Jens Jakob 1 ; Anna Simeonova 2 ; Bernd Kasper 3 ; Ulrich Ronellenfitsch 1 ; Frederik Wenz 2 ; Peter Hohenberger 1 1 Department of Surgery, 2 Department of Radiation Oncology, 3 Interdisciplinary Tumor Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany 1 Experience with combined radiation therapy and sunitinib for preoperative treatment of soft tissue sarcoma

no conflict of interest

Treatment strategy in locally advanced, non metastatic STS Standard therapy is surgery and irradiation Irradiation is most frequently applied preoperatively Systemic chemotherapy or ILP are administered in selected cases Aim of RT: improvement of margins by devitalizing tumor Up to 15% local recurrences Need to improve efficacy

Radiation therapy combined with anti-angiogenic treatment - rationale  Addition of a tumoractive drug  Transient ‘‘normalization’’ of abnormal tumor vasculature may lead to improved oxygen delivery and irradiation efficacy (Jain 2005)  Experimental data demonstrate additive, possibly synergistic effects (Nieder 2006)  Optimal therapy sequence unclear Radiation therapy

Sunitinib  Oral multi receptor tyrosine kinase inhibitor with anti- angiogenic properties  Approved by the FDA and EMA (e.g. advanced renal cell carcinoma, imatinib-resistant GIST)  Single agent sunitinib demonstrated evidence of metabolic response in patients with non-GIST sarcoma (George 2009)  Sunitinib improved the efficacy of irradiation in a STS mouse model (Yoon 2009)

Preoperative radiation therapy combined with sunitinib Primary end point: toxicity of combined treatment Secondary end points: postoperative morbidity, treatment response Recruitment Phase I completed, data not available yet (GISG 03, NCT ) 16 patients treated off label but according to protocol Tumor resection after 5-8 weeks Radiotherapy 50,4 Gy Sunitinib p.o., max. 37.5mg Locally advanced non metastatic STS

Patients total number16 age (median, range)55 (18-79) years tumor site retroperitoneum lower extremity trunk/groin tumor size (median, range)15.5 (6-33) cm tumor grade (FNLCC) low grade high grade 1 15 histological subtype DDLS myxoid liposarcoma NOS other

Toxicity of combined therapy according to CTCAE 4.0 grade 0Grade1Grade 2Grade 3Grade 4 Hematologic1/ Skin4/ Gastrointestinal7/ Arterial hypertension12/ Hand-foot syndrome12/ Other8/164400

Dose adjustments week off 37.5mg sunitinib on 37.5mg sunitinib Reason for dose adjustments Hematologic toxicity Hand-foot syndrome Gastrointestinal toxicity

Postoperative morbidity, 14/16 patients Tumor localization Complications ≥ grade 3 Lower extremity/ trunk 2/5 seroma lymphatic fistula Retroperitoneal2/9 anastomotic leak septic bleeding 2/16 patients did not undergo surgery because of tumor progression or irresectability

Treatment response Response RECIST Pathologic response (% necrosis) PR100 PR100 PR>90 SD>90 SD51-90 SD51-90 SD51-90 SD<50 SD<50 SD<50 SDnot stated SDnot stated SDnot stated SDno resection PD100 PDno resection

Oncological Outcome median follow-up 38 (6-59) months 2/16 progressive disease (no tumor resection) 2/14 local recurrence (after tumor resection) 6/16 metastatic disease 1/16 died of disease

Summary Acceptable treatment toxicity of combined radiation therapy and sunitinib 50% of the patients require dose adjustments of sunitinib All patients received planned irradiation dose Protocol even feasible in retroperitoneal STS Postoperative morbidity not increased

Conclusion Combining irradiation and anti-angiogenic substances feasible Optimal treatment regimen still in the project phase Timing, cumulative dose and selection of anti-angiogenic drug Irradiation dose Phase II/III clearly justified