scholarly journals Downstaging and Resection of Initially Unresectable Hepatocellular Carcinoma with Tyrosine Kinase Inhibitor and Anti-PD-1 Antibody Combinations

Liver Cancer ◽  
2021 ◽  
pp. 1-10 ◽  
Author(s):  
Xiao-Dong Zhu ◽  
Cheng Huang ◽  
Ying-Hao Shen ◽  
Yuan Ji ◽  
Ning-Ling Ge ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Partial Response ◽  
Adverse Effects ◽  
Tyrosine Kinase ◽  
Stable Disease ◽  
Tumor Response ◽  
R0 Resection ◽  
Tumor Diameter ◽  
Remnant Liver ◽  
Unresectable Hepatocellular Carcinoma

<b><i>Background:</i></b> Combined therapy with tyrosine kinase inhibitors (TKIs) and anti-PD-1 antibodies has shown high tumor response rates for patients with unresectable hepatocellular carcinoma (HCC). However, using this treatment strategy to convert initially unresectable HCC to resectable HCC was not reported. <b><i>Methods:</i></b> Consecutive patients with unresectable HCC who received first-line therapy with combined TKI/anti-PD-1 antibodies were analyzed. Tumor response and resectability were evaluated via imaging every 2 months (±2 weeks) using RECIST v1.1. Resectability criteria were (1) R0 resection could be achieved with sufficient remnant liver volume and function; (2) intrahepatic lesions were evaluated as partial responses or stable disease for at least 2 months; (3) no severe or persistent adverse effects occurred; and (4) hepatectomy was not contraindicated. <b><i>Results:</i></b> Sixty-three consecutive patients were enrolled. Of them, 10 (15.9%) underwent R0 resection in 3.2 months (range: 2.4–8.3 months) after the initiation of combination therapy. At baseline, these 10 patients had a median largest tumor diameter of 9.3 cm, 7 had Barcelona Clinic Liver Cancer stage C (vascular invasion) disease, 2 had stage B, and 1 had stage A. Before surgery, 6 patients were evaluated as a partial response, 3 stable disease, and 1 partial response in the intrahepatic lesion but a new metastatic lesion in the right adrenal gland. Six patients (60%) achieved a pathological complete response. One patient died from immune-related adverse effects 2.4 months after hepatectomy. After a median follow-up of 11.2 months (range: 7.8–15.9 months) for other 9 patients, 8 survived without disease recurrence, and 1 experienced tumor recurrence. <b><i>Conclusions:</i></b> Combination of TKI/anti-PD-1 antibodies is a feasible conversion therapy for patients with unresectable HCC to become resectable. This study represents the largest patient cohort on downstaging role of combinational systemic therapy on TKI and PD-1 antibody for HCC.

Initially unresectable hepatocellular carcinoma treated by combination therapy of tyrosine kinase inhibitor and anti-PD-1 antibody followed by resection.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16690-e16690
Author(s):  
Hui-Chuan Sun ◽  
Xiao-Dong Zhu ◽  
Cheng Huang ◽  
Ying-Hao Shen ◽  
Yuan Ji ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Combination Therapy ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Vascular Invasion ◽  
Tumor Recurrence ◽  
Tumor Response ◽  
Kinase Inhibitor ◽  
R0 Resection

