Hypofractionated Radiotherapy With Hyperthermia in Unresectable or Marginally Resectable Soft Tissue Sarcomas

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) or body computed tomography (CT) scan, blood tests and case analysis on Multidisciplinary Team (MDT) meeting, a patient will receive the hypofractionated radiotherapy 10x 3.25 Gy with regional hyperthermia (twice a week) within two weeks. The response analysis in CT or DWI-MRI and toxicity assessment will be performed after at least 6 weeks. At the second MDT meeting, a final decision about resectability of the tumor will be made. In case of resectability or consent for amputation, if required, a patient will be referred to surgery. In case of unresectability or amputation refusal, the patient will receive the second part of the treatment which consists of 4x 4 Gy with hyperthermia (twice a week).

Detailed Description
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There is a lack of standard treatment of unresectable and marginally resectable sarcomas. Results of commonly used approaches are unsatisfactory, especially in patients who are not candidates for neoadjuvant chemotherapy due to poor performance status, comorbidities, radioresistant pathology or disease progression on the commonly used chemotherapy regimens. The addition of regional hyperthermia to irradiation and in the prolonged gap between the end of hypofractionated 10x 3.25 Gy radiotherapy and surgery may allow obtaining the long-term local control with the maintenance of a good treatment tolerance. 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 which 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). Hyperthermia is a method of increasing the temperature in the tumor to damage cancer cells with minimum injury to the normal cells. It should be combined with another treatment modality (radio- or chemotherapy) rather than used alone. Its efficacy was proven in clinical trials. The treatment tolerance is usually very good.

Official Title
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Hypofractionated Radiotherapy With Hyperthermia in Unresectable or Marginally Resectable Soft Tissue Sarcomas

Conditions
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Sarcoma, Alveolar Soft Part Sarcoma, Clear Cell Sarcoma, Malignant Peripheral Nerve Sheath Tumors, Myxoid Liposarcoma, Liposarcoma, Dedifferentiated, Synovial Sarcoma, Leiomyosarcoma, Undifferentiated Pleomorphic Sarcoma, Fibrosarcoma, Pleomorphic Rhabdomyosarcoma

Intervention / Treatment
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* Radiation: Hypofractionated radiotherapy
* Other: Hyperthermia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to provide informed consent; age ≥18 years old Eastern Cooperative Oncology Group performance status 0 - 2 Histologic diagnosis of locally advanced soft tissue sarcoma Marginally resectable or unresectable tumor (assessed at Multidisciplinary Tumor Board) Radioresistant sarcoma subtype (low-grade tumor or radioresistant histology) or contradictions to chemotherapy (assessed at Multidisciplinary Tumor Board) or progression after neoadjuvant chemotherapy Exclusion Criteria: Radiation-induced sarcoma or previous radiation to the affected volume Histologic diagnosis of rhabdomyosarcoma (except pleomorphic subtype), osteogenic sarcoma, Ewing's sarcoma/PNET, aggressive fibromatosis Contraindications to radiotherapy or hyperthermia Distant metastases

Ages Eligible for Study
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Minimum Age: 18 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: Radiotherapy with hyperthermia<br>10x 3.25 Gy + hyperthermia + surgery or radiotherapy boost (4x 4 Gy + hyperthermia) | Radiation: Hypofractionated radiotherapy<br>* Preoperative hypofractionated 10x 3.25 Gy radiotherapy (5 consecutive days in a week, two weeks) prescribed on planned target volume (tumor volume + elective margins + setup/error margin) with daily image guidance with cone beam-CT or kV-portal position verification. Radiotherapy boost 4x 4 Gy within one week in case of unresectability after 6 weeks.<br>Other: Hyperthermia<br>* Deep hyperthermia (Celsius TCS or BSD-2000) according to local protocol combined with radiotherapy, twice a week.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of the treatment schedule | The exact 95% confidence interval for an estimated feasibility proportion of 80% (23 of 30 patients) does not include (60-80%) a value of 50%. Thus, for a sample size of 30 patients, the feasibility of 80% is above chance level performance (50%). | Up to 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| One-year local control rate |  | 12 months after treatment completion | 
| One-year progression-free survival |  | 12 months after treatment completion | 
| One-year sarcoma-specific survival |  | 12 months after treatment completion | 
| Rate of late toxicities | Rate of late toxicities of a planned schedule of therapy according to CTCAE 5.0 | Two years 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, Sarcoma, Hyperthermia, Dose Fractionation