Neoplasms

All Conditions

Digestive System Diseases

Symptoms and General Pathology

Carcinoma

Carcinoma, Hepatocellular

Liver Cirrhosis

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Fibrosis

Hematinics

All Drugs and Chemicals

Coagulants

Liver Extracts

Thrombin

The control group will be composed of patients who will be candidates for HCC surveillance, i.e. those with liver cirrhosis or chronic hepatitis of any aetiology without HCC seen at our institution.

Included in this group are:

1. Patients newly enrolled and who will be tested for α-FP, α-FP-L3%, and DCP as part of their regular follow-up;
2. Patients who had previously given consent for the storage of a serum sample in the Biobank and who had authorized the dosage of α-FP, α-FP-L3% and DCP.

The case group will be composed of patients with newly diagnosed HCC in the context of cirrhosis or any other aetiology during the same study period. This group will include:

1. Patients newly enrolled and who will be tested for α-FP, α-FP-L3%, and DCP as part of their regular follow-up;
2. Patients who had previously given consent for the storage of a serum sample in the Biobank and who had authorized the dosage of α-FP, α-FP-L3% and DCP at the time of tumor diagnosis.

The simultaneous dosage of the 3 serum biomarkers will be performed at the Clinical Pathology Laboratory, using the instrument: µTASWakoTM i30 (Micro Total Analysis System) - Fujifilm.

Biomarker dosage

Endrit Shahini, MD

Raffaele Cozzolongo, MD

The objective of this observational study is to evaluate the clinical utility of the combined assay of 3 biomarkers: α-FP, α-FP-L3 and DCP (simultaneously measured by µTASWakoTM i30 automated in vitro diagnostic system) in high-risk subjects to develop this neoplasm.

In particular, it aims to:

* Evaluate the clinical utility of the combined use of α-FP, α-FP-L3 and DCP in predicting the onset of HEPATOCARCINOMA (HCC);
* Evaluate the performance of GALAD and GALADUS scores in the early diagnosis of HCC;
* Evaluate the association between the levels of the three biomarkers (individually and in combination with each other) and the stage of HCC

HCC occurs in 70-95% of cases in patients with chronic liver disease, rarely in a "healthy" liver. Globally about 80% of HCCs are associated with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and their geographical distribution closely correlates with their epidemiology. Approximately 1/3 of patients with liver cirrhosis will develop HCC in the long term, with an annual risk ranging from 1%-8%.

Chronic viral hepatitis C (CHC) and chronic viral hepatitis B (CHB) together with cirrhosis of the liver respectively represent the most important risk factors in Western and Eastern Europe and therefore prolonged surveillance and prevention is recommended in these patients.

Therefore, early diagnosis of HCC is of paramount importance to prolong overall survival. Today, only about 30% of patients in Europe are diagnosed at an early stage, where curative treatments are possible.

Patients with a history of chronic liver disease are at risk of developing HCC and for this reason should undergo a screening program aimed at the early diagnosis of HCC. Asymptomatic patients but with familial predisposition on a genetic basis, according to recent international guidelines, they must be monitored periodically.

Imaging (ultrasonography, CT, and MRI), biopsy with histological examination, and blood alpha-fetoprotein measurements are used in diagnostics and staging. However, current screening/surveillance tools are not perfect.

The most popular screening tools for HCC are as follows and are performed on a semi-annual basis:

1. Abdominal ultrasound: Abdominal ultrasound is the diagnostic tool of first choice, with a sensitivity of 48% (95%CI:34-62%) and a specificity of 97% (95%CI:95-98%) as emerges from a rigorous systematic review of 14 studies of 2524 cases.
2. Tumor markers: Alpha-fetoprotein (α-FP) is a specific tumor marker. Its diagnostic sensitivity of HCC is 25-60% while its specificity is 76-96%. An α-FP level above 400 ng/mL is strongly diagnostic, but approximately two-thirds of patients with HCC \<4 cm has α-FP levels \<200 ng/mL and also approximately 20% of HCCs do not produce α-FP. The carbohydrate chain of α-FP is modified by fucosyltransferase during HCC development to give rise to lectin-bound α-FP (α-FP-L3) (sensitivity:40-90%; specificity:\>90%) . The ratio of fucosylated α-FP to total α-FP is expressed as α-FP-L3%. Des-γ-carboxy-prothrombin (DCP or PIVKA-II) is an immature prothrombin, lacking carboxylation at various residues of glutamate (sensitivity: 48-62%; specificity: 81-98%). α-FP-L3 and DCP have been used routinely for 20 years in Japan. The combined use of these markers has increased the possibility of early detection of small HCCs. Prothrombin is formed after γ-carboxylation of vitamin K-dependent propeptides. DCP is produced due to an acquired post-translational defect in the carboxylase-vitamin K-dependent sequence of malignant cells.

