Original Article
High-Dose Chemotherapy and Stem-Cell Rescue for Metastatic Germ-Cell Tumors
N Engl J Med 2007; 357:340-348July 26, 2007
- Abstract
Background
Metastatic testicular tumors that have not been successfully treated by means of initial chemotherapy are potentially curable with salvage chemotherapy.
Methods
We conducted a retrospective review of 184 consecutive patients with metastatic testicular cancer that had progressed after they received cisplatin-containing combination chemotherapy. We gave 173 patients two consecutive courses of high-dose chemotherapy consisting of 700 mg of carboplatin per square meter of body-surface area and 750 mg of etoposide per square meter, each for 3 consecutive days, and each followed by an infusion of autologous peripheral-blood hematopoietic stem cells; the other 11 patients received a single course of this treatment. In 110 patients, cytoreduction with one or two courses of vinblastine plus ifosfamide plus cisplatin preceded the high-dose chemotherapy.
Results
Of the 184 patients, 116 had complete remission of disease without relapse during a median follow-up of 48 months (range, 14 to 118). Of the 135 patients who received the treatment as second-line therapy, 94 were disease-free during follow-up; 22 of 49 patients who received treatment as third-line or later therapy were disease-free. Of 40 patients with cancer that was refractory to standard-dose platinum, 18 were disease-free. A total of 98 of 144 patients who had platinum-sensitive disease were disease-free, and 26 of 35 patients with seminoma and 90 of 149 patients with nonseminomatous germ-cell tumors were disease-free. Among the 184 patients, there were three drug-related deaths during therapy. Acute leukemia developed in three additional patients after therapy.
Conclusions
Testicular tumors are potentially curable by means of high-dose chemotherapy plus hematopoietic stem-cell rescue, even when this regimen is used as third-line or later therapy or in patients with platinum-refractory disease.
Media in This Article
Figure 1
Kaplan–Meier Estimates of Overall Survival.Figure 2
Disease-free Survival.Article Activity
- Article
Germ-cell tumors are curable even in the presence of metastatic disease.1-3 An international collaboration has established that metastatic germ-cell tumors can be classified into good-, intermediate-, and poor-risk disease, with corresponding cure rates of 90 to 95%, 75%, and 40 to 50%, respectively.4 Hereinafter, we refer to these categories as low-, intermediate-, and high-risk disease, respectively. Patients with tumors that relapse or with tumors that progress despite initial chemotherapy are candidates for salvage therapy. The few patients with anatomically confined disease are amenable to surgical extirpation.5 For most patients, however, the options include salvage chemotherapy with cisplatin plus ifosfamide plus vinblastine6 or paclitaxel7 for four courses, or high-dose chemotherapy with autologous hematopoietic stem-cell transplantation to rescue the bone marrow from the myeloablative effects of chemotherapy.8-10 We began treating patients with carboplatin-based high-dose chemotherapy in 1986.11 Earlier studies of such treatment based on high-dose cyclophosphamide were unsuccessful.12
Initially, we used autologous bone marrow cells to rescue the hematopoietic system after high-dose chemotherapy. In February 1996, we shifted to peripheral-blood stem cells, which rapidly engrafted, thereby permitting a second course of high-dose chemotherapy with fewer delays. In this article, we present a retrospective study of 184 consecutive patients treated at Indiana University with high-dose carboplatin plus etoposide (high-dose chemotherapy) and rescue of the hematopoietic system by infusion of peripheral-blood stem cells. Our goal was to examine the efficacy of this treatment for cisplatin-resistant, progressively growing testicular cancer.
Methods
Patients
We conducted a review of 184 consecutive patients who received high-dose chemotherapy and peripheral-blood stem-cell rescue between February 1996 and December 2004. Patient interviews and medical charts were used to obtain the data analyzed in this study. The institutional review board at Indiana University approved the study. The requirement for informed consent was waived.
Before high-dose chemotherapy was initiated, peripheral-blood stem cells were collected and purified according to a technique that has been described previously.8 We harvested the cells after stimulation of the patient's marrow with granulocyte colony-stimulating factor and enriched these cells for CD34+ hematopoietic cells. Patients who received high-dose chemotherapy as initial salvage treatment and whose tumor had not progressed within 4 weeks after the last round of this treatment received standard doses of vinblastine plus ifosfamide plus cisplatin6 to reduce the bulk of the tumor and prevent progression before we administered high-dose chemotherapy. Patients who had already received ifosfamide-based salvage chemotherapy were offered high-dose chemotherapy without any further treatment. Patients with primary mediastinal nonseminomatous germ-cell tumors or tumors with late relapse (>2 years after previous therapy) were not offered high-dose chemotherapy during the specified period.
All patients received therapy in the outpatient clinic except for patients with complications requiring inpatient care. Antibiotics, including prophylactic acyclovir, fluconazole, ciprofloxacin, and either penicillin or vancomycin, were used routinely.
