This research was supported by Taipei Medical University Hospital (106TMUH-NE-02).

Taipei Medical University Joint Institutional Review Board approval was obtained for this study.
1. SBRT Consultation
<ol>
	<li>Assess patient eligibility for SBRT for the treatment of liver metastases by consulting a multidisciplinary tumor board. 
	NOTE: The need for local ablation as well as operation and other treatment options must be evaluated by the tumor board. Our selection criteria were as follows: 1) adult patients with a good performance status (Eastern Cooperative Oncology Group 0-1), 2) controlled cancer status through anticancer medication and with only oligometastases in the liver, 3) number of hepatic lesions &#8804;3 and largest tumor &#8804;6 cm in diameter, 4) liver volume (liver excluding gross tumor) greater than 700 cm3, and 5) without acute hepatitis or chronic hepatitis B under stable antiviral control.</li>
	<li>Discuss SBRT and its associated risks as well as the differences between SBRT and conventional radiotherapy with the patient9,19.</li>
</ol>
2. CT Simulation
<ol>
	<li>Place the patient in a supine position, head-first on the couch with arms over the head.
	<ol>
		<li>Use a system (e.g., BodyFIX) to immobilize the patient. Position the patient in a personalized, evacuated vacuum bag and cover the patient with a cover sheet.</li>
		<li>Apply an abdominal compressor (AC), and mark the depth of the AC. 
		NOTE: The AC restricts the patient&#39;s breathing motion; therefore, some patients may develop dyspnea during this procedure. Oxygen supplementation through the nasal cannula should be provided to relieve their discomfort.</li>
		<li>Place the breath-tracking sensor on the chest wall and monitor the respiratory waveform.</li>
	</ol>
	</li>
	<li>Acquire CT images for radiotherapy treatment planning.
	<ol>
		<li>Choose 4D-CT scan mode with a 3 mm slice thickness.</li>
		<li>Conduct a surview scan (120 kV, 30 mA) to obtain both anterior-posterior (AP) and lateral view of the patient. Click on &#34;Go&#34; on both the screen and the control panel.</li>
		<li>Determine the CT scanning coverage under &#34;Helical scan&#34; pagination and decide the scanning field of 4D-CT under &#34;Pulmonary gating scan&#34; pagination. 
		NOTE: The coverage of the helical scan should extend from the apex of both the lungs to a distance of at least 5 cm from the caudal border of the liver. The field of pulmonary gating scan, which is smaller than helical scan, should cover the liver with a 3-5 cm extend from both cranial and caudal borders of the liver.</li>
		<li>Monitor the respiratory waveform until it remains stable for 3 min.</li>
		<li>Inject 100 mL of contrast agent (e.g., Omnipaque), at a rate of 4-5 mL/s, through an 18 G i.v. catheter into antecubital vein.</li>
		<li>Conduct a contrasted contiguous helical CT scan (120 kV, 400 mAs/slice), 15 s after the contrast injection.</li>
		<li>Subsequently conduct a non-contrasted 4D-CT scan (120 kV, 2,000 mAs/slice) by clicking &#34;Next Series&#34;.</li>
	</ol>
	</li>
</ol>
3. Radiotherapy Treatment Planning
<ol>
	<li>Import images from the CT simulation and diagnostic scans into the planning system. 
	NOTE: Diagnostic images may include positron emission tomography (PET)/PET-CT, magnetic resonance image, or diagnostic helical CT scans.</li>
	<li>Contour metastatic tumors into gross tumor volume and adjacent organs at risk (OARs).
	<ol>
		<li>Choose an organ (here, the stomach) and use the brush, pencil, etc. to contour the organ in each slice of the CT image. Circle or define the organ of interest. Use &#34;Up&#34; and &#34;Down&#34; buttons to view each image slice. 
		NOTE: The OARs include the lungs, stomach, duodenum, spinal cord, liver, small bowel, ribs, and kidneys.</li>
	</ol>
	</li>
	<li>Contour the internal target volume (ITV) of the tumors according to organ motion observed on dynamic tracking images. Add a 5-mm margin to the ITV to obtain the planning target volume (PTV).
	<ol>
		<li>Choose an organ (here, the stomach) and use the brush, pencil, etc. to contour the organ in each slice of the CT image. Circle or define the organ of interest. Use &#34;Up&#34; and &#34;Down&#34; buttons to view each image slice.</li>
	</ol>
	</li>
	<li>Prescribe radiation doses of 48 Gy in three fractions or 35 Gy in five fractions to the PTV for relatively large tumors. 
	NOTE: A treatment plan must consider constraints due to the OARs; a relatively high prescription dose may be acceptable if the radiation dose to the OARs is within the constraints (Table 1).</li>
</ol>
4. Treatment Delivery
<ol>
	<li>Reconfirm the radiation beam data by using daily quality assurance and ensure that the data are within the normal range.</li>
	<li>Identify the patient using the patient&#39;s name, birth date, and ID card. Position the patient in the vacuum bag, place the cover sheet, and fix the AC according to the procedure described in the CT simulation section.</li>
	<li>Acquire a 4D cone-beam CT (CBCT) image and adjust the couch to correlate the target location obtained on the 4D-CBCT image to that obtained on the simulation CT images.
	<ol>
		<li>Select 4D CBCT mode and confirm setup data. Click &#34;Go&#34; on the panel.</li>
	</ol>
	</li>
	<li>After 4D CBCT, load the acquired 4D CBCT images into the IGRT system. The upper left and lower right images are from CT simulation as the contouring and treatment planning. The upper right and lower left images are from 4D CBCT, which is performed daily before each fraction.
	<ol>
		<li>Use the software to adjust the set up. Then, manually adjust each parameter on the couch. The couch has only 3 linear motions in X, Y, and Z axes while the system could have adjustment in 6, including rotation, pitch and roll. Therefore, the technicians need to corroborate the adjustment.</li>
		<li>Record and print out the parameters for daily adjustment. 
		NOTE: If the tumor position shifts beyond the tolerance limit of 5 mm on any one of six axes, the patient should be repositioned.</li>
	</ol>
	</li>
	<li>Deliver radiation treatment. Confirm treatment plan and the system configuration. Click Go to start the treatment. Monitor the patient using real-time cameras during the entire treatment to ensure patient safety.</li>
</ol>

<ol>
	<li>Mountain, C. F., McMurtrey, M. J., Hermes, K. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Surgery+for+pulmonary+metastasis:+a+20-year+experience.">Surgery for pulmonary metastasis: a 20-year experience.</a> Ann Thorac Surg. 38 (4), 323-330 (1984).</li><li>Hellman, S., Weichselbaum, R. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Oligometastases.">Oligometastases.</a> J Clin Oncol. 13 (1), 8-10 (1995).</li><li>Weichselbaum, R. R., Hellman, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Oligometastases+revisited.">Oligometastases revisited.</a> Na. Rev Clin Oncol. 8 (6), 378-382 (2011).</li><li>Comito, T., Clerici, E., Tozzi, A., D'Agostino, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Liver+metastases+and+SBRT:+A+new+paradigm?.">Liver metastases and SBRT: A new paradigm?.</a> Rep Pract Oncol Radiother. 20 (6), 464-471 (2015).</li><li>Scorsetti, M., Clerici, E., Comito, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stereotactic+body+radiation+therapy+for+liver+metastases.">Stereotactic body radiation therapy for liver metastases.</a> J Gastrointest Oncol. 5 (3), 190-197 (2014).</li><li>Shady, W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Percutaneous+Radiofrequency+Ablation+of+Colorectal+Cancer+Liver+Metastases:+Factors+Affecting+Outcomes--A+10-year+Experience+at+a+Single+Center.">Percutaneous Radiofrequency Ablation of Colorectal Cancer Liver Metastases: Factors Affecting Outcomes--A 10-year Experience at a Single Center.</a> Radiology. 278 (2), 601-611 (2016).</li><li>van Hazel, G. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=SIRFLOX:+Randomized+Phase+III+Trial+Comparing+First-Line+mFOLFOX6+(Plus+or+Minus+Bevacizumab)+Versus+mFOLFOX6+(Plus+or+Minus+Bevacizumab)+Plus+Selective+Internal+Radiation+Therapy+in+Patients+With+Metastatic+Colorectal+Cancer.">SIRFLOX: Randomized Phase III Trial Comparing First-Line mFOLFOX6 (Plus or Minus Bevacizumab) Versus mFOLFOX6 (Plus or Minus Bevacizumab) Plus Selective Internal Radiation Therapy in Patients With Metastatic Colorectal Cancer.</a> J Clin Oncol. 34 (15), 1723-1731 (2016).</li><li>Salama, J. K., Milano, M. T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Radical+irradiation+of+extracranial+oligometastases.">Radical irradiation of extracranial oligometastases.</a> J Clin Oncol. 32 (26), 2902-2912 (2014).</li><li>Rusthoven, K. E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Multi-institutional+phase+I/II+trial+of+stereotactic+body+radiation+therapy+for+liver+metastases.">Multi-institutional phase I/II trial of stereotactic body radiation therapy for liver metastases.</a> J Clin Oncol. 27 (10), 1572-1578 (2009).</li><li>Ricardi, U., Badellino, S., Filippi, A. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+applications+of+stereotactic+radiation+therapy+for+oligometastatic+cancer+patients:+a+disease-oriented+approach.">Clinical applications of stereotactic radiation therapy for oligometastatic cancer patients: a disease-oriented approach.</a> J Radiat Res. 57 (Suppl 1), i58-i68 (2016).</li><li>Wild, A. T., Yamada, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Treatment+Options+in+Oligometastatic+Disease:+Stereotactic+Body+Radiation+Therapy+-+Focus+on+Colorectal+Cancer.">Treatment Options in Oligometastatic Disease: Stereotactic Body Radiation Therapy - Focus on Colorectal Cancer.</a> Visc Med. 33 (1), 54-61 (2017).</li><li>Gill, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Patient-reported+complications+from+fiducial+marker+implantation+for+prostate+image-guided+radiotherapy.">Patient-reported complications from fiducial marker implantation for prostate image-guided radiotherapy.</a> Br J Radiol. 85 (1015), 1011-1017 (2012).</li><li>Eldredge-Hindy, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Active+Breathing+Coordinator+Reduces+Radiation+Dose+to+the+Heart+and+Preserves+Local+Control+in+Patients+with+Left+Breast+Cancer:+Report+of+a+Prospective+Trial.">Active Breathing Coordinator Reduces Radiation Dose to the Heart and Preserves Local Control in Patients with Left Breast Cancer: Report of a Prospective Trial.</a> Pract Radiat Oncol. 5 (1), 4-10 (2015).</li><li>Swanson, T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Six-year+experience+routinely+using+moderate+deep+inspiration+breath-hold+for+the+reduction+of+cardiac+dose+in+left-sided+breast+irradiation+for+patients+with+early-stage+or+locally+advanced+breast+cancer.">Six-year experience routinely using moderate deep inspiration breath-hold for the reduction of cardiac dose in left-sided breast irradiation for patients with early-stage or locally advanced breast cancer.</a> Am J Clin Oncol. 36 (1), 24-30 (2013).</li><li>Sweeney, R. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Accuracy+and+inter-observer+variability+of+3D+versus+4D+cone-beam+CT+based+image-guidance+in+SBRT+for+lung+tumors.">Accuracy and inter-observer variability of 3D versus 4D cone-beam CT based image-guidance in SBRT for lung tumors.</a> Radiat Oncol. 7, 81 (2012).</li><li>Takahashi, W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Verification+of+Planning+Target+Volume+Settings+in+Volumetric+Modulated+Arc+Therapy+for+Stereotactic+Body+Radiation+Therapy+by+Using+In-Treatment+4-Dimensional+Cone+Beam+Computed+Tomography.">Verification of Planning Target Volume Settings in Volumetric Modulated Arc Therapy for Stereotactic Body Radiation Therapy by Using In-Treatment 4-Dimensional Cone Beam Computed Tomography.</a> Int J Radiat Oncol Biol Phys. 86 (3), 426-431 (2013).</li><li>Yeo, U. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Evaluation+of+dosimetric+misrepresentations+from+3D+conventional+planning+of+liver+SBRT+using+4D+deformable+dose+integration.">Evaluation of dosimetric misrepresentations from 3D conventional planning of liver SBRT using 4D deformable dose integration.</a> J Appl Clin Med Phys. 15 (6), 4978 (2014).</li><li>Shinmohigashi, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Tumor+motion+changes+in+stereotactic+body+radiotherapy+for+liver+tumors:+an+evaluation+based+on+four-dimensional+cone-beam+computed+tomography+and+fiducial+markers.">Tumor motion changes in stereotactic body radiotherapy for liver tumors: an evaluation based on four-dimensional cone-beam computed tomography and fiducial markers.</a> Radiat Oncol. 12, 61 (2017).</li><li>Goodman, B. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Long-term+safety+and+efficacy+of+stereotactic+body+radiation+therapy+for+hepatic+oligometastases.">Long-term safety and efficacy of stereotactic body radiation therapy for hepatic oligometastases.</a> Pract Radiat Oncol. 6 (2), 86-95 (2016).</li><li>Scorsetti, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Is+stereotactic+body+radiation+therapy+an+attractive+option+for+unresectable+liver+metastases?+A+preliminary+report+from+a+phase+2+trial.">Is stereotactic body radiation therapy an attractive option for unresectable liver metastases? A preliminary report from a phase 2 trial.</a> Int J Radiat Oncol Biol Phys. 86 (2), 336-342 (2013).</li><li>Andratschke, N. 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The authors have no disclosures.