   Thus, DCP production is not increased in chronic hepatitis or cirrhosis, making it a potential marker to be used in the diagnosis of HCC. However, DCP measurement has no prognostic value in cases of vitamin K deficiency or inhibition of vitamin K function (for example in subjects on TAO with dicumarols) since its synthesis is also induced by the absence of vitamin K causing false values positive. For this reason DCP is also known as PIVKA-II (protein induced in vitamin K absence). Notwithstanding these limitations, many studies have demonstrated that PIVKA-II has a high sensitivity and specificity compared to α-FP in differentiating HCC from other chronic liver diseases. Liebman et al. demonstrated that PIVKA-II can be used not only as a very specific marker for HCC but also as a prognostic factor of HCC patients. The sensitivity, specificity, and odds ratio in HCC \<5 cm is 0.14-0.54, 0.95-0.99, and 6.86-29.7, respectively, with a cut-off of 40mAU /ml, and 0.07-0.56, 0.72-1 and 3.56-3 with a cut-off of 100mAU/ml. In a large study of 270 HCC patients who all had serum α-FP levels below 20 ng/mL, the combined use of the biomarkers α-FP-L3 and DCP detected 49% of all HCC patients of size less than 2cm. Furthermore, α-FP-L3 measurements with the highly sensitive method before treatment were more useful for the diagnosis and prognosis of HCC than with the conventional method. More recently, the three markers (α-FP, α-FP-L3 and DCP) showed a sensitivity and specificity of 85% (n=304 HCC patients versus 403 controls) in the early diagnosis of HCC in a German cohort.
3. Second-level investigations are CT and MRI: Useful in confirming the diagnosis and staging the disease in order to set up the correct therapeutic procedure.

"Biomarkers of HCC and their clinical significance"

Ideally, the use of serum biomarkers with adequate sensitivity and specificity could allow early diagnosis of HCC by avoiding surveillance with ultrasonography. A number of serum biomarkers, other than α-fetoprotein (α-FP) have been included in some score systems for the prediction of HCC.

However, at present, none of the biomarkers have been validated in phase III clinical trials and are used in clinical practice, except for α-FP and DCP (or PIVKAII), which are recommended by the Japanese HCC guidelines. This can be explained by the high heterogeneity of HCC biology, where alterations of different biochemical pathways are involved in the tumourigenesis process. Indeed, patients with HCC show various patterns of positivity for biomarkers of HCC.

CLINICAL STUDY DESIGN As previously indicated, this is a retrospective and prospective observational study in which the biomarkers useful for evaluating the possible progression of chronic liver disease in HCC will be dosed in two groups, a "Case" group and a "Control" group.

The need to identify biomarkers useful for predicting the possible onset of HCC in patients with chronic liver disease arises from the fact that:

1. For the majority of patients, HCC is completely asymptomatic;
2. HCCs can only be symptomatic if large;
3. α-FP tumor marker is a specific tumor marker but its diagnostic sensitivity is reduced and also about 20% of HCCs do not produce α-FP;
4. Although α-FP is being diagnosed and screened as a specific and well-established tumor marker, there is a pressing need to use highly specific and new generation biomarkers to allow an even earlier and more accurate diagnosis in patients at risk ;
5. Several studies have demonstrated that α-FP-L3 and DCP are complementary and essential markers in the early detection of HCC;
6. The combined use of α-FP, α-FP-L3 and DCP with HCC surveillance could increase the chance of detecting HCC at an early stage;
7. The combined use of these three markers would provide: Greater clinical sensitivity and effective prognostic and predictive value for early recognition of HCC;
8. The GALAD score (and GALADUS) demonstrated the efficacy of these new biomarkers in HCC prevention and surveillance programs especially in patients with liver cirrhosis almost regardless of etiology.

The following will be enrolled in the study, after signing the informed consent:

1. Patients newly diagnosed with HCC (Case group)
2. Follow-up patients with viral, NASH and/or alcoholic cirrhosis who carry out HCC prevention programs at the Gastroenterology Department I of the IRCCS "Saverio de Bellis". (control group).

The study will last for two years, and it is expected to enroll at least 30 patients for each group.

Upon enrollment and after 6 months, at follow-up, the patients belonging to both groups will have a blood sample taken to proceed with the dosage of the biomarkers.

The control group will be composed of patients who will be candidates for HCC surveillance, i.e. those with liver cirrhosis or chronic hepatitis of any aetiology without HCC seen at our institution.

Included in this group are:

1. Patients newly enrolled and who will be tested for α-FP, α-FP-L3%, and DCP as part of their regular follow-up;
2. Patients who had previously given consent for the storage of a serum sample in the Biobank and who had authorized the dosage of α-FP, α-FP-L3% and DCP.

Control patients will be required to undergo a 6-month follow-up following GALAD score evaluation to confirm the absence of HCC. These patients should have a negative multiphasic contrast-enhanced CT, MRI, or liver biopsy at the time of GALAD score evaluation.

The case group will be composed of patients with newly diagnosed HCC in the context of cirrhosis or any other aetiology during the same study period. This group will include:

1. Patients newly enrolled and who will be tested for α-FP, α-FP-L3%, and DCP as part of their regular follow-up;
2. Patients who had previously given consent for the storage of a serum sample in the Biobank and who had authorized the dosage of α-FP, α-FP-L3% and DCP at the time of tumor diagnosis.

Any patients undergoing therapy with Warfarin, an anticoagulant, will be excluded since it can increase DCP levels in the absence of HCC, risking giving false positives.

Considering that the study foresees a follow-up of at least 6 months of the recruited subjects and therefore rather long times are envisaged for its completion, it is conceivable that some patients will be lost and that the initial population will decrease. For this reason, recruitment will proceed throughout the study.

Use of Blood Biomarkers for the Early Diagnosis of Hepatocellular Carcinoma (HCC)

Determine the GALAD alghoritm (Gender,Age, AFP-L3, AFP and Des-carboxy-prothrombin) by evaluating the values of AFP, AFP-L3, Des-carboxy-prothrombin for each patient, since the GALAD score had a high diagnostic performance as compared to each standalone markers in identifying HCC at any stage.

Dr. Raffaele Cozzolongo

Dr. Palma Aurelia Iacovazzi

Dr. Vito Giannuzzi

Dr. Francesco Losito

Dr. Marianna Zappimbulso

Azienda Ospedaliera Specializzata in Gastroenterologia Saverio de Bellis

Principal Investigator

Infections

Hepatitis A

Hepatitis C

Hepatitis

End Stage Liver Disease

Communicable Diseases

Blood-Borne Infections

Hepatitis, Viral, Human

Virus Diseases

Flaviviridae Infections

RNA Virus Infections

Hepatic Insufficiency

Liver Failure

Triphasic CT of the abdomen with and without contrast every 12 months with alpha-fetoprotein every 6 months.

Ultrasound of the upper left quadrant with alpha-fetoprotein testing every 6 months.

Triphasic CT of the abdomen with and without contrast every 12 months and alpha-fetoprotein testing every 6 months. Repeated until HCC diagnosed for up to 10 years.

Ultrasound of the upper left quadrant every 6 months with alpha-fetoprotein testing every 6 months. Repeated until HCC diagnosed for up to 10 years.

Screening

Christine Pocha, MD, PhD

Kelly A McMaken, MPH

Kelly McMaken, MPH

The purpose of this study is to determine whether ultrasound or CT scanning is more effective at detecting early liver cancer in patients with advanced liver disease.

Most cases of hepatocellular carcinoma (HCC) arise in patients with advanced liver disease, usually cirrhosis. Most patients with clinically evident HCC are not candidates for treatment with curative intent because of large tumor size, invasion of hepatic or portal veins, or metastatic disease. For this reason, screening for HCC at an asymptomatic and potentially curable stage in patients with advanced liver disease has been recommended by some authorities. Screening with various methods, of which ultrasound (US) and alpha-fetoprotein (AFP) have been the most extensively studied, has become accepted practice. Recently the technique of imaging the liver with or during both the hepatic arterial and portal venous phases of intravenous contrast ("liver-shuttle") has shown increased sensitivity in detecting HCCs compared to US.

