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      The 111 Study: A Single-arm, Phase 3 Trial Evaluating One Cycle of Bleomycin, Etoposide, and Cisplatin as Adjuvant Chemotherapy in High-risk, Stage 1 Nonseminomatous or Combined Germ Cell Tumours of the Testis

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          Standard management in the UK for high-risk stage 1 nonseminoma germ cell tumours of the testis (NSGCTT) is two cycles of adjuvant bleomycin, etoposide (360 mg/m 2), and cisplatin (BE 360P) chemotherapy, or surveillance.


          To test whether one cycle of BE 500P achieves similar recurrence rates to two cycles of BE 360P.

          Design, setting, and participants

          A total of 246 patients with vascular invasion–positive stage 1 NSGCTT or combined seminoma + NSGCTT were centrally registered in a single-arm prospective study.


          One cycle comprising bleomycin 30000 IU on days 1, 8, and 15, etoposide 165 mg/m 2 on days 1–3, and cisplatin 50 mg/m 2 on days 1–2, plus antibacterial and granulocyte colony stimulating factor prophylaxis.

          Outcome measurements and statistical analysis

          The primary endpoint was 2-yr malignant recurrence (MR); the aim was to exclude a rate of ≥5%. Participants had regular imaging and tumour marker (TM) assessment for 5 yr.

          Results and limitations

          The median follow-up was 49 mo (interquartile range 37–60). Ten patients with rising TMs at baseline were excluded. Four patients had MR at 6, 7, 13, and 27 mo; all received second-line chemotherapy and surgery and three remained recurrence-free at 5 yr. The 2-yr MR rate was 1.3% (95% confidence interval 0.3–3.7%). Three patients developed nonmalignant recurrences with localised teratoma differentiated, rendered disease-free after surgery. Grade 3–4 febrile neutropenia occurred in 6.8% of participants.


          BE 500P is safe and the 2-yr MR rate is consistent with that seen following two BE 360P cycles. The 111 study is the largest prospective trial investigating one cycle of adjuvant BE 500P in high-risk stage 1 NSGCTT. Adoption of one cycle of BE 500P as standard would reduce overall exposure to chemotherapy in this young population.

          Patient summary

          Removing the testicle fails to cure many patients with high-risk primary testicular cancer since undetectable cancers are often present elsewhere. A standard additional treatment in Europe is two cycles of chemotherapy to eradicate these. This trial shows one cycle has few adverse effects and comparable outcomes to those seen with two cycles.

          Take Home Message

          The 111 trial aimed to exclude a 2-yr recurrence rate of >5% with adjuvant one cycle of bleomycin, etoposide (500 mg/m2), and cisplatin (BE500Px1) in stage 1, high-risk nonseminomatous germ cell testis tumours. This was achieved, with 1.3% malignant recurrences among 236 cases. BE500Px1 should replace BE360Px2 as standard care for such patients.

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          Most cited references 30

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          International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group.

          Cisplatin-containing chemotherapy has dramatically improved the outlook for patients with metastatic germ cell tumors (GCT), and overall cure rates now exceed 80%. To make appropriate risk-based decisions about therapy and to facilitate collaborative trials, a simple prognostic factor-based staging classification is required. Collaborative groups from 10 countries provided clinical data on patients with metastatic GCT treated with cisplatin-containing chemotherapy. Multivariate analyses of prognostic factors for progression and survival were performed and models were validated on an independent data set. Data were available on 5,202 patients with nonseminomatous GCT (NSGCT) and 660 patients with seminoma. Median follow-up time was 5 years. For NSGCT the following independent adverse factors were identified: mediastinal primary site; degree of elevation of alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG), and lactic dehydrogenase (LDH); and presence of nonpulmonary visceral metastases (NPVM), such as liver, bone, and brain. For seminoma, the predominant adverse feature was the presence of NPVM. Integration of these factors produced the following groupings: good prognosis, comprising 60% of GCT with a 91% (89% to 93%) 5-year survival rate; intermediate prognosis, comprising 26% of GCT with a 79% (75% to 83%) 5-year survival rate; and poor prognosis, comprising 14% of GCT (all with NSGCT) with a 48% (42% to 54%) 5-year survival rate. An easily applicable, clinically based, prognostic classification for GCT has been agreed on between all the major clinical trial groups who are presently active worldwide. This should be used in clinical practice and in the design and reporting of clinical trials to aid international collaboration and understanding.
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            Maintaining success, reducing treatment burden, focusing on survivorship: highlights from the third European consensus conference on diagnosis and treatment of germ-cell cancer

