Is once ever enough?

When Jeff Demanes at the California Endocurietherapy Center, then in Oakland, CA, started doing high dose rate brachytherapy (HDRBT) as a monotherapy (i.e., without any additional external beam therapy or hormone therapy), he arbitrarily chose a treatment schedule of 42 Gy delivered in 6 treatments or fractions. The first 3 fractions were given in one overnight hospital stay after a single insertion of the catheters, which stayed in place for all 3 fractions. Then the whole process was repeated a week later. At the same time, Alvaro Martinez, then at William Beaumont Hospital in Detroit, MI, arbitrarily chose 38 Gy in 4 fractions (twice a day for two days). Although the biologically effective dose (BED) is somewhat higher for the 4-fraction schedule, they had equally excellent oncological and quality-of-life outcomes. This established that prostate cancer responded to fewer larger doses (hypofractionation) -- an intrinsic quality of the cancer, called a low alpha/beta ratio.

Over the years, alternative treatment schedules that might be more convenient for patients were tried. Last year, we saw that 27 Gy delivered in 2 fractions afforded equivalent outcomes to a high fraction schedule (see this link). Several new studies show that HDRBT can be delivered in just a single fraction without causing any extra side effects for the patient. A single fraction translates to a much lower cost treatment, with the added convenience of no prolonged hospital stays, less time under anesthesia, and quicker recuperation. It also means that a patient can travel to a central location for a one-day treatment with no costs incurred for hotels, and without taking a week off from work.

Morton et al. at Sunnybrook Cancer Center in Toronto randomized 170 low- and intermediate-risk patients to either the one- or two-dose schedule. With median follow-up of 20 months, they reported:

• Acute grade 2 urinary toxicity: 51%; grade 3 in one patient
• No significant difference between the 1- and 2-dose schedule
• Acute grade 2 rectal toxicity: 1%
• Chronic grade 2 urinary toxicity: 31%; grade 3 in one patient 
• No significant difference between the 1- and 2-dose schedule
• Chronic grade 2 rectal toxicity: none
• There was no grade 3 rectal toxicity.
• Grade 2 ED rates were 29% for the 2-fraction arm, 11.5% for the single fraction arm.
• Sexual domain scores on the EPIC questionnaire declined by twice as much in the 2-fraction arm.

(note: physician-reported toxicities may be higher when patients are probed about specific issues using the EPIC questionnaire.)

(Update 11/16/2017) In an update, 8 of the 87 (9%) of the patients treated with a single fraction were found to have a local recurrence, and 7 of those 8 patients still had cancer in exactly the same place that was treated initially, and it was more aggressive than the initial Gleason score. Close inspection of the treatment plan showed that the dose received in that place was very high. While the authors conclude that the dose needed to be even higher, I believe it is more likely that the degree of fractionation was inadequate for the reasons explained below (cancer cells in the "S-phase" of mitosis and hypoxia).

(Update 9/15/2020) In a longer-term update of the same trial, a third suffered biochemical failure within 5 years, and 78% were biopsy-confirmed local failures. They also held a trial among 60 patients who received a single fraction of HDR brachytherapy but with a focal boost of at least 23 Gy to the largest prostate tumor. Those patients fared no better.

(Update 3/12/2021) Gomez-Itturiaga et al. reported the results of 44 low and intermediate-risk patients treated with a single 19 Gy fraction of HDR brachytherapy. After 4 years of median f/u, 14 patients (32%) experienced biochemical relapse, and 11 were confirmed to have relapsed in the dominant lesion. 

Hoskin et al. at Mt. Vernon Hospital, Middlesex, UK treated 165 patients: 115 with the 2-dose schedule, 24 with a single 19 Gy dose, and 26 with a single 20 Gy dose.

• At two weeks after treatment, severe prostate/urinary symptoms were higher among those who received the 20 Gy dose.
• Acute catheter use was higher among those getting a single dose (21% and 29% for 19 Gy and 20 Gy, respectively) compared to those receiving the split dose (3%)
• By 12 weeks after treatment, all scores were at baseline or better.
• Acute grade 3 urinary symptoms occurred in about 9% of patients.

