Showing posts with label liver cancer. Show all posts
Showing posts with label liver cancer. Show all posts

Sunday, August 19, 2018

FDA approves LENVIMA® for first-line treatment of unresectable liver cancer

MedPage Today:
FDA OKs First-Line Tx for Unresectable Liver Cancer First new upfront treatment option in over a decade 
by Ian Ingram, Deputy Managing Editor, MedPage Today 
August 16, 2018
WASHINGTON -- The FDA on Thursday approved the kinase inhibitor lenvatinib (Lenvima) for the first-line treatment of hepatocellular carcinoma (HCC) patients with unresectable disease.

Approval was based on the REFLECT study, a multicenter non-inferiority trial, which randomized 954 HCC patients 1:1 to either 8 mg or 12 mg oral lenvatinib (depending on the patient's weight) versus 400 mg sorafenib twice daily until disease progression or unacceptable toxicity. The drug is approved at the 8 mg once-daily dose for patients <60 kg and at the 12 mg once-daily dose for those ≥60 kg.
Continue reading:
 https://www.medpagetoday.com/hematologyoncology/othercancers/74612

Press Release:
Eisai And Merck Announce FDA Approval Of LENVIMA® (lenvatinib) Capsules For First-line Treatment Of Unresectable Hepatocellular Carcinoma (HCC) 

- Approval was based on REFLECT, the first-ever positive Phase 3 trial against an active comparator in previously untreated patients with unresectable HCC 

- Marks second approval under Eisai-Merck global collaboration to co-develop and co-commercialize LENVIMA, following Japan in March 2018

Aug 16, 2018
WOODCLIFF LAKE, N.J. and KENILWORTH, N.J., Aug. 16, 2018 /PRNewswire/ -- Eisai Inc. and Merck (NYSE: MRK), known as MSD outside of the United States and Canada, announced today that the U.S. Food and Drug Administration (FDA) approved the kinase inhibitor LENVIMA® (lenvatinib) for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). This approval was based on results from REFLECT (Study 304), where LENVIMA demonstrated a proven treatment effect on overall survival (OS) by statistical confirmation of non-inferiority, as well as statistically significant superiority and clinically meaningful improvements in progression-free survival (PFS) and objective response rate (ORR) when compared with sorafenib in patients with previously untreated unresectable HCC.

"Unresectable hepatocellular carcinoma is an extremely difficult-to-treat cancer, with no new first-line systemic therapy options for more than a decade," said Dr. Ghassan Abou-Alfa, medical oncologist, Memorial Sloan Kettering Cancer Center. "REFLECT is the first-ever positive Phase 3 trial against an active comparator in unresectable HCC. The efficacy and safety data from REFLECT are important findings for oncologists and others in the multidisciplinary teams who treat liver cancer, as well as for our patients who are affected by it."

Adverse reactions, some of which can be serious or fatal, may occur with LENVIMA, including hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure or impairment, proteinuria, diarrhea, fistula formation and gastrointestinal perforation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid stimulating hormone suppression/thyroid dysfunction, and wound healing complications. Based on the severity of the adverse reaction, LENVIMA should be monitored, withheld or discontinued. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should be advised to use effective contraception. For more information, see "Important Safety Information" below.

REFLECT showed that LENVIMA achieved the primary endpoint, demonstrating a treatment effect on OS by statistical confirmation of non-inferiority to sorafenib. Patients treated with LENVIMA experienced a median OS of 13.6 months compared to 12.3 months with sorafenib (HR: 0.92; 95% CI: 0.79–1.06). The OS analysis was conducted when 351 events had occurred in the LENVIMA arm and 350 events had occurred in the sorafenib arm, as prespecified in the statistical analysis plan. In addition, LENVIMA showed statistically significant superiority and clinically meaningful improvements in the secondary efficacy endpoints of PFS and ORR, as confirmed by a blinded independent imaging review (IIR):

Median PFS was doubled with LENVIMA compared to sorafenib: 7.3 months versus 3.6 months (HR: 0.64; 95% CI: 0.55–0.75; p<0.001) per blinded independent imaging review based on mRECIST criteria, and 7.3 months with LENVIMA versus 3.6 months with sorafenib (HR: 0.65; 95% CI: 0.56–0.77) per RECIST 1.1.
LENVIMA showed nearly 3.5 times the ORR of sorafenib: 41% (95% CI: 36-45%) vs. 12% (95% CI: 10-16%) per blinded independent imaging review based on mRECIST criteria, respectively (p<0.001), and 19% (95% CI: 15-22%) with LENVIMA versus 7% (95% CI: 4-9%) with sorafenib per RECIST 1.1.
Per mRECIST: Treatment with LENVIMA resulted in complete response (CR) = 2.1% (n=10) vs. 0.8% (n=4) with sorafenib; treatment with LENVIMA resulted in partial response (PR) = 38.5% (n=184) vs. 11.6% (n=55) with sorafenib
Per RECIST 1.1: Treatment with LENVIMA resulted in CR = 0.4% (n=2) vs. 0.2% (n=1) with sorafenib; treatment with LENVIMA resulted in PR = 18.4% (n=88) vs. 6.3% (n=30) with sorafenib

In addition, median time to progression (TTP) was doubled with LENVIMA compared to sorafenib: 7.4 months versus 3.7 months (HR: 0.60; 95% CI: 0.51–0.71; p<0.0001) per blinded independent imaging review based on mRECIST criteria, and 7.4 months with LENVIMA versus 3.7 months with sorafenib (HR: 0.61; 95% CI: 0.51–0.72; p<0.0001) per RECIST 1.1. Time to progression is defined as time from randomization to radiological progression. Deaths during follow-up without evidence of radiological progression are censored. This differs from PFS and is less correlative to overall survival.

In REFLECT, the most common adverse reactions (≥20%) observed in patients treated with LENVIMA were hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism and nausea. The most common serious adverse reactions (≥2%) reported in patients treated with LENVIMA were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%) and decreased appetite (2%).

The most common adverse reactions (≥20%) observed in patients who received sorafenib were palmar-plantar erythrodysesthesia syndrome, diarrhea, fatigue, hypertension, abdominal pain, decreased appetite, rash, decreased weight and arthralgia/myalgia. The most common serious adverse reactions (≥2%) reported in patients who received sorafenib were ascites (2%) and abdominal pain (2%).

It is also important to note that the dose for LENVIMA for patients with unresectable HCC is based on the patient's weight (12 mg for patients weighing 60 kilograms or more, 8 mg for patients weighing less than 60 kilograms); the recommended dosage and dose adjustments are described in the full prescribing information.

"Eisai strives to be a leading global R&D-based pharmaceutical company, driven by our human health care (hhc) mission to improve the lives of patients and their loved ones," said Shaji Procida, President and Chief Operating Officer, Eisai Inc., and Commercial Head of the Oncology Business Group, Americas at Eisai. "That purpose is what has propelled us toward this win for patients with unresectable hepatocellular carcinoma. Our goal is to bring monumental solutions to patients and health care providers, changing expectations for the oncology landscape, and we look forward to continuing this work in our ongoing collaboration with Merck."

"We are pleased by the FDA approval of LENVIMA as it marks an important advancement in the treatment of unresectable hepatocellular carcinoma," said Dr. Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories. "With our shared mission to find solutions for difficult-to-treat cancers, we look forward to working with Eisai to help bring this needed option to patients and physicians."

LENVIMA, a kinase inhibitor, was first approved in the U.S. in February 2015 for patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). In May 2016, LENVIMA was approved in the U.S. in combination with everolimus, for patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy. Under the collaboration, Eisai and Merck initiated co-commercialization activities for LENVIMA in the U.S. in June 2018. Since the initial launch, more than 10,000 patients were treated with LENVIMA, which is approved in more than 50 countries worldwide.

