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© 1999 American Society for Clinical Oncology First-Line High-Dose Chemotherapy Compared With Standard-Dose PEB/VIP Chemotherapy in Patients With Advanced Germ Cell Tumors: A Multivariate and Matched-Pair AnalysisFrom the Department of Hematology/Oncology, University of Tuebingen Medical Center, and Institute for Medical Information Processing, University of Tuebingen, Tuebingen; Department of Internal Medicine, West German Cancer Center, Essen; Department of Hematology/Oncology, Rudolf-Virchow University Clinic, Berlin; Department of Hematology/Oncology, Hannover University Medical School, Hannover; and Department of Hematology/Oncology, University of Halle, Halle, Germany; Department of Hematology/Oncology, Indiana University, Indianapolis, IN; and Division of Hematology/Oncology, Oregon Health Science University, Portland, OR. Address reprint requests to C. Bokemeyer, MD, Department of Hematology/Oncology, University of Tuebingen Medical Center, Otfried-Mueller-St 10, 72076 Tuebingen, Germany.
PURPOSE: To compare first-line high-dose chemotherapy (HD-CT) with autologous blood stem-cell transplantation to standard-dose chemotherapy (SD-CT) in male patients with advanced germ cell tumors (GCTs), a matched-pair analysis was performed within a homogenous group of patients classified as having either Indiana advanced disease or a poor prognosis according to International Germ Cell Cancer Consensus Group (IGCCCG) criteria. PATIENTS AND METHODS: A multivariate analysis was performed that included 147 consecutive patients who had received sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) therapy (HD-CT) in a German multicenter trial between 1993 and 1997 and 309 patients who had been treated with standard-dose cisplatin, etoposide, and bleomycin (PEB) or VIP chemotherapy (SD-CT) within two randomized trials at Indiana University between 1984 and 1992. RESULTS: Multivariate analysis demonstrated HD-CT to be significantly superior to SD-CT when adjustments were made for prognostic factors (P = .021). Primary tumor site (mediastinal v retroperitoneal/gonadal, P = .035) and presence of visceral metastases (P = .0004) were shown to be significant prognostic factors for overall survival. On the basis of these factors, as well as on tumor marker levels (good, intermediate, or poor, according to IGCCCG criteria), 146 of 147 HD-CT patients were fully matched to an SD-CT patient. Median follow-up was 21 months (range, 0 to 70 months) for the HD-CT patients and 22 months (range, 0 to 90 months) for the SD-CT patients. Two-year progression-free survival (75% v 59%) and overall survival (82% v 71%) were significantly prolonged in HD-CT patients (P = .0056 and P = .0184, respectively). CONCLUSION: The results indicate that first-line HD-CT in patients with poor-prognosis GCT may result in a significant improvement of progression-free and overall survival as compared with SD-CT. Salvage HD-CT seems not to compensate this survival advantage.
MAJOR ADVANCES HAVE been achieved in the treatment of malignant germ cell tumors (GCTs) during the past decades. The development of effective cisplatin-based combination chemotherapy has dramatically improved the prognosis of patients with metastatic GCTs.1 However, in patients with advanced disease, according to Indiana University criteria, or poor prognostic factors, according to the International Germ Cell Cancer Consensus Group (IGCCCG) classification, long-term survival rates range only between 45% and 55% after standard-dose chemotherapy (SD-CT).2,3 Several attempts have been made to improve the outcome of patients with far-advanced disease, including the use of cisplatin-intensified regimens and alternating chemotherapy sequences, such as the cisplatin, vincristine, methotrexate, and bleomycin/dactinomycin, cyclophosphamide, and etoposide regimen or the bleomycin, vincristine, and cisplatin/etoposide, ifosfamide, and cisplatin regimen.4-8 In recent years, high-dose chemotherapy (HD-CT) followed by autologous peripheral stem-cell or autologous bone marrow support has also been increasingly investigated in this group of patients.9-11 Chevreau et al were among the first who examined the role of first-line HD-CT but could not show a significant survival benefit. First-line HD-CT in poor-risk GCT patients has also been investigated by the Memorial Sloan-Kettering Cancer Center group. They demonstrated not only that HD-CT was better