The myth that younger men should not pursue active surveillance

In spite of no evidence to back up their assertion, I continue to hear urologists say things like "If you were older, I'd recommend active surveillance. But because you're young, you should have surgery for your low risk prostate cancer now while your recovery will be better." We saw, in a previous article, that immediate surgery rather than active surveillance only resulted in more years of expected misery from impotence and incontinence: see: "Can a man be too young for active surveillance?"

Now, a new study from Memorial Sloan Kettering Cancer Center examines the evidence for potency preservation. The authors, who include John Mulhall, the sexual medicine specialist, demonstrate that the expected loss of erectile function is never compensated for by better recovery in younger men and the age-related decline in erectile function over the years while waiting on active surveillance.

They used a standard questionnaire, the International Index of Erectile Function 6 (IIEF6). It is sometimes called the Sexual Health Inventory for men (SHIM). There are six questions, and the best score (excellent erectile function) is 30. The questions are:

1. Over the last month, how often were you able to get an erection during sexual activity?
2. Over the last month, when you had erections with sexual stimulation, how often were your erections hard enough for penetration?
3. Over the last month, when you attempted intercourse, how often were you able to penetrate your partner?
4. Over the last month, during sexual intercourse, how often were you able to maintain your erection after you had penetrated your partner?
5. Over the last month, during sexual intercourse, how difficult was it to maintain your erection to completion of intercourse?
15. Over the last month, how do you rate your confidence that you can get and keep your erection?

All men filled out the questionnaire before surgery and periodically for two years. They excluded high risk patients who wouldn't be eligible for active surveillance, and any men who did not have bilateral nerve-sparing surgery. Men who had hormone therapy or salvage radiation were also excluded. There were 1,103 men in their cohort of men treated with RP at MSKCC between 2009-2013. Needless to say, MSKCC has some of the best, most experienced surgeons in the world.

They first looked at the baseline scores by age to get an understanding of how erectile function declines with age. This defines the expected erectile function if there were no surgery. They also looked at actual scores after surgery for each age. The difference between actual and expected shows the true effect of surgery on erectile function, with compensation for age-related decline and for the time delay caused by active surveillance.

They found that:

• Each year increase in age reduced the IIEF6 score by -0.27
• Erectile function recovery after RP declined by -0.16 for each year older at the age of treatment

While younger men started with a higher erectile function score, and their recovery after RP was better, it was never good enough to be better than the erectile function of an older man who didn't have surgery. At all time points, they would have been better off if they had delayed treatment and stayed on active surveillance. There was no "window of opportunity" where younger age recovery exceeded what would be expected to happen if they waited.

The authors conclude:

Small differences in erectile function recovery in younger men are offset by a longer period of time living with decreased postoperative function. Better erectile recovery in younger men should not be a factor used to recommend immediate surgery in patients suitable for active surveillance, even if crossover to surgery is predicted within a short period of time.

I hope patients whose urologists spout the myth that "early surgery will lead to better long-term erectile function than delaying until he is older" will email this important study to them and ask for comment.

After failure of first-line radiation, both kinds of salvage brachytherapy are equally effective

A group of researchers at Memorial Sloan Kettering Cancer Center (MSKCC) reported in 2014 (see this link) on the outcomes of 42 patients with radio-recurrent prostate cancer treated with salvage high dose rate brachytherapy (sHDR-BT). The results were quite good - over two thirds had no evidence of further recurrence as of 5 years, and grade 3 toxicity (serious, requiring treatment) was limited to one patient with late-term urinary incontinence. Kollmeier et al. have now updated their results and compared them with outcomes of men treated with salvage low dose rate brachytherapy (sLDR-BT).

All patients were treated between 2003 and 2015, and all salvage treatments were whole gland, not focal or hemi-gland.

