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Clinical Study

Editor's Choice - Free Access

Impact of the Number of Metastatic Tumors Treated by Stereotactic Radiosurgery on the Dose to Normal Brain: Implications for Brain Protection

Rivers C.a · Tranquilli M.a · Prasad S.a · Winograd E.b, c · Plunkett R.J.b, c · Fenstermaker R.A.b, c · Fabiano A.J.b, c · Podgorsak M.B.a · Prasad D.a-c

Author affiliations

Departments of aRadiation Medicine and bNeurosurgery, Roswell Park Cancer Institute, and cDepartment of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA

Corresponding Author

Dheerendra Prasad

Department of Radiation Medicine

Roswell Park Cancer Institute

Buffalo, NY 14263 (USA)

E-Mail d.prasad@roswellpark.org

Related Articles for ""

Stereotact Funct Neurosurg 2017;95:352-358

Abstract

Purpose/Objectives: The purpose of this study was to evaluate the effect of the number of brain lesions for which stereotactic radiosurgery (SRS) was performed on the dose volume relationships in normal brain. Materials and Methods: Brain tissue was segmented using the patient's pre-SRS MRI. For each plan, the following data points were recorded: total brain volume, number of lesions treated, volume of brain receiving 8 Gy (V8), V10, V12, and V15. Results: A total of 225 Gamma Knife® treatments were included in this retrospective analysis. The number of lesions treated ranged from 1 to 29. The isodose for prescription ranged from 40 to 95% (mean 55%). The mean prescription dose to tumor edge was 18 Gy. The mean coverage, selectivity, conformity, and gradient index were 97.5%, 0.63, 0.56, and 3.5, respectively. The mean V12 was 9.5 cm3 (ranging from 0.5 to 59.29). There was no correlation between the number of lesions and brain V8, V12, V10, or V15. There was a direct and statistically significant relationship between the brain volume treated (V8, V10, V12, and V15) and total volume of tumors treated (p < 0.001). In our study, the integral dose to the brain exceeded 3 J when the total tumor volume exceeded 25 cm3. Conclusions: The number of metastatic brain lesions treated bears no significant relationship to total brain tissue volume treated when using SRS. The fact that the integral dose to the brain exceeded 3 J when the total tumor volume exceeded 25 cm3 is useful for establishing guidelines. Although standard practice has favored using whole brain radiation therapy in patients with more than 4 lesions, a significant amount of normal brain tissue may be spared by treating these patients with SRS. SRS should be carefully considered in patients with multiple brain lesions, with the emphasis on total brain volume involved rather than the number of lesions to be treated.

© 2017 S. Karger AG, Basel


Introduction

For patients with metastatic brain disease, treatment options may include corticosteroids, surgical resection, whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), or some combination thereof. Traditionally, WBRT has been the standard therapy for patients with disease not requiring surgery, or not amenable to surgical resection. More recently, SRS has become an equal (and potentially preferred) option for patients with up to 3 brain lesions [1]. While standard recommendations include SRS for 3-4 lesions or fewer, it is now becoming more common for providers to choose to treat a larger number of brain lesions with SRS alone. As many as 10 lesions or more have been safely treated with SRS [2,3,4].

One of the well-known and accepted long-term side effects of cranial irradiation is neurotoxicity, resulting in a decreased neurocognitive function over time [5,6,7]. Since patients with intracranial metastatic disease are living longer than ever before, these lasting adverse effects of treatment are of concern [8]. The risk of neurocognitive deficits from radiation is reported to be associated with the total volume of brain tissue treated [9], and therefore it is reasonable to predict that SRS for a small number of lesions would decrease the risk of these side effects.

A recent study by Trifiletti et al. [9] investigated the risk factors for leukoencephalopathy (LE), and by default, neurocognitive decline, in patients treated with SRS for metastatic brain disease. The authors found that the use of WBRT, a higher SRS integral dose to the cranium, and the total number of intracranial metastases were all significantly associated with increased LE. This supports the idea that an increasing number of lesions treated translates into an increased brain volume treated, and therefore worsening neurotoxicity. This implies that there should be some limit established for the maximum number of lesions treated with high-dose SRS.

We routinely treat patients with >10 metastatic brain lesions using Gamma Knife® SRS alone. Often, patients treated in this manner have a large number of very small lesions. The purpose of this study was to evaluate the extent of normal brain tissue treated using Gamma Knife SRS for varying numbers of metastatic brain lesions to better estimate the risk of neurotoxicity when treating patients with multiple lesions.

