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. A phase II trial of high-dose chemotherapy (HDCT) supported by hematopoietic stem-cell transplantation (HSCT) in germ-cell tumors (GCTs) patients failing cisplatin-based chemotherapy: the Multicentric TAXIF II study. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Paclitaxel-containing high-dose chemotherapy for relapsed or refractory testicular germ cell tumours High-dose carboplatin and etoposide for salvage chemotherapy of germ cell tumours. 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. A phase II multicenter study of oxaliplatin in combination with paclitaxel in poor prognosis patients who failed cisplatin-based chemotherapy for germ-cell tumors. Gemcitabine and oxaliplatin (GEMOX) in patients with cisplatin-refractory germ cell tumors: a phase II study. Paclitaxel, ifosfamide, and cisplatin second-line therapy for patients with relapsed testicular germ cell cancer. Salvage High‐Dose Chemotherapy for Relapsed Pure Seminoma in the Last 10 Years: Results From the European Society for Blood and Marrow Transplantation Series 2002‐2012 Sequential versus single high-dose chemotherapy in patients with relapsed or refractory germ cell tumors: long-term results of a prospective randomized trial. High-dose carboplatin, etoposide, and cyclophosphamide for patients with refractory germ cell tumors: treatment results and prognostic factors for survival and toxicity. Cisplatin and ifosfamide with either vinblastine or etoposide as salvage therapy for refractory or relapsing germ cell tumor patients: The Institut Gustave Roussy experience Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients. 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. Salvage high‐dose chemotherapy in patients with germ cell tumors Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors. Phase II study of cisplatin plus epirubicin salvage chemotherapy in refractory germ cell tumors. Paclitaxel-based high-dose chemotherapy with autologous stem cell rescue for relapsed germ cell cancer. 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. Salvage chemotherapy for patients with germ cell tumors. The memorial sloan‐kettering cancer center experience (1979–1989) Phase II study of paclitaxel plus gemcitabine in refractory germ cell tumors (E9897): a trial of the Eastern Cooperative Oncology Group. High-dose carboplatin and etoposide with autologous bone marrow transplantation in refractory germ cell cancer: an Eastern Cooperative Oncology Group protocol. High-dose chemotherapy in germ cell tumours: a large single centre experience. Combination of paclitaxel, cisplatin, and gemcitabine (TPG) for multiple relapses or platinum-resistant germ cell tumors: long-term outcomes. Treatment of germ cell cancer with two cycles of high-dose ifosfamide, carboplatin, and etoposide with autologous stem-cell support. Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. Successful treatment of resistant germinal neoplasms with VP-16 and cisplatin: results of a Southeastern Cancer Study Group trial. A multi-center prospective phase II study of high-dose chemotherapy in germ-cell cancer patients relapsing from complete remission. Hematopoietic rescue after high-dose chemotherapy using autologous peripheral-blood progenitor cells or bone marrow: a randomized comparison. TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis.
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 High-dose chemotherapy ( HDCT ) is an effective salvage treatment of germ-cell tumors ( GCTs ) patients . In the first salvage setting , 30%-70 % of patients may achieve durable remissions . Even when HDCT is administered as subsequent salvage treatment , up to 20 % of patients may still be definitively cured . However , patients with refractory/relapsed disease still have a very poor long-term prognosis , requiring earlier intervention of HDCT . PATIENTS AND METHODS This phase II trial was addressed to nonrefractory patients failing Cisplatin-based chemotherapy . Inclusion criteria included seminomatous GCT in relapse after two lines of chemotherapy , nonseminomatous GCT in relapse after first or second lines , partial remission after first line , primary mediastinal GCT in first relapse . Patients received two cycles combining Epirubicin and Paclitaxel ( Epi-Tax ) , followed by three consecutive HDCT , one using a