This research was supported by the Summa Cancer Institute.

Ethical statement: Summa Health System institutional review board approval was obtained for this study.
1. Treatment Consultation
<ol>
	<li>Describe the new lung SBRT treatment to the patient. 
	NOTE: The new SBRT platform delivers coplanar and non-coplanar high radiation dose to cancer targets while lowering radiation dose to non-target organs.</li>
	<li>Discuss the treatment risks. 
	NOTE: SBRT may result in possible short-term skin hyperpigmentation or erythema, tiredness, infrequent cough, nausea, esophagitis, and rare visceral organ injury. Pneumonitis, or inflammation of the lung with low-grade fever and non-productive cough, may occur up to three months after treatment. Acute or late injuries to the heart, other muscles, peripheral nerves or spinal cord, and bone are uncommon. There is a very small hazard for radiation-induced malignancy.</li>
</ol>
2. Fiducial Marker Placement
<ol>
	<li>Perform percutaneous CT-guided or bronchoscopic placement of a single gold-coated marker inserted into the tumor target center-of-mass.
	<ol>
		<li>Ask a radiologist to perform a 3-5 mm thick contiguous axial tomographic imaging of the patient&#8217;s chest7.</li>
		<li>Determine a safe needle approach minimizing aerated lung tissue traversed (avoiding bullae and fissures)7.</li>
		<li>Inject local subcutaneous anesthesia (e.g., 1% lidocaine).</li>
		<li>Introduce 17 or 18 G coaxial needle to place a single short (0.75 x 10 mm) or single long (0.75 x 20 mm) marker10.</li>
	</ol>
	</li>
	<li>Do an electromagnetic navigation bronchoscopy-guided fiducial marker placement by asking a pulmonologist to acquire tomographic imaging of the chest for endobronchial mapping21.
	<ol>
		<li>Wedge the bronchoscope in the suspected bronchial segment.</li>
		<li>Steer the bronchoscope sensor probe to the target lesion.</li>
		<li>Deploy a fiducial marker by transbronchial needle. 
		NOTE: Techniques for fiducial-free radiosurgery in the lung are considered investigational and subject to active research22,23.</li>
	</ol>
	</li>
	<li>As an alternative, order at least three short (1.6 x 3 mm) gold-coated markers to be positioned within a 6 cm &#8216;box&#8217; around the target. If more than one fiducial marker is placed, a physical separation of 2 cm between markers is recommended.</li>
</ol>
3. Treatment Planning
<ol>
	<li>Perform CT-guided simulation (described in steps 3.2 and 3.3) 4-7 days after fiducial marker placement.</li>
	<li>Ask the patient to lie in a supine-head-first on the treatment machine flat tabletop.
	<ol>
		<li>Position the patient&#8217;s arms over their head, supported by upper arm and wrist holders or a vacuum-bag immobilizer. Ensure that the thorax and abdomen are not immobilized.</li>
		<li>Optionally, use a two-pin localized knee sponge for indexing.</li>
		<li>Place at least 4 infrared-tracked body markers on the chest for localization. Infrared-tracked breathing markers overly body regions demonstrating consistent vertical respiratory motion (3 mm or more peak-to-peak motion is recommended).</li>
	</ol>
	</li>
	<li>Conduct a non-contrasted contiguous helical axial CT scan (1 mm slice thickness, voltage 120 kVp, 350 mAs). 
	NOTE: Treating physicians may order a 4D CT thorax scan12 or a 3D CT thorax scan that includes free-breathing, end-inspiration, and end-expiration breath-hold image sets24.</li>
	<li>Obtain 18F-FDG PET/CT scans for enhanced capture of lung tumor motion.
	<ol>
		<li>Ask the patients to lie in a head-first scanning position for contiguous helical CT scan (e.g., voltage 120 kVp, 450 mAs) from the orbitomeatal line to upper thighs during quiet breathing.</li>
		<li>Acquire 18F-FDG PET after intravenous administration of 11 mCi of 18F-FDG on average in the same scanning position from the orbitomeatal line to upper thighs during quiet breathing. If this technique is used, 18F-FDG PET/CT scans are auto-contoured by software set at a 40% SUVmax threshold, and then, co-registered with CT simulation images as described1.</li>
