causes of death other than disease in patients treated on cooperative osteosarcoma study group...

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%)

0

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2

3

4

5

6

7

8

9

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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