About the REFLECT Trial (Study 304)
REFLECT was a large (N=954) phase 3, randomized, multicenter, open-label trial conducted by Eisai to compare the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment in patients with unresectable hepatocellular carcinoma (HCC). Patients at 154 trial sites in 20 countries were randomized to receive lenvatinib 12 mg or 8 mg once a day depending on body weight (≥60 kg or <60 kg, respectively) (n=478) or sorafenib 400 mg twice a day (n=476). Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint of this study was overall survival, tested first for non-inferiority to sorafenib, then for superiority. Patients randomized to the LENVIMA arm did not have a statistically significant improvement in OS compared to those in the sorafenib arm. The key secondary efficacy endpoints of this study included progression-free survival, time to progression and objective response rate, tested for superiority to sorafenib. The results of the REFLECT trial were published online in The Lancet (Vol 391(10126):1163-1173) on February 9, 2018.

About Unresectable Hepatocellular Carcinoma (HCC)
The prevalence and mortality rate of hepatocellular carcinoma have been rising steadily over the past decade. Hepatocellular carcinoma is the most common type of liver cancer, accounting for about 90% of cases of primary liver cancer. The stage of disease at diagnosis largely determines treatment approach, with potentially curative options, like resection or transplantation, only available for early stage HCC. Unresectable HCC, a type of liver cancer that cannot be removed by surgery, has a worse prognosis, with a median survival of less than one year. Unfortunately, approximately 70% of patients are diagnosed too late to be eligible for resection or transplantation, and there have been limited treatment options available for patients with unresectable disease.

About LENVIMA® (lenvatinib) capsules 10 mg and 4 mg
LENVIMA® (lenvatinib) is a kinase inhibitor that is indicated:

For the treatment of patients with locally recurrent or metastatic, progressive radioactive iodine-refractory differentiated thyroid cancer (DTC)
In combination with everolimus, for the treatment of patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy
For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC)

LENVIMA, discovered and developed by Eisai, is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2α (FRS2α) phosphorylation.

Important Safety Information
Warnings and Precautions
Hypertension. In DTC, hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In RCC, hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% of patients, and 21% had diastolic blood pressure ≥100 mmHg. In HCC, hypertension occurred in 45% of LENVIMA-treated patients (24% grade 3). Grade 4 hypertension was not reported in HCC.

Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiation. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at reduced dose when hypertension is controlled or permanently discontinue based on severity.

Cardiac Dysfunction. Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC, and HCC, grade 3 or higher cardiac dysfunction occurred in 3% of LENVIMA-treated patients. Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Arterial Thromboembolic Events. Among patients receiving LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in RCC and HCC and 5% in DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials.

Permanently discontinue following an arterial thrombotic event. The safety of resuming after an arterial thromboembolic event has not been established and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity. Across clinical studies enrolling 1,327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of patients. In HCC, hepatic encephalopathy occurred in 8% of LENVIMA-treated patients (5% grade 3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated patients. 2% of patients discontinued LENVIMA due to hepatic encephalopathy and 1% discontinued due to hepatic failure.

Monitor liver function prior to initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Renal Failure or Impairment. Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment was reported in 14% and 7% of LENVIMA-treated patients in DTC and HCC, respectively. Grade 3-5 renal failure or impairment occurred in 3% of patients with DTC and 2% of patients with HCC, including 1 fatal event in each study. In RCC, renal impairment or renal failure was reported in 18% of LENVIMA + everolimus–treated patients (10% grade 3).

Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at reduced dose upon recovery or permanently discontinue for renal failure or impairment based on severity.

Proteinuria. In DTC and HCC, proteinuria was reported in 34% and 26% of LENVIMA-treated patients, respectively. Grade 3 proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In RCC, proteinuria occurred in 31% of patients receiving LENVIMA + everolimus (8% grade 3).

Monitor for proteinuria prior to initiation and periodically during treatment. If urine dipstick proteinuria ≥2+ is detected, obtain a 24-hour urine protein. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Diarrhea. Of the 737 LENVIMA-treated patients in DTC and HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea occurred in 81% of LENVIMA + everolimus–treated patients (19% grade 3). Diarrhea was the most frequent cause of dose interruption/reduction, and diarrhea recurred despite dose reduction.

Promptly initiate management of diarrhea. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Fistula Formation and Gastrointestinal Perforation. Of the 799 patients treated with LENVIMA or LENVIMA + everolimus in DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred in 2%. Fistulas and gastrointestinal perforations have also been reported in other lenvatinib clinical trials and in post-marketing experience. Pneumothorax has been reported with and without clear evidence of a bronchopleural fistula. Some reports of gastrointestinal perforation, fistula, and pneumothorax occurred in association with tumor regression or necrosis. In most cases of fistula formation or gastrointestinal perforation, risk factors such as prior surgery or radiotherapy were present.

Permanently discontinue in patients who develop gastrointestinal perforation of any severity or grade 3-4 fistula.

QT Interval Prolongation. In DTC, QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In RCC, QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA + everolimus and QTc interval >500 ms occurred in 6%. In HCC, QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%.

Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose upon recovery based on severity.

Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in 9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation with or without dose interruption or dose reduction. In RCC, grade 3-4 hypocalcemia occurred in 6% of LENVIMA + everolimus–treated patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients.

Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity.

Reversible Posterior Leukoencephalopathy Syndrome. Across clinical studies of 1,823 patients who received LENVIMA as a single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with MRI. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events. Serious including fatal hemorrhagic events can occur with LENVIMA. In DTC, RCC, and HCC clinical trials, hemorrhagic events, of any grade, occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. In DTC, grade 3-5 hemorrhage occurred in 2% of LENVIMA-treated patients, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5 hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients, including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage occurred in 5% of LENVIMA-treated patients, including 7 fatal hemorrhagic events.

Serious tumor-related bleeds, including fatal hemorrhagic events, occurred in LENVIMA-treated patients in clinical trials and in the postmarketing setting. In postmarketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than other tumors. Safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials.

Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (eg, carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction. LENVIMA impairs exogenous thyroid suppression. In DTC, 88% of patients had baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In patients with normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. In RCC and HCC, grade 1 or 2 hypothyroidism occurred in 24% of LENVIMA + everolimus–treated patients and 21% of LENVIMA-treated patients, respectively. In patients with normal or low TSH at baseline, elevation of TSH was observed post baseline in 70% of LENVIMA-treated patients in HCC and 60% of LENVIMA + everolimus–treated patients in RCC.

Monitor thyroid function prior to initiation and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Wound Healing Complications. Wound healing complications, including fistula formation and wound dehiscence, can occur with LENVIMA. Withhold for at least 6 days prior to scheduled surgery. Resume after surgery based on clinical judgment of adequate wound healing. Permanently discontinue in patients with wound healing complications.

Embryo-fetal Toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus; and advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 30 days after the last dose.

Adverse Reactions
In DTC, the most common adverse reactions (≥30%) observed in LENVIMA-treated patients were hypertension (73%), fatigue (67%), diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54%), decreased weight (51%), nausea (47%), stomatitis (41%), headache (38%), vomiting (36%), proteinuria (34%), palmar-plantar erythrodysesthesia syndrome (32%), abdominal pain (31%), and dysphonia (31%). The most common serious adverse reactions (≥2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of LENVIMA-treated patients; 18% discontinued LENVIMA. The most common adverse reactions (≥10%) resulting in dose reductions were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%).

In RCC, the most common adverse reactions (≥30%) observed in LENVIMA + everolimus–treated patients were diarrhea (81%), fatigue (73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting (48%), nausea (45%), stomatitis (44%), hypertension (42%), peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea (35%), rash (35%), decreased weight (34%), hemorrhagic events (32%), and proteinuria (31%). The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients.

In HCC, the most common adverse reactions (≥20%) observed in LENVIMA-treated patients were hypertension (45%), fatigue (44%), diarrhea (39%), decreased appetite (34%), arthralgia/myalgia (31%), decreased weight (31%), abdominal pain (30%), palmar-plantar erythrodysesthesia syndrome (27%), proteinuria (26%), dysphonia (24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea (20%). The most common serious adverse reactions (≥2%) were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%). Adverse reactions led to dose reductions or interruption in 62% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Treatment discontinuation due to an adverse reaction occurred in 20% of patients. The most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%).

Use in Specific Populations
Because of the potential for serious adverse reactions in breastfed infants, advise women to discontinue breastfeeding during treatment and for at least 1 week after last dose. LENVIMA may impair fertility in males and females of reproductive potential.

No dose adjustment is recommended for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. LENVIMA concentrations may increase in patients with DTC or RCC and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for patients with RCC or DTC and severe renal impairment. There is no recommended dose for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end stage renal disease.

No dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.

No dose adjustment is recommended for patients with DTC or RCC and mild or moderate hepatic impairment. LENVIMA concentrations may increase in patients with DTC or RCC and severe hepatic impairment. Reduce the dose for patients with DTC or RCC and severe hepatic impairment.

For more information about LENVIMA please see available full Prescribing Information.
http://eisai.mediaroom.com/2018-08-16-Eisai-And-Merck-Announce-FDA-Approval-Of-LENVIMA-R-lenvatinib-Capsules-For-First-line-Treatment-Of-Unresectable-Hepatocellular-Carcinoma-HCC

Monday, August 13, 2018

Listen: Fewer Australians are dying from hepatitis C, but thousands are still missing out on treatment

Article
Fewer Australians are dying from hepatitis C, but thousands are still missing out on treatment
By health reporter Olivia Willis
Monday 13 August 2018
The number of Australians dying from liver failure and liver cancer related to hepatitis C has dropped by 20 per cent in just two years, according to preliminary data released today by The Kirby Institute.
Read the article: http://www.abc.net.au/news/health/2018-08-13/fewer-australians-dying-from-hepatitis-c/10107326

ABC Radio Australia 
Deaths from Hep C liver failure and liver cancer improving
Listen to Monday's Health Report hosted by Dr. Norman Swan with guest Greg Dore discuss the latest hepatitis C-related liver failure and liver cancer figures in New South Whales.

Deaths from Hep C liver failure and liver cancer improving
New research is showing a return on the Federal Government's investment in free hepatitis C treatment aimed at curing blood-transmitted liver infection.

The latest figures from New South Wales show the number of people dying from hepatitis C-related liver failure and liver cancer has dropped 20 per cent in two years.

Listen here...…

Guest: Professor Greg Dore
Professor and Program Head, Viral Hepatitis Clinical Research Program, The Kirby Institute, University of New South Wales.

Monday 13 August 2018 5:45PM (full episode)

Saturday, August 11, 2018

Gut-Microbiome Biomarkers Identify Early Hepatocellular Carcinoma

We have demonstrated characteristic changes in the gut microbiota in early HCC across a large clinical cohort, illustrated crucial bacterial candidates that may contribute to HCC development, identified specific microbial markers and validated their diagnostic efficacy in the three cohorts from three different regions of China. Thus, we propose that gut microbiota-targeted biomarkers may become potential non-invasive tools for early diagnosis of HCC. Systematic investigation of the key bacterial genus or species by metagenomic sequencing may further improve the diagnostic value for HCC. The combination of microbial markers and currently used diagnostic approaches may further benefit HCC populations. The validation of gut microbial markers in much larger cohorts from different ethnic populations or different countries may further promote the efficacy and stability of HCC diagnosis. The ultimate goal would be to identify faecal microbial markers with strong diagnostic power to detect early HCC, which may further achieve early diagnosis and early therapy for HCC.

In the media - Reuters Health Information
Gut-Microbiome Biomarkers Identify Early Hepatocellular Carcinoma
08/10/2018
By Will Boggs MD 
NEW YORK (Reuters Health) - A panel of gut-microbiome biomarkers can be useful for identifying patients with early hepatocellular carcinoma (HCC), researchers from China report... 

Dr. Ren and colleagues characterized the gut microbiome and evaluated its potential as a noninvasive biomarker for HCC in their study of 75 patients with early HCC, 40 patients with cirrhosis and 75 healthy controls. They validated the results in 30 patients with early HCC, 45 patients with advanced HCC and 56 controls and further validated the biomarker panel's diagnostic potential in 98 patients with HCC....
Read the article: http://www.oncnet.com/news/gut-microbiome-biomarkers-identify-early-hepatocellular-carcinoma

Saturday, August 4, 2018

Direct Antiviral Therapy of Hep C May Not Boost Hepatocellular-Carcinoma Risk

Direct Antiviral Therapy of Hep C May Not Boost Hepatocellular-Carcinoma Risk
Treatment of hepatitis C (HCV) with direct-acting antiviral agents does not appear to increase the risk of hepatocellular carcinoma (HCC) in individuals with cirrhosis, researchers from France report.



On This Blog
HCC during and after direct-acting antiviral therapy in patients with hepatitis C
Index of research articles investigating the possible risk of developing liver cancer (hepatocellular carcinoma, or HCC) during and after direct-acting antiviral therapy in patients with hepatitis C.

Thursday, August 2, 2018

Liver Cancer After Treatment For Hepatitis C


Page updated: Aug 2018

Liver Cancer After Treatment For Hepatitis C
Research demonstrates that while SVR markedly reduced liver-related complications and liver cancer, some long-term risk for liver cancer remained in those who were cured of Hepatitis C. But after direct-acting antiviral therapy does the risk of developing liver cancer increase?

This page offers an index of links to current data investigating the possible risk of developing liver cancer (hepatocellular carcinoma, or HCC) during and after direct-acting antiviral therapy in patients with hepatitis C.

August 2018
Aug 4, 2018
Direct Antiviral Therapy of Hep C May Not Boost Hepatocellular-Carcinoma Risk
Treatment of hepatitis C (HCV) with direct-acting antiviral agents does not appear to increase the risk of hepatocellular carcinoma (HCC) in individuals with cirrhosis, researchers from France report.
Reuters Health Information, August 2018

June 2018
June 28, 2018
Washington—Eradication of chronic infection with the hepatitis C virus with the new class of antiviral agents is associated with a 71% reduction in the risk for de novo liver cancer, according to a large retrospective cohort study involving the Veterans Affairs health care system. The findings should provide some assurance for patients taking direct-acting antivirals (DAAs), according to lead study author George Ioannou, BMBCh, MS, the director of hepatology at Veterans Affairs Puget Sound Health Care System, in Seattle.

June 27, 2018
Should we cure HCV in patients with hepatocellular carcinoma while treating cancer?

June 15 2018
Alimentary Pharmacology & Therapeutics
Direct-acting Antiviral Treatment for Hepatitis C Virus Infection and Risk of Incident Liver Cancer
Does DAA-based HCV treatment reduce the risk of incident liver cancer compared to untreated HCV or interferon-based treatment?

May 2018
May 12, 2018
Nature reviews gastroenterology & hepatology
HCV therapy and risk of liver cancer recurrence: who to treat?
Article shared and download by Henry E. Chang on Twitter

May 4, 2018
This large real-life study proves that the efficacy of DAA in cirrhotic patients is not impaired by successfully treated HCC.

April 2018
April 21, 2018
Editorial
Hepatocellular carcinoma as a consequence of hepatitis C direct-acting anti-virals-the great urban myth of hepatology
Aliment Pharmacol Ther. 2018 May;47(10):1418-1419. doi: 10.1111/apt.14634.

April 17, 2018
Does interferon-free therapy for hepatitis C after curative treatment for hepatocellular carcinoma lead to unexpected recurrences of HCC?
PLOS ONE | https://doi.org/10.1371/journal.pone.0194704

April 11, 2018
New At Healio: 8 reports on liver cancer outcomes with HCV, DAA therapy

April 5, 2018
Hepatitis C - Interferon-free therapy did not increase the risk of liver cancer
LAY SUMMARY: We examined the risk of liver cancer among 857 patients with cirrhosis in Scotland who received hepatitis C antiviral therapy and achieved a cure. We compared the risk of first-time liver cancer in patients treated with the newest interferon-free regimens, to patients treated with interferon. After accounting for the different characteristics of these two treatment groups, we found no evidence that interferon-free therapy is associated with a higher risk of liver cancer.

Mar 19, 2018
Patients with hepatitis C who are successfully treated with direct-acting antiviral agents experience a dramatic reduction in their risk for liver cancer, new data show. However, the decrease is much lower for those diagnosed with cirrhosis before starting a DAA.

Mar 13, 2018
Persistence of hepatocellular carcinoma risk in hepatitis C patients with a response to IFN & cirrhosis

Stagnation of fibrosis regression is associated with a high risk for HCC after SVR

Mar 3, 2018

Feb 12, 2018
Hepatocellular carcinoma - Updated and evidence-based review
Alejandro Forner, MD, MD Alejandro Forner
Published: 04 January 2018
DOI: http://dx.doi.org/10.1016/S0140-6736(18)30010-2

Full Text
Hepatocellular carcinoma appears frequently in patients with cirrhosis. Surveillance by biannual ultrasound is recommended for such patients because it allows diagnosis at an early stage, when effective therapies are feasible. The best candidates for resection are patients with a solitary tumour and preserved liver function. Liver transplantation benefits patients who are not good candidates for surgical resection, and the best candidates are those within Milan criteria (solitary tumour ≤5 cm or up to three nodules ≤3 cm). Image-guided ablation is the most frequently used therapeutic strategy, but its efficacy is limited by the size of the tumour and its localisation. Chemoembolisation has survival benefit in asymptomatic patients with multifocal disease without vascular invasion or extrahepatic spread. Finally, sorafenib, lenvatinib, which is non-inferior to sorafenib, and regorafenib increase survival and are the standard treatments in advanced hepatocellular carcinoma. This Seminar summarises the scientific evidence that supports the current recommendations for clinical practice, and discusses the areas in which more research is needed....

Future perspectives
In the past 10 years, treatment of hepatocellular carcinoma has evolved considerably. Nowadays, patients with hepatocellular carcinoma can benefit from effective options that improve their survival whatever the evolutionary stage of disease at diagnosis. However, improvement can still be made in several areas. Prevention of the acquisition of the risk factors for development of hepatocellular carcinoma is the best strategy for decreasing mortality. The high efficacy of direct acting antivirals in elimination of chronic hepatitis C virus infection is expected to have an impact on the incidence of hepatocellular carcinoma, but further information about disease evolution in the patients after viral cure needs to be collected.......

Article Downloaded & shared by @HenryEChang via Twitter.
View Article: https://jumpshare.com/v/La5WS4Mn8Uwpi927nbeU

December 2017
Healio - December 8, 2017
Liver cancer incidence after HCV therapy linked to risk factors, not treatment
Li DK, et al. Hepatol. 2017;doi:10.1002/hep.29707. 
Direct-acting antiviral treatment for hepatitis C did not correlate with an increased risk for hepatocellular carcinoma in a large cohort study of both treated and untreated patients with or without cirrhosis. Those with incident HCC after DAA treatment had higher risk factors at baseline. “There was no increased risk for HCC as a result of having received DAA therapy whatsoever,” Raymond T. Chung, PhD, director of Hepatology and Liver Center at Massachusetts General Hospital, told Healio Gastroenterology and Liver Disease. “The risk was related to their preexisting likelihood of developing HCC. The fact that HCC developed post-DAA, we think, is more likely to be an accident of timing than the idea that it's related to receipt of DAA — these persons were at risk for HCC whether they received DAAs or not.”

Innes H, et al. J Hepatol. 2017;doi:10.1016/j.jhep.2017.10.033.
Recently published data suggest that higher hepatocellular carcinoma incidence after sustained virologic response with interferon-free hepatitis C treatment correlates to patient baseline risk factors, such as age, Child-Turcotte Pugh score and prior treatment, rather than IFN-free therapy.

HCV Clearance Lowers Liver Cancer Risk by 70% no Matter Drug of Choice
Reaching sustained virologic response with direct-acting antivirals reduced the occurrence of hepatocellular carcinoma by 71%, but all treatments that cleared the virus saw a similar reduction in risk, according to a presenter at The Liver Meeting 2017.


November 2017
HCV Advocate – Direct-Acting Antiviral Treatment & Decrease a Incidence of Liver Cancer
The studies on this blog looked at treatment with DAAs to find out if curing hepatitis C (HCV) with DAAs improved HCV disease progression and reduced the risk of liver cancer.

October 2017
Oct 23, 2017
The Liver Meeting® 2017 - Vets with HCV Might Settle Cancer Controversy
In the largest cohort analyzed to date -- some 62,000 patients in the VA system -- there is no evidence that therapy with newer agents that act directly against the virus (DAAs) increases the risk of hepatocellular carcinoma (HCC), according to George Ioannou, BMBCh, of the Veterans Affairs Puget Sound Health Care System in Seattle.

Oct 20, 2017
The Liver Meeting® - Direct‐Acting Antiviral Therapy Cuts Liver Cancer Risk By 71%
The study’s findings showed that DAA‐induced sustained virological response is associated with a 71 percent reduction in patients’ liver cancer risk, and showed treatment with DAAs is not associated with increased liver cancer risk compared to treatment with interferon.

Oct 16, 2017
Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting anti-viral treatment
In conclusion, our data showed no evidence of an increased risk of de novo HCC or recurrence by patients treated with interferon-free SOF-based regimens. However, cirrhosis was strongly associated with the short-term development of HCC after HCV eradication. Moreover, our findings underscore the fact that the serum EOT-AFP level is a useful marker for predicting de novo HCC for cirrhotic patients and that close HCC surveillance should be required for patients with a past history of HCC, especially for patients treated with noncurative procedures. Going forward, further studies will be required to elucidate the risk of HCC development over the long-term.....

Oct 3, 2017
HCV Treatment Not Associated with Liver Cancer, New Evidence Suggests
Kenneth Bender
An assessment of over 62,000 patients treated for hepatitis C (HCV) revealed no evidence to support the suggestion that direct acting antiviral (DAA) agents promote recurrence of hepatocellular carcinoma (HCC), and found instead that successful treatment with or without DAAs is associated with reduced risk of HCC.

September 2017
Sep 18, 2017
Coverage OncLive - 2017 International Liver Cancer Association Annual Conference
Study Shows DAAs Are Not Associated With Increased HCC Recurrence Risk
Angelica Welch
Published Online: Monday, Sep 18, 2017
Direct acting antivirals (DAA) are a novel and completely oral hepatitis C therapy that is associated with a high response rate. DAAs are used in most patients being treated for hepatitis C, including those with decompensated cirrhosis.

Sep 12, 2017
Full Text Article Provided by NATAP
"Most HCV-infected patients in the United States will undergo DAA-based antiviral treatment in the next few years and the vast majority of them will achieve SVR. Our results suggest that DAA-induced SVR is associated with a 71% reduction in HCC risk (AHR 0.29, 95% CI 0.23-0.37) compared to treatment failure. The reduction in HCC risk associated with SVR was similar irrespective of whether SVR was achieved by DAA-ONLY, DAA+IFN or IFN-ONLY regimens. This suggests that eradication of HCV reduces HCC risk independently of how it is achieved. In contrast to prior reports that suggested an increased HCC risk in patients treated with DAAs[[3], [7]], we found that receipt of DAA-ONLY antiviral treatment was not associated with increased risk of HCC when compared to receipt of IFN-ONLY antiviral treatment.....We found no evidence that treatment with DAAs was associated with increased risk of HCC compared to treatment with IFN.

Sept 5, 2017
Risk for hepatocellular carcinoma after HCV antiviral therapy with DAAs: case closed?
Several studies of patients treated with interferon -based therapy nicely documented that the risk for hepatocellular carcinoma (HCC) was markedly lower in patients who achieved SVR compared to those without SVR. 5-7 As a result, it was naturally assumed that with higher cure rates with DAAs, cancer rates would start to decline. It was therefore surprising and unsettling in 2016 to see a series of reports of unexpectedly high rates of ‘early’ HCC recurrence after ‘curative’ therapy as well as higher than expected rates of de novo HCC in patients who achieved SVR with DAAs.
PDF Full Text Article - Provided by @HenryEChang via Twitter

August 2017
Aug 15, 2017
How Do Direct-Acting Antivirals for HCV Affect HCC Risk?
The latest data on the controversial hepatitis C-hepatocellular carcinoma treatment link are examined.

Aug 10, 2017
The risks of hepatocellular carcinoma development after HCV eradication are similar between patients treated with peg-interferon plus ribavirin and direct-acting antiviral therapy
The risk of hepatocellular carcinoma (HCC) development is reduced following viral elimination by interferon therapy in chronic hepatitis C patients. However, the risk in patients treated with interferon-free direct-acting antivirals (DAAs) is unknown. We evaluated chronic hepatitis C patients who achieved viral eradication by pegylated-interferon plus ribavirin (PEG-IFN/RBV, n = 244) or daclatasvir plus asunaprevir (DCV/ASV, n = 154) therapy...

Aug 4, 2017
Liver cancer, mortality risks decrease with SVR after direct-acting antivirals
Patients who achieved sustained virologic response after direct-acting antiviral treatment also had significantly lower all-cause mortality and lower incident rates of…

July 2017
July 26, 2017
Medscape
With Hepatitis C Virus on the Run, Meet the New Challenge: Hepatocellular Carcinoma
Significant advances in the clinical practice of hepatology were addressed during this year's Digestive Disease Week. This review focuses on the concerns related to the apparent increase in the incidence of hepatocellular carcinoma (HCC).

July 16
Hepatitis C virus eradication with direct antiviral agents and liver cancer recurrence: Is the best the enemy of the good? Antiviral therapy has long been perceived as an adjuvant treatment modality worth to be offered to patients with chronic hepatitis C virus (HCV) infection after successful removal of a hepatocellular carcinoma (HCC), an approach dating more than two decades since interferon was first employed to treat non-A, non-B hepatitis.

July 10
DAAs do not affect HCC risk, SVR reduces risk
July 10, 2017
Recently published data showed a link between sustained virologic response and a reduced risk for hepatocellular carcinoma among patients treated with direct-acting…

July 3
Sustained response to direct-acting HCV antivirals tied to lower HCC risk
July 3, 2017
by Marilynn Larkin
NEW YORK (Reuters Health) - A sustained virologic response to direct-acting antiviral treatment of hepatitis C (HCV) is associated with a “considerable” reduction in the risk of hepatocellular carcinoma (HCC), researchers say. Dr. Fasiha Kanwal of Baylor College of Medicine in Houston, Texas and colleagues analyzed data on 22,500 HCV patients (mean age 62) from 129 Veterans Health Administration hospitals who filled more than one prescription of sofosbuvir, simeprevir, ledipasvir, a combination of paritaprevir/ritonavir or ombitasvir and dasabuvir, and daclatasvir in 2015.

June 2017
June 26, 2017
Challenges in Treatment of Hepatitis C among Patients with Hepatocellular Carcinoma

June 3, 2017
Medscape Coverage from the International Liver Congress (ILC) 2017
Navigating the Hep C Treatment and Cancer Risk Minefield

May 2017
May 26
Hepatocellular carcinoma and direct- acting antivirals: A never ending story?
Vincenza Calvaruso* andAntonio Craxì Version of Record online: 24 MAY 2017 DOI: 10.1111/liv.13421
Liver International
Volume 37, Issue 6, pages 812–814, June 2017

Key Points
• The benefit of SVR is higher in patients without clinically significant portal hypertension
• HCC occurrence in patients with compensated cirrhosis is comparable to historical controls of patients who achieved SVR after interferon-based therapy.
• Patients who achieve SVR with DAAs had a lower risk of developing liver cancer than those patients whose HCV infection was not cured.
• Data available on patients with previous HCC do not show an increased risk of HCC recurrence and report a comparable rate of reappearance of cancer among DAA-treated and untreated patients.

Full Text

Link Provided By
Henry E. Chang via Twitter

May 26
Summary Of  Available Data:
New Hep C Treatment Not Linked to Liver Cancer
Contrary to some earlier research, most recent studies see no association between response to DAAs and HCC

Do HCV DAAs Increase HCC Recurrence Risk or Not?
Does the administration of direct-acting antiviral (DAA) therapy increase a patient’s risk of hepatocellular carcinoma (HCC) recurrence?

Direct-acting-antivirals (DAA) can cure patients of the life-threating hepatitis C virus (HCV) infection, with cure rates exceeding 95%. However, questions have been raised about the long-term consequences of curing patients with DAAs, including a potential link between DAA treatment and the development of hepatocellular carcinoma (HCC).

Improved survival of patients with hepatocellular carcinoma and compensated HCV-related cirrhosis who attained SVR
Few studies examined the outcome of patients with HCV-related cirrhosis who developed hepatocellular carcinoma (HCC). The relative weight as determinant of death for cancer versus endstage-liver-disease (ESLD) and the benefit of HCV eradication remain undefined. This multicenter, retrospective analysis evaluates overall survival (OS), rate of decompensation and tumor recurrence in compensated HCC patients treated with IFN according to HCV status since HCC diagnosis.

Of Interest
HCC in presence of HCV decreases cure rate in DAA treatment
Patients with hepatocellular carcinoma and hepatitis C were less likely to achieve sustained virologic response while receiving direct-acting antiviral therapy compared with patients without HCC, according to results of a retrospective study.

International Liver Congress
April 21,2017
Direct-acting antivirals for hepatitis C not linked to higher liver cancer risk in most studies
People with hepatitis C who take treatment with direct-acting antivirals (DAAs) do not appear to have a higher risk of developing liver cancer compared to those treated with interferon, and the seemingly higher rates seen in some studies are attributable to risk factors such as older age and more advanced liver disease, according to a set of studies presented on Thursday at the International Liver Congress in Amsterdam. The congress is the annual meeting of the European Association for the Study of the Liver (EASL).

April 20, 2017
#ILC 2017: Is direct-acting antiviral therapy for Hepatitis C associated with an increased risk of liver cancer? The debate continues
Eight studies being presented at The International Liver Congress™ 2017 demonstrate contrasting evidence on the potential link between direct-acting antiviral treatment for Hepatitis C and liver cancer

Commentary on this study
Hepatitis C Patients At No Elevated Risk of Developing HCC Following DAA Compared To Interferon
Patients were at no elevated risk of developing hepatocellular carcinoma (HCC) after achieving sustained virologic response (SVR) following treatment with direct-acting antiviral therapy (DAA) for hepatitis C compared to interferon therapy, according to results of a meta-analysis reported at the 2017 International Liver Congress (ILC).

Timing of DAA therapy and HCC response may impact recurrence rate
April 20, 2017
AMSTERDAM — Unexpectedly high hepatocellular carcinoma recurrence rates were reported among patients who achieved sustained virologic response after receiving direct-acting antiviral therapy, according to data presented at the International Liver Congress.
“This update further supports our findings about an unexpected high recurrence rate associated in time with DAA, but also exposes a more aggressive pattern of recurrence and faster tumor evolution,” Maria Reig, MD, of the Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clinic Barcelona, at the University of Barcelona, said in her presentation.

Liver International
April 20, 2017
Download PDF - Full Text
Direct-acting antiviral therapy decreases hepatocellular carcinoma recurrence rate in cirrhotic patients with chronic hepatitis C
Arrival of direct-acting antiviral (DAA) agents against hepatitis C virus (HCV) with high-sustained virological response (SVR) rates and very few side effects has drastically changed the management of HCV infection. The impact of DAA exposure on hepatocellular carcinoma (HCC) recurrence after a first remission in patients with advanced fibrosis remains to be clarified

Editorial - Healio
April 20, 2017
HCC After DAAs Requires More Study, but no Cause for Withheld Treatment
HCV Next, April 2017
As we continue to see the success of direct-acting antiviral therapy in treating hepatitis C virus, we must be aware of any potential complications from the underlying liver disease after successful treatment, especially hepatocellular carcinoma.

March 15, 2017
Full Text - Download PDF
Hepatitis C-related hepatocellular carcinoma in the era of new generation antivirals
Abstract
Hepatitis C virus infection is a major cause of hepatocellular carcinoma worldwide. Interferon has been the major antiviral treatment, yielding viral clearance in approximately half of patients. New direct-acting antivirals substantially improved the cure rate to above 90%. However, access to therapies remains limited due to the high costs and under-diagnosis of infection in specific subpopulations, e.g., baby boomers, inmates, and injection drug users, and therefore, hepatocellular carcinoma incidence is predicted to increase in the next decades even in high-resource countries. Moreover, cancer risk persists even after 10 years of viral cure, and thus a clinical strategy for its monitoring is urgently needed. Several risk-predictive host factors, e.g., advanced liver fibrosis, older age, accompanying metabolic diseases such as diabetes, persisting hepatic inflammation, and elevated alpha-fetoprotein, as well as viral factors, e.g., core protein variants and genotype 3, have been reported. Indeed, a molecular signature in the liver has been associated with cancer risk even after viral cure. Direct-acting antivirals may affect cancer development and recurrence, which needs to be determined in further investigation.
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Feb 27, 2017
People with HIV and hepatitis C virus (HCV) co-infection who are successfully treated for hepatitis C using interferon-free direct-acting antiviral (DAA) therapy do not appear to have an increased likelihood of developing hepatocellular carcinoma (HCC), according to a study presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2017) this month in Seattle.

Accepted Manuscript
Gastroenterology Accepted Date: 23 January 2017
Genome-wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection

Media Coverage of this Article
Feb 22, 2017
Genetic variant linked to risk of liver cancer after hep C eradication
NEW YORK (Reuters Health) – A single nucleotide polymorphism (SNP) in the tolloid-like 1 (TLL1) gene is associated with the development of hepatocellular carcinoma (HCC) after eradication of hepatitis C virus (HCV) infection, researchers from Japan report.
“When we constructed different models for predicting HCC in patients with mild as opposed to advanced hepatic fibrosis by combining this TLL1 variant with other distinct risk factors, these proposed models including TLL1 variant could be useful for predicting the occurrence of HCC after achieving sustained virological response (SVR) in the clinical practice,” Dr. Yasuhito Tanaka from Nagoya City University Graduate School of Medical Sciences told Reuters Health by email.
Continue reading...

Feb 8, 2017
High Rates of Hepatocellular Carcinoma After Hepatitis C Treatment
NEW YORK (Reuters Health) - Patients treated with direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV)-related cirrhosis appear to have high rates of hepatocellular carcinoma (HCC).

"If these findings are confirmed from other centers, studies are suggested to examine mechanisms of these findings," Dr. Ashwani Singal from University of Alabama at Birmingham told Reuters Health by email.

Some studies have shown unexpectedly high HCC recurrence rates after DAA therapy, whereas others have shown no such association.

Dr. Singal and colleagues examined the occurrence of de novo HCC in their retrospective study of 66 patients with HCV-related cirrhosis who received DAA between 2015 and 2016.

Typically, patients with HCV cirrhosis have an HCC incidence of 3%-5% per year, the researchers say.

But six of these patients (9.1%) developed HCC during or within six months after treatment, and two additional patients (3%) developed indeterminate liver lesions, according to their letter online February 1st in Gastroenterology.

They note that another study showed a reduced risk of HCC occurrence among DAA-treated patients who achieved sustained viral responses (SVR) versus those not achieving SVR, so they suggest prospective multicenter studies to confirm these findings.

"Be aware of this potential issue and consider more intensive HCC surveillance of HCV cirrhotics during and after HCV therapy," Dr. Singal concluded.

Dr. Gaetano Serviddio from University of Foggia, Italy, who has reported on the outcomes of DAA therapy, told Reuters Health by email, "DAAs have completely changed the prognosis of chronic hepatitis C patients who have a unique possibility to be cured definitively. To discover that such drugs have some tumor risks is particularly terrible. In any case, the number of events is small, and the data are not enough to support the hypothesis that the risk is directly related to the drugs."

"DAAs are safe and powerful drugs; millions of lives will be saved with such drugs," he said. "Studies should be supported to completely define patients at risk of HCC recurrence."
SOURCE: http://bit.ly/2lmDbXa
Gastroenterol 2017.

January 2017
In Press, Corrected Proof
Digestive and Liver Disease
Available online 21 January 2017
HCV clearance by direct antiviral therapy and occurrence/recurrence of hepatocellular carcinoma: A “true-or-false game”
Three years ago, the new direct antiviral therapies (DAAs) were approved for HCV treatment and the scenario completely changed. The share of patients in whom eradication is obtained raised to over 90% [7], the limits in the stage of the disease that can be treated disappeared, but solid data on the long-term outcome of cirrhotics treated with these new drugs are lacking.

A totally unexpected, intriguing and somehow hard-to-believe report of an increased incidence of HCC with rapid recurrence after HCV eradication with DAAs was first presented at the 2016 EASL meeting and then published in the Journal of Hepatology.....
Continue to full text article...

2016
AASLD 2016 and International Liver Congress 2016
Two studies presented at The Liver Meeting® 2016, and research presented in April at the International Liver Congress 2016.

Patients With HCV Who Treated With Interferon-based Therapy  
We begin with a study presented at AASLD 2016; The impact of sustained virological response to HCV infection on long term risk of hepatocellular carcinoma: the BC Hepatitis Testers Cohort, that suggested patients achieving SVR were still at risk for hepatocellular carcinoma, more specifically older patients and those with cirrhosis, commentary on the study is available over at Healio; SVR post–interferon-based therapy reduces, not eliminates risk for HCC, below is a summary of the study followed by slides @ NATAP 

Liver cancer risk reduced in patients cured of HCV
A large study found that the risk of hepatocellular carcinoma was reduced by 80% in people cured of HCV compared to those who were not cured.

This was a study of the entire population of people treated for HCV in British Columbia province, Canada, between 1990 and 2013. The study identified 8147 people treated with interferon-based regimens, 57% of whom were cured. Treated individuals were followed for a median of 5.6 years.

The liver cancer incidence was highest among those with cirrhosis who did not achieve a SVR (21 cases per 1000 patient-years of follow-up). In comparison, the liver cancer incidence was 6.4 per 1000 patient-years in those with cirrhosis who achieved SVR, 7.2 in those without cirrhosis who did not achieve SVR12 and 1.1 per 1000 patient-years in those without cirrhosis who achieved SVR12.

In a multivariable analysis liver cancer was associated with cirrhosis, age over 50 years, genotype three infection versus genotype one, alcohol consumption and being male in those who were not cured. In those who were cured of hepatitis C, only cirrhosis, age over 50 and being male were associated with an increased risk of liver cancer.

The researchers concluded that although curing HCV greatly reduces the risk of developing liver cancer, it does not eliminate the risk entirely. Older people and those with cirrhosis are at higher risk than others, underlining the importance of early diagnosis and treatment.

Reference
The impact of sustained virological response to HCV infection on long term risk of hepatocellular carcinoma: the BC Hepatitis Testers Cohort. Janjua NZ et al. The 67th Meeting of the American Association for the Study of Liver Diseases, Boston 2016. Abstract 175
Summary Source - https://www.basl.org.uk/

Review Slides

Patients With HCV Who Treated With Oral DAAs
In a prospective study presented at the 2016 AASLD; Incidence and pattern of "de novo" hepatocellular carcinoma in HCV patients treated with oral DAAs, reported that treatment with direct-acting antiviral therapy did not increase the risk of developing hepatocellular carcinoma in patients with HCV, but patients with advanced liver disease should continue to be monitored for liver cancer after treatment, here is the AASLD press release, followed by slides @ NATAP.