Paclitaxel/Thiotepa ( Thio-Tax ) association and two using the 5-day Ifosfamide-Carboplatin-Etoposide regimen . The main objective was to determine the complete response rate . RESULTS Forty-five patients were included between September 2004 and December 2007 : 44 received the first HDCT cycle , 39 two HDCT cycles , 29 could receive the whole protocol . Sixteen patients did not receive the entire protocol , including eight ( 17.7 % ) for toxic side-effects . Two patients ( 4.4 % ) died of toxicities , and 17 ( 37.7 % ) of disease progression . With a median follow-up time of 26 months ( range , 4 - 51 ) , the final overall response rate was 48.8 % ( including a complete response rate of 15.5 % and a partial response/negative serum markers rate of 26.6 % ) in an intent-to-treat analysis . The median progression-free survival ( PFS ) and overall survival ( OS ) times were 22 months [ 95 % confidence interval ( CI ) 2-not reached ] and 32 months ( 95 % CI 4 - 49 ) , respectively . The 2-year PFS was a plateau setup at 50 % ( 95 % CI 32 - 67 ) and the 2-year OS was 66 % ( 95 % CI 44 - 81 ) . CONCLUSION The TAXIF II protocol was effective in nonrefractory GCT patients failing Cisplatin-based chemotherapy . The toxic death rate remained acceptable in the field of HDCT regimens . TRIAL REGISTRATION NUMBER NCT00231582 STUDY OBJECTIVE To determine the efficacy of the addition of ifosfamide to cisplatin plus etoposide ( VIP ) , or vinblastine ( VeIP ) , in patients with recurrent germ cell tumors . DESIGN Nonr and omized , prospect i ve phase II trial . SETTING Tertiary referral university hospital . PATIENTS Fifty-six of fifty-eight entered patients with measurable and progressive recurrent germ cell tumors of testicular ( 46 patients ) , ovarian ( 1 patient ) , and extragonadal ( 9 patients ) origin were evaluable for response after not being cured with cisplatin , vinblastine , and etoposide regimens . INTERVENTIONS Patients were administered cisplatin ( 20 mg/m2 body surface area daily for 5 days ) , ifosfamide ( 1.2 g daily for 5 days ) , plus either etoposide ( 75 mg daily for 5 days ) or vinblastine ( 0.11 mg/kg body weight on days 1 and 2 ) . In addition , vigorous intravenous hydration therapy with normal saline ( 100 to 125 mL/h ) was administered during the treatment course . Uroepithelial protective agents , N-acetylcysteine ( orally ) or mesna ( intravenously ) , were administered . Four courses were administered to responding patients every 3 weeks . When complete excision was feasible , surgical resection of residual tumor was done approximately 6 to 8 weeks after chemotherapy . MEASUREMENTS AND MAIN RESULTS Twelve of fifty-six evaluable patients had a complete remission with chemotherapy alone , whereas 8 additional patients were free of disease after resection of teratoma ( 3 patients ) or carcinoma ( 5 patients ) for a total disease-free rate of 36 % ( 95 % CI , 23.4 to 49.6 ) . The 95 % CI median duration of remission for these patients is 34 months ( range , 3 to more than 42 ; 95 % CI , 9 months to infinity ) , and the median survival for all eligible patients is 12.7 months ( 95 % CI , 10 months to 26 months ) , with 15 of the 20 patients who achieved disease-free status alive 18 to 53 months or more . Nine of fifty-eight patients remain free of disease , including 7 patients for 2 years or longer . Hematologic and nephrotoxicity were the predominant drug-related toxicities , with one drug-related death secondary to pneumonia . CONCLUSIONS Ifosfamide combination chemotherapy as third-line or greater therapy can produce durable complete remissions in heavily pretreated patients with recurrent germ cell tumors High-dose regimes containing etoposide , carboplatin and an oxazaphospharine can salvage 30–40 % of patients with relapsed or refractory male germ cell tumours ( GCTs ) . The additional benefit of paclitaxel in such high-dose therapy has not been tested . Between March 1995 and November 2002 , 36 male GCT patients were treated with Carbop-EC-T ( paclitaxel 75 mg m−2 , etoposide 450 mg m−2 , carboplatin AUC 10 on days −7 , −5 and −3 and cyclophosphamide 60 mg kg−1 on days −5 and −3 ) followed by peripheral blood stem cell infusion ( day 0 ) . The 1-year overall survival rate for all patients is 67 % ( median follow-up 29 months ) . For the 24 patients with cisplatin-sensitive disease , the 1-year overall