Foster D. Lasley

Treatment variables related to liver toxicity in patients with hepatocellular carcinoma, Child-Pugh class A and B enrolled in a phase 1-2 trial of stereotactic body radiation therapy

PURPOSE An analysis was performed on patients enrolled in a phase 1-2 trial using stereotactic body radiation therapy for hepatocellular carcinoma evaluating variables influencing liver toxicity. METHODS AND MATERIALS Thirty-eight Child-Pugh class A (CPC-A) (39 lesions) and 21 CPC-B patients (26 lesions) were followed for ≥6 months. Six months local control using modified Response Evaluation Criteria in Solid Tumors criteria, progression-free survival, overall survival, and grade III/IV treatment-related toxicity at 3 months were analyzed. RESULTS Median follow-up was 33.3 months (2.8-61.1 months) for CPC-A and 46.3 months (3.7-70.4 months) for CPC-B patients. Local control at 6 months was 92% for CPC-A and 93% for CPC-B. Kaplan-Meier estimated 2- and 3-year local control was 91% for CPC-A and 82% for CPC-B (P = .61). Median overall survival was 44.8 months and 17.0 months for CPC-A and CPC-B. Kaplan-Meier estimated 2- and 3-year overall survival was 72% and 61% for CPC-A and 33% and 26% for CPC-B (P = .03). Four (11%) CPC-A patients and 8 CPC-B patients (38%) experienced grade III/IV liver toxicity. Overall, CPC-A patients with ≥grade III liver toxicity had 4.59 (95% confidence interval, 1.19-17.66) times greater risk of death than those without toxicity (P = .0268). No such correlation was seen for CPC-B patients; however, 3 of these CPC-B patients underwent orthotopic liver transplant. CPC-B patients experiencing grade III/IV liver toxicity had significantly higher mean liver dose, higher dose to one-third normal liver, and larger volumes of liver receiving doses <2.5 to 15 Gy in 2.5-Gy increments. For CPC-A patients, there was no critical liver dose or volume constraint correlated with toxicity. CONCLUSIONS In our experience, liver stereotactic body radiation therapy is a safe therapy for patients with hepatocellular carcinoma in the context of liver cirrhosis; however, for CPC-B patients, careful attention should be paid to low-dose volumes that could potentially result in increased liver toxicity.

Combined Modality Therapy

Radiation therapy can be modified by increasing the effectiveness of radiation on tumors (radiosensitizers), protecting normal tissues (radioprotectors), increasing oxygen concentration, or by using systemic therapy drugs. Radio-protectors are described by their dose reduction factor (DRF) while radio-sensitizers are described by their enhancement ratio (ER). Both numbers are a ratio of radiation doses required to achieve a biological effect. Systemic agents can be classified as: hypoxic radiosensitizers, hypoxic cytotoxins, classic alkylators, platinum agents, antibiotics, antimetabolites, vinca alkaloids, taxanes, topoisomerase inhibitors, hormonal agents, monoclonal antibodies, small molecule inhibitors (usually tyrosine kinase inhibitors), and immuno-modulators. Progress is also being made in the field of gene therapy, although this is not yet mainstream.

Quality Management Program

The Nuclear Regulatory Commission (NRC) is responsible for regulating nuclear material, including any nuclides used in brachytherapy. All medical sources are classified as nuclear byproduct material. Use of byproduct material requires an authorized user and a radiation safety officer, as well as a written directive and a quality management program (QMP). Deviations from the written directive may be classified as medical events (misadministrations) depending on their severity.

Fractionated Radiation Survival Models

Repair is the first “R” in the 4 R’s of radiation therapy. Irradiated cells can undergo both sublethal damage repair, which is modeled with split dose experiments, and potentially lethal damage repair, which is modeled with plating delay experiments. Post-radiation cell survival can be modeled in several different ways, using Poisson statistics as the basis for survival equations. The single-hit, multi-target model has parameters D0, the dose correlating with one hit per cell, and Dq which is the width of the “shoulder” and correlates with repair capacity. The linear quadratic (LQ) model utilizes the terms α (single hit kill), and β (two hit kill) which correlate with low-dose killing and high-dose killing respectively. The LQ model can be used to determine biologically equivalent doses between various dose fractionation schemes. In addition to these two commonly used models, there are multiple other models that have their own strengths and weaknesses.

