A Phase I Study of Stereotactic Body Radiation Therapy (SBRT) for Liver Metastases
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.
Physicians will treat with a stereotactic radiosurgery system using 6MV photons to deliver
stereotactic body radiotherapy.
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
The entire FDG-PET/CT scan procedure is expected to take about 2 hours.
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.
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
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
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose (MTD) and safety of SBRT for liver metastases using dose escalation
Dose limiting toxicity (DLT) will be defined as any grade III stomach, bowel, liver, or spinal cord toxicity, or any grade IV toxicity as defined by the RTOG. Only toxicities observed prior to 7 months after the last fraction of radiation will affect dose escalation. After escalation has stopped, de-escalation will begin at one dose level below the maximum achieved during escalation. If 3 pts have been treated, 3 pts are added; if 6 pts have been treated, this level will be declared the MTD, the highest dose level at which no more than 1 of 6 treated pt experiences a DLT.
Dwight E Heron, MD
United States: Institutional Review Board
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