AASLD Press Release;
AASLD 2016 - Is There an Increased Risk of Cancer After Taking Direct-Acting Antiviral Medication?
BOSTON, Nov. 11, 2016
A new study presented this week at The Liver Meeting® — held by the American Association for the Study of Liver Diseases — found patients with hepatitis C who take direct-acting antiviral medication are at no higher risk for developing liver cancer than those who do not take the medication. However, they might be at an increased for more aggressive, infiltrative patterns of cancer, should they develop it.

"Data on clinical outcomes in cirrhotic patients with hepatitis C treated with direct-acting antiviral agents (DAAs) are still scanty and somehow controversial, and this is particularly true for development of a liver cancer, one of the most frequent and deadly complications of the disease," says Alfredo Alberti; professor of gastroenterology at University of Padova in Padova, Italy, and lead investigator in the study.

Recent studies have suggested the possibility of increased risk of developing liver cancer (hepatocellular carcinoma, or HCC) during and after DAA treatment in patients with hepatitis C (HCV). Dr. Alberti's team recently looked at the incidence of new cases of liver cancer among 3,075 HCV patients with advanced liver disease who were treated with DAAs. Almost 70 percent of the patients studied were men, and nearly 86 percent had cirrhosis (scarring of the liver). HCV genotypes one through four were all represented in the study, and patients with a past history of liver cancer were excluded.

All participants were treated with oral DAA therapy and monitored monthly. At the time of Dr. Alberti's team's analysis, patients had an average follow up of nearly 305 days from the time they started DAA therapy. During this period, the researchers found 41 patients had developed liver cancer, and the overall incidence (per 100 patient years) was 1.64.

Dr. Alberti's team further noted an incidence rate of 0.23 in patients without cirrhosis and of 1.93 in those with cirrhosis (1.93 for men and 1.94 for women). Incidence rates varied among HCV genotypes as well, with HCV-1 at the low end (1.70) and HCV-3 at the high end (2.44). Finally, cirrhotic patients with a Child-Pugh score of 'A' had an incidence rate of 1.64 and those with more advanced disease and a score of 'B' had a rate of 2.92.

"These rate incidences were not significantly different from those observed in historical control cohorts of similar patients from the same geographic area, not receiving antiviral therapy, indicating that the risk of developing HCC is not increased by oral DAAs, being closely dependent on stage of disease as in untreated cases," says Dr. Alberti.

Liver cancer was diagnosed four weeks after starting DAA therapy in three patients, at week eight in three patients, week 12 in six patients, between week 12 and 24 in thirteen patients, and after treatment ended in sixteen patients. Fifty percent of patients who developed liver cancer developed a single nodular cancer with a typical vascular pattern, while 50 percent had a more aggressive pattern. Finally, 28 out of the 41 patients who developed cancer were successfully cured of HCV (reaching a sustained virological response at 12 weeks), while the remaining 13 relapsed.

In different analyses of the data, Dr. Alberti's team found elevated liver enzymes and low platelet count to be associated with liver cancer risk, while gender, age, HCV genotype and DAA regimen were not. The best baseline predictor of liver cancer risk was APRI scores (which calculate scarring in the liver). The researchers find the risk of developing liver cancer increased linearly by 10 percent at each one-point increase in APRI value.

"The results of this study, while confirming that DAAs treatment doesn't increase the overall risk of HCC, indicate that there is no pharmacological prevention of HCC even with successful antiviral therapy, at least during the first six to 12 months after initiation of treatment when microscopic and therefore initially invisible HCC foci might even be boosted in their growth as consequence of the profound immunological and molecular changes in the liver microenvironment following abrupt cessation of HCV replication," explains Dr. Alberti. "Therefore, it is mandatory that patients treated with DAAs with advanced liver disease should continue to be monitored for HCC."

This release contains updated data. Dr. Alberti will present these findings at AASLD's press conference in Room 313 at John B. Hynes Veterans Memorial Convention Center in Boston on Saturday, November 12 at 4pm. The study entitled "Incidence and pattern of "de novo" hepatocellular carcinoma in HCV patients treated with oral DAAs" will be presented by Antonietta Romano, MD in Ballroom A on Sunday, November 13 at 10am. The corresponding abstract (number 19) can be found in the journal, Hepatology – Special Issue: The 67th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2016.

View the slides @ NATAP Reported by Jules Levin
"Incidence and pattern of "de novo" hepatocellular carcinoma in HCV patients treated with oral DAAs"
Another look at both studies;  Incidence and pattern of `de novo` hepatocellular carcinoma in HCV patients treated with oral DAAs and The impact of sustained virological response to HCV infection on long term risk of hepatocellular carcinoma: the BC Hepatitis Testers Cohort.

Liver cancer risk reduced after hepatitis C treatment, but vigilance needed for aggressive cancers in months after treatment
Keith Alcorn
People who are cured of hepatitis C after a course of direct-acting antiviral treatment do not have a higher risk of developing liver cancer (hepatocellular carcinoma), and probably have a reduced risk, studies from Italy and Canada presented at The Liver Meeting this week in Boston have shown. However, Italian researchers also found that those people who did develop liver cancer during or shortly after antiviral treatment were more likely to develop an aggressive form of liver cancer, perhaps because of changes in immune surveillance in the liver as a result of treatment.

Patients With HCV And History Of Liver Cancer Who Treated With New Antivirals
As a reference point two studies presented in April at the International Liver Congress 2016 found; patients with a history of hepatocellular carcinoma have the highest risk of developing a tumor after direct-acting antiviral therapy, but new diagnoses were also reported. ​​Read the report; Liver Cancer Found in Hepatitis C Patients on New Antivirals provided below, or over at Medscape.

Liver Cancer Found in Hepatitis C Patients on New Antivirals
Kate Johnson
April 15, 2016
BARCELONA, Spain — In a surprising number of patients with hepatitis C and cirrhosis, hepatocellular carcinoma develops within weeks of starting treatment with direct-acting antivirals, new research suggests.

"I do not think that direct-acting antivirals are directly responsible," said lead investigator Stefano Brillanti, MD, from the University of Bologna, Italy.

"The hypothesis is that immune surveillance may be reduced too rapidly," he told Medscape Medical News. "You have an immediate drop in viremia, but also attenuation of inflammation. I think inflammation is a bad thing in terms of hepatitis progression, but it may be a good thing in terms of controlling cancer."

The study by Dr Brillanti's team, presented here at the International Liver Congress 2016, suggests that patients with hepatitis C should be closely monitored after treatment with direct-acting antivirals. Two days earlier, a study conducted by a team from the University of Barcelona in Spain suggested the same thing (J Hepatol. Published online April 12, 2016).

Both studies indicate that patients with a history of hepatocellular carcinoma have the highest risk of developing a tumor after direct-acting antiviral therapy, but new diagnoses were also reported.

The EMA has extended the scope of its review of the six direct-acting antivirals approved for use in the European Union for the treatment of chronic hepatitis  C infection to include the risk for early liver cancer recurrence, the agency reported.

Tumor Risk
"Patients with previous hepatocellular carcinoma are, of course, at risk of recurrence anyway," Dr Brillanti said. "A 30% rate over 3 years from initial surgery or ablation is normal. What was surprising to us was that we were observing 4 cm lesions after 12 weeks."

The retrospective cohort study involved 344 consecutive patients with hepatitis C and cirrhosis who were treated with one or two direct-acting antivirals and followed for 24 weeks after therapy. Median age was 63 years.
In this cohort, 237 patients were infected with hepatitis C genotype 1, 191 had received previous antiviral treatment, and 59 had been successfully treated for hepatocellular carcinoma.

