Surgery With or Without Neoadjuvant Chemotherapy in High Risk RetroPeritoneal Sarcoma
- Conditions
- Retroperitoneal SarcomaLiposarcomaLeiomyosarcoma
- Interventions
- Procedure: SurgeryDrug: Preoperative chemotherapy
- Registration Number
- NCT04031677
- Brief Summary
This is a multicenter, randomized, open label phase lll trial to assess whether preoperative chemotherapy, as an adjunct to curative-intent surgery, improves the prognosis of high risk DDLPS (dedifferentiated Liposarcoma) and LMS (Leiomyosarcoma) patients as measured by disease free survival.
After confirmation of eligibility criteria, patients will be randomized to either the standard arm or experimental arm.
- Detailed Description
Standard arm:
* Large en-bloc curative-intent surgery within 4 weeks following randomization- Experimental arm
Experimental arm:
* 3 cycles of neoadjuvant chemotherapy starting within 2 weeks following randomization:
* High grade LPS: ADM (doxorubicin) 75 mg/m2 (or the equivalent EpiADM 120 mg/m2) + ifosfamide 9 g/m3 Q3 weeks.
* LMS: ADM 75 mg/m2 + DTIC (dacarbazine) 1 g/m2 Q3 weeks
* re-assessment of operability
* curative-intent surgery within 3-6 weeks of last cycle of chemotherapy
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 250
-
Histologically proven primary high risk leiomyosarcoma (LMS) or Liposarcoma (LPS) of retroperitoneal space or infra-peritoneal spaces of pelvis.
-
LMS:
- Any grade LMS can be included
- Minimum size of LMS tumor should be 5 cm
-
LPS:
-
Diagnosis should be confirmed based on MDM2 (Mouse double minute 2 homolog) and CDK4 (Cyclin-dependent kinase 4) expression on IHC (immunohistochemistry), while proof of MDM2 amplification is highly recommended.
-
All grade 3 DDLPS can be included.
-
DDLPS with confirmed grade 2 on biopsy can be included when:
- The grade 2 DDLPS has an FNCLCC score=5 (Fédération Nationale des Centres de Lutte Contre Le Cancer), and clear necrosis on imaging (whether or not present on the biopsy).
- The tumors carry a high risk gene profile as determined by the Complexity INdex in SARComas (CINSARC-high)
-
Unifocal tumour
-
Resectable tumour: resectability is based on pre-operative imaging (CT-abdomen, potentially also with MRI) and has to be defined by the local treating sarcoma team. A patient is not considered resectable when the expectation is that only an R2 resection is feasible.
-
Criteria for non-resectability are:
-
Involvement of the superior mesenteric artery, aorta, coeliac trunk and/or portal vein
-
Involvement of bone
-
Growth into the spinal canal
-
Progression of retro-hepatic inferior vena cava leiomyosarcoma towards the right atrium
-
Infiltration of multiple major organs like liver, pancreas and or major vessels
-
Patient must have radiologically measurable disease (RECIST 1.1), as confirmed by imaging. CT thorax abdomen pelvis with IV contrast is the preferred imaging modality. In case of any contra-indications (medical or regulatory), it is allowed to perform a non-contrast CT thorax + MRI abdomen & pelvis
-
Collection of tumour tissue for central pathology review is mandatory.
-
For patients with LMS: if there is not enough tissue for assessing the grading, this is acceptable.
-
If tumour tissue is not available for the central pathology review, patient will not be eligible.
-
If the biopsy was not done or the FFPE of the biopsy not available but at least 10 unstained slides or one pathological block are available for the central review, that will be considered as acceptable.
-
For the biopsy if fine needle aspiration (FNA) is performed instead of core needle biopsy (CNB) recommended by the standard guidelines, please contact the EORTC medical monitors for further evaluation.
-
Collection of tumour tissue and blood samples for translational research is mandatory.
-
In case there is not enough tissue for TR, a new biopsy is not required and if the patient fulfils all other eligibility criteria, he/she will be eligible.
-
If the blood samples are not collected, patient will not be eligible.
-
If the patient refuses the collection of biomaterial for TR, patient will not be eligible even if he/she fulfils all other eligibility criteria
-
≥ 18 years old (no upper age limit)
-
WHO performance status ≤ 2
-
Adequate haematological and organ function
-
American Society of Anaesthesiologist (ASA) score < 3
-
Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 3 days prior to randomization.
-
Note: a woman is considered of childbearing potential, i.e., fertile, if she is following menarche. She remains of childbearing potential until she becomes post-menopausal or permanently sterile.Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 consecutive months without menses, a single FSH measurement is insufficient.
