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1.
Commun Med (Lond) ; 3(1): 108, 2023 Aug 09.
Article in English | MEDLINE | ID: mdl-37558833

ABSTRACT

BACKGROUND: Genetically engineered mouse models (GEMMs) of cancer are powerful tools to study mechanisms of disease progression and therapy response, yet little is known about how these models respond to multimodality therapy used in patients. Radiation therapy (RT) is frequently used to treat localized cancers with curative intent, delay progression of oligometastases, and palliate symptoms of metastatic disease. METHODS: Here we report the development, testing, and validation of a platform to immobilize and target tumors in mice with stereotactic ablative RT (SART). Xenograft and autochthonous tumor models were treated with hypofractionated ablative doses of radiotherapy. RESULTS: We demonstrate that hypofractionated regimens used in clinical practice can be effectively delivered in mouse models. SART alters tumor stroma and the immune environment, improves survival in GEMMs of primary prostate and colorectal cancer, and synergizes with androgen deprivation in prostate cancer. Complete pathologic responses were achieved in xenograft models, but not in GEMMs. CONCLUSIONS: While SART is capable of fully ablating xenografts, it is unable to completely eradicate disease in GEMMs, arguing that resistance to potentially curative therapy can be modeled in GEMMs.


Mice can be used to model the types of cancer seen in people to investigate the effects of cancer therapies, such as radiation. Here, we apply radiation therapy treatments that are able to cure cancer in humans to mice that have cancer of the prostate or colorectum. We show that the mice do not experience many side effects and that the tumours reduce in size, but in some cases show progression after treatment. Our study demonstrates that mice can be used to better understand how human cancers respond to radiation treatment, which can lead to the development of improved treatments and treatment schedules.

2.
J Contemp Brachytherapy ; 6(4): 337-43, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25834576

ABSTRACT

PURPOSE: To assess detailed dosimetry data for prostate and clinical relevant intra- and peri-prostatic structures including neurovascular bundles (NVB), urethra, and penile bulb (PB) from postbrachytherapy computed tomography (CT) versus high resolution contrast enhanced magnetic resonance imaging (HR-CEMRI). MATERIAL AND METHODS: Eleven postbrachytherapy prostate cancer patients underwent HR-CEMRI and CT imaging. Computed tomography and HR-CEMRI images were randomized and 2 independent expert readers created contours of prostate, intra- and peri-prostatic structures on each CT and HR-CEMRI scan for all 11 patients. Dosimetry data including V100, D90, and D100 was calculated from these contours. RESULTS: Mean V100 values from CT and HR-CEMRI contours were as follows: prostate (98.5% and 96.2%, p = 0.003), urethra (81.0% and 88.7%, p = 0.027), anterior rectal wall (ARW) (8.9% and 2.8%, p < 0.001), left NVB (77.9% and 51.5%, p = 0.002), right NVB (69.2% and 43.1%, p = 0.001), and PB (0.09% and 11.4%, p = 0.005). Mean D90 (Gy) derived from CT and HR-CEMRI contours were: prostate (167.6 and 150.3, p = 0.012), urethra (81.6 and 109.4, p = 0.041), ARW (2.5 and 0.11, p = 0.003), left NVB (98.2 and 58.6, p = 0.001), right NVB (87.5 and 55.5, p = 0.001), and PB (11.2 and 12.4, p = 0.554). CONCLUSIONS: Findings of this study suggest that HR-CEMRI facilitates accurate and meaningful dosimetric assessment of prostate and clinically relevant structures, which is not possible with CT. Significant differences were seen between CT and HR-CEMRI, with volume overestimation of CT derived contours compared to HR-CEMRI.

