Therapy Trial to Determine the Safety and Efficacy of Heavy Ion Radiotherapy in Patients With Osteosarcoma

Study Overview
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Brief Summary
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The primary objectives of this trial are the determination of feasibility and toxicity of Heavy Ion Radiotherapy (C12) in patients with non-resectable osteosarcoma. Secondary endpoints are tumor response, disease free survival and overall survival. The aim is to improve outcome for patients with non-resectable osteosarcoma.

Detailed Description
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Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. For effective treatment, local control of the tumor is absolutely critical, because the chances of long term survival are <10% and might effectively approach zero if a complete surgical resection of the tumor is not possible. Up to date there is no curative treatment protocol for patients with non-resectable osteosarcomas, who are excluded from current osteosarcoma trials , e.g. EURAMOS1. Local photon radiotherapy has previously been used in small series and in an uncontrolled, highly individualized fashion, which, however, documented that high dose radiotherapy can, in principle, be used to achieve local control. Generally the radiation dose that is necessary for a curative approach can hardly be achieved with conventional photon radiotherapy in patients with non-resectable tumors that are usually located near radiosensitive critical organs such as the brain, the spine or the pelvis. In these cases Heavy Ion Radiotherapy (HIT) may offer a promising new alternative. Moreover, compared with photons, heavy ion particles provide a higher physical selectivity because of their finite depth coverage in tissue. They achieve a higher relative biological effectiveness. Phase I/II dose escalation studies of HIT in adults with non-resectable bone and soft tissue sarcomas have already shown favorable results. Methods/Design: This is a monocenter, non-randomized study for patients older than 6 years of age with non-resectable osteosarcoma. Desired target dose is 60-66 Cobalt Gray Equivalent (GyE). Weekly fractionation of 6 x 3 Gy E is used. HIT will be administered exclusively at the Ion Radiotherapy Center in Heidelberg. Furthermore, FDG-PET imaging characteristics of non-resectable osteosarcoma before and after HIT will be investigated prospectively. Systemic disease before and after HIT is targeted by standard chemotherapy protocols and is not part of this trial. The primary objectives of this trial are the determination of feasibility and toxicity of HIT. Secondary endpoints are tumor response, disease free survival and overall survival. The aim is to improve outcome for patients with non-resectable osteosarcoma.

Official Title
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Phase I/II Therapy Trial to Determine the Safety and Efficacy of Heavy Ion Radiotherapy in Patients With Osteosarcoma

Conditions
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Osteosarcoma

Intervention / Treatment
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* Radiation: heavy ion radiotherapy (C12)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological diagnosis of high grade osteosarcoma with or without metastases Non-resectable tumor of the pelvis, the skull base or the spine, respectively, incomplete or intralesional tumor resection - as confirmed after evaluation by two orthopedic surgeons (respectively neurosurgeons in case of spine tumors): one local surgeon and one referee surgeon of the University of Heidelberg. Age older than 6 years before start of radiotherapy Adequate performance status (Karnofsky >60%) Adequate blood cell production before the start of HIT in patients with pelvic or spine tumors as defined by: total white cell count (WBC) >1,0/nl; neutrophils > 200/µl; platelet count >20/nl No febrile neutropenia (neutrophils < 200/µl) Written informed consent of the patient or the legal guardians Non-resectable tumor site means primary tumors affecting anatomic areas of the human body where a surgical total resection (R0) of the tumor is not possible for technical reasons, for example osteosarcoma of the pelvis, spine or the skull base. In any other cases, surgical resection is recommended. Non-resectability has to be confirmed after evaluation by two orthopedic surgeons (respectively neurosurgeons in case of spine tumors): one local surgeon and one referee surgeon of the University of Heidelberg. In some cases surgery of the tumor might be possible after HIT. Then we recommend surgical resection of residual tumor afterwards. Exclusion Criteria: Age younger than 6 years Previous radiotherapy of the field that has to be radiated now Implanted metal within the planned radiation field, that leads to significant artefacts within the target volume Patients receiving any other investigational agents during the time of HIT Performance status (Karnofsky) < 60%) Pregnancy No written informed consent of patient or the legal guardians

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: heavy ion radiotherapy<br>Heavy ion radiotherapy of osteosarcoma with 60 to 66 GyE (20-22 days). Before and after radiotherapy, but not during radiotherapy, chemotherapy is recommended to standard therapy protocols like EURAMOS 1 which is not part of this study. | Radiation: heavy ion radiotherapy (C12)<br>* Desired target of Heavy ion radiotherapy is 60 to 66 Cobalt Gray Equivalent (GyE), whenever possible. It is applied through 1 - 3 isocenter treatment portals. Dose distributions are calculated and dose volume histograms (DVH) are generated. A α/β-ratio of 2 is used for biological plan optimization. Fractionation is planned to be equivalent to 6 x 3 GyE / week. Dosage to organs at risk is minimized. Treatment continues for 20 to 22 days or until one of the following criteria applies: Other illness that prevents further administration of treatment, Patient or legal guardian decides to withdraw from the study, or changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator.<br>* Other names: Ion therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| feasibility, toxicity (tox) measured by the CTC Criteria .Unacceptable:grade 4 tox. A rate of acute tox (≤ 3 months during/after RT) > grade 3 of ≤ 5% and a rate of late tox > grade 3 of ≤ 3% will be acceptable. |  | before, weekly during RT and at follow-up (1, 6 and 19 weeks, 6, 12, 24, 36 48 and 60 months after RT). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| tumor response (RECIST criteria), disease free survival, overall survival and description of FDG-PET characteristics before and after RT. |  | 6, 12, 24, 36 48 and 60 months after RT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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non-resectable osteosarcoma, heavy ion radiotherapy, particle therapy, safety, toxicity, survival, radiotherapy