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© 2001 American Society for Clinical Oncology Second-Line Chemotherapy in Patients With Relapsed Extragonadal Nonseminomatous Germ Cell Tumors: Results of an International Multicenter AnalysisFrom the Tuebingen University Medical Center II, Tuebingen; Klinikum Großhadern, Munich; Virchow Klinikum, Berlin; University of Halle, Halle, Germany; Indiana University, Indianapolis, IN; Oregon Health Sciences University, Portland, OR; Centre Léon-Berard, Groupe d’Etude des Tumeurs Uro-Geniales, Lyon, France; Royal Marsden Hospital, Sutton, United Kingdom; The Norwegian Radium Hospital, Oslo, Norway; and Kaiser Franz Josef Spital, Vienna, Austria. Address reprint requests to Carsten Bokemeyer, MD, Department of Hematology/Oncology/Immunology, UKL-University Medical Center II, Eberhard-Karls-University, Otfried-Mueller-Str 10, 72076 Tuebingen, Germany; email: carsten.bokemeyer{at}med.uni-tuebingen.de
PURPOSE: Relapsed extragonadal germ cell tumors patients (EGGCT) are treated with identical salvage chemotherapy regimens, as are patients with metastatic testicular cancer. This investigation evaluates the results of second-line chemotherapy in nonseminomatous EGGCT and tries to identify prognostic factors for survival. PATIENTS AND METHODS: We conducted a retrospective review of 142 patients treated at eleven European and American centers between 1975 and 1996. All had received cisplatin-containing regimens as induction treatment. RESULTS: Twenty-seven of 142 patients (19%) were long-term disease-free, 11% with primary mediastinal and 30% of patients with primary retroperitoneal disease. Median follow-up since start of salvage treatment was 11 months (range, 1 to 157) for all patients and 45 months (range, 6 to 157) for surviving patients. Forty-eight patients (34%) received high dose chemotherapy with autologous bone marrow transplant at relapse, and 10 of these patients (21%) are continuously disease-free. Primary mediastinal location (P = .003), sensitivity to cisplatin (P = .003), elevated ß-HCG at relapse (P = .04), and normal LDH at diagnosis (P = .01) were shown to be significant negative prognostic factors for overall survival in univariate; mediastinal location [relative risk ratios (HR) = 1.9; 95% confidence intervals (CI), 1.2 to 3.0] and sensitivity to cisplatin [HR = 2.4; 95% CI, 1.1 to 5.2] were significant negative prognostic factors in multivariate analysis. CONCLUSION: Although current salvage strategies will cure between 20% and 50% of recurrent metastatic testicular cancer, relapsed nonseminomatous EGGCT patients appear to have an inferior survival rate, in particular in case of primary mediastinal location. Mediastinal primary tumor and inadequate response to cisplatin-based induction chemotherapy have been identified as independent negative prognostic factors, both associated with an approximately two-fold higher risk for failure of salvage treatment.
PRIMARY EXTRAGONADAL germ cell tumors are rare and account for only 1% to 5% of all germ cell malignancies.1 In adults, these tumors most commonly arise from the retroperitoneum or the mediastinum but can rarely occur in the pineal gland, presacral area, or liver.2-4 The general histologic, serologic, and cytogenetic characteristics of extragonadal tumors are similar to those of primary testicular germ cell tumors. However, differences in clinical behavior suggest that gonadal and extragonadal germ cell tumors are biologically distinct. In particular, for mediastinal nonseminomas, a unique association with Klinefelter‘s syndrome5 and with hematologic malignancies has been reported.6,7 The introduction of cisplatin-based chemotherapy, along with aggressive postchemotherapy surgery, has substantially improved the prognosis of patients with metastatic testicular germ cell tumors.8 Similar chemotherapeutic regimens have demonstrated activity in extragonadal germ cell tumors, with a long-term survival rate approaching that of patients with advanced-stage testicular cancer, except for primary mediastinal location.9 Testicular cancer is one of the few neoplasms in the adult for which second- and even third-line chemotherapy still offer a chance of cure. Patients with extragonadal germ cell tumors who relapse after initial chemotherapy are treated with the same salvage regimens, as are patients with testicular germ cell cancer. However, because of the rarity of extragonadal germ cell tumors, data about the effectiveness of second-line chemotherapy are lacking. This report describes the outcome of salvage chemotherapy, including high-dose therapy (HDCT) with autologous stem cell transplantation, in patients with nonseminomatous extragonadal germ cell tumors and relapse after previous cisplatin-based chemotherapy.