Respiration-induced liver deformity and organ motion contribute to the difficulties associated with radiation delivery, as well as contouring (target delineation) problems. Improvements in the techniques used for organ motion management have led to improvements in treatment accuracy and precision, which is fundamental to SBRT. Several image-guided techniques and respiratory motion management systems are currently available. Fiducial marker implantation is a common technique for target localization. A fiducial marker is u...

Conventionally, metastasis is considered the terminal stage of cancer and is associated with poor prognosis and survival. However, Mountain et al. in 1984 reported that according to their 20-year experience, complete surgical removal of pulmonary metastasis results in a relatively higher survival rate if the primary tumor site is under systemic control at the time of surgery1. Hellman and Weichselbaum in 1995 first proposed oligometastases, an intermediate stage between localized lesions and systemic disease with polymetastases, which can be cured using additional local treatment2,3. Over the past decades, early detection of metastasis, novel surgical methods for treating oligometastases (metastasectomy), and effective chemotherapy have improved the prognosis in patients with metastasis. The liver is one of the most common metastatic organs for solid tumors, and surgical resection of hepatic oligometastases can improve survival. Local ablation methods, including radiofrequency ablation, radioembolization, and radiotherapy, for treating liver metastases have been recommended for some inoperable patients to achieve the necessary local tumor control3,4,5,6,7. In past years, several prospective and retrospective studies have reported effective local tumor control of hepatic metastases through stereotactic body radiotherapy (SBRT), also known as stereotactic ablative radiotherapy, with tolerable toxicity4,5,8,9.
Improvements have been made in patient positioning and immobilization methods; image acquisition, integration, and transfer to radiotherapy systems; respiratory motion management; high-dose output and fast radiation delivery; and steep dose gradients from target lesions to surrounding normal tissues. Because of these advances, SBRT achieves highly precise and accurate radiotherapy with minimal serious toxicity10,11. Respiratory motion management is fundamental to SBRT, particularly for hepatic and pulmonary lesions. A respiratory management technique that is noninvasive and clinically convenient would substantially increase the popularity of SBRT as a treatment option. This article details an SBRT protocol for liver metastases that uses four-dimensional computed tomography (4D-CT) with an abdominal compressor (AC) for image-guided assistance and liver motion management.

<table><tbody><tr><td>CT scan</td><td>Philips</td><td>Brilliance&amp;nbsp;Big Bore&amp;nbsp;16 Slice&amp;nbsp;CT, 7387</td><td>Acquire CT images for contouring and planning</td></tr><tr><td>CT contrast</td><td>GE Healthcare</td><td>Omnipaque 350 mg L/mL</td><td>Enhence lesion in CT images</td></tr><tr><td>Linear accelerator</td><td>Elekta</td><td>Synergy</td><td>Deliver radiotherapy</td></tr><tr><td>Palnning system</td><td>Pinnacle</td><td>Pinnacle 9.8</td><td>Implement radiotherapy planning</td></tr><tr><td>Immobilization: BlueBag BodyFix</td><td>Elekta</td><td>900 mm x 2325 mm, P10104840</td><td>Immobilize the patient</td></tr><tr><td>Immobilization: BodyFix Cover sheet</td><td>Elekta</td><td>2700 mm x 1400 mm, P10102-304</td><td>Immobilize the patient</td></tr><tr><td>Immobilization: BodyFix abdominal compressor</td><td>Elekta</td><td>diaphragm control, P10102-149</td><td>Restrict breath motion and organ/lesion motion</td></tr><tr><td>Immobilization: vacuum pump</td><td>Elekta</td><td>vacuum pump, p2 120V, P10102-110</td><td>Shape body bag and cover sheet according to the patient</td></tr></tbody></table>

treatment of liver metastases using an internal target volume method for stereotactic body radiotherapy

The prognosis of patients with metastatic cancers has improved in the past decades due to effective chemotherapy and oligometastatic surgery. For inoperable patients, local ablation therapies, such as stereotactic body radiotherapy (SBRT), can provide effective local tumor control with minimal toxicity. Because of its high precision and accuracy, SBRT delivers a higher radiation dose per fraction, is more effective, and targets smaller irradiation volumes than does conventional radiotherapy. In addition, steep dose gradients from target lesions to surrounding normal tissues are achieved using SBRT; thus, SBRT provides more effective tumor control and exhibits fewer side effects than conventional radiotherapy. The use of SBRT is prevalent for treating intracranial lesions (known as stereotactic radiosurgery); however, it is now also used for treating spinal and adrenal metastases. Because of advancements in image-guided assistance and respiratory motion management, several studies have investigated the use of SBRT for treating lung or liver tumors, which move as a patient breathes. The results of these studies have suggested that SBRT favorably controls tumors in the case of moving lesions.
Four-dimensional computed tomography (4D-CT) with an abdominal compressor (AC) is clinically convenient for effective respiratory motion management. Because this method is noninvasive and allows free breathing, its use reduces complications. Furthermore, patients consider this method convenient. Moreover, it is considered more efficient than other methods of respiratory motion management by physicians and therapists. The use of 4D-CT with an AC for treating pulmonary lesions has also been widely investigated, and the technique is gaining acceptance for treating hepatic lesions. However, the protocols for using 4D-CT with an AC for treating hepatic lesions are different from those used for treating pulmonary lesions. In this article, we describe a new protocol for SBRT with 4D-CT and an AC for treating liver metastases.

SBRT can be implemented by intense-modulated radiotherapy (IMRT) (with <img alt="image" src="/files/ftp_upload/57050/57050imgv2.jpg" /> 6 radiation beams) or volumetric arc radiotherapy (VMAT) (with continuous dose delivery and gantry rotation) to cover all targets in a single treatment because a single surgery may not achieve removal of all the tumors. A representative SBRT treatment plan demonstrated successful radiotherapy planning for two hepatic metastatic tumors when surgery was inf...

Watch this Scientific Journal Video about Treatment of Liver Metastases Using an Internal Target Volume Method for Stereotactic Body Radiotherapy at JoVE.com

Treatment of Liver Metastases Using an Internal Target Volume Method for Stereotactic Body Radiotherapy

Stereotactic body radiotherapy (SBRT) requires rigorous accuracy and precision for delivering high radiation doses per fraction to small treatment volumes to improve tumor control and simultaneously reduce toxicity. Herein, we present a noninvasive and clinically convenient respiratory motion management protocol for SBRT for liver metastases.

The prognosis of patients with metastatic cancers has improved in the past decades due to effective chemotherapy and oligometastatic surgery. For ...

treatment-liver-metastases-using-an-internal-target-volume-method-for

Research

JoVE Journal

Medicine

14.2K Views.  Taipei Medical University Hospital. Stereotactic body radiotherapy (SBRT) requires rigorous accuracy and precision for delivering high radiation doses per fraction to small treatment volumes to improve tumor control and simultaneously reduce toxicity. Herein, we present a noninvasive and clinically convenient respiratory motion management protocol for SBRT for liver metastases. 

