mRECIST Response Research Articles

Tumor response assessment by MRI following stereotactic body radiation therapy for hepatocellular carcinoma.

BackgroundTo evaluate the MRI features of a tumor response, local control, and predictive factors of local control after stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC).MethodsThirty-five consecutive patients with 48 HCCs who were treated by SBRT were included in this retrospective study. All patients provided written informed consent to be treated by SBRT, and prior to inclusion they authorized use of the treatment data for further studies. The assessment was made using MRI, with determination of local and hepatic responses according to Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST) criteria during a two-year follow-up.ResultsThe local response rate according to mRECIST was higher than with RECIST. A tumor diameter less than 20 mm at baseline was an independent predictive factor for RECIST and mRECIST responses, as was diffusion-weighted signal for RECIST. During follow-up, a tumor diameter of <20 mm (p = 0.034) and absence of a high intensity on T2-weighted (p = 0.006) and diffusion-weighted images (p = 0.039) were associated with a better response according to RECIST. Post-treatment changes include peritumoral ring-like enhanced changes with high intensity on T2-weighted images.ConclusionsSBRT is a promising technique for the treatment of inoperable HCC. Post-treatment changes on MRI images can resemble tumor progression and as such must be adequately distinguished. The regression of tumorous enhancement is variable over time, although diffusion-weighted and T2-weighted intensities are predictive factors for tumor RECIST responses on subsequent MRIs. They hence provide a way to reliably predict treatment responses.

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.

Sorafenib with or without everolimus in patients with advanced hepatocellular carcinoma (HCC): a randomized multicenter, multinational phase II trial (SAKK 77/08 and SASL 29)

Sorafenib (S), a multitargeted tyrosine kinase inhibitor, is the standard of care for first-line systemic treatment of advanced hepatocellular carcinoma (HCC). Everolimus (E) is a potent inhibitor of mTOR, a pathway frequently activated in HCC. Preclinical data suggest that the combination S + E has additive effects compared with single-agent S. Patients with unresectable or metastatic HCC and Child-Pugh ≤7 liver dysfunction were randomized to receive daily S 800 mg alone or with E 5 mg until progression or unacceptable toxicity. The primary end point was progression-free survival at 12 weeks (PFS12). The secondary end points included response rate, PFS, time to progression (TTP), overall survival (OS), duration of disease stabilization (DDS), safety, and quality-of-life (QoL) assessments. A total of 106 patients were randomized: 46 patients received S and 60 patients received S + E. Ninety-three patients were assessable for the primary end point and 105 patients for the safety analysis. The PFS12 rate was 70% [95% confidence interval (CI) 54-83] and 68% (95% CI 53-81) in patients randomized to S and S + E, respectively. The RECIST (mRECIST) response rate was 0% (23%) in the S arm and 10% (35%) in the S + E arm. Median PFS (6.6 versus 5.7 months), TTP (7.6 versus 6.3 months), DDS (6.7 versus 6.7 months), and OS (10 versus 12 months) were similar in the S and S + E arms, respectively. Grade 3/4 adverse events occurred in 72% and 86% of patients in arm S and arm S + E, respectively. Patients had similar QoL scores over time, except for a greater worsening in physical well-being and mood in the arm S + E. No evidence was found that S + E improves the efficacy compared with S alone. Combining 5 mg E with full-dose S is feasible, but more toxic than S alone. Further testing of this drug combination in molecularly unselected HCCs appears unwarranted. NCT01005199.

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

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). 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. 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. 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.

Does the Degree of Hepatocellular Carcinoma Tumor Necrosis following Transarterial Chemoembolization Impact Patient Survival?

Purpose. The association between transarterial chemoembolization- (TACE-) induced HCC tumor necrosis measured by the modified Response Evaluation Criteria In Solid Tumors (mRECIST) and patient survival is poorly defined. We hypothesize that survival will be superior in HCC patients with increased TACE-induced tumor necrosis. Materials and Methods. TACE interventions were retrospectively reviewed. Tumor response was quantified via dichotomized (responders and nonresponders) and the four defined mRECIST categories. Results. Median survival following TACE was significantly greater in responders compared to nonresponders (20.8 months versus 14.9 months, p = 0.011). Survival outcomes also significantly varied among the four mRECIST categories (p = 0.0003): complete, 21.4 months; partial, 20.8; stable, 16.8; and progressive, 7.73. Only progressive disease demonstrated significantly worse survival when compared to complete response. Multivariable analysis showed that progressive disease, increasing total tumor diameter, and non-Child-Pugh class A were independent predictors of post-TACE mortality. Conclusions. Both dichotomized (responders and nonresponders) and the four defined mRECIST responses to TACE in patients with HCC were predictive of survival. The main driver of the survival analysis was poor survival in the progressive disease group. Surprisingly, there was small nonsignificant survival benefit between complete, partial, and stable disease groups. These findings may inform HCC treatment decisions following first TACE.

Reproducibility of mRECIST in assessing response to transarterial radioembolization therapy in hepatocellular carcinoma.

The purpose of our study was to evaluate the reproducibility of Modified Response Evaluation Criteria in Solid Tumors (mRECIST) in hepatocellular carcinoma (HCC) lesions undergoing transarterial radioembolization (TARE) therapy and to determine whether mRECIST reproducibility is affected by the enhancement pattern of HCC. One hundred and three HCC lesions from 103 patients treated with TARE were evaluated. The single longest diameter of viable tumor tissue was measured by two radiologists at baseline; response to therapy was evaluated according to mRECIST. The enhancement pattern of HCC lesions was correlated with their mRECIST response. The response rate between mRECIST and RECIST 1.1 was compared. Wilcoxon signed-rank test, paired t test, Lin's concordance correlation coefficient (ρc ), Bland-Altman plot, kappa statistics, and Fisher's exact test were used to assess intra- and interobserver reproducibilities and to compare response rates. There were better intra- than interobserver agreements in the measurement of single longest diameter of viable tumor tissue (bias = 0 cm intraobserver versus bias = 0.3 cm interobserver). For mRECIST, good intraobserver (ĸ = 0.70) and moderate interobserver (ĸ = 0.56) agreements were noted. The mRECIST response for HCC lesions with homogeneous enhancement at both baseline and follow-up imaging showed better intra- and interobserver agreements (ĸ = 0.77 and 0.60, respectively) than lesions with heterogeneous enhancement at both scans (ĸ = 0.54 and 0.40, respectively). In the early follow-up period mRECIST showed a significantly higher response rate than RECIST (40.8% versus 3.9%; P = 0.025). In HCC patients treated with TARE, mRECIST captures a significantly higher response rate compared with RECIST; it also demonstrates acceptable intra- and interobserver reproducibilities for HCC lesions treated with TARE, and mRECIST reproducibility may be lower for HCC lesions with heterogeneous distribution of the viable tumor tissue.

ART Score and Predictive Factors of Prognosis in Hepatocellular Carcinoma Patients Treated With Transarterial Chemoembolization

Introduction: Transarterial chemoembolization (TACE) with drug-eluting beads is the frontline treatment for BCLC intermediate-stage hepatocellular carcinoma (HCC). Recently, ART score was developed to assess prognosis after TACE. We aimed to evaluate the efficacy, safety, and predictive factors of prognosis in HCC patients treated with TACE in clinical practice. Methods: Retrospective evaluation of TACE procedures performed between June 2007 and October 2013 in a single center. Treatment decision was made based on multidisciplinary HCC consultation. Patient and tumor characteristics, response to treatment (mRECIST criteria, 1 month after TACE), adverse events, and ART score were evaluated. Kaplan-Meier was used for survival estimation, α=0.05. Results: Ninety-three procedures were performed in 55 patients (median age 71 years; 85% male; 98% cirrhosis), with median procedure per patient: 2. Viral hepatitis (51%) and alcohol (28%) were the main causes of liver disease. BCLC intermediate stage was more frequent (72%). The median admission duration was 2 days, postembolization syndrome developed in 15% without any fatalities. Response to treatment was complete in 23%, partial in 51%, stable disease in 13%, and progression in 14%. Patients with only 1 HCC nodule (OR=4.9; p=0.01) had a better response. Mean estimated survival after TACE was 28.8 months. A single HCC nodule (p=0.002), Child-Pugh A (p=0.014), HCC nodules <5 cm (p=0.024), BCLC stage (p=0.04), and α-fetoprotein <50 ng/mL (p=0.049) were predictive of survival. Response to TACE (p=0.001), the absence of post-embolization syndrome (p=0.002), and ART score <2 (p=0.005) were associated with longer survival. Conclusion: In our cohort, TACE was found to be safe and efficacious, as mRECIST response was associated with increased survival. We validated the prognostic importance of ART score and identified predictive factors of TACE response and survival that could improve the selection of treatment options for patients. Disclosure - Helder Cardoso - Advisory Committee: Janssen, Abbvie; Speaking and Teaching: BMS, Bayer, Roche.

Recurrence of Hepatocellular Carcinoma: Importance of mRECIST Response to Chemoembolization and Tumor Size

Determining risk for recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT) is an important clinical need. We assessed consecutive patients who underwent LT for HCC following sequential transarterial chemoembolization (TACE). Treatment response was assessed using modified response evaluation criteria in solid tumors (mRECIST) categories: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Cox proportional hazard models were used to predict HCC recurrence. One hundred seventy-three patients underwent TACE and imaging to assess response prior to LT. TACE responses were: CR = 23.7%, PR = 24.3%, SD = 27.7% and PD = 24.3%. Five-year HCC recurrence rate was 5.3% in patients responding to TACE (CR/PR), versus 17.6%, among patients who did not respond (SD/PD, p = 0.014). In multivariate analysis, independent pre-LT predictors of recurrence were response to TACE and largest radiologic size of tumor (>3 cm vs. ≤3 cm). HCC recurrence rate for patients with tumor size >3 cm and no response to TACE was 35.8%, compared with 1.9% for patients with tumor size ≤3 cm and response to TACE (p = 0.0007). We conclude that mRECIST criteria and tumor size differentiate patients with high or low likelihood of HCC recurrence after LT. These findings raise the possibility of incorporating response to TACE and largest tumor size to identify patients at highest risk for HCC recurrence.

EASL- and mRECIST-Evaluated Responses to Combination Therapy of Sorafenib with Transarterial Chemoembolization Predict Survival in Patients with Hepatocellular Carcinoma

Published studies have not investigated the suitability of Response Evaluation Criteria in Solid Tumors (RECIST), European Association for the Study of the Liver (EASL) criteria, and modified RECIST (mRECIST) for assessing the response of patients with hepatocellular carcinoma to treatment with sorafenib combined with transarterial chemoembolization. Here, we aimed to define the earliest time at which the response to combination therapy could be accurately assessed and validate the prognostic value of these criteria at this early posttherapy time point. A total of 114 consecutive patients with hepatocellular carcinoma receiving combination therapy were retrospectively enrolled. The therapy response at different time points was assessed using RECIST, EASL, and mRECIST. Cox regression analysis and Kaplan-Meier curves were used to assess overall survival (OS) in the responders and nonresponders. At the third follow-up (median, 94 days; range, 89-102 days) after therapy, the response rates obtained using EASL (50.6%) and mRECIST (51.6%) were greater than that obtained using RECIST (16.5%). The agreement was strong between the mRECIST and EASL results (k = 0.9) but weak between mRECIST and RECIST (k = 0.3). The EASL and mRECIST responses significantly correlated with survival. Risk reductions of 52% and 50% were observed for EASL and mRECIST responders, respectively, compared with nonresponders. However, no significant association between the treatment response and survival was observed using RECIST. The earliest time to evaluate the response to combination therapy is 3 months (median, 94 days) after therapy. EASL and mRECIST responses are independent predictors for OS at this early time point.

Highlights of This Issue

MLN9708 (ixazomib citrate) is an oral next-generation proteasome inhibitor (PI) currently in phase III trials in multiple myeloma patients, but with a yet-unknown effect on myeloma-associated bone disease. Garcia-Gomez and colleagues show that clinically relevant concentrations of ixazomib promote osteoblast differentiation and function and inhibit osteoclast formation and resorption in vitro. Also, in a disseminated myeloma mouse model, ixazomib controls myeloma growth and prevents bone loss, as assessed by bone-forming and anticatabolic activities. Thus, it is conceivable that MLN9708, similar to the first-in-class PI bortezomib, will achieve beneficial bone effects, in addition to antimyeloma activity in myeloma patients.Hedgehog-GLI signaling is upregulated in a proportion of lung squamous cell carcinoma (LSCC), but no studies to date evaluate its role in LSCC. Here, Huang and colleagues identified overexpression of HEDGEHOG-GLI components in the classical subtype of LSCC via genomic analysis. In representative cell lines, they demonstrated that GLI2 was important for LSCC cell survival, whereas SMOOTHENED plays a minor role. Importantly, they reported that the GLI inhibitor GANT61 successfully suppressed tumor growth both in vitro and in vivo and thus shows promise as a novel targeted therapy for a subset of LSCC patients.The combination therapy of sorafenib and TACE is considered an alternative for patients with unresectable HCC. The assessment of tumor response to this therapy is particularly crucial in determining treatment success. To define the earliest time at which the response to combination therapy could be accurately assessed, Liu and colleagues demonstrated that the available criteria EASL and mRECIST responses assessed after 3 to 4 months of therapy are more reliable for detecting the early changes in the tumor and can be considered valuable early indicators for making subsequent therapeutic decisions and predicting long-term survival.Analysis of cell-free plasma DNA represents an attractive strategy for noninvasive genotyping of advanced cancer patients. Oxnard and colleagues designed quantitative plasma-based genotyping assays for EGFR, KRAS, and BRAF mutations using droplet digital PCR and demonstrated a high positive predictive value in patients with advanced lung cancer and melanoma. Serial analysis of plasma from lung cancer patients on a prospective trial of first-line erlotinib demonstrated high pretreatment EGFR levels, complete plasma response, and detection of a T790M resistance mutation weeks prior to clinical progression, suggesting potential as a noninvasive clinical tool for characterizing treatment response and resistance.

Radiologic response to transcatheter hepatic arterial chemoembolization and clinical outcomes in patients with hepatocellular carcinoma

The current study analysed the association between radiologic tumour response and survival times of patients with hepatocellular carcinoma (HCC) who were treated with transcatheter hepatic arterial chemoembolization (TACE). Among 493 consecutive patients presenting to our institution between July 2002 and June 2010 with radiologically (n = 398) or histologically (n = 95) confirmed HCC, 368 patients who met inclusion criteria, underwent TACE and had confirmed survival data were retrospectively reviewed. The radiologic response was assessed using RECIST 1.1, EASL and mRECIST criteria at 1 month after the initial TACE. By univariate analysis, higher Child-Turcotte-Pugh (CTP) score, bilobar and multifocal distribution of tumours, larger tumour size (>5 cm), higher serum alpha-foetoprotein (AFP) level (>200 ng/ml), no subsequent radiofrequency ablation, advanced ECOG, UNOS and BCLC staging, absence of complete necrosis and non-responder (SD or PD) in RECIST 1.1, EASL and mRECIST response assessment were significantly associated with shorter overall survival times. By Cox proportional hazards model, advanced age, presence of ascites, higher MELD score, advanced BCLC staging, absence of complete necrosis and non-responder by RECIST 1.1, EASL and mRECIST criteria were independent and significant prognosticators for overall survival times in patients with HCC who underwent TACE. By time-dependent ROC curve analysis, mRECIST response criteria showed greatest accuracy in predicting survival (AUROC = 0.8676), followed by EASL (AUROC = 0.8471) and RECIST 1.1 (AUROC = 0.7986). mRECIST and EASL criteria for assessing radiologic response 1 month after initial TACE more consistently predict the differences in overall survival between responders and non-responders than conventional RECIST 1.1 criteria.

Phase II trial of Pexa-Vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia virus, followed by sorafenib in patients with advanced hepatocellular carcinoma (HCC).

4122^ Background: Pexa-Vec is a vaccinia virus engineered to express granulocyte-macrophage colony stimulating factor (GM-CSF), thereby stimulating direct oncolysis, tumor vascular disruption and anti-tumor immunity (Nat Rev Cancer 2009). Pexa-Vec was shown to replicate in metastatic tumors following intratumoral (IT) or intravenous (IV) administration (Lancet Oncol 2008; Nature 2011). Preclinical and clinical data suggest that Pexa-Vec-induced acute vascular disruption sensitizes tumors to anti-angiogenic effects of sorafenib (Mol Ther 2011). Methods: Treatment-refractory HCC patients received Pexa-Vec for 3 weeks (Day 1 IV, Day 8 IT and Day 22 IT) followed by sorafenib at Day 25. The primary objective of the study was to determine the safety of Pexa-Vec followed by sorafenib. Secondary objectives include disease control rate based on mRECIST and Choi (hypodensity) response criteria after Pexa-Vec only (Day 25) and after sorafenib initiation (Week 6 and 12). Optional assessments included response by positron-emission tomography (PET). Data summarized prior to database lock. Results: Enrollment is completed: 25 patients of which 20 were refractory to sorafenib. The treatment regimen was well-tolerated. Transient flu-like symptoms, including fever (n=23; 92%), chills (n=19; 76%), headache and nausea (n=10; 40%), abdominal pain and lymphopenia (n=10; 40%) were the most common adverse events following Pexa-Vec. Sorafenib toxicities were consistent with the expected profile. After Pexa-Vec alone the Choi tumor response rate was 47%. Following subsequent sorafenib therapy, 75% had Choi responses, including 81% of sorafenib-failure patients. The mRECIST disease control rate was 62% with Pexa-Vec alone and 59% following initiation of sorafenib. Two of 4 patients evaluable for PET response exhibited decreased PET signal after Pexa-Vec. Conclusions: Pexa-Vec was well-tolerated and associated with Choi tumor responses and disease control in patients with advanced HCC. Subsequent sorafenib was well-tolerated and associated with Choi responses. Further trials of Pexa-Vec in HCC patients are warranted. Clinical trial information: NCT01171651.

EASL and mRECIST responses are independent predictors of survival in hepatocellular carcinoma patients treated with cryoablation

The aim of this study was to determine which response evaluation criteria will best help predict the treatment efficacy of cryoablation for hepatocellular carcinoma. We retrospectively analyzed clinical data of 64 patients with hepatocellular carcinoma treated with cryoablation. Triphasic helical computed tomography scans were analyzed on the basis of WHO, Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1), modified RECIST (mRECIST), and European Association for the Study of the Liver (EASL) guidelines. We assessed the concordance among response guidelines and selected the most reliable model depending upon the correlation with overall survival. Both objective response rates and disease control rates were higher for mRECIST and EASL than for WHO and RECIST 1.1 for both overall responses and target responses. The κ-value of comparisons between WHO and RECIST 1.1 and mRECIST and EASL was not more than 0.20 for both overall responses and target responses. There was consistency between WHO and RECIST 1.1 [κ=0.82, 95% confidence interval (CI): 0.72-0.91 for overall responses and κ=0.87; 95% CI, 0.76-0.94 for target responses], the same as that between mRECIST and EASL (κ=0.91, 95% CI, 0.73-0.98 for overall responses and κ=0.88, 95% CI, 0.72-0.95 for target responses). There was no significant association with survival for WHO and RECIST 1.1 responses or all target responses. The Cox-regression model showed that both mRECIST and EASL were independent predictors of overall survival, with a 51% risk reduction for mRECIST and a 61% risk reduction for EASL. The enhancement models including mRECIST and EASL guidelines should be used in preference to WHO, RECIST 1.1, or target responses to assess the efficacy of cryotherapy.

Unresectable Hepatocellular Carcinoma: MR Imaging after Intraarterial Therapy. Part II. Response Stratification Using Volumetric Functional Criteria after Intraarterial Therapy

To assess whether volumetric functional magnetic resonance (MR) results 3-4 weeks after initial intraarterial therapy can aid accurate distinction between responders and nonresponders, to determine whether overall survival (OS) is improved, and to compare volumetric functional MR response with anatomic response criteria (Response Evaluation Criteria in Solid Tumors [RECIST], modified RECIST [mRECIST], European Association for the Study of the Liver [EASL]), as well as α1-fetoprotein [AFP] level. In this single-institution HIPAA-compliant retrospective, institutional review board-approved study, informed consent was waived; 143 patients with hepatocellular carcinoma underwent intraarterial therapy between October 2005 and February 2011. Volumetric functional MR response (25% or more increase in apparent diffusion coefficient, 65% or more decrease in enhancement) was stratified as follows: Dual-parameter responders fulfilled both criteria, single-parameter responders fulfilled one criterion, and those with stable disease (SD) fulfilled neither. RECIST, mRECIST, EASL, and AFP response criteria were determined. Kaplan-Meier technique, log-rank tests, and the Cox proportional hazards model were used to test whether OS was different per response. OS differed significantly between single-parameter responders and dual-parameter responders (P = .01) and between single-parameter responders and those with SD (P = .001). Dual-parameter responders' response improved OS compared with single-parameter responders; risk of death decreased (hazard ratio [HR] = 0.28, P = .01). In those with SD compared with single-parameter responders, risk of death increased (HR = 2.09, P = .001). RECIST, mRECIST, and EASL stratification was short of significant; most lesions were classified as SD. Baseline AFP level increased in 55 patients; AFP responders versus AFP nonresponders had decreased risk of death (HR = 0.36, P = .002). Agreement between anatomic response criteria and volumetric functional MR findings (κ = 0.06-0.12) and between AFP response and imaging criteria (κ = -0.04 to 0.14) was low. Volumetric functional MR response 3-4 weeks after initial intraarterial therapy showed improved OS. Volumetric functional MR was superior to current imaging (RECIST, mRECIST, and EASL) and biochemical (AFP level) response criteria.

MRECIST and EASL responses at early time point by contrast-enhanced dynamic MRI predict survival in patients with unresectable hepatocellular carcinoma (HCC) treated by doxorubicin drug-eluting beads transarterial chemoembolization (DEB TACE)

BackgroundWe analyzed the magnetic resonance imaging (MRI) responses by world health organization (WHO), response evaluation criteria in solid tumor (RECIST), European Association for the Study of Liver (EASL), and modified RECIST (mRECIST) guidelines and correlated with survival after doxorubicin (Adriamycin; Pharmacia & Upjohn, Peapac, NJ). drug-eluting beads transarterial chemoembolization (DEB TACE) in patients with unresectable hepatocellular carcinoma (HCC). Patients and methodsThe early target and overall imaging responses were studied in 120 consecutive patients treated with DEB TACE for unresectable HCC, using RECIST, WHO, EASL, and mRECIST guidelines on contrast-enhanced dynamic liver MRI. The median period between the DEB TACE and assessment scan was 33.50 days. Survival analyses were carried out with the Kaplan–Meier method and the Cox proportional model. ResultsWHO and RECIST1.1 had poor correlation with survival. mRECIST and EASL had significant correlation with survival with target lesion response rates of 63.3% and 48.3% and with overall response rates of 52.5% and 39.2%, respectively. The responders of EASL and mRECIST had significant median survival (P ≤ 0.0001). Moreover, mRECIST was better than EASL in predicting survival, because the survival difference between responders and non-responders of overall response was statistically significant (P = 0.013) for mRECIST, but not for EASL (P = 0.064). ConclusionsEASL and mRECIST responses measured on MRI at an early time point after DEB TACE predicted survival. mRECIST response demonstrated higher survival correlation than EASL.

Assessment of Chemotherapy Response in Colorectal Liver Metastases in Patients Undergoing Hepatic Resection and the Correlation to Pathologic Residual Viable Tumor

The Response Evaluation Criteria in Solid Tumors (RECIST), which evaluates maximum tumor diameter only, is commonly used to determine response to chemotherapy in patients with colorectal liver metastases. Limitations of RECIST include its inability to assess the changes in tumor enhancement. The aim of this study was to assess the correlation of these criteria as well as the modified RECIST (mRECIST) with pathologic tumor response. A novel semi-automated volumetric assessment of tumor size was also investigated. A review of a 1,948-patient prospective hepatic database to assess response and pathologic criteria was performed. Patients undergoing preoperative chemotherapy before hepatic resection for colorectal liver metastases were reviewed. Radiographic responses according to RECIST and mRECIST were determined. The percentage of viable tumor cells compared with the total tumor area was determined from the pathologic specimens. We identified 38 patients with adequate imaging who had undergone anatomic hepatic resection and full pathologic evaluation. The percentages of residual viable tumor in the resected specimens were significantly different across RECIST categories (p = 0.045), but not mRECIST (p = 0.305). For mRECIST, there were improved and significant linear trends for residual viable tumor, necrosis, and necrosis + fibrosis when compared with RECIST (p = 0.056). Neither RECIST nor mRECIST responses were predictive of residual viable tumor burden in regression analyses. A novel semi-automated volumetric assessment of tumor size correlated well with pathologic tumor size. Neither RECIST nor mRECIST were predictive of residual viable burden, although the linear trend for mRECIST and residual necrosis + fibrosis compared favorably with RECIST. Continued evaluation for tumor enhancement and standardization of tumor size remain a critical unmet need in patients with solid organ disease.

Comparison of the methods for tumor response assessment in patients with hepatocellular carcinoma undergoing transarterial chemoembolization

Recently, new methods, including the concept of viable enhancing tumor such as EASL and mRECIST, have been proposed for substitution of the conventional WHO and RECIST criteria in hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). Herein, we evaluated the differences of four methods and compared the association of these methods with the prognosis of HCC patients undergoing TACE. We retrospectively reviewed 114 consecutive newly diagnosed HCC patients who underwent TACE as initial treatment. We evaluated the intermethod agreement (κ values) between the methods and compared their association with the prognosis of HCC patients. The κ values for EASL vs. WHO, EASL vs. RECIST, mRECIST vs. WHO, and mRECIST vs. RECIST were low, of 0.102, 0.088, 0.112, and 0.122, respectively. However, good correlations were observed for WHO vs. RECIST and EASL vs. mRECIST (κ=0.883, κ=0.759, respectively p<0.001). The median OS was 32.3 months. Hazard ratios (HR) for survival in responders compared with non-responders were 0.21 (95% CI; 0.12-0.37, p<0.001) for EASL and 0.27 (95% CI; 0.15-0.48, p<0.001) for mRECIST. The mean survival of responders was significantly longer than that of non-responders in both EASL (40.8 vs. 16.9 months, p<0.001) and mRECIST (41.1 vs. 20.7 months, p<0.001). In multivariate analysis, EASL response (HR 0.21, 95% CI 0.11-0.40, p<0.001) and mRECIST response (HR; 0.31, 95% CI, 0.17-0.59, p<0.001) were independently associated with survival. The response assessment by EASL and mRECIST could reliably predict the survival of HCC patients undergoing TACE and could be applicable in practice in preference to the conventional WHO and RECIST criteria.

Evaluation of the mRECIST and α-Fetoprotein Ratio for Stratification of the Prognosis of Advanced-Hepatocellular-Carcinoma Patients Treated with Sorafenib

Objective: To compare the assessment of response and prognosis of patients to sorafenib treatment by the Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST (mRECIST), α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP). Methods: Sixty-six patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib were enrolled in this retrospective study. The response to treatment was evaluated by RECIST, mRECIST and changes in AFP and DCP. Results: The median survival time of all patients was 8.6 months. The median time to radiological progression was 3.3 months. The response rates [complete response (CR) + partial response (PR)] by RECIST and mRECIST were 3.0 and 9.0%, respectively, while the disease control rates [CR + PR + stable disease (SD)] were 50 and 50%, respectively. Assessment by mRECIST of overall survival provided a better stratification of the patients according to the response to treatment (p = 0.009) than RECIST (p = 0.09). Assessment of overall survival by a change in AFP ratio of ≤1 at 8 weeks was better than that of >1 at 8 weeks (p = 0.002). The DCP ratio was not useful for assessment of overall survival. Multivariate analysis identified mRECIST response (CR + PR + SD; p = 0.001), AFP ratio at 8 weeks (≤1; p = 0.046) and Child-Pugh A before treatment (p = 0.012) as significant and independent determinants of survival. The combination of AFP ratio at 8 weeks, assessment by mRECIST and Child-Pugh score before treatment allows stratification of prognosis of patients treated with sorafenib. Conclusion: The combination of mRECIST and AFP ratio is useful for the assessment of prognosis of patients with advanced HCC treated with sorafenib.

A phase II trial of JX-594, a targeted multimechanistic oncolytic vaccinia virus, followed by sorafenib in patients with advanced hepatocellular carcinoma (HCC).

e14566 Background: JX-594 is a targeted oncolytic vaccinia virus designed to selectively replicate in and destroy cancer cells with epidermal growth factor receptor (EGFR)/ ras pathway activation. Direct oncolysis plus GM-CSF expression is accompanied by tumor vascular disruption and anti-tumoral immunity (Reviewed in Nat Rev Cancer 2009). JX-594 was well-tolerated intravenously (IV) (Nature 2011) and intratumorally (IT) (Lancet Oncol 2008). Complementary anti-tumor effects are predicted with JX-594 followed by sorafenib due to acute vascular disruption effects with JX-594 and anti-angiogenic effects with sorafenib. Methods: Treatment-refractory HCC patients received JX-594 for three weeks (Day 1 IV, Day 8 IT and Day 22 IT) followed by sorafenib. An IT boost dose of JX-594 at Week 12 was optional. The primary objective of the study was to determine the safety of JX-594 followed by sorafenib in patients with advanced HCC. Secondary objectives include disease control rate (DCR) based on mRECIST and/or Choi response criteria at Day 6 (optional), Day 25 (after JX-594 only), 6 and 12 weeks. Results: Twenty (20) patients were treated in this study; fifteen (15) were refractory to sorafenib. The sequential treatment regimen was well-tolerated. Transient flu-like symptoms (Grade 1-2) and transient leukopenia (lymphopenia, neutropenia) were the most common adverse events following JX-594 therapy. Sorafenib toxicities were consistent with the expected toxicity profile. At the time of this interim analysis, thirteen patients were evaluable for radiographic response by Choi criteria (mRECIST pending). After JX-594 alone at Day 25, 10 of 13 evaluable patients (77%) had Choi tumor responses (range 19-48% reduced enhancement). Following subsequent sorafenib therapy, 11 of 13 patients (85%) had Choi responses at Week 6-12, including 9 of 10 (90%) sorafenib-failure patients. Conclusions: JX-594 was well-tolerated and associated with Choi tumor responses following IV and IT injections in patients with advanced HCC. Subsequent sorafenib was associated with the expected toxicity profile. Further trials of JX-594 in HCC patients are warranted.

EASL and mRECIST responses are independent prognostic factors for survival in hepatocellular cancer patients treated with transarterial embolization

Standard RECIST criteria may not be the optimal method to assess response to loco-regional therapy for hepatocellular cancer (HCC). EASL and mRECIST, which measure changes in arterialized tumor, have been proposed. Here we compare the three criteria and their associations with survival. Response was determined using RECIST 1.1, EASL, and mRECIST criteria in 83 consecutive patients with HCC undergoing palliative therapy with transarterial (chemo) embolization. Results were compared at the first assessment after therapy. Cox regression and Kaplan-Meier survival analyses were used to explore differences in overall survival between the responders and non-responders defined by each method. There was a good correlation between EASL and mRECIST with overall response rates; 58% and 57%, and target lesion responses; 74% and 73%, respectively. There was a poor correlation with RECIST 1.1 with overall and target response rates of 7%. Overall and target lesion progression rates were similar for all three assessments; 27% and 2% for both EASL and mRECIST and 28% and 6% for RECIST 1.1. There was a significant association between survival and overall EASL and mRECIST responses, which was retained in multivariate analysis. EASL response was associated with a 44% risk reduction and mRECIST with a 42% reduction. There was no significant association between survival for RECIST 1.1 responses or target EASL and mRECIST responses. When measured at a single, early time point post-therapy, EASL and mRECIST overall response rates are associated with survival and should be used in preference to RECIST 1.1 or target responses.