Originally published as JCO Early Release 10.1200/JCO.2007.12.0899 on May 5 2008

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

Peter Albers, Roswitha Siener, Susanne Krege, Hans-Uwe Schmelz, Klaus-Peter Dieckmann, Axel Heidenreich, Peter Kwasny, Maik Pechoel, Jan Lehmann, Sabine Kliesch, Kai-Uwe Köhrmann, Rolf Fimmers, Lothar Weiβbach, Volker Loy, Christian Wittekind, Michael Hartmann

From the Department of Urology, Klinikum Kassel GmbH, Kassel; Department of Urology, Bonn University; Institute of Medical Biometry, Informatics and Epidemiology, Bonn University, Bonn; Department of Urology, Essen University, Essen; Department of Urology, Military Hospital Ulm, Ulm; Department of Urology, Albertinen Hospital; Department of Urology, Military Hospital Hamburg, Hamburg; Department of Urology, Cologne University, Cologne; Department of Urology, Städtisches Klinikum Dortmund; Department of Urology, Greifswald University; Department of Urology, Homburg University; Department of Urology, Münster University; Department of Urology, Theresien Hospital, Mannheim; Division of Urology, Euromed Clinic, Fürth; Institute of Pathology, Vivantes Klinikum Berlin; and the Institute of Pathology, Leipzig University, Leipzig, Germany

Corresponding author: Peter Albers, MD, Department of Urology, Düsseldorf University, Moorenstr 5, D-40225 Düsseldorf, Germany; e-mail: sekurol{at}uni-duesseldorf.de

	ABSTRACT

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Purpose Retroperitoneal lymph node dissection (RPLND) and adjuvant chemotherapy are two adjuvant treatment options for patients with clinical stage I nonseminomatous germ cell tumors of the testis (NSGCT). Aim of this trial was to prove the advantage of one cycle of bleomycin, etoposide, and cisplatin (BEP) chemotherapy compared with RPLND in terms of recurrence.

Patients and Methods Between 1996 and 2005, 382 patients were randomly assigned to receive either RPLND (n = 191) or one course of BEP (n = 191) after orchidectomy. The primary study end point was the rate of recurrence. The trial was powered to detect a 7% reduction (from 10% to 3%) of recurrence with chemotherapy compared with surgery.

Results After a median follow-up of 4.7 years, two and 15 recurrences were observed in the intention-to-treat population with chemotherapy and surgery, respectively (P = .0011). The difference in the 2-year recurrence-free survival rate between chemotherapy (99.46%; 95% CI, 96.20% to 99.92%) and surgery (91.87%; 95% CI, 86.87% to 95.02%) was 7.59% (95% CI, 3.13% to 12.05%). The hazard ratio to experience a tumor recurrence with surgery as opposed to chemotherapy was 7.937 (95% CI, 1.808 to 34.48).

Conclusion To our knowledge, this is the largest randomized trial investigating adjuvant treatment strategies in clinical stage I NSGCT, which showed the superiority of one course BEP over RPLND performed according to community standards to prevent recurrence. Although not standard treatment, one course of BEP is active in an unselected group of patients with clinical stage I disease and merits further investigation.

	INTRODUCTION

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In young men, testicular germ cell tumors are the most frequent solid malignancies. At the time of diagnosis, 70% to 78% of patients are clinically stage I using current staging methods.^1-3 Nonseminomatous germ cell tumors of the testis (NSGCT) account for 42% of cases.² After orchidectomy, 30% of patients with stage I NSGCT relapse during active surveillance.^4-6 Retroperitoneal lymph node dissection (RPLND) and chemotherapy with two cycles of bleomycin, etoposide, and cisplatin (BEP) have been introduced as adjuvant treatment options for micrometastatic disease reducing the risk of relapse to 8% and 2%, respectively.^7,8 The cancer-specific survival of surveillance, adjuvant chemotherapy, or RPLND is close to 99%.⁹ The disadvantage of adjuvant treatment strategies is the considerably high number of patients with overtreatment. Adjuvant RPLND harbors surgical morbidity such as intra- and postoperative complications and loss of antegrade ejaculation.^10,11 Adverse effects of adjuvant chemotherapy include acute toxicity (alopecia, neutropenia, temporarily reduced fertility) and potentially dose-dependent long-term complications like secondary malignancies,^12,13 cardiovascular toxicity,^14,15 and depression.¹⁶ In order to reduce acute and long-term toxicities, risk factors of recurrence have been identified, systematically reviewed,^4,17,18 and used to select patients for adjuvant chemotherapeutic treatment.^5,7,19,20 The dose of adjuvant chemotherapy was reduced to one cycle of BEP in order to diminish toxicity.^21-23 The long-term efficacy of one cycle BEP, however, is still unclear. The primary hypothesis of this trial was that one cycle of BEP is efficacious and leads to a lower recurrence rate than RPLND.

