Dose matters and extreme dose escalation with the combination of external beam radiation therapy (EBRT) and brachytherapy (BT) boost for subsets of high risk prostate cancer patients may improve clinically meaningful endpoints including distant metastasis free survival (DMFS), and potentially prostate cancer specific mortality (PSCM).
Kishan et al. recently published in
on outcomes of over 1800 patients with Gleason 9 and 10 disease treated at 12 different institutions. In a propensity score adjusted analysis, EBRT + BT was associated with a significant improvement in DMFS and PSCM as compared to EBRT or radical prostatectomy. Interestingly, an additional subset analysis comparing patients receiving EBRT + BT to those receiving “optimal” EBRT management, comprised of at least 78 Gy and 24 months of androgen deprivation therapy, revealed EBRT + BT was still associated with improved DMFS . The authors, and a recent commentary by Ong et al., note the limitations of this analysis. Limitations include biases inherent to a retrospective design such as; non-standardized treatment selection, the fact not all centers contributed patients in each category of treatment, and the potential for differential time to imaging amongst the cohorts [2, 3]. However, these data remain congruent with population based studies and prior retrospective studies investigating high risk patients.
Stone et al. previously analyzed the association of BED and outcomes for over a thousand patients treated across six institutions, focusing on Gleason 7 – 10 patients and including a substantial number of patients with Gleason 8 – 10 (n=233). For Gleason 8 – 10 patients, receipt of a BED >220 was associated with better biochemical failure free survival, DMFS, and overall survival (OS) . Johnson et al. found a similar result when analyzing the NCDB for patients treated between 2004 to 2012 with EBRT versus EBRT + BT in the setting of unfavorable risk prostate cancer. Brachytherapy boost was independently associated with improved OS on multivariate analysis. This advantage for EBRT+BT persisted even when the analysis was restricted to patients less than 60 years old without recorded comorbidities.
Are the existing data enough to accept brachytherapy boost as the treatment of choice for Gleason 9 and 10 disease? If not, we are left to await longer term results of ASCENDE-RT for level I evidence. One limitation of this study, like all previously published studies assessing the role of BT boost, is that it is underpowered in regards to PCSM or DMFS due to a somewhat heterogeneous patient cohort and relatively small sample size. PIVOTALBoost, a recently initiated trial sponsored by the Institute of Cancer Research in the United Kingdom, is investigating the role of both HDR and IMRT boost and plans to enroll over 1900 patients . This study promises to add important data to this discussion, but results are not expected for approximately 10 years. In the interim, we are also left to determine what we consider a meaningful endpoint, if not biochemical failure free survival, as Dr. Petereit previously discussed in a Brachyblast .
Emerging technologies, such as advanced imaging techniques and genomic classifiers (GC), may improve patient selection and outcomes in future studies of men with Gleason 9 and 10 (ISUP Grade Group 5) prostate cancer. In the initial report of ASCENDE-RT trial, 86% of the metastatic events were noted to occur within 2 years of biochemical failure, with a median interval of time to metastasis after biochemical failure of only 4 months, representing a cohort of patients who likely had occult metastatic disease at initial presentation . Using prostate cancer-specific PET radiotracers  may help identify a portion of patients with occult metastases prior to treatment. For example, an analysis of PSMA based imaging in the primary setting showed a detection rate of nodal or distant metastases in 48% of patients with Grade Group 5 . Novel biomarkers such as GC may identify patients with a significantly higher risk for early metastatic progression. These patients may derive less benefit from intensification of local therapy and instead have their outcomes improve by augmented systemic therapies such as novel androgen axis drugs or cytotoxic chemotherapy.
If we accept EBRT with BT boost as the treatment of choice for appropriately selected high risk prostate cancer patients based on the available data, important questions remain to be answered. Additional studies are needed to minimize the modest increase in toxicity that has been associated with BT boost. Determining the optimal boost technique (LDR versus HDR)  and ideal organ at risk dosimetric constraints will help optimize the therapeutic window. Additionally, the appropriate duration of ADT in the setting of extreme dose escalation remains uncertain, and warrants further investigation. However, designing and conducting research in order to optimize the efficacy of BT boost may be hindered by the concerning trends being reported of declining BT utilization and trainee exposure to these techniques. In the words of Dr. Crook,
“If the addition of a brachytherapy boost is indeed indispensable in the optimal management of unfavorable prostate cancer, meeting the training demands of a nation so that optimal treatment can be offered to all who require it will be a major challenge.” 
In our opinion, there is a group of patients where the superior biochemical and local control offered by EBRT + BT outweighs the small risk for intermediate grade toxicity and the advantages may translate into meaningful improvements in quality, and potentially, quantity of life. Uncertainty remains in precisely defining these patients, and further prospective trials are warranted.
1. Kishan, A.U., et al.,
Radical Prostatectomy, External Beam Radiotherapy, or External Beam Radiotherapy With Brachytherapy Boost and Disease Progression and Mortality in Patients With Gleason Score 9-10 Prostate Cancer.
Jama, 2018. 319(9): p. 896-905.
2. Kishan, A.U., R.R. Cook, and C.R. King,
Optimal Treatment for High-Risk Prostate Cancer-Reply.
Jama, 2018. 320(4): p. 405.
3. Ong, W.L., T.L. Koh, and J. Millar,
Optimal Treatment for High-Risk Prostate Cancer.
Jama, 2018. 320(4): p. 404-405.
4. Stone, N.N., et al.,
Multicenter analysis of effect of high biologic effective dose on biochemical failure and survival outcomes in patients with Gleason score 7-10 prostate cancer treated with permanent prostate brachytherapy.
Int J Radiat Oncol Biol Phys, 2009. 73(2): p. 341-6.
5. Johnson, S.B., et al.,
Brachytherapy Boost Utilization and Survival in Unfavorable-risk Prostate Cancer.
European Urology, 2017. 72(5): p. 738-744.
Institute of Cancer Research in the United Kingdom [Internet]. PIVOTALBoost: A phase III randomised controlled trial of prostate and pelvis versus prostate alone radiotherapy with or without prostate boost
. Available from:
7. D’Amico, A.V.,
Active Surveillance Versus Treatment of Prostate Cancer: Should Metastasis Be the Primary End Point?
Journal of Clinical Oncology, 2017. 35(15): p. 1638-1640.
8. Morris, W.J., et al.,
Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (the ASCENDE-RT Trial): An Analysis of Survival Endpoints for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy Boost to a Dose-Escalated External Beam Boost for High- and Intermediate-risk Prostate Cancer.
Int J Radiat Oncol Biol Phys, 2017. 98(2): p. 275-285.
9. Evans, J.D., et al.,
Prostate cancer-specific PET radiotracers: A review on the clinical utility in recurrent disease.
Pract Radiat Oncol, 2018. 8(1): p. 28-39.
10. Meyrick, D.P., et al.,
The role of 68Ga-PSMA-I&T PET/CT in the pretreatment staging of primary prostate cancer.
Nuclear Medicine Communications, 2017. 38(11): p. 956-963.
British Columbia Cancer Agency [Internet]. H13-02139 (NCT01936883): Improving Quality of Life After Prostate Brachytherapy: a Comparison of HDR and LDR Brachytherapy (BrachyQOL)
. Available from:
12. Crook, J.,
Optimal Radiotherapy for Unfavorable-risk Prostate Cancer.
Eur Urol, 2017. 72(5): p. 745-746.