Advanced Inoperable Hepatocellular Carcinoma Research Articles

Tivozanib in advanced inoperable hepatocellular carcinoma: considerations for patients with liver cirrhosis

Tivozanib in advanced inoperable hepatocellular carcinoma: considerations for patients with liver cirrhosis

Relationship of Tumor Radiation-absorbed Dose to Survival and Response in Hepatocellular Carcinoma Treated with Transarterial Radioembolization with 90Y in the SARAH Study.

Background Little is known about factors that influence the efficacy of transarterial radioembolization (TARE). Purpose To determine the relationship between tumor radiation-absorbed dose and survival and tumor response in locally advanced inoperable hepatocellular carcinoma treated with TARE. Materials and Methods This was a secondary analysis of prospectively acquired data (between December 2011 and March 2015) from participants who received TARE in the Sorafenib versus Radioembolization in Advanced Hepatocellular Carcinoma (SARAH) trial (ClinicalTrials.gov identifier: NCT01482442). Tumor-absorbed dose was computed using technetium 99m (99mTc) macroaggregated human albumin (MAA) SPECT/CT. Visual agreement among CT, 99mTc-MAA SPECT/CT, and yttrium 90 (90Y) SPECT/CT or PET/CT was scored as optimal, suboptimal, or not optimal. Overall survival (OS) and tumor response at 6-month follow-up CT (Response Evaluation Criteria in Solid Tumors, version 1.1) were assessed. OS was evaluated using Kaplan-Meier tests. A propensity score comparing participants receiving a tumor dose greater than or equal to 100 Gy (best cut-off according to the receiver operating characteristic curve and median tumor radiation-absorbed dose values in the study groups) with those receiving sorafenib was calculated. Results One hundred twenty-one participants (median age, 67 years; interquartile range [IQR]: 61-73 years; 110 men) were evaluated in the dose-survival group, and 109 (median age, 66 years; IQR: 61-71 years; 100 men) were evaluated in the dose-tumor response group. In the dose-survival group, median OS was 9.3 months (95% confidence interval [CI]: 6.7 months, 10.7 months), and median tumor radiation-absorbed dose was 112 Gy (IQR: 68-220 Gy). Participants who received at least 100 Gy (n = 67) had longer survival than those who received less than 100 Gy (median, 14.1 months [95% CI: 9.6 months, 18.6 months] vs 6.1 months [95% CI: 4.9 months, 6.8 months], respectively; P < .001), and those with optimal agreement (n = 24) had the longest median OS (24.9 months; 95% CI: 9.6 months, 33.9 months). In the dose-tumor response group, tumor radiation-absorbed dose was higher in participants with disease control versus those with progressive disease (median, 121 Gy [IQR: 86-190 Gy] vs 85 Gy [IQR: 58-164 Gy]; P = .02). The highest disease control rate was observed in 31 of 40 participants (78%) with a tumor radiation-absorbed dose greater than or equal to 100 Gy and optimal agreement. Conclusion Higher tumor radiation-absorbed dose computed at technetium 99m macroaggregated human albumin SPECT/CT was associated with better overall survival and disease control in hepatocellular carcinoma treated with transarterial radioembolization with yttrium 90 in the Sorafenib versus Radioembolization in Advanced Hepatocellular Carcinoma trial. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Sofocleous and Kamarinos in this issue.

A multicentre phase 1b/2 study of tivozanib in patients with advanced inoperable hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is a major cause of cancer-related death. It is a highly vascular tumour with multiple angiogenic factors, most importantly vascular endothelial growth factor (VEGF), involved in HCC progression. Tivozanib is an oral inhibitor of VEGFR-1/2/3 with promising activity against HCC in vivo.MethodsWe conducted a phase 1b/2 study of tivozanib in patients with advanced HCC. The safety, dosing, pharmacokinetics, pharmacodynamics, and preliminary antineoplastic efficacy of tivozanib were evaluated.ResultsTwenty-seven patients received at least one dose of tivozanib. Using a 3+3 design, the recommended phase 2 dose (RP2D) of tivozanib was determined to be 1 mg per os once daily, 21 days on–7 days off. The median progression-free and overall survival were 24 weeks and 9 months, respectively, for patients treated at RP2D. The overall response rate was 21%. Treatment was well tolerated. A significant decrease in soluble plasma VEGFR-2 was noted, assuring adequate target engagement.ConclusionsAlthough this study did not proceed to stage 2, there was an early efficacy signal with a very favourable toxicity profile. A phase 1/2 trial of tivozanib in combination with durvalumab is currently underway.Trial registrationClinicalTrials.gov NCT01835223, registered on 15 April 2013.