	PATIENTS AND METHODS

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Patients
Eligible patients had a histologically confirmed NSGCT after orchidectomy as reported by the local pathologist. Staging investigations by computed tomography (CT) of the chest, abdomen, and pelvis as well as serum tumor markers (alpha-fetoprotein [AFP], β chain of human chorionic gonadotropin [HCG], lactate dehydrogenase [LDH]) to confirm clinical stage I (TNM classification). Patients were not eligible if the CT scan showed lymph nodes larger than 10 mm in the transverse diameter and localized in the ipsilateral template. Treatment had to start fewer than 4 weeks after orchidectomy and directly after random assignment. If for any reason start of treatment was delayed, restaging was recommended. In cases of pathologic stage II after RPLND, two cycles of BEP chemotherapy were applied as adjuvant treatment. Ethical board review approval was obtained for each study center. Each patient gave his informed consent before trial inclusion.

Reference Pathology and Study Design
Participating centers were asked to send paraffin tumor tissue blocks of every patient to the reference pathologists (C.W., V.L.).

This was an open-labeled, randomized trial of two treatment options. Patients were centrally randomly assigned at Bonn University using a telephone-based block randomization pattern by center. Primary end point of the trial was recurrence. Overall survival, cancer-specific survival, and toxicity were secondary end points.

Treatment and Follow-Up
Arm A. One cycle of BEP chemotherapy was administered using following dosages: cisplatin 20 mg/m², days 1 to 5, 60-minute infusion; etoposide 100 mg/m², days 1 to 5, 60-minute infusion; bleomycin 30,000 U, days 1, 8, and 15, bolus infusion.

Arm B. For RPLND, an ipsilateral nerve-sparing approach or at least a modified ipsilateral template dissection was recommended. RPLND was performed as open surgery. In cases of metastasis in the retroperitoneal regions, two cycles of BEP chemotherapy (dosage as described under arm A) were given as 21-day cycles.

Toxicity and adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.²⁴ Patients were observed on an every-other-month basis in the first year, once every 3 months in the second year, and once every 6 months thereafter for a total of 5 years. Follow-up investigations always included physical examination and serum tumor markers (AFP, HCG, LDH). Chest x-ray was performed three times in the first year, two times in the following years. CT scans of the abdomen and pelvis were performed at months 4, 8, 12, and 24. Thereafter ultrasound of the abdomen was recommended.

Definition of Recurrence
Recurrence was defined as any of the following criteria: serum tumor marker elevation after exclusion of false-positive values; progressive lesion with serum tumor marker elevation; or progressive lesion without serum tumor marker elevation, but histological confirmation. Treatment of recurrences was performed according to the recommendations of the principal investigator.

Three cycles of BEP chemotherapy were recommended in cases of progression after pathological stage I after RPLND. Recurrences and treatment of recurrences were closely followed by the data center.

Statistical Analysis
The study was designed to compare the recurrence rates of adjuvant RPLND and adjuvant chemotherapy. The sample size calculation was based on the previously published cumulative recurrence rates for RPLND (10%) and chemotherapy (3%) to achieve a power of 80%.^7,25-27 The comparison was intended to be made by a one-sided log-rank test (level 5%) applied to the time to recurrence. Using these criteria, a total of 180 patients per treatment arm had to be randomly assigned. The test which was finally applied was the more appropriate two-sided log-rank test. Due to the fact that the observed recurrence rates were by far smaller than expected (0.6% v 7.6% for 2-year recurrence-free survival), especially in the chemotherapy group, the risk ratio was much more in favor of the adjuvant chemotherapy than initially assumed. We were able to show the superiority of one of the treatment regimes using the conservative and more appropriate two-sided test strategy. The hazard ratio for recurrence was estimated, assuming proportional hazard in both treatment groups, from the regression parameter (b) of a Cox proportional hazards model with therapy as only factor (hazard ratio = exp(b)). Both intention-to-treat (ITT) and per-protocol analyses were performed. The time-to-event analysis (rate of recurrences) are depicted in Kaplan-Meier curves.

All patients with completed treatment were analyzed for toxicity. Statistical analysis was performed using SPSS version 12.0 (SPSS Inc, Chicago, IL) and SAS version 9.0.

