Specific Antigen: Recurrence After Therapy

Prostate Cancer Information

Advanced Prostate Cancer

E. David Crawford, M.D.
Professor of Surgery and Radiation Oncology
University of Colorado Health Sciences Center
Denver, Colorado

Welcome to the Prostate Cancer Education Council's Article Series: 2000 website.

Below is the first in a series of six articles by a select panel of distinguished urologist addressing a topic related to advancements in prostate cancer treatment, research, and prevention. Informative sidebars throughout the article, along with highlighted technical vocabulary hyperlinked to a prostate cancer glossary, create an easily digestible format for consumers.

Article Series: 2000 is presented on behalf of the Prostate Cancer Education Council (PCEC). Founded in 1988, the PCEC is a consortium of physicians, health educators, scientists, and patient advocates dedicated to increasing prostate cancer awareness and knowledge. Here is a list of currently available and upcoming articles.

The author of this article is Dr. E. David Crawford, chairman of the PCEC since 1989. Dr. Crawford is professor of surgery, professor of radiation oncology, and head of the Section of Urologic Oncology at the University of Colorado Health Sciences Center (UCHSC) in Denver.

A nationally recognized expert in prostate cancer, Dr. Crawford is the recipient of more than 69 research grants for the study of the following topics: treatment of advanced bladder cancer; metastatic adenocarcinoma of the prostate; hormone-refractory prostate cancer; and several areas of urologic infections and malignancies. He has authored or coauthored over 300 articles published in such journals as Urology, The New England Journal of Medicine, and the Journal of the National Cancer Institute. Dr. Crawford is also an editorial reviewer or consultant for a large number of publications, including Urology, Journal of Urology, The New England Journal of Medicine, Cancer and the Journal of Clinical Oncology.

Dr. Crawford is also an active member of many national and international organizations, including the American Society of Clinical Oncology, the American Urological Association (AUA), and the American Association for the Advancement of Science. Within the AUA, he is a member of the Committee to Study Urologic Research Funding and the Prostate Cancer Clinical Trials Subcommittee. Dr. Crawford also currently serves on the board of the Southwest Oncology Group.

Dr. Crawford's involvement in the national prostate cancer arena is highly recognized. He has received several honors and awards, including, as co-investigator, the 1999 CaP Cure Annual Award for Scientific Presentation. In 1997, he was presented with a "Freddie Award" at the AMA International Health and Medical Film Competition for the program, ITV: The Cutting Edge Medical Report (Prostate Cancer: Understanding, Diagnosing, and Defeating), which Dr. Crawford hosted with special guest, retired General Norman Schwarzkopf.

Abstract

Patients with perfect continence and PSA levels of less than 2.0 ng/mL are those most likely to benefit from salvage radiation therapy.

Options for patients with organ-confined disease whose radiation therapy failed include salvage surgery or cryotherapy.

Hormone therapy treats PSA-only recurrence efficiently, but does not necessarily prolong life.

Some promising experimental therapies include dietary manipulation, gene therapy, and vaccines for immune-system therapy.

The occurrence of rising serum levels of prostate specific antigen (PSA) after local treatment of prostate cancer is one of the most hotly debated issues in urologic oncology; it is almost synonymous with therapy failure. Biochemical failure may be the only manifestation of disease recurrence. Gleason score, timing, velocity of detectable PSA, and PSA doubling time are the most helpful assessment predictors of recurrence. Transrectal ultrasound (TRUS)-guided biopsies of the prostatic fossa or prostate are more sensitive than digital rectal examination (DRE) when local recurrence is suspected, but are not routinely recommended unless invasive salvage therapy is being contemplated. The validity or accuracy of a bone scan is limited until serum PSA rises above 30 ng/mL; the role of immunoscintigraphy is yet to be fully defined. Early intervention is warranted in patients in the high-risk groups, whereas observation and delayed therapy could be a reasonable approach in low- and intermediate-risk patient groups. Local salvage therapies include radiation for patients who underwent radical prostatectomy (RP) and experienced treatment failure, and surgery (prostate removal) or cryotherapy for those whose initial radiation therapy failed. The patients most likely to benefit from salvage radiation therapy are those with perfect continence, and a PSA level of <2.0 ng/mL. Salvage surgery or cryotherapy is an option for patients with organ-confined disease who failed radiation. These therapies carry a high risk of incontinence and should be reserved for carefully selected patients. Hormone therapy is the most efficient way to treat PSA-only recurrence but it has not yet been proved to offer survival benefit. Dietary manipulation, gene therapy, and vaccines are still experimental in the treatment of recurrent prostate cancer but the preliminary results appear promising.

