Long-term renal function after treatment for malignant germ-cell tumours. Superior survival after sequential high-dose chemotherapy (HDCT) as compared to single HDCT in patients with relapsed or refractory germ cell tumors (GCT): Six-year long-term follow-up of a prospective, randomized phase II trial. Paclitaxel plus Ifosfamide followed by high-dose carboplatin plus etoposide in previously treated germ cell tumors. Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours. Sequential high-dose chemotherapy protocol for relapsed poor prognosis germ cell tumors combining two mobilization and cytoreductive treatments followed by three high-dose chemotherapy regimens supported by autologous stem cell transplantation. Results of the phase II multicentric TAXIF trial. Preclinical and clinical activity of sunitinib in patients with cisplatin-refractory or multiply relapsed germ cell tumors: a Canadian Urologic Oncology Group/German Testicular Cancer Study Group cooperative study. Cisplatin, etoposide and either bleomycin or ifosfamide in the treatment of disseminated germ cell tumors A randomized phase II trial of intensive induction chemotherapy (CBOP/BEP) and standard BEP in poor prognosis germ cell tumors (MRC TE23, CRUK 05/014, ISRCTN53643604). Salvage treatment with paclitaxel, ifosfamide, and cisplatin plus high-dose carboplatin, etoposide, and thiotepa followed by autologous stem-cell rescue in patients with relapsed or refractory germ cell cancer. A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours. Gemcitabine and oxaliplatin (GEMOX) in patients with cisplatin-refractory germ cell tumors: a phase II study. Acute chemotherapy-induced cardiovascular changes in patients with testicular cancer. A randomized trial of etoposide + cisplatin versus vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin in patients with good-prognosis germ cell tumors. Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: a multiinstitutional study. Long-term results of first-line sequential high-dose carboplatin, etoposide and ifosfamide chemotherapy with peripheral blood stem cell support for patients with advanced testicular germ cell tumor. Paclitaxel, ifosfamide, and cisplatin second-line therapy for patients with relapsed testicular germ cell cancer. Combination chemotherapy with gemcitabine, oxaliplatin, and paclitaxel in patients with cisplatin-refractory or multiply relapsed germ-cell tumors: a study of the German Testicular Cancer Study Group. High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. A phase II trial of early intensive chemotherapy with autologous bone marrow transplantation in the treatment of poor prognosis non seminomatous germ cell tumors. High-dose carboplatin, etoposide, and cyclophosphamide for patients with refractory germ cell tumors: treatment results and prognostic factors for survival and toxicity. Gemcitabine in patients with relapsed or cisplatin-refractory testicular cancer. High-dose carboplatin, etoposide, and cyclophosphamide with autologous bone marrow transplantation in first-line therapy for patients with poor-risk germ cell tumors. Importance of bleomycin in favorable-prognosis disseminated germ cell tumors: an Eastern Cooperative Oncology Group trial. Phase II trial of sunitinib in patients with relapsed or refractory germ cell tumors Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated or refractory germ cell cancer: a study of the German Testicular Cancer Study Group. Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients. Phase II trial of gemcitabine in refractory germ cell tumors. Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group protocol. Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant. Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. High-dose chemotherapy and autologous haematopoietic support in poor risk non-seminomatous germ-cell tumours: an effective first-line therapy with minimal toxicity. First-line high-dose chemotherapy compared with standard-dose PEB/VIP chemotherapy in patients with advanced germ cell tumors: A multivariate and matched-pair analysis. Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors. Early predicted time to normalization of tumor markers predicts outcome in poor-prognosis nonseminomatous germ cell tumors. A randomized phase III study comparing standard dose BEP with sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) plus stem-cell support in males with poor-prognosis germ-cell cancer. An intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC 30974). 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. Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: a Southeastern Cancer Study Group and Southwest Oncology Group protocol. Salvage chemotherapy for patients with germ cell tumors. The memorial sloan‐kettering cancer center experience (1979–1989) Phase I/II study of sequential dose-intensified ifosfamide, cisplatin, and etoposide plus paclitaxel as induction chemotherapy for poor prognosis germ cell tumors by the German Testicular Cancer Study Group. Phase II study of paclitaxel plus gemcitabine in refractory germ cell tumors (E9897): a trial of the Eastern Cooperative Oncology Group. Single versus sequential high-dose chemotherapy in patients with relapsed or refractory germ cell tumors: a prospective randomized multicenter trial of the German Testicular Cancer Study Group. Phase II Study of Imatinib Mesylate in Chemotherapy Refractory Germ Cell Tumors Expressing KIT Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study. Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group. Comparison of two standard chemotherapy regimens for good-prognosis germ-cell tumours: a randomised trial Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis.
OBJECTIVE To evaluate prospect ively renal function in patients with malignant germ-cell tumours ( MGCTs ) > 10 years after retroperitoneal lymph node dissection alone ( RPLND ) , radiotherapy alone ( RAD ) or different schedules of cisplatin-based chemotherapy with or without surgery/radiotherapy ( CHEM ) .  PATIENTS AND METHODS In 85 patients , three groups were identified : RPLND , 14 ; RAD , 18 ; CHEM , 53 , with subdivision of the latter group according to the cumulative cisplatin dose or the additional use of radiotherapy .  Renal function was determined by 131Iodine Hippuran clearance or 99 m DTPA glomerular filtration rate , and was assessed before treatment and four times during 14 years of follow-up . A value of < 70 % of the upper limit of the normal range identified impaired renal function . RESULTS Twenty-five patients displayed long-term impaired renal function , 23 of them from the RAD or CHEM group . In the RAD group , renal function decreased by 8 % , whereas a 14 % reduction of renal function was observed in the CHEM group . In the CHEM group the cumulative dose of cisplatin , and in the RAD group the age at treatment , were associated with impairment of renal function . Combining all patients , age at treatment and the type of treatment were associated with impaired renal function . CONCLUSIONS In 20 - 30 % of the patients with germ-cell tumour , st and ard radiotherapy and chemotherapy strategies are followed by long-term sub clinical impaired renal function . These findings support current intentions to avoid overtreatment with these treatment modalities 4507 Background : Sequential and single high-dose chemotherapy ( HDCT ) can both be curative in patients ( pts ) with relapsed or refractory germ-cell tumors ( GCT ) . The long-term efficacy of either modality is unknown . METHODS Between 11/99 and 11/04 , 211 pts with relapsed or refractory GTC were prospect ively r and omized to treatment with either one cycle of cisplatin 100 mg/m² , etoposide 375 mg/m² and ifosfamide 6 g/m² ( VIP ) plus three cycles of high-dose carboplatin 1,500 mg/m² and etoposide 1,500 mg/m² ( CE , arm A ) or three cycles of VIP plus one cycle of high-dose carboplatin 2,200 mg/m² , etoposide 1,800 mg/m² and cyclophosphamide 6,400 mg/m² ( CEC , arm B ) followed by stem cell reinfusion ( JCO 2007,25:2778 ) . Five pts were excluded from further analysis due to non-GCT histologies at review . We evaluated long-term progression-free ( PFS ) and overall survival ( OS ) six years after r and omization of the last patient . Survival probabilities were compared using the logrank test . RESULTS Overall , 108 and 103 pts were r and omized to arms A and B respectively . The study was stopped prematurely due to excess treatment-related mortality in am B ( 14 % ) compared to arm A ( 4 % ) ( p=0.01 ) . As of December 2010 , 9/211 ( 4 % ) pts were lost-to-follow at 31 , 32 + , 36 + , 47 + , 47 + , 51 + , 55 , 61 + , 71 + months . Median follow-up was 7.5 years ( range 2.5 to 10.5 years ) . Alive are 94/211 ( 45 % ) and 88/94 pts are progression-free . All but 6 relapsed patients died from progressive disease , 4 pts became disease-free with third-line treatment and two were alive with disease at last follow-up . Five year PFS is 47 % ( 95%CI : 37 - 56 % ) in arm A and 45 % ( 95%CI : 35 - 55 % ) in arm B ( HR=1.16 ( 95%CI : 0.79 - 1.70 , p=0.454 ) . Five year OS is 49 % ( 95%CI : 40 - 59 % ) in arm A and 39 % ( 95%CI : 30 - 49 % ) in arm B ( HR=1.42 ( 95%CI : 0.99 - 2.05 , p=0.057 ) . Relapses more than two years after r and omization occurred in 5/211 ( 2.4 % ) pts . One patient developed secondary acute myeloid leukemia . CONCLUSIONS In this prospect i ve , r and omized trial in pts with relapsed or refractory GCT , sequential HDCT was superior to single HDCT with respect to long-term OS PURPOSE To evaluate the optimal dose of carboplatin as well as the efficacy and tolerability of sequential , dose-intense chemotherapy with paclitaxel and ifosfamide followed by carboplatin and etoposide ( TICE ) plus peripheral-blood stem-cell ( PBSC ) support in patients with germ cell tumors ( GCT ) who are likely to experience treatment failure with conventional-dose salvage treatment . This prospect i ve trial followed a similarly design ed report of TICE , which used a different means of carboplatin dosing . PATIENTS AND METHODS The 48 patients entered onto this trial had progressive GCT and unfavorable prognostic features after chemotherapy . Two cycles of paclitaxel plus ifosfamide were administered with leukapheresis , followed by three cycles of carboplatin plus etoposide with reinfusion of PBSC . RESULTS Twenty-three ( 49 % ) of 47 assessable patients achieved a complete response ( CR ) to chemotherapy . An additional three patients ( 6 % ) achieved a CR to chemotherapy and surgery . The CR rate was 55 % . Six patients experienced relapse , but 24 patients ( 51 % ) are alive and free of disease at a median follow-up time of 40 months . Four patients who experienced relapse or achieved an incomplete response were rendered disease free by salvage surgical resection . When combined with results of the prior trial of similar design , TICE chemotherapy yielded an overall CR of 56 % ( n = 84 ) , with 50 % of patients alive with no evidence of disease . CONCLUSION TICE is an effective and tolerable dose-intense treatment for patients with previously treated metastatic GCT who have a poor predicted outcome to conventional-dose salvage chemotherapy BACKGROUND Bleomycin pulmonary toxicity ( BPT ) has been known since the early clinical trials of bleomycin in the 1960s . Postulated risk factors include cumulative bleomycin dose , reduced glomerular filtration rate ( GFR ) , raised creatinine , older age and supplemental oxygen exposure . PATIENTS AND METHODS From our prospect ively collected testicular cancer research data base , we review ed 835 patients treated at the Royal Marsden NHS Trust ( Sutton , UK ) with bleomycin-containing regimens for germ-cell tumours between January 1982 and December 1999 , to identify those with BPT . RESULTS Fifty-seven ( 6.8 % ) patients had BPT , ranging from X-ray/CT ( computed tomography ) changes to dyspnoea . There were eight deaths ( 1 % of patients treated ) directly attributed to BPT . The median time from the start of bleomycin administration to documented lung toxicity was 4.2 months ( range 1.2 - 8.2 ) . On multivariate analysis , the factors independently predicting for increased risk of BPT were GFR < 80 ml/min [ hazard ratio ( HR ) 3.3 ] , age > 40 years ( HR 2.3 ) , stage IV disease at presentation ( HR 2.6 ) and cumulative dose of bleomycin > 300,000 IU ( HR 3.5 ) . CONCLUSIONS Patients with poor renal function are at high risk of BPT , especially if they are aged > 40 years , have stage IV disease at presentation or receive > 300,000 IU of bleomycin . In such cases alternative drug regimens or dose restriction should be considered BACKGROUND High-dose chemotherapy ( HD-CT ) is able to circumvent platinum resistance of resistant/refractory germ-cell tumors ( GCTs ) , but expectancy of cure remains low . New strategies are needed with new drugs and a sequential approach . MATERIAL S AND METHODS Patients with relapsed poor-prognosis GCTs were scheduled to receive two cycles combining epirubicin and paclitaxel ( Taxol ) followed by three consecutive HD-CT supported by stem cell transplantation [ one course combining cyclophosphamide , 3 g/m(2 ) + thiotepa , 400 mg/m(2 ) , followed by two ICE regimens ( ifosfamide , 10 g/m(2 ) , carboplatin , AUC 20 , etoposide , 1500 mg/m(2 ) ) ] . RESULTS From March 1998 to September 2001 ( median follow-up , 31.8 months ) , 45 patients ( median age , 28 years ) were enrolled in this phase II study . Twenty-two patients received the complete course . Twenty-five patients died from progression and five from toxicity . The overall response rate was 37.7 % , including an 8.9 % complete response rate . The median overall survival was 11.8 months . The 3-year survival and progression-free survival rate was 23.5 % . The ' Beyer ' prognostic score predicted the outcome after HD-CT . CONCLUSION Although our results warrant further studies on HD-CT in relapsed poor prognosis GCTs , patients with a Beyer score > 2 did not benefit from this approach and should not be enrolled in HD-CT trials . Better selection criteria have to be fulfilled in forthcoming studies BACKGROUND The objective of the study was to investigate the activity of sunitinib in a cell line model and subsequently in patients with cisplatin-refractory or multiply relapsed germ cell tumors ( GCT ) . METHODS The effect of sunitinib on cell proliferation in cisplatin-sensitive and cisplatin-refractory GCT cell lines was evaluated after 48-h sunitinib exposure by MTT [ 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide ] assay , and IC(50 ) ( concentration that causes 50 % inhibition of growth ) doses were determined . Sunitinib was subsequently administered at a dose of 50 mg/day for 4 weeks followed by a 2-week break to 33 patients using a Simon two-stage design . RESULTS Sunitinib demonstrated comparable dose-dependent growth inhibition in cisplatin-sensitive and cisplatin-resistant cell lines , with IC(50 ) between 3.0 and 3.8 μM. Patient characteristics were as follows : median of 2 ( 1 - 6 ) cisplatin-containing regimens ; high-dose chemotherapy 67 % ; late relapse 33 % ; and cisplatin refractory or absolute cisplatin refractory 54 %  . Toxic effects included fatigue ( 39 % ) , anorexia ( 21 % ) , diarrhea ( 27 % ) , mucositis ( 45 % ) , nausea ( 33 % ) , h and -foot syndrome ( 12 % ) , dyspepsia ( 27 % ) , and skin rash ( 18 % ) . No unexpected side-effects were observed . Thirty -two of 33 patients were assessable for response . Three confirmed partial responses ( PRs ) and one unconfirmed PR were seen for a total response rate of 13 % . Median progression-free survival ( PFS ) was 2 months , with a 6-month PFS rate of 11 % . CONCLUSIONS Sunitinib shows in vitro activity in cisplatin-resistant GCT cell lines . Modest clinical activity in heavily pretreated GCT patients was observed Various staging systems have been proposed for disseminated germ cell neoplasms . The Indiana University staging system was based on clinical and radiographic findings only , whereas the newly created International Germ Cell Cancer Collaborative Group ( IGCCCG ) staging system also utilized serum markers as a prognostic factor . This study up date d the intergroup trial that compared the st and ard therapy of bleomycin , etoposide , and cisplatin ( BEP ) with etoposide , ifosfamide , and cisplatin ( VIP ) in advanced germ cell tumors and reanalyzed the results using the IGCCCG staging system 4508 Background : Up to 50 % of patients ( pts ) with IGCCCG poor prognosis non-seminomatous tumours die yet st and ard chemotherapy has remained bleomycin ( BLM ) , etoposide and cisplatin ( BEP ) for many years . This trial evaluated a new intensive induction chemotherapy regimen , CBOP/BEP , in a r and omized phase II trial also establishing current BEP response rate ( RR ) . METHODS Pts were r and omized to st and ard 4xBEP ( 12 weeks [ wks ] ) or CBOP/BEP  ( Wks 1 and 3 : cisplatin 50mg/m2 D1&2 ; vincristine ( VCR ) 2 mg D1 ; BLM 15000iu D1 . Wks 2 and 4 : cisplatin 40mg/m2 , VCR 2 mg , carboplatin AUC3 , all D1 ; BLM 15000iu D1 - 5 . Wks 5 and 6 : VCR 2 mg D1 ; BLM 15000iu D1 . Wks 7 - 15 3xBEP with BLM 15000iu weekly ) . The primary endpoint was RR with favourable outcomes : ( i ) complete response ( no residual mass or complete resection and no viable tumor , and normal markers ) or ( ii ) partial response ( residual mass unresected ) and normal markers . Toxicity , progression-free survival ( PFS ) and overall survival ( OS ) were secondary outcomes . 60 % RR was anticipated with BEP . Assuming 80 % RR with CBOP/ BEP , 44 pts were needed to exclude a RR < 60 % with 90 % power ( 1-sided α=5 % ) . Patients were r and omised to BEP to benchmark RR but the trial was not powered to compare arms . RESULTS Between 2005 and 2009 89 pts ( 43 CBOP/BEP ) were r and omized , median follow up 33 mths . Forty CBOP/ BEP , and 41 BEP completed treatment , CBOP/BEP toxicity , largely haematological , was high ( 96 % had CTC grade ≥3 , 63 % with BEP ) . RRs were 74 % with CBOP/BEP and 61 % with BEP ( 90 % CIs [ 61 % , 85 % ] and [ 48 % , 73 % ] ) . Additionally 2 BEP and 0 CBOP/BEP had complete resection of viable tumour . 1-year PFS was 65 % and 43 % respectively ( hazard ratio [ HR ] 0.6 , 95 % CI [ 0.33 , 1.07 ] ) and OS was 74 % and 72 % ( HR 0.78 , 95 % CI [ 0.39 , 1.57 ] ) . 3/14 CBOP/BEP and 2/18 BEP deaths were attributed to toxicity , one ( BLM toxicity on CBOP/BEP ) after an overdose during treatment . CONCLUSIONS The trial met its primary outcome with a 90 % CI for CBOP/BEP excluding RRs < 61 % but CBOP/BEP was more toxic . PFS is promising and similar to that seen after high dose chemotherapy in EORTC 30974 ( ASCO 2010 ) though with no clear impact on survival . Results should be confirmed in an international phase III trial PURPOSE To study feasibility and efficacy of a new salvage regimen in patients with relapsed and /or refractory germ cell tumors . PATIENTS AND METHODS Between May 1995 and February 1997 , 80 patients were entered onto a phase II study . Conventional-dose salvage treatment with three cycles of paclitaxel 175 mg/m(2 ) , ifosfamide 5 x 1.2 g/m(2 ) , and cisplatin 5 x 20 mg/m(2 ) ( TIP ) was followed by one cycle of high-dose chemotherapy ( HDCT ) with carboplatin 500 mg/m(2 ) x 3 , etoposide 600 mg/m(2 ) x 4 , and thiotepa 150 to 250 mg/m(2 ) x 3 ( CET ) . In 23 patients , one additional cycle of paclitaxel 175 mg/m(2 ) and ifosfamide 5 g/m(2 ) ( TI ) was given immediately before TIP to improve stem-cell mobilization . RESULTS Fifty-five ( 69 % ) of 80 patients responded to TIP , 24 ( 30 % ) of 80 patients had stable disease ( n = 5 ) or tumor progression ( n = 19 ) , and one patient died . Only 62 ( 78 % ) of 80 patients received subsequent HDCT . Among those , 41 ( 66 % ) of 62 patients responded and 20 ( 32 % ) of 62 patients had stable disease ( n = 3 ) or tumor progression ( n = 17 ) . One patient died after HDCT from multiorgan failure . Survival probabilities at 3 years were 30 % for overall and 25 % for event-free survival . Peripheral neurotoxicity with sensorimotor impairment grade 2 through 4 in 29 % , paresthesias grade 2 through 4 in 24 % , and skin toxicity grade 2 through 3 in 15 % of patients were the most relevant side effects . CONCLUSION Treatment with TIP followed by high-dose CET is feasible and can induce long-term remissions in 25 % of patients with relapsed or refractory germ cell tumors . Peripheral nervous toxicity in approximately one third of patients is a disadvantage of this salvage strategy BACKGROUND Incomplete remission or relapse from first-line chemotherapy has poor prognosis in male germ cell tumour patients . This phase III r and omised trial compares conventional salvage to high-dose-intensification chemotherapy . PATIENTS AND METHODS Between February 1994 and September 2001 , 280 patients from 43 institutions in 11 countries , were r and omly assigned to receive either four cycles of cisplatin , ifosfamide and etoposide ( or vinblastine ) ( arm A ) , or three such cycles followed by high-dose carboplatin , etoposide and cyclophosphamide ( CarboPEC ) with haematopoietic stem cell support ( arm B ) . RESULTS Similar complete and partial response rates were observed in both treatment arms ( 56 % ; 95 % CI 50 % to 62 % ) . There were 3 % and 7 % toxic deaths in arms A and B , respectively . No significant improvements with CarboPEC were observed in either 3-year event-free survival ( 35 % versus 42 % , P=0.16 ) or overall survival ( 53 % ; 95 % CI 46 % to 59 % ) . Complete responders with CarboPEC had a significant improvement in disease-free survival ( 55 % versus 75 % at 3 years , P < 0.04 ) . CONCLUSIONS The single cycle of high-dose salvage chemotherapy after three cycles of st and ard dose chemotherapy had no effect on treatment outcomes . These results suggest that data from uncontrolled studies should not be used to justify routine use of a toxic and expensive treatment without confirmation in a r and omised trial BACKGROUND To investigate the efficacy and toxicity of the combination of gemcitabine and oxaliplatin ( GEMOX ) in patients with relapsed or cisplatin-refractory non-seminomatous germ cell tumors ( NSGCT ) . PATIENTS AND METHODS Twenty-nine patients with relapsed or cisplatin-refractory NSGCT were treated with gemcitabine 1000 mg/m2 on days 1 and 8 followed by oxaliplatin 130 mg/m2 on day 1 every 3 weeks for a maximum of six cycles . Twenty-four patients ( 83 % ) were considered refractory and five ( 17 % ) absolutely refractory to cisplatin . RESULTS Twenty-eight patients were assessable for response . Overall , nine patients ( 32 % ) achieved a favourable response ( complete response , four ; partial response , five ) . One of the complete responders relapsed after 7 months and went into disease-free status lasting for 11 + months after resection of lung metastases . The rest of the complete responders are continuously disease-free at 14 + , 19 + and 28 + months with the study regimen plus or minus surgery . One of the complete responders had absolutely cisplatin-refractory disease and another one presented with a late relapse . Toxicity was primarily hematological and generally manageable : 62 % of patients experienced grade 3/4 neutropenia , 10 % neutropenic fever and 41 % grade 3/4 thrombocytopenia . Non-hematological toxicity consisted mainly of nausea/vomiting . Three patients ( 10 % ) developed grade 3 neurotoxicity and discontinued treatment . CONCLUSIONS The combination of GEMOX is an active , moderately toxic and easily administered regimen in patients with relapsed or cisplatin-refractory NSGCT . The 14 % long-term disease-free status accomplished in this heavily pretreated patient population is quite encouraging PURPOSE After cisplatin- and bleomycin-containing chemotherapy for testicular cancer , part of the patient population will develop acute or long-term cardiovascular toxicity . It is largely unknown whether st and ard tests can be used to assess chemotherapy-induced cardiovascular changes . PATIENTS AND METHODS In 65 testicular cancer patients ( median age , 27 years ; range , 18 to 48 years ) , we measured the following cardiovascular parameters before and within 10 weeks after completion of cisplatin-based chemotherapy :  platelet numbers , plasma levels of hemostatic and fibrinolytic factors , 24-hour ambulatory blood pressure , baroreflex sensitivity , intima-media thickness of the common carotid artery , and flow-mediated vasodilation of the brachial artery . RESULTS Compared with prechemotherapy values , the intima-media thickness of the carotid artery and plasma von Willebr and factor levels increased significantly after treatment . Platelet numbers and plasma levels of other hemostatic and fibrinolytic factors did not appear to change significantly . Blood pressure decreased significantly , but flow-mediated vasodilation and baroreflex sensitivity did not change . CONCLUSION In testicular cancer patients treated with cisplatin-based chemotherapy  , we found an increase in plasma von Willebr and factor levels and in the intima-media thickness of the carotid artery . These changes may indicate chemotherapy-induced vascular damage and be of prognostic significance for the development of cardiovascular complications in the long term St and ard chemotherapy for disseminated germ cell tumors ( GCT ) cures most patients but causes considerable acute toxicity , including treatment-related death due to septicemia during neutropenia and pulmonary fibrosis . In addition , chronic and delayed toxicities , particularly Raynaud 's phenomenon , have been reported in 6 % to 37 % of treated patients . In an attempt to minimize the acute and chronic effects of treatment which are related primarily to vinblastine and bleomycin , a r and omized trial comparing the efficacy and toxicity of vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin ( VAB-6 ) and etoposide + cisplatin ( EP ) was conducted on 164 eligible patients with good-prognosis GCT . Seventy-nine of 82 ( 96 % ) patients receiving VAB-6 and 76/82 ( 93 % ) receiving EP achieved a complete remission ( CR ) with or without adjunctive surgery . Similar proportions of patients in both arms were found at surgery to have necrosis/fibrosis or mature teratoma . With a median follow-up of 24.4 months in the VAB-6 arm and 25.9 months in the EP arm , the total , relapse-free , and event-free survival distributions were similar in the two arms . Patients receiving EP experienced less emesis ( P = .05 ) , higher nadir WBC ( P = .06 ) and platelet counts ( P = .01 ) , less magnesium wasting ( P = .0001 ) , less mucositis ( P = .09 ) , and no pulmonary toxicity . No treatment-related mortality was observed . EP is an efficacious and less toxic regimen and is recommended for good-prognosis patients with disseminated GCT PURPOSE This multicenter , r and omized phase III clinical trial evaluated the efficacy of etoposide plus carboplatin ( EC ) versus etoposide plus cisplatin ( EP ) in good-risk germ cell tumor ( GCT ) patients . PATIENTS AND METHODS Between October 1986 and December 1990 , 270 patients with good-risk GCTs were r and omized to receive four cycles of either EP or EC . The etoposide dose in all patients was 100 mg/m2 on days 1 through 5 . EP patients received cisplatin at 20 mg/m2 on days 1 through 5 and therapy was recycled at 21-day intervals . For EC patients , the carboplatin dose was 500 mg/m2 on day 1 of each cycle and the EC recycling interval was 28 days . RESULTS Two hundred sixty-five patients were assessable : 131 patients treated with EC and 134 treated with EP .  One hundred fifteen of 131 assessable patients ( 88 % ) treated with EC achieved a complete response ( CR ) versus 121 of 134 patients ( 90 % ) treated with EP ( P = .32 ) . Sixteen patients ( 12 % ) treated with EC relapsed from CR versus four patients ( 3 % ) treated with EP . Therefore , 32 patients ( 24 % ) who received carboplatin experienced an event ( incomplete response [ IR ] or relapse ) compared with 17 of 134 patients ( 13 % ) who received cisplatin ( P = .02 ) . At a median follow-up of 22.4 months , event-free and relapse-free survival were inferior for patients treated with EC ( P = .02 and P = .005 , respectively ) . No difference in overall survival was evident ( P = .52 ) . CONCLUSION Two-drug therapy with EC using this dose and schedule was inferior to therapy with EP . Cisplatin remains as the st and ard platinum analog in the treatment of patients with good-risk GCTs .  Carboplatin should be restricted to investigational trials in GCT OBJECTIVE St and ard chemotherapy shows relatively low long-term survival in patients with poor-risk testicular germ cell tumor ( GCT ) .  First-line high-dose chemotherapy ( HD-CT ) may improve the result . High-dose carboplatin , etoposide , ifosfamide chemotherapy followed by autologous peripheral blood stem cell transplantation ( PBSCT ) was investigated as first-line chemotherapy in patients with advanced testicular GCT . METHODS Fifty-five previously untreated testicular GCT patients with Indiana ' advanced disease ' criteria received three cycles of bleomycin , etoposide and cisplatin ( BEP ) followed by one cycle of HD-CT plus PBSCT , if elevated serum tumor markers were observed after three cycles of the BEP regimen . RESULTS Thirty patients were treated with BEP alone , because the tumor marker(s ) declined to normal range . Twenty-five patients received BEP and HD-CT . One patient died of rhabdomyolysis due to HD-CT . Three and six ( 13 % and 25 % ) out of 24 patients treated with BEP and HD-CT achieved marker-negative and marker-positive partial responses , respectively . The other patients achieved no change . Fifteen ( 63 % ) are alive and 14 ( 58 % ) are free of disease at a median follow-up time of 54 months . Severe toxicity included treatment-related death ( 4 % ) . CONCLUSIONS HD-CT with peripheral stem cell support can be successfully applied in a multicenter setting . HD-CT demonstrated modest anticancer activity for Japanese patients with advanced testicular GCT and was well tolerated . This regimen might be examined for further investigation in r and omized trials in first-line chemotherapy for patients with poor-risk testicular GCT PURPOSE To evaluate the dose , toxicity , and efficacy of paclitaxel in combination with ifosfamide and cisplatin as salvage therapy for patients with relapsed testicular germ cell tumors ( GCTs ) . PATIENTS AND METHODS Thirty patients with previously treated GCTs were treated with paclitaxel and ifosfamide plus cisplatin ( TIP ) as second-line therapy . All had favorable prognostic features for response ( testis primary tumor site and prior complete response to first-line chemotherapy program ) . Four cycles of paclitaxel , ifosfamide 5 g/m(2 ) , and cisplatin 100 mg/m(2 ) were given 21 days apart with granulocyte colony-stimulating factor support , followed by resection of radiographic residua . The dose of paclitaxel was increased among cohorts with dose levels of 175 , 215 , and 250 mg/m(2 ) ; the largest dose was selected for the phase II part of the trial . RESULTS Twenty-three ( 77 % ) of 30 patients achieved a complete response to chemotherapy alone , and one patient achieved a durable partial response with normal tumor markers . Therefore , 24 ( 80 % ) achieved a favorable response . Eleven patients with normalized markers after chemotherapy underwent resection of residual tissue , with only necrosis found in 10 and mature teratoma in one . Two patients relapsed , and 22 ( 73 % ) of the favorable responses remain durable at a median follow-up duration of 33 months . Myelosuppression was the major toxicity , and two patients had grade 3 neurotoxicity . CONCLUSION Four cycles of TIP was associated with a high proportion of patients who achieved a complete response , a lack of relapse , and relative tolerability as an ifosfamide-containing salvage regimen for testicular GCTs . The high durable complete response proportion emphasizes the importance of patient selection according to prognostic factors for a favorable outcome to conventional-dose salvage therapy BACKGROUND The aim of this study is to determine feasibility and efficacy of the combination regimen gemcitabine , oxaliplatin , and paclitaxel ( GOP ) in patients with cisplatin-refractory or multiply relapsed germ-cell tumors . PATIENTS AND METHODS From April 2003 to October 2006 , 41 patients refractory to cisplatin-based chemotherapy or with relapse after high-dose chemotherapy ( HDCT ) plus stem-cell support ( peripheral blood stem-cell transplantation : PBSCT )  received 800 mg/m2 gemcitabine , 80 mg/m2 paclitaxel ( Taxol ) , both on days 1 + 8 , and oxaliplatin 130 mg/m2 on day 1 of a 3-week cycle for a minimum of two cycles . Primary end point was response rate .  Patients were pretreated with a median of two lines of platin-based chemotherapy ( range , 1 - 3 ) , and 78 % had relapsed after HDCT/PBSCT . RESULTS Seventy-three percent of patients had relapsed within 3 months after the last cisplatin-based chemotherapy . Five percent of the patients achieved a complete response , and 34 % and 12 % a marker-negative and marker-positive partial response , respectively ( overall response rate 51 % ) . After a median follow-up of 5 months ( range , 0 - 20 ) , 15 % of the patients remain in complete remission after GOP chemotherapy + /- residual tumor resection with a median response duration of 8 months ( 1 to 17 + ) . Main toxicity was leucocytopenia grade 3/4 in 15 % , anemia in 7 % , and thrombocytopenia in 49 % of the patients . CONCLUSION Combination chemotherapy with GOP is feasible and effective with acceptable toxicity in patients with treatment-refractory germ-cell tumors PURPOSE To assess the role of high-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer . PATIENTS AND METHODS From August 1992 to April 1998 , 65 patients with testicular cancer were treated with high-dose carboplatin and etoposide followed by peripheral-blood stem-cell transplantation or autologous bone marrow transplantation rescue as initial salvage chemotherapy at Indiana University . An identical course was given after hematopoietic reconstitution . Postchemotherapy resection of residual disease was performed in selected patients with incomplete radiographic response associated with normalization of markers . The median follow-up was 39 months ( range , 16 to 91 months ) . RESULTS Thirty-seven ( 57 % ) of the 65 patients are continuously disease-free . Three additional patients are disease-free with subsequent surgery . High-dose chemotherapy was associated with significant morbidity but no treatment-related mortality . CONCLUSION High-dose chemotherapy as initial salvage chemotherapy achieved impressive long-term survival with acceptable toxicity in patients with relapsed testicular cancer Twenty-eight patients with poor prognosis , advanced metastatic non seminomatous germ cell tumors ( NSGCT ) were treated with early high dose chemotherapy and autologous bone marrow transplantation ( ABMT ) rescue .  The primary tumor was testicular in 19 patients and extragonadal in nine patients . For 19 patients with a testicular primary , the median probability of complete remission ( CR ) was 0.05 according to our prognostic mathematical model based on pretreatment levels of serum HCG and AFP . The same prognostic model was used for extragonadal primaries . Treatment consisted of two cycles of a modified double dose of cisplatin , vinblastine , bleomycin , VP-16 regimen ( mPVeBV ) followed by a high dose cisplatin-etoposide-cyclophosphamide regimen ( PEC ) followed by ABMT . Of the 28 patients , 17 ( 61 % ) achieved CR , one of which was surgical CR ( sCR ) , five died of rapidly progressive disease early during the first cycle of mPVeBV , two had treatment-related deaths , three did not respond and one patient refused treatment . Of the 17 patients initially in CR , three relapsed after 4 , 4 and 7 months respectively and have subsequently died . Two other patients died while still in CR : one committed suicide and one died of an infectious complication due to transfusion-related AIDS . Twelve patients are alive in CR after a median follow-up of 66 months ( range 7 - 72 months ) . The non parametric 3-year survival rate is 40 % . To demonstrate the effect of intensive chemotherapy with ABMT , a r and omized multicenter French study was set up to evaluate the PVeBV regimen with or without high dose treatment and ABMT in poor risk NSGCT patients PURPOSE The efficacy and toxicity of high-dose carboplatin , etoposide , and cyclophosphamide with autologous bone marrow transplantation ( AuBMT ) was investigated in a prospect i ve trial for patients with cisplatin-refractory germ cell tumor ( GCT ) . Prognostic factors for survival and treatment-related toxicity were identified . PATIENTS AND METHODS Fifty-eight patients with refractory GCT were treated with high-dose carboplatin , etoposide , and cyclophosphamide plus AuBMT . Prognostic factors for toxicity and survival were examined in multivariate analyses . RESULTS Twenty-three patients ( 40 % ) achieved a complete response and 12 ( 21 % ) are alive and free of disease at a median follow-up time of 28 months . Myelosuppression was severe and there were seven ( 12 % ) treatment-related deaths . Independently predictive factors that result ed in faster blood count recovery were the use of granulocyte colony-stimulating factor ( G-CSF ) for the number of days to neutrophil count recovery ( P = .013 ) and prior treatment with cisplatin limited to six cycles or less for the number of days to platelet count recovery ( P = .0012 ) . Both were predictive for the number of days of hospitalization ( P = .04 and .03 , respectively ) . The two independently predictive variables for survival were pretreatment level of HCG ; human chorionic gonadotrophin ( HCG ; < or = 100 times the upper limit of normal [ xnl ] v > 100 xnl , P = .02 ) and the presence of retroperitoneal metastases ( yes or no , P = .04 ) . Patients grouped by HCG < or = 100 xnl with retroperitoneal metastases , HCG < or = 100 xnl without retroperitoneal metastases , and all patients with HCG more than 100 xnl had median survival times of 14 , 11 , and 3 months , respectively ( P = .04 ) . CONCLUSION High-dose carboplatin , etoposide , and cyclophosphamide is an effective therapy for patients with refractory GCT , and results in a complete response proportion of 40 % and a 2-year survival rate of 31 % at a median follow-up time of 28 months . This was accomplished in a group of patients with a dismal prognosis to conventional-dose therapy PURPOSE Despite generally high cure rates in patients with metastatic testicular germ cell tumors , patients with incomplete response to cisplatin-based first-line therapy or with relapsed disease after high-dose salvage chemotherapy have a very poor prognosis . This phase II study evaluates the use of gemcitabine in patients with intensively pretreated or cisplatin-refractory testicular germ cell cancers . PATIENTS AND METHODS Thirty-five patients ( median age , 33 years ) were enrolled ; 31 patients were fully assessable . All patients had metastatic nonseminomatous germ cell tumors ; eight patients had extragonadal primary tumors . Twenty patients ( 63 % ) had lung metastases , and 12 patients ( 39 % ) had liver metastases . The median number of prior cisplatin-based chemotherapy cycles was seven ; 22 patients ( 71 % ) had received high-dose chemotherapy with autologous stem-cell transplantation , and 19 patients ( 61 % ) had received treatment with paclitaxel . Seventeen patients ( 54 % ) were considered refractory or absolutely refractory to chemotherapy . RESULTS Six of 31 assessable patients ( 19 % ) responded favorably to gemcitabine , 11 patients ( 35 % ) displayed no change , and 14 patients ( 45 % ) had disease progression . The median time to treatment failure was 4 months ( range , 2 to 9 + months ) , and the median survival was 6 months ( range , 2 to 23 months ) . Patients received a median of six gemcitabine applications . Ten patients ( 32 % ) required dose reductions , mainly owing to hematologic toxicity . Grade 3/4 granulocytopenia occurred in four patients ( 13 % ) and grade 3/4 thrombocytopenia in seven patients ( 22 % ) . One case of severe sepsis was observed . CONCLUSION Gemcitabine displays antitumor activity in intensively pretreated and refractory germ cell tumors . Responses were observed in approximately 20 % of patients , including three of 22 patients after previous high-dose chemotherapy and one of four patients with mediastinal tumors . Gemcitabine may be a reasonable palliative option for intensively pretreated patients and should be further investigated to define its role in the risk-adapted treatment strategies for germ cell tumors PURPOSE A treatment program that included high-dose carboplatin , etoposide , and cyclophosphamide ( CEC ) followed by autologous bone marrow transplantation ( AuBMT ) was investigated as first-line therapy in patients with poor-risk germ cell tumors ( GCTs ) . PATIENTS AND METHODS Previously untreated GCT patients with poor-risk features were treated with etoposide , ifosfamide , and cisplatin ( VIP ) with or without high-dose CEC plus AuBMT . Patients qualified for a change to high-dose CEC if a prolonged clearance of elevated serum tumor markers was observed after two cycles of the cisplatin-containing regimen . RESULTS Sixteen patients were treated with VIP alone and 14 with VIP and high-dose CEC . Seventeen patients ( 57 % ) achieved a complete response . Twenty are alive ( 67 % ) and 15 ( 50 % ) are free of disease at a median follow-up time of 30 months . For 23 cycles of high-dose CEC , the median time from AuBMT to a granulocyte count > or = 0.5/microL was 11 days ( range , 0 to 14 ) and to a platelet count 50,000/microL , 19 days ( range , 14 to 34 ) . The survival of 58 patients treated in two of our center 's programs that incorporated high-dose chemotherapy ( high-dose carboplatin plus etoposide [ CE ] and CEC ) was compared with our prior experience with conventional-dose cisplatin chemotherapy alone in poor-risk GCT . Patients treated with marker-dependent , early-intervention high-dose chemotherapy experienced longer survival ( P = .001 ) . CONCLUSION In this setting , high-dose CEC was well tolerated , cumulative toxicity was lacking , and the recovery of blood counts after AuBMT was rapid . A r and omized trial has been initiated to investigate further the role of high-dose CEC in first-line therapy for patients with poor-risk GCT PURPOSE This prospect i ve , r and omized trial was design ed to determine if three cycles of cisplatin plus etoposide ( PVP16 ) can produce therapeutic results comparable to three cycles of cisplatin , etoposide , and bleomycin ( PVP16B ) in patients with disseminated germ cell tumors . PATIENTS AND METHODS One hundred seventy-eight patients with minimal- or moderate-stage disease ( Indiana staging system ) were r and omized to receive cisplatin ( 20 mg/m2 on days 1 to 5 ) plus etoposide ( 100 mg/m2 on days 1 to 5 ) with or without weekly bleomycin ( 30 IU/wk for 9 consecutive weeks ) . Following three cycles of chemotherapy over 9 weeks , patients with residual radiographic disease underwent surgical resection . If persistent carcinoma was noted , two additional 3-week courses of chemotherapy were administered . RESULTS One hundred seventy-one patients were fully assessable for response and survival . The two treatment groups were similar with respect to patient characteristics . The toxicities were comparable between the two arms . No clinical ly significant incidence of pulmonary toxicity occurred with PVP16B . Overall , 81 of 86 patients ( 94 % ) who received PVP16B and 75 of 85 patients ( 88 % ) who received PVP16 achieved a disease-free status with chemotherapy and /or surgery . However , greater numbers of treatment failures , including persistent carcinoma in postchemotherapy resected residual disease and relapses from complete remission , occurred on the arm without bleomycin ( overall adverse outcome , P = .004 ) . The failure-free ( 86 % v 69 % ; P = .01 ) and overall survival ( 95 % v 86 % ; P = .01 ) rates were inferior on the PVP16 arm . CONCLUSION Bleomycin is an essential component of PVP16B therapy in patients who receive three cycles of treatment for minimal- or moderate-stage disseminated germ cell tumors Summary Vascular endothelial growth factor ( VEGF ) overexpression and increased angiogenesis have been proposed as having biologic importance in germ cell tumors ( GCT ) . We conducted a single-institution phase II trial of sunitinib , an oral inhibitor of the VEGF receptor , in patients with relapsed or refractory GCT . A Simon ’s two-stage design was used to determine the number of patients for enrollment . Responses were assessed using a modified version of Response Evaluation Criteria in Solid Tumors ( RECIST ) , taking into account tumor marker changes . Dose modifications were made according to a nomogram for adverse events . Ten patients were enrolled . The first five received sunitinib 50 mg for four consecutive weeks , followed by a two-week break ( 4/2 ) . Since four of five treated on this schedule had some tumor marker decline during the four-week “ on ” period , with subsequent rise during the two-week break , the dose was changed to 37.5 mg continuously for patients six to ten . However , only marker stabilization ( no declines ) was seen . Overall , there were no objective responses : Five had stable disease and five progressive disease ( PD ) .  Sunitinib was well tolerated ; only one patient required a dose reduction due to grade 3 mucositis . Two patients experienced tumor-related hemorrhage ( grade 3 and grade 1 ) . All patients developed PD within three cycles . Sunitinib is well tolerated , but at st and ard doses , does not demonstrate significant activity in highly refractory GCT . Correlation between sunitinib treatment and tumor marker changes on the 50 mg 4/2 schedule suggest some pathways targeted by sunitinib ( ie , angiogenesis ) may be important to GCT biology PURPOSE Long-term survival is rarely achieved in patients with cisplatin-refractory germ cell cancer ( GCT ) . Both single-agent gemcitabine and oxaliplatin have shown activity in patients who experience relapse or are refractory to cisplatin treatment . This study investigates the activity of a gemcitabine plus oxaliplatin regimen in these patients . PATIENTS AND METHODS Gemcitabine was administered at a dose of 1,000 mg/m(2 ) on days 1 and 8 ; oxaliplatin was administered at a dose of 130 mg/m(2 ) on day 1 . Response was evaluated every 4 weeks . RESULTS Thirty-five patients with a median age of 37 years ( range , 21 to 54 years ) were enrolled onto the study . Primary tumor localization was gonadal , retroperitoneal , or mediastinal in 30 , one , and four patients , respectively . Patients had been pretreated with a median of six platinum-containing cycles ( range , four to 13 cycles ) and 89 % of patients previously had experienced treatment failure after high-dose chemotherapy with peripheral-blood stem-cell transplantation . Sixty-three percent of patients were considered absolutely cisplatin-refractory or cisplatin-refractory . A median of two cycles ( range , 1 to 6 cycles ) per patient were applied . Toxicity consisted mainly of myelosuppression , with Common Toxicity Criteria grade 3 occurring in 54 % of patients . Only 9 % of patients developed neutropenic fever . Three patients attained a complete remission ( CR ) , two patients attained a marker-negative partial remission , and 11 patients attained a marker-positive partial remission , result ing in an overall response rate of 46 % ( 95 % CI , 30 % to 64 % ) . All three patients with CR and one patient with a marker-negative partial remission remained disease free at 16 + , 12 + , 4 + , and 2 + months of follow-up . Seven ( 44 % ) of these 16 responses , including one CR , occurred in cisplatin-refractory patients . CONCLUSION Gemcitabine plus oxaliplatin demonstrates antitumor activity with acceptable toxicity in heavily pretreated patients with relapsed or cisplatin-refractory GCT , and may offer a chance of long-term survival for selected patients PURPOSE To evaluate the efficacy and toxicity of sequential , dose-intensified chemotherapy with paclitaxel/ifosfamide and carboplatin/etoposide administered plus peripheral blood-derived stem-cell ( PBSC ) support for patients with germ cell tumors ( GCT ) who have unfavorable prognostic features in response to conventional-dose salvage programs .  Carboplatin was dose escalated by target area under the curve ( AUC ; in [ milligrams per milliliter ] x minutes ) among patient cohorts , and pharmacokinetic studies were performed for comparison . PATIENTS AND METHODS Thirty-seven previously treated patients who had cisplatin-resistant GCT and unfavorable prognostic features for response to conventional-dose salvage therapy were treated . Two cycles of paclitaxel 200 mg/m(2 ) plus ifosfamide 6 g/m(2 ) were given 2 weeks apart with leukapheresis , followed by three cycles of carboplatin plus etoposide given 14 to 21 days apart with reinfusion of PBSCs . The dose of etoposide was 1 , 200 mg/m(2 ) , and the carboplatin target AUC ranged among cohorts from 12 to 32 ( mg/mL ) x min . Pharmacokinetic studies of carboplatin were performed for comparison of target to measured AUC . RESULTS Twenty-one patients ( 57 % ) achieved a complete response and an additional two patients ( 5 % ) achieved a partial response with normal tumor markers ; therefore , 23 ( 62 % ) achieved a favorable response . Eight patients relapsed , and 15 ( 41 % ) of the favorable responses remained durable at a median follow-up of 30 months . Myelosuppression was the major toxicity ; 58 % of carboplatin/etoposide cycles were associated with hospitalization for nadir fever . The AUC of carboplatin  measured in serum was lower than the target AUC ; this may be related to underestimation of the glomerular filtration rate used in the dosing formula . CONCLUSION Dose-intense therapy with sequential , accelerated chemotherapy of paclitaxel/ifosfamide and carboplatin/etoposide administered with PBSC support was relatively well tolerated . The durable complete response proportion was substantial in patients with unfavorable prognostic features for achieving durable complete response to conventional-dose salvage programs . Optimal dosing of carboplatin in the high-dose setting warrants further investigation PURPOSE This phase II study was design ed to determine the toxicity and activity of single-agent gemcitabine in heavily pretreated patients with germ cell tumors . PATIENTS AND METHODS From March 1996 through November 1997 , 21 patients were enrolled onto a phase II study of  gemcitabine 1,200 mg/m2 , given on days 1 , 8 , and 15 every 4 weeks . One patient was unassessable because he never received any gemcitabine .  Thirteen of 20 patients had received three prior regimens , and 13 patients were platinum refractory ( progression during or within 4 weeks of platinum treatment ) . There were five extragonadal cases and two patients with late relapse ( relapse beyond 2 years ) . RESULTS Gemcitabine was well tolerated . Only one patient had grade 3 or 4 nonhematologic toxicity ( grade 3 nausea ) . Six of 20 patients had grade 3 leukopenia . There were no episodes of granulocytopenic fever , and no patient required platelet transfusion . Three ( 15 % ) of 20 patients achieved an objective response , including one complete remission . Three additional patients had a minor radiographic or serologic response . CONCLUSION Gemcitabine had definite activity in this heavily pretreated germ cell tumor patient population Four courses of PVP16B ( cisplatin plus etoposide [ VP-16 ] plus bleomycin ) has been st and ard chemotherapy for disseminated germ cell tumors at Indiana University and the Southeastern Cancer Study Group ( SECSG ) since 1984 . We began a r and om prospect i ve phase III study in patients with favorable-prognosis ( minimal and moderate extent ) disseminated germ cell tumors comparing four courses of PVP16B over 12 weeks to the identical dose PVP16B administered in three courses over 9 weeks . The categories of minimal and moderate disease constitute approximately two thirds of all disseminated germ cell tumors that require chemotherapy . One hundred eighty-four patients entered this trial , and all patients have a minimal follow-up of 1 year . Overall , 106 of 107 ( 99 % ) minimal extent and 73 of 77 moderate patients ( 95 % ) achieved an initial disease-free status ( NED ) , confirming the favorable prognostic categories . Eighty-six of 88 patients ( 98 % ) r and omized to three courses and 93 of 96 r and omized to four courses ( 97 % ) of PVP16B achieved disease-free status . There have been ten relapses ( 5 % ) , with five on each arm . Currently , 81 of 88 ( 92 % ) and 88 of 96 ( 92 % ) patients r and omized to three v four courses of PVP16B are continuously disease-free . This study confirms the high cure rate with PVP16B in favorable-prognosis germ cell tumors . The deletion of the fourth course of PVP16B  significantly reduces the toxicity , cost , and inconvenience of this curative regimen . We conclude that three courses of PVP16B is the preferred regimen for favorable-prognosis germ cell tumors PURPOSE To determine long-term survival and potential cure with salvage chemotherapy with paclitaxel plus gemcitabine after progression after both cisplatin combination chemotherapy and subsequent high-dose chemotherapy with t and em transplantation . PATIENTS AND METHODS One hundred eighty-four patients received salvage high-dose chemotherapy at Indiana University ( Indianapolis , IN ) from February 1996 to December 2004 . After further evidence of progressive disease , 32 patients were subsequently treated with paclitaxel 100 mg/n2 over 1 hour plus gemcitabine 1,000 mg/m2 over 30 minutes , days 1 , 8 , and 15 every 4 weeks for a maximum of six courses . This is a retrospective review of this patient population . Patients were evaluated for response , duration of response , and survival .  Patients were ineligible if they received prior paclitaxel or gemcitabine .  RESULTS Ten ( 31 % ) of 32 patients achieved objective response , including four partial remissions ( 2- to 6-month duration ) and six complete responses ( CRs ) . Four of these six CRs ( 12.5 % of total patient population ) are continuously disease free ( NED ) with paclitaxel plus gemcitabine alone ( no postchemotherapy surgery ) at more than 20 , 40 , 44 , and 57 months from start of paclitaxel plus gemcitabine , respectively . One additional CR is currently NED more than 63 months after paclitaxel plus gemcitabine with two subsequent resections of carcinoma . CONCLUSION Long-term disease-free survival is possible with paclitaxel plus gemcitabine in this patient population that progressed after high-dose chemotherapy , and had not received prior paclitaxel or gemcitabine PURPOSE This study was design ed to assess the effectiveness of vinblastine , ifosfamide , and cisplatin ( VeIP ) as second-line therapy in patients with recurrent germ cell tumors with previous treatment with cisplatin plus etoposide , usually in combination with bleomycin .  PATIENTS AND METHODS From July 1984 through December 1989 , 135 patients with progressive , disseminated germ cell tumors after cisplatin-etoposide-based combination therapy induction chemotherapy were treated with VeIP .  Patients who progressed within 3 weeks of previous cisplatin therapy were not eligible . Progression was documented by biopsy or increasing serum markers . No exclusion was made on the basis of metastatic site or performance status . The dosages were vinblastine 0.11 mg/kg/d ( days 1 and 2 ) , ifosfamide 1.2 gm/m2/d ( days 1 through 5 ) , and cisplatin 20 mg/m2/d ( days 1 through 5 ) , with courses repeated every 21 days for four cycles . RESULTS Sixty-seven ( 49.6 % ) patients achieved a disease-free status after chemotherapy with or without surgical resection of residual carcinoma or teratoma . Overall , 42 ( 32 % ) patients are alive and 32 ( 23.7 % ) are continuously free of disease . None of the 32 patients with nonseminomatous extragonadal tumors are disease-free compared with 30 of 100 patients with gonadal primaries . Two of three extragonadal seminomas are continuously disease-free . CONCLUSION VeIP is capable of producing durable complete remissions in patients with disseminated germ cell cancer who relapse after cisplatin-etoposide-based induction therapy . Long-term disease-free survival is not seen in those patients with extragonadal nonseminomatous germ cell tumors BACKGROUND The prognosis of patients with high-risk germ-cell cancer is poor . The toxicity and efficacy of first-line high-dose chemotherapy ( HDCT ) with stem-cell support was evaluated , following induction chemotherapy with BEP . PATIENTS AND METHODS Twenty patients with poor prognosis non seminomatous germ-cell tumour by the International Consensus prognostic criteria received induction with BEP followed by one cycle of HDCT ( CEC ) given with carboplatin ( 1800 mg/m2 ) , etoposide ( 1800 mg/m2 ) , and cyclophosphamide ( 140 mg/kg ) . Of the above 20 patients only 3 received a second cycle of HDCT . Peripheral blood stem cells were infused on day 0 . RESULTS Twenty patients were assessable for toxicity and response . After a median follow-up of 27 months 15 patients ( 75 % ) are alive , 12 ( 60 % ) are disease free and 3 ( 15 % ) are alive with disease . Median survival has not been reached and overall survival at four years is 66 % with a durable complete response rate of 50 % . There were no deaths or cases of severe toxicity . Median time to a granulocyte count > 500/microl and platelets > 20,000/microl was 10 and 12 days respectively . Five patients have died from progressive disease 5 - 35 months after HDCT . CONCLUSIONS These results support the case of first-line HDCT . The excellent toxicity profile of BEP/CEC and the two-year overall survival of 78 % are encouraging and support further the ongoing r and omised US intergroup study evaluating high-dose CEC after BEP PURPOSE To compare first-line high-dose chemotherapy ( HD-CT ) with autologous blood stem-cell transplantation to st and ard-dose chemotherapy ( SD-CT ) in male patients with advanced germ cell tumors ( GCTs ) , a matched-pair analysis was performed within a homogenous group of patients classified as having either Indiana advanced disease or a poor prognosis according to International Germ Cell Cancer Consensus Group ( IGCCCG ) criteria . PATIENTS AND METHODS A multivariate analysis was performed that included 147 consecutive patients who had received sequential high-dose cisplatin , etoposide , and ifosfamide ( VIP ) therapy ( HD-CT ) in a German multicenter trial between 1993 and 1997 and 309 patients who had been treated with st and ard-dose cisplatin , etoposide , and bleomycin ( PEB ) or VIP chemotherapy ( SD-CT ) within two r and omized trials at Indiana University between 1984 and 1992 . RESULTS Multivariate analysis demonstrated HD-CT to be significantly superior to SD-CT when adjustments were made for prognostic factors ( P = .021 ) . Primary tumor site ( mediastinal v retroperitoneal/gonadal , P = .035 ) and presence of visceral metastases ( P = .0004 ) were shown to be significant prognostic factors for overall survival . On the basis of these factors , as well as on tumor marker levels ( good , intermediate , or poor , according to IGCCCG criteria ) , 146 of 147 HD-CT patients were fully matched to an SD-CT patient . Median follow-up was 21 months ( range , 0 to 70 months ) for the HD-CT patients and 22 months ( range , 0 to 90 months ) for the SD-CT patients . Two-year progression-free survival ( 75 % v 59 % ) and overall survival ( 82 % v 71 % ) were significantly prolonged in HD-CT patients ( P = .0056 and P = .0184 , respectively ) . CONCLUSION The results indicate that first-line HD-CT in patients with poor-prognosis GCT may result in a significant improvement of progression-free and overall survival as compared with SD-CT . Salvage HD-CT seems not to compensate this survival advantage PURPOSE The efficacy of paclitaxel was evaluated in combination with ifosfamide and cisplatin as second-line chemotherapy for patients with relapsed testicular germ cell tumors ( GCTs ) . PATIENTS AND METHODS Forty-six patients with progressive metastatic GCTs were treated with paclitaxel and ifosfamide plus cisplatin ( TIP ) as second-line therapy . Eligibility required that patients have both a testis primary tumor site and a prior complete response ( CR ) to a first-line chemotherapy program , which had been identified previously as favorable prognostic factors to conventional-dose salvage chemotherapy . RESULTS Thirty-two ( 70 % ) of 46 patients achieved a CR to treatment . Three patients ( 7 % ) who achieved a CR relapsed after TIP chemotherapy . Twenty-nine patients are continuously disease free at a median follow-up time of 69 months , result ing in a 63 % durable CR rate and a 2-year progression-free survival rate of 65 % ( 95 % CI , 51 % to 79 % ) . CONCLUSION Four cycles of TIP as second-line therapy achieved a durable CR rate in a high proportion of patients with relapsed testicular GCT . The high CR rate emphasizes the importance of patient selection according to prognostic factors to achieve a favorable outcome to conventional-dose salvage therapy PURPOSE The prognostic relevance of the rate of decline of serum alpha-fetoprotein ( AFP ) and human chorionic gonadotropin ( HCG ) during the first 3 weeks of chemotherapy for nonseminomatous germ cell tumors ( NSGCT ) was studied in the context of the International Germ Cell Cancer Collaborative Group ( IGCCCG ) classification . PATIENTS AND METHODS Data from 653 patients prospect ively recruited in clinical trials were studied . Tumor markers were obtained before chemotherapy and 3 weeks later . Decline rates were calculated using a logarithmic formula and expressed as a predicted time to normalization ( TTN ) . A favorable TTN was defined when both AFP and HCG had a favorable decline rate , including cases with normal values . RESULTS The median follow-up was 50 months ( range , 2 to 151 months ) . Tumor decline rate expressed as a predicted TTN was associated with both progression-free survival ( PFS ; P < .0001 ) and overall survival ( OS ; P < .0001 ) . The 4-year PFS rates were 64 % and 38 % in patients from the poor-prognosis group who had a favorable and an unfavorable TTN , respectively . The 4-year OS rates were 83 % and 58 % , respectively . This effect was independent from the initial tumor marker values , the primary tumor site , and the presence of nonpulmonary visceral metastases : tumor marker decline rate remained a strong predictor for both PFS ( hazard ratio = 2.5 ; P = .01 ) and OS ( hazard ratio = 4.6 ; P = .002 ) in patients from the IGCCCG poor-prognosis group in multivariate analysis . CONCLUSION Early predicted time to tumor marker normalization is an independent prognostic factor in patients with poor-prognosis NSGCT and may be a useful tool in the therapeutic management of these patients BACKGROUND To compare the efficacy of one cycle of st and ard dose cisplatin , etoposide , and ifosfamide ( VIP ) plus three cycles of high-dose VIP followed by stem-cell infusion [ high-dose chemotherapy ( HD-CT arm ) ] to four cycles of st and ard cisplatin , etoposide , and bleomycin ( BEP ) in patients with poor-prognosis germ-cell cancer ( GCC ) . PATIENT AND METHODS Patients with poor-prognosis GCC were assigned to receive either BEP or VIP followed by HD-CT . To show a 15 % improvement in a 1-year failure-free survival ( FFS ) , the study aim ed to recruit 222 patients but closed with 137 , due to slow accrual . RESULTS One hundred thirty-one patients were included in this analysis . The complete response rates in the HD-CT and in the BEP arm did not differ : ( intention to treat ) 44.6 % versus 33.3 % ( P = 0.18 ) . There was no difference in FFS between the two treatment arms ( P = 0.057 , 66 events ) . At 2 years , the FFS rate was 44.8 % [ 95 % confidence interval ( CI ) 32.5 - 56.4 ] and 58.2 % , respectively ( 95 % CI 48.0 - 71.9 ) ; but this 16.3 % ( st and ard deviation 7.5 % ) difference was not statistically significant ( P = 0.060 ) . Overall survival did not differ between the two groups ( log-rank P > 0.1 , 47 deaths ) . CONCLUSION This study could not demonstrate that high-dose chemotherapy given as part of first-line therapy improves outcome in patients with poor-prognosis GCC PURPOSE 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 . PATIENTS AND METHODS 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 .  RESULTS 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 % ) . CONCLUSION 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 Between 1984 and 1989 , 159 patients presenting with advanced germ cell cancer were entered on a r and omized clinical trial comparing the efficacy and toxicity of etoposide and bleomycin and either st and ard-dose cisplatin ( 20 mg/m2 daily for 5 days ) or high-dose cisplatin ( 40 mg/m2 daily for 5 days ) . Of the 159 patients , 153 were assessable for toxicity and response .  As expected , patients receiving the high-dose cisplatin regimen experienced significantly more neurotoxicity , ototoxicity , nausea and vomiting , and myelo-suppression . Four patients ( 3 % ) died related to therapy . Despite the toxicity encountered , dose intensity was maintained . Overall , 84 % of patients in the high-dose arm received 80 % or more of the projected dose of cisplatin , etoposide , and bleomycin ; and 90 % of patients on the st and ard-dose arm received 80 % or more of the projected dose . Of the 76 eligible patients r and omized to receive the high-dose  cisplatin regimen , 52 ( 68 % ) became disease-free with chemotherapy alone or with subsequent resection of residual teratoma or cancer . Of the 77 patients r and omized to the st and ard-dose arm , 56 ( 73 % ) became disease-free with chemotherapy alone or with surgery . Median follow-up is now 24 months . Eleven patients ( three high-dose and eight st and ard-dose ) relapsed from disease-free status . Overall , 74 % of patients receiving the high-dose cisplatin regimen are alive , and 63 % are continuously free of disease . Of the patients receiving the st and ard-dose cisplatin regimen , 74 % are alive , and 61 % are continuously free of disease . This r and omized prospect i ve trial in advanced germ cell cancer achieved dose intensity of the most active single agent in this disease . This dose intensity did not translate into an improved survival or cure . We conclude that dose escalation of cisplatin beyond st and ard doses results in excess toxicity with no accompanying therapeutic benefit Twenty‐eight of 124 ( 23 % ) advanced germ cell tumor ( GCT ) patients who were treated on four successive platin‐based induction regimens  and who failed to achieve a durable complete response ( CR ) remain alive ( median follow‐up , 50 months ) . An analysis of prognostic factors for response and survival was conducted on the 94 patients who received salvage chemotherapy .  Survival and /or response to salvage therapy were significantly enhanced for patients with a prior CR to induction chemotherapy , treatment with a  cisplatin‐based salvage regimen  , a testis primary site , a normal serum human chorionic gonadotropin level , a normal serum lactate dehydrogenase level , one site of metastasis , and an Indiana Class of 6 or less . Patients with a prior incomplete response ( IR ) had a particularly poor prognosis ( P = 0.00007 ) with only 4 of 52 ( 9 % ) patients alive ( median follow‐up , 37 months ) compared with 15 of 42 ( 36 % ) patients with a prior best response of a CR ( median follow‐up , 35 months ) . The poor survival of patients who fail to achieve a durable CR to induction chemotherapy warrants the continued investigation of new salvage therapy . The identification of prognostic features may direct salvage therapy and aid in the interpretation of clinical trials of salvage regimens PURPOSE To evaluate the feasibility and the toxicity of sequential , dose-intensified chemotherapy combined with paclitaxel plus peripheral blood-derived hematopoietic stem-cell support ( PBSC ) for patients with untreated metastatic germ cell tumors ( GCTs ) who have poor International Germ Cell Consensus Cancer Group prognostic features . PATIENTS AND METHODS Paclitaxel was added to high-dose ( HD ) etoposide , ifosfamide , and cisplatin ( VIP ; etoposide 1,500 mg/m2 , ifosfamide 10,000 mg/m2 , and cisplatin 100 mg/m2 ; cumulative dose ; days -6 through -2 per cycle ) at three dose levels ( 135 , 175 , and 225 mg/m2 ) applied on day -6 . Cycles were supported by PBSC and granulocyte colony-stimulating factor . One cycle of st and ard VIP was administered before start of HD-VIP plus paclitaxel cycles to collect autologous PBSC . RESULTS Fifty-two of 53 patients receiving 152 cycles were assessable . As expected , myelosuppression was the major adverse effect . Median duration s of leukocytes less than 1,000/microL and thrombocytes less than 25,000/microL were 6 and 4 days , respectively , independently of the dose of paclitaxel applied . WHO grade 2 neurotoxicity and grade 3 encephalopathy were observed in 5 % of patients each . Other main adverse effects observed were stomatitis , diarrhea , and obstipation . Seventy-nine percent of patients achieved a favorable response to chemotherapy plus secondary surgery . After a median follow-up time of 41 months in surviving patients , the calculated 2- and 5-year survival rates were 77.6 % ( 95 % CI , 65.4 % to 89.9 % ) and 75.2 % ( 95 % CI , 62.5 % to 87.8 % ) , respectively . CONCLUSION Dose-intensive , sequential HD-VIP plus paclitaxel up to a dose of 225 mg/m2 in patients with poor prognosis GCT is a feasible approach . The regimen warrants investigation for its therapeutic potential in an exp and ed cohort of poor prognosis GCT patients PURPOSE Despite great success in the treatment of disseminated germ cell tumors , 20 % of patients are incurable and become c and i date s for investigational therapy . Paclitaxel and gemcitabine have shown activity as single agents in refractory germ cell tumors and can be combined with manageable toxicity . PATIENTS AND METHODS Patients with germ cell tumors believed to be incurable with chemotherapy or surgery were treated with paclitaxel 110 mg/m(2 ) and gemcitabine 1,000 mg/m(2 ) intravenously on days 1 , 8 , and 15 of a 4-week cycle for a maximum of six cycles . Patients were evaluated for response and toxicity . RESULTS Twenty-eight of 30 enrolled patients were assessable . Toxicity was primarily hematologic but was manageable with only a single case of neutropenic fever . Six ( 21.4 % ) of 28 patients responded , including three complete responses . Two of the complete responders were continuously disease-free at 15 + and 25 + months . CONCLUSION Paclitaxel plus gemcitabine is an active regimen in refractory germ cell tumors , with an acceptable toxicity profile . This regimen has the possibility for long-term disease-free survival in this refractory patient population PURPOSE To compare single versus sequential high-dose chemotherapy ( HDCT ) as first or subsequent salvage treatment in patients with relapsed or refractory germ cell tumors ( GCTs ) . PATIENTS AND METHODS Between November 1999 and November 2004 , 230 patients were planned to be recruited in a prospect i ve , r and omized , multicenter trial comparing one cycle of cisplatin 100 mg/m2 , etoposide 375 mg/m2 , and ifosfamide 6 g/m2 ( VIP ) plus three cycles of high-dose carboplatin 1,500 mg/m2 and etoposide 1,500 mg/m2 ( CE ; arm A ) versus three cycles of VIP plus one cycle of high-dose carboplatin 2,200 mg/m2 , etoposide 1,800 mg/m2 , and cyclophosphamide 6,400 mg/m2 ( CEC ; arm B ) . RESULTS The study was stopped prematurely after recruitment of 216 patients as a result of excess treatment-related mortality in arm B. One hundred eleven ( 51 % ) of 216 patients were r and omly assigned to sequential HDCT , and 105 ( 47 % ) of 216 patients were r and omly assigned to single HDCT .  