The first randomized clinical trial comparing active surveillance, surgery and external beam radiation tells us little :-(

This was supposed to be HUGE! The first clinical trial ever where patients were randomly assigned to active surveillance (AS), radical prostatectomy (RP) or external beam radiotherapy (EBRT). The results were published in The New England Journal of Medicine (see this link). They started signing up men in the UK in 1999 and continued recruitment for 10 years. By 2009, they screened over 82,000 men for prostate cancer and found 1,643 men with newly diagnosed localized prostate cancer who were willing to be randomized to initial treatment with AS, RP or EBRT, about a third in each. They then followed them for a median of ten years to see how well they did with each therapy. Imagine the effort involved! Sounds good so far -- what could go wrong?

The bottom line was that all 3 therapies did about the same in preventing death. AS was found to cause higher rates of disease progression and metastases. We will explore why below.

There were several problems that arose.

1. They planned to detect mortality differences, but couldn't.

They thought there would be more deaths in the ten years of follow-up, but almost all the men defied those expectations. That's partly because of all the great new life-prolonging drugs that became available in the 21st century; drugs like docetaxel, Xtandi, Zytiga, and Xofigo. Also, in a clinical trial, patients are very closely diagnosed, treated, and monitored. They get far better care than the average patient in community practice. There were only 17 prostate-cancer related deaths

Men also survived longer because of progress in treating other diseases. But most of all, men lived longer because they frequently visited doctors as part of the study, during which they were  closely monitored for other illnesses. There were only 152 deaths from all other causes, only 9% of the total sample size. Men were 50 to 69 years of age  (62 years median) at the start of the study and were tracked for 10 years. On average, based on US actuarial tables, about 18% should have died from all causes. So the mortality rate was half of what was expected. On the average, men in the UK live two years longer than men in the US - not enough to account for the difference.

No worries. Instead of looking for mortality differences, the researchers had a secondary objective to look for differences in disease progression and rates of metastases. Those are excellent surrogate endpoints. But...

2. The intended treatment wasn't always what patients wound up doing

Although men were randomized to one of the 3 therapies, a lot of the men apparently changed their minds, as was their right. The authors of the study analyzed everything based on the intended treatment at the time they were randomized. This is how they said they would analyze the data, and they stuck with the plan. The switching that occurred was as follows:

• Of the 545 men randomly assigned to AS,  482 (88%) stayed with it at least for 9 months. The rest decided to have surgery, radiation, no therapy, or dropped out.
• Of the 553 men randomly assigned to RP, 391 (71%) did have surgery within the first 9 months following randomization. Most of the remainder switched to AS, the rest to radiation or other treatment, and a few chose no treatment or dropped out.
• Of the 545 men randomly assigned to EBRT, 405 (74%) did have EBRT within the first 9 months following randomization. Most of the remainder switched to AS, the rest to surgery, other treatment, no treatment or dropped out.
• In all, 22% of the men did not have the therapy they were originally randomized to, yet they are including in the analysis as if they did. It is unknown how this may have skewed the findings.

3. Their AS protocol was nothing like contemporary protocols.

     a. Inclusion criteria were much less restrictive

In contemporary AS protocols, almost all men are in the "low risk" category. "Low Risk" means they are stage T1c or T2a, their Gleason score is 6, and their PSA is less than 10. Some of the more restrictive AS programs, like Johns Hopkins, also include the "Epstein criteria." That means there were no more than 2 positive cores, no more than 50% cancer in any positive cores, and the PSA density must be less than 0.15 ng/ml/g. For the first time this year, NCCN included AS as an option for men with Gleason score 3+4 if no more than half the cores were positive, but only if they were otherwise low risk.

In the ProtecT trial, the only inclusion criterion was that the men had to have localized prostate cancer. See this link for their protocol. This means that they allowed men who were higher stage (T2b and T2c), higher grade (Gleason score ≥ 7), and higher PSA (PSA could be as high as 10-20 ng/ml). In fact, they previously reported that, among the AS cohort:

• 10% had an initial PSA between 10 and 20 ng/ml
• 22% had an initial Gleason score≥ 7 (2% were GS 8-10)
• 25% had a clinical stage of T2 - they do not break that into subcategories, presumably most were T2a

So, many of those higher risk men would have been screened out of a contemporary AS program. The authors did not analyze this higher risk subgroup to tell us how many of the 33 cases of metastases or 112 cases of clinical progression were among them, but they do report (Table 2) that of the 8 prostate-cancer deaths in the AS group, 5 were among men with Gleason score ≥ 7 at diagnosis (vs. 2 each for RP and EBRT). The remaining 3 deaths among those diagnosed as Gleason 6 was similar to the number for RP (3) and EBRT (2). It seems that all extra deaths were attributable to higher Gleason scores in their AS program.

     b. Monitoring of men on AS was below contemporary standards.

