Overall survival and objective response in advanced unresectable hepatocellular carcinoma: A subanalysis of the REFLECT study.

BACKGROUND & AIMS: Validated surrogate endpoints for overall survival (OS) are important for expediting the clinical study and drug-development processes. Herein, we aimed to validate objective response as an independent predictor of OS in individuals with unresectable hepatocellular carcinoma (HCC) receiving systemic anti-angiogenic therapy. METHODS: We investigated the association between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST and RECIST v1.1) and OS in REFLECT, a phase III study of lenvatinib vs. sorafenib. We conducted landmark analyses (Simon-Makuch) of OS by objective response at 2, 4, and 6 months after randomization. RESULTS: Median OS was 21.6 months (95% CI 18.6-24.5) for responders (investigator-assessed mRECIST) vs. 11.9 months (95% CI 10.7-12.8) for non-responders (hazard ratio [HR] 0.61; 95% CI 0.49-0.76; p <0.001). Objective response by IRR per mRECIST and RECIST v1.1 supported the association with OS (HR 0.61; 95% CI 0.51-0.72; p <0.001 and HR 0.50; 95% CI 0.39-0.65; p <0.001, respectively). OS was significantly prolonged for responders vs. non-responders (investigator-assessed mRECIST) at the 2-month (HR 0.61; 95% CI 0.49-0.76; p <0.001), 4-month (HR 0.63; 95% CI 0.51-0.80; p <0.001), and 6-month (HR 0.68; 95% CI 0.54-0.86; p <0.001) landmarks. Results were similar when assessed by IRR, with both mRECIST and RECIST v1.1. An exploratory multivariate Cox regression analysis identified objective response by investigator-assessed mRECIST (HR 0.55; 95% CI 0.44-0.68; p <0.0001) and IRR-assessed RECIST v1.1 (HR 0.49; 95% CI, 0.38-0.64; p <0.0001) as independent predictors of OS in individuals with unresectable HCC. CONCLUSIONS: Objective response was an independent predictor of OS in individuals with unresectable HCC in REFLECT; additional studies are needed to confirm surrogacy. Participants achieving a complete or partial response by mRECIST or RECIST v1.1 had significantly longer survival vs. those with stable/progressive/non-evaluable disease. GOV NUMBER: NCT01761266. IMPACT AND IMPLICATIONS: This analysis of data taken from a completed clinical trial (REFLECT) looked for any link between objective response and overall survival time in individuals with unresectable HCC receiving anti-angiogenic treatments. Significantly longer median overall survival was found for responders (21.6 months) vs. non-responders (11.9 months). Overall survival was also significantly longer for responders vs. non-responders (based on objective response status at 2, 4, and 6 months) in the landmark analysis. Our results indicate that objective response is an independent predictor of overall survival in this setting, confirming its validity as a rapid marker of efficacy that can be applied in phase II trials; however, further validation is required to determine is validity for other systemic treatments (e.g. immunotherapies), or as a surrogate of overall survival.

Optimal imaging criteria and modality to determine Milan criteria for the prediction of post-transplant HCC recurrence after locoregional treatment.

OBJECTIVES: We aimed to investigate the optimal radiologic method to determine Milan criteria (MC) for the prediction of recurrence in patients who underwent locoregional treatment (LRT) for hepatocellular carcinoma (HCC) and subsequent liver transplantation (LT). METHODS: This retrospective study included 121 HCC patients who underwent LRT and had both liver dynamic CT and MRI. They were classified with MC using four cross combinations of two imaging modalities (CT and MRI) and two diagnostic criteria (modified Response Evaluation Criteria in Solid Tumors [mRECIST] and Liver Imaging Reporting and Data System treatment response algorithm [LI-RADS TRA]). Competing risk regression was performed to analyze the time to recurrence after LT. The predictive abilities of the four methods for recurrence were evaluated using the time-dependent area under the curve (AUC). RESULTS: Competing risk regression analyses found that beyond MC determined by MRI with mRECIST was independently associated with recurrence (hazard ratio, 6.926; p = 0.001). With mRECIST, MRI showed significantly higher AUCs than CT at 3 years and 5 years after LT (0.597 vs. 0.756, p = 0.012 at 3 years; and 0.588 vs. 0.733, p = 0.024 at 5 years). Using the pathologic reference standard, MRI with LI-RADS TRA showed higher sensitivity (61.5%) than CT with LI-RADS TRA (30.8%, p < 0.001) or MRI with mRECIST (38.5%, p < 0.001). CONCLUSIONS: MRI with mRECIST was the optimal radiologic method to determine MC for the prediction of post-LT recurrence in HCC patients with prior LRT. KEY POINTS: • MRI with modified RECIST (mRECIST) is the optimal preoperative method to determine Milan criteria for the prediction of post-transplant HCC recurrence in patients with prior locoregional treatment. • With mRECIST, MRI was better than CT for the prediction of post-transplant recurrence.

