Why Does Prostate Cancer Return After Prostate Surgery?

Throughout history, there were noteworthy treasure hunts that were doomed from the start. Turning base metal into gold, a Fountain of Youth, the Holy Grail—all proved fruitless. Today, however, we have every reason to believe that scientific exploration for a universal prostate cancer (PCa) cure is destined to succeed. But until that day comes, patients who are diagnosed with localized PCa face three broad disease management strategies:

  1. Active Surveillance (AS)
  2. Radical or whole gland treatments including radical prostatectomy (RP), radiation therapy, and whole gland ablation using cryo or HIFU
  3. Sub-radical treatments including hemi-ablation and focal therapy.

None of these comes with a 100% guarantee of cure, no matter how accurately the tumor is diagnosed nor how well the treatment is matched.

This means that until the wished-for day arrives, AS patients must be monitored for disease progression and treated patients must be monitored for recurrence. This article focuses on recurrence after radical prostatectomy (RP).

Monitoring after RP

All prostate cells, whether healthy or cancerous, carry a surface protein called prostate specific antigen, or PSA. When the prostate is surgically removed, any PCa cells that have already migrated out of the gland are called circulating tumor cells. They are helpless unless they can implant somewhere else (lymph node, bone, another organ) and start to multiply. If this occurs, they will generate a PSA biomarker trail just as if they were still in the prostate.

After RP, a man’s PSA is expected to drop to zero and remain there for each subsequent PSA test. This is why post-RP patients have blood draws at specified intervals. If a test detects PSA greater than 0.2 (the commonly accepted cut point), it is assumed that the cancer has recurred. This is called biochemical recurrence (BCR) or biochemical failure; conversely, a patient whose PSA stays at zero is considered to be biochemically disease-free (BCR-free).

For example, a journal article reporting “70% BCR-free at 5 years” means that for that study, 70% of RP patients had no sign of BCR five years after surgery. Note: this doesn’t mean the authors think that 70% are cured; they are only saying there is no indication that cancer came back. National recurrence rates at 5 years range from 20-30% BCR, depending on the study. Also, recurrence can still happen a decade or more after RP. For this reason, it is not safe to stop PSA testing until a patient has 10 or fewer years of life expectancy, at which point he will likely die of something else.

Why PCa recurs after RP

So why does PCa come back after the whole gland is removed? Here are the main theories:

Extracapsular extension (ECE) is found during the surgery. In such cases, a tumor near the outer edge of the prostate capsule had grown to a size that broke through into the surrounding tissue (prostate bed). When the gland is removed, it is immediately taken to a specialist whose job is to examine the specimen under a microscope while the patient is still unconscious on the operating table. If the specialist sees ECE, he relays the news to the surgeon who then takes more tissue from the prostate bed in hopes of capturing all the PCa. When the patient awakes, he is given the news and offered either active surveillance or a course of radiation to the area and/or hormones.

The cancer is upgraded at the time of surgery. When the specialist examines the gland, what was originally diagnosed at one Gleason grade is now found to be one or two grades higher. For example, a Gleason 3+3 is now found to be Gleason 3+4, Gleason 4+3, or Gleason 4+4. Even without evidence of ECE, research data shows that Gleason 4+3 or 4+4 tumors have higher rates of BCR at 3-5 years after RP. One hypothesis is that some hardy aggressive breakaway cells had migrated into the lymph system or blood stream, where they were more able to implant and reproduce. 

PCa cells travel into the lymph system. According to the Prostate Cancer Foundation, “Lymph nodes are normal parts of the body that fight off infection. Lymphatic ducts connect organs like the prostate to lymph nodes, and prostate cancer can occasionally move along these ducts to spread into lymph nodes. There are hundreds of lymph nodes throughout the body, but prostate cancer tends to first spread to lymph nodes in the lower abdomen and pelvis.”

The cancer uses the tumor blood vessels to escape into the bloodstream. Tumors hijack the body’s ability to construct chaotic blood vessels. This is how they bring the nourishment they need to reproduce themselves. Breakaway tumor cells may use this blood supply to migrate. It’s not easy for a lone cancer cell to implant elsewhere and grow into a tumor. The body’s structure plus the immune system pose many obstacles against implantation. However, when enough cells migrate from the primary tumor, the chances for remote recurrence increase.

Predicting recurrence of prostate cancer

Before RP, doctors try to anticipate if a patient is likely to suffer recurrence. Some risk factors include obesity, family history, lack of regular vigorous exercise, and exposure to certain toxins like Agent Orange—but none of these actually dooms a man to recurrence. Instead, doctors compare an individual’s clinical factors (age, PSA, Gleason grade, tumor stage) with a special type of statistical “calculator” called a nomogram that computes the probability of recurrence. The classic nomogram, the Partin tables, are regularly updated and are even available online for patient use. For example, one online Prostate Calculator predicts that a 65-year old man whose PSA is 5.3 with a Gleason grade 3+4 tumor at stage T2B has an 82.2% chance that the cancer has left the gland at the time of RP. You can click on the link above and try it for yourself.

82.2% is a probability, not a fact. There is, however, a way to gain a more factual picture of prostate cancer before making a treatment decision. Pre-prostatectomy Multiparametric MRI has been well researched in comparison with actual RP specimens and found to be highly accurate. In fact, one study tested an MRI-based nomogram that was generated from specific prostate tumor characteristics clearly detected by MRI, including

  • Tumor location
  • Tumor diameter
  • Diffusion weighted imaging results (apparent diffusion coefficients or ADCs)
  • PI-RADS v2 score
  • Dynamic contrast-enhanced MRI
  • T-stage as determined by MRI scan

The authors found that the MRI nomogram offered better predictive performance than both the standard D’Amico classification and CAPRA. However, adding the MRI nomogram to the D’Amico stratification system significantly improved its performance. The authors concluded, “Multiparametric MRI, when converted into a prognostic nomogram, can predict the clinical outcome in patients with PCa after prostatectomy.”[i]

In short, multiparametric MRI clearly identifies the location, size, and shape of a prostate tumor, and an experienced reader can use the PI-RADS score as an important indicator of its aggression. Armed with this information, a patient considering prostatectomy can have an informed discussion with his doctor about the likelihood of recurrence. Some things to consider:

  1. If recurrence happens following prostatectomy, “salvage” therapy choices are limited by the fact that there is no longer a capsule containing the cancer. A local ablation (cryotherapy, HIFU, focal laser ablation) is not an option without a prostate gland.
  2. Diagnostic tests and imaging will be aimed at finding out where the recurrence is. If it is still in the immediate pelvic area, radiation may be effective with or without hormones. Beyond the pelvic bed, the conventional strategy is to put the patient on hormones.
  3. If a patient is candidate for an initial focal treatment—which requires careful diagnosis and multiparametric MRI—there is a risk of recurrence just as there is with RP. However, if there is local recurrence in the untreated portion of the gland, all treatments including RP or repeat ablation remain open.

With today’s promising immunotherapies, cancer vaccines and molecular delivery of cancer-killing agents, a prostate cancer cure lies in the not-too-distant future. Until then, PCa patients considering RP are well advised to undergo multiparametric MRI to validate nomogram results.

References: Zhang YD, Wu CJ, Bao ML, Li H et al. MR-based prognostic nomogram for prostate cancer after radical prostatectomy. J Magn Reson Imaging. 2016 Sep 21. doi: 10.1002/jmri.25441. [Epub ahead of print]

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