Radiotherapy With Hyperthermia in Recurrent and Radiation-Induced Sarcomas

Study Overview
=================
Brief Summary
-----------------
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 with radiation-induced or in-field recurrent sarcoma will receive the hypofractionated radiotherapy with deep hyperthermia (twice a week) within three weeks. The response analysis in CT or DWI-MRI and toxicity assessment will be performed after 6 weeks. In resectable tumors, a patient will be referred to surgery. In the case of unresectability, the patient will followed-up.

Detailed Description
-----------------
Due to the rarity of radiation-induced (RIS) or previously irradiated recurrent (PIRS) sarcomas, no guidelines nor randomized prospective clinical trials on this topic exist. Thus the management of RIS and PIR is challenging. The only curable modality in non-metastatic RIS/PIRS is radical resection with wide negative margins. The role of secondary radiotherapy in locally advanced RIS/PIRS is unclear, mostly due to the concerns about possible severe side effects after re-irradiation. The addition of deep hyperthermia to irradiation and in the prolonged gap between the end of moderately hypofractionated radiotherapy (with or without integrated boost) and surgery may allow obtaining the long-term local control with the maintenance of a good treatment tolerance 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. Treatment tolerance is usually very good.

Official Title
-----------------
Hyperthermia and Radiotherapy in the Treatment for In-field Recurrent and Radiation-induced Soft Tissue and Bone Sarcomas

Conditions
-----------------
Radiation Induced Neoplasms, Radiation-Induced Cancer, Recurrent Sarcoma, Recurrent Soft Tissue Sarcoma

Intervention / Treatment
-----------------
* Radiation: Hypofractionated radiotherapy
* Other: Hyperthermia
* Radiation: Hypofractionated radiotherapy with boost


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Able to provide informed consent Eastern Cooperative Oncology Group performance status 0 - 2 Age ≥18 years old Histologically-proven diagnosis of radiation-induced or recurrent soft tissue sarcoma Previous radiotherapy within the planned target volume Exclusion Criteria: Histologic diagnosis of rhabdomyosarcoma (except spindle cell and pleomorphic subtype), osteogenic sarcoma, Ewing's sarcoma/PNET, aggressive fibromatosis Contraindications to radiotherapy or hyperthermia Predicted unacceptable high risk of reirradiation-related toxicity, in the Investigator's judgment Unresectable metastases

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiotherapy with hyperthermia in resectable sarcomas<br>12x 3 Gy (4 fractions per week) + hyperthermia (6x) + surgery | Radiation: Hypofractionated radiotherapy<br>* Resectable or marginally resectable tumors: preoperative hypofractionated 12x 3 Gy radiotherapy (4 days in a week, three 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.<br>Other: Hyperthermia<br>* Deep hyperthermia (Celsius TCS or BSD-2000) according to local protocol combined with radiotherapy, twice a week.<br>|
| Experimental: Radiotherapy with hyperthermia in non-resectable sarcomas<br>12x 3 Gy with simultaneous integrated boost 3.5 Gy (4 fractions per week) + hyperthermia (6x) | Other: Hyperthermia<br>* Deep hyperthermia (Celsius TCS or BSD-2000) according to local protocol combined with radiotherapy, twice a week.<br>Radiation: Hypofractionated radiotherapy with boost<br>* Non-resectable/inoperable tumors: definitive hypofractionated 12x 3 Gy radiotherapy prescribed on planned target volume (tumor volume + elective margins + setup/error margin) with simultaneous integrated boost 3.5 Gy per fraction prescribed on boost planned target volume (tumor volume + setup/error margin), 4 days in a week, three weeks. Radiotherapy with daily image guidance with cone beam-CT or kV-portal position verification.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio of late adverse events | Ratio of grade 3 or higher late adverse events related to reirradiation, according to CTCAE 5.0 | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local control rate |  | 18 months | 
| Progression-free survival |  | 18 months | 
| Cancer-specific survival |  | 18 months |