Histologically proven primary high risk leiomyosarcoma (LMS) or liposarcoma (LPS) of retroperitoneal space or infra-peritoneal spaces of pelvis
* LMS:
** Any grade and size > 5 cm
* DDLPS
** MDM2 and CDK4 expression on immunohistochemistry [IHC]; additional proof of MDM2 amplification is highly recommended but not mandatory)
** Grade 3
** Grade 2 with: 
*** Federation Nationale des Centres de Lutte Contre Le Cancer (FNCLCC) score = 5 and clear necrosis on imaging (whether or not present on the biopsy) OR 
*** Complexity INdex in SARComas (CINSARC-high) (high risk gene profile as determined by the Complexity INdex in SARComas)

Unifocal tumor

Resectable tumor: 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 operable when the expectation is that only an R2 resection is feasible
* Criteria for non-resectability:
** 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 tumor tissue for central pathology review is mandatory.
* For patients with LMS: if there is not enough tissue for assessing the grading, no need to repeat a biopsy
* If tumor tissue is not available for the central pathology review, patient will not be eligible
* If biopsy was not done or the formalin-fixed paraffin-embedded (FFPE) of the biopsy is not available but tumor tissue** is available for the central pathology review, it will be considered as acceptable
* If fine needle aspiration (FNA) is performed instead of core needle biopsy (CNB) recommended by the standard guidelines, and if the diagnosis is confirmed locally and tumor material** is available for central path review, it will be considered as acceptable
**: at least 10 unstained slides or one pathological block

>= 18 years old (no upper age limit)

World Health Organization (WHO) performance status =< 2

Hemoglobin > 9.0 g/dL or 5.6 mmol/L with a buffer of +/- 5% for all
* Note: Platelet transfusions is allowed to achieve these baseline values; red blood cell transfusion is not allowed

Absolute neutrophils > 1.5 x 10^9/L with a buffer of +/- 5% for all
* Note: Platelet transfusions is allowed to achieve these baseline values; red blood cell transfusion is not allowed

Platelets > 100 x 10^9/L with a buffer of +/- 5% for all
* Note: Platelet transfusions is allowed to achieve these baseline values; red blood cell transfusion is not allowed

Partial thromboplastin time (APPT) and prothrombin time (PT) within 2 seconds of the upper limit of normal (ULN). For international normalized ratio (INR) and APTTR within normal range of ratio +/- 5%
* Note: Patients receiving anticoagulant therapy are eligible if their PT or INR and APTT or APTTR are stable and within 2 sec of ULN (PT, APTT) or with +/- 5% of the recommended range (INR, APTTR), for the desired level of anticoagulation

Estimated glomerular filtration rate (eGFR) > 50 ml/min/m^2 (modification of diet in renal disease [MDRD] formula)

No proteinuria >= grade 2 (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5.0)

Bilirubin =< 1.0 x ULN of institutional limits with a buffer of +/-5%. If isolated elevated bilirubin < 2 x ULN and Gilberts syndrome suspected, suggest repeating bloods after food. If bilirubin improves to meet the criteria above this is acceptable. More severe persistent hepatic impairment of whatever cause would exclude the patient from treatment till resolved

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =< 1.5 x ULN with a buffer of +/- 5%

Clinically normal cardiac function based on left ventricular ejection fraction (LVEF) >= 50% as assessed either by multi-gated acquisition scan (MUGA) or cardiac ultrasound and 12 lead electrocardiogram (ECG) without clinically relevant abnormalities (within 21 days prior to randomization)

American Society of Anaesthesiologist (ASA) score < 3

Women of child bearing 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 sterilization 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 6 months after the last study treatment

Before patient randomization, written informed consent must be given according to International Conference on Harmonisation (ICH)/Good Clinical Practice (GCP), and national/local regulations

Sarcoma originating from bone structure, abdominal or gynecological viscera

Extension through the sciatic notch or across the diaphragm

Tumor grading not assessable from biopsy

Metastatic disease

Any previous surgery (excluding diagnostic biopsy), radiotherapy or systemic therapy for the present tumor

Hypersensitivity to doxorubicin, ifosfamide, dacarbazine or to any of their metabolites or to any of their excipients

Congestive heart failure

Angina pectoris

Acute inflammatory heart disease

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:
** initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry
** blood pressure must be re-assessed on two occasions that are separated by a minimum of 1 hour. The mean systolic blood pressure (SBP)/ diastolic blood pressure (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 (450 mg/m^2 doxorubicin or equivalent 900 mg/m^2 epirubicin) of doxorubicin, daunorubicin, epirubicin, idarubicin, and/or other anthracyclines and anthracenediones