High-dose chemotherapy consisted of two cycles of 700 mg of carboplatin per square meter of body-surface area plus 750 mg of etoposide per square meter, both given intravenously 5, 4, and 3 days before the infusion of peripheral-blood stem cells. A minimum of 1 million CD34+ cells per kilogram of body weight was required for each cycle of high-dose chemotherapy. There were no planned reductions or escalations in the doses of chemotherapy. The second cycle of high-dose chemotherapy was given after recovery of granulocyte and platelet counts, unless there was a grade 4 nonhematologic toxic effect or no response to the first course. Most patients who had a complete or partial remission after the two cycles of high-dose chemotherapy and who had normal serum levels of human chorionic gonadotropin (hCG) and alpha-fetoprotein received a maintenance oral dose of 50 mg of etoposide per square meter daily for 21 consecutive days every 4 weeks for three cycles.13
Complete remission was defined as no clinically or radiographically detectable disease and normal serum levels of hCG and alpha-fetoprotein. Patients with a resectable residual mass after high-dose chemotherapy were offered surgery. Disease-free survival, defined as no evidence of disease at all follow-up visits after high-dose chemotherapy, was the primary end point for this analysis. Survival time was measured from the first day of high-dose chemotherapy. Disease-free survival was measured from the initiation of high-dose chemotherapy to tumor progression or death.
Statistical Analysis
Analyses were carried out with the use of SAS (version 9.1) and S-PLUS (version 7.0) software. The Kaplan–Meier method14 was used to calculate overall and disease-free survival according to the risk group (low, intermediate, or high), which was defined on the basis of the prognostic scoring algorithm described below. The association of disease-free survival with each prognostic variable was assessed with the use of Fisher's exact test.
A multivariate proportional-hazards regression analysis was used to construct a prognostic scoring algorithm for disease-free survival. Because the individual prognostic variables correlated with each other significantly, and because our goal was to devise a prognostic scoring algorithm that was easy to implement clinically, we used the branch-and-bound algorithm of Furnival and Wilson15 to find the best model among all possible models that contained three prognostic variables. This algorithm fits all possible three-variable models and identifies the model with the highest likelihood score (chi-square statistic). The best four-variable model was also obtained to determine whether the value added by including a fourth variable was meaningful. This model did not perform better than the best three-variable model. We used a bootstrap method in which 1000 samples of 184 patients were randomly selected from the original patient cohort.16 For each sample, the branch-and-bound algorithm was applied.
Next, the model with the highest frequency of selection among the 1000 samples was identified. The best three- and four-variable models identified by the bootstrap algorithm were both identical to the best three- and four-variable models for the original sample, providing support for the validity of the final model. With the use of the method of Rassi et al.,17 the β regression coefficients from the final model applied to the original sample were used to develop prognostic scores (with low scores reflecting a greater probability of disease-free survival) for each variable in the model. These prognostic scores were then summed and split three ways (by comparing the overall patterns of survival according to prognostic score with a Kaplan–Meier plot and forming three groups with similar patterns) to create an overall stratification of patients into low-, intermediate-, and high-risk groups.
Results
We analyzed the disease-free and overall survival of patients who received high-dose chemotherapy for at least 1 day. The one patient who was lost to follow-up was counted in the group of patients in whom treatment failed.
Table 1Table 1
Characteristics of 184 Patients at the Beginning of High-Dose Chemotherapy. lists characteristics of the patients at the start of high-dose chemotherapy. The median age was 31 years (range, 15 to 58). Patients with a low Eastern Cooperative Oncology Group (ECOG) performance status were not excluded, but most patients had an ECOG performance status of 0 or 1. Thirty-five patients had seminoma only, with no elements of nonseminomatous germ-cell tumor, and the remaining 149 patients had nonseminomatous germ-cell tumors. The Beyer score was used to stratify patients in low-, intermediate-, or high-risk categories.18 With this scoring system, 1 point was assigned for platinum-refractory or absolute platinum-refractory disease and 2 points were assigned for each primary mediastinal tumor and for a serum hCG level greater than or equal to 1000 IU per liter. Platinum-refractory disease was defined as tumor progression within 4 weeks after the most recent cisplatin-based chemotherapy. Absolute platinum-refractory disease was defined as no response to the initial cisplatin-based chemotherapy.Eleven patients did not receive the scheduled second course of high-dose chemotherapy; five had progressive disease, and four of these five patients died within 10 months after the initiation of high-dose chemotherapy. The fifth patient has no evidence of disease more than 33 months after two salvage surgeries. Five of the 11 patients did not receive a second course of high-dose chemotherapy because of grade 4 toxic effects (nephrotoxicity in 2, hepatotoxicity in 2, and pulmonary toxicity in 1). Of these five patients, two remained continuously disease-free 65 and 43 months after recovering from the toxic effects of the single course of high-dose chemotherapy. One patient who received a single course had apparently false elevations of serial serum alpha-fetoprotein levels in the absence of liver disease; he has been disease-free for more than 100 months.
