Surgery With or Without Radiation Therapy in Untreated Nonmetastatic Retroperitoneal Sarcoma

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Giving radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known whether surgery is more effective with or without radiation therapy in treating nonmetastatic retroperitoneal soft tissue sarcoma. PURPOSE: This randomized phase III trial is studying radiation therapy followed by surgery to see how well it works compared with surgery alone in treating patients with previously untreated nonmetastatic retroperitoneal soft tissue sarcoma.

Detailed Description
-----------------
OBJECTIVES: Primary To assess whether there is a difference in abdominal recurrence-free survival between retroperitoneal soft tissue sarcoma patients undergoing curative intent surgery alone and those undergoing preoperative radiotherapy followed by curative-intent surgery. Secondary To assess whether there is a difference in metastasis-free survival, abdominal recurrence-free interval, and overall survival between these patients. To assess tumor response in patients undergoing preoperative radiotherapy. To assess toxicity of preoperative radiotherapy given prior to curative-intent surgery in these patients. OUTLINE: This is a multicenter study. Patients are stratified according to institution and WHO performance status (0-1 vs 2). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients undergo surgical resection of the tumor mass within 4 weeks following randomization. Arm II: Patients undergo 3-dimensional conformal radiation therapy (RT) or intensity-modulated RT within 8 weeks after randomization. RT continues 5 days a week for approximately 5.5 weeks. Patients undergo surgical resection of the tumor mass within 4-8 weeks after the completion of RT. Tumor tissue, normal abdominal wall fat, and peripheral blood may be collected during surgery to identify new prognostic factors for translational research. After completion of study therapy, patients are followed at day 60 post-surgery and every 6 months thereafter.

Official Title
-----------------
A Phase III Randomized Study of Preoperative Radiotherapy Plus Surgery Versus Surgery Alone for Patients With Retroperitoneal Sarcoma (RPS)

Conditions
-----------------
Sarcoma

Intervention / Treatment
-----------------
* Procedure: therapeutic conventional surgery
* Radiation: 3-dimensional conformal radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed retroperitoneal sarcoma (RPS) by local pathologist, imaging-guided or surgical biopsy, including the following: Primary soft tissue sarcoma of retroperitoneal space or infra-peritoneal spaces of pelvis Sarcoma not originated from bone structure, abdominal, or gynecological viscera Unifocal tumor (not multifocal disease) Absence of extension through the sciatic notch or across the diaphragm The following histological sub-types are not allowed: Gastrointestinal stromal tumor (GIST) Rhabdomyosarcomas Primitive neuroectodermal tumor (PNET) or other small round blue cells sarcoma Osteosarcoma or chondrosarcoma Aggressive fibromatosis Sarcomatoid or metastatic carcinoma No metastatic disease Untreated disease Tumor must be operable and suitable for radiotherapy, based on the following criteria: Pre-treatment CT scan/MRI and multidisciplinary consultation with surgeon, radiation oncologist, and radiologist (anticipated macroscopically complete resection, R0/R1 resection) No surgery anticipated to be R2 on the CT scan before randomization Must have American Society of Anesthesiologist (ASA) score ≤ 2 None of the following unresectable criteria: Involvement of superior mesenteric artery Involvement of aorta Involvement of bone Must have radiologically measurable disease (RECIST 1.1), as confirmed by abdomino-pelvic CT (with IV and PO contrast) or MRI (with IV contrast) PATIENT CHARACTERISTICS: WHO performance status 0-2 WBC ≥ 2,500/mm^3 Platelet count ≥ 80,000/mm^3 Total bilirubin < 1.5 times the upper limit normal Calculated creatinine clearance normal Functional contra-lateral kidney to the side involved by the RPS as assessed by intravenous pyelogram Adequate cardiac function (NYHA class I-II) ECG normal (without clinically significant abnormalities) No history of any of the following disorders: Bowel obstruction Mesenteric ischemia Severe chronic inflammatory bowel disease Negative pregnancy test Not pregnant or nursing concurrently and for at least 1 month after the surgery Fertile patients must use effective contraception during the study treatment period and for at least 1 month after the surgery No co-existing malignancy within the past 5 years, except for adequately treated basal cell carcinoma of the skin or carcinoma in situ of the cervix No psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule PRIOR CONCURRENT THERAPY: No prior surgery (excluding diagnosis biopsy), radiotherapy, or systemic therapy No prior abdominal or pelvic irradiation for another prior malignancy or other disease No concurrent systemic anticancer treatment (chemotherapy, molecular-targeted therapy) No postoperative radiotherapy planned

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 Years

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Surgery alone<br>En-bloc resection of surrounding tissues and organs when located within 1 to 2 cm from the surface tumor, even when not infiltrated. | Procedure: therapeutic conventional surgery<br> <br> |
| Experimental: Preoperative radiotherapy followed by en-bloc surgery<br>3D-CRT or IMRT to a dose of 50.4 Gy/28 daily fractions | Procedure: therapeutic conventional surgery<br> <br> Radiation: 3-dimensional conformal radiation therapy<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Abdominal Recurrence or Death | Abdominal recurrence was defined by one of the following events: local/abdominal or distant progressive disease during preoperative radiotherapy (as per RECIST 1.1), tumor or patient becoming inoperable (ASA score of 3 or involvement of superior mesenteric artery, aorta, or bone), peritoneal metastasis found at surgery, macroscopic residual disease left in at surgery (R2 resection), or local relapse (after macroscopically complete resection). Liver metastases were regarded as distant metastatic events. Patients with distant metastases were followed until local failure was detected. Patients without one of these events were censored at the date of last follow-up. | ARFS was measured from date of randomization to date of abdominal relapse or death, whichever occurred first, up to a maximum of 7 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Toxicity Profile of Preoperative Radiotherapy. | The acute toxicity was assessed in randomized patients who received at least one dose of preoperative radiotherapy (RT). It follows Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 in the RT safety population, assuming the following classification: Grade 0 No event reported Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. For each item of the CTCAE, the worst grade of acute toxicity from the data of randomization prior to surgery was taken | From date of randomization to the date of surgical procedure, prior to surgery | 
| Perioperative Complications | Adverse events and side effects possibly related to surgery were assessed according to the Dindo's classification. This scales the observed side effects as Grade 0 No event Grade I Any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic and radiological interventions Grade II Requiring pharmacological treatment with drugs other than such allowed for grade I complications. Grade III Requiring surgical, endoscopic or radiological intervention Grade IV Life-threatening complication (including CNS complications) requiring IC/ICU-management Grade V Death of a patient For each item, the frequency of the worst grade of the observed toxicity was tabulated by treatment group. The perioperative period commence at the time of surgery (at the time of the induction anaesthesia) to the complete closure of the wound. | From the date of surgery, up to 60 days following surgery | 
| Late Complications | The late toxicities occurring more than 60 days after surgery. These were reported using Common Terminology Criteria for Adverse Events (CTCAE) v4.0. This scales the observed toxicity from Grade 1 to 5, assuming the following classification: Grade 0 no event Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. Full AE reporting can be found in the Adverse Event Section. | From day 60 after surgery till end of follow-up, up to 7 years | 
| Tumor Response to Preoperative Radiotherapy | For patients that received preoperative radiotherapy, the tumor response was assessed using RECIST 1.1. Response criteria were essentially based on a set of measurable lesions identified at baseline as target lesions, and followed at the end of the radiotherapy. Response was not the primary endpoint, so a confirmatory CT-scan was not mandatory. | Two weeks after completion of Pre-operative Radiotherapy, before Surgery | 
| Number of Patients With an Abdominal Recurrence | Abdominal recurrence was defined in the ARFS section. The following are considered competing events: death in the absence of abdominal failure distant metastases diagnosed before abdominal failure Patients without one of these events were censored at the date of last follow-up. | ARFI was measured from the date of randomization to the date of abdominal relapse, up to a maximum of 7 years | 
| Number of Patients With Metastases or Death | Alive and metastases free patients will be censored at the date of last follow-up. | Metastases free survival was measured from the date of randomization to the date of occurrence of distant metastases or death, whichever occurred first, up to a maximum of 7 years. | 
| Number of Patients Alive | Alive patients were censored at the date of last follow-up. Causes of death were recorded and reported as a table. | Overall survival was measured from the date of randomization to the date of death, whatever the cause, up to a maximum of 7 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adult angiosarcoma, adult fibrosarcoma, adult leiomyosarcoma, adult liposarcoma, adult malignant fibrous histiocytoma, adult malignant mesenchymoma, stage I adult soft tissue sarcoma, stage II adult soft tissue sarcoma, stage III adult soft tissue sarcoma