• 37 patients received sLDR-BT
• 61 received sHDR-BT
• 45% received adjuvant androgen deprivation therapy (ADT)
• All patients were screened for distant metastases with a CT or MRI and a bone scan at least
• All patients had biopsy-confirmed cancer in the prostate

After a median follow-up up 31 months:

• 3-year PSA relapse-free survival (RFS) was 60%
• Both therapies were similar
• RFS=39% for those with PSA doubling times (PSADT) less than 1 year vs. 72% for those with PSADTs of a year or more.
• No statistically significant differences in urinary or rectal toxicity between the two therapies: most returned to baseline function.
• sLDR-BT had a higher rate of acute urinary toxicity
• Erectile function was not measured because of high rates of pre-existing impotence and ADT usage

In the Fuller study of salvage SBRT (see this link), bRFS was 82% at 2 years, and ADT was not used. NIH will soon begin recruitment for a clinical trial of salvage SBRT (NCT03253744), which includes detection using the DCFPyL PET/CT - the best of the new generation. Dr. Kollmeier mentioned that MSKCC has treated a few select patients with salvage SBRT as well. They are also looking at using a more tailored approach: adding systemic therapy for higher grade recurrences and focal/hemi-gland treatment for less aggressive cases. MSKCC is on the leading edge of using the new generation of PET/MRI scans which will undoubtedly improve patient selection going forward.

How soon after surgery should salvage radiation begin?

Patients and their doctors often have to make a critical decision soon after surgery – at what point after surgery, if at all, should salvage radiation therapy be started? Immediate treatment is often too early, and waiting can be too late. Two new papers give us much-needed help in finding the “Goldilocks moment.”

 Let’s begin with a shared understanding of the definitions of some commonly used terms and abbreviations:

• Adverse pathology means that the post-op pathology report indicates that cancer was found in one or more of the following places:
  • Outside of the prostate capsule (pathological stage T3a), or
  • In the seminal vesicles (pathological stage T3b), or
  • Locally, but at a distance from the prostate (pathological stage T4), or
  • At the surgical margin, where the surgeon has cut through the cancer — a “positive surgical margin” (PSM).
• Adjuvant radiation therapy (aRT) means radiation given after prostatectomy when there is adverse pathology, but before the PSA becomes detectable.
• Salvage radiation therapy (sRT) means radiation given after prostatectomy but also only after a biochemical recurrence (BCR).
• Early salvage radiation therapy (early sRT) means radiation given after the point that aRT would be given, but before sRT would be given.
• Wait-and-see is the strategy of waiting until after a BCR to decide what to do. The wait-and-see decision may be sRT at any time after BCR, or the patient may decide to forgo radiation, use hormone therapy, or do nothing until there is evidence of clinical progression.
• Biochemical recurrence (BCR) post-surgery is now defined as a confirmed PSA ≥ 0.2 ng/ml. This was chosen in 2007 because it was the most frequently used threshold in published studies. When those studies began, a PSA of 0.1 ng/ml was as low as could reliably be measured. Anything below that was undetectable at the time, and 0.2 ng/ml was arbitrarily deemed a biochemical recurrence.
• An ultrasensitive PSA (uPSA) test is any PSA test that can reliably detect PSAs below 0.1 ng/ml. While the definition of biochemical recurrence has not been changed, detectable levels of PSA are now as low as 0.001 ng/ml on some commercially available ultrasensitive tests.

The above definitions can be illustrated as potential decision points along a line showing uPSA values after prostatectomy and adverse pathology:

Why start sooner than sRT/wait-and-see, but later than aRT?

Three major randomized clinical trials have shown that there is an oncological advantage to aRT over a wait-and-see strategy in patients with adverse pathology after prostatectomy. This is hardly surprising, especially because “wait-and-see” includes patients who never even received salvage radiation, or may have only received palliative hormone therapy. There has never yet been a randomized clinical trial comparing aRT to sRT.

Based on those studies, both the American Urological Association (AUA) and the American Society of Radiation Oncologists (ASTRO) endorse aRT in their guidelines. However, in spite of those guidelines, only 43 percent of men who get radiation after prostatectomy do so within the first 6 months of their surgery (see Sheets et al.). Why aren’t more patients choosing aRT?

Patients (and many doctors too) worry about over-treatment, and the adverse effects of radiation on recently cut tissues. Immediate aRT may represent over-treatment for many men for whom small, detectable amounts of PSA are leaked into the serum from benign tissue left behind by surgery, or men in whom any tiny amounts of malignant tissue left behind may be indolent or susceptible to scavenging by the immune system. Kang et al.found that, among men with capsular perforation, PSMs, or seminal vesicle invasion after surgery, only 17 percent actually went on to have a true biochemical recurrence. The other advantage to waiting is that it may allow for better recovery of continence and erectile function after surgery in at least some patients.

