The biological characterization of an individual patient’s tumor by noninvasive imaging will have an important role in cancer care and clinical research if the molecular processes that underlie the image data are known. Spatial heterogeneity in the dynamics of magnetic resonance imaging contrast enhancement (DCE-MRI) is hypothesized to reflect variations in tumor angiogenesis. Here we demonstrate the feasibility of precisely colocalizing DCE-MRI data with the genomic and proteomic profiles of underlying biopsy tissue using a novel MRI-guided biopsy technique in patients with prostate cancer.
Angiogenesis; molecular imaging; interventional MRI; prostate cancer; micro-array analysis
We investigated the accuracy and feasibility of a system that provides transrectal needle access to the prostate concurrent with 1.5 Tesla MRI which previously has not been possible.
Materials and Methods
In 5 patients with previously diagnosed prostate cancer, MRI guided intraprostatic placement of gold fiducial markers (4 procedures) and/or prostate biopsy (3 procedures) was performed using local anesthesia.
Mean procedure duration was 76 minutes and all patients tolerated the intervention well. Procedure related adverse events included self-limited hematuria and hematochezia following 3 of 8 procedures (all resolved in less than 1 week). Mean needle placement accuracy was 1.9 mm for the fiducial marker placement studies and 1.8 mm for the biopsy procedures. Mean fiducial marker placement accuracy was 4.8 mm and the mean fiducial marker placement accuracy transverse to the needle direction was 2.6 mm. All patients who underwent the procedure were able to complete their course of radiotherapy without delay or complication.
While studies of clinical usefulness are warranted, transrectal 1.5 T MRI guided prostate biopsy and fiducial marker placement is feasible using this system, providing new opportunities for image guided diagnostic and therapeutic prostate interventions.
magnetic resonance imaging; prostate; prostatic neoplasms; biopsy; radiology; interventional
This paper reports the development, evaluation, and first clinical trials of the access to the prostate tissue (APT) II system—a scanner independent system for magnetic resonance imaging (MRI)-guided transrectal prostate interventions. The system utilizes novel manipulator mechanics employing a steerable needle channel and a novel six degree-of-freedom hybrid tracking method, comprising passive fiducial tracking for initial registration and subsequent incremental motion measurements. Targeting accuracy of the system in prostate phantom experiments and two clinical human-subject procedures is shown to compare favorably with existing systems using passive and active tracking methods. The portable design of the APT II system, using only standard MRI image sequences and minimal custom scanner interfacing, allows the system to be easily used on different MRI scanners.
Image-guided intervention; MRI; prostate cancer; robot manipulators
This paper reports a novel remotely actuated manipulator for access to prostate tissue under magnetic resonance imaging guidance (APT-MRI) device, designed for use in a standard high-field MRI scanner. The device provides three-dimensional MRI guided needle placement with millimeter accuracy under physician control. Procedures enabled by this device include MRI guided needle biopsy, fiducial marker placements, and therapy delivery. Its compact size allows for use in both standard cylindrical and open configuration MRI scanners. Preliminary in vivo canine experiments and first clinical trials are reported.
Biomedical imaging; cancer; magnetic resonance imaging; medical diagnosis; medical treatment
Early and accurate prediction of response to cancer treatment through imaging criteria is particularly important in rapidly progressive malignancies such as Glioblastoma Multiforme (GBM). We sought to assess the predictive value of structural imaging response criteria one month after concurrent chemotherapy and radiotherapy (RT) in patients with GBM.
Thirty patients were enrolled from 2005 to 2007 (median follow-up 22 months). Tumor volumes were delineated at the boundary of abnormal contrast enhancement on T1-weighted images prior to and 1 month after RT. Clinical Progression [CP] occurred when clinical and/or radiological events led to a change in chemotherapy management. Early Radiologic Progression [ERP] was defined as the qualitative interpretation of radiological progression one month post-RT. Patients with ERP were determined pseudoprogressors if clinically stable for ≥6 months. Receiver-operator characteristics were calculated for RECIST and MacDonald criteria, along with alternative thresholds against 1 year CP-free survival and 2 year overall survival (OS).
13 patients (52%) were found to have ERP, of whom 5 (38.5%) were pseudoprogressors. Patients with ERP had a lower median OS (11.2 mo) than those without (not reached) (p < 0.001). True progressors fared worse than pseudoprogressors (median survival 7.2 mo vs. 19.0 mo, p < 0.001). Volume thresholds performed slightly better compared to area and diameter thresholds in ROC analysis. Responses of > 25% in volume or > 15% in area were most predictive of OS.
