1 Istituto Oncologico Romagnolo-Santa Maria delle Croci Hospital, Ravenna, Italy; 2 Ankara University Medical School, Ankara, Turkey; 3 Klinikum Nuremberg, Germany; 4 University Hospital, Zürich, Switzerland; 5 Charite Humboldt University, Berlin, Germany; 6 University Hospital, Dresden, Germany; 7 University Hospital, Prague, Czech Republic; 8 Istituto Oncologico Romagnolo, Forlì, Italy
* Correspondence to: Dr U. De Giorgi, Department of Oncology and Hematology, Santa Maria delle Croci Hospital, viale Randi 5, I-48100 Ravenna, Italy. Tel: +39-0544-285247, Fax: +39-0544-285330; Email: ugo_degiorgi{at}yahoo.com
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients and methods: Between 1987 and 1999, 59 registered patients with retroperitoneal (n=37) and mediastinal (n=22) primary NSGCT, median age 28 years (range 1860), were treated with second-line HDCT. All had received cisplatin-containing chemotherapy as first-line treatment.
Results: Toxic death occurred in three cases (5%). With a median follow-up of 58 months (range 14114), 18/59 patients (30%) continue to be disease-free. Of three patients who had a disease recurrence after HDCT, one patient achieved a disease-free status with further chemotherapy and surgery. In total, 19 patients (32%) are currently disease-free. Sixteen of 37 patients (43%) with retroperitoneal NSGCT, and three of 22 patients (14%) with mediastinal NSGCT are currently alive and disease-free.
Conclusions: Second-line HDCT might represent a possible option for patients with retroperitoneal primary NSGCT. New salvage strategies are needed for patients with mediastinal NSGCT.
Key words: EBMT, extragonadal, high-dose chemotherapy, non-seminomatous germ cell tumor, second-line chemotherapy
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Fossa et al. [8] defined prognostic factors in patients with NSGCT progressing or relapsing after primary platinum-based chemotherapy, identifying a poor prognosis group with no patient surviving after 3 years. This group included patients with all the following three prognostic factors: progression-free interval after first-line chemotherapy of less than 2 years; no complete remission to induction therapy; and high markers at relapse [
-fetoprotein >100 ng/ml or ß-human chorionic gonadotropin (HCG) >100 IU/l]. These results have not been validated either in extragonadal NSGCT patients or in patients receiving high-dose chemotherapy (HDCT) as salvage therapy.
Beyer et al. [9] validated a prognostic index for patients with germ cell tumor receiving HDCT as salvage treatment. One point each was given for progressive disease before HDCT and mediastinal primary NSGCT or refractory disease. Two points were given for ß-HCG levels >1000 IU/l before HDCT or absolute refractory disease. Patients with a cumulative score
3 were placed in the poor risk category.
To characterize better the role of HDCT in patients with extragonadal NSGCT, the large database of the patients registered with the European Group for Blood and Marrow Transplantation (EBMT) was reviewed. This report describes the EBMT experience of second-line HDCT in patients with mediastinal and retroperitoneal primary NSGCT.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patient characteristics
Details of the 59 patients with extragonadal NSGCT relapsing after or during primary cisplatin-based chemotherapy are listed in Table 1. The median age was 28 years (range 1860). Fifty-five patients were male and four were female. Thirty-seven patients (63%) had primary retroperitoneal and 22 (37%) had primary mediastinal NSGCT. The majority (n=37, 63%) of these patients received cisplatin, etoposide and bleomycin (PEB) as first-line chemotherapy. Table 2 summarizes first-line chemotherapy regimens and response.