Methods

A list of patients with brain metastases (of any primary) treated with Gamma Knife® (Elekta Instruments Inc., Atlanta, GA, USA) radiosurgery alone at our institution between January 1, 2013, and December 31, 2014, was identified using a database search after obtaining institutional review board approval for the purpose of this retrospective analysis. For each patient, the Gamma Knife planning MRI was identified and exported from the PACS imaging system to Eclipse® planning system (Varian Medical Systems, Palo Alto, CA, USA). For patients without MRI scans, brain CT scans were used instead. Brain tissue, including cerebrum, basal ganglia, brainstem, and cerebellum, was segmented using Eclipse software. To expedite brain segmentation in a large number of patients, the “flood fill” feature was used to create brain contours and then each contour was edited manually as needed to create an accurate brain volume. Brain contours were then exported from Eclipse into the Gamma Knife planning system. For each plan, the following data points were recorded: total brain volume, number of lesions treated, volume of brain receiving 8 Gy (V8), V10, V12, and V15. Patients treated more than once were included as a separate entry for each treatment session. The cumulative effects of repeated treatment on the same patient have been reported separately by us [10]. Descriptive statistics and correlations were analyzed using SPSS software, version 24 (IBM, Armonk, NY, USA).

Results

A total of 225 patients were included in the analysis. The number of lesions treated ranged from 1 to 29. The isodose for prescription ranged from 40 to 95% (mean 65%) and the mean prescription dose to the tumor edge was 18.7 Gy. The mean coverage and selectivity was 0.975 and 0.63, respectively. The mean Paddick Conformity Index (PCI) [11] was 0.56 and mean Gradient Index (GI) [12] was 3.5. The mean V8, V10, V12, and V15 were 17.7, 12.7, 9.5, and 6.3 cm3, respectively. The integral dose delivered to the whole brain varied from 0.2 to 5.6 J with a mean of 1.2 J. Details of the treatments and brain volumes are shown in Table 1. Fifteen (6.5%) of the patients received WBRT prior to their SRS treatment.

Table 1

Treatment parameters and brain dose and volume measurements

/WebMaterial/ShowPic/885885

There was no correlation between the number of lesions and brain V8, V10, V12, or V15 (R = 0.25, 0.18, 0.12, and 0.05, respectively; Fig. 1). In contrast, there was a direct and statistically significant correlation (p < 0.001) between brain V8, V10, V12, and V15 (R = 0.93, 0.89, 0.92, and 0.94, respectively) and the total volume of tumors treated (Fig. 2).

Fig. 1

Relationship between the number of lesions treated and the volume of brain receiving 8 (V8), 10 (V10), 12 (V12), and 15 Gy (V15).

/WebMaterial/ShowPic/885884

Fig. 2

Relationship between total tumor volume treated and volume of brain tissue receiving 8 (V8), 10 (V10), 12 (V12), and 15 Gy (V15).

/WebMaterial/ShowPic/885883

The relationship between total treated tumor volume and integral dose to brain was best approximated by a quadratic regression line (R = 0.808) as shown in Figure 3. In our study, the integral dose to the brain exceeded 3 J (a value deemed as a threshold for significant risk of LE by Trifiletti et al. [9]) when the total tumor volume exceeded 25 cm3. Both the plan conformity and gradient indices had a significant influence on the integral dose to brain tissue as well. Plans with PCI <0.56 (mean PCI for the series) had a significantly higher integral dose delivered to the brain for equal target volume treated in comparison with plans with PCI >0.56 (p < 0.05 by the Fisher test), as shown in Figure 4. For the plans with GI >3.5 (mean for the series), the integral dose to the brain was significantly higher than when plans had a GI <3.5 (p < 0.03; Fig. 5).

Fig. 3

Relationship between total tumor volume treated and the integral dose delivered to the brain. The integral dose crosses 3 J at 25 cm3 of total treated volume.

/WebMaterial/ShowPic/885882

Fig. 4

Difference in the total tumor volume and integral brain dose relationship based on PCI.

/WebMaterial/ShowPic/885881

Fig. 5

Difference in the total tumor volume and integral brain dose relationship based on plan GI.

/WebMaterial/ShowPic/885880

Discussion

This study was designed to evaluate the volume of brain treated as a function of the number of lesions in a large number of patients treated with SRS for brain metastases. Trifiletti et al. [9] reported that LE was associated with an increased number of brain lesions, but not with the total brain volume treated. However, 30% of the 103 patients included in their study had prior WBRT, which could have had a confounding effect on their data since there is no way to isolate those effects from those of the SRS. In patients treated with SRS alone, the integral dose to the cranium was the only factor significantly associated with LE. They did not report an association between total number of lesions treated and total brain volume treated.

By contrast, in our study 6.5% of patients had prior WBRT. There was no correlation observed between the number of treated tumors and the integral dose to brain tissue. The relationship between the total treated tumor volume and integral dose observed was quadratic. One explanation for this is the volume-dependent decrease in prescription dose in patients with larger or more numerous tumors. It is unclear why the total treated tumor volume did not correlate with LE in the study by Trifiletti et al. [9].

