Correspondence
Germ-Cell Tumors
N Engl J Med 2007; 357:1771-1774October 25, 2007
- Article
To the Editor:
Einhorn et al. (July 26 issue)1 report on high-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. One of the limitations of this study is the lack of a validation set for the prognostic scoring system. We addressed this lack of validation with support from the Orchid Cancer Appeal, by using our prospective database of 112 patients from a single institution who received dose-dense rather than high-dose chemotherapy for the treatment of germ-cell tumors.2,3 The characteristics of the patients in our cohort and those of the patients in the study by Einhorn et al. were very similar, with no significant difference in the proportion of patients in each of the three risk groups (P>0.05).
The prognostic scoring system in the study by Einhorn et al. was not validated by our data set (P=0.55) (Figure 1Figure 1
Overall Survival among 112 Patients with Metastatic Germ-Cell Tumors Who Received Dose-Dense Chemotherapy.). This result may be due to the different treatments used or to the small number of patients in the data sets, and it highlights the previous difficulty in finding consistent prognostic factors in patients with relapsed germ-cell tumors.4,5 5 ReferencesJonathan Shamash, M.D.
Justin Stebbing, Ph.D.
Thomas Powles, M.D.
St. Bartholomew's Hospital, London EC1A 7BE, United Kingdom1
Einhorn LH ,Williams SD ,Chamness A ,Brames MJ ,Perkins SM ,Abonour R . High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med 2007;357:340-348
Full Text | Web of Science | Medline2
Shamash J ,Powles T ,Ansell W , et al. GAMEC -- a new intensive protocol for untreated poor prognosis and relapsed or refractory germ cell tumours. Br J Cancer 2007;97:308-314
CrossRef | Web of Science | Medline3
Shamash J ,Oliver RT ,Ong J , et al. Sixty percent salvage rate for germ-cell tumours using sequential m-BOP, surgery and ifosfamide-based chemotherapy. Ann Oncol 1999;10:685-692
CrossRef | Web of Science | Medline4
Fossa SD ,Stenning SP ,Gerl A , et al. Prognostic factors in patients progressing after cisplatin-based chemotherapy for malignant non-seminomatous germ cell tumours. Br J Cancer 1999;80:1392-1399
CrossRef | Web of Science | Medline5
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 | Medline
To the Editor:
We tested the prognostic model of Einhorn et al. in 211 similar patients with relapsed or refractory germ-cell tumors whom we treated in a multicenter, prospective, randomized, trial in Germany.1 Indeed, the model did categorize groups of patients in our study population in a very similar fashion, albeit with inferior overall results. We believe the model can be further improved. It includes a second or subsequent salvage treatment as a strong negative factor, but as Einhorn et al. correctly state in the Discussion section of their article, such patients require high-dose treatment anyway, unless they have limited and resectable disease. The pressing question regarding whether to use high-dose or conventional-dose treatment arises in the first salvage setting. For first salvage treatment, no universally accepted score exists. Several groups have published systems that also include the primary tumor site, marker levels, and other factors.2,3 An analysis of prognostic factors only for first salvage treatment will probably require a much larger database than that of Einhorn et al. and should preferably be based on multicenter data.
3 ReferencesAnja Lorch, M.D.
Universitätsklinikum Giessen–Marburg, 35033 Marburg, GermanyJörg Beyer, M.D.
Vivantes Klinikum am Urban, 10967 Berlin, Germany
joerg.beyer@vivantes. de Carsten Bokemeyer, M.D.
Universitätsklinikum Hamburg–Eppendorf, 20246 Hamburg, Germany1
Lorch A ,Kollmannsberger C ,Hartmann JT , et al. Single versus sequential high-dose chemotherapy in patients with relapsed or refractory germ cell tumors: a prospective randomized multicenter trial of the German Testicular Cancer Study Group. J Clin Oncol 2007;25:2778-2784
CrossRef | Web of Science | Medline2
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 | Medline3
Fossa SD ,Stenning SP ,Gerl A , et al. Prognostic factors in patients progressing after cisplatin-based chemotherapy for malignant non-seminomatous germ cell tumours. Br J Cancer 1999;80:1392-1399
CrossRef | Web of Science | Medline
To the Editor:
In the retrospective study by Einhorn et al., paclitaxel chemotherapy was not administered. In other reports involving 84 patients with high-risk disease who were treated with paclitaxel and ifosfamide followed by high-dose chemotherapy (carboplatin and etoposide) with stem-cell transplantation, 55% had a durable complete remission, and 3 of 9 patients with mediastinal primary germ-cell tumors had a durable complete remission.1,2 Conventional paclitaxel, ifosfamide, and cisplatin chemotherapy in a low-risk population (e.g., in patients with testicular primary tumors and previous complete responses) yielded a rate of durable complete remission of 63% and was not associated with the toxic effects associated with high-dose chemotherapy with stem-cell transplantation.3 Stringent patient-selection criteria for high-dose chemotherapy with stem-cell transplantation may lead to better outcomes independently of therapy. Therefore, the question of whether salvage high-dose chemotherapy with stem-cell transplantation is superior to conventional chemotherapy in a low-risk population can be definitively answered only by means of a randomized trial.
3 ReferencesVaruni Kondagunta, M.D.
Matthew D. Galsky, M.D.
