Nonseminomatous Germ Cell Tumors Of The Testis Research Articles

TAMs PD-L1(+) in the reprogramming of germ cell tumors of the testis

BackgroundIn recent years, several studies focused on the process of reprogramming of seminoma (S) cells, which regulates the transition from pure S (P-S) to S component (S-C) of mixed germ cell tumors of the testis (GCTT) and finally to embryonal carcinoma (EC) and other nonseminomatous GCTT (NS-GCTT). The accepted pathogenetic model is driven and regulated by cells (macrophages, B- and T-lymphocytes) and molecules of the tumor microenvironment (TME). Herein, we tested a series of GCTT with double staining (DS) for CD68-PD-L1 to evaluate tumor-associated macrophages (TAMs) expressing programmed death-ligand 1 (PD-L1) [TAMs PD-L1(+)] and clarify if these cells may be involved in establishing the fate of GCTT. MethodsWe collected 45 GCTT (comprising a total of 62 different components of GCTT). TAMs PD-L1(+) were evaluated with three different scoring systems [TAMs PD-L1(+)/mm2, TAMs PD-L1(+)/mm2H-score, TAMs PD-L1(+) %], and compared using pertinent statistic tests (Student’s t-test and Mann-Whitney U test). ResultsWe found that TAMs PD-L1(+) values were higher in S rather than EC (p = 0.001, p = 0.015, p = 0.022) and NS-GCTT (p < 0.001). P-S showed statistically significant differences in TAMs PD-L1(+) values compared to S-C (p < 0.001, p = 0.006, p = 0.015), but there were no differences between S-C and EC (p = 0.107, p = 0.408, p = 0.800). Finally, we found statistically significant differences also in TAMs PD-L1(+) values between EC and other NS-GCTT (p < 0.001). ConclusionsTAMs PD-L1(+) levels gradually decrease during the reprogramming of S cells {P-S [(high values of TAMs PD-L1(+)] → S-C and EC [(intermediate values of TAMs PD-L1(+)] → other NS-GCTT [(low values of TAMs PD-L1(+)], supporting a complex pathogenetic model where the interactions between tumor cells and TME components [and specifically TAMs PD-L1(+)] play a key role in determining the fate of GCTT.

Late toxicities and recurrences in patients with clinical stage I nonseminomatous germ cell tumor after one cycle of adjuvant BEP versus primary retroperitoneal lymph node dissection: A 13-years follow-up analysis of a phase III trial cohort.

5512 Background: One cycle of adjuvant BEP has shown superiority in recurrence free survival over RPLND in patients (pts) with clinical stage (CS) I nonseminomatous germ cell tumor of the testis (NSGCT) (JCO 2008). We report recurrences and late toxicities of this randomized trial after 13 yrs of follow-up (FU). Methods: Questionnaires of 382 unselected pts with CS I NSGCT treated within a phase III trial comparing recurrence rate after 1 cycle of adjuvant BEP (arm A) vs. RPLND (arm B) were evaluated regarding recurrences and late toxicity. Overall (OS) and progression free survival (PFS) was calculated by Kaplan-Meier and arms were compared using logrank test. Categorial data were analyzed by chi-square test (PRISM v8). Results: In each arm 191 pts were analyzed as intention-to-treat with a median FU of 13.75 yrs (0-22.9 yrs); 3/191 pts (1.6 %) in arm A and 16/191 pts (8.4 %) in arm B had a recurrence. 20-yrs PFS in arm A / B was 97 % (CI 96-99 %) / 92 % (CI 90-95 %), ( p = .0049). 20-yrs OS in arm A / B was 90 % (CI 86-94 %) / 88 % (CI 86-94 %), ( p = .83). 23/382 (6 %) pts have died, 22/23 not related to testis cancer, 1/23 died of a recurrence in arm B. 8/191 pts (4.2 %) in arm A and 4/191 pts (2.1 %) in arm B showed metachronous secondary testis cancer ( p = .26). 5/191 pts (2.6 %) in arm A and 4/191 pts (2.1 %) in arm B developed other malignancies. 170/382 questionnaires were evaluable (arm A: 95; arm B: 75). 45 pts were lost to FU. There were no significant differences comparing both treatment arms regarding potentially treatment-related late toxicities. However, excluding pre-existing complaints, ototoxicity (9/95 (9 %) vs. 4/75 (5 %) pts, p = .31) was reported more frequently in arm A. Excluding pre-existing neurological conditions, peripheral neuropathy of all grades was more frequently reported in arm A (15/95 pts; 16 % vs. 9/75 pts; 12 % pts; p = .48). Retrograde ejaculation occurred more frequently after RPLND (9/95 pts; 9% vs. 18/75 pts; 24 %, p = .01). Conclusions: After more than 13 yrs of FU, recurrences in non-risk factor selected pts with CS I NSGCT remain to be significantly more frequent with RPLND. No excess mortality due to secondary malignancies was observed. Late toxicities did not differ between 1 cycle of BEP and RPLND. Only retrograde ejaculation was observed significantly more frequent after RPLND. With long-term observation, 1 cycle of BEP has not only a high efficacy to prevent recurrence but also seems to be tolerated without clinically relevant long-term toxicity.

