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Introduction
The principle objective of all radiation therapy is to maximize the dose to the
target and minimize the dose to normal tissues. Arguably, no other treatment
technique in use today adheres to this imperative more closely than does
stereotactic radiosurgery (SRS) for brain and body targets. In the brain, especially,
the need for extreme selectivity is paramount, which has made SRS techniques
such as Gamma Knife® radiosurgery so important.
Gamma Knife SRS has been the gold standard for treatment of brain metastases
for years for its ability to create a tight dose distribution around often very
small targets, while ensuring a sharp dose fall-off outside the tumor margins.
The precision of Gamma Knife radiosurgery and the capability to deliver the
therapy in a single session have made it the preferred treatment option over
whole brain radiation therapy (WBRT) in many cases. Despite the existence
of guidelines recognizing the role of SRS in the treatment of multiple
metastases1, payers have questioned the role of SRS in cases involving more
than three metastases. Researchers at Cooper University Hospital (Camden,
New Jersey) view three (mets) as an arbitrary number, with no level 1
evidence to support a cut-off of three lesions versus 5 or 10 or more.2-5
White Paper
Comparing Dose to CNS Critical Structures
in Multiple Metastatic Brain Tumor Cases:
WBRT vs. Gamma Knife Radiosurgery
Study demonstrates dosimetric advantages of SRS versus WBRT for multiple brain metastases
Investigators: Jinyu Xue, PhD, Medical Physicist, Cooper University HospitalGregory J Kubicek, MD, Radiation Oncologist, Cooper University Hospital
The importance of dose to CNS structuresOne concern with treating increasingly higher numbers of metastases seems to be centered on the impact of overlapping dose from multiple targets on normal CNS structures, including the brain, brainstem, chiasm and hippocampus. This white paper discusses the work of Cooper University Hospital investigators Dr. Jinyu Xue and Dr. Gregory Kubicek, who compared the biologically effective dose (BED) and treatment characteristics between WBRT and SRS using their Leksell Gamma Knife® Perfexion system™ for two patients with multiple (> 10) brain metastases. The focus was to explore the biological implications of the doses to the targets and those CNS critical structures of clinical concern. Understanding the dose tolerance limits of critical CNS structures can aid in the determination of the optimal prescription dose to the tumor and the selection of a more effective treatment modality.
Two multiple brain metastases patientsThe dosimetric data of two representative patients with 13 and 16 mets, respectively are presented below. The patients were treated with Leksell Gamma Knife® Perfexion™ at Cooper University Hospital in December 2012 and October 2012, respectively.
For both patients, the prescribed doses for each metastatic tumor ranged from 15-20 Gy at the 50-60 percent isodose line, depending on the size and location of the tumor.
All the targets and critical structures were delineated during Gamma Knife treatment planning by a neurosurgeon based on high resolution MR images. Dose planning was performed on Leksell GammaPlan™ system and treatment was delivered automatically by a Perfexion unit. The MR images, together with all the structure sets, were transferred via DICOM to the XiO® planning system and a WBRT plan was developed (but not delivered) for 30 Gy to isocenter (the middle of the brain) in 10 fractions with two opposing lateral beams. The hypothetical treatment would have been performed on a modern IGRT-equipped linear accelerator available at Cooper University Hospital. Doses were calculated without heterogeneity corrections.
