Saturday, September 17, 2016

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.





Thursday, September 15, 2016

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.

Monday, September 12, 2016

Most of the recurrences after primary radiation failure are salvageable

Salvage therapy is curative in about half of men who have a biochemical failure after primary therapy. That's true whether the primary therapy was surgery or radiation. It's true when the salvage therapy was radiation after surgery. And it's true whether the salvage therapy was surgery, cryotherapy, or brachytherapy after radiation. Salvage success rates can be as high as 3 in 4, in certain well-selected patients treated with appropriate therapies (see this link, for example), but it can be a lot lower too. Salvage therapy always increases the complications over what they were for the primary therapy, so we would avoid it if we knew it was likely to be futile. Thanks to the new generation of PET scans, we are beginning to understand why, and what we may be able to do to improve those odds.

For any salvage therapy to be effective, two conditions must be met:
  1.  The recurrence must be local. Local means in the prostate, seminal vesicles, the prostate bed, nearby organs (e.g., bladder, rectum, etc.), and/or in the pelvic lymph nodes.
  2.  The recurrence must not be distant. Distant means metastases in the bones; remote organs like the lungs, liver, or remote lymph nodes; or in systemic circulation in the bloodstream.
In the past, it has been difficult to ascertain that both conditions were met. Bone scans are not very reliable when the PSA is below 20 ng/ml, and they are not specific for metastases. Moreover, by the time the PSA increases that much, the cancer is almost certainly distant and incurable. The NaF18 PET/CT scan can detect metastases sometimes at a PSA as low as 4 ng/ml, but it only detects bone metastases, and it is not specific for metastases. An Ultra-Small Superparamagnetic Iron Oxide (USPIO) MRI may sometimes detect metastases, but only in lymph nodes.  A multiparametric MRI may sometimes detect local recurrences, and may be used to target areas for biopsy in the prostate and prostate bed. It may be reliable after primary radiation (see this link). However, it tells us nothing about distant metastases.  CT scans only detect the larger lesions that may be suspect. A transperineal template mapping biopsy may detect prostate cancer in the prostate, but tells us nothing about distant metastases. It should be noted that biopsied prostate tissue looks very different after radiation, and it should be analyzed by highly experienced pathologists.

Clinical trials have proved that adjuvant radiation after prostatectomy has better outcomes than waiting, and recent studies suggest that overtreatment may be avoided by using early salvage radiation rather than adjuvant radiation therapy. Perhaps early salvage therapy after primary radiation therapy may have improved outcomes too. That is, it may be more successful if started before the patient's PSA reaches the nadir+2 level, which is the official definition of biochemical recurrence after primary radiation therapy.

The FDA-approved C-11 Choline PET/CT (or the similar C-11 Acetate PET/CT) fills some of the critical information gaps. It can detect prostate cancer in the radiation-treated prostate, the local area, and throughout the entire body at a PSA as low as 2 ng/ml, especially if the PSA has been rapidly rising. However, its sensitivity is not very good for small sites of cancer (they must be larger than 5mm), or cancer in lymph nodes. And when used to detect cancer within the prostate, prostatitis and BPH may generate false positives. Some of the new experimental PET scans (e.g., DCFPyL) may be more sensitive. Now that we have an adequate tool for detecting both of the above-mentioned conditions (local and not distant), we are beginning to be able to select which recurrences can be cured with salvage therapy, and which can only be managed with lifelong hormone therapy.

Parker et al. report on the Mayo Clinic experience with 184 patients with rising PSAs after primary radiation therapy on whom the C-11 Choline PET/CT was used to detect local and/or distant prostate cancer progression.

