Recent questioning - even dismissal - of the ground-breaking ASCENDE-RT (Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy) trial data highlight a blinkered view of prostate cancer treatment options. Yet both trial and on-the-ground evidence provide an opportunity to challenge clinical practice, expand treatment options and improve health outcomes for intermediate- and high-risk prostate cancer patients and cannot be ignored.
The first randomized, controlled trial to compare the use of a dose-escalated external beam radiation therapy (DE-EBRT) versus low-dose-rate prostate brachytherapy (LDR-PB) boost in combination with external beam radiotherapy in men with intermediate and high-risk prostate cancer, ASCENDE-RT provides level-one evidence that LDR-PB offers significantly improved biochemical progression free survival.
Despite this, sceptics are choosing to highlight the study’s toxicity level data. Specifically that “Cumulative 5-year grade 3 urologic toxicity was found to be significantly higher in the LDR-B group compared to the DE-EBRT group (19% vs 5%, p < 0.001). The prevalence of late grade 3 or higher toxicity was noted to be higher in the LDR-B group (8%) compared to the DE-EBRT group (~2%).” Yet <80% of patients in the LDR group reported no or minimal GU side effects.
Equally, others dismiss the data saying surgery gives an equivalent result, but with no evidence to support the claim!
However, according to brachytherapy specialist consultants, both assertions are fundamentally flawed. Dr. James Morris asserts that increased GU toxicity is likely related to irregular dose planning and obsolete imaging technology, which have changed substantially. Toxicity levels, if monitored using todays’ procedures, would be much lower. Moreover, morbidity levels today are being managed more effectively than they were at the start of the ASCENDE-RT study 10 years ago, through a new clinical protocol being used by treatment centres where the LDR-B boost has changed from 115Gy to 110Gy and the prostate and seminal vesicles are treated instead of the whole pelvis.
Likewise, he argues, comparative results for surgery simply don’t compare: After LDR-PB boost, the 10 year biochemical progress free survival is around 80% using the surgical threshold of >0.2 ng/mL. Yet the 5 year rate* after surgery for Gleason 4+3 =7 is 65.1%.
A recent multi-institutional comparative analysis**, as published in the European Urology Journal (May 2017), supports the ASCENDE-RT findings. This significant study sought to establish optimal treatment for patients and considered over 25,000 people globally. Within this, the outcomes of 487 patients with Gleason 9-10 treated between 2000 – 2013 with EBRT, EBRT & brachytherapy (BT), and Radical Prostatectomy (RP) were compared. As with ASCENDE-RT, this study found that five-year and 10-year distant metastasis-free survival rates were significantly higher with EBRT + BT (94.6% and 89.8%) than with EBRT (78.7% and 66.7%, p = 0.0005) or RP (79.1% and 61.5%, p < 0.0001). Indicating that even for the highest risk patients, brachytherapy boost is the most effective treatment option.
Dr. Morris says: “ASCENDE-RT provides irrefutable, level-one evidence that an LDR-PB boost in combination with external beam radiation therapy is superior to a DE-EBRT. Patients receiving a DE-EBRT boost are twice as likely to experience biochemical failure compared to LDR-PB boost. ASCENDE-RT shows that at 9 years biochemical progression free survival in the LDR-PB arm was 83% compared to 62% in DE-EBRT boost subjects.”
The study also highlights a significant difference in PSA values in subjects treated with an LDR-PB boost. Nadir PSA is an important post-treatment metric, with low PSA values considered the best indicator of long-term biochemical progression-free survival. In non-relapsed LDR-PB subjects with at least 4 years’ follow-up, 54% of patients had undetectable PSA levels, compared to just 8% in DE-EBRT subjects. Median PSA levels were 0.01 ng/mL and 0.25 ng/mL respectively.
The findings of the ASCENDE-RT trial are reinforced by those from brachytherapy treatment centres such as Belfast Hospital in Northern Ireland. Dr. Darren Mitchell, Consultant Clinical Oncologist at the Belfast Health and Social Care Trust first carried out the combination therapy in Northern Ireland in 2009.
He says: “Treatment options have significantly evolved in recent years, in particular brachytherapy treatment which allows us to accurately place radiation directly into the prostate gland. In 2009 we were made aware of ASCENDE-RT, which was showing very positive results by combining external beam radiotherapy with low dose rate brachytherapy. We had the expertise in Belfast to offer this locally and felt that it could have a very significant and positive impact on our patients.
“We carried out our first combination treatment in 2009. To date nearly 500 men have had prostate brachytherapy in Northern Ireland, with almost 60 men treated with the combined radiotherapy and brachytherapy treatment. ASCENDE–RT has shown that 89% of men have no sign of recurrent prostate cancer at 5 years after their combination therapy. In Northern Ireland, all of our patients treated with combination therapy are still alive today which is hugely encouraging. As a team we are proud to have brought this combination therapy to our patients. The recent UK and Ireland prostate brachytherapy meeting hosted in Belfast has focused on the very encouraging results from ASCENDE-RT and impact on survival rates.”
ASCENDE-RT is more than good news for both oncology services and prostate cancer patients. It not only underlines that seed brachytherapy is effective; it shows that LDR-PB is superior to DE-EBRT and works even for high-risk patients. Furthermore, with LDR-PB indicating significant improvements in progression-free survival, its use could save money in the long-term through a reduction in treatments associated with biochemical failure.
So, why are more people not being treated with LDR?
Currently, UK awareness of brachytherapy remains low, with investment in brachytherapy services, at best, patchy across the NHS. Indeed, a survey of clinical delegates at the recent UK and Ireland Prostate Brachytherapy Conference, found that 100% of attendees confirmed high or very high interest in the ASCENDE-RT LDR boost findings. In addition, 65% and 59% respectively felt that the conference changed their perspective on LDR brachytherapy either significantly or very significantly for intermediate and high risk patients.
ASCENDE-RT provides ground-breaking evidence that should enable clinical oncologists to extend treatment options for prostate cancer patients – and drive referrals to brachytherapy services where they exist. To ignore it is nothing less than restricting patients’ access to life-enhancing care.
* Pierorazio PM, Walsh PC, Partin AW, and Epstein JI. 2013 Prognostic Gleason grade grouping: data based on the modified Gleason scoring system. BJU International; 111(5):689–852