e16690 Background: Combination of tyrosine kinase inhibitor (TKI) and anti-PD-1 antibody showed a high tumor response for advanced hepatocellular carcinoma (HCC). We are aiming to study the effect of combination therapy followed by resection in pts with initially unresectable HCC. Methods: 60 consecutive pts with unresectable or advanced HCC were treated with combination therapy as first-line treatment, including 2 in BCLC-A (China Liver Cancer stage [CNLC]-Ib), and 13 in BCLC-B (CNLC-IIa and IIb), 26 in BCLC-C (vascular invasion, CNLC-IIIa) and 19 in BCLC-C (extrahepatic metastasis, CNLC-IIIb). Tumor response and resectability were evaluated by imaging every 2 months (± 1 week). The criteria of resectability included: (1) R0 resection can be achieved; (2) remnant liver volume ≥ 40%; (3) Child-Pugh score is 5; (4) no contra-indications for hepatectomy. Results: Conversion to resectable HCC was identified in 11 (18.3%) pts after combination therapy. Of them, 2 pts are still under treatment for immune-related adverse events, and 9 underwent hepatectomy as of January 2020. Of the 9 pts, the initial tumor was unresectable because of macro-vascular invasion (n = 6, 1 Vp3, 3 Vp4, 1 hepatic vein, 1 inferior vena cava), extrahepatic metastasis (n = 1, right adrenal gland), tumor nodules ≥ 4 (n = 1) and recurrent HCC within 2 months after first resection (n = 1). The TKIs used were lenvatinib (n = 6) and apatinib (n = 3); anti-PD-1 antibodies used were pembrolizumab (n = 4), sintilimab (n = 3), camrelizumab (n = 1) and nivolumab (n = 1). The median interval between start of combination therapy and resection was 99 days (range, 73–251). The median post-operative hospital stay was 14 days (range, 11–68). The prevalence of post-hepatectomy liver dysfunction (the criteria by ISGLS) is 5 (55.6%) pts, and the post-operative complications (by Clavien–Dindo classification) occurred in 4 (44.4%) pts, including grade I in 1, grade IIIa in 2, and grade V in 1 (died from immune-related adverse events). Tumor response (RECIST v1.1) evaluated before surgery were PR (n = 5), SD (n = 3), and PD (n = 1). Pathological CR (pCR) was found in 5 (55.6%) cases. After a median follow up of 72 days (range, 11–184), tumor recurrence were diagnosed in 1 patient, and mortality without tumor recurrence in 1 patient, the other 7 cases remained tumor-free. Conclusions: This is to date the largest cohort of pts underwent R0 resection after combination therapy for initially un-resectable HCC. The combination of a TKI and anti-PD-1 antibody is feasible as a conversion therapy.

scholarly journals Radiomics analysis for predicting pembrolizumab response in patients with advanced rare cancers

2021 ◽  
Vol 9 (4) ◽  
pp. e001752
Author(s):  
Rivka R Colen ◽  
Christian Rolfo ◽  
Murat Ak ◽  
Mira Ayoub ◽  
Sara Ahmed ◽  
...  
Keyword(s):  
Partial Response ◽  
Stable Disease ◽  
Progressive Disease ◽  
Tumor Response ◽  
Complete Response ◽  
Classification Model ◽  
P Value ◽  
Rare Cancer ◽  
Rare Cancers ◽  
Contrast Enhanced Ct

BackgroundWe present a radiomics-based model for predicting response to pembrolizumab in patients with advanced rare cancers.MethodsThe study included 57 patients with advanced rare cancers who were enrolled in our phase II clinical trial of pembrolizumab. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related RECIST (irRECIST). Patients were categorized as 20 “controlled disease” (stable disease, partial response, or complete response) or 37 progressive disease). We used 3D-slicer to segment target lesions on standard-of-care, pretreatment contrast enhanced CT scans. We extracted 610 features (10 histogram-based features and 600 second-order texture features) from each volume of interest. Least absolute shrinkage and selection operator logistic regression was used to detect the most discriminatory features. Selected features were used to create a classification model, using XGBoost, for the prediction of tumor response to pembrolizumab. Leave-one-out cross-validation was performed to assess model performance.FindingsThe 10 most relevant radiomics features were selected; XGBoost-based classification successfully differentiated between controlled disease (complete response, partial response, stable disease) and progressive disease with high accuracy, sensitivity, and specificity in patients assessed by RECIST (94.7%, 97.3%, and 90%, respectively; p<0.001) and in patients assessed by irRECIST (94.7%, 93.9%, and 95.8%, respectively; p<0.001). Additionally, the common features of the RECIST and irRECIST groups also highly predicted pembrolizumab response with accuracy, sensitivity, specificity, and p value of 94.7%, 97%, 90%, p<0.001% and 96%, 96%, 95%, p<0.001, respectively.ConclusionOur radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer.InterpretationOur radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer.

scholarly journals Elevated Preoperative Serum CA125 Predicts Larger Tumor Diameter in Patients with Hepatocellular Carcinoma and Low AFP Levels

2019 ◽  
Vol 2019 ◽  
pp. 1-7
Author(s):  
Sanshun Zhou ◽  
Zusen Wang ◽  
Manjiang Li ◽  
Liqun Wu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Disease Free Survival ◽  
Clinicopathological Characteristics ◽  
R0 Resection ◽  
Tumor Diameter ◽  
Cancer Antigen 125 ◽  
Preoperative Serum ◽  
Serum Ca125 ◽  
Serum Ca125 Level ◽  
Patient Groups

