About Hepatocellular Carcinoma, in terms of treatments and its clinical trials

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and ranks among the top causes of cancer-related deaths. The current treatment options for HCC include the following:

1. Surgical Resection and Liver Transplantation

In the early stages of HCC, complete surgical resection is often possible. Liver transplantation is a suitable treatment for patients with liver function impairment, as it is the only way to completely remove the tumor and restore liver function.

2. Local Therapies

Local therapies include Radiofrequency Ablation (RFA), Transarterial Chemoembolization (TACE), radiation therapy, and others. These treatments are effective for patients with good liver function and small tumors.

3. Systemic Therapy

For advanced HCC or cases where surgery is not feasible, systemic therapy is primarily used. Systemic therapies include:

• Multi-kinase Inhibitors: Sorafenib and Lenvatinib are major multi-kinase inhibitors used in HCC treatment. They inhibit tumor angiogenesis and block the growth of cancer cells.
• Immunotherapy: Recent advances in immunotherapy, especially combinations of PD-1 or PD-L1 inhibitors (e.g., Nivolumab, Pembrolizumab) and CTLA-4 inhibitors (e.g., Tremelimumab), have shown efficacy in clinical trials.

Surgical consideration

Determining whether a patient has advanced HCC or is not suitable for surgery involves considering several factors. The key factors determining this include:

1. Tumor Stage and Size

The size, number, and location of tumors are critical in assessing surgical feasibility. For example, multiple tumors or tumors close to major blood vessels may make surgery difficult or impossible.

2. Liver Function

Liver function is assessed using the Child-Pugh classification system. Severe liver dysfunction (e.g., Child-Pugh class C) often makes surgery risky.

3. Presence of Metastasis

If there is evidence of cancer spreading beyond the liver (e.g., to the lungs or bones), the disease is considered advanced, and surgery is typically not considered.

4. Overall Health of the Patient

The patient’s age, presence of other concurrent illnesses (e.g., heart disease, diabetes), and overall health status can influence the risks associated with surgery and the patient’s ability to recover.

5. Imaging Diagnosis

CT scans, MRI, ultrasound, and other imaging tools are used to evaluate the location, size, number, and relationship of the tumor to surrounding structures.

6. Biopsy and Pathological Evaluation

Pathological evaluation of tissue samples obtained through biopsy helps determine the nature of the tumor and the type of cancer cells involved.

Clasification of HCC

The Child-Pugh classification system is a widely used method for assessing the severity of chronic liver disease. This classification predicts the prognosis of patients with cirrhosis and aids in determining treatment plans based on the severity of liver disease. The Child-Pugh score is based on five clinical and laboratory criteria:

1. Total Bilirubin Level

• Below normal upper limit
• 1-2 times normal upper limit
• More than 2 times normal upper limit

2. Albumin Level

• Above normal level
• 3.5-2.8 g/dL
• Below 2.8 g/dL

3. INR (International Normalized Ratio)

• Below normal upper limit
• 1.7-2.3
• Above 2.3

4. Ascites (Fluid Accumulation in the Abdomen)

• Absent
• Slight or controlled with medication
• Severe ascites unresponsive to treatment

5. Hepatic Encephalopathy (Brain Dysfunction Due to Liver Disease)

• Absent
• Grade 1-2 (manageable with medication)
• Grade 3-4 (unresponsive to treatment)

Each criterion is scored as 1 point (best condition), 2 points (intermediate condition), or 3 points (worst condition). These scores are summed to calculate the total score, which is then used to classify patients into Child-Pugh categories A, B, or C.

Child-Pugh A: 5-6 points (best prognosis)
Child-Pugh B: 7-9 points (moderate)
Child-Pugh C: 10-15 points (worst prognosis)

The Child-Pugh classification reflects the degree of liver dysfunction and prognosis of the patient, particularly when planning treatments for patients with cirrhosis. For example, it is used to assess the suitability of surgery, liver transplantation, and specific drug treatments.

The Barcelona Clinic Liver Cancer Staging System (BCLC) is one of the key frameworks for the diagnosis and treatment of hepatocellular carcinoma (HCC). This classification system is widely used to evaluate the diagnosis, prognosis, and treatment decisions for HCC, considering liver function, tumor characteristics, the patient’s overall health, and the presence of symptoms comprehensively.

