Very early salvage radiation has up to fourfold 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 percent 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 ng/ml, 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 to 0.2 ng/ml — the “very early salvage” cohort
    • > 0.2 to 0.5 ng/ml — the “early salvage” cohort
    • > 0.5 ng/ml — the “later salvage” cohort (the median PSA was 0.4 ng/ml)
  2. At an earlier time from completion of prostatectomy
    • < 9 months
    • 9 to 21 months
    • 22 to 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 had 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 percent 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 percent of patients for a median of 6 months (range, 4 to 24 months), was significantly associated with freedom from biochemical recurrence after SRT. There were 40 percent fewer failures.

The 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 to 0.5 ng/ml) were twice as likely to develop metastases and die of prostate cancer as those who were treated at the earliest PSA (< 0.2 ng/ml). 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 had three large randomized clinical trials that proved that beneficial 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 over-treatment 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 state that,

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.

Editorial note: This commentary was written by Allen Edel for The “New” Prostate Cancer InfoLink.

12 Responses

  1. What were the results for high-risk patients? Did any high-risk patients (you know the definition) benefit from very early SRT? I waited until PSA of 0.2 twice using the “standard of care” but my pathology was bad (Gleason 9, SVI, EPE, positive margin) so I doubt that very early SRT would have helped.

  2. There seems to be a problem with the median PSA level of the “later salvage” cohort.

  3. There are men who have low level PSA after prostatectomy which is felt to be due to prostate tissue left back at the time of surgery.

    How can this be differentiated from persistent cancer tissue without a second PSA level?

  4. Thanks Allen for another excellent article on a key issue in using radiation. I thought this piece was particularly outstanding! A lot of us will now be thinking differently about the role of salvage RT.

    There may be grounds for optimism even for those of us who have distant metastasis at the time of salvage radiation. (You commented: “… 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. …”) I’ve had friends in this situation who were scanned to determine whether their post-radiation recurrences were oligometastatic, and at least one of them is doing very well after two separated rounds of radiation that pin-pointed isolated oligometastases.

    Also, of course, we can keep in mind the drug Xofigo, which can wipe out metastases in bone, and there is reason to hope that within a few years we may have a similar hunter/killer combo that goes after distant metastasis in soft tissue (such as the investigational lutetium/PSMA combo that has been reported in this forum). Thus, the salvage radiation may do its work in wiping out more localized metastasis, while newer and emerging therapies wipe out the rest. In other words, time is on our side.

  5. Bob:
    Those with worse disease characteristics on their pathology, particularly those with higher Gleason score and positive margins, had significantly worse outcomes, of course. But the pre-RT PSA alone explained 91% of the variance in outcomes. This shows that waiting for PSA to rise above 0.2 is not a good idea. I agree with the authors that discussions with an RO should start at the earliest detectable PSA, well, at least over 0.03 ng/ml.

    Thanks for pointing that out. I meant the parenthetical remark about median PSA to explain why they used the 0.5 ng/ml cut-point. The 0.4 ng/ml median applies to all the patients in their study, not just the ones who had later salvage. So all in all, about half the patients had a pre-SRT PSA of 0.5 or higher. I should have made that more clear.

    It now seems that there is no appreciable persistent PSA from benign tissue left behind after the prostatectomy. PSA does leak out from any prostate tissue that is freshly cut, but it does not persist. The serum half-life of PSA is only 2 to 3 days, so surgical sources are rapidly dissipated. See this link for a study showing that benign prostate sources very rarely (6 in a thousand) contribute to detectable PSA over 0.04 ng/ml.

    Thanks for the kind words. Unfortunately, as evidence accumulated, the hypothesis that, for many of those with oligometastatic (M1) prostate cancer, it could be cured with current methods now seems like wishful thinking on our part. The exception may be when it is only detected in pelvic lymph nodes (N1). Perhaps a few, and hopefully your friend, will benefit. I share your hope about the possibility that systemic treatments will continue to lengthen the time we can live with it as a manageable disease.

  6. Allen:

    Regarding your response to Jim, have any studies been done of men with oligometastatic prostate cancer found only in pelvic lymph nodes as to whether SRT to those nodes stopped the spread of prostate cancer to other parts of the body?