	RESULTS

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Patients’ Characteristics, Treatment, and Follow-Up
Between September 1996, and February 2005, 382 patients from 61 centers throughout Germany (online-only Appendix) were randomly assigned to receive either RPLND (n = 191) or one course of BEP chemotherapy (n = 191; ITT population).

According-to-Protocol Population
After being randomly assigned, 35 patients had to be excluded due to protocol violations. The main protocol violations were changes of treatment (ie, two courses BEP instead of one and surveillance instead of adjuvant chemotherapy in cases of pathologic stage II disease; Fig 1). Thus, the according-to-protocol population consisted of 347 patients (arm A, 1 x BEP: 174; arm B, RPLND: 173).

View larger version (42K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. CONSORT diagram. BEP, bleomycin, etoposide, and cisplatin; RPLND, retroperitoneal lymph node dissection.

Staging Results
The distribution of pathologic stages after RPLND is given in Table 1. Eighty-one point five percent of patients were found to have pathologic stage I. For 329 (94.8%) of 347 patients in the according-to-protocol population, results from reference pathology were available. Pathologic T stage categories including vascular invasion (RPLND, 42.1%; chemotherapy, 41.8%) were evenly distributed between the groups (Table 2). The median time interval between orchidectomy and start of treatment for chemotherapy and RPLND was 26 days (range, 7 to 113) and 28 days (range, 7 to 131), respectively.

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Recurrences in the intention-to-treat population. BEP, bleomycin, etoposide, and cisplatin; RPLND, retroperitoneal lymph node dissection.

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Recurrences in the according-to-protocol population. BEP, bleomycin, etoposide, and cisplatin; RPLND, retroperitoneal lymph node dissection.

Toxicity of Treatment
National Cancer Institute Common Terminology Criteria for Adverse Events grade 4 toxicities have been observed in 2.3% of patients who received one course of BEP (n = 174) and RPLND (n = 173) with additional adjuvant BEP in 32 patients, respectively. Cumulative grade 3 toxicities (events) were reported in 8.7% of patients with surgery; however, most of these events were grade 3 hematologic and nonhematologic toxicities due to the additional two courses of adjuvant BEP in cases of pathologic stage II. Cumulative grade 3 toxicities (events) in patients with one course of BEP were seen in 37.4%; however, most of these events were a short lasting episode of grade 3 leukopenia (n = 37 of 65 events) without clinical complications (Table 3). Neutropenic fever occurred in only four patients with one course BEP.

	DISCUSSION

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Surveillance with a relapse risk of 30%⁵ was not acceptable due to uncertainties in the compliance of patients and noncentralized health care structures. Therefore, a trial was designed to improve the recurrence rate of patients with proactive adjuvant treatment of NSGCT in a community-based setting aimed at covering all regions in Germany.

If adjuvant chemotherapy was efficacious in reducing recurrence rates to the same low rate as already proven in high-risk patients (2%) with less toxicity, it would be an attractive option for patients with clinical stage I disease. At the time the trial was designed, the available data for one cycle of BEP was scarce. There was only one published series of 12 patients with clinical stage I disease.²¹ The relapse rate did not differ from that of two adjuvant chemotherapy cycles. Comparable data were communicated and later published by Spanish and Swiss groups.^22,23

The hypothesis of this trial was that adjuvant chemotherapy with one cycle of BEP might considerably reduce the recurrence rate in patients with clinical stage I NSGCT compared to RPLND.

Accrual and Patients’ Characteristics
Sixty-one centers participated, 12 of which enrolled more than two thirds of the patients. Therefore, the goal of the study to test a change of treatment with a community-based acceptance in community hospitals and not in specialized centers was met. Furthermore, the enrollment mirrors the reality of health care for patients with testis cancer in Germany between 1996 and 2005. Fifteen patients were enrolled with pure seminoma or with rising markers presenting higher stage. In addition, reference pathology yielded data on the risk profile of the patients. As expected, vascular invasion was present in 42% of the tumors in both groups.^20,29

Eight-two percent of patients had pathologic stage I disease. However, within the group of 18% of patients with stage II disease, six of 32 patients had stage IIB and one patient had stage IIC disease at the time of surgery (Table 1). Staging with modern imaging missed only 18% of patients with retroperitoneal disease as opposed to approximately 30% in previous series of the early 1990s.³⁰ In contrast, this trial again demonstrates how important it is to have an expert opinion on imaging studies and an adequate restaging before treatment if the marker decline is prolonged or if other reasons delay treatment in order to safely exclude patients with stage IIB and IIC disease.³¹ Taken together, one course of BEP was given to a population of patients with an approximately 18% chance of retroperitoneal disease at the time of adjuvant treatment and to 42% of patients with high-risk features of the primary tumor.