During a median follow-up of 48 months (range, 14 to 118), 116 of 184 patients (63%) were continuously disease-free. Of these 116 patients, 104 (90%) were disease-free for more than 2 years. Six additional patients had complete remission of disease, four after receiving paclitaxel plus gemcitabine19 and two after undergoing subsequent resection of a germ-cell tumor. Figure 1Figure 1
Kaplan–Meier Estimates of Overall Survival. shows the Kaplan–Meier estimate of survival.Table 2Table 2
Prognostic Variables in 184 Patients. lists prognostic variables for the 184 patients in our study. Variables that were significantly associated with progression-free survival were the use of high-dose chemotherapy as second-line as compared with third-line chemotherapy, response of the tumor to cisplatin (platinum sensitivity), response to initial chemotherapy, favorable prognosis,20 and favorable International Germ Cell Cancer Collaborative Group (IGCCCG) score.4 Of the 61 patients who had favorable prognostic features, 49 had disease that was in continuous remission for a median of 46 months (range, 25 to 112). A total of 18 of 40 patients with progressive metastatic disease and tumors that were refractory to platinum remained disease-free for a median of 49 months (range, 22 to 110).To develop the prognostic scoring algorithm with the use of multivariate proportional-hazards regression, we included all individual variables (timing of high-dose chemotherapy, hCG level, platinum sensitivity, response to initial chemotherapy, histologic types, and IGCCCG score) in the branch-and-bound algorithm except for an alpha-fetoprotein level greater than or equal to 1000 μg per liter, since only eight patients had an alpha-fetoprotein level of that elevation. The best three-variable model included timing of high-dose chemotherapy, platinum sensitivity or refractoriness, and IGCCCG stage (Table 3Table 3
Results of Multivariate Cox Proportional-Hazards Analysis and Prognostic Score.). The prognostic scoring algorithm, based on the three-variable model, assigned a score of 3 points for third-line chemotherapy, 2 for platinum refractoriness, and 2 for advanced IGCCCG stage. High scores indicated a low probability of disease-free survival. Figure 2Figure 2Disease-free Survival. illustrates overall survival according to this scoring algorithm, which stratifies patients according to the level of risk (low, 0 points; intermediate, 2 to 3 points; or high, 4 to 7 points). The results of log-rank tests comparing the disease-free survival curves among the three risk groups were all statistically significant (P<0.05).The toxic effects of high-dose chemotherapy were primarily myelosuppression, mucositis, nausea, vomiting, dehydration, peripheral neuropathy, and otologic abnormalities.8 There were three sudden drug-related deaths; two were due to hepatic failure, and one was due to pulmonary toxic effects. Table 4Table 4
Toxic Effects of High-Dose Chemotherapy (Grade 3 or Higher) among 184 Patients. lists the toxic effects that were grade 3 or higher. Acute leukemia developed in three patients 11, 21, and 60 months after high-dose chemotherapy. None of these patients had received maintenance therapy with oral etoposide. All three had been treated with high-dose chemotherapy as third-line or later chemotherapy. Two of these patients died during follow-up; the third remained alive with cancer that was in complete remission after antileukemia therapy plus allogeneic bone marrow transplantation. Two of these three patients have been described previously.21 Glioblastoma multiforme developed in one patient 6 years after high-dose chemotherapy. He had received radiation therapy for brain metastases of the germ-cell tumor at the time of the initial diagnosis.Discussion
Cisplatin-containing combination chemotherapy cures 70% of patients with newly diagnosed metastatic germ-cell tumors. Prognostic factors, based on data from more than 5000 such patients, are well established.4 The factors associated with long-term survival after salvage therapy, however, are less well established.
In 1996, Beyer et al.18 reported a multivariate analysis of factors that can predict cure after high-dose chemotherapy. Adverse prognostic variables in the 283 patients in that study included refractoriness to platinum (progression within 4 weeks after treatment with cisplatin), absolute refractoriness to platinum (no response to initial platinum-based chemotherapy), mediastinal nonseminomatous germ-cell tumor, and a serum hCG level greater than or equal to 1000 IU per liter. A prognostic score based on these variables was developed. Primary mediastinal tumors and an hCG level greater than or equal to 1000 IU per liter were each assigned 2 points, whereas all other variables were each assigned 1 point. For patients with a score of 3 or higher, the rate of disease-free survival at 2 years was only 5%, as compared with 51% for patients with a Beyer score of 0. This scoring system, however, was based on data from patients who were treated between 1984 and 1993; most of these patients had received only a single course of high-dose chemotherapy. A total of 91% of these patients received two or more induction regimens before receiving high-dose chemotherapy.
There are some similarities between the prognostic variables in our study (Table 2) and the Beyer scores, but our list of variables reflects some additions and deletions. Beyer and colleagues assigned 2 points for “absolute refractory disease,” defined as progression with initial cisplatin-based chemotherapy. Forty-three of the 283 patients (15%) in that study were assigned to this category. In our series, only 2 of 184 patients had absolute refractory disease. In the study reported by Beyer et al., serum hCG levels greater than or equal to 1000 IU per liter were assigned 2 points. In our series, there was no difference in disease-free survival on the basis of hCG levels (P=1.00).