The hypothesis of this study is that CT using a "liver-shuttle" protocol once a year is more sensitive and specific than US twice a year, both in combination with AFP for identification of potentially curable HCC in patients with cirrhosis. Patients will be randomized to "routine," accepted screening with hepatic US and AFP testing every 6 months or AFP testing every 6 months wtih triphasic CT every 12 months.

Screening for Liver Cancer With CT vs. Ultrasound in Patients With Advanced Liver Disease

Screening for Hepatocellular Carcinoma With Triphasic Helical CT vs. US With Alpha-fetoprotein in Patients With Advanced Liver Disease

Confirmed diagnosis of hepatocellular carcinoma by biopsy or imaging according according to BCLC recommendations

Cost of each screening protocol to identify one very early/early stage HCC

Minneapolis Veterans Affairs Medical Center

Christine Pocha/Staff Physician

Hepatitis B

Hepadnaviridae Infections

DNA Virus Infections

Participants in this arm will undergo current standard of care surveillance procedures i.e. liver ultrasound with or without alpha fetoprotein (AFP) measurement.

For participants in this arm, study team will order GALAD measurement every 6 months +/- 3 months.

GALAD is a 3 biomarker panel incorporating AFP, AFP-L3% and DCP (all FDA approved), with patient age and sex.

GALAD

This intervention consists of current standard of care ultrasound based surveillance with or without alpha-fetoprotein measurement.

Liver Ultrasound with or without AFP

Amit Singal, MD, MS

Sneha Deodhar, MS

Kali Zhou, MD

Rae Davis

Neil Mehta, MD

Sherri Cummins

Naga Chalasani, MD

Irun Bhan, MD

Shay Robison

Neehar Parikh, MD, MS

Jessica Peruski

Reena Salgia, MD

Dibnain Nanda

Sanjaya Satapathy, MBBS, MS

Grace Kim

Jorge Marrero, MD,MS

Sara Fares

Fasiha Kanwal, MD, MSHS

The National Liver Cancer Screening Trial is an adaptive randomized phase IV Trial comparing ultrasound-based versus biomarker-based screening in 5500 patients with cirrhosis from any etiology or patients with chronic hepatitis B infection. Eligible patients will be randomized in a 1:1 fashion to Arm A using semi-annual ultrasound and AFP-based screening or Arm B using semi-annual screening using GALAD alone. Randomization will be stratified by sex, enrolling site, Child Pugh class (A vs. B), and HCC etiology (viral vs. non-viral). Patients will be recruited from 15 sites (mix of tertiary care and large community health systems) over a 3-year period, and the primary endpoint of the phase IV trial, reduction in late-stage HCC, will be assessed after 5.5 years.

The TRACER phase IV biomarker study is a randomized trial comparing ultrasound-based screening versus a biomarker-based strategy in patients with cirrhosis. In brief, 5500 patients with cirrhosis from any etiology would be randomized in a 1:1 fashion to Arm A offering semi-annual ultrasound +/- AFP-based screening or Arm B offering semi-annual biomarker-based screening. Randomization will be stratified by site, Child Pugh class (A vs. B), liver disease etiology (viral, non-viral, and non-cirrhotic HBV infection) and sex. Patients will be recruited from 15 sites (mix of tertiary care and large community health systems) over a 3-year period, and reduction in the proportion of late-stage HCC, will be assessed at the end of Year 5.5. If the results are promising, study team will continue extended follow-up and compare the incidence of late-stage HCC between the two arms at Year 8 and reduction in HCC mortality during long term follow up.

Study team will include adult patients, age ≥ 18 years, with Child Pugh class A or B cirrhosis of any etiology or non-cirrhotic chronic hepatitis B virus infection with PAGE-B score \>9. Study team will exclude patients post liver transplantation, patients with Child Pugh C cirrhosis, patients with significant comorbidity and limited life expectancy, and those with history of other malignancy, except non-melanoma skin cancer or indolent tumors, within 3 years prior to enrollment given lack of screening recommendations in those patient populations. Study team will also exclude patients with suspicious liver masses at baseline as well as those with a solid lesion ≥1 cm on ultrasound or AFP ≥20 ng/mL without diagnostic evaluation to exclude HCC. Study team will also exclude patients in whom the provider plans to follow the patient with CT or MRI-based surveillance. GALAD is not recommended in patients with pregnancy or active warfarin use given known impact on biomarker performance, so these patients will be excluded.

