1. Clinical Case Nº3 Dr. Markus Schuler

2. Case description 58-year-old man History of severe cardiac problems Large tumour in the left thigh Tests results: Crossectional imaging: 30 x 14 x 11 cm lobulated tumour Crossectional imaging: 30 x 14 x 11 cm lobulated tumour Scan: No metastases detected Scan: No metastases detected Incision biopsy: High-grade sarcoma without distinct classification Incision biopsy: High-grade sarcoma without distinct classification Schuler MK et al. Case Rep Oncol Med. 2013:320797. doi: 10.1155/2013/320797

3. What therapeutic approach would you choose? a.Surgical removal of the tumour b.Neoadjuvant chemotherapy c.Preoperative radiation d.Best supportive care

4. Neoadjuvant chemotherapy in STS Clinical data high-risk STS patients Survival benefits in patients who receive neoadjuvant chemotherapy combined with radiotherapy: 1 OS rate at 10 years 56% vs. 38% (p=0.003) Survival benefits in patients who receive neoadjuvant chemotherapy combined with radiotherapy: 1 OS rate at 10 years 56% vs. 38% (p=0.003) Conflicting results from chemotherapy in the neoadjuvant setting 2-6 ESMO guidelines: Not standard treatment in STS 7 “adjuvant chemotherapy can be proposed as an option to the high-risk individual patient (high-grade, deep, >5 cm tumor) for shared decision-making with the patient” “if the decision is made to use chemotherapy as upfront treatment, it may well be used preoperatively, at least in part. A local benefit may be gained, facilitating surgery” 1. Mullen JT, et al. Cancer. 2012; 118(15):3758-65; 2. Pervaiz N, et al. Cancer. 2008;113:573–81; 3. Frustaci S, et al. J Clin Oncol. 2001;19:1238- 47; 4. J Woll, P et al. Lancet. 2012;13(10):1045–54; 5. Italiano A, et al. Ann Oncol. 2010;21:2436–41; 6. Tierney, JF et al. Lancet 1997; 350:1647–54; 7. The ESMO / European Sarcoma Network Working Group. Ann Oncol. 2014;25 Suppl 3:iii102-iii112.

5. What treatment would you use? a.Anthracycline +/- ifosfamide b.Trabectedin c.Gemcitabine + docetaxel d.Pazopanib e.HD Ifosfamide

6. Why not anthracycline-based chemotherapy? Contraindicated in patients with impaired cardiac function. Quite toxic regimens, not applicable to a proportion of elderly and frail people. Schuler MK et al. Case Rep Oncol Med. 2013:320797. doi: 10.1155/2013/320797

7. Why trabectedin? Trabectedin is indicated for the treatment of patients with advanced STS: –after failure of anthracyclines and ifosfamide –or who are unsuited to receive these agents Trabectedin is a suitable treatment even in elderly and fragile patients: –Similar antitumour efficacy and safety profile were shown in patients younger and older than 60 years 1 In contrast with anthracyclines, no cumulative cardiotoxicity was noted with trabectedin despite many patients remaining on active therapy for more than 1 year 2 Previous encouraging data with trabectedin in the neoadjuvant setting 3 1. Le Cesne A, et a. Br J Cancer (2013); 109: 1717-1724 ;2. Demetri GD, et al. J Clin Oncol. 2009; 27(25):4188-96.; 3. Gronchi A, et al. Ann Oncol. 2012;23:771–6

8. Treatment and outcomes When using RECIST criteria for tumour evaluation, stable disease was observed: Schuler MK et al. Case Rep Oncol Med. 2013:320797. doi: 10.1155/2013/320797

9. How would you interpret these results? a.As positive treatment continuation b.As negative treatment interruption c.Difficult to interpret further tests required

10. Treatment and outcomes Trabectedin 1.5 mg/m 2 body surface area, as an intravenous infusion over 24h. After 2 cycles, 18F-FDG-PET showed no significant tumour decrease: Schuler MK et al. Case Rep Oncol Med. 2013:320797. doi: 10.1155/2013/320797 However, a large proportion of the central tumour area showed no metabolic activity.

11. Treatment and outcomes After three cycles of trabectedin, the patient requested surgery. An analysis of tumor volumetric revealed a 35 % decrease (from 956 cm 3 to 621 cm 3 ) of the tumor mass. Limb preserving operation with R0 resection was achieved. The only vital tumor area was in the dorso-cranial area with viability of 15%, while all other parts showed a complete necrosis: Schuler MK et al. Case Rep Oncol Med. 2013:320797. doi: 10.1155/2013/320797 Postoperative classification: pleomorphic sarcoma Postoperative classification: pleomorphic sarcoma

12. What therapeutic approach would you choose now? a.Post-operative radiation b.Additional cycles of trabectedin c.Additional cycles of trabectedin followed by radiation d.Follow-up only

13. Conclusions Trabectedin is a valuable first treatment option for patients unsuited to receive doxorubicin-based chemotherapy. The RECIST criteria as the only efficacy measure of trabectedin treatment can lead to underestimate the benefit of this drug on tumor devitalisation. The results previously reported in the neoadjuvant treatment of myxoid liposarcoma patients were reproduced in this clinical case of a high grade pleomorphic sarcoma.

14. YON0914-731