The improved results in our series, as compared with the 283 patients in the analysis by Beyer et al., reflect the benefit of high-dose chemotherapy given as second-line rather than third-line chemotherapy and the administration of two consecutive rounds of high-dose chemotherapy with hematopoietic stem-cell rescue. We did not use a third agent such as cyclophosphamide, ifosfamide, or thiotepa, as others have,22-27 because adding a third agent requires dose reductions of the two most active drugs, carboplatin and etoposide. Only a randomized study could show whether the addition of a third agent is beneficial.
Some variables were associated with very high rates of continuous disease-free survival. Of 35 patients with a pure seminoma (defined as no other cell types and normal serum alpha-fetoprotein levels) that relapsed after first- or second-line chemotherapy, 26 remained disease-free for a median of 43 months (range, 19 to 118). Sixty-one patients had favorable prognostic features; these features included cancer that was in complete or partial remission and normal serum hCG and alpha-fetoprotein levels for more than 6 months after the first chemotherapy treatment and then high-dose chemotherapy as the initial salvage therapy.7 Of these 61 patients, 49 had disease that was in continuous remission for a median of 46 months (range, 25 to 112). In a recently reported series, 29 of 46 similar patients had disease that was in a durable complete remission (median, 69 months) after treatment with paclitaxel plus ifosfamide plus cisplatin.20 The minimum follow-up was 2 years.
Patients with primary mediastinal nonseminomatous germ-cell tumors were not eligible for high-dose carboplatin plus etoposide during this study. From 1988 to 1996, 13 patients with this tumor received high-dose chemotherapy with bone marrow transplantation. None of them survived disease-free for more than 2 years.28 A larger international study had poor results with any type of salvage chemotherapy, with only 9 of 79 patients (11%) alive and disease-free for more than 2 years.29
In a recent study, 219 patients in the high-risk group were randomly assigned to receive initial treatment with four courses of bleomycin plus etoposide plus cisplatin or two courses of this initial treatment followed by two courses of high-dose chemotherapy with stem-cell rescue.30 There was no benefit from the high-dose chemotherapy. Pico et al. randomly assigned 280 patients to receive salvage chemotherapy with either four courses of vinblastine (or etoposide) plus ifosfamide plus cisplatin or three similar cycles followed by a single course of high-dose carboplatin plus etoposide plus cyclophosphamide.31 The single cycle of high-dose chemotherapy had no effect on the outcome. To our knowledge, these two studies are the only randomized trials of high-dose chemotherapy in patients with germ-cell tumors, and it is disappointing that they did not show an advantage of such treatment.
There should be little or no debate on the use of high-dose chemotherapy for a patient with a germ-cell tumor that is refractory to platinum-based chemotherapy or that is not cured by a cisplatin–ifosfamide regimen as salvage chemotherapy. In our study, 18 of 40 patients with progressive metastatic disease and tumors that were refractory to platinum remained disease-free for a median of 49 months (range, 22 to 110), and 22 of 49 patients who received high-dose chemotherapy as third-line or later therapy remained disease-free for a median of 46 months (range, 25 to 112).
Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, June 2–6, 2006.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Division of Hematology–Oncology, Indiana University School of Medicine (L.H.E., S.D.W., A.C., M.J.B., R.A.); the Walther Cancer Institute (L.H.E., S.D.W., A.C., M.J.B., R.A.); and the Division of Biostatistics, Indiana University (S.M.P.) — all in Indianapolis.
Address reprint requests to Dr. Einhorn at the Indiana University Cancer Center, 535 Barnhill Dr., Rm. 473, Indianapolis, IN 46202-5289, or at leinhorn@iupui.edu.
- References
References
1
Einhorn LH . Treatment of testicular cancer: a new and improved model. J Clin Oncol 1990;8:1777-1781
Web of Science | Medline2
Bosl GJ ,Motzer RJ . Testicular germ-cell cancer. N Engl J Med 1997;337:242-253[Erratum, N Engl J Med 1997;337:1403.]
Full Text | Web of Science | Medline3
Williams SD ,Birch R ,Einhorn LH ,Irwin L ,Greco FA ,Loehrer PJ . Treatment of dissemination germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 1987;316:1435-1440
Full Text | Web of Science | Medline4
International Germ Cell Collaborative Group
Web of Science | Medline5
Murphy BR ,Breeden ES ,Donohue JP , et al. Surgical salvage of chemorefractory germ cell tumors. J Clin Oncol 1993;11:324-329
Web of Science | Medline6
Loehrer PJ Jr ,Gonin R ,Nichols CR ,Weathers T ,Einhorn LH . Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol 1998;16:2500-2504
Web of Science | Medline7
Motzer RJ ,Sheinfeld J ,Mazumdar M , et al. Paclitaxel, ifosfamide, and cisplatin second-line therapy for patients with relapsed testicular germ cell cancer. J Clin Oncol 2000;18:2413-2418
Web of Science | Medline8
Bhatia S ,Abonour R ,Porcu P , et al. High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. J Clin Oncol 2000;18:3346-3351
Web of Science | Medline9
Motzer RJ ,Mazumdar M ,Sheinfeld J , et al. Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients. J Clin Oncol 2000;18:1173-1180
Web of Science | Medline10
Rick O ,Beyer J ,Kingreen D , et al. High-dose chemotherapy in germ cell tumours: a large single centre experience. Eur J Cancer 1998;34:1883-1888
CrossRef | Web of Science | Medline11
Nichols CR ,Tricot G ,Williams SD , et al. Dose-intensive chemotherapy in refractory germ cell cancer -- a phase I/II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation. J Clin Oncol 1989;7:932-939
Web of Science | Medline12
Buckner CD ,Clift RA ,Fefer A , et al. High-dose cyclophosphamide (NSC-26271) for the treatment of metastatic testicular neoplasms. Cancer Chemother Rep 1974;58:709-714
Medline13
Cooper MA ,Einhorn LH . Maintenance chemotherapy with daily oral etoposide following salvage therapy in patients with germ cell tumors. J Clin Oncol 1995;13:1167-1169
Web of Science | Medline14
Kaplan EL ,Meier P . Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-481
CrossRef | Web of Science15
Furnival GM ,Wilson RW . Regression by leaps and bounds. Technometrics 1974;16:499-511
CrossRef | Web of Science16
Efron B, Tibshirani RJ. An introduction to the bootstrap. Boca Raton, FL: Chapman & Hall/CRC, 1998.