Contemporary Treatment Patterns and Outcomes for Clinical Stage IS Testicular Cancer

BackgroundControversy exists regarding the optimal management strategy for clinical stage IS seminomatous (SGCT) and nonseminomatous germ cell tumors (NSGCT) of the testis. ObjectiveTo assess contemporary treatment patterns and outcomes for clinical stage IS testicular cancer. Design, setting, and participantsUsing the National Cancer Data Base (2004–2012), we identified 1362 patients with clinical stage IS SGCT and NSGCT of the testis, treated with either adjuvant treatment (AT) or observation. Outcome measures and statistical analysisWe calculated the annual percent change (APC) to assess treatment trends. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves and Cox regression analyses were used to compare overall survival (OS) between AT and observation groups. Analyses were stratified by histologic type. Results and limitationsOverall, there were 581 (43%) and 781 (57%) men with SGCT and NSGCT, respectively. Among men with SGCT, the use of AT decreased over the study period (APC=–2.7, 95% confidence interval [CI]: –4.4, –1.1, p=0.001). The 5-yr IPTW-adjusted rates of OS were 99% and 97% in the AT and observation groups, respectively (hazard ratio = 0.36, 95% CI: 0.12, 1.14, p=0.08). Among men with NSGCT, the use of AT remained stable over the study period (APC = +0.8, 95% CI: –0.7, +2.2, p=0.29). The 5-yr IPTW-adjusted rates of OS were 97% and 95% in the AT and observation groups, respectively (HR=0.66, 95% CI: 0.27, 1.61, p=0.36). Limitations include the lack of full treatment details and cancer-specific survival information. ConclusionsTrends in the use of AT significantly decreased over time for SGCT, while it remained stable for NSGCT. Nonetheless, we report 5-yr OS rates of ≥95% for both histologies without any significant benefit with the use of AT. Further studies are warranted to confirm these findings. Patient summaryWe evaluated treatment trends and outcomes for stage IS testicular cancer. We found that treatment changed over time for seminoma and remained stable for nonseminoma; there was no significant survival benefit in the use of adjuvant treatment versus observation for both seminomatous and nonseminomatous germ cell tumors.

Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer.

BACKGROUNDIntratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype.METHODSIn this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next‐generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations.RESULTSSix hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P = .0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac‐seminoma subgroup had the poorest clinical outcome (P = .0015). These tumors tended to undergo somatic transformation (P < .0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected.CONCLUSIONSThe current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT. Cancer 2016;122:1836–43. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) for advanced nonseminomatous germ cell tumor (NSGCT): Correlation of teratoma in the primary tumor and RPLND histology.

e15537 Background: PC-RPLND plays an important role in the management of residual masses of advanced NSGCT of the testis. Teratomatous elements in the primary tumor is a risk factor for teratoma in...

Nonseminomatous germ cell tumor of the testis: Prognostic factors for a lethal phenotype.

390 Background: Cancer is a heterogeneous disease. Studying cancer heterogeneity may enable us to elucidate the various subtypes of a particular cancer, and improve the diagnosis, prognostication, and therapy of cancer. Nonseminomatous germ cell tumor (NSGCT) is a prime example of a heterogeneous disease. We determined potential lethality of NSGCT by characterizing the histological makeup of primary testicular tumors, the tumor burden, psychosocial issues, and surgical factors. Methods: From November 1997 to October 2012, 142 consecutive patients diagnosed with a NSGCT of the testis were evaluated for this study. The log-rank test was used to identify prognostic factors in univariate Kaplan-Meier analysis. A multivariate Cox regression model was used to evaluate predictive factors for overall survival. Results: Patient and tumor characteristics: median (range) age 25 (12 to 53); pathology – embryonal carcinoma 15%, teratoma 6%, and mixed NSGCT 79%; stage – I 46%, II 32%, and III 21%. Ten (7%) patients died from their NSGCT. Seven (5%) patients had incurable NSGCT. Multivariate analysis showed that presence of seminoma (p=0.007), presence of yolk sac tumor (p=0.019), clinical stage (p=0.027), and psychosocial issues (p=0.04), have unfavorable prognostic significance. Conclusions: Certain subtypes of NSGCT containing yolk sac tumor and seminoma are inherently chemotherapy resistant and potentially lethal. Psychosocial factors can delay the diagnosis and treatment of patients with such tumors and adversely affect their clinical outcome. Results of this study need to be validated in another data base or a prospective clinical trial.

