We predict, for the first time, that by using United States Food and Drug Administration approved concentrations of cisplatin, major radiosensitization may be achieved via photoelectric mechanism during concomitant chemoradiotherapy (CCRT). Our analytical calculations estimate that radiotherapy (RT) dose to cancer cells may be enhanced via this mechanism by over 100% during CCRT. The results proffer new potential for significantly enhancing CCRT via an emerging clinical scenario, where the cisplatin is released in-situ from RT biomaterials loaded with cisplatin nanoparticles.
Cisplatin nanoparticles; Dose enhancement; Chemoradiotherapy; Radiotherapy; Brachytherapy
To investigate the dosimetric variability associated with interobserver organ-at-risk delineation differences on computed tomography in patients undergoing gynecologic interstitial brachytherapy.
Methods and Materials
The rectum, bladder and sigmoid of 14 patients treated with gynecologic interstitial brachytherapy were retrospectively contoured by 13 physicians. Geometric variability was calculated using κ statistics, conformity index (CIgen), and coefficient of variation (CV) of volumes contoured across physicians. Dosimetric variability of the single-fraction D0.1cc and D2cc was assessed through CV across physicians, and the standard deviation of the total EQD2 (equivalent dose in 2 Gy per fraction) brachytherapy dose (SDTOT) was calculated.
The population mean ± 1 standard deviation of κ, CIgen and volume CV were, respectively: 0.77 ± 0.06, 0.70 ± 0.08 and 20% ± 6% for bladder; 0.74 ± 06, 0.67 ± 0.08 and 20% ± 5% for rectum, and 0.33 ± 0.20, 0.26 ± 0.17 and 82% ± 42% for sigmoid. Dosimetric variability was: for bladder, CV = 31% ± 19% (SDTOT = 72 ± 64 Gy) for D0.1cc and CV = 16% + 10% (SDTOT = 9 ± 6 Gy) for D2cc; for rectum, CV = 11% ± 5% (SDTOT = 16 ± 17 Gy) for D0.1cc and CV = 7% ± 2% (SDTOT = 4 ± 3 Gy) for D2cc; for sigmoid, CV = 39% ± 28% (SDTOT = 12 ± 18 Gy) for D0.1cc and CV = 34% ± 19% (SDTOT = 4 ± 4 Gy) for D2cc.
Delineation of bladder and rectum by 13 physicians demonstrated substantial geometric agreement and resulted in good dosimetric agreement for all dose-volume histogram parameters except bladder D0.1cc. Small delineation differences in high-dose regions by the posterior bladder wall may explain these results. The delineation of sigmoid showed fair geometric agreement. The higher dosimetric variability for sigmoid compared with rectum and bladder did not correlate with higher variability in the total brachytherapy dose but rather may be due to the sigmoid being positioned in low-dose regions in the cases analyzed in this study.
Radiation therapy (RT) is the treatment of cancer and other diseases with ionizing radiation. The ultimate goal of RT is to destroy all the disease cells while sparing healthy tissue. Towards this goal, RT has advanced significantly over the past few decades in part due to new technologies including: multileaf collimator-assisted modulation of radiation beams, improved computer-assisted inverse treatment planning, image guidance, robotics with more precision, better motion management strategies, stereotactic treatments and hypofractionation. With recent advances in nanotechnology, targeted RT with gold nanoparticles (GNPs) is actively being investigated as a means to further increase the RT therapeutic ratio. In this review, we summarize the current status of research and development towards the use of GNPs to enhance RT. We highlight the promising emerging modalities for targeted RT with GNPs and the corresponding preclinical evidence supporting such promise towards potential clinical translation. Future prospects and perspectives are discussed.
cancer; gold nanoparticle; nanomedicine; radiotherapy; retinal disease
To investigate the dose distributions associated with a novel balloon sleeve placed over a standard cylinder applicator.
Material and methods
A computed tomography (CT) scan of a sleeve balloon shaped to inflate into the vaginal fornices was used to digitize 1-, 3-, and 5-catheter configurations. Point doses for rectum, apex, and fornix were calculated and compared to the values associated with a standard cylinder plan not targeting the vaginal fornices. Inflation of the sleeve balloon in the vaginal fornices and dose coverage with constraints to the rectum, bladder, and sigmoid D2cc were evaluated.
Rectum, apex, and fornix doses were respectively 76%, 119%, and 44% for a standard cylinder; 190%, 310%, and 93% for a 1-catheter configuration; 98%, 109%, and 109% for a 3-catheter configuration; and 91%, 107%, and 96% for the 5-catheter configuration. In a patient analysis, expansion of the sleeve balloon into the vaginal fornices was confirmed. The 5-catheter configurations were associated with best coverage of the fornices and acceptable doses to rectum, bladder, and sigmoid.
A 1-catheter configuration cannot be used clinically due to high rectal and apex dose. In theoretical analysis, the 3- and 5-catheter configurations showed > 96% coverage to the vaginal fornices with a clinically acceptable rectal dose. In a treatment simulation in a patient, a 5-catheter configuration showed 90% coverage of the fornices with acceptable doses to the organs at risk. The treatment of deep vaginal fornices results in an increased rectal dose compared to a standard cylinder plan.
brachytherapy; intracavitary; vaginal fornices; multi-channel; applicator
Prostate volume can affect whether patients qualify for brachytherapy (desired size ≥20 mL and ≤60 mL) and/or active surveillance (desired PSA density ≤0.15 for very low risk disease). This study examines variability in prostate volume measurements depending on imaging modality used (ultrasound versus MRI) and volume calculation technique (contouring versus ellipsoid) and quantifies the impact of this variability on treatment recommendations for men with favorable-risk prostate cancer.
We examined 70 patients who presented consecutively for consideration of brachytherapy for favorable-risk prostate cancer who had volume estimates by three methods: contoured axial ultrasound slices, ultrasound ellipsoid (height × width × length × 0.523) calculation, and endorectal coil MRI (erMRI) ellipsoid calculation.
Average gland size by the contoured ultrasound, ellipsoid ultrasound, and erMRI methods were 33.99, 37.16, and 39.62 mLs, respectively. All pairwise comparisons between methods were statistically significant (all p < 0.015). Of the 66 patients who volumetrically qualified for brachytherapy on ellipsoid ultrasound measures, 22 (33.33%) did not qualify on ellipsoid erMRI or contoured ultrasound measures. 38 patients (54.28%) had PSA density ≤0.15 ng/dl as calculated using ellipsoid ultrasound volumes, compared to 34 (48.57%) and 38 patients (54.28%) using contoured ultrasound and ellipsoid erMRI volumes, respectively.
The ultrasound ellipsoid and erMRI ellipsoid methods appeared to overestimate ultrasound contoured volume by an average of 9.34% and 16.57% respectively. 33.33% of those who qualified for brachytherapy based on ellipsoid ultrasound volume would be disqualified based on ultrasound contoured and/or erMRI ellipsoid volume. As treatment recommendations increasingly rely on estimates of prostate size, clinicians must consider method of volume estimation.
Prostate volume; Favorable-risk prostate cancer; Brachytherapy; Active surveillance; MRI; Ultrasound
The advent of nanotechnology has bolstered a variety of nanoparticles based platforms for different biomedical applications. A better understanding for engineering novel nanoparticles for applications in cancer staging and therapy requires careful assessment of the nanoparticle’s physico-chemical properties. Herein we report a facile synthesis method for PEGylated PLGA nanoparticles encapsulating anti-cancer drug doxorubicin for cancer imaging and therapy. The simple nanoprecipitation method reported here resulted in very robust PEGylated PLGA nanoparticles with close to 95% drug encapsulation efficiency. The nanoparticles showed a size of ~110 nm as characterized by TEM and DLS. The nanoparticles were further characterized by optical UV-Visible and fluorescence spectroscopy. The encapsulated doxorubicin showed a sustained release (>80%) from the nanoparticles matrix over a period of 8 days. The drug delivery efficiency of the nanoparticles was confirmed in vitro confocal imaging with PC3 and HeLa cell lines. In vitro quantitative estimation of drug accumulation in PC3 cell line showed a 22 times higher concentration of drug in case of nanoparticles based formulation in comparison to free drug and this was further reflected in the in vitro cytotoxicity assays. Overall the synthesis method reported here provides a simple and robust PLGA based platform for efficient drug delivery and imaging of cancer cells in vitro and in vivo.
PEGylation; PLGA nanoparticles; Doxorubicin; Nanoprecipitation; Drug release; Fluorescence imaging
Gynecologic malignancies, including cervical, endometrial, ovarian, vaginal and vulvar cancers, cause significant mortality in women worldwide. The standard care for many primary and recurrent gynecologic cancers consists of chemoradiation followed by brachytherapy. In high dose rate (HDR) brachytherapy, intracavitary applicators and/or interstitial needles are placed directly inside the cancerous tissue so as to provide catheters to deliver high doses of radiation. Although technology for the navigation of catheters and needles is well developed for procedures such as prostate biopsy, brain biopsy, and cardiac ablation, it is notably lacking for gynecologic HDR brachytherapy. Using a benchtop study that closely mimics the clinical interstitial gynecologic brachytherapy procedure, we developed a method for evaluating the accuracy of image-guided catheter placement. Future bedside translation of this technology offers the potential benefit of maximizing tumor coverage during catheter placement while avoiding damage to the adjacent organs, for example bladder, rectum and bowel. In the study, two independent experiments were performed on a phantom model to evaluate the targeting accuracy of an electromagnetic (EM) tracking system. The procedure was carried out using a laptop computer (2.1GHz Intel Core i7 computer, 8GB RAM, Windows 7 64-bit), an EM Aurora tracking system with a 1.3mm diameter 6 DOF sensor, and 6F (2 mm) brachytherapy catheters inserted through a Syed-Neblett applicator. The 3D Slicer and PLUS open source software were used to develop the system. The mean of the targeting error was less than 2.9mm, which is comparable to the targeting errors in commercial clinical navigation systems.
gynecologic brachytherapy; electromagnetic tracking; catheter placement; image-guided therapy; radiation therapy
Patient-reported quality of life following salvage brachytherapy for radiorecurrent prostate cancer has not been well-characterized prospectively.
We examined 25 men who recurred after primary radiotherapy for prostate cancer and received MRI-guided salvage brachytherpy as part of a prospective phase II study. These patients prospectively received a validated patient-reported quality of life questionnaire to fill out at baseline, as well as 3, 15, and 27 months after re-irradiation to determine the degree of sexual, bowel, and urinary dysfunction (maximum dysfunction score = 100).
On average, sexual function continued to decline with time, and patients had significantly worse sexual function scores at 27 months than baseline (p=0.01). However, while bowel and urinary symptoms worsened acutely at 3 or 15 months, they showed on average some improvement by 27 months, and there were no significant differences between baseline and 27 month urinary or bowel scores. An interval to re-irradiation less than 4.5 years and prior brachytherapy were each significantly associated with the largest decrements in bowel function (p=0.035).
Similar to the patterns seen in the de novo setting, patients who receive salvage brachytherapy report a worsening of bowel and urinary symptoms followed by some improvement by 27 months, while sexual function steadily declines over time. Interval to re-irradiation and type of prior radiation received may be used to counsel and optimize selection of men for salvage brachytherapy with regard to quality-of-life endpoints.
Quality of Life; Salvage Therapy; Brachytherapy; Magnetic Resonance Imaging; Prostate Cancer; Prostate-Specific Antigen
Segmentation of interstitial catheters from MRI needs to be addressed in order for MRI-based brachytherapy treatment planning to become part of the clinical practice of gynecologic cancer radiotherapy. This paper presents a validation study of a novel image-processing method for catheter segmentation. The method extends the distal catheter tip, interactively provided by the physician, to its proximal end, using knowledge of catheter geometry and appearance in MRI sequences. The validation study consisted of comparison of the algorithm results to expert manual segmentations, first on images of a phantom, and then on patient MRI images obtained during MRI-guided insertion of brachytherapy catheters for the treatment of gynecologic cancer. In the phantom experiment, the maximum disagreement between automatic and manual segmentation of the same MRI image, as computed using the Hausdorf distance, was 1.5 mm, which is of the same order as the MR image spatial resolution, while the disagreement between automatic segmentation of MR images and “ground truth”, manual segmentation of CT images, was 3.5 mm. The segmentation method was applied to an IRB-approved retrospective database of 10 interstitial brachytherapy patients which included a total of 101 catheters. Compared with manual expert segmentations, the automatic method correctly segmented 93 out of 101 catheters, at an average rate of 0.3 seconds per catheter using a 3GHz Intel Core i7 computer with 16 GB RAM and running Mac OS X 10.7. These results suggest that the proposed catheter segmentation is both technically and clinically feasible.
validation; segmentation; catheter; MRI
This communication reports the first experimental evidence of gold nanoparticle (AuNP) radiosensitization during continuous low-dose-rate (LDR) gamma irradiation with low-energy brachytherapy sources. HeLa cell cultures incubated with and without AuNP were irradiated with an I-125 seed plaque designed to produce a relatively homogeneous dose distribution in the plane of the cell culture slide. Four sets of irradiation experiments were conducted at low dose rates ranging from 2.1 cGy/h to 4.5 cGy/h. Residual γH2AX was measured 24 hours after irradiation and used to compare radiation damage to the cells with and without AuNP. The data demonstrate that the biologic effect when irradiating in the presence of 0.2 mg/ml concentration of AuNP is about 70 – 130% greater than without AuNP. Meanwhile, without radiation, the AuNP showed minimal effect on the cancer cells. These findings provide in vitro evidence that AuNP may be employed as radiosensitizers during continuous LDR brachytherapy.
Gold-nanoparticles; radiosensitizers; brachytherapy; radiotherapy; in vitro
We report updated results of magnetic resonance imaging guided partial prostate brachytherapy and propose a definition of biochemical failure following focal therapy.
Materials and Methods
From 1997 to 2007, 318 men with cT1c, prostate specific antigen less than 15 ng/ml, Gleason 3 + 4 or less prostate cancer received magnetic resonance imaging guided brachytherapy in which only the peripheral zone was targeted. To exclude benign prostate specific antigen increases due to prostatic hyperplasia, we investigated the usefulness of defining prostate specific antigen failure as nadir +2 with prostate specific antigen velocity greater than 0.75 ng/ml per year. Cox regression was used to determine the factors associated with prostate specific antigen failure.
Median followup was 5.1 years (maximum 12.1). While 36 patients met the nadir +2 criteria, 16 of 17 biopsy proven local recurrences were among the 26 men who also had a prostate specific antigen velocity greater than 0.75 ng/ml per year (16 of 26 vs 1 of 10, p = 0.008). Using the nadir +2 definition, prostate specific antigen failure-free survival for low risk cases at 5 and 8 years was 95.1% (91.0–97.3) and 80.4% (70.7–87.1), respectively. This rate improved to 95.6% (91.6–97.7) and 90.0% (82.6–94.3) using nadir +2 with prostate specific antigen velocity greater than 0.75 ng/ml per year. For intermediate risk cases survival was 73.0% (55.0–84.8) at 5 years and 66.4% (44.8–81.1) at 8 years (the same values as using nadir +2 with prostate specific antigen velocity greater than 0.75 ng/ml per year).
Requiring a prostate specific antigen velocity greater than 0.75 ng/ml per year in addition to nadir +2 appears to better predict clinical failure after therapies that target less than the whole gland. Further followup will determine whether magnetic resonance imaging guided brachytherapy targeting the peripheral zone produces comparable cancer control to whole gland treatment in men with low risk disease. However, at this time it does not appear adequate for men with even favorable intermediate risk disease.
prostatic neoplasms; brachytherapy; magnetic resonance imaging
Transrectal ultrasound (TRUS) facilitates intra-treatment delineation of the prostate gland (PG) to guide insertion of brachytherapy seeds, but the prostate substructure and apex are not always visible which may make the seed placement sub-optimal. Based on an elastic model of the prostate created from MRI, where the prostate substructure and apex are clearly visible, we use a Bayesian approach to estimate the posterior distribution on deformations that aligns the pre-treatment MRI with intra-treatment TRUS. Without apex information in TRUS, the posterior prediction of the location of the prostate boundary, and the prostate apex boundary in particular, is mainly determined by the pseudo stiffness hyper-parameter of the prior distribution. We estimate the optimal value of the stiffness through likelihood maximization that is sensitive to the accuracy as well as the precision of the posterior prediction at the apex boundary. From a data-set of 10 pre- and intra-treatment prostate images with ground truth delineation of the total PG, 4 cases were used to establish an optimal stiffness hyper-parameter when 15% of the prostate delineation was removed to simulate lack of apex information in TRUS, while the remaining 6 cases were used to cross-validate the registration accuracy and uncertainty over the PG and in the apex.
Registration of pre- to intra-procedural prostate images needs to handle the large changes in position and shape of the prostate caused by varying rectal filling and patient positioning. We describe a probabilistic method for non-rigid registration of prostate images which can quantify the most probable deformation as well as the uncertainty of the estimated deformation. The method is based on a biomechanical Finite Element model which treats the prostate as an elastic material. We use a Markov Chain Monte Carlo sampler to draw deformation configurations from the posterior distribution. In practice, we simultaneously estimate the boundary conditions (surface displacements) and the internal deformations of our biomechanical model. The proposed method was validated on a clinical MRI dataset with registration results comparable to previously published methods, but with the added benefit of also providing uncertainty estimates which may be important to take into account during prostate biopsy and brachytherapy procedures.
prostate; registration; uncertainty; elastic
To investigate the impact of bladder filling state on dosimetry and determine the best bladder dosimetric parameter in vaginal-cuff brachytherapy.
Materials and Methods
Twenty women received vaginal cylinder high-dose-rate (HDR) brachytherapy with each fraction followed by a planning CT scan on a prospective clinical trial. The bladder was full for fraction 2 and empty for fraction 3. Dose volume histogram (DVH) and dose surface histogram (DSH) values were generated for the bladder, rectum, and urethra. The midline maximum bladder point (MBP) and the midline maximum rectal point (MRP) were recorded. Paired t-tests, Pearson correlations, and regression analyses were performed.
The volume and surface area of bladder irradiated were significantly smaller when the bladder was empty than when full. Of several DVH and DSH parameters evaluated, the bladder D2cc, V50, V70 and SA50 significantly predicted the difference in empty versus full filling states. The V70 and D2cc were significantly correlated with the MBP. Bladder filling did not alter the volume or surface area of rectum irradiated. However, an empty bladder did result in the nearest point of bowel being significantly closer to the vaginal cylinder than when the bladder was full.
In order to minimize radiation dose to the bladder, patients receiving vaginal-cuff HDR brachytherapy should be treated with an empty bladder if feasible. The MBP correlates well with the volumetric assessments of bladder dose and provides a non-invasive method for reporting maximum bladder point dose using 3D imaging. The MBP can therefore be used as a surrogate for complex dosimetry in the clinic.
Vaginal cuff brachytherapy; CT bladder dosimetry
Background and Purpose
To evaluate the proximity, variance, predictors of dose, and complications to the sigmoid in cervical-cancer brachytherapy using 3D planning.
Materials and Methods
Over 36 months, 50 patients were treated for cervical cancer with either low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy. The distance from the central tandem to the sigmoid, the D0.1cc and the D2cc to the sigmoid, rectum and bladder doses, and toxicity were analyzed.
The median sigmoid EQD2 D0.1cc and D2cc were 84 Gy and 68.3 Gy for HDR versus 71.1 Gy and 65.9 Gy for LDR (p=0.02 and 0.98, respectively). Twenty percent of the HDR fractions required manipulation of the superior dwell positions to decrease the sigmoid dose. The median distance from the sigmoid to the tandem was 1.7 cm (range [rg], 0.1 – 6.16 cm) for HDR and 2.7 cm (rg, 1.17 – 4.52 cm) for LDR; from the sigmoid to the 100% isodose region the median distances were – 0.1 cm (rg, -1.4 – 2.5 cm) and 0.44 cm (rg. -0.73 – 5.2 cm), respectively. The proximity of the sigmoid to the tandem is significantly related to sigmoid dose (p<0.0001). Within-patient (among-fraction) variation in sigmoid-to-tandem distance during HDR was substantial (coefficient of variation = 40%). No grade 3-4 sigmoid toxicity was seen after a median 31-month follow-up period.
3D imaging in cervical cancer brachytherapy shows the sigmoid in close proximity to the tandem. The sigmoid to tandem distance varies substantially between fractions, indicating the importance of sigmoid dose-volume evaluation with each fraction.
cervical cancer; brachytherapy; normal tissue dose
To assess the radiation dose delivered to the heart and ipsilateral lung during accelerated partial breast brachytherapy using a MammoSite™ applicator and compare to those produced by whole breast external beam radiotherapy (WBRT).
Materials and methods
Dosimetric analysis was conducted on patients receiving MammoSite breast brachytherapy following conservative surgery for invasive ductal carcinoma. Cardiac dose was evaluated for patients with left breast tumors with a CT scan encompassing the entire heart. Lung dose was evaluated for patients in whom the entire lung was scanned. The prescription dose of 3400 cGy was 1 cm from the balloon surface. MammoSite dosimetry was compared to simulated WBRT fields with and without radiobiological correction for the effects of dose and fractionation. Dose parameters such as the volume of the structure receiving 10 Gy or more (V10) and the dose received by 20 cc of the structure (D20), were calculated as well as the maximum and mean doses received.
Fifteen patients were studied, five had complete lung data and six had left-sided tumors with complete cardiac data. Ipsilateral lung volumes ranged from 925–1380 cc. Cardiac volumes ranged from 337–551 cc. MammoSite resulted in a significantly lower percentage lung V30 and lung and cardiac V20 than the WBRT fields, with and without radiobiological correction.
This study gives low values for incidental radiation received by the heart and ipsilateral lung using the MammoSite applicator. The volume of heart and lung irradiated to clinically significant levels was significantly lower with the MammoSite applicator than using simulated WBRT fields of the same CT data sets.
Dana Farber Trial Registry number 03-179