Surgery With or Without Radiation Therapy in Untreated Nonmetastatic Retroperitoneal Sarcoma (STRASS)

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

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.

Study Overview

• Status: Completed
• Conditions: Sarcoma
• Intervention / Treatment: Procedure: therapeutic conventional surgery; Radiation: 3-dimensional conformal radiation therapy

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.

• Study Type: Interventional
• Enrollment (Actual): 266
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Anne Kirkpatrick; Phone Number: +32 27741691; Email: anne.kirkpatrick@eortc.be

Study Locations

• Belgium
  • Brussels, Belgium, 1000
    • Hopitaux Universitaires Bordet-Erasme - Institut Jules Bordet (101)
  • Leuven, Belgium, 3000
    • U.Z. Gasthuisberg
• Canada
  • Ontario
    • Toronto, Ontario, Canada
      • Mount Sinai Hospital
  • Quebec
    • Montreal QUEBEC, Quebec, Canada, 1560
      • CHUM - Centre Hospitalier de l'Université de Montreal - Hopital Notre-Dame
• Denmark
  • Herlev, Denmark, 2730
    • University Copenhagen
• France
  • Bordeaux, France, 33076
    • Institut Bergonié
  • Lyon, France
    • Centre Leon Bérard
  • Villejuif, France, 94805
    • Institut Gustave Roussy
• Germany
  • Koeln, Germany, 50937
    • Universitaetsklinikum
  • Mannheim, Germany
    • Universitaetsmedizin Mannheim
  • Muenchen, Germany, 81377
    • Klinikum der Universitaet
  • Muenchen, Germany
    • Technische Universitaet Muenchen
• Italy
  • Aviano, Italy, 33081
    • Centro Di Riferimento Oncologico
  • Milano, Italy
    • Fondazione IRCCS Istituto Nazionale dei Tumori
  • Milano, Italy, 20089
    • Istituto Clinico Humanitas
  • Padova, Italy, 35128
    • Istituto Oncologico Veneto
• Netherlands
  • Amsterdam, Netherlands
    • The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis
  • Groningen, Netherlands
    • University Medical Center Groningen
  • Leiden, Netherlands, 2300
    • Leiden University Medical Centre
  • Nijmegen, Netherlands, 6500
    • Radboud University Medical Center
• Norway
  • Oslo, Norway, 0310
    • Radium Hospitalet
• Poland
  • Warsaw, Poland, 02781
    • Maria Sklodowska-Curie Memorial Cancer Center
• Spain
  • Barcelona, Spain, 08035
    • Hospital General Vall D'Hebron
  • Madrid, Spain, 28040
    • Hospital Universitario San Carlos
• Sweden
  • Stockholm, Sweden, 60500
    • Karolinska University Hospital
• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
    • Queen Elizabeth Medical Center
  • Bristol, United Kingdom
    • University Hospitals Bristol NHS Foundation Trust - Bristol Haematology and Oncology Centre
  • Edinburgh, United Kingdom, EH4 2XU
    • General Western Hospital
  • Glasgow, United Kingdom, G12 0YN
    • Beatson-Gartnavel General Hospital
  • Leeds, United Kingdom
    • Leeds Teaching Hospitals NHS Trust - St. James's University Hospital
  • London, United Kingdom, NW1 2PG
    • University College Hospital
  • London, United Kingdom
    • Royal Marsden Hospital - Chelsea, London
  • Manchester, United Kingdom
    • Christie NHS Foundation Trust
  • Newcastle, United Kingdom, NE7 7DN
    • Freeman Hospital
  • Nottingham, United Kingdom
    • Nottingham University Hospitals NHS Trust - City Hospital campus
  • Sheffield, United Kingdom, S10 2SJ
    • Weston Park Hospital
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute & Harvard Medical School

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 118 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Surgery alone; 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
Experimental: Preoperative radiotherapy followed by en-bloc surgery; 3D-CRT or IMRT to a dose of 50.4 Gy/28 daily fractions	Procedure: therapeutic conventional surgery; Radiation: 3-dimensional conformal radiation therapy

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

Collaborators and Investigators

• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Investigators: Study Chair: Sylvie Bonvalot, Gustave Roussy, Cancer Campus, Grand Paris; Study Chair: Rick LM Haas, MD, The Netherlands Cancer Institute

Publications and helpful links

General Publications

• Bonvalot S, Gronchi A, Le Pechoux C, Swallow CJ, Strauss D, Meeus P, van Coevorden F, Stoldt S, Stoeckle E, Rutkowski P, Rastrelli M, Raut CP, Hompes D, De Paoli A, Sangalli C, Honore C, Chung P, Miah A, Blay JY, Fiore M, Stelmes JJ, Dei Tos AP, Baldini EH, Litiere S, Marreaud S, Gelderblom H, Haas RL. Preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (EORTC-62092: STRASS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020 Oct;21(10):1366-1377. doi: 10.1016/S1470-2045(20)30446-0. Epub 2020 Sep 14.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2012
• Primary Completion (Actual): March 1, 2019
• Study Completion (Actual): March 1, 2019

Study Registration Dates

• First Submitted: April 27, 2011
• First Submitted That Met QC Criteria: April 27, 2011
• First Posted (Estimate): April 28, 2011

Study Record Updates

• Last Update Posted (Actual): April 24, 2023
• Last Update Submitted That Met QC Criteria: April 21, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: adult angiosarcoma; adult fibrosarcoma; adult leiomyosarcoma; adult liposarcoma; adult malignant fibrous histiocytoma; adult malignant mesenchymoma; stage III adult soft tissue sarcoma; stage II adult soft tissue sarcoma; stage I adult soft tissue sarcoma
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma
• Other Study ID Numbers: EORTC-62092-22092; EORTC-62092 (Other Identifier: EORTC); EORTC-22092 (Other Identifier: EORTC); EU-21113 (Other Identifier: EU)