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Case 1: 13 lesions
Left frontal lobe: 3
Right frontal lobe: 2
Left cerebellar lobe: 1
Right cerebellar lobe: 1
Right occipital lobe: 5
Right basal ganglia: 1
Median lesion size: 1.65 cc in volume (range: 0.04 cc to 10.54 cc) and 11.7 mm in cross-section (range: 3.4 mm to 34.0 mm).Total volume:?cc
Case 2: 16 lesions
Left frontal lobe: 1
Right frontal lobe: 3
Left cerebellar lobe: 3
Right cerebellar lobe: 1
Left occipital lobe: 2
Right occipital lobe: 2
Left putamen: 1
Right caudate: 1
Septum: 1
Pons: 1
Median lesion size: 0.21 cc in volume (range: 0.02 cc to 1.65 cc) and 10.25 mm in cross-section (range: 3.1 mm ~ 18.4 mm). Total volume:?cc
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Case #1 SRS WBRT
Phy. Dose BED Phy. Dose BED
Mean 26.0 93.6 31.9 42.0
Range 21.8~34.3 69.3~151.9 30.1~32.0 39.1~42.2
Max 34.9 156.7 32.1 42.4
Range 30.9~36.9 126.4~173.1 30.1~32.6 39.1~43.2
Case #2 SRS WBRT
Phy. Dose BED Phy. Dose BED
Mean 27.3 101.8 31.0 40.5
Range 21.3~34.5 66.7~153.5 29.5~31.9 38.3~42.1
Max 36.9 173.1 31.2 40.9
Range 27.9~40.9 105.7~208.2 29.7~32.1 38.5~42.4
Table 1: Summary of target mean dose and maximum dose in units of Gy for both SRS and WBRT given as physical dose and BED with α/β of 10 Gy.
ResultsInvestigators calculated the mean dose and maximum dose to each target for both Gamma Knife SRS and WBRT. They also calculated the Biological Equivalent Dose (BED) by the Linear Quadratic (LQ) model with α/β = 10 Gy for lesions and with α/β = 1 Gy for the CNS critical structures. (The α/β ratios chosen are a “worst case scenario” for target and normal tissues, and for many treatments the α/β ratios would show an even greater advantage for radiosurgery.) Table 1 summarizes the maximum and mean doses for both SRS and WBRT.
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Dose implications The results (see tables 1-2) show that the WBRT plan delivers a fairly uniform dose to the brain, in which both targets and critical structures receive similar maximum and mean doses. In contrast, SRS delivers a non-uniform dose to the brain, in which the target receives much higher mean and maximum doses, and critical structures in general receive lower doses. Biologically, Gamma Knife radiosurgery appears to have a higher probability of local tumor control and a lower probability of toxicity for most critical structures, especially the hippocampus and normal brain.
The Cooper University Hospital researchers found that the WBRT BED to the tumor was much less than that of SRS and contend that this is the reason why patients treated with WBRT alone have a higher likelihood of subsequent CNS progression versus patients who receive SRS.
Table 2 summarizes the maximum and mean BEDs for each patient’s SRS treatment and the BED ratio of
the SRS doses and WBRT uniform doses for tumor and normal tissues. In both cases, the tumor BED is higher for SRS than for WBRT, by factors of 2.4–2.6 in mean dose and by factors of 4.0–4.4 in maximum dose. However, the mean BED from SRS is between 3% (optic nerve) and 34% (normal brain) when compared to WBRT
Important predictor – dose to normal tissueOne of the issues of concern when treating multiple lesions with SRS is the dose to normal brain tissue. The investigators found that in SRS, the mean dose to normal brain tissue is significantly less than the threshold dose that would cause CNS necrosis (ref?). A study of 80 patients with 10 or more mets confirmed that the cumulative whole radiation doses for these patients were not considered to exceed the threshold level of normal brain necrosis.6 In contrast, a randomized trial suggested that patients treated with SRS plus WBRT were at a greater risk of a considerable decline in learning and memory functions by four months compared with
Case #1 SRS WBRT SRS/WBRT
Max Mean Max Mean Max Mean
Targets 156.7 93.6 4.02 2.40
Normal Brain 538.0 27.8 4.48 0.23
Brainstem 41.7 15.0 0.35 0.13
Chiasm 11.9 6.0 0.10 0.05
Rt Optic Nerve 6.0 3.4 0.05 0.03
Lt Optic Nerve 3.8 3.4 0.03 0.03
Rt Hippocampus 56.0 20.9 0.47 0.17
Lt Hippocampus 29.8 16.6 0.25 0.14
Case #2 SRS WBRT SRS/WBRT
Max Mean Max Mean Max Mean
Targets 173.1 101.8 4.44 2.61
Normal Brain 655.1 12.7 5.46 0.11
Brainstem 424.1 25.8 3.53 0.22
Chiasm 11.9 2.3 0.10 0.02
Rt Optic Nerve 6.0 0.9 0.05 0.01
Lt Optic Nerve 11.9 1.6 0.10 0.01
Rt Hippocampus 29.7 3.7 0.25 0.03
Lt Hippocampus 130.9 6.4 1.09 0.05
Table 2: Summary of BED in units of Gy to both target and some critical structures in SRS and their ratio to BED in WBRT assuming the uniform dose distribution of 30 Gy in 10 fractions, which is 39 Gy for target (α/α of 10 Gy) and 120 Gy for the CNS critical structures (α/β of 1 Gy), respectively.