3.
Int J Radiat Oncol Biol Phys ; 84(1): 274-82, 2012 Sep 01.
Article in English | MEDLINE | ID: mdl-22284685

ABSTRACT

PURPOSE: Stereotactic radiosurgery (SRS) is an effective alternative to microsurgical resection or embolization for definitive treatment of arteriovenous malformations (AVMs). Digital subtraction angiography (DSA) is the gold standard for pretreatment diagnosis and characterization of vascular anatomy, but requires rigid frame (skull) immobilization when used in combination with SRS. With the advent of advanced proton and image-guided photon delivery systems, SRS treatment is increasingly migrating to frameless platforms, which are incompatible with frame-based DSA. Without DSA as the primary image, target definition may be less than optimal, in some cases precluding the ability to treat with a frameless system. This article reports a novel solution. METHODS AND MATERIALS: Fiducial markers are implanted into the patient's skull before angiography. Angiography is performed according to the standard clinical protocol, but, in contrast to the previous practice, without the rigid frame. Separate images of a specially designed localizer box are subsequently obtained. A target volume projected on DSA can be transferred to the localizer system in three dimensions, and in turn be transferred to multiple CT slices using the implanted fiducials. Combined with other imaging modalities, this "virtual frame" approach yields a highly precise treatment plan that can be delivered by frameless SRS technologies. RESULTS: Phantom measurements for point and volume targets have been performed. The overall uncertainty of placing a point target to CT is 0.4 mm. For volume targets, deviation of the transformed contour from the target CT image is within 0.6 mm. The algorithm and software are robust. The method has been applied clinically, with reliable results. CONCLUSIONS: A novel and reproducible method for frameless SRS of AVMs has been developed that enables the use of DSA without the requirement for rigid immobilization. Multiple pairs of DSA can be used for better conformality. Further improvement, including using nonimplanted fiducials, is potentially feasible.


Subject(s)
Fiducial Markers , Intracranial Arteriovenous Malformations/surgery , Radiosurgery/methods , Algorithms , Angiography, Digital Subtraction/methods , Cerebral Angiography/methods , Humans , Image Processing, Computer-Assisted/methods , Immobilization/instrumentation , Intracranial Arteriovenous Malformations/diagnostic imaging , Phantoms, Imaging , Radiosurgery/trends , Reproducibility of Results , Tomography, X-Ray Computed/methods
4.
Int J Radiat Oncol Biol Phys ; 81(5): e813-8, 2011 Dec 01.
Article in English | MEDLINE | ID: mdl-21300455

ABSTRACT

PURPOSE: To analyze the relationship between overall survival (OS) and radiation treatment time (RTT) and overall treatment time (OTT) in a well-described sequential therapy paradigm for locally advanced head-and-neck carcinoma (LAHNC). METHODS AND MATERIALS: TAX 324 is a Phase III study comparing TPF (docetaxel, cisplatin, and fluorouracil) with PF (cisplatin and fluorouracil) induction chemotherapy (IC) in LAHNC patients; both arms were followed by carboplatin-based chemoradiotherapy (CRT). Prospective radiotherapy quality assurance was performed. This analysis includes all patients who received three cycles of IC and a radiation dose of ≥70 Gy. Radiotherapy treatment time was analyzed as binary (≤8 weeks vs. longer) and continuous (number of days beyond 8 weeks) functions. The primary analysis assessed the relationship between RTT, OTT, and OS, and the secondary analysis explored the association between treatment times and locoregional recurrence (LRR). RESULTS: A total of 333 (of 501) TAX 324 patients met the criteria for inclusion in this analysis. There were no significant differences between the treatment arms in baseline or treatment characteristics. On multivariable analysis, PF IC, World Health Organization performance status of 1, non-oropharynx site, T3/4 stage, N3 status, and prolonged RTT (hazard ratio 1.63, p=0.006) were associated with significantly inferior survival. Performance status, T3/4 disease, and prolonged RTT (odds ratio 1.68, p=0.047) were independently and negatively related to LRR on multivariable analysis, whereas PF was not. Overall treatment time was not independently associated with either OS or LRR. CONCLUSIONS: In this secondary analysis of the TAX 324 trial, TPF IC remains superior to PF IC after controlling for radiotherapy delivery time. Even with optimal IC and concurrent chemotherapy, a non-prolonged RTT is a crucial determinant of treatment success. Appropriate delivery of radiotherapy after IC remains essential for optimizing OS in LAHNC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/mortality , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/mortality , Aged , Analysis of Variance , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carboplatin/administration & dosage , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/radiotherapy , Cisplatin/administration & dosage , Docetaxel , Female , Fluorouracil/administration & dosage , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/radiotherapy , Humans , Induction Chemotherapy/methods , Induction Chemotherapy/mortality , Male , Middle Aged , Radiotherapy Dosage , Severity of Illness Index , Squamous Cell Carcinoma of Head and Neck , Survival Analysis , Taxoids/administration & dosage , Time Factors
5.
Urol Oncol ; 26(4): 372-7, 2008.
Article in English | MEDLINE | ID: mdl-18367113

