Stereotactic Body Radiation Therapy (SBRT) for Liver Mets

Prior to enrollment all patients will be evaluated with a physical exam, review of pathology
and laboratory values to confirm diagnosis, and baseline imaging studies.

Accelerator

Physicians will treat with a stereotactic radiosurgery system using 6MV photons to deliver
stereotactic body radiotherapy.

Doses

Patients will receive a total dose ranging from 50-75 Gy in 5 fractions (10-15 Gy/fx). Dose
escalation will be via the traditional "up and down" scheme.

In determining the radiation dose and fractionation scheme for this protocol, we used the
linear-quadratic formalism for radiation cell killing to "equate" schemes that vary the
dose/fraction and number of fractions. This concept of biologically equivalent dose (BED)
states that the total effect is given by:

nd x (1 + d/(alpha-beta ratio))

where n is the # of fractions and d is the dose/fraction. The "alpha-beta ratio"
characterizes the radiation response of a particular tissue; a higher value is indicative of
a tissue that responds acutely to the effects of radiation. Due to their highly proliferative
nature, most tumors fall into this category.

This final dose scheme (total dose 75 Gy) is biologically equivalent to the previously
studied doses in the literature (60 Gy in 3 fractions), meaning the first two sets of
patients will be treated to a radiobiologically smaller (and likely safer) dose. We would
favor treating in five fractions, as opposed to three, to allow more repair of normal tissue,
reoxygenation of tumor cells, and redistribution of tumor cells to more radiosensitive parts
of the cell cycle. Using a smaller fraction size, 10-15 Gy compared to 20 Gy, will also help
reduce late effects of radiation therapy. SBRT treatment will be given on an every other day
schedule, excluding weekends. The prescription dose will be prescribed to the isodose line
best encompassing the planning target volume (PTV) depending on the volume of tumor (HCC).

Localization, immobilization, and simulation

Within 5 - 10 days after fiducial placement, pPatients will undergo 4D FDG-PET/CT simulation
with the goal of evaluating tumor motion to allow for gated treatment when indicated. This
goal will be accomplished by using the Real-time Position Management (RPM) system (Varian
Medical Systems, Palo Alto, CA) to create a retrospective 4D CT scan. Following the
institutional protocol, a helical CT scan and a 4D positron emission tomography (PET) scan
with a patient with body immobilization device will be acquired. A patient will not eat or
drink anything for four hours before the PET scan. Before the PET scan, blood sample will be
taken from either a finger stick or a vein in the arm to check the sugar level. An injection
of a small amount of a radioactive drug called FDG ( [F18] fluorodeoxyglucose) which is a
chemical similar to sugar will be administered into a vein in the arm or hand. Approximately
45 to 60 minutes after the injection of FDG, the patient will be asked to urinate (to empty
the bladder).

The patient will be set up in the PET/CT scanner using a vacuum cushion for immobilization in
the supine position with feet tied and hands across the chest or above the head. There will
also be a respiration-monitoring device called a marker block placed 5cm below the patient's
xyphoid process. An infrared camera at the foot of the CT table will capture the images of
the marker block and relay them to the RPM computer, which in turn will translate the images
into a respiratory pattern. The audio coach (which instructs the patient in regulating
breathing) will be calibrated to both patient comfort and time of expiration, inspiration,
and full breathing cycle. The placing of the patient in a body immobilization device will
take about 10-15 minutes. The patient will need to lie still for about 30 minutes before the
completion of the 4D PET scan. The PET/CT scanner will then be programmed to acquire a
retrospective 4D CT scan with a set of images for each phase of the breathing cycle. This
scan will take place immediately after the PET scan. It will take around 5-10 minutes. The
physician or physicist will then select the number of breathing phases to use while the
software program selects the best image for each selected breathing phase.

The entire FDG-PET/CT scan procedure is expected to take about 2 hours.

Treatment Planning

Treatment planning will be carried out using the planning station for the radiosurgery
equipment being used for treatment. The gross tumor volume (GTV) will be contoured on the
fused image set. Two GTV volumes will be contoured; the gross tumor as seen on CT alone and
the gross tumor corresponding to FDG avidity. No margins will be added for clinical target
volume (CTV), but custom margins will be added for the planning target volume (PTV) based on
the findings of the 4D FDG-PET/CT motion study assessment. The treatment will be prescribed
to the isodose line that best covers the planning target volume, which will typically be the
80% isodose line.