Trifiletti et al. [9] reported a threshold of 3 J as the integral dose to the brain critical for developing LE in patients receiving SRS alone. In our study, the integral dose to the brain exceeded 3 J when the total tumor volume exceeded 25 cm3. When we evaluated the influence of dose plan characteristics, we found both the reduced plan conformity and high gradient indices had a significant adverse effect on the integral dose to brain tissue.

Of note, Trifiletti et al. [9] calculated the integral dose by using the outer head contour as a surrogate for brain volume, which overestimates the actual brain volume. In our study, brain volume was contoured directly based on the MRI scan. Accordingly, their estimation of dose to total brain was based on a brain weight of 1.5 kg, and a 3-J integral dose resulted in a dose to the brain of 2 Gy as the threshold for LE. With exact segmentation of the brain in the current study, a more reasonable mean brain weight would be 1.265 kg. This would correspond to a total brain dose of 2.4 Gy. As a frame of reference, traditional fractionation schemes for WBRT deliver more than 2.37 Gy in 1 fraction, and a complete course delivers an integral brain dose of 37.95 Gy.

The fact that the integral brain dose is significantly lower for plans with higher conformity (PCI) and lower gradient indices indicates that the plan quality and radiosurgical technique can have important effects on the integral dose and consequently the risk of LE. In general, a reduction in brain volume treated is one strategy to reduce neurotoxicity and improve patient outcomes. One such example is the sparing of hippocampal volumes when using WBRT, which has resulted in improved memory and quality of life compared to historical controls [7]. In a randomized controlled trial, the addition of WBRT to SRS resulted in a significantly increased risk for decline in learning and memory function when compared with SRS alone [13]. While patients receiving SRS alone were more likely to have recurrent disease, the authors concluded that treatment with SRS followed by close monitoring and retreatment as needed is preferable to WBRT up front. This is supported by JSORG-99-1, in which patients with 1-4 brain metastases were randomized to either SRS or SRS followed by adjuvant radiation [14]. While quality of life measures were not assessed in this trial, overall survival was not statistically different between the 2 groups. This suggests that while treating a larger brain volume may initially delay recurrence, it does not lead to improved survival, and it may produce greater neurotoxicity.

Existing literature supports the benefit of selecting SRS over WBRT for patients with 1-3 brain metastases; however, little is known about the relative merits of SRS versus WBRT for patients with 5 or more brain metastases. There is a general trend toward treating a larger number of lesions with SRS, and this appears to be safe and effective [2,3,15]. JLGK0901, a prospective observational study of patients with 5-10 brain metastases treated with either WBRT or SRS, found that SRS alone was a noninferior treatment [15]. As the authors of that study point out, SRS has several advantages over WBRT, including fewer side effects (minimal hair loss), the completion of treatment in a single day allowing for the continuation of other therapies (e.g. chemotherapy), and the potential for WBRT to be given in the future for progression. In addition, SRS allows for the sparing of as much normal brain tissue as possible, thus potentially preserving cognitive function and quality of life. While there are few data evaluating quality of life in treated patients with >5 brain metastases, this is the subject of a clinical trial (NCT01731704) that is currently enrolling patients.

The above studies favoring SRS over WBRT to preserve quality of life suggest that a lower brain volume treated may be the mechanism for improved memory and executive function. It would seem to be a natural assumption that with a large number of brain lesions treated, the volume of brain treated also increases in a linear fashion. If this were the case, it would follow that setting a limit on the number of brain lesions treated with SRS would be reasonable. However, our study does not support this hypothesis. We found no correlation between the number of lesions treated and the total volume of brain irradiated. Instead, if one goal of SRS is to preserve normal brain function, the focus should perhaps shift from the number of lesions to the total volume of the targeted lesions.

There are several weaknesses in our study, which the authors recognize. The retrospective nature of the study analysis comes with inherent flaws. A large and variable patient population was included, with metastatic disease from many different primary cancers. We did not include an analysis of clinical patient outcomes, including either survival or neurocognitive function. Thus, we cannot comment on the success of the treatment in controlling disease or the potential improvement in quality of life. Finally, while the connection between sparing normal brain tissue and prevention of neurotoxicity is a logical one that follows from prior studies, it is not yet supported by the results of a randomized controlled trial.

Conclusions

Current standard practice that selects patients with <4 lesions for SRS treatment, and automatically assigns patients with >4 lesions to WBRT, is falling out of favor, and is based almost solely on arbitrarily chosen inclusion criteria for randomized controlled trials. Our data support the individualization of treatment plans for patients, taking into account various treatment options with the goals of both prolonging survival and preserving quality of life. In a patient with metastatic brain disease, the number of lesions should never be the sole factor in determining the course of treatment.