ABSTRACT

OBJECTIVES: To compare the impact of bicalutamide (B) vs. luteinizing hormone-releasing hormone analogues (LHRHa) on prostate volume, patient-reported side effects, and postimplant urinary toxicity in the setting of interstitial brachytherapy for early-stage prostate cancer. METHODS: Between May 1998 and January 2004, 81 patients received androgen-deprivation therapy (ADT) for cytoreduction prior to interstitial brachytherapy alone. Fifty-six patients received LHRHa and 25 patients received B. Prostate volumes were measured prospectively prior to initiating therapy, and then intraoperatively at the time of implant by a single, blinded ultrasonographer. Patient-reported quality of life data were obtained prospectively, and postimplant urinary toxicity (catheter dependency and need for surgical intervention) was recorded during follow-up. Median follow-up was 53 (range 23-78) months. RESULTS: The median percentage prostate volume reductions of 26% for B and 32% for LHRHa were not statistically different (P = 0.61). Decrements in libido (92% vs. 44%, P < 0.001) and erectile function (79% vs. 20%) were reported in more respondents treated with LHRHa than B. The incidence of recatheterization (28% vs. 24%, P = 0.34), and the need for subsequent surgical intervention (11% vs. 4%, P = 0.16) were similar for patients treated with LHRHa and B. CONCLUSIONS: The degree of prostate downsizing with B is similar to that achieved with LHRHa. B was associated with fewer patient-reported sexual side effects and similar urinary morbidity. A randomized trial is needed to establish whether LHRHa or B should be the standard of care for prostate downsizing before interstitial brachytherapy.


Subject(s)
Androgen Antagonists/therapeutic use , Anilides/therapeutic use , Antineoplastic Agents, Hormonal/therapeutic use , Brachytherapy , Goserelin/therapeutic use , Leuprolide/therapeutic use , Nitriles/therapeutic use , Prostatic Neoplasms/therapy , Tosyl Compounds/therapeutic use , Aged , Aged, 80 and over , Combined Modality Therapy , Goserelin/adverse effects , Humans , Leuprolide/adverse effects , Male , Middle Aged , Morbidity
6.
Brachytherapy ; 6(4): 267-71, 2007.
Article in English | MEDLINE | ID: mdl-17959423

ABSTRACT

PURPOSE: We examined whether prostate volume reduction after a short course of androgen deprivation (AD) lowered the risks of acute and chronic urinary morbidity related to radioactive seed implantation for low-risk prostate cancer. METHODS AND MATERIALS: Eighty-one patients received AD for cytoreduction before interstitial brachytherapy alone. Urinary morbidity was carefully assessed for all patients during a median followup of 53 (range, 23-78) months after treatment. Outcomes were then compared with those of a control group of 81 patients who were matched 1:1 based on identical prostate volume measured at the time of radioactive seed implant, but who had not received AD. RESULTS: Despite effective cytoreduction (median, 30% prostate volume reduction) with AD, prolonged catheterization was required significantly more often for patients who had received AD when compared with the control group of patients who were implanted at identical prostate volumes but who had not received AD (27% vs. 9%, p = 0.02). This finding remained statistically significant on multivariate analysis (p = 0.04). Surgical intervention (9% vs. 4%, p = 0.09) and subsequent urinary incontinence (4% vs. 1%, p = 0.16) were also more frequent among patients who had received AD when compared with implant volume-matched controls. CONCLUSIONS: Patients who achieved smaller prostate volumes through the use of AD maintained a significantly elevated risk (threefold) for urinary complications, commensurate with their initially large prostate volume, when compared with a control group of patients who were implanted at identical prostate volumes but who had not received AD. Therefore, patients presenting with larger prostate glands that would warrant a short course of AD before implant should be counseled accordingly when discussing options for local therapy.


Subject(s)
Androgen Antagonists/therapeutic use , Brachytherapy/adverse effects , Brachytherapy/methods , Dysuria/etiology , Prostate/pathology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/radiotherapy , Aged , Humans , Male , Neoadjuvant Therapy , Prostatic Neoplasms/pathology , Risk , Urinary Catheterization
7.
Brachytherapy ; 5(3): 147-51, 2006.
Article in English | MEDLINE | ID: mdl-16864065