Five ( 2 % ) of 216 patients had to be excluded because of non-GCT histologies at review . With a median follow-up time of 36 months , 109 ( 52 % ) of 211 patients were alive , and 91 ( 43 % ) of 211 patients were progression free . At 1 year , event-free , progression-free , and overall survival rates were 40 % , 53 % , and 80 % , respectively , in arm A compared with 37 % , 49 % , and 61 % , respectively , in arm B ( P > .05 for all comparisons ) . Treatment-related deaths , mainly as a result of sepsis and cardiac toxicity , were less frequent in arm A ( four of 108 patients , 4 % ) compared with arm B ( 16 of 103 patients , 16 % ; P < .01 ) . CONCLUSION We found no difference in survival probabilities between single HDCT using CE and sequential HDCT using CEC . Sequential HDCT was better tolerated and result ed in fewer treatment-related deaths Objective : This phase II study was conducted to determine the activity of imatinib ( gleevec ) in heavily pretreated patients with KIT-positive metastatic germ cell tumor . Material s and Methods : From June 2002 through April 2005 , 18 patients with refractory germ cell tumors were tested for KIT expression by immunohistochemistry . All patients screened were deemed to be incurable with further st and ard chemotherapy or surgery . Six patients were eligible and treated with imatinib 600 mg/d orally . Results : There were no complete or partial remissions . Five of 6 patients had progressive disease and 1 patient had stable disease with a > 50 % decline in serum alpha-fetoprotein for 3 months before developing further progression . Conclusion : In this small sample size , there was no evidence of significant antitumor activity of  imatinib  in patients with KIT-positive refractory germ cell tumors PURPOSE To compare st and ard therapy with bleomycin , etoposide , and cisplatin ( BEP ) to experimental therapy with etoposide , ifosfamide , and cisplatin ( VIP ) as primary treatment of men with advanced , disseminated germ cell tumors . PATIENTS AND METHODS A total of 304 men with advanced disseminated germ cell tumors were r and omly allocated to receive four courses of BEP or VIP .  Two hundred ninety-nine patients were assessable for toxicity and 286 were assessable for response . Complete response rates , favorable response ( complete remission , surgical free of disease , continuous partial remission for 2 + years ) , time to treatment failure , and overall survival were assessed . RESULTS Overall complete remission rate ( VIP , 37 % ; BEP , 31 % ) , favorable response rate ( VIP , 63 % ; BEP , 60 % ) , failure-free at 2 years ( VIP , 64 % ; BEP , 60 % ) , and 2-year overall survival ( VIP , 74 % ; BEP , 71 % ) were not significantly different between the two treatments . Grade 3 or worse toxicity , particularly hematologic and genitourinary toxicity , was significantly more common in patients who received VIP . CONCLUSION BEP and VIP produce comparable favorable response rate and survival in patients with poor-risk germ cell tumors . The substitution of ifosfamide for bleomycin , however , was associated with significantly greater toxicity . Four courses of BEP remain the st and ard treatment for advanced disseminated germ cell tumors PURPOSE This prospect i ve r and omized trial was design ed to compare the efficacy of etoposide plus cisplatin ( EP ) versus bleomycin , etoposide , and cisplatin ( BEP ) chemotherapy in patients with good-prognosis metastatic nonseminomatous testicular cancer . PATIENTS AND METHODS Four hundred nineteen patients with good-prognosis nonseminomatous testicular cancer were r and omized to receive four cycles of cisplatin 20 mg/m2 on days 1 to 5 plus etoposide 120 mg/m2 on days 1 , 3 , and 5 with or without bleomycin 30 mg weekly . RESULTS Of 395 eligible patients , 169 of 195 patients allocated to EP ( 87 % ) and 189 of 200 patients allocated to BEP ( 95 % ) achieved a complete response with chemotherapy alone or after postchemotherapy surgery . These results are significantly different ( P = .0075 ) . After a median follow-up duration of 7.3 years , eight patients ( 4 % ) on each treatment arm relapsed . In view of the low number of unfavorable treatment outcomes ( 11 % ) , no significant differences were detected in time to progression ( P = .136 ) and survival ( P = .262 ) . Both the acute and late pulmonary toxicity and neurotoxicity were significantly greater in patients who received BEP , whereas Raynaud 's phenomenon occurred exclusively in patients who received BEP ( P < .001 ) . Two patients treated with BEP died of  bleomycin pulmonary toxicity . CONCLUSION BEP is the most effective combination regimen in the treatment of disseminated nonseminomatous germ cell cancer . In this particular BEP regimen with etoposide at a dose of 360 mg/m2 per cycle , even in good-prognosis patients , bleomycin can not be deleted without compromising treatment efficacy , but its use is associated with more toxicity ( particularly pulmonary ) and efforts to reduce this merit further exploration BACKGROUND Most patients with metastatic germ-cell tumours are cured with chemotherapy . However , the optimum chemotherapy regimen is uncertain , and there is variation in international practice . We did a multicentre r and omised trial to compare two st and ard chemotherapy regimens for men with good-prognosis germ-cell tumours . METHODS Good prognosis was defined by modified Memorial Sloan-Kettering criteria . The first regimen ( regimen A ) was based on treatment recommendations from Indiana University and comprised three cycles of 20 mg/m2 cisplatin on days 1 - 5 , 100 mg/m2 etoposide on days 1 - 5 , and 30 kU bleomycin on days 1 , 8 , and 15 , repeated every 21 days . The second regimen ( regimen B ) was based on the control regimen of a published r and omised clinical trial and comprised four cycles of 100 mg/m2 cisplatin on day 1 , 120 mg/m2 etoposide on days 1 - 3 , and 30 kU bleomycin on day 1 , repeated every 21 days . The primary outcome measure was overall survival . Analysis was by intention to treat . FINDINGS 166 patients were r and omised , 83 to each regimen . The trial was stopped when the second planned interim analysis met predefined stopping rules . The median follow-up was 33 months . Overall survival was substantially better with regimen A ( three vs 13 deaths , hazard ratio 0.22 [ 95 % CI 0.06 - 0.77 ] , p=0.008 ) . This difference was due to deaths from cancer ( one vs nine ) , and not deaths from treatment ( two vs two ) and remained significant after adjustment for other prognostic factors ( 0.25 [ 0.07 - 0.88 ] , p=0.03 ) . INTERPRETATION In men with good-prognosis germ-cell tumours , the regimen developed at Indiana University is superior to the alternative regimen studied in this trial . The lower total dose and dose-intensity of bleomycin and the lower dose-intensity of etoposide in regimen B could be responsible for the worse outcome St and ard chemotherapy for disseminated germ-cell tumors includes a combination of cisplatin , vinblastine , and bleomycin , but this regimen produces substantial neuromuscular toxicity . In a r and omized clinical trial in 261 men with disseminated germ-cell tumors , we substituted etoposide for the vinblastine in this regimen in half the patients to compare the efficacy and toxicity of the two treatments . Among 244 patients who could be evaluated for a response , 74 percent of those receiving the regimen including vinblastine and 83 percent of those receiving the regimen including etoposide became disease-free with or without subsequent surgery ( P not significant ) . Among the 157 patients with high tumor volume , 61 percent became disease-free on the regimen that included vinblastine , as compared with 77 percent on the regimen that included etoposide ( P less than 0.05 ) . Survival among the patients who received etoposide was higher ( P = 0.048 ) . The regimens were similar in terms of myelosuppressive effects and pulmonary toxicity . However , the etoposide regimen caused substantially fewer paresthesias ( P = 0.02 ) , abdominal cramps ( P = 0.0008 ) , and myalgias ( P = 0.00002 ) . We conclude that etoposide with cisplatin and bleomycin is superior to vinblastine with cisplatin and bleomycin in the treatment of disseminated germ-cell tumors because of diminished neuromuscular toxicity and , among patients with advanced disease , better efficacy PURPOSE We previously reported a dose-finding and phase II trial of the TI-CE regimen ( paclitaxel [ T ] plus ifosfamide [ I ] followed by high-dose carboplatin [ C ] plus etoposide [ E ] with stem-cell support ) in germ cell tumor ( GCT ) patients predicted to have a poor prognosis with conventional-dose salvage therapy . We now report the efficacy of TI-CE with prognostic factors for disease-free survival ( DFS ) and overall survival ( OS ) in our full data set of 107 patients . PATIENTS AND METHODS Eligible patients had advanced GCTs with progressive disease following chemotherapy and unfavorable prognostic features ( extragonadal primary site , incomplete response [ IR ] to first-line therapy , or relapse/IR to ifosfamide-cisplatin-based conventional-dose salvage ) . Univariate and multivariate analyses ( MVAs ) of prognostic factors were performed . The predictive ability of the Einhorn and Beyer prognostic models was assessed . RESULTS Most patients were platinum refractory and had an IR to first-line chemotherapy . There were 54 ( 5 % ) complete and eight ( 8 % ) partial responses with negative markers ; 5-year DFS was 47 % and OS was 52 % ( median follow-up , 61 months ) . No relapses occurred after 2 years . Five ( 24 % ) of 21 primary mediastinal nonseminomatous GCTs are continuously disease free . On MVA , primary mediastinal site ( P < .001 ) , two or more lines of prior therapy ( P < .001 ) , baseline human chorionic gonadotropin > or = 1,000 U/L ( P = .01 ) , and lung metastases ( P = .02 ) significantly predicted adverse DFS . Poor-risk patients did worse than good- or intermediate-risk patients according to both Beyer ( P < .002 ) and Einhorn ( P < .05 ) models . CONCLUSION TI-CE is effective salvage therapy for GCT patients with poor prognostic features . Mediastinal primary site and two or more lines of prior therapy were most predictive of adverse DFS . Beyer and Einhorn models can assist in predicting outcome
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 .
St and ard treatment of metastatic GCTs has evolved on the basis of r and omised 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 st and ard treatment .