In contemporary AS protocols, there is always a confirmatory follow-up biopsy within a year of the first screening biopsy. The repeat biopsy schedule varies from that point on, and may be every year, as it was originally at Johns Hopkins. Some AS protocols utilize mpMRI to search for suspicious areas and only biopsy as suspicion arises, others implement a biopsy schedule that may vary depending on the findings of the last biopsy. Some do TRUS biopsies, some do mpMRI-targeted biopsies, some combine the two, and some do follow-up transperineal template-mapping biopsies. But all good AS programs include follow-up biopsies.

In the ProtecT trial, patients were screened for a high PSA (> 20 ng/ml), emergent symptoms, or a 12-month PSA increase ≥ 50%. So those who had a form of prostate cancer with a low PSA output (such as some of those with predominant Gleason pattern 5) would never be discovered until symptomatic metastases occurred. I don’t know what percent ever got a second biopsy.

We recently saw what happened in Göteborg when there was no pre-determined biopsy schedule: 54 out of 474 men (11%) failed on AS. They used a similar monitoring system as the ProtecT trial: quarterly, and then semi-annual PSA tests, and re-biopsy at the discretion of the doctor.

I sometimes talk to patients who get periodic PSA tests and claim they are on active surveillance. They are putting themselves in danger. Time and again, PSA kinetics have been rejected as a sole indicator of progression for very good reasons, mainly (1) PSA is affected by many non-cancer causes, and (2) some of the most virulent prostate cancer cells put out very little PSA. There is no substitute for confirmatory and follow-up biopsies.

Let's put perspective just how egregious a difference it is when active surveillance does not include follow-up biopsies. Current estimates are that one in three TRUS-guided biopsies (12 through the rectum) will miss a higher grade of cancer. So, if one biopsy failed to detect a higher grade cancer with odds of 33%, then the odds of missing it on two biopsies is (.33) squared, etc. As the following table shows, the odds of missing the higher grade cancer with annual biopsies for ten years is about 1 in a hundred-thousand.

Biopsy	Odds of missing higher grade in ALL the biopsies
1st	33%
2nd	11%
3rd	4%
4th	1%
5th	0.4%
6th	0.1%
7th	0.04%
8th	0.01%
9th	0.005%
10th	0.001%

Now, at Johns Hopkins, for example, it was their active surveillance policy to have annual biopsies, and they used the Epstein criteria discussed above. After 15 years of follow-up, the metastasis-free survival rate was 99.4%. Laurence Klotz at Sunnybrook in Toronto has the longest running trial of active surveillance in North America. They allowed some patients as high as favorable intermediate risk, and while there was always a confirmatory biopsy in the first year, their biopsy schedule was not as rigorous as Johns Hopkins. After 20 years, of follow-up, they report metastasis-free survival of 97.2%. In the ProtecT trial, there were 33 men out of the 545 men in the AS cohort - 6.1% had already been diagnosed with metastases after only 10 years of follow-up. The outcomes of the AS cohort are very out-of-line compared to active surveillance programs that have more rigorous selection criteria and monitoring protocols.

Selection criteria	Biopsy schedule	Active Surveillance Program	Follow-up	Metastasis-free survival
Strictest: Epstein protocol	Annual	Johns Hopkins	15 years	99.4%
Less strict: favorable risk only	Confirmatory and periodic thereafter	Sunnybrook	20 years	97.2%
Any localized regardless of PSA or grade	none	ProtecT	10 years	93.9%

4. Their EBRT protocol was below today's standards.

In the years prior to 1999 when they were planning this study, there were very different radiation therapies in place than have now become standard of care. This is a problem with all long-term clinical trials involving radiation technology. By the time we get the results, they are irrelevant because the technology and understanding has progressed so much. For an expanded discussion of this issue, see this link.

