Ultrasound-stimulated microbubbles enhancement of fractionated radiation for tumor treatment.

BACKGROUND: Radiation therapy (XRT) causes numerous biological changes in tumor microenvironment. Radiation vascular response, due to endothelial disruption, can influence treatment outcomes in a dose-dependent manner. Ultrasound-stimulated microbubbles (USMB) have also been demonstrated to create a vascular response in the tumor microenvironment and enhance tumor response when used in combination with XRT. Single doses of 8-10 Gy are known to induce activation of acid sphingomyelinase (ASMase)-induced ceramide production, causing vascular damage. Destruction of vasculature results in endothelial apoptosis followed by tumor cell death. The effect of tumor response is known to be synergistic by 10-fold higher cell kill observed when USMB is combined with radiation. METHODS: In this study, we used an USMB approach in combination with conventional low dose fractionated radiation to enhance endothelial cell responses to XRT in human PC3 prostate cancer xenograft model. Mice were divided into untreated, USMB therapy, fractionated XRT, and combined USMB therapy followed by XRT (USMB + XRT) groups. USMB therapy was delivered twice per week in the USMB-alone and combined USMB + XRT treatment groups over four weeks. Radiation treatments were delivered in fractions of 2 Gy/day (total 40 Gy in 20 fractions, BED10 = 48 Gy) in the XRT-alone and combined USMB + XRT groups. The treatment outcome was evaluated using histopathology, power Doppler, and immunohistochemistry assays. RESULTS: Tumor growth assessment showed that sizes of tumors increased in the control and the single treatment groups over a treatment period of four weeks, but significantly decreased with the combined treatments of USMB + XRT. Immunohistochemical analysis indicated a statistically significant vascular disruption in mice that received treatment involving a full 4-week schedule of combined (USMB + XRT) treatments. A statistically significant increase in vascular disruption was demonstrated through CD68 and trichrome fibrosis staining. Changes in local perfusion assessed using high-frequency power Doppler imaging demonstrated attenuated blood flow in the combined group. DISCUSSION AND CONCLUSIONS: This work demonstrates the efficacy of using USMB as a radiation sensitizer in a mouse model of human PC3 tumor xenograft. This radiation treatment enhancement modality has the advantage of targeting tumor vasculature with ultrasound stimulation that can be implemented prior to radiation treatment.

Predictors of pathologic fracture and local recurrence following stereotactic body radiation therapy to 505 non-spine bone metastases.

PURPOSE: Stereotactic Body Radiation Therapy (SBRT) is increasingly applied to treat non-spine bone metastases (NSBM) though data remains limited on this approach. In this retrospective study, we report outcomes and predictors of local failure (LF) and pathological fracture (PF) post-SBRT for NSBM using a mature single-institution database. METHODS: Patients with NSBM treated with SBRT between 2011 and 2021 were identified. The primary objective was to assess the rates of radiographic LF. Secondary objectives were to assess the rates of in-field PF, overall survival (OS), and late grade ≥ 3 toxicity. Competing risks analysis was used to assess rates of LF and PF. Univariable regression and multivariable regression (MVR) were performed to investigate predictors of LF and PF. RESULTS: A total of 373 patients with 505 NSBM were included in this study. Median follow-up was 26.5 months. The cumulative incidence of LF at 6, 12, and 24 months were 5.7%, 7.9%, and 12.6%, respectively. The cumulative incidence of PF at 6, 12, and 24 months were 3.8%, 6.1%, and 10.9%, respectively. Lytic NSBM (HR = 2.18; p < 0.01), a lower biologically effective dose (HR = 1.11 per 5 Gy10 decrease; p = 0.04), and a PTV ≥ 54 cc (HR = 4.32; p < 0.01) predicted for a higher risk of LF on MVR. Lytic NSBM (HR = 3.43; p < 0.01), mixed (lytic/sclerotic) lesions (HR = 2.70; p = 0.04), and rib metastases (HR = 2.68; p < 0.01) predicted for a higher risk of PF on MVR. CONCLUSION: SBRT is an effective modality to treat NSBM with high rates of radiographic local control with an acceptable rate of PF. We identify predictors of both LF and PF that can serve to inform practice and trial design.

Evaluation of an Online Education Resource on Radiation Therapy Created for Patients with Postprostatectomy Prostate Cancer and Their Caregivers.

INTRODUCTION: Radiation therapy (RT) after prostatectomy is an important curative treatment option for patients with prostate cancer. It can be delivered immediately after surgery as adjuvant treatment, or after biochemical PSA failure as salvage treatment. There is currently a lack of consensus regarding whether salvage RT in the event of biochemical failure or immediate adjuvant RT is the optimal postprostatectomy RT treatment. Although both types of postprostatectomy RT are generally well tolerated, patients may develop some toxicity that can impact their quality of life and the duration and frequency of treatments can be challenging for patients. It is imperative that patients be provided with evidence-based information so that they are able to make a treatment decision most aligned with their values. METHODS: To help address patients' informational needs, an online education resource was created for patients with prostate cancer considering postoperative RT. Patients and their families were asked to evaluate the effectiveness of this resource using a validated purpose-based information assessment. RESULTS: Nineteen patients were approached and 14 participated, but only five patients returned their evaluations (35%). Sixty percent found the information to be important with regards to each of the six commonly identified purposes in the purpose-based information assessment: organizing, understanding, decision-making, planning, emotional support, and discussing. Only one participant found the information hard to understand and had difficulty finding specific information. DISCUSSION: Patients should be encouraged to actively participate in their treatment decision-making process involving postprostatectomy RT. For patients to make well-informed decisions, patients must be provided with clear and accessible information so that they may understand their disease and the treatment options. CONCLUSION: An online education resource has been developed that most study respondents found clear and helpful for a variety of identified purposes. Overall, this online education resource has the potential to reach a large number of patients and their caregivers who desire specific information and involvement in future treatment decisions.

Dosimetric impact of inter-observer catheter reconstruction variability in ultrasound-based high-dose-rate prostate brachytherapy.

PURPOSE: To investigate the dosimetric impact of interobserver catheter reconstruction variability in transrectal ultrasound-guided prostate high-dose-rate (HDR) brachytherapy. METHODS AND MATERIALS: Twenty consecutive patients with intermediate- or high-risk prostate cancer were treated with a single, 15-Gy HDR brachytherapy boost as part of this study. The treated plan was used as the study reference plan (PR). Three expert treatment planners (observers) manually reconstructed the catheter paths on the static three-dimensional transrectal ultrasound images, and new plans were generated from the updated positions (POBS); subsequently, the dwell time and positions from the POBS plans were superimposed on the PR catheter paths to evaluate the dosimetric effect of the interobserver variations (PEVAL). Plans from each group were stratified by observer and by number of catheters (12 or 16) and then compared using a one-way Kruskal-Wallis H test with post hoc Mann-Whitney U tests reserved for significant variations (α = 0.05). RESULTS: Greater than 98.9% of catheter reconstruction variations were <3 mm. When stratified by observer, there was a significant decrease (p << 0.05) in planning target volume (PTV) V100% and increases in the urethral Dmax between the POBS plans propagated to the PR catheter paths and dosimetry evaluated and PR plans only. Stratification of plans by catheter number showed nonclinically significant decreases in PTV V100%, and D90% and increases in urethral Dmax for the 12-catheter plans. CONCLUSIONS: Limiting interobserver variability, and its effects on prostate HDR brachytherapy plan quality, is critical to achieving good dosimetric outcomes; small variations in catheter reconstruction may translate to inadequate PTV coverage, excessive urethral dose, or both.