Surgery With or Without Neoadjuvant Chemotherapy in High Risk RetroPeritoneal Sarcoma (STRASS2)
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
- Large en-bloc curative-intent surgery within 4 weeks following randomization- 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
Intervention / Treatment
Study Design
Treatment
Randomized
Parallel Assignment
None (Open Label)
Arm Groups
Other: Standard arm
Surgery alone
Experimental: Experimental arm
Preoperative chemotherapy and surgery
Eligibility Criteria
- 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 SARCcomas (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.
- 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 < 150/90 mmHg 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 ≤ 6 prostate 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
- 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.
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.
Outcome Measures
Disease free survival
Disease free survival will be measured from the date of randomization (as reference) to the date of recurrence or death, whichever occurs first.
7 years from first patient in
Overall survival (OS)
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.
8 years from first patient in
Recurrence free survival
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.
8 years from first patient in
Distant metastases free survival
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.
8 years from first patient in
Cumulative incidence of local recurrences
Cumulative incidence of local recurrences will be measured from the date of randomization (as reference) to the date of local recurrence.
8 years from first patient in
Cumulative incidence of distant metastases
Cumulative incidence of distant metastases will be measured from the date of randomization to the date of occurrence of distant metastases.
8 years from first patient in
Radiological response to neoadjuvant chemotherapy according to RECIST
For patients receiving neo-adjuvant chemotherapy, the radiological response will be assessed using RECIST 1.1 by comparison of the baseline and preoperative imaging.
8 years from first patient in
Radiological response to neoadjuvant chemotherapy according to CHOI
For patients receiving neo-adjuvant chemotherapy, the radiological response will be also assessed using Choi criteria by comparison of the baseline and preoperative imaging.
8 years from first patient in
Pathological response
Response evaluation will be done according to the EORTC response score.
8 years from first patient in
Safety and toxicity of neoadjuvant chemotherapy
Safety and toxicity of neoadjuvant chemotherapy will be evaluated and graded using CTCAE V5.0.
8 years from first patient in
Perioperative complications
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.
8 years from first patient in
Late complications
Late complications (after the 60th day following the surgery) will be evaluated and graded according to the CTCAE version 5.0.
8 years from first patient in
Health-Related Quality of life (EORTC QLQ-C30 + Item list from QLQ-STO22)
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.
8 years from first patient in
Health utility, calculated from the collected patient-reported HRQoL data and patient demographics economics.
The EORTC QLQ C30 data will be mapped to health utility values using an established indirect mapping approach.
8 years from first patient in
Where is this study conducted?
We provide these clinical trial listings as a free service to the medical community based on public information sourced from ClinicalTrials.gov. We do not charge any fees for posting these types of trials. Please be aware that we are not responsible for the information displayed, as it is based on external public records.