Popovic L, Matovina-Brko G, Popovic M, Petrovic D, Cvetanovic A, Vukojevic J, Jovanovic D. High dose chemotherapy with stem cell support in the treatment of testicular cancer. World J Stem Cells 2015; 7(11): 1222-1232 [PMID: 26730267 DOI: 10.4252/wjsc.v7.i11.1222]
Corresponding Author of This Article
Lazar Popovic, MD, PhD, Department for Medical Oncology, Oncology Institute of Vojvodina, Put Dr Goldmana 4, 21204 Sremska Kamenica, Serbia. lazar.popovic@yahoo.com
Research Domain of This Article
Oncology
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Review
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Lazar Popovic, Gorana Matovina-Brko, Milica Popovic, Jelena Vukojevic, Darjana Jovanovic, Medical School, University of Novi Sad, 21000 Novi Sad, Serbia
Lazar Popovic, Gorana Matovina-Brko, Dragana Petrovic, Jelena Vukojevic, Darjana Jovanovic, Department for Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia
Milica Popovic, Department for Internal Medicine, Clinical Center of Vojvodina, 21000 Novi Sad, Serbia
Ana Cvetanovic, Department for Oncology, Clinical Center Nis, 18000 Nis, Serbia
ORCID number: $[AuthorORCIDs]
Author contributions: Popovic L wrote core of the manuscript, collected the data; Matovina-Brko G, Petrovic D and Vukojevic J collected the data; Popovic M collected the data and tables; Cvetanovic A collected the data, finalized the manuscript writing; Jovanovic D wrote parts of the manuscript.
Conflict-of-interest statement: Authors declare no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Lazar Popovic, MD, PhD, Department for Medical Oncology, Oncology Institute of Vojvodina, Put Dr Goldmana 4, 21204 Sremska Kamenica, Serbia. lazar.popovic@yahoo.com
Telephone: +381-21-4805569
Received: December 31, 2014 Peer-review started: January 1, 2015 First decision: February 7, 2015 Revised: September 18, 2015 Accepted: November 13, 2015 Article in press: November 17, 2015 Published online: December 26, 2015 Processing time: 359 Days and 0.9 Hours
Abstract
Testicular germ cell cancer (TGCC) is rare form of malignant disease that occurs mostly in young man between age 15 and 40. The worldwide incidence of TGCC is 1.5 per 100000 man with the highest rates in North Europe. After discovery of cisplatin cure rates of TGCC are very favorable between 90%-95% and unlike most solid tumors, cure rate for metastatic TGCC is around 80%. Metastatic TGCC is usually treated with 3-4 cycles of bleomycin, etoposide, cisplatinum chemotherapy with or without retroperitoneal surgery and cure rates with this approach are between 41% in poor risk group and 92% in good risk group of patients. Cure rates are lower in relapsed and refractory patients and many of them will die from the disease if not cured with first line chemotherapy. High dose chemotherapy (HDCT) approach was used for the first time during the 1980s. Progress in hematology allowed the possibility to keep autologous haematopoietic stem cells alive ex-vivo at very low temperatures and use them to repopulate the bone marrow after sub-lethal dose of intesive myeloablative chemotherapy. Despite the fact that there is no positive randomized study to prove HDCT concept, cure rates in relapsed TGCC are higher after high dose therapy then in historical controls in studies with conventional treatment. Here we review clinical studies in HDCT for TGCC, possibilities of mobilising sufficient number of stem cells and future directions in the treatment of this disease.
Core tip: High dose chemotherapy with autologous haematopoietic stem cell transplantation is effective option in treating relapsed metastatic germ-cell cancer. We reviewed this topic in regard of clinical studies, optimal mobilising and conditioning regimens, with special review on plerixafor in this indication. We also analysed riska adapted approach in those patients and future directions in field.