tolerated as first-line treatment compared with its use as salvage therapy in extensively pretreated patients but also that a significant improvement in survival may be achieved in these patients as compared with historical controls.9 The German Testicular Cancer Study Group has examined a sequential dose-intensive cisplatin, etoposide, and ifosfamide (VIP) regimen supported by peripheral-blood stem cells and hematopoietic growth factors as first-line therapy in high-risk patients.12 The dosages of the high-dose regimen were escalated over seven dose levels, with patients treated at dose levels 3 to 7 receiving peripheral-blood stem-cell support. Between 1989 and 1997, 239 patients who met advanced-disease criteria (Indiana classification) were enrolled onto this study. After a median follow-up of 3.2 years, an overall survival (OS) rate of approximately 80% and a progression-free survival (PFS) rate of approximately 72% were observed. The results of this trial indicate that an approximately 10% to 15% increase in cure rate is achievable in this patient population through the use of first-line HD-CT. To define the role of first-line HD-CT in patients meeting the IGCCCG's poor- or intermediate-prognosis criteria, a randomized United States intergroup trial was initiated in 1996 to compare four cycles of cisplatin, etoposide, and bleomycin (PEB) with two cycles of PEB followed by two cycles of high-dose carboplatin, etoposide, and cyclophosphamide chemotherapy. Because of the lack of results from ongoing randomized trials, we performed a matched-pair analysis of HD-CT versus SD-CT based on data from three large controlled clinical trials in patients with advanced GCT.
Patients We used the data of 456 patients with nonseminomatous germ cell cancer who were treated with either first-line HD-CT or SD-CT for advanced disease (according to the Indiana classification) or poor prognosis (according to the IGCCCG classification). All patients had been treated within three prospective, randomized trials. Eligibility criteria for all three trials were similar and consisted of the following: any primary tumor site, any histologic subtype, advanced disease according to Indiana University criteria,2 any performance status, normal kidney function, and no prior therapy. The high-dose group was composed of 147 consecutive patients who had been treated with sequential high-dose VIP chemotherapy (HD-CT) followed by autologous peripheral-blood stem-cell transplantation within the German multicenter trial between January 1993 and November 1997. Treatment for these patients consisted of one cycle of standard-dose VIP chemotherapy (cisplatin 20 mg/m2, etoposide 75 mg/m2, and ifosfamide 1,200 mg/m2 daily for 5 days) followed by three to four cycles of high-dose VIP chemotherapy with peripheral-blood stem-cell transplantation. The dosages of the high-dose regimen were escalated over seven dose levels, and all patients treated from level 3 to level 7 who required peripheral-blood stem-cell support were included. The lowest dose level contained cisplatin 30 mg/m2, etoposide 200 mg/m2, and ifosfamide 1,600 mg/m2; the highest dose level consisted of cisplatin 20 mg/m2, etoposide 300 mg/m2, and ifosfamide 2,400 mg/m2. For all dose levels, chemotherapy was administered daily for 5 consecutive days every 3 weeks for a total of three HD-CT cycles.12 These patients had received autologous peripheral-blood stem-cell support and granulocyte colony-stimulating factor after HD-CT according to treatment protocol and institutional practice. Three-hundred nine patients formed the standard-dose group. These patients had been treated with four cycles of SD-CT, either PEB (cisplatin 20 mg/m2 on days 1 through 5, etoposide 100 mg/m2 on days 1 through 5, and bleomycin 30 units weekly for 12 weeks) or VIP (cisplatin 20 mg/m2 on days 1 through 5, etoposide 75 mg/m2 on days 1 through 5, and ifosfamide 1.2 g/m2 daily for 5 days), within two randomized trials conducted by Indiana University between October 1987 and April 1992 and October 1984 and August 1989, respectively.4,13 VIP was shown to be as equally active as PEB in the treatment of patients with advanced disease.13 The objectives of the present analysis included the comparison of the PFS and OS of patients treated with HD-CT to those of the patients treated with SD-CT. Follow-up duration, PFS, and OS were calculated from the beginning of treatment to the date of last follow-up evaluation or date of death.