Video: Treatment of Liver Metastases Using an Internal Target Volume Method for Stereotactic Body Radiotherapy

PET and MRI Guided Irradiation of a Glioblastoma Rat Model Using a Micro-irradiator

For decades, small animal radiation research was mostly performed using fairly crude experimental setups applying simple single-beam techniques without the ability to target a specific or well-delineated tumor volume. The delivery of radiation was achieved using fixed radiation sources or linear accelerators producing megavoltage (MV) X-rays. These devices are unable to achieve sub-millimeter precision required for small animals. Furthermore, the high doses delivered to healthy surrounding tissue hamper response assessment. To increase the translation between small animal studies and humans, our goal was to mimic the treatment of human glioblastoma in a rat model. To enable a more accurate irradiation in a preclinical setting, recently, precision image-guided small animal radiation research platforms were developed. Similar to human planning systems, treatment planning on these micro-irradiators is based on computed tomography (CT). However, low soft-tissue contrast on CT makes it very challenging to localize targets in certain tissues, such as the brain. Therefore, incorporating magnetic resonance imaging (MRI), which has excellent soft-tissue contrast compared to CT, would enable a more precise delineation of the target for irradiation. In the last decade also biological imaging techniques, such as positron emission tomography (PET) gained interest for radiation therapy treatment guidance. PET enables the visualization of e.g., glucose consumption, amino-acid transport, or hypoxia, present in the tumor. Targeting those highly proliferative or radio-resistant parts of the tumor with a higher dose could give a survival benefit. This hypothesis led to the introduction of the biological tumor volume (BTV), besides the conventional gross target volume (GTV), clinical target volume (CTV), and planned target volume (PTV).
At the preclinical imaging lab of Ghent University, a micro-irradiator, a small animal PET, and a 7 T small animal MRI are available. The goal was to incorporate MRI-guided irradiation and PET-guided sub-volume boosting in a glioblastoma rat model.

In the past, small animal irradiation was usually performed without the ability to target a well-delineated tumor volume. The goal was to mimic the treatment of human glioblastoma in rats. Using a small animal irradiation platform, we performed MRI-guided 3D conformal irradiation with PET-based sub-volume boosting in a preclinical setting.

For decades, small animal radiation research was mostly performed using fairly crude experimental setups applying simple single-beam techniques without ...

Cancer Research

Stereotactic Radiosurgery for Gynecologic Cancer

Stereotactic body radiotherapy (SBRT) distinguishes itself by necessitating more rigid patient immobilization, accounting for respiratory motion, intricate treatment planning, on-board imaging, and reduced number of ablative radiation doses to cancer targets usually refractory to chemotherapy and conventional radiation. Steep SBRT radiation dose drop-off permits narrow 'pencil beam' treatment fields to be used for ablative radiation treatment condensed into 1 to 3 treatments.
Treating physicians must appreciate that SBRT comes at a bigger danger of normal tissue injury and chance of geographic tumor miss. Both must be tackled by immobilization of cancer targets and by high-precision treatment delivery. Cancer target immobilization has been achieved through use of indexed customized Styrofoam casts, evacuated bean bags, or body-fix molds with patient-independent abdominal compression.1-3 Intrafraction motion of cancer targets due to breathing now can be reduced by patient-responsive breath hold techniques,4 patient mouthpiece active breathing coordination,5 respiration-correlated computed tomography,6 or image-guided tracking of fiducials implanted within and around a moving tumor.7-9 The Cyberknife system (Accuray [Sunnyvale, CA]) utilizes a radiation linear accelerator mounted on a industrial robotic arm that accurately follows patient respiratory motion by a camera-tracked set of light-emitting diodes (LED) impregnated on a vest fitted to a patient.10 Substantial reductions in radiation therapy margins can be achieved by motion tracking, ultimately rendering a smaller planning target volumes that are irradiated with submillimeter accuracy.11-13
Cancer targets treated by SBRT are irradiated by converging, tightly collimated beams. Resultant radiation dose to cancer target volume histograms have a more pronounced radiation "shoulder" indicating high percentage target coverage and a small high-dose radiation "tail." Thus, increased target conformality comes at the expense of decreased dose uniformity in the SBRT cancer target. This may have implications for both subsequent tumor control in the SBRT target and normal tissue tolerance of organs at-risk. Due to the sharp dose falloff in SBRT, the possibility of occult disease escaping ablative radiation dose occurs when cancer targets are not fully recognized and inadequate SBRT dose margins are applied. Clinical target volume (CTV) expansion by 0.5 cm, resulting in a larger planning target volume (PTV), is associated with increased target control without undue normal tissue injury.7,8 Further reduction in the probability of geographic miss may be achieved by incorporation of 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET).8 Use of 18F-FDG PET/CT in SBRT treatment planning is only the beginning of attempts to discover new imaging target molecular signatures for gynecologic cancers.

