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Purpose: Survival in stage I seminoma is almost 100%. Computed tomography (CT) surveillance is an international standard of care, avoiding adjuvant therapy. In this young population, minimizing irradiation is vital. The Trial of Imaging and Surveillance in Seminoma Testis (TRISST) assessed whether magnetic resonance images (MRIs) or a reduced scan schedule could be used without an unacceptable increase in advanced relapses., Methods: A phase III, noninferiority, factorial trial. Eligible participants had undergone orchiectomy for stage I seminoma with no adjuvant therapy planned. Random assignment was to seven CTs (6, 12, 18, 24, 36, 48, and 60 months); seven MRIs (same schedule); three CTs (6, 18, and 36 months); or three MRIs. The primary outcome was 6-year incidence of Royal Marsden Hospital stage ≥ IIC relapse (> 5 cm), aiming to exclude increases ≥ 5.7% (from 5.7% to 11.4%) with MRI ( v CT) or three scans ( v 7); target N = 660, all contributing to both comparisons. Secondary outcomes include relapse ≥ 3 cm, disease-free survival, and overall survival. Intention-to-treat and per-protocol analyses were performed., Results: Six hundred sixty-nine patients enrolled (35 UK centers, 2008-2014); mean tumor size was 2.9 cm, and 358 (54%) were low risk (< 4 cm, no rete testis invasion). With a median follow-up of 72 months, 82 (12%) relapsed. Stage ≥ IIC relapse was rare (10 events). Although statistically noninferior, more events occurred with three scans (nine, 2.8%) versus seven scans (one, 0.3%): 2.5% absolute increase, 90% CI (1.0 to 4.1). Only 4/9 could have potentially been detected earlier with seven scans. Noninferiority of MRI versus CT was also shown; fewer events occurred with MRI (two [0.6%] v eight [2.6%]), 1.9% decrease (-3.5 to -0.3). Per-protocol analyses confirmed noninferiority. Five-year survival was 99%, with no tumor-related deaths., Conclusion: Surveillance is a safe management approach-advanced relapse is rare, salvage treatment successful, and outcomes excellent, regardless of imaging frequency or modality. MRI can be recommended to reduce irradiation; and no adverse impact on long-term outcomes was seen with a reduced schedule.

