Brachytherapy alone is enough for favorable intermediate risk patients

RTOG 0232 was a large clinical trial conducted to determine whether low dose rate brachytherapy (BT) alone was of equal benefit compared to external beam radiation therapy with a brachytherapy boost (EBRT+BT) in intermediate risk patients.

The study was conducted at 68 cancer centers in the US and Canada from 2003 to 2012. 588 intermediate risk men were treated. For the purposes of this study, “intermediate risk” was defined as:

• Stage T1c – T2b, and
• Either Gleason Score of 7 and PSA less than 10 ng/ml, or
• Gleason score of 6 and PSA between 10 and 20 ng/ml

They did not collect detailed data and report separately those who would now be classified as “favorable intermediate risk” by the Zumsteg definition (Gleason score 3+4, less than half the biopsy cores positive, and otherwise low risk). However, Howard Sandler, the Principal Investigator, wrote:

It was deliberately a favorable intermediate group largely. At the time (2002) we felt that combination therapy was mandatory for the more advance patients and we weren’t comfortable randomizing to brachy alone for those patients.

So it is important that we do not generalize their findings to unfavorable intermediate-risk or high-risk patients.

The patients were treated as follows:

• BT: 145 Gy of I-125 seeds or 125 Gy of Pd-103 seeds
• EBRT+BT: 45 Gy of EBRT and a boost with 110 Gy of I-125 seeds or 100 Gy of Pd-103 seeds

After 5 years of follow-up:

• Progression-free survival was 85% for EBRT+BT patients, 86% for BT patients (no difference)
• Acute grade 3 (serious) side effects were suffered by 8%  in each group.
•  Late-term grade 3 (serious) side effects were higher (12%) in the EBRT+BT compared to 7% in the BT group

o   Urinary side effects: 7% in the EBRT+BT group vs. 3% in the BT group

o   Rectal side effects: 3% in the EBRT+BT group vs. 2% in the BT group

So, the addition of external beam radiation added nothing to cancer control, at least out as long as 5 years. While side effects were low for both groups, combination therapy increased them.

We saw recently in an analysis of the patients at Cleveland Clinic who were treated exclusively with BT only (see this link, especially the section on intermediate risk), that progression-free survival was very good for “low intermediate risk” patients. Furthermore, Drs. Stone and Zelefsky agreed that the combination therapy is unnecessary for this group, especially when treated with a sufficient brachytherapy dose. Radiotherapy Clinics of Georgia has built a business out of treating even low-risk patients with the combination therapy. This is now proved to be an overtreatment that is needlessly toxic.

5-year SBRT trial: high cancer control, low toxicity

(9/10/2018)
Meier et al reported the results of a 5-year multi-institutional trial, (also reported at the 2017 ASTRO meeting), finding that SBRT had high rates cancer control and low toxicity.

This was a prospective clinical trial in which all 21 institutions treated 309 patients according to the same protocol. The institutions were community, regional and academic hospitals across the US. All patients were low (56%) or intermediate risk (44%). Of the 137 intermediate risk patients,  61% were favorable and 39% were unfavorable intermediate risk. The treatment was:

• 40 Gy in 5 treatments to the prostate
• 36.25 Gy to the seminal vesicles in intermediate risk patients
• No concurrent or adjuvant androgen deprivation therapy was allowed.

At five years after SBRT treatment, the following oncological outcomes were reported:

• 97.1% had no biochemical progression; that is, no increases in PSA to over 2 ng/ml from the lowest value achieved 
  o 97.3% for low risk patients, compared to 92.3% for IMRT historically
  o 97.1% for intermediate risk patients, compared to 91.3% for IMRT historically
       - 100% among favorable intermediate risk
       - 93.1% among unfavorable intermediate risk

By five years after SBRT treatment, the late toxicity outcomes were reported:

• No grade 3 (serious) rectal side effects
• Grade 2 rectal side effects in 2%

• Grade 3 (serious) urinary side effects in 4 of the 309 patients (1.3%)
• Grade 2 urinary side effects in 12%

These are certainly excellent outcomes, and are in-line with or better than retrospective SBRT studies that have previously been reported. So far, the longest running SBRT single institution study has been reported by Alan Katz (see this link). I’ve heard that a ten-year update is in the works. That will be as long and larger than the longest running IMRT trial.

