Implementation of Magnetic Resonance Imaging-Guided Radiation Therapy in Routine Care: Opportunities and Challenges in the United States.

Purpose: Magnetic resonance image (MRI)-guided radiation therapy with the 1.5 Tesla magnetic resonance linear accelerator (MR-Linac) is a rapidly evolving and emerging treatment. The MR-Linac literature mainly focused on clinical and technological factors in technology implementation, but it is relatively silent on health care system-related factors. Consequently, there is a lack of understanding of opportunities and barriers in implementing the MR-Linac from a health care system perspective. This study addresses this gap with a case study of the US health care system. Methods and Materials: An exploratory, qualitative research design was used. Data collection consisted of 23 semistructured interviews ranging from clinical experts at the radiation therapy and radiology department to insurance commissioners in 7 US hospitals. Analysis of opportunities and barriers was guided by the Nonadoption, Abandonment, Scale-up, Spread and Sustainability framework for new medical technologies in health care organizations. Results: Opportunities included high-precision MR-guidance during radiation therapy with potential continued technical advances and better patient outcomes. MR-Linac also offers opportunities for research, professional, and economic development. Barriers included the lack of empirical evidence of clinical effectiveness, technological complexity, and large staffing and structural investments. Furthermore, the presence of patients with disadvantaged socioeconomic background, and the lack of appropriate reimbursement as well as regulatory conditions can hinder technology implementation. Conclusions: Our study confirms the current literature on implementing the MR-Linac, but also reveals additional challenges for the US health care system. Alongside the well-known clinical and technical factors, also professional, socioeconomic, market, and governing influences affect technology implementation. These findings highlight new connections to facilitate technology uptake and provide a richer start to understanding its long-term effect.

Value of Targeted Biopsies and Combined PSMA PET/CT and mp-MRI Imaging in Locally Recurrent Prostate Cancer after Primary Radiotherapy.

Radiorecurrent prostate cancer is conventionally confirmed using systematic and/or targeted biopsies. The availability of multiparametric (mp) MRI and prostate specific membrane antigen (PSMA) PET/CT has increased diagnostic accuracy. The objective was to determine the positive predictive value (PPV) of combined mp-MRI and PSMA PET/CT and whether pathology verification with MR-targeted biopsies remains necessary for patients with radiorecurrent prostate cancer. Patients with locally recurrent prostate cancer who were referred for 19 Gy single-dose MRI-guided focal salvage high dose rate (HDR) brachytherapy between 2015 and 2018 were included in the current analysis. Patients were selected if they underwent pre-biopsy mp-MRI and PSMA PET/CT. Based on these images, lesions suspect for isolated tumor recurrence were transperineally biopsied using transrectal ultrasound fused with MRI. A total of 41 patients were identified from the database who underwent cognitive targeted (n = 7) or MRI/PSMA-transrectal ultrasound (TRUS) fused targeted (n = 34) biopsies. A total of 40 (97.6%) patients had positive biopsies for recurrent cancer. Five patients initially had negative biopsies (all MRI/PSMA-TRUS fusion targeted), four of whom recurrence was confirmed after a re-biopsy. One (2.4%) patient refused re-biopsy, leading to a positive predictive value (PPV) for combined imaging of 97.6%. Biopsies can therefore safely be withheld when the results of the combined mp-MRI and PSMA PET/CT are conclusive, avoiding an unnecessary invasive and burdensome procedure.

Patterns of Failure Following External Beam Radiotherapy With or Without an Additional Focal Boost in the Randomized Controlled FLAME Trial for Localized Prostate Cancer.