and event-free survivals are 88 and 64 % , respectively . For those with cisplatin refractory or absolutely refractory disease , the 1-year overall survival is 25 % . In all , 12 patients relapsed at a median duration of 5 months , 11 of whom have died . There were also six treatment-related deaths , five associated with pneumonitis . Pulmonary toxicity has been reported with paclitaxel in other high-dose regimes . Since altering our protocol so that paclitaxel is infused over 24 h with steroid prophylaxis , only one of 18 patients ( 13 testicular GCTs and five other tumour types ) has had a treatment-related death . Our results suggest that Carbop-EC-T may enable a greater proportion of patients with relapsed and refractory GCTs to enter long-term remission We evaluated high-dose carboplatin and etoposide with autologous bone marrow stem cell support in the salvage treatment of patients with metastatic germ cell tumours who had failed previous chemotherapy . The treatment programme comprised initial conventional dose chemotherapy .  23 patients received a first cycle of high-dose treatment , and 12 who showed no evidence of progression had a second cycle 2 - 3 months later . 8 of the 23 patients treated with high-dose chemotherapy are alive in remission 4 - 29 months from the start of high-dose treatment . 3 of these 8 required further treatment for recurrence . In the initial part of the study , the dose of carboplatin was escalated in successive patients . Grade 3/4 treatment-related toxicity occurred in 4 of 18 patients ( 1 fatal ) who received carboplatin doses to give a AUC ( area under the serum concentration/time curve ) of 30 mg.min/ml or less and 3 of 5 patients ( 2 fatal ) who received higher doses . We , therefore , recommend 30 mg.min/ml for further evaluation in chemotherapy sensitive patients 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 The aim of this study is to determine feasibility and efficacy of the combination regimen oxaliplatin and paclitaxel in patients with cisplatin (CDDP)-refractory germ-cell tumors ( GCT ) . PATIENTS AND METHODS Patients with either a cisplatin absolute-refractory GCT defined as progressive disease ( PD ) during or within 1 month of CDDP administration or with a poor prognosis relapse , defined as PD between the second and the sixth month after CDDP administration , were treated with a combination of oxaliplatin ( 130 mg/m(2 ) ) and paclitaxel ( 175 mg/m(2 ) ) administered every 21 days . Primary end point was efficacy . RESULTS Twenty-seven patients were included . Patients were pretreated with a median of two lines of cisplatin-based chemotherapy ( range 1 - 5 ) . Sixteen patients were absolute refractory . Five patients had relapsed after high-dose chemotherapy plus stem-cell support . There were no complete responses but there was one marker-positive partial response and nine disease stabilization ( 34 , 6 % ) . After a median follow-up of 65 months , two patients are disease-free survivors . Main toxicity was leucocytopenia grade 3/4 in 30 % of the patients . CONCLUSION Combination chemotherapy with oxaliplatin and paclitaxel is feasible with acceptable toxicity and may be effective if combined with additional treatment in patients with CDDP-refractory GCT 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 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 & NA ; In a retrospective analysis of data from 13 European Society for Blood and Marrow Transplantation ( EBMT ) centers , we evaluated the contemporary outcomes of high‐dose chemotherapy ( HDCT ) as salvage therapy of advanced seminoma . The results supported the use of HDCT , particularly for patients with chemosensitive disease . This proof of concept needs to be prospect ively vali date d in a r and omized trial of HDCT versus st and ard‐dose chemotherapy . Background : The optimal management of advanced seminoma that relapses after chemotherapy remains unknown . We retrospectively analyzed outcomes with the use of high‐dose chemotherapy ( HDCT ) . Patients and Methods : Eligibility included adult male patients with pure seminomatous histology and treatment with salvage HDCT . Data of patients who received HDCT from 13 European Society for Blood and Marrow Transplantation ( EBMT ) centers were used . Multivariable Cox analyses evaluated the association of prespecified factors ( line of treatment , prior radiotherapy , and chemosensitivity according to st and ard definition ) , with progression‐free ( PFS ) and overall survival ( OS ) . The prognostic ability of the model was assessed through the concordance statistic . Results : From December 2002 to December 2012 , 46 cases were identified . Median age was 38 years ( interquartile range , 35‐46 years ) . HDCT was provided as second‐line therapy ( n = 14 , 30.4 % ) and in third‐line or beyond third‐line therapy ( n = 20 , 43.5 % ; 12 had missing information ) . Sixteen patients ( 34.8 % ) received paraortic and /or iliac radiotherapy , and 10 ( 21.7 % ) had disease that was cisplatin refractory or absolutely refractory . Median follow‐up was 22 months ( interquartile range , 8‐56 ) . On multivariable Cox analysis , refractory disease was a significantly negative prognostic factor for both PFS ( hazard ratio , 6.04 ; 95 % confidence interval , 1.86‐19.64 ) and OS ( hazard ratio , 3.93 ; 95 % confidence interval , 1.07‐14.45 ) , while prior radiotherapy trended to significance for both . The c index was 0.74 and 0.66 for PFS and OS , respectively . The small numbers and the lack of any comparison with conventional‐dose chemotherapy are major study limitations . Conclusion : Despite our small sample size , this retrospective analysis suggested that HDCT may represent a valuable therapeutic option for patients with a pure seminoma after st and ard‐dose chemotherapy failure . Our observation requires validation through a prospect i ve study PURPOSE To evaluate the long-term survival rates in patients with relapsed or refractory germ cell tumors ( GCTs ) after single  or sequential high-dose chemotherapy ( HDCT ) . PATIENTS AND METHODS Between November 1999 and November 2004 , 211 patients with relapsed or refractory GCT were r and omly assigned to treatment with either one cycle of cisplatin 100 mg/m(2 ) , etoposide 375 mg/m(2 ) , and ifosfamide 6 g/m(2 ) ( VIP ) plus three cycles of high-dose carboplatin 1,500 mg/m(2 ) and etoposide 1,500 mg/m(2 ) ( CE , arm A ) or three cycles of VIP plus one cycle of high-dose carboplatin 2,200 mg/m(2 ) , etoposide 1,800 mg/m(2 ) , and cyclophosphamide 6,400 mg/m(2 ) ( CEC , arm B ) followed by autologous stem-cell reinfusion .  Long-term progression-free survival ( PFS ) and overall survival ( OS ) 6 years after r and om assignment of the last patient were compared by using the log-rank test . RESULTS Overall , 108 and 103 patients were r and omly assigned to arms A and B , respectivelyl . The study was stopped prematurely because of excess treatment-related mortality in arm B ( 14 % ) compared with that in arm A ( 4 % ; P = .01 ) . As of December 2010 , nine ( 5 % ) of 211 patients were lost to follow-up ; 94 ( 45 % ) of 211 are alive and 88 ( 94 % ) of 94 patients are progression free . Five-year PFS is 47 % ( 95 % CI , 37 % to 56 % ) in arm A and 45 % ( 95 % CI , 35 % to 55 % ) in arm B ( hazard ratio [ HR ] , 1.16 ; 95 % CI , 0.79 to 1.70 ; P = .454 ) . Five-year OS is 49 % ( 95 % CI , 40 % to 59 % ) in arm A and 39 % ( 95 % CI , 30 % to 49 % ) in arm B ( HR , 1.42 ; 95 % CI , 0.99 to 2.05 ; P = .057 ) . CONCLUSION Patients with relapsed or refractory GCT achieve durable long-term survival after single as well as sequential HDCT . Fewer early deaths related to toxicity translated into superior long-term OS after sequential HDCT 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 Approximately 30 % of patients with metastatic germ cell tumors require salvage chemotherapy for recurrent or refractory disease after first‐line treatment . The optimal salvage chemotherapy regimen remains to be determined 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 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 High‐dose chemotherapy ( HDCT ) followed by hematopoietic stem cell support ( HSCS ) potentially may be curative in patients with germ cell tumor ( GCT ) who develop recurrent tumors or who have an inadequate response after receiving st and ard‐dose chemotherapy . The authors report their experience with HDCT as salvage therapy for patients with GCT 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 Initial cisplatin ( CIS ) combination chemotherapy will cure 70 % of patients with disseminated testicular cancer . This phase II clinical trial evaluated the combination of CIS plus epirubicin ( CIS-EPI ) in