Purpose: The classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium., Materials and Methods: Data on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients., Results: Compared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH., Conclusion: PFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor., Competing Interests: Jörg BeyerHonoraria: Roche, Janssen Oncology, AstraZeneca, Astellas Pharma, Bayer, Ipsen Gedske DaugaardConsulting or Advisory Role: Sanofi/Aventis, Astellas Pharma, Bayer, MSD Oncology, Bristol-Myers Squibb/PfizerTravel, Accommodations, Expenses: Astellas Pharma Darren R. FeldmanResearch Funding: Novartis, Seattle Genetics, Decibel Therapeutics, Astellas PharmaOther Relationship: UpToDate Alexey TryakinConsulting or Advisory Role: BioCad, Roche/Genentech, Bristol-Myers Squibb, Eisai, Merck Sharp & DohmeSpeakers' Bureau: Bayer Health, BioCad, Lilly, Merck Serono, Sanofi, Amgen, Bristol-Myers Squibb, Eisai, Merck Sharp & DohmeTravel, Accommodations, Expenses: Novartis, BioCad, Bayer, Veropharm, Sanofi Olof StahlHonoraria: Bayer Enrique Gonzalez-BillalabeitiaTravel, Accommodations, Expenses: Bristol-Myers Squibb, Pfizer, Janssen-Cilag, Astellas Pharma, Sanofi, Roche Ugo De GiorgiConsulting or Advisory Role: Pfizer, Janssen, Astellas Pharma, Sanofi, Bristol-Myers Squibb, Bayer, Ipsen, Merck, MSD, PharmaMar, NovartisResearch Funding: Sanofi, AstraZeneca, RocheTravel, Accommodations, Expenses: Bristol-Myers Squibb, Ipsen, Janssen, Pfizer, Roche Stephane CulineConsulting or Advisory Role: Bayer, Janssen, Astellas PharmaSpeakers' Bureau: Takeda, JanssenResearch Funding: Astellas PharmaTravel, Accommodations, Expenses: Ipsen, Janssen Ronald De WitHonoraria: Sanofi, Merck Sharp & DohmeConsulting or Advisory Role: Sanofi, Merck Sharp & Dohme, Janssen, Bayer, Astellas PharmaResearch Funding: Sanofi, BayerTravel, Accommodations, Expenses: Bayer Aaron HansenConsulting or Advisory Role: Merck, GlaxoSmithKline, Bristol-Myers Squibb, EisaiResearch Funding: Karyopharm Therapeutics, Merck, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, Janssen, AstraZeneca/MedImmune, Astellas Pharma, Macrogenics Marko BebekHonoraria: Roche, Novartis, Janssen Oncology, Sanofi, Sandoz, Astellas PharmaResearch Funding: Roche, Astellas PharmaTravel, Accommodations, Expenses: Roche, Astellas Pharma, Sanofi, Janssen, Novartis Angelika TerbuchResearch Funding: Roche, AstraZeneca, MSD, Bristol-Myers Squibb Costantine AlbanyStock and Other Ownership Interests: AdvaxisHonoraria: Sanofi, AstraZeneca, Seattle GeneticsConsulting or Advisory Role: Seattle Genetics, AstraZeneca/MedImmuneSpeakers' Bureau: SanofiResearch Funding: Astex Pharmaceuticals, Merck, Bristol-Myers Squibb, Lilly, BayerTravel, Accommodations, Expenses: Sanofi Marcus HentrichConsulting or Advisory Role: Amgen, Janssen-Cilag, Sanofi, Hexal, Jazz Pharmaceuticals, TakedaSpeakers' Bureau: Amgen, Janssen-Cilag, Sanofi, Takeda, Bristol-Myers Squibb, Gilead SciencesTravel, Accommodations, Expenses: Celgene, Janssen-Cilag, Takeda Jourik A. GietemaResearch Funding: Roche/Genentech, Abbvie, Siemens Robert A. HuddartEmployment: Aspen Parkside HospitalLeadership: Cancer Clinic London limited liability partnershipHonoraria: Janssen OncologyConsulting or Advisory Role: Bristol-Myers Squibb, Roche, Merck Sharp & Dohme, Janssen Oncology, Nektar, BayerSpeakers' Bureau: Roche, MSDResearch Funding: Merck Sharp & Dohme, Roche, Bristol-Myers Squibb, JanssenPatents, Royalties, Other Intellectual Property: Royalties for drug discovery from JanssenTravel, Accommodations, Expenses: Janssen Oncology, Roche/Genentech, MSD Oncology, Nektar Anja LorchHonoraria: MSD Oncology, Merck, MSDConsulting or Advisory Role: Bristol-Myers Squibb, Novartis, AstraZeneca, Roche, MSD Oncology, Janssen Oncology, Ipsen, Merck, PfizerTravel, Accommodations, Expenses: Ipsen, AstraZeneca Daniel Y. C. HengConsulting or Advisory Role: Pfizer, Novartis, Bristol-Myers Squibb, Janssen, Astellas Pharma, Ipsen, Eisai, MerckResearch Funding: Pfizer, Novartis, Exelixis, Bristol-Myers Squibb, Ipsen Christopher J. SweeneyStock and Other Ownership Interests: LeuchemixConsulting or Advisory Role: Sanofi, Janssen Biotech, Astellas Pharma, Bayer, Genentech/Roche, AstraZeneca, Pfizer, Amgen, Celgene, LillyResearch Funding: Janssen Biotech, Astellas Pharma, Sanofi, Bayer, Dendreon, PfizerPatents, Royalties, Other Intellectual Property: Leuchemix, Parthenolide, Dimethylaminoparthenolide. Exelixis: Abiraterone plus cabozantinib combination Eric WinquistHonoraria: Merck, Bayer, Eisai, Amgen, RocheResearch Funding: Roche/Genentech, Merck, Pfizer, Eisai, Ayala Pharmaceuticals Peter GrimisonResearch Funding: Tilray, Pfizer, MSD, Gilead Sciences, Boston Biomedical, Tigermed, Halozyme, Specialised Therapeutics, Medimmune, Pfizer, ASLAN Pharmaceuticals, Genentech, Eisai, Five Prime Therapeutics, QED Therapeutics, Janssen-Cilag Andrea NecchiEmployment: BayerStock and Other Ownership Interests: BayerHonoraria: Roche, Merck, AstraZeneca, Janssen, Foundation Medicine, Bristol-Myers SquibbConsulting or Advisory Role: Merck Sharp & Dohme, Roche, Bayer, AstraZeneca, Clovis Oncology, Janssen, Incyte, Seattle Genetics/Astellas, Bristol-Myers Squibb, Rainier Therapeutics, GlaxoSmithKline, FerringResearch Funding: Merck Sharp & Dohme, AstraZeneca, IpsenTravel, Accommodations, Expenses: Roche, Merck Sharp & Dohme, AstraZeneca, Janssen, Rainier TherapeuticsOther Relationship: Bayer Ben TranHonoraria: Astellas Pharma, Janssen-Cilag, Sanofi, Tolmar, Amgen, Bristol-Myers SquibbConsulting or Advisory Role: Amgen, Astellas Pharma, Bayer, Sanofi, Tolmar, Janssen-Cilag, Bristol-Myers Squibb, Ipsen, MSD Oncology, IQvia, Novartis, Pfizer/EMD Serono, AstraZeneca, Roche Molecular DiagnosticsResearch Funding: Astellas Pharma, Janssen-Cilag, Amgen, Pfizer, Genentech, AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharp & Dohme, IpsenTravel, Accommodations, Expenses: Amgen, Astellas Pharma Axel HeidenreichHonoraria: Amgen, Astellas Pharma, Bayer, Ferring, Ipsen, Janssen-Cilag, Sanofi, TakedaConsulting or Advisory Role: Astellas Pharma, Bayer, Janssen-Cilag, Clovis Oncology, BMS Global, AstraZeneca, MSD OncologySpeakers' Bureau: Amgen, Astellas Pharma, Bayer, Ipsen, Johnson & Johnson, Sanofi, Takeda, PfizerResearch Funding: Astellas Pharma, Bayer, Sanofi, Bristol-Myers Squibb Jonathan ShamashSpeakers' Bureau: Pfizer/EMD Serono Cora N. SternbergConsulting or Advisory Role: Bayer, MSD, Pfizer, Roche, Incyte, AstraZeneca, Merck, Medscape, UroToday, Astellas Pharma, Genzyme, Immunomedics, Foundation Medicine David J. VaughnResearch Funding: Merck Sharp & Dohme, Roche/Genentech, Astellas Pharma Ignacio DuranHonoraria: Bristol-Myers Squibb, Ipsen, Roche/Genentech, Janssen Oncology, MSD Oncology, Astellas Pharma, EUSA PharmaConsulting or Advisory Role: Roche/Genentech, MSD Oncology, Bayer, Bristol-Myers Squibb, Seattle Genetics, Pharmacyclics, Janssen Oncology, Novartis, ImmunomedicsResearch Funding: Roche/Genentech, AstraZeneca Spain, Janssen Oncology, Astellas PharmaTravel, Accommodations, Expenses: Roche/Genentech, AstraZeneca Spain, Ipsen Carsten BokemeyerHonoraria: Merck KGaA, Sanofi, Roche, Bayer, Bristol-Myers Squibb, AstraZeneca, Merck Sharp & DohmeConsulting or Advisory Role: Lilly/ImClone, Merck Serono, Sanofi, Bayer Schering Pharma, Merck Sharp & Dohme, GSO, AOK Health InsuranceResearch Funding: Abbvie, ADC Therapeutics, Agile Therapeutics, Alexion Pharmaceuticals, Amgen, Apellis Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, BerGenBio, Blueprint Medicines, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eisai, Gilead Sciences, Glycotope GmbH, GlaxoSmithKline, Incyte, iOMEDICO, Isofol Medical, Janssen-Cilag, Karyopharm Therapeutics, Lilly, Millennium, MSD, Nektar, Novartis, Rafael Pharmaceuticals, Roche, Springworks Therapeutics, Taiho PharmaceuticalTravel, Accommodations, Expenses: Merck Serono, Sanofi, Pfizer, Bristol-Myers Squibb Anna PatrikidouConsulting or Advisory Role: Basilea Richard CathomasHonoraria: Janssen-Cilag, Astellas Pharma, Bristol-Myers Squibb, Debiopharm GroupConsulting or Advisory Role: Astellas Pharma, Bristol-Myers Squibb, Pfizer, Roche, MSD Oncology, Janssen-Cilag, Bayer, Sanofi, IpsenTravel, Accommodations, Expenses: AstraZeneca Silke GillessenConsulting or Advisory Role: Astellas Pharma, Janssen, Bayer, Orion Pharma GmbH, Tolero Pharmaceuticals, MSD Oncology, Roche, Amgen, PfizerSpeakers' Bureau: Janssen-CilagPatents, Royalties, Other Intellectual Property: Method for biomarker (WO 3752009138392 A1)Travel, Accommodations, Expenses: ProteoMedixOther Relationship: ProteoMediX, Aranda PharmaNo other potential conflicts of interest were reported.

