A Scandinavian Sarcoma Group Protocol for Patients With High-risk Soft Tissue Sarcoma of the Extremities and Trunk Wall

Study Overview
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Brief Summary
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SSG XX is a phase II trial for high-risk soft tissue sarcomas (STS) of the extremities and trunk wall. Prognostic factors (histopathological markers) are used to identify high-risk tumors. SSG XX will evaluate chemo- and radiotherapy given adjuvantly to these patients. In a specified group of patients also preoperatively given therapy will be studied.

Detailed Description
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SSG XX, the third adjuvant STS protocol by SSG, is a phase II non-randomized trial in patients with high risk to develop metastases. SSG XX is based on a previous SSG trial (SSG XIII) regarding use of prognostic markers to identify high-risk tumors and include very similar chemo- and radiotherapy treatment schedules compared to SSG XIII, but the new protocol also includes a treatment arm with preoperative chemo- and radiotherapy for patients with an obvious risk for intralesional surgery initially. Patients: In this new adjuvant protocol SSG adopts an inclusion decision algorithm based on the following criteria: 1.vascular invasion or 2. presence of at least two of the risk factors: tumor size =>8 cm, necrosis or infiltrative growth(all defined microscopically by the pathologist. The system was developed retrospectively by evaluation of 434 primary histologically high grade (III-IV) STS from the SSG registry, and was later validated in a series of 175 patients in which patients with a high risk for metastases (>40 %) and low risk (<15 %) were separated (Engellau J et al.Eur J Ca 2007 43: 1927-34). Inclusion criteria: age ≥ 18 y and <75 y. Primary end point is metastasis-free survival. Local recurrence and toxicity will also be studied. Treatment: Six cycles of doxorubicin 60mg/m2 and ifosfamide 6g/m2 will be given adjuvantly (to patients ≥ 70y: 50mg/m2 and 5g/m2 ). Dependent on surgical resection margins, 36Gy or 45Gy (1,8Gy per fraction, two fractions daily) will be given interpolated with chemotherapy. Conclusion: SSG XX will evaluate chemo-and radiotherapy given adjuvantly to patients with STS and high risk for metastases (arm A). In a specified group of patients also preoperatively given therapy will be studied(arm B). Other sarcoma centers are invited to participate in the study.

Official Title
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A Scandinavian Sarcoma Group Treatment Protocol for Adult Patients With Non-metastatic High-risk Soft Tissue Sarcoma of the Extremities and Trunk Wall

Conditions
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Soft Tissue Sarcoma, Non Metastatic Disease

Intervention / Treatment
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* Drug: doxorubicin , ifosfamide
* Drug: doxorubicin, ifosfamide
* Drug: doxorubicin, ifosfamide
* Drug: doxorubicin, ifosfamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Group A: Histological high-grade malignancy soft tissue sarcomas of the extremity and trunk wall. Patients fulfilling the high-risk criteria defined above (see detailed description) Group B: Patients with histological high-grade malignancy soft tissue sarcomas of the extremity and trunk wall for whom surgery carries an obvious risk of intralesional margin Other inclusion criteria for therapy group A and group B Age ≥ 18 y and ≤ 75 y WHO grade 0-1 Adequate cardiac function (LVEF ≥ 50%) Normal GFR (clearance) Adequate haematologic and liver function All histotypes except those listed below Exclusion Criteria: The following histological types: Extraskeletal osteosarcoma and - chondrosarcoma, Ewing/PNET, rhabdomyosarcoma, Kaposi´s sarcoma, malignant mesenchymoma, clear cell sarcoma, alveolar soft part sarcoma, epithelioid sarcoma Radiation induced sarcoma No previous anthracycline treatment Less than 5 years free of another primary malignancy More than 12 weeks have elapsed since primary surgery (Group A) More than 4 weeks from diagnostic biopsy to start of chemotherapy (Group B)

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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Accepts Healthy Volunteers

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 2<br><70y: 6 cycles with doxorubicin 60mg/m2+ifosfamide 6g/m2 of each 21day cycle and radiotherapy 36Gy (1.8Gy per fraction, two fractions daily) will be given between cycle 3 and 4. (>=70y: doxorubicin 50mg/m2+ifosfamide 5g/m2) | Drug: doxorubicin , ifosfamide<br>* doxorubicin 60mg/m2+ifosfamide 6g/m2 every third week<br>* Other names: Holoxan;Drug: doxorubicin, ifosfamide<br>* <70y: 6 cycles with doxorubicin 60mg/m2+ifosfamide 6g/m2 of each 21day cycle and radiotherapy 36Gy (1.8Gy per fraction, two fractions daily) will be given between cycle 3 and four. (>=70y: doxorubicin 50mg/m2+ifosfamide 5g/m2)<br>* Other names: Holoxan;|
| Experimental: Arm 3<br><70y: 6 cycles with doxorubicin 60mg/m2+ifosfamide 6g/m2 of each 21day cycle and radiotherapy 45Gy (1.8Gy per fraction, two fractions daily) will be given between cycle 3 and 4. (>=70y: doxorubicin 50mg/m2+ifosfamide 5g/m2) | Drug: doxorubicin , ifosfamide<br>* doxorubicin 60mg/m2+ifosfamide 6g/m2 every third week<br>* Other names: Holoxan;|
| Experimental: Group B<br><70y: 6 cycles with doxorubicin 60mg/m2+ifosfamide 6g/m2 of each 21day cycle and radiotherapy 36Gy (1.8Gy per fraction, two fractions daily) will be given between cycle 2 and 3. (>=70y: doxorubicin 50mg/m2+ifosfamide 5g/m2) | Drug: doxorubicin , ifosfamide<br>* doxorubicin 60mg/m2+ifosfamide 6g/m2 every third week<br>* Other names: Holoxan;Drug: doxorubicin, ifosfamide<br>* <70y: 6 cycles with doxorubicin 60mg/m2+ifosfamide 6g/m2 of each 21day cycle and radiotherapy 36Gy (1.8Gy per fraction, two fractions daily) will be given between cycle 2 and 3. (>=70y: doxorubicin 50mg/m2+ifosfamide 5g/m2)<br>* Other names: Holoxan;|
| Experimental: Arm 1<br><70y: 6 cycles with doxorubicin 60mg/m2+ifosfamide 6g/m2 of each 21day cycle (>=70y: doxorubicin 50mg/m2+ifosfamide 5g/m2) | Drug: doxorubicin , ifosfamide<br>* doxorubicin 60mg/m2+ifosfamide 6g/m2 every third week<br>* Other names: Holoxan;Drug: doxorubicin, ifosfamide<br>* Doxorubicin and Ifosfamide given every three weeks, totally 6 courses.<br>* Other names: Holoxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metastases-free survival |  | time frame from start of treatment until the events metastases or death of any cause | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cumulative incidence of local recurrence,overall survival,acute and late toxicity,secondary malignancies |  | for ten years from start of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Soft-tissue sarcomas, prognostic factors, adjuvant, chemotherapy, radiotherapy, metastases-free survival, toxicity, High malignancy grade, High-risk for metastases, Adult