Addition of Y-90 radioembolization increases tumor response and local disease control in hepatocellular carcinoma patients receiving sorafenib.

PURPOSE: To compare the treatment response and progression-free survival (PFS) in advanced hepatocellular carcinoma (HCC) patients who received sorafenib treatment either alone or combined with radioembolization (RE). METHODS: Follow-up images of the patients treated within a multicenter phase II trial (SORAMIC) were assessed by mRECIST. A total of 177 patients (73 combination arm [RE + sorafenib] and 104 sorafenib arm) were included in this post-hoc analysis. Response and progression characteristics were compared between treatment arms. Survival analyses were done to compare PFS and post-progression survival between treatment arms. Multivariate Cox regression analysis was used to compare survival with factors known to influence PFS in patients with HCC. RESULTS: The combination arm had significantly higher objective response rate (61.6% vs. 29.8%, p < 0.001), complete response rate (13.7% vs. 3.8%, p = 0.022), and a trend for higher disease control rate (79.2% vs. 72.1%, p = 0.075). Progression was encountered in 116 (65.5%) patients and was more common in the sorafenib arm (75% vs. 52.0%, p = 0.001). PFS (median 8.9 vs. 5.4 months, p = 0.022) and hepatic PFS were significantly better in the combination arm (9.0 vs. 5.7 months, p = 0.014). Multivariate analysis confirmed the treatment arm as an independent predictor of PFS. CONCLUSION: In advanced HCC patients receiving sorafenib, combination with RE has an additive anticancer effect on sorafenib treatment resulting in a higher and longer tumor response. However, the enhanced response did not translate into prolonged survival. Better patient selection and superselective treatment could improve outcomes after combination therapy.

Immunotherapy-Based Treatments of Hepatocellular Carcinoma: AJR Expert Panel Narrative Review.

The advent of immunotherapy for patients with hepatocellular carcinoma (HCC) has changed the treatment landscape and conferred a survival benefit on patients with advanced HCC, who typically have a very poor prognosis. The most pronounced improvements in response, as documented by standardized response criteria based on CT or MRI, have been achieved when immunotherapy is combined with other systemic or locoregional therapies. Immune checkpoint inhibitor treatments result in unique patterns on CT and MRI that challenge the application of conventional response criteria such as RECIST, modified RECIST, and European Association for the Study of the Liver criteria. Thus, newer criteria have been developed to gauge therapy response or disease progression for patients receiving immunotherapy, including immune-related RECIST (iRECIST) and immune-modified RECIST (imRECIST), though these remain unvalidated. In this review, we describe the current landscape of immunotherapeutic agents used for HCC, summarize the results of published studies, review the pathobiologic mechanisms that provide a rationale for the use of these agents, and report on the status of response assessment for immunotherapy either alone or in combination with other treatment options. Finally, consensus statements are provided to inform radiologists about essential considerations in the era of a rapidly changing treatment paradigm for patients with HCC.

Preoperatively predicting early response of HCC to TACE using clinical indicators and MRI features.

BACKGROUND: We aimed to evaluate the value of using preoperative magnetic resonance imaging (MRI) features and clinical indicators to predict the early response of hepatocellular carcinoma (HCC) to transcatheter arterial chemoembolization (TACE). We also aimed to establish a preoperative prediction model. METHODS: We retrospectively reviewed data of 111 patients with HCC who underwent magnetic resonance imaging (MRI) before the first TACE and underwent MRI or computed tomography between 30 and 60 days after TACE. We used the modified response evaluation criteria in solid tumors for evaluating the TACE response. We used univariate and multivariate logistic regression analyses to identify independent predictors based on MRI features and clinical indicators. Moreover, receiver operating characteristic (ROC) curve analyses were performed to assess the diagnostic performance of the prediction model and each independent predictor. RESULTS: Among the 111 included patients, 85 were men (76.6%). Patient age was 31-86 years (average age, 61.08 ± 11.50 years). After the first treatment session, 56/111 (50.5%) patients showed an objective response (complete response + partial response), whereas the remaining showed non-response (stable disease + local progressive disease). In the univariate analysis, we identified irregular margins, number of nodules, and satellite nodules as predictors of early objective response. However, in the multivariate logistic regression analysis, irregular margins, number of nodules and pretreatment platelet were identified as the independent predictors of early objective response. A combined prediction model was then established, which factored in irregular margins, the number of nodules, and the pretreatment platelet count. This model showed good diagnostic performance (area under the ROC curve = 0.755), with the sensitivity, specificity, positive predictive value, and negative predictive value being 78.6%, 69.1%, 72.1%, and 76.0%, respectively. CONCLUSIONS: Irregular margins, the number of nodules and the pretreatment platelet count are independent predictors of the early response of HCC to TACE. Our clinical combined model can provide a superior predictive power to a single indicator.

