Neoadjuvant Irradiation of Extremity Soft Tissue Sarcoma With Ions

Study Overview
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Brief Summary
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This randomized prospective open-label phase 2 trial testes the safety and feasibility of a hypofractionated accelerated neoadjuvant proton or carbon ion radiotherapy based on the rate of wound healing disorders from beginning of radiotherapy to maximum 120 days after the planned tumor resection or discontinuation of treatment due to any reason. The treatment is of shorter duration (2-3 weeks vs. 5 weeks standard treatment), which should please most patients and thus enhance quality of life. The treatment regimen furthermore promises a reduced rate of late side effects and significant optimization of the current treatment standards. A phase II trial is mandatory not only for obtaining the safety and feasibility data, but also in order to prepare a concurrent phase III trial. Due to the low incidence of soft tissue sarcoma, only a well prepared multicenter study has a chance to be successfully completed based on previous experiences in trials for seldom tumor entities.

Detailed Description
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Oncologic complete local excision (wide resection) combined with radiotherapy forms the standard treatment for patients with soft tissue sarcoma. Especially patients with G2/G3 sarcomas profit from the combination of radiotherapy and surgery. Well-differentiated sarcomas (G1) after total resection (R0) receive no subsequent treatment besides surgery. The sequence of surgery and radiation therapy is widely discussed by the radiation oncologists and surgeons. The main advantages of neoadjuvant (pre-operative) radiotherapy are the smaller treatment target volumes and reduced prescribed radiation doses of 50 Gy vs. 66 Gy (postoperative) in 2 Gy single doses. Thus, due to these reductions in volumes and dose, neoadjuvant radiotherapy is associated with a lower rate of radiotherapy-associated edema and fibrosis. However, a randomized phase III study showed an increased rate of wound healing complications in patients with neoadjuvant radiotherapy compared to adjuvant (post-operative) radiotherapy (35% vs. 17%). For this reason, adjuvant radiotherapy in is currently preferred in cases with good operability. Particle therapy bears the chance to utilize the advantages of preoperative radiotherapy without compromising wound healing. The advantages of tumor treatment by ion therapy are based on their special biological and physical features. Protons and carbons ion lead to an improved dose distribution compared to photons which allows an improved sparing of the neighboring risk organs and at the same time an escalation of the dose prescribed to the tumor. Carbon ions are furthermore superior to protons by biological advantages based on their enhanced biological effectivity. In general, heavy ions are considered as a good treatment option for tumors of low radiosensitivity as sarcomas. Superior survival and decreased toxicity rates are expected from the use of protons and carbon ions. This randomized prospective open-label phase 2 trial testes the safety and feasibility of a hypofractionated accelerated neoadjuvant proton or carbon ion radiotherapy based on the rate of wound healing disorders from beginning of radiotherapy to maximum 120 days after the planned tumor resection or discontinuation of treatment due to any reason. The treatment is of shorter duration (2-3 weeks vs. 5 weeks standard treatment), which should please most patients and thus enhance quality of life. The treatment regimen furthermore promises a reduced rate of late side effects and significant optimization of the current treatment standards. A phase II trial is mandatory not only for obtaining the safety and feasibility data, but also in order to prepare a concurrent phase III trial. Due to the low incidence of soft tissue sarcoma, only a well prepared multicenter study has a chance to be successfully completed based on previous experiences in trials for seldom tumor entities.

Official Title
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Neoadjuvant Irradiation of Extremity Soft Tissue Sarcoma With Ions

Conditions
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Soft Tissue Sarcoma

Intervention / Treatment
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* Radiation: Protons
* Radiation: carbon ions


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed soft-tissue sarcoma of the extremities with an indication for perioperative radiation treatment Resectable or marginally resectable Karnofsky index of ≥ 70% Age ≥ 18 years Carried out patient education and written consent Patient is capable to give informed consent Exclusion Criteria: Stage IV (distant metastases) Lymph node metastasis Metal implants that influence treatment planning with ions Previous radiotherapy in the treatment area Desmoid tumors Simultaneous participation in another clinical trial that could influence the results of the study. Active medical implants for which no ion beam irradiation permit exists at the time of treatment (e.g., cardiac pacemaker, defibrillator)

Ages Eligible for Study
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Minimum Age: 18 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: Arm A: Protons, 39 Gy (RBE) in 13 fractions (single dose 3.0 Gy(RBE))<br>Arm A: Protons, 39 Gy (RBE) in 13 fractions (single dose 3.0 Gy(RBE)) | Radiation: Protons<br>* proton irradiation with a total dose of 39 Gy(RBE) in 3 Gy(RBE) fractions<br>|
| Experimental: Arm B: Carbon ions, 39 Gy(RBE) in 13 fractions (single dose 3.0 Gy(RBE))<br>Arm B: Carbon ions, 39 Gy(RBE) in 13 fractions (single dose 3.0 Gy(RBE)) | Radiation: carbon ions<br>* carbon ion irradiation with a total dose of 39 Gy(RBE) in 3 Gy(RBE) fractions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of therapies without wound healing disorders and/or discontinuation | Proportion of therapies without wound healing disorders and / or discontinuation in each study arm. | from the beginning of radiotherapy (day1) until a maximum of 120 days after the resection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LC: Local control | LC: Local control determined from local onset to local tumor progression | from start of radiotherapy to local onset to local tumor progression up to 5 years | 
| LPFS: locally progression-free survival determined from onset of therapy to local tumor progression | LPFS: locally progression-free survival determined from onset of therapy to local tumor progression | from start of radiotherapy to onset of therapy of local tumor progression up to 5 years | 
| DFS: Disease-free survival | DFS: Disease-free survival determined from onset of therapy until local and / or distant tumor progression | from start of radiotherapy to onset of therapy until local and / or distant tumor progression up to 5 years | 
| OS: Overall survival | OS: Overall survival until death or censorship | from start of radiotherapy until death or censorship up to 5 years |