Hypofractionated Radiotherapy With Sequential Chemotherapy in Marginally Resectable Soft Tissue Sarcomas of Extremities or Trunk Wall

NCT03651375 | Unknown Phase 2

• 1 other identifier: URESARC1
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

Dose Hypofractionation; Neoadjuvant Therapy; Chemoradiotherapy; Sarcoma; Dose Fractionation; Dose-Response Relationship; Antineoplastic Agents; Drug Therapy; Antineoplastic Combined Chemotherapy Protocols

Outcome Measures

Primary Outcomes (1)

• The ratio of en limb-sparing/conservative R0 resections.

  24 months

Secondary Outcomes (5)

• Radiological response in diffusion-weighted MRI

  24 months

• Pathological response in resected tumors according to EORTC Soft Tissue and Bone Sarcoma Group criteria

  24 months

• Toxicity of planned schedule of therapy according to CTCAE v.4.0.

  24 months after treatment completion

• 2-years overall survival

  24 months after treatment completion

• 2-years local control rate

  24 months after treatment completion

Other Outcomes (1)

• Assessment of biomarkers in biopsy and post-operative material

  24 months

Study Arms (1)

Sequential chemoradiotherapy

EXPERIMENTAL

1xAI (doxorubicin 75 mg/sqm and ifosfamide 10 g/sqm) + 5x5 Gy radiotherapy + 2xAI + surgery

Drug: Sequential chemotherapy - 3 courses of AI; Radiation: Hypofractionated radiotherapy

Interventions

Sequential chemotherapy - 3 courses of AI DRUG

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.

Sequential chemoradiotherapy

Hypofractionated radiotherapy RADIATION

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.

Sequential chemoradiotherapy

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Maria Sklodowska-Curie National Research Institute of Oncology: lead

Study Sites (1)

Maria Sklodowska-Curie Institute - Oncology Center

Warsaw, Mazovian, 02-781, Poland

Location

Related Publications (14)

• Barker HE, Paget JT, Khan AA, Harrington KJ. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer. 2015 Jul;15(7):409-25. doi: 10.1038/nrc3958.

  PMID: 26105538 BACKGROUND

• Dumars C, Ngyuen JM, Gaultier A, Lanel R, Corradini N, Gouin F, Heymann D, Heymann MF. Dysregulation of macrophage polarization is associated with the metastatic process in osteosarcoma. Oncotarget. 2016 Nov 29;7(48):78343-78354. doi: 10.18632/oncotarget.13055.

  PMID: 27823976 BACKGROUND

• Ellingsen C, Andersen LM, Galappathi K, Rofstad EK. Hypoxia biomarkers in squamous cell carcinoma of the uterine cervix. BMC Cancer. 2015 Oct 26;15:805. doi: 10.1186/s12885-015-1828-2.

  PMID: 26502718 BACKGROUND

• Fujiwara T, Fukushi J, Yamamoto S, Matsumoto Y, Setsu N, Oda Y, Yamada H, Okada S, Watari K, Ono M, Kuwano M, Kamura S, Iida K, Okada Y, Koga M, Iwamoto Y. Macrophage infiltration predicts a poor prognosis for human ewing sarcoma. Am J Pathol. 2011 Sep;179(3):1157-70. doi: 10.1016/j.ajpath.2011.05.034. Epub 2011 Jul 21.

  PMID: 21771572 BACKGROUND

• Ganjoo KN, Witten D, Patel M, Espinosa I, La T, Tibshirani R, van de Rijn M, Jacobs C, West RB. The prognostic value of tumor-associated macrophages in leiomyosarcoma: a single institution study. Am J Clin Oncol. 2011 Feb;34(1):82-6. doi: 10.1097/coc.0b013e3181d26d5e.

  PMID: 23781555 BACKGROUND

• 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

  BACKGROUND

• Jiang S, Yang Y, Fang M, Li X, Yuan X, Yuan J. Co-evolution of tumor-associated macrophages and tumor neo-vessels during cervical cancer invasion. Oncol Lett. 2016 Oct;12(4):2625-2631. doi: 10.3892/ol.2016.5014. Epub 2016 Aug 16.

  PMID: 27698836 BACKGROUND

• Kim YH, Yoo KC, Cui YH, Uddin N, Lim EJ, Kim MJ, Nam SY, Kim IG, Suh Y, Lee SJ. Radiation promotes malignant progression of glioma cells through HIF-1alpha stabilization. Cancer Lett. 2014 Nov 1;354(1):132-41. doi: 10.1016/j.canlet.2014.07.048. Epub 2014 Aug 7.