Introduction

A rising PSA after local treatment is a sign of biochemical failure and of possible recurrent or persistent disease.

The advent of prostate specific antigen (PSA) serum analysis has revolutionized our approach to the detection, treatment, and follow-up of prostate cancer. Most cancers diagnosed today are clinically organ-confined and thus amenable to local treatment. The decline in mortality and metastatic disease are the direct consequences of the PSA revolution. Radical prostatectomy (RP), external beam radiation, or brachytherapy are the primary treatments for patients with localized disease. The anatomic RP and improvement in radiation modalities are significant advances in the management of localized prostate cancer. Pretreatment selection of patients has led to even better outcomes with these techniques. A rising PSA level, seen after local treatment has been completed, is always regarded as a sign of treatment failure and a harbinger of recurrent or persistent disease.
When there is a postoperative rise of the PSA level, to that above the nadir threshold, the clinician has to answer the following questions:1

What is the origin of detectable PSA (benign vs malignant tissue)?
How should the patient be evaluated?
Where is the site of recurrence (local vs systemic disease or both)?
What is the outcome of standard therapeutic options (adjuvant radiation or hormone manipulation)?
What can be expected from using new therapeutic approaches?

The PSA level that defines biochemical failure varies according to the primary therapy (Table 1). Suprasensitive assays allow PSA detection at a lower level and may give the clinician a lead time of up to 1 year over the time allowed by a rising PSA measured by standard methods.

Table 1. Nadir PSA and the Definition of Biochemical Failure
Primary Therapy	Radical Prostatectomy	Radiation Therapy
Optimal PSA Nadir	Undetectable <0.1 ng/mL	No absolute level is a valid cut-off (ASTRO).² Post-radiation nadir <0.5 ng/mL is associated with less chance of recurrence. Most recently, Critz et al.³ have advocated <0.5 ng/mL.
Definition of Biochemical Failure	Two PSA values >0.2 ng/mL or a single value >0.5 ng/mL	Three consecutive increases in PSA level (ASTRO).² The same definition is assumed to apply to brachytherapy.
ASTRO = American Society for Therapeutic Radiology and Oncology

Rising PSA After Radical Prostatectomy

Radical prostatectomy is most often chosen by otherwise healthy men with localized cancer, who have a life expectancy of greater than 10 years

Radical prostatectomy is the treatment of choice for most men with clinically localized cancer who are otherwise healthy and have a life expectancy of 10 years or greater. The goal of surgery is disease cure and good quality of life.
What Is the Significance of Detectable PSA After Radical Prostatectomy?

A rising or elevated PSA has been called the most important tumor marker in oncology.

PSA is a protein that liquefies sperm. When levels of PSA are elevated in the blood (serum), it is associated with either benign prostatic hyperplasia or adenocarcinoma (cancer) of the prostate.

In 90% of cases involving organ-confined disease, serum PSA drops to undetectable levels within approximately 3 weeks.

Following a successful radical prostatectomy, all prostate tissue has been removed and the PSA should then be undetectable in the serum.

PSA level elevation after a radical prostatectomy usually indicates failure of treatment.

After RP, the serum PSA is expected to drop to undetectable levels within approximately 3 weeks.⁴ This occurs in 90% of patients with organ-confined disease. Benign prostatic tissue rarely accounts for postoperative PSA rise.⁵ Although rare, distant metastases without an increase of serum PSA level has been described in the literature.⁶ The percentage of free PSA is not helpful for distinguishing benign from malignant sources of PSA after RP. A significant proportion of aggressive tumors will exhibit a high, percent-free PSA.⁷ Positive margins are associated with a significant risk of biochemical failure.⁸ Some patients, who were initially considered to have organ-confined disease with negative margins, experience persistent or recurrent rises in postoperative PSA levels. After careful review of specimen slides in these patients, in most cases researchers have been able to relate the rising PSA levels to microcapsular invasion, or focal positive margins.⁹ Stamey et al have shown that high-grade Gleason scores (% grade 4/5) and large cancer volume are the primary predictors of failure to eradicate cancer; biochemical failure increases almost linearly with each 10% increase in Gleason grade 4/5.¹⁰ Graefen described similar findings.¹¹
Methods of Investigating a Rising PSA After Radical Prostatectomy

