A hybrid deformable registration method to generate motion-compensated 3D virtual MRI for fusion with interventional real-time 3D ultrasound.

PURPOSE: Ultrasound is often the preferred modality for image-guided therapy or treatment in organs such as liver due to real-time imaging capabilities. However, the reduced conspicuity of tumors in ultrasound images adversely impacts the precision and accuracy of treatment delivery. This problem is compounded by deformable motion due to breathing and other physiological activity. This creates the need for a fusion method to align interventional US with pre-interventional modalities that provide superior soft-tissue contrast (e.g., MRI) to accurately target a structure-of-interest and compensate for liver motion. METHOD: In this work, we developed a hybrid deformable fusion method to align 3D pre-interventional MRI and 3D interventional US volumes to target the structures-of-interest in liver accurately in real-time. The deformable multimodal fusion method involved an offline alignment of a pre-intervention MRI with a pre-intervention US volume using a traditional registration method, followed by real-time prediction of deformation using a trained deep-learning model between interventional US volumes across different respiratory states. This framework enables motion-compensated MRI-US image fusion in real-time for image-guided treatment. RESULTS: The proposed hybrid deformable registration method was evaluated on three healthy volunteers across the pre-intervention MRI and 20 US volume pairs in the free-breathing respiratory cycle. The mean Euclidean landmark distance of three homologous targets in all three volunteers was less than 3 mm for percutaneous liver procedures. CONCLUSIONS: Preliminary results show that clinically acceptable registration accuracies for near real-time, deformable MRI-US fusion can be achieved by our proposed hybrid approach. The proposed combination of traditional and deep-learning deformable registration techniques is thus a promising approach for motion-compensated MRI-US fusion to improve targeting in image-guided liver interventions.

First-in-human imaging using a MR-compatible e4D ultrasound probe for motion management of radiotherapy.

PURPOSE: Respiration-induced tumor or organ positional changes can impact the accuracy of external beam radiotherapy. Motion management strategies are used to account for these changes during treatment. The authors report on the development, testing, and first-in-human evaluation of an electronic 4D (e4D) MR-compatible ultrasound probe that was designed for hands-free operation in a MR and linear accelerator (LINAC) environment. METHODS: Ultrasound components were evaluated for MR compatibility. Electromagnetic interference (EMI) shielding was used to enclose the entire probe and a factory-fabricated cable shielded with copper braids was integrated into the probe. A series of simultaneous ultrasound and MR scans were acquired and analyzed in five healthy volunteers. RESULTS: The ultrasound probe led to minor susceptibility artifacts in the MR images immediately proximal to the ultrasound probe at a depth of <10 mm. Ultrasound and MR-based motion traces that were derived by tracking the salient motion of endogenous target structures in the superior-inferior (SI) direction demonstrated good concordance (Pearson correlation coefficients of 0.95-0.98) between the ultrasound and MRI datasets. CONCLUSION: We have demonstrated that our hands-free, e4D probe can acquire ultrasound images during a MR acquisition at frame rates of approximately 4 frames per second (fps) without impacting either the MR or ultrasound image quality. This use of this technology for interventional procedures (e.g. biopsies and drug delivery) and motion compensation during imaging are also being explored.

A Magnetic Resonance Compatible E4D Ultrasound Probe for Motion Management of Radiation Therapy.

We developed a magnetic resonance compatible real-time, three-dimensional imaging ultrasound probe for motion management of radiation therapy for liver cancer. The probe contains an 18,000-element, 46.8 mm × 21.5 mm matrix array constructed from three tiled transducer modules with integrated beamforming ASICs. The center frequency and -6 dB fractional bandwidth of the probe was 3.6 MHz and 85 percent respectively. Ferromagnetic materials in the acoustic stack, flex interconnect and electronics boards were greatly minimized for magnetic resonance compatibility. The probe and cable were shielded to minimize the impact of radiofrequency noise on both the ultrasound and magnetic resonance images. The probe's low-profile, side-viewing design allows it to be strapped to a patient so that images may be acquired hands-free. We present simultaneously acquired ultrasound and 3 Tesla magnetic resonance images with minimal artifacts in both images.

Ultra-high dose (86.4 Gy) IMRT for localized prostate cancer: toxicity and biochemical outcomes.