BACKGROUND: Focal dose escalation in external beam radiotherapy (EBRT) showed an increase in 5-yr biochemical disease-free survival in the Focal Lesion Ablative Microboost in Prostate Cancer (FLAME) trial. OBJECTIVE: To analyze the effect of a focal boost to intraprostatic lesions on local failure-free survival (LFS) and regional + distant metastasis-free survival (rdMFS). DESIGN, SETTING, AND PARTICIPANTS: Patients with intermediate- or high-risk localized prostate cancer were included in FLAME, a phase 3, multicenter, randomized controlled trial. INTERVENTION: Standard treatment of 77 Gy to the entire prostate in 35 fractions was compared to an additional boost to the macroscopic tumor of up to 95 Gy during EBRT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: LFS and rdMFS, measured via any type of imaging, were compared between the treatment arms using Kaplan-Meier and Cox regression analyses. Dose-response curves were created for local failure (LF) and regional + distant metastatic failure (rdMF) using logistic regression. RESULTS AND LIMITATIONS: A total of 571 patients were included in the FLAME trial. Over median follow-up of 72 mo (interquartile range 58-86), focal boosting decreased LF (hazard ratio [HR] 0.33, 95% confidence interval [CI] 0.14-0.78) and rdMF (HR 0.58, 95% CI 0.35-0.93). Dose-response curves showed that a greater dose to the tumor resulted in lower LF and rdMF rates. CONCLUSIONS: A clear dose-response relation for LF and rdMF was observed, suggesting that adequate focal dose escalation to intraprostatic lesions prevents undertreatment of the primary tumor, resulting in an improvement rdMF. PATIENT SUMMARY: Radiotherapy is a treatment option for high-risk prostate cancer. The FLAME trial has shown that a high dose specifically targeted at the tumor within the prostate will result in better disease outcome, with less likelihood of regional and distant disease spread. The FLAME trial is registered on ClinicalTrials.gov as NCT01168479.

Urethral and bladder dose-effect relations for late genitourinary toxicity following external beam radiotherapy for prostate cancer in the FLAME trial.

PURPOSE OR OBJECTIVES: The FLAME trial (NCT01168479) showed that by adding a focal boost to conventional fractionated EBRT in the treatment of localized prostate cancer, the five-year biochemical disease-free survival increased, without significantly increasing toxicity. The aim of the present study was to investigate the association between radiation dose to the bladder and urethra and genitourinary (GU) toxicity grade ≥2 in the entire cohort. MATERIAL AND METHODS: The dose-effect relations of the urethra and bladder dose, separately, and GU toxicity grade ≥2 (CTCAE 3.0) up to five years after treatment were assessed. A mixed model analysis for repeated measurements was used, adjusting for age, diabetes mellitus, T-stage, baseline GU toxicity grade ≥1 and institute. Additionally, the association between the dose and separate GU toxicity subdomains were investigated. RESULTS: Dose-effect relations were observed for the dose (Gy) to the bladder D2 cm3 and urethra D0.1 cm3, with adjusted odds ratios of 1.14 (95% CI 1.12-1.16, p < 0.0001) and 1.12 (95% CI 1.11-1.14, p < 0.0001), respectively. Additionally, associations between the dose to the urethra and bladder and the subdomains urinary frequency, urinary retention and urinary incontinence were observed. CONCLUSION: Further increasing the dose to the bladder and urethra will result in a significant increase in GU toxicity following EBRT. Focal boost treatment plans should incorporate a urethral dose-constraint. Further treatment optimization to increase the focal boost dose without increasing the dose to the urethra and other organs at risk should be a focus for future research, as we have shown that a focal boost is beneficial in the treatment of prostate cancer.

Focal Boost to the Intraprostatic Tumor in External Beam Radiotherapy for Patients With Localized Prostate Cancer: Results From the FLAME Randomized Phase III Trial.

PURPOSE: This study investigates whether focal boosting of the macroscopic visible tumor with external beam radiotherapy increases biochemical disease-free survival (bDFS) in patients with localized prostate cancer. PATIENTS AND METHODS: In the phase III, multicenter, randomized controlled Focal Lesion Ablative Microboost in Prostate Cancer trial, 571 patients with intermediate- and high-risk prostate cancer were enrolled between 2009 and 2015. Patients assigned to standard treatment received 77 Gy (fractions of 2.2 Gy) to the entire prostate. The focal boost arm received an additional simultaneous integrated focal boost up to 95 Gy (fractions up to 2.7 Gy) to the intraprostatic lesion visible on multiparametric magnetic resonance imaging. Organ at risk constraints were prioritized over the focal boost dose. The primary end point was 5-year bDFS. Secondary end points were disease-free survival (DFS), distant metastases-free survival, prostate cancer-specific survival, overall survival, toxicity, and health-related quality of life. RESULTS: Median follow-up was 72 months. Biochemical DFS was significantly higher in the focal boost compared with the standard arm (hazard ratio 0.45, 95% CI, 0.28 to 0.71, P < .001). At 5-year follow-up bDFS was 92% and 85%, respectively. We did not observe differences in prostate cancer-specific survival (P = .49) and overall survival (P = .50). The cumulative incidence of late genitourinary and GI toxicity grade ≥ 2 was 23% and 12% in the standard arm versus 28% and 13% in the focal boost arm, respectively. Both for late toxicity as health-related quality of life, differences were small and not statistically significant. CONCLUSION: The addition of a focal boost to the intraprostatic lesion improved bDFS for patients with localized intermediate- and high-risk prostate cancer without impacting toxicity and quality of life. The Focal Lesion Ablative Microboost in Prostate Cancer study shows that a high focal boost strategy to improve tumor control while respecting organ at risk dose constraints is effective and safe.