  • 87% of patients were PET-positive.
  • The C-11 Choline PET/CT correctly identified 98% of patients who were later found to have residual prostate cancer on subsequent histological analysis. 
  • However, 42% of patients that were identified as negative by the C-11 Choline PET scan later suffered from cancer progression - they were false negatives.
  • Patients were especially likely to be PET-positive if they had higher pretreatment PSA, were high risk, had higher PSA level at the time of the PET scan, had a greater increase from nadir PSA, had a shorter PSA doubling time, and had a higher PSA velocity. All of those with PSA≥ 10 ng/ml were PET-positive.
  • Risk category, PSA increase from nadir, and time since primary radiation therapy were independently associated with PET-positivity, and can help predict when recurrences are salvageable.
  • 59% of PET-positive patients were confirmed by histological analysis (either biopsy or salvage prostatectomy). 76% were confirmed by a multiparametric MRI.
  • 46% of those who were PET-positive had cancer only in the prostate and seminal vesicles. These patients were potentially salvageable with any of the salvage therapies mentioned above.
  • An additional 16% (62% in total) had cancer in the soft tissue pelvic region. These may be salvageable with extended pelvic lymph node dissection (ePLND) or radiation in select areas of the pelvis that were not treated originally.
  • While only a few patients (21) had a PET scan before their PSA reached nadir+2, half of them had a local recurrence only, and are potentially salvageable. This suggests that the  patient does not have to wait for nadir+2. However on this small sample, the salvageability does not seem to be very different for those who detect it earlier.
This study confirms the findings of the larger study at Memorial Sloan Kettering (MSKCC) (reviewed at this link).  In that study, 55% had a recurrence in the prostate and/or seminal vesicles only, compared to 46% at Mayo. At MSKCC, an additional 8% had recurrences in the pelvic lymph nodes only, compared to 16% at Mayo. There were important differences between the studies. At Mayo, unlike MSKCC, patients may have had brachytherapy as all or part of their primary therapy, they may have had enlarged lymph nodes from the start, they had significantly lower doses of radiation (76 Gy vs ~80 Gy), they were younger (65 vs 69), fewer had adjuvant hormone therapy (30% vs 54%), they all had rising PSA but not necessarily nadir+2, and they all received a C-11 Choline PET/CT, there was less histological confirmation (59% vs 71%), and the median follow-up time was shorter (68 months vs 83 months).

As noted in the commentary of the MSKCC study, these findings may not apply when the primary therapy used a very high biologically effective radiation dose, such as with brachy boost therapy, SBRT, or high dose rate brachytherapy.

It makes sense to rule out the possibility of distant metastases using an advanced PET scan. Even at a cost of $2,500 or so, it may save the patient much more than that for the cost of salvage therapy. However, unless the PET scan is done at Mayo using C-11 Choline, is done as part of the clinical trial using the newly FDA-approved PET indicator fluciclovine, or is one of the free ones at NIH, the out-of-pocket cost may be formidable. Hopefully, the FDA will approve more of them, and availability will expand. Unfortunately for those considering early salvage after a prostatectomy failure, none of them are accurate for PSAs that low (≤0.2 ng/ml).

The authors constructed a nomogram to help the prospective patient predict whether his recurrence, detected with a C-11 Choline PET/CT, is likely to be a salvageable recurrence or unsalvageable recurrence. In the first table, fill in the number of points that comes closest to your situation, and add them up. In the second table, look up the probability of a distant recurrence (unsalvageable) that comes closest to your total number of points.



Risk Factor
Points to assign
My Points
PSA increase from nadir
2 ng/ml: 13
5 ng/ml: 32
10 ng/ml: 63
15 ng/ml: 95

Years since RT
1 yr: 100
2 yrs: 95
3 yrs: 90
5 yrs: 80
10 yrs: 52
20 yrs: 0

Risk Group
Low: 0
Intermediate: 8
High: 45


TOTAL




My Total
Points
Probability of recurrence outside of the pelvic area
66
5%
88
10%
120
25%
153
50%
185
75%
216
90%
240
95%

This nomogram outperformed using a PSA threshold alone in its predictive power, and may help the patient decide whether potentially-curative salvage therapy or lifelong hormone therapy is the better course of action.

I'm not sure why radiation dose was not significantly correlated with the site of recurrence at Mayo (p = 0.1) as it was in the MSKCC study. In fact at MSKCC, those who received doses of at least 79.2 Gy had half the rate of recurrence compared to those who only received 75.6 Gy (which seemed to be the norm at Mayo). It may be that those who were treated at Mayo only received higher doses when their cancer was already systemic. We know that this is on the steep part of the dose/response curve where even a small increase in dose can increase its effectiveness greatly. Whatever the reason for the data discrepancy, higher doses do prevent local recurrences.