Aim. Little is known about the association between cancer antigen 125 (MUC16/CA125) concentrations and tumor diameter of patients with hepatocellular carcinoma (HCC) and low AFP levels. To fill this gap in our knowledge, we conducted a retrospective study of 427 patients with HCC with AFP ≤200 ng/mL who underwent R0 resection at our center. Methods. The associations between CA125 concentrations and patients’ clinicopathological characteristics were analyzed. Survival vs CA125 levels was also evaluated between patient groups with CA125 ≤30 U/mL or CA125 >30 U/mL. Independent risk factors of disease-free survival (DFS) and overall survival (OS) were analyzed with Cox hazard regression model. Results. Elevated preoperative serum CA125 was significantly associated with maximal tumor diameter (MTD) >5 cm and female sex (P<0.001 and P=0.044, respectively). The DFS and OS of patients with CA125 ≤30 U/mL (n = 392) were significantly higher compared with those with CA125 >30 U/mL (n = 35) (P=0.003 and P=0.001 respectively). Multivariate analysis revealed that MTD >5 cm was an independent risk factor of DFS (HR = 1.891, 95% CI: 1.379–2.592, P<0.001) and OS (2.709, 1.848–3.972, P<0.001). Conclusions. In conclusion, elevated preoperative serum CA125 predicted larger tumor diameter and poor prognosis after patients with HCC with AFP ≤200 ng/mL underwent R0 resection, which may be explained by the elevation of the preoperative serum CA125 level significantly associated with MTD>5 cm.

Efficacy and safety of anti-VEGF therapy in metastatic unresectable hepatocellular carcinoma: A meta-analysis.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15632-e15632
Author(s):  
Lakshmi Manogna Chintalacheruvu ◽  
Avanija Buddam ◽  
Arun Kanmanthareddy ◽  
Apar Kishor Ganti
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Adverse Effects ◽  
Disease Progression ◽  
Meta Analysis ◽  
Categorical Variables ◽  
Vegf Receptor ◽  
Efficacy And Safety ◽  
Unresectable Hepatocellular Carcinoma ◽  
Significant Difference

e15632 Background:Conventional chemotherapy has limited role in metastatic unresectable hepatocellular carcinoma (HCC). Sorafenib is currently approved for metastatic unresectable HCC. We wanted to assess the efficacy and safety of other tyrosine kinase inhibitors (TKI) targeting vascular endothelial growth factor (VEGF) receptor such as brivanib, linifanib and regorafenib in metastatic HCC. Methods: We have searched electronic databases Pubmed, Google scholar to identify published trials using brivanib, linifanib and regorafenib in HCC. The outcomes evaluated were overall survival, time to disease progression (TTDP) and adverse effects. Hazard ratios (HR) with their respective 95% confidence intervals (CI) were then computed using the appropriate model for categorical variables. We used STATA 13.0 and Comprehensive Meta Analysis 2.0 software for all analyses. Results: We included seven randomized control studies. A combined analysis of these seven randomised control trials showed improved overall survival (OS) in VEGF-TKI group when compared to placebo HR - 0.79; (95% CI 0.62-1.00). However, there was no significant survival benefit of the newer VEGF receptor inhibitors when compared to sorafenib (HR - 1.05; 95% CI 0.95-1.17). The time to disease progression (TTDP) was significantly better in VEGF-TKI group as compared to placebo (HR - 0.61; 95% CI 0.39-0.97). However, there was no significant difference in TTDP between VEGF-TKI group and Sorafenib (HR - 0.88; 95% CI 0.66-1.16). Adverse effects were noted to be higher in VEGF-TKI group when compared to placebo (HR- 1.07; 95% CI 1.01-1.13). Conclusions: Treatment with TKI targeting VEGF receptor is associated with a significant improvement in OS and TTDP with tolerable side effect profile. Inhibiting the VEGF receptor pathway could lead to improved outcomes in HCC.

