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Jens Jakob1; Anna Simeonova2; Bernd Kasper3; Ulrich Ronellenfitsch1; Frederik Wenz2; Peter Hohenberger1
1Department of Surgery, 2Department of Radiation Oncology, 3Interdisciplinary Tumor Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany
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 0148835)
• 16 patients treated off label but according to protocol
Tumor resection after 5-8 weeksRadiotherapy 50,4 Gy
Sunitinib p.o., max. 37.5mgLocally advancednon metastatic STS
Patients
total number 16
age (median, range) 55 (18-79) years
tumor siteretroperitoneumlower extremitytrunk/groin
1051
tumor size (median, range)
15.5 (6-33) cm
tumor grade (FNLCC)low gradehigh grade
115
histological subtype DDLSmyxoid liposarcomaNOSother
6145
Toxicity of combined therapy according to CTCAE 4.0
grade 0 Grade1 Grade 2 Grade 3 Grade 4
Hematologic 1/16 1 5 8 1
Skin 4/16 9 3 0 0
Gastrointestinal 7/16 4 5 0 0
Arterial hypertension 12/16 0 4 0 0
Hand-foot syndrome 12/16 1 2 1 0
Other 8/16 4 4 0 0
Dose adjustments
week 1 2 3 4 5 6 7 8
off 37.5mg sunitinib
0 1 1 3 8 9 9 9
on 37.5mg sunitinib
16 15 15 13 8 7 7 7
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
Retroperitoneal 2/9• anastomotic leak• septic bleeding
• 2/16 patients did not undergo surgery because of tumor progression or irresectability
Treatment response
Response RECISTPathologic response
(% necrosis)
PR 100
PR 100
PR >90
SD >90
SD 51-90
SD 51-90
SD 51-90
SD <50
SD <50
SD <50
SD not stated
SD not stated
SD not stated
SD no resection
PD 100
PD no 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