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.

Purpose: To evaluate the long-term survival rates in patients with relapsed or refractory germ cell tumors (GCTs) after single or sequential high-dose chemotherapy (HDCT)., Patients and Methods: Between November 1999 and November 2004, 211 patients with relapsed or refractory GCT were randomly assigned to treatment with either one cycle of cisplatin 100 mg/m(2), etoposide 375 mg/m(2), and ifosfamide 6 g/m(2) (VIP) plus three cycles of high-dose carboplatin 1,500 mg/m(2) and etoposide 1,500 mg/m(2) (CE, arm A) or three cycles of VIP plus one cycle of high-dose carboplatin 2,200 mg/m(2), etoposide 1,800 mg/m(2), and cyclophosphamide 6,400 mg/m(2) (CEC, arm B) followed by autologous stem-cell reinfusion. Long-term progression-free survival (PFS) and overall survival (OS) 6 years after random assignment of the last patient were compared by using the log-rank test., Results: Overall, 108 and 103 patients were randomly assigned to arms A and B, respectivelyl. The study was stopped prematurely because of excess treatment-related mortality in arm B (14%) compared with that in arm A (4%; P = .01). As of December 2010, nine (5%) of 211 patients were lost to follow-up; 94 (45%) of 211 are alive and 88 (94%) of 94 patients are progression free. Five-year PFS is 47% (95% CI, 37% to 56%) in arm A and 45% (95% CI, 35% to 55%) in arm B (hazard ratio [HR], 1.16; 95% CI, 0.79 to 1.70; P = .454). Five-year OS is 49% (95% CI, 40% to 59%) in arm A and 39% (95% CI, 30% to 49%) in arm B (HR, 1.42; 95% CI, 0.99 to 2.05; P = .057)., Conclusion: Patients with relapsed or refractory GCT achieve durable long-term survival after single as well as sequential HDCT. Fewer early deaths related to toxicity translated into superior long-term OS after sequential HDCT.

Purpose: To confirm the efficacy of a risk-adapted treatment approach for patients with clinical stage I seminoma. The aim was to reduce both the risk of relapse and the proportion of patients receiving adjuvant chemotherapy while maintaining a high cure rate., Patients and Methods: From 2004 to 2008, 227 patients were included after orchiectomy in a multicenter study. Eighty-four patients (37%) presented no local risk factors, 44 patients (19%) had tumors larger than 4 cm, 25 patients (11%) had rete testis involvement, and 74 patients (33%) had both criteria. Only the latter group received two courses of adjuvant carboplatin, whereas the rest were managed by surveillance., Results: After a median follow-up time of 34 months, 16 relapses (7%) have been documented (15 [9.8%] among patients on surveillance and one [1.4%] among those treated with carboplatin). All relapses occurred in retroperitoneal lymph nodes, except for one case in pelvic nodes. Median node size was 25 mm, and median time to recurrence was 14 months. All patients were rendered disease-free with chemotherapy. The actuarial 3-year disease-free survival rate was 88.1% (95% CI, 82.3% to 93.9%) for patients on surveillance and 98.0% (95% CI, 94.0% to 100%) for those treated with adjuvant chemotherapy. Overall 3-year survival was 100%., Conclusion: With the limitations of the short follow-up duration, we confirm that a risk-adapted approach is effective for stage I seminoma. Adjuvant carboplatin seems adequate treatment for patients with 2 risk criteria, as is active surveillance for those with 0 to one risk factors. More reliable predictive factors are needed to improve the applicability of this model.

Purpose: Initial results of a randomized trial comparing carboplatin with radiotherapy (RT) as adjuvant treatment for stage I seminoma found carboplatin had a noninferior relapse-free rate (RFR) and had reduced contralateral germ cell tumors (GCTs) in the short-term. Updated results with a median follow-up of 6.5 years are now reported., Patients and Methods: Random assignment was between RT and one infusion of carboplatin dosed at 7 × (glomerular filtration rate + 25) on the basis of EDTA (n = 357) and 90% of this dose if determined on the basis of creatinine clearance (n = 202). The trial was powered to exclude a doubling in RFRs assuming a 96-97% 2-year RFR after radiotherapy (hazard ratio [HR], approximately 2.0)., Results: Overall, 1,447 patients were randomly assigned in a 3-to-5 ratio (carboplatin, n = 573; RT, n = 904). RFRs at 5 years were 94.7% for carboplatin and 96.0% for RT (RT-C 90% CI, 0.7% to 3.5%; HR, 1.25; 90% CI, 0.83 to 1.89). One death as a result of seminoma (in RT arm) occurred. Patients receiving at least 99% of the 7 × AUC dose had a 5-year RFR of 96.1% (95% CI, 93.4% to 97.7%) compared with 92.6% (95% CI, 88.0% to 95.5%) in those who received lower doses (HR, 0.51; 95% CI, 0.24 to 1.07; P = .08). There was a clear reduction in the rate of contralateral GCTs (carboplatin, n = 2; RT, n = 15; HR, 0.22; 95% CI, 0.05 to 0.95; P = .03), and elevated pretreatment follicle-stimulating hormone (FSH) levels (> 12 IU/L) was a strong predictor (HR, 8.57; 95% CI, 1.82 to 40.38)., Conclusion: These updated results confirm the noninferiority of single dose carboplatin (at 7 × AUC dose) versus RT in terms of RFR and establish a statistically significant reduction in the medium term of risk of second GCT produced by this treatment.