BCLC Stage Descriptions:

Stage 0: Very Early Stage

• Single tumor, size ≤2 cm.
• Treatment options: Surgical resection, Radiofrequency Ablation (RFA), or liver transplantation.

Stage A: Early Stage

• Single tumor or up to 3 small tumors (each ≤3 cm).
• Treatment options: Surgical resection, RFA, Transarterial Chemoembolization (TACE), or liver transplantation.

Stage B: Intermediate Stage

• Multiple large tumors without vascular invasion.
• Treatment options: Primarily TACE.

Stage C: Advanced Stage

• Tumors with vascular invasion or metastasis.
• Treatment options: Systemic therapy (e.g., Sorafenib, Lenvatinib, immunotherapy).

Stage D: End Stage

• Severe liver function impairment (Child-Pugh C) and/or poor overall health.
• Treatment options: Primarily symptom relief and supportive care.

The Importance of BCLC:

The BCLC system plays a crucial role in determining appropriate treatment strategies for HCC patients. This system takes into account liver function, tumor characteristics, patient symptoms, and overall health, enabling the development of personalized treatment plans for individual patients. Additionally, it serves as a standardized patient classification method in clinical research, facilitating the comparison and generalization of research results.

Main treatment options

• Ablation: This procedure aims to destroy HCC tumors by either heating or cooling them or coagulating them. It is primarily used for small-sized tumors or when the patient is not suitable for surgery. Ablation methods include Radiofrequency Ablation (RFA), Microwave Ablation (MWA), and Ethanol Ablation, among others.

• Resection: Surgical resection is a procedure to completely remove HCC tumors within the liver through surgery. It can be considered depending on the size and location of the tumor and if the patient is a candidate for surgery.

• Transplantation: Liver transplantation is considered for advanced HCC patients when the tumor is within certain limits, and a liver transplant is necessary. It is one of the life-saving treatment options for patients with hepatocellular carcinoma.

• Chemoembolization: Transarterial Chemoembolization (TACE) is a procedure that blocks the blood vessels supplying the tumor and delivers anticancer drugs directly to the tumor area. It is used for advanced HCC patients to reduce and control tumor size.

• Systemic Therapy: Systemic therapy is considered when the tumor has progressed within the liver or when the patient’s condition is not suitable for surgery or other local treatments. This usually involves the administration of chemotherapy or immunotherapy. Recently, combination therapies involving immunotherapy and multi-kinase inhibitors have been researched.

The choice of these treatment options depends on the characteristics of the HCC tumor, the overall health of the patient, the stage of tumor progression, and other factors. Decisions about tumor management should be made in consultation with HCC specialists, taking into account the individual patient’s situation.

Drugs for system treatment

PD-1 (Programmed Death-1), PD-L1 (Programmed Death-Ligand 1), multi-kinase inhibitors, VEGF (Vascular Endothelial Growth Factor), and CTLA-4 (Cytotoxic T-Lymphocyte-Associated protein 4) inhibitors are drugs that play a crucial role in the treatment of various types of cancers, including hepatocellular carcinoma (HCC).

PD-1/PD-L1 Inhibitors

• Nivolumab: Used in various cancer types, including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, and hepatocellular carcinoma (HCC).
• Pembrolizumab: Targets PD-1 and is used in a wide range of cancer types.
• Atezolizumab: Targets PD-L1 and is primarily used in the treatment of NSCLC and bladder cancer.
• Durvalumab: A PD-L1 inhibitor used in the treatment of NSCLC and bladder cancer.

Multi-Kinase Inhibitors

• Sorafenib: Used in the treatment of HCC and renal cell carcinoma. It inhibits the growth of tumor cells and angiogenesis.
• Lenvatinib: Used in the treatment of HCC, renal cell carcinoma, and thyroid cancer. It targets the VEGF pathway.

VEGF Inhibitors

• Bevacizumab: Targets VEGF and is used in colorectal cancer, lung cancer, renal cell carcinoma, and cervical cancer.
• Ramucirumab: Used in the treatment of gastric cancer and NSCLC. It targets VEGF receptor 2.

