HepQuant: Study to Assess the Role of Blood-based Biomarkers and Quantitative MR Imaging for Patients Receiving Radiation Therapy for Liver Cancer

This is a pilot and feasibility study assessing the role of quantitative multiparametric MRI and blood-based biomarkers for the measurement of liver function in patients receiving radiation therapy for liver cancer, including hepatocellular carcinoma (HCC), cholangiocarcinoma, or liver metastases regardless of primary histology, that are undergoing photon radiation either in the de-novo or re-irradiation setting. The goal of this study is to prospectively evaluate the feasibility of using quantitative multiparametric MRI to monitor liver function at baseline and following liver radiation therapy.

Historically, the role of fractionated liver radiation therapy (RT) has been limited because of the potential for developing fatal radiation-induced liver disease (RILD), particularly in patients who already have poor liver function due to cirrhosis. Classic RILD generally occurs within 4 months following radiotherapy to the liver and consists of symptoms including fatigue, right upper quadrant pain, ascites, anicteric hepatomegaly, and elevation of liver enzymes especially alkaline phosphatase.

Technical advances in the delivery of RT, particularly using stereotactic body radiotherapy (SBRT) and proton therapy with respiratory gating and image guidance, have facilitated the safe use of radiation dose escalation in unresectable liver cancers. SBRT is a promising and attractive option for HCC patients with cirrhosis. Previous reported experiences have been largely kept to Child-Pugh (CP) A patients with significant liver reserves. The 1 to 2-year local control rate for CP A patients with early-stage tumor have generally been reported around 80-90%. Toxicities rates have also been acceptable with no classic RILD or grade 4 or 5 treatment related toxicities seen 3 months after SBRT. This impressive toxicity result is likely due to keeping with strict dosimetric constraints for the normal liver tissue. Dosimetric parameters reported in literature indicated mean liver disease (MLD) and V20 to be a significant predictor of RILD and elevated liver enzymes in CP A patients with primary HCC.

While there are no overt liver toxicities in CP A patients with primary liver cancer, 10 to 30% of patients will experience a decline in liver function 3 months after SBRT even without disease progression based on the referenced literature. Pre-treatment CP A6 has an increased risk of liver function decline when compared to CP A5. In addition, the tumor volume was also a significant predictor of liver function decline after SBRT.

Patients with CP B or C and primary HCC are more likely to experience liver toxicities as defined by worsening liver function. Dosimetric parameters to predict for fatal RILD for this group has also remained elusive. Yet, it is this particular group of patients that have the worst outcome due to limited treatment options as a result of poor liver reserve to tolerate currently available treatments. The median survival for patients with Child-Pugh B or C HCC treated with best supportive care or sorafenib is approximately 4-5 months according to the literature. Limited institutional experiences have shown that local treatment of these patients with SBRT can potentially improve survival; however, this also comes at a cost of significant potential toxicity. Current reported data are limited, but they do show that patients can experience liver function decline as early as 3 months.

The published experience with SBRT in the treatment of HCC clearly demonstrates a relationship of the underlying degree of hepatic impairment to risk for liver toxicity. However, the data also clearly demonstrate that CP class or score is insufficient to define risk or to monitor treatment effects. The proposed study will use blood-based biomarkers coupled with quantitative imaging (LiverMultiScan™) to fully characterize the effect of SBRT on the liver and the liver cancer.

In vivo Multiparametric MR imaging (mpMRI) is well established at quantifying measures of liver health in patients with liver disease and pre-clinical models of liver disease. In patients with pre-existing/co-existing parenchymal liver disease and liver tumors (primary or secondary), mpMRI can be used to assess the health of the parenchyma and the anatomical and tissue characteristics of the tumor. This allows for decision-making to be based on the health of the liver and the resectability of the tumor. Initial data suggests that this approach can predict which operations will carry higher risk and cost, measured by length of stay in hospital after surgery.

A more sensitive laboratory measure that is currently available in the U.S. as a Laboratory Developed Test (LDT) to measure liver function and will be used in this study as an investigational assay, is the HepQuant DuO test. It measures cholate hepatic uptake from portal circulation and estimates hepatic uptake from systemic circulation to calculate degree of portosystemic shunting as well as hepatic function using the disease severity index (DSI). Both of these measures have been shown to correlate with severity of chronic liver disease and in studies detected and measured the severity and progression of disease and the response to treatments. The HepQuant DuO test is done by oral administration of unconjugated cholate and collection of two serum samples up to 60 minutes after administration. HepQuant DuO may offer a unique capability to assesses liver functional impairment across the spectrum of injury and fibrosis in patients undergoing radiation therapy to better predict clinical outcomes and risk of liver function deterioration.

Eligibility Criteria:
The following criteria must be met for subjects to be considered for the trial. Additional exclusion criteria must be met for subjects interested in the HepQuant subset of the trial. The first 20 qualifying subjects will be enrolled for the additional HepQuant test.

Inclusion Criteria:

* Age \> 18
* Patient has the psychological ability and general health needed to provide informed consent, completion of study requirements, and required follow-up
* Patient provides study-specific informed consent prior to study entry
* All primary histologies (Hepatocellular carcinoma or Cholangiocarcinoma) as well as hepatic metastases are eligible
* Prior history of radiation therapy (external beam or radioembolization) is allowed, with no limit to the number of prior courses of radiation therapy
* Any number of lesions (with no size limit) of pathologically documented (histologically or cytologically) or radiographically proven tumor/metastasis that are being targeted
* Prior history of liver resection, transarterial chemoembolization (TACE), or ablation are allowed with no restriction on number of prior therapies, or time from current study registration
* Prior history of chemotherapy, immunotherapy, or targeted biological therapy is allowed
* Concurrent enrollment on other prospective registry or treatment intention trials is allowed

Exclusion Criteria:

* Pregnant or breast-feeding females
* Subjects with history of claustrophobia impacting ability to perform MRI during the study
* Subjects who fulfill any of the contraindications for MRI; examples include any ferromagnetic material, any metallic shrapnel or fragments or implanted electronic devices contained within the body or metal-containing tattoos
* Unable to participate in MR assessments due to physical limitations of equipment tolerances (MRI bore size and/or weight limit)
* Any person unable to lie still within the environment of the MRI scanner or maintain a breath hold for the required period to acquire images

Exclusion criteria for HepQuant SHUNT DuO testing ONLY:

* Known history or suspected hypersensitivity to human serum albumin, or its preparations
* Subjects with extensive resection of large segments of small intestine (short gut) or severe gastroparesis (e.g., diabetic or medication-induced gastroparesis)
* Subjects on either a non-selective beta blocker (propranolol, nadolol), or an angiotensin converting enzyme (ACE) inhibitor, or angiotensin receptor blocker (ARB) who are unwilling or unable to delay taking their normal dose the morning of their testing
* Subjects who are allergic to any ingredient in the formulations or components in the HepQuant SHUNT DuO kit including the human serum albumin (HSA) or cholate compounds (theoretical - none yet reported)
* Subjects unwilling or unable to fast for at least 5 hours. Fasting means no intake of food or food supplements, including fiber preparations or biosimilars; or any preparations or resins (cholestyramine, colestipol, colesevelam) that might act within the gut lumen to bind the orally administered d4-cholate in the HepQuant test.