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Originally published as JCO Early Release 10.1200/JCO.2003.09.035 on October 20 2003 © 2003 American Society for Clinical Oncology Long-Term Results of First-Line Sequential High-Dose Etoposide, Ifosfamide, and Cisplatin Chemotherapy Plus Autologous Stem Cell Support for Patients With Advanced Metastatic Germ Cell Cancer: An Extended Phase I/II Study of the German Testicular Cancer Study GroupFrom the Department of Hematology/Oncology, University of Halle, Halle; Department of Internal Medicine, Div. of Hematology/Oncology, University of Tuebingen, Tuebingen; Department of Oncology/Hematology, Klinikum Oldenburg, Oldenburg; Department of Oncology, Westdeutsches Tumorzentrum Essen, Essen; Department of Hematology and Oncology, Hannover Medical School, Hannover; Department of Oncology, Katharinenhospital, Stuttgart; Department of Hematology/Oncology, Charite, Berlin; Department of Hematology/Oncology, University of Marburg, Marburg; Department of Hematology/Oncology, University of Hamburg, Hamburg; Department of Medicine/Hematology and Oncology, University of Muenster, Muenster; Department of Hematology/Oncology, University of Regensburg, Regensburg, Germany. Address reprint requests to H.-J. Schmoll, MD, Department of Hematology/Oncology; University of Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany; e-mail: hans-joachim.schmoll{at}medizin.uni-halle.de.
Purpose: Patients with disseminated germ cell cancer and poor prognosis (International Germ Cell Cancer Collaborative Group [IGCCCG] classification) achieve only a 45% to 50% long-term survival by standard chemotherapy. First-line high-dose chemotherapy might be able to improve the result. This analysis reports toxicity and long-term results of a large phase I/II study of sequential high-dose etoposide, ifosfamide, and cisplatin (VIP) in patients with advanced germ cell tumors. Patients and Methods: Between July 1993 and November 1999, 221 patients with either Indiana "advanced disease" (n = 39) or IGCCCG "poor prognosis" criteria (n = 182) received one cycle of VIP followed by three to four sequential cycles of high-dose VIP chemotherapy plus stem cell support, every 3 weeks, at six consecutive dose levels. Results: Dose limiting toxicity occurred at level 8 (100 mg/m2 cisplatinum, 1750 mg/m2 etoposide, 12 g/m2 ifosfamide) with grade 4 mucositis (three of eight patients), grade 3 CNS toxicity (one of eight patients), grade 4 renal toxicity (one of eight patients), and prolonged granulocytopenia (one of eight patients). After 4-year median follow-up, progression-free survival and disease-specific survival rates in the poor prognosis subgroup were 69% and 79% at 2 years and 68% and 73% at 5 years, with 76% for gonadal/retroperitoneal versus 67% for mediastinal primaries. Severe toxicity included treatment related death (4%), treatment-related acute myeloid leukemia (1%), long-term impared renal function (3%), chronic renal failure (1%), and persistant grade 2–3 neuropathy (5%). Conclusion: Repetitive cycles of high-dose VIP with peripheral stem cell support can be successfully applied in a multicenter setting. Dose level 6 with cisplatin 100 mg/m2, etoposide 1500 mg/m2, and ifosfamide 10 g/m2 is recommended for further investigation in randomized trials. An ongoing randomized trial within the European Organization for Research and Treatment of Cancer evaluates this protocol against four cycles of standard cisplatin, etoposide, and bleomycin.
