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High-dose treatment with carboplatin, etoposide, and ifosfamide followed by autologous stem-cell transplantation in relapsed or refractory germ cell cancer: a phase I/II study. The German Testicular Cancer Cooperative Study Group
Abstract
This trial evaluated the toxicity and efficacy of high-dose carboplatin, etoposide, and ifosfamide followed by autologous stem-cell transplantation in patients with refractory or relapsed germ cell cancer.
Between August 1989 and September 1992, 74 patients with refractory or recurrent germ-cell tumors received one cycle of escalating doses of carboplatin (1,500 to 2,000 mg/m2), etoposide (1,200 to 2,400 mg/m2), and ifosfamide (0 to 10 g/m2). Before high-dose therapy, two cycles of conventional-dose cisplatin, etoposide, and ifosfamide were administered to assess tumor responsiveness. Seventy-four patients were assessable for toxicity and 68 for response.
The doses of carboplatin 1,500 mg/m2, etoposide 2,400 mg/m2, and ifosfamide 10 g/m2 appeared to be safe. At this dosage, we treated 20 patients and observed World Health Organization (WHO) grade 3 and 4 hematotoxicity (100%), nausea (100%), diarrhea (30%), and hepatotoxicity (10%). All patients developed granulocytopenic fever. At carboplatin doses of 1,500 mg/m2, kidney toxicity was mild, with a median maximum creatinine level of 1.4 mg/dL (range, 1.1 to 3.0 mg/dL). However, at carboplatin doses of 1,750 and 2,000 mg/m2, we observed nonacceptable nephrotoxicity and neurotoxicity. Two (3%) patients died of treatment-related complications. Six patients required hemodialysis, which was temporary in five patients and permanent in one. Objective responses were obtained in 43 of 68 (63%) patients, including 21 (31%) complete remissions (CRs) and 14 (20%) inoperable partial remissions (PRs) with marker normalization. The median observation time of surviving patients was 12 months (range, 2 to 32). The probabilities of overall survival, event-free survival, and the relapse-free survival at 2 years were 44% (SD 8%), 35% (SD 6%), and 67% (SD 9%), respectively. Patients with disease refractory to conventional-dose pretreatment had a poor prognosis, with only one of 23 patients surviving event-free at 7 months after high-dose chemotherapy (HDT). In contrast, 24 of 45 (53.3%) patients with sensitive disease survive event-free with a probability of event-free survival at 2 years of 50% (SD 8%).
High-dose carboplatin, etoposide, and ifosfamide plus autologous stem-cell transplantation can be used in refractory and relapsed germ cell cancer with acceptable toxicity, and represents an effective, potentially curative salvage treatment.
... RPLND is also considered after PST for residual masses ≥ 1 cm [1]. Despite the high rate of long-term complete responses (CR) after this treatment strategy, patients with persistent and recurrent disease are burdened by a high rate of treatment failures [4][5][6][7][8][9][10][11]. Historically, NSGCT has been considered a radioresistant disease [12], and radiotherapy (RT) is consequently excluded from curative strategies. ...
... SBRT indeed produces a deep microenvironmental modification with endothelin dysfunction and enhanced vascular permeability. A single high dose of RT (8)(9)(10)(11) induces the activation of the acid sphingomyelinas enzyme at the endothelial cells' membrane, with consequent production of ceramide and activation of the apoptotic pathway [28,29]. This model of cell death is far different from the classical p53-driven death pathway causing of conventional fractionation dose of RT. ...
... Long-term complete response is obtained in 50-63% of patients treated with 2 cycles of VeIP followed by high dose chemotherapy or combination of Paclitaxel, Ifosfamide and Cisplatin (TIP) [6,7]. After second-line therapy, systemic treatment options yield a complete response rate of Tumor markers normalized within a month following RT and the residual thoracic mass receded within 6 months 15-20% [8][9][10][11]. Therefore, RT could play an important role in these patients, in view of the limited treatment options for platinum-refractory disease [50]. ...
Historically, non-seminomatous germ cell tumor (NSGCT) has been considered a radio-resistant disease, excluding radiotherapy (RT) from curative strategies. However, case series exploring the use of radiation treatment in this setting are often outdated, and prospective ongoing studies testing new radiotherapeutic approaches in NSGCT are lacking. Considering that tremendous advances in radiotherapy technology have enabled improved precision in RT delivery as well as dose escalation while decreasing treatment-related morbidity, we overviewed the currently available literature to explore the radiobiological basis, the technical issues, and potential strategies for implementation of RT in the management of this clinical entity. The purpose of the present overview is to provide insight for future research in this unexplored scenario. In summary, the biological rationale for RT use and potential implementation with systemic therapies exist, especially considering the advantage of new technologies, which were unavailable in the era of early literature reports. The NSGCT radioresistance paradigm could be based only on the fact that effective treatment schedules were simply undeliverable with older RT techniques due to toxicity issues, but the availability of actual techniques may prompt further exploration to offer treatment alternatives to these patients. Ongoing trials on this issue are lacking, but potential areas of research are platinum-refractory disease and consolidation therapy for residual masses after PST.
... Although carboplatin has dose-limiting toxicities such as myelosuppression, there are relatively few nonhematological toxicities [3][4][5][6]. It is thus an important agent to be used widely in high-dose settings such as high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) [7][8][9][10][11][12]. ...
... CD34 + cells were infused. Neutrophils engrafted in all of the patients at median 9 days (range, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. Two patients (9%) relapsed during the study period. ...
... The number and severity of renal and hepatic toxicities were lower than suspected. This may be due to lower total doses of carboplatin in this study, ranging between 1200 and 1600 mg/m 2 , compared with previous literatures, which used ranges between 2000 and 2400 mg/m 2 [11,35]. Nonetheless, it is notable that the patients who experienced renal insults, the patient who had creatinine increased, and the patient who had renal AKI, had highest AUC last among all of the patients, on both the first and the last day. ...
Body surface area (BSA)-based carboplatin dosing is used in various centers due to practical issues of renal function-based dosing with area under the curve (AUC) measurement. Pharmacokinetic (PK) analysis of high-dose carboplatin was performed in pediatric solid tumor patients undergoing high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) with BSA-based dosing to calculate the AUCs achieved with this dosing method and to find the correlation between the PK and the renal functions and the adverse events. Carboplatin was administered as once daily intravenous doses at 300, 400, or 500 mg/m2/day over 1 h for 3 or 4 days. On the first and the last day of carboplatin administration, PK samplings were done at 0, 1, 2, and 5 h and only at 0 h on any other days. Mean AUC on the first and the last day were 4.85 ± 0.95 min × mg/mL and 5.27 ± 1.04 min × mg/mL, respectively (n = 23). Overall, negative correlations between the renal functions and the AUCs were mild to moderate, but they were stronger in nephrectomized patients. 51Cr-EDTA clearance decreased with statistical significance with each additional dose of carboplatin (P = 0.020). Optimal high-dose carboplatin dosing method and optimal target AUCs for the different tumors need further analysis.
... Other studies also tried to add more agents to carboplatin and etoposide. In the late 1980s, Siegert et al. [31] incorporated ifosfamide to carboplatin and etoposide. This regimen showed a CR rate of 31%; however, all patients developed neutropenic fever and 3% of the participants had treatmentrelated deaths [31]. ...
... In the late 1980s, Siegert et al. [31] incorporated ifosfamide to carboplatin and etoposide. This regimen showed a CR rate of 31%; however, all patients developed neutropenic fever and 3% of the participants had treatmentrelated deaths [31]. At that same time Motzer et al. [32] added cyclophosphamide instead which resulted in 40% CR, less neutropenic fever but more treatment-related deaths (12%). ...
Purpose of Review
Germ cell tumors (GCTs) are the most common solid tumors affecting men between ages of 20 and 34 years. Most of the cases, even in advanced disease, will have good prognosis. However, around 20–30% of advanced disease will be refractory or develop relapse after treatment. Herein, we review the current management of refractory/relapsed GCTs.