ABSTRACT

PURPOSE: Ultrasound-guided implantation of permanent radioactive seeds is a treatment option for localized prostate cancer. Several techniques have been described for the optimal placement of the seeds in the prostate during this procedure. Postimplantation dosimetric calculations are performed after the implant. Areas of underdosing can only be corrected with either an external beam boost or by performing a second implant. We demonstrate the feasibility of performing computed tomography (CT)-based postplanning during the ultrasound-guided implant and subsequently correcting for underdosed areas. METHODS AND MATERIALS: Ultrasound-guided brachytherapy is performed on a modified CT table with general anesthesia. The postplanning CT scan is performed after the implant, while the patient is still under anesthesia. Additional seeds are implanted into "cold spots," and the resultant dosimetry confirmed with CT. RESULTS: Intraoperative postplanning was successfully performed. Dose-volume histograms demonstrated adequate dose coverage during the initial implant, but on detailed analysis, for some patients, areas of underdosing were observed either at the apex or the peripheral zone. Additional seeds were implanted to bring these areas to prescription dose. CONCLUSION: Intraoperative postplanning is feasible during ultrasound-guided brachytherapy for prostate cancer. Although the postimplant dose-volume histograms for all patients, before the implantation of additional seeds, were adequate according to the American Brachytherapy Society criteria, specific critical areas can be underdosed. Additional seeds can then be implanted to optimize the dosimetry and reduce the risk of underdosing areas of cancer.


Subject(s)
Prostatic Neoplasms/radiotherapy , Radiotherapy Planning, Computer-Assisted/methods , Tomography, X-Ray Computed/instrumentation , Equipment Design , Feasibility Studies , Follow-Up Studies , Humans , Male , Prostatic Neoplasms/diagnostic imaging , Ultrasonography
8.
Radiother Oncol ; 79(1): 70-4, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16515813

ABSTRACT

BACKGROUND AND PURPOSE: Random seed placement error may adversely effect dose distribution in transperineal prostate seed implants. In this study, we investigated the extent to which individual seed activity influences dose-distribution degradation due to random seed placement error. PATIENTS AND METHODS: Separate initial treatment plans were prepared for three prostate sizes, 27.3, 43.2 and 48.9 cc, using 0.35, 0.55 and 0.75 mCi iodine-125 seeds. All stated activities are understood to be apparent activities. The combinations produced a total of nine treatment plans. Each initial treatment plan was subjected to 1000 stochastic three-dimensional Gaussian perturbations of seed location, with a standard deviation of 4mm for a total of 9000 treatment plans. The resulting plans were evaluated for target coverage and urethra involvement. RESULTS: Satisfactory initial treatment plans were prepared for all prostate sizes and seed activities. All 9000 perturbed treatment plans showed acceptable target coverage under the D90/90 criterion. Some of the perturbed plans for the 27.3 and 43.2 cc prostates with 0.55 and 0.75 mCi seeds failed the V100/90 criterion. Some of the randomly perturbed seed distributions showed significantly increased doses to the urethra relative to the unperturbed treatment plan. This effect was more pronounced with greater seed activity. CONCLUSIONS: There may be a higher probability of unfavorable target coverage due to random seed placement error when performing transperineal iodine-125 prostate seed implants using seeds with activity greater than 0.35 mCi. There may also be a higher probability of unfavorable urethra involvement when using higher activity seeds.


Subject(s)
Brachytherapy/methods , Iodine Radioisotopes/therapeutic use , Medical Errors , Prostate/radiation effects , Prostatic Neoplasms/radiotherapy , Radiotherapy Planning, Computer-Assisted/adverse effects , Evaluation Studies as Topic , Humans , Male , Radiation Dosage , Radiotherapy, Computer-Assisted
9.
Brachytherapy ; 3(1): 7-9, 2004.
Article in English | MEDLINE | ID: mdl-15110307