17
Rassi A Jr ,Rassi A ,Little WC , et al. Development and validation of a risk score for predicting death in Chagas' heart disease. N Engl J Med 2006;355:799-808
Full Text | Web of Science | Medline18
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 1996;14:2638-2645
Web of Science | Medline19
Einhorn LH ,Brames MJ ,Juliar B ,Williams SD . Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant. J Clin Oncol 2007;25:513-516
CrossRef | Web of Science | Medline20
Kondagunta GV ,Bacik J ,Donadio A , et al. Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors. J Clin Oncol 2005;23:6549-6555
CrossRef | Web of Science | Medline21
Houck W ,Abonour R ,Vance G ,Einhorn LH . Secondary leukemias in refractory germ cell tumor patients undergoing autologous stem-cell transplantation using high dose etoposide. J Clin Oncol 2004;22:2155-2158
CrossRef | Web of Science | Medline22
Siegert W ,Beyer J ,Strohscheer I , et al. High dose treatment with carboplatin, etoposide, and ifosfamide by autologous stem-cell transplantation in relapsed or refractory germ cell cancer: a phase I/II study. J Clin Oncol 1994;12:1223-1231
Web of Science | Medline23
Beyer J ,Kingreen D ,Krause M , et al. Long-term survival of patients with recurrent or refractory germ cell tumors after high dose chemotherapy. Cancer 1997;79:161-168
CrossRef | Web of Science | Medline24
Rodenhuis S ,de Wit R ,de Mulder PHM , et al. A multi-center prospective phase II study of high-dose chemotherapy in germ-cell cancer patients relapsing from complete remission. Ann Oncol 1999;10:1467-1474
CrossRef | Web of Science | Medline25
Rick O ,Bokemeyer C ,Beyer J , et al. Salvage treatment with paclitaxel, ifosfamide, and cisplatin plus high-dose carboplatin, etoposide, and thiotepa followed by autologous stem-cell rescue in patients with relapsed or refractory germ cell cancer. J Clin Oncol 2001;19:81-88
Web of Science | Medline26
Rosti G ,DeGiorgi U ,Salvioni R , et al. Salvage high-dose chemotherapy in patients with germ cell tumors: an Italian experience with 84 patients. Cancer 2002;95:309-315
CrossRef | Web of Science | Medline27
Lotz JP ,Bui B ,Gomez F , et al. Sequential high-dose chemotherapy protocol for relapsed poor prognosis germ cell tumor combining two mobilization and cytoreductive treatments followed by three high-dose chemotherapy regimens supported by autologous stem cell transplantation: results of the phase II multi-centric TAXIF trial. Ann Oncol 2005;16:411-418
CrossRef | Web of Science | Medline28
Vaena DA ,Abonour R ,Einhorn LH . Long-term survival after high-dose salvage chemotherapy for germ cell malignancies with adverse prognostic variables. J Clin Oncol 2003;21:4100-4104
CrossRef | Web of Science | Medline29
Hartmann JT ,Einhorn L ,Nichols CR , et al. Second-line chemotherapy in patients with relapsed extragonadal nonseminomatous germ cell tumors: results of an international multicenter analysis. J Clin Oncol 2001;19:1641-1648
Web of Science | Medline30
Motzer RJ ,Nichols CJ ,Margolin KA , et al. Phase III randomized trial of conventional-dose chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors. J Clin Oncol 2007;25:247-256
CrossRef | Web of Science | Medline31
Pico JL ,Rosti G ,Kramar A , et al. A randomized trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumors. Ann Oncol 2005;16:1152-1159
CrossRef | Web of Science | Medline
- Citing Articles (59)
Citing Articles
1
Olav Dahl, Marianne Brydøy. (2012) Testicular germ cell tumours – still many challenges. Acta Oncologica 51:2, 147-150
CrossRef2
Hege S. Haugnes, Anna Laurell, Ulrika Stierner, Roy M. Bremnes, Olav Dahl, Eva Cavallin-Ståhl, Gabriella Cohn-Cedermark. (2011) High-dose chemotherapy with autologous stem cell support in patients with metastatic non-seminomatous testicular cancer – a report from the Swedish Norwegian Testicular Cancer Group (SWENOTECA). Acta Oncologica1-9
CrossRef3
Juan Antonio Vílchez Aguilera, Francisco Avilés Plaza, Juan F. Martínez-Lage Sánchez, Pedro Martínez Hernández, Soledad Parra Pallarés. (2011) Isoenzima de fosfatasa alcalina placental-like, importancia clínica como marcador en tumores de tipo germinal. Revista del Laboratorio Clínico
CrossRef4
