://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdf

Taking tumour necrosis into account:mRECIST for HCC In mRECIST for HCC, tumor response is a result of the combined assessment of target lesions and non target lesions EASL–EORTC ClinicalPracticeGuidelines: Management of hepatocellular carcinoma J Hepatology 2012;56:908-43 Available on: http://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdf

RECIST vs mRECIST in HCC PatientsTreated with TAE / DEB-TACE mRECIST RECIST p = 0.009 p = 0.63 83 eligible patients (at baseline 69 CPA; 13CPB;1 not documented); There was a median of 30 days (range, 1–123) between the date of the baseline scan and the embolisation procedure and 64 days (range, 18–129) between the embolisation and assessment scan. Adapted from Gillmore R et al. J Hepatol 2011;55:1309-1316

Non–responders vs responders to TACE according to mRECISTcriteria B A Target lesion responses Overall responses Kaplan–Meier curves were generated to compare survival rates between responders and non-responders according to mRECIST radiological assessment methods. Assessments were also defined according to overall responses (A)and target lesion responses (B) Adapted from Gillmore R et al. J Hepatol 2011;55:1309-1316

Indipendentprognosticfactor for survival in TACE treatedpatients The overall responses measured with mRECIST criteria between 2 and 3 months after the first TACE are independently associated with survival Adapted from Gillmore R et al. J Hepatol 2011;55:1309-1316

WhichResponseCriteria Best Help to PredictSurvivalafter TACE in HCC Patients? Size criteria Enhancement criteria Adapted from Shim JH et al. Radiology 2012;262:708-718

WhichResponseCriteria Best Help to PredictSurvivalafter TACE in HCC Patients? Adapted from Shim JH et al. Radiology 2012;262:708-718;

Which Response Criteria Best Help to Predict Survival after TACE in HCC Patients? Survival of 332 BCLC stage B patients, as determined with EASL criteria. Data were stratified into four response categories. Adapted from Shim JH et al. Radiology 2012;262:708-718;

Which Response Criteria Best Help to Predict Survival after TACE in HCC Patients? * Numbers in parentheses are the 95% CIs Survival of 332 BCLC stage B patients, as determined with mRECIST criteria. Data were stratified into four response categories. Adapted from Shim JH et al. Radiology 2012;262:708-718;

Antiangiogenic drugs response rate by RECIST criteria is very low: 2% in SHARP, 3.3% in Asia–Pacific however, mRECIST criteria - as adapted by EASL - which reflect changes in tumor vascularization may be a much more appropriate criteria to measure response Sorafenib: how to evaluate efficacy RECIST mRECIST Lencioni R, Llovet JM. Semin Liver Dis. 2010;30:52‐60.

Sorafenib: how to evaluate efficacy Baseline After treatment Evaluation according to RECIST and mRECISTof a voluminous lesion with central necrosis before treatment and discontinuous peripheral enhancement after treatment with sorafenib. (A,B) RECIST measurement of the lesion (arrows) before (A) and aftertreatment (B). (C,D) mRECIST measurement of the same lesion before (C) and after treatment (D). mRECIST measurements were not taken at the same level as RECIST measurements to ensure that the greatest dimension of continuous enhancement was measured. RECIST mRECIST For patients with HCC who are receiving antiangiogenic drugs, mRECIST should be used for the standard assessment of treatment efficacy Edeline J, et al. Cancer. 2012 Jan 1;118(1):147-56

Sorafenib: how to evaluate efficacy • Retrospective analysis of 53 patients who received sorafenibfor advanced HCC • Patients have undergone a 4-phase CT scan before treatment and repeatedly thereafter • mRECIST were evaluated and compared with RECIST 1.1 • Results : RECIST mRECIST OR: 23% SD: 57% PD: 21% OR: 2% SD: 79% PD: 19% • Patients with an OR according to mRECIST had a longer OS than nonrespondingwith SD or PD (median OS, 18 months and 8 months, respectively; P = 0,013) • In the 42 patients with SD according to RECIST, OS differed depending on tumor response according to mRECIST • Median OS for patients who achieved an OR (n = 11), SD (n = 29), and PD (n = 2) was 17, 10 and 4 months, respectively (P = 0,016). For patients with HCC who are receiving antiangiogenic drugs, mRECIST should be used for the standard assessment of treatment efficacy Edeline J, et al. Cancer. 2012 Jan 1;118(1):147-56

EASL may more accurately reflect tumour burden in HCC than RECIST Prospective study of 38 patients with advanced HCC receiving sorafenib (18% BCLC-B; 82% BCLC-C) 22 evaluable patients assessed by CT scan Overall, progression significantly less frequent by EASL criteria than by RECIST criteria (p=0.006) BCLC, Barcelona Clinic Liver Cancer; CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. Iavarone M, et al. AASLD 2009 Abstract #936

mRECIST may reflect response to sorafenib in HCC more accurately than RECIST • 34 of 39 patients with advanced HCC were evaluable for therapeutic effects of sorafenib treatment by MDCT imaging with contrast medium • Mean age was 70.2 years, HCC stage III (n=7), IVa (n=13), and IVb (n=14) • Overall response to therapy was evaluated using both RECIST (v1.1) and mRECIST before therapy initiation and 4-6 weeks after therapy initiation CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. Kuzuya T, et al. AASLD 2010 Abstract #1781.