Rapamycin in patients with advanced hepatocellular carcinoma progressing on prior antiangiogenic therapy.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 356-356
Author(s):  
Mohamed Bouattour ◽  
Johanna Wassermann ◽  
Chantal Dreyer ◽  
Valérie Vilgrain ◽  
Valerie Paradis ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stable Disease ◽  
Tumor Response ◽  
Antiangiogenic Therapy ◽  
Mtor Inhibitors ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Disease Stabilization ◽  
Heavily Pretreated ◽  
Grade 3

356 Background: PI3K/Akt/mTOR is a critical survival pathway in hepatocellular carcinoma (HCC) often correlated with poor prognosis. Rapamycin (sirolimus) and its analogue everolimus, are specific mTOR inhibitors that showed promising antitumor activity in preclinical models and clinical cases of HCC Aims: To evaluate the safety and efficacy of rapamycin in patients (pts) with advanced HCC after failure or intolerance to prior antiangiogenic therapy Methods: In this retrospective cohort, we analyzed consecutive patients with progressive HCC after 1 to 3 lines of treatment including at least sorafenib. All pts received oral rapamycin at 20 to 30 mg once a week. Adverse events (AEs) were assessed using NCI-CTCAE v3.0, and tumor response was evaluated according to RECIST criteria. Results: Nine patients (F/M: 1/8) with compensated liver cirrhosis (Child A, n = 6; Child B7, n = 2) or no cirrhosis (n=1) and histologically proven HCC were included in this study. Overall, therapy with rapamycin was well tolerated. Most common toxicities were asthenia (grade 1-2: 5 pts) anaemia (all grade: 5 pts; grade 3: 2 pts ) and thrombocytopenia (grade 1-2: 2 pts). Liver function deterioration was observed in 2 pts with advanced cirrhosis (Child B7). Radiological evaluation was available in 6 pts. No objective tumor response was observed however stable disease ≥ 3 months was observed in 4 cases. Moreover, 2 pts showed stable disease at 6 months. Prolonged stabilization under rapamycin was observed in pts who were previously controlled at least for 6 months with sorafenib. Rapamycin was discontinued due to disease progression in 7/8 pts, toxicity in 1/8 pts. One pt shows ongoing long-lasting disease stabilization (8 + months). Conclusions: Rapamycin displayed an acceptable safety profile and may achieved disease stabilization in patients with heavily pretreated advanced HCC.

A phase I study of olaparib in combination with capecitabine-based chemoradiation (CRT) in patients (pts) with locally advanced pancreatic cancer (LAPC).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 709-709
Author(s):  
T.R. Jeffry Evans ◽  
Martin McKinlay Eatock ◽  
Liz-Anne Lewsley ◽  
Caroline Kelly ◽  
Elaine McCartney ◽  
...  
Keyword(s):  
Partial Response ◽  
Induction Chemotherapy ◽  
Stable Disease ◽  
Excision Repair ◽  
Critical Role ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Hair Follicles ◽  
Tumor Diameter ◽  
Grade 3

709 Background: Olaparib is a potent inhibitor of PARP-1, which has a critical role in signalling DNA single strand breaks (SSB) as part of the base excision repair pathway, and may have radio-sensitizing effects due to impaired resolution of radiation induced SSB. We hypothesize that O may potentiate the effects of X-CRT in pts with LAPC. Methods: Eligible pts with LAPC, ECOG < 1, tumor diameter < 6cm, with stable disease (SD) or response after 12 weeks’ induction chemotherapy, were treated with 1 of 4 escalating doses of O given bid po starting on day -3, and then in combination with X (830 mg/m2 bid) and radiation (50·4 Gy in 28 fractions) all administered Mon-Fri. Dose limiting toxicities (DLT) were determined on clinical and lab toxicity assessments (NCI-CTC AE v4.03) performed weekly from the start of O until completion of O plus X-CRT (i.e. 6 weeks). Dose escalation continued with a rolling-six design until the Maximum Tolerated Dose (MTD) was reached. Blood samples for PK analyses of O and PD measurement (inhibition of PARP activity) were collected on day -3 (O monotherapy) and during week 1 of O + X-CRT. Results: 18 pts, (9 m, 9 f, ECOG 0/1 [n=6/12]), age range 49-81 (median=70) years, with histologic (14) or cytologic (4) proven LAPC, had received induction chemotherapy with gemcitabine [GEM] (n=2), GEM + X (12), or FOLFIRINOX (3) with partial response (n=4) or stable disease (14). Pts received 50 (3), 100 (4), 150 (6), or 200 (5) mgs bid of O with X+CRT. DLTs were observed in 2 pts (both at 200mgs bid): 1 pt with grade 3 nausea (on optimal anti-emetics) and grade 3 fatigue, 1 pt with grade 3 anorexia. 6 pts were subsequently recruited at 150mgs bid with no DLTs. No pts had complete response, 2 pts had partial response (1 pt each at 100 and 150 mgs bid) and 1 pt (at 100 mgs bid) had progressive disease; the remaining 14 pts had SD. Conclusions: The recommended dose (RP2) of O is 150mgs bid when given in combination with X + CRT in LAPC. Recruitment of up to 12 pts with borderline operable LAPC at the RP2 is ongoing. PK analyses of O, PD studies (PARP inhibition – PBMCs; cytokeratin 18 – serum; γH2AX foci – hair follicles), and exploratory predictive marker studies (tumor – NGS; RNA exome sequencing) are ongoing. Clinical trial information: ISRCTN10361292.