Citation: Popovic L, Matovina-Brko G, Popovic M, Petrovic D, Cvetanovic A, Vukojevic J, Jovanovic D. High dose chemotherapy with stem cell support in the treatment of testicular cancer. World J Stem Cells 2015; 7(11): 1222-1232
Testicular germ cell cancer (TGCC) is a rare form of malignant disease that occurs mostly in young man between age 15 and 40. The worldwide incidence of TGCC is 1.5 per 100000 man with the highest rates in Northern Europe[1]. One half of all TGCC are seminomas and other half are non-seminomas. The majority of TGCC arise from the gonads while around 5% arise from extragonadal sites in the body’s mid-line: retroperitoneum, mediastinum or brain[2]. After discovery of cisplatin TGCC cure rates have become very favorable ranging between 90%-95% and unlike most solid tumors, cure rate for metastatic TGCC is around 80%[1,2]. Metastatic TGCC is usually treated with 3-4 cycles of bleomycin, etoposide, cisplatinum (BEP) chemotherapy with or without retroperitoneal surgery and cure rates with this approach are between 41% in poor risk group and 92% in favourable risk group of patients[3] (Table 1). Cure rates are lower in relapsed and refractory patients and many of them will die from the disease if not cured with first line chemotherapy[3]. High dose chemotherapy (HDCT) approach was first used during the 1980s. Progress in hematology allowed the possibility to keep autologous haematopoietic stem cells alive ex-vivo in very low temperatures and using them to repopulate the bone marrow after sub-lethal dose of intensive myeloablative chemotherapy[4].
Table 1 Prognostic criteria for metastatic germ cell tumors[3].
Good prognosis group
Intermediate prognosis group
Poor prognosis group
Seminoma
90% of cases 5 yr PFS 82% 5 yr OS 86% All of the following criteria: Any primary site No non-pulmonary visceral metastases Normal AFP Any hCG Any LDH
10% of cases 5 yr PFS 67% 5 yr OS 72% Any of the following criteria: Any primary site Non-pulmonary visceral metastases Normal AFP Any hCG Any LDH
-
Non-seminoma
56% of cases 5 yr PFS 89% 5 yr OS 92% All of the following criteria: Testis/retroperitoneal primary Non non-pulmonary visceral metastases AFP < 1000 ng/mL hCG < 5000 IU/L (1000 ng/mL) LDH < 1.5 × ULN
28% of cases 5 yr PFS 75% 5 yr OS 80% Testis/retroperitoneal primary Non non-pulmonary visceral metastases AFP 1000-10000 ng/mL hCG 5000-50000 IU/L (1000 ng/mL) LDH 1.5-10 × ULN
28% of cases 5 yr PFS 75% 5 yr OS 80% Any of the following criteria: Mediastinal primary Non-pulmonary visceral metastases AFP > 10000 ng/mL hCG > 50000 IU/L (1000 ng/mL) LDH > 10 × ULN
RATIONALE FOR HIGH DOSE CHEMOTHERAPY
Resistance to chemotherapy is a major problem in the treatment of patients with malignant diseases. Large number of studies are directed towards finding and overcoming resistance mechanisms. One of the simplest and most logical way is to increase the dose of cytotoxic drugs[5]. The evidence that higher doses of cytotoxic drug kill more malignant cells has been well known for decades. Back in 1964, Skipper et al[6] demonstrated that the curve showing the dose dependency of the treatments with cytotoxic drugs is very steep, indicating that even a small increase of the cytotoxic drug dose will kill more malignant cells. Also, this curve for cytotoxic drugs, unlike the curves from other drugs, has no plateau, which means that a constant increase of the dose of cytotoxic drugs leads to a steady increase in numbers of destroyed malignant cells[6]. During the 1980s, Frei et al[7] showed a dose-dependent killing of malignant cells in AKR and L1210 cell lines. Frei et al[8] demonstrated the same on MCF7 breast cancer cells treated with alkylating agents BCNU, melphalan and nitrogen mustard. However, it was not possible to administer the 5 to 10-fold higher dose of chemotherapy in vivo due to the high toxicity and virtually lethal toxicity on bone marrow. Therefore, the researchers started to scrutinize bone marrow transplantation as a method for overcoming this high toxicity after chemotherapy[9]. Afterwards, numerous studies of high dose chemotherapy and autologous stem cell transplantation in a large number of solid tumor cases were completed, however, this form of treatment has remained standard practice only for TGCC[10-13].