We show that while a subjective interpretation of early radiological progression from baseline is generally associated with poor outcome, true progressors cannot be distinguished from pseudoprogressors. In contrast, the magnitude of early imaging volumetric response may be a predictive and quantitative metric of favorable outcome.
Glioblastoma Multiforme; Imaging response; radiotherapy; RECIST
This paper reviews the integration of imaging and radiation oncology, and discusses challenges and opportunities for improving the practice of radiation oncology with imaging.
An inherent goal of radiation therapy is to deliver enough dose to the tumor to eradicate all cancer cells or to palliate symptoms, while avoiding normal tissue injury. Imaging for cancer diagnosis, staging, treatment planning, and radiation targeting has been integrated in various ways to improve the chance of this occurring. A large spectrum of imaging strategies and technologies has evolved in parallel to advances in radiation delivery. The types of imaging can be categorized into offline imaging (outside the treatment room) and online imaging (inside the treatment room, conventionally termed image-guided radiation therapy). The direct integration of images in the radiotherapy planning process (physically or computationally) often entails trade-offs in imaging performance. Although such compromises may be acceptable given specific clinical objectives, general requirements for imaging performance are expected to increase as paradigms for radiation delivery evolve to address underlying biology and adapt to radiation responses. This paper reviews the integration of imaging and radiation oncology, and discusses challenges and opportunities for improving the practice of radiation oncology with imaging.
Image-guided radiation therapy; Imaging; Radiation oncology
To define a prostate fossa clinical target volume (PF-CTV0 for Radiation Therapy Oncology Group (RTOG) trials utilizing post-operative radiotherapy for prostate cancer.
Methods and Materials
An RTOG sponsored meeting was held to define an appropriate PF-CTV after radical prostatectomy. Data was presented describing radiographic failure patterns after surgery. Target volumes used in previous trials were reviewed. Using contours independently submitted by 13 radiation oncologists, a statistical imputation method derived a preliminary “consensus” PF-CTV.
Starting from the model derived CTV, consensus was reached for a CT image-based PF-CTV. The PF-CTV should extend superiorly from the level of the caudal vas deferens remnant to > 8-12mm inferior to vesicourethral anastomosis (VUA). Below the superior border of the pubic symphysis, the anterior border extends to the posterior aspect of the pubis and posteriorly to the rectum where it may be concave at the level of the VUA. At this level the lateral border extends to the levator ani. Above the pubic symphysis the anterior border should encompass the posterior 1-2cm of the bladder wall and posteriorly it is bounded by the mesorectal fascia. At this level the lateral border is the sacrorectogenitopubic fascia. Seminal vesicle remnants, if present, should be included in the CTV if there is pathologic evidence of their involvement.
Consensus on postoperative PF-CTV for RT after prostatectomy was reached and is available as a CT image atlas on the RTOG website. This will allow uniformity in defining PF-CTV for clinical trials that include post-prostatectomy RT.
Prostate cancer; conformal radiation therapy; target volumes; postoperative
A biomechanical model-based deformable image registration incorporating specimen-specific changes in material properties is optimized and evaluated for correlating histology of clinical prostatectomy specimens with in vivo MRI. In this methodology, a three-step registration based on biomechanics calculates the transformations between histology and fixed, fixed and fresh, and fresh and in vivo states. A heterogeneous linear elastic material model is constructed based on magnetic resonance elastography (MRE) results. The ex vivo tissue MRE data provide specimen-specific information for the fresh and fixed tissue to account for the changes due to fixation. The accuracy of the algorithm was quantified by calculating the target registration error (TRE) by identifying naturally occurring anatomical points within the prostate in each image. TRE were improved with the deformable registration algorithm compared to rigid registration alone. The qualitative assessment also showed a good alignment between histology and MRI after the proposed deformable registration.
Biomechanical models; correlative pathology; deformable registration; finite element model; magnetic resonance elastography
Magnetic resonance imaging (MRI) provides superior visualization of the prostate and surrounding anatomy, making it the modality of choice for imaging the prostate gland. This pilot study was performed to determine the feasibility and dosimetric quality achieved when placing high-dose-rate prostate brachytherapy catheters under MRI guidance in a standard “closed-bore” 1.5T scanner.