Of the 382 ITT patients, 174 received one course of BEP and 173 had a RPLND and adjuvant chemotherapy in cases of pathologic stage II disease. The difference between the ITT and the according-to-protocol population (n = 35) was in part due to patients who refused to get two cycles of adjuvant BEP after being diagnosed with pathologic stage II disease at RPLND (n = 8) and patients who have chosen two instead of one cycle of BEP. This demonstrates the reluctance of patients and doctors to accept the decision that was made at the time of random assignment. The main reasons to exclude patients from the ITT population could have potentially biased the ITT results in favor of chemotherapy. However, only two more recurrences in the RPLND arm were seen in the ITT population.

Recurrences
Regarding the according-to-protocol population, after a median of 4.7 years, two relapses have been reported in the group of patients treated with one course of adjuvant BEP as opposed to 13 patients with relapse in the arm treated with RPLND. This was a statistically significant difference in favor of adjuvant chemotherapy (P = .0033) with a hazard ratio of 7.937 (95% CI, 1.808 to 34.48; Fig 3). Although the recurrence rates were lower than expected in both arms, the risk ratio was higher.

All relapses in the RPLND arm occurred within 17 months after surgery, which is in line with previous surgical series.²⁵ Patients who were treated with two adjuvant courses of BEP in cases of pathologic stage II disease did not recur at all, which again is known from the literature.³² Contrary to specialized single center experiences, the rate of relapses in the retroperitoneum (seven of 13) was comparatively high in this community-based study. However, the retroperitoneal relapses were mainly located outside the resected template. Another two relapses occurred in the inguinoscrotal region after orchidectomy. The German group has previously reported the results of RPLND for stage I disease with a 1.2% rate of retroperitoneal recurrence if surgery is performed in tertiary referral centers.¹¹ The results of this trial demonstrate the importance of experienced surgeons and quality control if RPLND is used as a treatment option. Most of the recurrences were detected by marker elevation or abdominal CT.^33-35

In the population treated with one course of adjuvant BEP, only one patient had a relapse with a rising AFP. CT and positron emission tomography scans were negative and it was decided to treat this patient with three courses of BEP chemotherapy instead of waiting for a marker lesion. The second patient with relapse after one course of BEP had a marker negative relapse in the retroperitoneum 5 years after the initial adjuvant treatment with BEP. This relapse was treated by radical retroperitoneal resection. Not surprisingly, histology revealed mature teratoma. Treatment with one course of adjuvant BEP harbors the risk of late relapse. However, this was not reported in the recently published British and Swiss series of 22 and 44 patients, respectively, treated with one course of BEP with a median follow-up of longer than 10 and 8 years, respectively.^36,37 If teratoma relapse occurs, it can be treated by surgery and usually does not lead to a decline in cancer-specific survival. However, CT follow-up longer than 24 months is recommended if chemotherapy is used as adjuvant treatment to detect teratoma relapse and potential long-term adverse effects of chemotherapy. One course of BEP still is an experimental regimen and as for surgery quality differences between community and specialized centers should be considered.

In summary, to our knowledge, this is the largest randomized trial in patients with clinical stage I nonseminomatous germ cell tumors of the testis comparing RPLND with one adjuvant course of BEP chemotherapy which showed a significant reduction in recurrences after a median follow-up of almost 5 years in favor of chemotherapy. Therefore, if adjuvant proactive treatment without risk factor analysis is the desired option, one course of BEP is a possible treatment option compared with RPLND in a community-based setting. In a compliant patient, surveillance even without risk factor analysis has proven to be effective as well.³⁸

In turn, if a risk-adapted strategy is favored to reduce overtreatment, the results of this study should encourage investigators to test the promising approach of one course BEP, instead of two, in the high-risk population of stage I patients in order to further reduce the overall toxicity of treatment for both high-risk and low-risk patients with low stage nonseminomatous testis cancer.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "Urdquo; are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Michael Hartmann, Deutsche Krebshilfe Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Peter Albers, Lothar Weißbach, Michael Hartmann

