The Contemporary Role of Chemotherapy for Advanced Testis Cancer: A Systematic Review of the Literature

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1 EUROPEAN UROLOGY 61 (2012) available at journal homepage: Collaborative Review Testis Cancer The Contemporary Role of Chemotherapy for Advanced Testis Cancer: A Systematic Review of the Literature Fabio Calabrò a, *, Peter Albers b, Carsten Bokemeyer c, Chris Martin d, Lawrence H. Einhorn e, Alan Horwich f, Susanne Krege g, Hans Joachim Schmoll h, Cora N. Sternberg a, Gedske Daugaard i a Department of Medical Oncology, San Camillo Forlanini Hospital, Rome, Italy; b Department of Urology, Heinrich-Heine-University, Düsseldorf, Germany; c Department of Oncology, Hematology, University Hospital, Hamburg-Eppendorf, Germany; d The Institute of Cancer Research: Royal Cancer Hospital, London and Sutton, UK; e Indiana University, Melvin and Bren Simon Cancer Centre, Indianapolis, IN, USA; f Department of Clinical Oncology, Royal Marsden Hospital and Institute of Cancer Research, Sutton, Surrey, UK; g Department of Urology, Krankenhaus Maria-Hilf, Krefeld, Germany; h Department of Internal Medicine IV, Oncology/Haematology, Centre for Cell and Gene Therapy, Martin-Luther-University, Halle, Germany; i Department of Oncology, University Hospital Copenhagen Rigshospitalet, Copenhagen, Denmark Article info Article history: Accepted March 16, 2012 Published online ahead of print on March 23, 2012 Keywords: Metastatic germ cell tumours Chemotherapy Prognostic factors High-dose chemotherapy Conventional-dose chemotherapy Tumour markers Long-term toxicity Abstract Context: Germ cell tumours (GCTs) of the testis are the most common cancer in young men; they are also one of the most curable cancers. Standard treatment of metastatic GCTs has evolved on the basis of randomised trials and prognostic factors. Objective: This review summarises the evolving role of chemotherapy in the treatment of previously treated and untreated patients with metastatic GCTs and outlines the current standard treatment. Evidence acquisition: Randomised and nonrandomised trials of first-line, salvage, and palliative therapy were reviewed. Evidence synthesis: Three cycles of standard bleomycin, etoposide, and platinum (BEP) can be considered the gold-standard treatment in good-risk patients, and four cycles of the same combination can result in cure in approximately 80% of intermediate-risk and 50% of poor-risk patients. The routine use of high-dose chemotherapy in patients with intermediate- or poor-prognosis GCT has not improved treatment outcome, but the role of tumour marker decline during the first cycles may provide useful prognostic information. Prognostic variables in patients who experience treatment failure after cisplatin-based chemotherapy can be used to guide salvage strategies, and many new drugs or combinations have shown activity in this setting. Patients and physicians should be aware of the risk of short- and long-term toxicity of treatments, and guidelines for screening and prevention of this risk should be established. Conclusions: A risk-based strategy offers the best chance of cure, even in patients with refractory GCT. # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Medical Oncology, San Camillo Forlanini Hospital, Circonvallazione Gianicolense 87, Rome 00152, Italy. address: fabiocalabro1@alice.it (F. Calabrò). 1. Introduction Testicular cancer is the most common malignancy in young men yr of age. The current incidence is 63 of /yr, with the highest rate in northern European countries (68 of /yr). The death rate, however, is low (3.8 cases of /yr) [1], and survival becomes equivalent to that of the general population after 1 yr. Although patients with metastatic disease have a significantly poorer survival rate than those with localised or regional disease, this /$ see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 EUROPEAN UROLOGY 61 (2012) Table 1 The International Germ Cell Cancer Collaborative Group risk classification for metastatic disease [4] Classification Seminoma Nonseminoma Good risk Any hcg AFP <1000 ng/ml Any LDH HCG <5000 mu/ml LDH <1.5 UNL Nonpulmonary visceral metastases absent Nonpulmonary visceral metastases absent Any primary site