	</ol>
	</li>
	<li>Contour the primary lung gross target volume or volumes (GTVp) by hand drawing on 4D CT datasets, preferably the exhale phase. Expanding the GTVp with a 5 mm margin creates the planning tumor volume (PTV). Radiation dose planning occurs on the end-expiration phase scan for dynamic tracking. 
	NOTE: As an alternative and when using 3D CT datasets, the free-breathing CT simulation scan is the reference scan. Using this technique, the treating radiation oncologist contours the GTV on the free-breathing (GTVfb), inspiration (GTVi), and expiration (GTVe) CT simulation scans. A thresholded 40 percent maximum standard uptake value contour on the 18F-FDG PET images creates an 18F-FDG PET clinical target volume (CTVpet)1. A composite ITV represents the added sum of the GTVfb, GTVi, GTVe, and CTVpet volumes. A 5 mm margin expansion of the composite ITV creates a PTV. Here, radiation dose planning occurs on the free-breathing scan for dynamic tracking.</li>
	<li>Contour nearby normal tissue structures by hand drawing on 4D CT datasets, preferably the exhale phase. This may include normal lung, heart plus pericardium, esophagus, liver, bilateral kidneys, brachial plexus, and spinal cord. A contour of the trachea, right mainstem bronchus, and left mainstem bronchus may be generated, expanded 3 mm, and used as a high-priority planning constraint to avoid late toxicity airway fibrosis.</li>
	<li>Click on the dynamic tracking button in the planning software. This action engages the gimbaled pan-and-tilt tracking on the new SBRT platform.</li>
	<li>Prescribe a radiation dose to the PTV. Consider one of three radiation Monte Carlo dose prescriptions: 3 x 17 Gy = 51 Gy daily for peripheral lung lesions; 4 x 12 Gy = 48 Gy for central lung lesions and peripheral chest wall lesions; or every other day 5 x 10 Gy = 50 Gy. Uncommonly when PTV volume constraints (i.e., 95% coverage) or organ-at-risk constraints are not met, a prescription of 8 x 7.5 Gy = 60 Gy may be used.</li>
</ol>
4. Treatment Delivery and Workflow
<ol>
	<li>Build a quiet breathing correlation model after supine-head-first alignment.
	<ol>
		<li>Place 4 (or up to 6) infrared body markers on the body in the same marked locations identified at CT simulation.</li>
		<li>Verify positional accuracy of the body markers and patient alignment by infrared camera and screens at the treatment console. 
		NOTE: Body marker position serves as a beam-on check for irregular movement, such a cough.</li>
		<li>Acquire cross-plane dual-diagnostic kV x-rays or cone-beam CT images at the treatment console to detect implanted markers for internal positional accuracy.</li>
		<li>Associate and correlate body marker motion (as a surrogate for respiration) and internal implanted marker motion with computer software linked to the new SBRT platform workflow. 
		NOTE: An alternative localization method involves orthogonal alignment of the patient according to anterior and lateral tattooed CT simulation laser triangulation marks and use of a standardized reference array (star) with six impregnated infrared body markers.</li>
	</ol>
	</li>
	<li>Generate a lung tumor motion correlation model.
	<ol>
		<li>Derive a gimbal pan-and-tilt path for the accelerator to track tumor motion using computer software linked to the new SBRT platform workflow.</li>
		<li>Visually assess the lung tumor motion correlation model prior to radiation delivery.</li>
	</ol>
	</li>
	<li>Observe for fiducial marker drift during radiation delivery.</li>
	<li>Evaluate machine-patient collisions due to gantry rotation, O-ring pivot, and gimbal pan-and-tilt actions prior to plan delivery. 
	NOTE: The radiation staff will perform this step. Treatment may entail five to nine static coplanar and noncoplanar treatment beams, manually and visually checked by radiation delivery staff. Treatments may last 15-30 min, with lung tumor motion correlation model verifications done approximately every 7 min.</li>
</ol>

