Alejandra Méndez Romero

Stereotactic body radiation therapy for primary and metastatic liver tumors: A single institution phase i-ii study

The feasibility, toxicity and tumor response of stereotactic body radiation therapy (SBRT) for treatment of primary and metastastic liver tumors was investigated. From October 2002 until June 2006, 25 patients not suitable for other local treatments were entered in the study. In total 45 lesions were treated, 34 metastases and 11 hepatocellular carcinoma (HCC). Median follow-up was 12.9 months (range 0.5–31). Median lesion size was 3.2 cm (range 0.5–7.2) and median volume 22.2 cm3 (range 1.1–322). Patients with metastases, HCC without cirrhosis, and HCC < 4 cm with cirrhosis were mostly treated with 3×12.5 Gy. Patients with HCC ≥4cm and cirrhosis received 5×5 Gy or 3×10 Gy. The prescription isodose was 65%. Acute toxicity was scored following the Common Toxicity Criteria and late toxicity with the SOMA/LENT classification. Local failures were observed in two HCC and two metastases. Local control rates at 1 and 2 years for the whole group were 94% and 82%. Acute toxicity grade ≥3 was seen in four patients; one HCC patient with Child B developed a liver failure together with an infection and died (grade 5), two metastases patients presented elevation of gamma glutamyl transferase (grade 3) and another asthenia (grade 3). Late toxicity was observed in one metastases patient who developed a portal hypertension syndrome with melena (grade 3). SBRT was feasible, with acceptable toxicity and encouraging local control. Optimal dose-fractionation schemes for HCC with cirrhosis have to be found. Extreme caution should be used for patients with Child B because of a high toxicity risk.

Radiotherapy for Liver Metastases: A Review of Evidence

Over the past decade, there has been an increasing use of radiotherapy (RT) for the treatment of liver metastases. Most often, ablative doses are delivered to focal liver metastases with the goal of local control and ultimately improving survival. In contrast, low-dose whole-liver RT may be used for the palliation of symptomatic diffuse metastases. This review examines the available clinical data for both approaches. The review found that RT is effective both for local ablation of focal liver metastases and for palliation of patients with symptomatic liver metastases. However, there is a lack of a high level of evidence from randomized clinical trials.

Reduction of Respiratory Liver Tumor Motion by Abdominal Compression in Stereotactic Body Frame, Analyzed by Tracking Fiducial Markers Implanted in Liver

PURPOSE To investigate in a three-dimensional framework the effectiveness and reproducibility of reducing the respiratory motion of liver tumors using abdominal compression in a stereotactic body frame. METHODS AND MATERIALS A total of 12 patients with liver tumors, who were treated with stereotactic body radiotherapy, were included in this study. These patients had three gold fiducial markers implanted in the healthy liver tissue surrounding the tumor. Fluoroscopic videos were acquired on the planning day and before each treatment fraction to visualize the motion of the fiducial markers during free breathing and varying levels of abdominal compression. Software was developed to track the fiducial markers and measure their excursions. RESULTS Abdominal compression reduced the patient group median excursion by 62% in the craniocaudal and 38% in the anteroposterior direction with respect to the median free-breathing excursions. In the left-right direction, the median excursion increased 15% (maximal increase 1.6 mm). The median residual excursion was 4.1 mm in the craniocaudal, 2.4 mm in the anteroposterior, and 1.8 mm in the left-right direction. The mean excursions were reduced by compression to <5 mm in all patients and all directions, with two exceptions (craniocaudal excursion reduction of 20.5 mm to 7.4 mm and of 21.1 mm to 5.9 mm). The residual excursions reproduced well during the treatment course, and the craniocaudal excursions measured on the treatment days were never significantly (alpha = 0.05) greater than on the planning days. Fine tuning the compression did not considerably change the excursion on the treatment days. CONCLUSIONS Abdominal compression effectively reduced liver tumor motion, yielding small and reproducible excursions in three dimensions. The compression level established at planning could have been safely used on the treatment days.

