Today the prostate-specific antigen (PSA) screening test is often the first indicator that cancer may be present in the prostate gland. The usefulness of PSA testing, however, is not confined to the initial screening and decision making. After treatment, PSA monitoring is the primary tool for measuring treatment success and for detecting early signs of cancer recurrence.
The PSA value and its velocity (its rate of change over time) are valuable tools for assessing options for further treatment. You will continue to have regular PSA tests throughout life as an early-warning system to detect residual or recurrent disease. Let’s not forget that a significant percentage of men with a normal PSA will have an abnormal digital rectal exam (DRE), and both should be done!
PSA levels after treatment for localized disease
Once a man is diagnosed with early-stage prostate cancer and treated surgically by radical prostatectomy, his PSA level should drop to undetectable levels — zero nanograms per milliliter (ng/ml) — since the entire gland has been removed. In men who have not been diagnosed with prostate cancer, a PSA of 4 ng/ml or more may trigger a biopsy. (In healthy men, there is really no “normal” level of PSA; increasing numbers indicate a continuum of risk.) In a man who has already undergone treatment for prostate cancer, any detectable PSA level signifies a problem. Neither the physician nor the patient should have a false sense of security if the PSA is 2 or 3 ng/ml. It means that the patient has residual or recurrent prostate cancer. Often, the PSA is the first harbinger of recurrent disease, even though it may predate any symptoms or clinical evidence of the disease by months or years.
For the patient treated with radiation, the evaluation is a bit more complex. Often the value does drop to zero. If, however, the value is 1 or 2 ng/ml, it may be the case that some of the normal prostate tissue survived radiation treatment and is still producing PSA. If the value continues to rise, there is reason to be concerned that either cancer has spread outside the gland or the radiation treatment did not eradicate the cancer within the gland. Recent studies have shown that for optimal results, PSA levels should be lower than 1 ng/ml, and even lower than 0.5 ng/ml. Levels that are above 1 or 2 ng/ml 12 to 18 months following completion of radiation treatments are very worrisome, because they indicate that the cancer may not have been eradicated.
Unlike the situation in which patients have an elevated PSA value following radical prostatectomy, patients who have been treated with radiation therapy are probably more likely to have residual rather than metastatic disease — cancer that was not eradicated by the treatment and survives in the prostate gland itself. The best management of these cases is unclear, particularly when the only evidence of disease is the elevated PSA. The physician’s responsibility is to treat the patient, not the lab value, yet often patients in this situation are too worried to accept an approach of active surveillance.
Melvin Parks is a 72-year-old retired African American who in 1987 had a diagnosis of a stage T2a, Gleason 3 + 3 cancer. He opted for definitive radiation treatments, which were completed without complications. His initial PSA was 14 ng/ml, and reverted to normal several months after he completed his radiation treatments. About four years later, his PSA, which was in the 1–1.5 ng/ml range, started slowly creeping up. His value is now 7 ng/ml. He has been extensively evaluated with repeat abdominal computed tomography (CT) scans, bone scans, transrectal ultrasound, and physical exams, including a DRE. There is no evidence of detectable metastatic disease.
While there are several potential diagnostic and therapeutic interventions, which include biopsy of the prostatic fossa (the area in which the prostate gland is located), initiation of hormonal treatments, and cryosurgery, Mr. Parks opted to “hold tight” and monitor the rate of the PSA rise. Is it possible that the slow and very modest rise in the PSA could be due to normal prostate tissue? This is very doubtful. However, given the slow rate of rise, it is possible that many years may pass before active intervention is necessary for either local disease control or disseminated disease management. In general, doctors now look at PSA doubling time before making any treatment decisions. If Mr. Parks’ PSA should double within a period of several months to a year, then treatment may be considered. But if the doubling time takes longer than a year, it is more likely that he will be advised to continue monitoring the PSA.
On rare occasions, an area of recurrence can be detected during a rectal examination as the only evidence of recurrent or residual disease following radiation treatments. Under these circumstances, and in very special situations, a “salvage” radical prostatectomy may be an option. This procedure is difficult to do and should be attempted only by experienced surgeons, since the complication rates can be significant. As the late Dr. William Fair, former chief of urology at Memorial Sloan-Kettering Cancer Center in New York, pointed out, for this procedure the patient needs to be braver than the surgeon! This is a very difficult operation because the radiation treatments eliminate the “anatomic landmarks” that the surgeon depends on to know where important nerves and blood vessels lie. It is difficult to locate the normal planes of tissue to be dissected, and there is often a great deal of diffuse bleeding that is hard to control. Nonetheless, for the patient with a focal, anatomically limited recurrence, plus a reluctance to undergo long-term hormonal treatments, it may be a possibility.