A detectable PSA serum level within the first year following first-line therapy may predict distant vs. local tumor recurrence

Research has found that with no treatment, clinical signs of recurrence occurred at an average of 8 years from the time when the PSA level first rose.

The elevation of PSA is a sensitive indicator of recurrent or persistent disease after surgery. The interval from initial detectable, elevated PSA levels to subsequent clinical recurrence is highly variable. When exploring a rising PSA after RP, the review of pathologic characteristics and the PSA history are valuable in determining the source of the recurrence. Among the most important variables that distinguish distant from local recurrence are a specimen Gleason score of greater than 7, invasion of seminal vesicles, and lymph nodes positive for tumor cell invasion. The timing of the recurrence and the kinetics of PSA provide valuable clues to the potential site of recurrence.¹²
The occurrence of a detectable rise in PSA levels within the first year following therapy is the most predictive variable for distinguishing distant from local recurrence. Partin showed that PSA velocity of greater than 0.75 ng/mL/year was associated with a high probability of distant metastases.¹³ Prostate specific antigen doubling time had a better correlation with time-to-clinical-recurrence than did the Gleason score, pathologic stage, and margin status. A short PSA doubling time (less than 6 months), regardless of the time when PSA becomes detectable, was highly associated with distant clinical failure.¹⁴ A summary of variables for distinguishing distant from local recurrence is shown in Table 2.¹⁵

Table 2. Summary of Local vs Distant Recurrence in Patients With Detectable PSA Following Radical Prostatectomy
Local Recurrence	Distant Metastasis
Gleason score <7 No seminal vesicle invasion Negative pelvic lymph nodes PSA detectable >1 year following RP PSA velocity <0.75 ng/mL Log slope PSA <0.12 (doubling time <6 months)	Gleason score >7 Seminal vesicle invasion Positive pelvic lymph nodes PSA detectable <1 year following RP PSA velocity >0.75 ng/mL Log slope PSA >0.12 (doubling time >6 months)
¹⁵Jhaveri FM, et al. Semin Urol Oncol. 1999;17(3):130-134.

Pound et al found that PSA recurrence translated to clinical recurrence at an average of 8 years from initial PSA rise when no treatment was administered.¹² A PSA recurrence in the first 24 postoperative months, a Gleason score greater than 7 and a PSA doubling time of less than 10 months were all predictive of more rapid clinical recurrence.

Determination of Recurrence Site: Local vs Distant

Local Recurrence: Digital rectal examination (DRE) and/or transrectal ultrasound (TRUS)-guided biopsy
Detectable PSA may be the only manifestation of recurrent cancer in 80% of patients.¹⁴ Local recurrence may be detected by DRE and TRUS-guided biopsy. Digital rectal examination is inaccurate for assessing local recurrence, and the sensitivity to change is examiner-dependent.¹⁶ Connolly et al have shown that TRUS has a higher sensitivity (90%) to change than DRE, but lacked specificity.¹⁷ More than one ultrasound-guided biopsy was required to make the diagnosis in 33% of the patients. The majority of recurrences were at the anastomotic site (66%), followed by recurrence at the bladder neck (16%) and posterior to the trigone (13%).

Distant Recurrence: radionuclide bone scintigraphy and immunoscintigraphy

If administered when PSA levels are low, bone scans are of little use in making a differential diagnosis.