Statistical Analysis
The following factors were included in the univariate analysis: type of therapy (HD-CT v SD-CT), location of primary tumor (mediastinal v gonadal/retroperitoneal), presence of lung metastases, presence of liver metastases, presence of CNS metastases, presence of bone metastases, presence of visceral metastases, presence of an abdominal tumor mass, size of abdominal tumor mass (no tumor, < 10 cm, All variables were tested for colinearity. In cases of colinearity, only one variable was included in the multivariate analysis. If one variable was a subset of another variable, the one that was easiest to measure or the total group was chosen. Therefore, the variables "presence of CNS metastases," "presence of liver metastases," and "presence of bone metastases" were excluded from the multivariate analysis in favor of the variable "presence of visceral metastases"; the variable "size of abdominal mass" was excluded in favor of the variable "presence of abdominal tumor." Interactions between type of therapy and prognostically relevant factors were also investigated. No such interactions were found. The criteria for the matching process between HD-CT and SD-CT patients were based on the results of the above-described multivariate analysis and on the criteria of the IGCCCG classification, which include location of primary tumor (mediastinal v gonadal/retroperitoneal), presence of visceral metastases, and tumor marker levels of AFP, ß-HCG, and LDH (good, intermediate, or poor). Due to the small number of patients, AFP, ß-HCG, and LDH levels were combined under one variable, "markers combined," and classified into good, intermediate, or poor markers, according to the highest marker value. In case in which more than one SD-CT patient could be matched to an HD-CT patient, one SD-CT patient was randomly chosen by computer matching. HD-CT patients who could not be matched to an SD-CT patient were excluded from further analysis. Survival curves were estimated by the method of Kaplan-Meier.15 The level of significance was set to .05. All tests were performed using SAS software (version 6.11; SAS Institute, Cary, NC).
All 456 patients were included in the statistical analysis.
Multivariate Analysis The distribution of variables between the standard-dose and the high-dose groups was very similar; however, patients in the HD-CT group had more metastatic sites and exhibited more frequently poor markers, while slightly more patients with mediastinal primary tumors were included in the standard-dose group. These differences were not significantly different (Table 1).
Univariate analysis revealed a significant advantage for HD-CT patients in PFS and OS as compared with SD-CT patients. Location of the primary tumor, the presence of liver, bone and CNS metastases, the presence of visceral metastases, the presence of an abdominal tumor, and the AFP value were identified as significant factors for PFS. Location of the primary tumor, the presence of visceral metastases, the presence of an abdominal tumor, and the AFP value were identified as significant factors for OS. Multivariate analysis demonstrated the significant superiority of first-line HD-CT as compared with SD-CT for both PFS and OS when adjusted for the prognostic factors available in this study. Location of primary tumor and presence of visceral metastases were identified as independent prognostic factors for OS, and location of primary tumor, presence of visceral metastases and lung metastases, and AFP and ß-HCG levels (classified according to the IGCCCG) were found to be significant independent prognostic factors for PFS (Table 2).
For the 423 patients who were included in the multivariate analysis, median follow-up was 21 months (range, 0 to 70 months) for the high-dose group and 22 months (range, 0 to 90 months) for the standard-dose group. The differences in the 2-year PFS (75% v 62%) and OS (81% v 73%) rates between the HD-CT group and the SD-CT group were statistically significant (P = .002 and P = .021, respectively, adjusted for prognostic factors).
Matched-Pair Analysis One hundred forty-six of 147 HD-CT patients could be assigned to a comparable SD-CT patient who matched all three above-mentioned criteria. One HD-CT patient could not be matched to an SD-CT patient and was therefore excluded from the matched-pair analysis. In both treatment groups of this matched-pair analysis, the patients' characteristics were well balanced, not only for the matching criteria but also for the subgroups of tumor markers and for other criteria not used for the matching process, such as age, presence of lung metastases, and presence of an abdominal mass. Notably, more patients suffered from bone or CNS metastases in the HD-CT group as compared with the SD-CT group. Details of patients' characteristics and their distribution among both treatment groups are listed in Table 3.
Eleven patients (7.5%) progressed during treatment with SD-CT as compared with only three patients (2.1%) treated with HD-CT. However, six toxic deaths (4.1%) were observed in the HD-CT group, whereas only four (2.7%) occurred in the SD-CT group. All but four relapses (one SD-CT patient and three HD-CT patients) occurred within the first 2 years after therapy. After a median follow-up of 21 months (range, 0 to 70 months), 110 HD-CT patients (75.3%) showed no evidence of active disease and 19 (13.0%) had died of their disease. In contrast, in the SD-CT group, 95 patients (65.1%) were disease-free and 41 (28.1%) had died of their disease after a median follow-up of 22 months (range, 0 to 90 months) (Table 4).