Gonadal or retroperitoneal primary tumour Intermediate risk Any hcg AFP ng/ml Any LDH HCG mu/ml LDH UNL Nonpulmonary visceral metastases absent Nonpulmonary visceral metastases absent Any primary site Gonadal or retroperitoneal primary tumour Poor risk None AFP ng/ml HCG mu/ml LDH 10 UNL Mediastinal primary site Nonpulmonary visceral metastases present HCG = human chorionic gonadatropin; LDH = lactic dehydrogenase; AFP = a-fetoprotein; UNL = upper limit of normal. difference disappears after having survived for 3 yr after diagnosis [2]. The European mean age-adjusted 5-yr survival has been calculated at 97.3% (95% confidence interval [CI], ) [3]. A risk classification based on primary and metastatic sites together with the level of tumour marker elevation was proposed by the International Germ Cell Cancer Collaborative Group (IGCCCG) in 1997, and this classification has obtained general acceptance [4] (Table 1). According to this model, patients with metastatic disease are categorised into a good-, intermediate-, or poor-risk group on the basis of histology, primary site, marker levels, and the presence of nonpulmonary visceral metastases, with a projected 5-yr survival rate of approximately 90%, 75%, and 45%, respectively. Serum concentrations of a-fetoprotein (AFP) and/or human chorionic gonadotropin (hcg) are elevated in 80% of patients with advanced nonseminomatous germ cell tumours (GCT) and in nearly all patients with intermediateand poor-risk disease. In seminoma, lactic dehydrogenase (LDH) and to some extent hcg are used markers. However, hcg levels >200 mu/ml would clearly question the presence of pure seminoma. Guidelines on the appropriate use of serum tumour markers have been developed [5]. 2. Evidence acquisition We conducted a literature search using PubMed and American Society of Clinical Oncology or European Society for Medical Oncology abstracts through June 2011 with the search terms for chemotherapy and testis cancer and a focus on metastatic disease. Papers were synthesised by one of the authors, with input from the other authors as to inclusion or exclusion of relevant publications; all the authors approved the final manuscript. 3. Evidence synthesis 3.1. Good-risk germ cell tumours Approximately 60% of metastatic GCTs can be allocated to the good risk group. The expected cure rate is approximately 90% with conventional chemotherapy, followed by surgery in cases of persistent radiographic abnormalities. In 1987, a randomised phase 3 trial comparing two cisplatin-based regimens showed that four cycles of the combination of bleomycin, etoposide, and platinum (BEP) were not inferior to but were less toxic than four cycles of cisplatin, vinblastine, and bleomycin (PVB) [6]. In 1988, a randomised trial conducted at Memorial Sloan-Kettering Cancer Centre (MSKCC) in good-risk patients showed that four cycles of etoposide and cisplatin (EP) were therapeutically equivalent to three cycles of vinblastine, dactinomycin, bleomycin, cyclophosphamide, and cisplatin [7]. A subsequent study demonstrated that three cycles of BEP had equivalent efficacy but less toxicity than four cycles of the same regimen [8]. None of these trials was directed specifically at the IGCCCG good prognosis category. To directly compare four BEP to three BEP cycles in a noninferiority study, 812 patients with good-risk disease according to the IGCCCG criteria were randomised. The 2-yr progression-free survival (PFS) rate was similar in the twoarms(90.4%vs89.4%).thisstudyalsoinvestigated whether the same dose of chemotherapy could be delivered in 3 d instead of 5 d. The 2-yr PFS was similar, but nausea and late ototoxicity occurred more frequently in the 3-d arm. The conclusion was that three cycles of BEP can be regarded as standard treatment in the good-prognosis group [9]. Reducing toxicity without losing efficacy has been an important goal in patients with good prognosis, and three options have been pursued. Reducing the number of cycles has been successful, but removing bleomycin from treatment and changing cisplatin to carboplatin has failed (Table 2). Both the disease-free survival (DFS) and overall survival (OS) are superior when bleomycin is part of the treatment [9 13]. If bleomycin is contraindicated, three cycles of BEP can be replaced by four cycles of EP. A randomised trial compared BEP 3 to EP 4. The 4-yr event-free survival rates were 97% with three cycles of BEP and 93% in patients on the four cycles of EP arm [14]. However, this study was not powered to detect superiority nor to establish noninferiority. Two additional studies have clearly indicated that carboplatin

