Wednesday, March 15, 2017

Brachy Boost: The gold standard for progression-free survival of high risk prostate cancer

Several randomized clinical trials have established the superior oncological outcomes of the combination of external beam radiotherapy with a high dose rate brachytherapy boost (see this link). Last year, the results of the first randomized clinical trial of the combination of external beam radiotherapy with low dose rate brachytherapy, the ASCENDE-RT trial, was presented at the 2015 Genitourinary Conference (reported here). We now have the full details of the oncological outcomes (toxicity outcomes will be reported separately).

Morris et al. reported on 398 intermediate (31%) and high risk (69%) patients treated at 6 facilities in British Columbia and Toronto. All patients received 12 months of androgen deprivation beginning 8 months before radiation therapy. and continuing 4 months after the start. Androgen deprivation consisted of a GnRH agonist (Eligard or Suprefact) with an antiandrogen (bicalutamide or flutamide) given for the first 4 weeks. The radiation treatment was either of:
  • EBRT-only: 78 Gy in 39 fractions using 3D-CRT
  • Brachy boost: 46 Gy in 23 fractions of EBRT (3D-CRT) + 115 Gy of I125 seeds
It is worth noting that the brachy boost dose used in this trial is compared to an EBRT dose that is considered to be high enough to be curative by today's standards.

With 6.5 years of median follow-up, the 9-year biochemical progression-free survival (bPFS) was:
  • 85% for the brachy boost cohort vs. 65% for EBRT only
  • The hazard ratio was 2.3 (i.e., those getting EBRT only were 2.3 times as likely to relapse compared to those getting the brachytherapy boost)
  • Among those with high-risk prostate cancer, 9-year bPFS was 83% for the brachy boost cohort vs. 62% for EBRT-only.
  • Among those with intermediate-risk prostate cancer, 9-year bPFS was 94% for the brachy boost cohort vs. 70% for EBRT-only.
  • Among those who did not relapse, the median nadir PSA was 0.01 ng/ml (54% undetectable) for the brachy boost cohort vs. 0.25 for EBRT-only (8% undetectable).
  • In this length of follow-up, metastases, prostate cancer-specific mortality, and overall mortality were rare events, and were not statistically significantly different. Median age was 68.
This analysis did not address toxicity outcomes, but, as previously reported, the improved oncological outcomes came at the expense of toxicity:
  • Late term Grade 2 or higher genitourinary (GU) toxicity was higher for the brachy-boost group. 
  • Late term Grade 3 GU toxicity reached 19% for the brachy-boost group vs. 5% for the EBRT-only group. 
  • Late term gastrointestinal (GI) toxicity was similarly mild for both groups.
The use of 3D-CRT rather than IMRT (which is now the more prevalent form of EBRT) probably affected toxicity, especially with the wider field of the brachy-boost therapy.

This should establish brachy boost therapy (using either a high dose rate or low dose rate brachy boost) as the gold standard for oncological control for high risk prostate cancer. Perhaps equivalent outcomes with less toxicity may be achievable for both high risk and intermediate risk patients using high dose rate brachy monotherapy, SBRT monotherapy, or SBRT boost therapy. But for now, those are experimental approaches in high risk patients. The optimal duration of ADT use has yet to be defined. Patients with pre-existing urinary conditions should approach boost therapy with caution.

Sadly, a recent analysis of the National Cancer Database showed that utilization of brachy boost therapy for high risk patients has declined precipitously from 28% in 2004 to 11% in 2013. If a patient sees anyone other than the first urologist, he often only sees a single radiation oncologist who only informs him about IMRT. In most parts of the US, there is a dearth of experienced brachytherapists.

note: Thanks to Dr. James Morris for allowing me to review the full text.

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