Data Collection We reviewed the medical records of 635 patients with extragonadal germ cell tumors treated at 11 cancer centers in the United States and Europe between 1975 and 1996. Extragonadal germ cell tumor was defined as a germ cell tumor arising in the mediastinum, retroperitoneum, or other site, without demonstrable testicular abnormalities, as determined by physical examinations or testicular ultrasonography. Testicular biopsies or orchidectomies were performed in patients with suspicious findings on palpation or by testicular ultrasonography. For the present analysis, the clinical records of extragonadal germ cell tumor patients with nonseminomatous histology were evaluated in detail. The patients’ histological slides were reviewed by each center’s pathology department. Nonseminomatous germ cell tumor were classified as embryonal carcinoma, teratocarcinoma, choriocarcinoma or mixed germ cell tumors, mature or immature teratoma, polyembryoma, and yolk sac tumor according to the World Health Organization classification. Patients with histologically undifferentiated tumors with markedly elevated germ cell tumor serum markers who were treated according to germ cell tumor protocols are included in this report. The contributing centers were internationally recognized for their experience in the treatment of germ cell tumors: Indiana University, Indianapolis, IN (n = 216; time period, 1989 through 1996); Institute Gustave-Roussy, Villejuif; Centre Léon-Berard, Lyon; and the Groupe d’Etude des Tumeurs Uro-Geniales (GETUG), France (n = 93 from these three centers; time period, 1975 through 1996); Eberhard-Karls-University Medical Center II, Tuebingen, Germany (n = 13; time period, 1986 through 1993); Hannover University Medical School, Hannover, Germany (n = 88; time period, 1978 through 1995); The Norwegian Radium Hospital, Oslo, Norway (n = 48; time period, 1980 through 1995); Klinikum Großhadern, Munich, Germany (n = 63; time period, 1979 through 1996); The Royal Marsden Hospital, Sutton, United Kingdom (n = 65; time period, 1979 through 1994); Kaiser-Franz-Josef Spital, Vienna, Austria (n = 19; time period, 1975 through 1996); and Virchow-Klinikum, Berlin, Germany (n = 30; time period, 1987 through 1994). The reason for referral of patients to each center was the diagnosis of extragonadal germ cell tumor. For data collection, a standardized questionnaire was sent to each center and completed by the responsible coinvestigator. All patient’s data were obtained in an anonymous manner. Detailed information on patient characteristics, such as location and histology of the primary tumor; extent of disease, including serum tumor marker concentrations of beta-human gonadotropin (ß-HCG), alpha-fetoprotein (AFP), and lactate dehydrogenase (LDH); history of testicular abnormalities; details on diagnostic methods, treatment, response to treatment, and follow-up period; and data on secondary testicular cancer and other secondary cancers were acquired. The completed questionnaires were checked for plausibility and data consistency at Tuebingen University Medical Center. When important data were missing, the questionnaires were returned to the principal investigator at each center. For the present report, the clinical records of patients who progressed during or relapsed after adequate primary chemotherapy for extragonadal nonseminomatous germ cell tumor were reviewed in detail. Duration of follow-up and survival in this analysis were calculated based on the date of the first day of salvage chemotherapy until the date of last contact, if the patient was still alive, or until the date of death. For all living patients, the status as of August 1998 was verified. Tumor response was classified as follows: complete remission (CR) was defined as a complete disappearance of all clinical, radiological, and biochemical evidence of disease, with normalization of ßb-HCG and/or AFP and/or LDH for at least a 1-month duration. A partial response was defined as a decrease in 50% or more of the sum of the products of perpendicular diameters of measurable disease, lasting at least for 1 month. If elevated markers were the only evidence of disease, a decrease of 90% or greater was required for a partial response. Progressive disease was defined as either residual lesions increasing in size or as occurrence of new lesions and/or elevation of tumor markers at repeated controls.10 Patients who achieved a normalization of tumor markers but an incomplete radiographic response were submitted to postchemotherapy surgery. However, in some patients who had attained serologic CR but with persistent minor radiographic abnormalities, individual investigators had chosen to observe such patients without surgery. Those patients were formally coded as partial remissions if their residual abnormalities remained stable or decreased on imaging studies over a 1-year period. In the majority of patients, surgery after second-line chemotherapy was not performed because of progressive disease on CT scans and/or rising tumor markers. In fewer cases, the residual abnormalities were considered as technically inoperable. Patients who underwent complete surgical resection of vital carcinoma or mature teratoma were classified as having no evidence of disease (NED)carcinoma or as having NEDteratoma, respectively.
