Dosimetric feasibility of neurovascular bundle-sparing stereotactic body radiotherapy with periprostatic hydrogel spacer for localized prostate cancer to preserve erectile function.

OBJECTIVE: We aim to test the hypothesis that neurovascular bundle (NVB) displacement by rectal hydrogel spacer combined with NVB delineation as an organ at risk (OAR) is a feasible method for NVB-sparing stereotactic body radiotherapy. METHODS: Thirty-five men with low- and intermediate-risk prostate cancer who underwent rectal hydrogel spacer placement and pre-, post-spacer prostate MRI studies were treated with prostate SBRT (36.25 Gy in five fractions). A prostate radiologist contoured the NVB on both the pre- and post-spacer T2W MRI sequences that were then registered to the CT simulation scan for NVB-sparing radiation treatment planning. Three SBRT treatment plans were developed for each patient: (1) no NVB sparing, (2) NVB-sparing using pre-spacer MRI, and (3) NVB-sparing using post-spacer MRI. NVB dose constraints include maximum dose 36.25 Gy (100%), V34.4 Gy (95% of dose) <60%, V32Gy <70%, V28Gy <90%. RESULTS: Rectal hydrogel spacer placement shifted NVB contours an average of 3.1 ± 3.4 mm away from the prostate, resulting in a 10% decrease in NVB V34.4 Gy in non-NVB-sparing plans (p < 0.01). NVB-sparing treatment planning reduced the NVB V34.4 by 16% without the spacer (p < 0.01) and 25% with spacer (p < 0.001). NVB-sparing did not compromise PTV coverage and OAR endpoints. CONCLUSIONS: NVB-sparing SBRT with rectal hydrogel spacer significantly reduces the volume of NVB treated with high-dose radiation. Rectal spacer contributes to this effect through a dosimetrically meaningful displacement of the NVB that may significantly reduce RiED. These results suggest that NVB-sparing SBRT warrants further clinical evaluation. ADVANCES IN KNOWLEDGE: This is a feasibility study showing that the periprostatic NVBs can be spared high doses of radiation during prostate SBRT using a hydrogel spacer and nerve-sparing treatment planning.

Stereotactic body radiotherapy with periprostatic hydrogel spacer for localized prostate cancer: toxicity profile and early oncologic outcomes.

BACKGROUND: Multiple phase I-II clinical trials have reported on the efficacy and safety of prostate stereotactic body radiotherapy (SBRT) for the treatment of prostate cancer. However, few have reported outcomes for prostate SBRT using periprostatic hydrogel spacer (SpaceOAR; Augmenix). Herein, we report safety and efficacy outcomes from our institutional prostate SBRT experience with SpaceOAR placement. METHODS: Fifty men with low- or intermediate-risk prostate cancer treated at a single institution with linear accelerator-based SBRT to 3625 cGy in 5 fractions, with or without androgen deprivation therapy (ADT) were included. All patients underwent SpaceOAR and fiducial marker placement followed by pre-treatment MRI. Toxicity assessments were conducted at least weekly while on treatment, 1 month after treatment, and every follow-up visit thereafter. Post-treatment PSA measurements were obtained 4 months after SBRT, followed by every 3-6 months thereafter. Acute toxicity was documented per RTOG criteria. RESULTS: Median follow up time was 20 (range 4-44) months. Median PSA at time of diagnosis was 7.4 (2.7-19.5) ng/ml. Eighteen men received 6 months of ADT for unfavorable intermediate risk disease. No PSA failures were recorded. Median PSA was 0.9 ng/mL at 20 months; 0.08 and 1.32 ng/mL in men who did and did not receive ADT, respectively. Mean prostate-rectum separation achieved with SpaceOAR was 9.6 ± 4 mm at the prostate midgland. No grade ≥ 3 GU or GI toxicity was recorded. During treatment, 30% of men developed new grade 2 GU toxicity (urgency or dysuria). These symptoms were present in 30% of men at 1 month and in 12% of men at 1 year post-treatment. During treatment, GI toxicity was limited to grade 1 symptoms (16%), although 4% of men developed grade 2 symptoms during the first 4 weeks after SBRT. All GI symptoms were resolving by the 1 month post-treatment assessment and no acute or late rectal toxicity was reported > 1 month after treatment. CONCLUSIONS: Periprostatic hydrogel placement followed by prostate SBRT resulted in minimal GI toxicity, and favorable early oncologic outcomes. These results indicate that SBRT with periprostatic spacer is a well-tolerated, safe, and convenient treatment option for localized prostate cancer.

A low percentage of metastases in deep brain and temporal lobe structures.

BACKGROUND: Whole-brain radiotherapy (WBRT) in patients with brain metastases (BM) is associated with neurocognitive decline. Given its crucial role in learning and memory, efforts to mitigate this toxicity have mostly focused on sparing radiation to the hippocampus. We hypothesized that BM are not evenly distributed across the brain and that several additional areas may be avoided in WBRT based on a low risk of developing BM. METHODS: We contoured 2757 lesions in a large, single-institution database of patients with newly diagnosed BM. BM centroids were mapped onto a standard brain atlas of 55 anatomic subunits and the observed percentage of BM was compared with what would be expected based on that region's volume. A region of interest (ROI) analysis was performed in a validation cohort of patients from 2 independent institutions using equivalence and one-sample hypothesis tests. RESULTS: The brainstem and bilateral thalami, hippocampi, parahippocampal gyri, amygdala, and temporal poles had a cumulative risk of harboring a BM centroid of 4.83% in the initial cohort. This ROI was tested in 157 patients from the validation cohort and was found to have a 4.1% risk of developing BM, which was statistically equivalent between the 2 groups (P < 1 × 10-6, upper bound). CONCLUSION: Several critical brain structures are at a low risk of developing BM. A risk-adapted approach to WBRT is worthy of further investigation and may mitigate the toxicities of conventional radiation.

A novel model to correlate hydrogel spacer placement, perirectal space creation, and rectum dosimetry in prostate stereotactic body radiotherapy.

BACKGROUND: The SpaceOAR hydrogel is employed to limit rectal radiation dose during prostate radiotherapy. We identified a novel parameter - the product of angle θ and hydrogel volume - to quantify hydrogel placement. This parameter predicted rectum dosimetry and acute rectal toxicity in prostate cancer patients treated with stereotactic body radiotherapy to 36.25 Gy in 5 fractions. METHODS: Twenty men with low- and intermediate-risk prostate cancer underwent hydrogel placement from 2015 to 2017. Hydrogel symmetry was assessed on the CT simulation scan in 3 axial slices (midgland, 1 cm above midgland, 1 cm below midgland). Two novel parameters quantifying hydrogel placement - hydrogel volume and angle θ formed by the prostate, hydrogel, and rectum - were measured, and the normalized product of θ and hydrogel volume calculated. These were then correlated with perirectal distance, rectum maximum 1-3 cc point doses (rDmax 1-3 cc), and rectum volumes receiving 80-95% of the prescription dose (rV80-95%). Acute rectal toxicity was recorded per RTOG criteria. RESULTS: In 50% of patients, hydrogel placement was symmetric bilaterally to within 1 cm of midline in all three CT simulation scan axial slices. Lateral hydrogel asymmetry < 2 cm in any one axial slice did not affect rectum dosimetry, but absence of hydrogel in the inferior axial slice resulted in a mean increase of 171 cGy in the rDmax 1 cc (p < 0.005). The perirectal distance measured at prostate midgland, midline (mean 9.1 ± 4.3 mm) correlated strongly with rV95 (R2 0.6, p < 0.001). The mean hydrogel volume and θ were 10.3 ± 4.5 cc and 70 ± 49°, respectively. Perirectal distance, rV95 and rDmax 1 cc correlated with hydrogel angle θ (p < 0.01), and yet more strongly with the novel metric θ*hydrogel volume (p < 0.001). With a median follow up of 14 months, no rectal toxicity >grade 2 was observed. Low grade rectal toxicity was observed in a third of men and resolved within 1 month of SBRT. Men who had these symptoms had higher rDmax 1 cc and smaller θ*hydrogel volume measurements. CONCLUSIONS: Optimal hydrogel placement occurs at prostate midgland, midline. The novel parameter θ*hydrogel volume describes a large proportion of rectum dosimetric benefit derived from hydrogel placement, and can be used to assess the learning curve phenomenon for hydrogel placement.

Velocity-based Adaptive Registration and Fusion for Fractionated Stereotactic Radiosurgery Using the Small Animal Radiation Research Platform.

PURPOSE: To implement Velocity-based image fusion and adaptive deformable registration to enable treatment planning for preclinical murine models of fractionated stereotactic radiosurgery (fSRS) using the small animal radiation research platform (SARRP). METHODS AND MATERIALS: C57BL6 mice underwent 3 unique cone beam computed tomography (CBCT) scans: 2 in the prone position and a third supine. A single T1-weighted post-contrast magnetic resonance imaging (MRI) series of a murine metastatic brain tumor model was selected for MRI-to-CBCT registration and gross tumor volume (GTV) identification. Two arms were compared: Arm 1, where we performed 3 individual MRI-to-CBCT fusions using rigid registration, contouring GTVs on each, and Arm 2, where the authors performed MRI-to-CBCT fusion and contoured GTV on the first CBCT followed by Velocity-based adaptive registration. The first CBCT and associated GTV were exported from MuriPlan (Xstrahl Life Sciences) into Velocity (Varian Medical Systems, Inc, Palo Alto, CA). In Arm 1, the second and third CBCTs were exported similarly along with associated GTVs (Arm 1), while in Arm 2, the first (prone) CBCT was fused separately to the second (prone) and third (supine) CBCTs, performing deformable registrations on initial CBCTs and applying resulting matrices to the contoured GTV. Resulting GTVs were compared between Arms 1 and 2. RESULTS: Comparing GTV overlays using repeated MRI fusion and GTV delineation (Arm 1) versus those of Velocity-based CBCT and GTV adaptive fusion (Arm 2), mean deviations ± standard deviation in the axial, sagittal, and coronal planes were 0.46 ± 0.16, 0.46 ± 0.22, and 0.37 ± 0.22 mm for prone-to-prone and 0.52 ± 0.27, 0.52 ± 0.36, and 0.68 ± 0.31 mm for prone-to-supine adaptive fusions, respectively. CONCLUSIONS: Velocity-based adaptive fusion of CBCTs and contoured volumes allows for efficient fSRS planning using a single MRI-to-CBCT fusion. This technique is immediately implementable on current SARRP systems, facilitating advanced preclinical treatment paradigms using existing clinical treatment planning software.

Single institution validation of a modified graded prognostic assessment of patients with breast cancer brain metastases.

AIM: The number of breast cancer brain metastases is a prognostic clinical variable in the modified graded prognostic assessment (GPA) Index for breast cancer. PATIENTS & METHODS: We retrospectively gathered data from 127 breast cancer patients who underwent radiation therapy for brain metastasis. Patients were stratified by both breast GPA and modified breast GPA scores, and survival was determined using the Kaplan-Meier curves and Cox proportional hazards model. RESULTS & CONCLUSION: The Kaplan-Meier curve for patients under the breast GPA classification were not significant, but were significant under the modified breast GPA classification. The inclusion of number of brain metastases into the modified breast GPA index improved prognosis, thus validating the use of the modified breast GPA in prognosticating patient outcome.

Breast cancer subtype and stage are prognostic of time from breast cancer diagnosis to brain metastasis development.

Breast cancer brain metastasis (BCBM) is associated with high morbidity and mortality. Patients with breast cancer risk factors associated with rapid development of BCBM could potentially benefit from early brain metastasis screening. We retrospectively reviewed all BCBM patients treated with brain radiotherapy at our institution from 1997 to 2015. Interval time to BCBM was defined as date of pathologic breast cancer diagnosis to date of radiographic evidence of brain metastasis. Patients were stratified by breast cancer molecular subtype and stage at diagnosis. Kaplan Meier analysis was conducted on time to development of BCBM. Breast cancer risk factors were correlated with time to BCBM on Cox proportion hazard analysis. The study cohort comprised 121 BCBM patients, with median interval time to BCBM of 46 months. Times to BCBM for Her2+/2HR+, Her2+, Her2-/HR+, and triple-negative (TNBC) subtypes were 70, 44, 42, and 28 months respectively (p = 0.002). Time to BCBM for stages I, II, III, and IV were 70, 54, 29, and 24 months, respectively (p = 0.000). BCBM patients were further stratified by both molecular subtype (TNBC vs. non-TNBC) and stage (I, II vs. III, IV). Median times to BCBM for non-TNBC/stage I-II, TNBC/stage I-II, non-TNBC stage III-IV, and TNBC/stage III-IV were 68, 47, 29, and 6 months respectively (p = 0.000). Subtype and stage were associated with shorter time to BCBM on multivariate analysis. Subtype and initial stage are independently correlated with decreased time to development of BCBM. Patients with advanced high stage and triple negative breast cancer develop brain metastases significantly earlier.

Dependence of PEI and PAMAM Gene Delivery on Clathrin- and Caveolin-Dependent Trafficking Pathways.

PURPOSE: Non-viral gene delivery vehicles such as polyethylenimine and polyamidoamine dendrimer effectively condense plasmid DNA, facilitate endocytosis, and deliver nucleic acid cargo to the nucleus in vitro. Better understanding of intracellular trafficking mechanisms involved in polymeric gene delivery is a prerequisite to clinical application. This study investigates the role of clathrin and caveolin endocytic pathways in cellular uptake and subsequent vector processing. METHODS: We formed 25-kD polyethylenimine (PEI) and generation 4 (G4) polyamidoamine (PAMAM) polyplexes at N/P 10 and evaluated internalization pathways and gene delivery in HeLa cells. Clathrin- and caveolin-dependent endocytosis inhibitors were used at varying concentrations to elucidate the roles of these important pathways. RESULTS: PEI and PAMAM polyplexes were internalized by both pathways. However, the amount of polyplex internalized poorly correlated with transgene expression. While the caveolin-dependent pathway generally led to effective gene delivery with both polymers, complete inhibition of the clathrin-dependent pathway was also deleterious to transfection with PEI polyplexes. Inhibition of one endocytic pathway may lead to an overall increase in uptake via unaffected pathways, suggesting the existence of compensatory endocytic mechanisms. CONCLUSIONS: The well-studied clathrin- and caveolin-dependent endocytosis pathways are not necessarily independent, and perturbing one mechanism of trafficking influences the larger trafficking network.

Degradable self-assembling dendrons for gene delivery: experimental and theoretical insights into the barriers to cellular uptake.

This paper uses a combined experimental and theoretical approach to gain unique insight into gene delivery. We report the synthesis and investigation of a new family of second-generation dendrons with four triamine surface ligands capable of binding to DNA, degradable aliphatic-ester dendritic scaffolds, and hydrophobic units at their focal points. Dendron self-assembly significantly enhances DNA binding as monitored by a range of experimental methods and confirmed by multiscale modeling. Cellular uptake studies indicate that some of these dendrons are highly effective at transporting DNA into cells (ca. 10 times better than poly(ethyleneimine), PEI). However, levels of transgene expression are relatively low (ca. 10% of PEI). This indicates that these dendrons cannot navigate all of the intracellular barriers to gene delivery. The addition of chloroquine indicates that endosomal escape is not the limiting factor in this case, and it is shown, both experimentally and theoretically, that gene delivery can be correlated with the ability of the dendron assemblies to release DNA. Mass spectrometric assays demonstrate that the dendrons, as intended, do degrade under biologically relevant conditions over a period of hours. Multiscale modeling of degraded dendron structures suggests that complete dendron degradation would be required for DNA release. Importantly, in the presence of the lower pH associated with endosomes, or when bound to DNA, complete degradation of these dendrons becomes ineffective on the transfection time scale-we propose this explains the poor transfection performance of these dendrons. As such, this paper demonstrates that taking this kind of multidisciplinary approach can yield a fundamental insight into the way in which dendrons can navigate barriers to cellular uptake. Lessons learned from this work will inform future dendron design for enhanced gene delivery.