jens jakob 1 ; anna simeonova 2 ; bernd kasper 3 ; ulrich ronellenfitsch 1 ; frederik wenz 2 ; peter...

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