CLINICAL TRIALS WITH HDCT TGCC
As already mentioned, the majority of patients with metastatic TGCC are cured with standard chemotherapy: 3-4 cycles of BEP protocols[3]. However, in patients with a poor prognosis, cure rate is below 50%. In these patients, and in patients with relapsed testicular cancer, unsatisfactory performance standard chemotherapy has directed researchers to search for new forms of treatment. The rationale of using high dose chemotherapy in chemo-sensitive cancer lead on investigators to start clinical trials with high dose chemotherapy and stem cell support[3,14].
HDCT AS THE INITIAL TREATMENT IN PATIENTS WITH POOR PROGNOSIS
The initial studies of high dose chemotherapy for patients with poor prognosis in the first line setting were completed in the nineties. Motzer et al[15,16] from Memorial Sloan-Kettering Cancer Center in phase II studies demonstrated slightly better response to HDCT compared to a historical control with the standard dose chemotherapy (SDCT). In a study from 1993, 15 of 27 patients (56%) achieved a complete remission, 46% were free of disease, and 57% alive after a median of 31.2-mo follow-up[15]. In another study by the same authors 30 patients were treated, 16 with etoposide, ifosfamide, cisplatin (VIP) chemotherapy, while 14 patients after VIP therapy, received HDCT, combination carboplatin, etoposide, cyclophosphamide (CEC). Patients selected for HDCT included those in whom tumour markers did not normalise after two cycles of chemotherapy. After a median follow-up of 30 mo, 15 (50%) patients remained progression-free. Patients treated with marker-dependent, early-intervention HDCT experienced longer survival[16]. Bokemeyer et al[17] published in 1999 a match-paired multivariate analysis which compared the outcomes of patients with poor prognosis metastatic TGCC treated sequentially with standard VIP protocol and HDCT in a multicentric study including patients from German group studies and patients treated in two studies from Indiana University, with BEP or VIP conventional chemotherapy. High dose chemotherapy group included 147 patients, while 309 patients were in the SDCT group. Patients treated with HDCT had a longer progression free survival (PFS) 75% vs 59% (P = 0.0056) and a longer overall survival (OS) 82% vs 71% (P = 0.0184)[17]. After that, Schmoll et al[18] from German Testicular Cancer Study Group (GTCSG) published a phase I/IIa study where they treated poor prognosis TGCC patients with a VIP-escalated protocol. After one cycle of standard VIP protocol, they applied dose escalated VIP with autologous stem cell transplantation, three to four cycles. Five-year PFS in this group of patients was 68%, which is longer than the historical control with SDCT. After the advent of paclitaxel, and proven effectiveness of this drug in cisplatin-resistant TGCC, GTCSG announced the study of addition of a paclitaxel to dose-escalated VIP protocol[19]. Addition of paclitaxel to high dose-VIP (HD-VIP) protocol resulted in higher response rate of 79%, and five-year PFS and OS of 64.1% and 75.2% respectively.
The only completed randomized phase III study is the one of Motzer et al[20]. This study included 219 untreated patients with metastatic TGCC intermediate and poor prognosis. One group of patients was treated with standard therapy, four cycles of BEP, while the experimental group received two cycles of BEP and afterwards two cycles high dose CEC (HD-CEC) protocol. Proportion of one year complete remission was not different in the two groups of patients (52% PEB + HD-CEC vs 48% BEP, P = 0.53). Benefit of a high dose chemotherapy, in this clinical trial, was observed only in those patients with unsatisfactory tumor markers decline. The study concludes that there is no benefit of adding a HDCT in this group of patients. Two other studies have started the third phase, but due to poor recruiting of patients they are not fully completed[21-23]. The analysis of the included patients from high dose chemotherapy did not show the expected benefit in first-line treatment of metastatic TGCC with a poor prognosis. A review of studies of the first line is given in Table 2.