- WOCBP in both arms should use highly effective birth control measures, during the study treatment period and for at least 6 months after the last dose of chemotherapy or date of surgery (except for women receiving chemotherapy with ifosfamide who should continue contraception until 1 year after last day of treatment). A highly effective method of birth control is defined as a method which results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly.
- For men in the experimental arm: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm.
- Female subjects who are breast feeding should discontinue nursing prior to the first day of study treatment and until 6months after the last study treatment.
- Before patient randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.
Exclusion criteria:
- Sarcoma originating from bone structure, abdominal or gynecological viscera
- Extension through the sciatic notch or across the diaphragm
- Metastatic disease
- Any previous surgery (excluding diagnostic biopsy), radiotherapy or systemic therapy for the present tumour
- Hypersensitivity to doxorubicin, ifosfamide, dacarbazine or to any of their metabolites or to any of their excipients
- Congestive heart failure
- Angina pectoris
- Myocardial infarction within 1 year before randomization
- Uncontrolled arterial hypertension defined as blood pressure ≥ 150/100 mm Hg despite optimal medical therapy.
Note: in case of high blood pressure: 1) initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry; 2) blood pressure must be re-assessed on two occasions that are separated by a minimum of 1 hour. The mean SBP / DBP values from each blood pressure assessment must be ≤ 150/90mmHg in order for a patient to be eligible for the study.
- Uncontrolled cardiac arrhythmia
- Previous treatment with maximum cumulative doses (450mg/m² Doxorubicin or equivalent 900mg/m² Epirubicin) of doxorubicin, daunorubicin, epirubicin, idarubicin, and/or other anthracyclines and anthracenediones
- Active and uncontrolled infections
- Vaccination with live vaccines within 30 days prior to study entry
- Inflammation of the urinary bladder (interstitial cystitis) and/or obstructions of the urine flow.
- Other invasive malignancy within 5 years, with the exception of adequately treated non-melanoma skin cancer, localized cervical cancer, localized and Gleason ≤ 6prostate cancer.
- Uncontrolled severe illness, infection, medical condition (including uncontrolled diabetes), other than the primary LPS or LMS of the retroperitoneum.
- Female patients who are pregnant or breastfeeding or female and male patients of reproductive potential who are not willing to employ effective birth control method.
- Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before randomization in the trial
- Known contraindication to imaging tracer and to MRI
-
-
Selection criteria for STREXIT 2
- Patients with histologically proven primary resectable localized high-risk DDLPS or LMS of retroperitoneal space or infra-peritoneal spaces of pelvis (as described in the inclusion criteria of STRASS 2) and amenable to receive chemotherapy but for whom the list of eligibility criteria for the study is too restrictive (tumour grading not available, inadequate organ function, concomitant diseases)
- Patients who meet all eligibility criteria of STRASS 2 but do not consent to randomization or are not enrolled for any other reason.
- Patients enrolled in a Registry collecting data on primary RPS patients in the centres participating in STRASS 2 (e.g., RESAR) and who satisfy the above criteria.
-
Selection criteria for preferences for neoadjuvant chemotherapy in STRASS 2 substudy
All patients recruited to STRASS 2 in participating centres (Australia +/- international sites) that are able to read, comprehend and write in English at a sufficient level to complete study materials.
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Standard arm Surgery Surgery alone Experimental arm Preoperative chemotherapy Preoperative chemotherapy and surgery
- Primary Outcome Measures
Name Time Method Disease free survival 7 years from first patient in Disease free survival will be measured from the date of randomization (as reference) to the date of recurrence or death, whichever occurs first.
- Secondary Outcome Measures
Name Time Method Overall survival (OS) 8 years from first patient in OS will be measured from the date of randomization to the date of death, whatever the cause. Alive patients will be censored at the date of last follow-up.
Recurrence free survival 8 years from first patient in Recurrence free survival will be measured in patients who were successfully operated (R0/R1 resection) from the date of surgery (as reference) to the date of recurrence (local or distant) or death, whichever occurs first. Patients without one of these events will be censored at the date of last follow-up.
Distant metastases free survival 8 years from first patient in Distant metastases free survival will be from the date of randomization (as reference) to the date of distant metastases or death (whatever the cause), whichever occurs first. Patients without any of these events will be censored at the date of last follow-up.
Cumulative incidence of local recurrences 8 years from first patient in Cumulative incidence of local recurrences will be measured from the date of randomization (as reference) to the date of local recurrence.
Pathological response 8 years from first patient in Response evaluation will be done according to the EORTC response score.
Cumulative incidence of distant metastases 8 years from first patient in Cumulative incidence of distant metastases will be measured from the date of randomization to the date of occurrence of distant metastases.