Surveillance or adjuvant treatments in stage 1 testis germ-cell tumours

All patients with stage 1 testicular germ-cell tumours (TGCT) can expect to be permanently cured with currently available management approaches. Orchidectomy alone cures 80% of pure seminomas and 70%-75% of nonseminomatous and combined seminoma plus nonseminomatous germ-cell tumours of the testis (NSGCTT). Currently there are well-validated criteria for estimating recurrence risk in NSGCTT. The presence of vascular invasion (VI+) in the testicular primary identifies a group with a recurrence risk approaching 50%. In VI-cases, the risk is ≤20%. Adjuvant chemotherapy with two cycles of bleomycin, etoposide, and cisplatin (BEP) is increasingly recommended in VI+ cases, and when offered is selected in place of surveillance by many VI- patients. In seminomatous germ-cell testicular tumours (SGCTT), there are no validated criteria for estimating recurrence risk. Concerns about second cancers complicating adjuvant radiotherapy are reducing its popularity and the absence of tumour markers, the need for frequent scans, long follow-up and evidence of poor compliance argue against surveillance. Single-dose carboplatin is well tolerated, cheap, reduces recurrence rates to <5% and also the risk of second primary TGCT. There remain concerns about long-term toxicity although evidence is accumulating to allay these. This article discusses the relevant issues affecting decision-making and choice in these intriguing, curable cancers.

Trends of Retroperitoneal Lymphadenectomy Use in Patients with Nonseminomatous Germ Cell Tumor of the Testis: A Population-Based Study

Retroperitoneal lymphadenectomy (RPLND), chemotherapy, and active surveillance represent treatment options for patients with nonseminomatous germ-cell tumors of the testis (NSGCTT). Our objective was to assess the utilization rate of RPLND in patients with NSGCTT. Within the Surveillance, Epidemiology and End Results (SEER) cohort, 4,620 and 1,671 patients with stage I and II NSGCTT were diagnosed between the years 1988 and 2006. Univariable and multivariable logistic regression analyses were performed to test the predictors of RPLND use in respectively patients with stage I and II NSGCTT. The rate of RPLND according to stage I and II was 27 and 58%, respectively. In patients with stage I disease, the rate of RPLND decreased from 39% in 1988-1995 to 18% in 2004-2006 (P < 0.001), and remained stable for stage II patients (62-56%, P = 0.2). Regional variability existed regarding the rate of RPLND use only in stage I (Utah: 51% vs. Louisiana: 16%). Multivariable analyses performed in stage I NSGCTT revealed that year of diagnosis, SEER registry, and age were significant predictors of RPLND use. However, none of these variables achieved statistical significance within stage II NSGCTT patients. In patients with stage I NSGCCT, the RPLND utilization rate decreased during the study span. This observation may be ascribed to wider use of surveillance or chemotherapy. No temporal difference was recorded in patients with stage II NSGCCT.

973 LAPAROSCOPIC RETROPERITONEAL LYMPH-NODE DISSECTION (L-RPLND): EVOLUTION TOWARDS A SINGLE-STATEGY MANAGEMENT IN CLINICAL STAGE I (CS I) NON-SEMINOMATOUS GERM-CELL TUMORS OF THE TESTIS (NSGCTT)