10. Clinical profile of hepatocellular carcinoma in a tertiary care centre in Coastal Eastern India

Background and Aims: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Aim of the study is to access the clinical profile HCC attending the liver clinic of our centre. Methods: Consecutive patients of HCC were enrolled in the study between 2015 and 2017. Results: Out of 37 patients majority were male with M: F 5:1 and average age of 63.21 ± 10.97 years. On etiological evaluation only 32.43% had HBV infection, rest 67.56% were cryptogenic. Underlying cirrhosis was found in (30/37) 81.08% of cases. Out of rest 7 cases 2 case had HBV and HCC without cirrhosis. About half of cryptogenic HCC had diabetes mellitus. Most common presentation were anorexia (89.64%), pain abdomen (72.92%), jaundice (48.64%), mass abdomen (37.83%) and fever of unknown origin in 21.62% of cases. Of all HCC 75% had multifocal lesion in the triphasic CT scan and all had portal vein thrombosis. Majority patients belongs to BCLC C and D. Serum AFP was elevated in about three fourth of cases. Patients were managed with supportive management due to advanced disease. Conclusions: Most of the patients had advanced inoperable HCC. Two third of the patients cryptogenic and one third had HBV infection in aetiology. Regular follow up of NASH related cirrhosis patients are required to diagnose HCC at early stage so that definite treatment can be offered to them. The authors have none to declare.

Selective Internal Radiotherapy vs. Sorafenib for Hepatocellular Carcinoma

For patients with advanced inoperable hepatocellular carcinoma (HCC), new therapeutic options beyond sorafenib have been approved. However, the optimal

Phase 1b/2 study of tivozanib in patients with advanced inoperable hepatocellular carcinoma.

364 Background: Sorafenib has been the only FDA-approved medication for inoperable HCC (iHCC) as first line. Agents with better tolerability and potential to improve progression-free-survival (PFS) are needed. Tivozanib (TIVO) is an inhibitor of vascular endothelial growth factor (VEGF) tyrosine kinase, inhibiting angiogenesis critical in HCC. Methods: This is a phase 1b/2 study with HCC patients (pts) having a measurable disease, Child-Pugh class A, and no prior systemic therapy. Phase 1b portion followed a modified 3 + 3 design; phase 2 portion was a two-stage, single arm, un-blinded study. Adverse events were categorized based on CTCAE, and tumor imaging was assessed per RECIST. Results: At 3 centers with IRB approval, 21 eligible pts were enrolled. In phase 1b, 8 pts were enrolled at a starting dose of 1mg once daily q21days with one week off. Upon escalation to 1.5mg, two pts had dose limiting toxicities (DLTs, grade 3 mucositis and hypertension) and came off study without completing the DLT period. The dose of TIVO was de-escalated to 1 mg, and the accrual of remaining patients to phase 2 portion occurred at 1 mg. In a total of 19 pts, median follow up was 16.9 months (mo). The primary endpoint of median PFS was 5.5 mo. Partial response (PR) was seen in 4/19 (21%) and stable disease (SD) in 8/19 (42%): disease control rate was 63%. Overall survival (OS) at 6 and 12 mo was 58% and 25%. Median OS was 7.5 mo. Three pts have remained on TIVO for &gt; 2 years. Viral loads of hepatitis B and C remained stable during the study. Adverse events (AEs) related to TIVO included grade 3 fatigue (15.7%), decreased appetite (5.3%), pulmonary embolism (5.3%), hand-foot syndrome (5.3%), elevated LFT (10.5%), and grade 4 hypertension (5.3%). Conclusions: TIVO is tolerable at 1 mg in iHCC. In few pts, TIVO had deep and durable responses. Biomarker driven studies of TIVO in the context of immunotherapy are warranted. Acknowledgment: We appreciate support from NCCN. Clinical trial information: NCT01835223.

Phase III multi-centre open-label randomized controlled trial of selective internal radiation therapy (SIRT) versus sorafenib in locally advanced hepatocellular carcinoma: The SIRveNIB study.

4002 Background: The optimal therapeutic regime for locally advanced hepatocellular carcinoma (HCC) with and without vascular invasion remains unclear. This study evaluates the efficacy of Selective Internal Radiation Therapy using SIR-Spheres yttrium-90 microspheres (Y90) versus sorafenib in Asian Barcelona Clinic Liver Cancer (BCLC) stage B and C patients without extra-hepatic metastasis. Methods: This investigator-initiated multi-center trial randomized eligible patients with locally advanced inoperable HCC to single injection of Y90 or sorafenib (oral 400mg BD) till progressive disease or unacceptable toxicity. The sample size, assuming type I error (two-sided) of 0.05 and power of 90% was 360 patients. Final analysis was planned at 266 reported deaths. Results: 360 patients (182 Y90, 178 sorafenib) were enrolled from 27 centers in 11 Asian countries. BCLC C patients without extra-hepatic metastasis comprised 41.4% of patients, 30.6% had portal vein thrombosis (PVT), 88.6% were Child-Pugh A, 57.2% were hepatitis B and 15.0% were hepatitis C. Altogether 28.6% and 9.0% of patients in the Y90 and sorafenib arms respectively failed to receive planned therapy. Intention-to-treat analysis was carried out with the overall survival (OS) in the Y90 and sorafenib arms being 8.54 and 10.58 months respectively (Hazard ratio (HR) 1.17, p =0.203). Tumour response rate (TRR) was 16.5% and 1.7% (p &lt; 0.001) respectively. Time-to-tumor -progression (TTP) was 5.88 vs 5.36 (overall) (HR 0.93) and 6.08 vs 5.39 (liver-specific) (HR 0.91) months for Y90 and sorafenib respectively. Progression-free-survival (PFS) was 5.29 vs 5.06 (overall) (HR 0.94) and 5.85 vs 5.06 (liver-specific) (HR 0.92) months respectively. At least one severe adverse event was found in 27.7% and 50.6% of patients in the Y90 and sorafenib arms respectively. Conclusions: Asian patients with locally advanced HCC without extra-hepatic metastasis treated with Y90 have statistically significant better TRR, and fewer SAEs when compared with those treated with sorafenib. There were no statistically significant differences in OS between Y90 and sorafenib. Clinical trial information: NCT01135056.

