(UroToday.com) The 2024 American Society for Radiation Oncology (ASTRO) Annual Meeting held in Washington, DC, was host to a presidential symposium of innovations in genitourinary cancers, specifically addressing radiotherapy innovations for prostate cancer that can be implemented in contemporary practice. Dr. Brandon Mahal discussed optimizing prostate radiation dosage and precision using an MRI-defined microboost.
Dr. Mahal noted that there is strong evidence to support the use of whole gland dose escalation to improve biochemical disease-free survival for prostate cancer patients.1
However, there are some challenges with whole gland dose escalation. While several randomized trials have demonstrated improvements in biochemical survival, further dose escalation to the whole gland is limited by ‘organs at risk’ (OAR), including the rectum, bladder, and urethra, as well as high risks of acute and late radiation toxicities. Importantly, local recurrences often originate at the location of the macroscopic tumor. As such, can we enhance oncologic outcomes without increasing toxicity by using an MRI-defined Microboost technique?
To date, microboost trials have demonstrated the safety of this approach, as well as its potential oncologic benefits.2
FLAME (Focal Lesion Ablative Microboost in prostatE cancer) was a multicenter, randomized phase III trial of 571 patients with intermediate- and high-risk prostate cancer who were randomized to either:
- Standard treatment: 77 Gy (fractions of 2.2 Gy) to the entire prostate (n=287)
- Focal boost: Additional focal simultaneous integrated boost (SIB) up to 95 Gy (fractions up to 2.7 Gy) to the intraprostatic lesion visible on multiparametric MRI (n=284)
Dr. Mahal noted that FLAME was initiated prior to the adoption of the PI-RADS scoring system and target ID was not standardized (at physician's discretion).
The median follow-up was 72 months. Biochemical disease-free survival was significantly longer in the focal boost arm (HR: 0.45, 95% CI: 0.28–0.71, p<0.001). At 5-year follow-up, biochemical disease-free survival was 92% and 85%, respectively. The cumulative incidence of late grade ≥2 genitourinary and gastrointestinal toxicities were 23% and 12% in the standard arm versus 28% and 13% in the focal boost arm, respectively. Both for late toxicity and health-related quality of life, differences were small and not statistically significant.3
What are some limitations (i.e., barriers to implementation) to the FLAME approach?
- Biochemical progression-free survival is not a validated surrogate for overall survival, and there was neither evidence for an overall (p=0.50) nor a cancer-specific survival (p=0.49) benefit for focal boost therapy in FLAME.3
- There is an MRI inter-rater variability in target identification and lesion detection (even with PI-RADS)
- This may be secondary to motion artifacts and geometric distortions
- Concerns regarding MRI lesion false positivity: ~40% of PIRADS 4-5 lesions will be Grade Group ≤1
- Also, false negatives (more difficult to quantify)
- Concerns about CT-MR registration and planning
- Impacts of spacers, fiducials, ADT
- Omitting clinical target and prostate target volumes (CTV/PTV) may compromise disease control
- GTVMRI underestimates the GTVHisto in > 90% of case.
Ad hoc data from FLAME has demonstrated that there is a dose-response relationship between the focal boost dose and the rate of both local and distant metastatic failures. As demonstrated below, there was a progressive decrease in the rates of local and regional/distant metastatic failures with increasing gross tumor volume (GTV) dosage. For patients who received 95 Gy, the local failure rate was 2.7%, compared to 7.8% for 77 Gy (HR: 0.33, 95% CI: 0.14–0.78).3
Additionally, there appears to be a dose-effect relationship between urethral dose administered and frequency of late genitourinary toxicity.3
What are some suggestions to improve contouring accuracy and, thus, overcome barriers to focal boost therapy?
- Get a “planning” MR on the same day as the planning CT
- Contour GTVMRI using all pulse sequences (T2, DWI/ADC, DCE).
