Combination Chemotherapy, PEG-Interferon Alfa-2b, and Surgery in Treating Patients With Osteosarcoma
Condition: Localized Osteosarcoma; Metastatic Osteosarcoma
MeSH terms: Osteosarcoma
Study type: Interventional
Phase: Phase 3

Summary: 
      This randomized phase III trial is studying combination chemotherapy followed by surgery and
      two different combination chemotherapy regimens with or without PEG-interferon alfa-2b to
      compare how well they work in treating patients with osteosarcoma. Drugs used in chemotherapy
      work in different ways to stop the growth of tumor cells, either by killing the cells or by
      stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill
      more tumor cells. Biological therapies, such as PEG-interferon alfa-2b, may interfere with
      the growth of tumor cells. Giving combination chemotherapy before surgery may shrink the
      tumor so it can be removed. Giving combination chemotherapy together with PEG-interferon
      alfa-2b after surgery may kill any remaining tumor cells. It is not yet known whether giving
      combination therapy together with PEG-interferon alfa-2b is more effective than two different
      combination chemotherapy regimens alone after surgery in treating osteosarcoma.
    

Detailed description: 
      PRIMARY OBJECTIVES:

      I. Compare whether adjuvant maintenance therapy comprising doxorubicin, cisplatin, and
      high-dose methotrexate (MAP) alone vs MAP combined with ifosfamide and etoposide improves
      event-free survival of patients with resectable high-grade osteosarcoma who achieve a poor
      histological response (HR) to neoadjuvant induction therapy comprising MAP.

      II. Compare whether adjuvant maintenance therapy comprising MAP alone vs MAP and
      PEG-interferon alfa-2b improves event-free survival of patients with resectable high-grade
      osteosarcoma who achieve a good HR to neoadjuvant induction therapy comprising MAP.

      SECONDARY OBJECTIVES:

      I. Compare overall survival of patients treated with these regimens. II. Compare short- and
      long-term toxicity of these regimens in these patients. III. Compare quality of life of
      patients treated with these regimens. IV. Compare event-free survival and overall survival of
      patients with localized osteosarcoma treated with these regimens.

      V. Correlate biological or clinical changes with histological response and outcomes in
      patients treated with these regimens.

      VI. Determine outcomes of patients treated with these regimens.

      OUTLINE: This is a randomized, controlled, multicenter study.

      INDUCTION THERAPY: (MAP; weeks 1-10) Patients receive doxorubicin IV continuously over 48
      hours on days 1-2 and cisplatin IV over 4 hours on days 1 and 2 in weeks 1 and 6. Patients
      also receive high-dose methotrexate (MTX)* IV over 4 hours on day 1 in weeks 4, 5, 9, and 10.
      Patients then proceed to surgery.

      NOTE: *Patients must receive >= 2 but =< 6 doses of high-dose MTX.

      SURGERY: Patients undergo amputation or limb salvage surgery in week 11. Tumor tissue is
      evaluated for histological response to induction therapy. Patients whose tumor is not
      amenable to macroscopically complete surgical resection undergo radiotherapy and/or other
      investigational therapy off study. Patients who undergo macroscopically complete surgical
      resection of the primary tumor or metastases AND who have no disease progression or
      unacceptable toxicity proceed to maintenance therapy.

      MAINTENANCE THERAPY: Patients are assigned to 1 of 2 groups according to histological
      response (good [< 10% viable tumor] vs poor [≥ 10% viable tumor]). Patients in each group are
      stratified according to site of primary tumor and presence of metastases.

      GROUP 1: (good histological response) Patient are randomized to 1 of 2 treatment arms within
      35 days after surgery.

      ARM I: (MAP; weeks 12-29) Patients receive doxorubicin IV continuously over 48 hours on days
      1-2 in weeks 12, 17, 22, and 26 and cisplatin IV over 4 hours on days 1 and 2 in weeks 12 and
      17. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 16, 20, 21, 24,
      25, 28, and 29.

      ARM II: (MAPifn; weeks 12-104) Patients receive doxorubicin, cisplatin, and high-dose MTX as
      in arm I. Patients than receive PEG-interferon alfa-2b subcutaneously once daily on day 1 in
      weeks 30-104.

      GROUP 2: (poor histological response) Patients are randomized to 1 of 2 treatment arms within
      35 days after surgery.

      ARM I: (MAP; weeks 12-29) Patients receive doxorubicin, cisplatin, and high-dose MTX as in
      group 1 arm I.

