Biochemical Recurrence - March 2019

This issue focuses on treatment issues for men with an increasing PSA after prostatectomy or prostate radiation. In this introduction, I will review some basic concepts that should help you follow the discussion more easily.

If surgery has successfully removed the prostate gland, the only source of PSA will be surviving cancer cells. After radiation, there can be normal prostate cells in addition to cancer cells. However, prostate cancer cells differ from normal prostate cells because the cancer cells are able to grow in a particular manner. Cancer cells grow by doubling: 1 cell becomes 2; 2 become 4; 4 become 8. Cancer cells do this at a constant rate.

 For example, if the cancer cells double every year, then on subsequent years, the number of cancer cells would be 1, 2, 4, 8, 16, 32, 64, 128, 256, and so on. As a general rule, it takes 15 doublings to go from 1 cancer cell to a mass 1 centimeter across. At 1 centimeter, cancer masses generally become detectable by CT scan. As a rough rule of thumb, it takes another 15 doublings to reach a lethal cancer burden.

The implication is that half of the cancer growth occurs below the level of detectability.

Unlike most cancers, our ability to follow prostate cancer is not limited to imaging tools like the CT or bone scans. We have PSA as a biochemical marker that can be used to follow the cancer. The PSA is a much more sensitive indicator of cancer presence than both CT or bone scan and can indicate the presence of recurrent cancer months to years earlier.

In most patients, the PSA level is roughly proportional to the size of the cancer mass: if the cancer doubles in size, the PSA will double. Thus, the PSA doubling time is thought to provide an estimate of the cancer doubling time. PSA doubling times faster than 3 months usually indicate rapidly growing disease associated with short survival unless treated aggressively. PSA doubling times slower than 9 months usually indicate much less aggressive cancers. PSA doubling times greater than two years are associated with prostate cancers that can take a decade or more to cause metastases detected by the scans.

As a result, it is common to see men after surgery or radiation who have an increasing PSA, but no other evidence of disease. In those patients, PSA doubling time represents the only well established tool to determine the aggressiveness of the cancer and how soon metastatic cancer might manifest itself.

PSA, however, provides no information about the location of the cancer. Is it present in bone, lymph node, liver, or lung?

The recent advances in PET scans mean that the cancer can now be detected while it is much smaller than would be the case with CT or bone scan. However, clinical trials have yet to prove this early detection improves the outcome of treatment.

Finally, there is the problem of late relapses. After surgery, patients can have an undetectable PSA for years—even more than a decade— and then recur. What was going on during that silent interval and what changed to trigger recurrent cancer? This phenomenon is called cancer dormancy and is also reviewed in this issue.

Charles E. Myers, Jr., MD

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