Darryl B. Sneag, Nikhil Ramaiya, Kevin N. O'Regan, Jyothi P. Jagannathan, Jason L. Hornick, Vincent T. Ho, Julia H. Hayes. (2011) Peritoneal Relapse of Testicular Seminomatous Germ Cell Tumor Treated Successfully With Salvage Chemotherapy and Autologous Stem Cell Transplantation. Clinical Genitourinary Cancer 9:2, 124-129
CrossRef5
Alan Horwich, Gedske Daugaard, Christian Kollmannsberger, Joerg Beyer, Michael A.S. Jewett. (2011) Salvage Therapy: SIU/ICUD Consensus Meeting on Germ Cell Tumors (GCT), Shanghai 2009. Urology 78:4, S469-S474
CrossRef6
M. Simonelli, G. Rosti, G. L. Banna, P. Pedrazzoli, . (2011) Intensified chemotherapy with stem-cell rescue in germ-cell tumors. Annals of Oncology
CrossRef7
A. Lorch, P. Albers, C. Winter, J. Beyer. (2011) Hochdosischemotherapie und Residualtumorresektion bei Patienten mit Hodentumor. Der Urologe 50:9, 1047-1054
CrossRef8
D. Koychev, K. Oechsle, C. Bokemeyer, F. Honecker. (2011) Treatment of patients with relapsed and/or cisplatin-refractory metastatic germ cell tumours: an update. International Journal of Andrology 34:4pt2, e266-e273
CrossRef9
Martin H Voss, Darren R Feldman, Robert J Motzer. (2011) High-dose chemotherapy and stem cell transplantation for advanced testicular cancer. Expert Review of Anticancer Therapy 11:7, 1093-1105
CrossRef10
Martin H. Voss, Darren R. Feldman, George J. Bosl, Robert J. Motzer. (2011) A Review of Second-line Chemotherapy and Prognostic Models for Disseminated Germ Cell Tumors. Hematology/Oncology Clinics of North America 25:3, 557-576
CrossRef11
Anuj K. Agarwala, Susan M. Perkins, Rafat Abonour, Mary J. Brames, Lawrence H. Einhorn. (2011) Salvage Chemotherapy With High-Dose Carboplatin and Etoposide With Peripheral Blood Stem Cell Transplant in Patients With Relapsed Pure Seminoma. American Journal of Clinical Oncology 34:3, 286-288
CrossRef12
C.A. Parkinson, H.M. Hatcher, H.M. Earl, T.V. Ajithkumar. (2011) Multidisciplinary management of malignant ovarian germ cell tumours. Gynecologic Oncology 121:3, 625-636
CrossRef13
M D Seftel, K Paulson, R Doocey, K Song, P Czaykowski, C Coppin, D Forrest, D Hogge, C Kollmansberger, C A Smith, J D Shepherd, C L Toze, N Murray, H Sutherland, S Nantel, T J Nevill, M J Barnett. (2011) Long-term follow-up of patients undergoing auto-SCT for advanced germ cell tumour: a multicentre cohort study. Bone Marrow Transplantation 46:6, 852-857
CrossRef14
Heather D Mannuel, Nirupama Mitikiri, Arif Hussain. (2011) Update on testicular germ cell tumors. Current Opinion in Oncology 23:3, 265-270
CrossRef15
Ugo De Giorgi, Giovanni Rosti, Roberto Salvioni, Giorgio Papiani, Michela Ballardini, Giorgio Pizzocaro, Maurizio Marangolo. (2011) Long-term outcome of salvage high-dose chemotherapy in patients with germ cell tumor with poor prognostic features. Urologic Oncology: Seminars and Original Investigations 29:3, 284-290
CrossRef16
G. Daugaard, I. Skoneczna, N. Aass, R. De Wit, M. De Santis, H. Dumez, S. Marreaud, L. Collette, J. R. G. Lluch, C. Bokemeyer, H. J. Schmoll. (2011) A randomized phase III study comparing standard dose BEP with sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) plus stem-cell support in males with poor-prognosis germ-cell cancer. An intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC 30974). Annals of Oncology 22:5, 1054-1061
CrossRef17
Kenneth A. Kesler, Laura E. Kruter, Susan M. Perkins, Karen M. Rieger, Katherine J. Sullivan, Matthew L. Runyan, John W. Brown, Lawrence H. Einhorn. (2011) Survival After Resection for Metastatic Testicular Nonseminomatous Germ Cell Cancer to the Lung or Mediastinum. The Annals of Thoracic Surgery 91:4, 1085-1093
CrossRef18
Ajjai S Alva, Noah M Hahn, Ana M Aparicio, Rakesh Singal, Sarvari Yellapragada, Guru Sonpavde. (2011) Hypomethylating agents for urologic cancers. Future Oncology 7:3, 447-463
CrossRef19
Silvia Park, Soohyeon Lee, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Won Ki Kang, Young Suk Park, Ho Yeong Lim. (2011) Salvage Chemotherapy with Paclitaxel, Ifosfamide, and Cisplatin (TIP) in Relapsed or Cisplatin-Refractory Germ Cell Tumors. Onkologie 34:8, 416-420
CrossRef20
Martin H. Voss, Darren R. Feldman. (2011) Paclitaxel, Ifosfamide and Cisplatin (TIP) Beyond Its Original Indication for Salvage Treatment of Germ Cell Tumors. Onkologie 34:8, 410-411
CrossRef21
Philip Lanzkowsky. 2011. Germ Cell Tumors. , 776-795.
