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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 2  |  Issue : 1  |  Page : 29-34

Different treatment planning strategies for whole-brain radiation therapy with simultaneous integrated boost for multiple brain metastases to protect neurocognitive function with hippocampal sparing


Department of Radiation Oncology, Istanbul Basaksehir Cam and Sakura City Hospital, Istanbul, Turkey

Date of Submission01-Apr-2022
Date of Decision25-Apr-2022
Date of Acceptance27-Apr-2022
Date of Web Publication15-Jun-2022

Correspondence Address:
Dr. Ilknur Harmankaya
Department of Radiation Oncology, Istanbul Basaksehir Cam and Sakura City Hospital, Istanbul
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aort.aort_8_22

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  Abstract 

PURPOSE: The aim of this study is to provide the dosimetric evaluation of the compound therapeutic concept of hippocampal avoidance for the whole brain radiotherapy (WBRT) with a simultaneous integrated boost (SIB) in patients with multiple brain metastases more than 3.
MATERIALS AND METHODS: Ten patients with multiple brain metastases previously treated with conventional WBRT followed by SIB on Radixact Tomotherapy Unit were selected. The whole-brain (WB) clinical target volume was generated by contouring the WB and excluding the hippocampal avoidance structure for the sake of WBRT while plan optimization of both approaches was performed with the aim of delivering 95% of the WB and receiving the prescription dose of 30 Gy; in addition, planning target volumes (PTVs) were given 45 Gy using SIB technique in 10 fractions. Dmax ≤16 Gy and D100% ≤9 Gy for hippocampi and V37 Gy for the WB-PTVs were evaluated in this study as well.
RESULTS: The D95% was 44.8 ± 0.15 Gy in helical tomotherapy (HT) which was calculated as 44.9 ± 0.11 Gy in volumetric modulated arc therapy (VMAT) plan. The volume receiving 37 Gy for brain-PTV was 3% ± 0.55% in HT and 10% ± 1.55% in the VMAT plan. The D2% and D100% values of hippocampi were calculated <2 Gy in HT plan compared to the VMAT plan.
CONCLUSION: Techniques used in both plans are feasible. However, the VMAT plan owns the ability to deliver SIB dose to each individual metastasis as well while it adequately delivers WBRT and conformably spares the hippocampus. On the negative side, providing the dosimetric criteria of hippocampus is not possible in some cases due to the close proximity of tumor locations to the hippocampus.

Keywords: Helical tomotherapy, hippocampal sparing, multiple brain metastases, volumetric arc radiation therapy, WBRT


How to cite this article:
Harmankaya I, Atilla O, Can S, Karacetin D. Different treatment planning strategies for whole-brain radiation therapy with simultaneous integrated boost for multiple brain metastases to protect neurocognitive function with hippocampal sparing. Ann Oncol Res Ther 2022;2:29-34

How to cite this URL:
Harmankaya I, Atilla O, Can S, Karacetin D. Different treatment planning strategies for whole-brain radiation therapy with simultaneous integrated boost for multiple brain metastases to protect neurocognitive function with hippocampal sparing. Ann Oncol Res Ther [serial online] 2022 [cited 2022 Jun 25];2:29-34. Available from: http://www.aort.com/text.asp?2022/2/1/29/347563


  Introduction Top


Recognized as a significant clinical problem, brain metastases are common findings occurring in 25%–45% of cancer patients.[1],[2] Whole-brain radiotherapy (WBRT), historically, is the standard cure protocol to treat brain metastases and to prevent recurrences elsewhere in the brain.[3] WBRT comes with the advantage of better distant intracranial tumor control yet is associated with relatively low control of existing metastases and considerable rate of late neurocognitive adverse effects.[4] Post-WBRT neurocognitive decline can occur through hippocampal atrophy and irradiation of the neural stem cell niche in charge of brain plasticity and repair as well as through whole-brain (WB) radiation dose, which can lead to long-term brain atrophy and leukoencephalopathy.[5],[6],[7] Furthermore, poor local tumor control and thus progressive brain metastases are correlated with significant neurocognitive deterioration suggesting local tumor control to play a highlighted role in preserving cognitive functions. Evidences obtained from clinical and preclinical studies suggest that the neurocognitive toxicity associated with WBRT may be the result of radiation-induced damage to the neural stem cell compartment of hippocampus.[6],[7],[8] Accordingly, it has been hypothesized that preferential sparing of this region during WBRT is hypothesized to possibly reduce neurocognitive decline.

