PET CT as Predictor of Response in Preoperative Chemotherapy for Soft Tissue Sarcoma

Study Overview
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Brief Summary
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RATIONALE: Diagnostic procedures, such as positron emission tomography (PET) scan and computated tomography (CT) scan, may help doctors predict a patient's response to treatment and may help plan the best treatment. Drugs used in chemotherapy, such as doxorubicin and ifosfamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. PURPOSE: This clinical trial is studying how well PET scan combined with CT scan predicts response in patients undergoing chemotherapy and surgery for soft tissue sarcoma.

Detailed Description
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OBJECTIVES: Primary Determine whether measurements of fludeoxyglucose (FDG) positron emission tomography (PET)/CT imaging can accurately predict disease-free survival of patients with soft tissue sarcoma who are receiving neoadjuvant chemotherapy. Secondary Correlate histological response to neoadjuvant chemotherapy for soft tissue sarcomas with FDG-PET/CT imaging findings. Tertiary Determine the changes in FDG-PET/CT imaging over time as each course of chemotherapy is given. OUTLINE: Patients receive 1 of 2 standard chemotherapy regimens: Preferred regimen: Patients receive pegylated doxorubicin HCl liposome IV on day 1, ifosfamide IV continuously on days 1-6, and pegfilgrastim subcutaneously (SC) on day 8. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Alternative regimen: Patients receive doxorubicin hydrochloride IV continuously on days 1-7. Patients also receive ifosfamide and pegfilgrastim as in the preferred regimen. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. All patients undergo a fludeoxyglucose positron emission tomography/CT scan at baseline, after course 1, and after completion of chemotherapy. Patients undergo surgery within 4-6 weeks after completion of chemotherapy. After completion of study treatment and surgery, patients are followed every 6 months for 5 years. PROJECTED ACCRUAL: A total of 62 patients will be accrued for this study.

Official Title
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An Evaluation of PET/CT Imaging as a Predictor of Disease Free Survival Following Neo-Adjuvant Chemotherapy for Soft Tissue Sarcoma

Conditions
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Sarcoma

Intervention / Treatment
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* Biological: pegfilgrastim
* Drug: doxorubicin hydrochloride
* Drug: ifosfamide
* Drug: pegylated liposomal doxorubicin hydrochloride
* Procedure: conventional surgery
* Radiation: fludeoxyglucose F 18


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically confirmed, high grade, soft tissue sarcoma including malignant fibrous histiocytoma, liposarcoma, fibrosarcoma, leiomyosarcoma, synovial carcinoma, malignant peripheral nerve sheath tumor (MPNST), epithelioid sarcoma, and sarcomas-not otherwise specified. NOTE: Ewings sarcoma, primitive neuroectodermal tumor, extraskeletal, osteosarcoma, extraskeletal chondrosarcoma, alveolar soft part sarcoma, rhabdomyosarcoma, carcinosarcoma, Kaposi's sarcoma, angiosarcoma, and mesothelioma patients are ineligible for this study. Measurable disease using traditional cross section measurements with the primary site's largest diameter > 5 centimeters by positron emission tomography/computated tomography (PET/CT), CT or magnetic resonance imaging (MRI) scan. Patients with either localized (primary or locally recurrent) or metastatic disease at presentation are eligible for study if they are to receive neoadjuvant treatment prior to excision of the primary (stage IIC, III, IVA, IVB.) Age ≥ 16 years, Karnofsky ≥ 70% Adequate organ function for receiving chemotherapy as determined by the treating physician. Women of childbearing potential and sexually active males are required to use an effective method of contraception (ie, a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) during the study. Exclusion Criteria: Previous treatment with chemotherapy or radiation therapy Females known to be pregnant or breast-feeding are excluded because PET/CT scan in pregnant women is not FDA approved. Serious concomitant systemic disorders (eg, active infection) that, in the opinion of the investigator, would compromise the safety of the patient or compromise the patient's ability to complete the study. Patients with PET-CT as an indicator of disease survival in soft tissue sarcoma untreated or symptomatic CNS metastases or uncontrolled diabetes will not be eligible. Patient must give written informed consent indicating the investigational nature of the study and its potential risks.

Ages Eligible for Study
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Minimum Age: 16 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: Diagnostic
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Preferred Standard Regimen<br>Subjects with soft tissue sarcoma who are receiving pegylated liposomal doxorubicin hydrochloride, Ifosfamide with mesna and pegfilgrastim - Repeat every 28 days for 4 cycles total | Biological: pegfilgrastim<br>* will be given at 6 mg subcutaneously (SC) at the end of the mesna infusion<br>* Other names: Neulasta(R);Drug: ifosfamide<br>* 9 g/m^2 by continuous intravenous (IV) infusion over 6 days beginning on day 1 with mesna 10.5 g/m^2 by continuous IV infusion over 7 days beginning on day 1<br>* Other names: Ifex;Drug: pegylated liposomal doxorubicin hydrochloride<br>* 45 mg/m2 intravenous (IV) Day 1, repeat every 28 days.<br>* Other names: doxorubicin-hydrochloride-liposome;Procedure: conventional surgery<br>* The surgical procedure will be decided by the treating physician and independent of study participation<br>Radiation: fludeoxyglucose F 18<br>* FDG is a radioactive sugar equal to a uniform whole-body exposure of approximately 1.5 rem for each scan. Post-operative radiation therapy may be given according to institutional guidelines in patients felt to have close surgical margins.<br>* Other names: FDG;|
| Active Comparator: Alternative Treatment Regimen<br>Subjects with soft tissue sarcoma who are receiving Doxorubicin hydrochloride, Ifosfamide with mesna and pegfilgrastim - Repeat every 28 days for 4 cycles total | Biological: pegfilgrastim<br>* will be given at 6 mg subcutaneously (SC) at the end of the mesna infusion<br>* Other names: Neulasta(R);Drug: doxorubicin hydrochloride<br>* 65 mg/m^2 by continuous intravenous (IV) infusion over 7 days beginning on day 1<br>* Other names: Adriamycin;Drug: ifosfamide<br>* 9 g/m^2 by continuous intravenous (IV) infusion over 6 days beginning on day 1 with mesna 10.5 g/m^2 by continuous IV infusion over 7 days beginning on day 1<br>* Other names: Ifex;Procedure: conventional surgery<br>* The surgical procedure will be decided by the treating physician and independent of study participation<br>Radiation: fludeoxyglucose F 18<br>* FDG is a radioactive sugar equal to a uniform whole-body exposure of approximately 1.5 rem for each scan. Post-operative radiation therapy may be given according to institutional guidelines in patients felt to have close surgical margins.<br>* Other names: FDG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival | Compare changes in baseline and follow-up fludeoxyglucose (FDG) positron emission tomography (PET)/CT imaging with disease-free survival by peak SUV and max SUV calculations. Changes in baseline and follow-up PET/CT, based on max SUV calculations, will be compared with disease free survival. Disease free survival will be measured in months from the time of study enrollment until the time that disease recurrence/relapse/progression is recorded. | Baseline through Survival Event | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlate histologic response with FDG-PET/CT imaging | The overall histologic response will be defined as: % histologic response = 100 - % viable tumor in the central slice as assessed histologically It should be noted that the % histologic response is different from % tumor necrosis as it includes an assessment of the % tumor necrosis along with the degenerative changes | At end of each cycle | 
| Compare changes in FDG-PET/CT imaging with disease-free survival by max SUV calculations | Changes in PET/CT from baseline will be compared to PET/CT done after one cycle and after completion of chemotherapy treatment before surgical excision using max SUV calculations. | Baseline Compared to 1 Cycle and Baseline to After Chemotherapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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soft tissue sarcoma, Malignant fibrous histiocytoma, Liposarcoma, Fibrosarcoma, Leiomyosarcoma, Synovial sarcoma, Malignant peripheral nerve sheath tumor (MPNST), Epithelioid sarcoma