CrossRef22
M.W. Kramer, S. Krege, I. Peters, A.S. Merseburger, M.A. Kuczyk. (2010) Die Target-Therapie urologischer Tumoren. Der Urologe 49:10, 1260-1265
CrossRef23
James Nicholson, Roger Palmer. 2010. Germ Cell Tumors. , 275-305.
CrossRef24
Yaron Ehrlich, Stephen D.W. Beck, Richard S. Foster, Richard Bihrle, Lawrence H. Einhorn. (2010) Serum tumor markers in testicular cancer. Urologic Oncology: Seminars and Original Investigations
CrossRef25
Debra L Zynger, John C McCallum, Chunyan Luan, Pauline M Chou, Ximing J Yang. (2010) Glypican 3 has a higher sensitivity than alpha-fetoprotein for testicular and ovarian yolk sac tumour: immunohistochemical investigation with analysis of histological growth patterns. Histopathology 56:6, 750-757
CrossRef26
A. Lorch, A. Neubauer, M. Hackenthal, A. Dieing, J. T. Hartmann, O. Rick, C. Bokemeyer, J. Beyer. (2010) High-dose chemotherapy (HDCT) as second-salvage treatment in patients with multiple relapsed or refractory germ-cell tumors. Annals of Oncology 21:4, 820-825
CrossRef27
David J. Gallagher, Jamie Riches, Dean F. Bajorin. (2010) False elevation of human chorionic gonadotropin in a patient with testicular cancer. Nature Reviews Urology 7:4, 230-233
CrossRef28
P Ljungman, M Bregni, M Brune, J Cornelissen, T de Witte, G Dini, H Einsele, H B Gaspar, A Gratwohl, J Passweg, C Peters, V Rocha, R Saccardi, H Schouten, A Sureda, A Tichelli, A Velardi, D Niederwieser. (2010) Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe 2009. Bone Marrow Transplantation 45:2, 219-234
CrossRef29
Koji Kawai, Hideyuki Akaza. (2010) Current status of chemotherapy in risk-adapted management for metastatic testicular germ cell cancer. Cancer Science 101:1, 22-28
CrossRef30
Habib Shaikh, J. Lee Villano. (2009) Incidental CNS involvement of testicular germ cell cancer: a growing trend?. Radiotherapy and Oncology 93:3, 654-656
CrossRef31
Christian Kollmannsberger, Joerg Beyer, Carsten Bokemeyer. (2009) High-dose chemotherapy in nonseminomatous germ cell cancer. BJU International 104:9b, 1398-1403
CrossRef32
Gedske Daugaard. (2009) Management of poor-prognosis or relapsed germ-cell cancer. BJU International 104:9b, 1392-1397
CrossRef33
M. Hentrich, X. Schiel, A. Niedermeier, L. Lutz, R. Rupec, C. Stief, J. Bogner, M. Karthaus, A. Gerl. (2009) Successful salvage high-dose chemotherapy and autologous stem-cell transplantation in HIV-related germ-cell tumor. Annals of Oncology 20:11, 1900-1901
CrossRef34
H.-J. Schmoll, K. Jordan. (2009) Current treatment of high risk testis cancer. European Journal of Cancer 45, 433-435
CrossRef35
Roisin M. Connolly, John A. McCaffrey. (2009) High-Dose Chemotherapy plus Stem Cell Transplantation in Advanced Germ Cell Cancer: A Review. European Urology 56:1, 57-64
CrossRef36
Jia-Hong Chen, Ping-Ying Chang, Nai-Shun Yao. (2009) Gemcitabine Plus Vinorelbine as an Effective Salvage Chemotherapeutic Regimen in Cisplatin-Refractory Germ Cell Tumor. Southern Medical Journal 102:5, 546-548
CrossRef37
A. Lorch, K. Oechsle, C. Bokemeyer, J. Beyer. (2009) Rezidivtherapie von Hodentumoren. Der Urologe 48:4, 364-371
CrossRef38
R Agarwal, C C Dvorak, K E Stockerl-Goldstein, L Johnston, S Srinivas. (2009) High-dose chemotherapy followed by stem cell rescue for high-risk germ cell tumors: the Stanford experience. Bone Marrow Transplantation 43:7, 547-552
CrossRef39
András Telekes. (2009) Off-label kezelések az onkológiában. Orvosi Hetilap 150:8, 363-372
CrossRef40
Dominique Levêque. (2008) Off-label use of anticancer drugs. The Lancet Oncology 9:11, 1102-1107
CrossRef41
Christian Kollmannsberger, Carsten Bokemeyer. (2008) Salvage chemotherapy after failure of first-line chemotherapy in patients with metastatic testicular cancer. Current Opinion in Supportive and Palliative Care 2:3, 167-172
