If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Whole-brain radiotherapy has been the standard palliative treatment for patients with brain metastases due to its effectiveness, availability, and ease of administration. Recent clinical trials have shown that limiting radiation dose to the hippocampus is associated with decreased cognitive toxicity. In this study, we updated an existing Knowledge Based Planning model to further reduce dose to the hippocampus and improve other dosimetric plan quality characteristics. Forty-two clinical cases were contoured according to guidelines. A new dosimetric scorecard was created as an objective measure for plan quality. The new Hippocampal Sparing Whole Brain Version 2 (HSWBv2) model adopted a complex recursive training process and was validated with five additional cases. HSWBv2 treatment plans were generated on the Varian HalcyonTM and TrueBeamTM systems and compared against plans generated from the existing (HSWBv1) model released in 2016. On the HalcyonTM platform, 42 cases were re-planned. Hippocampal D100% from HSWBv2 and HSWBv1 models had an average dose of 5.75 Gy and 6.46 Gy, respectively (p < 0.001). HSWBv2 model also achieved a hippocampal Dmean of 7.49 Gy, vs 8.10 Gy in HSWBv1 model (p < 0.001). Hippocampal D0.03CC from HSWBv2 model was 9.86 Gy, in contrast to 10.57 Gy in HSWBv1 (p < 0.001). For PTV_3000, D98% and D2% from HSWBv2 model were 28.27 Gy and 31.81 Gy, respectively, compared to 28.08 Gy (p = 0.020) and 32.66 Gy from HSWBv1 (p < 0.001). Among several other dosimetric quality improvements, there was a significant reduction in PTV_3000 V105% from 35.35% (HSWBv1) to 6.44% (HSWBv2) (p < 0.001). On 5 additional validation cases, dosimetric improvements were also observed on TrueBeamTM. In comparison to published data, the HSWBv2 model achieved higher quality hippocampal avoidance whole brain radiation therapy treatment plans through further reductions in hippocampal dose while improving target coverage and dose conformity/homogeneity. HSWBv2 model is shared publicly.
Brain metastasis, the most common form of brain cancer, is approximately 10-fold more common than primary brain tumors and affects nearly 170,000 Americans annually.
Roughly 20% of all patients with solid tumors will develop brain metastases over the course of their disease, with primary lung cancers being the most frequent source.
For the past 70 years, whole-brain radiotherapy (WBRT) has been the standard palliative treatment for patients with brain metastases due to its effectiveness, availability, and ease of administration.
However, with further improvements in systemic therapy and overall survival, recent efforts have been aimed at reducing cognitive toxicities associated with WBRT.
The hippocampal dentate gyrus, a complex temporal lobe structure that houses an exquisitely radiosensitive compartment of neural stem cells, plays an important role in learning and memory.
Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors.
A prospective multi-institutional randomized phase III trial, NRG-CC001 (ClinicalTrials.gov identifier: NCT02360215), found therapeutic radiation doses to the whole brain while limiting hippocampal radiation doses (D100% ≤ 9 Gy and Dmax ≤ 16 Gy) along with twice-daily memantine, significantly reduced cognitive toxicity at 4 and 6 months.
Despite strong clinical evidence that hippocampal avoidance during WBRT enhances clinical outcomes, cognitive function as a result of hippocampal dose gradient remains unknown. However, there has been a steep dose-response relationship between higher maximum dose to the bilateral hippocampus and deterioration in short-term memory.
steep dose-response relationship between maximum hippocampal dose and memory deficits following hippocampal avoidance whole brain radiation therapy (HA-WBRT) for brain metastases: A secondary analysis of NRG/RTOG 0933.
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.
In clinical practice, treatment planning is labor intensive and has high inter-planner variability for parameters, such as organ-at-risk (OAR) sparing, homogeneity index, and conformality index.
RapidPlanTM is a commercial implementation of Knowledge Based Planning (KBP) (Varian Medical Systems, Palo Alto, CA). KBP software utilizes geometric features (i.e., OAR distance to the planning target volume (PTV)) and OAR overlap volume histogram to search for the best prior case(s) from a database or to construct a dose prediction model (i.e., machine learning, statistical model). In 2016, the Hippocampal Sparing Whole Brain Model Version 1.0 (HSWBv1) was made publicly available.
HSWBv1 utilized a complex recursive model creation process and leveraged an intricate scorecard to assess plan quality. This scorecard, based on NRG-CC001, contained additional metrics to further reduce dose to the hippocampus and included additional OAR objectives (Table 1).