Purpose: To assess the long-term efficacy and toxicity of front-line cisplatin-based chemotherapy in patients with stage IIA or IIB testicular seminoma., Patients and Methods: Untreated patients with pure seminoma of the testis after orchiectomy, with clinical stage IIA or IIB, were considered eligible for this prospective observational study. Chemotherapy consisted of either four cycles of cisplatin and etoposide or three cycles of cisplatin, etoposide, and bleomycin., Results: Between April 1994 and March 2003, 72 patients were entered onto the study at 26 participating centers. Eighteen patients had stage IIA disease, and 54 patients had stage IIB disease. Eighty-three percent of patients achieved complete response, and 17% achieved partial response with residual mass. After a median follow-up time of 71.5 months, six patients with stage IIB disease experienced relapse, and one of these patients died as a result of seminoma. Three patients experienced non-seminoma-related deaths (two died from a further esophageal carcinoma, and one died from an upper digestive hemorrhage). The estimated 5-year progression-free survival rates for patients with stage IIA or IIB disease were 100% and 87% (95% CI, 77.5% to 97%), respectively. Five-year progression-free and overall survival rates for the whole group were 90% (95% CI, 82% to 98%) and 95% (95% CI, 89% to 100%), respectively. Severe granulocytopenia and thrombocytopenia were observed in eight and two patients, respectively. Mild to moderate emesis, stomatitis, and diarrhea were the most common nonhematologic effects., Conclusion: Chemotherapy is a highly effective and well-tolerated treatment for patients with stage IIA or IIB seminoma and represents an available alternative that could avoid some of the serious late effects associated with radiotherapy. Further studies focusing on long-term toxicities of different treatment modalities are needed.

Purpose: To evaluate the long-term risk of cardiovascular disease (CVD) in survivors of testicular cancer (TC)., Patients and Methods: We compared CVD incidence in 2,512 5-year survivors of TC, who were treated between 1965 and 1995, with general population rates. Treatment effects on CVD risk were quantified in multivariate Cox regression analysis., Results: After a median follow-up of 18.4 years, 694 cardiovascular events occurred, including 141 acute myocardial infarctions (MIs). The standardized incidence ratio (SIR) for coronary heart disease was 1.17 (95% CI, 1.04 to 1.31), with 14 excess cases per 10,000 person-years. The SIR for MI was significantly increased in nonseminoma survivors with attained ages of less than 45 (SIR = 2.06) and 45 to 54 years (SIR = 1.86) but significantly decreased for survivors with attained ages of 55 years or older (SIR = 0.53). In Cox analysis, mediastinal irradiation was associated with a 3.7-fold (95% CI, 2.2- to 6.2-fold) increased MI risk compared with surgery alone, whereas infradiaphragmatic irradiation was not associated with an increased MI risk. Cisplatin, vinblastine, and bleomycin (PVB) chemotherapy (CT) was associated with a 1.9-fold (95% CI, 1.7- to 2.0-fold) increased MI risk, and bleomycin, etoposide, and cisplatin (BEP) CT was associated with a 1.5-fold (95% CI, 1.0- to 2.2-fold) increased CVD risk and was not associated with increased MI risk (hazard ratio = 1.2; 95% CI, 0.7 to 2.1). Recent smoking was associated with a 2.6-fold (95% CI, 1.8- to 3.9-fold) increased MI risk., Conclusion: Nonseminomatous TC survivors experience a moderately increased MI risk at young ages. Physicians should be aware of excess CVD risk associated with mediastinal radiotherapy, PVB CT, and recent smoking. Intervention in modifiable cardiovascular risk factors is especially important in TC survivors. Whether BEP treatment increases CVD risk should be evaluated after more prolonged follow-up.

Purpose: To assess the efficacy of a risk-adapted treatment policy for patients with stage I seminoma by using universally accepted risk criteria., Patients and Methods: Between 1999 and 2003, 314 patients with clinical stage I seminoma after orchiectomy were prospectively included. One hundred patients (31.8%) presented no risk factors and were managed with surveillance. In contrast, 131 patients (41.7%) had tumors larger than 4 cm, 33 patients (10.5%) had rete testis involvement, and 50 patients (15.9%) had both risk factors. All the latter received two courses of adjuvant carboplatin., Results: Chemotherapy was well tolerated, as only 17 patients (7.9%) presented grade 3 to 4 toxicity. Relapses were observed in six patients (6.0%) on surveillance and in seven patients (3.3%) treated with carboplatin (0.8% of tumors larger than 4 cm, 9.1% of those involving the rete testis, and 6.0% of patients with both risk criteria). All were located at the retroperitoneum, except for one at the spermatic cord. Median tumor size was 25 mm (range, 11 to 70 mm), and median time to relapse was 9 months (range, 4 to 28 months). All patients were rendered disease-free with chemotherapy (etoposide plus cisplatin). Median follow-up was 34 months (range, 12 to 72 months). The actuarial 5-year disease-free survival rate was 93.4% for patients on surveillance and 96.2% for patients treated with adjuvant chemotherapy. Overall 5-year survival was 100%., Conclusion: Adjuvant carboplatin is effective in reducing the relapse rate in patients with stage I seminoma and risk factors. A risk-adapted strategy is safe and feasible and should be considered an alternative to systematic approaches, such as irradiation, chemotherapy, or surveillance.

Purpose: To define the clinical value of 2-18fluoro-deoxy-D-glucose positron emission tomography (FDG PET) as a predictor for viable residual tumor in postchemotherapy seminoma residuals in a prospective multicentric trial., Patients and Methods: FDG PET studies in patients with metastatic pure seminoma who had radiographically defined postchemotherapy residual masses were correlated with either the histology of the resected lesion or the clinical outcome documented by computer tomography (CT), tumor markers, and/or physical examination during follow-up. The size of the residual lesions on CT, either >3 cm or < or =3 cm, was correlated with the presence or absence of viable residual tumor., Results: Fifty-six FDG PET scans of 51 patients were assessable. All 19 cases with residual lesions >3 cm and 35 (95%) of 37 with residual lesions < or =3 cm were correctly predicted by FDG PET. The specificity, sensitivity, positive predictive value, and negative predictive value of FDG PET were 100% (95% CI, 92% to 100%), 80% (95% CI, 44% to 95%), 100%, and 96%, respectively, versus 74% (95% CI, 58% to 85%), 70% (95% CI, 34% to 90%), 37%, and 92%, respectively, for CT discrimination of the residual tumor by size (>3 cm/< or =3 cm)., Conclusion: This investigation confirms that FDG PET is the best predictor of viable residual tumor in postchemotherapy seminoma residuals and should be used as a standard tool for clinical decision making in this patient group.

Purpose: Independent prognostic variables for patients undergoing high-dose chemotherapy (HDCT) as salvage modality for germ cell tumors (GCT) were previously described, and a score was created. Patients with more than 2 points had a poor prognosis. However, these data were from patients treated from 1984 to 1993, and most received a single HDCT course. In this study, we evaluated outcomes at Indiana University and determined the applicability of the Beyer score to contemporary poor-risk patients., Patients and Methods: We performed a retrospective analysis of patients who received salvage HDCT between 1988 and 2001 and had at least one of the following characteristics: platinum-refractory or absolutely platinum-refractory GCT, primary mediastinal nonseminomatous GCT (PMNSGCT), human chorionic gonadotropin (HCG) > or = 1,000 mU/mL or alpha-fetoprotein (AFP) > or = 1,000 ng/mL before HDCT. Primary end points were overall and 2-year failure-free survival (FFS)., Results: Eighty patients were identified. Fifty-six were platinum refractory, 23 had a Beyer score greater than 2, and 13 had PMNSGCT. Fifty-six patients received two HDCT courses. HDCT included carboplatin and etoposide. Forty-three patients received HDCT as first salvage modality. Median overall survival was 14.7 months. The 2-year FFS was 32%. No relapses have occurred after 2 years from HDCT. Patients with greater than 2 points in the Beyer score, platinum-refractory patients, and patients with HCG > or = 1,000 mU/mL, AFP > or = 1,000 ng/mL, and PMNSGCT had 2-year FFS of 30%, 37%, 26%, 18%, and 0%, respectively., Conclusion: Results with PMNSGCT remained poor. However, other patients with poor prognosis should not be denied an attempt at curative salvage HDCT.

Purpose: A prospective multicenter trial was initiated to evaluate the role of modern radiotherapy with reduced treatment portals for stage IIA and IIB testicular seminoma., Patients and Methods: Patients with stages IIA/B disease (Royal Marsden classification) were assessable for the trial. Staging comprised computed tomography of the chest, abdomen, and pelvis as well as analysis of tumor markers alpha-fetoprotein and beta human chorionic gonadotropin. Linac-based radiotherapy was delivered to para-aortic and high ipsilateral iliac lymph nodes. The total doses were 30 Gy for stage IIA and 36 Gy for stage IIB disease., Results: Between April 1991 and March 1994, 94 patients were enrolled for the trial by 30 participating centers throughout Germany. Seven patients were lost to follow-up. Median time to follow-up of 87 assessable patients was 70 months. There were 66 stage IIA and 21 stage IIB patients. One mediastinal and one field-edge relapse were observed in the stage IIA group. In the stage IIB group, there was one mediastinal and one mediastinal/pulmonary relapse. All patients were treated with a salvage regimen of platinum-based chemotherapy. Actuarial relapse-free survival at 6 years was 95.3% (95% confidence interval [CI], 88.9% to 100%) and 88.9% (95% CI, 74.4% to 100%) for stage IIA and IIB groups, respectively. Maximum acute side effects were 8% grade 3 nausea for stage IIA and 10% grade 3 nausea and diarrhea for stage IIB groups. No late toxicity was observed., Conclusion: Radiotherapy for stages IIA/B seminoma with reduced portals yields excellent tumor control at a low rate of acute toxicity and no late toxicity, which supports the role of radiotherapy as the first treatment choice for these patients.

Purpose: Despite great success in the treatment of disseminated germ cell tumors, 20% of patients are incurable and become candidates for investigational therapy. Paclitaxel and gemcitabine have shown activity as single agents in refractory germ cell tumors and can be combined with manageable toxicity., Patients and Methods: Patients with germ cell tumors believed to be incurable with chemotherapy or surgery were treated with paclitaxel 110 mg/m(2) and gemcitabine 1,000 mg/m(2) intravenously on days 1, 8, and 15 of a 4-week cycle for a maximum of six cycles. Patients were evaluated for response and toxicity., Results: Twenty-eight of 30 enrolled patients were assessable. Toxicity was primarily hematologic but was manageable with only a single case of neutropenic fever. Six (21.4%) of 28 patients responded, including three complete responses. Two of the complete responders were continuously disease-free at 15+ and 25+ months., Conclusion: Paclitaxel plus gemcitabine is an active regimen in refractory germ cell tumors, with an acceptable toxicity profile. This regimen has the possibility for long-term disease-free survival in this refractory patient population.

Purpose: We describe the response to conventional or high-dose salvage chemotherapy in patients with advanced seminoma who experience disease progression after receiving first-line platinum-based treatment., Patients and Methods: Twenty-seven patients with progressive, advanced, pure seminoma were treated with salvage chemotherapy. Fifteen patients were treated with conventional-dose cisplatin-and-ifosfamide combination chemotherapy. Twelve patients were treated with high-dose chemotherapy followed by autologous stem-cell rescue., Results: Fifteen patients (56%) achieved a complete response (CR), nine achieved CR with a conventional-dose cisplatin and ifosfamide program, and six experienced CR after high-dose chemotherapy. Fourteen patients (52%) are alive and disease-free, with 13 (48%) continuously disease-free at a median follow-up of 72 months. Twelve (57%) of 21 patients whose pretreatment tumors were studied morphologically were found to have seminoma with atypia. Eight patients underwent resection after salvage chemotherapy; six with histologic findings of necrotic debris/fibrosis alone are alive and disease-free at last follow-up. Both patients with viable seminoma found at surgery died of disease., Conclusion: Most patients with advanced seminoma are cured with standard first-line programs of cisplatin and etoposide with or without bleomycin. A small minority of patients with pure seminoma have resistant tumors and require salvage chemotherapy. In this setting, approximately 50% of patients with recurrent pure seminoma achieve durable CR with conventional or high-dose salvage chemotherapy. Identification of biologic markers to predict clinical outcome and an enhanced understanding of the basic biologic features of seminoma may lead to improvements in the management of this disease.