  PMID: 25109450 BACKGROUND

• Kosela-Paterczyk H, Szacht M, Morysinski T, Lugowska I, Dziewirski W, Falkowski S, Zdzienicki M, Pienkowski A, Szamotulska K, Switaj T, Rutkowski P. Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas. Eur J Surg Oncol. 2014 Dec;40(12):1641-7. doi: 10.1016/j.ejso.2014.05.016. Epub 2014 Sep 20.

  PMID: 25282099 BACKGROUND

• Lee HJ, Yoon C, Park DJ, Kim YJ, Schmidt B, Lee YJ, Tap WD, Eisinger-Mathason TS, Choy E, Kirsch DG, Simon MC, Yoon SS. Inhibition of vascular endothelial growth factor A and hypoxia-inducible factor 1alpha maximizes the effects of radiation in sarcoma mouse models through destruction of tumor vasculature. Int J Radiat Oncol Biol Phys. 2015 Mar 1;91(3):621-30. doi: 10.1016/j.ijrobp.2014.10.047. Epub 2014 Dec 24.

  PMID: 25544668 BACKGROUND

• Messiou C, Bonvalot S, Gronchi A, Vanel D, Meyer M, Robinson P, Morosi C, Bloem JL, Terrier PH, Lazar A, Le Pechoux C, Wardelman E, Winfield JM, Boulet B, Bovee J, Haas RL. Evaluation of response after pre-operative radiotherapy in soft tissue sarcomas; the European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) and Imaging Group recommendations for radiological examination and reporting with an emphasis on magnetic resonance imaging. Eur J Cancer. 2016 Mar;56:37-44. doi: 10.1016/j.ejca.2015.12.008. Epub 2016 Jan 20.

  PMID: 26802529 BACKGROUND

• Wardelmann E, Haas RL, Bovee JV, Terrier P, Lazar A, Messiou C, LePechoux C, Hartmann W, Collin F, Fisher C, Mechtersheimer G, DeiTos AP, Stacchiotti S, Jones RL, Gronchi A, Bonvalot S. Evaluation of response after neoadjuvant treatment in soft tissue sarcomas; the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) recommendations for pathological examination and reporting. Eur J Cancer. 2016 Jan;53:84-95. doi: 10.1016/j.ejca.2015.09.021. Epub 2015 Dec 14.

  PMID: 26700077 BACKGROUND

• Yehia L, Boulos F, Jabbour M, Mahfoud Z, Fakhruddin N, El-Sabban M. Expression of HIF-1alpha and Markers of Angiogenesis Are Not Significantly Different in Triple Negative Breast Cancer Compared to Other Breast Cancer Molecular Subtypes: Implications for Future Therapy. PLoS One. 2015 Jun 5;10(6):e0129356. doi: 10.1371/journal.pone.0129356. eCollection 2015.

  PMID: 26046764 BACKGROUND

• Zhang M, Qiu Q, Li Z, Sachdeva M, Min H, Cardona DM, DeLaney TF, Han T, Ma Y, Luo L, Ilkayeva OR, Lui K, Nichols AG, Newgard CB, Kastan MB, Rathmell JC, Dewhirst MW, Kirsch DG. HIF-1 Alpha Regulates the Response of Primary Sarcomas to Radiation Therapy through a Cell Autonomous Mechanism. Radiat Res. 2015 Jun;183(6):594-609. doi: 10.1667/RR14016.1. Epub 2015 May 14.

  PMID: 25973951 BACKGROUND

MeSH Terms

Conditions

Sarcoma; Fibrosarcoma; Leiomyosarcoma; Liposarcoma; Myosarcoma; Histiocytic Sarcoma; Sarcoma, Synovial; Lymphangiosarcoma; Neurofibrosarcoma; Dermatofibrosarcoma; Liposarcoma, Myxoid; Histiocytoma, Malignant Fibrous

Interventions

Radiation Dose Hypofractionation

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Fibrous Tissue; Neoplasms, Connective Tissue; Neoplasms, Muscle Tissue; Neoplasms, Adipose Tissue; Histiocytic Disorders, Malignant; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases; Neoplasm, Lymphatic Tissue; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Peripheral Nervous System Neoplasms; Nervous System Neoplasms; Nervous System Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Histiocytoma

Intervention Hierarchy (Ancestors)

Dose Fractionation, Radiation; Radiotherapy Dosage; Radiotherapy; Therapeutics

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 27, 2018
• First Posted: August 29, 2018
• Study Start: February 11, 2017
• Primary Completion: December 31, 2019
• Study Completion: March 1, 2022
• Last Updated: January 22, 2021

Record last verified: 2020-12

Locations

PL (1)