You have accessJournal of UrologyPenis/Testis/Urethra: Benign & Malignant Disease1 Apr 2011973 LAPAROSCOPIC RETROPERITONEAL LYMPH-NODE DISSECTION (L-RPLND): EVOLUTION TOWARDS A SINGLE-STATEGY MANAGEMENT IN CLINICAL STAGE I (CS I) NON-SEMINOMATOUS GERM-CELL TUMORS OF THE TESTIS (NSGCTT) Nicola Nicolai, Davide Biasoni, Mario Catanzaro, Silvia Stagni, Tullio Torelli, Andrea Necchi, Luigi Piva, Angelo Milani, Giorgio Pizzocaro, and Roberto Salvioni Nicola NicolaiNicola Nicolai Milano, Italy More articles by this author , Davide BiasoniDavide Biasoni Milano, Italy More articles by this author , Mario CatanzaroMario Catanzaro Milano, Italy More articles by this author , Silvia StagniSilvia Stagni Milano, Italy More articles by this author , Tullio TorelliTullio Torelli Milano, Italy More articles by this author , Andrea NecchiAndrea Necchi Milano, Italy More articles by this author , Luigi PivaLuigi Piva Milano, Italy More articles by this author , Angelo MilaniAngelo Milani Milano, Italy More articles by this author , Giorgio PizzocaroGiorgio Pizzocaro Milano, Italy More articles by this author , and Roberto SalvioniRoberto Salvioni Milano, Italy More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.984AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES L-RPLND remains a controversial procedure for CS I NSGCTT patients (pts). Long-term efficacy has not been unraveled yet, as most of the pts with nodal metastases at RPLND undergo adjuvant chemotherapy (CT). METHODS We analyzed the data of 155 L-RPLND between July 1999 and October 2010. Two/thirds of patients had neither vascular invasion nor embryonal carcinoma component > 90% in primary tumor. Median number of removed nodes was 14 (IQR 10–19). Nodal metastases (pN+) were found in 18 (12%) pts, and 7 of them underwent adjuvant CT. Since October 2008, only patients with nodal metastasis having tumor density greater than 20% were candidate to adjuvant CT (2/8). All patients underwent a follow-up program. RESULTS After a median follow-up of 36 months, 9 patients (6%) relapsed, all of them occurring within 6 months. None the 7 patients who underwent adjuvant CT relapsed. Five (4%) relapses occurred among 137 patients with no nodal metastases while 4 (36%) occurred among 11 patients with nodal metastases not receiving adjuvant CT. Among the 8 pN+ pts recorded since Oct 2008, 2 underwent adjuvant chemotherapy and 6 were observed, 1/6 (17%) relapsing at 3 months. CONCLUSIONS The rate of relapses following L-RPLND compares with the data of open procedure. We had not an excess of relapses among pN0 patients. In the few pN+ patients not undergoing adjuvant chemotherapy we are experiencing results that seem to be comparable with open series. Mature results of L-RPLND in referral centers would endow the procedure of substantial reliability and less invasiveness than open RPLND to be fully discussed as an alternative for CSI NSGCTT pts. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e392-e393 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nicola Nicolai Milano, Italy More articles by this author Davide Biasoni Milano, Italy More articles by this author Mario Catanzaro Milano, Italy More articles by this author Silvia Stagni Milano, Italy More articles by this author Tullio Torelli Milano, Italy More articles by this author Andrea Necchi Milano, Italy More articles by this author Luigi Piva Milano, Italy More articles by this author Angelo Milani Milano, Italy More articles by this author Giorgio Pizzocaro Milano, Italy More articles by this author Roberto Salvioni Milano, Italy More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Retroperitoneal lymph node dissection for residual masses after chemotherapyin nonseminomatous germ cell testicular tumor

BackgroundRetroperitoneal lymph node dissection has been advocated for the management of post-chemotherapy (PC-RPLND) residual masses of non-seminomatous germ cell tumors of the testis (NSGCT). There remains some debate as to the clinical benefit and associated morbidity. Our objective was to report our experience with PC-RPLND in NSGCT.MethodsWe have reviewed the clinical, pathologic and surgical parameters associated with PC-RPLND in a single institution. Between 1994 and 2008, three surgeons operated 73 patients with residual masses after cisplatin-based chemotherapy for a metastatic testicular cancer. Patients needed to have normal postchemotherapy serum tumor markers, no prior surgical attempts to resect retroperitoneal masses and resectable retroperitoneal tumor mass at surgery to be included in this analysisResultsMean age was 30.4 years old. Fifty-three percent had mixed germ cell tumors. The mean size of retroperitoneal metastasis was 6.3 and 4.0 cm, before and post-chemotherapy, respectively. In 56% of patients, the surgeon was able to perform a nerve sparing procedure. The overall complication rate was 27.4% and no patient died due to surgical complications. The pathologic review showed presence of fibrosis/necrosis, teratoma and viable tumor (non-teratoma) in 27 (37.0%), 30 (41.1%) and 16 (21.9%) patients, respectively. The subgroups presenting fibrosis and large tumors were more likely to have a surgical complication and had less nerve sparing procedures.ConclusionPC-RPLND is a relatively safe procedure. The presence of fibrosis and large residual masses are associated with surgical complications and non-nerve-sparing procedure.

Differentiated rhabdomyomatous tumors after chemotherapy for metastatic testicular germ-cell tumors: a clinicopathological study of seven cases mandating separation from rhabdomyosarcoma

