Nonprostate Urologic Oncology: Tumor Vaccines for Metastatic Renal Cell Carcinoma

Nonprostate Urologic Oncology: Tumor Vaccines for Metastatic Renal Cell Carcinoma

REVIEWING THE LITERATURE News and Views From the Literature Pediatric Urology Hypercalciuria in Pediatric Stone Formers Ellen Shapiro, MD, FACS, FAAP New York University School of Medicine [Rev Urol. 2001;3(1):20] F or the past 2 decades, we have gained a greater understanding of the etiology of pediatric nephrolithiasis because of the work of H. Norman Noe, MD, and his colleagues. In a recent study, Dr Noe investigated the role of hypercalciuria in pediatric patients with recurrent calcium oxalate or other nonstruvite stones. Hypercalciuria and Pediatric Stone Recurrences With and Without Structural Abnormalities Noe HN. J Urol. 2000;164:1094-1096. Forty-four patients (average age, 9 years) were treated for kidney stones and found to have hypercalciuria. Hypercalciuria was defined as calcium excretion of more than 4 mg/kg/d.1 Patients were stone-free (determined by plain radiograph) for at least 3 years. Seven patients had various anatomic abnormalities, including ureteropelvic junction obstruction, reflux, megaureter, and calyceal diverticulum, and the remaining 37 had normal anatomy as defined by intravenous pyelography or renal ultrasonography and voiding cystourethrography. Long-term followup data were available for 27 patients. The overall stone recurrence rate was 33% (9 of 27). The 7 children with a structural anomaly had undergone repair, and the renal units were not hydronephrotic at the time of stone formation. An additional stone developed in 3 children (42%). Multiple stones occurred in 4 patients, 2 of whom had repaired structural anomalies. The average time to recurrence was 7.2 years (range, 3 to 15 years). There was a family history of stone disease in a first or close relative 20 REVIEWS IN UROLOGY WINTER 2001 in 8 of 9 patients identified with recurrences, while 8 of 18 nonrecurrent stone formers had a positive family history. These data suggest that counseling patients and their families is appropriate after the first stone recurrence and that a complete metabolic evaluation is warranted to identify potential risk factors for stone recurrence. This study is unique in that it defines the stone recurrence rate in childhood and not late adolescence, and it does not include patients who had hydronephrotic or other untreated structural anomalies, as reported in other studies.2,3 Although hypercalciuria is an important risk factor, a positive family history alone necessitates early metabolic stone evaluation. As Dr Noe points out, the metabolic evaluation in patients with family history may identify additional risk factors. He notes also that the oral calcium loading test is no longer recommended, since the type of hypercalciuria (absorptive versus reabsorptive) will not influence therapy. Dr Noe states that although long-term thiazide treatment is not practical, it is indicated in stone formers who develop significant gross hematuria or significant pain or other symptoms. Chronic thiazide therapy leads to elevated cholesterol and low-density lipoprotein levels, demineralization of bone, and potassium wasting. Dr Noe recommends alterations in diet that include increased hydration, sodium restriction, and avoidance of excess dietary calcium. Dietary calcium is not restricted, especially during the years of somatic growth and bone development. In addition, calcium restriction has been associated with increased formation of stones.4 References 1. Stapleton FB, Noe HN, Jerkins GR, et al. Urinary excretion of calcium following an oral calcium loading test in healthy children. Pediatrics. 1982;69: 594-597. 2. Diamond DA, Menon M, Lee PH, et al. Etiological factors in pediatric stone recurrence. J Urol. 1989;142:606-608. 3. Husmann DA, Milliner DS, Segura JW. Ureteropelvic junction obstruction with concurrent renal pelvic calculi in the pediatric patient: a long-term followup. J Urol. 1996;156:741-743. 4. Lemann J Jr. Composition of the diet and calcium kidney stone. N Engl J Med. 1993;328:880-882. Nonprostate Urologic Oncology Nonprostate Urologic Oncology Tumor Vaccines for Metastatic Renal Cell Carcinoma Stephen J. Freedland, MD, Allan J. Pantuck, MD, Amnon Zisman, MD, Arie S. Belldegrun, MD, FACS University of California, Los Angeles, School of Medicine [Rev Urol. 2000;3(1):21] T he concept of vaccination dates back thousands of years, but until recently, vaccines have been used primarily for the prevention of infectious diseases. With recent advances in cellular biology, molecular biology, and immunology, there has been increasing interest in the use of vaccines to treat patients with a wide variety of diseases, including cancer. For at least 100 years, immunologists have proposed activating the immune system to specifically target and eradicate tumor cells. The idea that tumor cells can be recognized as foreign to the host’s immune system is an essential concept of tumor immunology. As a tumor, renal cell carcinoma (RCC) is notable in that up to 1% of patients with RCC will experience spontaneous tumor regression, mainly involving pulmonary metastases. The reason for this is not well understood, but spontaneous tumor regression and the prolonged latency period between primary tumor removal and the appearance of metastases in some patients suggest the existence of important host immune-mediated mechanisms for spontaneous regressions. In addition, RCC is known to respond to cytokine-based immunotherapy. As a result, RCC is a good choice as a model for vaccine-based immunotherapy. Regression of Human Metastatic Renal Cell Carcinoma After Vaccination With Tumor Cell-Dendritic Cell Hybrids Kugler A, Stuhler G, Walden P, et al. Nat Med. 2000;6:332-336. Despite progress made in the last decade through the use of systemic and local cytokine therapy, the prognosis for RCC patients with metastatic disease remains poor. At the University of California, Los Angeles, and elsewhere, attempts are being made to harness dendritic cells for use in tumor vaccines. To try to alter the natural history of RCC, Kugler and colleagues vaccinated patients who had metastatic RCC with a tumor vaccine that contained irradiated hybrid cells formed by the fusion of autologous tumor cells and allogeneic monocyte-derived dendritic cells. This technique has been shown to provide protective immunity and cause rejection of established tumors in various rodent models.1 Between January 1998 and December 1999, 17 patients with RCC were enrolled in this study. All patients had documented metastatic disease and underwent either tumor nephrectomy or resection of metastatic lesions to generate autologous tumor. The tumor cells were then