(update 11/18/2018) Hayman et al. reported on 49 men who had a biochemical recurrence after whole pelvic primary radiation therapy and long-term ADT who were clinically staged as node positive (N1) via MRI. Using imaging (probably a PET/CT scan) they found the site(s) of recurrence in 46 of the men:

  • 25 (54%) had a recurrence in the prostate only
  • None had a recurrence in lymph nodes only
  • 21 (46%) had a recurrence that included a distant metastasis

This is very similar to Mayo and MSK.



note: Thanks to Dr. Will Parker for letting me review the full text of his published study.

Monday, September 5, 2016

Testosterone to TREAT prostate cancer - are they crazy? No - it just may work. (mHSPC)

This is Part 2. In Part 1 we saw why bipolar androgen therapy (BAT) may be effective for men with metastatic castration-resistant prostate cancer (mCRPC), and the evidence so far in support of that. In this part, we'll look at what we know about BAT in men with metastases who are still hormone sensitive (mHSPC). As you recall, BAT is an experimental therapy for metastatic prostate cancer involving the administration of rapidly alternating treatments of androgen deprivation (ADT) with high-dose testosterone.

In theory, the high doses of testosterone will help the patient feel better and perhaps offset some of the symptoms of ADT (e.g., loss of libido, hot flashes, bone loss, lean muscle loss, mental symptoms).

In pilot trials so far, BAT was able to restore sensitivity to second-line hormone therapy, like Zytiga or Xtandi, in some men who had become resistant to their effects. If it can reverse castration resistance, can it also slow down the development of castration resistance? 

Schweizer et al. report on 29 patients:
  • None of the men in the study had started on androgen deprivation yet.
  • None had symptoms.
  • 10 had a low burden of metastases.
  • 19 had no detectable metastases, but had recurrent disease after an attempt at a cure (i.e., their cancer was micrometastatic)
  • They were all hormone sensitive. That means their PSA went down to less than 4 ng/ml after 6 months of ADT

They then received 3 months of testosterone injections, and then 3 months of ADT. Those cycles continued for a total of 18 months. 
  • They report that 17 men (59%) were still able to achieve their PSA goal (<4 ng/ml) at the end of 18 months. That is, they were still hormone sensitive.
  • Of the 10 patients with detectable metastases at the start, metastases had shrunk completely in 4, and partially in 4. So 8 in 10 (80%) had a positive radiographic response to BAT.
  • Six patients had metastatic progression. 
  • So, 13-15 of the 19 (68-79%) men with recurrent PC with no detectable metastases at the start still had no detectable metastases after 18 months of BAT.
  • Evaluations of quality of life improved.
(Update 8/16/22) Denmeade et al. looked at responders and non-responders.
  • Responders achieved PSA<4 ng/ml after BAT
  • Non-responders had PSA≥4 ng/ml after BAT
  • They also looked at responders with a PSA≤9 ng/ml, and non-responders with a PSA>9 ng/ml after BAT

After 5 years of follow-up:
  • Progression-free survival was 21 months among non-responders with PSA>9 months vs. not reached if PSA≤ 9 months
  • Overall survival was 80 months among non-responders with PSA>9 months vs. not reached if PSA≤ 9 months
High PSA after BAT is an indicator that the therapy did not work.



Since the CHAARTED and STAMPEDE clinical trials, the new standard of care for mHSPC is the combination of ADT and docetaxel chemotherapy. Where would BAT fit in? We saw in Part 1 that BAT may work particularly well in conjunction with chemotherapy that targets the DNA responsible for cell replication. Docetaxel is usually administered in 6 three-week cycles. It may turn out that after an ADT induction period of 6 months, patients may be optimally treated by a high dose of testosterone and docetaxel concurrently. Testosterone would help the chemo patient feel better, and would also tend to raise his red blood cell counts, counteracting any chemo-induced anemia.


Another consideration is whether radiation ought to be included in the mix of early treatments. A few recent studies (see this link and this one) suggest that prostate radiation might still be beneficial to the metastatic patient. Moreover, a lab study suggests that radiation and BAT may be a particularly potent combination.

At this point, all of this is pure speculation. Future expanded clinical trials will have to determine whether BAT is useful for men with mHSPC, and what the optimal sequencing of therapies should be.