Treatment Delivery

SBRT will take place within 14 days of the treatment planning scan. The planning data
containing the coordinates of tumor isocenter, the external infrared markers, and the
implanted markers are transferred to the appropriate platform depending on the treating
machine. If the patient meets the criteria of gating technique then treatment delivery will
be accomplished using the appropriate gating technology. Depending on the technology used
external infrared markers attached to the patient's skin or a marker block placed on the
patient's chest is used to determine the breathing pattern. The size of beam-on window will
be determined based on the target motion as detected by the 4D FDG-PET/CT scan. The threshold
for gated treatment delivery is determined based upon the target motion due to respiration.

The daily initial positioning during treatment delivery will be performed using lasers and
skin marks and infrared optical markers as appropriate. The target isocenter will be verified
using daily imaging. Depending on the platform used, the moving target will be positioned
within the beam under infrared and/or image guidance

Inclusion Criteria:

- Male or female patients ≥ 18 years of age

- A life expectancy of at least 6 months with a Karnofsky performance status of at least
70

- The target lesion(s) can be accurately measured in at least one dimension according to
RECIST and must have a maximum tumor volume of ≤ 100 cm3

- No prior radiotherapy to the upper abdomen

- Previous systemic chemotherapy or non-radiation local therapy (such as surgery,
hepatic arterial therapy, chemoembolization, radiofrequency ablation, percutaneous
ethanol injection or cryoablation) is allowed. The lesion must however have shown
criteria of progression based on RECIST. Local therapy must be completed at least 4
weeks prior to the baseline scan. This is to create a safer treatment environment and
to help determine the effect of treatment by SBRT alone. Patients will be allowed to
go onto appropriate systemic therapy, as determined by their medical oncologist, 2
weeks following delivery of SBRT

- Patients with resectable disease will be eligible for participation if they have
comorbidities precluding surgery or refuse to undergo an operation

- Cirrhotic status of Child-Pugh class A or B

- Patients can have extra-hepatic disease, provided the hepatic disease is the highest
burden, the extra-hepatic disease is low burden and potentially treatable with
surgery, ablative radiation therapy, or US Food and Drug Administration-approved
first- or second-line systemic therapy regimens

- Patient's will have no evidence of gross vascular invasion.

- Patients will have no more than 3 distinct lesions, all being ≤ 3cm in greatest
dimension, OR 1 lesion ≤ 6cm in greatest dimension

- Platelet count ≥ 60 x 109/L, Hemoglobin ≥ 8.5 g/dL, WBC ≥ 2000/μL International
normalized ratio (INR) must be ≤ 2.3. Patients who are being therapeutically
anticoagulated with an agent such as Coumadin or heparin will be allowed to
participate provided that no prior evidence of underlying abnormality in these
parameters exists

- Other baseline labs must meet the following criteria: total bilirubin < 3mg/dl,
albumin> 2.5mg/dl, and liver enzymes less than three times the upper limit of normal.
Creatinine must also be < 1.8mg/dl or a creatinine clearance > 50ml/min

- Must be aware of the neoplastic nature of his/her disease and willingly provide
written, informed consent after being informed of the procedure to be followed, the
experimental nature of the therapy, alternatives, potential benefits, side-effects,
risks and discomforts

Exclusion Criteria:

- Renal failure requiring hemo- or peritoneal dialysis

- Uncontrolled inter-current illness including, but not limited to ongoing or active
infection (> grade 2 National Cancer Institute [NCI]-Common Terminology Criteria for
Adverse Events [CTCAE] version 4.0), congestive heart failure (> New York Heart
Association (NYHA) class 2), active coronary artery disease (CAD), cardiac arrhythmias
requiring anti-arrhythmic therapy other than beta blockers or digoxin), uncontrolled
hypertension and any condition which could jeopardize the safety of the patient and
his/her compliance in the study . Myocardial infarction more than 6 months prior to
study entry is permitted

- A history of variceal bleeding where the varices have not been eradicated or
decompressed by shunt placement

- History of an active connective tissue disorder

- Substance abuse, medical, psychological or social conditions that may interfere with
the patient's participation in the study or evaluation of the study results

- Pregnant or breast-feeding patients are excluded from this study because abdominal
radiation therapy has potential for teratogenic and/or abortifacient effects

- Portal vein occlusion

- Extensive liver tumor burden, defined as more than 75% of the liver.

- Patients with primary tumor histology of lymphoma, leukemia, or germ cell tumor

- Patients with hepatocellular carcinoma will be excluded from this study