Clinical trial NCT00346164
Conditions: Adult Alveolar Soft-part Sarcoma Adult Angiosarcoma Adult Epithelioid Sarcoma Adult Extraskeletal Chondrosarcoma Adult Extraskeletal Osteosarcoma Adult Fibrosarcoma Adult Leiomyosarcoma Adult Liposarcoma Adult Malignant Fibrous Histiocytoma Adult Malignant Hemangiopericytoma Adult Malignant Mesenchymoma Adult Neurofibrosarcoma Adult Synovial Sarcoma Childhood Alveolar Soft-part Sarcoma Childhood Angiosarcoma Childhood Epithelioid Sarcoma Childhood Fibrosarcoma Childhood Leiomyosarcoma Childhood Liposarcoma Childhood Malignant Mesenchymoma Childhood Neurofibrosarcoma Childhood Synovial Sarcoma Dermatofibrosarcoma Protuberans Metastatic Childhood Soft Tissue Sarcoma Nonmetastatic Childhood Soft Tissue Sarcoma Stage I Adult Soft Tissue Sarcoma Stage II Adult Soft Tissue Sarcoma Stage III Adult Soft Tissue Sarcoma Stage IV Adult Soft Tissue Sarcoma
Sponsor: Children's Oncology Group
Start date: 2007-02-05; Completion date: 2022-03-31
Enrollment: 588 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase III trial is studying observation to see how well a risk based treatment strategy works in patients with soft tissue sarcoma. In the study, patients are assigned to receive surgery +/- radiotherapy +/- chemotherapy depending on their risk of recurrence. Sometimes, after surgery, the tumor may not need additional treatment until it progresses. In this case, observation may be sufficient. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as ifosfamide and doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving chemotherapy and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments after surgery may kill any tumor cells that remain after surgery.

Detailed description:
PRIMARY OBJECTIVES:

I. Define a risk-based treatment strategy comprising observation only, adjuvant radiotherapy, or adjuvant chemoradiotherapy or neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without radiotherapy in young patients with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS).

II. Assess event-free and overall survival of patients treated with these regimens.

III. Assess the pattern of treatment failure in these patients.

SECONDARY OBJECTIVES:

I. Assess the feasibility of a neoadjuvant chemoradiotherapy approach in patients with intermediate- or high-risk NRSTS.

II. Assess the imaging and pathologic responses to neoadjuvant chemoradiotherapy in patients with intermediate- or high-risk NRSTS.

III. Correlate imaging and pathologic response with clinical outcomes in patients with intermediate- or high-risk disease who undergo neoadjuvant chemoradiotherapy.

IV. Prospectively define clinical prognostic factors associated with event-free survival, overall survival, local recurrence, and distant recurrence in these patients.

V. Correlate patient outcomes with findings of biologic studies performed on tissue specimens collected on protocol COG-D9902 from these patients.

VI. Determine whether the diagnosis and histologic grade of NRSTS assigned by the enrolling institution correlates with the diagnosis and histologic grade established by central expert pathology reviewers.

VII. Compare the Pediatric Oncology Group (POG) and Fédération Nationale des Centres de Lutte Contre le Cancer (French Federation of Cancer Centers \[FNCLCC\]) pathologic grading systems to determine which better correlates with clinical outcomes.

OUTLINE: This is a multicenter study. Patients are divided into 3 risk groups according to presence of metastatic disease (yes vs no), status of prior surgery (resected vs unresected), grade of tumor (low vs high), and size of primary tumor (≤ 5 cm vs \> 5 cm). Patients are assigned to different treatment regimens based on disease extent (nonmetastatic vs metastatic), tumor size (≤ 5 cm vs \> 5 cm), extent of resection of primary tumor (resected vs unresected), extent of resection of metastases (complete or microscopic residual vs gross residual), microscopic tumor margins (negative vs positive), and tumor grade (low vs high).

GROUP 1 (low risk \[nonmetastatic, grossly resected disease, except high-grade tumor \> 5 cm\]): Patients with low-grade tumor with either negative or positive microscopic margins or high-grade tumor ≤ 5 cm (in maximum diameter) with negative microscopic margins are assigned to regimen A. Patients with high-grade tumor ≤ 5 cm (in maximum diameter) with positive microscopic margins are assigned to regimen B.

REGIMEN A (observation only): Patients undergo observation only.