The estimated 2-year PFS rate for the HD-CT group is 75% (95% confidence interval [CI], 68% to 83%) and for the SD-CT group, 59% (95% CI, 51% to 64%; P = .0056) (Fig 1). The 2-year estimated OS rate is 82% (95% CI, 75% to 89%) and 71% (95% CI, 63% to 79%), respectively (P = .0184) (Fig 2).
Over the last decade, HD-CT has been increasingly investigated as salvage therapy for patients with refractory or relapsed GCTs and as first-line treatment for patients with poor-risk germ cell cancer. Today, with the availability of hematopoietic growth factors and peripheral-blood stem-cell transplantation techniques, HD-CT is considered an established therapeutic option with acceptable toxicity and a treatment-related mortality rate of less than 5%. However, despite favorable results of phase II studies, only now is the role of HD-CT as first-line treatment for patients with poor-prognosis germ cell cancer being addressed in randomized trials. The only published randomized study so far, which used HD-CT as consolidation treatment during first-line therapy for advanced metastatic disease, showed no benefit for the high-dose arm.11 Patients in this French study were treated with a four-drug regimen consisting of cisplatin, etoposide, vinblastine, and bleomycin, given for either four cycles (standard-dose arm) or for three cycles, followed by high-dose therapy with cisplatin, etoposide, and cyclophosphamide. The results of this trial are difficult to interpret because the four-drug regimen used is not considered standard treatment. In addition, the dose-intensity in the high-dose arm was low and approximately 30% of the patients initially randomized to the high-dose arm did not complete high-dose therapy because of toxicity or early death. In a phase II study, Motzer et al16 not only demonstrated that first-line HD-CT is well tolerated but also suggested a potential survival advantage after this approach compared with historical controls treated with cyclophosphamide, dactinomycin, vinblastine, bleomycin, and cisplatin. In a subsequent trial by the same investigators, poor-risk patients with insufficient marker decline after two cycles of standard-dose VIP received two cycles of high-dose carboplatin, etoposide, and cyclophosphamide therapy followed by autologous stem-cell transplantation. Among 58 patients treated with this regimen, 50% remained disease-free as compared with 25% of historical control patients who received standard-dose therapy.9 Data from randomized trials on the use of first-line HD-CT are not yet available. The group of poor-prognosis patients who are preferentially included in these trials comprises only 15% of all metastatic nonseminomatous GCTs.3 Thus, large multicenter trials are necessary to obtain significant patient numbers to answer these questions. Against this background, we performed this matched-pair analysis, in an attempt to estimate the possible advantage that might be expected from primary high-dose therapy as compared with standard-dose treatment. Our matched-pair analysis includes 292 patients, with 146 patients in each treatment group. This patient number reaches that planned in ongoing randomized trials. In addition, as in a randomized trial, all patients in the present study were analyzed on an intention-to-treat basis, meaning that all patients were evaluated according to the assigned therapy, regardless whether they completed this treatment as planned. Eighty-seven percent of all HD-CT patients throughout all dose levels received the complete HD-CT according to the treatment plan. The matching criteria, based on the multivariate analysis, were the same prognostic factors as described before by the IGCCCG3 and Bajorin et al.17 The results of the present analysis show significant 16% and 11% improvements in the 2-year PFS and OS rates, respectively, of patients treated with first-line, sequential, high-dose VIP therapy, as compared with patients who received standard PEB or VIP chemotherapy. Estimated 3-year OS rates for high-dose VIP and PEB/VIP chemotherapy are 80% and 61%, respectively. Only four patients relapsed after the 2 years of follow-up; all other recurrences occurred within the first 2 years after therapy. It is known that relapses that occur 2 years after therapy or later are rare, and no significant difference in survival seems to exist after long-term follow-up as compared with a 2-year follow-up.18 Thus, with a median follow-up of approximately 2 years, we are confident that the results will not change