Update: Hoskin et al. updated their study:

• 4-year biochemical recurrence-free survival was no different for the single fraction group (94%)
• Late term serious side effects were 2% urinary and none for rectal

Prada et al. reported on 40 low- and intermediate risk patients treated in Spain with a single 19 Gy fraction. They also all received a hyaluronic acid rectal spacer. With 19 months of median follow-up:

• There was no acute or chronic grade 2 or higher urinary or rectal toxicity
• Biochemical control at 32 months was 100% for low risk patients, and 88% for intermediate risk patients.

In an update on 60 patients, they reported that 6-year biochemical control was only 66%.

Siddiqui et al. treated 68 low and intermediate-risk patients at William Beaumont Hospital with a single dose of 19 Gy using HDRBT. With median follow-up of 3.9 years, the outcomes were as follows:

• Acute grade 2 urinary toxicity: 12.1%
• Acute grade 2 rectal toxicity: none
• Chronic grade 2 urinary toxicity: 14.7%
• Chronic grade 2 rectal toxicity: 3%
• There was no grade 3 toxicity.
• They did not report ED rates.
• 5-year disease-free survival: 77%
• 5-year biopsy-proven local failure:19%

The authors conclude:

Higher than expected rates of biochemical and local failure, however, raise concerns regarding the adequacy of this dose. Additional investigation to define the optimal single-fraction HDR brachytherapy dose is warranted, and single-fraction treatment should not currently be offered outside the context of a clinical trial.

(Update 11/23/2019) Barnes et al. reported the outcomes of a single 19 Gy fraction on 28 patients who were primary low-risk (14), and favorable intermediate-risk (10). After 2 years of median follow-up:

• 3-yr biochemical failure-free survival was 81%
• Acute grade 2 urinary toxicity=18%; grade 3 urinary=4% (1 case)
• Late-term grade 2 urinary toxicity= 18%; none grade 3
• No grade 2 or higher rectal toxicity, acute or late-tern

In addition to patient convenience, there is another reason that toxicity may be lower with a single dose: every time the patient moves between fractions, the catheters are dislocated into a slightly different position. Such movement puts radiation in areas that were not part of the pre-treatment simulation, so that organs at risk (e.g., bladder, rectum, and urethra) may receive a higher dose than planned. Use of fiducials and cone-beam CT between each fraction can mitigate this effect.

The sexual side effects deserve closer scrutiny; but otherwise, so far, so good. So why not just treat all patients with one dose of 19 Gy? For that matter, why not do that with SBRT? That would only entail a single painless, anesthesia-less short treatment - one and done, why not?

Radiobiological reasons for fractionation

The big outstanding question is whether cancer control will be as good with a single dose. At 10 years after treatment, Demanes reported biochemical control of 99% among low-risk patients, and 95% among intermediate-risk patients using his 6-fraction regimen. Most of the above studies of single-fraction HDRBT had only had very short follow-up. The longest follow-up was the Prada et al. update, which showed that after 6 years, biochemical control was only 66%.  However, the 4-year Hoskin et al. update showed biochemical control at 94%. It's unclear why those two studies would be so different. The William Beaumont Hospital trial of single dose HDRBT already had 7% biochemical failures at 3 years, and the Washington University study found a 19% failure rate at  3 years. Is this just patient selection, or does it reflect a failure of the treatment?

It's worth reviewing the reasons why fractionated radiation can fail; it's called the 5 R's of radiobiology: repopulation, repair, redistribution, re-oxygenation, and radioresistance.

Repopulation doesn't apply when cancer is slow-growing as prostate tumors are. It is a consideration for rapidly growing tumors, like head and neck cancers. In such cancers, ablation of some tumor tissue may actually speed up the growth of the rest. Very frequent treatments (hyperfractionation) is needed in such cases.

Repair refers to the fact that the cancer that was not lethally damaged can re-grow between treatments and even during treatments. This may be a problem for low dose rate brachytherapy because the prolonged damage may be sublethal. Some researchers in Sweden recently questioned whether the relatively long CyberKnife treatments (which may take an hour per fraction) may allow for some to occur during each treatment. (This concern would not apply to SBRT delivered on other platforms or to HDRBT.)