POTENTIALS AND LIMITATIONS OF GUIDING LIVER STEREOTACTIC BODY RADIATION THERAPY SET-UP ON LIVER-IMPLANTED FIDUCIAL MARKERS

PURPOSE We investigated the potentials and limitations of guiding liver stereotactic body radiation therapy (SBRT) set-up on liver-implanted fiducial markers. METHODS AND MATERIALS Twelve patients undergoing compression-supported SBRT in a stereotactic body frame received fluoroscopy at treatment preparation and before each treatment fraction. In fluoroscopic videos we localized the markers and diaphragm tip at expiration and the spine (measurements on free-breathing and abdominal compression). Day-to-day displacements, rotations (markers only), and deformations were determined. Marker guidance was compared to conventional set-up strategies in treatment set-up simulations. RESULTS For compression, day-to-day motion of markers with respect to their centers of mass (COM) was sigma = 0.9 mm (random error SD), Sigma = 0.4 mm (systematic error SD), and <2.1 mm (maximum). Consequently, assuming that markers were closely surrounding spherical tumors, marker COM-guided set-up would have required safety margins of approximately 2 mm. Using marker COM as the gold standard, other set-up methods (using no correction, spine registration, and diaphragm tip craniocaudal registration) resulted in set-up errors of 1.4 mm < sigma < 2.8 mm, 2.6 mm < Sigma < 5.1 mm, and 6.3 mm < max < 12.4 mm. Day-to-day intermarker motion of <16.7%, 2.2% median, and rotations between 3.5 degrees and 7.2 degrees were observed. For markers not surrounding the tumor, e.g., 5 cm between respective COMs, these changes could effect residual tumor set-up errors up to 8.4 mm, 1.1 mm median (deformations), and 3.1 mm to 6.3 mm (rotations). Compression did not systematically contribute to deformations and rotations, since similar results were observed for free-breathing. CONCLUSIONS If markers can be implanted near and around the tumor, residual set-up errors by marker guidance are small compared to those of conventional set-up methods, allowing high-precision tumor radiation set-up. However, substantial errors may result if markers are not implanted precisely, requiring further research to obtain adequate safety margins.

STEREOTACTIC BODY RADIATION THERAPY FOR LIVER TUMORS: IMPACT OF DAILY SETUP CORRECTIONS AND DAY-TO-DAY ANATOMIC VARIATIONS ON DOSE IN TARGET AND ORGANS AT RISK

PURPOSE To assess day-to-day differences between planned and delivered target volume (TV) and organ-at-risk (OAR) dose distributions in liver stereotactic body radiation therapy (SBRT), and to investigate the dosimetric impact of setup corrections. METHODS AND MATERIALS For 14 patients previously treated with SBRT, the planning CT scan and three treatment scans (one for each fraction) were included in this study. For each treatment scan, two dose distributions were calculated: one using the planned setup for the body frame (no correction), and one using the clinically applied (corrected) setup derived from measured tumor displacements. Per scan, the two dose distributions were mutually compared, and the clinically delivered distribution was compared with planning. Doses were recalculated in equivalent 2-Gy fraction doses. Statistical analysis was performed with the linear mixed model. RESULTS With setup corrections, the mean loss in TV coverage relative to planning was 1.7%, compared with 6.8% without corrections. For calculated equivalent uniform doses, these figures were 2.3% and 15.5%, respectively. As for the TV, mean deviations of delivered OAR doses from planning were small (between -0.4 and +0.3 Gy), but the spread was much larger for the OARs. In contrast to the TV, the mean impact of setup corrections on realized OAR doses was close to zero, with large positive and negative exceptions. CONCLUSIONS Daily correction of the treatment setup is required to obtain adequate TV coverage. Because of day-to-day patient anatomy changes, large deviations in OAR doses from planning did occur. On average, setup corrections had no impact on these doses. Development of new procedures for image guidance and adaptive protocols is warranted.

What intervention is best practice for vestibular schwannomas? A systematic review of controlled studies

Objective Largely, watchful waiting is the initial policy for patients with small-sized or medium-sized vestibular schwannoma, because of slow growth and relatively minor complaints, that do not improve by an intervention. If intervention (microsurgery, radiosurgery or fractionated radiotherapy) becomes necessary, the choice of intervention appears to be driven by the patients or clinicians preference rather than by evidence based. This study addresses the existing evidence based on controlled studies of these interventions. Design A systematic Boolean search was performed focused on controlled intervention studies. The quality of the retrieved studies was assessed based on the Sign-50 criteria on cohort studies. Data sources Pubmed/Medline, Embase, Cochrane Central Register of Controlled Trials and reference lists. Study selection Six eligibility criteria included a controlled intervention study on a newly diagnosed solitary, vestibular schwannoma reporting on clinical outcomes. Two prospective and four retrospective observational, controlled studies published before November 2011 were selected. Data analysis Two reviewers independently assessed the methodological quality of the studies and extracted the outcome data using predefined formats. Results Neither randomised studies, nor controlled studies on fractionated radiotherapy were retrieved. Six studies compared radiosurgery and microsurgery in a controlled way. All but one were confined to solitary tumours less than 30 mm in diameter and had no earlier interventions. Four studies qualified for trustworthy conclusions. Among all four, radiosurgery showed the best outcomes: there were no direct mortality, no surgical or anaesthesiological complications, but better facial nerve outcome, better preservation of useful hearing and better quality of life. Conclusions The available evidence indicates radiosurgery to be the best practice for solitary vestibular schwannomas up to 30 mm in cisternal diameter.