Purpose: To establish the predictive potential of 2-18fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) for detecting viable tumor tissue in residual postchemotherapy masses of seminoma patients., Patients and Methods: In this prospective multicenter trial, results of FDG PET studies in seminoma patients with postchemotherapy masses > or = 1 cm were correlated with either the histology of the resected lesion or the clinical outcome on follow-up without resection. Negative PET scans of residual lesions that were devoid of viable tumor tissue on resection or disappeared, shrunk, or remained stable in size for at least 2 years were rated as true-negative (TN). Positive scans without histologic or clinical evidence of tumor tissue were classified as false-positive. In patients with histologically positive or progressive lesions, positive PET scans were defined as true-positive (TP) and negative scans, false-negative (FN)., Results: Thirty-seven PET scans of 33 patients were assessable at a median follow-up time of 23 months (range, 2 to 46 months). Histologic data were available from nine patients who had undergone resection. Twenty-eight patients were followed-up clinically and radiologically. Twenty-eight scans were TN, eight were TP, and one was FN. All 14 residual lesions more than 3 cm and 22 (96%) of the 23 < or = 3 cm were correctly predicted by FDG PET. The specificity (100%; 95% confidence interval [CI], 87.7% to 100%), sensitivity (89%; 95% CI, 51.7% to 99.7%), positive predictive value (100%), and the negative predictive value (97%) of FDG PET were superior to data obtained by assessing residual tumor size (< or = or > 3 cm)., Conclusion: FDG PET is a clinically useful predictor of viable tumor in postchemotherapy residuals of pure seminoma, especially those greater than 3 cm.

Purpose: To test the equivalence of three versus four cycles of bleomycin, etoposide, and cisplatin (BEP) and of the 5-day schedule versus 3 days per cycle in good-prognosis germ cell cancer., Patients and Methods: The study was designed as a 2 x 2 factorial trial. The aim was to rule out a 5% decrease in the 2-year progression-free survival (PFS) rate. The study included the assessment of patient quality of life. A cycle of BEP consisted of etoposide 500 mg/m(2), administered at either 100 mg/m(2) days 1 through 5 or 165 mg/m(2) days 1 through 3, cisplatin 100 mg/m(2), administered at either 20 mg/m(2) days 1 through 5 or 50 mg/m(2) days 1 and 2. Bleomycin 30 mg was administered on days 1, 8, and 15 during cycles 1 through 3. The randomization procedure allowed some investigators to participate only in the comparison of three versus four cycles., Results: From March 1995 until April 1998, 812 patients were randomly assigned to receive three or four cycles: of these, 681 were also randomly assigned to the 5-day or the 3-day schedule. Histology, marker values, and disease extent are well balanced in the treatment arms of the two comparisons. The projected 2-year PFS is 90.4% on three cycles and 89.4% on four cycles. The difference in PFS between three and four cycles is -1.0% (80% confidence limit [CL], -3.8%, +1.8%). Equivalence for three versus four cycles is claimed because both the upper and lower bounds of the 80% CL are less than 5%. In the 5- versus 3-day comparison, the projected 2-year PFS is 88.8% and 89.7%, respectively (difference, -0.9%, (80% CL, -4.1%, +2.2%). Hence, equivalence is claimed in this comparison also. Frequencies of hematologic and nonhematologic toxicities were essentially similar. Quality of life was maintained better in patients receiving three cycles; no differences were detected between 3 and 5 days of treatment., Conclusion: We conclude that three cycles of BEP, with etoposide at 500 mg/m(2), is sufficient therapy in good-prognosis germ cell cancer and that the administration of the chemotherapy in 3 days has no detrimental effect on the effectiveness of the BEP regimen.

Purpose: During the past 30 years, radiation therapy with 28 to 30 Gy for para-aortic and ipsilateral iliac node areas was the standard adjuvant treatment for clinical stage I seminoma after orchiectomy. However, late effects of radiotherapy prompted a search for alternative adjuvant treatment approaches, including surveillance and application of carboplatin. In this retrospective analysis, we evaluated the efficacy and toxicity of two adjuvant single-agent carboplatin courses in 107 patients who were diagnosed with clinical stage I seminoma at our study centers between 1988 and 1999., Patients and Methods: All 107 patients (median age, 39 years; range, 24 to 63 years) received two postoperative adjuvant cycles of carboplatin (400 mg/m(2)). The pathologic tumor stage was pT1 in 84 patients, pT2 in 18 patients, and pT3 in five patients. Whole blood count and serum chemistry were evaluated weekly during treatment to assess hematologic and nonhematologic toxicity., Results: Six patients died from tumor-unrelated causes. The remaining 101 patients are currently alive and free of disease after a median follow-up of 74 months (range, 5 to 145 months). A detailed analysis of hematologic toxicity showed only World Health Organization (WHO) grade 1 leukocytopenia in 10.7% of all cycles and WHO grade 2 leukocytopenia in 2.1% of all cycles., Conclusion: Regarding the absence of tumor recurrences in our retrospective analysis and the favorable toxicity profile with no episodes of long-term toxicity, we suggest that two adjuvant courses of single-agent carboplatin for clinical stage I seminoma patients might be equivalent to radiotherapy.

Purpose: To assess the role of high-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer., Patients and Methods: From August 1992 to April 1998, 65 patients with testicular cancer were treated with high-dose carboplatin and etoposide followed by peripheral-blood stem-cell transplantation or autologous bone marrow transplantation rescue as initial salvage chemotherapy at Indiana University. An identical course was given after hematopoietic reconstitution. Postchemotherapy resection of residual disease was performed in selected patients with incomplete radiographic response associated with normalization of markers. The median follow-up was 39 months (range, 16 to 91 months)., Results: Thirty-seven (57%) of the 65 patients are continuously disease-free. Three additional patients are disease-free with subsequent surgery. High-dose chemotherapy was associated with significant morbidity but no treatment-related mortality., Conclusion: High-dose chemotherapy as initial salvage chemotherapy achieved impressive long-term survival with acceptable toxicity in patients with relapsed testicular cancer.

Purpose: To assess the ability of positron emission tomography (PET) scans in differentiating between necrosis and viable seminoma in postchemotherapy (PC) residual disease., Patients and Methods: We conducted a prospective study of 29 patients with seminoma at Indiana University. All patients had PC residual disease. Computed tomography and PET scans were performed for 19 patients after primary chemotherapy (group A) and for 10 patients after salvage chemotherapy (group B)., Results: In group A, the PC masses were >/= 3 cm in 14 patients, less than 3 cm in three patients, and not quantified in two patients. All of the patients in group A had negative PET scan results and have had stable or decreasing residual mass size (median follow-up duration, 11.5 months; range, 6 to 26 months). In group B, the PC masses were >/= 3 cm in four patients, less than 3 cm in five patients, and not quantified in one patient. One patient had a positive PET scan result for a posterior mediastinal mass. Pathologic diagnosis of the PET-positive mass showed only necrotic tissue. The same patient had a negative PET scan of the retroperitoneal mass but relapsed in that area. Overall, of patients in group B, five have stable or decreasing mass (median follow-up duration, 8 months; range, 7 to 22 months), and five had relapsed disease., Conclusion: PET scans have no apparent benefit in PC evaluation of residual masses in bulky seminoma.

