UN-RESARC: Hypofractionated Radiotherapy With Sequential Chemotherapy in Marginally Resectable Soft Tissue Sarcomas of Extremities or Trunk Wall
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Sequential chemoradiotherapy 1xAI (doxorubicin 75 mg/sqm and ifosfamide 10 g/sqm) + 5x5 Gy radiotherapy + 2xAI + surgery |
Drug: Sequential chemotherapy - 3 courses of AI
Three courses of doxorubicin and ifosfamide (AI, doxorubicin 75 mg/sqm and ifosfamide 10 g/sqm with prophylactic mesna), one before radiotherapy and two within the gap between radiotherapy and surgery.
Radiation: Hypofractionated radiotherapy
Preoperative hypofractionated 5x5 Gy radiotherapy (5 consecutive days) prescribed on planned target volume (tumor volume + elective margins + setup/error margin) with a daily image guidance with cone beam-CT-based position verification.
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Outcome Measures
Primary Outcome Measures
- The ratio of en limb-sparing/conservative R0 resections. [24 months]
Secondary Outcome Measures
- Radiological response in diffusion-weighted MRI [24 months]
Radiological assessment of tumor change, especially diffusion parameters in DWI-MRI 6 weeks after the end of irradiation, according to the EORTC criteria.
- Pathological response in resected tumors according to EORTC Soft Tissue and Bone Sarcoma Group criteria [24 months]
- Toxicity of planned schedule of therapy according to CTCAE v.4.0. [24 months after treatment completion]
The study will be stopped prematurely if the rate of non-hematological toxicity grade 3 >30%
- 2-years overall survival [24 months after treatment completion]
- 2-years local control rate [24 months after treatment completion]
Other Outcome Measures
- Assessment of biomarkers in biopsy and post-operative material [24 months]
HIF-1 (hypoxia-inducible factor 1) - marker of hypoxia, predicting tumor response on radiotherapy; CD105/CD31/VEGF-A - tumor microvessel density; CD14, CD163, CD68KP i CD68 PG-M1 - tumor associated macrophages.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Able to provide informed consent
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Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2
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Age ≥18 years old
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Histologic diagnosis of soft tissue sarcoma
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Primary or recurrent tumor localized on extremities or trunk
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Grade 2 or grade 3 tumor
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Marginally resectable tumor as assessed by a multidisciplinary team
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Adequate renal function (serum creatinine ≤ 1.5 ULN)
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Adequate liver function (total bilirubin, AST, ALT 3x < ULN)
Exclusion Criteria:
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Radiation-induced sarcoma
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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.
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History of radiation to the affected volume
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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
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Contraindications to radiotherapy, chemotherapy or surgery
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Metastatic disease except primary resectable isolated lung metastases
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Maria Sklodowska-Curie Institute - Oncology Center | Warsaw | Mazovian | Poland | 02-781 |
Sponsors and Collaborators
- Maria Sklodowska-Curie National Research Institute of Oncology
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
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- Koseła-Paterczyk H, Szacht M, Morysiński T, Ługowska I, Dziewirski W, Falkowski S, Zdzienicki M, Pieńkowski A, Szamotulska K, Switaj T, Rutkowski P. Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas. Eur J Surg Oncol. 2014 Dec;40(12):1641-7. doi: 10.1016/j.ejso.2014.05.016. Epub 2014 Sep 20.
- Lee HJ, Yoon C, Park DJ, Kim YJ, Schmidt B, Lee YJ, Tap WD, Eisinger-Mathason TS, Choy E, Kirsch DG, Simon MC, Yoon SS. Inhibition of vascular endothelial growth factor A and hypoxia-inducible factor 1α maximizes the effects of radiation in sarcoma mouse models through destruction of tumor vasculature. Int J Radiat Oncol Biol Phys. 2015 Mar 1;91(3):621-30. doi: 10.1016/j.ijrobp.2014.10.047. Epub 2014 Dec 24.
- Messiou C, Bonvalot S, Gronchi A, Vanel D, Meyer M, Robinson P, Morosi C, Bloem JL, Terrier PH, Lazar A, Le Péchoux C, Wardelman E, Winfield JM, Boulet B, Bovée J, Haas RL. Evaluation of response after pre-operative radiotherapy in soft tissue sarcomas; the European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) and Imaging Group recommendations for radiological examination and reporting with an emphasis on magnetic resonance imaging. Eur J Cancer. 2016 Mar;56:37-44. doi: 10.1016/j.ejca.2015.12.008. Epub 2016 Jan 20.
- Wardelmann E, Haas RL, Bovée JV, Terrier P, Lazar A, Messiou C, LePechoux C, Hartmann W, Collin F, Fisher C, Mechtersheimer G, DeiTos AP, Stacchiotti S, Jones RL, Gronchi A, Bonvalot S. Evaluation of response after neoadjuvant treatment in soft tissue sarcomas; the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) recommendations for pathological examination and reporting. Eur J Cancer. 2016 Jan;53:84-95. doi: 10.1016/j.ejca.2015.09.021. Epub 2015 Dec 14.
- Yehia L, Boulos F, Jabbour M, Mahfoud Z, Fakhruddin N, El-Sabban M. Expression of HIF-1α and Markers of Angiogenesis Are Not Significantly Different in Triple Negative Breast Cancer Compared to Other Breast Cancer Molecular Subtypes: Implications for Future Therapy. PLoS One. 2015 Jun 5;10(6):e0129356. doi: 10.1371/journal.pone.0129356. eCollection 2015.
- Zhang M, Qiu Q, Li Z, Sachdeva M, Min H, Cardona DM, DeLaney TF, Han T, Ma Y, Luo L, Ilkayeva OR, Lui K, Nichols AG, Newgard CB, Kastan MB, Rathmell JC, Dewhirst MW, Kirsch DG. HIF-1 Alpha Regulates the Response of Primary Sarcomas to Radiation Therapy through a Cell Autonomous Mechanism. Radiat Res. 2015 Jun;183(6):594-609. Epub 2015 May 14.
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