Assessment of the Long-term Efficacy of Moderately Hypofractionated Neoadjuvant Radiotherapy Soft Tissue Sarcoma in the Limbs or Trunk Wall

Local control of the disease will be assessed by cumulative incidence of local progression / recurrence. The main primary outcome analysis will focus on this incidence at the two-year follow-up.

The cumulative incidence of local progression / recurrence will be estimated by considering the time between the start of radiotherapy and the date of local progression / recurrence.

For patients who are free of local progression / recurrence, this time will be censored at the last follow-up.

Death without prior local progression / recurrence and metastatic progression / recurrence without prior local progression / recurrence will be considered competing events.

Pre-operative tumor assessment will be performed according to the RECIST 1.1 criteria. For the main analysis, a progressive disease according to RECIST 1.1 criteria during or at the end of radiotherapy will not be considered as an event if the patient remains eligible for surgical resection.

Recurrence-free survival will be defined as the time between the start of radiotherapy and the date of progression / recurrence (local or metastatic) or death, whatever the cause. Observations of patients who were alive and free of progression / recurrence at the last follow up will be censored at that date.

The three components of recurrence-free survival will be described: cumulative incidence of local progression / recurrence as described in the primary outcome, cumulative incidence of metastatic recurrence (time between the start of radiotherapy and the date of metastatic progression / recurrence), and cumulative incidence of death without prior progression / recurrence (time between the start of radiotherapy and the date of death without prior progression / recurrence).

Local control of the disease will be assessed as described in the main primary outcome but:

• For the first sensitivity analysis, metastatic progression / recurrence prior to local progression will not be considered a competing event.
• For the second sensitivity analysis, a progressive disease according to RECIST 1.1 criteria during or at the end of radiotherapy will be considered as an event even if the patient remains eligible for surgical resection.

Overall survival will be defined as the time between the start of radiotherapy and the date of death, regardless of the cause. Patients who are alive at the last study follow-up will be consored at that date.

The incidence of amputation will be defined as the time between the start of radiotherapy and the date of amputation regardless of the cause (progressive disease/recurrence, severe trophic complications, ...). Patients who were alive and free of amputation at the last follow-up will be censored at that date. Death without prior amputation will be considered as a competing event. Local or metastatic progression/recurrence will not be considered as a competing event.

The radiological response to radiotherapy will assessed by comparing the post-radiotherapy MRI with the Baseline MRI according to the RECIST 1.1 criteria. The objective response will be defined as complete or partial response.

The percentage of tumor necrosis will be assessed on Baseline and post-radiotherapy MRI (using the larger slice plan).

The histological response to radiotherapy will be assessed by determining the percentage of residual tumor in the resected specimen.

Complete necrosis (<5% residual tumor) will be distinguished. The percentage of hyalinisation, necrosis and fibrosis will also be assessed.

The quality of tumor resection will be described regardless of the completeness of the resection. A complete tumor resection with histological confirmation of completeness and healthy margin will be described as "R0" ; A complete tumor resection with margin that may contain tumor will be described as "R1" ; Incomplete surgery will be described as "R2".

The morbidity of treatments will be described using the NCI CTCAE v6.0 scale. This will include radiotherapy-related toxicity, from the first session of radiotherapy to the end of the study follow-up, surgical complication from the surgery to the end of the study follow-up, duration of hospitalisation, surgical reoperation, new hospitalisation for surgical complication and time to healing, during the entire study follow-up.

Limb function will be assessed using the Musculoskeletal Tumor Society (MSTS). This questionnaire will be completed at registration, every 4 months for 2 years, then every 6 months for 3 years.

The quality of life will be assessed using the EORTC Core Quality of Life questionnaire (EORTC QLQ-C30). The EORTC QLQ-C30 will be completed at registration, and at the first follow-up planned 4 months after the surgery.

The quality of life will be assessed using the EORTC QLQ-F17 questionnaires. During the follow-up, the QLQ-F17 will be completed every 4 months for 2 years, then every 6 months for 3 years.