LDR brachytherapy (LDRBT) monotherapy across risk groups

New registry data from the Cleveland Clinic shows good oncological control with low dose rate brachytherapy (LDRBT) monotherapy, at least for low risk and low-intermediate risk groups. This is the first time I’ve seen LDRBT monotherapy data for higher risk groups. We expect the lower dose/tighter margin monotherapy to reduce toxicity over combination treatment with external beam radiation and a brachy boost. The question is whether the trade-off with oncological control is worthwhile.

Recent clinical trials have focused on whether the addition of combination of EBRT with a brachy boost was better than EBRT alone. The ASCENDE-RT trial showed it did, at least for the higher risk groups. Other studies have looked at the benefit of adding ADT. They found that adding ADT conferred a bigger benefit than adding EBRT among “unfavorable intermediate risk” patients.  Herbert et al. found that 6 months of ADT with LDRBT on Gleason 7 patients led to 5-year “no biochemical evidence of disease” of 95% independent of the predominant Gleason pattern  (3 or 4) even without EBRT. But in the modern era of dose-escalated LDRBT, we do not yet have any randomized comparisons of combination therapy to monotherapy. RTOG 0232 will address this question, at least for intermediate risk patients, when we get its results in 2017. The Cleveland Clinic data do not directly answer that question, but by providing monotherapy data for high risk patients, they help us understand the trade-offs.

In the Cleveland Clinic series, analyzed by Kittel et al., ADT was included for many in the high risk group, but external beam was not. From 1996 to 2009, 1,989 patients were treated with LDR I-125 brachytherapy monotherapy. Treatment guidelines were as follows:

• ·      Prescribed dose was 144 Gy
• ·      18.2% received ADT:

o   10% among low risk, 20% among intermediate risk, 64% among high intermediate risk and 81% among high risk patients

o   ADT use decreased over time: 56% in 1997, 9% in 2004

• ·      Baseline urinary function and prostate volume were not used to exclude patients
• ·      Urethral dose <150%
• ·      Intra-operative planning
• ·      Cold spots allowed in the anterior/superior region
• ·      Margins were 3mm to 5mm
• ·      Wider margins increased to 5mm- 1 cm for high risk cases
• ·      Seeds avoided within 3-5mm of rectal wall
• ·      Stranded seeds used on the periphery
• ·      CT within 4 weeks to check dosimetry
• ·      F/U every 6 months for 3 years, then annually
• ·      Classified into NCCN risk groups
• ·      Intermediate risk sub-classified into “low intermediate” if only one intermediate risk factor (i.e., either PSA between 10 and 20 or Stage T2b/c or Gleason Score=7), otherwise “high intermediate.”
• ·      Median follow-up was 6.8 years

As an aside, it’s worth noting that the intermediate risk sub-stratification they used, sometimes known as the “Zelefsky stratification”, was developed in the 1990s when brachytherapy protocols and outcomes were considerably inferior to what they are today. Dr. Zelefsky now advocates the “Zumsteg stratification” of intermediate risk as we recently discussed here and here.

The 5- and 10-year biochemical relapse-free survival (bRFS) by risk group are summarized in the following table.

Risk Group	# of patients	5-yr bRFS (percent)	10-yr bRFS (percent)
Low Risk	1,219	95	87
Low Intermediate Risk	592	90	79
High Intermediate Risk	90	81	*
High Risk	88	68	*
TOTAL	1,989	92	82

* small sample

The authors reported acute toxicity in a previous report, which I do not have. They did not report late-term Grade 1 and Grade 2 toxicity. Genitourinary (GU) toxicity was Grade 3 or higher in 7.6%, while gastrointestinal (GI) toxicity was Grade 3 or higher in 0.8%. The part of the data I saw did not break out separately what the toxicity was for high risk patients, whose margins were wider. The authors note that the observed toxicity rates were lower than those reported for combination therapy in other series.

Men with prostate length of 5 cm or more were 2.4 times more likely to suffer serious GU complications, while the association with prostate volume was not clinically significant. Men aged 70 or over were 71% more likely to suffer from significant GU problems. These risk factors should be taken into account in counseling men considering LDRBT.

Unfortunately, the authors did not track patient-evaluated quality-of-life outcomes, and there is no data on potency preservation.

Low Risk

Because this was not a randomized comparative trial of monotherapy vs. combined therapy, it is impossible to draw conclusions as to its relative efficacy. The control among low risk patients is good, although based on recent findings about active surveillance, many might be better served by deferred treatment.

High Risk

The control among high risk patients seems to be somewhat less than in other recent trials where combination therapy with EBRT was used instead:

• ·      In the ASCENDE-RT trial, the 7-year biochemical control was 83%.
• ·      At Memorial Sloan Kettering, the 5-year biochemical control was 80%. At Schiffler Cancer Center and UMichigan, the 8-year biochemical control was 86%.
• ·      Liss et al. reported 5-year biochemical control was 85% among men with Gleason pattern 5.

I think most men diagnosed with high risk prostate cancer would be willing to pay the cost of increased toxicity to get the additional oncological control from added EBRT, but that is certainly a matter of personal preference. The brachy monotherapy biochemical control for high risk is similar to what we might expect from surgery; however, the toxicity is quite a bit lower with LDRBT.

Intermediate Risk

The real controversy is in the intermediate risk category. The patient diagnosed with “favorable intermediate risk” prostate cancer is faced with a bewildering array of alternatives, including active surveillance, any of several kinds of focal ablation, surgery, SBRT, IGRT/IMRT, LDRBT monotherapy, HDRBT monotherapy, PBT,  (LDR or HDR)BT+IMRT, LDRBT+SBRT,  or PBT+IMRT. Piling on the radiotherapies has the potential to pile on side effects as well. Intermediate risk readers interested in brachytherapy will be interested in reading Spratt and Zelefsky’s argument for combined therapy, Stone’s counterargument, and Spratt and Zelefsky’s rebuttal. There are points of agreement. They agree that “favorable intermediate risk” patients do not need combined therapy. They also agree that treatment with high enough radiation dose is critical to success.

Aside from the references they cited, here are a few more for intermediate risk patients treated with combination therapy (including ADT):

• ·      ASCENDE-RT 7-yr bRFS: 94%
• ·      CALGB 99809 6-yr bRFS: 85%
• ·      RTOG 00-19  8-yr bRFS: 82% 

While the control rates look excellent, none of those studies divide the intermediate risk group into separate sub-categories. The Cleveland Clinic outcomes for “low-intermediate risk” are certainly within this range (the weighted average bRFS for the entire intermediate risk group was 89% at 5 years), but were accomplished without the potential for extra toxicity from the added external beam radiation.

The Cleveland Clinic data demonstrates the very disparate outcomes within the intermediate risk sub-groups. It would be interesting to see their outcomes, as well as the outcomes of the other cited studies, stratified according to the Zumsteg criteria. Lacking that, and pending the definitive randomized clinical trial data from RTOG 0232 in 2017, the decision about whether to add EBRT or ADT to LDRBT for intermediate risk patients should involve a close analysis of his individual risk factors and his attitudes about potential side effects.

 note: thanks to Dr. Jay Ciezki  for making the full text of the article available to me.