Prospective Clinical Trial Evaluating Metronomic Chemotherapy in Patients With High-grade, Operable, Non-metastatic Osteosarcoma of the Extremity

Study Overview
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Brief Summary
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Preclinical models show that a daily antiangiogenic regimen at low-dose may be effective against chemotherapy-resistant tumors. The aim of this study is to evaluate the efficacy of maintenance therapy with continuous oral cyclophosphamide and methotrexate in patients with high grade, operable, non-metastatic osteosarcoma (OST) of the extremities. The primary end point is event-free survival (EFS) from randomization.

Detailed Description
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The study design includes a backbone of 10 weeks of preoperative therapy using MAP (High-dose methotrexate, cisplatin, and doxorubicin). Following surgery, non-metastatic patients were randomized by blocks to complete 31 weeks of MAP or to receive 73 weeks of maintenance therapy following MAP; while metastatic patients received maintenance therapy in combination with MAP since the beginning of treatment.

Conditions
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High Grade Osteosarcoma

Intervention / Treatment
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* Drug: continuous oral cyclophosphamide and methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with high-grade malignancy osteosarcoma , biopsy-proven , newly diagnosed , previously untreated . Patients with osteosarcoma as a second malignancy should also be eligible . Patients with any primary site , with or without metastases at diagnosis , will be accepted and treated. Patients < 30 years. Patients must have normal body function and adequate renal function defined as serum creatinine < 1.5 x the normal value or creatinine clearance > 60ml/min/1 ,73m2 . Patients must have adequate hepatic function, defined as total bilirubin < 1.5 x normal, aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) < 2.5 x normal. Patients must have adequate cardiac function defined by a shortening fraction > 27 % by echocardiogram or ejection fraction > 47 % by radioisotopic angiogram . If pre- chemotherapy amputation is necessary, the patient is included in the study and eligible to survival analyzes, however the pathological analyze response will be not performed. Obtain material for pathological and molecular study is recommended . Whenever possible a central catheter should be placed against the intensity of chemotherapy and need for forced hydration . Patient or legal guardian must sign a consent form which will be explain the type of treatment and procedures that the patient will be submitted . Time > than 4 weeks between biopsy and initiation of treatment - Restaging Exclusion Criteria: Disease progression ( increase of at least 20% of the extent of the lesion, taking as reference the smallest measurement recorded from the start of treatment, or the appearance of one or more lesions ); Any properly documented clinical situation , which at the discretion of the attending physician , patient can not follow with chemotherapy , for safety reasons ; The evaluation of cardiac aspects will be done carefully , so will exclude patients with 20% reduction in the ejection fraction of the left ventricle compared to baseline or with a ventricular ejection fraction < 45 % regardless of baseline; The patient refusal to continue treatment ; Nephrotoxicity , neurotoxicity and ototoxicity grade 4 ; Delay greater than 40 days for the realization of the next treatment cycle , not related to toxicity; Refusal of surgery ; 8 . Variation above 20% of the recommended dose without justification.

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Maintenance therapy<br>73 weeks of continuous oral low dose chemotherapy with cyclophosphamide (CPM) and methotrexate (MTX) following 31 weeks of MAP. | Drug: continuous oral cyclophosphamide and methotrexate<br> <br> |
| No Intervention: Control<br>31 weeks of MAP. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-Free Survival | AT 5 YEARS | EFS AT 5 YEARS | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | AT 5 YEARS | OS AT 5 YEARS | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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of the extremity