CTLA-4 Inhibitors

• Ipilimumab: Used in the treatment of melanoma, it enhances immune response by increasing T-cell activation.
• Tremelimumab: Targets CTLA-4 and is currently in clinical trials for various cancer types, including hepatocellular carcinoma.

These drugs play a crucial role in inhibiting cancer cell growth, metastasis, and angiogenesis, or enhancing the immune system’s ability to fight cancer. They expand the treatment options for various cancer types, enabling personalized treatments tailored to individual patient needs and cancer characteristics.

Confirmed complete response

“Confirmed complete response” in clinical trials for liver cancer (hepatocellular carcinoma or HCC) refers to a state where a patient’s tumor has completely disappeared or vanished. This means that the tumor has significantly decreased and has not reappeared. After the tumor has disappeared, it is observed for a certain period of time and is confirmed by clinical doctors or evaluators before being classified as a “Confirmed complete response.”

This term is used to assess the effectiveness of the treatment on the tumor. When the tumor has completely disappeared and does not recur, it signifies the success of the treatment. The disappearance of the tumor means that the tumor-related symptoms may be resolved, and it can be associated with improved survival rates.

In clinical trials for liver cancer treatment, achieving a “Confirmed complete response” is a significant indicator of the treatment’s success, and it is considered a highly positive outcome.

Nonproportionality

“Nonproportionality” is an important concept used in survival analysis from a statistical perspective. The Kaplan-Meier survival curve is a graph that shows the probability of survival over time and is commonly used in clinical research. The sentence “The delayed separation of the overall survival Kaplan– Meier curves suggested the potential for nonproportionality” refers to the statistical properties of the shape of the survival curves.

Nonproportionality is interpreted as follows:

Proportional Hazard Assumption: In survival analysis, the Cox Proportional Hazard Model is commonly used, which assumes that the hazard ratio remains constant over time. In other words, it assumes that the hazard ratio remains constant across different time intervals. This means that the survival curves do not cross each other and remain relatively flat.

Delayed Separation of Curves: The phrase “The delayed separation of the overall survival Kaplan– Meier curves” signifies that the survival curves closely overlap for a certain period and only gradually separate over time. In other words, it indicates that initially, the survival curves are nearly identical, but they separate later.

Potential for Nonproportionality: “the potential for nonproportionality” indicates the possibility that the shape of these survival curves violates the assumption of the Cox Proportional Hazard Model. It means that the hazard ratio may not remain constant over time for the survival curves.

This is an important consideration when interpreting clinical research results. If the survival curves violate the proportional hazard assumption, alternative survival analysis models or adjusted analyses may be needed, which can impact the evaluation of treatment effects and prognosis predictions. Therefore, accurately assessing nonproportionality and accounting for it are crucial.

Treatment-emergent adverse events

“Treatment-emergent adverse events” is a term used in the medical and clinical research fields to refer to adverse events or events representing side effects that occur in a patient after receiving a particular treatment or drug. This term is especially important in clinical research and clinical trials and is used to describe newly occurring side effects in patients who have received specific treatment or medication.

In simple terms, treatment-emergent adverse events refer to side effects or unexpected events that manifest in a patient after they have undergone a specific treatment. These events are documented in clinical research and provide valuable information for evaluating and monitoring treatment efficacy and side effects.

These events can take various forms and assist in detecting significant side effects and taking necessary actions. In clinical research, recording treatment-emergent adverse events plays a crucial role in assessing the safety and side effects of treatments and interpreting study results.

