Record 10-year SBRT study among low risk patients

Alan Katz has now published the study with the longest-running follow-up of any study of external beam radiation therapy for prostate cancer among low risk patients, in this case, using SBRT. 10-year follow-up among intermediate and high-risk patients will be presented at next year's ASTRO meeting. This study ties in longest length of follow-up with the Memorial Sloan Kettering (MSK) study of IMRT. IMRT involves 40-45 radiation treatments over the course of about 9 weeks; SBRT shortens the number of treatments to 4 or 5 over the course of about 11 days.

Focusing on their low risk cohort only, the Katz study has a distinct advantage over the MSK study in sample size:

• The Katz study started with 230 low risk patients and, because of later start dates and some loss to follow-up, had 57 evaluable low-risk patients who were tracked for 10 years.
• The MSK study started with 49 low risk patients and, because of later start dates and loss to follow-up, ended with only 2 patients tracked for 10 years.
• Median follow-up was 108 months for Katz and 99 months for MSK

The IMRT study used a prescribed dose of 81 Gy in 45 fractions. The Katz study used a dose of 35 Gy in 5 fractions on 42 patients and 36.25 Gy in 5 fractions on 188 patients (average = 36 Gy). The biologically effective dose for cancer control was 17% higher in the Katz study.

It is risky to compare SBRT and IMRT when patients are not randomized to treatment with one or the other. There has been such a randomized trial, and partial results have been reported (see this link). The median age was the same in both studies (69 years of age), and the same definitions for the low risk category, and for biochemical failure were used. To highlight some of the differences and similarities in outcome:

• 10-year biochemical disease-free survival was 94% for Katz vs. 81% for MSK
• 10-year distant metastasis free-survival was 98.4% for Katz and 100% for MSK
• No prostate cancer-related deaths at 10 years in either study

Late-term urinary and rectal side effects were infrequent and mild in both studies:

• Late-term urinary side effects:
• Grade 2: 9%, Grade 3: 3% in the Katz study
• Grade 2: 9%, Grade 3: 5% in the MSK study
• Late-term rectal side effects:
• Grade 2: 4%, Grade 3: 0% in the Katz study
• Grade 2: 2%, Grade 3: 1% in the MSK study

Of those who were previously potent before radiation, 56% were potent (sufficient for intercourse) 10 years later (median age 79) in both studies.

Other interesting outcomes of the Katz study included:

• Median PSA fell to 0.1 ng/ml after a median of 48 months
• 21% experienced a PSA bounce along the way.
• Cure rates were independent of whether patients received 35 Gy or 36.25 Gy
• Urinary toxicity was higher in the group that got the higher dose
• Rectal toxicity was no different in the two groups
• Patient-evaluated urinary and rectal function declined acutely but returned to baseline within a year
• Sexual function declined by 23% at 6-12 months, and continued to decline by 38% by 8 years. It is unknown what percent of that decline was age related (but see this link).

Looking at the higher local control rates of SBRT and HDR brachytherapy, Dr. Katz sees evidence that IMRT is sub-optimal in delivering biological effective dose. He also believes that no more than 35 Gy in 5 fractions is necessary to achieve that control, and that it would minimize side effects.

Of course, probably half of the low risk men in this study might have gone those ten years without needing any kind of treatment at all. But for those who may not want or may not be good candidates for active surveillance, SBRT is a low cost, low bother, low side-effect alternative that delivers high rates of long-term oncological control.

Amazingly, I still hear that there are insurance companies that will not cover SBRT because longer follow-up is needed. Dr. Katz had already reported the nine-year follow-up (see this link), and with this addition and the 10-year higher-risk update at ASTRO next year, it's hard to see what any objection might be.

Dr. Katz is to be congratulated for continuing to update his study for 10 years. It is a lot of work to follow up with so many patients, and collect and tabulate their reported outcomes. He is a radiation oncologist not associated with a large tertiary care facility that might have more resources at its disposal.

Hypofractionation is non-inferior to conventional fractionation (redux)

It seems that several major randomized clinical trials of hypofractionation – fewer EBRT treatments at higher dose rates each – have all matured at the same time. While the Fox Chase Trial focused on patients with intermediate and high risk, RTOG 0415 only included men with low-risk prostate cancer.

Between 2006 and 2009, 1,115 low risk patients at about 300 sites in the US and Canada were randomly assigned to either hypofractionation or conventional fractionation:

• Hypofractionation: 70 Gy in 28 fractions (2.5 Gy per fraction)
• Conventional fractionation: 73.8 Gy in 41 fractions (1.8 Gy per fraction)
• The hypofractionated biologically effective dose is 15% higher.

Lee at al. report after a median follow up of 5.9 years:

• ·      7-year disease-free survival (DFS) was 76% for conventional RT, and 82% for hypofractionated RT.
• ·      Late grade 3 urinary toxicity was 2.6% for conventional RT, 4.1% for hypofractionated RT, and were not significantly different.
• ·      Late grade 3 rectal toxicity was 2.3% for conventional RT, 3.5% for hypofractionated RT, and were not significantly different.

This gives us Level 1 evidence that hypofractionated radiation is not inferior to conventionally fractionated radiation in either oncological outcomes or toxicity in low risk patients. Taken together with the CHHiP Trial and the Fox Chase trial, it will be hard to justify the added expense of a longer course of primary radiation therapy in any patient. Of course, this does not at all speak to whether even hypofractionated radiation is superior to active surveillance or to SBRT in low risk patients. Only time will tell if it is practice changing. Radiation oncologists who bill per treatment will naturally be resistant, while insurance companies may encourage hypofractionation.

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.