Yttrium-90 radioembolization for advanced inoperable hepatocellular carcinoma.

BackgroundAdvanced inoperable hepatocellular carcinoma (HCC) conferring a grave prognosis may benefit from yttrium-90 (90Y) radioembolization.MethodsThirty patients with advanced inoperable HCC including those with any lesion >8 cm in maximal diameter or multiple bi-lobar lesions (totally more than five lesions), or portal vein thrombosis treated with radioembolization were reviewed. Treatment efficacy and safety were evaluated. Univariate and multivariate analyses were performed for identifying potential prognostic factors.ResultsAfter a median follow-up of 18.3 months, the response rate was 30.0%, and the disease control rate was 50.0%. Median overall progression-free survival (PFS) and overall survival (OS) were 3.3 months and 13.2 months, respectively. Longer median PFS was noted in those who had transarterial chemoembolization before radioembolization (7.3 months vs 3.1 months; P=0.021) and duration of alfafeto protein (AFP) response ≥6 months (11.8 months vs 3.0 months; P<0.001). Longer median OS was also revealed in those without portal vein thrombosis (17.1 months vs 4.4 months; P=0.015) and those whose duration of AFP response was ≥6 months (21.2 months vs 8.6 months; P=0.001). Seventeen patients (56.7%) developed treatment-related complications including five (16.7%) grade 3 events. Multivariate analysis revealed that treatment responders (P=0.001) and duration of AFP response ≥6 months (P=0.006) were prognostic of PFS, whereas the absence of portal vein invasion (P=0.025), treatment responders (P=0.010), and duration of AFP response ≥6 months (P=0.001) were prognostic of OS.Conclusion90Y radioembolization is an alternative treatment with a promising outcome for poor-risk advanced inoperable HCC.

P-0093 - Treatment Outcomes of Patients with Extremely Advanced Inoperable Hepatocellular Carcinoma (HCC) After Yttrium-90 Radioembolization

Introduction: Inoperable hepatocellular carcinoma (HCC) confers a grave prognosis especially those exhibiting portal vein invasion. Radioembolization with yttrium-90 microspheres as selective internal radiation therapy demonstrated favorable outcomes for this intractable disease. We reported our series of patients with extremely advanced unresectable HCC treated with yttrium-90 micospheres.

Phase II study of irinotecan in combination with capecitabine as a first-line chemotherapy in Asian patients with inoperable hepatocellular carcinoma

Aim: Hepatocellular carcinoma (HCC) is one of the most commonly fatal malignancies in Asia but treatment options are limited. Methods: This multinational, nonrandomized phase II trial using the combination of irinotecan (Campto or CPT-11) and capecitabine (Xeloda) was conducted to determine efficacy and safety of this combination in Asian patients with advanced inoperable HCC. The starting dose was irinotecan 200 mg/m2 every 3 weeks followed by capecitabine 1000 mg/m2 orally twice daily for 14 days followed by a 7-day rest. The primary endpoint was tumor response rate, based on response evaluation criteria in solid tumors criteria. Secondary objectives included the safety and tolerability of the treatment combination, time to progression, duration of overall response, tumor growth control rate (complete response, partial response plus stable disease) and overall survival. Results: Of the 63 recruited patients, 47 were evaluable. Of these, three (6.4%) achieved a partial response (lasting 2.2, 3.4 and 8.0 months, respectively). The median overall survival was 4.5 months. Grade 4 diarrhea was reported in four patients. Hematologic grade 4 laboratory abnormalities observed in patients while on study treatment included neutropenia (5.2%) and anemia (1.7%). Seven patients (12.1%) had grade 4 elevations in their total bilirubin. Both irinotecan and capecitabine were generally well tolerated, with manageable and reversible toxicities. Conclusion: Combination therapy with irinotecan and capecitabine has limited efficacy in the treatment of advanced-stage HCC. Further investigation of this combination is not warranted.