Research indicates that one-half of the patients who receive treatment for localized prostate cancer show signs of lymph-node disease

    At low PSA levels, bone scans are of little value. The likelihood of a positive bone scintigram is less than 5% unless the PSA has increased above 30 ng/mL.¹⁸ Computed tomography (CT) has been shown to be inaccurate in assessing lymph-node metastasis.¹⁹ Indium-111 capromab pendetide (ProstaScint Scan) is a monoclonal antibody directed to the prostate specific membrane antigen (PSMA). Prostate specific membrane antigen (PSMA) is a type 2 transmembrane glycoprotein with three domains. Unlike PSA, it is more frequently expressed in aggressive cancers. Kahn et al studied the role of indium-111 capromab pendetide for detecting occult metastasis in 181 patients with biochemical failure after RP; 60% showed a positive scan, 34% of which was in the prostatic fossa; and 50% had proven recurrence documented by biopsy.²⁰ The indium-111 capromab pendetide scan has a sensitivity of 49% and specificity of 71%. In a comparative study, Seltzer demonstrated that both the computed tomography (CT) and the positron emission tomography (PET) detected evidence of metastatic lymph-node disease in 50% of patients who had previously received treatment for localized prostate cancer.²¹ The accuracy of detection was higher in patients with PSA levels of greater than 4 ng/mL and a PSA velocity of more than 0.2 ng/mL/month. Monoclonal antibody determination has a lower detection rate than CT and PET.
    One major limitation of ProstaScint analysis is that the monoclonal antibody targets the intracellular isotope of PSMA that is not available for binding in viable cells. Antibodies directed to the external domain of PSMA might prove useful in defining the site of recurrence.²²
    In a recent study, Kahn et al found that indium-111 capromab pendetide results did predict the likelihood of durable response to salvage radiotherapy for post-RP PSA recurrence.²³ In men who had recurrence limited to the prostate fossa or who had a negative scan, two-thirds had a 3-year, durable response to x-ray therapy (XRT). Conversely, when XRT was given in response to a positive distant scan, only one-third of the patients responded.

Managing Patients Who Have Rising Prostate Specific Antigen After Radical Prostatectomy

When PSA becomes detectable, it is important to assess the following:

-whether the patient was curable before the initial treatment,

-the likelihood of a cure when using a second treatment,

-the patient's life expectancy, and

-how treatment will affect the patient's daily activities.

Questions to consider with treatment failure:

Why did the treatment fail?

Is the patient still potentially curable with local radiation (if the patient had a prior radical prostatectomy) or with complete removal of the prostate (if radiation therapy has failed)?

What effect will treatment have on the patient's quality and quantity of life?

When approaching a patient with detectable PSA, it is important to assess the following:

whether or not the patient was curable before the primary treatment,
the probability of cure when using a second-line therapy,
the patient's life potential expectancy, and
the impact of treatment on the patient's quality of life.

Early or Delayed Intervention for Prostate Specific Antigen Rising

Once it is established that the PSA is rising, it is usually advisable to search for disease beyond the prostate organ site.

None of the tests performed to determine whether the cancer recurrence represents a local recurrence or distal metastases is 100% accurate.

If a bone scan is positive for disease, that is strong evidence of distant metastases beyond the prostate gland.

Reasons to wait before beginning second-round therapy for prostate cancer:

Prostate cancer grows slowly in most cases.

Second-round radiation therapy can cause uncomfortable side effects for some patients.

The physician may want to check PSA levels in a series, to see if it falls again after rising.

Reasons to begin second-round therapy for prostate cancer:

Some patients feel that "doing nothing" means accepting that treatment failed.

Some prostate cancer that has begun to spread to nearby tissue can grow faster than usual.

Administering early second-round therapy, while the prostate cancer is still relatively localized, may mean greater long-term success.

Arguments for early intervention versus observation before considering a second-line therapy, in the presence of biochemical failure, are listed in Table 3.²⁴

Table 3. The Pros and Cons of Observation vs Early Intervention
Rationale for Observation and Delayed Intervention	The Case for Early Therapy
Prostate cancer has a slow progression rate.	"Wait and see" attitude equates to the acceptance of treatment failure.
The morbidity and impact on the quality of life when using a second-line therapy (eg, androgen deprivation and radiotherapy).	The aggressive behavior of prostate cancer with unfavorable pathologic features (positive margins and seminal vesicle invasion).
The possibility of assessing the PSA recurrence profile.	Effective treatment with smaller tumor burden.
²⁴Ruffion A, et al. Semin Urol Oncol. 1999;17(3):135-140.