Stereotactic body radiotherapy (SBRT) involves image-guided, ablative radiation delivered to cancer targets refractory to chemotherapy or to conventional radiation treatment. The robotic-armed Cyberknife SBRT system, using sophisticated target localization, delivers hypofractionated radiation doses capable of sterilizing cancer targets. This article will consider new therapeutic roles of SBRT for gynecological cancers.

Stereotactic body radiotherapy (SBRT) distinguishes itself by necessitating more rigid patient immobilization, accounting for respiratory motion, ...

Modeling Brain Metastasis by Internal Carotid Artery Injection of Cancer Cells

Brain metastasis is a cause of severe morbidity and mortality in cancer patients. Critical aspects of metastatic diseases, such as the complex neural microenvironment and stromal cell interaction, cannot be entirely replicated with in vitro assays; thus, animal models are critical for investigating and understanding the effects of therapeutic intervention. However, most brain tumor xenografting methods do not produce brain metastases consistently in terms of the time frame and tumor burden. Brain metastasis models generated by intracardiac injection of cancer cells can result in unintended extracranial tumor burden and lead to non-brain metastatic morbidity and mortality. Although intracranial injection of cancer cells can limit extracranial tumor formation, it has several caveats, such as the injected cells frequently form a singular tumor mass at the injection site, high leptomeningeal involvement, and damage to brain vasculature during needle penetration. This protocol describes a mouse model of brain metastasis generated by internal carotid artery injection. This method produces intracranial tumors consistently without the involvement of other organs, enabling the evaluation of therapeutic agents for brain metastasis.

Brain metastasis is a cause of severe morbidity and mortality in cancer patients. Most brain metastasis mouse models are complicated by systemic metastases confounding analysis of mortality and therapeutic intervention outcomes. Presented here is a protocol for internal carotid injection of cancer cells that produces consistent intracranial tumors with minimal systemic tumors.

Brain metastasis is a cause of severe morbidity and mortality in cancer patients. Critical aspects of metastatic diseases, such as the complex neural ...

Isolated Hepatic Perfusion as a Treatment for Liver Metastases of Uveal Melanoma

Isolated hepatic perfusion (IHP) is a procedure where the liver is surgically isolated and perfused with a high concentration of the chemotherapeutic agent melphalan. Briefly, the procedure starts with the setup of a percutaneous veno-venous bypass from the femoral vein to the external jugular vein. Via a laparotomy, catheters are then inserted into the proper hepatic artery and the caval vein. The portal vein and the caval vein, both supra- and infrahepatically, are then clamped. The arterial and venous catheters are connected to a heart lung machine and the liver is perfused with melphalan (1 mg/kg body weight) for 60 min. This way it is possible to locally perfuse the liver with a high dose of a chemotherapeutic agent, without leakage to the systemic circulation.
In previous studies including patients with isolated liver metastases of uveal melanoma, an overall response rate of 33-100% and a median survival between 9 and 13 months, have been reported. The aim of this protocol is to give a clear description of how to perform the procedure and to discuss IHP as a treatment option for liver metastases of uveal melanoma.

Here, we present a protocol how to perform an isolated liver perfusion (IHP) with melphalan and we also discuss IHP as a treatment option for liver metastases of uveal melanoma.

Isolated hepatic perfusion (IHP) is a procedure where the liver is surgically isolated and perfused with a high concentration of the chemotherapeutic ...

Clinical Factors Influencing the Radiation Dose of Circulating Immune Cells during Radiotherapy for Small Cell Lung Cancer

Small cell lung cancer (SCLC) has garnered significant attention due to its high malignancy, propensity for distant metastasis, and poor prognosis. Radiotherapy remains the cornerstone of treatment for limited-stage small cell lung cancer (LS-SCLC). However, outcomes with radiotherapy alone or in combination with chemotherapy remain suboptimal. Radiotherapy can induce lymphopenia by directly irradiating hematopoietic organs or destroying mature circulating lymphocytes, leading to immunosuppression and consequently diminishing therapeutic efficacy. The estimated dose of radiation to immune cells (EDRIC) model integrates factors such as hemodynamics, lymphocyte radiosensitivity, and proliferation capacity. This study employs the EDRIC model with enhancements to calculate the circulating immune cell radiation dose. By utilizing the EDRIC methodology, the study explores the correlation between EDRIC and tumor target size, average lung dose, average heart dose, clinical features, and peripheral blood lymphocytopenia during radiotherapy for LS-SCLC, aiming to inform personalized patient treatment strategies.
This study analyzed data from 64 LS-SCLC patients who met the inclusion criteria at the General Hospital of Ningxia Medical University from January 2023 to January 2024, all of whom received radical thoracic conventional fractionated radiotherapy. Lymphocyte counts were recorded at the following points: before radiotherapy, at the lowest observed value during radiotherapy, at the end of radiotherapy, and one-month post-radiotherapy. Dosimetric data, including average lung, heart, and body doses, were extracted from the treatment planning system, and the circulating EDRIC was calculated using this model. The relationship between EDRIC values and therapeutic outcomes was analyzed. In LS-SCLC, the EDRIC model effectively predicts lymphocyte count reduction, correlating with planning target volume (PTV; cm3), TNM stage, and the percentage of target lesion shrinkage. Post-radiotherapy, there was a significant decrease in peripheral blood lymphocyte counts, with greater EDRIC values indicating more pronounced lymphocyte reduction.

