Relapsed Prostate Cancer After Surgery

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What is the most frightening thing about cancer? For many, it’s the chance the cancer might return after surgery. With most common cancers—colon, breast, brain, melanoma, or lung, for example—these recurrences are almost universally fatal. Prostate cancer, however, is different. You might find it hard to believe, but men with relapsed disease are more likely to die from old age than from prostate cancer.

 

Prostate Cancer Is Different

Why is prostate cancer relapse so different? Several reasons. First, it grows and spreads far more slowly than other types of cancer. Second, medications that inactivate testosterone (hormonal blockade) are shockingly effective. Men go into remission for an average of 10 years! But what makes prostate cancer most unique is a particular type of protein produced in the prostate gland called prostate specific antigen, otherwise known as PSA.

PSA Is Amazing

Even though measuring the amount of PSA in one’s blood to screen for cancer has been seriously questioned, PSA is the gold standard for detecting relapsed disease. In fact, other types of cancer have nothing that even approaches the accuracy of PSA. PSA detects microscopic cancer. Unfortunately, other cancers can only be detected with scans, after the recurrent tumors become large enough to be seen with the naked eye.

For tumors to be visualized on a scan, they must be over a half-inch in diameter and contain at least one billion cancer cells. The PSA blood test, on the other hand, detects recurrences with as few as 100,000 cells.

PSA Doubling Time Is More Accurate Than Gleason Score

Detecting recurrence with PSA at the earliest possible stage creates an opportunity to determine the seriousness of the relapse.

With repeated, sequential testing of PSA—say with monthly blood draws—the rate of PSA increase can be accurately determined. How quickly the PSA doubles reveals the grade of relapse. This information is very important because low-grade relapses are treated very differently than high-grade relapses. Most people are familiar with the Gleason grading system, the most popular methodology for cancer grading in newly diagnosed men, that is, prior to relapse. With the Gleason system, the cancer cells are graded by a special doctor called a pathologist. The pathologist views the biopsy specimen under a microscope and assigns a grade to the cancer. The Gleason system is the most powerful prognostic indicator for grading newly-diagnosed prostate cancer and has a very important role in determining optimal treatment for newly diagnosed men. However, in relapsed prostate cancer, the PSA doubling time easily supersedes the accuracy of the Gleason score. Knowledge of the cancer’s growth rate is the most accurate way to grade the cancer’s aggressiveness, and, luckily, the PSA determines this with unparalleled exactitude.

Once the PSA doubling time reveals the severity of the relapse, a treatment strategy is implemented.

Treatment varies drastically depending on the grade of relapse, so the optimal type of treatments for each grade of relapse is discussed below.

Low-Grade Relapse

For descriptive purposes, three different grades of relapses can be described: low, intermediate, and high. Knowing the grade of relapse is the basis for treatment selection. Some relapses, for example, are so low-grade that no treatment at all will be required. This occurs when PSA requires more than a year to double. When the doubling time is this slow, the best approach is to withhold treatment and continue monitoring the PSA every three to six months.

Many of these patients remain off treatment indefinitely.   

Intermediate-Grade Relapse

When men have PSA doubling times that are somewhat brisker, say in the six to 12-month range, they will usually be candidates for some form of therapy. Historically, treatment has consisted of a blind shot of radiation to the area of the body where the prostate was located prior to its removal. The area that is targeted is called the prostate fossa. Sometimes radiation used in this fashion will be curative. Studies show that cure rates are best if the radiation is initiated before the PSA rises above 0.5. Like so many types of cancer therapy, the earlier treatment is started the better it works. 

Hormonal Therapy

If the radiation is unsuccessful, hormonal therapy is the next line of defense. The most common approach is to select an agent from a long list of active hormonal agents of more or less equal effectiveness—Lupron, Trelstar, Eligard, Firmagon, or Zoladex. These injectable medications are typically implemented as a backup if the radiation fails to control the rising PSA. Prostate cancer cells require testosterone to survive, and these medications work by lowering testosterone. Depriving the cancer cells of testosterone causes them to die. Hormonal blockade induces a sustained anticancer effect that is maintained for an average of 10 years, assuming that treatment is initiated early, that is, before the onset of bone metastases. The duration of disease control is much shorter if prostate cancer is allowed to progress into the bones before treatment is started.   

Intermittent Therapy

To reduce the side effects from having low testosterone, periodic treatment holidays are often recommended. The usual approach is to administer Lupron for six to eight months and then take a holiday. Usually the PSA drops to less than 0.1 within six months of starting therapy. After the medication is stopped and its effects wear off, testosterone slowly recovers and the PSA begins to rise. A second cycle of Lupron is started when the PSA rises to a prespecified threshold, say between three and six. Studies prove that this intermittent approach effectively controls the cancer just as well as if the Lupron is given continuously.  

A Milder Type of Hormone Therapy

Sometimes milder, oral forms of hormone therapy such as Casodex (bicalutamide), with or without Avodart (dutesteride), can be substituted for Lupron to reduce side effects. This type of approach might be preferred, for example, in patients who are older or frailer. The most common side effects associated with the standard injectable types of hormonal therapy—fatigue, weakness, and weight gain—tend to be less severe. However, there is one side effect that is more common with Casodex—breast growth.  This problem, however, can be counteracted with an estrogen blocking pill called Femara. Alternatively, a moderate dose of radiation administered to the breast area before Casodex is initiated usually prevents breast enlargement.

Treating a High-Grade Relapse

Men with relapsing prostate cancer whose PSA doubling time is less than six months face a more daunting situation. If the disease is not kept in check with effective therapy, the cancer is likely to spread quickly and become life-threatening. Here, the most prudent therapeutic approach is to adopt an aggressive plan that relies on a combination of treatments given simultaneously, aka a multi-modality approach. The remainder of this article will address the treatment of high-grade relapses.

State-of-the-Art Scans

The first step is to use optimal scanning technology to determine where in the body the cancer is located. Presently, the best available lymph node scans (lymph nodes are usually the first site of metastases) are C11 Acetate or C11 Choline PET scans. Unfortunately, in the United States these scans are only available at Phoenix Molecular or at the Mayo Clinic. Recently, a new type of PET scan called Axumin has become more widely available. Studies comparing the relative accuracy of Axumin with C11 PET are in process. Another, newer type of PET scan called Gallium68 PSMA is now entering into clinical trials at various centers around the US.

In addition to lymph nodes, advancing prostate cancer often spreads to the bones. The importance of accurate scans to detect early disease cannot be overemphasized. Recently, bone scan technology has been greatly improved with the use of new F18 PET technology. Whenever possible, F18 PET bone scans should be used rather than the older Technisium99 methodology. PET scans for prostate cancer are a revolutionary new development, enabling doctors to apply potentially curative radiation in a far more intelligent manner.

Radiation Plus Lupron Plus Casodex

Once the extent of disease has been determined by accurate scanning, assuming the number of metastases is relatively limited, (say no more than five), the first step it to initiate treatment with Lupron plus Casodex with the plan of continuing it for at least a year. Generally, a couple of months after starting Lupron, radiation is administered to the known metastatic sites (the ones that were detected by scanning) along with further “blind” radiation treatment to the prostate fossa and to the “normal” pelvic lymph nodes. These areas of the body are treated because they are the most common location for microscopic disease, and even the modern PET scans may fail to detect cancer here.

Microscopic Disease Outside the Radiation Field

Studies clearly show that when radiation is directed at known sites of disease, sterilization of the cancer at those sites is usually achieved. So, treatment failures are usually related to small amounts of microscopic disease in other parts of the body that were undetected, despite the best available scanning technology. Therefore, when dealing with these more dangerous types of prostate cancer that have very fast doubling times, using an aggressive strategy that employs systemic medications that have anticancer activity  throughout the entire body makes a whole lot of sense. As was already noted above, anticancer therapy is most effective when starting treatment at an earlier stage, while the disease is still microscopic. 

Multiple Medications to Eradicate Microscopic Disease

Since Lupron and Casodex can be such integral players in the treatment game, some might wonder if other types of effective anticancer therapies exist. When the question is framed this way, two medications immediately come to mind, Zytiga and Xtandi. These powerful agents have demonstrated anticancer efficacy even when treating men whose cancer has developed resistance to Lupron!  Considering that they are convenient oral agents with a manageable side effect profile, it is logical to consider substituting Zytiga or Xtandi for Casodex.     

What About Chemotherapy?

In addition to using a combination of medications, as was the approach outlined in the previous paragraph, reports also indicate that the addition of chemotherapy with a medication called Taxotere has the potential to further improve survival. While such conclusions are preliminary, studies evaluating the combination of Taxotere with Xtandi or Zytiga indicate that this approach may be feasible.

Conclusion

Men whose prostate cancer recurs after surgery cannot adopt a one-size-fits-all treatment approach.  When the PSA doubling time is very slow, men can be safely watched. When the PSA doubling time is somewhat faster, radiation, Lupron, or both can effectively forestall disease progression for over a decade. Men with aggressive relapses signaled by a very fast PSA doubling time should strongly consider the prompt initiation of multiple therapies in combination. 

Sources:

Kishan AU et al. Clinical outcomes for patients with Gleason score 9–10 prostate adenocarcinoma treated with radiotherapy or radical prostatectomy: A multi-institutional comparative analysis. European Urology. 71.5: 766, 2017.

Nabid A et al. Duration of androgen deprivation therapy in high-risk prostate cancer: A randomized trial. Journal of Clinical Oncology. 31.18 suppl:LBA4510, 2013.

Sandblom G et al. Positron emission tomography with C11-acetate for tumor detection and localization in patients with prostate-specific antigen relapse after radical prostatectomy. Urology. 67.5: 996, 2006.

Scholz M et al. Retrospective evaluation of gm-csf, low-dose cyclophosphamide, and celecoxib on psa doubling time (dt) in men with prostate cancer and psa relapse after surgery or radiation. Journal of Clinical Oncology. 28.10 suppl: abstr e15061, 2010.

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