High-dose-rate brachytherapy (HDRBT) monotherapy — 10 year results


Reporting ten-year results for any radiation therapy is a rare privilege. It’s especially exciting for HDRBT monotherapy because, based on what was known about prostate cancer radiobiology at the time it was first tried, it should not have worked. Well, it exceeded all expectations, forced radiation oncologists to re-write the textbooks, and paved the way for new radiation technologies.

HDRBT had been used as an adjunct to external beam radiation since 1986 at Kiel University in Germany, since 1989 at the Seattle Prostate Institute, and since 1991 at William Beaumont Hospital near Detroit and at the California Endocurietherapy Center in Oakland. The “boost” delivered to the prostate capsule yielded some of the best oncological results at the time. Galalae et al have recently reported the 15-year results from Kiel. It was tried in the era before dose escalation, when external beam alone could not reliably deliver curative doses, and raising the dose was highly toxic with the technology available at the time.

The first trial of HBRBT monotherapy began in Osaka, Japan in 1995. Jeff Demanes (then in Oakland) and Alvaro Martinez (at William Beaumont Hospital near Detroit) tried using it as a monotherapy in 1996 in some of their favorable risk cases. The technique involves inserting about a dozen or more narrow tubes called catheters up through the perineum. These serve as the guides for radioactive iridium-192 needles, and hold the prostate rigidly in place. The process is monitored by cone beam CT, and the dwell times of the radioactive needles are calculated by computer and controlled robotically. Unlike “seeds,” areas outside of the prostate capsule, like the seminal vesicles, may be treated, and nothing is left inside. Also, there is no limit on prostate volume as there is with seeds. Some readers may be interested in a comprehensive review of HDR brachytherapy monotherapy written by Demanes and Ghilezan last year.

There does not seem to be a single best schedule for fractionation and implantation. Demanes started in 1996 with two catheter implants a week apart with three fractions delivered during each implant. He now offers other dosing schedules. Martinez recently reported on a single implant with just two fractions, all in one day.

The skeptics did not believe it could work. Demanes was delivering only 42 Gy of radiation (7 Gy in each of 6 fractions), while the typical external beam dose was about 70 Gy (delivered in 1.8 Gy or 2.0 Gy doses) at the time. It was conventional wisdom that prostate cancer responded best to many small doses of radiation in exactly the same way that all other cancers do. Radiobiologists express this as a quantity called the alpha/beta ratio, which they believed would be about 10 for prostate cancer. This would result in a biologically effective dose (BED) 15 percent lower than the external beam dose that many believed was already too low.

It is now widely accepted that the alpha/beta ratio for prostate cancer is about 1.5. This means that Demanes was delivering a BED to the cancer that was actually almost 50 percent higher than the prevalent external beam doses of the time (and is still about 37 percent higher than the current BED for dose-escalated IMRT). It also means that those doses were very sparing of the early-responding healthy tissues of the bladder and rectum (which do, in fact, have an alpha/beta ratio of about 10). Those tissues were receiving from HDRBT a dose that was effectively 15 percent lower in its biological impact. This was the best of all possible situations: higher dose to cancer cells, lower dose to healthy tissue. As a result of Demanes’s work, Christopher King at Stanford in 2003 used Accuray’s new CyberKnife platform to mimic the prostate HDRBT treatment using external beam radiation. Others have experimented with less extreme forms of shorter, more intense dose schedules, called hypofractionation. IMRT hypofractionation has now proved its efficacy and safety in a large-scale randomized clinical trial (see our recent report).

Hauswald et al. reported the 10-year results on 448 favorable risk patients treated by the California Endocurietherapy Cancer Center (now at UCLA) from 1996 to 2009. The patient characteristics were as follows:

  • 288 low risk; 160 intermediate risk
  • 76 percent Gleason score ≤ 6; 20 percent Gleason 3 + 4 = 7
  • Median age: 64 years
  • Only 9 percent received neoadjuvant androgen deprivaton therapy (ADT)
  • Median prostate volume: 33 cm3 (range, 9 to 134 cm3)
  • Median follow up: 6.5 years

The ten-year results were as follows:

  • Biochemical progression-free survival: 98 percent
    • Low risk: 99 percent
    • Intermediate risk: 95 percent
  • Local control: 100 percent
  • Distant metastasis-free survival: 99 percent
  • Prostate cancer-specific survival: 99 percent
  • Overall survival: 77 percent
  • None of the outcomes were statistically different for low-risk or intermediate-risk groups.
  • Late grade 2 genitourinary (GU) toxicity: 10 percent; grade 3: 5 percent; 1 patient had grade 4.
  • Late grade 2 gastrointestinal (GI) toxicity: 1 percent; no grade 3 or 4
  • 60 percent of previously potent patients were able to have erections suitable for intercourse, with or without medication (at median age of 69)

The potency preservation rate reported for HDRBT, at 69 to 89 percent, is the highest reported for any radical therapy. As we’ve seen in other radiation studies, and contrary to popular wisdom, any decline in erectile function typically occurs within the first 9 months. Subsequent declines are mostly attributable to normal aging.

The 10-year cancer control rates on these favorable-risk patients was remarkably high, and late toxicity was low. Such patients are often good candidates for active surveillance, but for those who are not, HDRBT is certainly a good alternative. Perhaps the most interesting use is as a monotherapy even among men with unfavorable-risk prostate cancer. We recently saw that early investigations of this use are encouraging.