Statistical Analysis
Patients’ Characteristics Details of the 142 patients with nonseminomatous extragonadal germ cell tumors relapsing after or during primary cisplatin-based chemotherapy are listed in Table 1. The median age was 29 years (range, 17 to 67). All patients were male. Seventy-nine patients (56%) had primary mediastinal germ cell tumors and 61, primary retroperitoneal tumors (43%). Two patients (1%) had widespread pulmonary, mediastinal, and retroperitoneal involvement without definable primary site.
The majority (n = 82; 58%) of these patients had only a partial response (PR) to primary chemotherapy; however, 37 of the 82 patients (45%) were rendered disease-free with surgical resection of either residual teratoma (n = 12) or carcinoma (n = 25). An additional 44 patients had achieved a complete response after initial chemotherapy. Table 2 summarizes the distribution of patients among the different contributing centers, the time period, and the type of salvage chemotherapy.
Details of Salvage Treatment All patients examined here received salvage chemotherapy as second-line treatment. The salvage regimens for extragonadal germ cell tumor patients were adapted based on the chemotherapeutic regimens given as initial therapy ( Table 3). Salvage chemotherapy included drugs proven to be active in germ cell tumors, such as ifosfamide, vinblastine, paclitaxel, or (HDCT) based on carboplatin and etoposide. The most commonly used conventional dose salvage protocol included cisplatin and ifosfamide (± other; n = 43 patients [30%]). Twenty-nine patients (20%) received cisplatin plus either etoposide or vinblastine ± other, and three patients (2%), cisplatin plus paclitaxel ± other. One third of the patients (n = 48 patients [34%]) were treated with HDCT including carboplatin and etoposide ± either ifosfamide or cyclophosphamide, followed by autologous bone marrow transplantation (ABMT). Nineteen additional patients (13%) were treated with single agents, such as ifosfamide, etoposide, gemcitabine, or oral etoposide (Table 4). Thirty-six patients (25%) underwent a secondary resection of residual tumor masses after second-line chemotherapy.
Survival of Patients With Relapsed Extragonadal Germ Cell Tumors One hundred patients died either of disease progression (n = 92) or therapy-related toxicity (n = 8). Another 12 patients were last recorded as alive with disease. The median follow-up period from the start of second-line chemotherapy for all patients is 11 months (range, 1 to 159) and 45 months (range, 6 to 157) for surviving patients. Only 27 of 142 patients (19%) were alive without evidence of disease: 17 of 94 patients (18%) treated with conventional chemotherapy and 10 of 48 patients (21%) treated with HDCT plus ABMT. Seven of 22 (32%) patients with retroperitoneal germ cell tumor and 3 of 25 (12%) patients with mediastinal primary receiving HDCT were alive without disease. Twelve of the 27 patients (44%) achieved their disease-free status with the use of postchemotherapy surgery. Of the 81 patients who had been free of disease after initial therapy, 21 (26%) again became disease-free after salvage chemotherapy, whereas five of 45 patients (11%) who only had a partial remission without marker normalization or a stable disease during their first-line therapy were disease free after salvage chemotherapy. Eighteen of 61 patients (30%) with relapsed primary retroperitoneal tumors were free of disease as of this study’s last assessment; this was true of 9 of 79 patients (11%) with relapsed mediastinal primary germ cell tumors. Of the nine patients with primary mediastinal location who attained a disease-free status, three had received oral etoposide as subsequent salvage treatment, followed by surgical resection of residual tumor masses.