To gain insight concerning prognosis, we investigated seven cases of post-chemotherapy retroperitoneal lymph-node dissections from patients with testicular germ-cell tumors that contained sizable nodules of differentiated skeletal muscle, but that lacked both a primitive cellular component and mitotic activity. The patients were 18–28 years old at the time of retroperitoneal lymph-node dissection. All had a previous non-seminomatous germ-cell tumor of the testis, five of which had a teratoma component. In one the testicular tumor had foci of embryonal rhabdomyosarcoma. The retroperitoneal lymph-node dissections were performed 0.2–4.7 years after orchiectomy, all following cisplatin-based chemotherapy, and contained rhabdomyomatous tumors that ranged from 0.8–5 cm. These consisted of nodular to diffuse aggregates of fetal-type rhabdomyocytes with central to peripheral nuclei and abundant, eosinophilic, fibrillary cytoplasm with occasional cross striations. Elongated myotubes with multiple nuclei in a common sarcoplasm occurred at least focally in all cases. Mild to moderate nuclear atypia, including nuclear enlargement and nucleolar prominence, was present, but mitotic activity, necrosis, and a primitive cellular component were absent. All but one retroperitoneal lymph-node dissection also contained other teratomatous elements. Follow-up in six patients showed three were disease free at 2.2–3.4 years; two developed recurrent teratoma at 1.3–3.7 years; and a sixth developed recurrent teratoma at 0.5 and 2 years, followed at 17 years by progressive tumor with elevated α-fetoprotein. No patient with available follow-up developed progressive sarcoma. We conclude that rhabdomyomatous tumors in retroperitoneal lymph-node dissection specimens after chemotherapy for metastatic testicular germ-cell tumors show clinical behavior similar to teratoma rather than rhabdomyosarcoma. We believe the most likely explanation for the finding of pure rhabdomyomatous tumors in this setting, a phenomenon sometimes termed ‘cytodifferentiation,‘ is selective persistence of differentiated tumor cells because of chemotherapy.

7169 Association of preoperative sodium concentration with prognosis in renal cell carcinoma

Retroperitoneal lymph node dissection (RPLND) and adjuvant chemotherapy are two adjuvant treatment options for patients with clinical Stage I nonseminomatous germ cell tumors of the testis (NSGCT). Aim of this trial was to prove the advantage of one cycle of bleomycin, etoposide, and cisplatin (BEP) chemotherapy compared with RPLND in terms of recurrence.Between 1996 and 2005, 382 patients were randomly assigned to receive either RPLND (n = 191) or one course of BEP (n = 191) after orchidectomy. The primary study end point was the rate of recurrence. The trial was powered to detect a 7% reduction (from 10% to 3%) of recurrence with chemotherapy compared with surgery.After a median follow-up of 4.7 years, 2 and 15 recurrences were observed in the intention-to-treat population with chemotherapy and surgery, respectively (P = 0.0011). The difference in the 2-year recurrence-free survival rate between chemotherapy (99.46%; 95% CI, 96.20%–99.92%) and surgery (91.87%; 95% CI, 86.87%–95.02%) was 7.59% (95% CI, 3.13%–12.05%). The hazard ratio to experience a tumor recurrence with surgery as opposed to chemotherapy was 7.937 (95% CI, 1.808–34.48).To our knowledge, this is the largest randomized trial investigating adjuvant treatment strategies in clinical Stage I NSGCT, which showed the superiority of 1 course BEP over RPLND performed according to community standards to prevent recurrence. Although not standard treatment, 1 course of BEP is active in an unselected group of patients with clinical Stage I disease and merits further investigation.

Stage I nonseminomatous germ cell tumors of the testis: Clinical outcome of 45 patients on a surveillance protocol after orchiectomy alone at a single institution in Japan

e16165 Background: In Japan, risk-adapted treatment for patients with clinical stage I nonseminomatous germ cell tumor of the testis (NSGCTT) has been performed in very few institutions. This retrospective study was performed to evaluate histopathologic prognostic factors with stage I NSGCTT for whom careful follow-up with a surveillance protocol was possible at a single institution. Methods: We included 45 patients with a median age of 31 years (range 16 - 58) who were managed with a surveillance strategy after orchiectomy in our department between 1972 and 2006. Mean duration of follow-up was 8.1 years (range 1.4 –30). The patients were monitored at follow-up evaluation for tumor marker (AFP, beta-hCG) levels and by abdominal CT scan, chest x-ray, and physical examination. Primary testis tumor samples were assessed for prognostic factors including lymphatic and/or vascular (LV) invasion and pathological components such as the presence of embryonal carcinoma. Log-rank analyses were performed to identify prognostic factors. Results: All patients were alive and disease-free. Relapses occurred in 16 (35.6%) patients after a median follow-up of 5.7 months (range 3–45). In 11 patients (68.8 %), relapse was detected in the retroperitoneal lymph nodes. Two patients (12.5%) had metastases in the retroperitoneal lymph nodes and lungs, two patients (12.5%) had metastases in the lungs alone, and one patient (6.2%) had metastases in the retroperitoneal lymph nodes, lungs, and brain. LV invasion was identified in 17 patients, 53% of whom had relapsed, and relapse was found in 25% of 28 patients without LV invasion (p&lt;0.01). Of 31 patients with an embryonal carcinoma component, 13 patients (42%) developed metastases, whereas 21% of those without an embryonal carcinoma component developed metastases (p=0.04). After chemotherapy and/or surgical treatment for relapse, the 5-year overall survival rate was 100%. Conclusions: As in previous reports, the presence of an embryonal carcinoma component and LV invasion appeared to be factors suggesting a high likelihood of relapse. The surveillance protocol described here is a reliable strategy for stage I NSGCTT patients if careful long-term follow-up is possible. No significant financial relationships to disclose.

