|Year : 2015 | Volume
| Issue : 2 | Page : 358-363
Which is the most optimal technique to spare hippocampus?-Dosimetric comparisons of SCRT, IMRT, and tomotherapy
Vikas Kothavade1, SV Jamema2, Tejpal Gupta1, Sona Pungavkar3, Mahesh Upasani1, Shashikant Juvekar4, Rakesh Jalali1
1 Department of Radiation Oncology, Global Hospital, Mumbai, Maharashtra, India
2 Department of Medical Physics, Global Hospital, Mumbai, Maharashtra, India
3 Department of Radiodiagnosis, Global Hospital, Mumbai, Maharashtra, India
4 Departmet of Radiodiagnosis, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||7-Jul-2015|
Professor of Radiation Oncology, 1129, Homi Bhabha Block, Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
Aims: To evaluate current focal high precision radiotherapy (RT) techniques to spare hippocampi most optimally, in view of mounting clinical evidence to preserve neurocognition.
Materials and Methods: Computed tomography/magnetic resonance imaging (CT/MRI) datasets of 10 patients with benign/low-grade brain tumors, treated with focal conformal RT were replanned with helical tomotherapy (Tomo), intensity-modulated radiotherapy (IMRT) with high definition multileaf collimator (HD-MLC), and forward planning stereotactic conformal radiotherapy (SCRT). The primary planning objective was to encompass 99% of planning target volume (PTV) by 95% of prescribed dose (54 Gy/30#). Assessments included target coverage (TC), homogeneity index (HI), and maximum (max) and minimum (min) dose. Hippocampal dose was assessed with mean, maximum, minimum, median dosem and various dose levels.
Results: Mean V 95 for PTV coverage in Tomo, IMRT, and SCRT were 99.7, 99.4, and 98.3%, respectively. PTV coverage was significantly better in Tomo and IMRT compared to SCRT (P = 0.03). Tomotherapy (HI ≤ 0.06) and IMRT (HI ≤ 0.06) plans were more homogenous than SCRT (HI > 0.7) (P = 0.00). Right hippocampus mean dose with Tomo (20Gy) was 18.5% less than SCRT (30 Gy); but for left hippocampus, difference decreased to 3.3% (Tomo-32.2Gy and SCRT-34Gy). At 30% dose level, 9% more volume of right hippocampus was treated in IMRT and 20% in SCRT when compared to Tomo plan. At 80% dose, 6 and 12% more volumes were treated with IMRT and SCRT, respectively, in comparison to Tomo plan. For left hippocampus all three techniques were comparable.
Conclusion: Tomotherapy and Linear accelerator (LINAC)-based IMRT achieved significantly better PTV coverage than forward planned SCRT. Tomo as compared to SCRT and IMRT plans showed trend towards significant sparing of the contralateral hippocampus, in eccentrically located tumors.
Keywords: Dosimetry, hippocampal sparing, tomotherapy
|How to cite this article:|
Kothavade V, Jamema S V, Gupta T, Pungavkar S, Upasani M, Juvekar S, Jalali R. Which is the most optimal technique to spare hippocampus?-Dosimetric comparisons of SCRT, IMRT, and tomotherapy. J Can Res Ther 2015;11:358-63
|How to cite this URL:|
Kothavade V, Jamema S V, Gupta T, Pungavkar S, Upasani M, Juvekar S, Jalali R. Which is the most optimal technique to spare hippocampus?-Dosimetric comparisons of SCRT, IMRT, and tomotherapy. J Can Res Ther [serial online] 2015 [cited 2019 Nov 18];11:358-63. Available from: http://www.cancerjournal.net/text.asp?2015/11/2/358/157310
| > Introduction|| |
Radiotherapy (RT) for progressive benign and low-grade brain tumors results in excellent long-term control and survival, but is tempered with risk of significant late toxicity.  Unfavorable neuropsychological and cognitive dysfunction have been reported in 20-60% of the long-term survivors of brain tumors.  A significant correlation between intelligent quotient (IQ) decline and dose to the left temporal lobe has been earlier demonstrated by our group.  Preclinical and a few emerging clinical studies suggest that radiation-induced damage to the hippocampus plays a considerable role in the neurocognitive decline. ,,, Hence, these clinical observations place the hippocampus at the center of radiation planning in these long-term survivors. Central location of the hippocampus within the brain necessitates the use of advanced technology to avoid it from receiving clinically significant radiation dose, without compromising target coverage (TC).