Active and uncontrolled infections, in particular urinary tract 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, medical condition (including uncontrolled diabetes), other than the primary LPS or LMS of the retroperitoneum

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

STREXIT 2 COHORT: Patients with histologically proven primary resectable localized high-risk DD LPS or LMS of retroperitoneal space or infra-peritoneal spaces of pelvis (as described in the inclusion criteria of STRASS2) and amenable to receive chemotherapy but for whom the list of eligibility criteria for the study is too restrictive (tumor grading not available, inadequate organ function, concomitant diseases)

STREXIT 2 COHORT: Patients who meet all eligibility criteria of STRASS2 but do not consent to randomization or are not enrolled for any other reason

STREXIT 2 COHORT: Patients enrolled in a registry collecting data on primary RPS patients in the centers participating in STRASS 2 (e.g., RESAR) who satisfy the above criteria

STREXIT 2 COHORT: All patients recruited to STRASS 2 in participating centers (Australia +/- international sites) able to read, comprehend and write in English at a sufficient level to complete study materials

PRIMARY OBJECTIVE:
I. To assess whether preoperative chemotherapy, as an adjunct to curative-intent surgery, improves the prognosis of high risk dedifferentiated liposarcoma (DDLPS) and leiomyosarcoma (LMS) patients as measured by disease free survival.

SECONDARY OBJECTIVES:
I. To assess whether there is a difference in the overall survival, recurrence free survival, distant metastases free survival, cumulative incidence of local recurrences and cumulative incidence of distant metastases between patients undergoing curative-intent surgery alone and those undergoing preoperative chemotherapy followed by curative intent surgery.
II. To assess tumor response in patients undergoing preoperative chemotherapy.
III. To assess the toxicity profile of preoperative chemotherapy given as "neoadjuvant" treatment to curative intent surgery in patients with retroperitoneal sarcoma (RPS), and of surgery alone.
IV. To assess whether there is a difference in quality of life between patients undergoing curative intent surgery alone and those undergoing preoperative chemotherapy followed by curative intent surgery.
V. To transform self-reported quality of life data into health utility values, ready to be used in subsequent health economic analyses.
VI. To compare the outcome of these patients with the outcome of an observational cohort of patients (STREXIT 2) eligible for but not randomized into STRASS 2 to see how the outcome of the randomized patients compares with real-life, clinical practice data.
VII. If feasible, to augment the analysis of STRASS 2 with patients from the STREXIT 2 cohort to compare the outcome of patients treated with preoperative chemotherapy followed by surgery versus surgery alone in the pooled patient populations, as well as in the liposarcoma (LPS) and LMS subgroups separately.

EXPLORATORY OBJECTIVES:
I. Assessment and comparison of Choi, Response Evaluation Criteria in Solid Tumors (RECIST) at post-C3 to predict histological response, disease free survival (DFS), overall survival (OS).
II. To investigate whether a radiomics approach can predict histological response, DFS, OS.
III. To investigate what minimum survival benefits patients judge sufficient to make 9 weeks of neoadjuvant chemotherapy for high risk RPS worthwhile.
IV. To study the effect on preferences of baseline characteristics of patients.
V. To assess differences in preferences between patients randomized to neoadjuvant chemotherapy and control; and differences in preferences before and after patients have experienced neoadjuvant chemotherapy.

OUTLINE: Patients who enroll in STRASS 2 are randomized to arm 1 or 2. Patients who enroll in STREXIT 2 are assigned to observational arm III.

ARM I (STRASS 2): Patients undergo surgery on study. Patients also undergo collection of blood samples throughout the study and undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) at screening and follow up.

ARM II (STRASS 2): Patients receive doxorubicin (or equivalent epirubicin) IV bolus infusion on day 1 with ifosfamide IV over 4 hours on days 1-3 or dacarbazine IV over 15-30 minutes on days 1-4. Cycles repeat every 21 days for 3 cycles and then patients undergo surgery on study. Patients also undergo collection of blood samples and undergo CT and/or MRI throughout the study. Patients may optionally undergo positron emission tomography (PET) scan throughout the study. 

ARM III (STREXIT 2): Patients have their medical records reviewed throughout the study.

After completion of study treatment, patients are followed up at 12, 18, 24, 36 and 48 weeks and every 4 months until month 24 after randomization. After 24 months, patients are followed every 6 months until occurrence of recurrence or death.