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