EASL and mRECIST may more accurately reflect tumour burden in HCC than RECIST v1.1 • Retrospective analysis of 25 patients with inoperable HCC treated with sorafenib MRI images from patient with PD by RECIST v1.1 and PR by EASL and mRECIST Baseline After 5 weeks of sorafenib treatment MRI, magnetic resonance imagingSpira D, et al. Academic Radiol 2011;18:89-96 Long arrows, viable tumour; Short arrows and red circles, necrotic areas

Survival of HCC patients treated with sorafenib.Association with radiologic response OS according to mRECIST in 42 patients with SD according to RECIST OS according to mRECIST Median OS of patients with mRECIST OR (18.2 months, 95% CI 15.4–20.9) was significantly better than patients with SD or PD (7.7 months, 95% CI 6.3–9.0; P=0.013) Responders SD PD Responders Non-responders In the 42 patients with RECIST SD, median OS differed depending on mRECIST: 17.1 months (OR, n=11), 9.7 months (SD, n=29) and 3.7 months (PD, n=2) OR=objective response Edeline J, et al. Cancer. 2012 Jan 1;118(1):147-56

Survival of HCC patients treated with sorafenib.Usefulness of AFP ratioand mRECIST combination OS according to mRECIST, Child-Pugh, AFP ratio OS according to AFP ratio Median OS of patients with a predictor score of 3 (24 months, P=0.001) was significantly better than patients with score of 0 (3 months), 1 (5 months) and 2 (21 months) AFP ratio≤1 at 8weeks AFP ratio≥1 at 8weeks * OS of patients with AFP ratio≤1 at 8 weeks from the start of the treatment was significantly better than patients with AFP ratio>1 (P=0.002) The combination of mRECIST and AFP ratio is useful for the assessment of prognosis of patients with advanced HCC treated with sorafenib. * : score was calculated as sum of the response by mRECIST (PD:0, CR or PR of SD:1), Child-Pugh score (B:0, A:1) and AFP ratio at 8 weeks from the start of the treatment (>1:0, ≤1:1) Kawaoka T, et al. Oncology 2012;83:192–200

Survival of HCC patients treated with sorafenib.Usefulness of AFP response OS according to RECIST OS according to AFP response In 32 patients with 20% AFP decrease ( AFP OR), median OS was significantly better (13.3 months, P=0,022) than in 53 AFP non-responder patients (8,2 months) In 82 patients with DC or PD examined for baseline and follow-up CT, median OS was not significantly different (DC=10.1 and PD=7.5 months, P=0.823) AFP response is an independent surrogate end point for survival that should be consider in conjunction with radiologic response evaluation. OR=objective response Personeni N, et al. Journal of Hepatology. 2012 ;57:101-07

Survival of HCC patients treated with sorafenib.Usefulness of AFP response Overall survival Progression Free Survival Patients (n=19) with an early AFP level 20% higher than the baseline value had shorter OS and PFS than the other patients (OS, 6.9 vs. 18.3 months; P=0.0002; OS rate at 1 year, 20.3 vs. 55.8%; PFS, 1.4 vs. 4.2 months; P=0.0006; PFS rate at 1 year, 7 vs. 23%). Earlyincrease in AFP of more than 20% within 4 weeks after the initiation of sorafenibtreatment predictssubsequentdiseaseprogression. Nakazawa T, et al. Journal of Hepatology. 2012 ;57:101-07

Considerations for future application of mRECIST and serum biomarkers The proposedmRECISTassessment is expected to provide a reliable method for assessing tumor response in HCC 1 Requirement for adequate skills and expertise – education and trainin1 Hardware requires standardization to ensure reproducibility and reliable comparisons, e.g.: 1 optimization of image acquisition protocols uniform image acquisition parameters rigorous quality control blinded assessments The use of changes in serum levels of biomarkers (i.e. AFP levels) for the assessment of response in HCC is under investigation 2 1. LencioniR, Llovet JM. Semin Liver Dis. 2010;30:52‐60. 2 EASL–EORTC ClinicalPracticeGuidelines: Management of hepatocellular carcinoma J Hepatology 2012;56:908-43 Available on: http://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdf

Assessment of treatment response for Hepatocellular Carcinoma (HCC)