They used an older technology (3D-CRT) to deliver only 74 Gy in 37 treatments while adding 3-6 months of hormone therapy before and during treatment. Now, with IGRT/IMRT technology, the patients would safely receive about 80 Gy. Low and favorable risk patients probably do not benefit from adjuvant ADT -- it adds sexual side effects without adding to cancer control in most of them. Some have questioned whether the increase is justified for low or intermediate risk patients (see this link), but, as we saw, 10 years is not long enough to judge that, and there is no consequence to the higher dose in terms of side effects. It is entirely possible that the low dose they gave patients only delayed progression but did not cure the cancer.  If that is true, we may see the EBRT outcomes deteriorate when they present their planned 15-year follow-up.

ProtecT was a vast and expensive undertaking. It will probably never be repeated, and there isn't likely to ever be a US equivalent. Sadly, we can't learn very much from their current analysis of this major study, although it may yield more fruit with some subsequent analyses.

Radiation treatment of men with inflammatory bowel disease (IBD)

A analysis of a tumor registry in Texas challenges the notion that men suffering from inflammatory bowel disease ought not have radiation therapy for prostate cancer.  Gestault and Swanson presented their findings at the recent ASCO Genitourinary Conference (Abstract 15). They searched a tumor registry and found 18 patients who suffered from inflammatory bowel disease (either Crohn’s disease or ulcerative colitis) and were treated with radiation between 2000 and 2010.

• ·      12 were treated with EBRT – either IMRT or 3D-CRT
• ·      6 were treated with low dose rate brachytherapy
• ·      22% were in remission before treatment
• ·      56% were taking a 5-ASA medication
• ·      17% were taking prednisone
• ·      6% were taking Remicade
• ·      6 patients (40%) had grade 1 diarrhea at baseline
• ·      2 had had an ostomy

After a median follow-up of 9.5 years:

• ·      4 patients (22%) had grade 1 diarrhea, none of higher grade
• ·      3 patients (17%) had grade 2 proctitis, none of higher grade

o   All of those had 3D-CRT, rather than IMRT

The authors conclude:

“Our findings suggest that IBD patients experience minimal toxicity with IMRT-based radiation therapy.”

While a study of 18 patients is far too small to draw any projectable conclusions, it does raise the interesting hypothesis that patients with IBD should not automatically be ruled out for primary radiation treatment. It might be prudent, however, to use a rectal spacer with such patients.

EBRT with 2 years of ADT better than 4 months in patients treated for locally advanced prostate cancer

It will come as no surprise that long-term ADT improved outcomes among men treated for locally advanced prostate cancer with external beam radiation. While this study is largely irrelevant now because a more recent study, DART 01/05 (discussed here), proved much the same thing with dose-escalation, this study also included pelvic lymph node treatment and has a median of 20 years of follow up.

The final results of RTOG 0902 were reported at the recent ASTRO meeting by Lawton et al. and in a news release. In this multi-institutional study, 1,992 patients were treated between 1992 and 1995. They were all high risk (T2c-T4) with no detectable distant metastases and PSA<150. All patients ere treated according to the following protocol:

• ·      44-46 Gy to the pelvic lymph nodes
• ·      65-70 Gy to the prostate
• ·      The short-term ADT group (STADT) received 4 months of flutamide and goserelin, starting 2 months before EBRT.
• ·      The long-term ADT group (LTADT) received 24 additional months of goserelin.

At 15 years after treatment:

• ·      Disease-free survival was 16% for the LTADT group vs. 10% for the STADT group, and was statistically significant.
• ·      PSA increase was 45% for the LTADT group vs. 61% for the STADT group, and was statistically significant.
• ·      Local progression was 13% for the LTADT group vs. 23% for the STADT group, and was statistically significant.
• ·      Distant metastases rate was 17% for the LTADT group vs. 26% for the STADT group, and was statistically significant.
• ·      Disease-specific survival was 10% higher for the LTADT group vs. the STADT group, and was statistically significant.
• ·      Overall survival was 30% for the LTADT group vs. 27% for the STADT group, and was not statistically significant.
• ·      No difference in urinary toxicity and minimal difference in bowel toxicity between the two groups.

While all the survival numbers are very low in both groups, it should be recalled that the radiation dose received back then was well below the dose now considered curative. Also, most of such men would now be diagnosed at a much earlier stage of disease progression. There was a clear benefit to long-term compared to short-term androgen suppression, and DART 01/05 proved that the benefit was still true with dose escalation in high-risk patients.

Testosterone Replacement Therapy (TRT) after Radiation Therapy

Many urologists these days are fairly comfortable prescribing testosterone replacement therapy (TRT) for men who have had a radical prostatectomy and whose PSA has stayed at undetectable levels for some time. However, considerations may be somewhat different after radiation therapy.