|
|
|
|
Statistical analysis
Descriptive statistics are presented as the median and range. 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. Probabilities of disease-free and overall survival were calculated using the KaplanMeier product limit estimate [11]. The log-rank test was used for comparisons of overall survival between groups [12
]. A P value of <0.05 was considered to be significant.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Response and survival
Overall, 21 (36%) patients achieved a CR. Of these patients, 16 obtained a radiological CR, the other five achieved a radiological PR and received post-HDCT resection of residual masses without evidence of viable malignant cells. Sixteen of 37 patients (43%) with retroperitoneal primary NSGCT, and five of 22 patients (23%) with mediastinal primary NSGCT achieved a CR. Results are presented in detail in Table 5. The median follow-up period for all patients was 14 months (range 1114) and 58 months (range 14114) for surviving patients. Eighteen of 59 patients (30%) continue to be disease-free. Of three patients who had a disease recurrence after HDCT, one underwent further chemotherapy and surgery and achieved a disease-free status. In total, 19 patients (32%) are currently disease-free (Table 5). Sixteen of 37 patients (43%) with retroperitoneal primary NSGCT, and three of 22 patients (14%) with mediastinal primary NSGCT are currently alive and disease-free. Figure 1 illustrates the outcome of patients with extragonadal NSGCT, according to the primary site. The median survival time was 28 months for patients with retroperitoneal NSGCT, and 11 months for patients with mediastinal primary. The 3-year overall survival rates were 48% and 14%, respectively.
|
|
According to the prognostic index validated by Beyer et al. [9], the only two patients stratified into the poor risk category died of disease after 5 and 14 months, respectively.
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We analyzed our results according to the prognostic index validated by the study of Fossa et al., which identified a poor prognosis group of NSGCT patients progressing after platinum-based first-line chemotherapy [8]. Patients with all three risk factors had a very poor prognosis and none of these patients survived beyond 16 months. Therefore, in the EBMT experience, the prognostic index also predicted outcome in patients with extragonadal NSGCT who received HDCT as salvage treatment.
In addition, we evaluated our results according to the Beyer prognostic classification for patients with germ cell tumor, treated with salvage HDCT [9]. Only two patients were stratified into the poor risk category and died of disease after 5 and 14 months, respectively. The publication in 1996 of the Beyer classification could have induced a better patient selection for salvage HDCT.
Several studies of salvage chemotherapy for patients with NSGCT included patients with extragonadal primary, but these patients usually represented a small percentage. Loehrer et al. [13] reported the largest experience with vinblastine, ifosfamide and cisplatin as second-line therapy for germ cell tumor. None of the 32 patients with non-seminomatous extragonadal tumors are disease-free compared with 30 of 100 patients with gonadal primaries. Other studies have investigated the use of HDCT in patients with relapsed NSGCT [9
, 14
16
]. Saxman et al. [14
] presented a series of 73 extragonadal NSGCT treated with salvage chemotherapy. Only 7% of their patients achieved long-term disease-free survival. None of the 28 patients who received HDCT as initial salvage treatment (n=8) and as third-line treatment (n=20) were long-term disease-free. In the large multivariate analysis reported by Beyer et al., including 282 patients with germ cell tumors treated with salvage HDCT, mediastinal primary site and refractory disease were identified as the most important poor prognostic factors [9
]. Recently, Vaena et al. [15
] showed a 37% long-term survival rate in 63 patients with platinum-refractory germ cell tumors treated with early tandem HDCT, but no patients with mediastinal primary NSGCT survived disease-free at 2 years.
In the largest reported series including 142 patients with relapsed extragonadal NSGCT treated with second-line chemotherapy, patients with retroperitoneal primary NSGCT achieved a long-term survival rate of 30%, but those with mediastinal primary had salvage rates of less than 10% [7]. Both primary mediastinal location and refractoriness to cisplatin were found to be independent negative factors. In this series, 28% of patients with mediastinal primary and 41% of patients with retroperitoneal NSGCT were treated with second-line HDCT. The median survival time was 15 months for patients receiving HDCT and 11 months for patients treated with standard-dose chemotherapy. Although, the survival curves are in favor of HDCT, there was no statistically significant difference between both groups in term of median survival (P=0.27). However, seven of 22 (32%) patients with retroperitoneal NSGCT receiving HDCT and 11/39 (28%) who underwent conventional-dose chemotherapy were alive without disease. In total, the 3-year overall survival for the subpopulation of patients with chemosensitive retroperitoneal primary NSGCT was 26%, while for patients with chemosensitive mediastinal primary it was 11%.