Radiological response to neoadjuvant chemotherapy according to RECIST 8 years from first patient in For patients receiving neo-adjuvant chemotherapy, the radiological response will be assessed using RECIST 1.1 by comparison of the baseline and preoperative imaging.
Radiological response to neoadjuvant chemotherapy according to CHOI 8 years from first patient in For patients receiving neo-adjuvant chemotherapy, the radiological response will be also assessed using Choi criteria by comparison of the baseline and preoperative imaging.
Safety and toxicity of neoadjuvant chemotherapy 8 years from first patient in Safety and toxicity of neoadjuvant chemotherapy will be evaluated and graded using CTCAE V5.0.
Late complications 8 years from first patient in Late complications (after the 60th day following the surgery) will be evaluated and graded according to the CTCAE version 5.0.
Health utility, calculated from the collected patient-reported HRQoL data and patient demographics economics. 8 years from first patient in he EORTC QLQ C30 data will be mapped to health utility values using an established indirect mapping approach.
Health-Related Quality of life (EORTC QLQ-C30 + Item list from QLQ-STO22) 8 years from first patient in Health-Related Quality of life assessment will be based on the EORTC QLQ C30 questionnaire version 3.0, with additional questions from the QLQ-STO22 module.
Perioperative complications 8 years from first patient in Perioperative complications will be evaluated with the Dindo scale for the events related to the surgery and CTCAE V5.0 will be used for all other events.
Trial Locations
- Locations (145)
Bank Of Cyprus Oncology Centre
🇨🇾Stróvolos, Cyprus
HMH-Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Rhode Island Hospital
🇺🇸Providence, Rhode Island, United States
Mayo Clinic Hospital in Arizona
🇺🇸Phoenix, Arizona, United States
City of Hope Comprehensive Cancer Center
🇺🇸Duarte, California, United States
UC Irvine Health/Chao Family Comprehensive Ca Ctr
🇺🇸Orange, California, United States
UCHealth University of Colorado Hospital
🇺🇸Aurora, Colorado, United States
Smilow Cancer Hospital-Derby Care Center
🇺🇸Derby, Connecticut, United States
Smilow Cancer Hospital Care Center-Fairfield
🇺🇸Fairfield, Connecticut, United States
Smilow Cancer Hospital Care Center at Glastonbury
🇺🇸Glastonbury, Connecticut, United States
Smilow Cancer Hospital Care Center at Greenwich
🇺🇸Greenwich, Connecticut, United States
Smilow Cancer Hospital Care Center - Guiford
🇺🇸Guilford, Connecticut, United States
Smilow Cancer Hospital Care Ctr at Saint Francis
🇺🇸Hartford, Connecticut, United States
Yale University
🇺🇸New Haven, Connecticut, United States
Yale-New Haven Hospital North Haven Medical Center
🇺🇸North Haven, Connecticut, United States
Smilow Cancer Hospital Care Center at Long Ridge
🇺🇸Stamford, Connecticut, United States
Smilow Cancer Hospital Care Center-Trumbull
🇺🇸Trumbull, Connecticut, United States
Smilow Cancer Hospital-Waterbury Care Center
🇺🇸Waterbury, Connecticut, United States
Smilow Cancer Hospital Care Center - Waterford
🇺🇸Waterford, Connecticut, United States
Mayo Clinic in Florida
🇺🇸Jacksonville, Florida, United States
Moffitt Cancer Center-International Plaza
🇺🇸Tampa, Florida, United States
Moffitt Cancer Center - McKinley Campus
🇺🇸Tampa, Florida, United States
Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
Emory University Hospital Midtown
🇺🇸Atlanta, Georgia, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
Mount Sinai Hospital
🇨🇦Toronto, Canada
University of Illinois at Chicago MBCCOP
🇺🇸Chicago, Illinois, United States
Indiana Univ/Melvin and Bren Simon Cancer Center
🇺🇸Indianapolis, Indiana, United States
University of Kansas Cancer Center
🇺🇸Kansas City, Kansas, United States
University of Kansas Cancer Center-Overland Park
🇺🇸Overland Park, Kansas, United States
University of Kansas Hospital-Westwood Cancer Ctr