Table 2 Studies of first line high dose chemotherapy for poor prognosis patients.
Therapeutic options of SDCT in patients with relapsed/refractory testicular cancer can achieve long-term remission of 25% of the cases with vinblastine, etoposide, ifosfamide (VeIP) protocol[24], to about 65% of patients treated with paclitaxel, ifosfamide, cisplatin (TIP)[25]. Considering the chemosensitivity of TGCC and relative modest results of conventional chemotherapy protocols, a large number of researchers have designed a variety of studies which applied HDCT with the support of haematopoietic autologous stem cell transplantation (Table 3).
Table 3 High dose chemotherapy as second line treatment.
Rodenhuis et al[26] have demonstrated a 54% PFS after a median follow-up of 37 mo in a phase II study on 35 patients. In this study they used two cycles of a HDCT after the induction with conventional chemotherapy. Similar design study was published in 2000[27]. Two cycles of intensification were used and the results were almost the same as in the previous study. The same year, Motzer et al[28] demonstrated overall survival of 54% after a median of nearly three years of follow-up. They used the induction regimen with paclitaxel and ifosfamide, and three cycles of high dose protocol carboplatin/etoposide (TI-CE). A slightly worse result was achieved in the study by Rick et al[29] which included only one cycle of high dose protocol after the induction with three cycles of TIP. Three-year survival in this study was 30%. The explanation for the slightly worse result in this study could be the application of only one cycle of high dose protocol.
The only prospective, randomized phase III study by Pico et al[30] compared four cycles of conventional chemotherapy VeIP or VIP with three cycles of of SDCT with the addition of one cycle of high dose carboplatin/etoposide (HD-CE) protocol. This study included a total of 263 patients. It did not demonstrate the superiority of the addition of one cycle of HDCT. Based on that study and study by Rick et al[29], it was concluded that one cycle of HDCT was not sufficient to achieve better results in treatment compared to conventional chemotherapy, so further studies had two or even three cycles of HDCT.
The study which probably had the greatest impact on the practice of treating relapsed TGCC and utilization of HDCT was that by Einhorn et al[31].
One hundred and eighty-four patients were retrospectively analysed, and 135 of 184 patients received two cycles of HD-CE protocol in the first relapse, while the other 49 were treated in second and subsequent relapses with the same protocol. After a median follow-up of four years, progression free survival in patients treated in the first relapse was 70%. Lorch et al[32] compared one cycle of high dose therapy with three cycles of to HD-CE. After long-term follow-up PFS was 49% vs 39% in favor of the sequential approach while overall survival did not differ between these two groups. Feldman et al[33] demonstrated in a prospective study of 107 patients a five-year PFS of 48% using the TI-CE protocol with three cycles of high dose chemotherapy.
A multicenter retrospective analysis of 1984 patients by Lorch et al[34] compared the standard and high dose chemotherapy in patients with metastatic TGCC after progression on first-line chemotherapy. Patients were divided into five prognostic groups according to previously established criteria: Very low risk, low risk, intermediate risk, high and very high risk[35]. Total of 1594 patients had all the data necessary for analysis, 773 of which received conventional chemotherapy, while 821 patients received HDCT. Two-year PFS and five-year OS was longer in the group with HDCT: 49.6% vs 27.8% (HR = 0.44; P < 0.001), 53.2% vs 40.8% (HR = 0.65; P <0.001). This difference was seen in all prognostic groups except in low-risk group[34].