Cell and Tissue Kinetics

The response of cells to low LET radiation is often dependent upon phase of the cell cycle at the time of irradiation, but the response of tumors and normal tissue is dependent on other additional parameters such as growth fraction and cell loss. G2/M phase cells are most radiosensitive, while late S-phase cells are most radioresistant. The cell cycle can stop at various checkpoints if DNA damage is detected; progression of cells into S phase or mitosis is usually delayed in normal cells if DNA is damaged. Flow cytometry can be used to measure the proportion of cells in various phases of the cell cycle. This may be used to calculate cell cycle time, growth fraction, cell loss factor, doubling time and potential doubling time of tumors. Cell repopulation can counteract cell killing during a prolonged course of radiotherapy. On the other hand, redistribution allows cells to progress to a more sensitive phase of the cell cycle, increasing cell killing after administration of subsequent fractions of IR.

Normal Tissue Radiation Responses

Radiation toxicity in normal tissues can be classified as early effects, late effects and consequential late effects. These effects vary based on the tissue type, radiation dose, fractionation, and the volume of tissue irradiated. Parallel organs such as the lung can tolerate high doses to a small volume better than low doses to the whole organ. Serial structures such as the spinal cord can tolerate low doses to the whole organ, but cannot tolerate high doses to a small volume. Two major schemes for tissue classification are the Casarett classifications and Michalowski classifications. Radiation effects on normal tissues are described in a series of paragraphs split up by organ or tissue. Toxicity observed in human patients is scored on a variety of schemas, including Late Effects of Normal Tissue, Subjective Objective Management Analytic (LENT-SOMA) and Common Toxicity Classification for Adverse Events (CTC-AE).

Primary Liver Cancer

Hepatocellular carcinoma (HCC) is the most frequently occurring primary tumor of the liver in adults and the fourth most common cause of cancer-related deaths in the world. Its rising incidence in the United States and Europe is attributed to the increased incidence of hepatitis C infection. Currently, the optimal treatment for HCC is orthotopic liver transplant or surgical resection for selected patients. However many patients are not able to undergo these radical interventions. Historically, radiotherapy for hepatocellular carcinoma has been shown to be poorly tolerated in the cirrhotic liver and has had suboptimal results with standard fractionation. With the introduction of stereotactic body radiotherapy (SBRT) techniques, there are emerging data indicating that the use of targeted, highly conformal, hypofractionated ablative radiotherapy can provide results that compare favorably with other ablative procedures for HCC in terms of local control, safety and survival. Therefore, SBRT is gaining interest as an alternative, safe, non-invasive and effective technique for the treatment of appropriately selected patients who are not able to undergo orthotopic liver transplantation.

Advanced Treatment Planning for EBRT

Treatment planning techniques include patient immobilization, imaging, radiation field design, verification and evaluation. Modern radiotherapy takes advantage of many different imaging modalities, including traditional radiography, computed tomography (CT), magnetic resonance (MR), positron emission tomography (PET) and ultrasound (US). Once target and avoidance volumes are defined, radiation fields may be planned using 2D, 3D, or IMRT techniques, and evaluated using dose volume histograms (DVHs). Additional imaging may be performed on the day of treatment to verify that the patient is properly positioned.

Acute Effects of Total Body Irradiation (TBI)

Total body irradiation effects depend on the dose. At TBI doses of 1 Gy or more, individuals may experience a prodromal reaction involving fatigue, anorexia and vomiting. At doses of 2.5 Gy or more, individuals may die from the hematopoietic syndrome. They can sometimes be rescued through supportive care and stem cell transplant. At doses of 10 Gy or more, individuals will manifest symptoms of the gastrointestinal syndrome, causing death within 3–10 days. At very high doses, the cerebrovascular syndrome results in death within 24–48 h. There are various methods to estimate total body exposure, but treatment typically consists of isolation, antibiotics, and fluids or blood products as necessary.

Cell Death and Survival Assays

There are many ways that a cancer cell can die from radiation injury. Severe DNA damage may cause mitotic catastrophe, leading to necrosis and inflammation. Alternatively some cell types may undergo apoptosis, an orderly dismantling of the cell that avoids inflammation. Apoptosis is triggered by caspases acting through two signaling pathways, intrinsic and extrinsic. Cell survival under various conditions can be measured using in vitro (“within glass”) and in vivo (“within the living”) assays. Different assays are suitable for measuring different endpoints in tumors and normal tissues.