Barcelona Clinic Liver Cancer (BCLC) Stage A, B or C HCC
Conditions
Keywords
HCC
Brief summary
This proposal describes a non-therapeutic diagnostic clinical trial to estimate the ability of DNP-MRS imaging of hyperpolarized 1-13C-pyruvate uptake and metabolism to predict response following LRT with TACE/TARE/Microwave Ablation or ST in patients with Barcelona Clinic Liver Cancer (BCLC) stage A, B or C HCC. The primary hypothesis is that intratumoral pyruvate, lactate, alanine and carbon dioxide/bicarbonate measured by DNP-MRSI correspond to cellular viability resulting from recurrent or progressive HCC following LRT or ST. The secondary hypothesis is that lactate-to-alanine ratios measured by DNP-MRSI can distinguish well- vs. poorly perfused tumor regions as identified on contrast-enhanced MR imaging.
Detailed description
Hepatocellular carcinoma (HCC) is the most rapidly increasing cause of cancer mortality in the United States (US)1. HCC is a notoriously chemo-resistant malignancy. Surgical resection or liver transplantation remain the therapies of choice; however, fewer than 20% of HCC patients are candidates for resection, and transplantation rates are limited both by a static donor pool and HCC progression which precludes eligibility. Locoregional therapies for HCC include (i) trans-arterial chemoembolization (TACE), an endovascular locoregional embolotherapy that involves hepatic artery embolization with intra-arterial infusion of a chemotherapeutic agent, (ii) trans-arterial radioembolization (TARE), an endovascular locoregional embolotherapy that involves hepatic artery embolization with intra-arterial infusion of a non-absorbable microspheres containing the radioactive material yttrium-90 (Y90) and (iii) microwave ablation, a percutaneous therapy that targets tumor cells using thermal energy. Together with systemic therapies (ST), these approaches represent the most commonly used treatments for HCC in the United States. While these therapies have a proven survival benefit, local recurrence and progressive disease are common, and long-term survival rates are poor even following a complete radiographic response (49% over median follow-up of 72 months), due at least in part, to suboptimal measures of response. Conventional imaging approaches have been unsuccessful in providing representative measures of response that are essential for guiding locoregional and systemic therapies for HCC. These approaches apply established guidelines for measurements provided by anatomic imaging, such as tumor size, and were originally intended to allow a uniform response assessment following conventional chemotherapeutics. The general inability of these guidelines to characterize the response to LRT or systemic therapy underscores fundamental limitations in the applied imaging paradigms which fail to provide functional measures of the intended therapeutic effect or the associated tumor response. This challenge requires the development of new imaging paradigms applying knowledge of the underlying tumor biology to enable the detection of treatment refractory, viable tumor domains.
Interventions
DRUGHyperpolarized 1-13C -Pyruvate
The 1-13C pyruvate dose for each DNP-MRSI session is approximately 0.43ml/kg of 250mM (approximate range for all studies is anticipated to be between 185-285 mM) of hyperpolarized 1-13C-pyruvate (11.9 mg/kg).
Sponsors
Abramson Cancer Center at Penn Medicine
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female, aged ≥ 18 years 2. At least one HCC tumor meeting criteria for diagnosis of BCLC A, B or C HCC based on cross-sectional imaging as determined by a board-certified, sub-specialty trained radiologist 3. Baseline systolic blood pressure \>90 mmHg or \<180 mmHg 4. Signed and dated informed consent form 5. Willingness to comply with all study procedures and availability for the duration of the study
Exclusion criteria
1. Females who are pregnant or breast feeding at the time of screening will not be eligible for this study. Females who are breast feeding are excluded because breast feeding is not recommended during the therapies which are included in the inclusion criteria for this study. For females with childbearing potential, a serum or urine pregnancy test will be performed within 1 day prior to the injection of \[1-13C\]-pyruvate in women of child-bearing potential. A lack of childbearing potential is defined as A) ≥50 years old, without menstrual activity for \>12 consecutive months, or B) Surgical sterilizations other than only tubal ligation. Females who do not meet the criteria defined in A, but have had tubal ligation, must still undergo pregnancy testing. Patient self-reporting the use of contraception, abstinence or same-sex partnership does not replace the need for pregnancy testing in women of childbearing potential 2. Prior LRT or systemic cancer therapy to the target lesion 3. Contraindication to MRI including prior MRI contrast reaction 4. Metallic implant within the liver 5. Inability to tolerate imaging procedures in the opinion of an investigator or treating physician including but not limited to the inability to lie still in the magnet for 1 hour and/or cooperate with breath holding instructions 6. Serious or unstable medical or psychological conditions that, in the opinion of the investigator, would compromise the subject's safety or successful participation in the study 7. Baseline systolic blood pressure \<90 mmHg or \>180 mmHg, or symptomatic orthostatic hypotension, measured within 1 hour prior to injection of hyperpolarized 1-13C-pyruvate 8. Congestive heart failure with New York Heart Association (NYHA) status ≥2 9. A history of clinically significant EKG abnormalities, including QT prolongation, a family history of prolonged QT interval syndrome, or myocardial infarction (MI) within 6 months of study entry 10. Decompensated cirrhosis (Child-Pugh C) 11. Estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73 m2 within 28 days prior to contrast-enhanced MRI, unless patient is already on chronic dialysis 12. Current use of high-dose beta-adrenergic antagonists (e.g., propranolol \> 160 mg/day, metoprolol \>200 mg/day, as these medications may impair compensatory tachycardia in response to pyruvate-induced vasodilation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Objective: | 5 Years | To estimate the accuracy of metabolic imaging using DNP-MRS imaging of hyperpolarized 1-13C-pyruvate uptake and metabolism for (i) predicting time to recurrence of HCC in patients following LRT or systemic therapy as determined by mRECIST criteria applied to standard-of- care (SOC) imaging. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Secondary Objective: | 5 Years | To measure alterations in metabolism of hyperpolarized 1-13C-pyruvate uptake and metabolism to 1-13C-lactate, 1- 13C-alanine and/or 13C-carbon dioxide/bicarbonate in enhancing and non- enhancing regions of tumor following LRT and ST. |
Contacts
CONTACTTerence Gade, MD, PhD
CONTACTJelsia Cottone
Outcome results
None listed