Selle et al[36] in the study TAXIF II demonstrated efficiency of a complex protocol which included several high dose cycles of paclitaxel, thiotepa, ifosfamide, carboplatin and etoposide, after induction with a combination of paclitaxel/epirubicin. The median PFS was 22 mo and OS was 32 mo. Two-year PFS was 50%, with Kaplan-Meier curve that showed a plateau at that value, and two-year OS of 66%[36]. German Testicular Cancer Study Group retrospectively analyzed 143 patients and compared the HDCT (n = 95) with CDCT (n = 48). They showed a significantly longer median PFS 8 mo vs 42 mo (P < 0.001) with HDCT, but this difference was not seen when they analyzed overall survival[37].
HDCT FOR REFRACTORY AND HEAVILY PRETREATED PATIENTS
Patients who progressed during standard cisplatin based chemotherapy have the worst prognosis. This group of patients also includes those who have not been cured after two lines cisplatin protocol. For this group of patients there have been several studies that, despite the very poor prognostic characteristics, showed some benefit from HDCT (Table 4).
Table 4 High dose chemotherapy for third or subsequent lines, refractory/absolute refractory.
Vaena et al[38] retrospectively analyzed the results of HDCT in platinum-refractory patients. Two-year PFS was 32%, while two-year OS was 40%. Lotz et al[39] applied a different concept in refractory patients. In TAXIF study they prospectively treated 45 patients with absolutely refractory metastatic TGCC. After mobilization therapy with paclitaxel/epirubicin, they gave two cycles of high dose ifosfamide, carboplatin, etoposide (ICE) protocol. Three-year PFS and OS were 23.5%[39]. Kondagunta et al[40] prospectively treated 47 refractory patients with high dose chemotherapy. After a median of 40 mo of observation the PFS was 51%. The Study by Einhorn et al[31] treated 49 patients with HDCT in third and subsequent lines of chemotherapy. Time to disease progression and OS in these patients was 45% and 55% respectively. In patients with third and subsequent lines of therapy, Lorch et al[41] reached five-year OS of 17% at five-year PFS 27%. In a pilot study, we have treated 8 heavily pretreated patients with HDCT. We used a modified TAXIF protocol[39]. All patients had previously received four lines of different therapies. The median OS was 11 mo, with no long-term survival[42,43].
HDCT FOR EXTRAGONADAL GCC
Extragonadal GCC tumors occur most often in retroperitoneum and mediastinum and have worse prognosis compared to TGCC[2]. Several studies with high dose chemotherapy administration has addressed this subgroup of patients (Table 5). Bokemeyer et al[44] have treated patients with primary mediastinal germ cell tumors (PMNSGCT) initially with high dose chemotherapy. They included 28 patients and achieved 56% and 64% PFS and OS, respectively. Banna et al[45] also used HDCT in the first line of treatment PMNSGCT and reached a three-year OS 41%. Rosti et al[46] retrospectively analyzed 22 patients who had primary extragonadal non-seminomatous germ cell tumor (EGNSGCT) and received HDCT. Five-year survival in this group of patients was 75%. Hartmann et al[47] and De Giorgi et al[48] in two studies published in 1999 showed retrospective results of a treatment of EGNSGCT after progression on first-line therapy. Results were rather modest with 12%-14% long term survival.
Table 5 High dose chemotherapy for extragodadal germ cell cancer.
The first prognostic score related to the outcome of a HDCT was developed Beyer et al[49]. They have analyzed a series of 310 patients treated with HDCT in four centers in Europe and the United States and by multivariate analysis of prognostic factors determined the data which had influenced the outcome. Progressive disease before HDCT, primary mediastinal localization, refractory or absolute refractory disease to cisplatin therapy and the value of human chorionic gonadotropin (HCG) over 1000 were independent factors for failure-free survival (FFS) after HDCT. These parameters separated patients into groups with good, intermediate and poor prognosis. Patients with good, intermediate and poor prognosis had 51% FFS after HDCT, 27%, and 5% (P < 0.001) respectively. The International Prognostic Factors Study Group (Table 6) analyzed data of 1984 patients with TGCC, who have progressed after at least three cycles of cisplatin based chemotherapy. Patients’ data were collected from 38 centers worldwide and 1594 patients had sufficient data for analysis. Patients were treated with SDCT or HDCT based on carboplatin. Factors that influenced the outcome were: Site of primary tumor, previous response to therapy, progression free survival on previously applied therapy, alpha-fetoprotein and HCG above 1000 and the presence of metastases in the liver, bone and/or bone[35].