Purpose: This study sought to determine factors that predict response to chemotherapy for patients with advanced germ cell tumors (GCTs), to evaluate different methods by which serum tumor markers can be used to predict response independent of assay method, and to develop criteria to guide allocation to clinical trials., Methods: Pretreatment data from 796 patients treated with platinum-based chemotherapy on Memorial Hospital protocols from 1975 to 1990 were analyzed. Multivariate analyses were performed on a developmental data set (n = 597) to assess for independently significant predictors of response. Predictive models developed using these methods were confirmed on the validation set (n = 199)., Results: Independently significant factors for response included a mediastinal primary tumor (.015), pure seminomatous histology (.002), metastases to nonpulmonary visceral sites (bone, liver, and brain; .0001), and the pretreatment values of lactate dehydrogenase (LDH; .0001) and human chorionic gonadotropin (HCG; .0001). The likelihood of complete response (CR) was increased by seminomatous histology and decreased by the other factors. Serum levels of HCG and LDH could predict outcome independent of assay methodology. A model to predict good-, intermediate-, and poor-risk categories with CR rates of 92%, 76%, and 39%, respectively, was developed., Conclusion: The independent prognostic factors of serum tumor markers LDH and HCG, the sites of metastases, and the primary origin of GCTs can predict outcome in patients with advanced GCT. These factors should be considered in the allocation of patients with advanced disease to clinical trials and have been included in the new tumor-node-metastasis (TNM) staging systems developed for the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC).

Purpose: To assess the results of treatment, patterns of failure, and prognostic factors for relapse in a contemporary cohort of patients with stage II seminoma., Materials and Methods: From January 1981 and December 1993, 99 patients (median age, 35 years) with stage II seminoma (IIA, 41; IIB, 28; IIC, 24; IID, six) were managed at our institution. Eighty were treated with radiation therapy (RT) and 19 with chemotherapy (ChT)., Results: With a median follow-up of 6.7 years, the five-year overall actuarial survival was 94%, the 5-year cause-specific survival was 94%, and the 5-year relapse-free rate was 83%. Sixteen (20%) of the 80 patients treated with RT relapsed (median time to relapse, 9 months). Relapse occurred outside the irradiated area in all but two patients. Distant relapse sites included the supraclavicular fossa, bone (four patients, three with spinal cord compression), and lung/mediastinum. All 19 patients treated primarily with ChT achieved disease control and none has relapsed. The relapse rate at 5 years for patients with stage IIA to IIB was 11% (seven of 64), and 56% (nine of 16) for those with stage IIC to IID disease (P < .0001). No patient with IIC or IID disease treated with ChT relapsed as compared with 56% of patients treated with RT (0 of 14 v nine of 16, P = .002)., Conclusion: Radiation therapy is highly effective in patients with stage IIA or IIB seminoma (89% were relapse free). In stage IIC or IID disease, although local control with RT is excellent, a 50% risk of distant relapse is unacceptable, and not all patients who relapse can be salvaged. Chemotherapy should clearly be the primary treatment in patients with stage IIC or IID seminoma.

Purpose: Salvage therapy for disseminated germ cell tumors of all histologic subtypes with vinblastine, ifosfamide, and cisplatin (VeIP) will cure approximately 25% of patients. The purpose of this study was to evaluate the activity of VeIP in patients with recurrent seminoma., Patients and Methods: We conducted a retrospective review of 24 patients with recurrent seminoma who were treated at Indiana University with VeIP as second-line chemotherapy. All patients had received cisplatin-containing regimens as primary chemotherapy and seven had also received prior pelvic radiotherapy. All patients received four courses of VeIP., Results: The minimum follow-up duration was 2 years (range, 2 to 9.1), with a median follow-up time of 7 years. Twenty of 24 patients (83%) achieved a complete remission (CR) following VeIP alone. One additional patient was rendered disease-free (NED) with the resection of residual carcinoma. Eight patients have relapsed. Four of six patients with extragonadal primary tumors and two of four who failed to achieve CR with initial chemotherapy are continuously NED with VeIP. Overall, 13 of 24 (54%) are long-term survivors with VeIP salvage chemotherapy., Conclusion: VeIP has significant curative potential in patients with recurrent seminoma and appears to produce a higher CR rate and more long-term survivors than is achieved in patients with nonseminomatous disease.

Purpose: Guidelines for management of postchemotherapy residual mass in patients with advanced seminoma remain controversial. We sought to characterize independent prognostic factor(s) for persistence of tumor to identify patients with a high risk of residual carcinoma., Patients and Methods: One hundred four patients with advanced seminoma were assessed. All had achieved a complete response or partial response with normal markers to induction cisplatin-based chemotherapy and had radiographs available for review. Selected prechemotherapy and postchemotherapy characteristics were compared for patients who had either germ cell tumor histology at surgery or relapsed at the assessed site (defined as site failure) versus those who had only necrosis or fibrosis found at surgery and did not relapse at the assessed site (defined as site nonfailure)., Results: At a median follow-up time of 47 months (range, 5 to 153), 94 patients (90%) were designated as site nonfailures and 10 (10%) as site failures. Site failure correlated only with size of the residual mass (< 3 cm or normal v > or = 3 cm; P = .0006). Two of 74 patients (3%) with residual masses less than 3 cm were considered site failures, compared with eight of 30 (27%) with residual masses > or = 3 cm., Conclusion: Patients with advanced seminoma who have normal radiographs or residual masses less than 3 cm after chemotherapy can be observed without further intervention. The following three options exist for patients with a residual mass > or = 3 cm: observation, radiotherapy, or surgical intervention. We prefer the latter to define response, resect viable tumor when possible, and direct further treatment.