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The authors have nothing to disclose.

Promising early stereotactic radiosurgery clinical experiences have driven clinical trial investigation of ablative radiation for treatment of lung cancers25,26. Experience has led investigators to use ablative radiation against a variety of tumor types metastasizing to the lung27,28. The new SBRT platform introduces a radiation delivery system particularly attuned to the treatment of moving tumors.
The new SBRT platform delivers an unseen x-ray treatment that is generated by a linear accelerator mounted within a pivoting O-ring gantry. A gimbal mechanism enables pan-and-tilt motion of the linear accelerator, providing in-time dynamic tumor motion tracking. Dual cross-plane kV x-rays are obtained before and during treatment to verify 6 degree-of-freedom patient positioning. Coplanar and non-coplanar unique degrees of freedom enhance delivery of high radiation dose to cancer targets while simultaneously minimizing radiation dose to critical visceral organs. It is anticipated that treatment sterilizes cancer cell targets without irreparable damage to normal cells&#8212;lowering radiation-related toxicity. Future study of the new SBRT platform will document any gains in target control and any reduction in side effects.
Initial experience with the new SBRT platform shows promise10. Nuances of dynamic tracking of lung tumors continue to be explored; however, some generalizations are apparent. Lung tumors demonstrating motion less than seven millimeters may be best treated by a composite ITV plus 5 mm expansion approach. For lung tumors showing 7 mm or more vertical translation, a dynamic tracking approach using a GTVp plus 5 mm expansion may be best for treatment. Further research defining these limits is needed. Also, 18F-FDG PET images superimposed upon 3D CT image datasets usually increase composite ITV volumes. This approach assumes volume expansion due to 18F-FDG signal smear occurring during the PET scanner&#8217;s 3-5 min bin time. A 40% thresholded 18F-FDG clinical target volume has been studied and has been used in one of our programs1. Further research characterizing whether 18F-FDG PET images adequately replicates tumor hysteresis is needed. Lastly, up to 3 lesions in a single lung may be considered for treatment at one time. Otherwise, a sequential approach is done.
Dynamic tracking on the new SBRT platform uses a lung tumor motion correlation model to predict lung tumor motion up to 40 msec into the future. Position and velocity of the infrared body and respiratory markers are included in the model. A marker detection rate of 70% in acquired kV x-rays is a requisite for dynamic tracking. Fiducials are tracked in three dimensions (i.e., x, y, z). Images generated by the kV x-ray units are automatically registered and compared real-time. Observed latency in dynamic tracking is due to limitations in pan-and-tilt gimbal hardware, software processing, and positional control performance of the kV x-ray units. Research investigators are engaged in improving tracking latency.
During radiation delivery using dynamic tracking on the new SBRT platform, it is critical to watch for fiducial marker drift. Trends in fiducial marker drift beyond predefined 3 mm tolerances in any direction results in operator-initiated treatment pause or in automatic beam hold. If a treatment pause occurs, it is recommended that operators allow for resumption of quiet breathing motion over the next several patient breaths and then treatment resumption prior to correlation model rebuild. If pauses are unsuccessful, patient repositioning, infrared breathing marker motion detection, kV marker detection, correlation modeling rebuild are done to resume treatment. In our experience, breathing correlation models are accurate for up to 7 min, often limited by patient tension or relaxation while resting on the treatment tabletop.
Unanswered questions remain. What are the radiobiological consequences and mode of cell death in normal cells and cancer cells occurring after ablative radiation dose? Why has it been so difficult to merge high-precision ablative radiation with radiosensitizing chemotherapies? While it is essential to investigate other modalities of delivering ablative radiation in the chest, it remains unclear as to whether ablative radiation can provide equivalent therapeutic effectiveness as thoracic surgery. Indeed, thoracic surgery is the more commonly used and validated technique to achieve tumor eradication in the lung when conventional therapies have already been applied. Here, the new SBRT platform provides an innovative non-invasive means of therapy for women and men with lung tumors showing motion.