Table 6 International Germ Cell Cancer Collaborative Group-2 prognostic criteria for relapsed germ cell cancer patients.
Parameter
Score points
0
1
2
3
Primary site
Gonadal
Extragonadal
-
Mediastinal non-seminoma
Prior response
CR/PRm-
PRm+/SD
PD
-
PFI, mo
> 3
≥ 3
-
-
AFP salvage
Normal
≤ 1000
> 1000
HCG salvage
≤ 1000
> 1000
-
-
LBB
No
Yes
-
-
Score sum (0-10) Regroup into categories: (0) = 0; (1 or 2) = 1; (3 or 4) = 2; (5 or more) = 3 Add histology points: Seminoma = -1; Non-seminoma or mixed = 1 Final prognostic score: -1 = Very low risk; 0 = Low risk; 1 = Intermediate risk; 2 = High risk; 3 = Very high risk
Based on these factors, patients were divided into five categories: Very low risk with a two-year PFS of 72%, low risk with PFS 51%, medium risk with 40%, high risk with 26% and very high risk with 6%. This is followed by the already mentioned retrospective analysis by Lorch et al[34] which showed benefits in all prognostic categories, except in the low risk group. Given that the benefit was demonstrated even in the category of very low risk, there is a question in which prognostic groups, in patients with relapsed GCC, HDCT should be applied and which groups should receive conventional chemotherapy. Opinions differ greatly, and certain groups of authors believe that high dose chemotherapy should be applied in all patients with relapsed GCC, while some groups believe that patients with a low risk should be treated with the conventional chemotherapy in the second line, and HDCT should be applied in patients with medium and higher risk as well as in those with a low risk who relapse after second-line of conventional chemotherapy[50]. Our position is closer to the second opinion.
STEM CELLS MOBILISATION AND OPTIMAL PROTOCOL OF CONDITIONING
Collection of sufficient numbers of hematopoietic stem cells is a key step in the further implementation of a HDCT, and the possibility of treating patient with multiple cycles of HDCT. Combination of chemotherapy with granulocyte growth factor (G-CSF) is a standard for the mobilization of hematopoietic stem cells. However, in heavily pretreated patients, this method of mobilization is not enough to collect a sufficient number of stem cells. In our cohort of heavily pretreated patients median collected hematopoietic stem cells was 3.6 × 106 cells/kg of BW. Consequently, it was not possible for us to apply tandem transplantation in some patients[43]. Some other authors as well conclude that the mobilization with chemotherapy + G-CSF was inadequate for obtaining a sufficient number of stem cells, especially in cases of highly pretreated patients[4,51-53].
Plerixafor is the CXCR4 receptor antagonists which separate hematopoietic stem cells from bone marrow stroma and can lead to better mobilization of these cells into peripheral blood[54]. After the positive outcome in poor-mobilisers with lymphoma and multiple myeloma increased enthusiasm for using plerixafor to mobilize hematopoietic stem cells in patients with TGCC. The four smaller cohorts and three case studies[52-60] showed the efficiency of plerixafor in heavily pretreated patients with TGCC. Worel et al[55] showed the efficiency of plerixafor in 33 patients with non-hematologic diseases, of which 11 were metastatic GCC. A total of 28 (85%) patients gathered a sufficient number of stem cells. Kobold et al[57] showed a series of 6 patients who had previously received chemotherapy for 3.5 lines metastatic GCC and were not able to mobilize a sufficient number of stem cells for transplantation. After the use of plerixafor, five of these six patients mobilized an adequate number of cells for a minimum one transplant. Kosmas et al[52], in a pilot study, showed stem cells mobilization in pretreated patients with GCC, in which 7 out of 10 patients could yield an adequate number of hematopoietic stem cells for transplantation. The remaining three, poor-mobilisers, have amassed an adequate number of stem cells after applying plerixafor. In all these publications, engraftment of stem cells obtained after the mobilization with plerixafor was adequate.