In an attempt to determine which type of patient might benefit from the two different approaches mentioned above, three subgroups of patients have been individualized in Table 4.²⁵

Table 4. Different Levels of Risk
Group	High Risk	Intermediate Risk	Low Risk
Features	Positive lymph nodes Seminal vesicle invasion Extensive positive margins Specimen Gleason score >8	pT3 Limited positive margins Negative lymph nodes Negative seminal vesicle Final Gleason score <8	pT2/pT3 Limited extracapsular extension Negative margins Negative lymph nodes Final Gleason score <7
Biochemical Failure Rate	80% to 95%	50% within 5 years	30% to 40% over 5 years
²⁵D'Amico AV, et al. J Urol. 1995;154(1):131-138.

An aggressive attitude is recommended in high-risk patients; early intervention with hormone manipulation or combined adjuvant hormonal therapy plus radiation are the treatments of choice. As for patients in intermediate- and low-risk groups, observation and delayed treatment seem to be reasonable options.²⁴ However, when clinical trials are available, it is this author's recommendation that patients should be encouraged to participate.

Radiation Therapy for Rising PSA After RP

Not everyone who shows a cancer that is confined to the prostate and detected early is cured through radiation therapy.

It is vital to continue to follow the PSA levels in radiation therapy.

Salvage prostatectomy still offers a chance to cure some patients whose radiation therapy has failed.

Between 5% to 20% of these patients will eventually show treatment failure. Local recurrence may be due to prostate tissue inadvertently left behind, implantation of cancer into the area of removal that occurred at the time of surgery, or possibly due to unrecognized early spread of the disease even when it was thought to be confined to the prostate

The use of radiation for patients whose only sign of recurrence is a rising PSA after RP is controversial. The physician does not know whether or not the patient has local or distant disease, or if the tolerable radiation dose given to the prostatic fossa will eradicate recurrent or persistent cancer.²⁶ Forman and Velasco recommended early intervention when the PSA level was <2.0 ng/mL.²⁷ When using radiation doses of 66 Gy to 77 Gy, they found that patients with PSA levels <2.0 ng/mL had an 80% chance of being disease-free 4 years after postoperative radiation (Figure 1). Tiguert et al found that assessing preradiation PSA levels was the most important predictor of complete and prolonged disease-free survival.²⁸ When preradiation levels were <2.0 ng/mL, 74% of patients were disease free at 4 years. When patients had PSA values of greater than 2.0 ng/mL, only 22% were disease free at 4 years. Recently, ASTRO has recommended that patients be selected for salvage XRT before their PSA levels reach 1.5 ng/mL.

Figure 1. Disease-Free Survival of Patients Receiving Post-Prostatectomy Radiation Based on Pretreatment Serum PSA Level

²⁷Forman JD, et al. Oncology. 1998;12(3):33-39.

There are no studies to substantiate the value of adjuvant radiation after RP, even in high-risk patients. The results of the Southwest Oncology Group (SWOG) study that have evaluated this treatment are not yet published.
Of the patients who experienced biochemical failure after salvage radiotherapy, eventually 50% were found to have distant metastases.²⁹ PSA monitoring during therapy is important. The patient who experiences a rising PSA during treatment has a nearly 100% chance of developing metastases within 18 months.³⁰ The side effects of radiation are rectal bleeding (in up to 10% of the patients), increased incontinence (in 5% to 10% of the patients), and most likely, impairment of erectile function.²⁸

Hormonal Manipulation for Rising Prostate Specific Antigen After Radical Prostatectomy

Low doses of Eulexin® and Proscar® to treat rising PSA after failed local therapy appear to be active in lowering the PSA, while not affecting libido or causing weight gain, loss of muscle mass, or osteoporosis

A recent study at the University of Colorado and Walter Reed Army Medical Center found excellent results for over 70 patients treated with low dose Eulexin/Proscar, particularly for men whose PSA was less than 5 ng/mL when beginning treatment

Even though there are no studies that suggest hormonal therapy will improve survival, there are some suggestions that early administration of hormonal therapy is better than later administration.