Disclosure Statement

Dr. Prasad reports personal fees from Elekta Inc. (Atlanta, GA, USA) unrelated to the submitted work. All other authors have nothing to disclose. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.


References

  1. Linskey ME, et al: The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96:45-68.
  2. Yamamoto M, et al: Gamma Knife radiosurgery for numerous brain metastases: is this a safe treatment? Int J Radiat Oncol Biol Phys 2002;53:1279-1283.
  3. Yamamoto M, Kawabe T, Barfod BE: How many metastases can be treated with radiosurgery? Prog Neurol Surg 2012;25:261-272.
  4. Grandhi R, et al: Stereotactic radiosurgery using the Leksell Gamma Knife Perfexion unit in the management of patients with 10 or more brain metastases. J Neurosurg 2012;117:237-245.
  5. Aoyama H, et al: Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone. Int J Radiat Oncol Biol Phys 2007;68:1388-1395.
  6. Filley CM, Kleinschmidt-DeMasters BK: Toxic leukoencephalopathy. N Engl J Med 2001;345:425-432.
  7. Gondi V, et al: Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol 2014;32:3810-3816.
  8. Knisely JP, et al: Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J Neurosurg 2012;117:227-233.
  9. Trifiletti DM, et al: Leukoencephalopathy after stereotactic radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys 2015;93:870-878.
  10. Rivers C, et al: Brain and hippocampal doses in patients with repeated stereotactic radiosurgery for brain metastasis. J Radiat Oncol 2017, DOI: 10.1007/s13566-017-0296-5.
  11. Paddick I: A simple scoring ratio to index the conformity of radiosurgical treatment plans: technical note. J Neurosurg 2000;93(suppl 3):219-222.
    External Resources
  12. Paddick I, Lippitz B: A simple dose gradient measurement tool to complement the conformity index. J Neurosurg 2006;105(suppl):194-201.
  13. Chang EL, et al: Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 2009;10:1037-1044.
  14. Aoyama H, et al: Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 2006;295:2483-2491.
  15. Yamamoto M, et al: Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014;15:387-395.

Author Contacts

Dheerendra Prasad

Department of Radiation Medicine

Roswell Park Cancer Institute

Buffalo, NY 14263 (USA)

E-Mail d.prasad@roswellpark.org


Article / Publication Details

First-Page Preview
Abstract of Clinical Study

Received: March 17, 2017
Accepted: August 23, 2017
Published online: October 11, 2017
Issue release date: November 2017

Number of Print Pages: 7
Number of Figures: 5
Number of Tables: 1

ISSN: 1011-6125 (Print)
eISSN: 1423-0372 (Online)

For additional information: https://www.karger.com/SFN


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References

  1. Linskey ME, et al: The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96:45-68.
  2. Yamamoto M, et al: Gamma Knife radiosurgery for numerous brain metastases: is this a safe treatment? Int J Radiat Oncol Biol Phys 2002;53:1279-1283.
  3. Yamamoto M, Kawabe T, Barfod BE: How many metastases can be treated with radiosurgery? Prog Neurol Surg 2012;25:261-272.
  4. Grandhi R, et al: Stereotactic radiosurgery using the Leksell Gamma Knife Perfexion unit in the management of patients with 10 or more brain metastases. J Neurosurg 2012;117:237-245.
  5. Aoyama H, et al: Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone. Int J Radiat Oncol Biol Phys 2007;68:1388-1395.
  6. Filley CM, Kleinschmidt-DeMasters BK: Toxic leukoencephalopathy. N Engl J Med 2001;345:425-432.
  7. Gondi V, et al: Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol 2014;32:3810-3816.
  8. Knisely JP, et al: Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J Neurosurg 2012;117:227-233.
  9. Trifiletti DM, et al: Leukoencephalopathy after stereotactic radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys 2015;93:870-878.
  10. Rivers C, et al: Brain and hippocampal doses in patients with repeated stereotactic radiosurgery for brain metastasis. J Radiat Oncol 2017, DOI: 10.1007/s13566-017-0296-5.
  11. Paddick I: A simple scoring ratio to index the conformity of radiosurgical treatment plans: technical note. J Neurosurg 2000;93(suppl 3):219-222.
    External Resources
  12. Paddick I, Lippitz B: A simple dose gradient measurement tool to complement the conformity index. J Neurosurg 2006;105(suppl):194-201.
  13. Chang EL, et al: Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 2009;10:1037-1044.
  14. Aoyama H, et al: Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 2006;295:2483-2491.
  15. Yamamoto M, et al: Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014;15:387-395.
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