SBRT is about half the cost of IMRT, and at only 5 treatments, is certainly a lot less bother for the patients. It has excellent outcomes even without adjuvant ADT in unfavorable intermediate risk patients. With large long-term studies now available, it is difficult to understand why some insurance companies still don’t cover it.

Toxicity equal for SBRT and conventional external beam radiation

There has been some question as to whether the toxicity of delivering very high doses of external beam radiation per treatment (or fraction) in fewer fractions (called “extreme hypofractionation” or SBRT) would be high compared to conventional dose rates per fraction. While SBRT practitioners have reported very low toxicity rates (see table in this link), there has always been some doubt because there may have been some bias in how patients were selected in the various studies.

The HYPO-RT-PC trial was the first trial ever to randomly assign patients to one kind of radiation or the other. Between 2005 and 2015, they enrolled 1200 intermediate-risk patients in Scandinavia to receive either:

1.  Conventional fractionation: 78 Gy in 39 fractions
2. SBRT: 42.7 Gy in 7 fractions

The biologically effective dose is 19% higher for SBRT in terms of cancer control. The biologically effective doses are equivalent in terms of toxicity.

There were a few differences from some US practices:

• “Intermediate risk” was defined as one or two of the following 3 risk factors:

1. Stage T1c-T3a (T3a is a high risk factor in the commonly used US definition)
2. PSA> 10 ng/ml (PSA> 20 ng/ml is a high risk factor in the commonly used US definition)
3. Gleason score ≥7 (Gleason scores greater than 7 are a high risk factor in the commonly used US definition)

• 80% of the men were treated with a technology called 3D-CRT, which is seldom used for external beam therapy anymore at major tertiary care centers. It is never used for SBRT in the US because it is considered not precise enough, and too toxic.

• SBRT is usually delivered in 4 or 5 fractions in the US. CyberKnife and VMAT are the most common technologies in use, and use of sophisticated image guidance throughout each treatment is a common practice.

The toxicity results are based on 866 patients who had 2-year follow-up results. There were some differences in acute toxicity:

• Acute urinary toxicity was 27.6% for the SBRT group and 22.8% for the conventional fractionation group, but the difference was not statistically significant.
• Acute rectal toxicity was 9.4% for the SBRT group and 5.3% for the conventional fractionation group. The difference was statistically significant, but narrowed by 3 or 6 months.

Neither physician-reported toxicity nor patient-reported late-term toxicity differed by the fractionation schedule they received. By two years:

• Late-term urinary side effects were reported by 5.4% of the SBRT group and 4.6% of the conventional fractionation group. The difference was not statistically significant.
• Late term rectal side effects were reported by 2.2% of the SBRT group and 3.7% of the conventional fractionation group. The difference was not statistically significant.
• Impotence was reported by 34% of both groups, up from 16% at baseline.
• Patient-reported bother from urinary, rectal and sexual side effects were not different.

Given their use of the largely outmoded 3D-CRT technology, it was not surprising that acute toxicity would be elevated. I’m frankly surprised that late-term toxicity was not higher for SBRT.

They plan to present their findings on oncological outcomes at a future time.

Very early salvage radiation has up to 4-fold better outcomes and saves lives

Another  subject that has come up a lot recently is when to have salvage radiation. It is always a pressing decision for those 30% of prostatectomy patients who have detectable PSA after prostatectomy. We have seen (see this link) that a low PSA on an ultrasensitive PSA test, as low as 0.03, can be a predictor of full biochemical recurrence later. This latest analysis of this subject looked at how treating sooner rather than later was associated with better cancer control and survival.

Abugharib et al. examined the records of 657 men who had salvage radiation therapy (SRT) from 1986 to 2013 at the University of Michigan and the University of Texas Southwestern. They were all discovered to have detectable PSA following prostatectomy. Researchers were looking for evidence to confirm or contradict their hypothesis that earlier SRT had better outcomes.