Prognostic Factors for Survival
Role of Salvage HDCT Plus ABMT A retrospective statistical analysis was done to compare relevant patient characteristics between those patients receiving either high-dose or conventional-dose salvage chemotherapy. Except for two variables—presence of additional abdominal lymph node metastases and elevation of LDH at relapse (P < .05)—neither group revealed any significant differences (data not shown). These two variables showed no influence on survival in the univariate analysis or in the multivariate analysis in the total group of patients with relapsed extragonadal germ cell tumor patients (see Prognostic Factors for Survival). Figure 2 illustrates the outcome of patients with relapsed nonseminomatous extragonadal germ cell tumors according to the type of salvage treatment—high-dose or conventional-dose chemotherapy. Twenty-two of 79 patients with mediastinal (28%) and 25 of 61 (41%) patients with retroperitoneal germ cell tumor received HDCT at relapse (P = .2). The median survival time was 15 months for patients treated with high-dose chemotherapy and 11 months for patients given conventional-dose salvage chemotherapy (P = .27). Overall survival rates after HDCT did not differ from the results of standard-dose salvage treatment; the rates were 12% for mediastinal and 32% for retroperitoneal germ cell tumors.
Metastatic testicular cancer is one of the few solid tumors in the adult for which salvage chemotherapy still offers a curative chance. Although patients with relapsed metastatic nonseminomatous tumors will still achieve objective remissions in the range of 30% to 60%, with different cisplatin-based salvage chemotherapy regimens, only 20% to 50% will be long-term survivors,14 depending on different prognostic factors, such as achievement of a CR after induction chemotherapy, primary testicular tumor location, limited disease extent at relapse, progression-free interval of less than 2 years, and the levels of AFP and ß-HCG at relapse.15,16 Several trials have investigated the use of high-dose chemotherapy with ABMT (HDCT) in patients with relapsed germ cell tumors to improve the results of salvage treatment. Most investigators have used the combination of carboplatin and etoposide with or without the addition of an oxazaphosphorine derivate.17-19 A recent matched-pair analysis comparing HDCT with standard-dose salvage chemotherapy in patients with relapsed germ cell tumors has indicated a long-term survival benefit of approximately 10% in favor of the dose-escalated approach.20 Many series of salvage chemotherapy for patients with metastatic germ cell tumors have also included patients with extragonadal primary tumors. However, these patients usually represent a small subpopulation and are rarely discussed or evaluated separately. Hainsworth et al21 reported their experience with 31 patients with extragonadal germ cell tumors. Twelve patients relapsed after primary chemotherapy. Although the salvage regimens used were not mentioned, only one patient achieved long-term disease-free survival (3%). Josefsen et al22 reported the results of salvage treatment in 55 patients with relapsed germ cell tumor, 12 of whom had extragonadal primary tumors. The disease-free survival rate for the total group was 27% at 5 years. Three of the 12 patients (25%) with extragonadal germ cell tumor were long-term disease-free survivors. Delgado et al23 also reported their experience in extragonadal germ cell tumors. Among five patients with extragonadal seminoma who had relapsed after chemotherapy, none achieved long-term survival. Motzer et al24 reported an overall survival rate of 20% after a median follow-up of 37 months after salvage chemotherapy. Fourteen of their 94 patients (15%) had extragonadal primary tumors, and none of these patients was alive at 2 years after salvage treatment. Loehrer et al25 reported the so-far largest experience with standard-dose salvage chemotherapy as initial salvage treatment in 1998. Their study was designed to assess the effectiveness of vinblastine, ifosfamide, and cisplatin as second-line therapy. Whereas 30 of 100 patients with progressive, disseminated gonadal germ cell tumors were free of disease, none of the 32 patients with extragonadal nonseminomatous tumors included in this study was cured. Saxman et al26 have presented the only series reporting the results of salvage chemotherapy exclusively for patients with extragonadal germ cell tumor. All of the 73 patients analyzed had extragonadal germ cell tumors with nonseminomatous histology. In contrast to the results of salvage chemotherapy in testicular germ cell tumors, only 7% of their patients achieved long-term disease-free survival. Eight patients had received HDCT as initial salvage treatment and 28 patients had received it as third-line treatment. None of the 28 patients were long-term disease-free survivors. Primary mediastinal tumor location was suggested as a negative prognostic factor, but the number of patients was too small to draw definitive conclusions. Depending on the use of conventional or high-dose salvage chemotherapy and—even more important—individual prognostic factors, approximately 20% to 50% of patients with recurrent testicular cancer will be cured. However, in the present series