A Randomized Trial of the European and American Osteosarcoma Study Group to Optimize Treatment Strategies for Resectable Osteosarcoma Based on Histological Response to Pre-operative Chemotherapy
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,334
- 试验地点
- 218
- 主要终点
- Event-free Survival (EFS)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 5 Years 至 40 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed high-grade osteosarcoma, including second malignancies
- •Localized or metastatic disease
- •The primary tumor must be located in the limbs or axial skeleton, including any of the following sites*:
- •Long bone of upper limb
- •Short bone of upper limb
- •Long bone of lower limb
- •Short bone of lower limb
- •Vertebral column
- •Ribs, sternum, clavicle, or scapula
- •Pelvic bones, sacrum, or coccyx
- •Tumor (primary, metastatic, or both) resectable OR is expected to become resectable after neoadjuvant induction chemotherapy
- •Suitable for neoadjuvant chemotherapy
- •Performance status - Lansky 50-100% (for patients under 16 years of age)
- •Performance status - Karnofsky 50-100%*
- •Performance status - WHO or ECOG 0-2*
- •Platelet count ≥ 100,000/mm³
- •Neutrophil count ≥ 1,500/mm³
- •WBC ≥ 3,000/mm³
- •Bilirubin ≤ 1.5 times upper limit of normal
- •Creatinine clearance ≥ 70 mL/min
- •Creatinine based on age as follows:
- •No greater than 1.0 mg/dL (for patients 5 to 10 years of age)
- •No greater than 1.2 mg/dL (for patients 11 to 15 years of age)
- •No greater than 1.5 mg/dL (for patients over 15 years of age)
- •Ejection fraction ≥ 50% by radionuclide angiogram
- •Shortening fraction ≥ 28% by echocardiogram
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use effective contraception
- •No known HIV positivity
- •No prior chemotherapy for any disease
- •Prior radiotherapy for another malignancy allowed
- •No prior treatment for osteosarcoma
- •No patients with any of the following:
- •Craniofacial osteosarcoma
排除标准
- 未提供
研究组 & 干预措施
Maintenance therapy group 1 arm I
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.
干预措施: Cisplatin (Drug)
Maintenance therapy group 1 arm I
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.
干预措施: Doxorubicin Hydrochloride (Drug)
Maintenance therapy group 1 arm I
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.
干预措施: Methotrexate (Drug)
Maintenance therapy group 1 arm I
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.
干预措施: Quality-of-Life Assessment (Other)
Maintenance therapy group 1 arm I
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.
干预措施: Questionnaire Administration (Other)
Maintenance therapy group 1 arm I
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.
干预措施: Therapeutic Conventional Surgery (Procedure)
Maintenance therapy group 1 arm II
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.
干预措施: Cisplatin (Drug)
Maintenance therapy group 1 arm II
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.
干预措施: Doxorubicin Hydrochloride (Drug)
Maintenance therapy group 1 arm II
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.
干预措施: Methotrexate (Drug)
Maintenance therapy group 1 arm II
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.
干预措施: Peginterferon Alfa-2b (Biological)
Maintenance therapy group 1 arm II
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.
干预措施: Quality-of-Life Assessment (Other)
Maintenance therapy group 1 arm II
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.
干预措施: Questionnaire Administration (Other)
Maintenance therapy group 1 arm II
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.
干预措施: Therapeutic Conventional Surgery (Procedure)
Maintenance therapy group 2 arm I
Patients receive doxorubicin, cisplatin, and high-dose MTX as in group 1 arm I.
干预措施: Cisplatin (Drug)
Maintenance therapy group 2 arm I
Patients receive doxorubicin, cisplatin, and high-dose MTX as in group 1 arm I.
干预措施: Doxorubicin Hydrochloride (Drug)
Maintenance therapy group 2 arm I
Patients receive doxorubicin, cisplatin, and high-dose MTX as in group 1 arm I.
干预措施: Methotrexate (Drug)
Maintenance therapy group 2 arm I
Patients receive doxorubicin, cisplatin, and high-dose MTX as in group 1 arm I.
干预措施: Quality-of-Life Assessment (Other)
Maintenance therapy group 2 arm I
Patients receive doxorubicin, cisplatin, and high-dose MTX as in group 1 arm I.
干预措施: Questionnaire Administration (Other)
Maintenance therapy group 2 arm I
Patients receive doxorubicin, cisplatin, and high-dose MTX as in group 1 arm I.
干预措施: Therapeutic Conventional Surgery (Procedure)
Maintenance therapy group 2 arm II
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.
干预措施: Cisplatin (Drug)
Maintenance therapy group 2 arm II
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.
干预措施: Doxorubicin Hydrochloride (Drug)
Maintenance therapy group 2 arm II
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.
干预措施: Etoposide (Drug)
Maintenance therapy group 2 arm II
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.
干预措施: Ifosfamide (Drug)
Maintenance therapy group 2 arm II
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.
干预措施: Methotrexate (Drug)
Maintenance therapy group 2 arm II
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.
干预措施: Quality-of-Life Assessment (Other)
Maintenance therapy group 2 arm II
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.
干预措施: Questionnaire Administration (Other)
Maintenance therapy group 2 arm II
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.
干预措施: Therapeutic Conventional Surgery (Procedure)
结局指标
主要结局
Event-free Survival (EFS)
时间窗: From date of randomization to date of the event.
EFS is defined as time from randomisation to the first of: death, detection of local recurrence or metastasis, progression of metastatic disease, or detection of a secondary malignancy. EFS will be assessed using the logrank test and expressed using hazard ratios with appropriate confidence intervals. Follow up per participant will be assessed for up to 10 years. The 3 year EFS is provided as a summary.
次要结局
- Percentage of Patients With Overall Survival(From date of randomization to date of death.)
- Toxicity as Measured by Common Terminology Criteria for Adverse Events (CTCAE) v3.0(Adverse events are assessed for up to 10 years per participant.)
研究者
Babasola (Sola) Popoola
Matthew Sydes, Professor of Clinical Trials and Methodology
University College, London