Recent Findings
Salvage treatment of GCTs has been a controversial topic for the last few decades. Conventional dose chemotherapy (CDCT), high-dose chemotherapy (HDCT) with stem cell infusion, and surgical salvage were proven to be effective and curative options in some cases. The international randomized trial (TIGER) will ultimately answer which chemotherapy approach may be optimal. Furthermore, the usage of immunotherapy is still under investigation with limited data so far in the setting of relapsed/refractory GCTs.
Summary
Curative paradigms including with CDCT and HDCT are possible, although novel approaches beyond HDCT are still needed to eliminate mortality from this disease.
... PEI chemotherapy is used as a salvage protocol in germ cell tumors [50,51] and may be considered a PBSC mobilization regimen before high-dose chemotherapy and ABSCT [52][53][54][55]. Studies reporting on chemomobilization with PEI do not necessarily provide information on the timing of G-CSF application and PBSC assessment [53][54][55]. ...
... PEI chemotherapy is used as a salvage protocol in germ cell tumors [50,51] and may be considered a PBSC mobilization regimen before high-dose chemotherapy and ABSCT [52][53][54][55]. Studies reporting on chemomobilization with PEI do not necessarily provide information on the timing of G-CSF application and PBSC assessment [53][54][55]. We identified 4 germ cell tumor patients, 1 ovarian cancer patient, and 1 pancreatoblastoma patient who underwent chemomobilization with PEI during the past 2 years at our department. ...
Successful collection of peripheral blood stem cells (PBSCs) depends on the optimal orchestration of mobilization chemotherapy, granulocyte colony stimulating factor (G-CSF) application, and CD34⁺ cell number assessment in the peripheral blood (PB). However, determining the optimal timing in accordance to the applied chemomobilization regimen can be challenging. Although most centers apply their own local timing schedules, a reliable timetable including the currently most often used mobilization regimens is lacking. We present a comprehensive analysis of the timing modalities for 11 of the most commonly used chemomobilization regimens. A retrospective analysis was performed on the clinical and PBSC collection parameters (including duration of G-CSF application, time point of CD34⁺ assessment, PB CD34⁺ cell count, number of leukapheresis [LP] sessions, processed blood volume, and CD34⁺ collection results) of 91 representatively selected patients who had undergone stem cell mobilization at 2 collection centers.
Six to 10 patients were analyzed per regimen with a variety of diagnoses, including multiple myeloma, malignant lymphoma, and sarcoma. No collection failures (<2 × 10⁶ CD34⁺ cells/kg body weight) were observed. All analyzed patients successfully reached their individual collection goal in adherence to the given schedule of chemotherapy, application of G-CSF, measurement of CD34⁺ cells, and subsequent LP.
The presented data on the timing of chemomobilization, G-CSF application, and stem cell collection may be helpful in clinical decision making and contribute to a more transparent and predictable treatment process.
... New strategies are needed for patients with EGGCTs. Salvage chemotherapy and HDCT+ASCT do not provide long-term survival in patients with incomplete response, and complete response rates are low compared to gonadal GCTs 31,34 . Especially patients with mediastinal primary tumours and non-seminomatous patients have worse survival 5,6 . ...
Background
We aimed to evaluate the survival analysis, response rates and factors affecting response to high-dose chemotherapy (HDCT) and autologous stem cell transplantation (OSCT) in patients with relapsed/refractory extragonadal germ cell tumours.
Methods
The study included patients diagnosed with extragonadal germ cell tumors who underwent HDCT + ASCT between November 2016 and January 2023 at Gülhane Training and Research Hospital. Clinical characteristics and follow-up data were retrospectively analyzed from patient records and the hospital electronic system. Patients under 18 years of age and those without medical records were excluded. Patient characteristics, post-HDCT progression-free survival (PFS), overall survival (OS) data, factors affecting survival, and treatment-related mortality (TRM) were examined. The relationship between clinical factors and OS/PFS was analyzed.
Results
Twenty-five patients were included. After HDCT + ASCT, complete response (CR) was observed in 6 patients (24%), partial response (PR) in 15 patients (60%) and progressive disease (PD) in 4 patients (16%). TRM was observed in 1 (4%) patient. Median follow-up was 25.4 months. Median PFS and OS after HDCT + ASCT were calculated to be 4.9 months and 12.2 months, respectively.
Conclusions
Salvage HDCT + ASCT is an option in the treatment of extragonadal germ cell tumours, offering the potential for prolonged survival and cure.
... High peak plasma-free platinum concentrations, previous CPT chemotherapy, concomitant nephrotoxic agents, and history of renal failure are the most important risk factors (62)(63)(64). ...
Toxin and drug-induced nephrotoxicity (DIN) account for about 25% of all acute kidney injury cases and are associated with morbidity and increased utilization of healthcare services. No approved preventive compound is available for DIN. Saffron (Crocus sativus) has important biological properties like antioxidant and anti-inflammatory effects. The protective effects of saffron and its main constituents in different tissues including the brain, heart, liver, kidney, and lung have been confirmed against some toxic materials or drugs in animal studies. This review covers all aspects of saffron's preventive and therapeutic effects against toxins and DIN including proposed mechanism of action, dosing schedule, and effects on renal biomarkers and histological changes. PubMed, Embase, Scopus, and Web of Science databases were searched by these search terms: "saffron" OR "Crocus sativus" OR "crocetin" OR "crocin "OR "safranal" AND "Drug induced nephrotoxicity" OR "Renal Injury" OR "Kidney Injury" OR "Nephrotoxicity". All 25 relevant in vitro and in vivo studies up to the date of publication were included. Promising protective effects were reported particularly on aminoglycosides, cisplatin, and ethanol. Saffron and its constituents significantly prevented biochemical and histopathological changes, mediating via antioxidant, anti-apoptosis, and anti-inflammatory effects. Despite success in animal models, no human study is available in this field and further well-designed clinical trials are necessary for better judgment.
... 6 Second malignancies especially acute leukemia had been reported in < 2% cases. [23][24][25] Our study had similar toxicities as described in the literature with no treatment-related mortality or second malignancies. ...
Background Germ cell tumor (GCT) of the testis is one of the highly curable solid organ malignancies. Those who experience relapse after platinum-based chemotherapy can be salvaged with systemic therapy followed by high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). Complete remission can be obtained in approximately 50 to 60% of patients treated with HDCT. Our experience reports the efficacy and safety of HDCT followed by ASCT in relapsed GCT.
Methods Analysis of patient records (2012–2019) showed that three patients had received HDCT and ASCT.
Results All the three patients were treated with BEP (bleomycin, etoposide, and cisplatin) as first-line therapy. HDCT was done in Case 1 after third-line salvage and in other two patients after second-line salvage chemotherapies. High-dose carboplatin and etoposide were used as conditioning regimen. Granulocyte colony-stimulating factor was used for the mobilization of stem cells. After ASCT, complete remission was documented in all the patients. All were alive and disease-free till the last follow-up. Grade ¾ toxicities including myelosuppression, diarrhea, and mucositis were observed in all three patients.
Conclusion This is the first report from India on HDCT with ASCT in GCT. HDCT/ASCT seems to be feasible, safe, and effective in relapsed testicular GCTs.
... The CE regimen protocol included 700mg/m 2 carboplatin combined with 750 mg/m 2 etoposide on days one to three and autologous stem cell reinfusion on day six [13]. For the ICE regimen, ifosfamide 12 g/m 2 (divided into one to six days), carboplatin 1,200 mg mg/m 2 (divided into one to six days) and etoposide 1,200 mg/m 2 (divided into one to six days) were used and autologous stem cell reinfusion on the eighth day [14]. ...
Purpose:
Testicular cancer is the most commonly diagnosed solid organ malignancy in 15 to 35 year-old men with 1% incidence among all malignancies. Sixty percent of patients with mild and poor-risk factors need additional treatments. Starting in 1980s, high dose chemotherapy regimens (HDCT) that were not applicable before due to hematological toxicity have been brought into use, and survival and cure possibility have increased. To date, no randomized trial has been conducted to demonstrate superiority of high-dose chemotherapy protocols used for autologous stem cell transplantation (ASCT). Our study aims to compare two commonly used HDCT regimens for a long period, with real-life data.