of 142 patients with relapsed extragonadal germ cell tumors, only those with primary retroperitoneal tumors achieved a comparable long-term survival rate of 30%. The prognosis of patients with mediastinal germ cell tumors at relapse was clearly inferior, with salvage rates of less than 10%. The role of dose-intensive chemotherapy with ABMT has also been explored in patients with relapsed and refractory germ cell tumors.17 Our study might indicate—in accordance with results of smaller series—that the use of second-line, high-dose chemotherapy has no substantial impact on the outcome of patients with extragonadal nonseminomatous germ cell tumors, particularly in patients with mediastinal primary site. However, this hypothesis is only based on the results of a retrospective investigation. A systematic bias based on patient selection for high-dose chemotherapy might have influenced these findings. However, the group of patients receiving either conventional-dose or HDCT in this analysis did not differ with respect to relevant prognostic characteristics. Thus, according to our results, patients with first relapse of retroperitoneal and mediastinal nonseminomatous germ cell tumors have chances of long-term survival of approximately 30% and 10%, respectively. Individual prognostic factors—as identified by multivariate analysis—were of ultimate importance for outcome. Only 1 of 30 patients with mediastinal primary tumor and without complete response to first-line therapy has become disease-free after salvage treatment, suggesting that this subgroup of patients with two negative prognostic factors has almost no chance of benefitting from second-line chemotherapy. Whether HDCT might offer a higher chance of cure cannot definitively be answered in the current analysis because of the lack of a randomized comparison. In an analysis of 283 patients with testicular germ cell tumors who have received high-dose salvage chemotherapy, primary mediastinal germ cell cancer and refractory disease have been identified as the most important prognostic factors for a negative outcome after treatment.27 In accordance with results reported in patients with testicular primary tumor, resistance to cisplatin-based induction chemotherapy is associated with an approximately two-fold higher risk of failure after salvage treatment in extragonadal germ cell tumor patients. In the current series, nearly half of the patients being cured had undergone a multidisciplinary treatment approach, including aggressive postchemotherapy surgery. Surgical resection of residual masses after second-line chemotherapy had not been performed on the majority of patients because of progressive disease on computed tomography scans and/or rising tumor markers. In accordance with the case of metastatic gonadal germ cell tumor patients, radical surgical resection of all residual mass after first-line chemotherapy in extragonadal germ cell tumor patients is indicated where appropriate, either as a one-stage or as a sequential procedure.9,28,29 There is evidence that patients with mediastinal nonseminomatous germ cell tumors may benefit from aggressive resections, even when thoracic surgery has necessitated prosthetic replacement of the superior vena cava.30 Recently, Vuky et al reported their experience regarding the role of surgery in patients with primary mediastinal nonseminomatous germ cell tumors. In their retrospective analysis of 49 patients who had been treated from 1979 to 1999, 32 patients (65%) underwent postchemotherapy resection, 24 of 37 patients (65%) after first-line and 8 of 12 patients (67%) after second-line chemotherapy. Vital tumor at resection was found in approximately 65% of patients, regardless of first-line or second-line chemotherapy. Patients who had normal tumor markers before surgery achieved a disease-free status in 37% compared with 23% of patients with elevated markers.31 Thus, surgical resection might even be beneficial in selected patients with elevated tumor markers for whom no effective further salvage chemotherapy regimen is available.32 In summary, the present study demonstrates that the therapeutic advances achieved in the second-line therapy of patients with testicular cancer are not easily applicable to patients with nonseminomatous extragonadal germ cell tumors. New salvage strategies are needed, particularly for patients with primary mediastinal germ cell tumors. The option of surgical resection after second-line chemotherapy should be taken into consideration whenever technically feasible. Investigational approaches in progress will explore whether the outcome of patients with mediastinal primary tumors can be improved with the use of first-line sequential high-dose chemotherapy at the time of initial diagnosis in an attempt to reduce the relapse rate.33 For patients with primary retroperitoneal germ cell tumors who did not achieve a remission response to first-line chemotherapy, salvage HDCT outside of controlled clinical trials cannot be recommended based on the results of this analysis and former research.26 To improve the management of patients with extragonadal germ cell tumors relapsing after or progressing during induction chemotherapy, it still appears mandatory to include these patients in controlled clinical trials.
