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PURPOSE In 2016, Kaiser Permanente Northern California began regionalizing testicular cancer care using population-based tumor board review. This mixed methods evaluation describes implementation outcomes and learnings. METHODS We conducted in-depth interviews with key stakeholders, administered surveys to local oncologists and urologists, and used clinical data to evaluate changes in care delivery during 2015-2018. RESULTS An average of 135 patients with testicular cancer were diagnosed each year. Interviews with 16 key stakeholders provided several insights. Implementation resulted in high levels of satisfaction, was dependent on leadership and staff at various levels, and required technology and consulting solutions aligned to user agreements and clinical workflows. Of 123 local oncologists and urologists who completed surveys, 97% understood why care was regionalized and 89% agreed that tumor board review improved treatment decisions. Among 177 patients with stage I seminoma, the percentage appropriately observed rather than treated with adjuvant chemotherapy or radiation therapy increased from 48% (95% CI, 35 to 62) in 2015 to 87% (75 to 99) in 2018. Review altered care based on pathology and radiology re-review in 14.5 % of cases. CONCLUSION Regionalization was feasible and effective.

Management of testicular germ cell tumor (GCT) patients is based on clinical determinants, mainly CT scan and serum tumor markers (alpha-fetoprotein, beta subunit of HCG and LDH). Treatment decisions are usually straightforward for patients with clear evidence of metastatic disease, confirmed either by imaging tests or by unequivocal elevated tumor markers. However, there are several clinical scenarios where the assessment of metastatic disease is complicated by the limited specificity of the current imaging tests and serum tumor markers. These include patients with clinical stage IIA GCT with negative tumor markers and patients with post-chemotherapy residual disease where, in absence of clear indicators of GCT, decision making and patient treatment allocation become challenging. Therefore, more accurate biomarkers are critical to reduce the risk of under-or over-treatment and to always deliver the most optimal therapy. The objectives of this narrative review are to review the available publications about micro-RNAs in GCT s and their potential clinical applications. Two clusters of micro-RNAs, miR-371a-3p and miR-302/367, specifically expressed by both seminoma and non-seminoma GCT and easily detectable in the peripheral blood, have demonstrated to be promising in this endeavor. Large prospective trials are ongoing to define the operating characteristics of these biomarkers and their clinical utility to improve GCT patient management and reduce the error rate deriving from clinical uncertainty, therefore reducing the risk of sub-optimal treatments.

407 Background: Active surveillance is routinely recommended to manage patients (pts) with clinical stage I (CSI) germ cell testicular tumors (GCT), the most common presentation of newly diagnosed GCT. Circulating plasma miR371a-3p (miR371) has shown high sensitivity and specificity in pts with metastatic non teratoma GCT or in pts with clinically detectable testicular GCT prior to orchiectomy. However, limited data are available about this biomarker accuracy to detect minimal residual disease post-orchiectomy in pts on active surveillance for early stage disease. Methods: CSI GCT pts with available plasma samples after radical orchiectomy enrolled in the British Columbia provincial biobank research program were selected for this study. RT-PCR was used for qualitative miR371 analysis. Sensitivity, specificity, negative and positive predictive values (NPV, PPV) and AUC in predicting tumor recurrence were evaluated for miR371 and compared to the same operating characteristics of current gold standard diagnostic tests. Relapse free survival (RFS) was correlated to post-orchiectomy miR371 (positive or negative) status. Fisher’s exact test was used to evaluate the sensitivity and specificity, unpaired t-test for comparison of miR371 expression. RFS was calculated using the Kaplan-Meier method, and differences between groups were estimated using the log rank test, 2-sided and with 5% significance threshold. Results: With a median follow-up of 41 months, 101 pts with CSI GTCwere included, of whom 35 (34.6%) experienced a disease relapse during the follow-up. miR371 was positive in 22/35 (62.8%) of the relapsed pts. miR371 positivity preceded clinical evident disease by a median of 3 months (range: 1-12 months).The specificity and PPV were 100% (95% CI: 94.5 - 100 for both), sensitivity 62.8% (95% CI: 44.9 - 78.5), NPV 83.5% (95% CI: 76.7 - 88.6) and AUC 0.81 (95% CI: 0.71 - 0.91). No false positive results were observed. The RFS of the pts with positive post-orchiectomy miR371 was significantly shorter (median: 3.5 months vs. not reached; p seminoma). Conclusions: miR371 has high specificity and PPV in detecting GCT at an early stage and could be used to guide treatment selection after orchiectomy. Further studies, including the SWOG S1823 clinical trial, are ongoing or have been planned in this setting for validation of clinical utility.

Active germ cell malignancies express high levels of specific circulating micro-RNAs (miRNAs), including miR-371a-3p (miR371), which is undetectable in teratoma. Teratoma markers are urgently needed for theselection of patients and treatments because of the risk of malignant transformation and growing teratoma syndrome. To assess the accuracy of plasma miR375 alone or in combination with miR371 in detecting teratoma, 100 germ cell tumor patients, divided into two cohorts, were enrolled in a prospective multi-institutional study. In the discovery cohort, patients with pure teratoma and with no/low risk of harboring teratoma were compared; the validation cohort included patients with confirmed teratoma, active germ cell malignancy, or complete response after chemotherapy. The area under the receiver operating characteristic curve values for miR375, miR371, and miR371-miR375 were, respectively, 0.93 (95% confidence interval [CI]: 0.87-0.99), 0.59 (95% CI: 0.44-0.73), and 0.95 (95% CI: 0.90-0.99) in the discovery cohort and 0.55 (95% CI: 0.36-0.74), 0.74 (95% CI: 0.58-0.91), and 0.77 (95% CI: 0.62-0.93) in the validation cohort. Our study demonstrated that the plasma miR371-miR375 integrated evaluation is highly accurate to detect teratoma. PATIENT SUMMARY: The evaluation of two micro-RNAs (miR375-miR371) in the blood of patients with germ cell tumors is promising to predict teratoma. This test could be particularly relevant to the identification of teratoma in patients with postchemotherapy residual disease. info:eu-repo/semantics/publishedVersion

Background The coronavirus disease 2019 (COVID-19) pandemic has become a public health emergency affecting frail populations, including patients with cancer. This poses the question of whether cancer treatments can be postponed or modified without compromising their efficacy, especially for highly curable cancers such as germ cell tumors (GCTs). Materials and Methods To depict the state-of-the-art management of GCTs during the COVID-19 pandemic, a survey including 26 questions was circulated by e-mail among the physicians belonging to three cooperative groups: (a) Italian Germ Cell Cancer Group; (b) European Reference Network–Rare Adult Solid Cancers, Domain G3 (rare male genitourinary cancers); and (c) Genitourinary Medical Oncologists of Canada. Percentages of agreement between Italian respondents (I) versus Canadian respondents (C), I versus European respondents (E), and E versus C were compared by using Fisher's exact tests for dichotomous answers and chi square test for trends for the questions with three or more options. Results Fifty-three GCT experts responded to the survey: 20 Italian, 6 in other European countries, and 27 from Canada. Telemedicine was broadly used; there was high consensus to interrupt chemotherapy in COVID-19–positive patients (I = 75%, C = 55%, and E = 83.3%) and for use of granulocyte colony-stimulating factor primary prophylaxis for neutropenia (I = 65%, C = 62.9%, and E = 50%). The main differences emerged regarding the management of stage I and stage IIA disease, likely because of cultural and geographical differences. Conclusion Our study highlights the common efforts of GCT experts in Europe and Canada to maintain high standards of treatment for patients with GCT with few changes in their management during the COVID-19 pandemic.