Redistribution refers to cell cycles that cancer cells go through as they duplicate their DNA and divide in a process called mitosis. One phase of the cell cycle, called the S-phase, is where DNA repair and replication occurs. Cells are less sensitive to the lethal effects of radiation during the S phase, and some portion of cancer cells are in the S-phase at any given moment. Fractionation increases the odds that cancer cells will not be in the S-phase across all the times radiation hits them. With a single dose, the odds of some cells being in a radioresistant phase are higher.

Re-oxygenation refers to the fact that oxygen is required for radiation to kill cancer cells. Tumors are relatively hypoxic (low oxygen environments) compared to healthy tissue, because their blood supply is often malformed and leaky. This means that cancer cells in the center of a large tumor may lack the oxygen needed for radiation to kill them. With each fraction, the radiation kills the cells at the surface of the tumor that may have a better blood supply. And with repeated fractions, layers of surface cells are stripped away until the tumor is gone. A single dose may not be optimal when the index tumor is large.

Radioresistance means that some kinds of cells, particularly those that don't replicate quickly, like nerves and muscle, are inherently less subject to lethal radiation damage. Like many slow-growing tissues, prostate cancer is known to be radioresistant. That's why dose escalation has been necessary to cure it. 19 Gy in a single dose actually exceeds the biologically effective dose of 42 Gy in 6 fractions, so it is probably more than enough to overcome any radioresistance.

It may not be feasible to deliver 19 Gy in one fraction to every patient. Because of variations in individual pelvic anatomy, visceral fat and prostate size, a large single dose may violate the dose constraints for organs at risk.

It will be a few more years before the above clinical trials have matured enough to tell us whether the single dose treatment is adequate for the job. Until then, it is prudent to use a fractionated treatment schedule.

Can brachytherapy spread prostate cancer?

In an earlier commentary (see this link), we looked at the available evidence that invasive procedures, including surgery, biopsy, and brachytherapy, could spread prostate cancer. There have been very few cases reported where it is likely that brachytherapy has spread prostate cancer: 5 cases from seeds migrating to the lungs (see this link), and one case where a catheter probably spread the cancer to the bladder wall during high dose rate brachytherapy (see this link).

Tsumura et al. report the results of their study to determine whether circulating tumor cells (CTCs) were dislodged from the prostate into systemic circulation by brachytherapy. They took blood samples from 59 patients before and immediately following brachytherapy.

• 30 patients were treated with a combination of hormone therapy, external beam radiation, and high dose rate brachytherapy (HDRBT) for high risk or locally advanced prostate cancer.
• 29 low- and intermediate-risk patients were treated with low dose rate brachytherapy (LDRBT) as a monotherapy.

The blood samples were analyzed using CellSearch technology. They found that:

• None of the samples taken before brachytherapy had any CTCs
• CTCs were detected immediately after brachytherapy in 7 patients (11.8%), 13.3% among LDRBT patients, 10.5% among HDRBT patients.
• There was no statistically significant association with risk category, clinical stage, tumor volume, Gleason score, PSA, prostate volume, needle concentration, age, hormone therapy or type of brachytherapy.

While it is too soon to know whether those CTCs will cause a recurrence in the 7 brachytherapy patients, a similar study done by Eshwege et al. before and after prostatectomy suggests that they will not. In that study, there was increased risk of recurrence only if CTCs were found before the prostatectomy. The additional shedding of tumor cells during the procedure did not correlate with recurrence within 5 years.

Even high risk/advanced prostate cancer cells are not capable of survival outside of the prostate environment. To metastasize, they must first undergo a series of genetic alterations called epithelial-to-mesenchymal transition (EMT). Some researchers believe that small numbers of such metastatic-capable cancer cells may exist in small numbers within the prostate. If so, it seems to be a rarity.

Is there an optimal treatment schedule for high dose rate brachytherapy?

