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.

Brachy boost may lower mortality in high-risk patients

 The ASCENDE-RT randomized clinical trial demonstrated that the combination of external beam radiation with a brachytherapy boost (EBRT+BT) significantly reduced biochemical progression-free survival. A new data analysis suggests that the benefit may extend to prostate cancer survival as well.

Xiang and Nguyen searched the SEER database to identify 52,535 high- and intermediate-risk patients who were treated with EBRT+BT or EBRT alone in 2004-2011. Of that total, 20% received EBRT+BT, and one-third were high risk. They matched patients for risk factors, and adjusted for other variables that affect survival. By 8 years after treatment, the adjusted prostate cancer-specific mortality was:

• ·      1.8% for EBRT+BT
• ·      2.7% for EBRT
• ·      5.4% for EBRT+BT among high-risk patients
• ·      7.6% for EBRT among high-risk patients
• ·      Mortality was not significantly reduced among intermediate-risk patients

The authors conclude:

“BT boost was associated with a moderate reduction to PCSM in men with localized unfavorable-risk prostate cancer. Those most likely to benefit are younger patients with high-risk disease.”

Of course, this was a database analysis and not a randomized clinical trial, so the findings are provisional until better data are available. The mortality numbers are small, reflecting the long natural history of prostate cancer progression even among high risk patients, and the fact that at modern dose levels, both the monotherapy and the combined modality may cure or delay progression for a long time. As we’ve seen, the combined modality approach does increase the side effects of treatment. The fact that there is so far no discernable survival benefit for intermediate risk patients, should dissuade those with “favorable intermediate risk” prostate cancer from pursuing boost therapy. Each unfavorable risk patient will have to assess for himself whether the added toxicity is worthwhile.

External beam radiation therapy (EBRT) with a low dose rate brachytherapy (LDRBT) boost provides superior cancer control compared to EBRT alone.

Numerous retrospective analyses have suggested that the combination of external beam radiation therapy (EBRT) with a low dose rate brachytherapy (LDRBT) boost is highly effective in controlling prostate cancer in unfavorable risk patients. For the first time, to my knowledge, we have a randomized comparative trial confirming that. An abstract was presented at the GU Conference and there is a press release about it.

ASCENDE-RT was a randomized clinical trial among 122 intermediate and 276 high risk patients treated in 6 Canadian centers from 2002-2011. The treatment specifications were:

• All patients received:
• Whole pelvis EBRT of 46 GY
• 8 months of neoadjuvant ADT + 4 months of concurrent and adjuvant ADT
• The EBRT-only group of 200 patients received an additional 32 Gy to the prostate (total = 78 Gy)
• The LDRBT-boost group of 198 patients received an additional boost of 115 Gy I-125 seeds in the prostate.
• Median follow up was 6.5 years, and was as long as 9 years for 65 patients.

The researchers found:

• After 9 years, the biochemical progression-free survival  (bPFS) was 83% for the LDRBT-boost group compared to 62% for the EBRT-only group.
• bPFS deteriorated by about 6% per year for the EBRT-only group.
• bPFS was fairly stable for the LDRBT-boost group after reaching 89% at 5 years.
• After 7 years, LDRBT-boost had better bPFS than EBRT-only both among intermediate risk men (94% vs. 80%), and among high risk men (83% vs. 72%).
• Median PSA at latest follow up was 0.02 ng/ml for the LDRBT-boost group and 0.24 ng/ml for the EBRT-only group.
• Reflecting the long natural history of disease progression, there were no significant differences in metastasis-free survival, prostate cancer-specific survival, or overall survival. Differences may emerge with longer follow up.

The improved oncological control came at the expense of increased toxicity for the combination therapy.

• Late term Grade 2 or higher genitourinary (GU) toxicity was higher for the LDRBT-boost group. Late term Grade 3 GU toxicity reached 19% for the LDRBT-boost group vs. 5% for the EBRT-only group.
• Late term gastrointestinal (GI) toxicity was similarly mild for both groups
• This early report did not include an analysis of acute toxicity, or an analysis of erectile function.

I look forward to the full analysis of the data when published. I hope they will break out the results separately for favorable and unfavorable intermediate risk patients to the extent that sample size may allow. Perhaps the favorable intermediate risk patients can be spared the extra toxicity of the LDRBT-boost treatment while still enjoying oncological control.

For the high risk patients especially, this study establishes LDRBT-boost therapy as the preferred treatment compared to EBRT-only, unless pre-existing urinary issues rule it out. It is unclear whether the 12 months of ADT and the whole-pelvis radiation would be necessary for all patients.

In an earlier randomized clinical trial (Sathya et al.), high dose rate brachytherapy (HDRBT) boost was shown to reduce the biochemical and clinical failure rate by 50% compared to EBRT-only (66 Gy). Other randomized clinical trials of HDRBT-boost (Hoskin et al., Guix et al.) also found that the boost improved outcomes. It is unclear whether boost with HDRBT, LDRBT, or treatment with SBRT alone will eventually emerge as the preferred treatment for unfavorable risk patients, or whether it will make a difference.