In this study, we developed a new multi-institutional Hippocampal Sparing Whole Brain RapidPlanTM Model Version 2.0 (HSWBv2) to further improve hippocampal sparing, homogeneity, conformity, and other OAR constraints over HSWBv1. The steep dose relationship between hippocampal dose and cognitive decline suggests tighter constraints may be beneficial.
steep dose-response relationship between maximum hippocampal dose and memory deficits following hippocampal avoidance whole brain radiation therapy (HA-WBRT) for brain metastases: A secondary analysis of NRG/RTOG 0933.
Target and OAR contouring and treatment planning guidelines
Fifty anonymized whole brain DICOM computed tomography (CT) and structure sets were obtained from Northwestern Medicine Cancer Center Warrenville and Washington University in St. Louis for patients treated per NRG-CC001 protocol. A planning CT protocol that encompassed the entire head was obtained for all patient cases, with maximum axial slice thickness of 2.5 mm or smaller. T1 contrast enhanced magnetic resonance imaging with similar axial slice thickness were registered to CT images. Bilateral hippocampal volumes, OARs, and optimization structures were then generated on the planning CT.
All training and validation cases used head-first supine orientation with the head in a neutral position immobilized with an Aquaplast mask. A 4-arc volumetric modulated arc therapy technique was utilized with 4 full coplanar arcs on HalcyonTM (Varian Medical Systems, Palo Alto, CA). Arcs had alternating clockwise and counterclockwise gantry rotations with collimator positions set at 315, 0, 45, and 90 degrees. The coplanar arcs had 359.8 degrees of arc rotation for each field. Arcs were positioned at a single isocenter located in the center of the target. Each arc utilized 6X Flattening Filter-Free energy at a dose rate of 800 MU per minute. HSWBv2 was also tested with various arc geometries (both coplanar and non-coplanar) on TrueBeamTM/C-series (Millennium120 MLC). Full validation with different number of arcs, geometries, energies, and dose calculation methods, including a quantification of the relative dosimetric performance of each method, can be seen in Annex A of the clinical description document included with HSWBv2.
New scorecard tool used
Dosimetric scorecards were used to guide the RapidPlanTM model creation process. The PlanScoreCard Eclipse Scripting Application Programming Interface tool, available free on the Varian Innovation Center GitHub, was used to create scoring metrics, automatically generate additional optimization and evaluation structures, and score candidate plans throughout the process. These dosimetric scorecards use established scoring methodology of multiple piecewise linear score functions which measure specific plan quality metrics.
Dosimetric scorecards as objective measure of plan quality
The original plan quality metrics scorecard Version 1.0 (100 points in total) was developed in 2016 for HSWBv1 and was based on dose constraints from NRG-CC001. The Version 1.0 scorecard awarded points for OAR doses lower than those cited in NRG-CC001 and added additional metrics for OARs and plan quality indexes not listed in the protocol. The new Version 2.0 dosimetric scorecard used in this study was further revised from the 2016 scorecard to address perceived plan quality issues with HSWBv1 plans (142 points in total). Additional points were awarded to prior metrics and new metrics were added, in-part, via four derived structures (Fig. 1). These new structures and their associated metrics quantify reducing dose to the face, improving conformity, and reducing heterogeneity in the target.
Fig. 1Derived structures. PTV_Brain (Brain – [Hippocamus +05]) defined in NRG-CC001, used for scorecard evaluation but not used in optimization. oPTV (Brain – [Hippocamus +07]) used as primary target during optimization. Ring ([Brain +20) – [Brain +03]) used to minimize radiation dose outside the brain. Face ([Eyes +100] – [Brain +20]) used to minimize unnecessary lower doses. BS PTV (Brainstem – [Hippocampus +08]) used as secondary target to prevent <Rx dose between Hippocampus structures. (Units: mm). PTV, planning target volume.
Further hippocampal sparing was also rewarded in the Version 2.0 scorecard. For the maximum dose goal (D0.03CC) points are earned from 8 to 17 Gy, minimum dose (D100%) 5 to 10Gy, and Dmean 6 to 12 Gy.
This Version 2.0 scorecard, once finalized, guided the model creation process by providing a singular objective measure of plan quality.