Methods and Materials:
Patients with intermediate-risk and high-risk localized prostate cancer received MRI-guided high-dose-rate brachytherapy boosts before and after a course of external beam radiotherapy. Using a custom visualization and targeting program, the brachytherapy catheters were placed and adjusted under MRI guidance until satisfactory implant geometry was achieved. Inverse treatment planning was performed using high-resolution T2-weighted MRI.
Ten brachytherapy procedures were performed on 5 patients. The median percentage of volume receiving 100% of prescribed minimal peripheral dose (V100) achieved was 94% (mean, 92%; 95% confidence interval, 89–95%). The urethral V125 ranged from 0% to 18% (median, 5%), and the rectal V75 ranged from 0% to 3.1% (median, 0.3%). In all cases, lesions highly suspicious for malignancy could be visualized on the procedural MRI, and extracapsular disease was identified in 2 patients.
High-dose-rate prostate brachytherapy in a standard 1.5T MRI scanner is feasible and achieves favorable dosimetry within a reasonable period with high-quality image guidance. Although the procedure was well tolerated in the acute setting, additional follow-up is required to determine the long-term safety and efficacy of this approach.
Prostate cancer; Brachytherapy; MRI; Image guidance
A technique for transperineal high-dose-rate (HDR) prostate brachytherapy and needle biopsy in a standard 1.5 T MRI scanner is demonstrated. In each of eight procedures (in four patients with intermediate to high risk localized prostate cancer), four MRI-guided transperineal prostate biopsies were obtained followed by placement of 14–15 hollow transperineal catheters for HDR brachytherapy. Mean needle-placement accuracy was 2.1 mm, 95% of needle-placement errors were less than 4.0 mm, and the maximum needle-placement error was 4.4 mm. In addition to guiding the placement of biopsy needles and brachytherapy catheters, MR images were also used for brachytherapy treatment planning and optimization. Because 1.5 T MR images are directly acquired during the interventional procedure, dependence on deformable registration is reduced and online image quality is maximized.
MRI; brachytherapy; prostate; prostatic neoplasms; biopsy; interventional MRI
To test whether intrarectal Amifostine limits symptoms of radiation proctitis as measured by the RTOG GI toxicity score and the expanded prostate cancer index composite (EPIC) score.
Methods and Materials
Patients with localized prostate cancer recieved Amifostine as a rectal suspension 30–45 min before daily 3D-conformal radiation treatments (3D-CRT). The first 18 patients received 1gm of Amifostine and the next 12 patients received 2gm. Toxicity was assessed at baseline, during treatment, and at follow-up visits using RTOG grading and the EPIC Quality of Life (QoL) 50 item questionnaire. The “Bowel Function” subset of the bowel domain (EPIC-BF), which targets symptom severity, and “Bowel Bother” subset of the bowel domain (EPIC-BB), which assesses quality of life, were evaluated and compared to the RTOG GI toxicity score.
Median follow-up was 30 months (range 18–36). Overall, the EPIC-BF and EPIC-BB scores both track closely with the RTOG GI toxicity score. Seven weeks after the start of radiation therapy, the incidence of RTOG Grade 2 toxicity was 33% in the 1gm group (6/18) compared with 0% (0/12) in the 2gm group and trended towards statistical significance (p=0.06). A significant difference between Amifostine groups was observed using the EPIC-BF score at 7 weeks (p=0.04). A difference in EPIC-BB score between dose groups was evident at 7 weeks (p=0.07) and was significant at 12 months (p=0.04).
Higher doses of Amifostine produce significant improvements in acute and late bowel QoL (up to one year following therapy) as measured by the EPIC score.
Amifostine; Prostate; Radiation-induced Proctitis; EPIC; Quality of Life
To report early observation of transient PSA elevations on this pilot study of external beam radiation therapy and magnetic resonance imaging (MRI) guided high dose rate (HDR) brachytherapy boost.