Another option for patients who have developed recurrent or residual cancer after radiation therapy is to administer three to six months of hormonal therapy and then consider a radical prostatectomy. Complications do occur but may be minimized if the patient received 3-D conformal radiation treatments (which minimize damage to surrounding tissues) in the past.
This course of action was not considered in Mr. Parks’ case because he had no clear-cut evidence of a localized recurrence. We have continued to monitor him for signs of progression, with periodic bone scans, CT scans, and prostate biopsies. In all likelihood, he will elect to receive hormonal treatment, but in cases such as his, it is unclear how long the hormonal therapy should be continued. Prolonged hormonal therapy does result in loss of sexual desire and potency for the duration of the treatments. In addition, early, continuous therapy could encourage the development of resistance to hormonal therapy in the surviving tumor cells, so a shorter course of therapy or intermittent hormonal therapy may be preferable.
Monitoring the patient with a “positive margin”
Daniel Husik, a 58-year-old teacher, faced an all-too-common issue shared by large numbers of men treated surgically for localized prostate cancer. Mr. Husik was monitored annually with a DRE. In 1988, his physician noted a small “ridge.” A PSA test was 6.4 ng/ml, and several months later, returned as 6.5 ng/ml. A biopsy showed a Gleason 3 + 3 score. All other staging evaluations were negative and a radical prostatectomy was scheduled. His postoperative course was noteworthy for two events. There was an excessive amount of bleeding postoperatively, requiring intensive care for 24 hours after the operation; and there was a pathologic finding of a positive margin — in this case, microscopic cancer in the area of the urethral anastomosis, the part of the urethra that is cut and then reconnected during the prostatectomy.
This is one example of a so-called positive margin. The borders or margins of the surgically removed gland can be positive for cancer in any one of several places and, when this is detected, pose a particular dilemma for treatment after the operation. The surgeon strives to structure the operation so that the cancer is contained within the boundaries of the prostate gland when it is removed. The problem with a positive margin is that even though the cancerous area is microscopic, it is found at the cut margin of the gland. This implies that on the margin that was not removed from the patient, additional cancer cells may lurk. Most experts agree that the patient with a positive margin is likely to have a recurrence of the cancer, but the big questions remain:
- When will such a recurrence take place?
- Where in the body is the recurrence likely to occur — will the cancer recur as an extension of the localized disease, or will it metastasize?
- Can anything be done pre-emptively (in the immediate postoperative period) to minimize the risk of a recurrence?
- If something can be done, what should it be — postoperative radiation to the area of the positive margin? More surgical removal of the area containing the positive margin thought to be left in the patient? Hormonal treatments? Cryosurgery?
- Can the PSA help guide physicians in these circumstances?
The likelihood that a recurrence will take place is very high. The recurrence may take three to eight years to show up clinically — that is, as disease that can be detected by DRE, diagnostic tests, or scans. Unfortunately, there is no way of knowing if that recurrence is going to manifest itself in the area of the prostate gland, or in lymph nodes or bone. The location may be important in determining the type of treatment. For example, if the recurrence is limited to a small area in the prostate region, a small field of radiation treatments may be offered. In certain circumstances, a small local recurrence in the prostate area years after the original surgery can be successfully treated with another surgical procedure. If, however, the cancer manifests itself as a recurrence in the bones with no evidence of recurrence in the prostate region, a systemic approach would be more appropriate, since the presence of the cancer in the bones or other distant site would be best treated by hormonal therapy.
Let’s return to Mr. Husik as we untangle the answers to questions 3, 4, and 5. Treatment options for patients with a positive surgical margin have been debated for years. Some physicians advise observation only while others undertake active treatment interventions such as postoperative radiation treatments or systemic treatments with hormonal agents. Unfortunately, there are no convincing data to support the use of any of the active modalities; hence, many physicians would wait for the recurrence to manifest itself. By following the PSA value, we can get good assessment of whether a recurrence has taken place.
When the PSA rises following a radical prostatectomy, with or without a known positive margin, the general approach is to “restage” the patient with a DRE, an MRI, a bone scan, and an abdominal pelvic CT scan. An ultrasound exam may provide some useful information, especially if there is a discrete localized recurrence in the area previously operated on, but sometimes it is too insensitive to show anything.
