Faculty Bibliography

BACKGROUND AND PURPOSE/OBJECTIVE:Magnetic resonance (MR) only radiation therapy for prostate treatment provides superior contrast for defining targets and organs-at-risk (OARs). This study aims to develop a deep learning model to leverage this advantage to automate the contouring process. MATERIALS AND METHODS/METHODS:Six structures (bladder, rectum, urethra, penile bulb, rectal spacer, prostate and seminal vesicles) were contoured and reviewed by a radiation oncologist on axial T2-weighted MR image sets from 50 patients, which constituted expert delineations. The data was split into a 40/10 training and validation set to train a two-dimensional fully convolutional neural network, DeepLabV3+, using transfer learning. The T2-weighted image sets were pre-processed to 2D false color images to leverage pre-trained (from natural images) convolutional layers' weights. Independent testing was performed on an additional 50 patient's MR scans. Performance comparison was done against a U-Net deep learning method. Algorithms were evaluated using volumetric Dice similarity coefficient (VDSC) and surface Dice similarity coefficient (SDSC). RESULTS:< 0.001). Average VDSC was 0.93 ± 0.04 (bladder), 0.83 ± 0.06 (prostate and seminal vesicles [CTV]), 0.74 ± 0.13 (penile bulb), 0.82 ± 0.05 (rectum), 0.69 ± 0.10 (urethra), and 0.81 ± 0.1 (rectal spacer). Average SDSC was 0.92 ± 0.1 (bladder), 0.85 ± 0.11 (prostate and seminal vesicles [CTV]), 0.80 ± 0.22 (penile bulb), 0.87 ± 0.07 (rectum), 0.85 ± 0.25 (urethra), and 0.83 ± 0.26 (rectal spacer). CONCLUSION/CONCLUSIONS:A deep learning-based model produced contours that show promise to streamline an MR-only planning workflow in treating prostate cancer.

PURPOSE:The current oligometastatic (OM) model postulates that the disease evolves dynamically with sequential emergence of OM (SOM) lesions requiring successive rounds of SOM ablation to afford tumor cure. The present phase 2 study explores the ablative efficacy of 24 Gy single-dose radiation therapy (SDRT), its feasibility in diverse OM settings, and the impact of radioablation on polymetastatic (PM) dissemination. METHODS AND MATERIALS:One hundred seventy-five consecutive patients with 566 OM or SOM lesions underwent periodic positron emission tomography/computed tomography (PET/CT) imaging to stage the disease before treatment, determine tumor response, and monitor timing of PM conversion after SDRT. When 24 Gy SDRT was restricted by dose or volume constraints of serial normal organs, radioablation was diverted to a nontoxic 3×9 Gy SBRT schedule. RESULTS:(cutoff at 6.5) yielded a 3-tiered PMFS categorization of 89%, 58% and 17% actuarial 5-year PMFS in categories 1, 2, and 3, respectively (P < .001), defining OM disease as a syndrome of diverse clinical and prognostic phenotypes. CONCLUSION:Long-term risk of PM dissemination, predicted by preablation PET/CT staging, provides guidelines for phenotype-oriented OM therapy. In categories 1 and 2, radioablation should be a primary therapeutic element when pursuing tumor cure, whereas in the PM-prone category 3, radioablation should be a component of multimodal trials addressing primarily the risk of PM dissemination. PET/CT baseline staging also provides a platform for discovery of pharmacologically accessible PM drivers as targets for new phenotype-oriented treatment protocols.