They defined "earlier" in two ways:

1. At a lower PSA. Because of the treatment dates, there was relatively little data from ultrasensitive PSA tests. They divided PSA at the time of SRT into three categories:

• 0.01-0.2 ng/ml - the "very early salvage" cohort
• >0.2 - 0.5 ng/ml - the "early salvage" cohort
• >0.5 ng/ml - the "later salvage" cohort (0.5 was selected because the median PSA was 0.4 ng/ml)

2. At an earlier time from completion of prostatectomy

• < 9 months   
• 9-21 months
• 22-47 months
• > 48 months

They looked at "outcomes" in four ways:

1. freedom from biochemical recurrence (PSA> 0.2 ng/ml) after SRT
2. freedom from starting salvage, life-long androgen deprivation therapy (ADT) after SRT
3. freedom from detectable metastases after SRT
4. prostate cancer specific survival

After a median follow-up of 9.8 years, they found:

• The time in months since completion of prostatectomy had no bearing on any of the outcomes.
• The PSA at which they were treated has a major impact on all outcomes.
• The "early salvage" group had outcomes that were about twice as poor as those who had "very early salvage." This was true after correcting for all the variables (like Gleason score and positive margins) that would have made a difference.
• The "later salvage group" had outcomes that were about four times as poor as those who had "very early salvage." This was true after correcting for all the variables (like Gleason score and positive margins) that would have made a difference.
• 91% of the variance in biochemical recurrence after SRT was explained by the PSA at which patients were treated.
• Adjuvant ADT, which was given to 24% of patients for a median of 6 months (range 4-24 months), was significantly associated with freedom from biochemical recurrence after SRT. There were 40% fewer failures. 

Researchers did not have data on PSA doubling time and velocity, and the number who had persistently elevated PSA, all of which almost certainly would affect outcomes. Perhaps such other variables as the length of the positive margins and the Gleason score there ought to be incorporated into a fuller analysis.

Patients who were treated at an early sign of detectable PSA  (0.2-0.5) were twice as likely to develop metastases and die of prostate cancer as those who were treated at the earliest PSA (below 0.2). Those who waited for PSA to rise above 0.5 ng/ml were four times as likely to develop metastases and die from prostate cancer compared to those treated when PSA first became detectable.

We have three large randomized clinical trials proving that outcomes are diminished by about half by waiting rather than treating within the first 6 months, even before there are detectable PSAs (called adjuvant radiation). But few elect to have adjuvant radiation, and the number has been declining (see this link). To avoid overtreatment and protect patients from perhaps unnecessary side effects of SRT, early salvage has emerged as a compromise.

The authors point out that it may take 7 months or more for adequate healing of urinary and erectile complications (see this link). Also, this is an important decision for the patient, which he ought not make hastily. Yet here, more than in the primary therapy decision, very early action can save lives. As a compromise, they suggest early use of neoadjuvant ADT (prior to SRT) which could slow the cancer down and give tissues more time to heal. The extra time may help the patient recover better urinary function, if not erectile function.

They recommend,

"Our data would suggest potentially a traditional cut-off of 0.2 to define biochemical failure may be too late, and that at the first sign of a detectable PSA that SRT (or SRT + ADT) should be initiated."

This remains a difficult decision, and the patient with a detectable PSA after surgery should begin discussions with a good radiation oncologist as soon as possible. Age and comorbidities enter into the decision as well. Unfortunately at these low PSAs, even the most accurate of the new generation of PET scans are incapable of finding distant metastases that might help rule out those cases where SRT would be futile. Nomograms and Decipher scores may help in cases where the decision is equivocal.

Hypofractionated radiation therapy using IMRT has a clear advantage

I was reticent to write about hypofractionation yet again after writing about it so often in the last year. See this link for my latest summary. In a sea of randomized trials demonstrating that hypofractionated radiation therapy (i.e., it is delivered in fewer treatments or fractions) was no worse in cancer control or in toxicity to conventionally fractionated (40-44 treatments), there was one study, the Dutch HYPRO study, where the toxicity was a bit worse. At the time (see this link), I speculated that that was because they included an older radiation technique called 3D-CRT rather than the IMRT technology that is now prevalent in the US. A new study from MD Anderson suggests that may indeed be the case.

