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In an earlier issue of The Urologic Clinics of North America (volume 20, number 4, 1993) on prostatic tumor markers, we discussed a variety of issues that were involved in the assessment of prostate-specific antigen (PSA) immunoassays. 31 These included the various forms of PSA, molecular heterogeneity, free and complexed PSA, the generation of antibodies to PSA, the need for standardization of PSA assays, criteria for assessing PSA assay performance, heterophile antibodies to PSA that may perturb current PSA assay results, and ultrasensitive PSA assays. Many of the discussions in that article remain relatively current, and updates are not warranted. There are four specific areas, however, in which substantial progress has been made, and new information is now available, and we therefore focus our attention in this update on PSA assay standardization, free and complexed PSA, PSA epitope mapping, and hK2, the twin of PSA.

A definitive conclusion about the value of ART is not possible from the data available: Both the methods of radiation therapy and the techniques in the diagnosis of locally persistent disease have evolved over the years. Currently, the data lead to the conclusion that ART decreases local recurrence but does not improve overall survival. Yet the PSA data strongly suggest that only locally persistent disease is a common event after radical prostatectomy (particularly in margin-positive disease only) and that current ART techniques are inadequate in many but not all of these patients. Certainly some men seem to have their local disease eliminated by ART to remain NED, but it is unclear exactly how to select them. Many experts also believe that keeping the PSA as low as possible for as long as possible, with sequential applications of ART and then androgen ablation as necessary, is a good emotional if not medical strategy. For example, all patients now wish to know their PSA level and worry about it. Also, potency can be maintained or regained after ART but becomes improbable after androgen ablation because of loss of libido. Clearly, a study randomizing high-risk postoperative patients into observation versus ART is needed and indeed such a study is under way in the Southwestern and Eastern Cooperative oncology groups, but to date accrual is inadequate (Ian Thompson, Jr, MD, personal communication, May 1994). This study must be supported. When participation in the randomized study is not possible, we believe four tentative recommendations about the application of ART can be made based on the available data (Fig. 1): (1) For high-risk patients (e.g., high Gleason score and/or high pathologic stage) with initially undetectable PSA levels, we recommend instituting ART before any rise in postoperative PSA levels because low-volume disease may best respond to this therapy. (2) For patients with rapidly rising or initially detectable postoperative PSA levels (especially if NBA is negative), we believe that the disease has most likely already spread to distant sites and would initiate therapy aimed at systemic disease. (3) For those patients with rapidly rising postoperative PSA but with positive NBA, we recommend local irradiation. (4) if the postoperative PSAlevels rise gradually, we would initiate ART regardless of the needle biopsy result because of the possibility of NBA sampling error and the fact that the gradual increase in PSA suggests that the disease is still local.(ABSTRACT TRUNCATED AT 400 WORDS)

SUMMARY The physician and laboratorian have several proven PSA assays from which to choose, and several more are likely to achieve FDA approval soon. Furthermore, an assay that is FDA approved offers considerable reassurance that the many aspects of assay design and manufacturing processes meet an acceptable standard. This will become even more critical as assays report values in the ultrasensitive range. We have attempted to review here some of the most important issues related to PSA assay performance and standardization. Standardization particularly is a complex problem for which solutions are just now appearing. Yet efforts must continue to minimize controversies, because many more assays will be forthcoming and because newer applications of PSA determinations will place more pressure on proper assay evaluations. For example, measurement of free PSA, PSA-ACT complexes, and the ratio of one to the other are intriguing possibilities for added clinical benefit. Also, ultrasensitive PSA assays add a new dimension to the detection of residual disease and may provide unique opportunities for the implementation of new therapies and their timely evaluation. In our opinion, the impact of PSA on the management of prostate cancer is still growing, and the opportunities for better and new assays are still great.

The exact usefulness of prostate-specific antigen for staging before radical prostatectomy is still unclear. Perhaps the marker's most exciting feature is its value in detecting residual disease after radical prostatectomy. The author also discusses the technical questions in testing and interpretation.

The modified dorsal lithotomy position is excellent for radical pelvic operations. Use of modified Krauss arm supports as stirrups, along with pneumatic devices that intermittently compress the legs, significantly reduces postoperative morbidity in patients who undergo operations in this position.

SUMMARY The discipline and techniques of immunology have been an important part of recent advances in genitourinary oncology. Although the initial promise of tumor immunology has not been realized in man, discoveries in the laboratory are revitalizing the expectation that this field will yet be of significant assistance in the diagnosis and treat ment of cancer. Already tumor immunology studies along with new immunologic assay techniques have produced clinically important tumor markers, such as alpha-fetoprotein, human chorionic gonadotropin, and prostatic acid phosphatase, and have intensified the search for other markers. Finally, research activity is increasingly focusing on the tumor cell itself, again often using immunologic methods. Although most of this activity is still experimental, analysis of bloodgroup antigens in transitional cell carcinoma has produced sufficient data to suggest that such an approach will soon be a part of the urologist’s clinical armamentarium in his efforts to treat patients with bladder tumors.