Here, we present a protocol to evaluate the effects of radiation therapy on immune system lymphocytes in small cell lung cancer.

Small cell lung cancer (SCLC) has garnered significant attention due to its high malignancy, propensity for distant metastasis, and poor prognosis. ...

Dynamic Lung Tumor Tracking for Stereotactic Ablative Body Radiation Therapy

Physicians considering stereotactic ablative body radiation therapy (SBRT) for the treatment of extracranial cancer targets must be aware of the sizeable risks for normal tissue injury and the hazards of physical tumor miss. A first-of-its-kind SBRT platform achieves high-precision ablative radiation treatment through a combination of versatile real-time imaging solutions and sophisticated tumor tracking capabilities. It uses dual-diagnostic kV x-ray units for stereoscopic open-loop feedback of cancer target intrafraction movement occurring as a consequence of respiratory motions and heartbeat. Image-guided feedback drives a gimbaled radiation accelerator (maximum 15 x 15 cm field size) capable of real-time &#177;4 cm pan-and-tilt action. Robot-driven &#177;60&#176; pivots of an integrated &#177;185&#176; rotational gantry allow for coplanar and non-coplanar accelerator beam set-up angles, ultimately permitting unique treatment degrees of freedom. State-of-the-art software aids real-time six dimensional positioning, ensuring irradiation of cancer targets with sub-millimeter accuracy (0.4 mm at isocenter). Use of these features enables treating physicians to steer radiation dose to cancer tumor targets while simultaneously reducing radiation dose to normal tissues. By adding respiration correlated computed tomography (CT) and 2-[18F] fluoro-2-deoxy-&#7429;-glucose (18F-FDG) positron emission tomography (PET) images into the planning system for enhanced tumor target contouring, the likelihood of physical tumor miss becomes substantially less1. In this article, we describe new radiation plans for the treatment of moving lung tumors.

Stereotactic ablative body radiation therapy (SBRT) involves the precise delivery of high-dose radiation to cancer tumor targets. A novel SBRT platform offers a first-of-its-kind gimbaled radiation accelerator mounted within a pivoting O-ring gantry capable of dynamic image-guided tumor tracking. Here, we describe dynamic tumor tracking for lung targets.

Physicians considering stereotactic ablative body radiation therapy (SBRT) for the treatment of extracranial cancer targets must be aware of the sizeable ...

Targeted and Selective Treatment of Pluripotent Stem Cell-derived Teratomas Using External Beam Radiation in a Small-animal Model

The growing number of victims of &#34;stem cell tourism,&#34; the unregulated transplantation of stem cells worldwide, has raised concerns about the safety of stem cell transplantation. Although the transplantation of differentiated rather than undifferentiated cells is common practice, teratomas can still arise from the presence of residual undifferentiated stem cells at the time of transplant or from spontaneous mutations in differentiated cells. Because stem cell therapies are often delivered into anatomically sensitive sites, even small tumors can be clinically devastating, resulting in blindness, paralysis, cognitive abnormalities, and cardiovascular dysfunction. Surgical access to these sites may also be limited, leaving patients with few therapeutic options. Controlling stem cell misbehavior is, therefore, critical for the clinical translation of stem cell therapy.
External beam radiation offers an effective means of delivering targeted therapy to decrease the teratoma burden while minimizing injury to surrounding organs. Additionally, this method avoids genetic manipulation or viral transduction of stem cells-which are associated with additional clinical safety and efficacy concerns. Here, we describe a protocol to create pluripotent stem cell-derived teratomas in mice and to apply external beam radiation therapy to selectively ablate these tumors in vivo.

Research on treatment strategies for pluripotent stem cell-derived teratomas is important for the clinical translation of stem cell therapy. Here, we describe a protocol to, first, generate stem cell-derived teratomas in mice and, then, to selectively target and treat these tumors in vivo using a small-animal irradiator.

The growing number of victims of &#34;stem cell tourism,&#34; the unregulated transplantation of stem cells worldwide, has raised concerns about the ...

Proton Therapy Delivery and Its Clinical Application in Select Solid Tumor Malignancies

Radiation therapy is a frequently used modality for the treatment of solid cancers. Although the mechanisms of cell kill are similar for all forms of radiation, the in vivo properties of photon and proton beams differ greatly and maybe exploited to optimize clinical outcomes. In particular, proton particles lose energy in a predictable manner as they pass through the body. This property is used clinically to control the depth at which the proton beam is terminated, and to limit radiation dose beyond the target region. This strategy can allow for substantial reductions in radiation dose to normal tissues located just beyond a tumor target. However, the degradation of proton energy in the body remains highly sensitive to tissue density. As a consequence, any changes in tissue density during the course of treatment may significantly alter proton dosimetry. Such changes may occur through alterations in body weight, respiration, or bowel filling/gas, and may result in unfavorable dose deposition. In this manuscript, we provide a detailed method for the delivery of proton therapy using both passive scatter and pencil beam scanning techniques for prostate cancer. Although the described procedure directly pertains to prostate cancer patients, the method may be adapted and applied for the treatment of virtually all solid tumors. Our aim is to equip readers with a better understanding of proton therapy delivery and outcomes in order to facilitate the appropriate integration of this modality during cancer therapy.