fused with monocyte-derived dendritic cells by electrofusion to generate tumor cell–dendritic cell hybrids. These hybrid cells were then irradiated and injected into patients subcutaneously in close proximity to the inguinal nodes. Patients were revaccinated at 6 weeks and underwent reevaluation at 12 weeks following inoculation. All patients without evidence of disease progression received booster vaccines every 3 months. The vaccinations were well tolerated, with only 4 of 17 patients reporting mild fever lasting 1 to 2 days. There were no serious toxicities associated with vaccine treatment. The investigators report that 11 of 17 patients developed delayed-type hypersensitivity to challenge with irradiated autologous tumor; no patient had exhibited hypersensitivity before treatment. Among the 11 patients, 7 showed an initial partial or complete response to the treatment. Of the 6 patients who did not develop delayed-type hypersensitivity, none showed an initial response, and in only 1 did an eventual partial response develop. Ultimately, 4 patients showed a complete response, 2 showed a partial response, and 1 had a mixed response, for a total response rate of 41% (7 of 17). Mean follow-up time was 13 months. This report presents an exciting new avenue of immunotherapy—namely, hybrid cell vaccines. A 41% response rate with greater than 20% complete responses is higher than the response rate for historic controls using cytokine-based immunotherapy. Moreover, the lack of significant toxicity is reassuring. The results of this small pilot study will need to be repeated with larger studies and validated through prospective trials. Longer follow-up will be necessary to assess the durability of the responses. Further research is needed to identify both patients who are likely to respond to such treatment and methods to increase the efficacy of this type of treatment. Possible future avenues for research include combining ex vivo gene transfer of various cytokine genes into the tumor cell and/or dendritic cells before hybridization and vaccination. Reference 1. Gong J, Chen D, Kashiwaba M, et al. Induction of antitumor activity by immunization with fusions of dendritic and carcinoma cells. Nat Med. 1997;3:558-561. continued WINTER 2001 REVIEWS IN UROLOGY 21 Prostate Cancer continued Prostate Cancer Laparoscopic Radical Prostatectomy Steven R. Potter, MD, Alan W. Partin, MD, PhD The Brady Urological Institute, The Johns Hopkins Hospital, Baltimore [Rev Urol. 2001;3(1):22-23] I n the past 2 decades, we have seen a series of critical anatomic discoveries transform the surgeon’s ability to cure localized prostate cancer while reducing attendant morbidity. Definition of the anatomy of the dorsal vein complex allowed radical prostatectomy (RP) to be performed in a controlled fashion and in a relatively bloodless field.1 Further anatomic studies led to delineation of the autonomic innervation to the corpora cavernosa, which runs outside the prostate and Denonvilliers fascia between the levator fascia and prostatic fascia.2 The identification of these nerves and their relationship to the capsular vessels and layers of fascia investing the prostate allowed attainment of wider margins of resection and preservation of the neurovascular bundles, making it possible to preserve sexual function in many men.3,4 The performance of RP laparoscopically was first reported in 1992.5 Limited but important experience was gained with this approach during the ensuing 8 years, and improvements in laparoscopic instrumentation and suturing techniques allowed easier performance of this demanding procedure.6 Technical improvements, increasing experience with laparoscopy, and the anatomic foundations laid by the evolutionary development of open RP led to standardization of the laparoscopic technique. Initial experiences from the first 2 large studies have been reported recently. Laparoscopic Radical Prostatectomy: Preliminary Results Abbou CC, Salomon L, Hoznek A, et al. Urology. 2000;55:630-634. Abbou and associates performed laparoscopic RP on 43 men with clinically organ-confined prostate cancer using a 5-port, transabdominal approach. Dissection was initiated posteriorly, first incising the peritoneum overlying the pouch of Douglas from above, and then dissecting the bladder and prostate away from the rectum. The remainder of the dissection was carried out analogous to the 22 REVIEWS IN UROLOGY WINTER 2001 open RP technique. In the last 33 patients, the vesicourethral anastomosis was constructed using 2 running, hemicircumferential sutures. Laparoscopic RP took a median of 7 hours (8.6 hours with pelvic lymph node dissection [PLND]) in the first 10 patients and 4.3 hours (5.1 hours with PLND) in the next 33 men. One patient had a rectal injury requiring colostomy, and 4 patients required reoperation for anastomosis revision. Hospital stays were not reported explicitly, but 50% of the last 33 men remained inpatients 6 days after surgery. Hospital stays were not reported for the initial 10 patients undergoing surgery. A total of 12 patients (28%) had positive surgical margins. One patient had lymph node metastasis, and 2 had seminal vesicle invasion. At 1-month follow-up, all patients had an undetectable prostate-specific antigen (PSA) level, 36 men (84%) were dry, and 4 (9%) were potent. The authors conclude that laparoscopic RP “offers short-term oncologic and functional efficacy rates equivalent to those for open surgery,” and that “postoperative morbidity is decreased.” Comparison with contemporary RP series does not support the claim of decreased morbidity, as measured by either hospital stays or complication rates. While continence rates are laudable, follow-up is insufficient to assess cancer recurrence likelihood or potency rates. The number of patients with positive surgical margins is not comparable with those from contemporary series and raises concerns about long-term recurrence rates. Laparoscopic Radical Prostatectomy: The Montsouris Experience Guillonneau B, Vallancien G. J Urol. 2000;163:418-422. Guillonneau and Vallancien reported on 120 men undergoing laparoscopic RP between February 1998 and May 1999. The operative approach was similar to that reported by Abbou and associates. Mean operative time was 4 hours (PLND inclusive), and the reoperation rate was 1.7%. Mean postoperative hospital stay was 6 days, although the authors point out that cultural preferences likely had an impact on lengthening stays. Major and minor complications occurred in 3 and 27 men, respectively. PSA results were evaluable for 94 men and were undetectable in 89 (95%) at a mean follow-up of 2.2 months. At a mean follow-up of 1.7 months in all 120 men, 85 men (71%) were continent. A self-administered questionnaire