However, there is a need to define the appropriate focal RT techniques to spare hippocampus among available high precision techniques. We studied hippocampal sparing in imaging datasets of already treated patients as 'proof of principle', in benign/low-grade brain tumors located in close proximity or involving hippocampus. Comparison was done between Tomotherapy (Tomo), stereotactic conformal radiotherapy (SCRT), and intensity-modulated radiotherapy (IMRT) using high definition multileaf collimator (HD-MLC) of Novalis Tx9 (Varian Medical system, Palo Alto). We did this dosimetric study to address the technical feasibility of sparing hippocampus with the best present techniques. Our patient group consisted of young adults with low-grade brain tumors where the benefit of sparing the hippocampus would be more beneficial.
| > Materials and methods|| |
Imaging [computed tomography (CT)/magnetic resonance imaging (MRI) fused images] datasets of 10 patients (six males and four females) with sellar and suprasellar brain tumors who had been earlier treated with RT were used. As these were already treated patients, same clinical target volume (CTV), planning target volume (PTV), and organs at risk (OAR) volumes were taken for replanning. OAR outlined included bilateral temporal lobes, eyes, lens, optic chiasm (except in optic chiasmal glioma), brain stem, and hippocampii. Only structure contoured retrospectively in these data sets was the hippocampus. Fusion of planning CT with MRI was done on Eclipse with rigid registration. Maximization of mutual information algorithm was used in transverse plane using pixel data. The hippocampus was contoured on gadolinium contrast-enhanced T1-weighted MRI axial sequence of 1.5-mm slice thickness. Hippocampus contouring was done as per guidelines by RTOG0933 and Chera et al.  It was easier to outline the hippocampii by following the strip of gray matter on the sagittal images. The contouring was performed on the axial images, heading anterior to posterior, that is, from the head of hippocampus to the tail, while localizing the hippocampii on the sagittal images. The contours were verified by the neuroradiologist and corrections made as suggested.
Datasets were replanned with i) helical tomotherapy, ii) IMRT with HD-MLC of Novalis Tx, and iii) forward planning SCRT using HD-MLC of Novalis Tx. In all Tomo plans, a fan beam thickness (FBT) of 2.5 cm, pitch of 0.3, and a modulation factor of 3 was used during optimization and dose computation. Directional blocking option available on Tomo was used to block hippocampus and complete block for lenses. As part of optimization, the dose was calculated using collapsed cone algorithm. IMRT and SCRT planning were done on eclipse configured with Novalis Tx data. Beam arrangement for IMRT was done using 5-9 fields; whereas, for SCRT it was 6-9 non-coplanar fields. Both plans were calculated using anisotropic analytical algorithm in Eclipse version 8.6 (Varian Medical System). Planning's were done by a single experienced medical physicist.
Treatment plan evaluation
A dose of 54 Gy in 30 fractions was prescribed at the isocenter. The primary planning objective was to encompass 99% of PTV by 95% of the prescribed dose, while maintaining the maximum dose limit at 107%. PTV coverage was assessed with TC, homogeneity index (HI), volume receiving 95% dose (V 95 ), dose maximum (Dmax), andminimum dose (Dmin). Hippocampal dose was assessed with mean dose, Dmax, Dmin, median dose, and volume receiving 95% (V 95 ), 80%(V 80 ), 50%(V 50 ), and 30% (V 30 ) dose. While doing evaluation constraints of other OARlike temporal lobe dose (V 27 (volume receiving 27 Gy) and V 43.2 (volume receiving 43.2 Gy), brainstem, lens, and eyes max dose were taken into consideration for each technique. Multiple plans were generated and evaluations of plans were done from dose volume histogram as well as from 'slice by slice' assessments. Clinically accepted plan from each modality was selected for comparison.
Dose homogeneity was quantified in terms of HI, as recommended by International Commission on Radiation Units and Measurements.  The HI was defined as maximum dose delivered to 2% of target volume (D2%) minus the dose delivered to 98%(D98%) target volume divided by median dose of the target volume (Dmedian): HI = (D2% − D98%)/Dmedian Smaller values for the HI correspond to more homogeneous dose across the target volume, and values close to 0 are optimal.