3 1214 EUROPEAN UROLOGY 61 (2012) Table 2 Randomised trials in good-risk germ cell tumours First author Regimen No. CR, % Survival Comments Levi [10] PVB DFS 34% pulmonary toxicity in bleomycin arm PV Bleomycin deletion compromised outcome Deaths from progressive disease in 15% of patients on PV and 5% on PVB ( p = 0.02) Loehrer [11] BEP OS p = 0.01 EC Indiana Staging System Inferior outcome without bleomycin De Wit [12] BE360P DFS Etoposide at 360 mg/mq per cycle E360P EORTC risk classification Bleomycin cannot be deleted Toner [13] BEP OS p = BEP mod BEP modified = P 100 mg/mq day 1, E 120 mg/m 2 days 1 3, B 30 U day 1, repeated every 21 d Trial stopped after second interim analysis Bajorin [15] EP DFS p = ECarbo No difference in OS MSKCC risk criteria EP superior; more patients hospitalized in EC arm for neutropenic fever Horwich [16] BEP OS p = 0.03 BEC BEC = E 120 mg/m 2 on days 1, 2, and 3; B 30 U on day 2; carboplatin AUC 5 BEP superior (cisplatin superior to carboplatin) De Wit [9] BEP OS 2 2 factorial design 3 d vs 5 d BEP 3EP Nausea and late ototoxicity occurred more frequently in the 3-d arm of BEP-1 EP BEP 3 standard 3-d regimen only for patients for whom three cycles of therapy are sufficient Culine [14] BEP OS p = EP BEP 3 standard arm EP 4 alternative regimen for patients at increased risk of bleomycin-induced toxicity CR = complete response; PVB = cisplatin, vinblastine, and bleomycin; PV = cisplatin and vinblastine; DFS = disease-free survival; BEP = bleomycin, etoposide, and platinum; EC = etoposide and cisplatin; OS = overall survival; EORTC = European Organisation for Research and Treatment of Cancer; ECarbo = etoposide and carboplatin; MSKCC = Memorial Sloan-Kettering Cancer Centre; BEC = bleomycin, etoposide, and carboplatin; AUC = area under the curve. cannot replace cisplatin in the treatment of patients with good-risk metastatic GCT [15,16] (Table 2). In conclusion, three cycles of 5-d standard BEP can be considered the gold standard, and four cycles of EP can be considered an alternative regimen to standard BEP 3 in patients with increased risk of bleomycin-induced lung toxicity (>40 yr of age, renal function impairment, and pulmonary comorbidities) [17] Intermediate- and poor-risk germ cell tumours Intermediate- and poor-risk GCTs account for approximately 20 30% of patients with metastatic disease. Many attempts have been made to improve the efficacy of the standard BEP 4 regimen by increasing doses, incorporating new drugs, and alternating or sequencing different regimens (Table 3) [6,18 22]. Taken together, the results Table 3 Randomised trials in patients with intermediate- to poor-risk germ cell tumours First author Treatment No. CR, % OS, % Comments Williams [6] PVB (2 yr) BEP preferable because of less neurologic toxicity BEP Indiana risk classification De Wit [18] BEP No differences in CR, OS, and PFS PVB/BEP PVB/BEP more toxic EORTC risk classification Nichols [19] BEP High-dose cisplatin not superior P(200)EB Indiana risk classification Nichols [20] BEP p = 0.78 VIP VIP more toxic; alternative for patients with pulmonary disease Indiana risk classification Kaye [21] BEP 4/EP p = BOP 3/VIP-B VIP-B not superior and more toxic EORTC/MRC risk classification Culine [22] BEP p = 0.24 CISCA/VB Alternating regimen not superior and more toxic Institute Gustave Roussy risk classification CR = complete response; OS = overall survival; PVB = cisplatin, vinblastine, and bleomycin; BEP = bleomycin, etoposide, and platinum; PFS = progression-free survival; EORTC = European Organisation for Research and Treatment of Cancer; VIP = etoposide, ifosfamide, and cisplatin; EC = etoposide and cisplatin; BOP = bleomycin, vincristine, and cisplatin; VIP-B = etoposide, ifosfamide, cisplatin, and bleomycin; MRC = Medical Research Council; CISCA = cyclophosphamide, cisplatin, and adriamycin; VB = vinblastine and bleomycin.