Assessment of various efficacy outcomes using ERIVANCE-like criteria in patients with locally advanced basal cell carcinoma receiving sonidegib: results from a preplanned sensitivity analysis.

BACKGROUND: The BOLT study for sonidegib, a Hedgehog pathway inhibitor (HHI) approved for patients with locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy, used modified Response Evaluation Criteria in Solid Tumors (mRECIST) for laBCC tumor evaluation. The ERIVANCE study for vismodegib, another HHI, used a composite RECIST endpoint of ≥30% reduction in externally visible tumor or radiographic dimension, or complete ulceration resolution. This preplanned sensitivity BOLT analysis evaluated efficacy outcomes using ERIVANCE-like criteria in patients with laBCC who received sonidegib 200 mg once daily. METHODS: This phase 2, double-blind study randomized patients 1:2 to sonidegib 200:800 mg daily, respectively. Key endpoints included objective response rate (ORR), duration of response (DOR), complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). laBCC tumors were assessed by both mRECIST and ERIVANCE-like criteria. Per mRECIST, an overall response of CR was based on negative histology; photographic assessment of CR, PR (scar/fibrosis only), SD (scar/fibrosis only), or not available (NA); and a magnetic resonance imaging response of CR or NA. An overall response of CR was primarily based on negative histology using ERIVANCE-like criteria. RESULTS: Per mRECIST criteria, ORR (95% confidence interval [CI]) by central and investigator review for patients with laBCC (n = 66) was 56.1% (43.3-68.3%) and 71.2% (58.7-81.7%), respectively. CR per central review was achieved in 3 (4.5%) patients and PR, SD, and PD occurred in 34 (51.5%), 23 (34.8%), and 1 (1.5%) patient, respectively. Median (95% CI) DOR was 26.1 months (not estimable [NE]). Using ERIVANCE-like criteria, efficacy outcomes per central and investigator review were higher, with an ORR (95% CI) of 60.6% (47.8-72.4%) and 74.2% (62.0-84.2%), respectively. CR per central review was reached in 14 (21.2%) patients and PR, SD, and PD occurred in 26 (39.4%), 20 (30.3%), and 1 (1.5%) patient, respectively. DOR was unchanged with a median (95% CI) of 26.1 months (NE). CONCLUSIONS: Overall, applying ERIVANCE-like criteria to patients with laBCC receiving sonidegib 200 mg daily yielded higher response rates vs mRECIST criteria. TRIAL REGISTRATION: BOLT registration: ClinicalTrials.gov ( NCT01327053 ) on March 30, 2011.

Including mRECIST in the Metroticket 2.0 criteria improves prediction of hepatocellular carcinoma-related death after liver transplant.

BACKGROUND & AIMS: In the context of liver transplantation (LT) for hepatocellular carcinoma (HCC), prediction models are used to ensure that the risk of post-LT recurrence is acceptably low. However, the weighting that 'response to neoadjuvant therapies' should have in such models remains unclear. Herein, we aimed to incorporate radiological response into the Metroticket 2.0 model for post-LT prediction of "HCC-related death", to improve its clinical utility. METHODS: Data from 859 transplanted patients (2000-2015) who received neoadjuvant therapies were included. The last radiological assessment before LT was reviewed according to the modified RECIST criteria. Competing-risk analysis was applied. The added value of including radiological response into the Metroticket 2.0 was explored through category-based net reclassification improvement (NRI) analysis. RESULTS: At last radiological assessment prior to LT, complete response (CR) was diagnosed in 41.3%, partial response/stable disease (PR/SD) in 24.9% and progressive disease (PD) in 33.8% of patients. The 5-year rates of "HCC-related death" were 3.1%, 9.6% and 13.4% in those with CR, PR/SD, or PD, respectively (p <0.001). Log10AFP (p <0.001) and the sum of number and diameter of the tumour/s (p <0.05) were determinants of "HCC-related death" for PR/SD and PD patients. To maintain the post-LT 5-year incidence of "HCC-related death" <30%, the Metroticket 2.0 criteria were restricted in some cases of PR/SD and in all cases with PD, correctly reclassifying 9.4% of patients with "HCC-related death", at the expense of 3.5% of patients who did not have the event. The overall/net NRI was 5.8. CONCLUSION: Incorporating the modified RECIST criteria into the Metroticket 2.0 framework can improve its predictive ability. The additional information provided can be used to better judge the suitability of candidates for LT following neoadjuvant therapies. LAY SUMMARY: In the context of liver transplantation for patients with hepatocellular carcinoma, prediction models are used to ensure that the risk of recurrence after transplantation is acceptably low. The Metroticket 2.0 model has been proposed as an accurate predictor of "tumour-related death" after liver transplantation. In the present study, we show that its accuracy can be improved by incorporating information relating to the radiological responses of patients to neoadjuvant therapies.