ABSTRACT

PURPOSE: Brachytherapy for prostate cancer with permanent low-dose-rate seeds has been shown to be an effective treatment for early stage prostate cancer. Due to the rapid falloff of dose, accurate seed placement is critical for optimal dosimetry. One approach to achieve optimal dosimetry is the use of seeds embedded in suture material. Seeds embedded in suture may not move after implantation as much as loose seeds. This would improve implant dosimetry. To evaluate this hypothesis a formal study was conducted in which half the gland was implanted with seeds embedded in suture and half with loose seeds. Final dosimetry is compared between both halves of the prostate. METHODS AND MATERIALS: Patients entered this Investigational Review Board approved prospective trial after completion of informed consent. At time of implant, the side of the gland to be implanted with loose as opposed to suture embedded seeds was randomly assigned. The patients then underwent intraoperative preplanned implantation. None of the preplans directed seed locations outside the prostate. Both the seeds embedded in suture and the loose seeds were implanted using needles with stylettes. At 4-6 weeks post implant, seed location was determined with CT. Both sides of the gland on CT were contoured and used for final dosimetric calculations. A cost function analysis was used to determine individual seed position deviation from intended to actual seed location. RESULTS: Eight patients were enrolled in the study. A total of 549 seeds were implanted; 240 seeds embedded in suture and 309 loose seeds. Prostate volumes ranged from 24.0-45.5 cc with a mean of 38.6 cc. The average radial deviation of the loose seeds from planned position was determined to be 3.1 mm compared with the average radial deviation of the suture embedded seeds of 3.7 mm. There was no improvement in the final dosimetry when suture embedded seeds where used. The D90 and V100 values for the half of the prostate implanted with suture embedded seeds were 71-140 (mean, 92.1) and 80.2-99.5 (mean, 89.6), respectively, for the half of the prostate implanted with loose seeds. (All D90, V100 values are % of prescription dose.) CONCLUSION: Seeds embedded in suture material do not lead to superior precision in seed deposition when compared with loose seeds, when implanted inside the prostate.


Subject(s)
Brachytherapy/methods , Prostatic Neoplasms/radiotherapy , Humans , Iodine Radioisotopes , Male , Radiometry
10.
Int J Radiat Oncol Biol Phys ; 55(5): 1420-31, 2003 Apr 01.
Article in English | MEDLINE | ID: mdl-12654455

ABSTRACT

PURPOSE: Many authors have studied the problems associated with the three-field breast treatment, yet the proposed solutions present their own difficulties. This study presents a technique that overcomes these difficulties, reduces scatter to the contralateral breast, and improves setup reproducibility. METHODS AND MATERIALS: Patients are set up with both arms raised superiorly on a breast board. A precise field-match is achieved by rotating the couch and collimator of the tangents, while the supraclavicular field is half-beam blocked using an independent jaw. The posterior borders of the tangents are conformally defined by multileaf collimation. Measurements were performed to verify the field matching and evaluate scatter doses. RESULT: A smooth dose transition was found at the match line at all depths. Corner blocks and lower wedges were not used, which reduced the scatter to the contralateral breast compared with our prior technique. CONCLUSION: The technique achieves a precise match while removing constraints on the tangents' length and decreasing scatter dose. Procedures for simulation, planning, and treatment have been devised, along with a new patient setup routine incorporating orthogonal setup films and tattoos. This technique has been successfully implemented in routine treatment since September 2001. A program calculating the setup parameters is available at our website.


Subject(s)
Breast Neoplasms/radiotherapy , Particle Accelerators/instrumentation , Radiotherapy, Conformal/instrumentation , Breast Neoplasms/diagnostic imaging , Equipment Design , Female , Fluoroscopy , Heart/radiation effects , Humans , Lung/radiation effects , Mathematics , Phantoms, Imaging , Posture , Radiation Injuries/prevention & control , Radiotherapy, Conformal/methods , Reproducibility of Results , Scattering, Radiation , Tattooing , Tomography, X-Ray Computed
11.
Magn Reson Imaging ; 20(3): 295-9, 2002 Apr.
Article in English | MEDLINE | ID: mdl-12117612

ABSTRACT

To report a technique for target directed transperineal ultrasound guided biopsy using high resolution endorectal MRI images Ultrasound fusion. Two patients presented after external beam irradiation for prostate cancer with a rising PSA. An Endorectal MRI using a 1.5 Tesla scanner was obtained. Subsequently a Transrectal Ultrasound guided biopsy was performed. The Ultrasound probe was fixed to a stepper-stabilizer to provide a reference coordinate system for stereotaxic needle biopsy needle placement. The MRI image set was fused to the Ultrasound images in real time. Abnormal areas determined in the MR images were targeted for biopsy. Recurrent prostate carcinoma was detected pathologically in 3 of 4 stereotactic biopsies. Abnormal areas suspicious for cancer detected on T1 weighted images obtained in a strong field Endorectal MRI scan can be targeted for stereotactic biopsy using Transrectal Ultrasound. This image guide technique may be very useful in directing biopsies.


Subject(s)
Biopsy, Needle/methods , Magnetic Resonance Imaging/methods , Prostate/pathology , Prostatic Neoplasms/diagnosis , Humans , Male , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/pathology , Prostatic Neoplasms/radiotherapy , Stereotaxic Techniques , Ultrasonography
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