Lung cancers account for the greatest number of cancer-related deaths in women and men worldwide2. Up to 63% of persistent or recurrent lung cancers involve lung tissue that is already taxed by chemotherapy or previously irradiated.3,4. Further irradiation at sites of persistent or recurrent lung tumors may lead to intolerable lung morbidity5,6, especially when conventional surgery, chemotherapy, and radiation therapy already have been tried. Thus, women and men in such clinical circumstances have need of new cancer therapy strategies similar to treatments presented before in this journal7. Stereotactic ablative body radiation therapy (SBRT) may satisfy this therapeutic need by sterilizing lung tumors through precisely targeted, high-dose radiation8,9.
There is a novel SBRT platform capable of this therapeutic task10-12. It separates itself from other SBRT platforms by integrating dual-diagnostic Exactrac kV x-ray units (capable of cone-beam computed tomography target localization) and an infrared camera unit (capable of body surface marker tracking as a surrogate for internal motion) that both allow stereoscopic open-loop feedback of cancer target intrafraction motion. It also has a unique &#177;4 cm gimbaled pan-and-tilt radiation accelerator that has its radiation beam shaped by 60 tungsten alloy leaves (0.25 cm physical width, 11 cm physical height). It uses a full over-center-travel multi-leaf collimator for a maximum 15 x 15 cm field size. It incorporates a robot-driven &#177;60&#176; pivoting O-ring and &#177;185&#176; rotational gantry allowing for coplanar and non-coplanar accelerator beam set-up angles and unique treatment degrees of freedom. Lastly, it has submillimeter accuracy (0.4 mm at isocenter)13. In contrast, other SBRT radiotherapy platforms mount a clinical radiation accelerator either to an industrial robotic arm14, or to a helical slice-by-slice gantry15, or within a conventional machine linked to image-guided intensity modulated radiation therapy or dynamic arc delivery software16. Each platform engages a variety of machine components to track motion resulting from respiration motion, heartbeat, or digestion. Lung radiosurgery has had clinical success17,18, rendering the modality a novel treatment option in radiation oncology19,20. This how-to article provides one new radiation therapy protocol that describes dynamic lung tumor tracking for therapeutic treatment intent.

<table><tbody><tr><td>Vero SBRT Linac System 1.0</td><td>Brainlab, Inc. (Munich, Germany)&lt;br /&gt;Mitsubishi Heavy Industries, Ltd. (Tokyo, Japan)</td><td>46300</td><td>High accuracy first-of-its-kind gimbaled irradiation head with tilt function and gantry rotation</td></tr><tr><td>Visicoil fiducial marker</td><td>IBA Dosimetry America (Bartlett, TN, USA)</td><td>67245</td><td>0.75 x 10 mm marker or 0.75 x 20 mm marker</td></tr><tr><td>Gold fiducial marker</td><td>Civco Medical Solutions (Orange City, IA, USA)</td><td>MTNW887860</td><td>Sterile placement needle (14 G ETW x 20 cm) with one 1.6 x 3 mm marker</td></tr></tbody></table>

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.

SBRT on the new platform currently involves multiple static radiation beams converging on single or multiple closely-associated clinical radiation targets, as depicted for example in Figure 1. A representative good planning outcome delivers ablative radiation with 95% coverage of cancer target volume and cancer target dose conformity. Figure 1 shows 5 coplanar and 4 non-coplanar beams (i.e., ring rotation +20&#176; for beams 2, 4, 6, and 8) used to treat a single PTV representing squamous cell carcinoma in the right lung. Beam margins for the PTV were one-millimeter. Radiation dose, prescribed to the 95% isodose line, rendered 95% PTV coverage with a conformity index of 1.48. The prescription was 50 Gy in five every other day 10 Gy fractions. Structures depicted here include the planning target volume (red), internal target volume (white), spinal cord (green), and esophagus (light blue). Isodose lines are as indicated.
<img alt="Figure 1" src="/files/ftp_upload/52875/52875fig1highres.jpg" width="700" /> 
Figure 1: Dynamic tumor tracking of a right-sided lung tumor. Pictured is an example of ablative radiation dose (50 Gy in five 10 Gy every other day fractions) delivered to a single right-sided lung tumor using nine static beams (blue/green, 34&#176; apart). The 4 planning software windows depict: (A) a beam and critical structure collision map, (B) beam&#8217;s-eye-view (here, beam 1), (C) three-dimensional CT and beam reconstruction map, and (D) axial CT with dose distribution.
<table border="0" cellpadding="0" cellspacing="0">
	<tbody>
		<tr>
			<td>Structure</td>
			<td>Metric</td>
			<td>Volume&#160;</td>
			<td>Acceptable variation</td>
		</tr>
		<tr>
			<td>PTV</td>
			<td>V50Gy</td>
			<td>&#8805;95%</td>
			<td>&#8805;90%</td>
		</tr>
		<tr>
			<td>Minimum dose</td>
			<td>0.03 cm3</td>
			<td>&#8805;46 Gy (92%)</td>
			<td>&#8805;45 Gy (90%)</td>
		</tr>
		<tr>
			<td>Maximum dose</td>
			<td>0.03 cm3</td>
			<td>&#8804;60 Gy (120%)</td>
			<td>&#8804;62.5 Gy (125%)</td>
		</tr>
		<tr>
			<td>Spinal cord</td>
			<td>0.03 cm3</td>
			<td>&#8804;15 Gy</td>
			<td>&#8804;22 Gy</td>
		</tr>
		<tr>
			<td>Lung (minus GTV)</td>
			<td>V20Gy</td>
			<td>&#8804;10%</td>
			<td>&#8804;15%</td>
		</tr>
		<tr>
			<td></td>
			<td>Mean dose</td>
			<td>&#8804;8 Gy</td>
			<td>&#8804;10 Gy</td>
		</tr>
		<tr>
			<td>Heart / Pericardium</td>
			<td>15 cm3</td>
			<td>&#8804;32 Gy</td>
			<td>&#8804;36 Gy</td>
		</tr>
		<tr>
			<td>Esophagus</td>
			<td>Mean dose</td>
			<td>&#8804;18 Gy</td>
			<td>&#8804;20 Gy</td>
		</tr>
		<tr>
			<td></td>
			<td>0.03 cm3</td>
			<td>&#8804;27 Gy</td>
			<td>&#8804;30 Gy</td>
		</tr>
		<tr>
			<td>Brachial plexus</td>
			<td>0.03 cm3</td>
			<td>&#8804;24 Gy</td>
			<td>&#8804;30 Gy</td>
		</tr>
	</tbody>
</table>
Table 1: Structure treatment planning constraints.