completed by 60 men 6 months postoperatively revealed a continence rate of 73%. Potency was evaluated only in the third tertile of 40 men, with 20 of these classified as potent preoperatively and 1 man potent postoperatively at short-term follow-up. Guillonneau and Erectile Dysfunction Vallancien have recently summarized their technique after performing 260 operations and are gathering followup data on this remarkable series.7 As with the series of Abbou and associates, no conclusions regarding prostate cancer recurrence likelihood can be drawn given the short follow-up available. Conclusions. Advances in surgical technique and perioperative care provide the ability to cure organ-confined prostate cancer with acceptable morbidity. The critical outcomes measures after RP by any approach are cure of cancer, preservation of urinary continence, and preservation of potency. The outcomes following anatomic radical retropubic prostatectomy are very good and steadily improving in an incremental fashion. Patients have little postoperative pain and are typically discharged from the hospital 2 to 3 days after surgery. The argument for a laparoscopic approach to RP based on decreased morbidity is, therefore, less than compelling. The reported series from 2 centers of excellence, with surgery performed by gifted laparoscopists with vast experience, cannot claim equivalence to standard RP in any of the important outcomes measures. This may change, as reports with follow-up of adequate length to assess cancer control rates appear, but until then, care is needed in interpretation of the results of laparoscopic RP. References 1. Walsh PC, Donker PJ. Impotence following radical prostatectomy: insight into etiology and prevention. J Urol. 1982;128:492-497. 2. Reiner WG, Walsh PC. An anatomical approach to the surgical management of the dorsal vein and Santorini’s plexus during radical retropubic surgery. J Urol. 1979;121:198-200. 3. Walsh PC, Lepor H, Eggleston JC. Radical prostatectomy with preservation of sexual function: anatomical and pathological considerations. Prostate. 1983;4:473-485. 4. Walsh PC, Epstein JI, Lowe FC. Potency following radical prostatectomy with wide unilateral excision of the neurovascular bundle. J Urol. 1987;138: 823-827. 5. Schuessler WW, Kavoussi LR, Clayman RV, et al. Laparoscopic radical prostatectomy: initial case report. J Urol. 1992;147:246A. 6. Schuessler WW, Schulam PG, Clayman RV, Kavoussi LR. Laparoscopic radical prostatectomy: initial short-term experience. Urology. 1997;50:854-857. 7. Guillonneau B, Vallancien G. Laparoscopic radical prostatectomy: the Montsouris technique. J Urol. 2000;163:1643-1649. Erectile Dysfunction Duplex Scans, Apomorphine, and Peyronie Disease Jacob Rajfer, MD University of California at Los Angeles [Rev Urol. 2001;3(1):23-24] A trio of topics at the forefront of current research on erectile dysfunction (ED): the need for double dosing of medication during duplex scanning, problems with apomorphine, and choice of grafts for correction of Peyronie disease. Is a Second Injection of Vasoactive Medication Necessary During Color Duplex Doppler Evaluation of Young Patients With Veno-Occlusive Erectile Dysfunction? Chen J, Greenstein A, Matzkin H. Urology. 2000;55:927-930. In the evaluation of the penile vascular system of men with ED, it is standard to use a duplex scan to check the arterial side and dynamic infusion cavernosometry (DIC) to test veno-occlusive dysfunction. In the latter test, the response of the cavernosal tissue to veno-occlusion depends on the “stress” or sympathetic tone of the patient. This explains why additional injections of vasoactive agents during DIC may overcome this sympathetic response and accurately identify those men with normal veno-occlusion.1 What about the duplex scan? If the scan shows that the inflow is reduced through the cavernosal arteries, could this be caused by an overactive sympathetic tone during the test, resulting in failure to relax the arterial smooth muscle? To shed light on this issue, Chen and colleagues evaluated 35 patients twice with duplex scanning; patients received 2 injections of prostaglandin E1 (10 mg, 20 minutes apart), followed by a scan performed 20 minutes after each injection. The authors, who looked at peak systolic and end diastolic velocities and resistive indices, found that there were no differences in the data between the injections; giving the second injection did not significantly change the interpretation of the scan after the first injection. From these data, the authors concluded that there is no reason to redose patients who are being evaluated for ED with duplex scanning, a practice that is commonly used for patients undergoing DIC. continued WINTER 2001 REVIEWS IN UROLOGY 23 Erectile Dysfunction continued Reference 1. Hatzichristou, DG, Saenz de Tejada, I, Kupferman S, et al. In vivo assessment of trabecular smooth muscle tone, its application in pharmaco-cavernosometry, and analysis of intracavernous pressure determinants. J Urol. 1995;153:1126-1135. Efficacy and Safety of Fixed-Dose and DoseOptimization Regimens of Sublingual Apomorphine Versus Placebo in Men With Erectile Dysfunction Dula E, Keating W, Siami PF, et al, for the Apomorphine Study Group. Urology. 2000;6:130-135. Apomorphine, a dopamine agonist, acts centrally, presumably in the paraventricular and medial preoptic nuclei areas. As such, it stimulates these nuclei to initiate a pathway from the cerebrum via the spinal cord to the cavernosal nerve, where the well-known effect of cavernosal nerve stimulation occurs. The observation in the research laboratory that animals treated with this chemical develop a penile erection led to studies during which a sublingual form of the chemical was developed and used in humans. Dula and the Apomorphine Study Group performed a 4-group, double-blind, randomized, placebo-controlled trial in 569 patients with ED; patients received placebo or a 2-, 5-, or 6-mg dose of apomorphine. The International Index of Erectile Function and the Brief Sexual Function Inventory were used to evaluate efficacy. The data demonstrated that the various apomorphine groups showed an increase of about 12% to 18% in outcomes when compared with the placebo groups. The major side effect was nausea, with a dose-dependent increase of from 12% to 44% in the highest doses. The 1 side effect that was not listed in the tables (because it was not common) was syncope, which appeared to be neurogenic rather than cardiogenic. Because doses greater than 4 mg caused a high prevalence of side effects, the investigators recommended using only 2 or 4 mg of the drug. The manufacturer retracted the drug from consideration by the FDA in mid-2000 to perform additional studies, presumably as a