PURPOSE Our objective was to evaluate operating characteristics, particularly specificity and positive predictive value (PPV), by mapping plasma miR371 expression to actual clinical events in patients with a history of germ cell tumor. PATIENTS AND METHODS One hundred eleven male patients with a history of or newly diagnosed germ cell tumors were evaluable. Biospecimens obtained before confirmed clinical events were analyzed for miR371 expression with blinding of providers and laboratory personnel to analytic results or clinical status, respectively. Cases (patients with clinically confirmed active germ cell malignancy [aGCM]) and controls (patients with no clinically confirmed aGCM) were assigned over the course of the management. Patients were assigned risk status (high, low, or moderate) based on the composite clinical picture at time points in management. RESULTS Considering all cases and controls and results of prospectively obtained biosamples analyzed for miR371 expression, 46 (35%) of 132 samples had clinically confirmed aGCM over the course of management; 44 (96%) of these 46 patients had plasma miR371 expression (true positives) with no false positives. Two (4%) of 46 patients had no miRNA expression despite pathologic confirmation of aGCM (false negatives). Plasma miR371 expression in confirmed aGCM had a specificity, sensitivity, positive predictive value, and negative predictive value of 100%, 96%, 100%, and 98%, respectively. Interpretation of sensitivity and negative predictive value is limited by modest follow-up. Specificity and sensitivity were 100% and 98%, 100% and 92%, and 100% and 97% in the low-, moderate-, and high-risk groups, respectively, with a median follow-up time of 15 months. CONCLUSION Plasma miR371 expression predicts aGCM with high specificity and positive predictive value. Although other operating characteristics of miR371 await longer follow-up for more complete definition, the findings of a highly specific liquid biopsy strongly support moving forward with large-scale, real-world clinical trials to further define full operating characteristics and to identify clinical utility and areas of patient benefit.

Two clusters of microRNAs have been discovered highly expressed by seminoma and nonseminoma germ cell tumors. They are secreted in blood of patients with testicular germ cell tumors and can be extracted from the serum or plasma and quantified by real-time-polymerase chain reaction. Results have confirmed the feasibility of the technique and demonstrated that sensitivity and specificity of those microRNAs in detecting viable germ cell tumors are higher than with current methods. If operation characteristics are confirmed in larger studies, those microRNAs will be valuable to manage equivocal clinical scenarios characterized by high uncertainty and high risk of over-treatment or under-treatment.

Progress toward improvement in cancer therapy relies on clinical trials. Yet, only a minority of eligible patients with cancer enroll as a result of multiple barriers at the patient, investigator, center, and national level. However, the rise of the Internet and mobile technology has created a slew of tools with medical applications, from Web sites to apps to social media platforms, all of which may aide clinicians in our quest to improve the clinical research enterprise. SWOG is one of five members in the National Cancer Institute’s National Clinical Trials Network—the nation’s oldest and largest publicly funded cancer research network—and is taking a leadership role in exploring and testing the promise of digital engagement through the empaneling of the Digital Engagement Committee. This article outlines the mission, principles, and priorities of the Digital Engagement Committee and proposes how this work may inform the use of digital tools for the cancer research community and, hopefully, translate to improved outcomes for our patients.

At the Canadian Testis Cancer Workshop, the multidisciplinary management of testis cancer care was discussed. The two-day workshop involved urologists, medical and radiation oncologists, pathologists, radiologists, physician’s assistants, residents, fellows, nurses, patients, and patient advocacy group members. This review summarizes the discussion regarding clinical dilemmas in local and regional testis cancer. We present cases that highlight the need for a coordinated approach to individualize care. Overarching themes include the importance of a multidisciplinary approach to testis cancer, willingness to involve a high-volume experienced center, and given that the oncological outcomes are excellent, a reminder that clinical decisions need to prioritize selecting a strategy with the least treatment-related morbidity when safe to do so.

In November 2018, The Canadian Testis Cancer Workshop was convened. The two-day workshop involved urologists, medical and radiation oncologists, pathologists, radiologists, physician’s assistants, residents and fellows, nurses, patients and patient advocacy groups. One of the goals of the workshop was to discuss the challenging areas of testis cancer care where guidelines may not be specific. The objective was to distill through discussion around cases, expert approach to working through these challenges. Herein we present a summary of discussion from the workshop around controversies in the management of clinical stage 1 (CS1) disease. CS1 represents organ confined non-metastatic testis cancer that represents approximately 70-80% of men at presentation. Regardless of management, CS1 has an excellent prognosis. However, without adjuvant treatment, approximately 30% of CS1 nonseminomatous germ cell tumors (NSGCT) and 15% of CS1 seminoma relapse. The workshop reviewed that while surveillance has become the standard for the majority of patients with CS1 disease there remains debate in the management of patients at high-risk of relapse. The controversy in the management of CS1 testis cancer surrounds the optimal balance between the morbidity of overtreatment and the identification of patients who may derive most benefit from adjuvant treatment. The challenge lies in a shared decision process where discussion of options extends beyond the simple risk of relapse but to include the long-term toxicities of adjuvant treatments and the favorable cancer-specific survival.

At the Canadian Testis Cancer Workshop, the rationale and feasibility of regionalization of testis cancer care were discussed. The two-day workshop involved urologists, medical and radiation oncologists, pathologists, radiologists, physician’s assistants, residents and fellows, and nurses, as well as patients and patient advocacy groups. This review summarizes the discussion and recommendations of one of the central topics of the workshop — the centralization of testis cancer in Canada. It was acknowledged that non-guideline-concordant care in testis cancer occurs frequently, in the range of 18–30%. The National Health Service in the U.K. stipulates various testis cancer care modalities be delivered through supra-regional network. All cases are reviewed at a multidisciplinary team meeting and aspects of care can be delivered locally through the network. In Germany, no such network exists, but an insurance-supported online second opinion network was developed that currently achieves expert case review in over 30% of cases. There are clear benefits to regionalization in terms of survival, treatment morbidity, and cost. There was agreement at the workshop that a structured pathway for diagnosis and treatment of testis cancer patients is required. Regionalization may be challenging in Canada because of geography; independent administration of healthcare by each province; physicians fearing loss of autonomy and revenue; patient unwillingness to travel long distances from home; and the inability of the larger centers to handle the ensuing increase in volume. We feel the first step is to identify the key performance indicators and quality metrics to track the quality of care received. After identifying these metrics, implementation of a “networks of excellence” model, similar to that seen in sarcoma care in Ontario, could be effective, coupled with increased use of health technology, such as virtual clinics and telemedicine.