Guru Sonpavde, M.D.
U.S. Oncology Research, Houston, TX 77598
guru.sonpavde@usoncology. com 1
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 | Medline2
Kondagunta GV ,Bacik J ,Sheinfeld J , et al. Paclitaxel plus ifosfamide followed by high-dose carboplatin plus etoposide in previously treated germ cell tumors. J Clin Oncol 2007;25:85-90[Erratum, J Clin Oncol 2007;25:2149.]
CrossRef | Web of Science | Medline3
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 | Medline
To the Editor:
Einhorn et al. report impressive results with the use of up-front tandem high-dose salvage chemotherapy in patients with germ-cell tumors. We analyzed the outcome for patients with germ-cell tumors with a poor prognosis who received a single course of high-dose chemotherapy or a multicycle, high-dose salvage chemotherapy regimen with a very-low-dose intensity. After a median follow-up of 8 years, 1 of 19 patients with refractory tumors (5%) and 4 of 39 with relapsed tumors (10%), all of whom were treated with high-dose salvage chemotherapy as third-line or later therapy, remained disease-free. Recent randomized trials have not shown a benefit of other high-dose salvage chemotherapy regimens for patients with relapsed or refractory germ-cell tumors.1,2
Einhorn et al. conclude, “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.” We think that the up-front tandem high-dose salvage chemotherapy regimen should be further investigated in prospective studies.
2 ReferencesUgo De Giorgi, M.D.
Ospedale Vito Fazzi, 73100 Lecce, Italy
ugo_degiorgi@yahoo.com Paolo Pedrazzoli, M.D.
Ospedale Niguarda Cà Granda, 20164 Milan, ItalyGiovanni Rosti, M.D.
Ospedale Cà Foncello, 31110 Treviso, Italyfor the Italian Germ-Cell Cancer Group and Gruppo Italiano per il Trapitianto di Midollo Osseo, Cellule Staminali Emopoietiche e Terapia Cellulare
1
Lorch A ,Kollmannsberger C ,Hartmann JT , et al. Single versus sequential high-dose chemotherapy in patients with relapsed or refractory germ cell tumors: a prospective randomized multicenter trial of the German Testicular Cancer Study Group. J Clin Oncol 2007;25:2778-2784
CrossRef | Web of Science | Medline2
Pico JL ,Rosti G ,Kramar A , et al. A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours. Ann Oncol 2005;16:1152-1159
CrossRef | Web of Science | Medline
Author/Editor Response
With regard to the comments by Shamash and colleagues and Lorch and colleagues concerning our prognostic model, no staging system is ever ideal. Perhaps more robust data will be produced by a new international effort spearheaded by Lorch and Beyer, as mentioned in their letter. Our group, the Shamash group, and numerous other centers will contribute patient data.
Kondagunta et al. address other salvage chemotherapy strategies. They imply that paclitaxel should be an integral part of treatment regimens.1,2 Unfortunately, there are no data to substantiate or refute this claim. Motzer et al. reported data on 37 previously treated patients with unfavorable prognostic features who received two cycles of paclitaxel plus ifosfamide followed by three cycles of high-dose carboplatin plus etoposide given 14 to 21 days apart. Of these 37 patients, 15 (41%) had durable remissions with a median follow-up of 30 months.1 A follow-up report assessed an additional 48 patients, and 24 of the 48 remained progression-free with a median follow-up of 40 months.2 In our study, 67 of 123 similar patients (54.5%) had a durable remission with a median follow-up of 48 months. Thus, there is no clear indication that paclitaxel, dose-dense therapy, or a third course of high-dose carboplatin plus etoposide is required.
Kondagunta and colleagues also question whether high-dose salvage chemotherapy is required for patients with a low risk of relapse. In the study by Kondagunta et al., 29 of 43 patients had a durable remission with four courses of standard-dose paclitaxel plus ifosfamide plus cisplatin.3 By contrast, in our study, 49 of 61 similar patients with low-risk disease had a durable remission. I agree with Kondagunta and colleagues that only a phase 3 trial can prove the superiority of treatment in these patients with low-risk disease. However, it is unknown whether four courses of paclitaxel (250 mg per square meter of body-surface area, given as a 24-hour continuous infusion) plus ifosfamide (1.2 g per square meter for 5 days) plus cisplatin (20 mg per square meter for 5 days) are less toxic than our tandem transplantation regimen. Treatment-related mortality was similar (2%), neutropenic fever resulted in 26 hospitalizations for 22 patients (48%), and 3 patients (7%) had grade 4 or 5 renal toxic effects.
De Giorgi et al. mention the less favorable results achieved when only a single course of high-dose therapy was used, providing further support for the value of a tandem transplantation regimen.
3 ReferencesLawrence H. Einhorn, M.D.
Indiana University Cancer Center, Indianapolis, IN 46202-5289
leinhorn@iupui.edu 1
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 | Medline2
Kondagunta GV ,Bacik J ,Sheinfeld J , et al. Paclitaxel plus ifosfamide followed by high-dose carboplatin plus etoposide in previously treated germ cell tumors. J Clin Oncol 2007;25:85-90[Erratum, J Clin Oncol 2007;25:2149.]
CrossRef | Web of Science | Medline3
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 | Medline
