Neoadjuvant Irradiation of Extremity Soft Tissue Sarcoma With Ions (EXTREM ION)

• ClinicalTrials.gov Identifier: NCT04946357
• Recruitment Status: Recruiting
• First Posted: June 30, 2021
• Last Update Posted: July 2, 2021
• Sponsor: University Hospital Heidelberg
• Information provided by (Responsible Party): Juergen Debus, University Hospital Heidelberg

Tracking Information

• First Submitted Date: June 21, 2021
• First Posted Date: June 30, 2021
• Last Update Posted Date: July 2, 2021
• Actual Study Start Date: June 21, 2021
• Estimated Primary Completion Date: July 1, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 29, 2021)

Proportion of therapies without wound healing disorders and/or discontinuation [ Time Frame: from the beginning of radiotherapy (day1) until a maximum of 120 days after the resection ]

Proportion of therapies without wound healing disorders and / or discontinuation in each study arm.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 29, 2021)

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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Neoadjuvant Irradiation of Extremity Soft Tissue Sarcoma With Ions
• Official Title: Neoadjuvant Irradiation of Extremity Soft Tissue Sarcoma With Ions
• Brief Summary: 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

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.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Soft Tissue Sarcoma

Intervention

• Radiation: Protons
  proton irradiation with a total dose of 39 Gy(RBE) in 3 Gy(RBE) fractions
• Radiation: carbon ions
  carbon ion irradiation with a total dose of 39 Gy(RBE) in 3 Gy(RBE) fractions

Study Arms

• Experimental: Arm A: Protons, 39 Gy (RBE) in 13 fractions (single dose 3.0 Gy(RBE))
  Arm A: Protons, 39 Gy (RBE) in 13 fractions (single dose 3.0 Gy(RBE))
  Intervention: Radiation: Protons
• Experimental: Arm B: Carbon ions, 39 Gy(RBE) in 13 fractions (single dose 3.0 Gy(RBE))
  Arm B: Carbon ions, 39 Gy(RBE) in 13 fractions (single dose 3.0 Gy(RBE))
  Intervention: Radiation: carbon ions

• Publications *: Brugemann D, Lehner B, Kieser M, Krisam J, Hommertgen A, Jaekel C, Harrabi SB, Herfarth K, Mechtesheimer G, Sedlaczek O, Egerer G, Geisbusch A, Uhl M, Debus J, Seidensaal K. Neoadjuvant irradiation of extremity soft tissue sarcoma with ions (Extrem-ion): study protocol for a randomized phase II pilot trial. BMC Cancer. 2022 May 12;22(1):538. doi: 10.1186/s12885-022-09560-x.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 29, 2021): 42
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: July 1, 2023
• Estimated Primary Completion Date: July 1, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Klaus Herfarth, Prof. Dr.; 06221 56 34093; studienkoordination.RAD@med.uni-heidelberg.de

• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT04946357
• Other Study ID Numbers: EXTREM ION
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Juergen Debus, University Hospital Heidelberg
• Original Responsible Party: Same as current
• Current Study Sponsor: University Hospital Heidelberg
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: University Hospital Heidelberg
• Verification Date: June 2021