Purpose of review miRNAs 371 and 302/367 clusters are abundantly secreted in the blood of patients with active germ cell malignancy (aGCM), both seminoma and nonseminoma. The serum concentration of those micro-RNAs correlates with tumor burden and to the activity of specific treatments; therefore, representing attractive biomarkers for the diagnosis and follow-up of patients with germ cell tumors. This review summarizes the most relevant evidence supporting their clinical validity in germ cell tumors. Recent findings Several retrospective studies have reported high sensitivity and specificity of those micro-RNAs in identifying aGCM prior to the orchiectomy or in patients with metastatic germ cell tumor prior to or during chemotherapy. Most recently, few prospective studies have confirmed their clinical validity during the follow-up of patients after surgery and/or chemotherapy. Large studies are panned across the spectrum of germ cell tumors to assess their clinical utility and several efforts to identify biomarkers of teratoma are underway. Summary The integration of those micro-RNAs in the management of germ cell tumors has the potential to refine the therapeutic decision, especially in some clinical situations characterized by high uncertainty, such as clinical stage I, clinical stage IIA with normal tumor markers and residual disease postchemotherapy.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A healthy 27-year-old man discovered a left testicular mass. Several months later he saw an urologist, who palpated a suspicious mass on the left testicle; an ultrasound confirmed a 2-cm solid mass. Serum tumor marker testing disclosed a slightly elevated alpha-fetoprotein (AFP) of 12.3 µg/L (upper limit of normal, 8.0 µg/L), and a normal β-human chorionic gonadotropin (HCG). Staging imaging with a contrast-enhanced computed tomography (CT) scan of the chest/abdomen/pelvis showed no evidence for retroperitoneal lymphadenopathy or distant metastases. He underwent a left radical orchiectomy, and pathology showed a 1.5-cm mixed germ cell tumor with 85% embryonal, 10% yolk sac tumor, and 5% mature teratoma histologies. Lymphovascular invasion was present. His AFP normalized after surgery. After discussion of management alternatives, he chose active surveillance, but 4 months later a scheduled surveillance CT scan identified a 1.4-cm left para-aortic lymph node just below the left renal hilum ( Fig 1 ). Serum tumor markers remained negative. He returns to discuss his results and potential management options.

375 Background: Chemotherapy or radiotherapy are standard treatments for stage II seminoma, though they are associated with significant long-term treatment-related toxicities. Retroperitoneal lymph node dissection (RPLND) is an established treatment for testicular germ cell tumors but little data exists on its efficacy as a front-line treatment in early metastatic (stage II) seminoma. This is a single-arm, multi-institutional (NCT02537548), phase II study of retroperitoneal lymph node dissection (RLND) as first-line treatment for testicular seminoma with isolated retroperitoneal disease. Methods: Twelve sites in the United States and Canada prospectively enrolled patients (16 years of age) with testicular seminoma and isolated retroperitoneal lymphadenopathy between 1-3 cm in size. Patients were excluded if they received prior therapy (except orchiectomy) for testicular cancer. Open, modified-template RPLND was performed by qualified surgeons with a primary endpoint of 2-year recurrence-free survival. Data on complication rates (short and long-term), pathologic up/downstaging, recurrence patterns, adjuvant therapies, and treatment-free survival were assessed. Results: A total of 55 patients were enrolled and underwent RPLND. Fourteen patients had initial stage I disease who developed isolated retroperitoneal relapse while 41 patients had clinical stage IIA-B at presentation. With a median follow-up of 24 months (8-52 months), there were a total of 10 recurrences. The overall recurrence rate was 18% with a median time to recurrence of 8 months. Of the recurrences, 8 underwent chemotherapy (6 BEP X 3, 1 EP X 4, 1 carbo/etoposide) and 2 underwent additional surgery. The two-year recurrence free survival was 87% and the overall survival was 100%. There were 7 (13%) patients who experienced short-term complications within 1 year of RPLND. Of these, 5 (9%) were classified as Clavien Dindo I-II and 2 (3.6%) were classified as Clavien Dindo III. No patients have reported long-term complications. Conclusions: This trial establishes RPLND as a therapeutic option as a first-line treatment in early metastatic seminoma. The surgery offers cancer control rates similar to those seen in non-seminomatous germ cell tumors. Clinical trial information: NCT02537548.

379 Background: miR371a-3p (miR371) is overexpressed in seminoma (S) and nonseminoma (NS) active germ cell malignancy (aGCM) and easily detectable in blood. We previously described1 a remarkably high accuracy of miR371 in detecting aGCM in early and advanced stages germ cell tumor (GCT) patients (pts). We here present the updated miR371 expression data with a longer follow-up, particularly relevant to assess miR371 clinical utility to predict GCT relapse in clinical stage I (CSI) and stage IIA pts. Methods:119 samples from 99 pts enrolled in the GU biobank program at the British Columbia Cancer – Vancouver were analyzed. The pts were divided according to their risk of aGCM in low (CSIA NS and CSI S), moderate (CSIB NS, stage IIA markers negative/low elevated S and NS), and high risk (definitively metastatic aGCM) groups. Blood of the low and moderate risk pts was collected post orchiectomy and at the time of the clinical relapse; prior to/post-chemotherapy in the high risk group. Plasma miR371 expression was evaluated by RT-PCR and quantified by ΔΔCT method. Sensitivity, specificity, negative and positive predictive values (NPV, PPV) and AUC of the ROC curve were analyzed. Results: Five (2 moderate - 3 low risks) pts were lost at follow-up and 1 high risk pt had deceased. Overall, 113 samples (50, 36, 27 in the low, moderate, and high risk groups, respectively) were analyzed. The median follow-up from study entry was 30 (6-51), 28 (20-52), and 29 (7-53) months for the low, moderate and high risk, respectively. Seven more relapses occurred: 4 in the low risk (3 S and 1 NS) and 3 in the moderate risk groups (2 NS and 1 S). miR371 was found falsely negative post-orchiectomy in 4 pts and truly negative in 3 relapsed pts (2 pure teratoma and 1 unconfirmed relapse). Serial analysis of the false negative relapsed pts showed that miR371 became detectable at the time of clinical relapse. The operating characteristics of miR371 are summarized in the table below. Conclusions: Our follow-up has exceeded the expected time of relapse even in the low risk pts. The high accuracy of miR371 in detecting aGCM was confirmed with a longer follow up. However, the few false negatives in relapsed pts and the serial analysis suggest a lack of sensitivity in the detection of microscopic disease post-orchiectomy with the current methodology while miR371 high sensitivity was confirmed in presence of radiologic measurable disease (≥ 1 cm). The definitive operating characteristics of miR371 post-orchiectomy and during the follow-up of stages I/ IIA pts will be prospectively validated by the S1823 study that is actively recruiting pts. [Table: see text]