PURPOSE: To report toxicity and preliminary biochemical outcomes with high-dose intensity-modulated radiation therapy (IMRT) to a dose of 86.4 Gy for localized prostate cancer. METHODS AND MATERIALS: Between August 1997 and March 2004, 478 patients were treated with 86.4 Gy using a 5- to 7-field IMRT technique. To adhere to normal tissue constraints, the mean D95 and V100 for the planning target volume were 83 Gy and 87%, respectively. Toxicity data were scored according to the Common Terminology Criteria for Adverse Events Version 3.0. Freedom from biochemical relapse was calculated. The median follow-up was 53 months. RESULTS: Thirty-seven patients (8%) experienced acute Grade 2 gastrointestinal (GI) toxicity. There was no acute Grade 3 or 4 GI toxicity. One hundred and five patients (22%) experienced acute Grade 2 genitourinary (GU) toxicity and three patients (0.6%) had Grade 3 GU toxicity. There was no acute Grade 4 GU toxicity. Sixteen patients (3%) developed late Grade 2 GI toxicity and two patients (<1%) developed late Grade 3 GI toxicity. Sixty patients (13%) had late Grade 2 GU toxicity and 12 (<3%) experienced late Grade 3 GU toxicity. The 5-year actuarial PSA relapse-free survival according to the nadir plus 2 ng/mL definition was 98%, 85% and 70% for the low, intermediate, and high risk NCCN prognostic groups. CONCLUSION: This report represents the largest data set of patients treated to ultra-high radiation dose levels of 86.4 Gy using IMRT for localized prostate cancer. Our findings indicate that this treatment is well tolerated and the early excellent biochemical control rates are encouraging.

Five-year outcome of intraoperative conformal permanent I-125 interstitial implantation for patients with clinically localized prostate cancer.

PURPOSE: To report the 5-year tumor control and toxicity outcomes for patients with localized prostate treated with I-125 permanent implantation using an intraoperative real-time conformal planning technique. METHODS AND MATERIALS: Between January 1998 and June 2002, 367 patients with prostate cancer were treated with I-125 permanent interstitial implantation using a transrectal ultrasound-guided approach. Real-time intraoperative treatment planning which incorporated inverse planning optimization was used. The median follow-up time was 63 months. RESULTS: The median V100 and D90 were 96% and 173 Gy, respectively. In 96% of cases a D90 of >140 Gy was achieved. The median urethral and rectal doses were 100% and 33% of the prescription doses, respectively. The 5-year PSA relapse-free survival outcomes for favorable and intermediate risk patients according to the ASTRO definition were 96% and 89%, respectively. In these patients no dosimetric parameter was identified which influenced the biochemical outcome. Of 38% who developed acute Grade 2 urinary symptoms, 63% had resolution of their symptoms within a median time of 6 months. The incidence of late rectal and urinary Grade 3 or higher toxicities were 1% and 4%, respectively. Seven percent (n = 27) developed late rectal bleeding (Grade 2) and 19% experienced late Grade 2 urinary symptoms. CONCLUSION: Real-time intraoperative planning consistently achieved optimal coverage of the prostate with the prescription dose with concomitant low doses delivered to the urethra and rectum. Biochemical control outcomes were excellent at 5 years and late toxicity was unusual. These data demonstrate that real-time planning methods can consistently and reliably deliver the intended dose distribution to achieve an optimal therapeutic ratio between the target and normal tissue structures.

Long-term outcome of high dose intensity modulated radiation therapy for patients with clinically localized prostate cancer.

PURPOSE: We report on the long-term results and late toxicity outcomes of high dose intensity modulated radiation therapy for patients with clinically localized prostate cancer. MATERIALS AND METHODS: Between 1996 and 2000 a total of 561 patients with clinically localized prostate cancer were treated with intensity modulated radiation therapy. All patients were treated to a dose of 81 Gy prescribed to the planning target volume. Prostate specific antigen relapse was defined according to the American Society for Therapeutic Radiology and Oncology consensus and Houston definitions (absolute nadir plus 2 ng/ml dated at the call). Median followup was 7 years (range 5 to 9). RESULTS: The 8-year actuarial PSA relapse-free survival rates for patients in favorable, intermediate and unfavorable risk groups according to the American Society for Therapeutic Radiology and Oncology definition were 85%, 76% and 72%, respectively (p <0.025). The 8-year actuarial prostate specific antigen relapse-free survival rates for patients in favorable, intermediate and unfavorable risk groups according to the Houston definition were 89%, 78% and 67%, respectively (p = 0.0004). The 8-year actuarial likelihood of grade 2 rectal bleeding was 1.6%. Three patients (0.1%) experienced grade 3 rectal toxicity requiring either 1 or more transfusions or a laser cauterization procedure. No grade 4 rectal complications have been observed. The 8-year likelihood of late grade 2 and 3 (urethral strictures) urinary toxicities were 9% and 3%, respectively. Among patients who were potent before intensity modulated radiation therapy, erectile dysfunction developed in 49%. The cause specific survival outcomes for favorable, intermediate and unfavorable risk cases were 100%, 96% and 84%, respectively. CONCLUSIONS: These long-term results confirm our previous observations regarding the safety of high dose intensity modulated radiation therapy for clinically localized prostate cancer. Despite the application of high radiation doses, the incidence of rectal bleeding at 8 years was less than 2%. Despite the increased conformality of the dose distribution associated with intensity modulated radiation therapy, excellent long-term tumor control outcomes were achieved.