4 EUROPEAN UROLOGY 61 (2012) of these studies have clearly indicated that four cycles of BEP have to be considered the standard treatment for patients with intermediate- or poor-risk GCTs according to the IGCCCG classification, but a combination of etoposide, ifosfamide, and cisplatin (VIP) can be considered as an alternative to the BEP regimen for poor-risk patients with compromised pulmonary function or other comorbidities that could preclude the treatment with bleomycin-containing regimens [20,23]. Different studies have tried to incorporate new promising agents or drug dose intensification. A randomised phase 2/3 trial has been conducted comparing Taxol and BEP (T-BEP) to standard BEP in patients with intermediate prognosis. After a median follow-up of 5.3 yr, PFS intent to treat (ITT) at 3 yr was 79.4% for T-BEP versus 71.1% for BEP (hazard ratio [HR]: 0.73; p = 0.153). PFS at 3 yr in all eligible patients was 82.7% for T-BEP versus 70.1% for BEP (HR: 0.60; p = 0.03). OS was not statistically different [24]. In another attempt to intensify treatment, a combination of bleomycin, vincristine, and cisplatin (BOP) followed by two cycles of bleomycin and vincristine (BO) and thereafter by three cycles of BEP (C-BOP/BEP) has been tested [25]. After a median follow-up of 40.4 mo, the 1-yr PFS rate was 81.8%, and the 2-yr OS rate was 84.5%. Because of the promising results of this combination, the Medical Research Council has conducted a randomised phase 2 study to compare the C-BOP/BEP regimen to standard BEP [26]. The 1-yr PFS was 65% and 43%, respectively, and OS was 74% and 72%, respectively. The trial met its primary outcome, but C-BOP/BEP was more toxic High-dose chemotherapy The observation of durable, complete responses in patients receiving high-dose carboplatin-containing regimens led to single-arm phase 2 trial of high-dose chemotherapy (HDCT) plus autologous blood stem cell support as a firstline treatment in poor-risk GCT patients. Response rates were high, with tolerable toxicity. When compared to historical controls of patients treated with conventionaldose chemotherapy (CDCT), a higher complete response (CR) rate and improved survival with acceptable toxicity were observed [27 32]. Three phase 3 trials evaluating the role of HDCT in the first-line setting have been performed. In a French study, 155 patients with intermediate- and poor-prognosis nonseminomatous GCTs (NSGCTs) were randomised to receive either four cycles of vinblastine, etoposide, cisplatin (200 mg/ mq), and bleomycin, (arm A) or a slightly modified regimen followed by HDCT including etoposide, cisplatin, and cyclophosphamide with bone marrow support (arm B). An ITT analysis showed 56% and 42% CRs in arms A and B, respectively ( p = 0.099). After a median follow-up of 9.7 yr, the 5-yr survival rates were 88% and 82% in the intermediaterisk group and 69% and 44% in the poor-risk group ( p =0.045) in arms A and B, respectively [33]. This trial failed to demonstrate an impact on response and survival of HDCT in the first-line treatment of patients with high-volume, metastatic NSGCT. In a second randomised phase 3 trial, 219 previously untreated patients with intermediate- or poor-risk GCT were randomised to receive either standard BEP 4, or two cycles of BEP followed by two cycles of HDCT containing carboplatin followed by haematopoietic stem-cell rescue (BEP plus HDCT). Serum AFP and hcg were correlated with treatment outcome as a secondary end point [34]. The 1-yr CR rate was 52% after BEP plus HDCT and 48% after BEP alone. There was no difference in survival. Some retrospective studies have shown that prolonged tumour marker half-life is associated with an inferior durable CR rate and survival as compared with patients with a satisfactory half-life [35 37]. This outcome was also observed in the study by Motzer et al. (2007). Patients with slow marker decline during the first two cycles had a shorter PFS and OS as compared to patients with satisfactory marker decline ( p = 0.02 and p = 0.03, respectively). Among 67 patients with unsatisfactory marker decline, the 1-yr durable CR proportion was 61% for patients who received HDCT versus 34% for patients receiving BEP alone ( p = 0.03). The third study randomised between a standard VIP regimen followed by sequential high-dose VIP and stem cell rescue versus standard BEP 4 in previously untreated poor-prognosis germ cell cancer (European Organisation for Research and Treatment of Cancer [EORTC] 30974). Two hundred twenty-two patients were needed to show a 15% improvement in 1-yr failure-free survival (FFS), but the study was closed after 137 patients because of poor accrual. The CR rates in the HDCT and BEP arms were similar (44.6% vs 33.3%; p = 0.18). At 2 yr, the FFS rate was 44.8% and 58.2%, respectively, but this difference was not statistically significant ( p = 0.06). OS did not differ between the two groups [38]. Interestingly, in this trial, the speed of marker decline seemed not to be prognostic for survival. In summary, the routine inclusion of HDCT in the first-line treatment of patients with intermediate- or poor-prognosis GCT has not improved treatment outcome. It remains to be shown whether tumour marker decline during the first one or two cycles of BEP provides useful prognostic information Salvage therapy A small subset of patients fails to achieve a CR to cisplatinbased chemotherapy. The biology underlying treatment failure is poorly understood. Resistance to cisplatin has been attributed to various mechanisms, such as loss of activation and execution of apoptosis, induction of cellular differentiation, and mechanism of DNA repair [39,40]. In addition, mismatch repair deficiency, microsatellite instability, and BRAF mutations are associated with cisplatin resistance in GCT [41,42]. Even though no uniform pattern of resistance has been identified in patients with refractory disease, potentially curative therapy exists for patients with relapsed or resistant disease. Both CDCT and HDCT therapy might have a role in this setting. Many phase 2 trials have shown that salvage CDCT has activity as a second-line therapy for patients with metastatic GCT (Table 4) [43 48]. Inclusionofnewdrugs like paclitaxel has probably contributed to these results.

5 1216 EUROPEAN UROLOGY 61 (2012) Table 4 Trials of salvage conventional-dose chemotherapy First author Design No. Regimen CR, % PFS Comments Harstrick [43] Phase 2 30 VIP d Myelosuppression dose limiting McCaffrey [44] Retrospective 56 VeIP/VIP mo Prognosis related to response at first-line therapy Loehrer [45] Phase VeIP NR 24 mo Survival correlated to CR to first therapy, minimal stage, primary testis Motzer [46] Phase 1/2 30 TIP mo All patients had favourable prognostic features: CR to first therapy, primary testis Kondagunta [47] Phase 2 46 TIP mo All patients had favourable prognostic features: CR to first therapy, primary testis Mead [48] Phase 2 51 TIP mo Paclitaxel at lower dose CR = complete response; PFS = progression-free survival; VIP = etoposide, ifosfamide, and cisplatin; VeIP = vinblastine, ifosfamide and cisplatin; NR = not reported; TIP = paclitaxel, ifosfamide, and cisplatin. Table 5 Phase 2 trials of salvage high-dose chemotherapy First author No. Regimen CR, % Survival Comments Motzer [49] 58 CEC 40 31% OS 2 yr HCG and retroperitoneal disease prognostic Siegert [50] 74 CEI OS 2 yr Two toxic deaths Motzer [51] 37 PICE OS 31 mo Carboplatin escalated by target AUC; pharmacokinetic studies; 58% hospitalisations Bhatia [52] 65 CE 43 60% NED at 39 mo Primary mediastinal excluded Rick [53] 80 TIP-CE 18 30% OS 3 yr Peripheral nerve toxicity in 1 of 3 of patients HDCT in only 78% Lotz [54] 45 Epi-T 9 23% OS 3 yr No benefit in Beyer score 2 CThio ICE Kondagunta [55] 47 TICE 49 51% OS 40 mo Long-term neurotoxicity and ototoxicity Feldman [56] 107 TICE 5 52% OS 5 yr No benefit in mediastinal primary and >2 lines CR = complete response; CEC = carboplatin, etoposide, and cyclophosphamide; OS = overall survival; HCG = human chorionic gonadatropin; CEI = carboplatin, etoposide, and ifosfamide; PICE = paclitaxel, ifosfamide, carboplatin, and etoposide; AUC = area under the curve; CE = carboplatin and etoposide; NED =no evidence of disease; TIP-CE = paclitaxel, ifosfamide, cisplatin, carboplatin, and etoposide; HDCT = high-dose chemotherapy; EpiT = epirubicin and paclitaxel; CThio ICE = cyclophosphamide, thiotepa, ifosfamide, carboplatin, and