Methods:
Approval for thiss retrospective study was obtained from the ethics committee of Gülhane Training and Research Hospital. Fifty refractory testicular cancer patients above 18 years were treated with HDCT and ASCT at Gülhane Training and Research Hospital (January 2011-July 2018).
Results:
Fifty metastatic, refractory testicular carcinoma patients with a median age of 34 were included in the study. Ninety per cent of the cases had stage III disease at diagnosis. Except for 8 patients (16%) at mild risk group, all the other patients were at high risk. CE was used as salvage treatment for half of the patients and ICE was used for the other half. Four patients responded completely and 30 responded partially to ASCT. Post transplantation median progression-free survival (PFS) was 22 months. Median overall survival (OS) in the general population was 223.4 months (76.1-370.7). Although there was a difference in OS between chemotherapy groups, the difference was not statistically significant. The mean duration of engraftment in patients treated with CE was 11.2 ± 2.3 days, while in patients receiving ICE it was 15.5 ± 2.1 days. This difference between chemotherapy groups was statistically significant (p<0.001).
... In a phase 2 study led by the Eastern Cooperative Oncology Group (ECOG) for patients with relapsed/refractory GCT, a regimen of HDCT with carboplatin and etoposide with autoHCT led to cure in 23% of cases [10]. Several other single-arm prospective and retrospective studies demonstrated a benefit with HDCT [7,11,12]. In an observational multicenter study of patients with advanced GCT who received either HDCT or CDCT as first-line salvage treatment, HDCT demonstrated better progression-free survival (PFS) in all prognostic groups [13]. ...
The curative potential of autologous hematopoietic cell transplantation (autoHCT) for male germ cell tumors (GCTs) is well established. The optimal timing and number (single transplant [ST] versus tandem transplants [TT] versus triple transplants) of autoHCT are controversial, with wide practice variations. We examined survival trends among 2395 recipients of autoHCT for male GCTs between 1990 and 2015 reported to the Center for International Blood and Marrow Transplant Research. Trends and outcomes were analyzed by year of transplantation for intervals 1990 to 1994 (N = 288), 1995 to 1999 (N = 351), 2000 to 2004 (N = 376), 2005 to 2009 (N = 509), and 2010 to 2015 (N = 871). Multivariate analysis was restricted to the subset from 2000 to 2015 with research-level data (n = 267). The median duration of follow-up was 51 months. The median age at autoHCT was 31 years; 633 patients (26%) had primary extragonadal GCT, and 1167 (49%) underwent TT. The 3-year progression-free (PFS) and overall survival (OS) improved from 24% (95% confidence interval [CI], 18% to 31%) and 35% (95% CI, 29% to 40%), respectively, in 1990 to 1994 to 47% (95% CI, 43% to 50%) and 54% (95% CI, 50% to 57%), respectively, in 2010 to 2015 (P < .0001). TT recipients were more likely than ST recipients to undergo autoHCT as first salvage treatment. The proportion of TTs increased from 38% of all autoHCTs in 2000 to 2004 to 77% in 2010 to 2015. Nonseminoma histology, residual disease at autoHCT, >1 line of pretransplantation chemotherapy, and ST versus TT were associated with inferior PFS and OS. Post-transplantation survival has improved significantly over time for relapsed/refractory male GCT and is associated with the increased use of TTs (compared with STs) and performance of autoHCT earlier in the disease course.
... Data such as patients' ages, stages of diseases, prior chemotherapy pro- tocols, and chemotherapy cure cycles, responses to chemotherapies, radiotherapy histories, metastasectomy histories, relapse or refractor situations, and blood groups were obtained retrospectively from the patients' files. HDC protocols of all patients were as follows: ifosfamide 12 g/m 2 (divided into 1e6 days), carboplatin 1200 mg/m 2 (divided into 1e6 days), etoposide 1200 mg/m 2 (divided into 1e6 days) and stem cell reinfusion was performed on day 8. 13 ...
Aim
Even though ABO blood group surface antigens are expressed in red blood cells, they can be observed in many normal and pathologic cells. Relationship between ABO blood groups and progression and prognosis of cancer has been mainly demonstrated in gastric and pancreatic cancer. However there is no study in current literature about its relation with testicular cancer. The aim of this study is to demonstrate the prognostic value of the ABO blood group in nonseminomatous testicular cancer patients who treated with high dose chemotherapy and autologous stem cell transplantation.
Material and method
64 patients who diagnosed as non-seminomatous testicular cancer and treated with HDC and OSCT in Gulhane Medical Oncology Clinic between January 2011 and December 2016 were enrolled to the study. Patients' age, TNM stage, chemotherapy protocols and blood group characteristics were obtained retrospectively.
Results
The mean age of patients was 31.4 (18–61) years. Blood groups of patients' were as follows: A blood group 19 (29.7%), B blood group 7 (10.9%), O blood group 34 (53.1%), AB blood group 4 (6.3%). Rh was negative in 3 patients (4.7%) and Rh positive in 61 patients (95.3%). 1-year progression-free survival (PFS) was 72.5% and 2-year PFS was 68.4%. 1-year overall survival (OS) was 82% and 2-years OS was 72%. While 1-year and 2-year OS was 88.2% and 84.4% in O blood group individuals, respectively, it was 75.6% and 59.5% in all other blood types, respectively. Although the OS was superior in individuals with O blood group, the difference was not reached the statistically significance (p = 0.071). When O blood group was compared with other blood groups in terms of PFS, 1 year PFS was 79.1% in O blood group and 65.2% in the all other blood groups (p = 0.19).
Conclusion
OS and PFS were superior in O blood group than other blood groups, however the difference was not reached statistical significance. In the literature, there is no study that focused on the relationship between stem cell transplantation and blood groups. ABO blood groups are the phenotype of a person's genotype and may reflect differences in the individual's immune mechanisms. However, due to small number of cases and heterogeneity of the group, the results and the strength of the study may have affected negatively. So, the prognostic importance of ABO blood groups can be shown with multi-center studies that performed with larger number of cases.
... A variety of strategies have been reported to optimize the efficacy of CE-HDCT comprising escalating dosages of the cytotoxic compounds, including a third cytotoxic drug, modifying the preceding mobilization chemotherapy, or, finally, increasing the number of HDCT cycles [2,[7][8][9][10]. Whereas the optimum number of HDCT cycles with ASCT in relapsed GCTs has so far never been formally proven, the majority of salvage strategies in GCT patients involve at least two HDCT/ASCT cycles [3,10,11]. ...
Sequential high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) is a curative option in relapsing germ cell tumor (GCT) patients, and complete remission (CR) after the first ASCT (early CR2) is associated with favorable outcome. Prognostic factors predicting early CR2 have not been investigated so far. We analyzed consecutive patients with a first relapse of GCT treated with three sequential cycles of carboplatin/etoposide-based HDCT with ASCT in the two largest academic centers in Switzerland. The cohort comprised 96 relapsing GCT patients, with 19 (19.8%) patients achieving early CR2 after the first HDCT cycle. The median progression-free survival and overall survival were not reached in patients achieving early CR2, whereas they were 9.6 months (P = 0.0301) and 34.8 months (P = 0.0684) for patients missing early CR2. Patients with early CR2 more often had CR1 after first-line bleomycin, etoposide, and cisplatin chemotherapy (68.4 vs. 31.6%; P = 0.0037) and an interval longer than 2 years between initial diagnosis and first HDCT (36.8 vs. 15.6%; P = 0.0373), but less often a histology of mixed nonseminomatous tumor (46.8 vs. 21.1%; P = 0.0418). These data suggest that response to first-line chemotherapy, late relapse, and histology are associated with achieving early CR2 after a first HDCT with ASCT in relapsing GCT patients.