All three of those above-mentioned clinical trials accrued participants before uPSA tests became routinely available. Although the use of uPSA testing is controversial, its widespread use has led many patients and clinicians to wonder whether waiting for some low PSA value – “early salvage radiation” – might be equivalent in outcomes to aRT.

There are randomized clinical trials underway in Canada and the UK, in Australia and New Zealand, and in France to determine whether early sRT might be equivalent to aRT in terms of survival. The combined results of those trials may have sufficient power to answer the question. Those findings will be definitive, but in the meantime two groups of researchers have retrospectively analyzed their patient outcomes for clues.

Ultrasensitive PSA reliably predicts eventual biochemical recurrence (a UCLA study)

Researchers at the University of California, Los Angeles (UCLA) looked at available evidence that the uPSA test might afford radiation oncologists the opportunity to treat patients late enough that they are assured to be on a path to clinical recurrence, yet early enough that waiting for treatment does no oncological harm. Kang et al. conducted a retrospective analysis of data from 247 patients treated at UCLA between 1991 and 2013 who were found on post-op pathology to have adverse disease characteristics — stage pT3-4 disease and/or positive surgical margins — and who received uPSA tests. That cohort had the following characteristics:

• Positive margins in 79 percent of patients
• Patients were excluded if
  • They had already received radiation and/or hormone therapy, or
  • They were found to be node-positive at the time of surgery
• Pathological stage T3/T4 in 55 percent of patients
• Gleason score ≥ 7 in 81 percent of patients
• Initial, pre-surgical PSA ≥ 10 in 29 percent of patients
• Time to first post-op PSA, 3 months
• Median number of PSAs post-surgery and before subsequent treatment, 4
• Median follow-up, 44 months

Kang et al. found that a uPSA ≥ 0.03 ng/ml was the optimal threshold value for predicting biochemical recurrence (BCR). Other findings included:

• uPSA ≥ 0.03 ng/ml was the most important and reliable predictor of BCR. It predicted all relapses (no false negatives: no one was under-treated), and hardly ever predicted relapses incorrectly. Only 2 percent would be over-treated by waiting for this cut-off.
• It was especially prognostic if found on the first uPSA test after surgery.
• Even if the first uPSA test was undetectable, any subsequent test where uPSA ≥ 0.03 ng/ml predicted BCR.
• Other lesser predictors of recurrence were pathologic Gleason grade, pathologic T stage, initial PSA before surgery, and surgical margin status.
• At 5 years of follow-up, 46 percent of patients had a BCR using the “standard” PSA ≥ 0.2 definition, 76 percent using the PSA ≥ 0.03 definition.
• Treating when an ultrasensitive PSA level reached 0.03 ng/ml gave a median lead time advantage of 18 months over waiting until PSA reached 0.2 ng/ml.
• It was necessary to monitor PSA for at least 5 years post-op, and to test at least every 6 months.

What is not known at this time is whether there is a survival disadvantage from waiting until uPSA reaches 0.03 ng/ml if it is not at that level immediately after surgery. (update 10/2018)  Kang et al. report that there is indeed a survival advantage from treating if the first uPSA level (at 3 months after surgery) reaches 0.03 ng/ml. So the lead-time advantage actually translates to a survival advantage for men with adverse pathology who have a persistent uPSA of at least 0.03 ng/ml.

If the findings of this study by Kang et al. are confirmed by randomized clinical trials, there is certainly a strong argument that all patients with adverse post-op characteristics should be monitored routinely using ultrasensitive PSA tests, and offered treatment with salvage radiation when their PSA level reaches 0.03 ng/ml. It is also arguable that the definition of biochemical recurrence after prostatectomy should then be changed to 0.03 ng/ml, which would be more practical.