            In November 2011, the Third European Consensus Conference on Diagnosis and Treatment of Germ-Cell Cancer (GCC) was held in Berlin, Germany. This third conference followed similar meetings in 2003 (Essen, Germany) and 2006 (Amsterdam, The Netherlands) [Schmoll H-J, Souchon R, Krege S et al. European consensus on diagnosis and treatment of germ-cell cancer: a report of the European Germ-Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377–1399; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part I. Eur Urol 2008; 53: 478–496; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part II. Eur Urol 2008; 53: 497–513]. A panel of 56 of 60 invited GCC experts from all across Europe discussed all aspects on diagnosis and treatment of GCC, with a particular focus on acute and late toxic effects as well as on survivorship issues. The panel consisted of oncologists, urologic surgeons, radiooncologists, pathologists and basic scientists, who are all actively involved in care of GCC patients. Panelists were chosen based on the publication activity in recent years. Before the meeting, panelists were asked to review the literature published since 2006 in 20 major areas concerning all aspects of diagnosis, treatment and follow-up of GCC patients, and to prepare an updated version of the previous recommendations to be discussed at the conference. In addition, ∼50 E-vote questions were drafted and presented at the conference to address the most controversial areas for a poll of expert opinions. Here, we present the main recommendations and controversies of this meeting. The votes of the panelists are added as online supplements.
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              Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas.

              The role of prophylactic antibacterial agents after chemotherapy remains controversial. We conducted a randomized, double-blind, placebo-controlled trial in patients who were receiving cyclic chemotherapy for solid tumors or lymphoma and who were at risk for temporary, severe neutropenia (fewer than 500 neutrophils per cubic millimeter). Patients were randomly assigned to receive either 500 mg of levofloxacin once daily or matching placebo for seven days during the expected neutropenic period. The primary outcome was the incidence of clinically documented febrile episodes (temperature of more than 38 degrees C) attributed to infection. Secondary outcomes included the incidence of all probable infections, severe infections, and hospitalization but did not include a systematic evaluation of antibacterial resistance. A total of 1565 patients underwent randomization (784 to placebo and 781 to levofloxacin). The tumors included breast cancer (35.4 percent), lung cancer (22.5 percent), testicular cancer (14.4 percent), and lymphoma (12.8 percent). During the first cycle of chemotherapy, 3.5 percent of patients in the levofloxacin group had at least one febrile episode, as compared with 7.9 percent in the placebo group (P<0.001). During the entire chemotherapy course, 10.8 percent of patients in the levofloxacin group had at least one febrile episode, as compared with 15.2 percent of patients in the placebo group (P=0.01); the respective rates of probable infection were 34.2 percent and 41.5 percent (P=0.004). Hospitalization was required for the treatment of infection in 15.7 percent of patients in the levofloxacin group and 21.6 percent of patients in the placebo group (P=0.004). The respective rate of severe infection was 1.0 percent and 2.0 percent (P=0.15), with four infection-related deaths in each group. An organism was isolated in 9.2 percent of probable infections. Among patients receiving chemotherapy for solid tumors or lymphoma, the prophylactic use of levofloxacin reduces the incidence of fever, probable infection, and hospitalization. Copyright 2005 Massachusetts Medical Society.

                Author and article information

                Eur Urol
                Eur. Urol
                European Urology
                Elsevier Science
                1 March 2020
                March 2020
                : 77
                : 3
                : 344-351
                [a ]University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
                [b ]The Institute Of Cancer Research, London, UK
                [c ]The Royal Marsden NHS Foundation Trust, London, UK
                [d ]The Leeds Teaching Hospitals NHS Trust, Leeds, UK
                [e ]Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK
                [f ]Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
                [g ]Barts Health NHS Trust, London, UK
                [h ]University Hospital Southampton NHS Foundation Trust, Southampton, UK
                [i ]Beatson West of Scotland Cancer Centre, NHS Greater Glasgow and Clyde, Glasgow, UK
                Author notes
                [* ]Corresponding author. The Institute of Cancer Research, London SM2 5NG, UK. Tel. +44 20 86613425. robert.huddart@ 123456icr.ac.uk

                Joint first authors.


                Chief investigator.

                © 2019 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).



                testicular cancer, nsgctt, surveillance, chemotherapy, bep, phase iii trial, adjuvant therapy


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