TC parameter describes the fraction of the target volume (VT) receiving at least the prescription dose (VTpres) and is defined as: TC = VTpres/VT.
For perfect coverage, TC equals 1.0.
Statistical analysis was performed using Statistical Package for Social Sciences (SPSS, version 17). Treatment plan metrics were compared using one-way analysis of variance (ANOVA) with Tukey's multiple comparison post-hoc tests.
| > Results|| |
The patient population dataset comprised children and young adults with a mean age of 14 years (range 5-23 years). In six patients, tumor location was central and in four patients although the tumor location was lateral, but in close proximity or involving hippocampus. Left hippocampus was involved in seven patients. Whole left hippocampus was part of PTV in two patients. Mean right and left hippocampus volume was 2.37 and 2.30 cc, respectively, which corresponds to available literature [Table 1].
PTV coverage and TC
PTV coverage with 95% dose was significantly better in Tomo and linear accelerator (LINAC)-based IMRT compared to SCRT (P = 0.03). Mean of V 95 in Tomo, IMRT, SCRT were 99.7,99.4, and 98.3% respectively [Figure 1] and [Figure 2]a and [Table 2]. TC with Tomo (TC-1) and IMRT (TC-0.99) was better than SCRT (TC-0.98) [Table 2].
|Figure 1: Dose distribution for a patient demonstrating PTV coverage and spillage in hippocampus. Red = 100% dose level, green = 70% dose level, blue = 20% dose level, PTV = planning target volume|
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|Figure 2: (a) Volume of target (in percentage) receiving prescribed doses. (b) Homogeneity index with tomotherapy, LA-based intensity modulated radiotherapy (IMRT), and stereotactic conformal radiotherapy (SCRT)|
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Tomo (HI ≤ 0.06) and IMRT (HI ≤ 0.06) plans were more homogeneous compared to SCRT (HI > 0.7) (P = 0.001), but there was no significant difference in Tomo and IMRT [Figure 2]b.
Maximum dose (Dmax)
SCRT delivered 4% more maximum dose (59.2Gy) than Tomo and IMRT (57 Gy) (P = 0.01). Volume receiving more than 107% dose was seen in one patient with Tomo, two patients with IMRT, and six patients with SCRT. There was significant difference in Tomo/IMRT and SCRT in V 107 parameter (P = 0.02).
Right hippocampal sparing was more than left in all three techniques. Median and mean doses showed trend towards sparing of right hippocampus with Tomo. In SCRT, right hippocampus received 23% more median dose compared to Tomo; whereas, it was 15% more compared to IMRT [Figure 3]a. Right hippocampus mean dose with Tomo (20Gy) was 9% and 18.5% less than IMRT (25 Gy) and SCRT (30 Gy), respectively; but for left, difference decreased to 4.6% (Tomo-32.2Gy and SCRT-34.7Gy) [Figure 3]a and b. At 30% dose, 9% more volume of right hippocampus was treated in IMRT and 20% in SCRT. At 80% dose, 6 and 12% more volume was treated with IMRT and SCRT, respectively [Figure 3]a and [Table 2].
|Figure 3: (a) Right hippocampus volume (percentage) receiving 95, 80, 50, and 30% of prescribed dose. (b) Left hippocampus volume (percentage) receiving 95, 80, 50, and 30% of prescribed dose|
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As most tumor locations were central and left-sided, differences among techniques were not as distinct as right hippocampus. Maximum dose to left hippocampus was 56.5,54.9, and 55.5Gy with Tomo, IMRT, and SCRT, respectively, which were comparable in all three techniques [Figure 3] b and [Table 2].
In normal tissue sparing, all three techniques achieved desired constraints.
| > Discussion|| |
RT is an effective treatment modality in children with low-grade gliomas regarding tumor control and improvement and/or preservation of neurologic function or vision, respectively. The role of RT for a long time was thought to be the main cause of cognitive deficits in patients with brain tumor. Preclinical work by Monje, "stem cell compartmental hypothesis", states that radiation injury to neural stem cell compartment causes apoptosis and decline in neurogenesis in young rat and mice resulted in failure of hippocampal dependent task.  Dosimetric study by MD Anderson suggests a correlation between the maximum dose to the left hippocampus and a decline in learning (P = 0.014) and delayed recall (P = 0.01).  In a study of 18 patients of benign or low-grade adult brain tumors treated with fractionated stereotactic radiotherapy (FSRT), an EQD2(equivalent dose in 2Gy/fraction) to 40% volume of the bilateral hippocampii receiving greater than 7.3 Gy was associated with long-term impairment in list learning delayed recall after 18 months follow-up.  Another study of 50 patients showed a clear significant correlation between doses to hippocampus with a decline in cognition at 3 and 5 years of IQ assessments.  Summation of these clinical observations provide rational for conformal avoidance of hippocampus and may spare from loss of hippocampal dependent task.