significantly. Salvage HD-CT seems not to compensate for the lower survival rate of SD-CT patients because most patients who relapsed after standard therapy were treated with intensive chemotherapy followed by autologous stem-cell support. Of the 146 patients each in the HD-CT and SD-CT groups, 33 and 56, respectively, relapsed. Of these 33 patients initially treated with HD-CT, only five could be treated successfully with salvage therapy and only 10 of the relapsed patients who had received primary SD-CT were long-term survivors after salvage therapy. This corresponds to 15% and 18% salvage rates within the group of HD-CT and SD-CT relapsed patients, respectively. However, the patients in the present study, particularly those in the matched-pair analysis, exhibited poor prognostic features, and the overall low rate of successful salvage treatment in both groups may indicate that the outcome of salvage chemotherapy may be worse in patients with advanced disease at initial diagnosis as compared with the total population of patients with GCTs with relapsed disease. In addition, salvage chemotherapy and the management of its toxicity have been substantially improved during the last several years.19,20Thus, the different study periods of the HD-CT group (1993 to 1997) and the SD-CT group (1984 to 1992) might have contributed to the relatively low rate of success among SD-CT patients who underwent salvage therapy. Unfortunately, due to the lack of exact data, we were unable to compare the toxicity of both treatment options. However, HD-CT is certainly more toxic than SD-CT, and the rate of early or toxic deaths was higher, although the observed difference of six (4%) versus four (2.7%) was not very marked in the present analysis.9,16 With an increased survival rate achievable in this generally young patient population, the evaluation of severe long-term toxicity, particularly secondary malignancies, is another important issue. Concern has been raised about the high leukemogenic potential of high cumulative doses of etoposide which might theoretically compensate for the survival advantage achieved with HD-CT.21,22 However, a recently published study examining 302 patients with germ cell cancer, who all had received a cumulative etoposide dose of more than 2 g/m2, reported a cumulative incidence of therapy-related leukemias of 1.3% after 5 years of follow-up, as compared with the 5% to 8% cumulative incidence initially reported by Pedersen-Bjergaard et al21 and Boshoff et al.22,23 Thus, the cumulative incidence of 1.3% after HD-CT seems to be two to three times higher than the frequency of therapy-related leukemias reported after cumulative etoposide doses less than 2 g/m2.24-26 Neither the small increase in the toxic death rate nor the slightly higher rate of secondary leukemias seems to outweigh the potential benefit of a 15% to 20% survival improvement. We are aware that the results of a matched-pair analysis are not comparable to those of a randomized trial, even if a large patient number is provided and the patients' clinical characteristics are well balanced. The results of the matched-pair analysis still have to be considered carefully, and recommendations of new standards of treatment cannot be derived from this type of analysis. Additional factors, such as the different time periods over which the patients were accrued, may have influenced the results. Biases, inherent to historical control studies, even if matched, tend to favor the more recently treated patients, meaning that a "negative" result from such a trial suggests that a new treatment may genuinely not benefit the patients whereas a "positive" result requires cautious interpretation. However, despite these limitations, the results of the present matched-pair analysis support the hypothesis that first-line HD-CT in patients with advanced GCTs may result in a significant prolongation of PFS and OS as compared with SD-CT. Therefore, it is of great importance to rapidly complete ongoing randomized trials that test the hypothesis of improving survival in patients with advanced disease by using up-front dose intensification, such as the United States intergroup trial that compares four cycles of bleomycin, etoposide, and cisplatin with two cycles of the same regimen followed by two cycles of high-dose carboplatin, etoposide, and cyclophosphamide with autologous stem-cell support. Data from randomized studies will allow us to conclusively define the role of first-line HD-CT with stem-cell support.
