Over 50,000 men relapse after surgery or radiation each year. With other types of cancer, colon or lung for example, relapse is not detected until a scan shows metastases. Prostate cancer is different because relapse can be detected with PSA when the disease is still microscopic. On average, scan-detected metastases appear more than ten years after a PSA relapse occurs. A PSA relapse, therefore, represents a sort of “twilight zone” between two extreme situations— men who are still in remission with stable low PSA levels, and men with scan-detected metastasis.
The only two exceptions to the rule that PSA always rises before cancer is known to be present is when margins are positive after surgery or, when biopsies are positive after radiation. In the former case, the amount of persistent disease after surgery is so small that PSA fails to register. In the latter case, PSA production from residual prostate gland “overshadows” the small amount of PSA coming from cancer in the residual prostate gland. Relapse after radiation generally can’t be confirmed with PSA until it rises above 1 or 2.
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. Even the finest surgeon must leave cancer behind if the cancer invades outside the gland. Cutting into the bladder or rectum is not an option.
Positive margins are reported a couple days after the operation by a pathologist who specializes in examining the gland under the microscope. When a positive margin occurs, the risk of PSA Relapse is 50%.
When surgical margins are positive several studies show that radiation to the prostate fossa, the location of where the prostate used to be, lowers PSA relapse rates and modestly improves the ten-year survival rate. However, in the studies showing improved survival with immediate radiation the men the comparison group of men whose radiation was delayed may have been delayed too long. Their PSA had risen above 1.0, a fairly high level considering we have sensitive assays that detect relapse below 0.1. Therefore, some experts believe men with minimal positive margins should be offered the option of forgoing immediate radiation if they watch their PSA closely, say every 3 months, and start radiation when the PSA rises up to 0.1 or 0.2. This approach is attractive because half of men with positive margins are spared radiation.
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.
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, an imaging tool such as ultrasound or MRI or by a biopsy. 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.
Radiation is the most common treatment for a local relapse after surgery. While radiation is often effective, the possibility of microscopic metastases needs to be considered since radiation to the fossa alone will fail if cancer is present in other parts of the body. Microscopic metastases are suspected more strongly when the Gleason score is high and when the rate of PSA rise is brisk. When suspicions are high, additional radiation to the lymph nodes in combination with testosterone inactivating pharmaceuticals (TIP) should be considered.
Biopsy-proven local relapse in the residual prostate after radiation is usually managed with cryotherapy rather than with surgery. Cryotherapy and surgery can both cause incontinence, though with cryosurgery the risk of incontinence is substantially lower. Experimental approaches are genetically altered viruses, laser, and in some cases, retreatment with radioactive seeds.
Local relapse after cryotherapy can be treated with an additional attempt at cryotherapy or with radiation.
Even though PSA has been questioned as a tool for screening, it’s the Gold Standard for confirming cancer recurrence. However, it’s possible for PSA to detect low-grade recurrences that may not even need treatment. The difference between a low-grade recurrence and a high-grade recurrence is determined by the rate of PSA Doubling.
Treatment usually consists of testosterone inactivating pharmaceuticals (TIP) given intermittently. After TIP is started, the PSA almost always drops below 0.1. After 9 to 12 months, TIP is stopped. When TIP wears off, testosterone recovers and PSA begins to rise. 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 cancer growth rate. When more than 12 months are required for the PSA to double, the disease is probably indolent enough to withhold therapy. PSA doubling rates less than 12 months are potentially dangerous and usually warrant treatment. Three-month or less PSA doubling signals aggressive disease requiring maximum intensity treatment. Additional factors predicting aggressiveness are high Gleason score and early relapse after treatment. However, the most powerful predictor of all is PSA nadir.
The lowest PSA achieved after starting testosterone inactivating pharmaceuticals (TIP) is called the PSA nadir. A drop in PSA to less than 0.05 after starting TIP predicts survival far better than PSA doubling time, Gleason score or how quickly a relapse occurred after treatment. A persistently detectable PSA in the face of treatment with TIP, termed a “high” nadir, is a reliable 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 (academicians prefer the terminology, castration resistance) is defined as a rising PSA with a low testosterone. Treatment selection is based achieving two goals: 1) stabilizing or reversing cancer growth and 2) minimizing side effects. Historically, men were administered treatments one by one, starting with the mildest treatments and advancing to more powerful agents depending on results. However, combinations of drugs may improve results. Commonly used agents are Casodex, Nilutamide, ketoconazole, estrogen, Zytiga, Leukine, Cyclophosphamide, Taxotere, Carboplatin, Avastin, Revlimid, Xeloda and Jevtana. Once treatment is started the PSA should stabilize or drop within 60-90 days. If the PSA continues rising or if unacceptable side effects occur, a different therapeutic approach is needed.
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. Initial chemotherapy to get the disease under control may be advisable. If a good response is attained, secondary hormonal agents can be used to suppress return of the disease and maintain a longer remission after the chemotherapy is stopped.
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 after careful evaluation and scanning metastases to other parts of the body appear to be absent).
When the pace of disease is slow, a treatment approach similar to castration resistant disease can be utilized. However, initial treatment with Taxotere or Jevtana is best when the disease progresses rapidly. Additional beneficial agents for men with bone metastasis are Zometa, Xgeva, Samarium, Strontium, and beam radiation to affected areas. Many promising new agents are being evaluated in clinical trials.
Pain Management & Radiation
With some exceptions, most bone metastases are painless. When bone pain is present relief is one of the first signs that a newly-initiated treatment is effective, often occurring long before PSA or scans improve. Spot radiation is effective. However, radiation to bone should be used judiciously because radiation permanently kills bone marrow in the area treated. Injectable forms of radiation like strontium and samarium have the same effect on the marrow. For this reason we use them very rarely. Pain management is both an art and a skill. Medical oncologists are trained in pain management. Other doctors who specialize in this area are anesthesiologists.
Radiation is occasionally recommended to prevent future bone fractures. Bone fractures from prostate cancer are uncommon probably due to their “sclerotic” nature. For this reason, undergoing bone radiation simply to prevent a fracture is rarely necessary.
Bone Scans & Anemia
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 of the bones with gadolinium contrast is the most accurate of all. Since the vast majority of 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.
Red blood cells carry oxygen from the lungs to the rest of the body. When prostate cancer advances and replaces marrow, red cells production is reduced and anemia results. Anemia, depending on its seriousness, can cause tiredness and shortness of breath. Sometimes blood transfusions are necessary. Hormonal medicines like Aranesp and Procrit may increase red cell production and help reverse anemia. Radiation and chemotherapy can suppress red cell production and exacerbate anemia.