... Seven studies using three cycles of high-dose therapy with autologous stem cell rescue and salvage paclitaxel plus ifosfamide followed by carboplatin plus etoposide (TI-CE regimen) has been summarized [45, 47-50, 56, 62] in Table 6. We included 11 studies [33,34,37,41,44,51,52,57,[59][60][61] regarding RR GCC patients treated with non-CE based regiments and one cycle of high-dose therapy. In Table 7, we summarized the results of five studies [14,35,[38][39][40] regarding RR GCC patients treated with non-CE-based regimens and two or more cycles of high-dose therapy with ASCT. ...
... 4,37 Salvage treatment includes CTX, RTX and myeloablative CTX with autologous stem cell transplantation. 38,39 Conclusion Intracranial germ cell tumours are a heterogeneous group of tumours that have different prognoses, and therefore accurate diagnosis and staging is essential for treatment planning. Since the number of patients that recover from these tumours is increasing over time, we should identify low-risk patients in whom treatment could be minimised to reduce its impact on the quality of life of survivors without jeopardising long-term survival, and intensify treatment in high-risk groups to achieve a higher rate of recovery. ...
Introduction
Intracranial germ cell tumours are rare in children. They are a heterogeneous group of neoplasms that show different clinical manifestations despite having a common origin.
Patients and methods
A retrospective analysis was carried out on the epidemiological and histological characteristics, clinical manifestations, and outcomes of 20 patients diagnosed with intracranial germ cell tumours in the Niño Jesús Children's Hospital of Madrid from 1994 to 2014.
Results
A total of 20 patients were identified: 14 boys and 6 girls. The mean age was 11.1 years (range 2–18 years). Histological confirmation of the diagnosis was obtained in 95% of the patients. Of the 20 patients, 14 were pure germinoma (70%) and 6 non-seminomatous germ cell tumours (30%). The most frequent locations were pineal (45%) and suprasellar (45%). The most frequent clinical symptoms in pineal tumours at diagnosis were headache and vomiting (77.77%), followed by visual disturbances (44.4%). In suprasellar tumours it was polydipsia and polyuria (100%). At diagnosis, 90% of the patients received radiotherapy, and 55% received chemotherapy combined with radiotherapy. There was a relapse in 4 patients (20%), and 3 of them died. Overall survival was 80%; 85.7% for pure germinomas and 60% for non-seminomatous germ cell tumours.
Conclusions
The most common histological subtype was pure germinoma. Germ cell tumours include heterogeneous disease entities that have a variable prognosis. Thus, an accurate diagnosis is vital for patient counselling and treatment planning.
... Initial phase I/II studies achieved durable remissions with HDCT for a small subset of heavily pre-treated platinum-refractory patients with relapsed disease. [1][2][3] Survival for metastatic GCTs has dramatically improved from 5% in the early 1970s to about 80% today. 4,5 This improvement has been largely attributed to the advent of cisplatinbased chemotherapy and modern surgical techniques. ...
... Применение высокодозной ХТ (ВДХТ) с поддержкой клеток-предшественников гемопоэза определяет общий ответ на уровне 40-50% [5][6][7], однако токсичность, возникающая при ВДХТ, превышает возможную пользу. В данной ситуации представляется важным прогнозирование течения рецидива болезни, что позволит интенсифицировать лечение у больных с неудовлетворительным прогнозом и ограничиться стандартной терапией при благоприятном прогнозе. ...
Objective: to define predictors that influence longevity in patients with recurrent non-seminomatous germinal testicular tumors (NGTT) on standard second-line chemotherapy (CT) including cisplatin and iphosphamide. Statistical analysis was performed using the statistical packages Graph Pad Prism 4.00 for Windows and SPSS 15.0 for Windows. Subjects and methods. Case history data were analyzed in 693 patients with disseminated NGTT who had received current CT and followed up at the Department of Clinical Pharmacology and CT, N.N. Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences. The median follow-up was 32 (range 3-215) months. The disease progressed in 181 (26%) patients. Detailed information was available on the nature of second-line CT in only 138 patients. Half (71 (51.7%) of the 138 patients had second-line CT including iphosphamide. Uni- and multivariate analyses were made to identify predictors that influence longevity in patients with recurrent NGTT on standard secondline CT including cisplatin and iphosphamide. Results. Five-year overall survival (OS) was 32% (95% confidence interval 25-41%). The multivariate analysis showed the morphological pattern of a primary tumor (a yolk sac tumor component), a pre-induction CT lactate dehydrogenase (LDH) level of ?d1.5 units of the upper normal range, progression during induction CT, and a pre-second-line CT LDH level of ?d 1000 U/l to be negative predictors. According to the number of negative factors, the patients were classified into 3 groups: 1) good prognosis [n = 10 (14%) of the 71 patients], 100% 3-year OS; 2) intermediate prognosis (one negative factor) [n = 33 (46.5%) of the 71 patients], 50.2% 3-year OS; 3) poor prognosis (?d 2 negative factors), 6.7% 3-year OS. Conclusion. Standard iphosphamide-containing therapy enables all patients to be treated in the good prognosis group of those with recurrent NGTT. That fails to achieve such striking results in the intermediate and poor prognosis groups of patients with recurrent NGTT, which necessiates to search for new treatment regimens and approaches for these patient groups.
Despite having a higher mortality risk than conventional chemotherapeutics, high-dose chemotherapy (HDCT) has the potential to be curative in relapsed/refractory germ-cell tumors. Therefore, selecting the best patient group for this treatment is critical. This study aimed to determine the factors that affect survival in our relapsed/refractory GCT cohort who received HDCT and autologous stem-cell transplantation. Between September 2010 and 2020, we included in the study 44 relapsed/refractory male patients with GCT treated with HDCT plus autologous stem-cell transplantation. The patients’ demographic features, clinical characteristics, and treatment outcomes were evaluated. Statistical analyses were performed to identify risk factors associated with survival. The median age of all cohorts was 28 years. Thirty-six patients had nonseminomatous tumors, and 8 patients had seminomatous tumors. The most common primary tumor sites were the gonads (75%), followed by the mediastinum (15.9%) and the retroperitoneum (9.1%). After HDCT, 11 patients had a complete response, 12 patients had a partial response, and 17 patients had a progressive disease, respectively. About 23 patients (52.3%) experienced at least 1 treatment-related grade 3 to 4 nonhematological toxicity. About 4 patients (10%) died due to HDCT-related toxicity. The total group’s median progression-free survival (PFS) was 7 months, and the median overall survival (OS) was 14.9 months. Primary tumor site (hazard ratio [HR]: 1.84; P = .028), type of HDCT regimen (HR: 0.35; P = .010), and best response to HDCT (HR: 11.0; P < .0001) were independent prognostic risk factors for PFS. The only independent prognostic risk factor associated with OS was the best response to HDCT (HR: 6.62; P = .001). The results of the study promise the best response to HDCT as a primary measure for predicting survival in relapsed/refractory GCT. In contrast, primary mediastinal GCT is not a good candidate for HDCT. Furthermore, a carboplatin–etoposide regimen in combination with cyclophosphamide and paclitaxel may improve PFS.
Relapsed testicular germ cell tumours (GCTs) might be cured with salvage chemotherapy. Accepted salvage treatment is conventional-dose chemotherapy (CDCT) or high-dose chemotherapy (HDCT). HDCT with peripheral blood stem cell transplant might produce a higher number of durable responses than CDCT. We discuss studies reporting on outcomes of salvage HDCT in relapsed GCTs. The most reproducible results were achieved with HDCT with two cycles of etoposide and carboplatin or three cycles of the paclitaxel, ifosfamide, carboplatin and etoposide regime. Using these two regimens, sustained cure rates of 50-66% were reported in phase I, phase II and retrospective studies published in the past two decades. Cure rates in patients with cisplatin-resistant disease are between 30% and 45%. Two phase III randomized studies were conducted with certain limitations and were unsuccessful in showing a survival benefit of HDCT. Thus, salvage treatment remains a controversial topic. Salvage HDCT with peripheral blood stem cell transplant and CDCT are two recommended treatment options for relapsed GCTs. Consistently reported cure rates from phase I, phase II and large retrospective studies support the use of HDCT in the hands of an experienced team of oncologists.
Purpose
In this review, we summarize and discuss contemporary treatment standards and possible selection criteria for decision making after failure of adjuvant or first-line cisplatin-based chemotherapy for primarily localized or metastatic germ cell tumors.
Methods
This work is based on a systematic literature search conducted for the elaboration of the first German clinical practice guideline to identify prospective clinical trials and retrospective comparative studies published between Jan 2010 and Feb 2021. Study end points of interest were progression-free (PFS) and overall survival (OS), relapse rate (RR), and/or safety.
Results
Relapses of clinical stage I (CS I) patients irrespective of prior adjuvant treatment after orchiectomy are treated stage adapted in accordance for primary metastatic patients. Surgical approaches for sole retroperitoneal relapses are investigated in ongoing clinical trials. The appropriate salvage chemotherapy for metastatic patients progressing or relapsing after first-line cisplatin-based chemotherapy is still a matter of controversy. Conventional cisplatin-based chemotherapy is the international guideline-endorsed standard of care, but based on retrospective data high-dose chemotherapy and subsequent autologous stem cell transplantation may offer a 10–15% survival benefit for all patients. Secondary complete surgical resection of all visible residual masses irrespective of size is paramount for treatment success.
Conclusions
Patients relapsing after definite treatment of locoregional disease are to be treated by stage-adapted first-line standard therapy for metastatic disease. Patients with primary advanced/metastatic disease failing one line of cisplatin-based combination chemotherapy should be referred to GCT expert centers. Dose intensity is a matter of ongoing debate, but sequential high-dose chemotherapy seems to improve patients’ survival.
As cancer survival has improved over the years, more cancer patients will experience side effects of treatment and survive long enough to develop conditions like chronic kidney disease. Kidney function is considered in the choice and dosing of chemotherapeutic drugs, and development of chronic kidney disease (CKD) and acute kidney injury can complicate medication and patient management. Development of acute kidney injury (AKI) is common during the clinical course of cancer patients and can be due to cancer-nonspecific causes like volume depletion and cancer-related causes like in multiple myeloma or can be therapy-related. The pathophysiology behind therapy-related AKI has broadened with the advent of targeted and immune-mediated cancer therapy. For patients who eventually progress to end-stage renal disease (ESRD), the discussion of pursuing renal replacement therapy is complex as both cancer and ESRD have their own impact on mortality and quality of life.
Résumé
Le taux de guérison des patients atteints d’une tumeur germinale métastatique tout pronostic confondu est de 80 %. Vingt à 30 % d’entre eux vont présenter une rechute après une première ligne de chimiothérapie ou sont réfractaires d’emblée aux sels de platine. Les formes de mauvais pronostic selon la classification internationale de consensus (IGCCCG) ont un moins bon pronostic avec une survie de l’ordre de 50 à 60 %. La plupart des rechutes proviennent de ce groupe de malades. Le bénéfice de la chimiothérapie intensive dans les formes de mauvais pronostic n’a pas été démontré en première ligne par rapport à la chimiothérapie standard. De nombreux essais ont évalué différents régimes de chimiothérapie pour les patients en rechute, et notamment la réalisation de chimiothérapie intensive (High-Dose Chemotherapy [HDCT]) avec recueil et réinjection de cellules souches hématopoïétiques périphériques (CSHP). La place de l’HDCT en traitement de rattrapage en deuxième et en troisième ligne a fait l’objet de nombreuses publications, et reste à démontrer. L’HDCT est une option thérapeutique importante, probablement chez des patients bien sélectionnés dès la première rechute et la communauté internationale attend les résultats de l’essai prospectif TIGER.
Peripheral blood stem cells (PBSCs) are preferentially used as a hematopoietic stem cell source for autologous blood stem cell transplantation (ABSCT) upon high-dose chemotherapy (HDT) in a variety of hemato-oncologic diseases. As a prerequisite, hematopoietic stem cells have to be mobilized into the peripheral blood (PB) and collected by leukapheresis (LP). Despite continuous improvements, e.g., the introduction of plerixafor, current challenges are the further optimization regarding the leukapheresis procedure, preventing collection failures, as well as benchmarking and harmonization of mobilization approaches between institutions.
Germ cell tumors (GCT) are the most common cancer in men between 15 and 35 years of age and the incidence has increased during the past several decades. This article reviews the current knowledge on high-dose chemotherapy (HDCT) and stem cell transplant for salvage treatment of patients with relapsed metastatic GCT. Furthermore, the authors attempt to dissect the controversy of using standard-dose versus high-dose therapy as initial salvage and identify patients who are most likely to benefit from HDCT and peripheral blood stem cell transplant.
Background
High-dose chemotherapy (HDCT) with autologous stem-cell transplantation (aSCT) has been a standard therapy for relapsed metastatic germ-cell tumors (GCTs) over the last 2 decades, but there have been many changes in practice over time with respect to stem-cell source, mobilization, and conditioning regimens. Mobilization is impaired with greater cisplatin exposure.
Patients and Methods
Patients with relapsed GCT who received HDCT/aSCT at Dana-Farber Cancer Institute between 1997 and 2017 were identified. Diagnosis, first-line chemotherapy, stem-cell mobilization, HDCT, toxicity, and survival outcomes were annotated and descriptively summarized. Univariable associations of clinicopathologic features and relapse and survival were assessed. Time-to-event analyses were performed by HDCT type and duration.
Results
Thirty-five eligible patients were identified. The most common regimen before HDCT was paclitaxel, ifosfamide, and cisplatin, and it resulted in a high rate of successful initial mobilization (95%). Ten patients (29%) were mobilized with filgrastim and plerixafor (CXCR4 antagonist). All plerixafor-treated patients were mobilized with sufficient cells for 2 transplants. Oxazaphosphorine (cyclophosphamide or ifosfamide)-containing (O-C) HDCT was provided between 1997 and 2008, and subsequent patients were treated with high-dose carboplatin plus etoposide (CE). O-C HDCT was associated with excessive cardiac (33%), severe liver (93%), and renal dysfunction compared to CE. Two O-C–treated patients died of drug-related lung toxicity. Fifty-one percent of the cohort experienced relapse, and 46% died.
Conclusion
Plerixafor has a role in stem-cell mobilization and aSCT for relapsed GCT when cisplatin in bridging before HDCT may be problematic. O-C and CE HDCT regimens have different toxicity patterns that are clinically meaningful.
Approximately 20-30% of patients with metastatic germ cell cancers (GCCs) can develop relapsed or refractory (RR) disease, about 40-50% of patients who relapse after salvage chemotherapy may reach long-term remission. The goal of this review was to identify patients who appear to benefit from high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT). To access this, we performed a systematic medical literature review to evaluate the effectiveness of HDCT in the frontline setting, as well as in patients with RR testicular cancer. We searched databases for interventional clinical studies and identified 5883 studies. We selected 49 studies for inclusion, which included a total of 5985 patients. Seventeen studies reported results of newly diagnosed poor-risk GCC patients and 32 studies reported results of RR patients. For newly diagnosed patients with poor prognostic predictors, a risk adjusted strategy using unfavorable tumor marker decline with initial standard chemotherapy regimen and upfront HDCT demonstrated improved outcomes. Our data suggest a minimum of two HDCT cycles with ASCT should be standard of care for patients with RR GCC. Failure of HDCT results in a poor prognosis with only 10% of patients achieving lasting remission with salvage therapy.
Introduced in the early 1970s for treatment of aplastic anemia and leukemia, hematopoietic cell transplantation (HCT) offers treatment for a growing number of patients with complex hematologic malignancies, dysfunctional or absent immune systems, inherited or acquired marrow failure, and selected genetic disorders including hemoglobinopathies and inborn errors of metabolism. The procedure involves a preparative regimen for suppression of the patient’s immune system followed by infusion of hematopoietic progenitor cells. There are two major forms of HCT: allogeneic and autologous. In allogeneic transplant, hematopoietic stem cells (HSC) are obtained from related or unrelated donor source after administration of high-dose cytotoxic therapy. Because of immunologic differences between the donor and recipient, graft-versus-tumor (GVT) or graft-versus-leukemia (GVL) effect can occur. Autologous HCT involves exposing patients to myeloablative doses of cytotoxic therapy followed by infusion of the patient’s previously stored hematopoietic stem cells. Current pediatric indications for autologous transplant include patients with certain lymphomas, neuroblastoma, and brain tumors.