Although technically feasible, the clinical benefit of use of high precision technologies in the treatment of benign and low-grade brain tumors with respect to saving of hippocampus remains unproven. All research done in hippocampal sparing is for brain metastasis using high precision techniques. Gondi et al., demonstrated the capability of Tomo to conformably avoid the hippocampus, and still deliver radiosurgically quality dose distributions to multiple metastases with a homogeneous dose distribution to the whole brain in a single treatment plan.  Volumetric modulated arc therapy also had shown adequate whole brain coverage with conformal hippocampal avoidance in 1-3 brain metastases.  The disadvantage is that as the survival of the brain metastasis patients is relatively poor, the implication on the neurocognition deficits may not be fully understood. However, these studies have given us a chance to identify the hippocampus as organ at risk; which we can spare in other primary central nervous system (CNS) tumors, specifically important in patients with low-grade and benign brain tumors involving part of hippocampus or in its close vicinity. The novelty of hippocampal sparing to delay the onset of neurocognitive deficits poses many unanswered questions such as "what is the dose threshold below which hippocampal stem cell neurogenesis is preserved to a clinically relevant extent?"Another potential concern is whether hippocampal avoidance leads to loss of tumor control for tumors found in or close to this region. But before that, feasibility study should be done about technical challenge in sparing in accordance to present techniques. Then only we can explore this population to such technique to get good neurocognitive results, as we will use this technique; especially in children where neurocognition does matter. Avoiding the hippocampus during cranial irradiation, without compromising TC, poses important challenges given the central location and unique anatomic shape of the hippocampus.
Our study involved benign and low-grade brain tumors located either centrally or laterally. In majority of tumors, hippocampus was involved or was in its close relation. All three modalities were compared simultaneously, that is, tomotherapy, SCRT, and IMRT.
Studies till date in relation to hippocampal dosimetry had PTV, which was quite small. For example, the mean PTV volume in study by Hsu et al., was 1.94 cc and in another study by Gutierrez et al., it was 4.2 cc. , In our series, PTV volumes were considerably larger with mean PTV of 84 ± 52 cc, as these were the PTVs of low-grade tumors. It is inevitable that sparing hippocampus would be difficult in an attempt to cover such large PTV. Another important difference is the location of the lesion and relation to the PTV. In patients with brain metastasis, there was no lesion within hippocampus proper and only 3.3% were in perihippocampal region (hippocampus + 5 mm margin).  However in our study, the lesion was frequently seen to be in the vicinity of hippocampus or involving a part of hippocampus. This study does indicate that indeeds paring may be achievable in laterally situated tumors. In our study, tumors were central or left-sided and we were able to achieve contralateral, that is, right hippocampal sparing was more than left with all of the three techniques. Median, mean, and various dose levels suggested trend towards sparing of right hippocampus by Tomo than other two techniques, which is due to rapid dose fall off in tomotherapy. Difference between helical Tomo and IMRT with Novalis Tx was not as distinct as with between SCRT and Tomo. One of the reasons may be attributable to HD-MLC of Novalis Tx.
In our study, HI was found to be equally better with Tomo and IMRT, but it was significantly better when compared to SCRT. In the available literature, Tomo was better than IMRT in terms of HI; however in our study, HI of Tomo and IMRT were not significantly different. Dose used in our study was 54 Gy; whereas in the literature, doses used were 30-35Gy to whole brain with boost to metastasis.
More dosimetric studies need to be undertaken to understand the technical challenges in hippocampal sparing in accordance to present techniques. For neurocognition, laterality in hippocampus is yet to be decided. It is also necessary to see whether both hippocampus volumes need to be taken together or separately. We know subventricular zone is vital in memory storage and forms fraction of hippocampus; hence, studies with long-term neurocognition data will reveal whether sparing of complete hippocampus is necessary or sparing of subventricular zone will suffice. In the patients presenting with a tumor in close proximity to the hippocampus, it may be possible to sacrifice portion of the hippocampus (or ipsilateral hippocampus entirely) adjacent to the lesion, while still avoiding the contralateral portion. As PTV volumes were significantly larger and involvement of hippocampus within PTV was really a challenge to get statistical difference.
Results of the present dosimetric study will form basis to design clinical studies with the ultimate aim of identifying dose constraints for hippocampus, and thereby minimize RT-induced cognitive dysfunction.
| > Conclusion|| |
Tomotherapy and LINAC-based IMRT achieved significantly better PTV coverage. Tomo as compared to SCRT and IMRT plans showed trend towards significant sparing of the contralateral hippocampus, in eccentrically located tumors.
| > References|| |
Woo SY, Donaldson SS, Cox RS. Astrocytoma in children: 14 years′ experience at Stanford University Medical Center. J Clin Oncol 1988;6:1001-7.
Jannoun L, Bloom HJ. Long-term psychological effects in children treated for intracranial tumors. Int J Radiat Oncol Biol Phys 1990;18:747-53.
Jalali R, Mallick I, Dutta D, Goswami S, Dutta D, Munshi A, et al
. Factors influencing neurocognitive outcomes in young patients with benign and low-grade brain tumors treated with stereotactic conformal radiotherapy. Int J Radiat Oncol Biol Phys 2010;77:974-9.
Abayomi OK. Pathogenesis of irradiation-induced cognitive dysfunction. Acta Oncol 1996;35:659-63.
Nagai R, Tsunoda S, Hori Y, Asada H. Selective vulnerability to radiation in the hippocampal dentate granule cells. Surg Neurology 2000;53:503-6.
Madsen TM, Kristjansen PE, Bolwig TG, Wortwein G. Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat. Neuroscience 2003;119:635-42.
Monje ML, Vogel H, Masek M, Ligon KL, Fisher PG, Palmer TD. Impaired human hippocampal neurogenesis after treatment for central nervous system malignancies. Ann Neurol 2007;62:515-20.
Chera BS, Amdur RJ, Patel P, Mendenhall WM. A radiation oncologist′s guide to contouring the hippocampus. Am J Clin Oncol 2009;32:20-2.
International Commission on Radiation Units and Measurements (ICRU). ICRU a. Report 62: Prescribing, recording, and reporting photon beam therapy (Supplement toICRUReport 50). Bethesda, MD: ICRU; 1999.
Mahajan A, Dong L, Prabhu S. Application of deformable image registration to hippocampal doses and neurocognitive outcomes. Neuro Oncol 2007;9:538.
Gondi V, Hermann BP, Mehta MP, Tome WA. Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors. Int J Radiat Oncol Biol Phys 2012;83:487-93.
Jalali R, Kothavade V, Gupta T, Goswami S, Swamidas J. Hippocampus as a dose constraint model to preserve neurocognition in young patients with low grade brain tumours treated with focal stereotactic conformal radiotherapy: Data from a prospective clinical trial. Neuro Oncol 2012;14 (Suppl 6);1-164.
Gondi V, Tolakanahalli R, Mehta MP, Tewatia D, Rowley H, Kuo JS, et al
. Hippocampal-sparing whole-brain radiotherapy: A "how-to" technique using helical tomotherapy and linear accelerator-based intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2010;78:1244-52.
Hsu F, Carolan H, Nichol A, Cao F, Nuraney N, Lee R, et al
. Whole brain radiotherapy with hippocampal avoidance and simultaneous integrated boost for 1-3 brain metastases: A feasibility study using volumetric modulated arc therapy. Int J Radiat Oncol Biol Phys 2010;76:1480-5.
Gutierrez AN, Westerly DC, Tome WA, Jaradat HA, Mackie TR, Bentzen SM, et al
. Whole brain radiotherapy with hippocampal avoidance and simultaneously integrated brain metastases boost: A planning study. Int J Radiat Oncol Biol Phys 2007;69:589-97.
Ghia A, Tome WA, Thomas S, Cannon G, Khuntia D, Kuo JS, et al
. Distribution of brain metastases in relation to the hippocampus: Implications for neurocognitive functional preservation. Int J Radit Oncol Biol Phys 2007;68:971-7.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]