PURPOSE/OBJECTIVE:To determine the impact of using fiducial match for daily image-guidance on pelvic lymph node (PLN) coverage for prostate cancer patients receiving stereotactic body radiation therapy (SBRT). METHODS:Thirty patients underwent SBRT treatment to the prostate and PLN from 2014 to 2016. Each patient received either 800cGy × 5 or 500cGy × 5 to the prostate and 500cGy × 5 to the PLN. A 5 mm clinical target volume (CTV)-to-planning target volume (PTV) margin around the PLN was used for planning. Two registrations with planning computed tomography (PCT) for each of the daily cone beam CTs (CBCTs) were performed: a rigid registration to fiducials and to the bony anatomy. The average translational difference between fiducial and bony match as well as percentage of fractions with differences > 5mm were calculated. Changes in bladder and rectal volume as well as center-of-mass (COM) position from simulation parameters, and their correlation with translational difference were also evaluated. The dosimetric impact of the translational differences was calculated by shifting the plan isocenter. RESULTS:The average translational difference between fiducial and bony match was 0.06 ± 0.82, 2.1 ± 4.1, -2.8 ± 4.3, and 5.5 ± 4.2 mm for lateral, vertical, longitudinal, and vector directions. The average change in bladder and rectal volume from simulation was -67.2 ± 163.04 cc (-12 ± 52%) and -1.6 ± 18.75 (-2 ± 30%) cc. The average change in COM of bladder from the simulation position was 0.34 ± 2.49, 4.4 ± 8.1, and -3.9 ± 7.5 mm along the LR, AP, and SI directions. The corresponding COM change for the rectum was 0.17 ± 1.9, 1.34 ± 3.5, and -0.6 ± 5.2 mm. CONCLUSIONS:The 5 mm margin covered ~75% of fractions receiving PLN irradiation with SBRT, daily CBCT and fiducial-guided setup. The dosimetric impact on PLN coverage was significant in 19% of fractions or 25% of patients. A larger translational shift was due to variation in rectal volume and changes in COM position of the bladder and rectum. A consistent bladder positioning and/or rectum filling compared with presimulation volume were essential for adequate coverage of PLN in a hypofractionated treatment regime.

PURPOSE/OBJECTIVE:To develop an Eclipse plug-in (MLC_MODIFIER) that automatically modifies control points to expose fiducials obscured by MLC during VMAT, thereby facilitating tracking using periodic MV/kV imaging. METHOD/METHODS:Three-dimensional fiducial tracking was performed during VMAT by pairing short-arc (3°) MV digital tomosynthesis (DTS) images to triggered kV images. To evaluate MLC_MODIFIER efficacy, two cohorts of patients were considered. For first 12 patients, plans were manually edited to expose one fiducial marker. Next for 15 patients, plans were modified using MLC_MODIFIER script. MLC_MODIFIER evaluated MLC apertures at appropriate angles for marker visibility. Angles subtended by control points were compressed and low-dose "imaging" control points were inserted and exposed one marker with 1 cm margin. Patient's images were retrospectively reviewed to determine rate of MV registration failures. Failure categories were poor DTS image quality, MLC blockage of fiducials, or unknown reasons. Dosimetric differences in rectum, bladder, and urethra D1 cc, PTV maximum dose, and PTV dose homogeneity (PTV HI) were evaluated. Statistical significance was evaluated using Fisher's exact and Student's t test. RESULT/RESULTS:Overall MV registration failures, failures due to poor image quality, MLC blockage, and unknown reasons were 33% versus 8.9% (P < 0.0001), 8% versus 6.4% (P < 0.05), 13.6% versus 0.1% (P < 0.0001), and 7.6% versus 2.4% (P < 0.0001) for manually edited and MLC_MODIFIER plans, respectively. PTV maximum and HI increased on average from unmodified plans by 2.1% and 0.3% (P < 0.004) and 22.0% and 3.3% (P < 0.004) for manually edited and MLC_MODIFIED plans, respectively. Changes in bladder, rectum, and urethra D1CC were similar for each method and less than 0.7%. CONCLUSION/CONCLUSIONS:Increasing fiducial visibility via an automated process comprised of angular compression of control points and insertion of additional "imaging" control points is feasible. Degradation of plan quality is minimal. Fiducial detection and registration success rates are significantly improved compared to manually edited apertures.

PURPOSE:We determined the prognostic importance of a positive posttreatment biopsy after prostate radiotherapy. MATERIALS AND METHODS:A total of 382 patients underwent a posttreatment biopsy after external beam radiotherapy for clinically localized prostate cancer. Posttreatment biopsies were classified as positive (prostatic adenocarcinoma without typical radiation induced changes), negative (no evidence of carcinoma) or adenocarcinoma with a severe treatment effect. Median followup in survivors was 9 years. Competing risks regression was used to assess relationships between prognostic predictors and cause specific mortality, distant metastasis and prostate specific antigen failure. RESULTS:The prevalence of positive biopsy, treatment effect and negative biopsy was 30%, 22% and 48%, respectively. Androgen deprivation therapy omission and high risk disease were associated with a 2.6 and 1.8-fold increase, respectively, in the odds of positive posttreatment biopsy. The 15-year PSA relapse rate associated with negative, severe treatment effect and positive posttreatment biopsies was 34%, 36% and 79%, respectively (p <0.001). After controlling for known predictors the risk of distant metastasis was 2.6-fold higher in patients with a positive biopsy (p <0.001) and cause specific mortality was twice as high in patients with a positive biopsy compared to those with negative and severe treatment effect biopsy outcomes (HR 2.00, p = 0.022). CONCLUSIONS:A positive posttreatment biopsy after external beam radiotherapy was associated with a higher risk of distant metastasis and prostate cancer related death. Patients with severe treatment effect classified biopsies have biological characteristics more like patients with a negative biopsy than a positive biopsy. Posttreatment biopsies were more often positive in the setting of external beam radiotherapy alone without androgen deprivation therapy or in the presence of high risk disease.

