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PERSISTENT DISEASE

Over 60,000 men relapse after surgery or radiation each year. With other types of cancer, colon or lung for example, relapse is detected when a scan shows metastases. Prostate cancer is different. Relapse can be detected by the PSA blood test when the cancer is still microscopic. With prostate cancer, scan-detected metastases may take ten or more years to appear after a PSA relapse occurs. In the context of the broader cancer world, therefore, a "PSA relapse," represents a "twilight zone" between two extreme situations— men who are still in remission and men with overt, scan-detected metastasis.

There are exceptions to the generally reliable rule that PSA is always detectable when cancer is present. These exceptions occur when, 1) There is a positive margin present after surgery and, 2) When there is a positive biopsy after radiation. In the former case, the amount of persistent disease after surgery is too tiny to be detected by PSA. In the latter case, PSA production originating from the residual prostate gland "overshadows" the PSA coming from cancer. Therefore, as a result, without biopsy, detection of relapse after radiation is generally delayed until the PSA rises above the 1 to 2.

 

Positive Margins

Positive margins occur after surgery in 10% to 50% of men (the percentage depends on patient variables and surgeon skill). Positive margins are common because the prostate is only a few millimeters from the bladder and rectum. Therefore, even the finest surgeon will leave cancer behind if the cancer invades outside the gland. Cutting out a bigger area around the prostate, i.e. into the bladder or rectum in an attempt to achieve a clear surgical margin, is not an option.

Positive margins are reported a couple days after the operation by a pathologist, a type of doctor who specializes in examining the gland under the microscope. When a positive margin occurs, the risk of future PSA relapse is about 50%.

Minimal Extent

When surgical margins are positive several studies show that radiation to the prostate fossa, the area of the body where the prostate used to be, lowers PSA relapse rates and may slightly improve the ten-year survival rate. Some experts argue, however, that men with minimal positive margins have a 50% chance of being cured and therefore should only undergo radiation when and if the PSA starts to rise. These doctors recommend monitoring PSA closely, say every 3 months, and starting radiation when the PSA rises up to 0.1 or 0.2. This approach is attractive because we know that half of men with positive margins will never relapse and can be spared the potential side effects from radiation.

Multiple Areas

Multiple positive margins usually mean the cancer was large, high grade and that surgery was probably ill-advised in the first place. In any case, multiple positive margins should be handled like locally advanced disease, i.e. with radiation administered to both the fossa and to the lymph nodes in combination with testosterone inactivating pharmaceuticals and possibly with second generation hormonal agents like Zytiga and Xtandi. A short course of Taxotere might also be considered.

 

Local Relapse

Cancer recurring after surgery, radiation, cryotherapy or HIFU, in the area of the body where the prostate used to be, is termed a local relapse. Local relapses can be detected by a rise in PSA, a nodule felt on digital rectal examination, imaging (ultrasound or MRI) or by a biopsy. In this section about locally relapsed cancer, for the sake of discussion, it is assumed we are talking about isolated local relapse, i.e., that no metastases are detected by bone and body scans. If scans show metastases, systemic therapy is required. When systemic metastases are extensive, local treatment may be superfluous.

After Surgery

Radiation is the most common treatment for a local relapse after surgery. While radiation is often effective, the possibility of microscopic metastases outside the prostate fossa needs to be considered since radiation to the fossa alone will fail to be curative if cancer is also present in other parts of the body. The actual presence or absence of microscopic metastasis is never certain since there is no technology capable of detecting them. Microscopic metastases are more likely when the Gleason score is high and when PSA is rising quickly. In these situations, when the likelihood of microscopic metastases is higher, additional radiation to the lymph nodes in combination with testosterone inactivating pharmaceuticals (TIP) should be considered.

After Radiation

Biopsy-proven local relapse in the residual prostate after radiation is usually managed with cryotherapy rather than with surgery. Cryotherapy and surgery both potentially cause incontinence. However, the risk of incontinence from cryotherapy is substantially lower than it is with surgery. New experimental approaches are under investigation using genetically altered viruses, laser, and in some cases, a second round of radiation using radioactive seeds.

After Cryotherapy

Local relapse after cryotherapy can be treated with an additional attempt at cryotherapy or with radiation.

 

PSA Relapse

Even though PSA has been questioned as a tool for screening, it's the Gold Standard for confirming cancer recurrence. However, a PSA rise from a low-grade recurrence that may not require treatment. Determining the difference between a low-grade recurrence and a high-grade recurrence is heavily influenced by the rate of PSA doubling.