THE DEVELOPMENT of effective cisplatin-based combination chemotherapy has dramatically improved the prognosis of patients with metastatic germ cell cancer, and today the long-term cure rate is 80% to 90%.1,2 However, patients with metastatic disease fulfilling the "advanced disease" criteria according to the Indiana University classification, or the "poor prognosis" criteria of the more recent International Germ Cell Cancer Collaborative Group (IGCCCG) classification, still achieve survival rates of only 50% to 60% following standard-dose cisplatin–based chemotherapy.3–5 Several attempts have been undertaken to improve the outcome of this patient group, including the use of double-dose cisplatin regimens or alternating dose-dense chemotherapy sequences such as the cisplatin, vincristine, methotrexate, bleomycin/actinomycin, cyclophosphamide, etopside (POMB/ACE) or the bleomycin, vincristine, cisplatin/etoposide, ifosfamide, cisplatin (BOP/VIP) regimen.6–9 In recent years, high-dose chemotherapy followed by autologous peripheral stem cell or autologous bone marrow support (HD-CT/PBSCT) has also been investigated in these patients.10–13 The rationale for the use of HD-CT in patients with germ cell cancer is based on preclinical and clinical data suggesting a dose-response relationship for certain drugs used in the treatment of germ cell cancer, particularly for etoposide and ifosfamide.14,15 Thus far, dose finding studies in the high-dose setting, usually using a combination of carboplatin, etoposide and cyclophosphamide, ifosfamide, or thiotepa have been conducted in heavily pretreated patients with relapsed or refractory disease.16,17 Recent small single center phase II trials have consistently reported 2-year survival rates of 70% to 80% using first-line HD-CT approaches in poor prognosis patients, but results of large phase II and, in particular, phase III trials are lacking.11–13 In addition, it is presently unclear whether the reported survival rates of 70% to 80% are maintained with longer follow-up or whether relapses are only delayed. In 1993, the German Testicular Cancer Study Group started a large multicenter phase I/II study with stepwise dose escalation of first-line chemotherapy with sequential cycles of high-dose etoposide, ifosfamide, and cisplatin plus autologous stem cell support. The study was designed as a phase I/II study and used four cycles of the standard VIP regimen as the backbone of treatment, but the doses of the individual drugs were escalated over several dose levels employing the support of myeloid hematopoietic growth factors and autologous peripheral stem cells. At dose levels 1 to 3, dose intensification was achieved by the application of granulocyte-macrophage colony-stimulating factor (GM-CSF) alone without peripheral stem cells. Prolonged thrombocytopenia and neutropenia were dose limiting at dose level 3 and all subsequent dose levels were applied together with autologous stem cell support plus granulocyte colony-stimulating factor (G-CSF). The result of dose levels 1 to 3 with GM-CSF support without stem cell support were published in 1993 and are therefore not included in this present analysis, which reports on the subsequent dose levels 3 to 8.18 After reaching the maximum-tolerated dose at dose level 8, the two dose levels below the dose-limiting level were more intensively investigated in a randomized phase II study. Initial toxicity data and preliminary results of the dose levels 3 to 8 using autologous stem cell support were reported in 1998.19 The study was closed in 1999 and we now report final data regarding the maximum tolerable dose level, efficacy, and in particular, long-term results of the total cohort of 221 patients, which received first-line high-dose chemotherapy with autologous stem cell support.
Between July 1993 and November 1999, 221 consecutive patients with advanced disease according to the Indiana University classification (n = 39) or poor prognosis criteria according to the IGCCCG classification (n = 182) were enrolled.3,4 Eligibility requirements included the presence of histologically proven nonseminomatous germ cell cancer, no prior treatment, advanced disease according to the Indiana classification or, since its publication in 1997, poor prognosis disease according to the IGCCCG classification. Further requirements were: adequate renal function defined by a creatinine clearance of  50 mL/min, adequate bone marrow function defined by leukocytes of 3,000/µL, thrombocytes 100,000/µL, no other major organ dysfunction, and age between 16 and 60 years. All patients had to give their written informed consent. The study protocol was approved by the Hannover University and Tuebingen University Ethics Committee as well as by the local Ethics Committees of other involved sites. Pretreatment evaluation included medical history and physical examination, computed tomography scans of the chest, abdomen, pelvis, and brain, audiometry, routine chemistry including creatinine clearance and serum tumor marker levels of alpha-fetoprotein, beta-human chorionic gonadutropin, and lactate dehydrogenase. A bone scan was performed only in case of clinical symptoms suggesting bone metastases.
Treatment
Dose level 3, which was the maximum-tolerated dose level with GM-CSF alone but without stem cell support, was restarted with PBSC support plus G-CSF (filgrastim). Patients treated at dose levels 3 to 5 received G-CSF at a dose of 12 µg/kg twice daily for 5 consecutive days in order to perform steady-state mobilization of peripheral blood stem cells. Stem cells were collected on days 6 and 7 and subsequently, the first high-dose chemotherapy cycle was started on day 8 (Fig 1A
Since an increasing number of severely ill patients had been included into the protocol who required immediate treatment as a result of life-threatening, widespread metastatic disease, the stem cell mobilization procedure was modified for patients included in dose levels 6 to 8. Several publications had demonstrated the feasibility of stem cell collection following VIP chemotherapy plus G-CSF and thus, at dose levels 6 to 8, patients were treated with one initial cycle of standard-dose VIP chemotherapy followed by 3 to 4 cycles of sequential high-dose VIP chemotherapy plus autologous peripheral stem cell support (Fig 1B  ).20 Stem cells were collected after the standard-dose VIP cycle, which consisted of cisplatin 20 mg/m2, etoposide 75 mg/m2, and ifosfamide 1,200 mg/m2 daily for 5 days, followed by G-CSF 5 µg/kg body weight. Peripheral blood stem cell separation was performed on days 10 to 12 of this cycle. It was planned to separate sufficient numbers of peripheral blood stem cells in order to support each high-dose cycle with approximately 2 x 106 CD34+ cells/kg body weight.
