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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Hypofractionated 5x5 Gy Radiotherapy With Sequential Doxorubicin and Ifosfamide-based Chemotherapy in Marginally Resectable Soft Tissue Sarcomas of Extremities or Trunk Wall

Conditions
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Fibrosarcoma, Sarcoma, 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

Intervention / Treatment
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* Drug: Sequential chemotherapy - 3 courses of AI
* Radiation: Hypofractionated radiotherapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequential chemoradiotherapy<br>1xAI (doxorubicin 75 mg/sqm and ifosfamide 10 g/sqm) + 5x5 Gy radiotherapy + 2xAI + surgery | Drug: Sequential chemotherapy - 3 courses of AI<br>* 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.<br>Radiation: Hypofractionated radiotherapy<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The ratio of en limb-sparing/conservative R0 resections. |  | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiological response in diffusion-weighted MRI | Radiological assessment of tumor change, especially diffusion parameters in DWI-MRI 6 weeks after the end of irradiation, according to the EORTC criteria. | 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. | The study will be stopped prematurely if the rate of non-hematological toxicity grade 3 >30% | 24 months after treatment completion | 
| 2-years overall survival |  | 24 months after treatment completion | 
| 2-years local control rate |  | 24 months after treatment completion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dose Hypofractionation, Neoadjuvant Therapy, Chemoradiotherapy, Sarcoma, Dose Fractionation, Dose-Response Relationship, Antineoplastic Agents, Drug Therapy, Antineoplastic Combined Chemotherapy Protocols