title: Bevacizumab/high-dose chemotherapy with autologous stem-cell transplant for poor-risk relapsed or refractory germ-cell tumors.
abstract: BACKGROUND
  High-dose chemotherapy (HDC) using sequential cycles of carboplatin/etoposide is curative for relapsed germ-cell tumors (GCT). However, outcomes of high-risk patients in advanced relapse remain poor. We previously developed a new HDC regimen combining infusional gemcitabine with docetaxel/melphalan/carboplatin (GemDMC), with preliminary high activity in refractory GCT. Given the high vascular endothelial growth factor expression in metastatic GCT and the synergy between bevacizumab and chemotherapy, we studied concurrent bevacizumab and sequential HDC using GemDMC and ifosfamide/carboplatin/etoposide (ICE) in patients with poor-risk relapsed or refractory disease.
  
  
  METHODS
  Eligibility criteria included intermediate/high-risk relapse (Beyer Model), serum creatinine ≤ 1.8 mg/dl and adequate pulmonary/cardiac/hepatic function. Patients received sequential HDC cycles with bevacizumab preceding GemDMC (cycle 1) and ICE (cycle 2). The trial was powered to distinguish a target 50% 2-year relapse-free survival (RFS) from an expected 25% 2-year RFS in this population.
  
  
  RESULTS
  We enrolled 43 male patients, median age 30 (20-49) years, with absolute refractory (N = 20), refractory (N = 17) or cisplatin-sensitive (N = 6) disease, after a median 3 (1-5) prior relapses. Disease status right before HDC was unresponsive (N = 24, progressive disease 22, stable disease 2), partial response with positive markers (PRm(+)) (N = 8), PRm(-) (N = 7) or complete response (N = 4). Main toxicities were mucositis and renal. Four patients (three with baseline marginal renal function) died from HDC-related complications. Tumor markers normalized in 85% patients. Resection of residual lesions (N = 13) showed necrosis (N = 4), mature teratoma (N = 2), necrosis/teratoma (N = 3) and viable tumor (N = 4). At median follow-up of 46 (9-84) months, the RFS and overall survival rates are 55.8% and 58.1%, respectively.
  
  
  CONCLUSIONS
  Sequential bevacizumab/GemDMC-bevacizumab/ICE shows encouraging outcomes in heavily pretreated and refractory GCT, exceeding the results expected in this difficult to treat population.
  
  
  BACKGROUND
  NCT00936936.
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy ynieto@mdanderson.org.
authors.forename: Y
authors.initials: Y
authors.lastname: Nieto
authors.affiliation: Department of Genitourinary Medical Oncology.
authors.forename: S-M
authors.initials: SM
authors.lastname: Tu
authors.affiliation: Department of Biostatistics.
authors.forename: R
authors.initials: R
authors.lastname: Bassett
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy.
authors.forename: R B
authors.initials: RB
authors.lastname: Jones
authors.affiliation: Department of Pharmacy, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: A M
authors.initials: AM
authors.lastname: Gulbis
authors.affiliation: Department of Genitourinary Medical Oncology.
authors.forename: N
authors.initials: N
authors.lastname: Tannir
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy.
authors.forename: A
authors.initials: A
authors.lastname: Kingham
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy.
authors.forename: C
authors.initials: C
authors.lastname: Ledesma
authors.affiliation: Department of Medical Oncology, Fred Hutchinson Cancer Research Center, Seattle, USA.
authors.forename: K
authors.initials: K
authors.lastname: Margolin
authors.affiliation: Department of Medical Oncology, Fred Hutchinson Cancer Research Center, Seattle, USA.
authors.forename: L
authors.initials: L
authors.lastname: Holmberg
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy.
authors.forename: R
authors.initials: R
authors.lastname: Champlin
authors.affiliation: Department of Genitourinary Medical Oncology.
authors.forename: L
authors.initials: L
authors.lastname: Pagliaro
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D016190:Carboplatin / Q000008:administration & dosage; D002648:Child; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D008297:Male; D008479:Mediastinal Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D009367:Neoplasm Staging; D009373:Neoplasms, Germ Cell and Embryonal / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D011379:Prognosis; D012186:Retroperitoneal Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D016879:Salvage Therapy; D015996:Survival Rate; D013736:Testicular Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D014182:Transplantation, Autologous; D055815:Young Adult; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D000068258:Bevacizumab; D005047:Etoposide; D016190:Carboplatin; D002945:Cisplatin; D007069:Ifosfamide; D000093542:Gemcitabine
keywords: autologous transplantation; bevacizumab; docetaxel; gemcitabine; germ-cell tumors; high-dose chemotherapy