All cases were prescribed 30 Gy in 10 fractions and satisfied the necessary contouring criteria for NRG-CC001 with additional OARs and structures. The original HSWBv1 model and Version 1.0 scorecard were used as a basis for this work. Treatment plans created from HSWBv1 with Varian HalcyonTM System were manually reoptimized to address feedback and improvements quantified using the new version 2.0 scorecard. Those manually improved, reoptimized plans became the training set for the initial HSWBv2 model. More cases were added, and a recursive model creation process was employed to ensure the final HSWBv2 training set consisted, exclusively, of plans generated from the initial HSWBv2 model. Evaluating plan scores at each step in the process informed multiple iterations of re-tuning the optimization objective set. As additional cases were added, geometric outliers became apparent. These outlier cases were omitted from the final HSWBv2 training set, resulting in 42 total cases. See Fig. 3 for process workflow details.
Fig. 3Flowchart of HSWBv2 Model Creation, Training, and Validation......
Primary dosimetric planning goals and scorecard comparison
Treatment plan comparisons were made between HSWBv1 and HSWBv2 for the hippocampus and PTV_3000 using student t-tests. Primary dose metrics for the hippocampus include dose at 0.03CC's (D0.03CC), mean dose (Dmean), and dose at 100% volume (D100%). PTV_3000 primary metrics include dose at 98% volume (D98%), dose at 2% volume (D2%), and volume receiving 105% of prescription dose (V105%). These are included as high scoring individual metrics on the version 2.0 scorecard. The total scorecard points were also compared using student t-tests. Correlation analysis was performed to determine volume associations with hippocampal Dmean, D100%, and D0.03CC.
Results
Hippocampal sparing comparisons between HSWBv1 and HSWBv2 on Halcyon
HSWBv2 has enhanced hippocampal sparing compared to HSWBv1. On the Halcyon platform, 42 training set cases were re-planned. Hippocampus D100% from HSWBv2 and HSWBv1 had an average dose of 5.75 ± 0.25 Gy and 6.46 ± 0.40 Gy, respectively (p < 0.001). HSWBv2 also achieved hippocampus Dmean of 7.49 ± 0.36 Gy, vs 8.10 ± 0.42 Gy from HSWBv1 (p < 0.001). The hippocampus D0.03CC from HSWBv2 was 9.86 ± 0.73 Gy, in contrast to 10.57 ± 0.75 Gy from HSWBv1 (p < 0.001). In addition to achieving significantly lower doses to the hippocampus, HSWBv2 reduced interplan variability, seen from the smaller standard deviations (Table 2).
Table 2HalcyonTM plan quality comparisons between the HSWBv2 and HSWBv1 models; values were averaged from 42 cases (training set for HSWBv2)
PTV comparisons between HSWBv1 and HSWBv2 on Halcyon
For PTV_3000 on the Halcyon platform, D98% and D2% from HSWBv2 were 28.27 ± 0.33 Gy and 31.81 ± 0.12 Gy, respectively, compared to 28.08 ± 0.40 Gy (p = 0.020) and 32.66 ± 0.20 Gy from HSWBv1 (p < 0.001). The smaller difference between D98% and D2% represents improved plan homogeneity. This was further exemplified by a large difference in V105%, 6.44 ± 2.56% and 35.35 ± 7.49% from HSWBv2 and HSWBv1, respectively, indicating less heterogeneity (“hot” spots) than HSWBv1 (Table 2).
Total score comparisons and correlation analysis between hippocampus volume and hippocampus D0.03CC, Dmean, and D100%
The average total score achieved by HSWBv2 and HSWBv1 were 132.97± 1.71 and 121.03 ± 3.48, respectively (p < 0.001). No correlation was found between hippocampal volume (mean = 4.46CC; SD = 0.94CC) and D0.03CC (p = 0.066), Dmean (p = 0.566), and D100% (p = 1.000).
HSWBv2 validation on Halcyon and TrueBeam
HSWBv2 exhibited superior dosimetry compared to HSWBv1 on the Halcyon platform and similar efficacies were seen on the TrueBeam platform. Using five separate validation cases, both Halcyon and TrueBeam plans created with HSWBv2 generally had improved hippocampal (D0.03CC, Dmean, and D100%) and PTV_3000 (D98%, D2%, and V105%) metrics, with few exceptions. Nevertheless, HSWBv2 plans always earn higher total scores over HSWBv1. Higher scores result, in part, from increased homogeneity (PTV V105%) across all validated beam geometries (Table 3).