Pastuszak et al. looked at the records of 98 men (median age 70) who were treated at 4 institutions with TRT after primary radiation therapy (brachytherapy or external beam). After a median follow up of 41 months, they found:

• ·      Testosterone increased from 209 ng/dl to 420 ng/dl
• ·      Median PSA was 0.08 ng/ml at baseline, and 0.09 ng/ml at end of follow-up (p=0.05)
• ·      PSA of high-risk patients increased from 0.10 ng/ml to 0.36 ng/ml (p=0.02)
• ·      Biochemical recurrence was found in 6.1 percent.

The authors note in an accompanying article that the biochemical recurrence rate was actually lower than expected based on historical data of men not given TRT after radiation therapy.

While it seems safe to give TRT after radiation, the authors caution:

“Nevertheless, the safety of testosterone therapy in the setting of prostate cancer can only be truly demonstrated in the setting of a prospective, controlled trial, an effort that, to date, has been limited by difficulties with patient accrual. Until such a study is available, the burden remains on the physician to judiciously select men for testosterone therapy, and perhaps more importantly, to regularly monitor them with appropriate testing and examination.”

It is important to also note that the men selected for TRT in this study had a very low PSA at baseline, which is an appropriate selection criterion. An issue that can arise with TRT after radiation is that the testosterone might aggravate some incipient BPH that might cause PSA to rise even though the cancer is eradicated. In that case, monitoring PSA as an indicator of biochemical failure can become problematic.

Some studies have noted that for reasons that remain poorly understood, natural testosterone production may be depressed temporarily after radiation (Pickles et al.) It may be a better strategy to wait for a natural rebound in serum testosterone than to supplement immediately. Supplementing will stop the natural production of testosterone by the testes, and it may sometimes cease permanently as a result.

The other interesting issue raised by the lower than expected recurrence rate found by this study is the hypothesis that normal levels of testosterone are required to keep healthy prostate tissue healthy. Clinical trials are in place to test this hypothesis.

Hypofractionated Radiation Therapy: Same results in less time

The largest yet randomized clinical trial comparing hypofractionated (fewer treatments or fractions) to normally fractionated IMRT has proved that oncological outcomes and late-term toxicities were the same for both treatment schedules.

The results of the CHHiP study were reported in an abstract by Dearnaly et al. delivered at the European Cancer Congress this week. There was also an interim toxicity analysis in 2012. There were 3,216 patients treated at 71 centers in the UK between 2002 and 2011. All patients were stage T1b-T3a, with <30% probability of seminal vesicle involvement. Patients were randomly assigned to one of three IMRT treatment schedules, for which I also show the relative biologically effective dose (BED) for oncological control compared to normal fractionation:

1.     74 Gy =2 Gy x 37 fractions (normal fractionation)

2.     60 Gy = 3 Gy x 20 fractions; relative BED: +4%

3.     57 Gy = 3 Gy x 19 fractions; relative BED: -1%

ADT began 3 months prior to the start of IMRT, and continued through treatment. The 2012 analysis showed that 93% of patients in each group received ADT.

Patient characteristics were as follows:

• ·      NCCN risk groups:

o   Low risk: 15%

o   Intermediate risk: 73%

o   High risk: 12%

• ·      Median age: 69 years
• ·      PSA: 10.1 ng/ml

After a median follow-up of 63.2 months, the 5-year progression-free (either biochemical or clinical) survival (PFS) rates were:

• ·      74 Gy: 88%
• ·      60 Gy: 91%
• ·      57 Gy: 85%

The difference in PFS for the 57 Gy vs. the 60 Gy schedule was statistically significant; the other differences were not statistically significant.

The toxicity outcomes reported as those with RTOG toxicity grades of 2 or higher were as follows:

• ·      Acute GI toxicity was lower with normal fractionation:

o   74 Gy: 25%

o   60 Gy: 39%

o   57 Gy: 38%

• ·      Acute GU toxicity was not significantly different among groups.
• ·      2-year GI toxicity was lower with hypofractionation in the 57 Gy group:

o   74 Gy: 4%

o   60 Gy: 3%

o   57 Gy: 2%

• ·      5-year GI toxicity was not significantly different among groups.

o   74 Gy: 1%

o   60 Gy: 2%

o   57 Gy: 2%

• ·      Neither 2-year nor 5-year GU toxicities were different among groups.

It is important to note that the normal fractionation schedule used in this trial (2 Gy x 37 fractions) is low compared to the current standard of care (2 Gy x 40 fractions), but was standard when this trial began in 2002. The 60 Gy schedule comes close to the current standard of care in terms of its biologically effective dose. Given this, it is not surprising that only the 60 Gy schedule achieved 5-year progression-free survival levels over 90%. The lowest dose schedule is on the steep part of the dose/response curve where even small increases in dose achieve large increases in cancer control.

While acute GI toxicity was higher at first with hypofractionation, the effect was transient, and had disappeared by 2 years. Lasting GI toxicity was negligible, and there were no differences at any time in GU toxicity.

Based on all this, the authors state, “Modest hypofractionated RT using 60Gy/20f appears effective and safe and may be recommended as a new standard of care.”

We should be clear that this is not SBRT; it is only IMRT with an accelerated dosing schedule. There are some important differences. SBRT typically uses doses of 6-8 Gy per fraction and just 4 or 5 fractions. Because of the extreme hypofractionation, it becomes critical to track prostate motion during each fraction and not just between fractions. Treatment margins are typically narrower with SBRT and may be as low as 0 on the rectal side. These differences are what make SBRT safe. In the current study, there was no allowance made for intra-fractional prostate motion and the margins were not altered, so it is not very surprising that rectal toxicity was higher at first, but it was perhaps surprising that there were no lasting differences.

We should also note a few similar randomized comparative trials in the last year. One, at Fox-Chase (n=333), looked at 76 Gy delivered in 38 fractions of 2 Gy each (normal fractionation) compared to 70 Gy delivered in 26 fractions of 2.7 Gy each (hypofractionated) among intermediate and high-risk patients. The 5-year biochemical and/or clinical disease failure rate was the same -- 21% for normal fractionation, 23% for hypofractionation -- and there was no difference in late term toxicity, except among men with compromised urinary function.

An M.D.Anderson study (n=203) compared the late toxicity of a normally fractionated schedule (76 Gy in 1.8 Gy fractions) to a hypofractionated schedule (72 Gy in 2.4 Gy fractions). As in the UK study, there were no differences in GU toxicity. There was an increase in GI toxicity in the hypofractionated group, although it was not statistically significant. Unsurprisingly, the authors found it was related to the volume of the rectum that received high doses.

A multi-institutional study from the Netherlands among intermediate and high-risk men (n=820) reported on the acute toxicity of a normally fractionated schedule (78 Gy in 2 Gy fractions) compared to a hypofractionated schedule (65 Gy in 3.4 Gy fractions). At 3 months, there was no difference in GI or GU toxicity. At 6 months, there was no difference in GU toxicity, but GI toxicity was higher in the hypofractionated group (42% vs. 31%).

We also saw recently (see: Can salvage radiation therapy be safely and effectively completed in less time?) that a shortened treatment schedule appeared to be safe and effective for salvage IMRT. However, this UK study is more compelling because it is a randomized comparative trial of great size.

The only impediment seems to be the higher rate of acute rectal side effects. The patient will have to decide if it is worth accepting those transient symptoms in exchange for the convenience of a 4-week treatment schedule. Given the lower rate of patient-reported adverse outcomes and the high rate of oncological control with SBRT, however, it would seem that the 10-day schedule (5 fractions, every other day) is a better alternative on all counts.

Risk factors for primary radiation failure and timing of progression

Zumsteg et al. searched the database at Memorial Sloan Kettering Cancer Center (MSKCC) to determine the risk factors associated with cancer progression after primary radiation treatment, and the timing of progression. Their retrospective analysis looked at records of 2,694 patients treated at MSKCC with radiation doses between 76 Gy to 86 Gy. The median follow-up was 83 months for all patients and 122 months for those who experienced biochemical failure (defined as nadir+2). They did not report what, if any, salvage treatment was used. The researchers found:

• ·      23% of patients experienced biochemical failure.
• ·      The median time from biochemical failure to detection of distant metastases was 5.4 years.
• ·      The median time from biochemical failure to prostate cancer-specific mortality was 10.5 years, 5.1 years after metastases were detected.
• ·      Risk of clinical progression following biochemical failure were independently associated with:

o   Shorter PSA doubling time

o   Higher clinical stage

o   Higher Gleason score

o   Shorter time to biochemical failure

John Hopkins reported that for men treated with surgery, 19% experienced biochemical failure. Some of the difference may be attributable to the inadequate dose of radiation (76 Gy) used on some patients, or that those patients were diagnosed with more aggressive disease. The median time from biochemical recurrence to detection of distant metastases was 8 years, 3 years among those who did not have salvage radiation after biochemical recurrence (Antonarakis et al.), The shorter time in the radiation study may reflect the fact that patients choosing radiation have historically been older and further progressed at time of diagnosis. The median time to death after metastases were detected was 5 years – identical in both studies. They all report the same risk factors for clinical progression.