Despite attempts with different drugs that would supplement carboplatin, such as thiotepa and ifosfamide, panelists of the third European consensus conference on the treatment of GCC, agreed that a combination of carboplatin and etoposide is a standard high dose protocol[50].
FUTURE DIRECTIONS
Although HDCT is considered standard treatment option for relapsed GCC in most major cancer centers, there are still no level IA evidence for applying HDCT in the current recommendations for the treatment of GCC[2,3,61]. The reason for this is the series of negative results of the randomized phase III studies by Motzer et al[20] in the first line, and Pico et al[30] in metastatic relapsed GCC, therefore TIGER (randomized phase III trial of initial salvage chemotherapy for patients with germ cell tumors) has been initiated[62]. The study design is shown in Figure 1. The plan is to include 390 patients, a group of which will receive four cycles of TIP protocol, while the second group will receive TI-CE protocol with three cycles of a HDCT. The hypothesis is that the overall survival of patients should be 13% higher after the treatment with the HDCT.
Figure 1 Training intervention and genetics of exercise response study design[62].
PD: Progressive disease; GCT: Germ cell tumors; HDCT: High dose chemotherapy; G-CSF: Granulocyte colony-stimulating factor.
The second concept is target therapy in addition to the treatment of relapsed GCC, for conventional, as well as for high dose chemotherapy. Vascular endothelial growth factor over-expression is an independent factor of poor prognosis for non-seminomatous germ cell tumor (NSGCT), especially for teratoma NSGCT which is the most refractory to chemotherapy[4]. Voigt et al[63] showed a case of successful treatment of patients absolutely refractory to cisplatin with bevacizumab and HD-ICE protocol. At the last ASCO meeting, Nieto et al[64] presented a phase II study for the first and the second relapse of intermediate and high risk metastatic GCC. They combined bevacizumab with tandem HDCT. In the first cycle of HDCT they combined bevacizumab with gemcitabine, docetaxel, melphalan and carboplatin, while in the second cycle they combined bevacizumab with HD-ICE protocol. One-year and 2 year-OS were 72% and 65% respectively[64]. In addition to these studies, there is an ongoing study TAXIF III, of the French group, with the addition of bevacizumab to HD-ICE protocol[65]. Approximately 70% of embryonic GCT express CD30 receptor on cell surface[66]. Brentuximab-vedotin is an anti-CD30 conjugated to a monoclonal antibody that has shown significant results in the treatment of Hodgkin’s and peripheral T-cell lymphomas[67]. The Italian group has started a phase II clinical study of efficiency brentuximab vedotin in refractory CD30-positive metastatic testicular cancer[68].
CONCLUSION
Although there are no randomized phase III trials that support HDCT as an effective treatment option for patients with metastatic GCT, the majority of centres use this type of therapy in patients with intermediate and high risk according International Germ Cell Cancer Collaborative Group-2 score[35]. TIGER study might give a definitive answer whether HDCT should be a standard treatment for these patients, and a better understanding of tumor biology, detection of markers of resistance to cisplatin, as well as if adding target therapy such as bevacizumab should improve the treatment of GCT, especially in the group of patients with a poor prognosis.
Footnotes
P- Reviewer: Aponte PM, Desai DJ, Yao CL S- Editor: Gong XM L- Editor: A E- Editor: Wu HL
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