At enrollment, study team will record patient demographics and clinical characteristics using a combination of electronic medical records and patient questionnaires. Patients will then be offered semi-annual surveillance as defined by their study arm: ultrasound and AFP for patients in Arm A and the biomarker, GALAD, for patients in Arm B. Repeat surveillance tests will be offered every six months (per assigned arm) for patients with normal surveillance results. Diagnostic evaluation with multi-phasic CT or contrast-enhanced MRI will be recommended for any patients with abnormal screening results. Patients with normal diagnostic testing (i.e., false positive result) will be recommended to return to their assigned surveillance arm. Standardized criteria from the AASLD and LI-RADS will be used to define incident HCC. Study team will use a set of validated surveys (e.g., Psychological Consequences Questionnaire, Decision Regret scale, FACIT-COST) to measure secondary outcomes of interest including psychological and financial harms.

This is a randomized open-label study comparing US ± AFP vs. GALAD-based surveillance every 6 (± 3-month window) months starting at randomization.

National Liver Cancer Screening Trial

Proportion of HCC detected at a late stage, defined as HCC beyond Milan Criteria (one tumor less than or equal to 5 cm or 2-3 tumors each less than or equal to 3 cm, in the absence of vascular invasion or extra-hepatic metastases)

Defined as proportion time covered by screening; each completed screening test (US +/- AFP or GALAD) will provide up to six months of coverage (numerator) divided by the total follow-up for each patient.

Defined as HCC beyond BCLC stage A (single tumor of any size without vascular invasion or extrahepatic spread; or 2-3 tumors equal to or less than 3 cm each, without vascular invasion or extrahepatic spread)

Defined as incidence of HCC (extended follow-up) beyond Milan Criteria or BCLC stage A

Defined as count of participants in receipt of liver transplantation, surgical resection, local ablative therapy, or radiation segmentectomy

Physical harms will be defined as count of participants in receipt of diagnostic imaging for false positive or indeterminate results.

Financial harms will be defined by direct costs (charges for all screening and diagnostic testing and co-pays) and indirect costs (e.g., travel and lost wages)

Count of participants who encountered Psychological harms that includes cancer-specific worry and decisional regret.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Use of Blood Biomarkers for the Early Diagnosis of Hepatocellular Carcinoma (HCC)	NCT05781568	HCC Cirrhosis, Live... NAFLD HBV HCV	Biomarker dosag...	-	Azienda Ospedaliera Specializzata in Gastroenterologia Saverio de Bellis
Use of Blood Biomarkers for the Early Diagnosis of Hepatocellular Carcinoma (HCC)	NCT05781568	HCC Cirrhosis, Live... NAFLD HBV HCV	Biomarker dosag...	-	Azienda Ospedaliera Specializzata in Gastroenterologia Saverio de Bellis
Screening for Liver Cancer With CT vs. Ultrasound in Patients With Advanced Liver Disease	NCT01350167	Cirrhosis End Stage Liver... Hepatitis C	Screening	18 Years -	Minneapolis Veterans Affairs Medical Center
Screening for Liver Cancer With CT vs. Ultrasound in Patients With Advanced Liver Disease	NCT01350167	Cirrhosis End Stage Liver... Hepatitis C	Screening	18 Years -	Minneapolis Veterans Affairs Medical Center
National Liver Cancer Screening Trial	NCT06084234	Carcinoma, Hepa... Liver Cancer Liver Cirrhosis Hepatitis B	GALAD Liver Ultrasoun...	18 Years - 85 Years	University of Texas Southwestern Medical Center
Screening for Liver Cancer With CT vs. Ultrasound in Patients With Advanced Liver Disease	NCT01350167	Cirrhosis End Stage Liver... Hepatitis C	Screening	18 Years -	Minneapolis Veterans Affairs Medical Center

Spots Global Cancer Trial Database for alpha fetoprotein