result of the side effects. Therefore, the anticipated arrival of a second-line drug to manage ED via a mechanism different from that of the phosphodiesterase inhibitors will require additional patience on the part of both urologists and patients. Evidence-Based Assessment of Long-Term Results of Plaque Incision and Vein Grafting for Peyronie’s Disease Montorsi F, Salonia A, Maga T, et al. J Urol. 2000;163:1704-1708. One of the most difficult patients for the urologist to treat is a man with Peyronie disease. First, the cause of the disorder is unknown, although trauma is believed to play a role in development of the plaque. Second, all current medical treatments are usually ineffective, and the available surgical therapies have major risks. The goal of surgery is to straighten or mold the penis to its normal shape without compromising function and/or length. (Reconstructive surgical therapy is probably not indicated in most men with ED; instead, a prosthesis should be recommended.) Because the curvature of the penis is such that 1 side of the shaft is shorter than the other, surgery is undertaken to, essentially, equalize the lengths of the sides of the penis. To this end, one can either lengthen the shorter side of the penis or shorten the longer side or do a combination of procedures. Shortening of the side of the penis is usually accomplished with plication of the tunica on the longer side. Lengthening the shorter side of the penis may be accomplished by placing a graft material within the tunica albuginea of the corpora. This can be either homologous (dermis, vein, or fascia) or heterologous (polytetrafluoroethylene or Dacron). The latter is not recommended, because all animal studies show poor compliance and acceptance of foreign materials on the tunica. Most surgeons who perform this procedure use dermis, vein, or fascia harvested from the patient. The advantage of using dermis is that the size of the graft is usually very large; the advantage of using vein is that it is much easier and quicker to harvest. In terms of disadvantages, a dermis graft, which takes time to harvest, relies for acceptance on development of a blood supply from the corporal tissue; a vein graft is usually less than what is needed to completely cover the defect in the corpora. Some early reports at the 2000 annual meeting of the American Urological Association1 centered on the use of cadaver pericardium, but peer review and long-term followup data are still lacking. Montorsi and colleagues (from Milan) reviewed their results with the vein graft, which was harvested from the saphenous vein in the inguinofemoral area. This overcomes the disadvantage of graft size and allows an adequate graft inlay for most curvatures. The authors treated 50 men and found they were able to straighten the penis in 80%. Penile shortening occurred in 40%, yet 94% retained preoperative penile rigidity. At our current stage of surgical correction of Peyronie disease, these results are very acceptable, most likely because the size of the saphenous vein graft is much larger than one removed from the area around the malleolus. It is hoped that as more technologic and pharmacologic innovations are brought to the operating table, further improvements in the surgical correction of this disease will be developed that will make this treatment acceptable to more patients. Reference 1. Chun JL, McGregor A, Krishnan R, Carson CC. A comparison of dermal and cadaveric pericardium graft in the Horton-Devine procedure for Peyronie’s disease [abstract]. Paper presented at: 95th Annual Meeting of the American Urological Association; April 29-May 4, 2000; Atlanta. continued on page 27 24 REVIEWS IN UROLOGY WINTER 2001 Prostatitis continued from page 24 Prostatitis Diagnosis and Management of Prostatitis: The American Approach J. Curtis Nickel, MD, FRCSC Queen’s University, Kingston, Ontario [Rev Urol. 2001;3(1):27] T hree very important papers, published over the last 3 years from the Prostatitis Research Group in Boston, provide considerable insight into the diagnosis and management of the prostatitis syndromes in North America. How Common Is Prostatitis? A National Survey of Physician Visits McNaughton-Collins M, Stafford RS, O’Leary MP, Barry MJ. J Urol. 1998;159:1224-1228. Distinguishing Chronic Prostatitis and Benign Prostatic Hyperplasia Symptoms: Results of a National Survey of Physician Visits McNaughton-Collins M, Stafford RS, O’Leary MP, Barry MJ. Urology. 1999;53:921-925. Diagnosing and Treating Chronic Prostatitis: Do Urologists Use the Four-Glass Test? McNaughton-Collins M, Fowler FJ, Elliott DB, et al. Urology. 2000;55:403-407. for sexual dysfunction. The most common reason coded for chronic prostatitis visits was painful urination (14%); this symptom accounted for only 1.7% of visits for BPH. For the American urologist, pain appears to distinguish chronic prostatitis from BPH better than any other urinary symptom. To examine the diagnosis and treatment patterns employed in American urologic practice, the authors surveyed 504 urologists who reported seeing, in the previous 12 months, a median of 30 patients (range, 11 to 60) with a new diagnosis of chronic prostatitis. Eighty percent of urologists responded that they “rarely” or “never” perform the Meares-Stamey 4-glass test, while only 4% answered “almost always.” Eighty-two percent of urologists reported that they prescribe antibiotics for the majority of their patients with prostatitis; -blockers were the second most common treatment prescribed. Urologists frequently make a diagnosis of prostatitis, yet rarely perform standardized lower urinary tract localization studies and almost always prescribe antibiotics, even when they believe that bacterial prostatitis is rare. Urologists diagnose chronic prostatitis in a substantial number of American men each year. Although urologists believe that they can easily differentiate symptoms of chronic prostatitis from those of BPH, the vast majority rarely perform the standardized Meares-Stamey lower urinary tract localization test when making a diagnosis or classifying a patient. Even among those urologists who used this test some of the time, it did not appear to significantly affect antibiotic treatment patterns. These important findings in the practice patterns of American urologists are probably very similar to those of urologists practicing elsewhere in the world and deserve very close scrutiny. Finding a simple diagnostic test that is accepted by the majority of urologists and would help rationalize therapy is imperative if our treatment of patients with this enigmatic condition is to improve. Employing a national database of the National Ambulatory Medical Care Surveys from 1990 to 1994, the authors discovered that