etoposide; TICE = paclitaxel, ifosfamide, carboplatin, and etoposide. So far, only phase 2 studies have been published, and the predominant proportion of patients has been in the good prognostic group (Table 4). Many retrospective and phase 2 studies have investigated the role of HDCT as a salvage option for patients with multiple relapses and for those with unfavourable prognostic factors (Table 5) [49 56]. Two randomised phase 3 trials have addressed the role of HDCT as a salvage treatment. In the first study, 263 patients were randomised to four cycles of VIP or three cycles of VIP followed by one cycle of HDCT with carboplatin, etoposide, and cyclophosphamide. No significant improvement in either 3-yr eventfree survival (35% vs 42%) or OS (53% vs 59%) was observed between the two arms [57]. A second study compared single versus sequential HDCT as a first or subsequent salvage treatment in patients with relapsed or refractory GCTs. In this trial, patients were planned to be randomised to either one cycle of standarddose VIP plus three cycles of high-dose carboplatin and etoposide (arm A) or three cycles of VIP plus one cycle of high-dose carboplatin, etoposide, and cyclophosphamide (arm B). The study was stopped after recruitment of 216 patients as a result of excess treatment-related mortality in arm B. At 1 yr, event-free survival, PFS, and OS rates were 40%, 53%, and 80% in arm A compared with 37%, 49%, and 61% in arm B, respectively ( p > 0.05 for all comparisons). Treatment-related deaths, mainly as a result of sepsis and cardiac toxicity, were less frequent in arm A than in arm B (4% vs 16%; p < 0.01) [58]. In a recent update of this trial at a median follow-up of 7.5 yr, 5-yr PFS was 47% in arm A and 45% in arm B (HR: 1.16; p = 0.454). Five-year OS was 49% in arm A and 39% in arm B (HR: 1.42; p = 0.057) [59]. A prognostic classification has been developed in patients who progressed after at least three cycles of cisplatin-based chemotherapy. Retrospective data on 1984 patients with GCTs were collected from 38 centres worldwide. The 1594 (80%) eligible patients were randomly divided into a training set and a validation set. Histology, primary tumour location, response, and progression-free interval after first-line treatment as well as levels of AFP and hcg and the presence of liver, bone, or brain metastases were independent prognostic variables used to build the prognostic model. According to the number of prognostic factors, patients were divided into five risk groups. The estimated 2-yr PFS rate was 75% in very low-risk, 51% in low-risk, 40% in intermediate-risk, 26% in high-risk, and only 6% in very high-risk patients [60]. Of the 1594 eligible patients, 773 received CDCT and 821 received HDCT. The PFS at 2 yr was significantly superior after HDCT compared with CDCT in each prognostic category, and this translated into an improved OS after HDCT with the exception of the low-risk group [61]. These studies have established the efficacy and feasibility of HDCT as a salvage treatment in GCT but did not show clear superiority over CDCT,

6 EUROPEAN UROLOGY 61 (2012) Table 6 Phase 2 trials of palliative regimens First author Regimen No. RR, % CRR, % MS Bokemeyer [67] Paclitaxel NR Einhorn [68] Gemcitabine NR Bokemeyer [69] Gemcitabine mo Bokemeyer [70] Oxaliplatin mo Hinton [71] Paclitaxel and gemcitabine mo Einhorn [72] Paclitaxel and gemcitabine mo Kollmannsberger [73] Oxaliplatin and gemcitabine mo De Giorgi [75] Oxaliplatin and gemcitabine mo Miki [76] Irinotecan and cisplatin % survival at 5 yr Pectasides [74] Irinotecan and oxaliplatin mo Bokemeyer [77] Gemcitabine, oxaliplatin, and paclitaxel mo RR = response rate; CRR = complete response rate; MS = median survival; NR = not reported. confirming the need for prospective randomised trials comparing CDCT to HDCT in this patient population. Two prognostic models have looked at the outcome after HDCT used as salvage chemotherapy. Beyer et al. [62] found the following factors to be of importance in a multivariate analysis of patients who had received one cycle of HDCT: progressive disease before HDCT, primary mediastinal NSGCT, refractory or absolute refractory