Sex cord stromal tumors of the testis comprise less than 5% of testicular neoplasms. Consequently, data regarding patterns of care and survival are sparse. Using a large national database, we sought to provide a more definitive analysis of outcomes and management of these malignancies.Data were obtained from the National Cancer Data Base. Patients diagnosed from 1998 to 2011 with 2 of the most frequent sex cord stromal tumors of the testis, including Leydig and Sertoli cell tumors, were selected for study. Overall survival estimates were assessed by the Kaplan-Meier method.Of the 79,120 cases of testicular cancer between 1998 and 2011, 315 (0.39%) were primary malignant Leydig or Sertoli cell tumors. Median patient age was 43 years for both tumors. Of the 315 patients 250 (79%) had malignant Leydig cell tumors and 65 (21%) had malignant Sertoli cell tumors, of which 94% and 78%, respectively, were stage I. Overall survival at 1 and 5 years for stage I Leydig cell tumors was 98% (95% CI 96-100) and 91% (95% CI 85-96), and for stage I Sertoli cell tumors overall survival was 93% (95% CI 83-100) and 77% (95% CI 62-95), respectively (p = 0.015). Of patients with stage I Leydig and Sertoli cell tumors 94% and 84%, respectively, received no further treatment following orchiectomy.Five-year survival estimates of stage I Leydig and Sertoli cell tumors are significantly lower compared to those of stage I germ cell tumors with Sertoli cell tumors significantly worse than Leydig cell tumors. These differences in the survival of sex cord stromal tumors indicate the importance of large databases to evaluate the efficacy of treatment for rare neoplasms.

39 Background: Research priorities in germ cell tumor (GCT) management have moved sharply from therapeutic improvements to cancer care delivery research and biomarker-based decision making. Early intervention with centralized decision support and oversight by expert teams result in best therapeutic outcomes and survivorship with decreased resource utilization. We describe Kaiser Permanente Northern California’s (KPNC) re-organization of care delivery through rapid case ascertainment and early expert input, as well as early results of reduction in practice variation and system-wide practice change. Methods: In 2016, KPNC reorganized oncology from a distributed generalist model to a model led by a centralized multidisciplinary expert team to share in initial and ongoing care delivery for all GCT patients in the system. Central to the re-organization was rapid ascertainment of the entire population of patients with GCT within the system and early expert engagement in treatment decision-making. Results: Between May 2016 and June 2018, 274 GCT patients were recorded in the tumor registry, of whom 69% were < 40 years of age, 16% were non-white, 56% had seminoma and 63% had stage 1 disease. Rapid case ascertainment identified 89% (95% CI, 86-93%) of the cases, increasing from 79% in 2016 to 97% in 2018 as false negatives were identified and used to improve the case finding algorithm. The overall positive predictive value was 57% (52-62%) and number needed to detect was 1.75 (1.62-1.91). Of the 274 cases, 92% (89-95%) were engaged by the expert team. In addition, the team reviewed 61 testicular cancer patients who had recurrences or metastatic cancers. Among 177 patients with stage I seminoma, the preferred use of active surveillance over adjuvant chemotherapy or radiation therapy rose from 48% (95% CI, 35-62%) in 2015 to 87% (75-99%) in 2018 (p = 0.0005). For patients with nonseminoma, the rate of the preferred option of retroperitoneal lymphadenectomies being performed by a high volume urologic surgeon increased markedly from 62% in 2015 to 95% in 2018. Conclusions: To our knowledge, the KPNC re-organization of GCT care delivery with comprehensive rapid case ascertainment is unique for integrated health care delivery systems in the USA. While early, KPNC has a working platform for early, expert multidisciplinary review and bidirectional communication with local care teams for population-based care. Early evidence points to system-wide reductions in practice variation and improvements in practice.

8035 Background: The goal of the North American Mantle Cell Lymphoma (MCL) Project is to evaluate the clinical, biological, and genomic markers that affect the outcome of patients with MCL. Methods: We have retrospectively studied the clinical and pathological features of 307/421 patients diagnosed with MCL between January 2000 to December 2012 from 23 institutions across North American. Results: The male to female ratio of MCL patients was 3.5:1, with a median age of 66 years (range: 24-106 years). Approximately 29% of patients (78/269) presented with B symptoms and 257 (257/307, 83.7%) patients had extranodal involvement at diagnosis. Median follow-up was 7.1 years (range, 0.03 to 16.6 years) with the five-year PFS and OS at 27.8%, and 54.4%, respectively. Univariate analysis revealed that the following factors were significantly associated with both inferior OS and PFS ( p< 0.05): older age (≥60 years), presence of B symptoms, advanced Ann Arbor stage, elevated LDH, low platelets (≤100K/ml), blastoid/pleomorphic cytology, Ki67 proliferation ≥30%, circulating tumor cells, no transplantation (vs. transplantation), and allogeneic (vs. autologous) stem cell transplantation. In addition, large tumor size (maximal diameter > 3cm), high WBC ( > 10×103/ml), CD5 or CD23 positivity, and a complex karyotype were associated with inferior OS ( p< 0.05). Multivariate Cox regression analysis showed age (≥ 60y; p= 0.0028, HR = 2.44, 95% CI: 1.36-4.38) and high LDH ( p= 0.0062, HR = 2.19, 95% CI: 1.25-3.84) were the two factors predicting the clinical outcome. MIPI-c, a commonly used prognostic scoring system which includes Ki67, stratified the 100 MCL cases into four group with distinct clinical outcomes ( p< 0.001). Using readily-available clinical and pathological variables, we developed a simple and robust scoring system, MIPI-P (pathology), which consisted of age (≥60 years), LDH (high), Ki67 index (≥30%), Ann Arbor stage (III/IV), and cytological type (blastoid/pleomorphic), each contributing one point. The MIPI-P system stratified 104 MCL cases into three distinct groups ( p< 0.001). Median survival for the different groups were: low grade (0-1 points): 11.8 years; intermediate grade (2-3 points): 4.9 years; and high grade (4-5 points): 1.6 years. We further validated this system in an independent cohort of 33 MCL cases and confirmed that the modified MIPI-P provided robust prognostic predication ( p= 0.014). Conclusions: The clinical and biologic characteristics of MCL can provide information assisting with the prognosis of patients with MCL.