prostatitis was listed as a diagnosis in almost 2 million annual visits. This represented 8% of visits to urologists during this period. Surprisingly, prostatitis was a more common diagnosis in men aged 36 to 65 than in men aged 18 to 35. The odds of a prostatitis diagnosis were 2-fold greater in the South than in the Northeast United States. Using the same database for the years 1990 to 1996, the investigators examined the most common symptoms reported by men with a diagnosis of chronic prostatitis compared with men with a diagnosis of benign prostatic hyperplasia (BPH). Among visits for chronic prostatitis, 20% were for pain, 19% for urinary complaints, and 1% continued WINTER 2001 REVIEWS IN UROLOGY 27 Incontinence continued Table Materials Used for Pubovaginal Slings Incontinence What Is the Best Sling Material: Autologous Fascia, Cadaveric Fascia, Synthetic Strip, or In Situ Vaginal Wall? Michael B. Chancellor, MD, Christopher P. Smith, MD University of Pittsburgh School of Medicine [Rev Urol. 2001;3(1):28-29] W hat is the ideal material to use for a pubovaginal sling operation? Choosing sling material used to be simple: make a large abdominal incision and harvest a piece of rectus fascia or make a painful thigh incision to get a piece of fascia lata. Both choices worked well, but the patients had a prolonged, painful postoperative course. The pain was not in the vaginal area where the sling was placed but always at the site of tissue harvest. The trend toward minimally invasive surgery has changed the material we use for pubovaginal sling surgery. Recently, there has been an avalanche of new materials approved for the pubovaginal sling. How do we decide which is best? The 2 articles reviewed address this important issue. The table lists materials presently used for bladder suspension. Is Modified In Situ Vaginal Wall Sling Operation the Treatment of Choice for Recurrent Genuine Stress Incontinence? Su T-H, Huang J-P, Wang Y-L, et al. J Urol. 1999;162:2073-2077. This well-done study answers a question that has been a point of contention at a number of urologic and urogynecologic meetings during the past few years. The authors studied a modified in situ vaginal wall sling procedure for recurrent genuine stress incontinence and assessed whether this type of sling operation is a substitute for the traditional suburethral sling procedure. Patients (23) with urodynamically proven recurrent genuine stress urinary incontinence were included in the study. A modified needle urethropexy technique was used; an island of in situ vaginal skin served as a sling to support the bladder neck and urethra. Investigators assessed surgical outcome, both subjectively and objectively, at a median of 15 months. Control patients (42) underwent a traditional polytetrafluoroethylene sling operation. Risk factors for 28 REVIEWS IN UROLOGY WINTER 2001 Autologous tissue Dermis Fascia lata Free-strip vaginal wall In situ vaginal wall Rectus fascia Skin Cadaveric banked tissue Dermis Dura Fascia Pericardium Small-intestine submucosa Synthetic material Polytetrafluoroethylene Tension-free vaginal tape surgical failure were lower maximal urethral pressure and urethral closing pressure, narrow vaginal capacity, and previous anterior colporrhaphy or Stamey operation (all, P < .05). When assessed objectively, the cure rate of the vaginal wall sling operation was 34.8%; this cure rate was lower than that of the traditional sling procedure (88.1%, P < .05). Subjective assessment produced the same results (vaginal sling, 60.9%; traditional sling, 92.9%; P < .05). Prolonged urinary retention or urethral erosion did not occur. A unique complication of the vaginal wall sling operation was that suburethral epithelial inclusion cysts developed in 3 patients (13.1%). It was previously assumed that inclusion cysts would not occur in a buried vaginal wall island, because vaginal epithelium is not cornified and thus not likely to form an epithelial inclusion cyst. This study proved that assumption incorrect. Su and associates concluded that the vaginal wall sling operation should not be recommended for patients with recurrent genuine stress urinary incontinence and particularly not for those who have risk factors for surgical failure. There are some suggestions that women with stress incontinence have 40% less collagen in their skin than have continent women. Because altered collagen content may cause reduction of vaginal tensile strength and contribute to stress incontinence, use of a vaginal wall strip may be less desirable in women with stress incontinence. In my practice, I have not performed in situ vaginal wall sling procedures, because so many of my patients with stress incontinence have had a previous vaginal wall sling that failed. Incontinence Erosion of Woven Polyester Pubovaginal Sling Kobashi KC, Dmochowski R, Mee SL, et al. J Urol. 1999;162:2070-2072. This retrospective 24-month chart review combines reports from 5 centers concerning complications requiring removal of a woven polyester sling that was treated with pressureinjected bovine collagen (ProteGen). Slings had been inserted 1 to 22 months previously. Presenting symptoms, interval between sling placement and removal, procedures following sling placement, and continence status before and after sling removal were evaluated. Erosion, pain, or infection necessitated sling removal in 34 women. The most common presenting complaints are shown in the Figure. Of these patients, 17 (50%) had vaginal erosion only, 7 (20%) had isolated urethral erosion, and 6 (17%) had urethrovaginal fistulas. In 4 patients, there was no obvious erosion, but slings were removed because of vaginal pain. Before removal of the sling, 16 patients (47%) were dry, 13 (38%) had some incontinence, and 3 (8%) had urinary retention. After removal of the sling, 7 patients (20%) were still dry, 25 (74%) had mild to severe stress urinary incontinence (with or without urgency and urge incontinence), and 2 (6%) were being followed. The authors concluded that woven polyester slings treated with pressure-injected bovine collagen are prone to cause erosion. The ProteGen sling was recalled in January 1999, but there are still patients with this sling in place who must be followed closely. Although I have never used this sling, I have managed complications following its insertion, including erosion, infection, pain, and obstruction. Removal and reconstruction of the urethra in these patients has been difficult, often with less than perfect outcomes. Perhaps not all synthetic material should be considered taboo for use as a pubovaginal sling. Polytetrafluoroethylene and woven polyester are quite different; the infection and erosion rates from polytetrafluoroethylene may be lower. It remains to be seen if similar complications develop following use of the popular tension-free vaginal tape. These 2 well-written articles do not end the controversy regarding what is the best sling material. My personal bias at this time is to be conservative, to avoid synthetic material, and to not trust use of the vaginal wall. Because almost all of my anti-incontinence operations are in women for whom 1 or more previous operations have failed, I tend to use either autologous fascia or banked dermis or fascia. I look forward to using good synthetic materials for slings when these can provide safe and effective long-term results. Figure. Presenting complaints of 34 women following insertion of a woven polyester pubovaginal sling. 