disease to conventional-dose cisplatin, and hcg levels >1000 U/l. These factors were independent adverse prognostic indicators of survival after HDCT, and a nomogram was created to predict the outcome (the Beyer score). The Beyer score categorises patients as having a good (0 points), intermediate (up to 2 points), or poor prognosis (>2 points). This model has been adopted by some to select patients to receive HDCT. In general, patients with a Beyer score >2 are not considered good candidates for HDCT, particularly those with absolute refractory GCT, because of a <10% chance of achieving a durable CR. Another prognostic scoring algorithm in 184 patients treated with HDCT was developed at Indiana University. This model included timing of HDCT (3 points for third line), platinum-refractory disease (2 points), and the IGCCCG poorprognosis group (2 points), with high scores indicating a low probability of DFS [63]. For patients with low-risk (0 points), intermediate-risk (2 3 points), and poor-risk (4 7 points) disease, the 5-yr survival rate was 80%, 60%, and 40%, respectively. The differences between these two prognostic models may be related to the patient populations studied and to different variables included in the models. Patients with gonadal primary tumours and a partial response or CR lasting >6 mo to first-line chemotherapy have a >60% chance of achieving cure with CDCT [64]. Other patients, such as those with primary refractory disease or remissions of short duration (<6 mo) and those with primary mediastinal disease have durable DFS and OS rates of <10% with similar regimens [65]. In contrast, HDCT can achieve durable CRs in 30 60% of such patients [55,63,66]. However, in the salvage setting, a prospective randomised trial between CDCT and HDCT is needed to clarify which treatment modality will be optimal. Prognostic variables are important in patients who have experienced treatment failure with cisplatin-based first-line chemotherapy and can be used to guide salvage strategies Palliative regimens in refractory patients Patients who relapse after HDCT or second-line chemotherapy can only be offered chemotherapy with a low probability of long-term remissions. Many chemotherapeutic agents and targeted therapies have been tested in this population. Gemcitabine, paclitaxel, oxaliplatin, and irinotecan have shown activity both as single drugs and in combination (Table 6) [67 77]. The experience with targeted therapy is still limited, with only a few studies having disappointing results have been published. No significant effect has been observed with imatinib [78], thalidomide [79], bevacizumab [80], or sunitinib [81,82]. Everolimus and multikinase inhibitors targeting BRAF are under study. Many drugs or combinations have shown activity in patients with refractory GCT, but the development of a standard therapy is hampered by the difficulty of conducting a phase 3 trial in this small population. A better understanding of the biology of these tumours will be helpful in defining the exact role of targeted therapies Short- and long-term morbidity of chemotherapy Patients with testicular cancer treated with chemotherapy are at risk of developing severe short-term and long-term side-effects. Short-term effects are those arising during or immediately after chemotherapy and persisting for <1 yr. The most frequent short-term side-effects of the standard BEP regimen are gastrointestinal, haematologic, renal, or neurologic and usually start after the third cycle [83]. Bleomycin-induced pulmonary toxicity has been recognised since the early clinical trials in the 1960s. It usually starts gradually during treatment, but development up to 6 mo after discontinuation of therapy has been reported [84]. Most patients recover with drug discontinuation or with corticosteroid treatment, and only a small percentage develop pulmonary fibrosis. Risk factors for bleomycinassociated pneumonitis are cumulative dose, age at diagnosis, smoking, renal dysfunction, mediastinal radiation therapy, and oxygen administration [17]. The late effects of testicular cancer and its treatment include second malignancies, cardiovascular disease, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism,