In the current analysis, the lowest dose level (dose level 3 with autologous stem cell support) consisted of cisplatin 30 mg/m2, etoposide 200 mg/m2, and ifosfamide 1,600 mg/m2 and the highest dose-level (dose level 8) of cisplatin 20 mg/m2, etoposide 350 mg/m2, and ifosfamide 2,400 mg/m2 daily for 5 consecutive days every 3 weeks for a total of three to four HD cycles (Table 1
Patients with brain metastases received radiation therapy that was applied either concomitantly to chemotherapy after stem cell collection in case of CNS symptoms or after the end of chemotherapy in asymptomatic patients who had achieved only a partial remission in the brain. Patients with a complete remission of CNS lesions following HD-CT were, if they agreed, not irradiated. The outcome for these patients following first-line HD-CT/PBSCT treatment has been reported separately.21
Secondary resection of residual masses, if technically feasible, was planned for all patients who had achieved a partial remission with normalization/
Toxicity DLT was defined as: any WHO grade 3/4 toxicity of the lungs, heart, urinary bladder, kidneys, neural system, or WHO grade 4 toxicity of the liver, skin, or mucositis and diarrhea/enteritis; granulocytopenia less than 500/µL or thrombocytopenia less than 20,000/µL for a period of > 12 and 15 days, respectively; and grade 4 infections.
Response Criteria Serum tumor markers were determined before each treatment cycle and 4 weeks after the end of therapy. Evaluation of measurable disease by radiographic means was performed after the first high-dose cycle and 4 to 6 weeks after the end of treatment. Subsequent follow-up tests including ultrasound, CT scans, serum tumor marker values, and routine blood tests were performed in 3-month intervals during the first 2 years and then every 6 months up to 5 years of follow-up.
Study Objectives and Statistics After its completion, the phase I part of the study was extended to a phase II part in order to investigate toxicity and determine efficacy in a larger group of patients. This phase II part was conducted as a randomized comparison between the maximally tolerable dose level and one dose level below in order to determine the least toxic but most effective dose level in a multicenter setting. A total of at least 60 patients were planned for each of the two dose levels in order to obtain sufficient data on toxicity and efficacy. Follow-up duration, progression-free (PFS) and DSS were calculated from the beginning of treatment to the date of last follow-up evaluation, date of relapse, or the date of death, respectively.
The DSS calculation used death as a result of metastatic germ cell cancer or related to treatment as the end point. Survival curves were estimated by the method of Kaplan-Meier and compared by the log rank test.23 Differences in the frequency of toxicities were calculated by using the
Patients Overall, 221 patients at 36 centers (see Appendix) were included onto this trial. Sixteen patients (7%) were treated at dose level 3, nine (4%) at dose level 4, 39 (18%) at dose level 5, 68 (31%) and 81 (37%) at dose levels 6 and 7 (including the patients treated in the phase II part), respectively, and eight patients (4%) at dose level 8. Patient characteristics are summarized in Table 2  . In 70% of patients, the primary tumor was located in the testis, in 17% it was located in the retroperitoneum, and 13% of patients presented with primary mediastinal tumor. Approximately 80% of all patients had lung metastases and involvement of abdominal lymph nodes. Overall, liver metastases were present in 31% of patients; 11% of patients had bone metastases and 12% had CNS metastases at diagnosis. All 87 patients initially considered at "Indiana advanced" stage were retrospectively reclassified according to the IGCCCG criteria, resulting in 39 Indiana advanced patients and 48 IGCCCG poor prognosis patients. Altogether, out of the 221 patients, 182 patients had poor prognosis according to IGCCCG criteria. The median follow-up for all patients at the time of this analysis was 47 months (range, 0–18 months).
