Publications by authors named "David A Larson"

65 Publications

Accelerated Wound Closure of Deep Partial Thickness Burns with Acellular Fish Skin Graft.

Int J Mol Sci 2021 Feb 4;22(4). Epub 2021 Feb 4.

Burn and Soft Tissue Injury Research Department, US Army Institute of Surgical Research, JBSA Fort Sam Houston, Houston, TX 78234, USA.

Thermal injuries are caused by exposure to a variety of sources, and split thickness skin grafts are the gold standard treatment for severe burns; however, they may be impossible when there is no donor skin available. Large total body surface area burns leave patients with limited donor site availability and create a need for treatments capable of achieving early and complete coverage that can also retain normal skin function. In this preclinical trial, two cellular and tissue based products (CTPs) are evaluated on twenty-four 5 × 5 deep partial thickness (DPT) burn wounds. Using appropriate pain control methods, DPT burn wounds were created on six anesthetized Yorkshire pigs. Wounds were excised one day post-burn and the bleeding wound beds were subsequently treated with omega-3-rich acellular fish skin graft (FSG) or fetal bovine dermis (FBD). FSG was reapplied after 7 days and wounds healed via secondary intentions. Digital images, non-invasive measurements, and punch biopsies were acquired during rechecks performed on days 7, 14, 21, 28, 45, and 60. Multiple qualitative measurements were also employed, including re-epithelialization, contraction rates, hydration, laser speckle, and trans-epidermal water loss (TEWL). Each treatment produced granulated tissue (GT) that would be receptive to skin grafts, if desired; however, the FSG induced GT 7 days earlier. FSG treatment resulted in faster re-epithelialization and reduced wound size at day 14 compared to FBD (50.2% vs. 23.5% and 93.1% vs. 106.7%, < 0.005, respectively). No differences in TEWL measurements were observed. The FSG integrated into the wound bed quicker as evidenced by lower hydration values at day 21 (309.7 vs. 2500.4 µS, < 0.05) and higher blood flow at day 14 (4.9 vs. 3.1 fold change increase over normal skin, < 0.005). Here we show that FSG integrated faster without increased contraction, resulting in quicker wound closure without skin graft application which suggests FSG improved burn wound healing over FBD.
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http://dx.doi.org/10.3390/ijms22041590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915828PMC
February 2021

Enzymatic Debridement of Porcine Burn Wounds via a Novel Protease, SN514.

J Burn Care Res 2020 09;41(5):1015-1028

Department of Burn and Soft Tissue Research, US Army Institute of Surgical Research, JBSA Fort Sam Houston, Texas.

Necrotic tissue generated by a thermal injury is typically removed via surgical debridement. However, this procedure is commonly associated with blood loss and the removal of viable healthy tissue. For some patients and contexts such as extended care on the battlefield, it would be preferable to remove devitalized tissue with a nonsurgical debridement agent. In this paper, a proprietary debridement gel (SN514) was evaluated for the ability to debride both deep-partial thickness (DPT) and full-thickness burn wounds using an established porcine thermal injury model. Burn wounds were treated daily for 4 days and visualized with both digital imaging and laser speckle imaging. Strip biopsies were taken at the end of the procedure. Histological analyses confirmed a greater debridement of the porcine burn wounds by SN514 than the vehicle-treated controls. Laser speckle imaging detected significant increases in the perfusion status after 4 days of SN514 treatment on DPT wounds. Importantly, histological analyses and clinical observations suggest that SN514 gel treatment did not damage uninjured tissue as no edema, erythema, or inflammation was observed on intact skin surrounding the treated wounds. A blinded evaluation of the digital images by a burn surgeon indicated that SN514 debrided more necrotic tissue than the control groups after 1, 2, and 3 days of treatment. Additionally, SN514 gel was evaluated using an in vitro burn model that used human discarded skin. Treatment of human burned tissue with SN514 gel resulted in greater than 80% weight reduction compared with untreated samples. Together, these data demonstrate that SN514 gel is capable of debriding necrotic tissue and suggest that SN514 gel could be a useful option for austere conditions, such as military multi-domain operations and prolonged field care scenarios.
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http://dx.doi.org/10.1093/jbcr/iraa111DOI Listing
September 2020

Tissue Source and Cell Expansion Condition Influence Phenotypic Changes of Adipose-Derived Stem Cells.

Stem Cells Int 2017 23;2017:7108458. Epub 2017 Aug 23.

Combat Trauma and Burn Injury Research, US Army Institute of Surgical Research, San Antonio Military Medical Center, JBSA Ft Sam Houston, San Antonio, TX, USA.

Stem cells derived from the subcutaneous adipose tissue of debrided burned skin represent an appealing source of adipose-derived stem cells (ASCs) for regenerative medicine. Traditional tissue culture uses fetal bovine serum (FBS), which complicates utilization of ASCs in human medicine. Human platelet lysate (hPL) is one potential xeno-free, alternative supplement for use in ASC culture. In this study, adipogenic and osteogenic differentiation in media supplemented with 10% FBS or 10% hPL was compared in human ASCs derived from abdominoplasty (HAP) or from adipose associated with debrided burned skin (BH). Most (95-99%) cells cultured in FBS were stained positive for CD73, CD90, CD105, and CD142. FBS supplementation was associated with increased triglyceride content and expression of adipogenic genes. Culture in hPL significantly decreased surface staining of CD105 by 31% and 48% and CD142 by 27% and 35% in HAP and BH, respectively ( < 0.05). Culture of BH-ASCs in hPL also increased expression of markers of osteogenesis and increased ALP activity. These data indicate that application of ASCs for wound healing may be influenced by ASC source as well as culture conditions used to expand them. As such, these factors must be taken into consideration before ASCs are used for regenerative purposes.
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http://dx.doi.org/10.1155/2017/7108458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5613713PMC
August 2017

Mosquito Vectors of Avian Malaria in Mississippi: A First Look.

J Parasitol 2017 12 2;103(6):683-691. Epub 2017 Aug 2.