Hoffman et al. presented the patient-reported outcomes of 173 men with localized prostate cancer who were treated at M.D. Anderson in Houston. They were randomized to receive either:

1. 75.6 Gy in 42 fractions (conventional fractionation) via IMRT
2. 72 Gy in 30 fractions (hypofractionation) via IMRT

The men filled out questionnaires at baseline, and at 2, 3, 4, & 5 years after treatment. Patients were probed on their urinary, rectal and sexual status. Patient-reported outcomes on validated questionnaires is a more reliable source of toxicity data because it does not rely on the patient volunteering information to the doctor or the doctor assessing or recording that information. Analysis of the two groups showed that:

• there was no difference with regard to rectal issues (urgency, control, frequency, or bleeding).
• there was no difference with regard to urinary issues (pain, blood in urine, waking to urinate at night, or leakage)
• there was no difference with regard to sexual issues (erections firm enough for intercourse)
• there were no differences at 2, 3, 4, or 5 years.

This should dispel any concerns that completing IMRT in less time may be more toxic. Just as with all forms of radiation, the technology has improved greatly over the years. In the hands of an experienced and careful radiation oncologist, there is no reason that external beam therapy cannot be completed in less time and at lower cost.

Patient-reported outcomes from ProtecT - the first randomized trial comparing surgery, radiation, and active surveillance

While there were no differences in 10-year mortality when patients were randomized to surgery (RP), external beam radiotherapy (EBRT), and active surveillance (AS) (see this link), the side effects patients suffered from those treatments differed markedly. Johnson et al. have published the patient-reported outcomes of the ProtecT trial in the New England Journal of Medicine (see this link).

In the ProtecT trial, all participants (or actually 85% of them) filled out a series of validated questionnaires (EPIC and others) that probed issues of urinary function, rectal function, sexual function, and general health. I will ignore the overall health, vitality and mental status questions for now. Suffice it to say that they did not differ among therapies, nor were they very much affected by them. Questionnaires were filled out before the biopsy (the baseline), and at 6 and 12 months after randomization, and annually thereafter until 6 years from the initial biopsy.

What is especially interesting is seeing how equivalent patients (they are equivalent because they were randomized to the 3 treatments) did over the 6 years after receiving each treatment. This means that, for the first time, the side effect profiles are completely comparable (well, almost) and almost without bias.

Some messy data

I say "almost" because there was some switching of treatments that did occur. 22% of the men did not get the therapy they were originally randomized to, and they self-selected some other therapy or no therapy. However, in the analysis they are treated as if they got therapy that they were originally intended to get. Strange, huh?

In addition, they may have received salvage therapy after biochemical failure, and 55% of those assigned to AS did get a radical therapy eventually. So for each intended therapy:

• Among those 291 men who started on AS but got radical treatment: 49% had surgery, 33% had radiation as specified, and 18% had another kind of radiation or HIFU
• Among those 391 men who started on RP, 14 (4%) had adjuvant or salvage radiation, and 1 went on lifelong androgen deprivation therapy (ADT) within a year.
• Among those 405 men who started on EBRT,  3 had salvage RP, 14 (3%) went on lifelong ADT, and 1 had HIFU.

Whether men had the assigned therapy or not, and irrespective of any other therapy they had, they are included with the group they were originally assigned to. It's messy.

Fortunately, there's hope in sight. In one of the Appendices (Section S3), they added the note:

"In future analyses, we intend to present patient-reported outcomes according to treatment received and an economic evaluation including assessment of therapies received for treatment impacts, as well as details about the reasons for change of management in the active monitoring arm to further inform individual and clinical decision-making"

That will give us a much truer picture of the side effects associated with the treatments they actually received.

