title: Personalised chemotherapy based on tumour marker decline in poor prognosis germ-cell tumours (GETUG 13): a phase 3, multicentre, randomised trial.
abstract: BACKGROUND
  Poor prognosis germ-cell tumours are only cured in about half of patients. We aimed to assess whether treatment intensification based on an early tumour marker decline will improve progression-free survival for patients with germ-cell tumours.
  
  
  METHODS
  In this phase 3, multicentre, randomised trial, patients were enrolled from France (20 centres), USA (one centre), and Slovakia (one centre). Patients were eligible if they were older than 16 years, had evidence of testicular, retroperitoneal, or mediastinal non-seminomatous germ cell tumours based on histological findings or clinical evidence and highly elevated serum human chorionic gonadotropin or alfa-fetoprotein concentrations that matched International Germ Cell Cancer Consensus Group poor prognosis criteria. After one cycle of BEP (intravenous cisplatin [20 mg/m(2) per day for 5 days], etoposide [100 mg/m(2) per day for 5 days], and intramuscular or intravenous bleomycin [30 mg per day on days 1, 8, and 15]), patients' human chorionic gonadotropin and alfa-fetoprotein concentrations were measured at day 18-21. Patients with a favourable decline in human chorionic gonadotropin and alfa-fetoprotein continued BEP (Fav-BEP group) for 3 additonal cycles, whereas patients with an unfavourable decline were randomly assigned (1:1) to receive either BEP (Unfav-BEP group) or a dose-dense regimen (Unfav-dose-dense group), consisting of intravenous paclitaxel (175 mg/m(2) over 3 h on day 1) before BEP plus intravenous oxaliplatin (130 mg/m(2) over 3 h on day 10; two cycles), followed by intravenous cisplatin (100 mg/m(2) over 2 h on day 1), intravenous ifosfamide (2 g/m(2) over 3 h on days 10, 12, and 14), plus mesna (500 mg/m(2) at 0, 3, 7 and 11 h), and bleomycin (25 units per day, by continuous infusion for 5 days on days 10-14; two cycles), with granulocyte-colony stimulating factor (lenograstim) support. Centrally blocked computer-generated randomisation stratified by centre was used. The primary endpoint was progression-free survival and the efficacy analysis was done in the intention-to-treat population. The planned trial accrual was completed in May, 2012, and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00104676.
  
  
  RESULTS
  Between Nov 28, 2003, and May 16, 2012, 263 patients were enrolled and 254 were available for tumour marker assessment. Of these 51 (20%) had a favourable marker assessment, and 203 (80%) had an unfavourable tumour marker decline; 105 were randomly assigned to the Unfav-dose-dense group and 98 to the Unfav-BEP group. 3-year progression-free survival was 59% (95% CI 49-68) in the Unfav-dose-dense group versus 48% (38-59) in the Unfav-BEP group (HR 0·66, 95% CI 0·44-1·00, p=0·05). 3-year progression-free survival was 70% (95% CI 57-81) in the Fav-BEP group (HR 0·66, 95% CI 0·49-0·88, p=0·01 for progression-free survival compared with the Unfav-BEP group). More grade 3-4 neurotoxic events (seven [7%] vs one [1%]) and haematotoxic events occurred in the Unfav-dose-dense group compared with in the Unfav-BEP group; there was no difference in grade 1-2 febrile neutropenia (18 [17%] vs 18 [18%]) or toxic deaths (one [1%] in both groups). Salvage high-dose chemotherapy plus a stem-cell transplant was required in six (6%) patients in the Unfav-dose-dense group and 16 (16%) in the Unfav-BEP group.
  
  
  CONCLUSIONS
  Personalised treatment with chemotherapy intensification reduces the risk of progression or death in patients with poor prognosis germ-cell tumours and an unfavourable tumour marker decline.
  
  
  BACKGROUND
  Institut National du Cancer (Programme Hospitalier de Recherche Clinique).
authors.affiliation: Institut Gustave Roussy, Department of Cancer Medicine, Villejuif, France. Electronic address: Karim.Fizazi@gustaveroussy.fr.
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Lance
authors.initials: L
authors.lastname: Pagliaro
authors.affiliation: Institut Gustave Roussy, Department of Biostatistics, Villejuif, France.
authors.forename: Agnes
authors.initials: A
authors.lastname: Laplanche
authors.affiliation: Centre Léon Bérard, Department of Cancer Medicine, Lyon, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Fléchon
authors.affiliation: National Cancer Institute, Bratislava, Slovakia.
authors.forename: Josef
authors.initials: J
authors.lastname: Mardiak
authors.affiliation: Centre Alexis Vautrin, Department of Cancer Medicine, Nancy, France.
authors.forename: Lionnel
authors.initials: L
authors.lastname: Geoffrois
authors.affiliation: Centre Eugène Marquis, Department of Cancer Medicine, Rennes, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Kerbrat
authors.affiliation: Centre Claudius Regaud, Department of Cancer Medicine, Toulouse, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Chevreau
authors.affiliation: Institut de Cancérologie de l'Ouest, Department of Cancer Medicine, Angers, France.
authors.forename: Remy
authors.initials: R
authors.lastname: Delva
authors.affiliation: Institut de Cancérologie de l'Ouest, Department of Cancer Medicine, Nantes, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Rolland
authors.affiliation: Hopital Foch, Department of Cancer Medicine, Suresnes, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Theodore
authors.affiliation: Institut Bergonié, Department of Cancer Medicine, Bordeaux, France.
authors.forename: Guilhem
authors.initials: G
authors.lastname: Roubaud
authors.affiliation: Institut Paoli Calmette, Department of Cancer Medicine, Marseille, France.
authors.forename: Gwenaëlle
authors.initials: G
authors.lastname: Gravis
authors.affiliation: Centre Jean Godinot, Department of Cancer Medicine, Reims, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Eymard
authors.affiliation: Centre Hospitalo-Universitaire, Department of Cancer Medicine, Brest, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Malhaire
authors.affiliation: Centre Hospitalo-Universitaire, Department of Cancer Medicine, Tours, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Linassier
authors.affiliation: Unicancer, Paris, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Habibian
authors.affiliation: Unicancer, Paris, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Martin
authors.affiliation: Institut Gustave Roussy, Department of Biostatistics, Villejuif, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Journeau
authors.affiliation: National Cancer Institute, Bratislava, Slovakia.
authors.forename: Maria
authors.initials: M
authors.lastname: Reckova
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Logothetis
authors.affiliation: Hôpital Saint Louis, Department of Cancer Medicine, Paris, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Culine
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D001761:Bleomycin / Q000008:administration & dosage; D006063:Chorionic Gonadotropin / Q000097:blood; D002945:Cisplatin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D007390:International Agencies; D000078224:Lenograstim; D008297:Male; D008479:Mediastinal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009373:Neoplasms, Germ Cell and Embryonal / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D017239:Paclitaxel / Q000008:administration & dosage; D010534:Peritoneal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D057285:Precision Medicine; D011379:Prognosis; D011994:Recombinant Proteins / Q000008:administration & dosage; D015996:Survival Rate; D013736:Testicular Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D055815:Young Adult; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D006063:Chorionic Gonadotropin; D009944:Organoplatinum Compounds; D011994:Recombinant Proteins; D000509:alpha-Fetoproteins; D000077150:Oxaliplatin; D001761:Bleomycin; D016179:Granulocyte Colony-Stimulating Factor; D005047:Etoposide; D000078224:Lenograstim; D017239:Paclitaxel; D002945:Cisplatin; D007069:Ifosfamide