Financial support: Peter Albers, Michael Hartmann

Administrative support: Peter Albers, Roswitha Siener, Michael Hartmann

Provision of study materials or patients: Peter Albers, Susanne Krege, Hans-Uwe Schmelz, Klaus-Peter Dieckmann, Axel Heidenreich, Peter Kwasny, Maik Pechoel, Jan Lehmann, Sabine Kliesch, Kai-Uwe Köhrmann, Lothar Weißbach, Michael Hartmann

Collection and assembly of data: Peter Albers, Roswitha Siener

Data analysis and interpretation: Peter Albers, Roswitha Siener, Rolf Fimmers, Lothar Weißbach, Michael Hartmann

Manuscript writing: Peter Albers, Roswitha Siener, Michael Hartmann

Final approval of manuscript: Peter Albers, Roswitha Siener, Susanne Krege, Hans-Uwe Schmelz, Klaus-Peter Dieckmann, Axel Heidenreich, Peter Kwasny, Maik Pechoel, Jan Lehmann, Sabine Kliesch, Kai-Uwe Köhrmann, Rolf Fimmers, Lothar Weißbach, Volker Loy, Christian Wittekind, Michael Hartmann

	Appendix

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Participating Centers (number of accrued patients in parentheses):
Bundeswehrkrankenhaus Hamburg (68); Universitätsklinik Essen (26); Bundeswehrkrankenhaus Ulm (22); Albertinen Krankenhaus Hamburg (20); Städtische Kliniken Dortmund (16); Universitätsklinik Bonn (15); Universitätsklinik Marburg (15); Universitätsklinik Greifswald (14); Universitätsklinik Münster (13); Universitätsklinik Mannheim (12); Diakonische Anstalten Dessau (10); Universitätsklinik Homburg/Saar (10); Kliniken der Stadt Köln Hohlweide (9); Universitätsklinik Rostock (8) Klinikum Schwerin (8); Kreiskliniken Aschersleben (7); Urologische Klinik Planegg (7); Allgemeines Krankenhaus Hagen (6); Bundeswehrkrankenhaus Koblenz (6); St Agnes Krankenhaus Bocholt (5); St Elisabeth Krankenhaus Köln (5); Universitätsklinik Köln (5); Kreiskrankenhaus Lüdenscheid (5); Stadtkrankenhaus Minden (5); Universitätsklinik Kiel (4); St Elisabeth Krankenhaus Neuwied (4); Klinikum Potsdam (4); St Hildegardis Krankenhaus Köln (3); Diakonissenkrankenhaus Mannheim (3); Kreiskrankenhaus Mechernich (3) Klinikum Osnabrück (3); Auguste Viktoria Krankenhaus Berlin (2); Universitätsklinik Berlin Charité Campus Benjamin Franklin (2); Städtisches Klinikum Darmstadt (2); St Vincenz Krankenhaus Datteln (2); Klinikum Gera (2); Vincenz Krankenhaus Hannover (2); Universitätsklinik Heidelberg (2); St Elisabeth Krankenhaus Ibbenbüren (2); Städtisches Krankenhaus Kemperhof Koblenz (2); Südharz Krankenhaus Nordhausen (2); Städtisches Krankenhaus Salzgitter (2); Städtisches Krankenhaus Bad Tölz (1); Krankenhaus Friedrichshain Berlin (1); Helios Klinik Blankenhain (1); Zentral Krankenhaus St. Jürgensstraβe Bremen (1); Stadtkrankenhaus Cuxhaven (1); Städtische Kliniken Delmenhorst (1); Urologische Praxis Rulf/Langhorst Erkrath (1); Kliniken Essen-Mitte (1); Städtische Kliniken Frankfurt Höchst (1); Städtisches Klinikum Fulda (1); Universitätsklinik Halle (1); Universitätsklinik Eppendorf Hamburg (1); Marienkrankenhaus Hamburg (1); Theresienkrankenhaus Mannheim (1); Städtisches Krankenhaus Bogenhausen München (1); Herz-Jesu Krankenhaus Münster (1); Evangelisches und Johanniter Klinikum Oberhause (1); Katharinenhospital Stuttgart (1); Universitätsklinik Tübingen (1).

	ACKNOWLEDGMENTS

 
We thank Hans-Joachim Schmoll, MD, Department of Haematology and Oncology, Martin-Luther University, Halle-Wittenberg, Germany, for valuable help in the trial design and promotion of the trial.

	NOTES

 
Supported by Grant No. 70-2074 from the German Cancer Aid (Deutsche Krebshilfe). Randomized trial registration No. 141 German Cancer Society (Deutsche Krebsgesellschaft).

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted April 9, 2007; accepted December 5, 2007.

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