Almost any form of hormonal therapy will lower PSA to undetectable levels following its initial rise, but the impact on survival is unknown. There are several treatment modalities for hormonal therapy, which can be subdivided into traditional and nontraditional methods:

Traditional Hormonal Therapy: Maximal Androgen Blockade
Orchiectomy and luteinizing hormone-releasing hormone (LHRH) agonists eliminate testicular production of testosterone. Antiandrogens work by blocking the androgen receptor. The usefulness of using this combination in the treatment of patients who have a rising PSA, post-prostatectomy, is controversial; there are conflicting data from the literature.³¹ It is possible that androgen blockade could result in improved survival. There are numerous ongoing trials to evaluate its activity.

Nontraditional Hormonal Therapy: Potency-Sparing Hormonal Manipulation
The use of nonsteroidal antiandrogens as monotherapy has minimized the side effects associated with castration. This treatment may be considered in patients with rising PSA after RP or radiation, especially in those who want to maintain potency and avoid the side effects of long-term androgen antagonist therapy. Finasteride, a 5a-reductase inhibitor, has shown to be synergic with flutamide, without producing major side effects. Finasteride and flutamide combination therapy may be a reasonable option in patients with rising PSA who do not desire medical or surgical castration. Moreover, if this combination fails, these patients are likely to respond to LHRH therapy.³²

Intermittent Androgen Suppression

There is an alternative to continuous androgen suppression that may produce fewer side effects -- intermittent androgen suppression. However, there are still many variables that need to be addressed, such as the timing of intervention, the length of therapy, the PSA level when treatment should be resumed, and the benefits of the addition of nonsteroidal antiandrogens. The advantages and disadvantages of antiandrogen therapy are reviewed in Table 5.³³

Table 5. Advantages and Disadvantages of Antiandrogen Therapy
Advantages	Disadvantages
Preserves sexual function Fewer side effects (eg, malaise, anemia, muscle mass loss, hot flashes) Less expensive than LHRH agonists Lowers PSA level and lessens anxiety	No evidence that early therapy prolongs survival Nipple tenderness More expensive than observation or orchiectomy
³³Fleshner NE, et al. J Urol. 1995;154(5):1642-1645.

Rising Prostate Specific Antigen After Radiation Therapy

Rising PSA after a local therapy such as radical prostatectomy, radiation therapy, or seed implants (brachytherapy) signals a treatment failure

It may not be necessary for the PSA to return to 0 for the patient to be considered cured.

Recent studies suggest that the time from when a patient exhibits treatment failure following radical prostatectomy to the time when they show documented metastatic disease is usually 5 to 8 years.

Recent studies suggest that a PSA nadir of 0.5 ng/mL, or even of less than 0.2 ng/mL, is a crucial cut-off point; patients who fail to achieve these levels within 2 years of radiation are likely to harbor residual or metastatic disease.^34,35 If the PSA nadir is less than 0.5 ng/mL is maintained 5 years after therapy, subsequent failure is uncommon. A higher rate of failure was noted if the nadir PSA was 0.5 ng/mL to 1 ng/mL at 5 years.³⁶ Ben-Josef has found a high rate of failure in patients with advanced stage, higher grade, higher pre-therapy PSA levels and nadir PSAs higher than 1.0 ng/mL.³⁷
Following I-125 radioactive seed implantation, the most significant decline in PSA occurs in the first 12 months; there is little change after 24 months. PSA levels higher than 1.0 ng/mL at 1 year are highly predictive of eventual biochemical failure.³⁸

Managing Patients With Rising Prostate Specific Antigen After Radiation Therapy

After radiation therapy fails, it is important to examine treatment methods and dosages of radiation, to try and determine why therapy failed.

Current methods to use salvage treatment after radiation therapy failure may be unsatisfactory.

After radiation therapy failure, it is important to review with the radiation oncologist the modality of radiation that was used, and the dose delivered, to rule out the occurrence of a technical problem. Current therapeutic options to salvage a radiotherapy failure are far from satisfactory. Androgen deprivation is capable of controlling systemic and local disease for a period of time but, ultimately, many patients may become refractory to hormonal therapy. Data from studies evaluating hormonal therapy in the presence of positive lymph nodes and asymptomatic metastatic disease suggest that there may be an advantage to initiating early therapy, in terms of improving survival, even though this therapy is associated with significant cost and some side effects. Prostate biopsy and extensive work up for metastatic disease, including bone scans, are indicated if a salvage therapy is considered.