mRECIST for HCC: Performance and novel refinements.

In 2010, modified RECIST (mRECIST) criteria were proposed as a way of adapting the RECIST criteria to the particularities of hepatocellular carcinoma (HCC). We intended to overcome some limitations of RECIST in measuring tumour shrinkage with local and systemic therapies, and also to refine the assessment of progression that could be misinterpreted with conventional RECIST 1.1, due to clinical events related to the natural progression of chronic liver disease (development of ascites, enlargement of lymph nodes, etc.). mRECIST has served its purpose since being adopted or included in clinical practice guidelines (European, American and Asian) for the management of HCC; it has also been instrumental for assessing response and time-to-event endpoints in several phase II and III investigations. Nowadays, mRECIST has become the standard tool for measurement of radiological endpoints at early/intermediate stages of HCC. At advanced stages, guidelines recommend both methods. mRECIST has been proven to capture higher objective response rates in tumours treated with molecular therapies and those responses have shown to be independently associated with better survival. With the advent of novel treatment approaches (i.e. immunotherapy) and combination therapies there is a need to further refine and clarify some concepts around the performance of mRECIST. Similarly, changes in the landscape of standard of care at advanced stages of the disease are pointing towards progression-free survival as a potential primary endpoint in some phase III investigations, as effective therapies applied beyond progression might mask overall survival results. Strict recommendations for adopting this endpoint have been reported. Overall, we review the performance of mRECIST during the last decade, incorporating novel clarifications and refinements in light of emerging challenges in the study and management of HCC.

ALBI and P-ALBI grade in Child-Pugh A patients treated with drug eluting embolic chemoembolization for hepatocellular carcinoma.

BACKGROUND: Treatment outcome for hepatocellular carcinoma (HCC) is related to tumor burden and liver function. Grading systems assessing liver function need validation in different clinical settings. PURPOSE: To evaluate drug-eluting embolic transarterial chemoembolization (DEE-TACE) in Child-Pugh A HCC with respect to albumin-bilirubin (ALBI) and platelet-albumin-bilirubin (P-ALBI) grade. MATERIAL AND METHODS: Forty-nine patients with Child-Pugh class A, diagnosed with HCC and allocated to DEE-TACE treatment, were retrospectively analyzed regarding tumor and treatment characteristics, radiological response (mRECIST) one month post treatment, overall survival (OS), and adverse events (AEs; CTCAE, grades ≥3) with respect to ALBI and P-ALBI grade. RESULTS: There were 21 ALBI 1 patients, 29 P-ALBI 1 patients, and 19 patients were both ALBI and P-ALBI 1. Objective response rate was 74% with no statistically significant difference for ALBI (1 vs. 2; P = 0.08), or P-ALBI (1 vs. 2; P = 0.49). OS was 14.8 months (range = 1.7-62.0; ALBI 1 vs. 2: P = 0.08; P-ALBI 1 vs. 2: P = 0.003). OS in responders with ALBI 1 and 2 was 28.9 vs.10.2 months ( P = 0.02), and P-ALBI 1 and 2 was 26.7 vs. 8.6 months ( P < 0.001). In multivariate analyses, both ALBI 2 (HR = 2.4, P = 0.02) and P-ALBI 2 (HR = 3.3, P < 0.01) were negative prognostic factors for survival. There were 15 AEs in 13 patients, with hepatic failure only occurring in ALBI 2 and P-ALBI 2 patients. CONCLUSION: P-ALBI grade 1 and 2 differentiated survival in Child-Pugh A patients treated with DEE-TACE. Both grading systems can differentiate survival in patients responding to treatment.

Reproducibility of European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors in patients treated with sorafenib.