patients with metastatic germ cell tumors ( GCT ) not amenable to cure with st and ard salvage therapy . PATIENTS AND METHODS Between March 2001 and August 2005 , 30 patients with GCT , who had received at least one previous CIS-based regimen , were enrolled . All patients were males , with median age 36 ( range , 24 to 45 years ) . Twenty-one patients ( 70 % ) had experienced late relapses ( > 2 years ) . Patients received EPI 90 mg/m2 on day 1 and CIS 20 mg/m2 on days 1 to 5 every 3 weeks for maximum of four cycles . RESULTS Nineteen ( 63 % ) of 30 patients received all four cycles . Toxicity was primarily hematologic : grade 3/4 neutropenia , four patients ( one neutropenic fever ) ; two patients had grade 3 thrombocytopenia , and five patients had grade 3/4 anemia . Nonhematologic toxicity was grade 3 acute renal failure in two patients ; grade 3 electrolyte wasting in two patients ; grade 3 nausea/vomiting in eight patients ; grade 3 elevation of aminotransferases in one patient ; and grade 3 diarrhea in one patient . There were no occurrences of severe mucositis , cardiotoxicity , or treatment-related deaths . Nine patients achieved a complete remission ; seven of these patients remain without evidence of disease at 25 + , 27 + , 29 + , 44 + , 45 + , 46 + , and 48 + months . One patient remains alive with stable pulmonary nodules at 28 + months . CONCLUSION CIS-EPI is an active regimen in metastatic GCT , with an acceptable toxicity profile . This regimen offers potential for long-term disease-free survival in this population We evaluated the antitumor activity of t and em cycles of high-dose chemotherapy with autologous peripheral stem cell transplantation ( aPSCT ) in relapsed germ cell tumors by using high-dose paclitaxel , carboplatin , etoposide , and ifosfamide .  Thirty-three patients were entered , and 31 underwent protocol therapy .  Paclitaxel 350 mg/m2 ( 5 patients ) or 425 mg/m2 ( 26 patients ) by 24-hour continuous intravenous infusion was followed by 3 daily doses of carboplatin and either etoposide ( cycle 1 ) or ifosfamide/mesna ( cycle 2 ) . The carboplatin dose had a calculated area under the curve of 7 mg-min/mL , and the daily dose of etoposide was 20 mg/kg ( cycle 1 ) . Ifosfamide 3 g/m2/d for 3 days ( with mesna uroprotection ) was substituted for etoposide in cycle 2 . Each cycle was supported by granulocyte colony-stimulating factor-mobilized peripheral blood stem cells . Thirty-one patients were evaluable for response , toxicity , and long-term disease control . Two patients did not undergo aPSCT because of rapid disease progression . Nineteen patients received both cycles of aPSCT , 8 progressed after cycle 1 , 3 refused the second cycle , and 1 died of fungal infection during cycle 1 . Twelve patients remain relapse free at a median of 67 months from the initiation of therapy . Whereas the International Germ Cell Cancer Collaborative Group category at the time of initial diagnosis did not seem to predict outcome , the patient 's probability of achieving durable remission was significantly associated with the Beyer prognostic score at the time of protocol entry . Regimens containing the most active agents in relapsed nonseminomatous germ cell tumors , including high-dose paclitaxel , are well tolerated and have promising activity even in patients with poor-risk features who do not achieve durable remissions with st and ard therapy . The Beyer prognostic system is a valuable predictor for patients undergoing aPSCT 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 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 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 A phase II trial was undertaken to assess the feasibility , toxicity , and efficacy of high-dose carboplatin and etoposide with autologous bone marrow transplantation in patients with relapsed or refractory germ cell tumors . PATIENTS AND METHODS Forty patients with recurrent germ cell cancer received carboplatin 500 mg/m2 and etoposide 400 mg/m2 given at 7 , 5 , and 3 days before marrow infusion . Autologous marrow infusion ( day 0 ) was accomplished using one half of the bone marrow harvested before chemotherapy . Patients who achieved a complete or partial response with the first cycle of treatment received a second identical cycle of chemotherapy followed by infusion of the remaining cryopreserved bone marrow . RESULTS Objective responses were obtained in 17 of the 38 patients ( 45 % ) assessable for response , including eight partial and nine complete remissions . Five of these patients remain in continuous complete remission with minimal follow-up of 1 year . Toxicity encountered was primarily hematologic , and five patients ( 13 % ) died of treatment-related complications . Significant toxicities often seen with high-dose cisplatin  ( ototoxicity , neurotoxicity , and renal toxicity ) were manageable in this regimen of high-dose carboplatin . CONCLUSIONS This trial confirms the curative potential of high-dose carboplatin and etoposide in highly refractory germ cell cancer High-dose chemotherapy ( HDCT ) has evolved as a strategy to improve the treatment outcome in patients with relapsed and /or refractory germ cell tumours . Between August 1989 and September 1995 , 150 consecutive patients with relapsed and /or refractory germ cell tumours were treated with conventional-dose salvage chemotherapy followed by one cycle of HDCT with carboplatin 1500 - 2000 mg/m2 , etoposide 1200 - 2400 mg/m2 and ifosfamide 0 - 10 g/m2 and were retrospectively analysed . With a median follow-up time of 55 months ( range 21 - 88 months ) 51/150 ( 34 % ) patients are alive and disease free . The projected event-free and overall survival are 29 % ( confidence interval 22 - 37 % ) and 39 % ( confidence interval 31 - 47 % ) respectively . The relevance of prognostic variables for long-term survival after HDCT were prospect ively confirmed . Persisting toxicities occurred in approximately one third of the long-term survivors . Treatment intensification with HDCT result ed in a significant proportion of the long-term survivors in patients with relapsed and /or refractory germ cell tumours . Trials to prospect ively evaluate HDCT as an early intervention in these patients seem justified BACKGROUND Rescue of patients who fail to be cured after 2 or 3 chemotherapy combinations ( including high-dose chemotherapy [ HDCT ] ) or whose disease is refractory to cisplatin  is still an unmet need . We assessed the efficacy of a triple-combination chemotherapy in the salvage setting , beyond second-line regimens . PATIENTS AND METHODS We retrospectively review ed institutional data on consecutive patients who received paclitaxel 80 mg/m(2 ) intravenously ( IV ) , cisplatin 50 mg/m(2 ) IV , and gemcitabine 800 mg/m(2 ) IV on days 1 and 8 every 3 weeks for a maximum of 8 administrations , followed by surgery .  Response , survival ( progression-free survival [ PFS ] and overall survival [ OS ] ) , and safety/toxicity outcomes were the end points . The Kaplan-Meier method was used for survival estimates , and multiple Cox regression models were used to analyze the prognostic factors . RESULTS Seventy-five patients were treated from April 1999 to July 2011 . Eight complete responses ( CR , 10.7 % ) , 29 partial responses with normal markers ( PRm(- ) , 38.7 % ) , and 13 cases of incomplete response/stable disease were recorded , for a major response rate ( CR + PRm(- ) ) of 49 % . Thirty-three patients ( 44 % ) underwent surgery , which was radical in 14 cases ( 42.4 % ) . Two-year PFS was 14.8 % ( 95 % confidence interval [ CI ] , 8.5%-25.8 % ) , whereas 2-year OS was 29.5 % ( 95 % CI , 20.3%-42.7 % ) . Five-year OS in disease-free patients ( no evidence of disease ) was 60.3 % ( 95 % CI , 42.2%-86.2 % ) , and median OS between patients with and without evidence of disease was significantly different ( 71 [ interquartile range { IQR } , 14 - 116 ] vs. 12.5 [ IQR , 8 - 19 ] months with a 6-month l and mark analysis ; P = .0019 ) . CONCLUSION TPG is an effective combination , and best results were achieved if a radical clearance of residual disease could be accomplished . A r and omized comparison with dose-intensified regimens is advisable PURPOSE To evaluate the activity of two cycles of high-dose ifosfamide , carboplatin , and etoposide ( ICE ) with autologous hematopoietic progenitor cell support ( aHPCS ) in patients with poor-prognosis , chemotherapeutically sensitive germ cell cancer . PATIENTS AND METHODS Twenty patients with germ cell tumor who had persistent disease or relapse from st and ard-risk or high-risk presentation were entered on this pilot study . The entry criteria included relapsed gonadal and extragonadal germ cell cancer unlikely to be cured