- To reduce the chance of false positives, incorporate:
- MRI-targeted biopsy for pathological confirmation
- PSMA-PET (especially for lesions with SUV>12)
- Additional tools to improve accuracy (RSIrs and HRS)
- Consider adding margin to GTV (while keeping plan isotoxic)
- 5 mm margin in focal brachy: >90% in field control
In 2023, Patel et al. demonstrated that incorporating PSMA-PET and adding a margin may improve target coverage/contouring accuracy.4
There is also evidence that Restriction Spectrum Imaging restriction score (RSIrs) maps may improve contouring (ReIGNITE). On conventional MRI alone, 134 of 762 contour attempts (18%) completely missed the target, compared with 18 of 842 (2%) with RSIrs maps. RSIrs maps improved contour accuracy metrics by approximately 50% and significantly improved the “contouring experience.”5
Habitat Risk Score (HRS) may improve microboost contouring. Habitat Risk Score (HRS) is an approach for scoring each pixel in the image with a score from 1 to 10 in increasing fashion of aggressiveness. It was developed in correlation with radical prostatectomy histopathology.
An example of HRS6 for microboost GTV contouring is illustrated below:
Future considerations to optimize the microboost paradigm include the following:
- Need to define optimal margin and boost dose.
- Need to clarify the risk of urethral toxicity.
- Hypofractionation, SABR, and pelvic nodal radiotherapy need to be evaluated in phase 3 randomized trials
- Impact of Spacer on SIB dose distribution and toxicity needs evaluation
- Motion management may improve accuracy
- Adaptive/MRI guided therapy, gating, bowel/bladder prep
- Image processing tools/AI may need to be studied as potential tools of improving contouring accuracy.
Dr. Mahal concluded his presentation as follows:
- MRI-defined microboost may optimize prostate radiation and improve biochemical and local recurrence outcomes.
- Patient selection: NCCN unfavorable intermediate (Gleason 4+3) or NCCN high risk prostate cancer (Gleason 8-10) with identifiable MRI lesion (especially those with MRI-guided biopsy and PSMA-PET correlates)
- Although MRI-microboost has not yet been shown to improve overall survival outcomes, SIB with isotoxic plans does not appear to be associated with excess toxicity and does reduce the risk of biochemical progression.
- “Golden Era”: Emerging technologies will improve prostate microboost accuracy and feasibility.
Presented by: Brandon Mahal, MD, Associate Professor, Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, Miami, Fl
Written by: Rashid Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter during the 2024 American Society for Radiation Oncology (ASTRO) annual meeting held in Washington D.C., between the 29th of September and the 2nd of October.
References:
- Kishan AU, Wang X, Sun Y, et al. High-dose Radiotherapy or Androgen Deprivation Therapy (HEAT) as Treatment Intensification for Localized Prostate Cancer: An Individual Patient–data Network Meta-analysis from the MARCAP Consortium. Eur Urol. 2022; 82(1):106-14.
- Poon D, Yuan J, Yang B, et al. Magnetic Resonance Imaging–guided Focal Boost to Intraprostatic Lesions Using External Beam Radiotherapy for Localized Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol Oncol. 2023; 6(2):116-27.
- Groen VH, Haustermans K, Pos FJ, et al. Patterns of Failure Following External Beam Radiotherapy With or Without an Additional Focal Boost in the Randomized Controlled FLAME Trial for Localized Prostate Cancer. Eur Urol. 2022; 82(3):252-7.
- Patel KR, Rydzewski NR, Schott E, et al. A Phase 1 Trial of Focal Salvage Stereotactic Body Radiation Therapy for Radiorecurrent Prostate Cancer. Pract Radiat Oncol. 2023; 13(6):540-50.
- Lui AJ, Kallis K, Zhong AY, et al. ReIGNITE Radiation Therapy Boost: A Prospective, International Study of Radiation Oncologists' Accuracy in Contouring Prostate Tumors for Focal Radiation Therapy Boost on Conventional Magnetic Resonance Imaging Alone or With Assistance of Restriction Spectrum Imaging. Int J Radiat Oncol Biol Phys. 2023; 117(5):1145-52.