414 Background: Viable germ cell tumors (vGCT) express high levels of certain circulating microRNAs, including miR-371a-3p (miR371) that has shown high specificity and sensitivity. However, neither tissue nor serum/plasma from patients with only teratoma are miR371 positive. miR375 is overexpressed in teratoma tissue, but detectability in blood is unknown. Methods: miR371 and miR375 expression was analyzed in 100 patients with various stages and histology of GCT. miR375 expression in teratoma was validated in patients with post-chemotherapy pathologically confirmed teratoma (PCPCT). The miRNAs expression was assessed by RT-PCR and quantified by ΔΔCT method. The optimal cut-off for miR375 expression was estimated by Youden index ( > 20). Spike-in cel-miR-39-3p, miR-451 and miR-30b-5p were used as internal controls. Sensitivity, specificity, AUC of the ROC of miR375 in detecting teratoma was analyzed. Results: In the discovery cohort miR371 and miR375 were measured in 62 pts: 27 CSI NED, 15 chemo-naïve metastatic seminoma and 20 with PCPCT. miR375 was over-expressed in pts with teratoma compared to CSI and seminoma pts (p = 0.002), while miR371 was expressed in the seminoma pts and undetectable in the PCPCT and CSI pts (p < 0.001). In the post-chemotherapy setting, 38 pts were analyzed: 21 PCPCT, 6 vGCT and 11 complete remission (CR). Also in this cohort, miR375 was over-expressed in pts with teratoma compared to the pts presenting vGCT and post-chemotherapy CR (p = 0.01), while miR371 was detectable only in the pts with vGCT (p < 0.001). Overall, sensitivity and specificity of miR375 in identifying teratoma were 78% and 80%, respectively; the AUC was 0.7 (95% CI: 0.5490-0.8186; p < 0.01). Conclusions: Pts with residual post-chemotherapy teratoma present higher plasma levels of miR375 compared to pts with vGCT in whom miR375 is low but miR371 is expressed at high levels. The simultaneous evaluation of miR371 and miR375 may be clinically useful to predict the histology of the GCT components in pts with post-chemotherapy residual disease to inform the best therapeutic options (surgery or chemotherapy). Further validation within larger studies is warranted.

Clinical stage I represents the most frequent presentation of both seminoma and nonseminoma testicular cancer. Despite a survival rate of close to 100%, the management of patients with this disease stage is controversial. The recurrence rate is 10% to 20% for patients with stage I seminoma and 15% to 50% for those with stage I nonseminoma. A highly sensitive and specific biomarker of relapse that is applicable to both seminoma and nonseminoma, and able to drive a definitive risk-adapted management of the patients, still is not available. Lymphovascular invasion (LVI) in the orchiectomy specimen has been used as a risk factor in patients with stage I nonseminoma. However, with a risk of recurrence of 50% for LVI-positive patients and 15% for LVI-negative patients, the discriminative power of LVI is modest at best. Various management options exist. In the absence of a predictive biomarker for recurrence, active surveillance avoids overtreatment in 50% to 85% of patients, with no risk of long-term side effects in nonrelapsing patients and a preserved overall survival of almost 100% after specific treatment for recurrent disease. However, although active surveillance has been accepted as the preferred option for stage I seminoma and low-risk stage I nonseminoma, its role in high-risk stage I nonseminoma remains controversial.

Context Cancer-specific survival for men with clinical stage I testicular cancer (CSITC) is uniformly excellent. Non–risk-adapted active surveillance (NRAS) is a management strategy for CSITC to minimize overtreatment and avoid possible long-term side effects of adjuvant therapy. Objective To review the evidence regarding oncologic outcomes for men with CSITC undergoing NRAS and discuss ongoing controversies in the management of CSITC. Evidence acquisition MEDLINE/PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched from January 1, 1987 through January 1, 2017. Evidence synthesis A total of 68 studies were included in the critical review. The rationale for NRAS, oncologic outcomes, surveillance protocols, and comparative efficacy of risk-adjusted active surveillance (AS) were reported with strength of evidence and risk of bias evaluated. Cancer-specific survival approaches 100% for men with CSITC undergoing NRAS. Active treatment is limited to 20–30% of patients who will recur; these patients will require salvage chemotherapy and possible retroperitoneal lymph node dissection. Existing AS protocols include imaging and laboratory evaluations that are initially intensive but less frequent with increasing follow-up. Conclusions NRAS is an attractive management option for men with CSITC, which maintains outstanding long-term cancer cure while sparing most patients treatment by avoiding prophylactic chemotherapy, radiation, or surgery. Patient summary Men with clinically localized (stage I) testicular cancer have an excellent prognosis, regardless of management. Non–risk-adapted active surveillance is an attractive management option where only patients destined to relapse will receive any treatment following orchiectomy. However, individual patient preferences should be discussed in selecting a management strategy.

Introduction Clinical stage I seminoma can be managed with surveillance, chemotherapy or radiotherapy with similar survival rates. However, costs and side effects vary among these treatment modalities. We created a model to estimate the direct and indirect costs during the first 5 years of treatment for the 3 treatment strategies. Methods Markov model based analyses were conducted to compare the costs of the 3 management strategies during the first 5 years. In this model clinicians and patients were assumed to be 100% compliant with the 2012 NCCN Guidelines® for testicular cancer. Model parameters were collected from the Washington State CHARS (Comprehensive Hospital Abstract Reporting System), published literature and Medicare reimbursement amounts. A 5% annual health inflation rate was assumed. Results The model predicts an initial cost premium for carboplatin (1 cycle—$9,199.49; 2 cycles—$10,613.85) and radiotherapy ($9,532.80) compared with surveillance ($9,065.31). Radiotherapy (145.8 hours) and surveillance (123.0 hours) require more patient time than carboplatin (1 cycle—93.2 hours, 2 cycles—106.3 hours). When the direct and indirect costs are considered, the least expensive management strategy is surveillance. Conclusions Surveillance is the most cost-effective management strategy for clinical stage I seminoma during the first 5 years of treatment. Although not evaluated in this analysis, costs of late side effects associated with radiotherapy and chemotherapy should be considered. Due to potentially minimal late side effects and superior cost-effectiveness, surveillance represents a safe, cost-effective and time effective option for the management of stage I seminoma.

526 Background: Identification of relapsing/residual viable germ cell malignancy (GCM) is often challenging in patients with CSI on surveillance or with residual post-chemotherapy disease. The presence of a biomarker for GCM would overcome the uncertainty of the current methods and improve the quality of care of those patients. Methods: A 2-cohorts pilot study involving patients with clearcut evidence of GCM (clinical stage IS, metastatic and GCM prior orchiectomy) for the development cohort and patients with CSI with or without signs of tumor relapse and patients with metastatic GCM post-chemotherapy for the validation cohort. Blood samples collected in Streck tubes were obtained prior to chemotherapy for the development cohort and post-orchiectomy, at the time of suspicious relapse or post-chemotherapy in the validation cohort. Plasma miR-371a-3p (miR371) was analyzed by RT-PCR. Positive predictive value (PPV), sensitivity, specificity, negative predictive values (NPV) and AUC of the ROC for miR371 and standard diagnostic tools (CT scan, AFP, BHCG and LDH) were calculated correlating qualitative miR371 expression to the presence of viable GCM. Results: 132 patients were enrolled into the development (33 pts) and validation (99 pts) cohorts. Within the development cohort 31/33 pts were miR371 positive, 2/33 pts were negative. 31 true positives were found among the 31 miR371 positive patients for a PPV of 100% (31/31). Two true negatives were found among the 2 patients who had no miR371 expression identified (teratoma, lymphoma). The validation cohort was chosen to evaluate the methodology among patients with predicted lower volumes or no clinically apparent disease. 13/99 patients within the validation cohort were miR371 positive and all 13 had subsequent confirmation of viable GCM. For the overall study of 132 pts, PPV was 100% (46/46), NPV 98%, sensitivity 96% and specificity 100%, the AUC of the ROC was 0.96. Conclusions: Detectable circulating miR-371a-3p levels predict viable GCM and may represent a strategy for biological rather than radiographic assessment for surveillance of early stage and for post-treatment patients. Larger studies to validate these and like results have been planned.