Watch this Scientific Journal Video about Dynamic Lung Tumor Tracking for Stereotactic Ablative Body Radiation Therapy at JoVE.com

Dynamic Lung Tumor Tracking for Stereotactic Ablative Body Radiation Therapy

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 ...

dynamic-lung-tumor-tracking-for-stereotactic-ablative-body-radiation

Research

JoVE Journal

Medicine

15.6K Views.  Summa Cancer Institute. 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.

Video: Dynamic Lung Tumor Tracking for Stereotactic Ablative Body Radiation Therapy

Endobronchial Ultrasound-guided Intratumoral Injection of Cisplatin for the Treatment of Isolated Mediastinal Recurrence of Lung Cancer

Isolated hilar and mediastinal recurrence (IMHR) following external beam radiation therapy (EBRT) in patients with lung cancer is common. These patients do not have many treatment options and are usually offered palliative chemotherapy or best supportive care. Endobronchial ultrasound (EBUS)-guided intratumoral injection of cisplatin (ITC) is a novel approach for these patients. The procedure is performed under conscious sedation. The lesion is located with a bronchoscopy using EBUS, and a 22-gauge EBUS needle is advanced through the working channel of the scope and locked in position. Under ultrasound guidance, the wall of the tracheobronchial tree is punctured and the needle is moved into the target lesion. The needle stylet is then removed and cisplatin (40 mg/40 mL) is injected into the lesion. One to two sites are treated per session. Details of the procedure are described in the protocol section of paper. At our center, 50 sites were treated in 36 patients (19 males, 17 females). The mean age of our cohort was 61.9 &#177;8.5 years. We performed final analyses on 35 patients and 41 sites. 24/35 (69%) had complete or partial response (responders), whereas 11/35 (31%) had stable or progressive disease (non-responders). Overall, survival in our group was 8 months (95% CI of 6-11 months), with patients who responded having significantly better survival than the ones who did not.

The management of isolated recurrent lung cancer in a previously-irradiated field is challenging. Here, we describe an endobronchial ultrasound (EBUS)-guided cisplatin injection for the management of patients with localized lung cancer recurrence in a previously-radiated field.

Isolated hilar and mediastinal recurrence (IMHR) following external beam radiation therapy (EBRT) in patients with lung cancer is common. These patients ...

Cancer Research

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 ...

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, ...

Detection of Lung Tumor Progression in Mice by Ultrasound Imaging

With ~1.6 million victims per year, lung cancer contributes tremendously to the worldwide burden of cancer. Lung cancer is partly driven by genetic alterations in oncogenes such as the KRAS oncogene, which constitutes ~25% of lung cancer cases. The difficulty in therapeutically targeting KRAS-driven lung cancer partly stems from having poor models that can mimic the progression of the disease in the lab. We describe a method that permits the relative quantification of primary KRAS lung tumors in a Cre-inducible LSL-KRAS G12D mouse model via ultrasound imaging. This method relies on brightness (B)-mode acquisition of the lung parenchyma. Tumors that are initially formed in this model are visualized as B-lines and can be quantified by counting the number of B-lines present in the acquired images. These would represent the relative tumor number formed on the surface of the mouse lung. As the formed tumors develop with time, they are perceived as deep clefts within the lung parenchyma. Since the circumference of the formed tumor is well-defined, calculating the relative tumor volume is achieved by measuring the length and width of the tumor and applying them in the formula used for tumor caliper measurements. Ultrasound imaging is a non-invasive, fast and user-friendly technique that is often used for tumor quantifications in mice. Although artifacts may appear when obtaining ultrasound images, it has been shown that this imaging technique is more advantageous for tumor quantifications in mice compared to other imaging techniques such as computed tomography (CT) imaging and bioluminescence imaging (BLI). Researchers can investigate novel therapeutic targets using this technique by comparing lung tumor initiation and progression between different groups of mice.

This protocol describes the steps taken to induce KRAS lung tumors in mice as well as the quantification of formed tumors by ultrasound imaging. Small tumors are visualized in early timepoints as B-lines. At later timepoints, relative tumor volume measurements are achieved by the measurement tool in the ultrasound software.

With ~1.6 million victims per year, lung cancer contributes tremendously to the worldwide burden of cancer. Lung cancer is partly driven by genetic ...

Positron Emission Tomography-based Dose Painting Radiation Therapy in a Glioblastoma Rat Model using the Small Animal Radiation Research Platform

A rat glioblastoma model to mimic chemo-radiation treatment of human glioblastoma in the clinic was previously established. Similar to the clinical treatment, computed tomography (CT) and magnetic resonance imaging (MRI) were combined during the treatment-planning process. Positron emission tomography (PET) imaging was subsequently added to implement sub-volume boosting using a micro-irradiation system. However, combining three imaging modalities (CT, MRI, and PET) using a micro-irradiation system proved to be labor-intensive because multimodal imaging, treatment planning, and dose delivery have to be completed sequentially in the preclinical setting. This also results in a workflow that is more prone to human error. Therefore, a user-friendly algorithm to further optimize preclinical multimodal imaging-based radiation treatment planning was implemented. This software tool was used to evaluate the accuracy and efficiency of dose painting radiation therapy with micro-irradiation by using an in silico study design. The new methodology for dose painting radiation therapy is superior to the previously described method in terms of accuracy, time efficiency, and intra- and inter-user variability. It is also an important step towards the implementation of inverse treatment planning on micro-irradiators, where forward planning is still commonly used, in contrast to clinical systems.

Here we present a protocol to perform preclinical positron emission tomography-based radiotherapy in a rat glioblastoma model using algorithms developed in-house to optimize the accuracy and efficiency.

A rat glioblastoma model to mimic chemo-radiation treatment of human glioblastoma in the clinic was previously established. Similar to the clinical ...

Examining Tumor Cell Dissemination from Lung Metastases

Tracking Tumor Cell Dissemination from Lung Metastases Using Photoconversion

Metastasis - the systemic spread of cancer - is the leading cause of cancer-related deaths. Although metastasis is commonly thought of as a unidirectional process wherein cells from the primary tumor disseminate and seed metastases, tumor cells in existing metastases can also redisseminate and give rise to new lesions in tertiary sites in a process known as &#34;metastasis-from-metastases&#34; or &#34;metastasis-to-metastasis seeding.&#34; Metastasis-to-metastasis seeding may increase the metastatic burden and decrease the patient&#39;s quality of life and survival. Therefore, understanding the processes behind this phenomenon is crucial to refining treatment strategies for patients with metastatic cancer.
Little is known about metastasis-to-metastasis seeding, due in part to logistical and technological limitations. Studies on metastasis-to-metastasis seeding rely primarily on sequencing methods, which may not be practical for researchers studying the exact timing of metastasis-to-metastasis seeding events or what promotes or prevents them. This highlights the lack of methodologies that facilitate the study of metastasis-to-metastasis seeding. To address this, we have developed - and describe herein - a murine surgical protocol for the selective photoconversion of lung metastases, allowing specific marking and fate tracking of tumor cells redisseminating from the lung to tertiary sites. To our knowledge, this is the only method for studying tumor cell redissemination and metastasis-to-metastasis seeding from the lungs that does not require genomic analysis.

Author Spotlight: Decoding Metastasis-to-Metastasis Seeding Using a New In Vivo Technique for Tracking Breast Cancer Spread 

We present a method for studying tumor cell redissemination from lung metastases involving a surgical protocol for the selective photoconversion of lung metastases, followed by the identification of redisseminated tumor cells in tertiary organs.

Metastasis - the systemic spread of cancer - is the leading cause of cancer-related deaths. Although metastasis is commonly thought of as a unidirectional ...

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. ...

Using Micro-computed Tomography for the Assessment of Tumor Development and Follow-up of Response to Treatment in a Mouse Model of Lung Cancer

Lung cancer is the most lethal cancer in the world. Intensive research is ongoing worldwide to identify new therapies for lung cancer. Several mouse models of lung cancer are being used to study the mechanism of cancer development and to experiment with various therapeutic strategies. However, the absence of a real-time technique to identify the development of tumor nodules in mice lungs and to monitor the changes in their size in response to various experimental and therapeutic interventions hampers the ability to obtain an accurate description of the course of the disease and its timely response to treatments. In this study, a method using a micro-computed tomography (CT) scanner for the detection of the development of lung tumors in a mouse model of lung adenocarcinoma is described. Next, we show that monthly follow-up with micro-CT can identify dynamic changes in the lung tumor, such as the appearance of additional nodules, increase in the size of previously detected nodules, and decrease in the size or complete resolution of nodules in response to treatment. Finally, the accuracy of this real-time assessment method was confirmed with end-point histological quantification. This technique paves the way for planning and conducting more complex experiments on lung cancer animal models, and it enables us to better understand the mechanisms of carcinogenesis and the effects of different treatment modalities while saving time and resources.

We describe a method for the detection of tumor nodule development in the lungs of an adenocarcinoma mouse model using micro-computed tomography and its use for monitoring changes in nodule size over time and in response to treatment. The accuracy of the assessment was confirmed with end-point histological quantification.

Lung cancer is the most lethal cancer in the world. Intensive research is ongoing worldwide to identify new therapies for lung cancer. Several mouse ...

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.

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 ...

Electromagnetic Navigation Transthoracic Nodule Localization for Minimally Invasive Thoracic Surgery

The increased use of chest computed tomography (CT) has led to an increased detection of pulmonary nodules requiring diagnostic evaluation and/or excision. Many of these nodules are identified and excised via minimally invasive thoracic surgery; however, subcentimeter and subsolid nodules are frequently difficult to identify intra-operatively. This can be mitigated by the use of electromagnetic transthoracic needle localization. This protocol delineates the step-by-step process of electromagnetic localization from the pre-operative period to the postoperative period and is an adaptation of the electromagnetically guided percutaneous biopsy previously described by Arias et al. Pre-operative steps include obtaining a same day CT followed by the generation of a three-dimensional virtual map of the lung. From this map, the target lesion(s) and an entry site are chosen. In the operating room, the virtual reconstruction of the lung is then calibrated with the patient and the electromagnetic navigation platform. The patient is then sedated, intubated, and placed in the lateral decubitus position. Using a sterile technique and visualization from multiple views, the needle is inserted into the chest wall at the prechosen skin entry site and driven down to the target lesion. Dye is then injected into the lesion and, then, continuously during needle withdrawal, creating a tract for visualization intra-operatively. This method has many potential benefits when compared to the CT-guided localization, including a decreased radiation exposure and decreased time between the dye injection and the surgery. Dye diffusion from the pathway occurs over time, thereby limiting intra-operative nodule identification. By decreasing the time to surgery, there is a decrease in wait time for the patient, and less time for dye diffusion to occur, resulting in an improvement in nodule localization. When compared to electromagnetic bronchoscopy, airway architecture is no longer a limitation as the target nodule is accessed via a transparenchymal approach. Details of this procedure are described in a step-by-step fashion.

Presented here is a protocol for lung nodule localization using dye marking via electromagnetically navigated transthoracic needle access. The technique described here can be accomplished in the peri-operative period to optimize nodule localization and to successful resection when performing minimally invasive thoracic surgery.

Dynamic Lung Tumor Tracking for Stereotactic Ablative Body Radiation Therapy

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