The treatments

RP was open and nerve sparing. While most men now have robotic surgery rather than open surgery, it seems to make little difference, except for some higher incidents of issues arising during the operation (see this link).

AS did not have required follow-up biopsies, so their side effects may be a little better than on contemporary AS programs. Biopsy complications are never long-lasting anyway.

EBRT was different from contemporary standards. The dose was lower (74 Gy vs. 80 Gy), so there may have been fewer complications due to dose. They used an older delivery technique (3D-CRT vs IMRT) which had higher rates of side effects. And it was given together with short term (3-6 months) of ADT, which would certainly increase the early sexual side effects. ADT is seldom given to favorable risk patients today.

note: all of the patient-reported outcomes include the effect of whatever remedies they used to treat them.

1. Urinary Adverse Outcomes

a. Incontinence

This was a big issue for RP, of course, but not for AS or EBRT. The percent using one or more pads per day is one commonly used measure. As one can see in the following table, incontinence was highest at the 6-month time point, but had gotten somewhat better by the end of the first year. 20% were incontinent by the end of two years, with little improvement from that point.

For EBRT, incontinence peaked at 5% at 6 months. Remember, this was 3D-CRT - a technology that has greater toxicity than the IMRT predominantly in use now. It hovered around 3-4% thereafter.

For AS, incontinence also peaked at 4% at 6 months, and stayed at that level for the next couple of years. From then, it steadily rose to 8% by the end of the 6 year study. Remember that for the purposes of this trial, men were still included in the AS cohort whether they were eventually treated or not. By 6 years, more than half the men had been treated, primarily with surgery.

Table 1. Incontinence: The percent who used one or more pads per day

Time point	AS	RP	EBRT
Baseline	0%	2%	0%
6 months	4%	46%	5%
1 year	4%	26%	4%
2 years	4%	20%	4%
3 years	5%	20%	3%
4 years	7%	17%	4%
5 years	7%	17%	3%
6 years	8%	17%	4%

b. Urinary Irritation/Obstruction

The researchers examined the question of whether urination become more difficult or more frequent after therapy. One way to look at this is a set of questions on the EPIC questionnaire asking about urinary frequency and retention. On that questionnaire, a score of 100% means that function is perfect in that regard, no issues whatever.

On this dimension only EBRT had a clinically detectable effect, and it was only at the 6 month mark. EPIC score dropped from 93% to 84%. After that, it returned quickly to baseline levels.

Table 2. Urinary Irritation/Obstruction EPIC scores, where 100% would be the best possible score.

Time point	AS	RP	EBRT
Baseline	93%	92%	94%
6 months	92%	89%	84%
1 year	93%	93%	93%
2 years	92%	93%	93%
3 years	91%	93%	93%
4 years	91%	94%	93%
5 years	92%	94%	93%
6 years	92%	94%	93%

2. Rectal Adverse Outcomes

The researchers asked the trial participants about their bowel function at baseline and after treatment. There were no discernable effects of AS or RP. Bowel function among the men enrolled for EBRT declined by 6 months (from a score of 93% to 86%). Thereafter, bowel function scores returned to near baseline levels. Other than the 6 month time point, there were no significant differences among the 3 treatments.

Table 3. Bowel function EPIC scores, where 100% would be the best possible score.

Time point	AS	RP	EBRT
Baseline	92%	91%	93%
6 months	91%	92%	86%
1 year	92%	93%	90%
2 years	92%	93%	90%
3 years	92%	93%	91%
4 years	92%	93%	91%
5 years	92%	93%	90%
6 years	92%	92%	91%

3. Sexual Adverse Outcomes

This is one of the few trials that asked men detailed questions about their sexual function at baseline and for 6 years thereafter. One of the key measures of sexual function is the ability to have erections firm enough for intercourse. At baseline, about two-thirds of these 62 year old men (range 50-69), some with other comorbidities like diabetes, cardiovascular disease, and smoking, had suitable erectile function. 