Association of gut microbiota and metabolites with tumor response to immune checkpoint inhibitors in patients with unresectable hepatocellular carcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16165-e16165
Author(s):  
Pei-Chang Lee ◽  
Chi-Jung Wu ◽  
Ya-Wen Hung ◽  
Chieh-Ju Lee ◽  
Yee Chao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Gut Microbiota ◽  
Healthy Volunteers ◽  
Ursodeoxycholic Acid ◽  
Bile Acids ◽  
Tumor Response ◽  
Checkpoint Inhibitors ◽  
Fecal Microbiota ◽  
Unresectable Hepatocellular Carcinoma ◽  
Secondary Bile Acids

e16165 Background: Immunotherapy with checkpoint inhibitors (ICI) is a promising treatment for unresectable hepatocellular carcinoma (HCC), but lack of effective biomarker to predict treatment response. Gut microbiome could modulate tumor response to immunotherapy in melanoma; but its effects on HCC are still unclear. Methods: From May 2018 to April 2020, 94 patients received ICI treatment for unresectable HCC (uHCC) in Taipei Veterans General Hospital, the feces samples were prospectively collected before ICI treatment. Finally, 20 patients with radiology proven objective tumor responses (OR; 3 complete responses and 17 partial responses) following immunotherapy, and 21 randomly selected patients with progressive disease (PD) were enrolled for fecal microbiota and metabolites investigation. In addition, feces from 17 healthy volunteers were taken as normal control. Results: Although the alpha diversity was not significantly different among groups, the principal component analysis of Bray-Curtis distance showed a significant clustering of fecal microbiota between HCC patients and healthy volunteers. The significant bacterial dissimilarity was observed between OR and PD patients following immunotherapy (p = 0.016 and 0.019 by Anoism and Adonis tests, respectively). According to linear discriminant analysis (LDA) effect size (LEfSe), a prominence of Prevotella usually regarded as a pathogenic bacterium, was more abundant in HCC patients with PD to ICI treatment. While Veillonella, Lachnospiraceae, Lachnoclostridium, Lactobacillales, Streptococcaceae and Ruminococcaceae were predominant in patients with OR (LDA score [log10] > 3). In addition, primary bile acids, including murocholic acid, α and β-muricholic acids, and secondary bile acids, including ursodeoxycholic acid, ursocholic acid, tauro-ursodeoxycholic acid, and taurohyocholic acid were significantly dominant in the feces of patients with OR to ICI treatment. Correlation network analysis in patients with OR showed significant linkages between Lachnoclostridium, Ruminococcus and secondary bile acids. Conclusions: Fecal microbiota and bile acids are associated with the response to immunotherapy for uHCC patients. These findings highlight the potential role of microbiota as a biomarker and strategy to enhance response to immunotherapy by modifying gut microbiota for uHCC.

Tyrosine kinase inhibitors for unresectable hepatocellular carcinoma in adults

2021 ◽  
Vol 2021 (11) ◽  
Author(s):  
Winson Cheung ◽  
Yuan Xu ◽  
Shiying Kong ◽  
Roberta Elisa Rossi ◽  
Paolo Baldo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Unresectable Hepatocellular Carcinoma
Sign in / Sign up

Export Citation Format

Share Document