Assessment of tumor response in patients receiving systemic and nonsurgical locoregional treatment of hepatocellular cancer
Executive Summary
This briefing document synthesizes the critical methodologies, challenges, and standards for assessing tumor response in patients with hepatocellular carcinoma (HCC) undergoing systemic and nonsurgical locoregional treatments. Accurate response evaluation is paramount for clinical management and as a surrogate endpoint for survival in clinical trials.
The central theme is the inadequacy of conventional, size-based tumor measurements (like RECIST) for evaluating the antitumor effects of modern HCC therapies. These treatments, particularly locoregional and targeted systemic agents, often induce tumor necrosis without an immediate change in lesion size. Consequently, response assessment has evolved to prioritize tumor viability, primarily identified through contrast enhancement on imaging, over simple dimensional changes.
Magnetic Resonance Imaging (MRI) is generally the preferred imaging modality over Computed Tomography (CT) due to its superior soft-tissue contrast resolution, sensitivity for post-treatment changes, and lack of ionizing radiation. Specific criteria have been developed to standardize this viability-based assessment, including the Modified RECIST (mRECIST) for HCC, which measures the diameter of the enhancing (viable) tumor, and the LI-RADS Treatment Response algorithm, used after locoregional therapies. For immunotherapy, specialized criteria like iRECIST are employed to account for unique response patterns such as pseudoprogression.
Emerging techniques like tumor markers (e.g., AFP), liquid biopsies (ctDNA), volumetric analysis, and functional imaging show promise for refining response assessment but are not yet standard clinical practice due to limitations in validation and standardization. Post-treatment surveillance involves a structured schedule of imaging, typically starting eight weeks after therapy and continuing at regular intervals, though timing may be adjusted for treatments with delayed responses, such as radiation therapy.
1. Overview of Hepatocellular Carcinoma and Treatment Approaches
Hepatocellular carcinoma (HCC) is an aggressive malignancy that frequently develops in the context of underlying liver disease, particularly cirrhosis. The primary factors determining a patient's prognosis and guiding treatment options are the tumor's mass and location, combined with the patient's hepatic reserve.
1.1. Treatment Algorithms
The management of HCC is stratified based on disease stage, liver function, and patient eligibility for various interventions.
Early-Stage HCC: The optimal treatment is surgical resection or liver transplantation.
Unresectable HCC: Patients with unresectable tumors who are not candidates for transplantation are typically managed with nonsurgical locoregional therapies. These therapies can also serve as a "bridging" or "downstaging" strategy to make a patient eligible for transplantation.
Advanced HCC: Systemic therapy is appropriate for patients with good performance status, adequate liver function, and disease that has spread beyond the liver (extrahepatic), is refractory to locoregional therapies, or involves extensive vascular invasion.
1.2. Nonsurgical and Systemic Therapies
A variety of nonsurgical and systemic treatments are available for patients who are not candidates for surgical resection.
Nonsurgical Locoregional Therapies:
Percutaneous Needle-Based Ablation: Includes techniques like radiofrequency ablation (RFA), microwave ablation, cryoablation, irreversible electroporation, percutaneous ethanol injection (PEI), and high-intensity focused ultrasound (US). These are most appropriate for one or two tumors that are no larger than 4 cm.
Arterially Directed Therapies: For patients not suited for ablation, these include transarterial chemoembolization (TACE), conventional drug-eluting bead TACE (DEB-TACE), radioembolization (also known as selective internal RT or SIRT), and bland embolization.
External Beam Radiation Therapy (RT): Approaches include photon irradiation, stereotactic body RT (SBRT), and charged particle irradiation (e.g., proton beam).
Systemic Therapies: These include immune checkpoint inhibitors and molecularly targeted agents. Key regimens mentioned are atezolizumab with bevacizumab, and sorafenib.
2. Techniques for Assessing Treatment Response
While pathological evaluation of tissue is the definitive gold standard for assessing treatment response, it is invasive and impractical for routine follow-up. Therefore, radiographic imaging serves as the primary noninvasive and robust method.
2.1. Imaging Modalities
Contrast-enhanced cross-sectional imaging with either CT or MRI is the cornerstone of response assessment.