We report the case of a patient who achieved complete remission (CR) of cisplatin-refractory metastatic pure seminoma after treatment with high-dose carboplatin and etoposide (CE) with peripheral blood stem cell transplantation as fourth-line chemotherapy. A 38-year-old man was diagnosed with advanced pure seminoma (pT3N3M1aS3). In the international germ cell consensus classification, his prognosis was classified as intermediate. He was treated with high-dose CE as fourth-line chemotherapy after treatment with BEP, VeIP, and TIN. After two cycles of high-dose CE, the concentrations of T-HCG and other tumor markers showed normal levels. A CT scan and PET–CT showed that the lymph node swelling had disappeared and there was no uptake. The CR has continued for 27 months after the treatment. High-dose CE might be less toxic and have a better prognostic outcome than other treatments as salvage chemotherapy for patients with cisplatin-refractory advanced testicular cancer.
Relapsed germ cell tumor (GCT) is a highly curable cancer with standard-dose platinum-based chemotherapy (CT); however, high-dose CT (HDCT) is seldom used as salvage therapy instead or after conventional CT. We conducted a systematic review of published trials to compare outcomes between standard-dose CT and HDCT in patients with relapsed GCT after first-line therapy for advanced disease. A literature search was carried out in multiple electronic databases (PubMed, Embase, Scopus, Web of Science, and The Cochrane Library), and studies reporting salvage treatment of relapsed GCT with standard-dose or carboplatin–etoposide-based HDCT were selected. Overall response rate, median overall survival (OS), and the 1-, 2-, 3-, and 5-year OS rates were pooled, and the significance of difference between arms was assessed with a Chi-square test. Twenty-nine standard-dose and 31 HD studies were included in the meta-analysis. For standard-dose CT versus HDCT, there was no significant difference in median OS (14.8 months and 24.09 months, respectively; P = 0.09) or in 1-, 2-, 3-, or 5-year survival rate (standard-dose CT, 64.2, 63.6, 45.1, and 43%, respectively; HDCT, 63.7, 51.2, 46.7, and 45%, respectively; P = 0.9, P = 0.4, P = 0.75, and P = 0.06). Conventional dose regimens and HDCT were associated with comparable efficacy when used as salvage therapies in relapsed GCTs as second-line therapy or beyond. However, the selection of ideal candidates for more or less intensive treatments deserves further research in the near future.
Overview
Cancer of the testis is a relatively uncommon disease, accounting for approximately 1% of all cancers in males. However, it represents a highly curable neoplasm, the incidence of which is focused on young patients at their peak of productivity. Curative treatment of disseminated nonseminomatous germ cell tumors often combines surgery and chemotherapy. The goal of initial therapy is never palliation or prolongation of survival, but cure.
The conventional therapy for CNS GCTs is irradiation [73], administered either alone (mainly for germinomas) or with chemotherapy (for non-germinomatous GCTs). Germinomas are exquisitely radiosensitive; 65% to 95% 5-year survival rates have been reported for patients with germinomas when the treatment is irradiation alone. Non-germinomatous GCTs are less sensitive to irradiation and the 5-year survival rates for patients afflicted with them range from 20% to 56% [58,82]. Notwithstanding its effectiveness, cranial irradiation may lead to long-term sequelae, including intellectual deterioration, not only in children [27], but also in adults [24]. It may also lead to growth retardation, endocrine dysfunction [22], hearing loss and about a 12% incidence of secondary tumors [52]. Craniospinal irradiation carries the additional morbidity of growth arrest, marrow suppression and damage to the gonadal organs. Reports of long term survivors of CNS GCTs treated with irradiation emphasize its long-term cognitive effects, including difficulties with school and social interactions.
Hodentumoren sind zu 98% Keimzelltumoren, der Rest sind Tumoren des Stroma- und Stützgewebes. In diesem Kapitel werden beide Gruppen getrennt dargestellt. Maligne Keimzelltumoren stellen die häufigsten bösartigen Tumoren junger Männer zwischen 20 und 35 Jahren dar. Bei einem Lebenszeitrisiko von 1: 500 (Davies 1981), an einem Keimzelltumor zu erkranken, bedeutete die Erkrankung vor der Ara cisplatinhaltiger Polychemotherapien wegen der hohen Malignität und Metastasierungsrate zugleich auch die häufigste Krebstodesursache von Männern in dieser Altersgruppe. Durch die Einführung der cisplatinhaltigen Polychemotherapien Ende der siebziger Jahre konnte die Heilungsrate auf insgesamt 90–95% gesteigert werden (Schmoll 1999a). Damit handelt es sich um den derzeit am besten behandelbaren Tumor im Erwachsenenalter mit der höchsten Heilungsrate.
Autologous hematopoietic progenitor-cell support (AHPCS), derived from bone marrow or from peripheral blood progenitor cells (PBPCs), allows for the dose escalation of chemotherapy up to 10-fold, exploiting the dose–response effect of alkylators and other drugs. While AHPCS circumvents myelosuppression, extramedullary organ toxicities become dose limiting. These substantial dose increments clearly increase the antitumor activity of high-dose chemotherapy (HDC) compared with standard dose chemotherapy (SDC), with the goal of improving patient outcome. Widespread substitution of PBPCs for bone marrow support and other improvements in patient care have increased the safety of HDC to current treatment-related mortality (TRM) rates below 5%. Since the advent of modern cisplatin-based chemotherapy, cure rates for metastatic germ-cell tumors have reached 70-80%. The standard first-line regimen of bleomycin/etoposide/cisplatin yields long-term event-free survival rates of 90% in advanced-disease good-risk patients.
Background:
High-dose chemotherapy (HDCT) has been studied in several clinical scenarios in advanced germ cell cancer (GCC).
Objective:
To establish a clinical practice guideline for HDCT use in the treatment of GCC patients.
Design, setting, and participants:
An expert panel reviewed information available from the literature. The panel addressed relevant issues concerning and related to HDCT. The guideline was externally reviewed by two international experts.
Results and limitations:
The efficacy of HDCT has been demonstrated in selected GCC patients. The most conclusive evidence comes from retrospective analyses that need to be interpreted with caution. HDCT can cure a significant proportion of heavily treated GCC patients. When indicated, sequential HDCT with regimens containing carboplatin and etoposide, as well as peripheral stem-cell support, is recommended. There is no conclusive evidence to recommend HDCT as first-line therapy. According to a multinational retrospective pooled analysis, HDCT might be superior to conventional CT as first salvage treatment in selected patients. There is an urgent need for prospective clinical trials addressing the value of HDCT in GCC patients who experience failure on first-line cisplatin-based CT. In patients who progress on conventional-dose salvage CT, HDCT should be considered. Treatment of these patients at experienced centers is strongly recommended.
Conclusions:
It has been demonstrated that HDCT cures selected GCC patients who experience disease progression on conventional rescue regimens. The panel recommends the inclusion of GCC patients in randomized clinical trials including HDCT.
Patient summary:
This consensus establishes clinical practice guidelines for the use and study of high-dose chemotherapy in patients with germ cell cancer.
Germ cell cancer (GCT) is an uncommon malignancy that occurs most often in young men, and accounts for about 1% of malignancies in men. Although highly curable, particularly when discovered early, stage at presentation is the predominant factor in determining outcome and treatment. Fortunately, even patients who present with disseminated disease can be cured with cisplatin-based combination chemotherapy (CT) and aggressive surgical extirpation of residual disease. There are, however, groups of patients who do poorly despite the best therapeutic efforts: Some of these have poor prognostic factors at diagnosis, such as far-advanced disease, choriocarcinoma, or markedly elevated serum markers; others do not achieve remission, or relapse following primary or salvage therapy; and, finally, a few patients demonstrate refractoriness to cisplatin. In each of these settings, high-dose therapy (HDT) with hematopoietic stem cell rescue (HSCR) has been attempted, with varying degrees of success. This chapter examines these various settings and the trials, which have been performed to alter the otherwise dismal course of these patients.