      ARM II: (MAPIE; weeks 12-40) Patients receive doxorubicin IV continuously over 48 hours on
      days 1-2 in weeks 12, 20, 28, and 36 and cisplatin IV over 4 hours on days 1 and 2 in weeks
      12 and 28. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 19, 23,
      27, 31, 35, 39, and 40. Patients receive ifosfamide IV over 4 hours on days 1-5 in weeks 16,
      24, and 32 and on days 1-3 in weeks 20 and 36 and etoposide IV over 1 hour on days 1-5 in
      weeks 16, 24, and 32.

      In both groups, treatment continues in the absence of disease progression or unacceptable
      toxicity. Quality of life is assessed periodically.

      After completion of study treatment, patients are followed every 1½-3 months for 2 years,
      every 2-4 months for 2 years, every 6 months for 6 years, and then every 6-12 months
      thereafter. Peer Reviewed and Funded or Endorsed by Cancer Research UK
    

Intervention name(s): Cisplatin; Doxorubicin Hydrochloride; Etoposide; Ifosfamide; Methotrexate; Peginterferon Alfa-2b; Quality-of-Life Assessment; Questionnaire Administration; Therapeutic Conventional Surgery
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Biological; Other; Other; Procedure
Intervention description(s): Given IV; Given IV; Given IV; Given IV; Given IV; Given subcutaneously; Ancillary studies; Ancillary studies; Undergo amputation or limb salvage surgery
Other intervention name(s): Abiplatin; Blastolem; Briplatin; CDDP; Cis-diammine-dichloroplatinum; Cis-diamminedichloridoplatinum; Cis-diamminedichloro Platinum (II); Cis-diamminedichloroplatinum; Cis-dichloroammine Platinum (II); Cis-platinous Diamine Dichloride; Cis-platinum; Cis-platinum II; Cis-platinum II Diamine Dichloride; Cismaplat; Cisplatina; Cisplatinum; Cisplatyl; Citoplatino; Citosin; Cysplatyna; DDP; Lederplatin; Metaplatin; Neoplatin; Peyrone''s Chloride; Peyrone''s Salt; Placis; Plastistil; Platamine; Platiblastin; Platiblastin-S; Platinex; Platinol; Platinol- AQ; Platinol-AQ; Platinol-AQ VHA Plus; Platinoxan; Platinum; Platinum Diamminodichloride; Platiran; Platistin; Platosin; 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI); ADM; Adriacin; Adriamycin; Adriamycin Hydrochloride; Adriamycin PFS; Adriamycin RDF; ADRIAMYCIN, HYDROCHLORIDE; Adriamycine; Adriblastina; Adriblastine; Adrimedac; Chloridrato de Doxorrubicina; DOX; DOXO-CELL; Doxolem; Doxorubicin HCl; Doxorubicin.HCl; Doxorubin; Farmiblastina; FI 106; FI-106; hydroxydaunorubicin; Rubex; Demethyl Epipodophyllotoxin Ethylidine Glucoside; EPEG; Lastet; Toposar; Vepesid; VP 16; VP 16-213; VP-16; VP-16-213; VP16; Asta Z 4942; Asta Z-4942; Cyfos; Holoxan; Holoxane; Ifex; IFO; IFO-Cell; Ifolem; Ifomida; Ifomide; Ifosfamidum; Ifoxan; IFX; Iphosphamid; Iphosphamide; Iso-Endoxan; Isoendoxan; Isophosphamide; Mitoxana; MJF 9325; MJF-9325; Naxamide; Seromida; Tronoxal; Z 4942; Z-4942; Abitrexate; Alpha-Methopterin; Amethopterin; Brimexate; CL 14377; CL-14377; Emtexate; Emthexat; Emthexate; Farmitrexat; Fauldexato; Folex; Folex PFS; Lantarel; Ledertrexate; Lumexon; Maxtrex; Medsatrexate; Metex; Methoblastin; Methotrexate LPF; Methotrexate Methylaminopterin; Methotrexatum; Metotrexato; Metrotex; Mexate; Mexate-AQ; MTX; Novatrex; Rheumatrex; Texate; Tremetex; Trexeron; Trixilem; WR-19039; PEG Interferon Alpha-2b; PEG Intron; PEG-IFN Alfa-2b; PEG-IFN-a 2b; PEG-Interferon Alfa-2b; PEG-Intron; Pegylated Interferon Alpha-2b; Polyethylene Glycol IFN-A2b; Polyethylene Glycol Interferon Alfa-2b; SCH 54031; Sylatron; Quality of Life Assessment
Intervention MeSH terms: Interferons; Interferon-alpha; Interferon alpha-2; Peginterferon alfa-2b; Interferon-alfa-1b; Cisplatin; Doxorubicin; Liposomal doxorubicin; Methotrexate; Etoposide; Etoposide phosphate; Ifosfamide; Isophosphamide mustard; Podophyllotoxin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment