Urologic Oncology

REVIEWING THE LITERATURE News and Views from the Literature Urinary Tract Infection Immunological Based Therapies for Urinary Tract Infection: The Future Is Almost Here! Reviewed by J. Curtis Nickel, MD, FRCSC Department of Urology, Queen’s University, Kingston, Ontario, Canada crobial therapy for UTIs in the near future. However, the use of vaccines to prevent UTIs in susceptible women is an exciting development. Although once appearing distant on the clinical horizon, it is now coming close to being reality. The hypothesis on which UTI vaccine Although once appearing distant on the clinical horizon, the use of vaccines for the prevention of urinary tract infection is now coming close to being reality. [Rev Urol. 2002;4(4):196–197] © 2002 MedReviews, LLC rinary tract infections (UTIs) in women with normal urinary tract anatomy remain a clinical problem, despite the plethora of antibiotics released over the last two decades. Forty to fifty percent of women will suffer a UTI in their lifetime; 25%–50% will recur within several months; and 2%–10% suffer multiple recurrent episodes.1 Repeat treatment with antibiotics is necessary, and many women develop significant side effects. Antibiotic-resistant organisms are increasing in prevalence, making many of the traditional front-line antimicrobial-based therapies, such as penicillins, sulfas, and even trimethoprim-sulfamethoxazole ineffective. As far as antibiotic therapy for UTI is concerned, there has been no major improvement in treatment for the last decade, and rising resistance rates to even our secondand third-line antibiotics is becoming a clinical problem. We have no expectations of major breakthroughs in antimi- U 196 VOL. 4 NO. 4 2002 REVIEWS IN UROLOGY development is based is that increased urinary antibody can prevent bacterial adherence to urinary epithelium, inhibit the biological activity of bacterial virulence factors, and therefore decrease infectivity or persistence. Two recent reports outlining the success of oral and vaginal preparations that stimulate the patients’ own immune system may provide the clinical breakthrough we are looking for. Vaginal Mucosal Immunization for Recurrent Urinary Tract Infection: Extended Phase II Clinical Trial Uehling DT, Hopkins WJ, Beierle LM, et al. J Infect Dis. 2002;183(suppl 1):S81–S83. This research group previously demonstrated with animal models that mucosal immunity could be stimulated through vaginal immunization, and they have furthered their studies through a number of clinical trials. Women Erectile Dysfunction receiving a whole-cell vaccine (SolcoUrovas, Solco, Basel, Switzerland) containing heat-killed bacteria from 10 human uropathogenic strains, including six Escherichia coli strains and one strain each of Proteus mirabilis, Proteus morganii, Enterococcus faecalis, and Klebsiella pneumoniae, had a significant delay in acquiring their first reinfection compared with women who were given placebo. In the trial reported here, the goal was to extend the protection period beyond 8 weeks (first randomized, placebo-controlled trial) by use of booster suppositories. The investigators randomized 36 patients to intermittent vaginal suppository treatments of vaccine or placebo; one group received real vaccine for 14 weeks (vaccine-vaccine), one group received real vaccine for 2 weeks and then placebo (vaccine-placebo), and the third group received placebo for 14 weeks (placebo-placebo). There were no reinfections in 50% of the vaccine-vaccine group, 25% of the vaccine-placebo group, and 17% of the placebo-placebo group. In patients with reinfections, the median times to reinfection were 46, 21, and 16 days, respectively, in these three groups. There were no significant side effects of treatment. Vaginal immunization for recurrent UTIs may someday be a safe and effective treatment method. was good, with no real difference in minor side effects compared to placebo and no serious side effects reported. Oral immunotherapy with this or similar products may turn out to be effective therapy in the prevention of UTIs. Prevention of Recurrent Urinary Infections with Immuno-Active E. coli fractions: A Meta-Analysis of Five Placebo-Controlled, Double-Blind Studies Prescribing PDE5 Inhibitors: Who Is the “Normal" Man? Bauer HW, Rahlfs VW, Lauener PA, Blessmann GS. Int J Antimicrob Agents. 2002;19:451–456. The authors performed a meta-analysis of five studies over the last decade to evaluate the effect of an oral vaccine (Uro-Vaxom, Sanofi Winthrop GmbH, Munich, Germany) developed from a bacterial extract consisting of 18 uropathogenic Escherichia coli strains. The efficacy of this oral vaccine has actually been investigated in 12 studies, but only five were placebo-controlled, randomized, doubleblind studies. The primary criterion in all studies was the number of recurrences per patient. The studies evaluated were all basically the same: 3 months’ treatment with observation and a further observation period of 3 months without treatment. A total of 717 patients were enrolled and randomized in the five studies; 501 were subsequently evaluable. There was a statistically significant decrease in recurrences in patients treated with the oral vaccine compared with placebo in every study. The pooled odds ratio (2.28) demonstrated at least statistical proof for a relevant drug effect, of modest size at least. The number of UTIs in patients treated with this vaccine was 0.15–0.82 per year, which compares favorably with low-dose antimicrobial prophylaxis. The safety and tolerability of the oral vaccine Conclusion Recurrent UTIs in women are currently being treated with episodic, physician-directed therapy, low-dose prophylaxis, postcoital therapy, and patient self-directed therapy. All these approaches employ antibiotics and are subject to resistance problems, side effects, and cost considerations. Immunotherapy, with a vaginal or oral preparation, may turn out to be an effective alternative to antibiotics in the prevention of recurrent UTIs. References 1. Nickel JC. Urinary Tract Infections in Adults. In: Teichman JMH, ed. 20 Common Problems in Urology. New York, NY: McGraw-Hill; 2001:63–76. Erectile Dysfunction Reviewed by Jacob Rajfer, MD UCLA School of Medicine and Division of Urology, Harbor-UCLA Medical Center, Los Angeles, CA [Rev Urol. 2002;4(4):197–198] © 2002 MedReviews, LLC ex, sex, sex! Men are imprinted to think about it all the time—not only when they are awake, but also when asleep. As men age and their erectile function changes for the worse—in some men as early as their 20s and noticeably in 40% of men by the time they reach age 40—nocturnal erections follow suit. Ever since the phosphodiesterase type 5 (PDE5) inhibitors were released for clinical use for the treatment of erectile dysfunction (ED) in 1998, the mantra has always been that these drugs should only be used in men with ED and not in “normal" men. The fear has always been that these drugs will be “abused" by normal men. How was “abuse” defined? It was defined as making erections last longer and decreasing the refractory time between ejaculations. As clinical experience with the use of PDE5 inhibitors has been gained over the past 4 years, the following have become apparent in men with ED: 1) that PDE5 inhibitors are not only effective in improving erectile function, but S VOL. 4 NO. 4 2002 REVIEWS IN UROLOGY 197 Erectile Dysfunction continued the drugs are relatively safe and free from any significant side effects; and 2) in addition to daytime erections, the drugs enhance nocturnal tumescence.1 Well, what about the drug in normal men? concern in prescribing it to men at any age, if they provide me with enough evidence on the history that a change has occurred in their erectile function. References Effects of Sildenafil on Nocturnal Penile Tumescence and Rigidity in Normal Men: Randomized, Placebo-Controlled, Crossover Study Rochira V, Granata AR, Balestrieri A, et al. 1. 2. Montorsi F, Maga T, Strambi LE, et al. Sildenafil taken at bedtime significantly increases nocturnal erections: results of a placebo-controlled study. Urology. 2002;56:906–911. Aversa A, Mazzili F, Rossi T, et al. Effects of sildenafil (Viagra) administration on seminal parameters and post-ejaculatory refractory time in normal males. Hum Reprod. 2000;15:131–134. J Androl. 2002;23:566–571. In 2000, Aversa and colleagues from Italy showed that the refractory time can be decreased in normal men who take sildenafil.2 In another, elegant study by Rochira and colleagues from Italy, 44 normal men (who supposedly did not have ED) were given sildenafil (50 mg) and/or placebo in a randomized, placebo-controlled, crossover study, and nocturnal penile erections (NPT) were monitored. The authors concluded from their observations that sildenafil was effective in improving NPT in normal men, and some of the normal men recognized this effect up to 9 hours post-administration. Does this mean that these drugs should be prescribed in “normal men" who request them? Let us think about this for a moment. Why would a man want to have a decreased refractory time—in other words, why would he want to decrease the time between coitus episodes? I assume that it would be because he had been able to at one time in his life and is now unable to do so as he ages. If we accept this premise, that the patient has recognized a change over time, then the “normal men" who we recruit into such studies as are described above should ideally be in their 20s, not close to 40 years of age as was the age group (40 ± 13 years) for the Rochira study. It is my assumption that the reason a man who is in his 20s, 30s, or whatever age requests something to improve his sexual function is because he has noticed a change from his “younger" days. And because 40% of the men in the Massachusetts Male Aging Study had some form of ED by age 40, I assume that many of Rochira’s subjects, though “normal" according to questionnaire data, were different physiologically from their “youth," and that is why the sildenafil improved the outcome parameters that were used in this study. What we need in the literature is a study of “normal" men in their 20s who are at the pinnacle of their sexual prowess. My belief at this time is that if such a study were performed, there would be very little significant change in erectile function and ejaculatory refractoriness in truly normal men who are administered a PDE5 inhibitor such as sildenafil. It is for the aforementioned reasons and because of the proven safety of this class of drugs that I have very little 198 VOL. 4 NO. 4 2002 REVIEWS IN UROLOGY Prostate Cancer Evolving Role of Pro-PSA as a New Serum Marker for the Early Detection of Prostate Cancer Reviewed by Masood A. Khan, MD, Alan W. Partin, MD, PhD Department of Urology, Johns Hopkins University Hospital School of Medicine, Baltimore, MD [Rev Urol. 2002;4(4):198–200] © 2002 MedReviews, LLC he development and subsequent routine use of prostate-specific antigen (PSA) over the past decade has revolutionized the management of prostate cancer. PSA has increased our ability to detect and, in turn, treat early prostate cancer; however, the major drawback of PSA is its relative lack of specificity. This is especially important in the critical diagnostic range of 4–10 ng/mL, where an elevated PSA may reflect either prostate cancer or benign disease, such as benign prostatic hyperplasia (BPH). This lack of specificity has led to unnecessary prostate biopsies, with associated anxiety, cost, and potential morbidity. It was discovered in 1991 that serum contains two distinct major forms of PSA: one form is covalently bound to endogenous serum protease inhibitors like 1-antichymotrypsin and is known as complexed PSA; the other form is present in a “free," nonactive, noncomplexed form and is known as free PSA.1,2 The measurement of the ratio of free to total PSA has led to a modest but significant improvement in the discrimination of prostate cancer from BPH in men with PSA levels between 4.0 and 10.0 ng/mL. This is attributable to the association of BPH with high levels of free PSA, compared with prostate cancer.3 The free PSA form is a heterogeneous group consisting of at least three different subforms of inactive PSA. One form has T Prostate Cancer been identified as the pro-enzyme or precursor form of PSA (pPSA), which contains a seven-amino-acid pro-leader peptide (APILSR) and is associated with prostate cancer.4,5 PSA is normally found in seminal fluid in a mature, active form with 237 amino acids, lacking the pro-leader peptide. The pro-leader peptide is removed extracellularly by human kallikrein 2 (hK2) to produce this active, mature form of PSA. Intracellularly, the pPSA form is itself truncated as a result of post-translational proteolytic cleavage of the pro-leader peptide, where either three or five of the seven pro-leader amino acids are removed. All forms of truncated pPSA (ie, [4] and [2]) remain enzymatically inactive. It is these truncated forms of pPSA that have recently generated a great deal of clinical interest, as they may have a diagnostic role in the early detection of prostate cancer. The following recent articles from Cancer Research investigate and discuss this possibility. A Precursor Form of Prostate-Specific Antigen Is More Highly Elevated in Prostate Cancer Compared with Benign Transition Zone Prostate Tissue Mikolajczyk SD, Millar LS, Wang TJ, et al. Cancer Res. 2000;60:756–759. Having previously reported that pPSA is a component of free PSA in the serum of prostate cancer patients, these authors examined matched sets of tissues harvested from patients undergoing radical prostatectomy (n = 18). From each prostate, samples of prostate cancer and adjacent, noncancerous peripheral-zone tissues were selected for analysis. Furthermore, a sample (n = 8) of benign transitional-zone tissue, obtained from transurethral resection The precursor form of PSA in serum may represent a more cancer-specific form of PSA that could help to distinguish prostate cancer from BPH, especially in patients with only mildly elevated PSA. of prostates, was also analyzed. PSA was immunoaffinity purified from these prostate tissues, and the authors found that pPSA was differentially elevated in the peripheral zone of cancer tissue and was largely undetected in the transition-zone tissue. N-terminal sequencing revealed that the pPSA was composed primarily of the truncated [2]pPSA with minor levels of [4]pPSA. The median value of pPSA was 3% in peripheral zone of cancer tissue and 0% (undetectable) in the transitional zone (P < .0026). pPSA was not detected in 13 of the 18 transitional-zone tissue specimens (72%). Of the 18 matched cancer specimens, 16 (89%) contained measurable pPSA. The authors conclude that pPSA is more highly correlated with prostate cancer than with BPH. In addition, pPSA in serum may represent a more cancer-specific form of PSA that could help to distinguish prostate cancer from BPH, especially in patients with only mildly elevated PSA. Identification of Precursor Forms of Free Prostate-Specific Antigen in Serum of Prostate Cancer Patients by Immunosorption and Mass Spectrometry Peter J, Unverzagt C, Krogh TN, et al. Cancer Res. 2001;61:957–962. The authors obtained serum from 5 patients with prostate cancer and subsequently isolated free PSA by immunopurification procedures using streptavidin-coated magnetic beads. They then identified pPSA forms using matrixassisted laser desorption ionization time-of-flight mass spectrometry, after producing peptides by endoproteinase from Lysobacter enzymogenes digestion of the SDS polyacrylamide gel electrophoresis–separated free PSA bands. They found that among the five serum samples investigated, all contained the [7], [5], and [4] pro-PSA forms, whereas the [1] and [2] forms were only present in three of them. The authors, therefore, were able to demonstrate that sera obtained from prostate cancer patients have the pro-PSA forms and occur in various combinations. The results, however, differed from those of Mikolajczyk and colleagues (reviewed above), who identified the [4] and [2] forms of pPSA in tissue extracts but did not find the longer precursor sequences (ie, [7] or [5]) forms of pPSA. The reason for this difference may reflect mere sample variability in a small population, or it may reflect the fact that these authors used serum with much higher serum PSA values (one patient’s PSA was 1890 ng/mL, and the other four samples had PSA values > 6000 ng/mL). In contrast, the serum by Mikolajczyk and colleagues had much lower serum PSA values. A Truncated Precursor Form of ProstateSpecific Antigen is a More Specific Serum Marker of Prostate Cancer Mikolajczyk SD, Marker KM, Millar LS, et al. Cancer Res. 2001;61:6958–6963. The authors have previously identified that the [2]pPSA truncated form of pPSA is selectively present in prostate VOL. 4 NO. 4 2002 REVIEWS IN UROLOGY 199 Prostate Cancer continued cancer tissues and have developed monoclonal antibodies to detect [2]pPSA and other isoforms of pPSA for Western blot analysis. PSA was immunoaffinity purified from 100–200 mL of serum from five men with biopsyproven prostate cancer (PSA range: 6–24 ng/mL; mean: 13.4 ng/mL) and three biopsy-negative patients (PSA range: 7–12 ng/mL; mean: 9.7 ng/mL). The truncated [2]pPSA was found to range from 25% to 95% of the free PSA in the five cancer samples; however, in the three biopsy-negative samples, this value was only 6%–19%. Immunohistochemical studies showed positive staining for [2]pPSA in prostate cancer tissue epithelium and that [2]pPSA was enriched in cancer cell secretions, thereby further strengthening the view that [2]pPSA is naturally present in prostate tissues and is not the artifactual result of tissue extraction methodologies. The authors also performed in vitro activation studies, which revealed that hK2 and trypsin readily activated full-length pPSA by release of the pro-leader peptide but were unable to activate [2]pPSA to mature PSA. Hence, once formed, [2]pPSA appears to be a stable but inactive isoform of PSA. From this work, the authors have concluded that truncated [2]pPSA may represent an important new diagnostic marker for the early detection of prostate cancer. The authors also reported preliminary results of an unpublished study that serum [2]pPSA levels were threefold higher in 20 biopsy-positive patients compared to 20 biopsy-negative patients with total serum PSA levels between 2 and 22 ng/mL. The investigations reviewed here are promising and may lead to the development of pPSA as a new marker for the early detection of prostate cancer. Clinical studies with much larger patient population are required, however. In addition, as free PSA constitutes only a small percentage of total PSA, at present, large volumes of serum are required to obtain pPSA information. This may negatively impact pPSA as a potential new marker. Further knowledge of the role of [2]pPSA will enable us to perform comprehensive trials of pPSA in prostate cancer early detection. References 1. 2. 3. 4. 5. Lilja H, Christensson A, Dahlan U, et al. Prostate-specific antigen in serum occurs predominantly in complex with 1-antichymotrypsin. Clin Chem. 1991;37:1618–1625. Stenman UH, Leinonen J, Alfthan H, et al. A complex between prostate specific antigen and 1-antichymotrypsin is the major form of prostate-specific antigen in serum of patients with prostate cancer: assay of the complex improves clinical sensitivity for cancer. Cancer Res. 1991;51:222–226. Catalona WJ, Partin AW, Slawin KM, et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA. 1998;279:1542–1547. Mikolajczyk SD, Grauer LS, Millar LS, et al. A precursor form of PSA (pPSA) is a component of the free PSA in prostate cancer serum. Urology. 1997;50:710–714. Mikolajczyk SD, Marks LS, Partin AW, Rittenhouse HG. Free prostate-specific antigen in serum is becoming more complex. Urology. 2002;59:797–802. 200 VOL. 4 NO. 4 2002 REVIEWS IN UROLOGY Urologic Oncology Testicular Microlithiasis, Chemotherapy for Stage I Seminoma, and Chemotherapy for Advanced Extragonadal Germ Cell Tumors Reviewed by Ken-ryu Han, MD, Jeff A. Wieder, MD, Matthew H.T. Bui, MD, PhD, Arie S. Belldegrun, MD, FACS Department of Urology, University of California School of Medicine, Los Angeles, CA [Rev Urol. 2002;4(4):200–202] © 2002 MedReviews, LLC revious reports have indicated that testicular microlithiasis may be associated with testicular cancer.1,2 Some physicians have recommended follow-up with scrotal ultrasound and physical examination every 6–12 months.1,2 However, many of these publications fail to distinguish between patients with only microlithiasis (isolated microlithiasis) and patients with associated sonographic abnormalities. P Testicular Microlithiasis: What Is Its Association with Testicular Cancer? Bach AM, Hann LE, Hadar O, et al. Radiology. 2001;220:70–75. In a recent publication, Bach and colleagues retrospectively reviewed the scrotal sonograms of 528 men with a mean age of 45 years (reason for referral was not mentioned but was presumably for genitourinary symptoms or Data suggest that isolated testicular microlithiasis is rarely associated with cancer. abnormal examination). Of the 48 patients with microlithiasis, 13 (27%) had testicular cancer. The authors concluded that intratesticular microlithiasis is highly associated with the presence of a testicular mass and testicular Urologic Oncology cancer. However, closer inspection of the data reveals that testicular cancer was present in 52% of patients with a sonographic testicular mass and microlithiasis, but in only 4% of patients with microlithiasis alone. These data suggest that isolated testicular microlithiasis is rarely associated with cancer. The Prevalence of Testicular Microlithiasis in an Asymptomatic Population of Men 18–35 Years Old. Peterson AC, Bauman JM, Light DE, et al. J Urol. 2001;166:2061–2064. Peterson and colleagues prospectively evaluated 1504 asymptomatic healthy men (mean age 22.4 years) attending the Army Reserve Officer Training Corps training camp. Of these subjects, 5.6% had microlithiasis on sonography and all had normal -fetoprotein (AFP) and human chorionic gonadotropin (B-HCG) levels. Only 1 patient with microlithiasis had testicular cancer (apparently identified as a mass on sonography). Because these reports did not follow patients with microlithiasis, they do Comprehensive follow-up data on patients with microlithiasis is lacking. not provide information on the risk of subsequently developing cancer. A few case reports describe patients with testicular microlithiasis that developed germ cell tumors from 10 months to 11 years later.1 However, comprehensive follow-up data on patients with microlithiasis is lacking. Currently there is no convincing evidence that testicular microlithiasis is premalignant or associated with an increased risk of developing cancer. Furthermore, when microlithiasis is the only testicular abnormality (isolated microlithiasis), associated cancer is rare. A small number of patients with microlithiasis may subsequently develop cancer; however, it is unclear if microlithiasis increases the risk of malignancy. In newly diagnosed patients with isolated microlithiasis, some recommend high-resolution sonography and serum markers (AFP and B-HCG) to search more thoroughly for associated neoplasm; however, current data does not justify testis biopsy or orchiectomy.2 How should patients with isolated microlithiases be followed up? Some authors recommend testicular sonography1,2 and serum tumor markers2 at least annually. Patients with a history of cryptorchidism are at risk for testicular malignancy; however, these patients are usually followed with physical examination, not with serial ultrasound and tumor markers. Why not follow patients with testicular microlithiasis in the same fashion? Unfortunately there is not enough data to make strong recommendations. Patients with microlithiasis should be advised of a possible association between microlithiases and malignancy and should perform periodic self-examination. Physical examination by a physician should probably be done at least once a year. Periodic scrotal ultrasound may be prudent. However, sonogram should definitely be performed if scrotal exam changes or symptoms develop. Twelve-Year Experience with Two Courses of Adjuvant Single-Agent Carboplatin Therapy for Clinical Stage I Seminoma. Reiter WJ, Brodowicz T, Alavi S, et al. J Clin Oncol. 2001;19(1):101–104. Seventy percent to 80% of all seminoma patients are classified as clinical stage I. Traditional treatment for these patients has consisted of radical inguinal orchiectomy followed by 28 to 30 Gy of radiation therapy to the retroperitoneum, including the ipsilateral iliac lymph nodes.3 Although survival and cure rates remain in excess of 90%, toxicities associated with radiation therapy include peptic ulcer disease and secondary malignancies. As a result of these morbidities, recent studies have investigated the roles of surveillance therapy and adjuvant chemotherapy. In a retrospective analysis, Reiter and colleagues investigated the effects of two cycles of outpatient carboplatin on 107 patients with clinical stage I seminoma. Compared to cisplatin, carboplatin does not cause nephrotoxicity, neuropathy, or ototoxicity. Side effects of carboplatin include nausea and myelosuppression, most notably thrombocytopenia. A total of 107 patients received 400 mg/m2 of carboplatin (dissolved in 500 ml saline) within 10 days of orchiectomy; 43 patients received the second course 28 days later, and the remaining 64 patients received the second course on day 21 (at a different institution). Patients were then followed every 3 months for the first 2 years, every 6 months from years 2 to 5, and then annually after that. Median follow-up in the study was 74 months. During the study, 6 patients died of unrelated causes (4 with myocardial infarction, 1 from a car accident, and 1 from metastatic rectal cancer). The remaining 101 patients were alive without evidence of disease. Toxicity was limited to nausea (31%) and vomiting (14%) in patients who were given antiemetics at the time of carboplatin adminis- VOL. 4 NO. 4 2002 REVIEWS IN UROLOGY 201 Urologic Oncology continued tration. Hematologic toxicities consisted of leukopenia (10.7% World Health Organization grade 1 and 2.1% grade 2). There were no reported cases of nephrotoxicity, neurotoxicity, ototoxicity, anemia, or thrombocytopenia. The results of this study support recent data that two courses of carboplatin are necessary when considering adjuvant chemotherapy for clinical stage I seminoma. The authors cited studies that included recurrence rates as high as 9% in regimens using only one course of carboplatin.4 The third treatment option for clinical stage I seminoma is surveillance. However, 20%–25% of patients on surveillance eventually relapse, adding psychological stress to patients already diagnosed with cancer. Furthermore, diligent patient compliance with follow-up is necessary. Radiation therapy for clinical stage I seminoma remains the standard of care to which adjuvant chemotherapy regimens must be compared. Delayed complications such as ulcer and secondary malignancies related to radiation have lead to the emergence of adjuvant therapy trials. Phase III trials comparing the efficacy of carboplatin and radiation therapy in these patient cohorts have been initiated by the German Testicular Cancer Study Group and the English Medical Research Council.5 Second-Line Chemotherapy in Patients with Relapsed Extragonadal Nonseminomatous Germ Cell Tumors: Results of an International Multicenter Analysis. Hartmann JT, Einhorn L, Nichols CR, et al. J Clin Oncol. 2001;19(6):1641–1648. Primary extragonadal germ cell tumors are rare, but relapses have generally been treated with chemotherapy regimens similar to those used in metastatic testicular cancer. In cases of metastatic testicular cancer, salvage chemotherapy still offers chances for cure, but the results for patients with relapsed extragonadal germ cell tumors are still uncertain. Clinical differences between gonadal and extragonadal tumors suggest that they may be biologically distinct. A retrospective study of 142 patients treated between 1975 and 1996 at 11 European and American centers was conducted to determine prognostic indicators of therapeutic efficacy of salvage chemotherapy in patients with nonseminomatous extragonadal germ cell tumors. Median follow-up was 11 months and median age was 29 years. Of these patients, 79 (56%) had primary mediastinal tumors and 61 (43%) had primary retroperitoneal tumors. The remaining two patients showed widespread pul- 202 VOL. 4 NO. 4 2002 REVIEWS IN UROLOGY monary, mediastinal, and retroperitoneal involvement. All patients either relapsed after or during primary cisplatinbased chemotherapy, but 44 patients initially had complete response (CR) to induction therapy. Salvage regimens included ifosfamide, vinblastine, paclitaxel, or high-dose therapy based on carboplatin and etoposide; 43 (30%) patients received a combination of cisplatin and ifosfamide, 29 (20%) received cisplatin with etoposide or vinblastine, and 48 (33%) received carboplatin and etoposide with ifosfamide or cyclophosphamide followed by autologous bone marrow transplantation. The remaining patients received single-agent therapy. Univariate statistical analyses showed that primary mediastinal tumor location, lack of response to cisplatin induction therapy, elevated -hCG, and normal LDH at initial diagnosis were negative prognostic factors for survival. Extent of disease, location of relapse, sites of visceral metastases, and type of salvage treatment did not significantly influence survival. Using multivariate analyses, both primary mediastinal location and lack of response to cisplatin were found to be independent negative factors with a twofold increased hazard ratio for death. Median survival for patients with either of these two factors was 6–10 months compared to 21 months for patients with primary tumors originally located in the retroperitoneum. Overall, the long-term survival of patients with primary retroperitoneal extragonadal tumors was 30%, whereas patients with primary tumors in the mediastinum had long-term survival rates that were less than 10%. In comparison, survival rates for patients undergoing salvage chemotherapy for recurrent/metastatic testicular cancer range from 20% to 50%.3 The authors concluded that the therapeutic advances of second-line therapy in patients with advanced testicular cancer do not lead to similar survival rates in patients with extragonadal germ cell tumors. New strategies are needed, especially for patients with primary mediastinal tumors and for patients who do not respond to induction therapy with cisplatin. References 1. 2. 3. 4. 5. Ganem JP, Wokman KR, Shaban SF. Testicular microlithiasis is associated with testicular pathology. Urology. 1999;53:209–213. Sheynkin YR, Goldstein M. Testicular microlithiasis. AUA Update Series. 1999;18:106. Hartmann JT, Kanz L, Bokemeyer C. Diagnosis and treatment of patients with testicular germ cell cancer. Drugs. 1999;58:257–281. Dieckmann KP, Bruggeboes B, Pichlmeier U, et al. Adjuvant treatment of clinical stage I seminoma: is a single course of carboplatin sufficient? Urology. 2000;55:102–106. Classen J, Souchon R, Hehr T, Bamberg M. Treatment of early stage testicular seminoma. J Cancer Res Clin Oncol. 2001;127:475–481.