Stratification factors in HCC clinical trials

Stratification factors are important factors used when randomizing patients into groups in clinical trials. These factors help in accurately analyzing and interpreting the results of clinical trials, increasing the reliability of the outcomes. In clinical trials for unresectable HCC (hepatocellular carcinoma) treatment, factors like Macrovascular invasion, Etiology of liver disease, and ECOG performance status are used as Stratification factors for the following reasons:

1. Macrovascular invasion (presence of vascular invasion):
   Some patients with hepatocellular carcinoma may have tumor invasion or expansion into blood vessels. This is related to how advanced the tumor is, and the extent of tumor spread can impact treatment responses and prognosis. Therefore, the presence or absence of Macrovascular invasion is an important factor in distinguishing the patient’s tumor status.
2. Etiology of liver disease (cause of liver disease):
   Hepatocellular carcinoma can occur due to various causes, primarily liver diseases such as hepatitis B or C viral infections. Depending on the underlying cause, the disease progression and treatment response can vary. Therefore, grouping patients based on the Etiology of liver disease is important.
3. ECOG performance status (assessment of daily living abilities of patients):
   ECOG (Eastern Cooperative Oncology Group) performance status is one of the metrics used to assess a patient’s daily living abilities. A score of 0 indicates a fully active state, while a score of 1 indicates a slightly reduced ability but the capability for light activities. Such performance status can influence a patient’s eligibility for certain treatments in clinical trials and their likelihood of treatment response.

Therefore, by using Stratification factors to adjust patient groups in clinical trials, it becomes possible to compare outcomes occurring within each group and interpret them effectively. This approach allows for a more accurate evaluation of treatment efficacy and side effects.

Macrovascular invasion in HCC

Macrovascular invasion in hepatocellular carcinoma (HCC) refers to the condition where the tumor has invaded or expanded into blood vessels. In this situation, the response to treatment and prognosis can generally be affected as follows:

Treatment Response:

Patients with HCC where Macrovascular invasion has occurred typically have a lower treatment response. This is because the tumor has extended into the blood vessels, making treatment more challenging, and it becomes difficult for drugs or radiation to effectively reach the tumor within the blood vessels.

Prognosis (Survival Period):

HCC with Macrovascular invasion indicates a more advanced stage of the tumor, potentially leading to a worsened overall prognosis. The spread of the tumor into blood vessels increases the likelihood of causing more damage to surrounding tissues or organs. Therefore, the prognosis for patients with HCC and Macrovascular invasion is generally poorer.

Treatment Approach:

The treatment approach for patients with HCC and Macrovascular invasion is determined based on factors such as the tumor’s location, extent of spread, and the patient’s overall health. Typically, interventions such as vascular occlusion procedures, percutaneous intravascular treatment, radiation therapy, or immunotherapeutic approaches may be considered to treat tumors within blood vessels.

HCC with Macrovascular invasion is generally more challenging to treat, given the advanced stage of the tumor. Therefore, specialized medical advice for tumor management and treatment is essential. These patients should work with tumor management specialists to develop treatment plans and determine the optimal treatment strategy tailored to the specific circumstances of the tumor.

Hepatitis B or C in HCC

The progression and treatment response of hepatocellular carcinoma (HCC) can differ depending on whether it is caused by Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection and cases where HBV or HCV is not involved. Below are the differences for each scenario:

1. HCC Caused by Hepatitis B or C:

In these cases, HCC originates in the liver due to HBV or HCV infection.

Progression: HCC caused by HBV or HCV is often associated with complex liver diseases such as liver cirrhosis and fibrosis. These patients may have risks not only related to tumors but also worsening of liver function and complications.

Treatment Response: The response to tumor treatment can vary based on the patient’s infection status, liver function, tumor size, and location. Combining HBV or HCV treatment with tumor treatment requires a specialized approach to tumor management.

2. HCC without Hepatitis B or C:

In these cases, HCC is more likely to have arisen due to other causes, such as alcohol consumption, non-viral hepatitis, fatty liver, and others.

Progression: When HCC is caused by factors unrelated to HBV or HCV, the progression may vary based on the patient’s overall health and underlying conditions. The presence of other underlying conditions can impact tumor management and prognosis.

Treatment Response: Treatment response can vary depending on tumor size, location, and the patient’s overall health. Tailored treatment plans considering each patient’s unique situation are required for tumor management.

These differences should be taken into account when determining strategies for managing and treating HCC patients. Tumor management should consider not only the characteristics of the tumor but also the patient’s infection status, liver function, underlying conditions, and overall health. It is essential to work with tumor management specialists to develop individualized treatment plans in such situations.