For a PSA relapse, treatment usually consists of testosterone inactivating pharmaceuticals (TIP) given intermittently. For example, after TIP is started, PSA usually drops to less than 0.1. Treatment is continued for 6 to 12 months. After TIP is stopped and the effects wear off, testosterone recovers and PSA will begin to rise. A second cycle of TIP is restarted when the PSA reaches a certain threshold (usually between 3 and 6). Immunotherapy administered during the holiday period may slow the rise in PSA and delay the need for restarting TIP.

PSA Doubling Time

The seriousness of relapsed prostate cancer is determined by the PSA doubling rate, an indicator of the rate of cancer growth. When PSA doubling requires more than 12-15 months to occur, the disease is low grade and therapy can usually be withheld. PSA doubling that occurs in less than 12 months is usually a sign that treatment will be required. PSA doubling in less than three months signals aggressive disease requiring maximal therapy. Additional factors that are predictive of greater aggressiveness are high Gleason score, a rapid relapse that occurs soon after local therapy and the presence of a high PSA nadir while taking TIP.

PSA Nadir

The lowest PSA achieved after starting testosterone inactivating pharmaceuticals (TIP) is called the PSA nadir. A favorable drop in PSA (to less than 0.05) after starting TIP predicts survival far better than PSA doubling time or Gleason score. A high PSA nadir in the face of ongoing treatment with TIP is an early indication of castrate resistance. A high PSA nadir strongly indicates the need for additional treatment including radiation, stronger hormone blockade, chemotherapy or immunotherapy.

 

Castrate Resistance (Hormone Refractory)

Hormone refractory is defined as a rising PSA with a low testosterone (academicians prefer calling men with hormone refractory disease castration resistant). The selection of optimal treatment for men with hormone refractory disease depends on balancing two major goals: 1) stabilizing or reversing cancer growth and 2) minimizing side effects to maintain quality of life.

Historically, individual treatments are administered sequentially one by one starting with the mildest treatments and advancing to more powerful agents as dictated by need. However, due to the development of newer drugs with fewer side effects creates the possibility of using them in combination to achieve better results. Medications that are in common use for prostate cancer are Casodex, Nilutamide, ketoconazole, estrogen, Zytiga, Xtandi, Xofigo, Leukine, Cyclophosphamide, Taxotere, Carboplatin, Avastin, Revlimid, Xeloda, Jevtana, Xgeva and Zometa.

Most treatments, when they are effective, will drop or stabilize PSA within 60-90 days after starting therapy (Provenge and Xofigo are exceptions to this rule). So if PSA continues rising or if unacceptable side effects occur, a change in therapy needs to be considered.

Rapid Doubling Time

Men with hormone refractory disease and a rapidly rising PSA, especially after an antiandrogen like Casodex has been tried, are less likely to respond to secondary hormonal maneuvers such as Nilutamide, ketoconazole and estrogen. However, newer agents such as Zytiga and Xtandi are much more likely to obtain a meaningful remission. Early chemotherapy with Taxotere or Jevtana may also be advisable in cases where the cancer is behaving more aggressively. If a good response is attained and the disease becomes stablized, immune therapy with Provenge can be considered.

Local Regional

As discussed in the newly-diagnosed section on early metastasis to pelvic lymph nodes, modern radiation (IMRT) has become much more effective and far less toxic. Men with hormone refractory disease may benefit from radiation to the pelvic lymph nodes if suspicions are high that disease may be confined to that region of the body.

 

Bone Metastases

Recent research indicates that men with bone metastases who have never had Lupron have improved survival with the early initiation of Taxotere . Additional agents used for men with bone metastasis are Zometa, Xgeva and Xofigo. Beam radiation to a limited number of bone metastases may be beneficial for some men.

Pain Management & Radiation

With some exceptions, most bone metastases tend to be painless. Spot radiation controls pain very effectively. However, radiation to bone should be used judiciously because radiation permanently kills bone marrow. Radiation is occasionally recommended to prevent future bone fractures. However, bone fractures from prostate cancer are uncommon. For this reason, undergoing bone radiation simply to prevent a fracture is rarely necessary. Xofigo, an injectable form of radiation, can be effective in reducing pain and seems to have only mild or moderate effects on the marrow.

Bone Scans

Metastatic disease is monitored with scans. Radioactive technetium bone scans have been the standard bone scanning method for years. More recently, Fluoride PET bone scans have demonstrated better accuracy. MRI is another accurate scanning technique for evaluating bone. Since many prostate cancer metastases occur in the pelvis or spine, MRI of these areas may pick up metastatic disease when all the other methods are read as clear.