Automated non-coplanar beam direction optimization improves IMRT in SBRT of liver metastasis

PURPOSE To investigate whether automatically optimized coplanar, or non-coplanar beam setups improve intensity modulated radiotherapy (IMRT) treatment plans for stereotactic body radiotherapy (SBRT) of liver tumors, compared to a reference equi-angular IMRT plan. METHODS For a group of 13 liver patients, an in-house developed beam selection algorithm (Cycle) was used for generation of 3D-CRT plans with either optimized coplanar-, or non-coplanar beam setups. These 10 field, coplanar and non-coplanar setups, and an 11 field, equi-angular coplanar reference setup were then used as input for generation of IMRT plans. For all plans, the PTV dose was maximized in an iterative procedure by increasing the prescribed PTV dose in small steps until further increase was prevented by constraint violation(s). RESULTS For optimized non-coplanar setups, D(PTV, max) increased by on average 30% (range 8-64%) compared to the corresponding reference IMRT plan. Similar increases were observed for D(PTV, 99%) and gEUD(a). For optimized coplanar setups, mean PTV dose increases were only approximately 4%. After re-scaling all plans to the clinically applied dose, optimized non-coplanar configurations resulted in the best sparing of organs at risk (healthy liver, spinal cord, bowel). CONCLUSION Compared to an equi-angular beam setup, computer optimized non-coplanar setups do result in substantial improvements in IMRT plans for SBRT of liver tumors.

Comparison of Macroscopic Pathology Measurements With Magnetic Resonance Imaging and Assessment of Microscopic Pathology Extension for Colorectal Liver Metastases

PURPOSE To compare pathology macroscopic tumor dimensions with magnetic resonance imaging (MRI) measurements and to establish the microscopic tumor extension of colorectal liver metastases. METHODS AND MATERIALS In a prospective pilot study we included patients with colorectal liver metastases planned for surgery and eligible for MRI. A liver MRI was performed within 48 hours before surgery. Directly after surgery, an MRI of the specimen was acquired to measure the degree of tumor shrinkage. The specimen was fixed in formalin for 48 hours, and another MRI was performed to assess the specimen/tumor shrinkage. All MRI sequences were imported into our radiotherapy treatment planning system, where the tumor and the specimen were delineated. For the macroscopic pathology analyses, photographs of the sliced specimens were used to delineate and reconstruct the tumor and the specimen volumes. Microscopic pathology analyses were conducted to assess the infiltration depth of tumor cell nests. RESULTS Between February 2009 and January 2010 we included 13 patients for analysis with 21 colorectal liver metastases. Specimen and tumor shrinkage after resection and fixation was negligible. The best tumor volume correlations between MRI and pathology were found for T1-weighted (w) echo gradient sequence (r(s) = 0.99, slope = 1.06), and the T2-w fast spin echo (FSE) single-shot sequence (r(s) = 0.99, slope = 1.08), followed by the T2-w FSE fat saturation sequence (r(s) = 0.99, slope = 1.23), and the T1-w gadolinium-enhanced sequence (r(s) = 0.98, slope = 1.24). We observed 39 tumor cell nests beyond the tumor border in 12 metastases. Microscopic extension was found between 0.2 and 10 mm from the main tumor, with 90% of the cases within 6 mm. CONCLUSIONS MRI tumor dimensions showed a good agreement with the macroscopic pathology suggesting that MRI can be used for accurate tumor delineation. However, microscopic extensions found beyond the tumor border indicate that caution is needed in selecting appropriate tumor margins.

Adaptive Liver Stereotactic Body Radiation Therapy: Automated Daily Plan Reoptimization Prevents Dose Delivery Degradation Caused by Anatomy Deformations

PURPOSE To investigate how dose distributions for liver stereotactic body radiation therapy (SBRT) can be improved by using automated, daily plan reoptimization to account for anatomy deformations, compared with setup corrections only. METHODS AND MATERIALS For 12 tumors, 3 strategies for dose delivery were simulated. In the first strategy, computed tomography scans made before each treatment fraction were used only for patient repositioning before dose delivery for correction of detected tumor setup errors. In adaptive second and third strategies, in addition to the isocenter shift, intensity modulated radiation therapy beam profiles were reoptimized or both intensity profiles and beam orientations were reoptimized, respectively. All optimizations were performed with a recently published algorithm for automated, multicriteria optimization of both beam profiles and beam angles. RESULTS In 6 of 12 cases, violations of organs at risk (ie, heart, stomach, kidney) constraints of 1 to 6 Gy in single fractions occurred in cases of tumor repositioning only. By using the adaptive strategies, these could be avoided (<1 Gy). For 1 case, this needed adaptation by slightly underdosing the planning target volume. For 2 cases with restricted tumor dose in the planning phase to avoid organ-at-risk constraint violations, fraction doses could be increased by 1 and 2 Gy because of more favorable anatomy. Daily reoptimization of both beam profiles and beam angles (third strategy) performed slightly better than reoptimization of profiles only, but the latter required only a few minutes of computation time, whereas full reoptimization took several hours. CONCLUSIONS This simulation study demonstrated that replanning based on daily acquired computed tomography scans can improve liver stereotactic body radiation therapy dose delivery.

Accurate CT∕MR vessel-guided nonrigid registration of largely deformed livers.

PURPOSE Computer tomography (CT) scans are used for designing radiotherapy treatment plans. However, the tumor is often better visible in magnetic resonance (MR) images. For liver stereotactic body radiation therapy (SBRT), the planning CT scan is acquired while abdominal compression is applied to reduce tumor motion induced by breathing. However, diagnostic MR scans are acquired under voluntary breath-hold without the compression device. The resulting large differences in liver shape hinder the alignment of CT and MR image sets, which severely limits the integration of the information provided by these images. The purpose of the current study is to develop and validate a nonrigid registration method to align breath-hold MR images with abdominal-compressed CT images, using vessels that are automatically segmented within the liver. METHODS Contrast-enhanced MR and CT images of seven patients with liver cancer were used for this study. The registration method combines automatic vessel segmentation with an adapted version of thin-plate spline robust point matching. The vessel segmentation uses a multiscale vesselness measure, which allows vessels of various thicknesses to be segmented. The nonrigid registration is point-based, and progressively improves the correspondence and transformation between two point sets. Moreover, the nonrigid registration is capable of identifying and handling outliers (points with no counterpart in the other set). We took advantage of the strengths of both methods and created a multiscale registration algorithm. First, thick vessels are registered, then with each new iteration thinner vessels are included in the registration (strategy A). We compared strategy A to a straightforward approach where vessels of various diameters are segmented and subsequently registered (strategy B). To assess the transformation accuracy, residual distances were calculated for vessel bifurcations. For anatomical validation, residual distances were calculated for additional anatomical landmarks within the liver. To estimate the extent of deformation, the residual distances for the aforementioned anatomical points were calculated after rigid registration. RESULTS Liver deformations in the range of 2.8-10.7 mm were found after rigid registration of the CT and MR scans. Low residual distances for vessel bifurcations (average 1.6, range 1.3-1.9 mm) and additional anatomical landmarks (1.5, 1.1-2.4 mm) were found after nonrigid registration. A large amount of outliers were identified (25%-55%) caused by vessels present in only one of the image sets and false positives in the vesselness measure. The nonrigid registration was capable of handling these outliers as was demonstrated by the low residual distances. Both strategies yielded very similar results in registration accuracy, but strategy A was faster than strategy B (≥2.0 times). CONCLUSIONS An accurate CT∕MR vessel-guided nonrigid registration for largely deformed livers was developed, tested, and validated. The method, combining vessel segmentation and point matching, was robust against differences in the segmented vessels. The authors conclude that nonrigid registration is required for accurate alignment of abdominal-compressed and uncompressed liver anatomy. Alignment of breath-hold MR and abdominal-compressed CT images can be used to improve tumor localization for liver SBRT.