The impressive 10-year results reported here are a testimony to the pioneering achievements of Dr. Demanes, who is retiring soon from active practice. His California Endocurietherapy Center at UCLA, which will continue to operate, is one of only a small number of centers where patients can get HDRBT monotherapy. The economics are such that it is not especially attractive for radiation oncologists to enter this specialty, but we hope that it will remain a treatment option for prostate cancer patients for many years to come.

Editorial note: This commentary was written for The “New” Prostate Cancer InfoLink by Allen Edel.

 

7 Responses

  1. It would seem that these excellent 10-year results from Hauswald et al. would auger well for the long-term prospects of so-called virtual HDR SBRT which tries to mimic HDR (e.g., Fuller DB, et al. Front Oncol. 2014). The hypofractionated approach of virtual HDR SBRT does not have the 10-year track record that HDR brachytherapy has, but for now it seems to be in-line with the trajectory of success of HDR brachytherapy.

  2. Thanks for this review, Alan. It is pertinent to a couple of Inspire discussions, and I will post the link.

    One point — You say, ‘Unlike “seeds,” areas outside of the prostate capsule, like the seminal vesicles, may be treated … ‘. Seeds can be used in some instances outside the gland … in my own case, they placed seeds in the prostate bed, confirming Dr. Shinohara’s T3a diagnosis. Seeds are occasionally now used for post-RP recurrence too.

    UCSF now prefers mono HDR brachyherapy too.

  3. Rick D.:

    You are quite right that seeds can be placed in the pelvic bed which is mostly firm muscle tissue, although that is rarely done with primary therapy. I was referring to the seminal vesicles and the loose fossa that surround the prostate — seeds won’t hold there. Because the placement of HDR is temporary, there is no need that they hold in place. Both HDR and LDR have been used for focal salvage.

  4. I am wondering about the relevance of treatment of men with Gleason scores 6 or under. My understanding is Dr. Laurence Klotz has accumulated some pretty compelling data that true Gleason score 6 has no capacity to metastisize and thus does not warrant treatment, absent high volume of it that potentially is masking something higher grade.

  5. I would rejoice at these results, as I had the combination treatment of EBRT + HDRBT + ADT. However, I am high risk, and that category is not covered. Still, the post gives me an idea that I hope to write about later today.

  6. Dear Cliff:

    There is now extensive evidence that true Gleason 6 disease has no ability to metastasize — much of it originally from an scrupulous clinical and pathological review of data from some 18,000 cases at Johns Hopkins as well as data from other sources.

    In addition, there is also extensive data from several series in Canada, the USA, and Australia that relatively low-volume Gleason 6 disease (classified as low- or very low-risk according the the NCCN criteria) can be managed extremely successfully on simple forms of monitoring (active surveillance) as opposed to invasive treatment. Indeed, the NCCN has been recommending active surveillance as a standard form of first-line management for such low- and very low-risk patients for the past 2 years.

    However, there are three key issues that are problematic.

    In the first place, it is very important for the doctor and the patient to do whatever they reasonably can to assure that the patient really does have true Gleason 3 + 3 = 6 disease (or lower if the cancer was originally found as a consequence of a TURP) and that there is no Gleason pattern 4 or 5 disease that just wasn’t found in the initial biopsy. It is for this reason that there are increasingly strong recommendations that every patient who is planning to be managed on an active surveillance protocol should be rebiopsied (preferably under MRI/TRUS fusion guidance) within 12 months of the initial diagnosis, with an especial emphasis on biopsying of “hard to reach” areas of the prostate such as the prostate apex.

    Second, there is a subgroup of men who, for various reasons (anxiety, family history, etc.) may simply not feel able to “live with” the knowledge that they have an indolent or extremely slowly growing cancer in their prostates — even if they can understand the logic of not treating it. These men will probably still need treatment, and there are evolving forms of treatment (focal therapies) that may allow them to receive limited treatment to ablate the cancerous tissue with minimal risk for side effects.

    Third, there are data suggesting that men of historic or recent African ethnicity (e.g., African Americans) may have somewhat more aggressive forms of low-risk prostate cancer that are less amenable to management on active surveillance. Further research is still needed to see if such men can be appropriately identified so that those who need treatment immediately can get it and those that can simply be monitored are advised of this possibility.

    There is evolving research as to the volume of Gleason 6 disease that can be managed on active surveillance (which depends on a variety of other factors, such as the life expectancy of the patient and whether the patient has problematic symptoms associated with his cancer such as difficulties with urination). There is also some evidence suggesting that at least some patients with low volume Gleason 3 + 4 = 7 disease (so-called “favorable” intermediate-risk disease) may also be managed for long-periods of time on active surveillance, but this would probably not be appropriate for all such patients, so the decision to start such patients on active monitoring is likely to be a very individualized one.

    The one other issue to all of this that is crucial is that there is also extremely good evidence that men initially managed on active surveillance can be treated later with a very high degree of efficacy if they show clear signs of increasing risk of progression over time. On other words, the risk for progression can be individually managed, and the number of patients on well managed active surveillance protocols who have gone on to have either metastatic prostate cancer or to die of their prostate cancer is very, very, very small indeed.

    The details related to all these different issues have been extensively discussed on this site over the past 2 to 3 years.

  7. Just to add to Sitemaster’s comprehensive response, a smaller Mayo study of some 14,000 cases found an incidence of metastasis of 0.16% amongst men diagnosed with Gleason 3 + 3 or less at the time they elected surgery.

    There is a discussion of this subject to be found on the UsTOO Inspire forum.

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