Introduction:
Intracranial germ cell tumours are rare in children. They are a heterogeneous group of neoplasms that show different clinical manifestations despite having a common origin.
Patients and methods:
A retrospective analysis was carried out on the epidemiological and histological characteristics, clinical manifestations, and outcomes of 20 patients diagnosed with intracranial germ cell tumours in the Niño Jesús Children's Hospital of Madrid from 1994-2014.
Results:
A total of 20 patients were identified: 14 boys and 6 girls. The mean age was 11.1 years (range 2-18 years). Histological confirmation of the diagnosis was obtained in 95% of the patients. Of the 20 patients, 14 were pure germinoma (70%) and 6 non-seminomatous germ cell tumours (30%). The most frequent locations were pineal (45%) and suprasellar (45%). The most frequent clinical symptoms in pineal tumours at diagnosis were headache and vomiting (77.77%), followed by visual disturbances (44.4%). In suprasellar tumours it was polydipsia and polyuria (100%). At diagnosis, 90% of the patients received radiotherapy, and 55% received chemotherapy combined with radiotherapy. There was a relapse in 4 patients (20%), and 3 of them died. Overall survival was 80%; 85.7% for pure germinomas and 60% for non-seminomatous germ cell tumours.
Conclusions:
The most common histological subtype was pure germinoma. Germ cell tumours include heterogeneous disease entities that have a variable prognosis. Thus, an accurate diagnosis is vital for patient counselling and treatment planning.
In the year 2002, there will be an estimated 7500 new cases of testicular germ cell tumor (GCT) in the United States, of which approximately 400 will prove fatal [1]. While testicular GCT accounts for less than 1 % of all cancers, it represents the most common malignancy diagnosed in men aged 15–35. Both seminoma and nonseminomatous germ-cell tumors (NSGCT) generally occur in early adulthood, with the incidence of seminoma peaking at a slightly older age than nonseminoma. The prevalence of GCT is higher in Scandinavia and Switzerland than in Asian and African countries; the prevalence in the United States falls between these extremes. The incidence of these tumors appears to be rising in the United States [2].
Die Möglichkeiten der systemischen Therapie bösartiger Erkrankungen sind mit der Entwicklung neuer gentechnologischer und molekularbiologischer Methoden erheblich erweitert worden. In den letzten Jahren wurden zahlreiche Zytokine, die entscheidende Funktionen in Regelkreisen der Hämatopoese und des Immunsystems haben, isoliert, charakterisiert und durch den Einsatz molekularbiologischer Techniken in großen Mengen für therapeutische Zwecke produziert. Die Verfügbarkeit größerer Mengen von gentechnologisch hergestellten hämatopoetischen Wachstumsfaktoren (G-CSF, GM-CSF und IL 3) eröffnet die Möglichkeit, Therapieschemata, deren dosislimitierende Toxizität die Myelosuppression ist, in ihrer Dosisintensität entscheidend zu steigern. Die immunmodulatorischen Zytokine Interferon, Interleukin-2 und Interleukin-4 üben direkten Einfluß auf die antitumorale Reaktion des Immunsystems aus und können in bestimmten Situationen therapeutisch eingesetzt werden. Eine ganz neue Entwicklung stellt die gentechnologische Insertion von kodierenden DNS-Sequenzen in Tumor- oder Effektorzellen (sog. Gentherapie) dar. Die Einsatzmöglichkeiten dieser neuen Therapieoptionen in der urologischen Onkologie sollen im folgenden Kapitel diskutiert werden.
Trotz deutlicher Fortschritte in der Chemotherapie von soliden Tumoren, die durch die Neuentwicklung von Kombinations-Chemotherapie-Protokollen und die Neueinfuhrung weiterer aktiver Substanzen in den letzten Jahren erzielt werden konnten, bleibt die Chemotherapie für die Mehrzahl der Patienten mit fortgeschrittenen soliden Tumorleiden palliativ. Zwar induzieren moderne Chemotherapieprotokolle bei einer Anzahl von soliden Tumoren, so z.B. kleinzelligen Bronchialkarzinomen oder Mammakarzinomen deutliche Tumorrückbildungen bis hin zur klinisch kompletten Remission; in der Regel rezidivieren allerdings die meisten Patienten nach relativ kurzer Zeit und es entwickelt sich eine sekundäre Chemotherapieresistenz auf die initial erfolgreich eingesetzten zytostatischen Substanzen. Diese klinischen Erfahrungen zeigen, daß bei diesen Tumorentitäten zunächst eine Sensibilität der Tumorzellen auf die gegebene Chemotherapie besteht; allerdings scheinen die verwendeten Dosierungen bei der Mehrzahl der Patienten nicht in der Lage zu sein, die Tumorzellpopulation komplett abzutöten. Unter konventionellen Therapiebedingungen sind einer weiteren Dosiseskalation der wirksamen Substanzen enge Grenzen gesetzt, die durch die therapiebedingten Nebenwirkungen vorgegeben werden. Für zahlreiche Substanzen besteht die dosislimitierende Nebenwirkung in der Supression der Hämatopoese.
Der Keimzelltumor ist der häufigste bösartige Tumor des jungen Mannes zwischen 20 und 35 Jahren. In dieser Zeit ist das Lebenszeitrisiko für einen Hodentumor hoch mit 1:500. Vor Einführung der modernen cisplatinhaltigen Kombinationschemotherapie war der Keimzelltumor zugleich auch die häufigste Krebstodesursache des Mannes in dieser Altersgruppe. Während vor dieser Zeit die meisten Patienten mit fortgeschrittenem Hodentumor an ihrer Erkrankung verstarben, hat die Mortalität durch die Einführung der modernen Chemotherapie dramatisch abgenommen; heute versterben nur noch 1–5% der Patienten mit weniger fortgeschrittenen Stadien an ihrem Tumor und nur noch 40% der Patienten mit weit fortgeschrittenen Stadien, so daß die Heilungsrate insgesamt 90% beträgt — die höchste Heilungsrate bei einem Malignom im Erwachsenenalter überhaupt.
Testikuläre Keimzelltumoren gehören zu den Malignomen des Erwachsenen, die selbst im metastasierten Stadium in hohem Maße heilbar sind. Addiert man die Therapieergebnisse für alle Krankheitsstadien, so liegt die Gesamtüberlebensrate nach 5 Jahren bei circa 80%.
Unter dem Begriff männlicher Hypogonadismus versteht man alle Unterfunktionszustände der Testes, also die inkretorische und die sekretorische Insuffizienz. Hypogenitalismus bedeutet Unterentwicklung der äußeren Genitalien, Enuchismus den Zustand der Kastration und Eunuchoidismus die angeborene oder erworbene Insuffizienz der Keimdrüse [13].
Germ-cell tumours are rare diseases. However they occur in young patients and their prognosis was unfavourable before the introduction of cisplatin in chemotherapy regimens. Cisplatin based chemotherapy followed by the surgical removal of residual disease is the standard treatment of these tumours (1). Different prognostic classifications or models allow to assign patients in good-risk or poor-risk groups (2). The standard chemotherapy regimen in the good-risk patients group is either three cycles of a combination of cisplatin, etoposide and bleomycin (BEP) or four cycles of combination of etoposide and cisplatin (EP) (1).
Background:
Salvage treatment with either conventional-dose chemotherapy (CDCT) or high-dose chemotherapy with autologous stem cell transplantation (HDCT) offers curative potential for patients with relapsed or refractory germ cell tumor (GCT). However, the optimal initial salvage strategy remains controversial, and the criteria for appropriate patient selection are not clear.
Methods:
This was a retrospective analysis of the clinical outcomes for GCT patients receiving initial salvage therapy using a risk-stratified treatment approach. In general, patients with favorable-risk disease received CDCT with 4 cycles of paclitaxel, ifosfamide, and cisplatin, while patients with unfavorable-risk disease received HDCT per institutional protocol. The prognostic validity of the International Germ Cell Cancer Collaborative Group (IGCCCG) and the International Prognostic Factors Study Group (IPFSG) risk groups were evaluated in this context.