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Bower M, Newlands ES, Holden L, et al: Treatment of men with metastatic non-seminomatous germ cell tumours with cyclical POMB/ACE chemotherapy. Ann Oncol8:477-483, 1997 6. Kaye SB, Mead GM, Fossa SD, et al: Intensive induction-sequential chemotherapy with BOP/VIP-B compared with treatment with BEP/EP for poor prognosis metastatic nonseminomatous germ cell tumor: A randomized Medical Research Council/European Organization for Research and Treatment of Cancer study. J Clin Oncol16:692-701, 1998[Abstract] 7. Culine S, Theodore C, Bekradda M, et al: Experience with bleomycin, etoposide, cisplatin (BEP) and alternating cisplatin, cyclophosphamide, doxorubicin (CISCA(II))/vinblastine, bleomycin (VB(IV)) regimens of chemotherapy in poor-risk nonseminomatous germ cell tumors. Am J Clin Oncol20:184-188, 1997[Medline] 8. de Wit R, Stoter G, Sleijfer DT, et al: Four cycles of BEP versus an alternating regime of PVB and BEP in patients with poor-prognosis metastatic testicular non-seminoma: A randomised study of the EORTC Genitourinary Tract Cancer Cooperative Group. Br J Cancer71:1311-1314, 1995[Medline]
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Motzer RJ, Mazumdar M, Bajorin DF, et al: High-dose carboplatin, etoposide, and cyclophosphamide with autologous bone marrow transplantation in first-line therapy for patients with poor-risk germ cell tumors. J Clin Oncol15:2546-2552, 1997 10. Bokemeyer C, Harstrick A., Beyer J, et al: High-dose (HD) VIP-chemotherapy (CTX) plus peripheral stem cell (PBSC) support as first-line therapy for advanced germ cell cancer. Proc Am Soc Clin Oncol 17:326a, 1998 (abstr 1258) 11. Chevreau C, Droz JP, Pico JL, et al: Early intensified chemotherapy with autologous bone marrow transplantation in first line treatment of poor risk non-seminomatous germ cell tumours: Preliminary results of a French randomized trial. Eur Urol23:213-217, 1993[Medline] 12. Bokemeyer C, Harstrick A, Beyer J, et al: The use of dose-intensified chemotherapy in the treatment of metastatic nonseminomatous testicular germ cell tumors: German Testicular Cancer Study Group. Semin Oncol25:24-32, 1998
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Nichols CR, Catalano PJ, Crawford ED, et al: Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: An Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B study. J Clin Oncol16:1287-1293, 1998 14. Cox DR, Oakes D: Analysis of survival data. London, United Kingdom, Chapman & Hall, 1984 15. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. Am J Stat Assoc53:457-481, 1958
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Motzer RJ, Mazumdar M, Gulati SC, et al: Phase II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation in first-line therapy for patients with poor-risk germ cell tumors. J Natl Cancer Inst85:1828-1835, 1993 17. Bajorin DF, Mazumdar M, Meyers M, et al: Metastatic germ cell tumors: Modeling for response to chemotherapy. J Clin Oncol16:707-715, 1998[Abstract] 18. Saxman SB, Finch D, Gonin R, et al: Long-term follow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-prognosis germ-cell tumors: The Indiana University experience. J Clin Oncol16:702-706, 1998[Abstract]
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Siegert W, Beyer J, Strohscheer I, et al: High-dose treatment with carboplatin, etoposide, and ifosfamide followed by autologous stem-cell transplantation in relapsed or refractory germ cell cancer: A phase I/II study. J Clin Oncol12:1223-1231, 1994
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Motzer RJ, Mazumdar M, Bosl GJ, et al: High-dose carboplatin, etoposide, and cyclophosphamide for patients with refractory germ cell tumors: Treatment results and prognostic factors for survival and toxicity. J Clin Oncol14:1098-1105, 1996 21. Pedersen BJ, Daugaard G, Hansen SW, et al: Increased risk of myelodysplasia and leukaemia after etoposide, cisplatin, and bleomycin for germ-cell tumours. Lancet338:359-363, 1991[Medline]
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Boshoff C, Begent RH, Oliver RT, et al: Secondary tumours following etoposide containing therapy for germ cell cancer. Ann Oncol6:35-40, 1995 23. Kollmannsberger C, Beyer J, Droz JP, et al: Secondary leukemia following high cumulative doses of etoposide in patients treated for advanced germ cell tumors. J Clin Oncol16:3386-3391, 1998[Abstract]
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10 cm), serum alpha-fetoprotein (AFP) levels (< 1,000 ng/mL, 1,000 to 10,000 ng/mL, > 10,000 ng/mL), beta-human chorionic gonadotropin (ß-HCG) levels (< 5,000 IU/L, 5,000 to 50,000 IU/L, > 50,000 IU/L), and lactate dehydrogenase (LDH) levels (< 1.5 times normal value, 1.5 to 10 times normal value, > 10 times normal value). 