🇺🇸Westwood, Kansas, United States
James Graham Brown Ca Ctr at Univ of Louisville
🇺🇸Louisville, Kentucky, United States
LSU Health Baton Rouge-North Clinic
🇺🇸Baton Rouge, Louisiana, United States
Our Lady of The Lake Hospital
🇺🇸Baton Rouge, Louisiana, United States
Our Lady of the Lake Physician Group
🇺🇸Baton Rouge, Louisiana, United States
Johns Hopkins Univ/Sidney Kimmel Cancer Center
🇺🇸Baltimore, Maryland, United States
Dana-Farber/Harvard Cancer Center
🇺🇸Boston, Massachusetts, United States
University of Michigan Comprehensive Cancer Center
🇺🇸Ann Arbor, Michigan, United States
Sanford Joe Lueken Cancer Center
🇺🇸Bemidji, Minnesota, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Siteman Cancer Center-West County
🇺🇸Creve Coeur, Missouri, United States
Washington University School of Medicine - Siteman Cancer Center
🇺🇸Saint Louis, Missouri, United States
Siteman Cancer Center-South Country
🇺🇸Saint Louis, Missouri, United States
Nebraska Medicine-Bellevue
🇺🇸Omaha, Nebraska, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Dartmouth Hitchcock Med Ctr/Dartmouth Cancer Ctr
🇺🇸Lebanon, New Hampshire, United States
Rutgers Cancer Institute of New Jersey
🇺🇸New Brunswick, New Jersey, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
NYU Langone Hospital - Long Island
🇺🇸Mineola, New York, United States
Laura and Issac Perlmutter Ca Ctr at NYU Langone
🇺🇸New York, New York, United States
University of Rochester
🇺🇸Rochester, New York, United States
Stony Brook University Medical Center
🇺🇸Stony Brook, New York, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Sanford Bismarck Medical Center
🇺🇸Bismarck, North Dakota, United States
Sanford Broadway Medical Center
🇺🇸Fargo, North Dakota, United States
Sanford Roger Maris Cancer Center
🇺🇸Fargo, North Dakota, United States
Ohio State University Comprehensive Cancer Center
🇺🇸Columbus, Ohio, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Saint Vincent Hospital
🇺🇸Erie, Pennsylvania, United States
Jefferson Hospital
🇺🇸Jefferson Hills, Pennsylvania, United States
Forbes Hospital
🇺🇸Monroeville, Pennsylvania, United States
Allegheny Valley Hospital
🇺🇸Natrona Heights, Pennsylvania, United States
University of Pennsylvania/Abramson Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Pennsylvania Hospital
🇺🇸Philadelphia, Pennsylvania, United States
Thomas Jefferson University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
Fox Chase Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Allegheny General Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
West Penn Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
UPMC Hillman Cancer Center
🇺🇸Pittsburgh, Pennsylvania, United States
Wexford Health and Wellness Pavilion
🇺🇸Wexford, Pennsylvania, United States
Smilow Cancer Hospital Care Center - Westerly
🇺🇸Westerly, Rhode Island, United States
Sanford Cancer Center Oncology Clinic
🇺🇸Sioux Falls, South Dakota, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸Sioux Falls, South Dakota, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States
M D Anderson Cancer Center
🇺🇸Houston, Texas, United States
Huntsman Cancer Institute/University of Utah
🇺🇸Salt Lake City, Utah, United States
VCU Massey Cancer Center at Hanover Medical Park
🇺🇸Mechanicsville, Virginia, United States
VCU Massey Cancer Center at Stony Point
🇺🇸Richmond, Virginia, United States
Virginia Commonwealth Univ/Massey Cancer Center
🇺🇸Richmond, Virginia, United States
Carilion Roanoke Memorial Hospital
🇺🇸Roanoke, Virginia, United States
VCU Community Memorial Health Center
🇺🇸South Hill, Virginia, United States
FHCC South Lake Union
🇺🇸Seattle, Washington, United States
Fred Hutchinson Cancer Center
🇺🇸Seattle, Washington, United States
University of Washington Medical Center - Montlake
🇺🇸Seattle, Washington, United States
Marshfield Medical Center-EC Cancer Center
🇺🇸Eau Claire, Wisconsin, United States
Marshfield Medical Center
