Monday, August 29, 2016

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 high dose rate brachytherapy (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 rewrite 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, at the Seattle Prostate Institute in 1989, at William Beaumont Hospital near Detroit in 1991, and at the California Endocurietherapy Center in Oakland in 1991. 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 the 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% 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% higher than the prevalent external beam doses of the time (and is still about 37% higher than the current dose-escalated IMRT BED). 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% lower in its biological impact. This was the best of all possible situation: 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 my 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% Gleason score ≤6, 20% Gleason 3+4
  • ·      Median age: 64
  • ·      Only 9% received neoadjuvant ADT
  • ·      Median prostate volume: 33 cc (range: 9-134 cc)
  • ·      Median follow up: 6.5 years

The ten-year results were as follows:
  • ·      Biochemical progression-free survival: 98%

o   Low risk: 99%
o   Intermediate risk: 95%
  • ·      Local control: 100%
  • ·      Distant metastasis-free survival: 99%
  • ·      Prostate cancer specific survival: 99%
  • ·      Overall survival: 77%
  • ·      None of the outcomes were statistically different for low risk or intermediate risk groups.
  • ·      Late grade 2 GU toxicity: 10%; grade 3: 5%; 1 patient had grade 4.
  • ·      Late grade 2 GI toxicity: 1%; no grade 3 or 4
  • ·      60% 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 69-89%, 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 nine months. Subsequent declines are mostly attributable to normal aging.

The ten-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 ten-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.

1 comment:

  1. Thank you for this review. As one who is about to experience it as a monotherapy it is most reassuring. 16/02/2021