BACKGROUND & AIMS: The European Association for the Study of the Liver criteria and the modified Response Evaluation Criteria in Solid Tumors are used for assessing the treatment outcomes of hepatocellular carcinoma. We investigated the inter- and intra-observer reproducibility of the European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors in patients with advanced hepatocellular carcinoma treated with sorafenib. METHODS: A total of 99 patients with treatment-naive advanced hepatocellular carcinoma receiving sorafenib were included. The κ-values for the inter- and intra-observer agreement of the treatment response were calculated. RESULTS: Inter-observer agreement for baseline tumour number was excellent, as reflected by the high κ-value. The κ-statistics showed "excellent" concordance between the 2 sets of measurements by observer A regarding the overall responses using the European Association for the Study of the Liver criteria (κ = .948, agreement rate = 84.8%) and modified Response Evaluation Criteria in Solid Tumors (κ = .944, agreement rate = 83.8%; all P < .001). In addition, high κ-values indicated concordance between the first sets of measurements by observers A and B (κ = .991 by the European Association for the Study of the Liver criteria and .988 by modified Response Evaluation Criteria in Solid Tumors, all P < .001). When agreements in radiological overall responses between the 2 sets of measurements by observer B and between the second sets of measurements by observers A and B were calculated, similar results regarding high κ-values (>.8) were obtained. CONCLUSIONS: The reproducibility of the European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors in assessing treatment outcomes was high in patients with advanced hepatocellular carcinoma treated with sorafenib.

mRECIST response combined with sorafenib-related adverse events is superior to either criterion alone in predicting survival in HCC patients treated with TACE plus sorafenib.

The mRECIST and dermatologic adverse events (AEs) can be used to assess the patient response to transarterial chemoembolization (TACE) and/or sorafenib for hepatocellular carcinoma (HCC). Here, we aimed to combine the two criteria to stratify the prognosis in patients with unresectable HCC receiving TACE plus sorafenib (TACE-S). In total, 176 consecutive HCC patients treated with TACE-S were enrolled. CT scans and laboratory tests were conducted pretreatment (at baseline, 5-7 days before the TACE-S) and post-treatment (at 1, 2 and 3 months). The radiological response was assessed according to mRECIST. Sorafenib-related AEs were recorded every 2 weeks after oral administration, and patients with dermatologic AEs of Grade 2 or more were defined as dermatologic responders. The earliest time at which mRECIST and dermatologic responses correlated with survival was 2 months after therapy. The mRECIST-dermatologic AE combination assessment stratified patients into three different prognoses; responders on both assessments exhibited the longest median overall survival (OS), followed by responders on one assessment and non-responders on both assessments (30.5, 17.4 and 8.3 months, respectively; p < 0.001). Achieving the highest C-index, the mRECIST-dermatologic AE combination showed better performance in predicting survival than either mRECIST or dermatologic AEs alone. Furthermore, the mRECIST-dermatologic AE combination remained a significant predictor of OS, even when the patients were stratified according to the BCLC stage, ECOG score or alpha-fetoprotein (AFP) value. This study showed that the combination of mRECIST response and dermatologic AEs is superior to either criterion used alone for predicting the survival of HCC patients treated with TACE-S.

Evaluation of HCC response to locoregional therapy: Validation of MRI-based response criteria versus explant pathology.

BACKGROUND AND AIMS: This study evaluates the performance of various magnetic resonance imaging (MRI) response criteria for the prediction of complete pathologic necrosis (CPN) of hepatocellular carcinoma (HCC) post locoregional therapy (LRT) using explant pathology as a reference. METHODS: We included 61 patients (male/female 46/15; mean age 60years) who underwent liver transplantation after LRT with transarterial chemoembolization plus radiofrequency or microwave ablation (n=56), or 90Yttrium radioembolization (n=5). MRI was performed <90days before liver transplantation. Three independent readers assessed the following criteria: RECIST, EASL, modified RECIST (mRECIST), percentage of necrosis on subtraction images, and diffusion-weighted imaging (DWI), both qualitative (signal intensity) and quantitative (apparent diffusion coefficient [ADC]). The degree of necrosis was retrospectively assessed at histopathology. Intraclass correlation coefficient (ICC) and Cohen's kappa were used to assess inter-reader agreement. Logistic regression and receiver operating characteristic analyses were used to determine imaging predictors of CPN. Pearson correlation was performed between imaging criteria and pathologic degree of tumor necrosis. RESULTS: A total of 97HCCs (mean size 2.3±1.3cm) including 28 with CPN were evaluated. There was excellent inter-reader agreement (ICC 0.77-0.86, all methods). EASL, mRECIST, percentage of necrosis and qualitative DWI were all significant (p<0.001) predictors of CPN, while RECIST and ADC were not. EASL, mRECIST and percentage of necrosis performed similarly (area under the curves [AUCs] 0.810-0.815) while the performance of qualitative DWI was lower (AUC 0.622). Image subtraction demonstrated the strongest correlation (r=0.71-0.72, p<0.0001) with pathologic degree of tumor necrosis. CONCLUSIONS: EASL/mRECIST criteria and image subtraction have excellent diagnostic performance for predicting CPN in HCC treated with LRT, with image subtraction correlating best with pathologic degree of tumor necrosis. Thus, MR image subtraction is recommended for assessing HCC response to LRT. LAY SUMMARY: The assessment of hepatocellular carcinoma (HCC) tumor necrosis after locoregional therapy is essential for additional treatment planning and estimation of outcome. In this study, we assessed the performance of various magnetic resonance imaging (MRI) response criteria (RECIST, mRECIST, EASL, percentage of necrosis on subtraction images, and diffusion-weighted imaging) for the prediction of complete pathologic necrosis of HCC post locoregional therapy on liver explant. Patients who underwent liver transplantation after locoregional therapy were included in this retrospective study. All patients underwent routine liver MRI within 90days of liver transplantation. EASL/mRECIST criteria and image subtraction had excellent diagnostic performance for predicting complete pathologic necrosis in treated HCC, with image subtraction correlating best with pathologic degree of tumor necrosis.