Contrast-enhanced ultrasonography and CT scans or MRIs were performed at baseline to exclude active hepatocellular carcinoma, and then again 12 and 24 weeks after treatment.
During the follow-up period, 26 of the 344 patients (7.6%) were diagnosed with hepatocellular carcinoma. This included 17 of the 59 patients previously treated for hepatocellular carcinoma, and nine of the 285 patients (3.2%) with no history of carcinoma.

There was no association between recurrence and hepatitis C genotype, direct-acting antiviral regimen, or treatment response for patients who did not develop hepatocellular carcinoma or for those who did. The sustained viral response rate at 12 weeks was 89% in the two groups.
For patients with a history of hepatocellular carcinoma, those who developed a recurrence were significantly younger than those who did not (56 vs 73 years), were more frequently treatment-experienced (88.2% vs 61.9%), and had more advanced liver fibrosis at baseline.

More patients who developed hepatocellular carcinoma during the follow-up period, regardless of history, had advanced cirrhosis than those who did not, indicated by a Child-Pugh class B score (26.9% vs 10.1%; P =.02). They also had more liver stiffness, indicated by a measure above 21.3 Kpa (61.5% vs 31.8%; P = .005), and fewer platelets at baseline (102.3 vs 124.4 × 1000/mm³; P = .02).

Second Study
In the Spanish study, all 58 hepatitis C patients had a history of hepatocellular carcinoma (with complete radiologic response), and all but three were cirrhotic at the start of direct-acting antiviral therapy. After a median follow-up of 5.7 months, the rate of tumor recurrence was 27.6%, with a median time to recurrence of 3.5 months. The sustained viral response rate at 12 weeks was 97.5%.

In their publication, the Spanish authors note that these findings "raise a concern about the benefits" of direct-acting antiviral therapy in the subgroup of hepatitis C patients with a history of hepatocellular carcinoma. Although the therapies "offer a major hope for current and future patients, we may face a drawback that may change these predictions in specific groups of patients," they point out.

Dr Brillanti said he is less concerned. "Clones of the hepatocellular carcinoma were present before the therapy," he pointed out, suggesting that direct-acting antivirals simply accelerated their inevitable progression. Either way, he said, an increased risk for hepatocellular carcinoma should not deter clinicians or patients from pursuing treatment with direct-acting antivirals when it is needed.

"This is a different cancer than elsewhere in oncology — it is a cancer within an advanced chronic disease — so the prognosis, the life expectancy, is related not only to the liver cancer but also to the liver disease and liver function," he explained. "If you don't treat these patients and ameliorate their liver function, and if hepatocellular carcinoma occurs, you have no chance of curing them. But if you ameliorate liver function and they develop hepatocellular carcinoma, you can cure it better because their improved liver function will allow an ablation."

This finding is "quite striking and unexpected, but we have to be cautious," said Laurent Castera, MD, PhD, from Hôpital Beaujon in Clichy, France, who is vice-secretary of the European Association for the Study of the Liver, and was not involved with the research.

"It is potentially worrying, but these are retrospective studies, with possible referral bias, and no long-term follow-up," he told Medscape Medical News.

Dr Brillanti reports receiving research grants from Gilead Sciences and being on the advisory board for Janssen and Gilead Sciences. Dr Castera reports serving on the speaker's bureau for Echosens.
International Liver Congress (ILC) 2016: Abstract LBP506. Presented April 14, 2016.
Source - Medscape

Feb 2017
Of Interest - In The News
Risk of liver cancer low in patients with cirrhosis, study finds
01 Feb 2017
The results of a study by researchers at The University of Nottingham suggest that the risk of liver cancer in patients with cirrhosis may be much lower than previously thought.

Liver cancer – or hepatocellular carcinoma (HCC) – is one of the most serious complications of cirrhosis, or scarring of the liver, caused by long-term liver damage.

However, an analysis of health records, published in the academic journal Alimentary Pharmacology and Therapeutics, found that the 10-year incidence of HCC in UK patients with cirrhosis is actually only four per cent, or lower.

Joe West, Professor of Epidemiology in the University’s School of Medicine, led the study and believes that the results could better inform doctors on how best to focus resources for the benefit of patients with liver damage.

He said: “This very low incidence of HCC occurrence in people with cirrhosis caused by alcohol or of unknown origin suggests that surveillance for HCC among these groups is likely to benefit patients little.

“As surveillance incurs substantial cost, it is therefore unlikely to represent value for money for the NHS. There may well be other ways of spending this money that would benefit patients far more.”

Cirrhosis is caused by long-term damage to the liver, which leads to a build-up of scar tissue which replaces healthy tissue and eventually can result in liver failure.

The researchers identified more than 3,000 patients with cirrhosis of the liver using the UK’s General Practice Research Database between 1987 and 2006 and then cross-referenced this information with diagnoses of HCC on linked national cancer registries.

The study found that only 1.2 per cent of patients with alcoholic cirrhosis and 1.1 per cent of patients with cirrhosis of unknown cause will develop HCC within a decade. The highest 10-year incidence of HCC was among those with cirrhosis due to chronic viral hepatitis (four per cent).
http://www.nottingham.ac.uk/news/pressreleases/2017/january/risk-of-liver-cancer-low-in-patients-with-cirrhosis-study-finds.aspx

March 2017
Antiviral medication successful for treating HCV in hepatocellular carcinoma

Hepatocellular Carcinoma Decreases the Chance of Successful Hepatitis C Virus Therapy with Direct-Acting Antivirals
The new medications for hepatitis C have excellent cure rates. However, our study shows that in patients with both liver cancer and hepatitis C, they do not achieve these cure rates. Patients with liver cancer are almost 6 times more likely to fail hepatitis C treatment than patients without liver cancer

AGA Institute Clinical Practice Update: Care of Patients Who Have Achieved a Sustained Virologic Response (SVR) Following Antiviral Therapy for Chronic Hepatitis C Infection
Ira M. Jacobson M.D., Joseph K. Lim, M.D., and Michael W. Fried, M.D.
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DOI: http://dx.doi.org/10.1053/j.gastro.2017.03.018

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Abstract
Chronic hepatitis C virus (HCV) infection is well-recognized as a common blood borne infection with global public health impact, affecting 3 to 5 million persons in the U.S. and over 170 million persons worldwide. Chronic HCV infection is associated with significant morbidity and mortality due to complications of liver cirrhosis and hepatocellular carcinoma (HCC). Current therapies with all-oral directly acting antiviral agents (DAAs) are associated with high rates of sustained virologic response (SVR), generally exceeding 90%. SVR is associated with a reduced risk of liver cirrhosis, hepatic decompensation, need for liver transplantation, and both liver-related and all-cause mortality. However, a subset of patients who achieve SVR will remain at long-term risk for progression to cirrhosis, liver failure, HCC, and liver-related mortality. Limited evidence is available to guide clinicians on which post-SVR patients should be monitored versus discharged, how to monitor and with which tests, how frequently should monitoring occur, and for how long. In this clinical practice update, available evidence and expert opinion are used to generate best practice recommendations on the care of patients with chronic HCV who have achieved SVR.

Index
Assessment of HCV RNA after SVR12 has been attained
With the initiation of trials of DAA regimens, initially in combination with interferon and later without it, the attainment of SVR 12 weeks after completion of treatment replaced SVR24 as the primary endpoint, defined as undetectable HCV RNA on a highly sensitive PCR assay (lower limit of detection <12 IU/mL). This transition was based upon the rarity of relapse after follow up week 12, and it helped move the field ahead by shortening the intervals between successive trials in development programs (22). It has become apparent that late relapse beyond this time point is no more common, and perhaps less so, than it was after interferon-based therapy
Ongoing surveillance for hepatocellular carcinoma after SVR Is HCC risk after SVR exclusive to patients with advanced fibrosis and cirrhosis?
Can HCC surveillance ever be discontinued?
How should screening for, and management of, varices be affected by SVR?
Should patients be routinely monitored for regression of advanced fibrosis or
cirrhosis?
Recurrent HCC After SVR
Reinfection
Lifestyle Measures
Conclusions
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