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

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ClinicalTrials.gov Identifier: NCT03651375
Recruitment Status : Recruiting
First Posted : August 29, 2018
Last Update Posted : June 17, 2019
Sponsor:
Information provided by (Responsible Party):
Maria Sklodowska-Curie Institute - Oncology Center

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 unresectable and 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 for 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)
Estimated Enrollment : 50 participants
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 Primary Unresectable or Marginally Resectable Soft Tissue Sarcomas of Extremities or Trunk Wall
Actual Study Start Date : February 11, 2017
Estimated Primary Completion Date : September 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. R0 resection rate [ Time Frame: 24 months ]
    The rate of micro- and macroscopically radical surgeries.

  2. Conservative/limb-sparing resection rate [ Time Frame: 24 months ]
    The rate of limb-sparing or conservative resections vs amputations or no possibility to perform surgery (unresectability).


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 and Clavier-Dindo scale for surgical complications [ Time Frame: 60 months ]
    The study will be stopped prematurely if the rate of grade 3 skin toxicity >30%.

  4. 3-years overall survival [ Time Frame: 60 months ]
  5. 3-years local control rate [ Time Frame: 60 months ]

Other Outcome Measures:
  1. Assessment of biomarkers in biopsy and post-operative material [ Time Frame: 60 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.



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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
Criteria

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 or unresectable 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 ClinicalTrials.gov identifier (NCT number): NCT03651375


Contacts
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Contact: Mateusz J Spałek, MD +48225462762 mateusz.spalek@coi.pl
Contact: Hanna Koseła-Paterczyk, MD PhD hanna.kosela@gmail.com

Locations
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Poland
Maria Sklodowska-Curie Institute - Oncology Center Recruiting
Warsaw, Mazovian, Poland, 02-781
Contact: Piotr Rutkowski, MD PhD Professor    +48226439375    piotr.rutkowski@coi.pl   
Principal Investigator: Mateusz J Spałek, MD         
Sub-Investigator: Hanna Koseła-Paterczyk, MD PhD         
Sub-Investigator: Aneta Borkowska, MD         
Sub-Investigator: Tadeusz Morysiński, MD PhD         
Sub-Investigator: Anna Czarnecka, MD PhD         
Sub-Investigator: Paweł Rogala, MD         
Sub-Investigator: Monika Dudzisz-Śledź, MD PhD         
Sub-Investigator: Tomasz Goryń, MD         
Sub-Investigator: Maciej Sałamacha, MD         
Sub-Investigator: Anna Szumera-Ciećkiewicz, MD PhD         
Sub-Investigator: Michał Wągrodzki, MD         
Sub-Investigator: Andrzej Cieszanowski, MD PhD Professor         
Sub-Investigator: Patrycja Castaneda-Wysocka, MD         
Sub-Investigator: Piotr Rutkowski, MD PhD Professor         
Sponsors and Collaborators
Maria Sklodowska-Curie Institute - Oncology Center

Publications:
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 https://academic.oup.com/annonc/article/27/suppl_6/LBA6_PR/2800561

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Responsible Party: Maria Sklodowska-Curie Institute - Oncology Center
ClinicalTrials.gov Identifier: NCT03651375     History of Changes
Other Study ID Numbers: URESARC1
First Posted: August 29, 2018    Key Record Dates
Last Update Posted: June 17, 2019
Last Verified: August 2018
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 Institute - Oncology Center:
Dose Hypofractionation
Neoadjuvant Therapy
Chemoradiotherapy
Sarcoma
Dose Fractionation
Dose-Response Relationship
Antineoplastic Agents
Drug Therapy
Antineoplastic Combined Chemotherapy Protocols
Additional relevant MeSH terms:
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Sarcoma
Rhabdomyosarcoma
Leiomyosarcoma
Liposarcoma
Sarcoma, Synovial
Nerve Sheath Neoplasms
Fibrosarcoma
Neurofibrosarcoma
Histiocytoma, Malignant Fibrous
Liposarcoma, Myxoid
Histiocytic Sarcoma
Myosarcoma
Lymphangiosarcoma
Neoplasms
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
Neurofibroma
Histiocytoma
Histiocytic Disorders, Malignant
Histiocytosis