|Year : 2014 | Volume
| Issue : 3 | Page : 519-525
Stereotactic body radiation therapy for liver metastasis-Case report and review of the literature. The role of patient preparation, treatment planning and its delivery
Marta Adamczyk1, Magdalena Fundowicz2
1 Department of Medical Physics, Greater Poland Cancer Centre, Poznan, Poland
2 Department of Radiotherapy Ward I, Greater Poland Cancer Centre, Poznan, Poland
|Date of Web Publication||14-Oct-2014|
M.Sc. Department of Medical Physics, Greater Poland Cancer Centre, 15th Garbary Street, 61-866 Poznan
Source of Support: None, Conflict of Interest: None
Background: Stereotactic body radiation therapy (SBRT) is reported as a well-tolerated treatment modality, which offers a long-term tumor control.
Aims: The aim of the following study is to present the place of proposed treatment preparation and its delivery for liver metastases with conventional linear accelerator among reported SBRT protocols.
Materials and Methods: We present our treatment preparation, planning and set-up verification procedure performed for liver metastasis. The prescription dose of 45 Gy was delivered in 3 fractions with cone beam computed tomography and 2-dimensional guidance.
Results: The conventional 3-dimensional conformal plan, which fulfilled all dose constraints for target and organs at risk, was accepted for the treatment. Almost for all performed patient position verifications, on-line evaluated results were kept under 5 mm.
Conclusions: The analysis presents the possible way of treating patients with liver metastasis. The SBRT treatment prepared and verified according our protocol can be implemented in clinical practice for a vast majority of such patients. The literature validation of our liver SBRT protocol showed that it has the potential for ensuring the effective and patient-friendly delivery.
Keywords: Fiducial markers, image guided radiation therapy, liver, stereotactic body radiation therapy, tumor set-up
|How to cite this article:|
Adamczyk M, Fundowicz M. Stereotactic body radiation therapy for liver metastasis-Case report and review of the literature. The role of patient preparation, treatment planning and its delivery. J Can Res Ther 2014;10:519-25
|How to cite this URL:|
Adamczyk M, Fundowicz M. Stereotactic body radiation therapy for liver metastasis-Case report and review of the literature. The role of patient preparation, treatment planning and its delivery. J Can Res Ther [serial online] 2014 [cited 2019 Sep 17];10:519-25. Available from: http://www.cancerjournal.net/text.asp?2014/10/3/519/137909
| > Introduction|| |
The number of patients with liver or early-stage non-small cell cancer treated using stereotactic body radiation therapy (SBRT) is increasing rapidly. ,,, It is a therapeutic option, which enables to irradiate the target with a high dose while at the same time sparing the surrounding healthy tissues. ,,, Thus, the study was designed to validate treatment planning and set-up verification protocol for SBRT liver metastasis, by presenting the clinical case and focusing on treatment preparation and its delivery with a conventional linear accelerator. The proposed scheme of treatment preparation, planning and set-up verification was compared with the literature data.
| > Materials and Methods|| |
The adult patient (54-year-old man) was qualified to receive the SBRT for colorectal adenocarcinoma with two liver metastases located so close to each other, that they were contoured as one connected target. The diameter of each metastasis was smaller than 30 mm.
In our center, the preparation for SBRT treatment starts during the operation. When it turns out that the tumor is larger than it was estimated before operation, a resection or radiofrequency ablation cannot be performed. In such cases, the surgeon with radiation oncologist implant between 2 and 4 fiducial markers in healthy tissues, in a strategic, non-planar geometric relationship with each other. The implantation process is visually conducted and it allows to monitor the tumor movement during the external beam radiation therapy (EBRT) treatment.
At 1-2 weeks after the operation, the appropriate preparation for SBRT treatment started by forming the vacuum pillow on which the patient is positioned frameless in a standard supine position.  To avoid the possible beams' entering through the patient's hands, his arms are abducted alongside the head.  In addition, to improve patient's comfort during the irradiation process the knee support is used. Before planning computed tomography (CT) acquisition, which is taken on Somatom Emotion Duo (Siemens, Erlangen, Germany), the patient is also instructed to avoid breathing too deeply. CT images are acquired at 3 mm slice spacing in different breathing conditions:
- Free shallow breathing for planning purpose ,
- Deep inspiration with maintaining the position
- Free shallow breathing with contrast enhancement (after intravenous radiographic contrast material infusion). 
All acquired CT sets are transferred to Eclipse v. 10.0 Treatment Planning System (Varian Medical Systems, Palo Alto, USA). Based on all images registration, target volumes and organs at risk (OARs) are delineated by the physician on a free breathing CT scan. , The information from other CT series is taken into account to expand the target contour to all possible positions. Target volume is delineated by a single physician assisted by a radiologist. The gross tumor volume (GTV) is considered to be identical with the clinical target volume (CTV) and expanded by 5-mm margin, except 10 mm in the craniocaudal direction, to create the planning target volume (PTV) ,, to account for the respiratory motion observed at the time of simulation.
The OARs outlined for this clinical case include the healthy liver (liver volume from which PTV is subtracted), spinal cord, stomach, esophagus, bowel, heart, right and left kidney. The dose delivered to those OARs is minimized to fulfill constraints presented in [Table 1]. Those dose constraints were adopted to the protocol according to the guidelines proposed by different groups. ,
|Table 1: Dose constraints to organs at risk (D700ml - the dose received by 700 ml of the analyzed organ; DX% - the dose delivered to x% of the analyzed organ; D1CC - the dose delivered to 1cc of the analyzed organ)|
Click here to view
The treatment planning guidelines were conventional in terms of preparing the isocentrical external beam delivery plan with isocenter established on the GTV center of the mass. According to the numerous literature findings as well as randomized trial assumptions published by the International Liver Tumor Group,  the dose is normalized to prescribe 100% of the dose to the mean GTV. At the same time, jaws and multileaf collimator (MLC) should be adopted and fitted to encompass GTV and PTV volumes by at least 95% and 67% - isodose, respectively. ,,
According to our SBRT treatment protocol, the upper limit of 20 Gy/fraction (total dose of 60 Gy in three fractions) was selected as the highest dose to be delivered. , Although liver as a parallel organ, appears capable of receiving high doses of radiation as long as a sufficient volume of healthy tissue is spared, now we limit the upper dose limit to 20-25 Gy, as further dose escalation increases the risk to adjacent abdominal structures. 
The protocol assumed that the treatment plan should be prepared in a conventional 3-dimensional conformal radiotherapy technique with 6 MV photons and dose rate of 600 MU/min. Dosimetric calculation should be conducted using the Anisotropic Analytical Algorithm with heterogeneity correction.  Apart from fulfilling the GTV, PTV and OARs requirements, treatment plan can be positively verified if it is prepared to maximally conform the target volume. Thus, the geometry of the plan should be proposed taking into account tumor size, its boundary or medial location and vasculature projection in the treated area.  These all should result in anatomical adjustment of gantry angles and collimator rotations. To enhance the dose homogeneity, field weighting and wedges can be used.
According to our clinical possibilities, Varian environment (Eclipse v. 10.0 Treatment Planning System, Clinac 2300C-D linear accelerator with On-board Imager, OBI and 120 Millennium MLC with 0.5 cm width in isocenter) is used to prepare and deliver the treatment.
| > Results|| |
For the presented case with prescription dose of 45 Gy delivered in 3 fractions, the beam arrangement consisted of eight coplanar beams with gantry angles at 5°, 35°, 175°, 200°, 240°, 270°, 305° and 335°. As the PTV was created as 177.2-cc structure, the field sizes were quite big with beams' length of 6.7 cm for almost all fields and their width ranged between 6.7 and 8.5 cm.
Finally, dose volume histogram (DVH) parameters and visual inspection of isodose distribution were evaluated for the acceptance of the prepared treatment plan. For the presented case, the volume of uninvolved liver (normal liver-PTV) equaled 2039.8cc and it was 177.2cc smaller than the whole liver volume. One of the most critical conditions ,, was fulfilled by giving 700cc of the healthy liver the dose of 14.4 Gy. The maximum dose per fraction for the spinal cord equaled <1.5 Gy. The maximum cumulative dose in the left kidney was minimized to the maximum dose of 2.2 Gy. The maximum dose administered to the right kidney equaled 27.2 Gy with the mean dose of 3.0 Gy. Thus, the dose delivered to its 50% equaled 0.8 Gy and the dose received by 35% of both kidneys volume was 0.7 Gy. All other OARs for which the dose delivered to 1cc should be minimized, as was presented in [Table 1], did not reach the maximum dose value >6.7 Gy. Detailed information about descriptive statistics for DVH parameters are presented in [Table 2].
|Table 2: The maximum, minimum, mean and median doses of treatment plan's dose volume histogram|
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For all hypofractionation schedules, three equal fractions were delivered according to two schemes proposed in our SBRT protocol: irradiation every 2 nd day - if the treatment starts on Monday (Monday, Wednesday and Friday). Otherwise fractions should be delivered on Tuesday, Thursday and Monday. Both irradiation patterns combined the criteria applied in different cancer centers: Three dose fractions delivered on 1 week (Erasmus), the total course of SBRT completed within 14 days  and each isocenter treated within 8 days with each fraction delivered with a minimum time interval of 40 h. 
Just before the first treatment fraction, the patient should be simulated on a simulation suite mainly due to the possibility of breathing motion observation and to give additional breathing instructions, if needed. Furthermore, the initial patient set-up and skin marks should be prepared during simulation.
Before each treatment session, a system of wall-mounted alignment lasers was used for initial, daily patient positioning. Then set-up prior to each fraction is performed using co-registration between kV cone beam CT scans (CBCT) and planning CT scans  to determine the actual position of the targeted liver volume (performed as marker-based verification) and the actual localization of the kidneys. In case of any, even smallest, deviation the plan's isocenter was adjusted according to the detected results.  After making a CBCT-based shift, the additional kV imaging was done, to confirm the proper position of the tumor on the basis of actual marker localization. Then, the irradiation started, but patient set-up was repeated after the first half of the treatment (after first four fields) in order to correct the possible intrafraction movement of the patient  and after all fields' delivery to observe the final tumor position.
For the presented case, before the first fraction, the pre-treatment CBCT verification results equaled 0.6, −0.5 and 0.0 cm in the vertical (vrt), longitudinal (lng) and lateral (lat) direction, respectively. This verification part was the only one during which the movement bigger than 0.5 cm was detected. The signs of individual values were introduced according to the signs of the Cartesian system with the beginning set in each treatment plan isocenter.  The positive directions of vrt, lng and lat axes correspond to the posterior, superior and left side of the patient, respectively. Detailed information about observed patient repositioning and tumor relocation accomplished by referencing markers is presented in [Table 3].
|Table 3: Values of CBCT and kV match results in three directions: Vertical, longitudinal and lateral|
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According to the protocol, all images registrations should be validated by a radiation oncologist and a medical physicist prior to treatment fields delivery. , For both imaging types, an approach of using only three translational directions in the image registrations was applied. Rotational errors were only monitored to be below the limited value of 3°,  as they could not be corrected by the treatment coach.  For the presented case, all observed rotational error values were under 0.8°.
| > Discussion|| |
SBRT is a treatment approach which enables to spare the surrounding healthy tissues while irradiating the target with a high dose (according to different reported SBRT treatment schedules, the total dose between 15-60 Gy is delivered in 3-6 fractions). Especially for patients with limited liver metastasis or primary tumor, who are not surgical candidates or refuse surgery or chemotherapy, SBRT is a rational therapeutic option. In general, patients with up to four metastases and with maximum diameter of largest metastasis of no more than 40 mm are selected for SBRT treatment,  but some authors describe even the treatment procedures performed for 110-mm hepatic metastasis.  To pass other important SBRT treatment patient selection criteria, all of them should have normal liver function, as well as adequate bone marrow function.  In the clinical practice, patients with colorectal adenocarcinoma with liver metastases occurs more frequently.  Rarely the breast, lung, kidney, pancreas or neuro-endocrine tumors are examined as primary tumors. 
SBRT, on one hand enables to provide better local control while on the other hand, it minimizes the probability of normal tissues' complication rates. , According to published data, this EBRT technique is a well-tolerated treatment modality which offers a long-term tumor control and subsequently, might have a positive effect on survival. , What also should be underlined, it is a promising treatment option for all medically inoperable patients with primary liver tumors as well as a number of other abdominal tumor types which are associated with a poor prognosis when resection is not possible. , Thus, SBRT seems to be an alternative mainly due to the fact that it is non-invasive and does not require anesthesia. 
Researchers have reported encouraging data for liver metastases treated with SBRT. For example Katz et al.  have reported a local control rate of 76% and 57% at 10 and 20 months respectively, after treatment in the group which consist of 69 patients. A study by Schefter et al.  in liver metastases phase I trial on 16 patients, reported the possibility to increase the dose delivered in three fractions up to 60 Gy without any toxicity limitations. The Schefter et al.  study results were updated with the data about actuarial local control rate at the level of 93% at 18 months.  Furthermore, Hoyer et al.  in the publication of Danish phase II study for liver metastases treated with total dose of 45 Gy in three fractions, demonstrated local control rates at 1 and 2 years after SBRT on the level of 89% and 79%, respectively. Finally, phase I-II study performed by Wulf et al.  demonstrated a local control rate of 76% 1 year after the treatment and 61% within the 2-year period for the group of patients treated mostly in 3 fractions to the total dose of 30 Gy.
Observed side effect is generally mild - range from grade 1-2 (grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; grade 2: Moderate; minimal, local or noninvasive intervention indicated) in the Common Terminology Criteria for Adverse Events (CTCAE v. 4). The most common acute toxicities for liver metastases patients treated with SBRT protocols include nausea, vomiting, gastritis, hepatic pain. 
Due to all those improvements, there has been a great interest in techniques, modalities and treatment schemes of SBRT that could be implemented in the clinical practice. Introducing the SBRT for patients with primary or secondary liver tumors  should start with preparing the procedure, which will cover all steps of treatment (from medical examination to irradiation and then follow-up) and validate it taking into account the technical possibilities of each cancer center.  Focusing on all stages connected with irradiation, first the prescription dose models should be selected, as different doses are prescribed and different planning strategies are employed in particular centers. According to the SBRT assumptions, the highest dose per fraction (starting from 5.0 Gy to even 25.0 Gy) ,,, is delivered to small targets' volumes. Although while higher radiotherapy doses are prescribed, the improved local control and survival rates have been observed. Even if the highest scheme of dose per fraction is used, all literature reports underline that if dose reduction is needed, based on localization of a tumor close to OARs (OARs: Esophagus, stomach, bowel and kidney), it is allowed to choose a lower dose level for this target. In cases when there is more than one metastasis, it is allowed to choose a lower dose level for the target, which is located near the critical structure and higher dose level for the non-critical targets.  In other cases, all tumors in one patient should be treated with the same dose level  following the rule that the best plan is the one with the highest prescribed dose, without exceeding any of the OARs constraint levels.  In most of the centers, the dose is delivered in 3 fractions, with exceptional irradiations, which were carried out by the external beam treatment in 2 or 4 fractions (Karolinska Institute)  or in 6 fractions (Toronto). It is important, as from radiobiological point of view fractionation enables to take advantage of tumor clonogens redistribution into sensitive phase and reoxygenation of otherwise radioresistant hypoxic tumor.  Knowing the prescribed dose and number of fractions, one can create a plan with as steep dose gradients of the dose outside the PTV as could be reached. It concerns not only minimizing the dose to OARs, but all surrounding normal tissues, because high ablative PTV doses, would also destroy them. , As a consequence, the dose is delivered from multiple beams accurately to ablate the target. , In most of the cases reported in literature, the field number is from five to ten. ,, Usually, the treatment is delivered using the coplanar beams with manually selected beams' orientations. ,,
As the presented SBRT procedure bases on delivering high radiation doses in single fractions with steep dose gradients outside the tumor volume,  creating a clinical protocol to prepare and deliver this kind of treatment is mandatory. Before performing new kind of treatment, the awareness what, why and in which order every step should be taken is necessary. Then, even if some in-house limitations occur, the protocol answers the question how to control the procedure nonetheless. In our study, such limiting factor is respiratory motion, which poses a significant challenge in abdomen region treatment. , According to the literature data reported by Balter et al.,  respiratory associated movement of the liver can range to even 30 mm in the superior-inferior direction. Such motion amplitude can distort the shape of an irradiated volume preventing effective dose escalation both during preparing target contours and verifying patient set-up before each fraction. Adding possible inter-observer variabilities to those mentioned above leads to a so-called "net effect,"  which is a limiting factor for obtaining a clinically accurate delivered dose distribution compared with the "real" one. Thus, breathing control is performed not only through each fraction but also during the acquisition of images done for the planning purpose. The potential of dealing with tumor motion in SBRT was improved by the introduction of 4-dimensional CT (4D CT) imaging. This imaging tool is widely used to accurately compensate for exhalation and inhalation. , Thus, with 4D CT, contoured internal target volume incorporates the tumor motion as it was visualized throughout the breathing cycle.  Without CT which enables to achieve 4-dimentional scanning or eventually ultra-slow scanning,  we prepared the reconstruction in different modes, which after registration, gave us the information about tumor expansion in different breathing conditions. According to our protocol, no external immobilization devices were used. If patient's general condition was good, we asked him to follow the instructions regarding shallow breathing. According to a study of Kim et al.  attempts to control internal movement by shallow, deep breathing or breath-hold resulted in minimizing the intrafractional diaphragm movement to 2-3 mm. The same authors, for the same breathing conditions, reported the 5-mm interfractional diaphragm movement, which consequently significantly reduced the liver movement reported by Balter et al.  Unfortunately, not every patient is able to follow breathing instructions.  Thus, to minimize the motion effects connected with breathing, a stereotactic body frame ,,, (rarely personalized body mask)  with abdominal compression is mostly used. The final effect of using breathing instructions as well as all external abdominal compression solutions is to make the patient breathe shallowly.  What should be underlined, the frame gives the external coordinate system that is visible on CT and establishes the reference system for positioning. , With the technology improvement, another group of solutions to minimize breathing motion effects on fraction dose distributions was developed. It is represented by all respiratory-gated systems which aim to irradiate the patient at selected phases of the respiratory cycle.  Its potential in reducing PTV margin size for compensating tumor motion was described by Law et al.  In this article, the group from China underlined that respiratory control increases the feasibility of dose escalation to tumor while sparing the normal tissues around it.  Unfortunately, Law et al.  agreed that the main drawback of using respiratory gating is a prolonged treatment time. This is a relevant consideration for SBRT delivery, as daily treatment times (considered as total time during which the patient is lying on the treatment table) are advised to be <45 min.  According to Schefter et al.,  on one hand this time restriction gives the possibility to minimize the patient inconvenience and discomfort associated with immobilized treatment position. On the other hand, time restriction is connected with radiobiological basis, specifically with the possibility of detrimental effects of intrafraction radiation repair, which, due to an American group, occurs during lengthy individual treatments.  The time restriction is the main criterion why non-coplanar linac-based delivery, which, according to de Pooter et al.  improves liver plans, is not widely used in clinical practice. This problem is solved in centers where the novel approach of treatment delivery techniques like volumetric-modulated arc therapy have been implemented but still the awareness of motion detection and its compensation prolongs the fraction time. The utilization of CyberKnife eliminates the use of any previously mentioned systems due to respiration compensation by real-time image-guidance with beam position adjustment (both intrafractional rotational and translational movements) according to the fiducials position (target-tracking Synchrony). , Apart from intrafraction real-time imaging with adjustment of beams position, before each CyberKnife treatment Xsight spine positioning is performed to check body alignment and to verify the possible fiducials migration.  Without CyberKnife, the guidance on the basis of images obtained using CT scanners within the treatment room (helical MV CT or kV cone-beam CT scanners) enables to guide and monitor the fraction treatment. Just like for CyberKnife Synchrony, the fiducials are recommended for CBCT positioning. Unfortunately, due to a poor image contrast between tumor and liver tissues on both non-contrast planning CT and CBCT images, without fiducials a tumor-based match between planning and pre-treatment CTs is unfeasible. , Among others, Worm et al.  or Dawood et al.  in their study have reported that using CT-guidance helps prevent critical errors connected with initial tumor positioning and ensure proper radiation delivery exactly to the target. According to Méndez Romero et al.  pre-treatment CT corrections implemented during liver SBRT reduced the loss in target volume irradiation from 6.8% to 1.7% without a significant impact on doses delivered to critical structures. The lack of information about OARs on 2-dimensional (2D) kV or MV images is the main reason why CT-guidance is recommended instead of performing 2D orthogonal images with fiducials as surrogates.  In clinics without the possibility of fiducial implantation during operation, through CT - or ultrasound guidance, usually liver-to-liver fusion  or bony landmarks registration  are used as the base for liver SBRT pre-treatment set-up. Strictly speaking, the position of the vertebral spine on the level of the lesion, called "surrogate isocenter," is verified as it was reported by Worn et al.  It is partly true, as liver and bony landmarks can move independently.  Of course, the direct proportion of losing the accuracy of positioning while the distance from tumor to the vertebral spine becomes larger, must be taken into account during bony anatomy patient set-up.  Except compensating the breathing motion by using different positioning approaches, the adequate CTV to PTV set-up margin adoption is necessary. The CTV-PTV margin should be applied according to the technical possibilities of radiation delivery (the type of immobilization devices and respiratory motion technique).  Thus, the proper margin size maximizes the probability of delivering a prescribed dose to the tumor.  According to our protocol, to create the PTV, the CTV was expanded by 5-mm margin, except 10 mm in the craniocaudal direction. This correlates with literature data presented by Schefter et al.  or Worm et al.  Such margins were applied in case of linear-accelerator based SBRT without 4D CT.  These numbers can be modified into 3-8 mm when dedicated machines like CyberKnife are used. 
| > Conclusion|| |
The analysis presents a possible way of treating patients with liver tumor and metastasis. The liver SBRT treatment prepared and verified according to our protocol with coplanar static beams have the potential to deliver accepted doses to the PTV while at the same time significantly reducing dose to critical organs. The adopted treatment preparation and image guided radiation therapy verification protocol was appropriate and can be implemented in clinical practice for a vast majority of patients. As our treatment approach bases on SBRT delivery with no motion restrictive external immobilization, breathing instructions and frequent on-line imaging cannot be neglected. Due to the mentioned capability of delivering various doses with different equipment and generally speaking, technical possibilities, literature validation of our liver SBRT protocol proves it suitable for patients with liver metastases and shows the potential for effective and patient-friendly delivery.
| > References|| |
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[Table 1], [Table 2], [Table 3]