Ultrasensitive PSA can reliably predict eventual biochemical recurrence at 2 months after surgery (a Czech study)

A Czech study (Vesely et al. and updated here) looked at a group of 116 patients (205 updated) who had PSMs after surgery. Unlike the UCLA study, staging was not a selection criterion. The two studies’ goals were somewhat different. While the UCLA study didn’t start uPSA testing until 3 months after prostatectomy, in this study uPSA testing was begun at 2 weeks post-surgery. Most urologists wait for 3 months because surgery sheds a lot of PSA into the serum, and it takes a while for that excess to clear out. The goal in this study was to find out just how early in time after prostatectomy they could detect a uPSA prognostic for BCR, whereas the UCLA study sought to find out how late in uPSA progression they could detect a PSA prognostic for progression. The Czech cohort had the following characteristics:

• Only patients with PSMs were included
• Patients who received aRT or hormone therapy were excluded
• Pathological stage T3/T4 in 54 percent of patients
• Gleason score ≥ 7 in 51 percent of patients
• Initial, pre-surgical PSA ≥ 9.2 in 50 percent of patients
• Time to first post-op PSA, 14 days

All patients’ PSA levels were measured on days 14, 30, 60, 90, and 180 post-surgery, and at 3-month intervals thereafter; the median follow-up was 31 months.

Vesely et al. found that the uPSA on day 30 had predictive accuracy of 74 percent for recurrence, and reached a maximum of 84 percent by day 60, when the uPSA was 0.04 ng/ml (increases in accuracy afterwards were not statistically significant). The following table summarizes their findings:

• Applying the uPSA cut-off at day 60 as the indicator for sRT would result in the decrease of over-treatment from 53 to 4 percent. Of the 33 percent who would be under-treated, 86 percent would eventually be discovered at subsequent follow-up at 3 months, and 98 percent by 4 years.
• uPSA at day 14 was not prognostic for recurrence.
• The following were not predictors of recurrence in men with PSMs: pathologic Gleason grade, pathologic T stage, initial PSA before surgery.
• Neither the location nor the extent of PSMs had any significant impact on the frequency of BCR.
• At 5 years of follow-up, 47 percent of patients had a BCR using the “standard” PSA ≥ 0.2 definition.

The main conclusion of this study is that uPSA tracking can begin earlier. Even as early as 30 days post-op, uPSA has good accuracy for predicting BCR in men with PSMs, and at 60 days, the accuracy is even better. If duplicated in larger studies, this implies that uPSA testing ought to begin 1 or 2 months earlier than it usually does at present.

The predictive accuracy of this study is somewhat lower than the UCLA study, perhaps in part because the sample size was half as big. The results in terms of uPSA prognostic threshold values, however, are surprisingly similar. Here, the threshold was 0.04, 0.01, and 0.02 ng/ml at 2, 3, and 6 months, respectively. In the UCLA study, the threshold was 0.03 ng/ml at any time from 3 months onward. Because the uPSA ≥ 0.03 at 90 days and onwards was 100 percent predictive of BCR in the UCLA study, and led to almost no under-treatment, it may well obviate the need for earlier uPSA testing advocated in the Vesely et al. study.

As in the UCLA study, however, it is not yet known whether early sRT translates to a survival advantage over waiting for BCR.

For the first time, these studies give the patient and doctor new insight into the timing and use of uPSA to predict BCR. If confirmed, setting a uPSA threshold at about 0.03 ng/ml would reduce over-treatment compared to aRT, and would reduce under-treatment compared to sRT. We await the completion of three randomized clinical trials before we have more reliable data.

written 1/4/2015

First US randomized clinical trial of oligometastasis-directed SBRT

In a recent commentary (see this link), we saw that some clinicians are making unsubstantiated claims of cancer control from treatment of oligometastases (less than 5 detected metastases). Only a randomized clinical trial (RCT) can prove that there is any benefit to such treatment. Johns Hopkins has announced the first such RCT in the US.

Stereotactic body radiation therapy (SBRT) is the treatment of choice because it is precise, as well as convenient for the patient (usually completed in 1-5 treatments). It is important to distinguish between two different situations that may involve oligometastases:

1. Metastasis-directed SBRT after primary treatment (prostatectomy or prostate radiation) and any local salvage radiation has failed. This is sometimes called "metachronous" treatment of recurrent prostate cancer.
2. Radiation to the prostate and oligometastases in newly-diagnosed men, or men who are radiation- or surgery-naive but have progressed to castration-resistance.
3. Radiation to metastases for the purposes of pain palliation, or to prevent fractures or spinal compression.