Salvage Radical Prostatectomy

15% to 50% of slavage RP patients experience post-prostatectomy incontinence, impotence, and risk of rectal injury.

Ideally, salvage prostatectomy candidates should be those who had a high likelihood of organ-confined disease before initial radiation therapy was begun.

Young patients tend to better tolerate and benefit from salvage radical prostatectomy.

Many patients decide to take radiation therapy, instead of surgery, in order to minimize the likelihood of potential side effects such as incontinence and impotence.

This therapy has been shown to produce an excellent long-term, disease-free survival in properly selected patients.³⁹ The morbidity is high; there is a 15% to 50% incidence of post-prostatectomy incontinence, universal impotence, and a risk of rectal injury.⁴⁰ Salvage prostatectomy should be considered in carefully selected patients who have a high probability of organ-confined disease before the initial radiation (Table 6). Patients should have clinical organ-confined disease at the time of PSA-only recurrence. Radical prostatectomy could also be an option to salvage brachytherapy failure.⁴¹

Table 6. Best Candidates for Salvage Radical Prostatectomy
Characteristics	Before Radiation	At the Time of PSA-Only Recurrence
PSA	<10 ng/mL	<2.0ng/mL
Tumor Stage	T1c, T2a	�T2b
Gleason score	<6	<6
²⁶Moul JW. Oncology. 1999;13(7):985-990,993.

Patients should be young at the time of salvage surgery, in order to better tolerate and benefit from the procedure. Importantly, many patients who qualify for surgery initially, but who choose to undergo radiation instead, do so to minimize such side effects as incontinence and impotence. It is unlikely that these patients would accept the high rate of incontinence associated with salvage prostatectomy (1% to 5% risk of occurrence), which is most likely the reason they decline the option.⁴²

Salvage Cryotherapy
Cryotherapy may result in substantial morbidity. The overall rate of incontinence is as high as 43%, and Cespedes et al found that 72% of incontinent men required two or more pads. There was no correlation found between the level of the surgeons' experience and the postoperative incontinence rate.⁴³ In light of these findings, cryotherapy should still be regarded as investigational. However, new methods of delivering the cryotherapy appear to reduce the complications.

Salvage Brachytherapy for Rising Prostate Specific Antigen After External Beam Radiation
Grado et al reported 48% and 34% actuarial biochemical, disease-free survival after salvage brachytherapy at 3 and 5 years, respectively. He also noticed that complications were lower than the other potentially curative therapies, such as salvage prostatectomy and cryoablation.⁴⁴ D'Amico suggested that candidates for this therapy should satisfy the following criteria:⁴⁵

Pre-radiation PSA of 10 ng/mL or less, biopsy Gleason score of 6 or less, and 1992 AJCC stage T1c or T2a
Interval to postradiation PSA failure longer than 1 year
Absolute level of PSA at the time of salvage therapy of less than 2.0 ng/mL

However, this is still investigational until more results are published.

Dietary Manipulation and New Therapeutics in Biochemical Failure

Research is currently under way to study the medical value of special diet as it relates to recurrent cancer.

Low-fat diets, supplemented by vitamins E and D, selenium, or soy products have been studied, though results are currently inconclusive.

A low-fat diet, vitamins E and D supplements, selenium, and soy products have been studied as chemopreventive agents for prostate cancer. The Prostate Interventional Nutrition Study (PINS) group, at the Memorial Sloan-Kettering Cancer Center, is conducting a research study to address the validity of dietary manipulation in the treatment of recurrent cancer. The study is ongoing and the results are not available at this time.⁴⁶ Prostate cancer cells express a variety of antigens; rationales for using either peptide- or carbohydrate-based vaccines or dendritic-cell treatments exist. Gene manipulation is also an attractive therapy option that uses viral transfection or nonviral techniques. One experimental approach uses transfection of cancerous cells by herpes simplex virus, to make them susceptible to antiviral drugs.⁴⁷ The combination of immunologic and molecular therapies may be beneficial, in the future, once more studies have been conducted.

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