Results:
Thirty-seven patients received initial salvage therapy. Twenty-four patients (65%) achieved a favorable response (including complete response to chemotherapy alone, complete response after post-chemotherapy surgical resection, or partial response with negative tumor markers). The favorable response rates for the CDCT and HDCT treatment groups were 69% and 62%, respectively. After a median follow-up of 31 months, the median survival for CDCT-treated patients has not been reached, and the median survival for the HDCT-treated group was 24 months. Both the International Germ Cell Cancer Collaborative Group and the International Prognostic Factors Study Group risk groups were significantly associated with progression-free survival (log-rank P = .009 and P = .039, respectively).
Conclusions:
Patients with favorable prognostic features may achieve durable remissions without requiring high-dose salvage chemotherapy. However, the criteria for optimal patient selection remain unclear, and these findings further support the need for a definitive randomized trial.
IntroductionDefinitionsPrognostic variablesConventional salvage therapiesHigh-dose chemotherapy of metastatic germ cell cancerLate relapse of germ cell cancerConclusion
In Europa befassen sich außerhalb der verschiedenen nationalen Krebsorganisationen einige Studiengruppen speziell mit dem Hodentumor: die Genitourinary Group (GU-Group) der EORTC (European Organization for Research on the Treatment of Cancer), das MRC (Medical Research Council) in Großbritannien, die Dateca in Dänemark, die Swenoteca in Schweden und Norwegen, das Institut Gustave Roussy (IGR) in Villejuif/Frankreich. In Deutschland arbeiten Urologen, internistische Onkologen und Radiologen in der „Interdisziplinären Arbeitsgruppe Hodentumoren“ sowie Urologen in der Arbeitsgemeinschaft Urologische Onkologie (AUO) der Deutschen Krebsgesellschaft (DKG) mit dem Ziel, möglichst viele Tumoren in gemeinsam abgestimmten Protokollen zu behandeln, so daß die aktuellen Fragen zur Therapie beantwortet werden können.
The management of testicular cancer has evolved over the last three decades. The importance of staging and prognostic group assessments at all points in disease management has allowed reduction in treatment exposure for patients with good outcomes including the increased use of surveillance for stage 1 disease. Combination cisplatin and etoposide- based therapy remains the cornerstone of management of metastatic disease. The likelihood of success can be predicted for an individual based on tumor marker levels and sites of metastases. Patients with very advanced disease at presentation remain a challenge as chemotherapy often needs to be modified. The quality of response to this initial therapy itself predicts for success with further therapy should relapse occur. High dose chemotherapy with autologous stem cell support is of value in chemo-sensitive second relapse although its use earlier in the disease remains controversial. Surgery to sites of metastatic disease remains an important component of curative therapy. Finally attention to long term side effects has become of increasing importance and has led to increased efforts to reduce unnecessary treatment.
Background High-dose chemotherapy (HDC) using sequential cycles of carboplatin/etoposide is curative for relapsed germ-cell tumors (GCT).
However, outcomes of high-risk patients in advanced relapse remain poor. We previously developed a new HDC regimen combining
infusional gemcitabine with docetaxel/melphalan/carboplatin (GemDMC), with preliminary high activity in refractory GCT. Given
the high vascular endothelial growth factor expression in metastatic GCT and the synergy between bevacizumab and chemotherapy,
we studied concurrent bevacizumab and sequential HDC using GemDMC and ifosfamide/carboplatin/etoposide (ICE) in patients with
poor-risk relapsed or refractory disease.
Patienten mit metastasierten Keimzelltumoren, die einen Progress oder ein Rezidiv ihrer Erkrankung nach einer cisplatinhaltigen Vortherapie erleiden, haben eine schlechte Prognose. Unter Verwendung einer erneuten konventionellen Chemotherapie können maximal 15-30% dieser Patienten geheilt werden, so dass die Mehrzahl der Patienten an ihrer Erkrankung verstirbt. Aus diesem Grund ist die Optimierung der therapeutischen Möglichkeiten ein wesentliches Ziel. Unsere Daten zeigen, dass die Hochdosischemotherapie (HDCT) eine wesentliche therapeutische Verbesserung darstellt und mittels dieser Therapie mit einem ereignisfreien Überleben von 30-60% zu rechnen ist. Eine "matched-pair" Analyse konnte im Hinblick auf das ereignisefreie und das Gesamtüberleben einen Vorteil von mehr als 10% zu Gunsten der HDCT feststellen. Darüber hinaus hat die zunehmende Erfahrung und die Verwendung von peripheren Blutstammzellen und hämatopoetischen Wachstumsfaktoren, den Einsatz der HDCT deutlich sicherer gemacht. Aus den genannten Gründen sollte alle Patienten mit Rezidiv oder Progress eines Keimzelltumors der HDCT zugeführt werden. Die operative Entfernung von residuellen Tumormanifestationen (RTR) nach primärere Chemotherapie ist heute Standard bei Patienten mit metastasierten Keimzelltumoren. Zwar findet sich in der histologischen Aufarbeitung bei den meisten Patienten ausschließlich nekrotisches Gewebe, doch werden bei einem Teil der Patienten auch Anteile von reifem Teratom und vitalen differenzierten und undifferenzierten Karzinomen gefunden. Während die Resektion von Nekrose keinen therapeutischen Benefit für den Patienten darstellt, ist die komplette Entfernung von reifem Teratom oder Zellen eines Karzinoms für die Prognose entscheidend. In Bezug auf die HDCT konnten bisher keine vergleichbaren Daten erhoben werden. Zur Evaluierung des Stellenwertes der RTR nach HDCT analysierten wir unser eigenes Patientenkollektiv und fanden, dass vergleichbar zur Primärtherapie alle Patienten nach Salvage-HDCT, die eine partielle markernegative oder markerpositive Remission erreicht haben, einer RTR zugeführt werden sollten. Bis auf intrazerebrale Reste sollten alle residuellen Tumormanifestationen komplett reseziert werden. Neben der Optimierung der therapeutischen Möglichkeiten ist auch die Minimierung der chemotherapieassoziierten Toxizitäten ein wesentlicher Bestandteil meiner wissenschaftlichen Arbeit. Aus diesem Grund evaluierten wir die Wirksamkeit der Substanz Amifostin im Hinblick auf die Verringerung von Toxizitäten, die Wirkung auf die Mobilisierung von peripheren Blutstammzellen und den Einfluß auf die Rekonstitution des Immunstatus bei Patienten mit rezidivierten oder progredienten Keimzelltumoren, die mittels einer konventionellen Chemotherapie und anschließender HDCT behandelt wurden. Der Einsatz von Amifostin erbrachte in diesem Zusammenhang und in diesem Patientenkollektiv keinen therapeutischen oder prophylaktischen Nutzen, so dass dessen Verwendung bei Patienten mit Keimzelltumoren nicht generell empfohlen werden kann.
Bei Patienten mit Keimzelltumoren werden Mobilisation und Separation peripherer Blut-stammzellen durch das Alter, die zytostatische Vorbehandlung und Art der Mobilisations-chemotherapie statistisch signifikant beeinfluát. Der beste prdiktive Parameter fr die gesammelten Stamm- und Vorluferzellen ist die Anzahl der peripheren CD34+ Zellen, die am Tag der Leukapherese im Blutkreislauf zirkulieren. Fr die Rekonstitution der Granulo- und Thrombozytopoese nach Hochdosischemotherapie ist die Dosis der trans-fundierten CD34+ Zellen von signifikantem Wert. Bei der Transplantation von mehr als 2,5 x 10 hoch 6 CD34+ Zellen/kg kann mit einer schnellen und sicheren Regeneration der Hmatopoese, einem niedrigeren Bedarf an Antibiotika, Erythrozyten- und Thrombozy-tenkonzentraten sowie einem krzeren Krankenhausaufenthalt gerechnet werden.
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