Protocols for high dose rate brachytherapy (HDR-BT) monotherapy vary. In recent years, practitioners have adopted various schedules for patient and physician convenience. Jawad et al. reported on the HDR-BT experience at William Beaumont Hospital. They treated 494 favorable risk patients using three different treatment schedules. Their definition of “favorable risk” was a Gleason score ≤7 and stage≤T2b and PSA≤15 ng/ml. The 3 treatment schedules they utilized, the number of patients who received each, and the relative biologically effective dose  (BED) were as follows:

1. 38 Gy in 4 fractions (n=319) – 1.29 relative BED 
2. 24 Gy in 2 fractions (n=79) – 1.00 relative BED 
3. 27 Gy in 2 fractions (n=96) – 1.25 relative BED

Dose schedules #1 and #3 delivered much higher relative dose compared to dose schedule #2. The questions addressed by the study are whether the higher dose is justified by greater cancer control, and whether dose increased at the expense of increased side effects.

After 5.5 years median followup for schedule #1, 3.5 years for schedule #2, and 2.5 years for schedule #3, the toxicity outcomes were as follows:

• No difference in clinical outcomes (cancer control) among the 3 treatment schedules.
• Acute (appearing in less than 6 months) and chronic (appearing 6 months or more after treatment) grade ≥2 genitourinary (GU) and gastrointestinal (GI) side effects were similar for all treatment schedules.
• Grade 2 acute GU toxicities:

o   Frequency/urgency: 14%

o   Dysuria (painful urination): 6%

o   Retention: 7%

o   Incontinence: 1.5%

o   Hematuria (blood in urine): 1.5%

• ·      Grade 2 chronic GU toxicities:

o   Frequency/urgency: 20%

o   Dysuria (painful urination): 7%

o   Retention: 4% (Urethral stricture: 2%)

o   Incontinence: 2%

o   Hematuria (blood in urine): 7%

• ·      There was minimal grade 3 GU toxicity
• ·      Grade 2 acute GI toxicities:

o   Diarrhea: 1%

o   Rectal pain/tenesmus: <1%

o   Rectal bleeding: 0%

o   Proctitis: <1%

• ·      Grade 2 chronic GI toxicities:

o   Diarrhea: 1%

o   Rectal pain/tenesmus: 0.5%

o   Rectal bleeding: 2%

o   Proctitis: 1%

• ·      No Grade 3 or higher GI toxicity
• ·      Time to maximal appearance of symptoms was similar across treatment schedules
• ·      They did not report ED rates, which are typically low for HDR-BT.

Given the equivalence of cancer control and toxicity with treatment schedule, and the lack of any effect due to increasing the biologically equivalent dose, there seems to be little basis, other than cost and convenience, for choosing among these treatment schedules, at least with the available follow-up reported here.

Aspects of treatment scheduling that affect the convenience of HDR-BT are the number of implantations of the catheters, and the time frame in which the fractions are delivered.  William Beaumont Hospital uses a single implantation of catheters for all treatment schedules. Schedule #1 involves a longer (overnight) hospital stay because they wait for several hours between fractions for healthy tissue to recover. It also means that anesthesia must be administered over a longer period.

The California Endocurietherapy Center at UCLA has typically used a different protocol. They deliver 42 Gy in 6 fractions, with 3 fractions delivered one week and 3 fractions delivered a week later. This involves 2 overnight hospital stays, with anesthesia each time. Recently, they added a protocol where they deliver 27 Gy in 2 fractions (similar to schedule #3), but those fractions are still inserted a week apart. While this is certainly a cost reduction for the patient, who can now be treated as an outpatient, the patient is inconvenienced by having to go through the full procedure twice. It is a convenience for the treatment team that no longer has to attend the patient over an extended timeframe.

The William Beaumont Hospital experience demonstrates that HDR-BT treatment schedules can be constructed so as to lower costs and increase convenience for patients and doctors, without sacrificing cancer control or quality of life.

How long is long enough? Length of follow-up on clinical trials for primary treatments

Many of us are faced with the difficulty of choosing a primary therapy based on data from clinical trials with follow-up shorter than our life expectancy. How can we know what to expect in 20 or 30 years? This is quite apart from the fact that most published studies only tell us how the treatment worked for a chosen group of patients treated by some of the top doctors at some of the top institutions – they never predict for the individual case that we really want to know about; i.e., “me.” The issue of length of follow-up is particularly problematic for radiation therapies, although it may be too short for surgery and active surveillance studies as well. How can we make a reasonable decision given the uncertainty of future predictions?