In recent years, an increasingly adopted approach is to attach stereotactic radiosurgery (SRS) to individual metastases. Adding WBRT to SRS is concerned with improved local tumor control and reducing distant recurrence in the brain, however, it does not contribute to improving the maintenance of functional status or overall survival.[9],[10] Interestingly, the most commonly used approach in patients with multiple brain metastases (more than 3) is still WBRT as it is less complex than SRS and offers better intracranial control of the disease. Unfortunately, the primary shortcoming of WBRT is neurocognitive toxicity[11] as adding WBRT to SRS significantly deteriorated the patient's memory in 4 months. In comparison with early observations, similar neurocognitive changes were noted after prophylactic cranial irradiation with WBRT in a dose-dependent manner. Findings achieved through exploring the combination of hippocampus-avoidance WBRT and SRS of the planned study reveal the fact that the best sparing of hippocampi can be achieved as long as the dose escalation to the metastases is planned as a simultaneous integrated boost (SIB) rather than sequential SRS. Moreover, a SIB has the biological advantage of dose fractionation.[12],[13],[14]

The process of WBRT with SIB for brain metastases is accomplished with image-guided intensity-modulated radiotherapy (IMRT) with HT. More recently, reports state the feasibility of delivering WBRT with hippocampal sparing and SIB for brain metastases through tomotherapy.[15] There are achievements in conformality and dose distribution quality with tomotherapy and IMRT as well; nonetheless, this comes with the price of prolonged treatment times, particularly when multiple treatment fractions are taken into consideration, yet the recent introduction of modulated (VMAT) allowed the expansion of conformal techniques to more cases including palliative scenarios.

VMAT is a novel plan optimization platform benefiting from a single dynamically modulated gantry arc rotation of up to 360° so that a conformal three-dimensional (3D) dose distribution is delivered accurately and efficiently. The technique owns proximity to tomotherapy in which a full 360° of beam directions are available for optimization, yet the difference is in the entirety of dose–volume delivered in a single gantry rotation as opposed to multiple slice-by-slice treatment delivery.[16],[17],[18] VMAT enables WBRT with hippocampal sparing inserting SIB to the regions of macroscopic tumor within one radiotherapy course in total. Since both WBRT and SIB doses are delivered at the same time within the same plan, there are advantages in terms of better dosimetry, radiobiology, and quality assurance compared to sequential WBRT and SRS boosts delivered in separate courses at different times.[19],[20],[21]

In case hippocampus is preferably avoided, complex treatment planning and initial studies on this subject ought to be employed through HT or linear accelerator-based IMRT. As a result, this study is aimed at providing the first systemic clinical information for the compound therapeutic concept of hippocampus-avoidance WBRT with a SIB in patients with multiple brain metastases of more than 3. In addition, the study is targeted at reporting dosimetric compliance criteria through comparing two different treatment planning strategies, namely VMAT and HT.