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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—The German Testicular Cancer Cooperative Study Group. J Clin Oncol 12: 1223-1231, 1994 20. Beyer J, Stenning S, Gerl A, et al: High-dose versus conventional first-salvage treatment in nonseminoma: A matched pair analysis. Proc Am Soc Clin Oncol 18: 326, 1999 (abstr) 21. Hainsworth JD, Einhorn LH, Williams SD, et al: Advanced extragonadal germ-cell tumors: Successful treatment with combination chemotherapy. Ann Intern Med 97: 7-11, 1982 22. Josefsen D, Ous S, Hoie J, et al: Salvage treatment in male patients with germ cell tumours. Br J Cancer 67: 567-572, 1993 23. Delgado FG, Tjulandin SA, Garin AM: Long term results of treatment in patients with extragonadal germ cell tumours. Eur J Cancer 29A: 1002-1005, 1993 24. Motzer RF, Geller NL, Tan C, et al: Salvage chemotherapy for patients with germ cell tumors. Cancer 67: 1305-1310, 1991[Medline] 25. Loehrer PJ, Gonin R, Nichols CR, et al: Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol 16: 2500-2504, 1998[Abstract] 26. Saxman S, Nichols CR, Einhorn LH: Salvage chemotherapy in patients with extragonadal nonseminomatous germ cell tumors: The Indiana University experience. J Clin Oncol 12: 1390-1393, 1994[Abstract]
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Beyer J, Kramar A, Mandanas R, et al: High-dose chemotherapy as salvage treatment in germ cell tumors: A multivariate analysis of prognostic variables. J Clin Oncol 14: 2638-45, 1996 28. Kay PH, Wells FC, Goldstraw P: A multidisciplinary approach to primary nonseminomatous germ cell tumors of the mediastinum. Ann Thorac Surg 44: 578-582, 1987[Abstract] 29. Wright CD, Kesler KA, Nichols CR, et al: Primary mediastinal nonseminomatous germ cell tumors: Results of a multimodality approach. J Thorac Cardiovasc Surg 99: 210-217, 1990[Abstract] 30. Dartevelle P, Chapelier A, Navajas M, et al: Replacement of the superior vena cava with polytetrafluoroethylene grafts combined withresection of mediastinal-pulmonary malignant tumors: Report of thirteen cases. J Thorac Cardiovasc Surg 94: 361-366, 1987[Abstract]
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Bokemeyer C, Kollmannsberger C, Meisner C, et al: First-line high-dose chemotherapy compared with standard-dose PEB/VIP chemotherapy in patients with advanced germ cell tumors: A multivariate and matched-pair analysis. J Clin Oncol 17: 3450-3456, 1999 Submitted August 8, 2000; accepted November 20, 2000.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50 years), tumor marker concentrations at diagnosis (elevated: yes/no) or tumor marker grouping (according to the IGCCCG classification);
