Keith M. Furutani

PD-1 Restrains Radiotherapy-Induced Abscopal Effect

Park, Dong, and colleagues show in mouse models of melanoma and renal cell carcinoma that stereotactic ablative radiotherapy synergized with PD-1 blockade to induce near-complete regression of the irradiated tumors, and a tumor-specific 66% reduction in the nonirradiated tumors outside the radiation field. We investigated the influence of PD-1 expression on the systemic antitumor response (abscopal effect) induced by stereotactic ablative radiotherapy (SABR) in preclinical melanoma and renal cell carcinoma models. We compared the SABR-induced antitumor response in PD-1–expressing wild-type (WT) and PD-1–deficient knockout (KO) mice and found that PD-1 expression compromises the survival of tumor-bearing mice treated with SABR. None of the PD-1 WT mice survived beyond 25 days, whereas 20% of the PD-1 KO mice survived beyond 40 days. Similarly, PD-1–blocking antibody in WT mice was able to recapitulate SABR-induced antitumor responses observed in PD-1 KO mice and led to increased survival. The combination of SABR plus PD-1 blockade induced near complete regression of the irradiated primary tumor (synergistic effect), as opposed to SABR alone or SABR plus control antibody. The combination of SABR plus PD-1 blockade therapy elicited a 66% reduction in size of nonirradiated, secondary tumors outside the SABR radiation field (abscopal effect). The observed abscopal effect was tumor specific and was not dependent on tumor histology or host genetic background. The CD11ahigh CD8+ T-cell phenotype identifies a tumor-reactive population, which was associated in frequency and function with a SABR-induced antitumor immune response in PD-1 KO mice. We conclude that SABR induces an abscopal tumor-specific immune response in both the irradiated and nonirradiated tumors, which is potentiated by PD-1 blockade. The combination of SABR and PD-1 blockade has the potential to translate into a potent immunotherapy strategy in the management of patients with metastatic cancer. Cancer Immunol Res; 3(6); 610–9. ©2015 AACR.

Seed localization and TRUS-fluoroscopy fusion for intraoperative prostate brachytherapy dosimetry

Objective: To develop and evaluate an integrated approach to intra-operative dosimetry for permanent prostate brachytherapy (PPB) by combining a fluoroscopy-based seed localization routine with a transrectal ultrasound (TRUS)-to-fluoroscopy fusion technique. Materials and Methods: Three-dimensional seed coordinates are reconstructed based on the two-dimensional seed locations identified from three fluoroscopic images acquired at different angles. A seed-based registration approach was examined in both simulation and phantom studies to register the seed locations identified from the fluoroscopic images to the TRUS images. Dose parameters were then evaluated and compared to CT-based dosimetry from a patient dataset. Results: Less than 0.2% error in the D90 value was observed using the TRUS-fluoroscopy image-fusion-based method relative to the CT-based post-implantation dosimetry. In the phantom study, an average distance of 3 mm was observed between the seeds identified from TRUS and the reconstructed seeds at registration. Isodose contours were displayed superimposed on the TRUS images. Conclusions: Promising results were observed in this preliminary study of a TRUS-fluoroscopy fusion-based brachytherapy dosimetry analysis method, suggesting that the method is highly sensitive and calculates clinically relevant dosimetry, including the prostate D90. Further validation of the method is required for eventual clinical application.

Dosimetry accuracy as a function of seed localization uncertainty in permanent prostate brachytherapy: increased seed number correlates with less variability in prostate dosimetry

The variation of permanent prostate brachytherapy dosimetry as a function of seed localization uncertainty was investigated for I-125 implants with seed activities commonly employed in contemporary practice. Post-implant imaging and radiation dosimetry data from nine patients who underwent permanent prostate brachytherapy served as the source of clinical data for this simulation study. Gaussian noise with standard deviations ranging from 0.5 to 10 mm was applied to the seed coordinates for each patient dataset and 1000 simulations were performed at each noise level. Dose parameters, including D90, were computed for each case and compared with the actual dosimetry data. A total of 81 000 complete sets of post-brachytherapy dose volume statistics were computed. The results demonstrated that less than 5% deviation of prostate D90 can be expected when the seed localization uncertainty is 2 mm, whereas a seed localization uncertainty of 10 mm yielded an average decrease in D90 of 33 Gy. The mean normalized decrement in the prostate V100 was 10% at 5 mm uncertainty. Implants with greater seed number and larger prostate volume correlated with less sensitivity of D90 and V100 to seed localization uncertainty. Estimated target volume dose parameters tended to decrease with increasing seed localization uncertainty. The bladder V100 varied more significantly both in mean and standard deviation as compared to the urethra V100. A larger number of implanted seeds also correlated to less sensitivity of the bladder V100 to seed localization uncertainty. In contrast, the deviation of urethra V100 did not correlate with the number of implanted seeds or prostate volume.

Model-based dose calculations for 125I lung brachytherapy

PURPOSE Model-baseddose calculations (MBDCs) are performed using patient computed tomography (CT) data for patients treated with intraoperative (125)I lung brachytherapy at the Mayo Clinic Rochester. Various metallic artifact correction and tissue assignment schemes are considered and their effects on dose distributions are studied. Dose distributions are compared to those calculated under TG-43 assumptions. METHODS Dose distributions for six patients are calculated using phantoms derived from patient CT data and the EGSnrc user-code BrachyDose. (125)I (GE Healthcare/Oncura model 6711) seeds are fully modeled. Four metallic artifact correction schemes are applied to the CT data phantoms: (1) no correction, (2) a filtered back-projection on a modified virtual sinogram, (3) the reassignment of CT numbers above a threshold in the vicinity of the seeds, and (4) a combination of (2) and (3). Tissue assignment is based on voxel CT number and mass density is assigned using a CT number to mass density calibration. Three tissue assignment schemes with varying levels of detail (20, 11, and 5 tissues) are applied to metallic artifact corrected phantoms. Simulations are also performed under TG-43 assumptions, i.e., seeds in homogeneous water with no interseed attenuation. RESULTS Significant dose differences (up to 40% for D(90)) are observed between uncorrected and metallic artifact corrected phantoms. For phantoms created with metallic artifact correction schemes (3) and (4), dose volume metrics are generally in good agreement (less than 2% differences for all patients) although there are significant local dose differences. The application of the three tissue assignment schemes results in differences of up to 8% for D(90); these differences vary between patients. Significant dose differences are seen between fully modeled and TG-43 calculations with TG-43 underestimating the dose (up to 36% in D(90)) for larger volumes containing higher proportions of healthy lung tissue. CONCLUSIONS Metallic artifact correction is necessary for accurate application of MBDCs for lung brachytherapy; simpler threshold replacement methods may be sufficient for early adopters concerned with clinical dose metrics. Rigorous determination of voxel tissue parameters and tissue assignment is required for accurate dose calculations as different tissue assignment schemes can result in significantly different dose distributions. Significant differences are seen between MBDCs and TG-43 dose distributions with TG-43 underestimating dose in volumes containing healthy lung tissue.PURPOSE Model-baseddose calculations (MBDCs) are performed using patient computed tomography (CT) data for patients treated with intraoperative125 I lung brachytherapy at the Mayo Clinic Rochester. Various metallic artifact correction and tissue assignment schemes are considered and their effects on dose distributions are studied. Dose distributions are compared to those calculated under TG-43 assumptions. METHODS Dose distributions for six patients are calculated using phantoms derived from patient CT data and the EGSnrc user-code BrachyDose.125 I (GE Healthcare/Oncura model 6711) seeds are fully modeled. Four metallic artifact correction schemes are applied to the CT data phantoms: (1) no correction, (2) a filtered back-projection on a modified virtual sinogram, (3) the reassignment of CT numbers above a threshold in the vicinity of the seeds, and (4) a combination of (2) and (3). Tissue assignment is based on voxel CT number and mass density is assigned using a CT number to mass density calibration. Three tissue assignment schemes with varying levels of detail (20, 11, and 5 tissues) are applied to metallic artifact corrected phantoms. Simulations are also performed under TG-43 assumptions, i.e., seeds in homogeneous water with no interseed attenuation. RESULTS Significant dose differences (up to 40% for D90 ) are observed between uncorrected and metallic artifact corrected phantoms. For phantoms created with metallic artifact correction schemes (3) and (4), dose volume metrics are generally in good agreement (less than 2% differences for all patients) although there are significant local dose differences. The application of the three tissue assignment schemes results in differences of up to 8% for D90 ; these differences vary between patients. Significant dose differences are seen between fully modeled and TG-43 calculations with TG-43 underestimating the dose (up to 36% in D90 ) for larger volumes containing higher proportions of healthy lung tissue. CONCLUSIONS Metallic artifact correction is necessary for accurate application of MBDCs for lung brachytherapy; simpler threshold replacement methods may be sufficient for early adopters concerned with clinical dose metrics. Rigorous determination of voxel tissue parameters and tissue assignment is required for accurate dose calculations as different tissue assignment schemes can result in significantly different dose distributions. Significant differences are seen between MBDCs and TG-43 dose distributions with TG-43 underestimating dose in volumes containing healthy lung tissue.

Modified COMS plaques for 125I and 103Pd iris melanoma brachytherapy.

PURPOSE Novel plaques are used to treat iris melanoma at the Mayo Clinic Rochester. The plaques are a modification of the Collaborative Ocular Melanoma Study (COMS) 22 mm plaque design with a gold alloy backing, outer lip, and silicone polymer insert. An inner lip surrounds a 10 mm diameter cutout region at the plaque center. Plaques span 360°, 270°, and 180° arcs. This article describes dosimetry for these plaques and others used in the treatment of anterior eye melanomas. METHODS AND MATERIALS The EGSnrc user-code BrachyDose is used to perform Monte Carlo simulations. Plaques and seeds are fully modeled. Three-dimensional dose distributions for different plaque models, TG-43 calculations, and (125)I (model 6711) and (103)Pd (model 200) seeds are compared via depth-dose curves, tabulation of doses at points of interest, and isodose contours. RESULTS Doses at points of interest differ by up to 70% from TG-43 calculations. The inner lip reduces corneal doses. Matching plaque arc length to tumor extent reduces doses to eye regions outside the treatment area. Maintaining the same prescription dose, (103)Pd offers lower doses to critical structures than (125)I, with the exception of the sclera adjacent to the plaque. CONCLUSION The Mayo Clinic plaques offer several advantages for anterior eye tumor treatments. Doses to regions outside the treatment area are significantly reduced. Doses differ considerably from TG-43 predictions, illustrating the importance of complete Monte Carlo simulations. Calculations take a few minutes on a single CPU, making BrachyDose sufficiently fast for routine clinical treatment planning.

The effects of intraocular silicone oil placement prior to iodine 125 brachytherapy for uveal melanoma: a clinical case series

PurposeTo investigate the role of silicone oil as an adjunct to iodine 125 (125I) brachytherapy in attenuating radiation dose and reducing radiation retinopathy.MethodsA 16-mm COMS plaque loaded with 125I seeds was simulated in vitro on an eye model containing silicone oil as a vitreous substitute using BrachyDose. The radiation dose ratio of silicone oil vs water to ocular structures was calculated at angles subtended from the centre of the eye. Silicone oil was then used in three choroidal melanoma patients who underwent 23-gauge vitrectomy, silicone oil placement, and 125I brachytherapy.ResultsSilicone oil reduced the ocular radiation dose in vitro to 65%. Radiation dose ratios on the retina increased from 0.45 to 0.99 when moving from points diametrically opposed to the plaque’s central axis. In 10–24 months’ follow-up, no patients have developed radiation retinopathy. Each patient required silicone oil removal and experienced cataract progression, and one also developed a retinal detachment.ConclusionsThis study confirms that silicone oil attenuates radiation dose in vitro, and may protect against radiation retinopathy clinically in patients, however it requires extensive surgical interventions. Further studies in only very selected populations using silicone oil as an adjunct to 125I brachytherapy will best elucidate its role in shielding radiation retinopathy.

Dosimetric effect of interfractional needle displacement in prostate high-dose-rate brachytherapy

PURPOSE To quantify the dosimetric deviations that would arise from delivering subsequent prostate high-dose-rate fractions with only needle readjustment and no replanning after the first fraction. METHODS AND MATERIALS Patients were treated with either two implant sessions (two 9.5-Gy fractions per session) separated by 2-4 weeks or with one implant session and external beam radiotherapy. After needle placement, needle positions were adjusted under CT guidance, after which dosimetric planning was performed before each fraction. To evaluate the consequence of not replanning before the second fraction, we analyzed the dosimetric parameters of 45 consecutive implants (26 patients). Needles with optimized dwell positions from the first fraction were transferred to the needle positions in the second fraction. Needle displacement between fractions was assessed as well as changes in plan metrics. RESULTS After adjustment, the mean interfractional needle displacement was 3.5 mm. If replanned, the probability of planning target volume D90% ≥ 95% is 100%, prostate V100% ≥ 95% is 87%, and urethra V115% ≤10% is 78%. If treated without replanning, the probability of planning target volume D90% ≥ 95% is 82%, prostate V100% ≥ 95% is 53%, and urethra V115% ≤ 10% is 69%. Even for implants with minimal needle displacement (<3 mm) and minimal prostate volume change (<3 cc), the dosimetric consequence of not replanning the second fraction would result in 46% of cases with a prostate V100% < 95%. CONCLUSION The dosimetric consequences of not replanning the second fraction for prostate high-dose-rate implants results in significantly inferior plan metrics.

High-Dose-Rate Brachytherapy in the Curative Treatment of Patients With Localized Prostate Cancer

High-dose-rate brachytherapy is a relatively new radiotherapeutic intervention that is used as a curative treatment for patients with many types of cancer. Advances in mechanical systems and computer applications result in a sophisticated treatment technique that reliably delivers a high-quality radiation dose distribution to the intended target. Patients with localized prostate cancer may benefit from high-dose-rate brachytherapy, which may be used alone in certain circumstances or in combination with external-beam radiotherapy in other settings. The authors comprehensively searched the MEDLINE database for clinical studies published from January 1, 2002, through December 31, 2007, using the key terms brachytherapy, high-dose-rate, and prostatic neoplasms. Criteria for study review were study design, English language, relevance to clinicians, and validity based on design and appropriateness of conclusions. The abstract proceedings of meetings sponsored by the American Brachytherapy Society and the American Society for Therapeutic Radiology and Oncology were reviewed to identify additional relevant material. These sources provided the basis for a concise review of the rationale and advantages of high-dose-rate brachytherapy in the management of localized prostate cancer, as well as the details of the clinical use and therapeutic outcomes of this treatment as observed in a contemporaneous time frame.

Endoscopically inserted nasobiliary catheters for high dose-rate brachytherapy as part of neoadjuvant therapy for perihilar cholangiocarcinoma.

BACKGROUND AND AIM Selected patients with unresectable perihilar cholangiocarcinoma can undergo neoadjuvant chemoradiotherapy followed by liver transplantation, which has been shown to improve survival. The aim of this study was to determine the feasibility and safety of endoscopic transpapillary insertion of nasobiliary tubes (NBTs) and brachytherapy catheters for high dose-rate (HDR) brachytherapy as part of this neoadjuvant chemoradiotherapy. PATIENTS AND METHODS Medical records of patients undergoing biliary brachytherapy for hilar cholangiocarcinoma at the Mayo Clinic, Rochester were reviewed. Patients were treated with curative intent using external beam radiotherapy (4500 cGy), chemotherapy (5-FU or capecitabine), and HDR brachytherapy (930 - 1600 cGy in one to four fractions delivered over 1 - 2 days) prior to planned liver transplantation. RESULTS Between 2009 and 2013, 40 patients underwent biliary HDR brachytherapy via endoscopically placed NBTs (8.5 - 10 Fr). Patients had a median age of 55 years (range 28 - 68); 25 patients (62.5 %) had primary sclerosing cholangitis. Prior to therapy, 29 patients (72.5 %) had plastic stents, two (5 %) had metal stents, and nine (22.5 %) had no stents. Bilateral NBTs were placed in five patients (12.5 %). NBT/brachytherapy catheter displacement was seen in eight patients (20 %) - five intraprocedure and three post-procedure. A radiotherapy error and NBT kinking each occurred once. Post-procedure adverse events included: cholangitis (n = 5; 12.5 %), severe abdominal pain (n = 3; 7.5 %), duodenopathy (n = 3; 7.5 %), gastropathy (n = 3; 7.5 %), and both duodenopathy and gastropathy (n = 2; 5 %). CONCLUSION HDR biliary brachytherapy administered via endoscopically placed NBTs and brachytherapy catheters is technically feasible and appears reasonably safe in selected patients with unresectable perihilar cholangiocarcinoma.

Prostate brachytherapy seed reconstruction using an adaptive grouping technique

Fluoroscopy-based three-dimensional seed localization as a component of intraoperative dosimetry for prostate brachytherapy is an active area of research. A novel adaptive-grouping-based reconstruction approach is developed. This approach can recover overlapped seeds that are not detected from the fluoroscopic images. Two versions of the adaptive-grouping-based reconstruction approach are implemented and compared to an epipolar geometry-based seed reconstruction technique. Simulations based on nine patient datasets are used to validate the algorithms. A total of 2259 reconstructions is performed in which different types of error such as random noise in seed image locations and ambiguities in projection geometry are incorporated. Among those reconstructions, nine of the cases with overlapping seeds and the different types of error are performed. It is demonstrated that the adaptive-grouping-based reconstruction method is more accurate than the epipolar geometry method and allows faster reconstruction. At a random noise level of 0.6 mm, the mean distance error in reconstructed seed locations is approximately 1.0 mm for one of the relevant cases examined in detail. The best adaptive-grouping-based approach successfully recovered overlapped seeds in the majority of simulated cases (89%), with the remainder of cases generating one false positive seed. Phantom validation is also performed, and overlapped seeds are successfully recovered with all 92 seeds correctly localized and reconstructed. The mean distance error between segmented seed images and projected seeds is 0.5 mm in the phantom study.