The Treasury of Images: exploring the opportunities for diagnosing and treating prostate cancer

External beam radiotherapy (EBRT) is often used to treat prostate cancer (PCa). Technological developments in radiation delivery techniques allowed increasing the dose to the entire prostate gland thereby improving treatment outcome. Unfortunately these positive results come often at the cost of increased toxicity and local recurrences are still observed, mostly at the site of the primary tumor. New strategies to further enhance local control while maintaining an acceptable level of toxicity are thus needed. An upcoming, more precise and accurate form of EBRT is stereotactic body radiotherapy (SBRT). This treatment technology is based on two principles: (1) precise 3D localization of the target (stereotaxis) by means of image guidance and (2) delivery of high doses of radiation in just a few treatment fractions (hypofractionation). Such hypofractionated treatment regimens could thus be used to biologically escalate the dose while maintaining current levels of toxicity. Furthermore, reducing the number of treatment fractions has several other advantages with respect to patient convenience, resources and costs as compared to the standard fractionation scheme. Alternatively, proton radiation therapy, which makes use of charged particles instead of photons, could also be an option to escalate the dose while improving treatment-related toxicity given the superior physical characteristics of protons. Instead of escalating the dose to the whole prostate gland, increasing the radiation dose only to the intraprostatic tumor nodule(s) (focal boosting) while keeping the exposure of surrounding tissues similar to treatment with a conventional, homogeneous dose to the prostate target volume, could be an ideal solution. Moreover, focal dose escalation may improve local disease control as local recurrences mostly occur at the site of the primary tumor location. Currently, this approach is being tested in several randomized phase III trials, including the FLAME trial in which our institute is participating. Importantly, dose escalation, being conventional, biological or focal, requires accurate and precise delivery of the radiation dose. Hence, the performance of the imaging technique used for this purpose will be of crucial importance. In this project we will investigate focal boosting strategies for the treatment of PCa making use of the latest technology in the field of radiation oncology, i.e. hypofractionated SBRT or proton therapy, thereby combining the potential advantages of the different dose escalation strategies to make a leap forward in the improvement of treatment outcome, both in terms of local tumor control and toxicity. To this end, a multicenter phase II study will be initiated to investigate the feasibility and safety of a simultaneous integrated focal SBRT boost to the macroscopic tumor in addition to whole gland prostate SBRT, called the hypo-FLAME study. In a translational side study, also the metabolic effect of this treatment regimen will be investigated, since there is emerging evidence that the metabolism plays a role in the response to radiation. As for proton therapy, an in-silico planning study on the potential benefit of focal boosting with this technique will be performed, striving at equal or better coverage of the focal boost regions and further reducing normal tissue toxicity. These results could serve as a sound base to decide on clinical trials in PCa patients in the future proton therapy center to be installed at UZ Leuven. In order to safely implement and maximally benefit from these innovative treatment strategies the performance of multiparametric MRI for tumor volume delineation will be studied since - although an invaluable tool for the diagnosis and staging of PCa - its value in defining the exact location and boundaries of the intraprostatic tumor is still less obvious. More specific, we will develop an image registration pipeline based on 3D-printed patient-specific moulds and whole organ ex vivo MRI that will allow precise spatial, anatomical, functional and molecular correlation of in vivo MR images with histology from patients undergoing surgery.status: publishe

Radiotherapie bij primaire prostaatkanker: als minder meer wordt

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Variation in adjuvant and early salvage radiotherapy after robot-assisted radical prostatectomy for prostate cancer: a populationbased cohort study

Purpose: The primary aim of the study was to assess the association between having a radiotherapy (RT) department on-site at the surgical centre and the performed postoperative treatment strategy for prostate cancer (PCa) patients. According to the current international guidelines, adjuvant radiotherapy (ART) or a regular prostate-specific antigen (PSA)-based follow-up with (early) salvage radiotherapy ((e)SRT) if needed is recommended in case of adverse pathological characteristics. Material and methods: Prospective data on consecutive robot-assisted radical prostatectomy (RARP) patients in Belgium from 2009 to 2016 were identified in the Belgian Robotic-Assisted-Laparoscopic-Prostatectomy (Be-RALP) database. Multivariable regression was used to evaluate patient- and facilityrelated factors associated with postoperative radiation treatment. Results: 2072 patients undergoing a RARP, suffering at least one of the following adverse pathological features, i.e., extracapsular extension (ECE), seminal vesicle invasion (SVI) or positive section margins (PSM), and with registered follow-up until 24months were enrolled. After RARP, ART was applied to 9.1% and (e)SRT to 12.6% of the patients. Multivariable analysis demonstrated that patients were more likely to receive ART or (e)SRT if they were operated in a hospital with a RT department on-site (odds ratio, ART: 1.49 [1.07-2.07]; (e)SRT: 1.55 [1.16-2.06]). Furthermore, the presence of higher tumour category (T-category) and/or PSM on final pathology was associated with a higher chance of getting ART and (e)SRT (p<.01). Conclusion: Variations in ART and (e)SRT are not only driven by patient-related characteristics. In our nationwide cohort, the availability of a RT department on-site at the surgical centre was found to be an independent predictor for ART and (e)SRT, with a 1.5 times higher odds of receiving postoperative RT during the first 24months after surgery.status: Published onlin

