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Hypofractionated Radiotherapy With Sequential Chemotherapy in Marginally Resectable Soft Tissue Sarcomas of Extremities or Trunk Wall (UN-RESARC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03651375
Recruitment Status : Active, not recruiting
First Posted : August 29, 2018
Last Update Posted : January 22, 2021
Information provided by (Responsible Party):
Maria Sklodowska-Curie National Research Institute of Oncology

Brief Summary:
After a screening, which consists of biopsy, physical examination, initial diffusion-weighted magnetic resonance imaging (DWI-MRI), body computed tomography (CT) scan, blood tests and case analysis on Multidisciplinary Team (MDT) meeting, a patient will receive the first course of chemotherapy - doxorubicin 75 mg/sqm and ifosfamide 10 g/sqm (AI regimen) with prophylactic mesna. Then a patient will be irradiated 5x5 Gy and after radiotherapy he or she will receive two courses of AI within 4-6 weeks, depending on the tolerance. Then the response analysis in DWI-MRI and toxicity assessment and will be performed. On the second MDT meeting, a final decision about resectability of the tumor will be made. In case of resectability, a patient will be referred to surgery.

Condition or disease Intervention/treatment Phase
Sarcoma Fibrosarcoma Leiomyosarcoma Liposarcoma Myosarcoma Histiocytic Sarcoma Synovial Sarcoma Lymphangiosarcoma Malignant Peripheral Nerve Sheath Tumors Myxofibrosarcoma Myxoid Liposarcoma Undifferentiated Sarcoma Pleomorphic Liposarcoma Undifferentiated Pleomorphic Sarcoma Dedifferentiated Liposarcoma Pleomorphic Rhabdomyosarcoma Malignant Triton Tumor Drug: Sequential chemotherapy - 3 courses of AI Radiation: Hypofractionated radiotherapy Phase 2

Detailed Description:

There is lack of standard treatment of marginally resectable sarcomas. Results of commonly used approaches are unsatisfactory. The addition of neoadjuvant/induction chemotherapy before the irradiation and in the prolonged gap between the end of hypofractionated 5x5 Gy radiotherapy and surgery may allow to obtain the R0 resection rate, high pathological response rate and/or a higher rate of limb-sparing/conservative surgery as well as to increase patients' survival.

Hypofractionation represents a variation of radiotherapy fractionation in which the total dose is divided into fewer fractions with an increased fraction dose. Such treatment may lead to additional biological effects when compared to conventionally fractionated radiotherapy (eg. vascular damage, increased immunogenicity, and antigenicity). The main advantages of hypofractionation are those related to the decreased overall treatment time what is more convenient for both patients and physicians, increased compliance and makes the treatment more cost-effective. Intriguing, such an approach may provide an additional benefit when treating non-radiosensitive tumors with a low alpha/beta ratio (eg. sarcomas).

The basis of the study was a trial conducted by Kosela et al. in our center, which showed that preoperative short 5x5 Gy radiotherapy with immediate surgery is an effective and well-tolerated treatment of resectable sarcomas of extremities or trunk wall.

The rationale of chemotherapy comes from the interim analysis of a multicenter, international EORTC study comparing neoadjuvant systemic approaches in high-risk sarcomas. It was proven that AI regimen, which consists of ifosfamide and anthracyclines allowed to obtain 20% benefit in relapse-free survival and overall survival as compared to pathologically-tailored chemotherapy.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 46 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Hypofractionated 5x5 Gy Radiotherapy With Sequential Doxorubicin and Ifosfamide-based Chemotherapy in Marginally Resectable Soft Tissue Sarcomas of Extremities or Trunk Wall
Actual Study Start Date : February 11, 2017
Actual Primary Completion Date : December 31, 2019
Estimated Study Completion Date : March 2022

Arm Intervention/treatment
Experimental: Sequential chemoradiotherapy
1xAI (doxorubicin 75 mg/sqm and ifosfamide 10 g/sqm) + 5x5 Gy radiotherapy + 2xAI + surgery
Drug: Sequential chemotherapy - 3 courses of AI
Three courses of doxorubicin and ifosfamide (AI, doxorubicin 75 mg/sqm and ifosfamide 10 g/sqm with prophylactic mesna), one before radiotherapy and two within the gap between radiotherapy and surgery.

Radiation: Hypofractionated radiotherapy
Preoperative hypofractionated 5x5 Gy radiotherapy (5 consecutive days) prescribed on planned target volume (tumor volume + elective margins + setup/error margin) with a daily image guidance with cone beam-CT-based position verification.

Primary Outcome Measures :
  1. The ratio of en limb-sparing/conservative R0 resections. [ Time Frame: 24 months ]

Secondary Outcome Measures :
  1. Radiological response in diffusion-weighted MRI [ Time Frame: 24 months ]
    Radiological assessment of tumor change, especially diffusion parameters in DWI-MRI 6 weeks after the end of irradiation, according to the EORTC criteria.

  2. Pathological response in resected tumors according to EORTC Soft Tissue and Bone Sarcoma Group criteria [ Time Frame: 24 months ]
  3. Toxicity of planned schedule of therapy according to CTCAE v.4.0. [ Time Frame: 24 months after treatment completion ]
    The study will be stopped prematurely if the rate of non-hematological toxicity grade 3 >30%

  4. 2-years overall survival [ Time Frame: 24 months after treatment completion ]
  5. 2-years local control rate [ Time Frame: 24 months after treatment completion ]

Other Outcome Measures:
  1. Assessment of biomarkers in biopsy and post-operative material [ Time Frame: 24 months ]
    HIF-1 (hypoxia-inducible factor 1) - marker of hypoxia, predicting tumor response on radiotherapy; CD105/CD31/VEGF-A - tumor microvessel density; CD14, CD163, CD68KP i CD68 PG-M1 - tumor associated macrophages.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Able to provide informed consent
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2
  • Age ≥18 years old
  • Histologic diagnosis of soft tissue sarcoma
  • Primary or recurrent tumor localized on extremities or trunk
  • Grade 2 or grade 3 tumor
  • Marginally resectable tumor as assessed by a multidisciplinary team
  • Adequate renal function (serum creatinine ≤ 1.5 ULN)
  • Adequate liver function (total bilirubin, AST, ALT 3x < ULN)

Exclusion Criteria:

  • Radiation-induced sarcoma
  • Second active malignancy, not including localized basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast; patients with a history of other malignancies are eligible if they have been continuously disease-free for > 10 years prior to the time of registration.
  • History of radiation to the affected volume
  • Histologic diagnosis of rhabdomyosarcoma (except pleomorphic subtype), angiosarcoma, epithelioid sarcoma, clear cell sarcoma, extraskeletal chondrosarcoma, alveolar soft part sarcoma, osteogenic sarcoma, Ewing's sarcoma/PPNET, aggressive fibromatosis, dermatofibrosarcoma protuberans
  • Contraindications to radiotherapy, chemotherapy or surgery
  • Metastatic disease except primary resectable isolated lung metastases

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03651375

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Maria Sklodowska-Curie Institute - Oncology Center
Warsaw, Mazovian, Poland, 02-781
Sponsors and Collaborators
Maria Sklodowska-Curie National Research Institute of Oncology
Gronchi A, Ferrari S, Quagliuolo, Broto M, J, Lopez-Pousa A, Grignani G, et al. Full-dose neoadjuvant anthracycline + ifosfamide chemotherapy is associated with a relapse free survival (RFS) and overall survival (OS) benefit in localized high-risk adult soft tissue sarcomas (STS) of the extremities and trunk wall: Interim analysis of a prospective randomized trial. Annals of Oncology, Volume 27, Issue suppl_6, 1 October 2016

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Responsible Party: Maria Sklodowska-Curie National Research Institute of Oncology Identifier: NCT03651375    
Other Study ID Numbers: URESARC1
First Posted: August 29, 2018    Key Record Dates
Last Update Posted: January 22, 2021
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Maria Sklodowska-Curie National Research Institute of Oncology:
Dose Hypofractionation
Neoadjuvant Therapy
Dose Fractionation
Dose-Response Relationship
Antineoplastic Agents
Drug Therapy
Antineoplastic Combined Chemotherapy Protocols
Additional relevant MeSH terms:
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Sarcoma, Synovial
Nerve Sheath Neoplasms
Histiocytoma, Malignant Fibrous
Liposarcoma, Myxoid
Histiocytic Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms, Muscle Tissue
Neoplasms, Adipose Tissue
Neoplasms, Connective Tissue
Neoplasms, Nerve Tissue
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Nervous System Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Neoplasms, Fibrous Tissue
Histiocytic Disorders, Malignant