Randomized Phase III Trial Comparing Retroperitoneal Lymph Node Dissection With One Course of Bleomycin and Etoposide Plus Cisplatin Chemotherapy in the Adjuvant Treatment of Clinical Stage I Nonseminomatous Testicular Germ Cell Tumors: AUO Trial AH 01/94 by the German Testicular Cancer Study Group

Retroperitoneal lymph node dissection (RPLND) and adjuvant chemotherapy are two adjuvant treatment options for patients with clinical stage I nonseminomatous germ cell tumors of the testis (NSGCT). Aim of this trial was to prove the advantage of one cycle of bleomycin, etoposide, and cisplatin (BEP) chemotherapy compared with RPLND in terms of recurrence. Between 1996 and 2005, 382 patients were randomly assigned to receive either RPLND (n = 191) or one course of BEP (n = 191) after orchidectomy. The primary study end point was the rate of recurrence. The trial was powered to detect a 7% reduction (from 10% to 3%) of recurrence with chemotherapy compared with surgery. After a median follow-up of 4.7 years, two and 15 recurrences were observed in the intention-to-treat population with chemotherapy and surgery, respectively (P = .0011). The difference in the 2-year recurrence-free survival rate between chemotherapy (99.46%; 95% CI, 96.20% to 99.92%) and surgery (91.87%; 95% CI, 86.87% to 95.02%) was 7.59% (95% CI, 3.13% to 12.05%). The hazard ratio to experience a tumor recurrence with surgery as opposed to chemotherapy was 7.937 (95% CI, 1.808 to 34.48). To our knowledge, this is the largest randomized trial investigating adjuvant treatment strategies in clinical stage I NSGCT, which showed the superiority of one course BEP over RPLND performed according to community standards to prevent recurrence. Although not standard treatment, one course of BEP is active in an unselected group of patients with clinical stage I disease and merits further investigation.

Redefining the Refined Retroperitoneal Lymph Node Dissection in Testis Cancer: A SWOT Analysis of Nonrandomized Data

A SWOT analysis, generally used in a business sense, comprises of a strategic evaluation that includes strengths, weaknesses, opportunities and threats. Here, it is applied to a body of nonrandomized clinical and scientific data. The historical significance of using a multimodality treatment approach to metastatic cancer is best exemplified by nonseminomatous germ cell tumors of the testis (NSGCTT). The high, durable, and meaningful remission rates achieved in the cisplatin-based era in patients with both retroperitoneal disease and more distant metastases have improved continually with the evolution of combination programs. These include cisplatin with vinblastine and bleomycin; the evolution to etoposide replacement of vinblastine, with associated decrements in significant toxicities; elimination of bleomycin for certain risk categories; and lessening the duration of treatments. These advances have fuelled great optimism in developing strategic treatments that enhance cure and minimize toxicity. Accompanying the refinements of curative chemotherapy programs have been evolutionary developments in the surgical management of NSGCTT. Once the mainstay of treatment for NSGCTT that had metastasized to the retroperitoneum, the retroperitoneal lymph node dissection (RPLND) has also undergone extraordinary improvements in operative technique, patient selection, approach (open v laparoscopic), anatomic understanding of disease landing zones, and refinements to minimize ejaculatory disturbances (both retrograde ejaculation and failure to ejaculate) that have led to nerve-sparing approaches. These are all welcome advances to the teams of physicians who care for the young and otherwise healthy men with stage II NSGCTT. In this issue of the Journal of Clinical Oncology, Carver et al, representing the disciplines of Urologic Surgery and Medical Oncology from Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY), provide masterly analyses that redefine the already established refinements of RPLND. Such an analysis is especially appropriate to emanate from MSKCC, given that institution’s incredible contributions to the field that have been so important in providing advances embraced by physicians worldwide. The issue at hand relates to the appropriate extent of RPLND for patients with retroperitoneal NSGCTT after chemotherapy (postchemotherapy [PC] -RPLND). Given the correlation of greater ejaculatory morbidity associated with more extensive bilateral infrahilar RPLND for stage I NSGCTT and a more refined (but still incomplete) understanding of nodal landing sites for metastases, the concept of modified dissection templates emerged that limited surgical boundaries to the areas most likely to contain microscopic metastases or disease below the detection of radiographic tests, and thereby minimize postoperative ejaculatory dysfunction. Although no fewer than five modified dissection templates have been described, and are now often applied to the stage II patient, the authors point out that none have undergone rigorous follow-up when applied to stage II disease in the PC setting. In other words, is the performance of a template-modified RPLND correct in the setting of patients with stage II disease of varying tumor burdens? Such an analysis would provide the much-needed comfort that less (surgery) is better or equivalent (in oncologic efficacy). Unfortunately, the results of the current study cast serious doubt on this optimistic assumption. Short of performing a randomized study that compares both the safety and oncologic efficacy of a modified template to the more extensive bilateral infrahilar dissection in the PC setting, the authors analyzed (deduced and imputed) the nature and extent of retroperitoneal disease (teratoma or viable germ cell tumor GCT) PC. Their results include the nature of disease that would have persisted had a template RPLND been performed instead of a more extensive bilateral dissection. Given the poorer prognosis of late and uncontrolled retroperitoneal relapses, and the treacherous and wildly uncertain natural history of unresected teratoma, they argue further that the 7% to 32% of patients who would have had extratemplate disease would not have been well served by a more limited template RPLND. Can the informed reader arrive at the same conclusion? To answer that, let us evaluate the strengths, weaknesses, opportunities, and threats of the data interpretation presented by Carver et al. What are the strengths of the article? First, by any standard of NSGCTT patient experience, the database is huge. In a 14-year period at MSKCC, 532 stage II patients underwent a PC-RPLND, of whom 269 had evidence of either teratoma or viable GCT; of these, 7% to 32% (depending on the template selected) would have had evidence of extratemplate disease had a template RPLND been performed. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 28 OCTOBER 1 2007