In the EBMT experience, all extragonadal NSGCT patients, but one, were chemosensitive (Table 2). The 3-year overall survival for patients with retroperitoneal primary NSGCT was 48%, while for patients with mediastinal primary it was 14%, as shown in Figure 1. Results in the subset of chemosensitive retroperitoneal NSGCT might appear in favor of the use of second-line HDCT, while HDCT has no substantial impact on the outcome of patients with mediastinal primary site. However, this hypothesis must be considered with caution because a systematic bias based on patient selection for HDCT might have influenced these findings.
In order to clarify the exact role of HDCT in patients with chemosensitive germ cell tumors, a phase III randomized study performed by EBMT (IT-94 study) was carried out [17]. This trial compared four courses of conventional salvage chemotherapy with three courses of the same regimen followed by one single shot of HDCT. Definitive results will possibly better define the role of HDCT in the subpopulation of patients with extragonadal NSGCT, but the number of these patients, not included in the present analysis, was too limited to draw any firm conclusion.
In summary, results of the EBMT experience showed a possible role for second-line HDCT for chemosensitive patients with retroperitoneal NSGCT. Final results from larger studies could eventually better define the role of salvage HDCT for patients with extragonadal NSGCT. New strategies are needed for salvage treatment of patients with mediastinal NSGCT.
![]() |
Appendix |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Received for publication May 1, 2004. Revision received August 25, 2004. Accepted for publication August 26, 2004.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Hainsworth CR, Greco FA. Extragonadal germ cell tumors and unrecognized germ cell tumors. Semin Oncol 1992; 19: 119127.[ISI][Medline]
3. Nichols CR, Roth BJ, Heerema N et al. Hematologic neoplasia associated with primary mediastinal germ-cell tumors. N Engl J Med 1990; 322: 14251429.[Abstract]
4. Hartmann JT, Nichols CR, Droz JP et al. Hematologic disorders associated with primary mediastinal nonseminomatous germ cell tumors. J Natl Cancer Inst 2000; 92: 5461.
5. Vuky J, Bains M, Bacik J et al. Role of post-chemotherapy surgery in the management of patients with noseminoma arising from the mediastinum. J Clin Oncol 2001; 19: 682688.
6. International Germ Cell Consensus Classification. A prognostic factor-based staging system for metastatic germ cell cancersInternational Germ Cell Cancer Collaborative Group. J Clin Oncol 1997; 15: 594603.[Abstract]
7. 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: 16411648.
8. 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: 13921399.[CrossRef][ISI][Medline]
9. 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: 26382645.[Abstract]
10. Miller AB, Hoogstraten B, Staquet M, Winckler A. Reporting results of anticancer treatment. Cancer 1981; 47: 207214.[ISI][Medline]
11. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457481.[ISI]
12. Cox DR. Regression models and life tablets. J R Stat Soc B 1972; 3: 187202.
13. 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 1998; 16: 25002504.[Abstract]
14. Saxman S, Nichols CR, Einhorn LH et al. Salvage chemotherapy in patients with extragonadal nonseminomatous germ cell tumors: The Indiana University experience. J Clin Oncol 1994; 12: 13901393.[Abstract]
15. 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: 41004104.
16. De Giorgi U, Rosti G, Papiani G et al. The status of high-dose chemotherapy with hematopoietic stem cell transplantation in patients with germ cell tumor. Haematologica 2002; 87: 95104.[ISI][Medline]
17. Rosti G, Pico JL, Wandt H et al. High-dose chemotherapy (HDC) in the salvage treatment of patients failing first-line platinum-based chemotherapy for advanced germ cell tumors (GCT); first results of a prospective randomised trial of the European Group for Blood and Marrow Transplantation (EBMT): IT-94 study. Proc Am Soc Clin Oncol 2002; 21: 180a (Abstr 716).