MRI-Guided Ultrafocal HDR Brachytherapy for Localized Prostate Cancer: Median 4-Year Results of a feasibility study.

PURPOSE: For the treatment of localized prostate cancer, focal therapy has the potential to cure with fewer side effects than traditional whole-gland treatments. We report an update on toxicity, quality of life (QoL), and tumor control in our magnetic resonance imaging (MRI)-guided ultrafocal high-dose-rate brachytherapy cohort. METHODS AND MATERIALS: Disease status was evaluated by systematic biopsies and 3T multiparametric MRI. The brachytherapy implant procedure under fused transrectal ultrasound/MRI guidance was followed by a 1.5 T MRI for contour adjustments and catheter position verification. A single dose of 19 Gy was delivered to the tumor with a margin of 5 mm. Genitourinary (GU) toxicity, gastrointestinal (GI) toxicity, and erectile dysfunction (ED) were graded with the Common Terminology Criteria for Adverse Events version 4.0. QoL was measured with RAND-36, European Organisation for Research and Treatment of Cancer QLQ-C30 and PR25. International Prostate Symptom Scores and International Index of Erectile Function scores were obtained. Prostate-specific antigen level was monitored, with biochemical recurrence defined as nadir + 2 ng/mL (Phoenix). RESULTS: Thirty patients with National Comprehensive Cancer Network low- (13%) to intermediate-risk (87%) prostate cancer were treated between May 2013 and April 2016. Median follow-up was 4 years. Median age was 71 years (interquartile range, 68-73) and median initial prostate-specific antigen level was 7.3 ng/mL (5.2-8.1). Maximum Gleason score was 4 + 3 = 7 (in 2 patients). All tumors were radiologic (MRI) stage T2. No grade >2 GU or >1 GI toxicity occurred. International Prostate Symptom Scores only deteriorated temporarily. Mild pretreatment ED deteriorated to moderate/severe ED in 50% of patients. Long-term clinically relevant QoL deterioration was seen in sexual activity and tiredness, whereas emotional and cognitive functioning improved. At 4 years, biochemical disease-free survival was 70% (95% confidence interval, 52%-93%), metastases-free survival was 93% (85%-100%), and overall survival was 100%. Of intraprostatic recurrences, 7 of 9 were out of field. CONCLUSIONS: Ultrafocal high-dose-rate brachytherapy conveys minimal GU or GI toxicity and has a marginal effect on QoL. An early decline in erectile function was seen. Tumor control outcomes are poor (biochemical disease-free survival of 70% [52%-93%] at 4 years), most likely as a result of poor patient selection.

Evolving management of colorectal cancer.

This article reviews recent advances in surgical techniques and adjuvant therapies for colorectal cancer, including total mesorectal excision, the resection of liver and lung metastasis and advances in chemoradiation and foreshadows some interventions that may lie just beyond the frontier. In particular, little is known about the intracellular and extracellular cascades that may influence colorectal cancer cell adhesion and metastasis. Although the phosphorylation of focal adhesion kinases and focal adhesion associated proteins in response to integrin-mediated cell matrix binding ("outside in integrin signaling") is well described, the stimulation of cell adhesion by intracellular signals activated by pressure prior to adhesion represents a different signal paradigm. However, several studies have suggested that increased pressure and shear stress activate cancer cell adhesion. Further studies of the pathways that regulate integrin-driven cancer cell adhesion may identify ways to disrupt these signals or block integrin-mediated adhesion so that adhesion and eventual metastasis can be prevented in the future.