Since 1985, the biological association of mediastinal germ cell tumors and certain hematologic malignancies has been recognized. Continued investigation of such patients and new cytogenetic information brings additional insights into the clinical aspects of this syndrome as well as hinting at the possible etiology. This syndrome only occurs in patients with non-seminomatous germ cell tumors arising within the mediastinum. The interval from the diagnosis of the germ cell tumor to the development of the hematologic malignancy is brief (usually less than 6 months). Careful characterization of the hematologic malignancies in this patient population suggests a predominance of abnormalities within the megakaryocytic lineage. Recent cytogenetic analysis in one patient identified the most common abnormality of germ cell cancers, isochromosome 12p, in the mediastinal germ cell tumor as well as in the subsequent leukemic blasts. i12p is not a cytogenetic abnormality associated with the development of leukemia. The clinical evidence as well as this new cytogenetic information suggest strongly that the two abnormalities are clonally related and that the hematologic malignancy may arise as a consequence of defferentiation of the multipotent malignant germ cell.

Retroperitoneal lymph node dissection (RPLND) for the treatment of testicular cancer is a relatively rare and complex operation that may contribute to differences in utilization. We sought to characterize the use of RPLND between different categories of cancer center facilities in the United States.The National Cancer Database was queried for patients with germ cell tumors treated at different types of cancer centers between 1998 and 2011. The proportion of patients who underwent RPLND was stratified by stage and histology and then compared between treatment facilities. RPLND utilization was then compared between facility types as a function of time.A total of 59,652 patients met inclusion criteria and 5,475 (9.2%) underwent RPLND. The proportion of patients treated with RPLND for non-seminomatous germ cell tumor (NSGCT) was significantly different between cancer center types for all stages (P0.001) and used most often in academic comprehensive cancer centers. There was no difference in the proportion of RPLND utilization for stage II and III seminoma stratified by treatment facility. There was a significantly decreased trend in the utilization of RPLND for stage I (P = 0.032) NSGCT whereas utilization was increased for stage III NSGCT (P≤0.001) over the study period.The proportion of patients undergoing RPLND for NSGCT varies significantly by the type of cancer center and is used most often in academic cancer centers. Utilization of RPLND decreased for stage I NSGCT and increased for stage III NSGCTs during the study period.

Young men presenting with testicular cancer enjoy a very high prospect of cure and look forward to an average of 40 additional years of life. As such, emphasis has focused on care algorithms that are not only curative, but also minimize the consequences of the disease and associated treatments on subsequent quality of life. Concerns regarding therapy-related second malignancies and cardiovascular disease have led to management strategies emphasizing the reduction or elimination of chemotherapy and radiation therapy and increase utilization of surveillance for early-stage patients. Germ cell tumors present typically in the late 20s or early 30s, occurring in a timeframe when many young men begin to consider their families seriously. Indeed, more than 80% of young patients report significant concerns regarding diminished fertility. The biology and anatomy of most germ cell tumors lead to significant potential for disrupted fertility from both disease-related factors-hypogonadism and diminished native spermatogenesis-and manifold treatment-related complications such as ejaculatory dysfunction, chemotherapy, and radiation effects on spermatogenesis and testosterone production. Despite these unique challenges of managing fertility in patients with germ cell tumors, such efforts are rewarded with a high rate of fertility preservation for most patients with no evidence that subsequent progeny are affected by the parent's disease or treatments. Herein, we review the biological and clinical issues associated with reduced fertility potential in patients with germ cell tumors, methods for evaluating and preserving fertility in such patients, and anticipated overall success rates.

To evaluate the clinicopathologic characteristics of patients undergoing adjuvant surgery during postchemotherapy retroperitoneal lymph node dissection (PC-RPLND). From 2004 to 2010, 85 testicular cancer patients underwent PC-RPLND by a single surgeon (S.D.). A bilateral template approach was utilized with nerve-sparing technique whenever feasible. The clinicopathologic and outcome of patients who underwent removal of any organ or structure during PC-RPLND were reviewed. Of 85 patients undergoing PC-RPLND, 28 (33%) required adjuvant procedures. Thirteen (15%) required vascular procedures including cavotomy/caval resection in 6, aortic resection in 8, common iliac vessels resection in 4, and renal vessels resection/reimplant in 2. Twelve patients (14%) required adjuvant nephrectomy (ten of 12 left-sided). There was one ureteral resection with appendiceal substitution, one partial duodenectomy, two cholecystectomy, two thoracotomies, four liver resection/biopsy, and one neck dissection. There were eight early complications (28%), including vocal cord paralysis, brachial plexus injury, lower extremities compartment syndrome, thigh numbness, upper gastrointestinal bleeding, retroperitoneal hematoma, and alcohol withdrawal. No perioperative death was reported. Retroperitoneal pathology revealed mature teratoma in 11 patients (39%), fibrosis in 8 (28%), and viable germ cell tumor (GCT) in 9 (32%). A total of 75, 82, and 66% of patients with fibrosis, teratoma, and viable GCT, respectively, had no evidence of recurrence at a mean follow-up of 18 months. Many patients undergoing PC-RPLND require adjuvant surgery, including vascular procedures and nephrectomy. The excellent outcomes associated with low operative morbidity and mortality validates such aggressive surgical approaches performed by experienced surgeons.

The development of effective chemotherapy has been the defining event in the history of testicular cancer treatment. The discovery of cisplatin-based chemotherapy created a massive inflection that sharply defined the relatively grim precisplatin era from the astonishing postcisplatin era. The ripple effects of this discovery continue today with the rewriting of management of early-stage germ cell tumors to surveillance-based programs. This article reviews the discovery, development, and delivery of cisplatin-based chemotherapy; expected outcomes of chemotherapy treatment; remaining controversies in primary chemotherapy treatment of disseminated disease; and practical management tips for delivery of bleomycin, etoposide, and cisplatin and after chemotherapy treatment.

4549Background: Determining the histology of borderline enlarged nodes in clinical stage I (CSI) or post-chemotherapy residual disease (PCRD) patients (pts) with germ cell tumor (GCT) is challengin...