Dose Escalation In contrast to the high-dose regimens used for relapsed patients, the first-line regimen used in this study contained cisplatin as the most active agent in the treatment of germ cell cancer. Initially, a cisplatin dose of 30 mg/m2 daily for 5 consecutive days was chosen based on data suggesting a benefit from cisplatin dose intensification.24 The established standard-5-day chemotherapy cycles of the VIP regimen were used as a backbone for the escalation of the treatment doses. Based on the results obtained in the prephase of the study with growth factor support alone, dose level 3 was restarted using autologous stem cell support given on day 7 following each treatment cycle (one day interval since the application of the last chemotherapy dose). Subsequently, either etoposide (50 mg/m2 per escalation step) or ifosfamide (400 mg/m2 per escalation step) were escalated within each subsequent dose level (Table 1 ). At dose level 6, the cisplatin dose was reduced to 20 mg/m2 daily since cisplatin dose intensified regimens had not shown to be of benefit in a randomized Southwest Oncology Group trial.6,25 At dose level 3, 16 patients were enrolled with three of them (19%) experiencing a DLT. Two patients with neutropenic sepsis died of multi-organ failure as a result of septic shock. One patient developed a grade 3 peripheral neurotoxicity and one patient developed cardiac arrhythmia. At dose level 4, one patient acquired a pneumonia with dyspnea in cycle 2, but recovered completely with antibiotic therapy. Among the first 12 patients on dose level 5, one died of neutropenic sepsis and one patient developed grade 4 mucositis. Because of these toxicities among the first dose levels, the patient number at dose level 5 was expanded to 39 patients in order to gain more experience with this regimen before proceeding to the next dose level. At dose level 6, two of the first 12 patients developed grade 4 mucositis and one patient died from neutropenic sepsis. Since no further DLT was observed among these patients, dose level 7 was entered. At dose level 7, two of the first 12 patients experienced grade 4 mucositis and one patient developed an ifosfamide-related psychosis, which was fully reversible after the administration of methylene-blue. Dose-limiting toxicity was reached at dose level 8. Three of eight (43%) patients at dose level 8 showed WHO grade 4 mucositis and one (14%) patient each developed WHO grade 4 neurotoxicity (most likely ifosfamide-related), renal failure, and prolonged granulocytopenia of more than 12 days duration. Thus, dose level 7 was considered the maximum tolerable dose level and dose levels 6 and 7 were chosen for further evaluation within the phase II part of the study. Fifty-six patients were enrolled at dose level 6 and 69 patients at dose level 7 within the randomized phase II part of this trial, resulting in a total of 68 patients treated at dose level 6 and 81 patients treated at dose level 7.
Hematologic Toxicity (n = 221)
Nonhematologic Toxicity
As expected, all patients developed transient alopecia. The most frequent grade 3/4 complications were nausea/vomiting and mucositis, which were, however, sufficiently controlled with antiemetic therapy and pain medication (Table 3
Overall, eight of 221 (4%) patients died of therapy-related complications; all of them suffered from severe neutropenic infections and septic multiorgan failure. In addition, four of 221 (2%) patients died from tumor-related complications during treatment. One patient with brain metastases from choriocarcinoma developed severe intracerebral bleeding on day 2 of the first chemotherapy cycle. One patient with choriocarcinoma presented with nonthrombocytopenic tumor-related pulmonary bleeding and subsequently developed pulmonary insufficiency. One patient died as a result of tumor progression during the third high-dose cycle, and the fourth patient from a tumor-related pulmonary embolism.
Dose-Intensity
Comparison of toxicity of dose levels 6 and 7 (phase II part).
Grade 3/4 nonhematologic toxicities, particularly mucositis (P = .032) and infectious complications (P = .036), were significantly less frequent at dose level 6 (n = 59) as compared with dose level 7 (n = 69; Table 3
Late Sequelae
Response and Survival
Overall, 154 (85%) of 182 patients achieved a favorable response, defined as either a complete remission, a partial remission with tumor marker normalization, or no evidence of disease following resection of residual masses (NED). The rate of unfavorable responses (marker positive partial response, incomplete resection with residual tumor, and marker elevation or progressive disease) was 15% (Table 4
In the 57% of patients who underwent resection of residual masses, histology revealed necrosis in 75%, mature teratoma in 14%, and vital carcinoma in 11% of specimens. Fifty-eight patients (26%) relapsed or progressed after or during first-line high-dose chemotherapy, respectively, and most of them received salvage treatment. Relapses were considerably less frequent in patients who underwent complete surgical resection of all residual masses than in patients without complete resection (18% v 33%). Five patients (2%) relapsed beyond 2 years and only one patient beyond 5 years after treatment. Of these 58 patients, 11 (19%) are currently alive and free of disease, two are alive with disease and 44 patients (77%) have died as a result of disease. One patient committed suicide. Currently, 71% of all patients in this study are alive without active disease (NED/complete remission/PRm-), whereas 26% have died of their disease or treatment-related complications. Three patients (2%) have died of causes unrelated to disease, and one patient (1%) was lost to follow-up.
The 2-year and 5-year PFS rates for all 182 poor prognosis patients are 69% (95% CI, 65% to 73%) and 68% (95% CI, 64% to 71%), respectively. Two-year and 5-year DSS rates are 79% (95% CI, 75% to 82%) and 73% (95% CI, 70% to 77%; Fig 2
For patients treated at dose levels 6 and 7, the 5-year PFS (66% [95% CI, 60% to 72%] v 70% [95% CI, 65% to 76%]) as well as DSS rates (73% [95% CI, 67% to 79%] v 76% [95% CI, 70% to 81%]) were not significantly different (P = .64 and P = .45, respectively). At dose levels 6 and 7 there was no difference between patients receiving three or four cycles of HD-CT/PBSCT regarding 5-year PFS (P = .54) or DSS rates (P = .93). The DSS according to the different dose levels was not statistically significant (Fig 3 ).
Patients with a primary gonadal or retroperitoneal tumor achieved a 5-year DSS of 76%, whereas patients with a mediastinal primary tumor reached only a 67% disease-specific 5-year survival (difference statistically not significant).
This study on first-line chemotherapy with sequential HD-CT plus stem cell support was carried out in cooperation with 36 centers within the German Testicular Cancer Study Group in order to examine the feasibility, toxicity and outcome of this approach in a multicenter setting. The primary objective of this trial was to determine the maximum-tolerated dose of sequentially administered cycles of HD-CT/PBSCT consisting of cisplatin, etoposide, and ifosfamide. The rationale for the sequential design of HD-CT/PBSCT cycles is based on the assumption that the front-line use of multiple intermediate high-dose chemotherapy cycles may induce cell kill in a higher fraction of sensitive and intermediate sensitive tumor cells before drug resistance develops. This assumption is based on the observation in several solid tumor types including lymphomas and testicular cancer, that applying chemotherapy with a higher dose-intensity may lead to improved outcome.26,27 In contrast to this approach, several phase II studies on the use of first-line HD-CT/PBSCT in testis cancer published thus far have investigated schedules consisting of two to three standard-dose cycles followed by one to two high-dose cycles.11,12,13 However, it is unclear which strategy of HD-CT/PBSCT—if any—is more powerful: either a single course of standard-dose chemotherapy followed by three to four sequentially administered HD-CT/PBSCT cycles, or a single HD-CT/PBSCT cycle as consolidation after three standard-dose cycles. Initially, high-dose regimens for patients with germ cell cancer were developed in pretreated patients with relapsed or refractory disease, and usually consisted of a combination of etoposide, cyclophosphamide or ifosfamide, and carboplatin, a drug that can more easily be dose-escalated than cisplatin because of its predominant myelotoxicity as the main side effect.16,17 Since cisplatin is still the most important agent in the first-line treatment of germ cell cancer, it was not replaced by carboplatin in this setting. The initial cisplatin dose was 150 mg/m2 per cycle based on data suggesting a benefit from cisplatin dose intensification.24,28 However, during the conduction of this study, a randomized trial in patients with advanced disease had demonstrated that doubling the dose of cisplatin does not lead to an improved outcome as compared with a standard cisplatin-dose regimen.6 Therefore, after initial dose escalation up to 150 mg/m2 per cycle, the cisplatin dose was reduced to the standard-dose of 100 mg/m2 per cycle at dose level 6, and only etoposide and ifosfamide were further dose-escalated. Within the setting of sequentially administered HD-CT/PBSCT cycles, the maximum tolerated doses of etoposide and ifosfamide when combined with cisplatin 20 mg/m2 were 300 mg/m2 and 2400 mg/m2, respectively, all given daily on days 1 to 5 of a 3-week cycle. With higher doses, up to 50% of patients experienced dose-limiting grade 3 or 4 nephrotoxicity, mucositis, and neurologic toxicity. Nevertheless, overall toxicity was acceptable and the feasibility of this HD-CT/PBSCT regimen was demonstrated even within a multicenter setting with 36 centers in Germany and Europe. As expected, all patients developed grade 4 neutropenia, but all of them recovered fully due to the stem cell support. Apart from hematologic toxicity, side effects consisted mainly of gastrointestinal events and infectious complications. Gastrointestinal side effects were mostly manageable by supportive measures such as antiemetic therapy and pain medication in order to overcome 3 to 4 days of severe mucositis. Infections occurred in approximately one-fourth of