by st and ard salvage therapy but without proven refractoriness to chemotherapy . Treatment consisted of two cycles of ICE chemotherapy with mesna uroprotection and aHPCS . On the first cycle , ifosfamide ( IFX ) , 2 gm/m2 ; carboplatin , 400 mg/m2 ; and etoposide , 20 mg/kg , were administered on days -6 , -5 , and -4 . On the second cycle , the doses and schedule of carboplatin and etoposide were identical , and patients with normal renal function received additional IFX , 2 g/m2 on day -3 and 1 g/ m2 on day -2 . Mesna , 600 mg/m2 every 6 hours , was given until 24 hours following the final dose of IFX on each cycle , and autologous bone marrow and /or peripheral stem-cells were infused on day 0 . RESULTS All twenty patients are assessable for toxicity and current disease status . Two patients received only one cycle of therapy , one because of the development of active hepatitis C following cycle 1 , and one because of renal insufficiency . No patient died as a result of protocol therapy , and no patient developed debilitating peripheral neuropathy , symptomatic hearing loss , or severe renal insufficiency requiring dialysis . The median time to recovery of > or = 500 neutrophils/microL and platelets > or = 50,000/microL was day + 11 and day + 15 , respectively . The median maximum creatinine was 1.6 mg/dL on each treatment cycle , and there was no other significant organ toxicity . With a median follow-up of 45 months , nine patients are alive and disease-free following protocol chemotherapy . One patient with embryonal cancer developed progressive pulmonary metastases 3 months after completing high-dose therapy , underwent complete resection of lung metastases , and remains disease-free at 63 + months . Eight patients are continuously disease free at 23 + to 70 + months after protocol therapy . Eleven patients died of progressive disease between 4 and 23 months following completion of treatment . CONCLUSION These results compare favorably to other studies in similarly selected patients undergoing salvage therapy with one or two cycles of  chemotherapy containing high-dose carboplatin and etoposide with or without cyclophosphamide ( CTX ) or IFX . The excellent safety and tolerability profile of this regimen and its encouraging activity in poor-prognosis patients make it worthy of further study as part of initial therapy in r and omized protocol s for high-risk disease and early in the treatment of relapsed germ cell cancer 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 Between July 1979 and May 1982 , we treated 45 male patients with refractory germinal neoplasms . All patients had previously received intensive cisplatin-containing combination chemotherapy regimens .  Patients received salvage chemotherapy with VP-16 and cisplatin + /- bleomycin + /- doxorubicin . Of 44 evaluable patients , 19 ( 43 % ) achieved complete remissions with salvage chemotherapy , 12 ( 27 % ) had partial remissions , and nine ( 21 % ) had no response . Four patients ( 9 % ) were not evaluable for response due to early death or noncompliance but are considered treatment failures . Ten patients ( 23 % ) remain alive and continuously disease free 20 to 39 months ( median , 29 months ) after completion of therapy . Hematologic toxicity was severe , with one death related to sepsis .  Bleomycin-induced pulmonary fibrosis occurred in 17 patients with two fatalities . The addition of bleomycin and /or doxorubicin to this regimen increases toxicity and probably does not improve treatment results . Salvage chemotherapy with VP-16 and cisplatin offers potentially curative therapy to men with resistant germinal tumors PURPOSE To prospect ively determine the efficacy of repeated high-dose alkylating chemotherapy to salvage patients with germ-cell tumors who relapsed after adequate first-line chemotherapy . PATIENTS AND METHODS Patients with germ-cell cancers relapsing from a first , second or third complete remission induced by chemotherapy were offered to participate in a Dutch national prospect i ve trial with broad entry criteria . The salvage treatment began with a conventional dose of ifosfamide ( 4 g/m2 on day 1 ) and etoposide ( 100 mg/m2 on days 1 , 2 and 3 ) followed by daily s.c . administration of G-CSF ( 10 micrograms/kg ) until peripheral blood progenitor cells had been harvested . Immediately after bone marrow recovery , an intermediate dose chemotherapy course of carboplatin ( target AUC : 10 mg.ml-1 min on day 1 ) and etoposide ( 500 mg/m2 on days 1 , 3 and 5 ) was given with G-CSF daily s.c . After bone marrow recovery , two subsequent courses of high-dose ' CTC ' chemotherapy were given , each containing cyclophosphamide ( 6 g/m2 ) , thiotepa ( 480 mg/m2 ) and carboplatin ( target AUC : 20 mg.ml-1 min ) . The high-dose chemotherapy was administered as 30 - 60-minute infusions , divided over 4 days and the stem-cell transplants were given 48 - 72 hours after the last chemotherapy infusion . Whenever possible , residual masses were resected at the end of treatment . RESULTS Thirty-five patients were treated between January 1994 and October 1997 . The toxicity of the treatment was manageable . Second CTC courses were administered in 25 patients and were associated with hemorrhagic cystitis and veno-occlusive disease in 3 and 4 patients , respectively . One patient who had recently undergone a partial hepatectomy , died of veno-occlusive disease . At the time of analysis , the median follow-up of the surviving patients was 37 months ( range 12 - 56 months ) . The median progression-free survival for all patients was 44 months , and the median overall survival has not been reached . According to the internationally accepted criteria for predicting the outcome of salvage chemotherapy in germ-cell cancer ( Beyer et al. J Clin Oncol 1996 ; 14 : 2638 - 45 ) , 30 patients had ' good risk ' criteria . Of these , 29 received high-dose chemotherapy . Of this group , the salvage rate at two years was 65 % ( 95 % confidence interval : 49.5%-85.1 % ) . CONCLUSIONS Over half of the germ-cell cancer patients relapsing from a chemotherapy-induced complete remission can be salvaged by a treatment strategy that incorporates high-dose chemotherapy , even when treatment is given in a multi-center setting . These data confirm the international prognostic model proposed by Beyer et al. in a prospect ively studied , independent patient group and provide further evidence that high-dose therapy has a role in the salvage setting of patients with germ-cell cancer PURPOSE To compare autologous bone marrow ( BM ) with peripheral-blood progenitor cells ( PBPC ) as hematopoietic rescue after high-dose chemotherapy ( HDCT ) . PATIENTS AND METHODS From January 1991 until April 1993 , 47 consecutive patients with relapsed or refractory germ cell tumors were r and omized to either BM harvest or collection of PBPC mobilized by chemotherapy plus granulocyte colony-stimulating factor ( G-CSF ) . After additional conventional-dose salvage treatment , all patients received HDCT with carboplatin 1,500 mg/m2 , etoposide 2,400 mg/m2 , and ifosfamide 10 g/m2 with either BM or PBPC rescue . RESULTS Forty-six patients were assessable for hematologic reconstitution  , and one patient died on day + 4 before engraftment . Rescue using PBPC result ed in a significantly shorter recovery time to neutrophil counts more than 500/microL ( 10.0 v 11.0 days , P < .01 ) , neutrophil counts more than 1,000/microL ( 10.0 v 12.0 days , P = .001 ) , and platelet counts more than 20,000/microL ( 10.0 v 17.0 days , P < .01 ) , as well as in fewer days to transfusion independence from RBCs ( 8.0 v 12.0 , P < .05 ) and platelets ( 9.0 v 12.0 , P < .01 ) and fewer days of intravenous ( IV ) antibiotics ( 9.0 v 11.0 , P < .05 ) . However , no statistical differences in transfusion requirements or in other clinical outcome variables were observed . Overall survival and event-free survival also were not different in the two study arms . CONCLUSION We conclude that the use of PBPC mobilized by chemotherapy plus G-CSF results in sustained trilineage reconstitution after HDCT , which occurs more rapidly as compared with BM . The earlier hematologic reconstitution in patients with PBPC rescue significantly reduces the time to transfusion independence 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
Relapsed germ cell tumor ( GCT ) is a highly curable cancer with st and ard-dose platinum-based chemotherapy ( CT ) ; however , high-dose CT ( HDCT ) is seldom used as salvage therapy instead or after conventional CT .
We conducted a systematic review of published trials to compare outcomes between st and ard-dose CT and HDCT in patients with relapsed GCT after first-line therapy for advanced disease .