Given the data described herein, there is reason for even greater optimism about the possibility of fertility among patients with testicular cancer. Fertility issues have been and will continue to be important as different therapies for nonseminomatous cancer are proposed. For example, we previously calculated that the difference in fertility between patients who are treated with expectant therapy versus lymph-adenectomy for clinical stage I disease was only 16 patients in favor of expectant therapy. If new data on relapse rates after expectant therapy (e.g., 30 per cent) and better ejaculation preservation rates after lymphadenectomy (e.g., 85 per cent) are incorporated into this calculation, the number benefited falls to 6 patients. It has also been proposed that patients with low-volume stage IIB disease should receive initial chemotherapy and that lymphadenectomy should be reserved for those patients with residual disease. Applying these calculations along with certain additional assumptions, the difference in fertility between these two treatment alternatives is only 4 patients in favor of initial chemotherapy (P.H. Lange; manuscript in preparation). However, this approach has significantly greater toxicity. Much more must be done to improve our understanding and management of infertility in patients with testicular cancer. Additional tasks include the need to establish the exact ratio of patients with testicular cancer who have infertility that precedes or is a result of their disease, and to develop methods for predicting fertility status so that treatment can be tailored accordingly. Also, we must consolidate and improve the indications, techniques, and results for fertility-sparing lymphadenectomy in ways that have been described herein. In addition, the exact damage-to-benefit ratio for the number of courses and types of chemotherapy administered to patients will need to be studied carefully and prospectively, preferably in cooperative groups. The accelerating advances in in vitro fertilization and cryopreservation must be watched carefully, and their application to appropriate patients with nonseminomatous cancer should be encouraged. Cryopreservation before therapy should continue to be advocated. All of these tasks are extremely difficult because they require precise analysis of carefully generated statistics and difficult judgments about individual human values.

SUMMARY It is now established that the sensitive radioimmune assays for alpha-fetoprotein and human chorionic gonadotropin are of substantial benefit in the management of patients with testicular tumors. • They can aid in the differential diagnosis of scrotal masses, but only if the levels are elevated. Negative values do not obviate surgical exploration. • They are a superior, though not infallible, method of staging prior to lymphadenectomy in patients with nonseminomatous germ cell tumors. • They are probably indispensible for following nonseminomatous germ cell tumors in Stage I or Stage II disease after initial therapy, and in assessing the effects of ongoing therapy in Stage III disease. • They may be helpful in predicting which patients with seminomas will not respond to conventional therapy. There are, of course, many aspects of the clinical applicability of these markers that are as- yet ill defined. For example, the exact frequency of false negatives in both preoperative evaluations and in patients with Stage III nonseminomatous germ cell tumors remains to be determined. Moreover, we do not know the prognostic implications of negative serum markers in the presence of viable nonseminomatous germ cell tumors. Also, as these assays become more readily available, the chemotherapist and radiation therapist must define the exact role that these markers will have in monitoring and influencing therapy. Is it possible that serial alpha-fetoprotein and human chorionic gonadotropin serum level determinations will allow the chemotherapist to titrate the dosage of chemotherapeutic agents effectively or to predict the response to these agents by first administering "challenge doses?" Will the radiotherapist decide whether and how to treat a patient with seminoma on the basis of human chorionic gonadotropin levels? These questions require that all physicians treating patients with testicular tumors use reliable and sensitive assays, measure alpha-fetoprotein and human chorionic gonadotropin levels frequently, and report their findings. Finally, clinical studies using these markers have stimulated interest in other aspects of testicular tumors that promise additional clinical benefit. For example, histochemical staining for alpha-fetoprotein and human chorionic gonadotropin of tissues obtained from testicular tumors may alter the pathologic classification of these neoplasms. As discussed by Dr. Jewett in another part of this symposium, marker studies in animal models have helped to advance our understanding of the cellular origins of germ cell tumors. Lastly, in vitro and in vivo laboratory experiments have demonstrated the feasibility and possible clinical applicability of using anti-alpha-fetoprotein and anti-human chorionic gonadotropin antibodies for diagnosis and as a new form of therapy.19.24

Recent experience with the implantation of the OmniPhase, FlexiFlate, and Hydroflex penile prostheses at our institution has shown all three to provide good axial rigidity and relatively good concealment, although the phallus tends to be much more expanded than normal with all three devices when they are in the nonfunctional position. Urologists who are familiar with penile implantation surgery will encounter no technical difficulties with the implantation of these new devices. Rather, long-term mechanical reliability will be the crucial factor that will cause implanting surgeons and their patients to shift from one prosthesis to another.