Objective response by mRECIST as a predictor and potential surrogate end-point of overall survival in advanced HCC.

BACKGROUND & AIMS: The Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was developed to overcome the limitations of standard RECIST criteria in response assessment of hepatocellular carcinoma (HCC). We aimed to investigate whether objective response by mRECIST accurately predicted overall survival (OS) in patients with advanced HCC treated with systemic targeted therapies and also to preliminarily assess this end-point as a potential surrogate of OS. METHODS: Individual patient data from the BRISK-PS randomized phase III trial comparing brivanib vs. placebo (the first to prospectively incorporate mRECIST) were used to analyze objective response as a predictor of OS in a time-dependent covariate analysis. Patients with available imaging scans during follow-up were included (n=334; 85% of those randomized). Moreover, a correlation of the survival probability in deciles vs. the observed objective response was performed to evaluate its suitability as a surrogate end-point. RESULTS: Objective response was observed in 11.5% and 1.9% of patients treated with brivanib and placebo respectively, and was associated with a better survival (median OS 15.0 vs. 9.4months, p<0.001). In addition, objective response had an independent prognostic value (HR=0.48; 95% confidence interval [CI], 0.26-0.91, p=0.025) along with known prognostic factors. Finally, objective response showed promising results as a surrogate of OS in this trial (R=-0.92; 95% CI, -1 to -0.73, p<0.001). It was an early indicator of the treatment effect (median time to objective response was 1.4months). CONCLUSIONS: Objective response by mRECIST in advanced HCC predicts OS and thus can be considered as a candidate surrogate end-point. Further studies are needed to support this finding. LAY SUMMARY: There is a need to identify surrogate end-points for overall survival in advanced hepatocellular carcinoma. We studied patients from the phase III BRISK trial, comparing brivanib treatment with placebo after sorafenib progression. We demonstrate that objective response is an independent predictor of survival and qualifies as a potential surrogate end-point for overall survival in this patient population. CLINICAL TRIAL NUMBER: NCT00825955.

ADCtotal ratio and D ratio derived from intravoxel incoherent motion early after TACE are independent predictors for survival in hepatocellular carcinoma.