  7. Bob:

    There have been no randomized clinical trials that I know of to date, although there is an ongoing one (RTOG 0534) that will determine whether salvage radiation to the whole pelvis is any better than salvage radiation to the prostate bed alone when positive nodes have not yet been identified. Three database analyses on this subject have found conflicting results. They are discussed in the next-to-last paragraph in this commentary.

  8. Does Early Salvage Radiation Therapy/SRT Following Failed Surgical Removal of the Prostate Gland Provide Increased longevity? My Personal Account 23 years Later

    I expect I received about as early salvage radiation therapy (SRT) as could be expected following “open” surgical removal of my prostate gland on December 16, 1992. My urologist wasn’t certain he “got it all” because a tumor extended into fatty tissue beyond where he felt it safe to “cut.” Pathology of the removed gland otherwise found seminal vesicles, vas deferens, and sample lymph nodes clear of cancer cell presence and a Gleason score of 3 + 4 = 7.

    37 sessions of SRT occurred in April and May 1993 with subsequent PSA < 0.1 ng/ml. All is well? Three years later, in November 1996, PSA on the rise thus SRT unsuccessful but apparently sufficiently successful that what remained “somewhere” turned out to be controllable by androgen deprivation Tterapy (ADT) begun when PSA level reached 0.81 ng/ml. Urologist kept me on years of Lupron accompanied by bicalutamide (Casodex) with PSA < 0.01 ng/ml, and when asked why I was still on ADT without a break his glib response was “Well it’s working, isn’t it?” Yes, but that constant ADT resulted in my testosterone no longer being able to recover.

    Moved to medical oncologist and began first intermittent ADT (IADT). PSA began elevation 18 months later but this time I added the 5-alpha-reductase inhibitor (5ARI) dutasteride (Avodart) to my return to Lupron and Casodex (triple hormonal blockade) with PSA dropping to < 0.01ng/ml, so 1 year later returned to IAD but continued the dutasteride/Avodart to inhibit any returning testosterone from converting to the more powerful stimulant to cancer cell growth/proliferation dihydrotestosterone (DHT). This time IADT was effective for 2 months short of 6 years before PSA again showed elevation. Return to Lupron and Casodex to accompany continuing Avodart was unsuccessful, with PSA continuing to elevate despite removal of Casodex as possible culprit. By the time PSA level reached 2.55 ng/ml added abiraterone (Zytiga) to continuing Lupron and Avodart. Though slowly — but definitely — PSA dropped to 0.31 ng/ml over 23 months, then began a very slow, but again definite, elevation t0 0.964 ng/ml 31 months later, then a slight drop to 0.941 ng/ml at 34 months, and most recently another slight drop to 0.88 ng/ml at 37 months — 5 years total now of apparent Zytiga success.

    I added metformin accompanied by vitamin B12 shortly before the first drop in PSA level 6 months ago that likely accounts for the more recent drops in PSA level. The location of existing cancer cells continues to be unknown with the variety of imaging unable to identify any accumulation of cells sufficient for such imaging. So, I am an example of the form of treatment “I” chose for my treatment having been successful in controlling my prostate cancer for the past 20 years on/off ADT, 24 years since initial diagnosis/treatment, and counting. I provided this information when reading this report considering that my “salvage radiation” occurred about as early as one could following recovery from open surgical removal of my prostate gland.

    Charles (Chuck) Maack
    Prostate Cancer Patient/Activist/Mentor (former due to heath issues)

  9. Chuck:

    That’s quite a journey! Congrats for staying with it for so long. I hope for similar results but my pathology is much worse than yours, being Gleason 9, stage pT3b.

    I’ve had open RP, SRT to bed, and finally IMRT to all pelvic nodes when two suspicious iliac nodes were found by scan. I’m coming off 13 months of triple blockade HT but staying on Avodart, metformin. I’ll probably be doing IADT and switching LHRH agonists like you did.

  10. Thanks Allen. I’ll just have to hope it works while recognizing the odds are not good.

  11. Thanks for this article. One editorial suggestion for clarification: in the first numbered paragraph where you define “early” using PSA, the first bullet point reads: 01 to 0.2 ng/ml. Without a decimal point, I had to go to the linked abstract to learn that the lower end of the “very early salvage cohort” is defined at 0.01 ng/ml and not 0.1 ng/ml.

  12. Thanks for pointing that out Dan. It has now been corrected. Sorry … typos happen! :O)

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