PURPOSE:To report toxicity outcomes, prostate-specific antigen (PSA) relapse, and cumulative incidence posttreatment biopsy results among patients treated on a prospective dose escalation study using ultra-hypofractionated stereotactic body radiation therapy (SBRT) for patients with low- and intermediate-risk prostate cancer. METHODS AND MATERIALS:. Patients treated with neoadjuvant androgen deprivation were excluded. The median follow-up in survivors for the 4 dose levels was 5.9, 5.4, 4.1, and 3.5 years, respectively. RESULTS:The incidence of acute grade 2 rectal toxicities for dose levels 1 to 4 were 0%, 2.9%, 2.8%, and 11.4% respectively. No grade 3 or 4 acute rectal toxicities were observed. The incidence of acute grade 2 urinary toxicities for dose levels 1 to 4 were 16.7%, 22.9%, 8.3%, and 17.1%, respectively. No grade 3 or 4 acute urinary toxicities were observed. No grade 2 or higher rectal toxicities were observed. The incidence of late grade 2 urinary toxicities for dose levels 1 to 4 was 23.3%, 25.7%, 27.8%, and 31.4%, respectively. Only 1 late grade 3 urinary toxicity (urethral stricture) developed in the 40-Gy dose arm; the stricture was corrected with transurethral resection. No grade 4 late urinary toxicity was observed. The 5-year cumulative incidence of prostate-specific antigen failure for dose levels 1 to 4 was 15%, 6%, 0%, and 0%. The incidence of a 2-year positive posttreatment biopsy was 47.6%, 19.2%, 16.7%, and 7.7%, respectively for the 4 dose arms (P = .013). CONCLUSIONS:SBRT doses ranging from 32.5 to 40 Gy in 5 fractions were well tolerated without severe urinary or rectal toxicities. Biopsy outcomes suggest improved rates of tumor clearance observed with higher doses.

Tumor cure with conventional fractionated radiotherapy is 65%, dependent on tumor cell-autonomous gradual buildup of DNA double-strand break (DSB) misrepair. Here we report that single-dose radiotherapy (SDRT), a disruptive technique that ablates more than 90% of human cancers, operates a distinct dual-target mechanism, linking acid sphingomyelinase-mediated (ASMase-mediated) microvascular perfusion defects to DNA unrepair in tumor cells to confer tumor cell lethality. ASMase-mediated microcirculatory vasoconstriction after SDRT conferred an ischemic stress response within parenchymal tumor cells, with ROS triggering the evolutionarily conserved SUMO stress response, specifically depleting chromatin-associated free SUMO3. Whereas SUMO3, but not SUMO2, was indispensable for homology-directed repair (HDR) of DSBs, HDR loss of function after SDRT yielded DSB unrepair, chromosomal aberrations, and tumor clonogen demise. Vasoconstriction blockade with the endothelin-1 inhibitor BQ-123, or ROS scavenging after SDRT using peroxiredoxin-6 overexpression or the SOD mimetic tempol, prevented chromatin SUMO3 depletion, HDR loss of function, and SDRT tumor ablation. We also provide evidence of mouse-to-human translation of this biology in a randomized clinical trial, showing that 24 Gy SDRT, but not 3×9 Gy fractionation, coupled early tumor ischemia/reperfusion to human cancer ablation. The SDRT biology provides opportunities for mechanism-based selective tumor radiosensitization via accessing of SDRT/ASMase signaling, as current studies indicate that this pathway is tractable to pharmacologic intervention.