2.2. Tumor Markers and Liquid Biopsy
Biomarkers can supplement imaging findings but have significant limitations.
Alpha-fetoprotein (AFP): In the subset of patients with elevated AFP at baseline, serial measurements can be useful. A decrease may indicate response, and elevations may precede radiographic evidence of progression. However, AFP levels are not elevated in up to 40% of patients with small HCCs (<2 cm).
Des-gamma-carboxy prothrombin (DCP): An alternative tumor marker, but available data does not consistently show it correlates with survival or adds value when AFP levels are monitored.
Plasma VEGF Levels: Investigated as a potential surrogate marker for benefit from sorafenib, but studies have yielded conflicting results.
Liquid Biopsy (ctDNA): Analysis of circulating tumor DNA shows potential for monitoring patients for recurrence after locoregional therapy. However, its clinical utility remains uncertain due to a lack of assay standardization and high risk of bias in existing studies.
3. Imaging Appearance and Interpretation of Treated HCC
The fundamental principle of post-treatment imaging is that the absence of contrast uptake within a tumor signifies necrosis and successful treatment, while the persistence or reappearance of enhancement indicates persistent or recurrent disease.
3.1. Response to Locoregional Therapy
Ablative Therapy (e.g., RFA): Successful ablation is defined by a nonenhancing zone that encompasses the entire tumor plus a safety margin of at least 5 mm. Residual or recurrent disease typically appears as nodular or irregular thickening at the periphery of the treated lesion.
Transarterial Chemoembolization (TACE): For conventional TACE using Lipiodol, complete retention of the iodized oil is highly correlated with complete necrosis. MRI with subtraction imaging is often superior to CT for assessing residual disease.
Radiation-Based Therapies (TARE/SIRT, SBRT): These treatments induce a delayed response. Tumor necrosis and shrinkage may not be evident for approximately 30 to 120 days. Therefore, the first assessment is typically performed at three months. Persistent arterial phase hyperenhancement can occur post-treatment and may be difficult to distinguish from viable tumor, though these changes often resolve after three months.
3.2. Response to Systemic Therapy
Molecularly Targeted Therapies (e.g., Sorafenib): Response can be challenging to evaluate as these agents may cause tumor necrosis without changing the overall size. An increase in tumor size due to necrosis, termed "pseudoprogression," has been reported. Therefore, quantifying necrosis/viability is more important than size measurement.
Immunotherapy: Patients may exhibit unique response patterns, including a transient worsening of disease (also called pseudoprogression) before stabilization or regression. Responses may take appreciably longer to appear compared to cytotoxic chemotherapy.
4. Standardized Criteria for Response Assessment
To overcome the limitations of simple size measurements, specialized criteria have been developed to incorporate tumor viability.
5. Guidelines for Post-Treatment Imaging and Surveillance
A structured imaging schedule is recommended to monitor for treatment response and disease recurrence.
Initial Post-Treatment Assessment:
For most systemic and nonsurgical locoregional therapies, the first cross-sectional imaging is performed approximately eight weeks after treatment initiation.
For radiation-based therapies (TARE, SBRT), the first assessment is delayed to three months to allow for a delayed tumor response.
Ongoing Monitoring:
Following the initial scan, imaging is continued every three months for at least the first year.
After the first year, imaging frequency is typically extended to every six months.
If there is no recurrence after two years, some institutions revert to standard HCC surveillance protocols (e.g., imaging with AFP assay every six months).
These recommendations are consistent with guidelines from major oncology networks like the European Association for the Study of the Liver (EASL) and the National Comprehensive Cancer Network (NCCN).
6. Future Trends in Response Assessment
Tumor Volume Measurement: Three-dimensional volumetric evaluation of the viable, enhancing tumor and its necrotic component is more accurate and reproducible than two-dimensional measurements. Although promising, especially for heterogeneous tumors, it has not yet been incorporated into standard response criteria.
Functional Imaging: Techniques that assess tumor biology—such as cellularity (DWI), vascularity (perfusion CT/MRI), and metabolism (FDG-PET)—can detect treatment-related changes earlier than anatomical imaging. While these modalities are promising, they have not yet been validated for routine clinical use in HCC response assessment.