I may have missed some studies, but the longest follow-up studies I have seen for each primary therapy treatment type are as follows:

• HDR brachy monotherapy - 10 years (CET/Demanes)
• HDR brachy+EBRT - 15 years (Kiel, Germany)
• IMRT - 10 years (MSKCC)
• LDR brachy monotherapy - 12 years (UWSeattle & Mt. Sinai)*
• LDR brachy+EBRT - 25 years (RCOG)
• Protons- 10 years (Loma Linda)
• SBRT - 9 years (Katz)
• Robotic RP - 10 years (Henry Ford Hospital, Detroit)
• Laparoscopic RP - 10 years (Heilbronn, Germany)
• Open RP - 25 years (Johns Hopkins)
• Active Surveillance - 20 years (Toronto)

*Mt. Sinai published a study with longer follow-up (15 years); however, all patients were treated from 1988 to 1992, before modern methods were used, and such results are irrelevant (see below) for decision-making today.

On a personal note, I was treated at the age of 57 and had an average life expectancy of 24 years, possibly more because I have a healthy lifestyle and no comorbidities. So there were no data that could help me predict my likelihood of cause-specific survival and quality of life out to the end of my reasonably expected days. What's more, the therapies with the longest follow-up (open RP, brachy boost) also have the highest rates of serious side effects. With my low-risk cancer, there seemed little need to take that risk with my quality of life.

While we may be tempted to wait for longer follow-up, (1) we don't always have that luxury, and (2) there very likely will not be any longer follow-up. Not only is follow-up expensive, there are also the problems of non-response, drop-outs, and death from other causes. The median age of patients in radiation trials is typically around 70, so many will leave the study. The 10-yr Demanes study, for example, started with 448 patients, but there were only 75 patients with 10 years of follow-up. The “10-year” study of IMRT at MSKCC started with 170 patients, but only 8 patients were included for the full ten years! After the sample size gets this small, we question the validity of the probability estimates, and there is no statistical validity in tracking further changes. (It is worth noting that IMRT became the standard of care without longer term or comparative evidence.)

An even bigger problem is what I call irrelevance. Technological and medical science advances continue at so brisk a pace that the treatment techniques ten years from now are not likely to resemble anything currently available (another argument for active surveillance, if that's an option). Dose escalation, hypofractionation, IGRT technology, intra-operative planning, VMAT, variable multi-leaf collimators, on-board cone-beam CT, and high precision linacs - all innovations that have mostly become available in the last 15 years - have dramatically changed the outcomes of every kind of radiation therapy, and made them totally incomparable to the earlier versions. Imagine shopping for a new MacBook based on the performance data of the 2000 clamshell iBook. By the time we get the long-term results, they are irrelevant to the decision now at hand.

What we want to learn from long-term clinical trials are the answer to two questions: (1) Will this treatment allow me to live out my full life? and (2) what are the side effects likely to be? To answer the first question, researchers look at prostate cancer-specific survival. It’s not an easy thing to measure accurately – cause of death may or may not be directly related to the prostate cancer. We usually look at overall survival as well. For a newly diagnosed intermediate risk man, prostate cancer survival is often more than 20 years, so we can’t wait until we have those results to make a decision. Taking one step back, we look at metastasis-free survival, but that is often over 15 years. Sometimes there is clinical evidence of a recurrence before a metastasis is detected (e.g., from a biopsy or imaging). More often, the only timely clue of recurrence is biochemical – a rise in PSA over some arbitrary point. That point is set by consensus. Researchers arrived at the consensus after weighing a number of factors, especially its correlation with clinically-detected progression. Biochemical recurrence-tree survival (bRFS), or its inverse, biochemical failure (BF), is the most commonly used surrogate endpoint.

We might be comfortable if outcomes seem to have reached a plateau. For some of the above studies, we are able to look at some of the earlier reported biochemical failure rates compared to those measures reported at the end of the study (ideally broken out by risk group).

