Saturday, August 27, 2016

Low detectable PSA after prostatectomy – watch or treat?

In a previous article, we looked at evidence that a low detectable level of PSA predicts eventual biochemical recurrence (a confirmed PSA greater than 0.2 ng/ml) when there is aggressive pathology. But what is one to do when the pathology report is not necessarily poor (that is, the cancer may be fully contained within the prostate, and all surgical margins may be negative), yet the PSA is detectable and possibly rising?

Because several randomized clinical trials have demonstrated an advantage to earlier treatment over waiting, the National Cancer Center Network (NCCN), which comprises many of the top US cancer centers, uses a lower threshold for defining biochemical recurrence:
  • ·      PSA detectable (≥ 0.03 ng/ml) after prostatectomy, or
  • ·      PSA undetectable after prostatectomy that is subsequently detectable on at least two tests

The NCCN definition may lead to overtreatment of patients in whom the small amounts of PSA may be attributable to benign tissue left behind, extra-prostatic sources, or indolent cancer that may never progress in the patient’s lifetime. On the other hand, waiting for the American Urological Association (AUA) definition of a confirmed PSA greater than 0.2 ng/ml may allow the cancer time to progress beyond the local area.

Koulikov et al. of Roswell Park Cancer Institute addressed this problem in a retrospective study published in the Journal of Urology. They wanted to determine whether the pattern of low detectable PSA during the first 3 years after surgery could be used to predict eventual biochemical recurrence (a confirmed PSA ≥ 0.2 ng/ml). Their institutional database analysis was based on 556 prostatectomy patients treated between 1993 and 2008 whom they assigned to three groups defined as:

  • 1.     “Undetectable PSA” (419 patients)

·      0.03 ng/ml or less
  • 2.     “Low detectable, stable PSA”  (93 patients)

·      PSA greater than 0.03 and less than 0.2 ng/ml
·      No two subsequent increases in PSA, and/or
·      PSA velocity less than 0.05 ng/ml/yr
  • 3.     “Low detectable, unstable PSA” (54 patients)

·      PSA greater than 0.03 and less than 0.2 ng/ml
·      Two subsequent increases in PSA, and/or
·      PSA velocity of 0.05 ng/ml/yr or greater

The primary endpoints they looked for were either biochemical recurrence (a confirmed PSA≥ 0.2 ng/ml) or salvage radiation therapy beyond 3 years of follow up. They could not draw any meaningful conclusions about survival because of the relatively short follow up.

The 7-year recurrence-free survival rates for the three groups were found to be:
  • ·      95% in the “undetectable PSA” group
  • ·      94% in the “low detectable, stable PSA” group
  • ·      37% in the “low detectable, unstable PSA” group

The post-surgical pathological findings of the “undetectable PSA” and the “low detectable, stable PSA” groups were nearly identical, while there were significant differences compared to the “low detectable, unstable PSA” group. Intermediate- and high-risk patients were more often found in the “low detectable, unstable PSA group” compared to the other groups.

The presence of a “low detectable, unstable PSA” was a significant predictor of biochemical recurrence, along with pathological stage, Gleason score, and positive surgical margins. It would be useful to know if those patients progressed to biochemical recurrence even if they did not have aggressive pathological characteristics; however, with only 54 patients, it would be impossible to draw reliable conclusions.

If these findings are confirmed in randomized clinical trials, post-prostatectomy patients with “undetectable PSA”, or “low detectable and stable PSA”, could be safely watched.

There is an open controversy as to whether salvage radiation therapy, even if given after biochemical recurrence (a confirmed PSA ≥ 0.2 ng/ml), translates to a survival benefit. Fewer than a third of patients with a post-prostatectomy biochemical recurrence experienced systemic progression, and it takes a median of 8 years for distant metastatic progression, and 13 years for mortality to occur, according to a Johns Hopkins study. This study may help inform patient and doctor discussion and choices.

note: Thanks to Dr. James Mohler for providing access to the full text of the study by Koulokov et al..

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