PURPOSE: To explore the threshold of intravoxel incoherent motion (IVIM) parameters, apparent diffusion coefficient [ADCtotal and ADC(0,500) ] ratios 24-48 hours after transarterial chemoembolization (TACE) to assess early response in patients with unresectable hepatocellular carcinoma (HCC) and to compare the association between diffusion-weighted imaging with the intravoxel incoherent motion (IVIM-DWI) and mRECIST with survival. MATERIALS AND METHODS: Institutional Review Board approval and informed consent were obtained for this prospective study. There were 30 patients undergoing 1.5T magnetic resonance imaging (MRI) with IVIM-DWI of 12 b values (0, 10, 20, 30, 40, 50, 70, 100, 200, 300, 500, 800 s/mm2 ) 1 week before and 24-48 hours after TACE. Response was assessed with the change of true diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (PF), ADCtotal , and ADC(0,500) values relative to baseline and with mRECIST. Receiver operating characteristic (ROC) curve analysis was used to explore the threshold of these parameters ratios. Kaplan-Meier, log-rank tests, and the Cox hazard model were used to correlate the response variables with progression-free survival (PFS) and to assess the incidence and potential clinical risk factors for PFS. Mann-Whitney U-test was used to compare the difference in parameters between different groups with progression within and beyond median PFS prior to TACE. RESULTS: Median PFS was 99 days, within which 16 patients progressed. The threshold of ADCtotal ratio, D ratio, and ADC(0,500) ratio were 13.1% (P = 0.001), 7.0% (P = 0.011), and 3.6% (P = 0.018) with sensitivity and specificity of 78.6% and 87.5%, 85.7% and 62.5%, 78.6% and 75%, respectively. The predictive utility of ADCtotal ratio, D ratio, and ADC(0,500) ratio for PFS were 0.848, 0.772, and 0.754, respectively. Survival analyses showed ADCtotal ratio, D ratio, ADC(0,500) ratio, liver cirrhosis, and mRECIST had a significant effect on PFS (P < 0.05). ADCtotal ratio and D ratio were independent predictors for 99-day PFS (P = 0.025, P = 0.036). There were no significant differences in pretreatment IVIM-DWI parameters between PFS > 99-day group and PFS ≤ 99-day group with P values of 0.547 for D, 0.394 for D*, 0.575 for PF, 0.901 for ADC(0,500) , and 0.506 for ADCtotal , respectively. CONCLUSION: The ADCtotal ratio and D ratio 24-48 hours after TACE were independent predictors for response to TACE for HCC, and showed stronger association with PFS than mRECIST. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:820-830.

Evaluation of response after SBRT for liver tumors.

Stereotactic body radiotherapy (SBRT) has developed over the last few years for the treatment of primary and metastatic hepatic tumors. The tumoral and adjacent peritumoral modifications caused by this radiosurgery limit the evaluation of response by anatomic imaging and dimensional criteria alone, such as with RECIST. This suggests that it is of interest to also take into account the residual enhancement and hyper metabolism of these hepatic targets. We have reviewed the English language literature regarding the response of hepatic lesions treated by SBRT, and found that only seven articles were specifically concerned with this problem. The response of the hepatocellular carcinoma after SBRT has been studied specifically with multiphase enhanced CT-scan. Criteria set by the European Association of Study of the Liver better estimate response at each time point of follow up than RECIST does. Non-enhancement, reflecting tumor necrosis, is additionally an early indicator of response with extended response in time and a best non-enhancement percentage is observed at 12 months. The response after treatment by SBRT of cholangiocarcinoma has not yet generated a specific report. Use of RECIST criteria is also inadequate in the evaluation of response after SBRT for hepatic metastases. Response of liver metastases to SBRT is better assessed with a combination of size and enhancement pattern. The occurrence of a lobulated enhancement during follow up is efficient to predict local progression in a specific, reproducible, and sensitive way. Patients with FDG-avid hepatic metastases are also better evaluated with PET-CT and functional criteria than routine imaging and metric evaluation alone.

Comparison of tumor response assessment methods in patients with metastatic colorectal cancer after locoregional therapy.

BACKGROUND: We evaluated the performance of the Response Evaluation Criteria in Solid Tumor (RECIST), modified RECIST, and the European Association for the Study of Liver (EASL) guidelines and correlated them with survival in patients with metastatic colorectal cancer (mCRC) treated with locoregional therapy (LRT). PATIENTS AND METHODS: Our LRT registry was evaluated from 2008 to 2013. 228 mCRC patients were treated with LRT (91% drug-eluting beads, 9% radioembolization) were evaluated. Cox regression and Kaplan-Meier (KM) statistics were utilized for survival analysis. RESULTS: Excellent inter-rater agreement between EASL/mRECIST (κ = 905) was seen. Correlations between RECIST/mRECIST (κ = 0.638) and EASL/RECIST were weaker (κ = 0.638 and 0.598, respectively). There were significant differences in KM and Cox regression survivals between responders and nonresponders with all three methods (all P < 0.0001). Multivariate analysis identified RECIST response, tumor extent, performance status, concomitant chemotherapy, and prior surgery/ablation as independent prognostic factors. EASL response and mRECIST response were not found to be independent prognostic factors. CONCLUSION: Imaging biomarkers are not efficient and do not represent ideal surrogates for survival; however, they all display prognostic significance. RECIST is superior to mRECIST/EASL given its ability to stratify survival benefit according to response category and demonstrate independent prognostic significance. J. Surg. Oncol. 2016;113:443-448. © 2016 Wiley Periodicals, Inc.

Threshold for Enhancement in Treated Hepatocellular Carcinoma on MDCT: Effect on Necrosis Quantification.