CrossRef42
C Kollmannsberger, F Honecker, C Bokemeyer. (2008) Pharmacotherapy of relapsed metastatic testicular cancer. Expert Opinion on Pharmacotherapy 9:13, 2259-2272
CrossRef43
Ronald de Wit, Martin van den Bent, Wim Kirkels. (2008) The management of cerebral metastasis from germ cell cancer; walking the tightrope. European Journal of Cancer 44:12, 1622-1624
CrossRef44
T. de La Motte Rouge, P. Pautier, P. Duvillard, A. Rey, P. Morice, C. Haie-Meder, P. Kerbrat, S. Culine, F. Troalen, C. Lhomme. (2008) Survival and reproductive function of 52 women treated with surgery and bleomycin, etoposide, cisplatin (BEP) chemotherapy for ovarian yolk sac tumor. Annals of Oncology 19:8, 1435-1441
CrossRef45
A. Lorch, K. Oechsle, C. Bokemeyer, J. Beyer. (2008) Rezidivtherapie und Prognosefaktoren im Rezidiv bei Hodentumoren. Der Onkologe 14:6, 611-617
CrossRef46
Ashwin Jathavedam, Darren R. Feldman, Nicole Ishill, Stefan Turkula, Sujata Patil, George J. Bosl, Robert J. Motzer, David M. Weinstock. (2008) Infectious Complications from High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Metastatic Germ Cell Tumors. Biology of Blood and Marrow Transplantation 14:5, 595-600
CrossRef47
Mohan K Tummala, Arif Hussain. (2008) Recent developments in germ cell tumors of the testes. Current Opinion in Oncology 20:3, 287-293
CrossRef48
Martin H Fenner, Gernot Beutel, Viktor Grünwald. (2008) Targeted therapies for patients with germ cell tumors. Expert Opinion on Investigational Drugs 17:4, 511-522
CrossRef49
Danielle M. Doyle, Lawrence H. Einhorn. (2008) Delayed Effects of Whole Brain Radiotherapy in Germ Cell Tumor Patients With Central Nervous System Metastases. International Journal of Radiation Oncology*Biology*Physics 70:5, 1361-1364
CrossRef50
J. Szer. (2008) Harvesting haemopoietic stem cells for future use: rainy days, real or imagined?. Internal Medicine Journal 38:4, 227-228
CrossRef51
Giovanni Rosti, Ugo De Giorgi, Paolo Pedrazzoli. (2008) Are metastatic testicular tumors curable with high-dose chemotherapy and stem-cell rescue?. Nature Clinical Practice Oncology 5:3, 126-127
CrossRef52
Darren R Feldman, Robert J Motzer, Dean F Bajorin. (2008) Is high-dose chemotherapy effective in patients with relapsed or refractory germ cell tumors?. Nature Clinical Practice Urology 5:2, 78-79
CrossRef53
R. Ramírez-Camacho, D. Esteban Fernández, J.M. Verdaguer, M.M. Gómez Gómez, A. Trinidad, J.R. García-Berrocal, M.A. Palacios Corvillo. (2008) Cisplatin-induced hearing loss does not correlate with intracellular platinum concentration. Acta Oto-laryngologica 128:5, 505-509
CrossRef54
C. Sammler, J. Beyer, C. Bokemeyer, J.T. Hartmann, O. Rick. (2008) Risk factors in germ cell tumour patients with relapse or progressive disease after first-line chemotherapy: Evaluation of a prognostic score for survival after high-dose chemotherapy. European Journal of Cancer 44:2, 237-243
CrossRef55
C. Massard, K. Fizazi. (2007) Autogreffe dans les cancers du testicule. Oncologie 9:12, 821-826
CrossRef56
(2007) News and Views. Clinical Pharmacology & Therapeutics 82:5, 484-485
CrossRef57
(2007) Germ-Cell Tumors. New England Journal of Medicine 357:17, 1771-1774
Full Text58
Paolo Pedrazzoli, Giovanni Rosti, Simona Secondino, Ornella Carminati, Taner Demirer. (2007) High-Dose Chemotherapy With Autologous Hematopoietic Stem Cell Support for Solid Tumors in Adults. Seminars in Hematology 44:4, 286-295
CrossRef59
Jacyntha A. Sterling. (2007) Hospital Pharmacy Pulse - Recent Publications on Medications and Pharmacy. Hospital Pharmacy 42:9, 866-870
CrossRef
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