Clinical trial NCT03651375: Hypofractionated Radiotherapy With Sequential Chemotherapy in Marginally Resectable Soft Tissue Sarcomas of Extremities or Trunk Wall
Official title: Hypofractionated 5x5 Gy Radiotherapy With Sequential Doxorubicin and Ifosfamide-based Chemotherapy in Marginally Resectable Soft Tissue Sarcomas of Extremities or Trunk Wall
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Sarcoma
Fibrosarcoma
Leiomyosarcoma
Liposarcoma
Myosarcoma
Histiocytic Sarcoma
Synovial Sarcoma
Lymphangiosarcoma
Malignant Peripheral Nerve Sheath Tumors
Myxofibrosarcoma
Myxoid Liposarcoma
Undifferentiated Sarcoma
Pleomorphic Liposarcoma
Undifferentiated Pleomorphic Sarcoma
Dedifferentiated Liposarcoma
Pleomorphic Rhabdomyosarcoma
Malignant Triton Tumor
Keywords: Dose Hypofractionation
Neoadjuvant Therapy
Chemoradiotherapy
Sarcoma
Dose Fractionation
Dose-Response Relationship
Antineoplastic Agents
Drug Therapy
Antineoplastic Combined Chemotherapy Protocols
Lead sponsor: Maria Sklodowska-Curie National Research Institute of Oncology
Sponsor class: OTHER
First posted: 2018-08-29
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: After a screening, which consists of biopsy, physical examination, initial diffusion-weighted magnetic resonance imaging (DWI-MRI), body computed tomography (CT) scan, blood tests and case analysis on Multidisciplinary Team (MDT) meeting, a patient will receive the first course of chemotherapy - doxorubicin 75 mg/sqm and ifosfamide 10 g/sqm (AI regimen) with prophylactic mesna. Then a patient will be irradiated 5x5 Gy and after radiotherapy he or she will receive two courses of AI within 4-6 weeks, depending on the tolerance. Then the response analysis in DWI-MRI and toxicity assessment and will be performed. On the second MDT meeting, a final decision about resectability of the tumor will be made. In case of resectability, a patient will be referred to surgery.

Detailed description: There is lack of standard treatment of marginally resectable sarcomas. Results of commonly used approaches are unsatisfactory. The addition of neoadjuvant/induction chemotherapy before the irradiation and in the prolonged gap between the end of hypofractionated 5x5 Gy radiotherapy and surgery may allow to obtain the R0 resection rate, high pathological response rate and/or a higher rate of limb-sparing/conservative surgery as well as to increase patients' survival.

Hypofractionation represents a variation of radiotherapy fractionation in which the total dose is divided into fewer fractions with an increased fraction dose. Such treatment may lead to additional biological effects when compared to conventionally fractionated radiotherapy (eg. vascular damage, increased immunogenicity, and antigenicity). The main advantages of hypofractionation are those related to the decreased overall treatment time what is more convenient for both patients and physicians, increased compliance and makes the treatment more cost-effective. Intriguing, such an approach may provide an additional benefit when treating non-radiosensitive tumors with a low alpha/beta ratio (eg. sarcomas).

The basis of the study was a trial conducted by Kosela et al. in our center, which showed that preoperative short 5x5 Gy radiotherapy with immediate surgery is an effective and well-tolerated treatment of resectable sarcomas of extremities or trunk wall.

The rationale of chemotherapy comes from the interim analysis of a multicenter, international EORTC study comparing neoadjuvant systemic approaches in high-risk sarcomas. It was proven that AI regimen, which consists of ifosfamide and anthracyclines allowed to obtain 20% benefit in relapse-free survival and overall survival as compared to pathologically-tailored chemotherapy.

Eligibility criteria: Inclusion Criteria:

* Able to provide informed consent
* Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2
* Age ≥18 years old
* Histologic diagnosis of soft tissue sarcoma
* Primary or recurrent tumor localized on extremities or trunk
* Grade 2 or grade 3 tumor
* Marginally resectable tumor as assessed by a multidisciplinary team
* Adequate renal function (serum creatinine ≤ 1.5 ULN)
* Adequate liver function (total bilirubin, AST, ALT 3x \< ULN)

Exclusion Criteria:

* Radiation-induced sarcoma
* Second active malignancy, not including localized basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast; patients with a history of other malignancies are eligible if they have been continuously disease-free for \> 10 years prior to the time of registration.
* History of radiation to the affected volume
* Histologic diagnosis of rhabdomyosarcoma (except pleomorphic subtype), angiosarcoma, epithelioid sarcoma, clear cell sarcoma, extraskeletal chondrosarcoma, alveolar soft part sarcoma, osteogenic sarcoma, Ewing's sarcoma/PPNET, aggressive fibromatosis, dermatofibrosarcoma protuberans
* Contraindications to radiotherapy, chemotherapy or surgery
* Metastatic disease except primary resectable isolated lung metastases

Primary outcomes:
measure: The ratio of en limb-sparing/conservative R0 resections.
timeFrame: 24 months
Secondary outcomes:
measure: Radiological response in diffusion-weighted MRI
timeFrame: 24 months
measure: Pathological response in resected tumors according to EORTC Soft Tissue and Bone Sarcoma Group criteria
timeFrame: 24 months
measure: Toxicity of planned schedule of therapy according to CTCAE v.4.0.
timeFrame: 24 months after treatment completion
measure: 2-years overall survival
timeFrame: 24 months after treatment completion
measure: 2-years local control rate
timeFrame: 24 months after treatment completion
Other outcomes:
measure: Assessment of biomarkers in biopsy and post-operative material
timeFrame: 24 months
Locations:
city: Warsaw
country: Poland
facility: Maria Sklodowska-Curie Institute - Oncology Center
state: Mazovian
Study officials:
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