In addition, the situation may be different depending on whether the oligometastases are in the visceral organs, bones, extra-pelvic lymph nodes, pelvic lymph nodes, or some combination of these.

Phuoc Tran is the lead investigator of the "ORIOLE" RCT (NCT0268058) at Johns Hopkins described at this link. It is a small, Phase 2 trial for men in situation A described above. It has some noteworthy characteristics:

• 36 men will receive SBRT, 18 men will receive standard-of-care treatment
• Oligometastases are diagnosed by bone scan and CT
• Patients will be balanced based on whether initial treatment was surgery or radiation, whether they've had hormone therapy, and whether the PSA doubling time was less than 6 months.
• The primary outcome will be radiographic or PSA progression (by >25% over nadir and by > 2 ng/ml) after 6 months.
• To be deemed successful, the treatment will have to reduce this measure of progression by 50%

There are several interesting secondary objectives of this RCT:

• identification of additional metastases using the DCFPyL PET/CT
• toxicity of treatment reported by doctors
• pain palliation reported by patients
• local control of metastases (see below)
• Number of circulating tumor cells (CTC)
• Genomic analysis of CTCs
• Immune (T cell) response to treatment
• Time until patients have to start life-long hormone therapy

We will see if the radiation activates a systemic T-cell response that may destroy cancer cells beyond the treated tumors (the abscopal effect).

It may seem odd that detection of fewer than 5 metastases by the DCFPyL PET/CT (developed at Johns Hopkins and now in expanded trials) is not a qualifying criterion. Perhaps they will change that for the Phase 3 trial. Or perhaps they want to prove the concept with a bone scan/CT because it will be several years before that PET scan (so far, the most accurate) is widely available and covered by insurance or Medicare. If it works for bone scan/CT-detected oligometastases, it will certainly work for DCFPyL PET-detected metastases.

Update (August 2017): Dr. Tran has made the following change in protocol:

We did change the criteria recently to allow men who had detectable disease on DCFPyL to enroll on the trial, BUT only if the DCFPyL did not show anything more than what is visible on conventional CT-AP and bone scan.  Our thought was that this would allow some patients of the "future" if you will (as PSMA-targeted imaging will be the SOC in 3-5 years) to be included on the trial, but because we do not allow men on the trial with DCFPyL scans that show us more than what is on conventional , we feel that still holds to original concept. 

It is also important to note what is not an objective of this early clinical trial. The outcome we most want to know is whether SBRT treatment of metastases extends overall survival. This 6-month trial will not tell us that. There is no doubt that local control will be excellent, but stopping the progression of 1-3 metastases does not necessarily mean that the cancer has been slowed down systemically at all. Certainly, PSA will fall as an immediate result of treatment. For those who are used to monitoring PSA as a measure of their cancer's systemic progression, this can be confusing. It's worth taking a moment to recall what serum PSA comes from in detectably metastatic disease. PSA is a protein on the surface of prostate cancer cells (and healthy prostate cells too.) It doesn't leak out into the blood from prostate cancer unless a tumor forms with its own blood supply. Tumor blood supply tends to be leaky, and so PSA is detected in the blood serum. Larger tumors with more blood supply put out more PSA. So irradiating those tumors and shrinking them is likely to eliminate the PSA they put out. But what about the micrometastases that do not yet have appreciable blood vessels? If there are thousands of them, will it matter that serum PSA was reduced for 6 months? No one knows the answer to that question and this Phase 2 study will not provide the answer. I hope they will provide radiographic progression-free survival separate from PSA progression-free survival.

For the answers to our most important questions we will have to look forward to the outcomes of some of the other RCTs that have longer follow-up than 6 months.