  Materials and Methods Top


Patient selection and volume definition

Ten patients diagnosed with multiple brain metastases were enrolled between September 2020 and August 2021 at Basaksehir Cam and Sakura City Hospital Radiation Oncology Clinic in this retrospective planning study. All patients had been treated with conventional WBRT followed by SIB on Radixact Tomotherapy Unit. Computed tomography (CT) simulation was performed on a 16-slice Philips Brilliance Big Bore CT Scanner (Philips, Cleveland, OH, USA), and each patient's head was immobilized using a thermoplastic mask at the base. The 3D-CT images were obtained at 1 mm slice thickness. All DICOM 3D-CT datasets were then transferred to the Accuray Precision Treatment Planning System (TPS) to be contoured and treatment planning be devised. The OARs were delineated on magnetic resonance images (MRI) fused with the 3D planning CT consisting of brain stem, optic chiasm and optic nerves, eyes, lenses, lacrimal glands, and hippocampi. The hippocampal avoidance structure was generated using a computer-automated 5-mm margin 3D margin expansion of the contoured hippocampi. RTOG-0933/NRG-CC001 criteria were used for hippocampi delineation. An experienced radiation oncologist was asked to delineate target volumes and organs at risk (OARs) on T1/T2-weighted MRI registered to the 3D planning CT. The gross tumor volume (GTV) for each target metastasis was identified as the contrast-enhancing lesion on the T1-weighted MRI. A PTV for each metastasis was outlined using a computer-automated 2-mm 3D margin expansion of the GTV for each metastasis. The PTV of each metastasis was used as the target volume for the boost. The WB clinical target volume was generated by contouring the WB and excluding the hippocampal avoidance structure so as to perform WBRT.

Treatment planning

Performed at Radixact Tomotherapy Unit, all patients were treated based on HT plans, which was the reference plan for treatment. Plan optimization was performed to deliver 95% of the WB receiving the prescription dose of 30 Gy in 10 fractions. In addition to WBRT, PTV metastases were given 45 Gy in 10 fractions with the fraction dose of 4.5 Gy using SIB technique. The field width was defined as 2.5 cm, pitch factor 0.250, and modulation factor between 3.5 and 4.0 in all HT plans. All planning CT images contoured on were transferred to the Monaco TPS v. 5.51 (Elekta Stockholm Sweden) in order to devise VMAT plans. The couch angle was 0° and two arcs for a single arc with fixed collimator rotational position at 0° for all plans. The grid spacing was 0.2 cm, beamlet width was 0.4 cm, and minimum segment width was 0.6 cm. In the first step, the pencil beam algorithm was used for rapid modeling; final dose optimization was done with the Monte Carlo algorithm as well.

Both treatment planning approaches come with a dose delivery schema of 30 Gy in 10 fractions with minimum 95% of the WB receiving 29 Gy and minimum 90% of WB receiving the prescription dose. The total dose inserted to multiple metastases was 45 Gy in 10 fractions with SIB. Plan optimization was done based on dose restriction criteria for OARs.

Plan evaluation

Based on both approaches, the dose–volume histogram (DVH) of all WBRT-SIB treatment plans was generated for the WB, multiple metastases PTVs, hippocampi, lacrimal glands, and OARs. All plans were evaluated following NRG-CC001 dosimetric compliance criteria. Dosimetric evaluation of the plans was performed by calculating conformity index (CI) and heterogeneity index (HI) using the DVH of the treatment plans. The CI was defined as follows:



where Vtr represented the treated volume enclosed by the prescription isodose line, Vtarget is the total PTV volume from all multiple metastases PTVs. The International Commission on Radiation Units and Measurements formula was used for HI.



where D2% and D98% correspond to the dose delivered to 2% and 98% of the target volumes, respectively. Dmedian is the median dose of target volume. The volume that received 107% of the prescription dose was considered for the maximum dose (Dmax). Dmax ≤16 Gy and D100% ≤9 Gy for hippocampi, Dmax ≤30 Gy for lacrimal glands, and V37 Gy for the WB-PTVs were evaluated in this study. The Dmax was considered for lenses, eyes, optic nerves, and chiasm.

Statistics

The radiation dose of PTVs, WB, and OARs was analyzed based on the aforementioned criteria. The statistical differences of each parameter obtained through all plans were examined by SPSS statistical software (SPSS, Statistics v22, Chicago, IL, USA). For the sake of statistical analysis, the test of the significant difference between two plan parameters was first applied to check whether the variables assume normality. Provided that the differences are distributed normally, paired-samples t-test will be applied, or else two-related-samples test would be taken advantage of. P < 0.05 was considered statistically significant for both tests.


  Results Top


Target volume coverage

Protecting critical organs at the maximum level while ensuring that 95% of the target volume receives the entire prescribed dose was aimed in both plans. D98%, D2%, D95%, and Dmean values of PTV were compared to analyze target coverage. The D95% and Dmean of PTV were 44.8 ± 0.15 Gy and 47.0 ± 0.14 Gy in HT plans, respectively. In VMAT plans, these values were calculated as 44.9 ± 0.11 Gy and 46.5 ± 0.23 Gy. There is no statistical difference between HT and VMAT plans in terms of target coverage. In addition, the volume receiving 107% of the treatment dose was evaluated for Dmax. In VMAT plan, Dmax was 0.07 ± 0.09 cc, while this value was 0.7 ± 0.23 cc in HT plan. Accordingly, the VMAT plan was superior to tomotherapy in controlling the maximum dose. Moreover, no statistical difference was observed between CI and HI values for both modalities (P > 0.05). The volume that received 37 Gy for brain-PTV was 3% ± 0.55% in HT plan and 10% ± 1.55% in VMAT plan. HT plan was superior to provide 37 Gy for brain-PTV, i.e., D2% value for brain-PTV was approximately 4 Gy higher in VMAT plan compared to HT plan. The data in terms of target coverage are listed in [Table 1].
Table 1: The data in terms of target coverage obtained from two different plan approaches

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Dosimetric evaluation of organ at risk

In this study, Dmax value of the lenses, eye, and optic nerves was evaluated. Even though the Dmax values of the lenses, eyes, and optic nerves were 5 ± 0.43 Gy, 10 ± 0.53 Gy, and 18 ± 7.12 Gy in VMAT plan, respectively, they were 4.5 ± 0.83 Gy, 12 ± 1.56 Gy, and 20.5 ± 5.76 Gy in HT plan. Despite the fact that Dmax values of eyes and optic nerves were obtained <2 Gy in VMAT plan compared to the HT plan, these differences were statistically significant (P > 0.05). Dmax values of brain stem and chiasm are approximately 2 Gy smaller in VMAT plan compared to the HT plan, and such differences were statistically significant (P > 0.05). As a result, VMAT plan was effective to reduce the OAR's dose. The dose of organs at risk is shown in [Table 2].
Table 2: Dosimetric comparison for organs at risk

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Hippocampal sparing

The D2% of lacrimal glands and the D2% along with D100% of hippocampi were evaluated in terms of plan comparison. The D2% values of the lacrimal glands were 9.7 ± 0.65 Gy and 9.5 ± 0.8 Gy in HT and VMAT plans. Both approaches provided the dose criteria for the lacrimal gland which is <30 Gy for D2%. In addition, the D2% and D100% values of hippocampi were calculated approximately <2 Gy in HT plan compared to the VMAT plan, and this difference was statistically significant (P > 0.05). On the other hand, both approaches did not provide the dosimetric criteria, which are D2% <16–17 Gy and D100% <9–10 Gy. Inserting sufficient SIB dose was prioritized in the study while hippocampal sparing was not attempted in the cases where lesions were close to the hippocampi. The dosimetric comparison for lacrimal gland and hippocampi is shown in [Table 3]. Moreover, the dose distribution around hippocampi in HT and VMAT plans is shown in [Figure 1].
Figure 1: Volumetric modulated arc radiation therapy versus helical tomotherapy plan in terms of hippocampal sparing for the selected case

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Table 3: The dosimetric comparison for lacrimal gland and hippocampi

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  Discussion Top


In an era filled with efficient local and systematic therapies as well as improved survival rates, preserving neurologic and neurocognitive functions become all the more important. Like brain metastases themselves, administering WBRT comes with the possibility of impairing neurocognitive functions in terms of memory loss and poor quality of life (QoL). Neural stem cells within the hippocampus may play an important role in this pathomechanism. In RTOG 0933, avoidance of hippocampus during WBRT was associated with preservation of memory and QoL compared with a nonsparing historical series. Even though functional endocrine deficiencies are common after brain radiotherapy, endocrine follow-up data on hormonal changes after WBRT are scarce.

Benefitting from VMAT and HT planning, SIB with and without hippocampal sparing dose delivery is studied by several researchers.[22] In these studies, a variety of prescription doses are used in the treatment of multiple metastases.[23] Recent data presented by Hsu et al. demonstrated hippocampal sparing WBRT treatment planning study with SIB boost for 1–3 brain tumors.[13] The WB dose prescribed for 10 patients was 32.25 Gy in 15 fractions, and the SIB dose to individual brain tumors ranged from 63 to 70.8 Gy. Treatment plans were generated using a full arc 6 MV-beam and were evaluated for the target coverage parameters, including homogeneity and conformity indices, as well as dose to the hippocampi. The study reveals that the hippocampus was conformally avoided with the mean normalized dose of <6 Gy, and treatment times ranging from 3.3 to 4.1 min were reported. Similarly, Prokic et al. performed a retrospective study involving patients treated with hippocampal sparing WBRT with SIB or sequential boost concepts.[24] For 10 patients, VMAT were generated with 2 full coplanar arcs with 6 MV beam. The prescribed dose for up to 8 brain tumors was 30 Gy to the WB and 51 Gy to individual brain tumors (in SIB) 30 Gy in 12 fractions to the WB as well as 18 Gy in 2 fractions to brain metastases (in SIB). Both planning techniques were able to achieve adequate whole-brain coverage and radiosurgical quality of dose distributions to each of the brain metastases and spared hippocampi. In a prospective study, Awad et al. presented clinical data on hippocampus sparing for WBRT patients treated using VMAT with SIB for brain metastases from primarily melanoma origin.[20] In their institution, 30 patients with 73 brain tumors were treated with VMAT. The median WB dose was 31 Gy, with a median SIB dose to brain metastases of 50 Gy in 15 fractions. For patients treated with hippocampal sparing technique, mean and maximum hippocampus doses were 20.4 and 32.4 Gy, respectively. All these peer-reviewed articles are evidences to clinical potential (fast and effective delivery) of SIB treatment to WBRT patients using VMAT planning and spare hippocampus as well.

On the other hand, two different treatment planning approaches (HT and VMAT) were compared in terms of hippocampal sparing for WBRT with SIB for multiple metastases in this retrospective study. Patients were treated with HT and their treatment planning was replanned based on VMAT. Plan optimization was performed to deliver 95% of the WB receiving the prescription dose of 30 Gy in 10 fractions. In addition to WBRT, PTV metastases were given 45 Gy in 10 fractions with the fraction dose of 4.5 Gy using SIB technique. In both approaches, prescription doses were delivered to the target volume while performing the treatment. The volume that received 37 Gy for brain-PTV was 3% ± 0.55% in tomotherapy plan and 10% ± 1.55% in the VMAT plan. In addition, treatment plans were evaluated for all OARs, including hippocampi and lacrimal gland. For critical structures, all dosimetric criteria were provided with both approaches; however, D2% and D100% of hippocampi were not provided in some patients. Giving sufficient SIB dose was prioritized while hippocampal sparing was not attempted in the cases where lesions had proximity to the hippocampi.


  Conclusion Top


This study evaluates different treatment plan approaches in terms of hippocampal and critical structure sparing for WBRT with SIB in multiple brain metastases in which all patients were treated with HT while VMAT plan was devised to compare plan parameters. Based on the results, both treatment plan techniques are feasible and tolerable. VMAT plan was able to deliver SIB dose to individual metastases as well while adequately delivering WBRT and conformably sparing the hippocampus. On the other hand, providing the dosimetric criteria for hippocampus in both approaches is not possible in some cases due to the close proximity of tumor locations to the hippocampus.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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