Low dose rate brachytherapy 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 combination of external beam radiation therapy (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 androgen deprivation therapy (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 in Gleason 7 patients led to a 5-year “no biochemical evidence of disease” rate of 95 percent, 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. The RTOG 0232 trial 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 EBRT was not. From 1996 to 2009, 1,989 patients were treated with LDR iodine-125 brachytherapy monotherapy. Treatment guidelines were as follows:

  • Prescribed dose was 144 Gy
  • 18.2 percent of patients received ADT:
    • Among 10 percent of low-risk patients, 20 percent of low intermediate-risk patients, 64 percent of high intermediate- risk, and 81 percent of high-risk patients
    • ADT use decreased over time — 56 percent in 1997, 9 percent in 2004
  • Baseline urinary function and prostate volume were not used to exclude patients
  • Urethral dose < 150 percent.
  • Intra-operative planning
  • Cold spots allowed in the anterior/superior region
  • Margins were 3 to 5 mm
  • Wider margins increased to 5 to 10 mm for high-risk cases
  • Seeds avoided within 3 to 5mm of rectal wall
  • Stranded seeds used on the periphery
  • CT scan within 4 weeks to check dosimetry
  • Follow-up visits 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 present (PSA between 10 and 20 ng/ml or clinical stage T2b/c or Gleason score of 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) outcomes by risk group are summarized in the following table:

Picture1

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 percent, while gastrointestinal (GI) toxicity was Grade 3 or higher in 0.8 percent of patients. 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 a 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 percent 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 Patients

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 Patients

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

I think most men diagnosed with high-risk prostate cancer today 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 disease is similar to what we might expect from surgery; however, the toxicity is quite a bit lower with LDRBT.

Intermediate-Risk Patients

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, PBRT, (LDR or HDR) BT + IMRT, LDRBT + SBRT, or PBRT + 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 a high enough radiation dose is critical to success.

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

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 percent at 5 years), but were accomplished without the potential for extra toxicity from the added EBRT.

The Cleveland Clinic data demonstrate 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 each individual patient’s risk factors and that patient’s attitudes about potential side effects.

Editorial comment: This commentary was written by Allen Edel. We also thank Dr. Jay Ciezki for making the full text of the article by Kittel et al. available to us.

6 Responses

  1. Hmmm. I got high dose rate BT, EBRT, and 3 years ADT. It was claimed that the dose escalation was at least as high in my case as had ever been given anywhere. It is now almost 5.5 years since initial treatment, and I am still progression free. I was PSA 31, Gleason 4 + 4, T2cN0M0. Keeping fingers crossed (if only as no hospital in Sweden can offer high quality cancer care now).

  2. Thanks, Allen, for this great article!

    (I read the article as well as the Spratt, Zelefsky, and Stone debate pieces.)

    Here’s a question for you or other participants: How good is the availability of skilled brachytherapy doctors who could participate in the combo brachy/IMRT treatment? Well-known brachytherapy expert Dr. Blasko, now retired, spoke at the 2012 edition of the conference on prostate cancer (sponsored by PCRI and UsTOO) about the importance of having a talented brachytherapist do implants (as have other experts in the past). However, beyond a few well-known experts with excellent results documented in published papers, there seems to be no reliable way for a patient to ensure his doctor can delivery the quality of care desired. Dr. Blasko was asked about that, but he did not provide a list either during or after the conference, based on my own search of the usual suspects.

    For my own challenging case, I seriously considered a brachy/IMRT/IGRT/ADT combo before selecting IMRT (TomoTherapy) with ADT (actually ADT3). One of the factors influencing my decision was the absence of a standout local brachytherapy doctor, though I thought I might have found one with further effort, and I had not ruled out traveling to see an expert. In fact, I had planned on being treated by Dr. Dattoli and his colleague in Florida until advanced scans found no signs of metastasis, which was a surprise; spending extended time in Florida would have been difficult in my circumstances. Another factor was my confidence in the approach I selected and our local IMRT doctors and facilities. (By the way, I continue to do very well based on post-RT/ADT PSAs, suggesting a cure with quite acceptable side effects.)

    While brachytherapy in expert hands appears to be an outstanding approach, it seems to me there is a shortage of brachytherapists with reliable expertise that can be assessed by patients.

  3. Jim:

    I am heartened to hear about your cure.

    The dearth of good brachytherapists is sad. The problem is that LDRBT is not a money-maker like robotic RP is. It’s time-consuming and there seems to be a very steep learning curve for it. Good seed placement is an art, and few are learning it. HDR brachytherapy, on the other hand, leaves a lot less judgment in the hands of the brachytherapist, IMHO. (I hope Drs. Demanes or Martinez don’t read this!) As with RP, a good argument can be made for not doing LDRBT outside of centers of excellence. And now, if SBRT for high-risk patients fulfills its promise, will that ring the death knell for BT/EBRT combo for high-risk disease?

  4. I do not know if this says a thing about skills. My two HDR sessions took 4.5 hours each. Two medical specialists were needed. One was an oncologist and the other either an oncologist or a urologist. It took them about 4 hours to study me and programme the insertions, but only 20 minutes for the afterloading and removal of the rods. I enjoyed it.

  5. For HDR brachy or external beam, the skill of the radiation oncologist (RO) is very much on the planning end. Once the plan is set in place, it is that plan software that runs the linac or catheter dwell times. Very little is left to human intervention at that point. Only technicians need to be on hand. I didn’t even see my RO throughout the actual treatment.

  6. @Allen:

    Thank you. I think the two doctors were planning then and there. After all, I was stuffed full of gadgets at times and one person did say that the planning took longer than the insertions and withdrawals. Maybe they wanted to be certain of the margins; they were wide.

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