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 Kager1,2, Reinhard Windhager3, Thomas Kühne4, Peter

Reichardt5, Stefan Bielack6 for the COSS Study Group

years

302520151050

survival

1,0

0,8

0,6

0,4

0,2

0,0

68.0%62.8%

60.1%56.1%

411220 541 196 42464

COSS: Overall survival in 2464 patients with high-grade osteosarcoma: 1980 –

2005810 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

COSS Database

N = 83/2464 pts (3.4%)

Treatment periods

Early Cohort

1st Jan 1980 - 31st Dec 1992

N = 52/1083 (4.8%)

Late Cohort

Jan 1st 1993 – Dec 31st 2005

N = 31/1381 (2.2%)

Primary disease N=62 (2.51%)(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

N=39 (1.58%)(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%)

Adjuvant therapy N=26 (1.06%)(1.06%)Early/late = 16/10(1.48% vs 0.72%)

Secondary malignanciesN=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%)

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 diseaseN = 26 (1.06%); Early/late = 16/10 (1.48% vs 0.72%)

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<10 11 to 20 21 to 30 31 to 40 41 to 50 51 to 100 >100

Weeks from Dx

Sex/Age (Years)

Treatment/Priode

Cause of death/Time from diagnosis to death (weeks)

Last medication before death

M/11.9COSS-80 (MAP+β-IFN)/early

Cardiomyopathy/18.1 HD-MTX + β-IFN

M/12.9COSS-86

(API)/earlyCardiomyopathy/6.8 IP

F/25.5COSS-86

(API)/earlyMyelotoxic gastrointestinal hemorrhage/4.4 IP

M/22.5COSS-86 (A)/early

Myelotoxic cerebral hemorrhage/6.1 A

M/12.8COSS-91

(MAPI)/earlyMyelotoxic infection (PA)/9.8 HD-MTX

M/14.6COSS-91

(MAPI)/earlyMyelotoxic infection/5.4 HD-MTX

F/14.2COSS-96

(MAPI)/latePulmonary thromboembolism/6.4 IP

Death during neoadjuvant therapy of primary disease

N = 7 (0.28%), Early/late = 6/1 (0.55% vs 0.07%)

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/15.2 Femur/Lung COSS-96/late ARDS/2.5Multiple lung surgeries, CR after

last surgery (resection of lower lob)

M/18.7 Rib/Lung COSS-96/late ARDS/0.7

1st surgery: Resection parts of the left thorax wall + left lower lobe + parts of left upper lobe; 2nd surgery:

resection of right lower lobe (46 metastases)

F/8.4 Femur/no COSS-86/earlyAnesthesia related

cardiopulmonary arrest/0.4Rotationplasty

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/46.5 pelvis†/no COSS-90*/lateSeptic multiorgan failure after hemipelvectomy (Candida)/1.8

Resection + hip prosthesis implantation, wound revisions (infections), hemi-pelvectomy

M/58.2 pelvis†/no COSS-86**/early

Kachexia and multiorgan failure after

hemipelvectomy/necrosectomy (MRSA)/4.1

Resection, Re-resection, inner hemi-pelvectomy, necrosectomy

Causes of death in CR1 N=23 (0.93%)Early/late = 16/7; (1.48% vs 0.50%)

Secondary malignanciesN=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)

Causes of death OTD in relapsed OS N=21 (0.85%), Early/late = 12/9; (1.11% vs 0.65%)

MyelotoxicityN=8 (0.33%), Early/late = 2/6 (0.18% vs 0.43%)

N=6, infections (0.24%); N=1, hemorrhage; N=1, multi-organ failureLast 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)

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)

DANKE – THANK YOU!

COSS Centre, StuttgartS BielackB Kempf-BielackM KevricB Sorg

MünsterH JürgensW Winkelmann

BerlinP ReichardtPU Tunn

HamburgK Winkler

FrankfurtT Klingebiel

SchweizT KühneGU ExnerG Jundt

ÖsterreichS LangR WindhagerA Zoubek