1. Causes of death other than disease in patients treated on Cooperative Osteosarcoma Study Group protocols for high-grade osteosarcoma: An investigation on 2464 patients Leo Kager 1,2, Reinhard Windhager 3, Thomas Kühne 4, Peter Reichardt 5, Stefan Bielack 6 for the COSS Study Group

2. years 302520151050 survival 1,0 0,8 0,6 0,4 0,2 0,0 68.0% 62.8% 60.1% 56.1% 41 12205411964 2464 COSS: Overall survival in 2464 patients with high-grade osteosarcoma: 1980 – 2005 810 pts died (median 2.2 y from Dx) 705 pts (87%) died from OS 22 pts (2.7%) died unknown cause 83 pts (10.3%) died cause other than disease

3. COSS Database N = 83/2464 pts (3.4%) Treatment periods Early Cohort 1 st Jan 1980 - 31 st Dec 1992 N = 52/1083 (4.8%) Late Cohort Jan 1 st 1993 – Dec 31 st 2005 N = 31/1381 (2.2%)

4. Primary disease (2.51%) N=62 (2.51%) Early/late = 40/22 (3.69% vs 1.59%) Relapsed disease N=21 (0.85%) Early/late = 12/9 (1.11% vs 0.65%) Died during therapy of primary disease (1.58%) N=39 (1.58%) Early/late = 24/15 (2.21% vs 1.09%) Died in CR1 after completion of therapy N=23 (0.93%) Early/late = 16/7 (1.48% vs 0.50%) Died during relapse therapy N=15 (0.61%) Early/late = 7/8 (0.65% vs 0.58%) Died in CR after completion of relapse therapy N=6 (0.24%) Early/late = 5/1 (0.46% vs 0.07%) Neoadjuvant CHT N=7 ( 0.28%) Early/late = 6/1 (0.55% vs 0.07%) Surg./Anesth. related N=6 (0.24%) Early/late = 2/4 (0.18% vs 0.30%) (1.06%) Adjuvant therapy N=26 (1.06%) Early/late = 16/10 (1.48% vs 0.72%) Secondary malignancies N=12 ( 0.49%) Early/late = 6/6 (0.55% vs 0.43%) Cardiomyopathy N=7 (0.28%) Early/late = 7/0 (0.64% vs 0%) Other N=4 (0.16%) Early/late = 3/1 (0.28% vs 0.07%)

5. Myelotoxic infections: N=19 (0.77%); Early/late = 13/6 (1.20% vs 0.43%) MTX-induced multi-organ failure: N=4 (0.16%); Early/late = 2/2 Others: N=3 (0.12%); Each one: Cardiomyopathy (early), pulmonary thromboembolism (late), suicide (late) Death during adjuvant therapy of primary disease N = 26 (1.06%); Early/late = 16/10 (1.48% vs 0.72%)

6. Sex/Age (Years) Treatment/ Priode Cause of death/ Time from diagnosis to death (weeks) Last medication before death M/11.9 COSS-80 (MAP+β- IFN)/early Cardiomyopathy/18.1HD-MTX + β-IFN M/12.9 COSS-86 (API)/early Cardiomyopathy/6.8IP F/25.5 COSS-86 (API)/early Myelotoxic gastrointestinal hemorrhage/4.4IP M/22.5 COSS-86 (A)/early Myelotoxic cerebral hemorrhage/6.1A M/12.8 COSS-91 (MAPI)/early Myelotoxic infection (PA)/9.8HD-MTX M/14.6 COSS-91 (MAPI)/early Myelotoxic infection/5.4HD-MTX F/14.2 COSS-96 (MAPI)/late Pulmonary thromboembolism/6.4IP Death during neoadjuvant therapy of primary disease N = 7 (0.28%), Early/late = 6/1 (0.55% vs 0.07%)

7. Death during/after surgery of primary disease N = 6 (0.24%), Early/late = 2/4 (0.18% vs 0.30%) Sex/Age (Years) Primary tumor site/Metastases Treatment/ Periode Cause of death/time from diagnosis to death (years) Surgery details M/15.2Femur/LungCOSS-96/lateARDS/2.5 Multiple lung surgeries, CR after last surgery (resection of lower lob) M/18.7Rib/LungCOSS-96/lateARDS/0.7 1 st surgery: Resection parts of the left thorax wall + left lower lobe + parts of left upper lobe; 2 nd surgery: resection of right lower lobe (46 metastases) F/8.4Femur/noCOSS-86/early Anesthesia related cardiopulmonary arrest/0.4 Rotationplasty M/18.2 Scapula (contiguous infiltration of thorax wall, lung and spine)/no COSS- 91modified/late Cardiopulmonary arrest during extensive surgery/0.4 Interthoraco-scapular amputation + resection of rib 1-4 + adjacent lung tissue + parts of vertebrae C7-Th4 F/46.5pelvis † /noCOSS-90*/late Septic multiorgan failure after hemipelvectomy (Candida)/1.8 Resection + hip prosthesis implantation, wound revisions (infections), hemi-pelvectomy M/58.2pelvis † /noCOSS-86**/early Kachexia and multiorgan failure after hemipelvectomy/necrosectomy (MRSA)/4.1 Resection, Re-resection, inner hemi- pelvectomy, necrosectomy

8. Causes of death in CR1 N=23 (0.93%) Early/late = 16/7; (1.48% vs 0.50%) Secondary malignancies N=12 ( 0.28%), Early/late = 6/6 (0.55% vs 0.43%) N=8 Hematological (AML, N=6; MDS/RAEB-t, N=1; c-ALL, N=1) N=4 Solid tumors (breast cancer, N=1; malignant fribrous histiozytoma N=1; hepatocellular carcinoma, N=1; malignant melanoma, N=1) In 3 patients OS was alread secondary cancer Cardiomyopathy N=7 (0.28%), Early/late = 7/0 (0.64% vs 0%) All diagnosed before 1990 Other N=4 (0.16%), Early/late = 3/1 (0.28% vs 0.72%) accident (N=2), HIV (N=1), cerebral hemorrhage (N=1)

9. Causes of death OTD in relapsed OS N=21 (0.85%), Early/late = 12/9; (1.11% vs 0.65%) Myelotoxicity N=8 (0.33%), Early/late = 2/6 (0.18% vs 0.43%) N=6, infections (0.24%); N=1, hemorrhage; N=1, multi-organ failure Last drugs administered before death: CE (N=3); AP, IE, IP, Bu/Mel and unknown (N=1) Surgery related N=7 (0.28%), Early/late = 5/2 (0.46% vs 0,14%) Died in CR after relapse therapy N=6 (0.24%), Early/late = 5/1 (0.46% vs 0.07%) Cardiomyopathy (N=2, early); secondary malignancy (AML; N=2; early/late); (N=1), anorexia nervosa (N=1, early), hepatic cirrhosis (N=1, early)

10. SUMMARY During 25y neoadjuvant COSS treatment trials (N=2464 pts) 3.4% of patients (N=83) died from causes other than disease (10% of all fatalities). Half of these deaths occured during therapy of the primary disease, ~25% in CR1, and ~25% after relapse Most common causes of death were myelotoxicity infections (N=27; 1.1%), adjuvant phase between weeks 20 and 40. Significant decrease in deaths in the later cohort (4.8% vs 2.2%). 12 pts (0.49%) died from cardiac failure, all in the early cohort (short-time Doxo infusions)

11. DANKE – THANK YOU! COSS Centre, Stuttgart S Bielack B Kempf-Bielack M Kevric B Sorg Münster H Jürgens W Winkelmann Berlin P Reichardt PU Tunn Hamburg K Winkler Frankfurt T Klingebiel Schweiz T Kühne GU Exner G Jundt Österreich S Lang R Windhager A Zoubek