Neoadjuvant and Adjuvant Chemotherapy in High-risk Soft Tissue Sarcoma (NeoWTS)

A Phase II Study Evaluating Neo-/Adjuvant EIA Chemotherapy, Surgical Resection and Radiotherapy in High-risk Soft Tissue Sarcoma

Neo- and adjuvant chemotherapy is used in high-risk soft tissue sarcoma to improve systemic control. Patients in this trial are treated with 4 cycles of chemotherapy (EIA, etoposide, ifosfamide, adriamycin) preoperatively, followed by local surgery and radiotherapy. An additional 4 cycles of adjuvant chemotherapy is administered. Treatment response is assessed by MRI and CT scans and FDG-PET in a subgroup of patients.

The role of chemotherapy in high-risk soft tissue sarcoma is controversial. Though many patients undergo initial curative resection, distant metastasis is a frequent event resulting in 5-year overall survival rates of only 50 - 60%. Neo-adjuvant and adjuvant chemotherapy has been applied to achieve pre-operative cytoreduction, assess chemosensitivity and to eliminate occult metastasis. The current protocol comprises for cycles of neoadjuvant chemotherapy ((EIA, etoposide 125 mg/m2 iv days 1 and 4, ifosfamide 1500 mg/m2 iv days 1 - 4, doxorubicin 50 mg/m2 day 1, pegfilgrastim 6 mg sc day 5), local surgery and radiotherapy as well as further 4 cycles of adjuvant EIA. Treatment response is assessed by MRI and CT scans and FDG-PET in a subgroup of patients.

All patients receive 4 cycles of EIA chemotherapy pre- and postoperatively. There is no further observation arm. The study is non-randomized.

ifosfamide 1500 mg/m² iv days 1 - 4, etoposide 125 mg/m² iv days 1 and 4, and adriamycin 50 mg/m² iv day 1

Disease-free survival will be calculated from the time of definite surgery to radiologically proven local or distant failure or patient´s death due to sarcoma related cause.

Overall survival will be calculated as the time interval from the date of therapy induction to patient's death or last follow up.

Grade of histological necrosis in tumor specimen will be assessed after surgery and graded according to Salzer-Kuntschik.

Hematological toxicity will be assessed by complete blood counts. Toxicity will be graded according to CTCAE.

Renal toxicity will be assessed by changes from baseline creatinin levels. Toxicity will be graded according to CTCAE.

Liver toxicity will be assessed by changes from baseline liver function tests, e.g. ASAT/ALAT. Toxicity will be graded according to CTCAE.

Decline in PET SUV will be correlated with grade of histological necrosis in tumor specimen after surgery.

Changes in cardiac ejection fraction will be assessed by echocardiograms. Toxicities will be graded according to CTCAE.

Tumor response to therapy will be assessed by MRI and CT scans. Response will graded according to RECIST criteria.

Inclusion Criteria: Soft tissue sarcoma histology Tumor size >= 5 cm Deep/extracompartimental localization Grade 2/3 (FNCLCC) Patients with inadequate previous therapy Age 18-65 years normal bone marrow function normal liver function normal renal function Karnofsky index >=80% Exclusion Criteria: Chordoma Chondrosarcoma Kaposi´ sarcoma Neuroblastoma Mesothelioma Osteosarcoma/Ewings´sarcoma

Roeder F, Lehner B, Schmitt T, Kasper B, Egerer G, Sedlaczek O, Grullich C, Mechtersheimer G, Wuchter P, Hensley FW, Huber PE, Debus J, Bischof M. Excellent local control with IOERT and postoperative EBRT in high grade extremity sarcoma: results from a subgroup analysis of a prospective trial. BMC Cancer. 2014 May 20;14:350. doi: 10.1186/1471-2407-14-350.

Schmitt T, Lehner B, Kasper B, Bischof M, Roeder F, Dietrich S, Dimitrakopoulou-Strauss A, Strauss LG, Mechtersheimer G, Wuchter P, Ho AD, Egerer G. A phase II study evaluating neo-/adjuvant EIA chemotherapy, surgical resection and radiotherapy in high-risk soft tissue sarcoma. BMC Cancer. 2011 Dec 7;11:510. doi: 10.1186/1471-2407-11-510.