Table 3The HSWBv2 model validation on HalcyonTM and TrueBeamTM using 5 cases (in addition to the 42 training cases)
Mean (SD)
Target/OAR
HalcyonTM
TrueBeamTM
4 Arcs (coplanar)
3 Arcs (coplanar)
HyperArc non-coplanar
4 Arcs non-coplanar
4 Arcs coplanar
3 Arcs coplanar
Hippocampus
D100% (Gy)
5.69 (0.19)
5.67 (0.26)
6.79 (0.11)
6.78 (0.12)
6.77 (0.15)
6.72 (0.07)
Dmean (Gy)
7.65 (0.20)
7.67 (0.22)
8.27 (0.13)
8.35 (0.15)
8.45 (0.17)
8.54 (0.19)
D0.03CC (Gy)
10.12 (0.45)
10.13 (0.52)
10.90 (0.22)
11.06 (0.34)
11.04 (0.30)
11.16 (0.36)
Brain PTV
D98% (Gy)
28.39 (0.15)
28.39 (0.14)
28.23 (0.09)
28.11 (0.15)
27.86 (0.22)
27.88 (0.21)
D2% (Gy)
31.72 (0.09)
31.87 (0.06)
31.73 (0.04)
31.78 (0.07)
31.94 (0.17)
31.99 (0.13)
V105% (%)
4.74 (1.29)
8.73 (1.87)
6.10 (1.06)
6.89 (1.65)
10.24 (4.56)
12.18 (4.38)
HSWBv2 score (out of 142)
133.00 (0.34)
132.21 (0.57)
129.93 (0.48)
129.08 (0.73)
127.19 (1.34)
126.91 (1.06)
HSWBv1 score (out of 142)
120.49 (1.50)
119.56 (0.81)
120.36 (1.69)
120.05 (3.65)
114.11 (1.89)
114.12 (1.68)
HalcyonTM SX2MLC coplanar collimator: 315°, (0°), 45°, 90°. TruebeamTM M120MLC HyperArc: full 4 arc arrangement. Four arcs non-coplanar: 2 full arcs 0° couch, 2 180° arcs 90° couch. Three arcs coplanar collimator: 315°, 45°, 90° 4 arcs coplanar collimator same as 3 arcs except 90° split X jaw superior/inferior to hippocampus. All calculations: 6X-FFF, AcurosXB, convergence mode: extended MR3.
KBP methods have several advantages over manually optimized plans in radiotherapy. KBP can streamline the treatment planning process by standardizing plan quality, reducing human input, and decreasing time to perform treatment planning.
For example, creating optimization objectives for a glioblastoma disease site took 2 minutes, accompanied by 5 additional minutes for optimization and dose calculation.
We developed a new KBP hippocampal avoidance whole brain radiation therapy treatment model (HSWBv2) with the goal of further reducing dose to the hippocampus, increasing dose homogeneity, and improving other dosimetric parameters. The version 2.0 scorecard added more robust scoring, resulting in a more complete evaluation of dosimetric plan quality. The revised scorecard integrated feedback from 5 years of clinical use of HSWBv1. The new scorecard tool allows for metrics which automatically generate complex, dynamic structure expansion/contraction and Boolean operations. This automation expedited the creation of the additional derived structures (Fig. 1). These structures were evaluated on the scorecard and used for both optimization and dose volume histogram prediction. Using these derived structures, HSWBv2 enforced enhanced target conformation, homogeneity, and OAR sparing (Fig. 4).
Fig. 44 Arc HalcyonTM treatment plans made with single click, RapidPlanTM. HSWBv1 (left) and HSWBv2 (right).
Some previous studies only segmented a limited number of cranial structures which included hippocampus and 2 to 3 other OARs (i.e., optic nerves and chiasm, lens).
Whole brain radiotherapy with hippocampal avoidance and simultaneous integrated boost for brain metastases: a dosimetric volumetric-modulated arc therapy study.
In comparison to published data, HSWBv2 achieved significantly lower hippocampus Dmean, D100%, and D0.03CC without compromising target coverage while also reducing hot spots substantially. Published series with a PTV prescription dose of ≥30 Gy generally achieved hippocampus D100% of approximately 8 Gy, in contrast to 5.75 Gy in our study (Table 1). Though Levra et al. report a D100% of 6.7 Gy, their study prescribed a PTV whole brain dose of 20Gy while including simultaneous integrated boost to targets greater than 30 Gy.
Whole brain radiotherapy with hippocampal avoidance and simultaneous integrated boost for brain metastases: a dosimetric volumetric-modulated arc therapy study.
HSWBv2 was tested on two Varian delivery platforms: HalcyonTM and TrueBeamTM of which TrueBeamTM is the most popular Varian delivery platform. Halcyon utilizes advanced dual-layer MLC which enables high modulation due to faster leaf speed and lower transmission. HSWBv2 created high quality plans on both platforms without user interaction or plan modification (“single click”), allowing for the model to be readily usable in clinics. The advantage of single click optimization is that the planner is not tied to the process. The total time taken for optimization is dependent on the speed of treatment planning system hardware and software configuration (i.e., convergence mode). For reference, HSWBv1 and HSWBv2 total optimization time on our system took 79 and 76 minutes, respectively. This HSWBv2 RapidPlanTM model is free to download to the community for all who can use such models.
HSWBv2 utilized statistical and machine learning methods available in RapidPlanTM software for selecting the training set cases. The recursive method generated a KBP model that produced narrow and accurate dose volume histogram prediction bands. These well-fit estimation bands allowed for more aggressive and improved OAR sparing.
Our HSWBv2 model contains more metrics/parameters/constraints than prior hippocampal avoidance whole brain radiation therapy treatment models. Preliminary model validation with five independent cases resulted in similar dosimetric quality and plan scores compared to the testing completed on the training set cases. During development, HSWBv2 included up to 50 cases in its training set. Eight outliers were omitted due to either irregular patient head position or questionable geometric shape and/or volume of hippocampus contours. Although hippocampus volume are approximately 3.00 cc in normal adults,
HSWBv2 training set cases averaged 4.46 cc and cases with hippocampus volume >7.50 cc were excluded.
The radiosensitive nature of the hippocampus further emphasizes the need to minimize hippocampus dose while maintaining dosimetric plan quality. In NRG-CC001, maximum doses of 14 Gy and 16 Gy were associated with a 10% and 25% risk of short-term memory deterioration at the 6-month mark.
steep dose-response relationship between maximum hippocampal dose and memory deficits following hippocampal avoidance whole brain radiation therapy (HA-WBRT) for brain metastases: A secondary analysis of NRG/RTOG 0933.
The hippocampus D0.03CC of 9.86 Gy and D100% of 5.75 Gy achieved in our study are significantly lower than prior studies or current existing clinical guidelines. In conclusion, we demonstrated plan quality improvements by using KBP and dosimetric scorecard to guide the process. Further clinical studies are needed to determine the impact of additional hippocampal dose reduction and its correlation to neurocognitive function.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Data Sharing Statement
Research data is stored in Varian repository and will be shared upon request to the corresponding author.
Conflict of Interest
Dr Sushil Beriwal has a leadership role as the Vice President of Medical Affairs at Varian Medical Systems, reports grant as an Elsevier consultant, and reports participation in advisory board at Xoft DSMB. Mr Ryan Clark reports employment at Varian Medical Systems. Mr Anthony Magliari reports employment at Varian Medical Systems. Dr Francisco Reynoso reports honoraria for lectures from Varian Medical Systems. Dr Heather Curry reports employment at Varian Medical Systems. Dr Patrick Kupelian reports employment at Varian Medical Systems. Dr Deepak Khuntia has a leadership role as the Senior Vice President and Chief Medical Officer at Varian Medical Systems. Mr Hefei Liu, Mr Robert Foster, Mr Matthew Schmidt, Dr Vinai Gondi, Dr Christopher Abraham have nothing to disclose.
References
Lamba N
Wen PY
Aizer AA
Epidemiology of brain metastases and leptomeningeal disease.
Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors.
steep dose-response relationship between maximum hippocampal dose and memory deficits following hippocampal avoidance whole brain radiation therapy (HA-WBRT) for brain metastases: A secondary analysis of NRG/RTOG 0933.
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.
Whole brain radiotherapy with hippocampal avoidance and simultaneous integrated boost for brain metastases: a dosimetric volumetric-modulated arc therapy study.
A 3-mm margin was added during contouring of the hippocampus.
00039-5&id=gr1.jpg){kind=link}
00039-5&id=gr2.jpg){kind=link}
00039-5&id=gr3.jpg){kind=link}
00039-5&id=gr4.jpg){kind=link}