REGIMEN B (adjuvant radiotherapy): Beginning between 6-42 days after surgical resection, patients undergo a total of 31 fractions of adjuvant radiotherapy.

GROUP 2 (intermediate risk \[nonmetastatic, resected or unresected disease\]): Patients with grossly resected, high-grade tumor \> 5 cm (in maximum diameter) are assigned to regimen C. Patients with unresected tumor are assigned to regimen D.

REGIMEN C (adjuvant chemoradiotherapy): Patients receive ifosfamide IV over 3 hours on days 1-3 in weeks 1, 4, 7, 10, 13, and 16 and doxorubicin hydrochloride IV over 24 hours on days 1 and 2 in weeks 1, 4, 13, 16, and 19. Beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy.

\*NOTE: \*Patients who receive brachytherapy will initiate radiotherapy in Week 1. If brachytherapy is administered, chemotherapy should begin within 2 weeks of completion of brachytherapy and the Weeks 1 and 19 doxorubicin should be given instead at Weeks 7 and 10.

REGIMEN D (neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without radiotherapy): Neoadjuvant chemoradiotherapy and surgery: Patients receive ifosfamide IV over 3 hours on days 1-3 in weeks 1, 4, 7, and 10 and doxorubicin hydrochloride IV over 24 hours on days 1 and 2 in weeks 1 and 4. Beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy\*\*. Patients undergo surgical resection in week 13.

NOTE: \*\*Patients with primary hepatic tumors do not receive radiotherapy in week 4.

Adjuvant chemotherapy with or without radiotherapy: Patients receive ifosfamide IV over 3 hours on days 1-3 in weeks 16 and 19 and doxorubicin hydrochloride IV over 24 hours on days 1 and 2 in weeks 16, 19\*\*\*, and 22. Beginning in week 16, patients achieving gross total resection with positive microscopic margins undergo a total of 6 fractions of adjuvant radiotherapy. Patients achieving less than total gross resection undergo a total of 11 fractions of adjuvant radiotherapy. Patients achieving total gross resection with negative microscopic margins do not receive adjuvant radiotherapy.

NOTE: \*\*\*Patients who receive adjuvant radiotherapy in week 16 receive doxorubicin hydrochloride in week 25 instead of week 19.

GROUP 3 (high risk \[metastatic, resected, incompletely resected, or unresected disease\]): Patients with low-grade, all-sites resected tumor with either negative or positive microscopic margins are assigned to receive treatment as in group 1 regimen A. Patients with high-grade, grossly resected primary tumor, and metastatic disease are assigned to receive treatment as in group 2 regimen C. Patients with unresected, high-grade metastatic tumor are assigned to receive treatment as in group 2 regimen D.

In all groups, treatment continues in the absence of disease progression. After completing study treatment, patients are followed periodically for at least 5 years.

Arms: arm 1: Patients with low-grade tumor with either negative or positive microscopic margins or high-grade tumor ≤ 5 cm (in maximum diameter) with negative microscopic margins are assigned to arm A: (observation only). arm 2: Patients with high-grade tumor ≤ 5 cm (in maximum diameter) with positive microscopic margins are assigned to arm B: (adjuvant radiotherapy). Beginning between 6-42 days after surgical resection, patients undergo a total of 31 fractions of adjuvant radiotherapy. arm 3: High risk \[metastatic, resected, incompletely resected, or unresected disease\] patients with high-grade, grossly resected primary tumor, with metastases are assigned to receive arm C: (adjuvant chemoradiotherapy). Patients receive ifosfamide IV; doxorubicin hydrochloride IV; beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. arm 4: High risk \[metastatic, resected, incompletely resected, or unresected disease\] patients with unresected, high-grade metastatic tumor are assigned to receive treatment as in arm D: (neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without radiotherapy): Patients receive ifosfamide IV; doxorubicin hydrochloride IV. Beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. Patients undergo surgical resection in week 13.
Interventions: intervention 1: doxorubicin hydrochloride intervention 2: clinical observation intervention 3: therapeutic conventional surgery intervention 4: 3-dimensional conformal radiation therapy intervention 5: ifosfamide
Intervention descriptions: intervention 1: Given IV intervention 2: Patients undergo observation intervention 3: Patients undergo surgery intervention 4: Patients undergo radiotherapy intervention 5: Given IV

Protocol documents: