Changes In AFP Research Articles

Transjugular Intrahepatic Portosystemic Shunt Is Associated With Better Waitlist Management of Liver Transplant Candidates With Hepatocellular Carcinoma.

Transjugular intrahepatic portosystemic shunt (TIPS) reduces portal hypertension complications. Its impact on hepatocellular carcinoma (HCC) remains unclear. We evaluated 42,843 liver transplant candidates with HCC from the Scientific Registry of Transplant Recipients (2002-2022). 4,484 patients with and without TIPS were propensity score-matched 1:3. Analysing wait-list changes in total tumor volume, HCC count, and alpha-fetoprotein levels, and assessing survival from listing and transplantation; TIPS correlated with a decreased nodule count (-0.24 vs. 0.04, p = 0.028) over a median wait period of 284 days (IQR 195-493) and better overall survival from listing (95.6% vs. 91.5% at 1year, p < 0.0001). It was not associated with changes in tumor volume (0.28 vs. 0.11cm³/month, p = 0.58) and AFP (14.37 vs. 20.67ng/mL, p = 0.42). Post-transplant survival rates (91.8% vs. 91.7% at 1year, p = 0.25) and HCC recurrence (5.1% vs. 5.9% at 5 years, p = 0.14) were similar, with a median follow-up of 4.98 years (IQR 2.5-8.08). While TIPS was associated with a reduced nodule count and improved waitlist survival, it did not significantly impact HCC growth or aggressiveness. These findings suggest potential benefits of TIPS in HCC management, but further studies need to confirm TIPS safety.

Impact of Transjugular Intrahepatic Portosystemic Shunt on Hepatocellular Carcinoma: Prospective Cohort of Liver Transplant Candidates’ Analysis

Impact of Transjugular Intrahepatic Portosystemic Shunt on Hepatocellular Carcinoma: Prospective Cohort of Liver Transplant Candidates’ Analysis

Association between posttreatment α-fetoprotein reduction and outcomes in real-world US patients with advanced hepatocellular carcinoma.

Clinical trials suggest α-fetoprotein (AFP) reduction may be prognostic among patients with advanced hepatocellular carcinoma. However, the association of AFP reduction with outcomes in real-world settings is unclear. Patients with advanced hepatocellular carcinoma between January 1, 2011, and June 30, 2021, first-line tyrosine kinase inhibitor, and baseline and posttreatment AFP values (closest to 8±2weeks after first-line initiation) were included. AFP reduction was defined as ≥20% decrease from baseline vs <20% or no decrease. Real-world overall survival and progression-free survival (rwPFS) were defined as time from posttreatment AFP measurement to death, and the first progression event or death, respectively. Adjusted hazard ratios (aHRs) were estimated using Cox proportional hazards models adjusted for potential confounders and baseline AFP. Effect modification by baseline AFP and hepatocellular carcinoma risk factors was assessed. Among 533 patients, median baseline AFP was higher in those with AFP reduction than those without (N=166, 210 µg/L vs N=367, 150 µg/L). There was a 35% decrease in hazard of death for patients with reduction vs without (aHR=0.65; 95% CI, 0.52-0.81; median, 10.3 vs 5.9months). Results were similar for rwPFS (aHR=0.66; 95% CI, 0.54-0.81; median, 4.6 vs 2.6months). AFP reduction was associated with better outcomes among patients with baseline AFP ≥400 µg/L or with history of hepatitis B virus, hepatitis C virus, or alcohol use. Only the interaction between baseline AFP and reduction in association with rwPFS was statistically significant. For certain etiologies, posttreatment AFP change may be more important than baseline AFP for prognosis. Further work should characterize the prognostic implications of longitudinal AFP changes during treatment. The prognostic value of the change in α-fetoprotein (AFP) concentration after treatment initiation is less established, particularly in real-world settings. Longitudinal data from a large nationwide cohort of patients with advanced hepatocellular carcinoma (HCC) treated with first-line tyrosine kinase inhibitor in routine practice revealed that ≥20% reduction in posttreatment AFP levels was associated with better real-world overall survival and progression-free survival after adjusting for baseline AFP levels and other factors. The results also suggested that the associations may be stronger among patients with a history of HCC risk factors (e.g., hepatitis C virus, alcohol) or with higher baseline AFP levels.

S3186 The Imaging Negative Hepatic Lesions: A Rare Case of Infiltrative Hepatocellular Carcinoma

Introduction: Hepatocellular Carcinoma (HCC) is the 6th most common cancer and the 4th leading cause of cancer-related death worldwide. The infiltrative subtype is the most difficult to diagnose with imaging because of its inherently ill-defined micronodules involving a segment or entire hepatic parenchyma without a distinguishable mass. Prognosis is poor and estimated at a 5-year survival rate of < 20%. Diagnosis of HCC requires a sensitive imaging test. In situations where imaging is not able to identify a mass, EUS-FNA has been shown to have a higher detection rate. Case Description/Methods: A 61-year-old female with a past medical history of HCV cirrhosis with sustained virology response (SVR), presented with abdominal pain and worsening lower extremity edema. Remarkable examination findings include a distended abdomen and bilateral pitting lower extremity edema. Significant work up showed platelet of 109k/cmm (150-440), AST of 159 unit/l (15-37), total bilirubin of 1.2mg/dl (0.2-1.0), AFP of >20,000ng/ml (0.5-8.0), peritoneal fluid cytology was negative. A right upper quadrant ultrasound, CT, and MRI showed no hepatic mass, Fig CD. With markedly elevated AFP and a high suspicion for HCC, the patient had EGD-EUS guided fine-needle aspiration showing multiple infiltrative hepatic lesions, Fig E. The biopsy report showed malignant cells positive for AFP with cells reactive for glypican-3 and negative for Hep-Par1 (Fig A), supporting the diagnosis of HCC. The patient was referred to oncology and a month later, she died. Discussion: SVR is associated with decreased risk of HCC, however, with a cirrhotic liver, patients still have an absolute risk of developing HCC. Initial diagnosis of HCC can be obtained non-invasively using abdominal ultrasound, CT, MRI, and EUS-FNA. Abdominal ultrasound is the best imaging modality recommended for HCC surveillance because it is readily available. However, its sensitivity for detecting early HCC is about 47%. AFP cut-off level of > 20ng/ml has a sensitivity of about 60% with low specificity. A level of > 400ng/ml is diagnostic for HCC with a specificity of almost 100%. Incremental changes in AFP are associated with an increased mortality rate. The median survival rate of infiltrative HCC with AFP of > 400 is estimated to be about 5 months. EUS is superior to CT in detecting small hepatic lesions, with a sensitivity of 100% compared to 71% of CT. We recommend that EUS be considered an integral modality while investigating the diagnosis of infiltrative HCC.Figure 1.: Fig A showing Hepatocellular carcinoma, 200x. Glypican-3 immunostain shows strong, diffuse staining in HCC (A). Background non-neoplastic liver is negative (B). Fig C is the cirrhotic liver with no identifiable mass. Fig D shows fluid around the liver and spleen. Fig E is the EUS showing multiple infiltrative hepatic lesions.

Extracellular Vesicles May Predict Response to Radioembolization and Sorafenib Treatment in Advanced Hepatocellular Carcinoma: An Exploratory Analysis from the SORAMIC Trial.

SORAMIC is a randomized controlled trial in patients with advanced hepatocellular carcinoma (HCC) undergoing sorafenib ± selective internal radiation therapy (SIRT). We investigated the value of extracellular vesicle (EV)-based proteomics for treatment response prediction. The analysis population comprised 25 patients receiving SIRT+sorafenib and 20 patients receiving sorafenib alone. Patients were classified as responders or nonresponders based on changes in AFP and imaging or overall survival. Proteomic analysis was performed on plasma EVs by LC/MS, followed by bioinformatics analysis. Clinical relevance of candidate EV proteins was validated by survival and receiver-operating characteristic analysis with bootstrap internal sampling validation. Origin of circulating EV was explored by IHC staining of liver and tumor tissues and transcriptomics of blood cells. Proteomic analysis identified 56 and 27 EV proteins that were differentially expressed in plasma EVs between responders and nonresponders receiving SIRT+sorafenib and sorafenib alone, respectively. High EV-GPX3/ACTR3 and low EV-ARHGAP1 were identified as candidate biomarkers at baseline from the 13 responders to SIRT+sorafenib with statistically significant AUC = 1 for all and bootstrap P values 2.23×10-5, 2.22×10-5, and 2.23×10-5, respectively. These patients showed reduced abundance of EV-VPS13A and EV-KALRN 6 to 9 weeks after combined treatment with significant AUC and bootstrap P values. In reverse, low GPX3 and high ARHGAP1 demonstrated better response to sorafenib monotherapy with AUC = 0.9697 and 0.9192 as well as bootstrap P values 8.34×10-5 and 7.98×10-4, respectively. HCC tumor was the likely origin of circulating EVs. In this exploratory study, EV-based proteomics predicted response to SIRT+sorafenib and sorafenib-only treatment in patients with advanced HCC of metabolic origin.

Prognostic role of serial alpha-fetoprotein levels in hepatocellular carcinoma treated with locoregional therapy

Background and aim: To evaluate early serial AFP changes in responders and non-responders to locoregional therapy and identify differences between significant AFP decliners and non-decliners post-treatment.Methods: Case records of hepatocellular carcinoma (HCC) patients having AFP ≥20 ng/ml and treated with locoregional therapy were examined retrospectively. Patients with complete details were included. Trends of serial AFP change (from baseline to post-treatment one month) in patients showing early tumor response (complete response (CR), partial response (PR), progressive disease (PD)) as assessed on multiphasic MRI/CT liver performed at one month following treatment. Receiver operating curves were drawn to estimate the best AFP reduction cut off for differentiating between responders (CR plus PR) from non-responders (PD). AFP decliners (those with AFP level reduction greater than 20% post-treatment) were identified and comparisons of their clinical parameters, tumor response and survival rate were made with AFP non-decliners.Results: HCC patients (n = 126) had mean age of 52.8 years, male:female ratio (4:1), Child’s A 94, BCLC stage A/B/C HCC 49/65/12, respectively. On 4–6 weeks’ MRI/CT, 46 patients developed CR, 55 PR and 25 PD. Reduction in median AFP level (83% in CR, 19% in PR) occurred in responders while 16% increase occurred in PD patients (non-responders). A 30% AFP reduction could differentiate responders from non-responders with 70% sensitivity and 68% specificity, AUROC 74% (CI 0.64–0.85). AFP decliners showed better survival and tumor response than non-decliners.Conclusions: Serial AFP change can predict tumor response to locoregional therapy in AFP producing HCC patients. AFP decliners have better survival and tumor response than AFP non-decliners.

Clinical impact of serum α-fetoprotein and its relation on changes in liver fibrosis in hepatitis C virus patients receiving direct-acting antivirals.

α-Fetoprotein (AFP) is used widely as a serological marker for hepatocellular carcinoma. However, the AFP value is elevated in chronic hepatitis C virus (HCV) patients without hepatocellular carcinoma. Yet, data on the impact of direct-acting antiviral agents (DAAs) therapy on AFP levels after viral eradication are still lacking. The aim of this study was to elucidate the changes in the serum AFP level in chronic hepatitis C patients treated with DAA-based therapy and their relation to response and liver fibrosis parameters. A total of 456 chronic HCV patients who received different DAAs-based treatment regimens were enrolled. Laboratory data including serum AFP, transient elastography values, and fibrosis scores were recorded at baseline and sustained virological response at 24 weeks after treatment (SVR24). The outcome was the changes in the AFP level from baseline to SVR24 and its relation to changes in liver fibrosis parameters at SVR24 using Spearman's rank correlation test. Overall, 96.9% of enrolled patients were responders. A statistically significant improvement in serum transaminases, albumin, transient elastography values, and fibrosis scores at SVR24 was reported. The AFP level was significantly decreased from a median (interquartile range) of 6 (3.2-10.8) ng/ml before DAAs to 4 (2.3-6) ng/ml at SVR24 (P < 0.0001). Only 22.6% of patients showed an increase in the AFP level after treatment. On multivariate analysis, the only independent baseline variable associated with an increase in the AFP level after treatment was baseline AFP (odds ratio: 0.95, 95% confidence interval: 0.91-0.99, P = 0.02). There is a significant correlation between changes in AFP and liver fibrosis parameters at SVR24. DAAs-based regimens are a highly efficient antiviral therapy for chronic hepatitis C patients that resulted in improvements in the serum AFP level.

Abstract 3856: MTLCEBPA, a drug candidate for hepatocellular-carcinoma enhances efficacy of Sorafenib

Abstract MTLCEBPA, a non-toxic therapeutic oligonucleotide formulated inside SMARTICLES (liposomal nanoparticles) is currently under a Phase I study for patients with advanced hepatocellular carcinoma (HCC). We have demonstrated in multiple in vivo liver disease models that MTLCEBPA can improve liver function and inhibit HCC tumor growth. Here we show that upregulation of hepatic CEBPA expression by MTLCEBPA enhances the effects of Sorafenib in a (Diethylnitrosamine) DEN induced cirrhotic HCC rat model by significantly reducing liver tumor volume after only two weeks of combination treatment when compared to untreated control or single agent treatment only. In this study, we established cirrhosis and HCC by exposing male Wistar rats to DEN for 6 weeks. Animals were randomized into 5 groups comprising of: 1. PBS control; 2. MTL-CEBPA treatment (TIW at 3mg/kg) for one week; 3. MTL-CEBPA treatment (TIW at 3mg/kg) for two weeks; 4. Sorafenib TIW at 10mg/kg for two weeks; and 5. MTLCEBPA at 3mg/kg at week one combined with Sorafenib 10mg/kg at week 2 group. The results here indicate that Sorafenib combined with MTLCEBPA significantly inhibits tumor growth when compared to single agent treatment. Tumor sizes averaged at 644.7mm3 (± 88.57) in group 1 compared to 326mm3 (± 53.05) in group 2; 199.7mm3 (± 54.73) in group 3 and 299.5mm3 (± 77.1) in group 4. In combination treatment (group 5) the tumor sizes averaged at 101.3mm3 (± 37.48). Serum AFP change (posttreatment values - pre-treatment) was more prominent in the MTLCEBPA/Sorafenib combination treatment (group 5) where there was a 4-fold reduction in values after treatment when compared to control groups 1-4. Serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and total bilirubin remained unchanged across all the treatment groups suggesting no deterioration in liver function during the study period. These results suggest that MTLCEBPA improved the efficacy of Sorafenib in this DEN induced HCC model, indicating a promising therapeutic option for advanced HCC patients who can no longer be treated with potentially more effective local therapies. Citation Format: Nagy A. Habib, Kai-Wen Huang, Vikash Reebye, Mikael Sodergren, John Rossi. MTLCEBPA, a drug candidate for hepatocellular-carcinoma enhances efficacy of Sorafenib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3856.

Correlation between Early Tumor Marker Response and Imaging Response in Patients with Advanced Hepatocellular Carcinoma Treated with Lenvatinib

Aim: This study investigated early tumor marker response and treatment response in patients with advanced hepatocellular carcinoma (HCC) treated with lenvatinib. Methods: Twenty patients with advanced HCC who received lenvatinib were enrolled in this retrospective study. α-Fetoprotein (AFP) and des-γ-carboxyprothrombin (DCP) levels were measured before treatment as well as 2 and 4 weeks after treatment. The objective response rate was evaluated by mRECIST at 6 weeks. Results: The response rate was 30% (complete response/partial response/stable disease/progressive disease: n = 0/6/6/8 cases) by mRECIST. At 4 weeks, the AFP levels of 12 patients (80%) were lower than at baseline. The AFP levels of 9 patients (60%) continued decreasing from 2 weeks to 4 weeks (sustained-reduction group). In this group, the response rate was 67%. The median AFP change rate was –39% at 4 weeks. In imaging responders, the AFP change rate significantly decreased (p = 0.02). The DCP change rate had no significant correlation with imaging response. The AFP-sustained-reduction group had significantly higher adherence to lenvatinib than the non-sustained-reduction group (p = 0.02). Conclusion: With lenvatinib therapy for HCC, the AFP levels of most patients had declined at 2 weeks, and at 4 weeks the AFP-sustained-reduction group demonstrated a higher objective response.

A retrospective analysis of clinical outcomes among patients with infiltrative hepatocellular carcinoma (iHCC): A single institution study.

e15667 Background: iHCC is an aggressive disease with poorly characterized treatment outcomes. We sought to describe clinical and radiographic features of iHCC, describe overall survival (OS), and compare outcomes of sorafenib (SOR) use with a cohort of non-infiltrative hepatocellular carcinoma (niHCC) patients. Methods: Radiology reports from the University of Washington with an Li-RADS (LR) assignment, 2013-2017, were reviewed (5037 reports, 1954 patients (pts)) for terms indicative of iHCC. Results: : 102 cases were identified, with 43% arising from known niHCC. iHCC size is difficult to measure but when reported, median was 8cm (interquartile range 5-10cm). Other radiographic features: vascular invasion 72%, R lobe only 62%. Clinical data were obtained via medical record review. The cohort was primarily male (83%), White (65%), age &gt; 55 (88%), HCV (74.5%), heavy alcohol use (67%). At diagnosis: BCLC stage C (76%), ALBI grade 2 (62%) and 3 (21%). Median OS after diagnosis was 5.7 months (m). 38 (37%) pts were too ill to receive therapy. OS for de novo iHCC and for iHCC arising from niHCC did not differ (7.5m vs 5.1m, p = NS). All niHCC pts who received SOR in any line of therapy were identified among pts with a LR 5 lesion in at least one of the aforementioned radiology reports, 2013-2017. Pts who received SOR on trial and/or combined with another agent were excluded. Clinical data for the 83 niHCC pts were abstracted and compared to the 25 iHCC pts who received SOR, any line of therapy. Based on χ2 analyses, the 2 groups did not differ by age, sex, race, BCLC stage at SOR initiation, ECOG status at SOR initiation, HCC etiology, ALBI grade at SOR initiation, or previous locoregional therapy. OS after initiation of SOR was 14.1m for niHCC, 10.5m for iHCC, p = NS. PFS after SOR was 3.7m for niHCC, 7m for iHCC, p = NS. AFP at the time of SOR initiation was higher in iHCC than niHCC (median 1331 vs 48, respectively, p = 0.004), with median %AFP change after 30 days -13% in iHCC and +6% in niHCC, p = NS. Decrease in AFP after 30 days of therapy was associated with improved OS among niHCC (21m versus 7m, p = 0.001) but not among iHCC pts (p = NS). Conclusions: iHCC is a poorly understood subset of HCC with underlying biology not well defined. Compared to niHCC, clinical outcomes with sorafenib do not appear to differ in this cohort. Future characterization of outcomes with Y-90 and immune checkpoint inhibitors is warranted.

Transient increases in serum α fetoprotein and protein induced by vitamin K antagonist II levels following proton therapy does not necessarily indicate progression of hepatocellular carcinoma.

Transient increases in α-fetoprotein (AFP) and protein induced by vitamin K antagonist II (PIVKA-II), so-called flares, are frequently observed after treatment of hepatocellular carcinoma (HCC). In the present study, changes in AFP and PIVKA-II levels after proton therapy (PT), and the relationship between the flare phenomenon and clinical response were investigated. In 82 patients with stage I/II HCC (59 with no recurrence and 23 with out-of-field recurrence within 1 year), serum AFP and PIVKA-II levels were measured at 1, 3, 6, 9 and 12 months post-PT. AFP and PIVKA-II flares were defined as a >20% increase from the preceding serum level above 20 ng/ml (AFP) or 40 mAU/ml (PIVKA-II), followed by a >20% drop. Among the 59 patients with no recurrence, 3 (5.1%) had an AFP flare, while 23 (39%) had a PIVKA-II flare. The median time to AFP and PIVKA-II flare peaks was 1 and 6 months, respectively. In 4 patients, PIVKA-II flares were observed twice during follow-up. In 1 patient, AFP and PIVKA-II flares were observed simultaneously at 1 month post-PT. The PIVKA-II level pre-PT was significantly higher in the PIVKA-II flare-positive group compared with that in the flare-negative group (P=0.015, odds ratio 4.3, 95% confidence interval, 1.3-14.0). In the 23 patients with out-of-field recurrence, the median increase rate of PIVKA-II (203%) was higher than that in the PIVKA-II-flare-positive group (111%, P=0.035) and the time to recurrence (median, 9 months) was longer than the time to peak AFP level (1 month) in the AFP-flare-positive group (P=0.033). There was no significant association between flares and clinical response. Increases in AFP and PIVKA-II levels following PT should be assessed with caution to avoid misinterpretation of therapeutic outcome.

Changes of alpha-fetoprotein levels could predict recurrent hepatocellular carcinoma survival after trans-arterial chemoembolization.

BackgroundThere is paucity of information concerning whether AFP change is a predictor of prognosis for recurrent hepatocellular carcinoma (RHCC) patients after trans-arterial chemoembolization (TACE).MethodsA total of 177 RHCC patients who received TACE as first-line therapy were retrospectively analyzed. The patients were classified into three groups according to their pre-TACE and post-TACE AFP levels (group A: AFP decreased, group B: AFP consistent normal, and group C: AFP increased). The recurrence to death survival (RTDS) and overall survival (OS) were estimated by the Kaplan-Meier method, and compared by the log-rank test. Multivariate analyses were performed to identify prognostic factors for OS and RTDS.ResultsThere was no significant difference among the three groups concerning the baseline characteristics. The median overall survival (OS) was 74.5 months in group A (95% confidence interval (CI): 63.5, 85.6), 64.0 months in group B (95% CI: 52.3, 75.7) and 29.0 months in group C (95% CI: 24.1, 33.9; P<0.001). The median recurrence to death survival (RTDS) was 66.5 months (95% CI: 53.4, 79.6) in group A, 50.4 months (95% CI: 39.5, 61.4) in group B and 17.7 months (95% CI: 13.4, 22.1; P<0.001) in group C. Multivariate analysis revealed that tumor size at resection stage, tumor number at recurrent stage, cycles of TACE, mRECIST response and AFP change after TACE were significant independent risk factors for RTDS and OS.ConclusionsAFP change could predict the prognoses of patients with RHCC who received trans-arterial chemoembolization, which may help clinicians make subsequent treatment decision.

A multi-institutional phase II study of high-dose hypofractionated proton beam therapy (HF-PBT) for unresectable primary liver cancers: Long-term outcomes in patients (pts) with hepatocellular carcinoma (HCC).

376 Background: Retrospective reports of PBT in hepatocellular carcinoma (HCC) demonstrate local control (LC) rates exceeding 85%. We prospectively replicate these findings and explore predictors of overall survival (OS) in pts with unresectable HCC receiving high dose, HF-PBT. Methods: Pts were enrolled on an NCI sponsored, multi-institutional, phase II study (NCT00976898). Key eligibility were unresectable HCC; Child’s A/B; ECOG PS 0-2; no extrahepatic disease; no prior RT. Maximum tumor size was 12 cm if solitary, 10 cm if 2 tumors, and 6 cm if 3. PBT was given in 15 fractions to a maximum total dose of 67.5 GyE. Sample size was calculated to demonstrate &gt; 80% LC at 2 yrs (LC-2). Results: From 2009-2015, 44 patients were treated. Median age was 70 years (53-89) and 37 (84.1%) were male. 35 (79.5%) pts had Child A or no cirrhosis. 32 (72.7%) pts had 1 tumor, 12 (27.2%) had multiple tumors. Median longest tumor dimension was 5.0 cm (range 1.9-12.0). Median baseline AFP was 18.6 ng/mL (range 1.3-66081) and 29 pts (67.4%) had elevated AFP ( &gt; 7.9 ng/mL). Median RT dose delivered was 58.0 GyE (range 40.5-67.5). 1 pt (2%) had grade 3 RT related toxicity (thrombocytopenia). With a median follow up 21.8 mo among 28 survivors, the LC-2 was 94.8% (95% CI 84.5-99.1%). mOS was 49.9 mo (95% CI 17.8 months- upper limit not reached) and mPFS was 13.9 mo (95% CI 8.4-49.9). OS did not differ by CLIP score, PS, prior treatment, vascular thrombus, baseline AFP, size, or dose. Median AFP change from baseline to 3 mo post treatment was a 32.8% reduction. Median time to AFP nadir in pts with elevated baseline levels was 3.9 mo (0-30.5). % decrease in AFP from baseline to 6 mo post-treatment was significantly associated with lower hazard of death. (HR = 0.993, p = 0.016). Conclusions: High dose hypofractionated proton beam therapy demonstrated a high local control rate for HCC with favorable safety profiles, supporting the ongoing evaluation of radiation in HCC in phase III studies. AFP decrease from baseline to 6 months post-radiation is associated with improved overall survival. Clinical trial information: NCT00976898.

231P - &Agr;-Fetoprotein (Afp) Response By Gc33 Correlates to Progression Free Survival (Pfs) in Patients with Advanced Hepatocellular Carcinoma (Hcc)

ABSTRACT Aim: GC33 is a first-in-class recombinant, humanized mAb that binds to glypican-3 which is highly expressed in HCC. The aims of the analysis were to investigate AFP response after administration of GC33 in patients with advanced HCC and to assess the relationship between AFP response and PFS. Methods: Placebo and GC33 1600 mg biweekly with two loading doses were administered to previously treated patients with advanced HCC in a double-blind manner with 1:2 randomization. Seventy-one patients (placebo: GC33 = 24:47) who had AFP measurements at baseline (AFPB) and 6 weeks post treatment (AFP6W) were evaluated. Patients with steady state GC33 trough concentration higher than230 µg/ml (the median of the projected trough concentration on cycle 3 day1) were included in GC33 high exposure group. AFP response was defined as a 20% decrease in AFP at 6 weeks post treatment. Results: Twenty seven out of 47 patients treated with GC33 had trough concentration higher than 230 µg/ml. AFP change (%) from baseline at 6 weeks post treatment (calculated as (AFP6W-AFPB)/AFPB) in high exposure group was significantly lower than that in placebo and GC33 low exposure group combined (p = 0.029). In addition, 2 out of 24 (8.3%), 2 out of 20 (10%), and 8 out of 27 patients (30%) were AFP responder in placebo, GC33 low exposure group, and GC33 high exposure group, respectively. In landmark analysis (n = 71), AFP response was a prognostic factor of PFS (HR = 0.63, 80%CI: 0.41-0.97) regardless of treatment. Within GC33 treatment group, hazard ratio of PFS comparing AFP non-responder (n = 37) vs. AFP responder (n = 10) was 0.56 (80% CI: 0.34-0.91). Conclusions: GC33 high exposure group had better AFP response than placebo and low exposure group. Early assessment of AFP response may potentially be a valuable biomarker for predicting antitumor response in patients with advanced HCC. Disclosure: Yuyan Jin, Jun Shi, Alex Phipps and Ruey-min Lee have declared: is an employee of Hoffmann-La Roche; Mikiko Nakamura and Toshihiko Ohtomo have declared: is an employee of Chugai Pharmaceutical Co. Ltd.Ya-Chi Chen is an employee of Hoffmann-La Roche and also holds stocks of Hoffmann-La Roche.

Clinical study on the sensitivity test guided hepato-arterial/portal-vein chemotherapy in patients with unresectable hepatocellar carcinoma

Purpose: Approximately 20 % of tumors have the opportunity to be resected in patients with hepatocellar carcinoma (HCC) and their prognoses were acceptable. For the unrespectable HCC, however, the outcomes were rather poor because the specialty of the tumor blood supply and the tumor was insensitive to the chemotherapy drug. The objective of this study was to find sensitive drugs for individual patients and determine the safety and antitumor activity of hepatic intra-arterial and portal vein infusion chemotherapy. Methods : A total of 120 patients with the mean patient age of 56 years and with unresectable HCC were randomly divided into experimental group and control group. The experiment group was infused through an intra-arterial and portal vein catheter 3 different drugs were chosen by the results of drug sensitive test, whereas the control group was treated for TACE. The changes in tumor-size and AFP, two-step operation rate, survival rate, and complications were observed in these patients. Results: The tumor size reduced in 28(47.6 %) cases, stabilized in 14(23.3 %) cases, and progressed in 18(30 %) cases in experimental group as measured by CT or MRI after six chemotherapy cycles, whereas the corresponding data was 17(28.5 %) cases, 7(11.5 %) cases and 36(60 %) cases in the control group (P &lt; 0.05). The AFP was declined in 51 cases in experimental group and in 30 cases in control group (P &lt; 0.05). In the experimental group, the median follow-up time was 21 months; the overall survival rates (OS) of 6 months, 12 months, and 18 months were 86 %, 72 %, and 65 %, respectively. In the control group, the median follow-up time was 16 months; the OS rates of 6 months and 12 months were 58 % and 40 %, respectively. Six patients in the experimental group and 3 patients in the control group had two-step operation. There was no severe incidence of complications in both groups. In the experimental group, 2 (3 %) patients had wound infection, 8 cases had the chemotherapy relative diarrhea, and 18 (30 %) cases had grade Ⅰ or Ⅱ bone marrow suppression. In the control group, the chemotherapy relative diarrhea were 15 (25 %) cases and grade Ⅰ or Ⅱ bone marrow suppression were 33 (55 %) cases. Conclusion : The artery and portal vein pump transfusion chemotherapy guided by drug sensitive test was efficient for HCC treatment. The patients can get longer OS and lower complication incidence. -------------------------------------------------------- Cite this article as: Wu D, Wei S, Luo C, Wu X, Feng Y, Zhang F, Nie L, Xia X. Clinical study on the sensitivity test guided hepato-arterial/portal -vein chemotherapy in patients with unresectable hepatocellar carci-noma. Int J Cancer Ther Oncol 2014; 2(2):02029. DOI: 10.14319/ijcto.0202.9

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.

Highlights for α-fetoprotein in determining prognosis and treatment monitoring for hepatocellular carcinoma

To explore the prognostic value in the monitoring of treatment efficacy of serial α-fetoprotein (AFP) in hepatocellular carcinoma (HCC) patients. We searched MEDLINE, EMBASE and COCHRANE LIBRARY through April 21, 2012, to find qualifying articles. Our overall search strategy included terms for HCC, AFP, treatment response, and prognosis. Literature was limited to English-language, human studies. Studies reporting cumulative survival rates were summarized qualitatively. For the prognostic meta-analysis, we undertook a series of meta-analyses that summarised the Cox proportional hazard ratios (HRs) by assuming a random effects model. With regards to the correlation of AFP change with radiologic response, the categorical dichotomous variables were assessed using Poisson relative risks (RRs), which were incorporated into the random effects model meta-analysis of accuracy prediction. Between-study heterogeneity was estimated by use of the I² statistic. Publication bias was evaluated using the Begg funnel plot and Egger plot. Sensitivity analyses were conducted first by separating systemic treatment estimates from locoregional therapy estimates, evaluating different AFP response cut-off point effects, and exploring the impact of different study sizes. Of 142 titles identified in our original search, 11 articles (12 clinical studies) met our criteria. Six studies investigated outcome in a total of 464 cases who underwent systemic treatment, and six studies investigated outcome in a total of 510 patients who received locoregional therapy. A random-effects model meta-analysis showed that AFP response was associated with an mortality HR of 0.55 (95%CI, 0.47-0.65) across HCC in overall survival (OS) and 0.50 (95%CI, 0.38-0.65) in progression-free survival. Restricting analysis to the six eligible analyses of systemic treatment, the pooled HRs were 0.64 (95%CI, 0.53-0.77) for OS. Limiting analysis to the six analyses of locoregional therapy, the pooled HRs for OS was 0.39 (95%CI, 0.29-0.53). We showed a larger pooled HR in the 50% definition studies (HR, 0.67, 95%CI, 0.55-0.83) compared with that from the 20% definition studies (HR, 0.41, 95%CI, 0.32-0.53). Restricting analysis to the four studies including over 100 patients individually, the pooled HR was 0.65 (95%CI, 0.54-0.79), with a pooled HR for OS of 0.35 (95%CI, 0.23-0.46) in the studies of less than 100 patients. As to radiological imaging, 43.1% (155/360) of the patients in the AFP response group presented with a radiological overall response, while the response rate decreased to 11.5% (36/313) in the patients from the AFP nonresponse group. The RR of having no overall response was significantly lower in the AFP response group than the AFP nonresponse group (RR, 0.67; 95%CI, 0.61-0.75). In terms of disease control rate, 86.9% (287/330) in the AFP response group and 51.0% (153/300) in the AFP nonresponse group showed successful disease control, respectively. The RR of disease control failure, similarly, was significantly lower in the AFP response group (RR, 0.37; 95%CI, 0.23-0.58). But these findings could be overestimates because of publication and reporting bias. HCC patients presenting with an AFP response are at decreased risk of mortality. In addition, patients with an AFP response also present with a higher overall response rate and disease control rate.

Tumor Marker Levels Before and After Curative Treatment of Hepatocellular Carcinoma as Predictors of Patient Survival

α-fetoprotein (AFP) is used as a marker for hepatocellular carcinoma (HCC), which is influenced by hepatitis. Protein-induced vitamin K absence or antagonist II (PIVKA-II) is a sensitive diagnostic marker. Changes in these markers after treatment may reflect curability and predict outcome. We conducted an analysis of prognosis in 470 HCC patients who received curative treatments, and examined the relationship between changes in AFP and PIVKA-II levels after 1month of treatment in 156 patients. Subjects were divided into three groups according to changes in both levels: (1) normal (L) group before treatment, (2) normalization (N) or (3) decreased but still above normal level or unchanged (ANU) group after treatment. High AFP and PIVKA-II levels were significantly associated with poor tumor-free and overall survival. The presence of large size and advanced stage were significantly associated with prevalence of DU group. Overall survival in the AFP-L group was significantly better than that of other groups and overall survival in PIVKA-II-L and N groups were significantly better than that of the PIVKA-II-ANU groups. The combination of changes in the AFP- ANU and PIVKA-II- ANU groups showed the worst tumor-free and overall survivals. Multivariate analysis identified high pre-treatment levels of AFP and PIVKA-II and combination of AFP- ANU and PIVKA-II- ANU as significant determinants of poor tumor-free and overall survival, particularly in patients who underwent hepatectomy. We conclude that high levels of AFP or PIVKA-II after treatment for HCC did not sufficiently reflect curative efficacy of treatment and reflected a poor predictor of prognosis in HCC patients.

Differential Effects of Vitamin K1 on AFP and DCP Levels in Patients with Unresectable HCC and in HCC Cell Lines

DCP is a useful HCC tumor marker, which reflects a defect in vitamin K metabolism. We tested the hypothesis that vitamin K treatment of HCC patients might suppress this marker and possibly AFP also. HCC patients who had both elevated AFP and DCP were included. A phase I cohort was treated with escalating vitamin K1 intravenous weekly doses and a 27-patient phase II cohort was then treated with a fixed oral daily dose. A maximum tolerated dose was not reached up to 100-fold the normal vitamin K1 dose. No toxicities were found up to 1,000 mg/infusion. In the phase II cohort, 93% of patients had tumor marker responses by decreased DCP levels, but only 22% had responses by decreased AFP levels. CT scans showed 11% of patients had PRs, 59% had stable tumors and 29.6% had tumor progression. Mechanism studies showed that vitamin K1 induced phosphorylation of JNK and c-Jun and caspase-mediated apoptosis. Vitamin K1 was non-toxic at high doses, strongly inhibited plasma DCP levels, but weakly suppressed AFP levels. The results provide evidence that the two tumor markers are not directly linked and that DCP levels may not reflect HCC cell growth, as DCP levels were decreased in patients without AFP change, and were suppressed in vitro at 1% of the vitamin K1 concentration needed to inhibit AFP.

Serum α-Fetoprotein Response as a Surrogate for Clinical Outcome in Patients Receiving Systemic Therapy for Advanced Hepatocellular Carcinoma

The role of serum alpha-fetoprotein (AFP) as a marker for treatment response in patients with hepatocellular carcinoma (HCC) receiving systemic therapy is poorly defined. A retrospective study was performed on patients with advanced HCC enrolled in five phase II clinical trials. Serum AFP was prospectively collected at baseline and at different time points through treatment in parallel with radiologic response and clinical outcome. Patients were separated into three groups based on a 50% change in serum AFP from baseline. Overall survival (OS), progression-free survival (PFS), and radiologic responses were compared between groups using log-rank and Wilcoxon tests. Of 144 patients, 107 met the eligibility criteria. Eighteen patients experienced a >50% AFP decline, 57 patients had a >50% AFP increase, and 32 patients had a <50% change in serum AFP in either direction. Compared with patients with a <50% change in serum AFP (median PFS, 5.6 months), patients with a >50% AFP decrease had a longer PFS time (median, 16.9 months; p = .029), whereas those with a >50% increase had a shorter PFS time (median, 2.3 months; p = .038). Patients with a >50% rise in AFP had a shorter OS time than those with a <50% change (median, 6.3 months versus 11.1 months, respectively; p = .004), whereas a >50% AFP decrease was not associated with a significant difference in OS (median, 13.0 months; p = .87). AFP changes were significantly associated with radiologic response. Our study suggests that serum AFP change during treatment may serve as a useful surrogate marker for clinical outcome in patients with advanced HCC receiving systemic therapy.