100 90 80 % of patients 70 62% 62% 60 50 40 32% 30 20 15% 10 0 Delayed vaginal discharge Vaginal pain or pressure Suprapubic pain Recurrent urinary tract infection continued WINTER 2001 REVIEWS IN UROLOGY 29 Pediatric Urology continued Pediatric Urology Proteinuria in Children Ellen Shapiro, MD, FACS, FAAP New York University School of Medicine, New York [Rev. Urol. 2001;3(1):30] W e are often asked to evaluate children who are found to have some degree of proteinuria. Recently, the Pediatric Nephrology Panel established at the National Kidney Foundation Conference on Proteinuria, Albuminuria, Risk, Assessment, Detection, and Elimination (PARADE) proposed recommendations for physicians who identify or are referred children or adolescents with proteinuria. Evaluation and Management of Proteinuria and Nephrotic Syndrome in Children: Recommendations From a Pediatric Nephrology Panel Established at the National Kidney Foundation Conference on Proteinuria, Albuminuria, Risk, Assessment, Detection, and Elimination (PARADE) Hogg RJ, Portman RJ, Milliner D, et al. Pediatrics. 2000;150:1242-1249. Proteinuria is usually detected by a dipstick test and is part of the routine urinalysis performed in both pediatric and adult urologic offices. The dipstick detects primarily albumin and no low molecular weight protein. The albumin reacts with tetrabromphenol blue to produce various shades of green, depending on the concentration of albumin. Therefore, tests of dilute urine may not detect sufficient protein, while alkaline urine or urine obtained following contrast studies would be falsely positive. To circumvent these problems, a protein/creatinine (Pr/Cr) ratio similar to the calcium/creatinine ratio used to detect microscopic hematuria is determined on a spot, first-morning urine specimen.1,2 Although more accurate, a 24-hour urine collection is not practical in young children. A normal value for the Pr/Cr ratio is less than 0.2 mg protein/mg creatinine in children older than 2 years and less than 0.5 mg protein/mg creatinine in children 6 to 24 months old. The review defines proteinuria as transient, orthostatic, or persistent. Transient proteinuria is associated with stress, fever, or exercise and does not have long-term sequelae. Orthostatic proteinuria refers to proteinuria that is elevated when patients are upright, but normal when they are supine. Thus, examining a first-morning specimen differentiates this. Orthostatic proteinuria is usually benign, although rarely it has been associated with glomerulosclerosis.3,4 Persistent proteinuria is defined as 1+ (≈ 30 mg/dL) or greater by dipstick determination on multiple occasions. This abnormal level necessitates further investigation. The authors provide a simple algorithm for the evaluation of asymptomatic proteinuria in children. As urologists, we should evaluate all children with 1+ or greater proteinuria, starting with the urinalysis and first-morning spot Pr/Cr ratio. The child must void before retiring and remain supine until the first-morning urine sample is obtained. If the ratio is less than 0.2 mg protein/mg creatinine, a diagnosis of orthostatic proteinuria is made, and no further studies are needed. If other abnormalities are noted on the urinalysis and/or the first-morning Pr/Cr ratio is greater than 0.2 mg protein/mg creatinine, a complete history and physical, including blood pressure determination, is suggested. Laboratory evaluations, including serum albumin, creatinine, cholesterol, and electrolyte levels should be obtained. In addition, renal sonography should be performed. Complement (C3, C4) and antinuclear antigen levels are needed, and serologic determination for hepatitis B and C is indicated. HIV testing should be considered. A full evaluation is then warranted by a pediatric nephrologist. Because increasing levels of proteinuria are a predictor of progressive renal damage and cardiovascular disease, it is important for the urologist to be aware of the indications and proper initial evaluation of proteinuria in children.5-9 This article should be kept in a convenient spot in one’s office so it can be referred to when patients with proteinuria are identified. References 1. Houser M. Assessment of proteinuria using random urine samples. J Pediatr. 1984;104:845-848. 2. Houser MT, Jahn MF, Kobayashi A, Walburn J. Assessment of urinary protein excretion in the adolescent: effect of body position and exercise. J Pediatr. 1986;109:556-561. 3. Rytand DA, Spreiter S. Prognosis in postural (orthostatic) proteinuria: forty to fifty-year follow-up of six patients after diagnosis by Thomas Addis. N Engl J Med. 1981;305:618-621. 4. Berns JS, McDonald B, Gaudio KM, Siegel NJ. Progression of orthostatic proteinuria to focal and segmental glomerulosclerosis. Clin Pediatr. 1986;25:165166. 5. Grimm RH Jr, Svendsen KH, Kasiske B, et al. Proteinuria is a risk factor for mortality over 10 years of follow-up. MRFIT Research Group. Multiple Risk Factor Intervention Trial. Kidney Int Suppl. 1997;63:S10-S14. 6. Haffner SM, Stern MP, Gruber MK, et al. Microalbuminuria: potential marker for increased cardiovascular risk factors in nondiabetic subjects. Arteriosclerosis. 1990;10:727-731. 7. Kannel WB, Stampfer MJ, Castelli WP, Verter J. The prognostic significance of proteinuria: the Framingham Study. Am Heart J. 1984;108:1347-1352. 8. Ruggenenti P, Perna A, Mosconi L, et al. Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies. Kidney Int. 1998;53:1209-1216. 9. Wingen AM, Fabian-Bach C, Schaefer F, Mehls O. Randomised, multicentre study of a low-protein diet on the progression of chronic renal failure in children. Lancet. 