patients. These were fatal in 4% of patients. However, most septic deaths occurred during the early phase of the study, and with increasing experience at the participating centers, the rate of severe and fatal infections diminished. This is demonstrated by the phase II part of the study where only four patients died from toxicities among 125 patients randomized to the two dose levels 6 and 7. Both the incidence of gastrointestinal side effects and the rate of infections were similar to the incidences reported in other trials investigating HD-CT/PBSCT in germ cell cancer patients.13,16,17,29 Symptomatic acute severe ototoxicity, nephrotoxicity, or peripheral neuropathy, which are common cisplatin-related toxicities, were rare. Considering the high cure rate of germ cell cancer patients after HD-CT/PBSCT, late toxicity is of particular interest. Ten percent of our patients suffered from late effects, mainly compensated renal failure and peripheral neuropathy, but two patients required hemodialysis for chronic renal failure. Neither the rate of chronic severe renal failure nor the rate of persisting peripheral neuropathy appears to be increased as compared to standard-dose chemotherapy. Persisting severe peripheral neuropathy has been reported in 5% to 11% of patients after standard-dose chemotherapy and chronic renal failure, which requires regular hemodialysis, and has rarely been observed following standard dose chemotherapy.30–32 However, this low rate of symptomatic late toxicities has to be considered carefully since these results are only based on the information obtained during routine follow-up visits. No specific investigations regarding persisting late complications have yet been performed and therefore, the incidence of late complications may be underestimated. Two patients (1%) developed a therapy-related leukemia after a median follow-up of 47 months for all patients. This is an already-described serious late complication following high cumulative etoposide doses, and both patients have died.33 The secondary objective of this trial was to determine the antitumor activity of this sequential first-line HD-CT/PBSCT regimen, and in particular, to assess the long-term results. Phase II studies have reported 2-year survival rates of 70% to 80% following first-line HD-CT/PBSCT, indicating that a 15% to 20% survival advantage may be achievable with first-line HD-CT/PBSCT as compared with standard cisplatin, etoposide, and ifosfamide (PEB) therapy.11–13 In a phase II study, Motzer et al11 not only demonstrated that first-line high-dose chemotherapy is well tolerated, but also suggested a survival advantage following this approach compared to a historical control group treated with vinblastine, actinomycin-D, cyclophosphamide, cisplatin, and bleomycin. In a subsequent trial by the same investigators, poor prognosis patients with insufficient marker decline following two cycles of standard-dose VIP therapy received two cycles of high-dose carboplatin, etoposide, and cyclophosphamide therapy followed by autologous stem cell support. Among 58 patients treated with this approach, 50% remained disease-free as compared to 25% of control patients who only received standard-dose therapy.12 The only randomized study investigating high-dose chemotherapy as part of the first line chemotherapy used the alternative "classical" approach, applying high-dose chemotherapy as consolidation after three cycles at standard doses. In this French study, patients received either four cycles of cisplatinum, etoposide, vinblastine, and bleomycin, or three cycles at standard doses followed by one cycle of high-dose cisplatinum, etoposide, and cyclophosphamide. This study failed to demonstrate a survival advantage for the high-dose arm. The results of this trial are difficult to interpret since the four-drug regimen used for the control arm is not considered standard treatment and, in particular, since the dose-intensity in the high-dose arm was low, with approximately 30% of the patients randomized to the high-dose treatment arm not completing high-dose therapy because of toxicity or early death.10 The above described study does not exclude that giving high-dose chemotherapy upfront by sequential cycles might be able to improve survival. Our own study group has conducted a matched pair analysis including 456 patients in which first-line HD-CT/PBSCT was compared with standard-dose chemotherapy.34 As in the phase II studies, an 11% improvement in the 2-year overall survival rate was demonstrated and a multivariate analysis revealed the use of first-line HD-CT/PBSCT to be an independent positive factor for improved survival. The results observed for the 182 poor prognosis patients with a median follow-up of nearly 4 years and a maximum of 10 years, demonstrate a 5-year survival of 73% and disease-specific survival of 79%. Following standard-dose therapy it has been known that relapses occurring more than 2 years after therapy are rare. This appears to be similar for patients receiving first-line HD-chemotherapy with only 2% of relapses occurring beyond 2 years. This study has proven the feasibility of a sequential HD chemotherapy treatment strategy within a multicenter trial with all centers being experienced in both the treatment of germ cell cancer patients and high-dose chemotherapy. However, the frequency of resection of residual mass in 58% of the patients appears rather low for this patient population. This apparently low frequency may mainly be because of the high number of patients with far advanced disease (eg, 52% of the patients had more than three metastatic sites) in whom complete surgical resection is usually very difficult to achieve. However, it cannot be excluded that within a large multi-institutional setting, the skills of the surgeons involved are different, which may have contributed to the decision on whether to operate residual masses in an individual patient. In order to define the optimal regimen for further studies, the number of patients at dose levels 6 and 7 in this trial was increased and both levels were compared in a randomized fashion. Progression-free as well as disease-specific survival rates were not significantly different at both dose levels (P > .05), indicating comparable efficacy of these two dose levels. However, toxicities, particularly mucositis and infectious complications, were significantly less severe at dose level 6 compared with dose level 7. Thus, dose level 6 is recommended for further randomized trials. In conclusion, upfront high-dose chemotherapy with sequential cycles of intermediate high-dose VIP plus stem cell support is a feasible approach in first line chemotherapy in patients with advanced germ cell cancer and poor prognosis (IGCCCG). This dose intense chemotherapy is associated with relatively high but acceptable acute toxicity. In particular, there is only a minimal risk for severe late toxicity or secondary chemotherapy-induced cancer. The randomized trial of the European Organization for Research and Treatment of Cancer genitourinary group currently compares this high-dose VIP-protocol at dose level 6 with four cycles of standard PEB. This study is complementary to the ongoing US trial, which compares two cycles of PEB followed by two cycles of high-dose CEC with standard treatment consisting of four cycles of PEB. These studies will demonstrate whether the higher burden of toxicity and costs of high-dose chemotherapy are outweighed by a significantly higher rate of long-term survival.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the past two years: C. Bokemeyer, Amgen, Bristol-Myers Squibb. Received more than $2,000 a year from a company for either of the past two years: C. Bokemeyer, Bristol-Myers Squibb, Asta Medica, Amgen.
We thank the following physicians for actively participating in the study: I. Kührer, University of Vienna, Austria; H. Link, Klinikum Kaiserslautern; C. Binder, University of Goettingen; R. Mayer-Steinacker, University of Ulm, Th. Mayer, Armed Forces Hospital, Ulm; M. Schroeder, St.-Johannes Hospital, Duisburg; E. Miesgold, University of Duesseldorf; M. Hentrich, Krankenhaus Harlaching, Munich; K. Kaesberger, Diakonissenkrankenhaus, Stuttgart; A. Glassmacher, University of Bonn; E. Thiel, Klinikum Steglitz, Berlin; K. Hoeffken, University of Jena; A.R. Hanauske, Technical University of Munich, N. Frickhofen, Klinikum Wiesbaden; R. de Wit, Erasmus University, Rotterdam, the Netherlands; H. Kirchner, Siloah Krankenhaus, Hannover; W. Haidt, Klinikum Essen-Werder, Essen; K.H. Pflüger, Klinikum Bremen, Bremen; G. Derigs, University of Mainz; T. Kubin, Klinikum Karlsruhe, Karlsruhe; J. Casper, University of Rostock; A. Knuth, Krankenhaus Nordwest, Frankfurt; A. Florschütz, Klinikum Dessau, Dessau; S. Rösel, Krankenhaus Gütersloh, Gütersloh; Th. Gehr, Krankenhaus Schwäbisch-Hall, Schwäbisch-Hall, Germany. We also thank Mrs A. Haupt and Mrs I. Boehlke at the Tuebingen University study office for documentation and support in the statistical analysis of the study.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. The level of significance was set to 0.05 (two-sided). All tests were performed using SAS software (SAS Institute, Cary, NC; version 6.11). 