Management of clinical stage (CS) I and II patients with non-seminomatous germ cell tumors of the testis (NSGCTT) avoiding upfront retroperitoneal lymph node dissection (RPLND)

5090 Background: CS I, Is, IIa and IIb may be treated by either upfront RPLND or upfront medical management followed by RPLND in selected cases. We retrospectively analyzed the later approach. Methods: From 1993 to 2003, 225 NSGCTT patients CS I and Is, IIa, IIb were treated at our center. In total, 148 patients with CS I were managed by surveillance followed by CT and surgical exeresis of residual disease in case of relapse and 77 with CS Is, IIa and IIb underwent upfront chemotherapy and RPLND in case of residual masses. Median follow-up was 52 months for all patients (0.16–165 months). Results: In CS I: 47/148 (32%) patients relapsed: 22/42 (52%) patients with microvascular involvement versus 25/106 without (24%). The median time to relapse was 5 months (0.16–79 months). All relapsing patients received CT except one for whom we have no information. Twenty-two patients (46%) had RPLND. Two patients died, one probably of haemorrhage one month after RPLND and one in a car accident. In CS II: 4 (5%) patients had CS Is, 40 (52%) CS IIa and 33 (43%) CS IIb. Respectively 71 (92%), 5 (6.5%) and 1 (1,5%) patients had good, intermediate or poor prognosis according to the IGCCCG. All patients received cisplatin-based chemotherapy. Forty-one (53%) patients had RPLND after CT and one refused surgery for residual disease. Histological review showed a teratoma in 22 cases (54%), necrosis in 16 (39%) and residual active disease in 3 (7%). Six patients (8%) relapsed: 1 of them had a growing teratoma. One patient died of disease and all others are alive with no evidence of disease. In total, after medical management of CS I and II, avoiding primary RPLND, only 124 (55%) and 63 (28%) patients had eventually CT and RPLND respectively. Ninety-nine percent patients were cured. Conclusions: Upfront medical treatment of CS I and CS II NSGCTT is a good option which allows to avoid unnecessary CT and RPLND indications. [Table: see text] No significant financial relationships to disclose.

Presentation of Nonseminomatous Germ Cell Tumor of the Testis with Symptomatic Solitary Bone Metastasis. A Case Report with Review of the Literature

Metastatic bone lesions are exceptional at diagnosis in germ cell tumors (GCTs). Bone involvement is usually a late event combined with synchronous metastasis in the retroperitoneal lymph nodes, lung and liver. Bone examination is not considered a standard procedure in the staging of GCTs, and this may contribute to underestimation of the real proportion of bone metastases. Here we report a case of nonseminomatous GCT of the testis with a synchronous, symptomatic, solitary pubic bone metastasis that was completely controlled by systemic chemotherapy and locoregional radiation therapy. Solitary bone metastases from GCTs seem to be chemosensitive and radiosensitive, but we do not know their prognostic value. We reviewed the literature where 3 similar cases have been reported. We propose individualized management for symptomatic GCT patients including bone scintigraphy and/or PET examination at diagnosis and a combined cytotoxic approach with chemotherapy and radiation therapy.