Department of Biological Sciences, Mississippi State University, Mississippi State, Mississippi 39762.

The vectors of avian malaria (Haemosporida) are an understudied component of wildlife disease ecology. Most studies of avian malaria have focused on the intermediate bird hosts. This bias leaves a significant gap in our knowledge and understanding of the insect hosts. This study investigates the diversity of malaria parasites carried by mosquitoes (Diptera, Culicidae) in the state of Mississippi. With the use of molecular techniques, haemosporidian infection rates were determined and parasites were identified. A total of 27,157 female mosquitoes representing 15 species were captured. Five of those species tested positive for malaria parasites with an overall infection rate of 4 per 1,000 mosquitoes infected. Mosquitoes were shown to harbor Plasmodium and Haemoproteus ( Parahaemoproteus) parasites. A unique lineage of parasites was discovered in Anopheles mosquitoes, potentially representing a new genus of haemosporidian parasites, reinforcing the need to continue investigating this diverse group of parasites.
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http://dx.doi.org/10.1645/17-66DOI Listing
December 2017

Stereotactic Body Radiotherapy for Spinal Metastases: Practice Guidelines, Outcomes, and Risks.

Cancer J 2016 Jul-Aug;22(4):280-9

From the *Department of Radiation Oncology, The Laurel Amtower Cancer Institute and Neuro-oncology Center, Sharp Healthcare, San Diego, CA; †Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA; ‡Department of Radiation Oncology, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, Ontario, Canada; §Department of Radiation Oncology, University of California San Francisco, San Francisco, CA; and ∥Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH.

Spine metastases can be a debilitating and difficult therapeutic challenge for a significant number of cancer patients. Surgical management of spine metastases is often limited because of the complexity, risks, and recovery delays associated with open invasive surgical procedures. Conventional palliative external beam radiation therapy is the most common treatment modality. However, it is associated with limited palliative efficacy and local tumor control, including in the postoperative setting. In the era of improving systemic disease control, spine stereotactic body radiotherapy is fast emerging as the therapeutic modality of choice for selected de novo, postoperative, and salvage reirradiation spine metastases patients. Considerable expertise, multidisciplinary collaboration, and rigid adherence to quality metrics are required for the safe application of this highly conformal ablative therapy. This review highlights the current state of the evidence, understanding of the late effects, and technological requirements for spine stereotactic body radiotherapy specific to spinal metastases.
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http://dx.doi.org/10.1097/PPO.0000000000000205DOI Listing
August 2017

Estimating the probability of underdosing microscopic brain metastases with hippocampal-sparing whole-brain radiation.

Radiother Oncol 2016 08 9;120(2):248-52. Epub 2016 Jul 9.

Department of Radiation Oncology, University of California, San Francisco, United States.

Purpose/objectives: Whole-brain radiation for brain metastases can result in cognitive side effects. Hippocampal-sparing techniques have been developed to decrease morbidity, but they carry the risk of underdosing lesions near the hippocampus due to the unavoidable dose gradient from the hippocampal surface to the prescription isodose surface. This study examines the impact of variable levels of hippocampal sparing on the underdosing of potential brain metastases.

Materials/methods: Helical intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) plans were developed for hippocampal-sparing whole-brain treatment. For all plans, 30Gy was prescribed in 10 fractions to result in mean hippocampal doses of 6-12Gy. From a series of expanded shells, we determined the distance from the hippocampus at which the parenchyma would receive less than specified doses. Then, using published data, a mathematical model was constructed to predict the incident probability of potential brain metastases receiving different doses for different levels of hippocampal sparing.

Results: Whole-brain radiation plans were able to spare the hippocampi to mean doses of 7-12Gy under our planning constraints; more stringent constraints compromised brain coverage. The dose gradients were ∼4% per mm, regardless of the hippocampal constraint, and they decreased sharply by a factor of almost 4 at approximately 15mm from the hippocampi. A mathematical model was constructed and combined the plan information with published data on the distribution of brain metastases, to determine the percentage of potential brain metastases receiving specified doses, as a function of technique and level of hippocampal sparing.

Conclusions: Our results describe the characteristics of an array of hippocampal-sparing whole-brain radiation dose distributions. These can be used as a decision-making guideline for weighing the benefit of decreased dose to the hippocampi against the cost of decreased dose to potential brain metastases when deciding on a hippocampal-sparing whole-brain irradiation treatment approach.
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http://dx.doi.org/10.1016/j.radonc.2016.05.030DOI Listing
August 2016

Discovery of additional brain metastases on the day of stereotactic radiosurgery: risk factors and outcomes.

J Neurosurg 2017 Jun 1;126(6):1756-1763. Epub 2016 Jul 1.

Departments of 1 Radiation Oncology.