None of the questionnaires asked about perceptions of penile shrinkage in length and girth, climacturia (urination at orgasm), or Peyronie's (abnormal penile curvature), which are often symptoms that affect sexual function post-prostatectomy. Nor do they ask about how the loss of ejaculate has affected sex. That is a certainty with surgery, a near-certainty after radiation, and is not affected by AS. Their definition of erectile function includes the effect of any erectile function aids (e.g. ED meds, injections, pumps, or implants) they may have been using.

For those randomized to RP, erectile function was reduced to 12% at 6 months (remember: they all had nerve-sparing surgery). It recovered somewhat to as much as 21% at 3 years but did not recover beyond that. At every time point, their erectile function was significantly worse than the other treatment cohorts.

For the AS cohort, erectile function declined by 6 months and continued to deteriorate thereafter as they elected to have radical therapies, predominantly surgery. 11% of this cohort had already elected to have radical treatment by the 6-month mark.

For the EBRT cohort, erectile function had dropped to a minimum value of 22% at 6 months. This may be largely attributable to the fact that all of the men in the EBRT cohort had 3-6 months of ADT. It is unknown how much, if any, of their testosterone came back after that and how long it took to recover. Erectile function snapped back a bit post-ADT, getting as high as 38% at 1 year, and declined to 27% by 6 years. Again, this was based on the 3D-CRT technology, and is below the rates usually seen for this age group with IMRT, brachytherapy, or SBRT.

Table 4. Erectile function - the percent who had erections firm enough for intercourse

Time point	AS	RP	EBRT
Baseline	68%	65%	68%
6 months	52%	12%	22%
1 year	49%	15%	38%
2 years	47%	19%	34%
3 years	41%	21%	34%
4 years	37%	20%	32%
5 years	35%	20%	27%
6 years	30%	17%	27%

Myths Exploded by this study:

Myth #1: The side effects end up about the same for surgery or radiation

That's clearly not true for incontinence or erectile function, It is true for urinary irritation and rectal function, which are at baseline levels and similar in all cohorts at 6 years.

Myth #2: With surgery, you get the side effects all at once and steadily recover; with radiation, the side effects come on steadily and may hit you many years later.

What we've seen here belies that myth. There is some recovery of continence up to two years later, but not thereafter. After radiation, incontinence was a minor symptom (except to those who had it, of course), but it did not increase over the years. Urinary irritation/obstruction increased at 6 months for EBRT, but returned to baseline permanently thereafter. Rectal function scores also permanently returned to baseline levels after the 6-month time point.

Myth #3: Over time, erectile function is about the same for surgery and radiation. 

As we've just seen, erectile function is much worse after surgery, and it never recovers much beyond 2 years. It is worth tracking this myth down to its source. I have even heard John Mulhall, the eminent Memorial Sloan Kettering sex specialist quote this myth.

I believe this myth started with the PROSTQA study published in 2008. Until the ProtecT trial, it was our best source of patient-reported outcomes after the various treatments. The patients were not randomly assigned, however, and differed markedly in their characteristics. Those characteristics, especially age, varied greatly with the treatments they chose. In the following table, hidden in an appendix (all the good stuff is usually back there), we can extract the following table:

Table 5. Percent with preserved erectile function sufficient for intercourse 2 years after treatment, broken down by age at treatment 

Age	RP	EBRT	BT
<50	55	100*	75*
50-59	43	52	67
60-69	27	39	44
70+	8*	30	24
Total	35	37	43
Median Age	60 years	70 years	66 years

* small sample size

Although the potency doesn’t seem to vary much between treatments in total (range 35% to 43%), it is only because the men who received EBRT and BT were older than the men who were treated with RP. Within every age group, potency preservation was higher with radiation.

There are other differences between the two studies, such as: 
• this table only includes men who were potent before therapy, which would exclude about a third of men in the ProtecT trial. This would lower all the percentages in Table 5 relative to Table 4. 
• ProtecT included only men in the 50-69 age range, while half of the findings in ProstQA came from men treated with radiation over the age of 70. 
• Finally, ProtecT didn't yet report erectile function according to the therapy or therapies they actually received.

It is gratifying to see these myths shattered. Patients are the beneficiary.