• ·      In the Demanes Study, the 10-year results are virtually unchanged from the 8-year results.
• ·      In the Kiel study of HDR brachy boost, the 5-, 10- and 15-year BF was 22%, 31%, and 36%.
• ·      In the RCOG study of LDR brachy boost, the 10-, 15-, 20- and 25-year BF was 25%, 27%, 27%, and 27%
• ·      In the Mt. Sinai study of LDR brachy, the 8- and 12-yr BF was 12% and 10% for low risk; 19% and 16% for intermediate risk; 35% and 36% for high-risk patients.
• ·      In the MSKCC study of IMRT, the 3-, 8- and 10-yr BF was 8%, 11%, and 19% for low risk; 14%, 22% and 22% for intermediate risk; 19%, 33% and 38% for high risk patients.
• ·      In the Katz SBRT study, the 5- and 7-year BF was 2% and 4% for low-risk, 9% and 11% for intermediate-risk, and 26% and 32% for high-risk patients.
• ·      For comparison, the 5- 10- 15- and 25- year recurrence rates for prostatectomy at Johns Hopkins were 16%, 26%, 34% and 32%.

For most of the therapies, HDR & LDR brachy monotherapy, LDR brachy boost therapy, and SBRT, the failure rates remained remarkably consistent over the years. However, for surgery and IMRT, failure rates increased markedly in later years. Most of us can’t wait 25 or more years to see if a therapeutic option remains consistent or not, and for radiation, the results would almost assuredly be irrelevant anyway.

Ralph Waldo Emerson is misquoted as saying, “Build a better mousetrap, and the world will beat a path to your door.” An important criterion for decision-making when there is only limited data is our answer to the question: Is this a better mousetrap? Arguably, robotic surgery was only an improvement over open surgery, and not an entirely new therapy requiring separate evaluation. It has never been tested in a randomized comparison, and I doubt we will ever know for sure. Arguably, IMRT was simply a “better mousetrap” version of the 3DCRT technique it largely superseded and didn’t need a randomized comparison to prove its worth. Was HDRBT monotherapy just an improvement over HDRBT+EBRT? Was SBRT just an improvement over IMRT, or should we view it as a variation on HDRBT, which it radiologically resembles by design? There are no easy answers to any of these questions. However, as a cautionary note, I should mention that proton therapy was touted as more precise because of the “Bragg peak effect,” yet in practice seems to be no better in cancer control or toxicity than IMRT.

There is also the problem of separating the effect of the therapy from the effect of the learning curve of the treating physician. Outcomes are always better for patients with more practiced physicians. The learning curve has been documented for open and robotic surgery, but less well documented for radiation therapies. Patients treated early (and perhaps less skillfully) in a trial are over-represented in the latest follow-up, and there may be very little follow-up time on the most recently (and perhaps more skillfully) treated patients.

So when do we have enough data to make a decision? That comfort level will vary among individuals. I was comfortable with 3-year data based on choosing a theoretically “better mousetrap”, and many brave souls (thank God for them!) are comfortable with clinical trials of innovative therapies. In the end, everyone must assess for himself how long is long enough. For doctors offering competing therapies and for some insurance companies, there never seems to be long enough follow-up. I suggest that patients who are frustrated by those doctors and insurance companies challenge them to come up with concrete answers to the following questions:

• ·      What length of follow-up do you want to see, and why that length?
• ·      What length of follow-up was used to determine the standard of care?
• ·      Do you need to see prostate-cancer specific survival, or are you comfortable with an earlier surrogate endpoint?
• ·      What is the likelihood of seeing longer term results, and will there be any statistical validity to them if we get them?
• ·      Have outcomes reached a plateau already?
• ·      What evidence is there that toxicity outcomes change markedly after 2 years?
• ·      Will the results still be relevant if we wait for longer follow-up?
• ·      Is the therapy just a “better mousetrap” version of a standard of care?
• ·      Are my results likely to be better now that there are experienced practitioners?

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.

HDR Brachy Boost and Monotherapy for High-Risk Prostate Cancer

Three randomized clinical trials (Sathya et al. 2005, Hoskin et al.2012, and Guix et al.2013) established combination therapy of external beam radiation (EBRT) with a high dose rate brachytherapy (HDRBT) boost as a standard of care in the treatment of high-risk prostate cancer. In all three of those trials, the outcomes exceeded those from EBRT alone, but at a cost of higher toxicity.