Materials and methods
Eleven patients with intermediate-risk and high-risk localized prostate cancer received MRI guided HDR brachytherapy (10.5 Gy each fraction) before and after a course of external beam radiotherapy (46 Gy). Two patients continued on hormones during follow-up and were censored for this analysis. Four patients discontinued hormone therapy after RT. Five patients did not receive hormones. PSA bounce is defined as a rise in PSA values with a subsequent fall below the nadir value or to below 20% of the maximum PSA level. Six previously published definitions of biochemical failure to distinguish true failure from were tested: definition 1, rise >0.2 ng/mL; definition 2, rise >0.4 ng/mL; definition 3, rise >35% of previous value; definition 4, ASTRO defined guidelines, definition 5 nadir + 2 ng/ml, and definition 6, nadir + 3 ng/ml.
Median follow-up was 24 months (range 18–36 mo). During follow-up, the incidence of transient PSA elevation was: 55% for definition 1, 44% for definition 2, 55% for definition 3, 33% for definition 4, 11% for definition 5, and 11% for definition 6.
We observed a substantial incidence of transient elevations in PSA following combined external beam radiation and HDR brachytherapy for prostate cancer. Such elevations seem to be self-limited and should not trigger initiation of salvage therapies. No definition of failure was completely predictive.
We sought to determine the intra- and inter-radiation therapist reproducibility of a previously established matching technique for daily verification and correction of isocenter position relative to intraprostatic fiducial markers (FM).
Materials and methods
With the patient in the treatment position, anterior-posterior and left lateral electronic images are acquired on an amorphous silicon flat panel electronic portal imaging device. After each portal image is acquired, the therapist manually translates and aligns the fiducial markers in the image to the marker contours on the digitally reconstructed radiograph. The distances between the planned and actual isocenter location is displayed. In order to determine the reproducibility of this technique, four therapists repeated and recorded this operation two separate times on 20 previously acquired portal image datasets from two patients. The data were analyzed to obtain the mean variability in the distances measured between and within observers.
The mean and median intra-observer variability ranged from 0.4 to 0.7 mm and 0.3 to 0.6 mm respectively with a standard deviation of 0.4 to 1.0 mm. Inter-observer results were similar with a mean variability of 0.9 mm, a median of 0.6 mm, and a standard deviation of 0.7 mm. When using a 5 mm threshold, only 0.5% of treatments will undergo a table shift due to intra or inter-observer error, increasing to an error rate of 2.4% if this threshold were reduced to 3 mm.
We have found high reproducibility with a previously established method for daily verification and correction of isocenter position relative to prostatic fiducial markers using electronic portal imaging.
DNA microarray profiling performed on clinical tissue specimens can potentially provide significant information regarding human cancer biology. Biopsy cores, the typical source of human tumor tissue, however, generally provide very small amounts of RNA (0.3–15 μg). RNA amplification is a common method used to increase the amount of material available for hybridization experiments. Using human xenograft tissue, we sought to address the following three questions: 1) is amplified RNA representative of the original RNA profile? 2) what is the minimum amount of total RNA required to perform a representative amplification? 3) are the direct and indirect methods of labeling the hybridization probe equivalent?
Total RNA was extracted from human xenograft tissue and amplified using a linear amplification process. RNA was labeled and hybridized, and the resulting images yielded data that was extracted into two categories using the mAdb system: "all genes" and "outliers". Scatter plots were generated for each slide and Pearson Coefficients of correlation were obtained.
Results show that the amplification of 5 μg of total RNA yields a Pearson Correlation Coefficient of 0.752 (N = 6,987 genes) between the amplified and total RNA samples. We subsequently determined that amplification of 0.5 μg of total RNA generated a similar Pearson Correlation Coefficient as compared to the corresponding original RNA sample. Similarly, sixty-nine percent of total RNA outliers were detected with 5 μg of amplified starting RNA, and 55% of outliers were detected with 0.5 μg of starting RNA. However, amplification of 0.05 μg of starting RNA resulted in a loss of fidelity (Pearson Coefficient 0.669 between amplified and original samples, 44% outlier concordance). In these studies the direct or indirect methods of probe labeling yielded similar results. Finally, we examined whether RNA obtained from needle core biopsies of human tumor xenografts, amplified and indirectly labeled, would generate representative array profiles compared to larger excisional biopsy material. In this analysis correlation coefficients were obtained ranging from 0.750–0.834 between U251 biopsy cores and excised tumors, and 0.812–0.846 between DU145 biopsy cores and excised tumors.
These data suggest that needle core biopsies can be used as reliable tissue samples for tumor microarray analysis after linear amplification and either indirect or direct labeling of the starting RNA.