Evaluation of postradiotherapy PSA patterns and correlation with 10-year disease free survival outcomes for prostate cancer.

PURPOSE: To describe the prostate-specific antigen (PSA) pattern profiles observed after external beam radiotherapy with and without short-term neoadjuvant androgen deprivation therapy (ST-ADT) and to report the association of established posttreatment PSA patterns with long-term disease-free survival outcomes. METHODS AND MATERIALS: A total of 1,665 patients were treated with conformal external beam radiotherapy for clinically localized prostate cancer. Of 570 patients who had the requisite>10 consecutive PSA measurements for statistical analysis, 194 patients received a median of 3 months of ADT before radiotherapy and 376 were treated with radiotherapy alone. The median follow up was 103 months. RESULTS: In the group treated with ST-ADT, three distinct postradiotherapy PSA patterns were identified: a stable trend (44%), an increasing trend followed by stabilization of the PSA (25%), and an increasing trend (31%). Among the subgroup that demonstrated a rising and subsequent stabilizing patterns, PSA levels had gradually risen to a median value of 0.9 ng/mL after therapy, stabilized, and remained durably suppressed. The only identified trends among patients treated with external beam radiotherapy without ST-ADT were declining PSA levels followed by stable PSA trends or declining patterns followed by rising levels. Patients whose PSA levels stabilized after an initial rise or those with slowly rising PSA profiles had a lower incidence of distant metastasis compared to those with accelerated rises after therapy. CONCLUSIONS: For those treated with external beam radiotherapy in conjunction with ST-ADT, a significant percentage who develop a rising PSA after treatment are expected to manifest subsequent stabilization at plateaued levels of approximately 1.0 ng/mL, which can remain durably suppressed. The likelihood of distant metastasis in these patients is low despite the PSA stabilization at levels 1.0 ng/mL or higher and comparable to outcomes observed for those with lower nonrising PSA values.

Outcome predictors for the increasing PSA state after definitive external-beam radiotherapy for prostate cancer.

PURPOSE: To identify predictors of distant metastases (DM) among patients who develop an isolated prostate-specific antigen (PSA) relapse after definitive external-beam radiotherapy for clinically localized prostate cancer. MATERIALS AND METHODS: A total of 1,650 patients with clinical stage T1 to T3 prostate cancer were treated with high-dose three-dimensional conformal radiotherapy. Of these, 381 patients subsequently developed three consecutive increasing PSA values and were characterized as having a biochemical relapse. The median follow-up time was 92 months from the completion of radiotherapy. RESULTS: The 5-year incidence of DM after an established PSA relapse was 29%. In a multivariate analysis, PSA doubling time (PSA-DT; P < .001), the clinical T stage (P < .001), and Gleason score (P = .007) were independent variables predicting for DM after established biochemical failure. The PSA-DT for favorable-, intermediate-, and unfavorable-risk patients who developed a biochemical failure was 20.0, 13.2, and 8.2 months, respectively (P < .001). The 3-year incidence of DM for patients with PSA-DT of 0 to 3, 3 to 6, 6 to 12, and more than 12 months was 49%, 41%, 20%, and 7%, respectively (P < .001). Patients with PSA-DT of 0 to 3 and 3 to 6 months demonstrated a 7.0 and 6.6 increased hazard of developing DM or death, respectively, compared with patients with a DT more than 12 months. CONCLUSION: In addition to clinical stage and Gleason score, PSA-DT was a powerful predictor of DM among patients who develop an isolated PSA relapse after external-beam radiotherapy for prostate cancer. Patients who develop biochemical relapse with PSA-DT < or = 6 months should be considered for systemic therapy or experimental protocols because of the high propensity for rapid DM development.