Purpose The management of patients with a radiographic complete response after chemotherapy remains controversial. The current study assesses the outcome for a modern, unselected patient population with disseminated testicular cancer with particular emphasis on those achieving a radiographic complete remission to combination chemotherapy. Patients and Methods All patients with disseminated nonseminoma seen between 1999 and 2007 at the British Columbia Cancer Agency (BCCA) as well as through the Oregon Testis Cancer Program were retrospectively reviewed. A total of 276 patients treated with combination chemotherapy were identified. A radiographic complete remission (CR) was defined as disappearance of all metastatic lesions or minimal residual tissue ≤ 1 cm. Results One hundred sixty-one patients achieved a CR. Results for the total population and CR subset were as follows: International Germ Cell Cancer Consensus Group stage good/intermediate/poor 84%/5%/11% (CR subset, 94%/3%/3%), presence of teratoma in the primary tumor 40% (CR subset, 55%), relapses 13%, death from disease 3% (CR subset, 6% and 0%, respectively). Two of the total 10 relapses in the CR group occurred beyond 2 years. Eight of the 10 relapses in the CR group were treated surgically for teratoma alone, whereas two required salvage chemotherapy. Disease-specific survival for the CR group was 100% after a median follow-up of 52 months (range, 3 to 135 months). Conclusion Modern risk-adapted systemic chemotherapy with or without surgery for current populations of patients with disseminated testicular nonseminoma results in superb outcomes. Patients with disseminated germ cell tumors who obtain a complete serologic remission and no or minimal radiographic residual can be safely observed without adjunctive regional surgery.

Purpose To evaluate patient-specific immunotherapy with mitumprotimut-T (idiotype keyhole limpet hemocyanin [Id-KLH]) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in CD20+ follicular lymphoma. Patients and Methods Patients with treatment-naive or relapsed/refractory disease achieving a complete response (CR), partial response (PR), or stable disease (SD) with four weekly rituximab infusions were randomly assigned to mitumprotimut-T/GM-CSF or placebo/GM-CSF, with doses given monthly for six doses, every 2 months for six doses, and then every 3 months until disease progression (PD). Randomization was stratified by prior therapy (treatment-naive or relapsed/refractory) and response to rituximab (CR/PR or SD). The primary end point was time to progression (TTP) from randomization. Results A total of 349 patients were randomly assigned; median age was 54 years, 79% were treatment naive, and 86% had stage III/IV disease. Median TTP was 9.0 months for mitumprotimut-T/GM-CSF and 12.6 months for placebo/GM-CSF (hazard ratio [HR] = 1.384; P = .019). TTP was comparable between the two arms in treatment-naive patients (HR = 1.196; P = .258) and shorter with mitumprotimut-T/GM-CSF in relapsed/refractory disease (HR = 2.265; P = .004). After adjusting for Follicular Lymphoma International Prognostic Index (FLIPI) scores, the difference in TTP between the two arms was no longer significant. Overall objective response rate, rate of response improvement, and duration of response were comparable between the two arms. Toxicity was similar in the two arms; 76% of adverse events were mild or moderate, and 94% of patients had injection site reactions. Conclusion TTP was shorter with mitumprotimut-T/GM-CSF compared with placebo/GM-CSF. This difference was possibly due to the imbalance in FLIPI scores.

Purpose The purpose of this study was to characterize the activity and toxicity of irinotecan in metastatic platinum-refractory urothelial carcinoma. Patients and Methods In a prospective multi-institutional phase II clinical trial, we evaluated the activity and safety of irinotecan 350 mg/m 2 (300 mg/m 2 in patients with previous radiation therapy to the pelvis) intravenously given every 21 days in patients with metastatic urothelial carcinoma and evidence of progression following one previous systemic chemotherapy regimen for metastatic disease that included cisplatin or carboplatin. The primary goal of this study was to evaluate the probability of confirmed complete or partial response. Results Forty eligible patients were registered between December 2003 and December 2006. One patient had a complete response, and 1 had a partial response (overall response rate, 5%; 95% CI, 1%-17%). Median progression-free survival was 2.1 months (95% CI, 1.8-2.3 months). Median overall survival was 5.4 months (95% CI, 3.4-7.1 months). Toxicity was similar to that reported previously for this schedule of irinotecan. Conclusion The response rate seen in this study is insufficient to recommend further evaluation of irinotecan in urothelial cancer that relapsed following initial platinumbased chemotherapy. Investigation of novel agents for this patient population remains a priority.

Objectives: The first consensus report presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in the year 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, Amsterdam, The Netherlands. Methods: Medical oncologists, urological surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference, and incorporated the new data into updated and revised guidelines. As for the first meeting, the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update. Results: The first part of the consensus paper describes the clinical presentation of the primary tumor, its treatment, the importance and treatment of testicular intraepithelial neoplasia (TIN), histological classification, staging and prognostic factors, and treatment of stage I seminoma and non-seminoma. Conclusions: Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early- and advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged. (C) 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.

BACKGROUND To the authors' knowledge, no satisfactory therapy is available for patients with refractory germ cell neoplasms. The activity and safety of arsenic trioxide in refractory germ cell tumors was assessed. METHODS Twenty patients were treated with arsenic trioxide at a dose of 0.25 mg/kg/day and administered intravenously over 1 to 2 hours on Days 1-5 and repeated every 28 days. RESULTS There were no complete or partial responses. The median progression-free survival was 1 month and the median overall survival was 2 months. Three patients died as a result of adverse events believed to be possibly related to treatment: ventricular arrhythmia, adult respiratory distress syndrome, and pneumonitis. CONCLUSIONS In the current study, arsenic trioxide in the dose regimen and schedule employed was found to have no activity in men with refractory germ cell malignancies. Treatment was associated with severe toxicity. Dismal overall survival reflects the poor outcome in this patient group and highlights the acute need for new agents with activity in refractory germ cell neoplasms. Cancer 2006. © 2006 American Cancer Society.

In the next 30 years, one in five Americans will be over 65 years of age [1,2]. Because 60% of malignant disease occurs in persons over 65 years of age, physicians will be seeing an increasing number of elderly patients with cancer. Recently, there have been more data suggesting that selected elderly patients with cancer can receive the same benefit from therapy as their younger counterparts, without a significant increase in morbidity [3–6]. The result of the changes will be an increase use of cancer therapeutics in the elderly patient population with accompanying intensive care management. In this article we will review issues related to the care of elderly cancer patients in the intensive care unit. Intensive care unit and the elderly Over the past 20 years, the nature of cancer treatment has changed dramatically with the introduction of new and intensified treatment protocols and improved supportive care. This has led to improved prognosis and survival times, and also to an increased number of complications, which may warrant intensive care [7]. These changes are not only reflected in the younger cancer patient population; the benefits of cancer therapeutics have also been demonstrated in the elderly [3,6]. The management of the critically ill cancer patients can be difficult, and decisions to admit cancer patients to the intensive care unit (ICU) are complex. The chances of a potentially curative cancer therapy must be weighed against the associated risk of significant morbidity and high mortality. These patients are