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WBRT SRS
Toxicity CTEP Grade Toxicity CTEP Grade
Acute(1st days to wks)
fatigue 1 fatigue 1
alopecia 2 nausea 2
dermatitis 2 vomiting 2
nausea 2 headache 2
vomiting 2 cerebral edema 1, 2, 3
decreased appetite 2
cerebral edema 1, 2, 3
encephalopathy 4
cerebral herniation 5
WBRT SRS
Early-delayed(1st wks to mths)
fatigue 1 fatigue 1
somnolence 3 cerebral edema 1, 2, 3
neurocognitive deficits 3
neurologic symptoms 3
somnolence syndrome 4
neurologic dysfunction 4
WBRT SRS
Late(after 90 days)
neurocognitive degeneration 4 radiation necrosis 4
(1st wks to mths) 4
radiation necrosis 4
moyamoya syndrome 4
Table 3: Summary of potential complications related to WBRT and SRS with likely grades by the CTEP criteria.
the group that received SRS alone.7 The decline in neurocognition may result from the radiation toxicity related to the high mean dose to hippocampus in WBRT. The randomized European Organisation for Research and Treatment of Cancer (EORTC) 22952-26001 clinical trial determined that WBRT was associated with an overall decrease in patient quality of life.8
When SRS is delivered, normal brain tissue and the brainstem can receive a fairly high maximum dose to a very small volume around the lesions, a dose that is normally well tolerated with little clinical consequence. However, the high mean brain dose in WBRT is likely
responsible for related to the higher incidence of radiation-induced complications observed. Table 3 lists the potential complications related to WBRT and SRS based on the review by McTyre, et al.9 Toxicity can be graded by the common toxicity criteria of the Cancer Therapy Evaluation Program (CTEP) for brain injury on the basis of symptoms (http://ctep.cancer.gov/reporting/ctc.html). Most of the toxicities are mild, moderate or asymptomatic (Grades 1 or 2), and some may need intervention, cause disability and even death (Grades 3-5). Based on the McTyre review, more severe radiation-induced complications are observed in WBRT than in SRS.9
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ConclusionThe Cooper University Hospital researchers concluded that radiosurgery for multiple brain mets is safe and effective based on dosimetric data, which clearly show that compared to WBRT the Gamma Knife radiosurgery dose to each target is significantly higher with SRS, with a correspondingly significantly lower dose to CNS normal tissues.
Studies have proven that WBRT results in neurocognitive and other toxicities, and that for patients with three or more CNS lesions, there is no difference in survival between WBRT and SRS alone.7 Chang, et al. indicated that for patients receiving WBRT alone, there is a higher chance of subsequent CNS failure. They pointed out that it is unknown if there is any difference in survival or time to failure for patients with more than three mets treated with SRS alone. While several retrospective studies have shown good outcomes with SRS for multiple brain mets10-13, ongoing prospective and randomized studies will be needed to better answer this question.
The Cooper University Hospital investigators theorize that there are some patients who do very well with SRS alone. To test this theory, they recently opened a phase II study looking at patients with multiple CNS mets (defined in this study as 5-25), who will be treated with SRS to all targets. They will attempt to determine survival and failure rates, and how to predict which patients may benefit from WBRT and radiosurgery, by analyzing tumor size and volume, in addition to the systemic status outside of the CNS.
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