The fundamentals of radiation planning and delivery for proton therapy using prostate cancer as a model are presented. The application of these principles to other selected disease sites highlights how proton radiotherapy may enhance clinical outcomes for cancer patients.

Radiation therapy is a frequently used modality for the treatment of solid cancers. Although the mechanisms of cell kill are similar for all forms of ...

Y-90 TARE and PD-1 Inhibition as Bridging Therapy in Hepatocellular Carcinoma

Y-90 Radioembolization and PD-1 Inhibitor as Neoadjuvant Treatment in Hepatocellular Carcinoma

This study showcases a comprehensive treatment protocol for high-risk hepatocellular carcinoma (HCC) patients, focusing on the combined use of Y-90 transarterial radioembolization (TARE) and Programmed Cell Death-1 (PD-1) inhibitors as neoadjuvant therapy. Highlighted through a case report, it offers a step-by-step reference for similar therapeutic interventions. A retrospective analysis was conducted on a patient who underwent hepatectomy following Y-90 TARE and PD-1 inhibitor treatment. Key demographic and clinical details were recorded at admission to guide therapy selection. Y-90 TARE suitability and dosage calculation were based on Technetium-99m (Tc-99m) macroaggregated albumin (MAA) perfusion mapping tests. Lesion coverage by Y-90 microspheres was confirmed through single photon emission computed tomography/computed tomography (SPECT/CT) fusion imaging, and adverse reactions and follow-up outcomes were meticulously documented. The patient, with a 7.2 cm HCC in the right hepatic lobe (T1bN0M0, BCLC A, CNLC Ib) and an initial alpha-fetoprotein (AFP) level of 66,840 ng/mL, opted for Y-90 TARE due to high recurrence risk and initial surgery refusal. The therapy's parameters, including the lung shunting fraction (LSF) and non-tumor ratio (TNR), were within therapeutic limits. A total of 1.36 GBq Y-90 was administered. At 1 month post-therapy, the tumor shrank to 6 cm with partial necrosis, and AFP levels dropped to 21,155 ng/mL, remaining stable for 3 months. After 3 months, PD-1 inhibitor treatment led to further tumor reduction to 4 cm and AFP decrease to 1.84 ng/mL. The patient then underwent hepatectomy; histopathology confirmed complete tumor necrosis. At 12 months post-surgery, no tumor recurrence or metastasis was observed in follow-up sessions. This protocol demonstrates the effective combination of Y-90 TARE and PD-1 inhibitor as a bridging strategy to surgery for HCC patients at high recurrence risk, providing a practical guide for implementing this approach.

This study illustrates the methodological potential of combining Yttrium-90 Trans-Arterial Radioembolization (Y-90 TARE) with an anti-PD-1 monoclonal antibody as an effective neoadjuvant strategy leading to hepatectomy in hepatocellular carcinoma (HCC) patients with a high initial recurrence risk. It emphasizes the safety, feasibility, and step-by-step procedural guidance of this approach.

This study showcases a comprehensive treatment protocol for high-risk hepatocellular carcinoma (HCC) patients, focusing on the combined use of Y-90 ...

Application of Separation Surgery Combined with Radiofrequency Ablation and Bone Cement Strengthening in Thoracolumbar Metastasis

The spine is a common site for metastatic tumors, with 5%-10% of patients developing epidural spinal cord compression (ESCC), which significantly reduces their quality of life and accelerates the process of death. When total en-bloc spondylectomy (TES) radical surgery does not achieve the desired tumor control, palliative care remains the primary treatment option. Traditional laminar decompression or partial tumor resection can only relieve local compression. Although the surgical trauma and complications are less, these methods cannot effectively address tumor recurrence and secondary compression. Therefore, separation surgery combined with radiofrequency ablation and bone cement strengthening was used to treat thoracolumbar metastatic tumors, aiming to achieve good clinical results. In this protocol, the steps and key points of separation surgery combined with radiofrequency ablation and bone cement reinforcement for thoracolumbar metastatic tumors are introduced in detail. Meanwhile, the clinical data of 67 cases of thoracolumbar metastatic tumors in our hospital meeting the inclusion criteria were retrospectively analyzed. Different treatment methods divided the patients into two groups: separation surgery combined with radiofrequency ablation and bone cement strengthening (group A, 33 cases) and the radiotherapy group (group B, 34 cases). All patients were evaluated using improved Tokuhashi, Tomita, SINS, and ESCC scores before treatment. VAS score, Frankel grading, and Karnofsky scores during different periods of the two treatments were compared to assess the clinical outcomes. Studies have shown that separation surgery combined with radiofrequency ablation and bone cement strengthening can significantly reduce pain, promote neurological function recovery, enhance mobility, and improve quality of life in treating thoracolumbar metastatic tumors.

This study investigates the efficacy of combining separation surgery with radiofrequency ablation and radiotherapy in treating thoracolumbar metastatic tumors.

The spine is a common site for metastatic tumors, with 5%-10% of patients developing epidural spinal cord compression (ESCC), which significantly reduces ...