Neoadjuvant Chemotherapy Combined With Targeted Treatment in High-risk Retroperitoneal Sarcoma

Study Overview
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Brief Summary
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The goal of this clinical trial is to explore the potential survival benefits of neoadjuvant chemotherapy combined with target treatments followed by radical surgery in patients with primary high-risk/grade retroperitoneal sarcoma. The main questions it aims to answer are: Whether the 1,3-year progression-free survival time(PFS) is prolonged in the neoadjuvant therapy group, compared with the surgery-only group. The Overall survival time in the two groups. The safety and tolerance in the neoadjuvant therapy group. Participants will be allocated into two groups once they meet the inclusion criteria. Surgery-only Group: Patients will directly undergo surgeries after the confirmation of diagnosis through pre-operative biopsy. Neoadjuvant therapy group: Patients will receive the neoadjuvant chemotherapy combined with target treatment for three circles before the following sarcoma resectional surgeries.

Official Title
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Neoadjuvant Chemotherapy Combined With Targeted Treatment in High-risk Retroperitoneal Sarcoma-- A Nationwide Multicentered Prospective Controlled Study

Conditions
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Retroperitoneal Sarcoma

Intervention / Treatment
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* Drug: Doxorubicin+Ifosfamide+Anlotinib(AI+A)
* Procedure: Radical Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven primary high-risk Retroperitoneal sarcoma(RPS) (Including Dedifferentiated liposarcoma (DDLPS), leiomyosarcoma(LMS), Undifferentiated pleomorphic sarcoma(UPS), Solitary fibrous tumor(SFT)). Primary localized RPS without histories of surgical resection, chemo- or radio-therapy, targeted therapy. Patients who underwent laparotomy with biopsy only will also be considered as primary cases. Without histories of second malignant tumors. In DDLPS Diagnosis should be confirmed based on MDM2(Mouse double minute 2 homolog) and CDK4(Cyclin-dependent kinase 4) expression on IHC (immunohistochemistry), while MDM2 amplification in the Fish test is highly recommended. All grade 2-3 DDLPS can be included. In LMS All grades of LMS can be included. Tumor size ≥10cm In UPS or SFT All grades of UPS can be included. High-risk SFT with a score ≥6 in 'Risk stratification of SFT for development of metastasis' introduced in The 5th edition of the WHO(World Health Organization) Soft tissue sarcoma classification. Sarcoma without protruding across the diaphragm Possibility of R0/R1 resection evaluated through preoperative MDT(multi-disciplinary team) discussion No multi-organ or system dysfunction/failure or patients with slight dysfunction of organ/system could be easily recovered Tolerable of chemotherapy and surgery through MDT evaluation and tests. American Society of Anesthesiologist (ASA) ≤3 Fully understand the informs and consent to participate in the study. Exclusion Criteria: Sarcoma confirmed originating from the GI tract, uterus, or urinal tract. Patients included in the study through preoperative biopsy or MDT discussion, with WDLPS, grade 1 LPS, or other types of tumors not mentioned in the Inclusion criteria evaluating through final pathological findings. Sarcoma protruded into the chest cavity evaluated through preoperative imaging or surgical reports. Metastasis confirmed pathologically or highly suspicious metastatic lesions through radiological findings, PET-CT(Positron emission tomography) is highly recommended, MDT discussion and evaluation are needed. Histories of administration of Anthracyclines, Ifosfamide, and targeted agents. Severe contradiction to surgery and chemotherapies, including persistent myelosuppression, myocardial/cerebral/pulmonary infarction, uncontrolled cardiac arrhythmia, etc within the last 6 months Indication of severe infection or undergoing surgeries with high-risk hemorrhages in one month. Persistent one or more organ or system dysfunctions, could not be recovered prior to the study. Female patients who are pregnant or breastfeeding or female and male patients of reproductive potential who are not willing to employ effective birth control methods. Patients with psychological conditions

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: It is a prospective non-randomized controlled study. After meeting the inclusion and exclusion criteria, patients will be allocated either into the Surgery-only Group or the Neoadjuvant therapy group. Patients in the surgery-only group will directly undergo surgeries after the confirmation of diagnosis through pre-operative biopsy, while in the neoadjuvant therapy group, patients will receive neoadjuvant chemotherapy combined with target treatment for three circles followed by the sarcoma resectional surgeries.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: The Neoadjuvant Therapy Group<br>Neoadjuvant chemotherapy + Target therapy+ Radical resectional Surgery Drugs: Doxorubicin（PLD） 40mg/㎡ d1, Ifosfamide 1g/㎡ d1-5, Anlotinib10mg d1-14 Q3weeks * 3 Circles, Watch-Wait 4-6 weeks | Drug: Doxorubicin+Ifosfamide+Anlotinib(AI+A)<br>* Doxorubicin（PLD） 40mg/㎡ d1, Ifosfamide（I） 1g/㎡ d1-5, Anlotinib（A）10mg d1-14 Q3weeks * 3 Circles<br>Procedure: Radical Surgery<br>* Radical sarcoma resectional surgery<br>|
| Active Comparator: The Surgery only Group<br>Procedure: Radical resectional surgery | Procedure: Radical Surgery<br>* Radical sarcoma resectional surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-year Progression Free Survival(PFS) | Progression free survival will be measured from the date of surgery to the date of progression or death, whichever occurs first. | 3 years after first patient enrolled in | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1-year PFS | Progression free survival will be measured from the date of surgery to the date of progression or death, whichever occurs first. | 1year after first patient enrolled in. | 
| 1 year Overall survival(OS) | OS will be measured from the date of surgery to the date of death, whatever the causes of death. | 1year after first patient enrolled in | 
| 3-year OS | OS will be measured from the date of surgery to the date of death, whatever the causes of death. | 3 years after first patient enrolled in | 
| 5-year PFS | Progression free survival will be measured from the date of surgery to the date of progression or death, whichever occurs first. | 5 years after first patient enrolled in. | 
| 5-year OS | OS will be measured from the date of surgery to the date of death, whatever the causes of death. | 5 years after first patient enrolled in | 
| Safety and toxicity of neoadjuvant therapy | Safety and toxicity will be evaluated through blood tests, echocardiography, ECG, etc. | 1-d, 7-d after the first date of each neoadjuvant therapy session. | 
| Postoperative morbidities | Operative outcomes including morbidities will be collected and compared in two groups. | 30-d, 90-d, 1-year separately after the date of surgery. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Retroperitoneal Sarcoma, Neoadjuvant therapy, Target therapy, Survival