1997;349:1117-1123. continued on page 33 30 REVIEWS IN UROLOGY WINTER 2001 Nonprostatic Urologic Oncology continued from page 30 Nonprostate Urologic Oncology New Diagnostic and Therapeutic Modalities for RCC, TCC, and Testicular Cancer Stephen J. Freedland, MD, Debby Chao, BS, Allan J. Pantuck, MD, Amnon Zisman, MD, Arie S. Belldegrun, MD, FACS University of California, Los Angeles, School of Medicine [Rev Urol. 2001;3(1):33-35] T he value of studies of management options for carcinoma is apparent in reviews of the use of positron emission tomography scans, peripheral-blood stemcell transplantation, and combination chemotherapy. Positron Emission Tomography Scans in the Evaluation of Postchemotherapy Residual Masses in Patients With Seminoma Ganjoo KN, Chan RJ, Sharma M, Einhorn LH. J Clin Oncol. 1999;17:3457-3460. Management of a residual mass after chemotherapy for seminoma remains controversial. Two patterns of recurrence have been described: a well-defined mass and a diffuse retroperitoneal, fibrotic reaction. With the former, the risk of residual cancer can rise above 50%. At Memorial Sloan-Kettering Cancer Center in New York, patients with a residual mass larger than 3 cm are advised to undergo surgical resection. At Indiana University Medical Center in Indianapolis, the advice to patients is watchful waiting with serial imaging to detect evidence of tumor progression. The issue at stake is that, unlike for nonseminomatous germ cell tumors, surgery for seminoma postchemotherapy is more difficult because of a severe desmoplastic reaction occurring in the retroperitoneum; this reaction increases the likelihood of surgical complications and decreases the likelihood of complete resection. Clearly, a noninvasive imaging modality that could prevent unnecessary surgery would be beneficial. In an effort to improve the ability to assess, preoperatively, the residual mass for active tumor, the authors (from Indiana University) prospectively examined whether positron emission tomography (PET) scans predicted who had residual tumor and who had necrosis. A total of 29 patients were enrolled in the study between February 1996 and March 1998. The first group had residual masses after 3 or 4 cycles of primary chemotherapy with regimens containing cisplatin/etoposide. The second group did not respond to primary therapy with that chemotherapy regimen and had undergone salvage chemotherapy with 3 or 4 cycles of vinblastine, ifosfamide, and cisplatin or high-dose chemotherapy with peripheral stem-cell support. All patients underwent a CT scan and PET scan at the completion of treatment. Patients were then followed serially with examinations and repeated CT scans to detect disease recurrence. In the first group, 14 of 19 patients had residual masses larger than 3 cm. In this group, 2 patients had minimal uptake on the PET scan, and the remaining 17 patients had no uptake. Based on the authors’ cutoff of positive PET scan, the 2 patients with minimal uptake were considered to have negative PET scans, so all patients in the first group were considered to have negative PET scans. No patients had recurrence, with a median follow-up of 11.5 months. In the second group, only 4 of 10 patients had residual masses that were larger than 3 cm. All patients had a negative PET scan for retroperitoneal masses, but 1 patient had a posterior mediastinal mass, which was positive on PET scan. This patient underwent resection of this mass, which showed only necrosis. Nine months later, despite a negative PET scan, a retroperitoneal recurrence developed in this patient. Of the 10 patients in the second group, 5 patients had clinical relapses, despite negative PET scans. These 5 patients were successfully treated with high-dose chemotherapy and stem-cell support. The authors found that the PET scan was 96% specific to detect true negatives, but 0% specific to detect true positives. Based on these disappointing results, the authors concluded that the PET scan has no role in prediction of carcinoma in patients with postchemotherapy residual masses in bulky seminoma. Thus, the management of residual masses remains controversial, and an individualized treatment regimen is necessary. Regression of Metastatic Renal-Cell Carcinoma After Nonmyeloablative Allogeneic Peripheral-Blood Stem-Cell Transplantation Childs R, Chernoff A, Contentin N, et al. N Engl J Med. 2000;343:750-758. Metastatic renal cell carcinoma (RCC) is associated with a poor prognosis. Rates of response to modern immunotherapy protocols in the range of only 20% are standard. In an attempt to improve these response rates, the authors WINTER 2001 REVIEWS IN UROLOGY 33 Nonprostatic Urologic Oncology continued treated patients who had metastatic RCC with infusions of a peripheral-blood stem-cell allograft from an HLA antigen–identical sibling or from a sibling with a mismatch at a single HLA locus. Between February 1998 and August 1999, 19 patients were enrolled in this study at the NIH. All patients had biopsy-proven metastatic RCC and had not responded to primary therapy. Patients were required to have a sibling who was either HLA antigen–identical or a single HLA locus mismatch to serve as a donor. Patients were given cyclophosphamide, fludarabine, and cyclosporine pretransplantation to prevent rejection of the graft. Patients were then infused with a median of 8  106 CD34 cells per kilogram. Following transplantation, cyclosporine was continued and then withdrawn between days 30 and 100 post-transplantation, depending on the engraftment of the donor lymphocytes. This engraftment was documented by measuring chimerism in both myeloid and T-cell lineages by polymerase chain reaction assay of microsatellite regions. Patients who had 100% chimerism at 30 days posttransplantation were estimated to be at high risk for graftversus-host disease (GVHD) and, therefore, cyclosporine was tapered more slowly than in those who had a mixed response at 30 days. Of the 19 patients enrolled in the study, 17 received lymphocytes from an HLA antigen–identical sibling and 2 received cells from a sibling with a mismatch at a single HLA locus. The 2 patients who received antigen-mismatch grafts were given additional immunosuppression, consisting of pretransplant antithymocyte globulin. If patients had progressive disease, they were eligible to receive up to 3 further infusions of donor lymphocyctes given monthly in escalating doses (5  106, 1  107, and 5  107 CD3 T cells per kilogram of recipient’s weight). The median number of CD3 T cells received was 4.2  108. Toxicity was high, with 2 of the 19 patients dying of transplantation-related complications (1 from GVHD, and 1 from sepsis). Ten of the 19 patients developed grade 2 or higher acute GVHD, which was amenable to treatment in 9 patients. Chronic GVHD developed in only 4 patients. Febrile neutropenia developed in all 19 patients at some point during therapy. Bacterial sepsis developed in only 1 patient. Of the 19 patients treated, 3 had complete responses and 7 had partial responses, for a response rate of 53% (10/19). Regression was seen at multiple metastatic sites. Regression was typically delayed, occurring