• The CORE RCT (active, no longer recruiting) at Royal Marsden Hospital in London will have 5 years of follow-up (completion in 2024), and will include freedom from widespread metastatic disease and overall survival among the outcomes looked at. 
• The STOMP RCT at University Hospital in Ghent had 2 years of follow-up looked at time to lifelong hormone therapy as its primary outcome (reviewed here). 
• The PCX IX RCT (among castration-resistant patients) at Jewish General Hospital in Montreal will have 5 years of follow-up (primary outcome in 2025) and has radiographic progression-free survival as its primary outcome. 
• The French RCT (recruiting, study completion in 2022) will look at radiographic progression-free survival with follow-up up to 3 years. 
• The FORCE RCT at the University of Michigan (primary completion in 2022) will compare systemic treatment with ADT and any of Taxotere, Zytiga or Xtandi (at the discretion of the treating physician) to similar systemic treatment plus metastasis-directed SBRT for men with mCRPC who have not yet had any of those advanced systemic therapies. They will evaluate progression-free survival after 18 months. "Progression" is defined as alive and at least a 20% increase (and at least 5 mm net increase) in the size of tumors or any new metastases. They will detect metastases via bone scan/CT, However, they will also test whether PSMA-based PET indicators are as useful in among men with mCRPC as it is in men with newly  recurrent disease.

Eighth randomized clinical trial of hypofractionated radiation therapy

We now have an eighth randomized clinical trial of hypofractionated radiation therapy. There are no surprises: it showed that oncological and toxicity outcomes were not significantly different between the two regimens. We last looked at it here. This trial is unusual because of the length of follow-up.

Arcangeli et al. report the 10-year outcomes of their study covering 168 high risk patients treated using 3D-CRT (not IMRT) at the Regina Elena Cancer Institute in Rome between 2003 and 2007. The details of the treatments were as follows:

• Half (85 patients) received conventionally fractionated (Conv)  80 Gy in 40 fractions
• Half (83 patients) received hypofractionated (Hypo) 62 Gy in 20 fractions

After a median of 9 years of follow-up:

• 10-year freedom from biochemical failure was 72% for the Hypo group vs. 65% for the Conv group.(no statistically significant difference)
• 10-year prostate cancer -specific survival was 95% for the Hypo group vs. 88% for the Conv group (no statistically significant difference)
• 10-year overall survival was 75% for the Hypo group vs. 64% for the Conv group (no statistically significant difference)
• Hypofractionation was a significant variable in determining prostate cancer-specific survival in multivariate analysis
• There were no differences in late-term grade 2 or higher urinary or rectal toxicity between the 2 groups.

There are a couple of caveats. For those who insist on rigorous analysis, the Hypo group had worse oncological and toxicity outcomes on an intention-to-treat basis. It was only after the patients were analyzed according to the treatment they actually received that the lack of statistically significant difference became apparent. James Yu, in an accompanying editorial, points out that blood in urine was 16.5% for the Hypo group vs. 3.6% for the Conv group. This may be a caution that hypofractionation should not be attempted using 3D-CRT. In the US, where IMRT is widely available, this should not be an issue.

Here's the table summarizing all 8 randomized clinical trials:

Randomized Clinical Trial	Risk Groups	Fractionation	5-yr bPFS	Urinary toxicity Grade 2+	Rectal toxicity Grade 2+	Ref.
PROFIT	100% intermediate	60 Gy/20fx 78 Gy/39fx	85% 85%	22% 21%	8% 14%	1
Fox Chase	67% Intermediate, 33% high	70.2 Gy/26fx 76 Gy/38fx	77% 79%	22% 13%	18% 23%	2
CHHiP	73% intermediate, 15% low, 12% high	60 Gy/20fx 74 Gy/37fx	91% 88%	12% 9%	12% 14%	3
MD Anderson	71% intermediate, 28% low, 1% high	72 Gy/30fx 75.6 Gy/42fx	89%† 85%†	16% 17%	10% 5%	4
RTOG 0415	100% low risk	70 Gy/28fx 73.8 Gy/41fx	94% 92%	30% 23%	22% 14%	5
HYPRO	>70% high, <30% intermediate	64.6 Gy/19fx 78 Gy/39fx	81% 77%	41% 39%	22% 18%	6, 7
Cleveland Clinic	49% low, 51% intermediate	70 Gy/28fx 78 Gy/39fx	94% 88%	1% 2%	5% 12%	8
Regina Elena	100% high risk	62 Gy/20 fx 80 Gy/40 fx	72%* 65%*	21% 14%	NA NA	9

*10-year figures for the Regina Elena trial
† 8-yr failure-free survival update for MD Anderson