OBJECTIVE High-resolution double-dose gadolinium-enhanced Gamma Knife (GK) radiosurgery-planning MRI (GK MRI) on the day of GK treatment can detect additional brain metastases undiagnosed on the prior diagnostic MRI scan (dMRI), revealing increased intracranial disease burden on the day of radiosurgery, and potentially necessitating a reevaluation of appropriate management. The authors identified factors associated with detecting additional metastases on GK MRI and investigated the relationship between detection of additional metastases and postradiosurgery patient outcomes. METHODS The authors identified 326 patients who received GK radiosurgery at their institution from 2010 through 2013 and had a prior dMRI available for comparison of numbers of brain metastases. Factors predictive of additional brain metastases on GK MRI were investigated using logistic regression analysis. Overall survival was estimated by Kaplan-Meier method, and postradiosurgery distant intracranial failure was estimated by cumulative incidence measures. Multivariable Cox proportional hazards model and Fine-Gray regression modeling assessed potential risk factors of overall survival and distant intracranial failure, respectively. RESULTS The mean numbers of brain metastases (SD) on dMRI and GK MRI were 3.4 (4.2) and 5.8 (7.7), respectively, and additional brain metastases were found on GK MRI in 48.9% of patients. Frequencies of detecting additional metastases for patients with 1, 2, 3-4, and more than 4 brain metastases on dMRI were 29.5%, 47.9%, 55.9%, and 79.4%, respectively (p < 0.001). An index brain metastasis with a diameter greater than 1 cm on dMRI was inversely associated with detecting additional brain metastases, with an adjusted odds ratio of 0.57 (95% CI 0.4-0.9, p = 0.02). The median time between dMRI and GK MRI was 22 days (range 1-88 days), and time between scans was not associated with detecting additional metastases. Patients with additional brain metastases did not have larger total radiosurgery target volumes, and they rarely had an immediate change in management (abortion of radiosurgery or addition of whole-brain radiation therapy) due to detection of additional metastases. Patients with additional metastases had a higher incidence of distant intracranial failure than those without additional metastases (p = 0.004), with an adjusted subdistribution hazard ratio of 1.4 (95% CI 1.0-2.0, p = 0.04). Significantly worse overall survival was not detected for patients with additional brain metastases on GK MRI (log-rank p = 0.07), with the relative adjusted hazard ratio of 1.07, (95% CI 0.81-1.41, p = 0.65). CONCLUSIONS Detecting additional brain metastases on GK MRI is strongly associated with the number of brain metastases on dMRI and inversely associated with the size of the index brain metastasis. The discovery of additional brain metastases at time of GK radiosurgery is very unlikely to lead to aborting radiosurgery but is associated with a higher incidence of distant intracranial failure. However, there is not a significant difference in survival. ▪ CLASSIFICATION OF EVIDENCE Type of question: prognostic; study design: retrospective cohort trial; evidence: Class IV.
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http://dx.doi.org/10.3171/2016.4.JNS152319DOI Listing
June 2017

Stereotactic radiosurgery (SRS) in the modern management of patients with brain metastases.

Oncotarget 2016 Mar;7(11):12318-30

Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.

Stereotactic radiosurgery (SRS) is an established non-invasive ablative therapy for brain metastases. Early clinical trials with SRS proved that tumor control rates are superior to whole brain radiotherapy (WBRT) alone. As a result, WBRT plus SRS was widely adopted for patients with a limited number of brain metastases ("limited number" customarily means 1-4). Subsequent trials focused on answering whether WBRT upfront was necessary at all. Based on current randomized controlled trials (RCTs) and meta-analyses comparing SRS alone to SRS plus WBRT, adjuvant WBRT results in better intracranial control; however, at the expense of neurocognitive functioning and quality of life. These adverse effects of WBRT may also negatively impact on survival in younger patients. Based on the results of these studies, treatment has shifted to SRS alone in patients with a limited number of metastases. Additionally, RCTs are evaluating the role of SRS alone in patients with >4 brain metastases. New developments in SRS include fractionated SRS for large tumors and the integration of SRS with targeted systemic therapies that cross the blood brain barrier and/or stimulate an immune response. We present in this review the current high level evidence and rationale supporting SRS as the standard of care for patients with limited brain metastases, and emerging applications of SRS.
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http://dx.doi.org/10.18632/oncotarget.7131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914287PMC
March 2016

Normal Brain Sparing With Increasing Number of Beams and Isocenters in Volumetric-Modulated Arc Beam Radiosurgery of Multiple Brain Metastases.

Technol Cancer Res Treat 2016 12 22;15(6):766-771. Epub 2015 Nov 22.

Department of Radiation Oncology, University of California, San Francisco, CA, USA

Recent studies have reported about the application of volumetric-modulated arc radiotherapy in the treatment of multiple brain metastases. One of the key concerns for these radiosurgical treatments lies in the integral dose within the normal brain tissue, as it has been shown to increase with increasing number of brain tumors treated. In this study, we investigate the potential to improve normal brain tissue sparing specific to volumetric-modulated arc radiotherapy by increasing the number of isocenters and arc beams. Adopting a multi-institutional benchmark study protocol of planning multiple brain metastases via a radiosurgical apparatus, a flattening filter-free TrueBeam RapidArc delivery system (Varian Oncology, Palo Alto, California) was used for a volumetric-modulated arc radiotherapy treatment planning study, where treatment plans for target combinations of N = 1, 3, 6, 9, and 12 targets were developed with increasing numbers of isocenters and arc beams. The treatment plans for each target combination were compared dosimetrically among each other and against the reference Gamma Knife treatment plan from the original benchmark study. We observed that as the number of isocenters or arc beams increased, the normal brain isodose volumes such as 12- to 4-Gy on average decreased by up to 15% for all the studied cases. However, when the best volumetric-modulated arc radiotherapy normal brain isodose volumes were compared against the corresponding reference Gamma Knife values, volumetric-modulated arc radiotherapy remained 100% to 200% higher than those of Gamma Knife for all target combinations. The study results, particularly for the solitary (N = 1) metastases case, directly challenged the general notion of dose equivalence among current radiosurgical modalities. In conclusion, multiple isocenter and multiple arc beam delivery solutions are capable of decreasing normal brain irradiation exposure for volumetric-modulated arc radiotherapy. However, there is further technological development in need for volumetric-modulated arc radiotherapy before similar dosimetric treatment plans could be achievable when compared to Gamma Knife radiosurgery.
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http://dx.doi.org/10.1177/1533034615614208DOI Listing
December 2016

Interval From Imaging to Treatment Delivery in the Radiation Surgery Age: How Long Is Too Long?

Int J Radiat Oncol Biol Phys 2015 Sep 7;93(1):126-32. Epub 2015 May 7.

Department of Radiation Oncology, University of California at San Francisco, San Francisco, California.

Purpose: The purpose of this study was to evaluate workflow and patient outcomes related to frameless stereotactic radiation surgery (SRS) for brain metastases.

Methods And Materials: We reviewed all treatment demographics, clinical outcomes, and workflow timing, including time from magnetic resonance imaging (MRI), computed tomography (CT) simulation, insurance authorization, and consultation to the start of SRS for brain metastases.

Results: A total of 82 patients with 151 brain metastases treated with SRS were evaluated. The median times from consultation, insurance authorization, CT simulation, and MRI for treatment planning were 15, 7, 6, and 11 days to SRS. Local freedom from progression (LFFP) was lower in metastases with MRI ≥ 14 days before treatment (P = .0003, log rank). The 6- and 12-month LFFP rate were 95% and 75% for metastasis with interval of <14 days from MRI to treatment compared to 56% and 34% for metastases with MRI ≥ 14 days before treatment. On multivariate analysis, LFFP remained significantly lower for lesions with MRI ≥ 14 days at SRS (P = .002, Cox proportional hazards; hazard ratio: 3.4, 95% confidence interval: 1.6-7.3).

Conclusions: Delay from MRI to SRS treatment delivery for brain metastases appears to reduce local control. Future studies should monitor the timing from imaging acquisition to treatment delivery. Our experience suggests that the time from MRI to treatment should be <14 days.
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http://dx.doi.org/10.1016/j.ijrobp.2015.05.001DOI Listing
September 2015

Hippocampal Dose With Radiosurgery for Multiple Intracranial Targets: The Rationale for Proactive Beam Shaping.

Technol Cancer Res Treat 2016 08 25;15(4):555-9. Epub 2015 Jun 25.

Department of Radiation Oncology, University of California, San Francisco, CA, USA.

Stereotactic radiosurgery provides conformal treatment of intracranial lesions, but when multiple lesions are treated, cumulative dose to structures such as the hippocampi may be increased. We analyzed hippocampal dose for patients treated with radiosurgery for multiple brain metastases. We then investigated a means to minimize hippocampal dose. We randomly selected 8 patients treated with single-session, frame-based radiosurgery for 6 to 12 intracranial metastases. Standard planning was employed to deliver 16 to 20 Gy to each lesion without hippocampal avoidance. Each case was replanned using the software's dynamic shaping function to minimize direct beam hippocampal irradiation, while maintaining conformality and target coverage. With standard planning, the maximum hippocampal dose varied from 0.8 to 9.0 Gy but was >3 Gy only when a lesion was <10 mm from the hippocampus. There was no clear correlation between hippocampal dose and the number or the total volume of lesions. Replanning with direct beam avoidance decreased the mean hippocampal dose by an average of 35% but increased treatment time by a mean of 20%. Sparing was most pronounced when the closest lesion was in close proximity to the hippocampus. This is the first study reporting hippocampal dose for multilesion intracranial radiosurgery. It illustrates that when multiple intracranial targets are treated with radiosurgery, substantial hippocampal dose can result. Active beam shielding and optimization can lower hippocampal dose, especially with lesions <10 mm from the hippocampus. These results raise the prospect that the risk of neurocognitive side effects may be further decreased with a hippocampal-sparing approach.
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http://dx.doi.org/10.1177/1533034615590934DOI Listing
August 2016

Letter: volumetric arc therapy (RapidArc) vs Gamma Knife radiosurgery for multiple brain metastases.

Neurosurgery 2015 Mar;76(3):E353

*Department of Radiation Oncology, University of California, San Francisco, California ‡Department of Radiation Oncology, University of Toronto, Toronto, Canada §Washington Fremont Hospital Gamma Knife Center, Fremont, California.

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http://dx.doi.org/10.1227/NEU.0000000000000654DOI Listing
March 2015

Clinical realization of sector beam intensity modulation for Gamma Knife radiosurgery: a pilot treatment planning study.

Int J Radiat Oncol Biol Phys 2015 Mar 24;91(3):661-8. Epub 2014 Dec 24.

Department of Radiation Oncology, Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada.

Purpose: To demonstrate the clinical feasibility and potential benefits of sector beam intensity modulation (SBIM) specific to Gamma Knife stereotactic radiosurgery (GKSRS).

Methods And Materials: SBIM is based on modulating the confocal beam intensities from individual sectors surrounding an isocenter in a nearly 2π geometry. This is in contrast to conventional GKSRS delivery, in which the beam intensities from each sector are restricted to be either 0% or 100% and must be identical for any given isocenter. We developed a SBIM solution based on available clinical planning tools, and we tested it on a cohort of 12 clinical cases as a proof of concept study. The SBIM treatment plans were compared with the original clinically delivered treatment plans to determine dosimetric differences. The goal was to investigate whether SBIM would improve the dose conformity for these treatment plans without prohibitively lengthening the treatment time.

Results: A SBIM technique was developed. On average, SBIM improved the Paddick conformity index (PCI) versus the clinically delivered plans (clinical plan PCI = 0.68 ± 0.11 vs SBIM plan PCI = 0.74 ± 0.10, P=.002; 2-tailed paired t test). The SBIM plans also resulted in nearly identical target volume coverage (mean, 97 ± 2%), total beam-on times (clinical plan 58.4 ± 38.9 minutes vs SBIM 63.5 ± 44.7 minutes, P=.057), and gradient indices (clinical plan 3.03 ± 0.27 vs SBIM 3.06 ± 0.29, P=.44) versus the original clinical plans.

Conclusion: The SBIM method is clinically feasible with potential dosimetric gains when compared with conventional GKSRS.
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http://dx.doi.org/10.1016/j.ijrobp.2014.10.043DOI Listing
March 2015

Radiation therapy of glioblastoma.

Cancer Treat Res 2015 ;163:49-73

Departments of Radiation Oncology and Neurological Surgery, University of California, 505 Parnassus Avenue, Room L08B, San Francisco, CA, 94143-0226, USA,

Glioblastoma multiforme (GBM) is the most common malignant brain tumor that affects approximately 17,000 patients annually. Clear survival advantages have been demonstrated with postoperative radiation therapy (RT) to doses of 5,000-6,000 cGy but dose-escalation attempts beyond 6,000 cGy have resulted in increased toxicity but no additional survival benefit. To improve local control and limit toxicity to normal brain tissue with these infiltrating tumors, novel imaging techniques are actively being explored to better define tumor extent and associated RT treatment fields. Hyperfractionated RT has been associated with a survival detriment. Current standard-of-care treatment involves concurrent use of temozolomide and RT to 6,000 cGy over 30 days followed by adjuvant temozolomide treatment for 6 months. Brachytherapy and stereotactic radiosurgery are effective therapies for relapsed GBM but tend to be associated with notable toxicity. More recently, re-irradiation strategies employ concurrent use of bevacizumab to limit treatment-related injury while still permitting delivery of meaningful doses. These clinical trials are ongoing and merits of these strategies are not yet clear but appear promising.
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http://dx.doi.org/10.1007/978-3-319-12048-5_4DOI Listing
February 2015

A novel use of foley catheters to prevent injury to the pelvic viscera during stereotactic radiosurgery for undifferentiated pleomorphic sarcoma of the sacrum.

Perm J 2014 ;18(3):e146-9

Associate Professor of Neurosurgery at the University of California, San Francisco.

The use of a Foley catheter to protect the small and large bowel from radiation injury during stereotactic radiosurgery to the spine has not previously been described in the surgical literature. Many spine tumors should be treated with stereotactic radiosurgery as opposed to external beam therapy, yet the proximity of visceral organs may preclude adequate target delivery of radiation. We describe the novel use of Foley catheters placed intraoperatively to displace the bowel during stereotactic radiosurgery, allowing for a full radiation dose to be safely delivered to the tumor. The advantages of this technique are the low cost, the ability to place multiple catheters intraoperatively, and the ability to withdraw all the catheters after radiation without the need for reoperation.
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http://dx.doi.org/10.7812/TPP/14-011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116273PMC
May 2015

Variable dose interplay effects across radiosurgical apparatus in treating multiple brain metastases.

Int J Comput Assist Radiol Surg 2014 Nov 20;9(6):1079-86. Epub 2014 Apr 20.

Department of Radiation Oncology, Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Canada.

Purpose: Normal brain tissue doses have been shown to be strongly apparatus dependent for multi-target stereotactic radiosurgery. In this study, we investigated whether inter-target dose interplay effects across contemporary radiosurgical treatment platforms are responsible for such an observation.

Methods: For the study, subsets ([Formula: see text] and 12) of a total of 12 targets were planned at six institutions. Treatment platforms included the (1) Gamma Knife Perfexion (PFX), (2) CyberKnife, (3) Novalis linear accelerator equipped with a 3.0-mm multi-leaf collimator (MLC), and the (4) Varian Truebeam flattening-filter-free (FFF) linear accelerator also equipped with a 2.5 mm MLC. Identical dose-volume constraints for the targets and critical structures were applied for each apparatus. All treatment plans were developed at individual centers, and the results were centrally analyzed.

Results: We found that dose-volume constraints were satisfied by each apparatus with some differences noted in certain structures such as the lens. The peripheral normal brain tissue doses were lowest for the PFX and highest for TrueBeam FFF and CyberKnife treatment plans. Comparing the volumes of normal brain receiving 12 Gy, TrueBeam FFF, Novalis, and CyberKnife were 180-290% higher than PFX. The mean volume of normal brain-per target receiving 4-Gy increased by approximately 3.0 cc per target for TrueBeam, 2.7 cc per target for CyberKnife, 2.0 cc per target for Novalis, and 0.82 cc per target for PFX. The beam-on time was shortest with the TrueBeam FFF (e.g., 6-9 min at a machine output rate of 1,200 MU/min) and longest for the PFX (e.g., 50-150 mins at a machine output rate of 350 cGy/min).

Conclusion: The volumes of normal brain receiving 4 and 12 Gy were higher, and increased more swiftly per target, for Linac-based SRS platforms than for PFX. Treatment times were shortest with TrueBeam FFF.
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http://dx.doi.org/10.1007/s11548-014-1001-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215114PMC
November 2014

Impact of millimeter-level margins on peripheral normal brain sparing for gamma knife radiosurgery.

Int J Radiat Oncol Biol Phys 2014 May;89(1):206-13

Department of Radiation Oncology, University of California, San Francisco, California.

Purpose: To investigate how millimeter-level margins beyond the gross tumor volume (GTV) impact peripheral normal brain tissue sparing for Gamma Knife radiosurgery.

Methods And Materials: A mathematical formula was derived to predict the peripheral isodose volume, such as the 12-Gy isodose volume, with increasing margins by millimeters. The empirical parameters of the formula were derived from a cohort of brain tumor and surgical tumor resection cavity cases (n=15) treated with the Gamma Knife Perfexion. This was done by first adding margins from 0.5 to 3.0 mm to each individual target and then creating for each expanded target a series of treatment plans of nearly identical quality as the original plan. Finally, the formula was integrated with a published logistic regression model to estimate the treatment-induced complication rate for stereotactic radiosurgery when millimeter-level margins are added.

Results: Confirmatory correlation between the nominal target radius (ie, RT) and commonly used maximum target size was found for the studied cases, except for a few outliers. The peripheral isodose volume such as the 12-Gy volume was found to increase exponentially with increasing Δ/RT, where Δ is the margin size. Such a curve fitted the data (logarithmic regression, R(2) >0.99), and the 12-Gy isodose volume was shown to increase steeply with a 0.5- to 3.0-mm margin applied to a target. For example, a 2-mm margin on average resulted in an increase of 55% ± 16% in the 12-Gy volume; this corresponded to an increase in the symptomatic necrosis rate of 6% to 25%, depending on the Δ/RT values for the target.

Conclusions: Millimeter-level margins beyond the GTV significantly impact peripheral normal brain sparing and should be applied with caution. Our model provides a rapid estimate of such an effect, particularly for large and/or irregularly shaped targets.
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http://dx.doi.org/10.1016/j.ijrobp.2014.01.011DOI Listing
May 2014

Vertebral compression fracture after stereotactic body radiotherapy for spinal metastases.

Lancet Oncol 2013 Jul;14(8):e310-20

Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.

The use of stereotactic body radiotherapy for metastatic spinal tumours is increasing. Serious adverse events for this treatment include vertebral compression fracture (VCF) and radiation myelopathy. Although VCF is a fairly low-risk adverse event (approximately 5% risk) after conventional radiotherapy, crude risk estimates for VCF after spinal SBRT range from 11% to 39%. In this Review, we summarise the evidence and predictive factors for VCF induced by spinal SBRT, review the pathophysiology of VCF in the metastatic spine, and discuss strategies used to prevent and manage this potentially disabling complication.
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http://dx.doi.org/10.1016/S1470-2045(13)70101-3DOI Listing
July 2013

Future directions in treatment of brain metastases.

Surg Neurol Int 2013 2;4(Suppl 4):S220-30. Epub 2013 May 2.

Department of Radiation Oncology, University of California, San Francisco, CA, USA.

Background: Brain metastases affect up to 30% of patients with cancer. Management of brain metastases continues to evolve with ever increasing focus on cognitive preservation and quality of life. This manuscript reviews current state of brain metastases management and discusses various treatment controversies with focus on future clinical trials. Stereotactic radiosurgery (SRS) and whole-brain radiotherapy (WBRT) are discussed in context of multiple (4+ brain metastases) as well as new approaches combining radiation and targeted agents. A brief discussion of modified WBRT approaches, including hippocampal-avoidance WBRT (HA-WBRT) is included as well as a section on recently presented results of Radiation Therapy Oncology Group (RTOG) 0614, a randomized, double-blind, placebo-controlled trial of menantine for prevention of neurocognitive injury after WBRT.

Methods: A search of selected studies relevant to management of brain metastases was performed in PubMed as well as in various published meeting abstracts. This data was collated and analyzed in context of contemporary management and future clinical trial plans. This data is presented in tabular form and discussed extensively in the text.

Results: The published data demonstrate continued evolution of clinical trials and management strategies designed to minimize and/or prevent cognitive decline following radiation therapy management of brain metastases. Hippocampal avoidance whole-brain radiation therapy (HA-WBRT) and radiosurgery treatments for multiple brain metastases are discussed along with preliminary results of RTOG 0614, a trial of memantine therapy to prevent cognitive decline following WBRT. Trial results appear to support the use of memantine for prevention of cognitive decline.

Conclusions: Different management strategies for multiple brain metastases (>4 brain metastases) are currently being evaluated in prospective clinical trials to minimize the likelihood of cognitive decline following WBRT.
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http://dx.doi.org/10.4103/2152-7806.111299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656563PMC
May 2013

American College of Radiology (ACR) and American Society for Radiation Oncology (ASTRO) Practice Guideline for the Performance of Stereotactic Radiosurgery (SRS).

Am J Clin Oncol 2013 Jun;36(3):310-5

Department of Radiation Oncology, The Oregon Clinic, Portland, OR 97213, USA.

American College of Radiology and American Society for Radiation Oncology Practice Guideline for the Performance of Stereotactic Radiosurgery (SRS). SRS is a safe and efficacious treatment option of a variety of benign and malignant disorders involving intracranial structures and selected extracranial lesions. SRS involves a high dose of ionizing radiation with a high degree of precision and spatial accuracy. A quality SRS program requires a multidisciplinary team involved in the patient management. Organization, appropriate staffing, and careful adherence to detail and to established SRS standards is important to ensure operational efficiency and to improve the likelihood of procedural success. A collaborative effort of the American College of Radiology and American Society for Therapeutic Radiation Oncology has produced a practice guideline for SRS. The guideline defines the qualifications and responsibilities of all the involved personnel, including the radiation oncologist, neurosurgeon, and qualified medical physicist. Quality assurance is essential for safe and accurate delivery of treatment with SRS. Quality assurance issues for the treatment unit, stereotactic accessories, medical imaging, and treatment-planning system are presented and discussed. Adherence to these practice guidelines can be part of ensuring quality and patient safety in a successful SRS program.
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http://dx.doi.org/10.1097/COC.0b013e31826e053dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4285440PMC
June 2013

Stereotactic body radiotherapy: a new paradigm in the management of spinal metastases.

CNS Oncol 2013 May;2(3):259-70

Department of Radiation Oncology, Yale School of Medicine, New Haven, CT, USA.

Spine stereotactic body radiotherapy is based on delivering high biologically effective doses to spinal metastases, with the intent to maximize both tumor and pain control. The purpose of this review is to outline the technical details of spine stereotactic body radiotherapy, contrast clinical outcomes to low biologically effective dose conventional palliative radiotherapy, discuss the role of surgery in the era of spine stereotactic body radiotherapy, and summarize the major serious adverse events that patients would otherwise not be at risk of with conventional radiotherapy.
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http://dx.doi.org/10.2217/cns.13.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166530PMC
May 2013

Reliability of contour-based volume calculation for radiosurgery.

J Neurosurg 2012 Dec;117 Suppl:203-10

Department of Radiation Oncology, University of California, San Francisco, CA 94143, USA.

Object: Determining accurate target volume is critical for both prescribing and evaluating stereotactic radiosurgery (SRS) treatments. The aim of this study was to determine the reliability of contour-based volume calculations made by current major SRS platforms.

Methods: Spheres ranging in diameter from 6.4 to 38.2 mm were scanned and then delineated on imaging studies. Contour data sets were subsequently exported to 6 SRS treatment-planning platforms for volume calculations and comparisons. This procedure was repeated for the case of a patient with 12 metastatic lesions distributed throughout the brain. Both the phantom and patient datasets were exported to a stand-alone workstation for an independent volume-calculation analysis using a series of 10 algorithms that included approaches such as slice stacking, surface meshing, point-cloud filling, and so forth.

Results: Contour data-rendered volumes exhibited large variations across the current SRS platforms investigated for both the phantom (-3.6% to 22%) and patient case (1.0%-10.2%). The majority of the clinical SRS systems and algorithms overestimated the volumes of the spheres, compared with their known physical volumes. An independent algorithm analysis found a similar trend in variability, and large variations were typically associated with small objects whose volumes were < 0.4 cm(3) and with those objects located near the end-slice of the scan limits.

Conclusions: Significant variations in volume calculation were observed based on data obtained from the SRS systems that were investigated. This observation highlights the need for strict quality assurance and benchmarking efforts when commissioning SRS systems for clinical use and, moreover, when conducting multiinstitutional cross-SRS platform clinical studies.
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http://dx.doi.org/10.3171/2012.7.GKS121016DOI Listing
December 2012

High-precision volume-staged Gamma Knife surgery and equivalent hypofractionation dose schedules for treating large arteriovenous malformations.

J Neurosurg 2012 Dec;117 Suppl:115-9

Department of Radiation Oncology, University of California, San Francisco, California 94143, USA.

Object: The goal of this study was to develop a technique for performing submillimeter high-precision volume-staged Gamma Knife surgery and investigate its potential benefits in comparison with hypofractionated stereotactic radiotherapy (SRT) for treating large arteriovenous malformations (AVMs).

Methods: The authors analyzed 7 pediatric AVM cases treated with volume-staged stereotactic radiosurgery (SRS) using the Gamma Knife Perfexion at the University of California, San Francisco. The target and normal tissue contours from each case were exported for hypofractionated treatment planning based on the Gamma Knife Extend system or the CyberKnife SRT. Both the Gamma Knife Extend and CyberKnife treatment plans were matched to yield the same level of target coverage (95%-98%) and conformity indices (1.24-1.46). Finally, hypofractionated treatment plans were compared with volume-staged treatment plans for sparing normal brain by using biologically equivalent 12-Gy normal brain volumes.

Results: Hypofractionated Gamma Knife Extend and CyberKnife treatment plans exhibited practically identical sparing of normal brain for the studied cases. However, when matching such values with volume-staged treatments for the biological effective dose, only conservative dose fractionation schemes, such as 27.3 Gy in 5 fractions and 25 Gy in 4 fractions, were found to be comparable to the volume-staged treatments. On average, this represents a mean 18.7% ± 7.3% reduction in the single-fraction biologically equivalent dose for hypofractionated treatments versus the reference volume-staged treatments (p < 0.001).

Conclusions: Volume staging remains advantageous over hypofractionation in delivering a higher dose to the target and for better sparing of normal brain tissue in the treatment of large AVMs. More clinical data are needed, however, to justify the clinical superiority of this increased dose when compared with a hypofractionated treatment regimen.
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http://dx.doi.org/10.3171/2012.7.GKS121023DOI Listing
December 2012

Assessing small-volume spinal cord dose for repeat spinal stereotactic body radiotherapy treatments.

Phys Med Biol 2012 Dec 8;57(23):7843-51. Epub 2012 Nov 8.

Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.

Spinal cord biologically effective dose (BED) limits are critical to safe spine stereotactic body radiotherapy (SBRT) delivery. In particular, when repeating SBRT to the same site, the problem of adding non-uniform BED distributions within small volumes of spinal cord has yet to be solved. We report a probability-based generalized BED (gBED) model to guide repeat spine SBRT treatment planning. The gBED was formulated by considering the sequential damaging probabilities of repeat spine SBRT treatments. Parameters from the standard linear-quadratic model, such as α/β = 2 Gy for the spinal cord, were applied. We tested the model based on SBRT specific spinal cord tolerance using a simulated and ten clinical repeat SBRT cases. The gBED provides a consistent solution for superimposing non-uniform dose distributions from different fractionation schemes, analogous to the BED for uniform dose distributions. Based on ten clinical cases, the gBED was observed to eliminate discrepancies in the cumulative BED of approximately 5% to 20% within small volumes (e.g. 0.1-2.0 cc) of spinal cord, as compared to a conventional calculation method. When assessing spinal cord tolerance for repeat spinal SBRT treatments, caution should be exercised when applying conventional BED calculations for small volumes of spinal cord irradiated, and the gBED potentially provides more conservative and consistently derived dose surrogates to guide safe treatment planning and treatment outcome modeling.
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http://dx.doi.org/10.1088/0031-9155/57/23/7843DOI Listing
December 2012

Probabilities of radiation myelopathy specific to stereotactic body radiation therapy to guide safe practice.

Int J Radiat Oncol Biol Phys 2013 Feb 17;85(2):341-7. Epub 2012 Jun 17.

Department of Radiation Oncology, Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada.

Purpose: Dose-volume histogram (DVH) results for 9 cases of post spine stereotactic body radiation therapy (SBRT) radiation myelopathy (RM) are reported and compared with a cohort of 66 spine SBRT patients without RM.

Methods And Materials: DVH data were centrally analyzed according to the thecal sac point maximum (Pmax) volume, 0.1- to 1-cc volumes in increments of 0.1 cc, and to the 2 cc volume. 2-Gy biologically equivalent doses (nBED) were calculated using an α/β = 2 Gy (units = Gy(2/2)). For the 2 cohorts, the nBED means and distributions were compared using the t test and Mann-Whitney test, respectively. Significance (P<.05) was defined as concordance of both tests at each specified volume. A logistic regression model was developed to estimate the probability of RM using the dose distribution for a given volume.

Results: Significant differences in both the means and distributions at the Pmax and up to the 0.8-cc volume were observed. Concordant significance was greatest for the Pmax volume. At the Pmax volume the fit of the logistic regression model, summarized by the area under the curve, was 0.87. A risk of RM of 5% or less was observed when limiting the thecal sac Pmax volume doses to 12.4 Gy in a single fraction, 17.0 Gy in 2 fractions, 20.3 Gy in 3 fractions, 23.0 Gy in 4 fractions, and 25.3 Gy in 5 fractions.

Conclusion: We report the first logistic regression model yielding estimates for the probability of human RM specific to SBRT.
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http://dx.doi.org/10.1016/j.ijrobp.2012.05.007DOI Listing
February 2013

Comparison between prone and supine patient setup for spine stereotactic body radiosurgery.

Technol Cancer Res Treat 2012 Jun;11(3):229-36

Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.

This paper investigates the dosimetric characteristics of stereotactic body radiotherapy (SBRT) treatment plans of spine patients in the prone position compared to the supine position. A feasibility study for treating spine patients in the prone position using a fiducial-less tracking method is presented. One patient with a multilevel spinal metastasis was simulated for SBRT treatment in both the supine and prone position. CT scans of the patient were acquired, and treatment plans were created using the CyberKnife® planning platform. The potential advantage of the prone setup as a function of lesion location and number of vertebral bodies involved was studied for targets extending over 1, 2 and 3 consecutive vertebral bodies in the thoracic and lumbar spine. The same process was repeated on an anthropomorphic phantom. A dose of 30 Gy in 5 fractions was prescribed to 95% of the tumor volume and the dose to the cord was limited to 25 Gy. To investigate the feasibility of a fiducial-less tracking method in the prone setup, the patient was positioned prone on the treatment table and the spine motion was monitored as a function of time. Patient movement with the respiratory cycle was reduced by means of a belly-board. Plans in the prone and supine position achieved similar tumor coverage and sparing of the critical structures immediately adjacent to the spine (such as cord and esophagus). However, the prone plans systematically resulted in a lower dose to the normal structures located in the anterior part of the body (such as heart for thoracic cases; stomach, lower gastrointestinal tract and liver for lumbar cases). In addition, prone plans resulted in a lower number of monitor units compared to supine plans.
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http://dx.doi.org/10.7785/tcrt.2012.500291DOI Listing
June 2012

Whole-brain radiation therapy of brain metastasis.

Prog Neurol Surg 2012 6;25:82-95. Epub 2012 Jan 6.

Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada.

The purpose of this report was to review the role of whole brain radiotherapy (WBRT) in the management of brain metastases. In particular, we review the role of WBRT as a prophylactic therapy, and the role of surgery and stereotactic radiousurgery (SRS) with respect to WBRT, by discussing the relevant randomized controlled trials. WBRT is associated with toxicities and this may influence the decision to use WBRT and, therefore, we review both the acute side effects of WBRT and the more serious late side effects of neurocognitive impairment and leukoencephalopathy. As patients are living longer with brain metastases the role of WBRT is moving forward; however, using modern radiation technology we may be able to reduce the morbidity of this therapy. We present an extreme case of re-re-treatment WBRT with hippocampal sparing and simultaneous integrated boosts to multiple lesions as one of the future directions under evaluation.
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http://dx.doi.org/10.1159/000331179DOI Listing
May 2012

A technique for achieving submillimeter accuracy of volume-staged stereotactic radiosurgery.

J Radiosurg SBRT 2012 ;2(1):11-17

Department of Radiation Oncology, Sunnybrook Odette Cancer Centre, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada.

A technique for delivering high-precision volume-staged stereotactic radiosurgery has been developed with Leksell Gamma Knife Perfexion for treating large arteriorvenous malformations (AVMs). The technique employs a hybrid method of combining landmark registration and voxel-based 3D image registration to enable multiple staged partial-volume treatments that accommodate repeated stereotactic frame placements. The technique was clinically implemented at our institution and the results were analyzed for a series (n=14) of large AVM cases treated since 2007. Overall, an averaged 0.34±0.09 mm in matching procedural accuracy versus standard single-fraction radiosurgery was found for these treatments. Such a result is a factor of 3-4 times lower than those previously reported, and it approaches the physical accuracy of the latest Leksell Gamma Knife Perfexion system. In conclusion, volume-staged radiosurgery has been demonstrated to be deliverable with the same level of accuracy as standard single-fraction radiosurgery.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658849PMC
January 2012

Stereotactic body radiotherapy is an effective treatment in reirradiating spinal metastases: current status and practical considerations for safe practice.

Expert Rev Anticancer Ther 2011 Dec;11(12):1923-33

Department of Radiation Oncology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada.

Spinal metastases are a relatively common manifestation in advanced cancer patients. Low-dose conventional radiotherapy has long been the mainstay of treatment under the assumption that patients have a limited life expectancy in the order of 3-6 months. However, with new developments in systemic therapies, patients are surviving longer than expected. As the spinal retreatment rates, secondary to conventional radiation, can approach 20-50%, retreatments are likely to be more frequent. Rather than a second course of even lower-dose conventional radiation, spine stereotactic body radiotherapy (SBRT) has been developed predominantly to overcome the limitations of conventional reirradiation. Spine SBRT permits a second course of high-dose radiation aimed at local tumor control while sparing the spinal cord, and other surrounding normal tissues, of a toxic dose. The focus of this review is to provide an overview of reirradiation spine SBRT, and address key issues surrounding safe and effective practice.
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http://dx.doi.org/10.1586/era.11.169DOI Listing
December 2011

Shot sequencing based on biological equivalent dose considerations for multiple isocenter Gamma Knife radiosurgery.

Phys Med Biol 2011 Nov 28;56(22):7247-56. Epub 2011 Oct 28.

Department of Radiation Oncology, University of California, San Francisco, CA 94143, USA.

Rapid delivery of multiple shots or isocenters is one of the hallmarks of Gamma Knife radiosurgery. In this study, we investigated whether the temporal order of shots delivered with Gamma Knife Perfexion would significantly influence the biological equivalent dose for complex multi-isocenter treatments. Twenty single-target cases were selected for analysis. For each case, 3D dose matrices of individual shots were extracted and single-fraction equivalent uniform dose (sEUD) values were determined for all possible shot delivery sequences, corresponding to different patterns of temporal dose delivery within the target. We found significant variations in the sEUD values among these sequences exceeding 15% for certain cases. However, the sequences for the actual treatment delivery were found to agree (<3%) and to correlate (R² = 0.98) excellently with the sequences yielding the maximum sEUD values for all studied cases. This result is applicable for both fast and slow growing tumors with α/β values of 2 to 20 according to the linear-quadratic model. In conclusion, despite large potential variations in different shot sequences for multi-isocenter Gamma Knife treatments, current clinical delivery sequences exhibited consistent biological target dosing that approached that maximally achievable for all studied cases.
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http://dx.doi.org/10.1088/0031-9155/56/22/015DOI Listing
November 2011
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