Purpose: To assess the ability of gallium scans to determine whether residual masses consist of viable tumor or necrotic fibrous tissue after chemotherapy for seminoma., Patients and Methods: Thirty-two patients were enrolled and 27 were assessable. Patients receiving first-line or salvage chemotherapy had gallium scans performed during their first and last scheduled course of chemotherapy and results were compared with restaging computed tomographic (CT) scans and subsequent clinical outcome., Results: Of 27 assessable patients, 22 received first-line chemotherapy (group A) and five salvage chemotherapy (group B). Eight patients were not gallium-avid before chemotherapy despite obvious clinical and radiographic evidence of metastatic seminoma. Eighteen of 19 gallium-positive patients had a persistent mass postchemotherapy on abdominal CT. Of 16 patients in group A whose tumors were gallium-avid, all 16 had normalized gallium scans after chemotherapy. However, two of these 16 patients recurred in their original disease site. In group B, there were three patients with gallium-avid tumors and all three had normalized scans postchemotherapy. Two patients who were not gallium-avid (one each in group A and B) also developed recurrent disease. Twenty-four of 27 patients are alive with no evidence of active disease at a median follow-up time of 18 months, including 20 with more than 1 year of follow-up data., Conclusion: Eight of 27 patients had false-negative gallium scans at the time of diagnosis. All nineteen gallium scans that were initially positive reverted to normal after chemotherapy. Two of 19 patients' follow-up gallium scans were false-negative. We therefore feel that gallium scans have minimal value in the prechemotherapy or postchemotherapy evaluation of metastatic seminoma.

Purpose: To determine how men infected with the human immunodeficiency virus (HIV) tolerate and respond to treatment for malignant germ cell tumors (GCTs), and how GCT histology and stage compare among HIV-infected versus non-HIV-infected men., Patients and Methods: Two hundred ninety-four cases of GCT diagnosed or treated from 1980 to 1993 were reviewed. Nine new cases among HIV-infected men were identified; these were analyzed together with six cases previously reported from our institution., Results: Low-stage tumors (stages I and IIA) comprised 67% of HIV-infected and 63% of non-HIV-infected cases. Sixty-seven percent of HIV-infected cases were seminomas versus 51% of non-HIV-infected cases. Ten patients had AIDS at the time of GCT diagnosis. Five patients underwent radiation therapy and one patient underwent retroperitoneal lymphadenectomy without complications. Seven patients received chemotherapy with four cycles of cisplatin, etoposide, and bleomycin (PEB) or cisplatin, vinblastine, and bleomycin (PVB) without excess cytopenias or new opportunistic infections. Of seven patients treated for advanced disease, there were five complete and two partial responses. Six patients have died of AIDS at a median of 20 months after diagnosis of GCT. The median follow-up time for surviving patients has been 42 months (range, 8 to 87) and all but one remain without evidence of active disease. In no case was a patient's HIV disease classification altered by antitumor therapy., Conclusion: The natural history of GCTs is comparable in HIV-infected and non-HIV-infected men and standard therapy including orchiectomy, retroperitoneal lymph node dissection, radiation therapy, and chemotherapy is well tolerated.

Purpose: This prospective, randomized trial was designed to determine if three cycles of cisplatin plus etoposide (PVP16) can produce therapeutic results comparable to three cycles of cisplatin, etoposide, and bleomycin (PVP16B) in patients with disseminated germ cell tumors., Patients and Methods: One hundred seventy-eight patients with minimal- or moderate-stage disease (Indiana staging system) were randomized to receive cisplatin (20 mg/m2 on days 1 to 5) plus etoposide (100 mg/m2 on days 1 to 5) with or without weekly bleomycin (30 IU/wk for 9 consecutive weeks). Following three cycles of chemotherapy over 9 weeks, patients with residual radiographic disease underwent surgical resection. If persistent carcinoma was noted, two additional 3-week courses of chemotherapy were administered., Results: One hundred seventy-one patients were fully assessable for response and survival. The two treatment groups were similar with respect to patient characteristics. The toxicities were comparable between the two arms. No clinically significant incidence of pulmonary toxicity occurred with PVP16B. Overall, 81 of 86 patients (94%) who received PVP16B and 75 of 85 patients (88%) who received PVP16 achieved a disease-free status with chemotherapy and/or surgery. However, greater numbers of treatment failures, including persistent carcinoma in postchemotherapy resected residual disease and relapses from complete remission, occurred on the arm without bleomycin (overall adverse outcome, P = .004). The failure-free (86% v 69%; P = .01) and overall survival (95% v 86%; P = .01) rates were inferior on the PVP16 arm., Conclusion: Bleomycin is an essential component of PVP16B therapy in patients who receive three cycles of treatment for minimal- or moderate-stage disseminated germ cell tumors.

Purpose: To investigate the efficacy of chemotherapy and to assess the relationship between selected pretreatment characteristics and survival in patients with advanced seminoma., Patients and Methods: One hundred forty-two patients with advanced seminoma treated with platinum-based chemotherapy were the subject of this study. Treatment regimens included cisplatin, vinblastine, bleomycin, cyclophosphamide, and dactinomycin (VAB-6) (45 patients), a six-cycle regimen of VAB-6 alternating with etoposide and cisplatin (two patients), cisplatin and etoposide (60 patients), and etoposide and carboplatin (35 patients)., Results: One hundred thirty of 140 (93%) assessable patients treated with platinum-based therapy achieved a favorable response (complete response or a partial response with negative serum tumor markers). One hundred twenty-five patients (88%) are alive and 120 (86%) remain progression-free at a median follow-up duration of 43 months. Fifty-seven of 60 patients (95%) who were treated with cisplatin and etoposide achieved a favorable response; 55 (92%) remain progression-free. The relative risks of death or of an event (death or relapse) related to human chorionic gonadotropin (HCG) elevation were 1.8 (P = .04) and 1.96 (P = .001), respectively. The relative risks of death or of an event associated with lactate dehydrogenase (LDH) elevation were 2.6 (P = .05) and 2.7 (P = .02), respectively. All 19 patients with a mediastinal primary tumor site achieved a complete response, and 18 of 19 (95%) remain progression-free., Conclusion: Four cycles of cisplatin and etoposide is highly effective therapy for seminoma and is the standard therapy at our center. Elevation of the serum markers HCG and LDH were of prognostic significance, while an extragonadal primary tumor site was not associated with an adverse prognosis. Studies of tumor biology, including genetic analysis, are ongoing to determine other parameters that may correlate with response and survival.