at a median of 4 months after transplantation, and was only seen following complete chimerism in the recipient. Clinical responses were only seen following withdrawal of cyclosporine in 8 of the 10 patients who responded to treatment. Moreover, in 9 of the 10 patients, response was associated with a grade 2 or higher GVHD. In fact, in mul- 34 REVIEWS IN UROLOGY WINTER 2001 tivariate analysis, the development of GVHD was the only factor that predicted a response (relative likelihood of response, 11.0; 95% confidence interval, 1.4 to 88.5). The 3 patients with complete responses remained tumor-free at 16, 25, and 27 months post-transplantation. Of the 7 patients with partial response, 2 died of transplantationrelated complications, and 1 died of progressive disease. The remaining 4 were alive without disease progression. The results of this small-scale study are impressive, with a 53% response rate. The finding of 2 treatment-related deaths among the 19 patients is concerning, but it may be warranted, given the grim prognosis for patients with metastatic RCC. It should be emphasized that patients in this study were only selected after failure to respond to primary therapy and were not allowed to have had any therapy within the 30 days before study enrollment. Therefore, by necessity, these patients had carried a diagnosis of metastatic RCC for at least several months. Thus, it is possible that the authors selected patients who were stronger and perhaps had less aggressive disease, which could have influenced the results. With a median survival of less than 12 months, many patients with metastatic RCC cannot afford a lengthy time to treatment or delay in treatment response. Moreover, only patients with a sibling who was HLA antigen–identical or a single HLA locus mismatch were eligible to participate in this study. Therefore, the pool of potential patients who could benefit from this treatment is limited. It will be interesting to see if these impressive results are validated using a larger patient series and using donors with more antigen mismatches to improve the pool of potential patients who might benefit from this exciting new therapy. Southwest Oncology Group Study of Paclitaxel and Carboplatin for Advanced Transitional Cell Carcinoma: the Importance of Survival as a Clinical Trial End Point Small EJ, Lew D, Redman BG, et al. J Clin Oncol. 2000;18:2537-2544. The poor prognosis associated with advanced urothelial transitional cell carcinoma (TCC) is well known. The standard treatment for these patients is the cisplatin-based chemotherapy regimen of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC). Complete remission of disease following M-VAC is uncommon, and the median survival time is approximately 12 months. The multiple toxicities associated with M-VAC, including neurologic, auditory, and renal, are also limiting factors. Because cisplatin is implicated in many of the side effects, replacement by carboplatin has been proposed to eliminate Nonprostatic Urologic Oncology or reduce these effects. Paclitaxel, which has significant antitumor activity, is one of the promising agents for TCC. The combination regimen of carboplatin and paclitaxel is being studied as a potential replacement for M-VAC, and a number of single-institution phase I trials have shown encouraging results. Small and colleagues report the results of the multicenter Southwest Oncology Group (SWOG) study of this combination. Twenty-nine patients with advanced TCC were included in the study. Exclusion criteria included brain metastasis, nonmeasurable disease 28 days before registration, soft tissue radiation therapy fewer than 28 days before registration, previous systemic treatment with cisplatin or carboplatin completed less than 1 year before enrollment, and SWOG performance status greater than 2. Patients received a 3-hour infusion of paclitaxel at 200 mg/m2 followed by an infusion of carboplatin targeted to an area under the curve of 5. This cycle was repeated every 21 days, depending on patient response. The median number of cycles received per patient was 5. Six patients had partial response, and none had complete response, yielding an overall response proportion of 20.7%. The overall median survival time was 9 months. The most common grade 4 toxicity was neutropenia or leukopenia, occurring in 38% of patients. Neurotoxicity and renal toxicity were seen in 55.2% and 6.9% of patients, respectively. Neurotoxicity was the most common reason for treatment discontinuation. This low response proportion stands in contrast to rates RESIDENTS IN UROLOGY YOU’RE INVITED from 4 previous studies using the carboplatin and paclitaxel regimen; these studies showed considerably higher response rates of 50% to 72%. When Small and colleagues compared the adverse prognostic factors of their patients with those of patients from the other studies, they found that their population had a lower incidence of node-only disease and a higher incidence of distant metastasis, suggesting that patient response to treatment may be directly correlated to the stage of disease. Despite the variations in response proportions, the overall median survival in 3 of the studies, including the current one, was comparable at approximately 9 months. These results are inferior to the 12-month survival demonstrated by the intergroup study of M-VAC.1 The relevance of response proportion as a surrogate end point for survival versus the actual survival time is a point of debate. Ultimately, it is the overall survival that will dictate the efficacy of a therapeutic regimen. In this regard, MVAC appears to be superior. Because the combination of carboplatin and paclitaxel continues to yield disparate results, its role in the treatment of patients with advanced bladder cancer remains unclear. For patients with advanced TCC who are able to tolerate the toxicities, M-VAC remains the standard of care. ■ Reference 1. Loehrer PJ Sr, Einhorn LH, Elson PJ, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992;10:1066-1073. Write a Case Review, including history, evaluation, treatment, and discussion. Submit your Case Review by e-mail or mail (instructions below). Those approved by the Medical Editors and peer reviewers will be edited for publication in Reviews in Urology. The primary author of a published Case Review will receive $250. Name by the Medical Editors of Reviews in Urology to Submit a Case Review for Publication in Reviews in Urology Title Mailing address Telephone ______________ Fax ____________________ E-mail __________________ Department head Case Review topic Mail to (include disk): Case Review, Reviews in Urology, 1333 Broadway, Suite 1120, New York, NY 10018; E-mail to: dgern@medreviews.com. WINTER 2001 REVIEWS IN UROLOGY 35