Stereotactic body radiation therapy with optional focal lesion ablative microboost in prostate cancer : Topical review and multicenter consensus

Stereotactic body radiotherapy (SBRT) for prostate cancer (PCa) is gaining interest by the recent publication of the first phase III trials on prostate SBRT and the promising results of many other phase II trials. Before long term results became available, the major concern for implementing SBRT in PCa in daily clinical practice was the potential risk of late genitourinary (GU) and gastrointestinal (GI) toxicity. A number of recently published trials, including late outcome and toxicity data, contributed to the growing evidence for implementation of SBRT for PCa in daily clinical practice. However, there exists substantial variability in delivering SBRT for PCa. The aim of this topical review is to present a number of prospective trials and retrospective analyses of SBRT in the treatment of PCa. We focus on the treatment strategies and techniques used in these trials. In addition, recent literature on a simultaneous integrated boost to the tumor lesion, which could create an additional value in the SBRT treatment of PCa, was described. Furthermore, we discuss the multicenter consensus of the FLAME consortium on SBRT for PCa with a focal boost to the macroscopic intraprostatic tumor nodule(s)

Primary endpoint analysis of the multicentre phase II hypo-FLAME trial for intermediate and high risk prostate cancer.

BACKGROUND AND PURPOSE: Local recurrences after radiotherapy for prostate cancer (PCa) often originate at the location of the macroscopic tumour(s). Since PCa cells are known to be sensitive to high fraction doses, hypofractionated whole gland stereotactic body radiotherapy (SBRT) in conjunction with a simultaneous ablative microboost to the macroscopic tumour(s) within the prostate could be a way to reduce the risk of local failure. We investigated the safety of this treatment strategy. MATERIALS AND METHODS: Patients with intermediate or high risk PCa were enrolled in a prospective phase II trial, called hypo-FLAME. All patients were treated with extreme hypofractionated doses of 35 Gy in 5 weekly fractions to the whole prostate gland with an integrated boost up to 50 Gy to the multiparametric (mp) MRI-defined tumour(s). Treatment-related toxicity was measured using the CTCAE v4.0. The primary endpoint of the trial was treatment-related acute toxicity. RESULTS: Between April 2016 and December 2018, 100 men were treated in 4 academic centres. All patients were followed up for a minimum of 6 months. The median mean dose delivered to the visible tumour nodule(s) on mpMRI was 44.7 Gy in this trial. No grade ≥3 acute genitourinary (GU) or gastrointestinal (GI) toxicity was observed. Furthermore, 90 days after start of treatment, the cumulative acute grade 2 GU and GI toxicity rates were 34.0% and 5.0%, respectively. CONCLUSION: Simultaneous focal boosting to the macroscopic tumour(s) in addition to whole gland prostate SBRT is associated with acceptable acute GU and GI toxicity.status: publishe

Genomic Classifiers in Personalized Prostate Cancer Radiation Therapy Approaches: A Systematic Review and Future Perspectives Based on International Consensus

Current risk-stratification systems for prostate cancer (PCa) do not sufficiently reflect the disease heterogeneity. Genomic classifiers (GC) enable improved risk stratification after surgery, but less data exist for patients treated with definitive radiation therapy (RT) or RT in oligo-/metastatic disease stages. To guide future perspectives of GCs for RT, we conducted (1) a systematic review on the evidence of GCs for patients treated with RT and (2) a survey of experts using the Delphi method, addressing the role of GCs in personalized treatments to identify relevant fields of future clinical and translational research. We performed a systematic review and screened ongoing clinical trials on ClinicalTrials.gov. Based on these results, a multidisciplinary international team of experts received an adapted Delphi method survey. Thirty-one and 30 experts answered round 1 and round 2, respectively. Questions with ≥75% agreement were considered relevant and included in the qualitative synthesis. Evidence for GCs as predictive biomarkers is mainly available to the postoperative RT setting. Validation of GCs as prognostic markers in the definitive RT setting is emerging. Experts used GCs in patients with PCa with extensive metastases (30%), in postoperative settings (27%), and in newly diagnosed PCa (23%). Forty-seven percent of experts do not currently use GCs in clinical practice. Expert consensus demonstrates that GCs are promising tools to improve risk-stratification in primary and oligo-/metastatic patients in addition to existing classifications. Experts were convinced that GCs might guide treatment decisions in terms of RT-field definition and intensification/deintensification in various disease stages. This work confirms the value of GCs and the promising evidence of GC utility in the setting of RT. Additional studies of GCs as prognostic biomarkers are anticipated and form the basis for future studies addressing predictive capabilities of GCs to optimize RT and systemic therapy. The expert consensus points out future directions for GC research in the management of PCa