The numbers reported for initial radiation therapy are similar, at first blush, to those reported for initial prostatectomy. Because there will probably never be a randomized clinical trial of surgery vs. radiation, it is tempting for the patient faced with the choice of initial therapy after diagnosis to compare these datasets, both from top institutions in their respective specialty. While I would very much like to see the patient characteristics and the data stratified by risk group and salvage treatment, if any, there does seem to be a similar overall pattern. Some patients will have already experienced undetected micrometastases before treatment, and they will not be cured by either therapy using current methods. Other patients, most in fact, will be cured by either therapy.

External beam radiation therapy (EBRT) with a low dose rate brachytherapy (LDRBT) boost provides superior cancer control compared to EBRT alone.

Numerous retrospective analyses have suggested that the combination of external beam radiation therapy (EBRT) with a low dose rate brachytherapy (LDRBT) boost is highly effective in controlling prostate cancer in unfavorable risk patients. For the first time, to my knowledge, we have a randomized comparative trial confirming that. An abstract was presented at the GU Conference and there is a press release about it.

ASCENDE-RT was a randomized clinical trial among 122 intermediate and 276 high risk patients treated in 6 Canadian centers from 2002-2011. The treatment specifications were:

• All patients received:
• Whole pelvis EBRT of 46 GY
• 8 months of neoadjuvant ADT + 4 months of concurrent and adjuvant ADT
• The EBRT-only group of 200 patients received an additional 32 Gy to the prostate (total = 78 Gy)
• The LDRBT-boost group of 198 patients received an additional boost of 115 Gy I-125 seeds in the prostate.
• Median follow up was 6.5 years, and was as long as 9 years for 65 patients.

The researchers found:

• After 9 years, the biochemical progression-free survival  (bPFS) was 83% for the LDRBT-boost group compared to 62% for the EBRT-only group.
• bPFS deteriorated by about 6% per year for the EBRT-only group.
• bPFS was fairly stable for the LDRBT-boost group after reaching 89% at 5 years.
• After 7 years, LDRBT-boost had better bPFS than EBRT-only both among intermediate risk men (94% vs. 80%), and among high risk men (83% vs. 72%).
• Median PSA at latest follow up was 0.02 ng/ml for the LDRBT-boost group and 0.24 ng/ml for the EBRT-only group.
• Reflecting the long natural history of disease progression, there were no significant differences in metastasis-free survival, prostate cancer-specific survival, or overall survival. Differences may emerge with longer follow up.

The improved oncological control came at the expense of increased toxicity for the combination therapy.

• Late term Grade 2 or higher genitourinary (GU) toxicity was higher for the LDRBT-boost group. Late term Grade 3 GU toxicity reached 19% for the LDRBT-boost group vs. 5% for the EBRT-only group.
• Late term gastrointestinal (GI) toxicity was similarly mild for both groups
• This early report did not include an analysis of acute toxicity, or an analysis of erectile function.

I look forward to the full analysis of the data when published. I hope they will break out the results separately for favorable and unfavorable intermediate risk patients to the extent that sample size may allow. Perhaps the favorable intermediate risk patients can be spared the extra toxicity of the LDRBT-boost treatment while still enjoying oncological control.

For the high risk patients especially, this study establishes LDRBT-boost therapy as the preferred treatment compared to EBRT-only, unless pre-existing urinary issues rule it out. It is unclear whether the 12 months of ADT and the whole-pelvis radiation would be necessary for all patients.

In an earlier randomized clinical trial (Sathya et al.), high dose rate brachytherapy (HDRBT) boost was shown to reduce the biochemical and clinical failure rate by 50% compared to EBRT-only (66 Gy). Other randomized clinical trials of HDRBT-boost (Hoskin et al., Guix et al.) also found that the boost improved outcomes. It is unclear whether boost with HDRBT, LDRBT, or treatment with SBRT alone will eventually emerge as the preferred treatment for unfavorable risk patients, or whether it will make a difference.