If there is no definite area of recurrence yet the PSA is rising, as it was in Mr. Husik, a patient is generally anxious for active intervention. In this particular case, we opted to treat the prostate bed (the area in the pelvis from which the prostate gland was removed) with doses of radiation therapy. While one could argue that the recurrence as manifested by the rising PSA may be coming from some other area, in this case, the PSA did return to normal several months after the completion of the radiation treatments and has stayed down.
An alternative approach would have been to initiate treatment with hormonal therapy. The idea here is that a rising PSA in a postprostatectomy patient almost always means the persistence of prostate cancer cells, even though they are undetectable by conventional testing. Because the cells may be lurking anywhere in the body, systemic hormonal treatments have the best chance of eliminating them. In the otherwise asymptomatic patient in whom it has taken several years for the PSA to go from undetectable to a level of 1 or 2 ng/ml, however, hormonal therapy and its attendant side effects may be too intensive a treatment.
Often, patients with an elevated PSA without any abnormalities on restaging evaluation will be “watched” for something to happen. This could be in the form of a bone scan turning from negative to positive, or evidence of a suspicious metastatic deposit shown on a CT scan. Another option is to biopsy the prostatic fossa (bed) even in the absence of palpable disease. If the biopsy is positive, the patient can receive radiation; if negative, systemic hormonal treatments can be considered, or the patient may opt to wait and get no active treatment. In the end, the treatment decision is made with the joint participation of the physician, patient, and family members. It should be made after a full discussion of the various options, side effects, and other issues of quality of life.
For the patient who has regained or maintained his sexual activity after the operation, treatment with hormonal therapy is very likely to eliminate both sexual desire and performance. Radiation therapy following prostatectomy often decreases sexual activity if given after the operation, but less certainly or severely than hormonal therapy. Mr. Husik was indeed sexually active after the operation. When his PSA went up ever so slightly from 0 ng/ml after the operation to 1.3 ng/ml nearly four to five years later, he was just too uncomfortable with accepting a policy of observation. Even though his restaging studies were normal, we decided on a program of radiation therapy. The treatment was remarkably well tolerated and did not interfere with any of his daily functions, including sexual relations with his wife. (This is unusual. Most men should not expect to be sexually active when radiation treatments follow prostatectomy.)
PSA monitoring for more advanced disease
Alfred Owens is a 70-year-old retired technician who in October 1993 was found to have both an elevated PSA value of 55 ng/ml and an enlarged prostate gland. A prostate biopsy showed a Gleason pattern carcinoma of 4 + 3. On staging evaluation with abdominal-pelvic CT scan, enlargement of the seminal vesicles was suspected. In the view of his physicians, this suspected enlargement, coupled with both the physical appearance of the gland and the elevated PSA, was strong enough evidence of stage T3 disease. The physicians recommended hormonal therapy and did not consider either radiation or surgery as options. Mr. Owens was placed on combination hormonal treatment with an LHRH analogue and an anti-androgen, which was well tolerated except for total loss of sexual activity.
When I consulted with Mr. Owens in July 1994, I found his prostate gland had returned to a normal size and showed no evidence of hardness or nodules. His PSA was less than 1 ng/ml, and a repeat CT scan demonstrated completely normal seminal vesicles. These findings led us to treat him with post-hormonal radiation therapy, with the hope that the hormonal treatments may have eradicated micrometastatic disease and the prostate cancer within his gland. We would not have considered the addition of radiation treatments had the PSA still been markedly elevated.
At the time, the combination hormonal therapy plus the addition of radiation therapy was considered investigational; today it has become the standard of care. Mr. Owens completed radiation treatments with only some mild discomfort with bowel movements but none of the severe radiation-treatment side effects. He had been told that his disease was incurable. He may still have a recurrence, but he is doing much better than anyone predicted at the time of his diagnosis, and his prognosis, based on his clinical stage, may have been too gloomy. The combination of modalities may have actually eradicated his prostate cancer or retarded its growth in such a fashion as to improve Mr. Owens’ quality of life and his ultimate survival. This, after all, is the goal of treatment.
Reprinted with permission from Marc B. Garnick, M.D., The Patient’s Guide to Prostate Cancer: An Expert’s Successful Treatment Strategies and Options (New York: Penguin Group, 1996), Chapter 11.