BACKGROUND Various staging systems have been proposed for disseminated germ cell neoplasms. The Indiana University staging system was based on clinical and radiographic findings only, whereas the newly created International Germ Cell Cancer Collaborative Group (IGCCCG) staging system also utilized serum markers as a prognostic factor. This study updated the intergroup trial that compared the standard therapy of bleomycin, etoposide, and cisplatin (BEP) with etoposide, ifosfamide, and cisplatin (VIP) in advanced germ cell tumors and reanalyzed the results using the IGCCCG staging system. METHODS From October 1987 to April 1992, 304 patients with advanced-stage germ cell tumors (using the Indiana University staging system) were randomized to receive four cycles of BEP or VIP. Two hundred and eighty-six patients were eligible and fully evaluable. With a median follow-up of 7.3 years, 283 of the 286 evaluable patients from the Eastern Cooperative Oncology Group protocol, E3887, were reclassified using the IGCCCG staging system. Progression-free survival (PFS), overall survival (OS), and toxicity were assessed for the treatment arms. RESULTS With a longer follow-up of 7.3 years and using the Indiana University staging system, the PFS rates were 64% versus 58% and the OS rates were 69% versus 67% in the VIP and BEP arms, respectively. For patients reclassified with the IGCCCG staging system, the PFS rates were 81%, 72%, and 54% and the OS rates were 89%, 81%, and 60% for good, intermediate, and poor-risk patients, respectively. Differences in OS (VIP, 62%; BEP, 57%) and PFS (VIP, 56%; BEP, 49%) for the subset of patients reclassified as poor risk by the IGCCCG staging system were not significantly different. More toxicity, primarily hematologic toxicity, occurred on the VIP arm. CONCLUSIONS With a median follow-up of 7.3 years and with a reclassification based on the IGCCCG, OS and PFS rates were comparable between BEP and VIP. Toxicity, primarily hematologic, was modestly greater with the ifosfamide-containing arm. The VIP regimen may be considered a treatment alternative for patients with underlying pulmonary disease. In most patients with poor and intermediate-risk germ cell tumors, four cycles of BEP remain the standard therapy. Cancer 2003;97:1869–75. © 2003 American Cancer Society. DOI 10.1002/cncr.11271

BACKGROUND Prostate cancer is the most common malignancy in American men, and as many as 70% of those initially treated for localized disease will ultimately progress and be considered candidates to receive therapy for metastatic cancer [Fuks et al.: Int J Radiat Oncol Bio Phys 21:537–547, 1991; Chodak et al.: N Engl J Med 330:246–248, 1994]. Although most will respond initially to hormone manipulation, essentially all will fail and require additional therapy. No standard chemotherapy approach has been shown to prolong survival significantly, and new agents are desperately needed. Topotecan is a new topoisomerase-1 inhibitor whose early investigation suggested possible activity in hormone-refractory prostate cancer. METHODS In this phase II trial, patients having failed one or two prior androgen ablative therapies were treated with 21-day continuous intravenous infusions of topotecan at a dose of 0.5 mg/m2 per day every 28 days. RESULTS Twenty-six eligible patients were entered on the study. There were no confirmed tumor responses. Median survival was 9 months. The most common toxicities were hematologic, with 8 of 24 assessable patients experiencing grade 4 toxicity. CONCLUSION Topotecan infusions at this dose are ineffective in the management of hormone-refractory prostate cancer. Prostate 52: 264–268, 2002. © 2002 Wiley-Liss, Inc.

This investigation evaluates prognostic variables in patients with seminomatous and non-seminomatous extragonadal germ-cell tumors (EGCT) in order to identify relevant factors for long-term outcome following cisplatin-based chemotherapy.Patients from six countries treated at 11 centers in Europe and the USA from 1975 to 1996 were evaluated retrospectively. Uni- and multivariate analyses of prognostic variables for survival and for response to chemotherapy were performed.Data were available for 635 EGCT patients, 104 with seminomatous and 524 with non-seminomatous EGCT (n = 7 not specified). For non-seminomatous EGCT the following independent adverse factors were identified: presence of either liver, lung or central nervous system metastases, primary mediastinal tumor or elevation of pretreatment beta-human gonadotropin; for extragonadal seminoma (only univariate) adverse factors were: presence of liver metastases, two or greater metastatic sites or International Germ Cell Cancer Collaborative Group (IGCCCG) grouping (intermediate versus good). Integration of these variables produced the following prognostic risk groupings: 'excellent prognosis', all seminomatous EGCT (89% 5-year survival rate); 'intermediate low', 'intermediate high' and 'poor', all non-seminomatous EGCT with a 69, 55 and 17% 5-year survival rate, respectively. The decreased survival among the different groups was due to a lower rate of favorable objective remissions and a higher rate of relapses. Classification and regression tree (CART) modeling confirmed histology and location of primary tumor as the major prognosticators. For the subgroup of patients with mediastinal non-seminoma, the 2-year survival rate ranged from 34 to 84%. Multivariate testing for the probability to respond to chemotherapy revealed non-seminomatous histology, primary mediastinal tumor site, and the presence of liver, lung or CNS metastases as independent adverse factors.In EGCT, prognostic variables for the outcome and for the response to chemotherapy could be identified, which in part differ from gonadal GCT. The proposed model might help to better understand the specific prognosis of EGCT and to tailor risk-adapted treatment strategies. In addition, CART analysis demonstrated the heterogenous prognosis of patients with mediastinal non-seminoma.

PURPOSE: To characterize the clinical and biologic features of extragonadal germ cell tumor (EGCT) and to determine the overall outcome with currently available treatment strategies. PATIENTS AND METHODS: Of an unselected population of 635 consecutive patients treated from 1975 through 1996 at 11 cancer centers, 341 patients (54%) had primary mediastinal EGCT, and 283 patients (45%) had retroperitoneal EGCT. Five hundred twenty-four patients (83%) had a nonseminomatous germ cell tumor (GCT), and 104 patients (16%) had a seminomatous histology. RESULTS: After platinum-based induction chemotherapy with or without secondary surgery, 141 patients (49%) with mediastinal nonseminomas (median follow-up, 19 months; range, 1 to 178 months) and 144 patients (63%) with retroperitoneal nonseminoma (median follow-up, 29 months; range, 1 to 203 months) are alive (P = .0006). In contrast, the overall survival rate for patients with a seminomatous EGCT is 88%, with no difference between patients with mediastinal or retroperitoneal tumor location (median follow-up, 49 months; range, 4 to 193 months; respective 70 months; range, 1 to 211 months). A significantly lower progression-free survival rate was found in seminoma patients treated with initial radiotherapy alone compared with chemotherapy. Nonseminomatous histology, presence of nonpulmonary visceral metastases, primary mediastinal GCT location, and elevated beta-human chorionic gonadotropin were independent prognostic factors for shorter survival. Hematologic malignancies (n = 17) occurred without exception in patients with primary mediastinal nonseminoma. Sixteen patients developed a metachronous testicular cancer despite the use of platinum-based chemotherapy. CONCLUSION: Whereas patients with pure seminomatous EGCT histology have a long-term chance of cure of almost 90% irrespective of the primary tumor site, 45% of patients with mediastinal nonseminomas are alive at 5 years. This outcome is clearly inferior compared with patients with nonseminomatous retroperitoneal primary tumors.