🇺🇸Weston, Wisconsin, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Marshfield Med Ctr-River Region at Stevens Point
🇺🇸Stevens Point, Wisconsin, United States
Princess Alexandra Hospital - University Of Queensland
🇦🇺Woolloongabba, Queensland, Australia
Peter Maccallum Cancer Institute
🇦🇺Melbourne, Victoria, Australia
Chris O'Brian Life House - Chris O'Brien Lifehouse
🇦🇺Camperdown, Australia
BCCA - Vancouver Cancer Centre
🇨🇦Vancouver, British Columbia, Canada
London Regional Cancer Center
🇨🇦London, Ontario, Canada
The Ottawa Hospital - General Campus
🇨🇦Ottawa, Ontario, Canada
Hopital Maisonneuve Rosemont
🇨🇦Montréal, Quebec, Canada
The Research Institute of the McGill University Health Centre
🇨🇦Montréal, Quebec, Canada
Masaryk Memorial Cancer Institute
🇨🇿Brno, Czechia
Herlev Hospital - University Copenhagen
🇩🇰Herlev, Copenhagen, Denmark
Aarhus University Hospitals - Aarhus University Hospital-Skejby
🇩🇰Aarhus, Denmark
Centre Leon Berard
🇫🇷Lyon, France
Institut du Cancer de Montpellier
🇫🇷Montpellier, France
Institut Curie- Hopital de Paris
🇫🇷Paris, France
Hopitaux Universitaires de Strasbourg - Hautepierre
🇫🇷Strasbourg, France
Institut Gustave Roussy
🇫🇷Villejuif, France
Universitaetsmedizin Goettingen - Georg-August Universitaet
🇩🇪Goettigen, Lower Saxony, Germany
Universitaetsklinikum Carl Gustav Carus
🇩🇪Dresden, Germany
UniversitaetsMedizin Mannheim
🇩🇪Mannheim, Germany
Centro Di Riferimento Oncologico
🇮🇹Aviano, Italy
IRCCS - Fondazione Piemonte Inst di Candiolo
🇮🇹Candiolo, Italy
IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori"
🇮🇹Meldola, Italy
Istituto Clinico Humanitas
🇮🇹Milano, Italy
Istituto Europeo di Oncologia
🇮🇹Milano, Italy
IRCCS - Istituto Nazionale dei Tumori
🇮🇹Milan, Italy
IRCCS - Istituto Oncologico Veneto
🇮🇹Padova, Italy
Policlinico Universitario Campus Bio-Medico- Oncology Center
🇮🇹Roma, Italy
Kyushu University Hospital
🇯🇵Higashi-ku, Fukuoka, Japan
Yokohama City University Hospital
🇯🇵Yokohama, Kanagawa, Japan
Kanagawa Cancer Center
🇯🇵Yokohama, Kanagawa, Japan
Tohoku University Hospital
🇯🇵Sendai, Miyagi, Japan
Aichi Cancer Center
🇯🇵Chikusa-ku, Nagoya, Japan
Nagoya University Hospital
🇯🇵Showa-ku, Nagoya, Japan
Niigata University Medical and Dental Hospital
🇯🇵Niigata City, Niigata, Japan
Okayama University Hospital
🇯🇵Kita-ku, Okayama, Japan
Osaka International Cancer Institute
🇯🇵Chuo-ku, Osaka, Japan
National Cancer Center Hospital
🇯🇵Chuo-ku, Tokyo, Japan
Cancer Institute Hospital of JFCR
🇯🇵Koto-ku, Tokyo, Japan
Saitama Medical Center, Jichi Medical University
🇯🇵Saitama, Japan
The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis
🇳🇱Amsterdam, Netherlands
Leiden University Medical Centre
🇳🇱Leiden, Netherlands
Radboudumc - Radboud University Medical Center Nijmegen
🇳🇱Nijmegen, Netherlands
Maria Sklodowska-Curie Memorial Cancer Centre - Maria Sklodowska-Curie National Research Institute of Oncology
🇵🇱Warsaw, Poland
National Cancer Institute
🇸🇰Bratislava, Slovakia
Hospital De La Santa Creu I Sant Pau
🇪🇸Barcelona, Spain
Institut Catala d'Oncologia - ICO Badalona - Hospital Germans Trias i Pujol
🇪🇸Barcelona, Spain
Hospital General Universitario Gregorio Maranon
🇪🇸Madrid, Spain
Hospital Universitario San Carlos
🇪🇸Madrid, Spain
University Hospitals Birmingham - Queen Elisabeth Medical Centre
🇬🇧Birmingham, United Kingdom
NHS Greater Glasgow and Clyde - Beatson West of Scotland Cancer Centre - Gartnavel General Hospital
🇬🇧Glasgow, United Kingdom
Leeds Teaching Hospitals NHS Trust - St. James's University Hospital
🇬🇧Leeds, United Kingdom
the Royal Marsden Hospital
🇬🇧London, United Kingdom
Newcastle Hospitals - Freeman Hospital, Northern Centre For Cancer Care
🇬🇧Newcastle, United Kingdom
Nottingham University Hospitals NHS Trust - City Hospital
🇬🇧Nottingham, United Kingdom
Oxford University Hospitals NHS Trust - Churchill Hospital
🇬🇧Oxford, United Kingdom
Clatterbridge cancer center
🇬🇧Wirral, United Kingdom