ProtecT Randomized Clinical Trial: Patient outcomes by treatment received - active monitoring, prostatectomy, or radiation

In an earlier article (see this link), we looked at the only trial that randomized men with localized prostate cancer to either "active monitoring" (AM), radical prostatectomy (RP), or external beam radiation (EBRT). AM was less restrictive than today's active surveillance protocols (it included men who were not low risk) and it did not include mpMRI or follow-up biopsies. EBRT was lower dose than contemporary guidelines, included short-term ADT for everyone, and used a more toxic technique (3D-CRT) than IMRT prevalent today. RP was open and nerve-sparing. The earlier analysis categorized patients according to the treatment they were randomized to receive, rather than the treatment they actually received. They did this because it eliminates "selection bias" - patients switched to the treatment that they or their doctors believed would benefit them most. Now, the authors report patient outcomes according to the treatment they actually received.

1. Treatment choice/ oncological outcomes

In the first year, 78% of patients received the treatment they were randomly assigned. Higher risk men chose radical treatment rather than AM. Conversely, men with low-risk PC were less likely to opt for EBRT.

In the ten years of follow-up, there were only 17 prostate cancer deaths out of 1643 men randomized in the trial. The pooled, adjusted risks and the percent of the AM group that suffered each oncological outcome after 10 years of follow-up were:

• 69% lower risk of prostate cancer death for radical therapy (RP or EBRT) vs AM 
• 1.8% PC deaths among AM
• 64% lower risk of metastases or death for radical therapy (RP or EBRT) vs AM 
• 6.0% metastases or death among AM
• 77% lower risk of progression for radical therapy (RP or EBRT) vs AM 
• 24% progression among AM
• 47% lower risk of salvage ADT for radical therapy (RP or EBRT) vs AM 
• 8.8% salvage ADT among AM
• No statistically significant differences between RP and EBRT

The inferior performance of their AM protocol was predictable (see this link - Section 3). Their AM protocol did not include mpMRI confirmation, biopsy follow-up, and allowed some higher-risk patients.


2. Urinary Adverse Outcomes

a. Incontinence

This was a big issue for RP, of course, but not for AM 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. 24% were incontinent by the end of two years, with little improvement from that point. Incontinence increased slowly in the AM group as they elected to have radical treatment.


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

Time point	AM	RP	EBRT
Baseline	0%	1%	0%
6 months	0%	55%	1%
1 year	1%	32%	2%
2 years	3%	24%	2%
3 years	3%	23%	2%
4 years	5%	20%	2%
5 years	5%	20%	2%
6 years	7%	21%	2%

b. Nocturia

The researchers examined the question of whether nighttime urination was more frequent after therapy. On this dimension, only EBRT had a clinically detectable effect, and it was only at the 6 month mark. After that, it returned quickly to AM levels. RP returned to baseline level.

Table 2. Nocturia - Twice or more per night

Time point	AM	RP	EBRT
Baseline	20%	22%	20%
6 months	24%	35%	65%
1 year	23%	26%	36%
2 years	28%	23%	32%
3 years	31%	25%	32%
4 years	33%	25%	33%
5 years	35%	23%	36%
6 years	38%	25%	34%

3. Rectal Adverse Outcomes

The researchers asked the trial participants whether they had blood in their stools half the time or more. There were no discernable effects of AM or RP. Blood in stools peaked at a low level (8%) of those who had EBRT.

Table 3. Blood in stools more than half the time

Time point	AM	RP	EBRT
Baseline	1%	1%	1%
6 months	1%	1%	4%
1 year	1%	0%	4%
2 years	0%	1%	7%
3 years	1%	1%	8%
4 years	1%	1%	8%
5 years	2%	1%	8%
6 years	1%	2%	6%

4. 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 AM. 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 possible for 5% at 6 months (remember: they all had nerve-sparing surgery). It recovered somewhat to as much as 13% at 2 years but did not recover appreciably beyond that. At every time point, their erectile function was significantly worse than the other treatment cohorts.

For the AM cohort, erectile function declined by 6 months and continued to deteriorate thereafter as they aged and elected to have radical therapies, predominantly surgery. 

For the EBRT cohort, erectile function had dropped to a minimum value of 18% 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 34% at 3 years. At 6 years, potency was twice ads high as those who had RP. 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	AM	RP	EBRT
Baseline	68%	66%	63%
6 months	59%	5%	18%
1 year	60%	6%	34%
2 years	54%	13%	32%
3 years	49%	14%	34%
4 years	43%	15%	31%
5 years	40%	16%	28%
6 years	35%	15%	29%

Myths Exploded by this study:

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

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.

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