An assessment of mid-chemotherapy CT scanning as a predictor of a residual retroperitoneal mass in good prognosis metastatic teratoma of the testis

4573 Background: There are 2 widely used approaches to treatment of stage 2 non-seminomatous germ cell tumours of the testis (NSGCT); in the UK, 3 or 4 cycles of chemotherapy (C) are generally followed by surgery in those (∼25%)with residual masses >1cm. In some US centres, intial surgery is followed by 2 cycles of C, with similarly good results (Williams et al, 1987). A critical view of US practice is that 2/3 of pts have unnecessary surgery. A US view of UK practice would be that 25% of pts have excessive C. We assessed whether a mid-C CT scan could predict which pts would require surgery, defined as those likely to have a residual post-C mass ≥ 1cm in maximum transverse diameter (MTD), and might thus be considered for early surgery after 2 cycles of C. Methods: Pts were recruited within MRC/EORTC TE20 (de Wit et al 2001), comparing 3 vs 4 x BEP and a 3 vs 5-day schedule. Pts had histologically proven seminoma (S) or NSGCT and were IGCCCG good prognosis. For this sub-study, pts had a pre-C retroperitoneal (RP) mass ≥ 1cm in MTD. Pts had CT scans at baseline, 4–5 weeks after the start of their 1st cycle of C and then 4 weeks post C to measure the MTD of the largest RP mass. Sensitivity and specificity were used via ROC curve analysis to assess the accuracy of predicting residual masses of <1cm by looking at various cut-offs in both absolute mid-C diameter (D) & pre- to mid-C shrinkage (SH). Results: 77 pts (76 testis 1o, 1 RP 1o). Using MTD at mid-C as a predictor of residual RP mass <1cm gave an optimal cutpoint of 2cm (sens=80%, spec=85%). Investigating SH from pre-C to mid-C as a predictor of residual RP mass <1cm gave an optimal SH of 70% (sens=57%, spec=82%). Combining SH and absolute D did not substantially improve on rules using D alone. Conclusions: This small study suggests a potential role for mid-C CT in selecting certain pts for early surgery. Our results suggest the best predictor of post-C residual mass requiring resection is one where pts with an RP mass >2cm by mid C are recommended to have their mass resected. This means that 80% of pts will be correctly predicted to have a residual RP mass <1cm, and should continue their C and 85% will be correctly predicted to have a residual RP mass ≥ 1 cm and thus require resection. No significant financial relationships to disclose.

Indication of post-chemotherapy retroperitoneal lymph-node dissection (RPLND) in the treatment of non-seminomatous germ-cell tumors of the testis (NSGCTT): the case of minimal initial and residual disease

4599 Background: Standard practice and indications of post-chemotherapy (CT) RPLND are based on the knowledge of retroperitoneal lymph-nodes (LN) extension (Donohue, J Urol 1982; 128: 315) and LN initial size and post-CT shrinckage (Toner, J Clin Oncol 1990; 8 : 1683). The justification of post-CT RPLND is to remove either residual cancer or teratoma (RCT) which are likely to eventually progress. The aim of the study was to delineate possible situations where RPLND could be omitted. Methods: Clinical, operative, histological charts of 153 advanced stage NSGCTT patients (pts) who had RPLND between 01/93 and 12/00 were retrospectively reviewed. Extension and size of initialy involved LN as well as size and histological patterns of LN at post-CT RPLND were studied. Results: The major predictive factor of RCT was the initial LN size : 17/41 and 74/112 pts had RCT when initial LN size was < and ≥ 30 mm respectively (p = 0.006). Pts with initial LN size < 30 mm and only one initialy involved anatomical area had...

Indication of post-chemotherapy retroperitoneal lymph-node dissection (RPLND) in the treatment of non-seminomatous germ-cell tumors of the testis (NSGCTT): the case of minimal initial and residual disease

4599 Background: Standard practice and indications of post-chemotherapy (CT) RPLND are based on the knowledge of retroperitoneal lymph-nodes (LN) extension (Donohue, J Urol 1982; 128: 315) and LN initial size and post-CT shrinckage (Toner, J Clin Oncol 1990; 8 : 1683). The justification of post-CT RPLND is to remove either residual cancer or teratoma (RCT) which are likely to eventually progress. The aim of the study was to delineate possible situations where RPLND could be omitted. Methods: Clinical, operative, histological charts of 153 advanced stage NSGCTT patients (pts) who had RPLND between 01/93 and 12/00 were retrospectively reviewed. Extension and size of initialy involved LN as well as size and histological patterns of LN at post-CT RPLND were studied. Results: The major predictive factor of RCT was the initial LN size : 17/41 and 74/112 pts had RCT when initial LN size was < and ≥ 30 mm respectively (p = 0.006). Pts with initial LN size < 30 mm and only one initialy involved anatomical area had still post-CT RCT in 10/21 cases. Pts with post-CT LN size less than 20 and 10 mm had RCT in 21/57 and 6/10 cases respectively. Conclusions: Presence of RCT is roughly 40–50 % of cases even in minimal initial or post-CT disease. These findings justify the indication of RPLND in case of any detectable residual disease. No significant financial relationships to disclose.