7 1218 EUROPEAN UROLOGY 61 (2012) decreased fertility, psychosocial disorders, and possibly cognitive impairment. The risk of developing a second malignancy during the lifetime is times higher in survivors than in an age-matched general population [85,86]. The relative risk of leukaemia induced by standard doses of etoposide is 2%, increasing to 4% when higher cumulative doses are given [87]. An increase in plasma von Willebrand factor levels and in the intima-media thickness of the carotid artery has been observed in patients with testicular cancer treated with cisplatin-based chemotherapy. These changes may indicate chemotherapy-induced vascular damage and be of prognostic significance for the development of cardiovascular complications in the long term [88]. Approximately 20% of survivors already have irreversible hypogonadism before their malignancy is diagnosed. With current standard chemotherapy, spermatogenesis usually recovers in 80% of patients [89], depending on gonadal function before treatment, patient age, and type of therapy. Long-term nephrotoxicity is frequently asymptomatic but may be associated with up to a 30% reduction in glomerular filtration rate [90], and this may have an adverse impact on the development of cardiovascular diseases. Genome-wide association studies and other translational molecular approaches now provide opportunities to identify testicular cancer survivors at greatest risk of treatmentrelated complications to develop evidence-based long-term follow-up guidelines and interventional strategies [91]. 4. Conclusions Development of the IGCCCG classification system has allowed us to compare trial results and determine riskadapted management of patients with advanced GCT on the basis of an accurate estimation of individual patient prognosis. Currently, three cycles of the BEP regimen remain the standard treatment of good-risk metastatic GCTs, and four cycles of the same regimen are the best option for patients with intermediate- and poor-prognosis tumours. Four cycles of EP and four cycles of VIP can be used in patients with good and intermediate-to-poor prognosis at high risk of developing bleomycin-induced pulmonary toxicity. At the present time, there is no established role for HDCT in the firstline setting of patients with poor prognosis. Patients with recurrent or refractory disease have a poor prognosis. The development of new prognostic models or the validation of the existing models will help to define which patients will benefit from CDCT or HDCT as salvage treatment. Patients with testicular cancer should be informed of the risk of shortand long-term toxicity of treatment, and guidelines for screening for long-term side effects should be established. Author contributions: Fabio Calabrò had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Calabrò, Albers, Bokemeyer, Martin, Einhorn, Horwich, Krege, Schmoll, Sternberg, Daugaard. Acquisition of data: Calabrò, Albers, Bokemeyer, Martin, Einhorn, Horwich, Krege, Schmoll, Sternberg, Daugaard. Analysis and interpretation of data: Calabrò, Albers, Bokemeyer, Martin, Einhorn, Horwich, Krege, Schmoll, Sternberg, Daugaard. Drafting of the manuscript: Calabrò, Albers, Bokemeyer, Martin, Einhorn, Horwich, Krege, Schmoll, Sternberg, Daugaard. Critical revision of the manuscript for important intellectual content: Calabrò, Albers, Bokemeyer, Martin, Einhorn, Horwich, Krege, Schmoll, Sternberg, Daugaard. Statistical analysis: Calabrò, Albers, Bokemeyer, Martin, Einhorn, Horwich, Krege, Schmoll, Sternberg, Daugaard. Obtaining funding: Calabrò, Albers, Bokemeyer, Martin, Einhorn, Horwich, Krege, Schmoll, Sternberg, Daugaard. Administrative, technical, or material support: Calabrò, Albers, Bokemeyer, Martin, Einhorn, Horwich, Krege, Schmoll, Sternberg, Daugaard. Supervision: Calabrò, Albers, Bokemeyer, Martin, Einhorn, Horwich, Krege, Schmoll, Sternberg, Daugaard. Other (specify): None. Financial disclosures: Fabio Calabrò certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. References [1] Schmoll HJ, Jordan K, Huddart R, et al. Testicular seminoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. 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