OBJECTIVE: The objective of our study was to determine whether the conventionally used enhancement threshold of 10 HU for assessing tumor viability in treated hepatocellular carcinoma (HCC) lesions is valid. MATERIALS AND METHODS: To distinguish pseudoenhancement from enhancement in a tumor, we used an in vivo model: The attenuation of 54 hepatic cysts during the unenhanced and portal venous phases of MDCT, similar to what may be observed in HCC with central necrosis, was used to determine the threshold for pseudoenhancement. To validate this model, we compared the attenuation value of liver parenchyma in this cohort with that of 22 HCCs during the late arterial phase of enhancement. We tested the effect of this pseudoenhancement on quantifying necrosis in HCC compared with the conventionally used threshold of 10 HU. RESULTS: Values of enhancing HCC tissue on arterial phase MDCT (mean, 121.3 HU) were comparable with normal liver parenchyma on venous phase MDCT (117.3 HU) (p = 0.27). The threshold of 17.1 HU was the best threshold for the detection of pseudoenhancement in cysts (99% accuracy, 100% sensitivity, and 98% specificity). When this threshold was used instead of the conventional threshold of 10 HU, the mean necrosis proportion of treated HCC increased from 34.0% to 42.6% and the mean viable tumor proportion decreased from 66.0% to 57.4%. The quantification of viable HCC tissue based on 10 HU and the quantification of viable HCC tissue based on 17.1 HU were found to be significantly different (p < 0.0001). CONCLUSION: The threshold of 17.1 HU may be the appropriate cutoff for nonenhancement in a necrotic HCC. Use of this threshold may potentially affect how response to therapy is quantified and categorized.

Transarterial chemoembolization: modalities, indication, and patient selection.

Transarterial chemoembolization (TACE) is the standard of care for patients with intermediate stage hepatocellular carcinoma (BCLC B). Further improvement of the use of TACE was the subject of intense clinical research over the past years. The introduction of DEB-TACE brought more technical standardization and reduction of TACE related toxicity. The use of dynamic radiologic response evaluation criteria (EASL, mRECIST), uncovered the prognostic significance of objective tumor response. Finally, new approaches for better patient selection for initial and subsequent TACE treatment schedules will limit the use of TACE to some extent but have the potential to improve outcome for patients at risk for TACE-induced harm.

Refining sorafenib therapy: lessons from clinical practice.

Understanding the best use of sorafenib is essential in order to maximize clinical benefit in hepatocellular carcinoma. Based on Phase III and noninterventional study data, as well as our extensive experience, we discuss dose modification in order to manage adverse events, disease response evaluation and how to maximize treatment benefit. Sorafenib should be initiated at the approved dose (400 mg twice daily) and reduced/interrupted as appropriate in order to manage adverse events. Dose modification should be considered before discontinuation. Appropriate tumor response assessment is critical. Focusing on radiologic response may result in premature sorafenib discontinuation; symptomatic progression should also be considered. If second-line therapies or trials are unavailable, continuing sorafenib beyond radiologic progression may provide a clinical benefit. Our recommendations enable the maximization of treatment duration, and hence clinical benefit, for patients.

Degradable starch microspheres versus ethiodol and doxorubicin in transarterial chemoembolization of hepatocellular carcinoma.

PURPOSE: To compare outcomes of transarterial chemoembolization with degradable starch microspheres (DSMs) and conventional transarterial chemoembolization with doxorubicin and Ethiodol in patients with unresectable intermediate-stage hepatocellular carcinoma (HCC). MATERIALS AND METHODS: A total of 69 patients underwent 169 chemoembolization procedures with Ethiodol (n = 35) or DSMs (n = 34) as the embolic agent. The same chemotherapeutic agent was used for all patients (50 mg doxorubicin). The primary endpoint was patient survival, and secondary endpoints were local tumor response and incidence of therapy-associated complications with conventional or DSM chemoembolization. Tumor response was evaluated by consensus reading by two radiologists in accordance with modified Response Evaluation Criteria In Solid Tumors. Mean survival was calculated according to Kaplan-Meier analysis, and differences in survival curves were assessed by univariate log-rank test. The statistical significance of quantitative variables was determined by parameter-free Wilcoxon-Mann-Whitney U test. RESULTS: The study groups were similar with regard to demographic data and disease stage. For the DSM chemoembolization group, the objective response rate (ie, complete or partial response) was 44.1%, and the rate of stable disease was 38.2%. The respective rates for the conventional chemoembolization group were 48.6% and 31.4%. Mean survival (P = .337) and complications did not significantly differ between groups (P = .907; P = 1.000). CONCLUSIONS: DSM chemoembolization represents an alternative method of HCC treatment with a safety profile similar to that of conventional transarterial chemoembolization. Regarding local tumor response and overall survival, results of DSM chemoembolization were similar to those of conventional chemoembolization.