Biochemical PSA Recurrence

[Updated December 22, 2009]

Introduction

In an particularly useful review article in the February 2008 Canadian Family Physician Wilkinson, Brundage and Siemens write

An increasing PSA level after curative therapy is termed a biochemical recurrence (BCR). Approximately one-third to half of patients will experience BCR during the course of their follow-up, regardless of modality of treatment. [PMID: 10886105] [PMID: 16600730] The significance of a BCR is in itself unclear, as not all men who have experienced BCRs will go on to experience metastatic disease. [PMID: 12605977] In one study, fewer than one-third of patients with BCR after RP developed systemic recurrence.[PMID: 12605977] In those patients who progress, BCR usually predates metastatic disease progression by an average of 7 years and prostate-cancer specific mortality by 15 years.[PMID: 16921049] [Full Text] Therefore it is useful in allowing enough lead time to implement effective salvage therapeutic strategies in those patients whose recurrences are deemed to be local. (See [Table 1] which lists factors that suggest biochemical recurrence (BCR) represents local vs distant disease after primary treatment with surgery or radiotherapy).

In [PMID: 18603352] [Full Text] the authors indicate that of those with biochemical recurrence, "25% progress to distant metastases and 11% die of prostate cancer". This same reference also contains information on predicting biochemical recurrence. Several claculators on the Calculators page also can be used to estimate the risk of biochemical recurrence.

Ultrasensitive Testing

After prostatectomy the PSA value should go down to close to zero. If it goes below 0.01 then multiple studies with 2 to 5 year follow up have shown that the chance of biochemical recurrence is quite small.

• In a 2000 study of 200 patients over 2 years, Doherty et al [PMID: 11076649] concluded that patients who achieved a PSA of less than 0.01 after surgery had only a 3% chance of subsequent recurrence vs. 76% for those who did not achieve this level. The 0.01 level was achieved at a median of 10.4 weeks after surgery. Biochemical relapse was defined as three successive PSA rises.
  
• In a study of 225 patients Taylor et al (2006) [PMID: 16925750] followed 225 patients for 5-65 months and concluded that, like the Doherty study, low levels of PSA were also associated with favorable outcomes although they did not quantify the result. Biochemical relapse was defined as two succesive rising after PSA reached 0.20
  
• In a 2006 study Sakai et al, [PMID: 16601384] followed 127 patients for 6-75 months, and got consistent results with recurrence rates of 6.3%, 25% and 91.7% for patients achieving a PSA of less than 0.01, 0.01-0.05 and greater than or equal to 0.05. Biochemical relapse was defined as PSA persistently above 0.20.

The Taylor et al study cited above indicated that both malignant disease and indolent disease exhibited PSA values in the ultrasensitive range (i.e. PSA values which are below the 0.1 detection limit of a normal PSA test) suggesting that the cutoff for recurrence after RP should be higher than that. This also calls into question the utility of ultrasensitive testing over the long term for detection of recurrence although this and the other studies just listed show that for monitoring in the weeks immediately after surgery it does have predictive value.

Conventional PSA Testing

Freedland et al 2003 found the following probabilities of PSA progression:

PSA After Surgery Prob of progression (i.e. sensitivity) 0.11 - 0.2 36% (at 1 year), 67% (at 3 years) 0.2 - 0.3 86% (at 1 year), 100% (at 3 years)

which suggests 0.2 as the level defining recurrence [PMID: 12597949]; however, Stephenson [PMID: 16921049] concludes that using 0.4 as a cutoff to define recurrence would better correlate with eventual metastatic disease. There is some question regarding the interpretation of very low PSA levels but it has been hypothesized that a consistent increase in PSA over time as evidenced by a stable PSA velocity or doubling time, even at a low level of PSA, might be an early warning of disease. On the other hand, according to this 1997 paper [PMID: 9338734] "low but detectable serum PSA levels less than or equal to 30 pg/mL [i.e. 0.03 ng/mL] can be produced by nonmalignant sources of PSA" which could obscure the situation.

Work done in 1999 [PMID: 10235151] found that:

With regard to timing of PSA progression after RP, this commonly occurs within the first 2 years (44.7%), and nearly all progressions occur within 5 years (76.6%) according to Pound et al. Progression as late as 9 years has been noted in only 4% of cases. If PSA progression does occur, then freedom from metastasis at 3 years has been reported in a study at 78% and at 5 and 7 years as 63% and 52%, respectively. Patients with higher Gleason score tumours [Gleason score 8-10] have a lower metastasis-free rate compared with men with low Gleason score tumours [Gleason score 5-7]: 29 vs. 62% at 7 years. [link] based on data from: [PMID: 10235151]

AUA Criteria for Biochemical Recurrence

Need for Different Defintions for Surgery and Radiation

In surgery the primary source of PSA is removed so a level near zero can be expected if no cancer cells remain. The issue is more complex with radiation and cryotherapy since, as Nielsen and Partin, 2007, write:

"The detection of recurrent disease was in fact the original clinical application of PSA in prostate cancer. This is a relatively straightforward task following radical prostatectomy, because the primary source for PSA production has been removed. Biochemical failure among surgically treated patients is generally defined as a measurable or detectable PSA level. As such, patients with biochemical "success" after surgery have been essentially cured of their disease. The definition of failure after radiation therapy is complicated, in that currently available technologies by design incompletely ablate all functioning prostatic epithelium. This limits the definition of a clinically meaningful post-treatment nadir analogous to the postsurgical undetectable PSA." [PMID: 17592538] [Full Text]

Surgery

For post surgical monitoring, in February 2007 a panel of the American Urological Association, AUA, recommended "defining biochemical recurrence as an initial serum prostate specific antigen of greater than or equal to 0.2 ng/mL, with a second confirmatory level of prostate specific antigen of greater than 0.2 ng/mL". See [PMID: 17222629].

Radiation

At the same time, the panel also recommended that the 2005 ASTRO criteria be used for monitoring patients after radiation: (1) a rise by 2 ng/mL or more above the nadir PSA be considered the standard definition for biochemical failure after EBRT with or without HT; (2) the date of failure be determined "at call" (not backdated). [PMID: 16798415] The ASTRO definition was developed as having the best sensitivity (probability of subsequent failure given the criterion is met) and specificity (probability that subsequent failure does not occur given that criterion is not met) of the considered criteria. See [table]. The probabilities in the last two columns of the table are the fraction of men who will not meet the recurrence criteria (that is they will be free from recurrence) at 5 and 10 years.

One phenomenon to note is that frequently there is a temporary rise in PSA after radiation thought to be due to inlammation induced by the procedure itself. This rise is known as PSA Bounce and is further discussed [here].

Other

A [European Consensus] (summary) (post RP chart) (post RT chart) also agreed on these definitions. The summary and chart links just cited provide useful brief overviews of treatment and it is recommended that all readers review them. We have also added these links to the Links in the right side of this blog under "Guidelines - Europe" to keep them easily available.

For Cryotherapy, Cooperberg and Carroll of UCSF define PSA recurrence in the cryotherapy context as a rise in PSA level of 0.2 ng/mL points after a nadir (i.e. lowest point achieved) of less than 0.5 ng/mL.

Post Treatment Recurrence Calculator

There is a Memorial Sloan Kettering calculator for post treatment recurrence that implements a predictive model for PSA progression that readers may wish to try out. Also see the Calculators page on this site for that and other calculators. The d'Amico risk category (discussed in the Favorable Outlook section of this post and the subject of an April 2008 validation study at the Mayo Clinic [PMID: 18289596] specifically within the context of biochemical recurrence) has also been used for assessing progression risk.

Local Recurrence vs. Systemic Disease

Local recurrence refers to rising PSA without further spread of the disease (i.e. without metastases). If the disease has spread then it is referred to as systemic. At the 2009 ASCO meeting John Hopkins researchers reported on a 25 year follow up to patients who had surgery and subsequent recurrence. They found that PSA doubling time (PSADT), Gleason score, and time to PSA progression were "strong independent predictors of metastasis-free survival". Of the patients experiencing recurrence, patients with with PSADT of less than 3 months, 9 months and 15 months had 20x, 6.3x and 2.4x the risk of systemic disease relative to those whose PSADT was longer respectively. Also patients with a Gleason score of 8 or more had double the risk of those with a lower Gleason score. Those for whom progression was evidenced within 3 years of surgery had roughly 3x the risk of those whose recurrence occurred later than 3 years. See [abstract] and [Science Daily News]. For more about PSADT see this [4 part post on PSADT]. (Note that the ratios (20x, etc.) described above were actually hazard ratios rather than relative risks. [PMID: 15273082] [Free Full Text]. To take the example of Gleason scores, the hazard ratio of 2 cited means that the odds that a patient with recurrence and Gleason score of at least 8, say, exhibits systemic disease before a patient with recurrence and a lower Gleason score is 2. Hazard ratios measure relative risk but are not necessarily numerically equal to the relative risk. See references just cited for details.)

Treatment Options

A discussion of treatment options for recurrence, including two case studies, was presented at a session of the conference: Challenges in the Management of Urological Cancers (Amsterdam, The Netherlands) June 30, 2006 chaired by Thomas Keane and is summarized [here] and in a subsequent paper [PMID: 18163938].

Trock et al (2008) [PMID: 18560003] [Full Text] present a retrospective study of 635 men with a median follow up of 6 years after recurrence and 9 years after surgery. They found that:

• 22% of men with recurrence and no salvage therapy died in the follow up period vs.
• 11% of those who had salvage radiation and
• 12% of those who received salvage radiation + hormones

After case mix adjustment the group with radiation salvage had 3x the survival rate of the no salvage group. Salvage therapy had to be administered within 2 years of recurrence and PSA doubling time had to be less than 6 months for salvage radiation to be effective. The authors recommended that the results be validated in a randomized trial.

Stephenson published a nomogram for Recurrence after Salvage Radiotherapy that can be found in the section of that name on our Calculators page.