When first-line treatment fails the patient with early stage disease

Moul et al. estimate that in the USA, each year, about 60,000 to 70,000 men who have received prior, front-line, “curative” treatment for early stage (presumed to be localized) prostate cancer will have what is known as “biochemical failure.” This is a term that is less than helpful for most patients, but one that has become common in the world of prostate cancer.

What is “Biochemical Failure”?

So what do we mean by “biochemical failure” (or sometimes “biochemical recurrence” or PSA recurrence)?

The answer depends on the type of treatment the patient first received, but is always based on changes in the patient’s PSA level:

  • If the patient’s initial management was by use of watchful waiting or active surveillance, then “biochemical failure” cannot occur because the patient has yet to receive an active form of first-line treatment. A rise in such a patient’s PSA is simply a potential indication for rebiopsy or the decision to undergo active, first-line treatment.
  • If the patient’s first-line treatment was surgery, and surgery was successful (i.e., the patient’s PSA dropped to an undetectable level post-surgery), then biochemical failure is defined as a rising PSA that has reached a level of ≥ 0.2 ng/ml. Note, however, that this does not necessarily mean that this is the PSA level at which a new form of treatment should be initiated.
  • If the patient’s first-line treatment was any form of therapy except surgery or hormone therapy (e.g., external beam radiation, brachytherapy, cryotherapy, or HIFU), the situation is a little more complicated because for most such patients the PSA never becomes undetectable. The most recent recommendations regarding this type of biochemical failure require the definition of both a PSA nadir and then the so-called Phoenix definition of biochemical failure:
    • A patient’s PSA nadir is the absolute lowest value that his PSA reaches after radiotherapy (and similar non-surgical forms of treatment). It may take as long as 12-18 months for a patient to achieve a PSA nadir post-treatment.
    • The Phoenix definition of biochemical failure is then a PSA value that is higher than the individual patient’s PSA nadir + 2 ng/ml
  • If for some reason  a patient’s first-line treatment for presumed localized disease was hormonal therapy, biochemical failure would be any significant rise in the patient’s PSA from its initial nadir level.

To give an example of the application of the Phoenix definition of a biochemical failure, if the patient had cryotherapy for localized prostate cancer, and his PSA gradually dropped to 0.4 ng/ml over a period of 14 months, stabilized at that level, and then started to rise again, he would be said to have biochemical failure of the cryotherapy when his PSA reached a level ≥ 2.41 ng/ml. Again, this does not mean that such a PSA level would necessarily be the right time to implement a new form of treatment.

Why is it called the Phoenix definition? Because the conference at which this definition was established was held in Phoenix, Arizona. It has nothing to do with cancer “rising from the ashes!”

When Can Biochemical Failure Occur?

Although prostate cancer is, in general, a very slowly progressing disease, the “natural history” of biochemical failure, as defined by a rising PSA after first-line treatment, has enormous variation. A man who has achieved either an undetectable PSA post-surgery or a low, stable PSA post-radiotherapy may have a rising PSA that meets the criteria for biochemical recurrence after as little as a few months … or it may not happen for 20+ years!

For this reason, every man who is treated for prostate cancer should subsequently receive regular PSA tests for life. In the beginning these tests are normally conducted every 3 months or so. If the PSA remains undetectable or stable, the physician may recommend testing only every 6 months. After a 2-3 years of stable PSA levels, the physician may even recommend only an annual PSA test.

A study conducted by Pound et al., and published in 1999, described a group of 304 men who received initial surgical treatment for prostate cancer. Of these men, 201 had a rising PSA but never received additional therapy within the timeframe of the study; the other 103 never received hormone therapy until they had clearly defined metastatic prostate cancer. In this group of 304 men, the median time to biochemical recurrence was 8 years, and the median time from identification of metastasis to death was 5 years.

In a more recent study from the same institution, Freedland et al. investigated the outcomes among 379 men who initially received surgery for presumed localized disease between 1982 and 2000, all of whom had a post-surgical, biochemical recurrence. In this group of men, median survival had not been reached 16 years after biochemical recurrence. However, in this study too, prostate cancer-specific deaths were seen (albeit rarely) within 1 year of biochemical recurrence.

What Does One Do About Biochemical Failure?

The management of non-metastatic patients who have biochemical failure following definitive first-line treatment for prostate cancer that was presumed to be localized at the time of treatment (and, in the case of surgical patients, is still believed to be localized after pathological examination of the prostate post-surgery) is not simple! Somehow, we suspect you aren’t going to be surprised by this.

There are many, many options available, and we are going to address them all, so here’s the complete list:

Selection of the most appropriate form of second-line management for a man who has biochemical failure following first-line therapy is enough to make even prostate cancer specialists weep! And there are few really sound data to guide them.

The links provided above will take you to pages that address every one of these many, many options! However, before you read any of those pages you may want to understand something about the speed of progression of prostate cancer and the prognosis for men who have biochemical recurrence after first-line therapy.

Content on this page last reviewed and updated December 31, 2008.
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