In previous studies of this combination therapy for high-risk patients, freedom from biochemical relapse have ranged from 67-97% at 5 years, and from 62 -74% at 10 years. Late term genitourinary (GU) grade 3 toxicity ranged from 0-14.4% (median 4.5%); gastrointestinal (GI) grade 3 toxicity ranged from 0-4.1% (median .5%); chronic incontinence ranged from <1%-3.8%; urethral strictures ranged from .9-7.4% (median 4.5%); and erectile dysfunction ranged from 10-51% (median 31.5%).

It may be helpful to understand how large the effective doses of radiation were that were used in all of the aforementioned studies. The term “biologically effective dose” (BED) enables us to compare the cancer-killing power of the absorbed radiation across different radiation modalities. To provide a point of comparison, I show the BED as a % of the BED of a typical modern IMRT schedule, 80 Gy in 40 fractions (fx), which has a BED of 187 Gy.

Table 1 – Improved recurrence-free survival, but higher GU toxicity from boost therapy

Study	Modalities	Dose Schedule	BED Compared to 80 Gy IMRT	Freedom from recurrence among high risk	Follow up	Late grade 3 GU toxicity
Sathya et al. (2005)	HDRBT + EBRT	35 Gy over 48 hrs. +40 Gy/20 fx	-6%	71%	8.2 yrs median	14%
	EBRT only	66 Gy/33 fx	-17%	39%	8.2 yrs median	4%
Hoskin et al. (2012)	HDRBT + EBRT	17 Gy/2 fx + 35.75 Gy/13 fx	+15%	66%	7 yrs	11%
	EBRT only	55 Gy/20 fx	-17%	48%	7 yrs	4%
Guix et al. (2013)	HDRBT + EBRT	16 Gy/2 fx + 46 Gy/23 fx	+12%	98%	8 yrs	NA
	EBRT only	76 Gy/38 fx	-5%	91%	8 yrs	NA

Could equal oncological outcomes be accomplished but with less toxicity by using high dose rate brachytherapy as a monotherapy? The maturing of data from a clinical trial in Japan suggests it can be.

Yoshioka et al. (2015) have used HDRBT monotherapy on 111 high-risk patients treated from 1995 to 2012. Almost all of them (94%) received ADT as well. They evaluated 3 dosing schedules: 48 Gy/8 fractions, 54 Gy/9 fractions, or 45.5 Gy/7 fractions inserted over 4 to 5 days. 

With a median of 8 years of follow up, the authors report:

• ·      Biochemical no evidence of disease – 77%
• ·      Metastasis-free survival – 73%
• ·      Overall survival – 81%
• ·      Cause-specific survival – 93%
• ·      Late GU grade 3 toxicity – 1%
• ·      Late GI grade 3 toxicity – 2%

Unfortunately, they haven’t reported rates of erectile dysfunction. Other monotherapy series report ED rates of about 25%, and there’s no reason to suppose it would be particularly different for high-risk patients. They report no significant differences in oncological control or toxicity according to total dose or dose schedule used.

The biochemical control rates are well within the range seen for combination therapy at 5 to 10 years after treatment. At the same time, the rates of serious late term GU and GI side effects seem to be improved by the monotherapy.

Other recent studies have reported excellent results for HDRBT monotherapy for high-risk patients. Zamboglou et al. (2012) reported the monotherapy outcomes of 146 high-risk patients treated between 2002 and 2009. 60% received ADT as well. They evaluated 3 dosing schedules: 38 Gy in four fractions in one implant, 38 Gy in four fractions in two implants, and 34.5 Gy in three fractions in three implants. After 5 years, biochemical control was 93%, late grade 3 GU toxicity was 3.5%, and late grade 3 GI toxicity was 1.6%. The differences in toxicity among the dosing schedules were not statistically significant. Among previously potent men, only 11% lost potency sufficient for intercourse. The highest dose schedule did not have better oncological control or worse toxicity than the lower dose schedules.

Hoskin et al. (2012) reported the monotherapy outcomes of 86 high-risk patients treated between 2003 and 2009. Almost all of them (92%) received ADT as well. They evaluated 4 dosing schedules: 34 Gy in four fractions, 36 Gy in four fractions, 31.5 Gy in three fractions, and 26 Gy in two fractions. After 4 years, biochemical control was 87%, late grade 3 GU toxicity was 12%, and late grade 3 GI toxicity was 1%. It is not clear why GU toxicity was higher than in the other two studies. They did not report erectile dysfunction. Although higher rates of strictures, ranging from 3-7%, and urinary toxicity occurred on the most aggressive dosing schedules, the differences were not statistically significant on this sample size. Similarly, the difference in recurrence-free survival at the lowest dose was not statistically significant.

Table 2. Clinical trials of HDRBT monotherapy for high risk

Study	Dose Schedule	BED Compared to 80 Gy IMRT	Freedom from recurrence among high risk	Follow up	Late grade 2+ GU toxicity	Late grade 3+ GU toxicity
Yoshioka et al. (2015)	48 Gy/8 fx	+29%	77%	8 yrs	NA	1%
	54 Gy/9 fx	+45%			7%
	45.5 Gy/7 fx	+30%			6%
Zamboglou et al. (2012)	38 Gy/4 fx/1 implant	+49%	97%*	5 yrs	9% retention 9%incontinence	3% retention 1% incontinence
	38 Gy/4 fx/2 implants	+49%	94%*	5 yrs	7% retention 5% incontinence	2% retention <1%incontinence
	34.5 Gy/3 fx/3 implants	+60%	95%*	3 yrs	5% retention 8% incontinence	1% retention 1% incontinence
Hoskin et al. (2012)	34 Gy/4 fx	+21%	77%	5 yrs (median)	33%	3%
	36 Gy/4 fx	+35%	91%	4.5 yrs (median)	40%	16%
	31.5 Gy/3 fx	+35%	87%	2.8 yrs(median)	34%	14%
	26 Gy/2 fx	+35%	NA	.5 yrs (median)	NA	NA

*across all risk groups, high risk only was 93%

Within all three published studies, there were no statistically significant dose-response relationships in terms of either oncological control or toxicity. However, looking across the three, it may be that the higher doses provided better control at the cost of some higher toxicity. I hope someone will do a meta-analysis on the full data sets to confirm that. Larger studies will be needed to determine whether toxicity increases with the more aggressive dosing schedules. All the control rates were within the range of the combination therapies, and all of the toxicities were acceptable. Evidently, all of the studies applied enough radiation to effectively kill the high-risk cancer. Nor did the dosing schedule used have an impact on results. HDR brachy monotherapy as currently practiced uses anywhere from a single fraction to nine fractions, and anywhere from a single implant to three implants.

It is difficult to draw conclusions about the use of ADT. All three studies utilized high rates of adjuvant ADT – over 90% in two of the studies. The study with the lowest rate of ADT utilization, Zamboglou et al., at 60%, also used the highest radiation doses. Although Demanes et al. found that ADT had no incremental benefit when used with combination therapy, that study was in the early years (1991-1998) when relatively low radiation doses were used. Until there is a randomized clinical trial of its use with HDRBT monotherapy, it will be hard to walk away from using ADT.

Unlike low dose rate brachytherapy (seeds), HDRBT can treat areas outside of the prostate, including the prostate bed and the seminal vesicles. However, to my knowledge, it has not been used to treat pelvic lymph nodes, which would be impossible to find using current imaging technology. In all three studies, patients were screened for evidence of lymph node involvement. Clearly, HDRBT monotherapy is not a good choice if LN involvement is suspected. There are calculators for predicting such risk based on Gleason score, PSA and cancer volume. High-risk patients may have a statistically high risk for LN involvement without showing evidence, but even the “high risk” levels are not very high, so treatment remains controversial. One clinical trial (Lawton et al.) demonstrated a benefit to full-pelvic IMRT coupled with neoadjuvant ADT, and there is a current clinical trial that allows for a brachy boost (RTOG 0924) that may confirm that finding.

SBRT is radiologically identical to HDRBT, and as discussed in a recent article, its use for high-risk patients is also being explored. Both of these treatments have the potential to provide excellent cancer control while minimizing the side effects of treatment, and with a considerable time and cost advantage over IMRT-combo treatments. I encourage high-risk patients to enroll in clinical trials for both alternatives. HDRBT monotherapy for high risk is part of a clinical trial at Stanford (NCT02346253).