Thursday, August 15, 2019

The definition of SECOND biochemical recurrence (after prostatectomy AND salvage radiation)

There is no standard definition of SECOND biochemical (PSA-detected) recurrence (BCR); that is, after both prostatectomy and salvage radiation (SRT). There are two reasons to have a standard definition of second BCR:

  1. Time for next treatment: BCR (after any treatment) is the first indicator of treatment failure, and a signal that it may be time to consider additional treatment. It is not at all clear that immediate additional treatments are beneficial, although the TOAD RCT suggested that early systemic treatment may be beneficial. If a treatment becomes the standard of care after biochemical failure, then it will be necessary to define the PSA or PSA doubling time (PSADT) at which that treatment should begin.
  2. Comparison among radiation protocols: Lacking randomized clinical trials among all the variables of when and how salvage radiation are given (pathological characteristics, PSA, PSADT, radiation dose, adjuvant ADT, prostate bed radiation, radiation of pelvic lymph nodes), we can only look at effectiveness across studies to help us hypothesize that one strategy might be better than another. It helps if we have a consistent definition of success.
Miyake et al. looked at three definitions of second BCR:
  1. NARA definition: PSA never falls below 0.2 ng/ml; or, it falls below 0.2 ng/ml but later rises over it in two consecutive readings.
  2. RTOG 9601 definition: any post-SRT PSA over 0.5 ng/ml; or, nadir + 0.3 ng/ml; or the start of hormone therapy.
  3. GETUG definition: nadir + 0.5
They evaluated 118 patients using the 3 definitions. With 49 months of median follow-up after salvage radiation:
  • The Nara definition had the highest rate of second BCR; 53%, 45% and 40% for Nara,  RTOG and GETUG respectively.
  • Gleason score and Pre-SRT PSA independently predicted Nara BCR, while negative margins and PSADT also predicted RTOG and GETUG BCR.
  • There were no discrete cut-offs of the patient characteristics that reliably predicted BCR by any definition
It's worth noting that the definitions may differ for study entry and endpoint (it is usually called "biochemical progression" when used as an endpoint). Many clinical trials use the 0.2 ng/ml definition for the second BCR too.  This trial used PSA≥ 0.2 ng/ml or 3 consecutive rises after RP or SRT. We recently saw that another RTOG trial, the SPPORT trial, used a BCR endpoint definition of nadir + 2 because it correlated well with clinical recurrence.

It is sometimes necessary to define a THIRD BCR as an endpoint to determine whether a therapy that began after a second BCR was successful. For example, an ongoing trial of hormonal therapies for SRT-recurrent men uses a second BCR definition of PSA > 0.5 ng/ml and PSADT ≤ 9 months, and a third BCR definition of a confirmed 25% rise in PSA and nadir + 2 during therapy, and a fourth BCR definition of a confirmed PSA > 0.2 after hormonal therapy.

The definition for FIRST BCR of a confirmed PSA after prostatectomy of 0.2 ng/ml was an artifact of the current lowest discernible PSA before the 21st century, which was 0.1 ng/ml at the time. The American Urological Association decided that anything higher than that would be deemed a BCR. With the growing and widespread use of ultrasensitive PSAs in the 21st century, many question that definition. Radiation oncologists at the top institutions recommend that SRT should be undertaken at the lowest PSA that indicates that clinical recurrence is likely. That may be as low as 0.03 ng/ml when there was significant adverse pathology, or a much higher value if pathology was clean and Gleason score was minimal.

BCR is just one of a number of elements to be evaluated after SRT. A BCR with a high Decipher score may suggest that immediate salvage ADT is appropriate. With the new generation of PET scans, which can detect metastases at low PSAs, it may sometimes be beneficial to treat pelvic lymph node metastases and possibly distant metastases if SRT had only included the prostate bed.

This small, retrospective study will not establish a new definition, but it does raise the interesting question of whether we need a standard definition, or whether the definition ought to depend upon the purpose for which it is used. When we have definitive evidence that early treatment after failed SRT is beneficial, that will force researchers to investigate the optimum PSA (or PSADT) cutpoint.

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