BONE SARCOMA€¦ · Journal of the Royal College of Surgeons of Edinburgh 1955 Radiotherapy for inoperable osteosarcoma? Osteosarcoma local therapy T ake home messages operate ,

esmo.org

BONE SARCOMA

Stefan Bielack

Cooperative Osteosarcoma Study Group COSS

Klinikum Stuttgart – Olgahospital

Pädiatrie 5 (Onkologie, Hämatologie, Immunologie)

[email protected]

„If you do not operate, they die.

If you do operate, they die just the same.

Gentlemen, this meeting

should be concluded

with prayers.“

Sir Stanford Cade(1895–1973)

Problem 1: Tumor Growth Problem 2: (Lung) Metastases

Bone Sarcoma: Current Therapeutic Strategies

Ewing Sarcomastandard approach

imaging/biopsy

neoadjuvant chemotherapy

surgery/radiotherapy

adjuvant chemotherapyprim. pulm. mets: plus

(surgery), adjuvant lung RT? HDT?

VCR

IFO/CYC

DOX

ActoDETO

Osteosarcomastandard approach

imaging/biopsy


surgery

adjuvant chemotherapyplus surgery for primary mets

ADR

DDP

MTX

IFO

Osteosarcoma

WHO classification 2013

• Conventional

- chondroblastic

- fibroblastic

- osteoblastic

- various unusual subtypes

• Teleangiectatic

• Small cell

• High grade surface

• Parosteal

• Periosteal

• Low grade central

OsteosarcomaEpidemiology

incidence: 2-3/million/year

age: adolescence

sex: m:f ca. 1.4:1

site: metaphyses of long bonesdistal femur, prox. tibia, prox. humerus, prox. fibula

Osteosarcoma

Incidence peaks in AYA

Studies performed in AYA

Knowledge derived from AYA

Benchmark for outcomes = AYA

Best served population = AYA (?)

Adult vs. pediatric osteosarcoma


Proportion of axial tumors higher


More „secondary“ osteosarcomas

primary

with Paget‘s

all

≥2nd cancer

More axial More secondary

• the same treatment principles should apply

but

• adults don‘t tolerate pediatric protocols

„Adult“ vs. „pediatric“ osteosarcoma

Treatment - Assumptions

„Adult“ vs. „pediatric“ osteosarcomaAdults don‘t necessarily experience more toxicity!

• Grade 3 or 4 thrombopenia children > adolescents/adults

• Grade 3 or 4 neutropenia children > adolescents/adults

• Grade 3 or 4 mucositis no age related difference

• Death due to toxicity children > adolescents/adults

=> „true“ or- less intensive treatment?- reporting bias?

4.403 patients≤ 50 years

„Young“ adults 18-40Treatment usually feasible (MTX?)

„Older“ adults > 41-65(Modified) chemo feasible, but rather toxic (EURO-B.O.S.S.)

„Very old“ adults 65+Little data - chemo probably even more toxic

- probably often not feasible


Osteosarcoma: Overall Survival

years

302520151050

surv

ival

1,0

0,8

0,6

0,4

0,2

0,0

localized extremity

axial or / and primary metastatic

localized limb (n=2,017)

axial or metastatic (n=444)

Bielack et al., Cancer Treat Res 2009; based on n= 2,464 COSS osteosarcomas


Is imaging sensitive and specific?

Osteosarcoma Metastases

Osteosarcoma: Chest-CT

Lesion-size not sufficient to distinguish mets

Osteosarcoma: Chest-CT

Mets may present atpically

CT finds small lesions,

but is non-specific

Met No mets

Osteosarkom

(Pulmonale) Primärmetastasen

V. a. Knochensarkom Why is reliable detection of primary (lung) mets so important?

Osteosarcoma- primary metssurgery & survival

COSS: Kager et al., J Clin Oncol 2003

Chest-CT• is the best available technique

• is not particularly specific < 0,5-1 cm • others, specifically PET, add little

• chest-MRI remains investigational

„Small“ nodules

Only limited correlation between imaging and „true“ metastases:

any small lesion might be a met or something else

if in doubt, get it out

Osteosarcoma (Lung-)Metastases

OsteosarcomaStandard approach – since early/mid 1980s

imaging/biopsy


surgery

adjuvant chemotherapy

plus surgery for primary mets

HD-MTX

ADR (=DOX)

DDPIFOS???

benefit of additional agents ??????

SURGERY OF THE PRIMARY TUMOR:

WHEN ?

n 5-year EFS p

POG*

delayed 45 61% .8

immediate 55 69%

COSS**

delayed 1,451 54.4% .404

immediate 157 59.9%

*prospective, localized extremity osteosarcoma. Goorin et al., J Clin Oncol 2003

**retrospective, loc. or metastatic, limb or trunk. Bielack et al., J Clin Oncol 2002

=> similar prognosis (with identical chemo)

Timing of surgery & event-free survival

SURGERY OF THE PRIMARY TUMOR:

WHICH TECHNIQUE ?

Surgical margins (Enneking et al., 1981)

radical

wide

marginal

intralesional

Osteosarcoma: Type of surgery(COSS, >2.800 extremity osteosarcomas)

Is limb-salvage always the best option?

An open question!

Extremity functionBetter after limb-salvage than after amputation (not: rotation plasty)

Some limb-salvage drawbacksLocal recurrence risk

More long-term pain

Higher complication rate

More revisions (more hospital episodes, secondary amputations)

Some reassuring wordsMost patients adjust well to either type of surgery

QoL often rather good

Journal of the Royal College of Surgeons of Edinburgh 1955

Radiotherapyfor inoperable osteosarcoma?

Osteosarcoma local therapyTake home messages

• operate, operate, operate!

• limb salvage is often feasible

• local recurrence risk can be reduced- by good imaging- by smart planning- by good chemo- by good surgery

• radiotherapy may be an option for selectedinoperable lesionsstudies with proton / heavy ion radiotherapy ongoing

Are things getting

better?



0

10

20

30

40

50

60

70

1978-1982 1983-1987 1988-1992 1993-1997

Osteosarcoma: 5-year survival rates

0

10

20

30

40

50

60

70

1973-1978 1984-1993 1994-2003

Stiller et al., Eur J Cancer 2006 Mirabello et al., Cancer 2009

Europe (EU & others) North America

MTX DOX DDP IFO

Does it matter how many

of these drugs are used?

Osteosarcomastandard approach

imaging/biopsy


surgery

adjuvant chemotherapyplus surgery for primary mets

ADR

DDP

MTX

IFO

Might results be improved by

increasing dose or dose-

intensity?

n(risk)Regimen 1245 (50) 169 (39) 93 (8) 45 (1) 21Regimen 2252 (44) 175 (41) 98 (7) 58 (3) 18

0.0

0.2

0.4

0.6

0.8

1.0

Propor

tion ali

ve

0 24 48 72 96Time from randomisation (months)

CDDP+Dox CDDP+Dox+GCSF

All patients and timed from randomisation

KM plot of overall survival

n(risk)Regimen 1245(64)169(46)112(17) 82 (2) 68 (5) 49 (1) 32 (0) 21Regimen 2252(55)185(56)117(15) 91 (5) 76 (4) 55 (1) 45 (0) 30

0.0

0.2

0.4

0.6

0.8

1.0

Ppn ali

ve and

progr

ession

-free

0 12 24 36 48 60 72 84Time from randomisation (months)

Regimen 1 Regimen 2

All patients and timed from randomisation

KM plot of progression-free survival

MRC BO06 EORTC 80931

EOI: Lewis et al., JNCI 2007

G-CSF?

+ -

Osteosarcoma:

Dose / Dose-Intensity

• importance remains unproven

G-CSF for interval compression

• not useful

biopsy surgical specimen

Response to preop chemo

years

302520151050

surv

ival

1,0

0,8

0,6

0,4

0,2

0,0

grade 1

grade 2

grade 3

grade 4

grade 5

grade 6

Salzer-Kuntschik Grades

Osteosarcoma: Response & Survival

Can outcomes be improved for poor responders?

COG Childrens’ Oncology Group

COSSCooperative Osteosarcoma Study Group

EOIEuropean Osteosarcoma Intergroup

SSGScandinavian Sarcoma Group

European and American Osteosarcoma Study

COG Childrens’ Oncology Group

COSSCooperative Osteosarcoma Study Group

EOIEuropean Osteosarcoma Intergroup

SSGScandinavian Sarcoma Group

European and American Osteosarcoma Study

eligible:

≤40 yearsat osteosarcoma diagnosis

Design and eligibility

Biopsy-proven diagnosis of resectable osteosarcoma

REGISTER

MAP (induction)

Surgery

Histological response assessment

Poor Good

RANDOMIZE RANDOMIZE

MAP MAPIE MAP MAPifn

Registration

• Resectable high-grade osteosarcoma

• Extremity or axial

• Localized or metastatic

• Age ≤40yr

• No pretreatment for osteosarcoma

• No previous chemo for any disease

• No contraindication to treatment

• Registration & chemo ≤30day after biopsy

EURAMOS1-POOR RESPONSE: Design

Primary tumor

resectionRAP MM

IE M

A MM

wk 1-10 wk 11

wk 12-40

Ai M

wk 12-29

x2

AP MM A MMAP MM

AP MM IE M AP MM IE M Ai MM

MAPIE

MAP

Induction MAP

Poor Response

Poor Response - MAPIE vs. MAP

55% (49%-60%)

53% (46%-58%)

MAPIE more toxic than MAP

• Grad III/IV non-hematological toxicity

p=0.0024

• Secondary leukemia

8/307 vs. 2/308

EURAMOS-1 Poor Response : Conclusion

◆ Adding ifosfamide and etoposide to

MAP is associated with additional

morbidity and has no effect on

survival outcomes.


bisphosphonates?

Zoledronate added to chemo:

Randomized French trial suggests potential inferiority!


“immunotherapy”?

Design and eligibilityRandomization

• Good response

• <10% viable tumor

• Assessment by reference pathologist if possible

• Age ≥ 5 yrs

• No disease progression

• If mets, complete removalfeasible

• Recovery from prior therapy

• Randomization ≤ 35 days post-op


REGISTER

MAP (induction)

Surgery


Poor Good

RANDOMIZE RANDOMIZE


Design and eligibility

Randomization

• Good response • <10% viable tumor

• Assessment by reference pathologist if possible

• Age ≥ 5 yrs

• No disease progression

• If mets, complete removal feasible

• Recovery from prior therapy

• Randomization ≤ 35 days post-op

• Written informed consent


REGISTER

MAP (induction)

Surgery


Poor Good

RANDOMIZE RANDOMIZE


0.00

0.25

0.50

0.75

1.00

Pro

porti

on e

vent

-free

356 323(25) 235(41) 184(9) 112(4) 62(0) 22(2)MAPifn

358 318(32) 231(38) 167(13) 106(5) 58(3) 8(1)MAP

N

0 12 24 36 48 60 72

Time from randomisation (months)

MAP MAPifn

intention-to-treat population

Event-Free Survival - Good Responders randomisation

EFS - intention to treat

74% at 3yr

77% at 3yr

MAP (n=358) MAPifn (n=357)

Events, n (%) 93 (26%) 81 (23%)

3 year EFS 74% (69%-79%) 77% (72%-81%)

Hazard ratio* (95%CI)p-value

0.82 (0.61-1.11) p=0.201

*Cox model adjusted for data center, metastases status, site and location of tumor on bone

0.00

0.25

0.50

0.75

1.00

Pro

porti

on e

vent

-free

356 323(25) 235(41) 184(9) 112(4) 62(0) 22(2)MAPifn

358 318(32) 231(38) 167(13) 106(5) 58(3) 8(1)MAP

N

0 12 24 36 48 60 72

Time from randomisation (months)

MAP MAPifn

intention-to-treat population

Event-Free Survival - Good Responders randomisationEFS - intention to treat

74% at 3yr

77% at 3yr

MAP (n=358) MAPifn (n=357)

Events, n (%) 93 (26%) 81 (23%)

3 year EFS 74% (69%-79%) 77% (72%-81%)

Hazard ratio* (95%CI)p-value

0.82 (0.61-1.11) p=0.201

*Cox model adjusted for data center, metastases status, site and location of tumor on bone Bielack et al., J Clin Oncol 2015

0.00

0.25

0.50

0.75

1.00

Pro

port

ion

star

ted

Ifn

353 132(219) 79(51) 72(0) 62(1)

N

0 6 12 18 24months from randomisation

cumulative incidence

Time from randomisation to starting interferon

Starting interferon

82 (23%) report never starting,

→ main reason is refusal (63)

271 (76%) report starting ifn

Median start = 5.4 months (95% CI 5.2-5.5)

4 no ifn data yet

0.00

0.25

0.50

0.75

1.00

Pro

porti

on s

till o

n in

terfe

ron

270 202(67) 163(24) 39(116) 8(26) N

0 6 12 18 24months from starting ifn

Time from starting to stopping Ifn

Duration of interferon

Median duration ifn14.9 mo (IQR 4.6-15.1)

234/271 stopped ifn

- 128 (55%) completed ifn

- 106 (45%) terminated early

44 Toxicity

25 Progression

17 Refusal

20 Other

- 37 still on ifn at data freeze

Interferon treatment

Bielack et al., J Clin Oncol 2015

EURAMOS-1: Conclusions

◆ Evidence from EURAMOS-1 does NOT

support adaptation of postoperative

chemotherapy based on histological

response!

Liposomal muramyl-triphospate-ethanolamine L-MTP-PE• Macrophage activator derived from mycobacterial cell wall

• Preclinical testing in animals (dogs)

• Phase 2: macrophage infiltration into osteosarcoma mets

better survival than historical controls?

toxicity: mainly fever, chills etc.(Kleinermann et al. J Clin Oncol 10:1310-1316, 1992)

Prospective, randomized clinical trial POG/CCG INT01332 x 2 factorial design (+/- IFO, +/-MTP):

Preop Postop

A- DOX, MTX, DDP DOX, MTX, DDP,

A+ DOX, MTX, DDP DOX, MTX, DDP, MTPx48

B- DOX, MTX, IFO DOX, MTX, IFO, DDP

B+ DOX, MTX, IFO DOX, MTX, IFO, DDP, MTPx48

no preop DDP

INT 0133 Meyers et al., J Clin Oncol 26:633-638, 2008

n = 662 localized resectable osteosarcoma; end points EFS & overall survival

EFS overall survivalregimen 4-year 6-year 4-year 6-year

A- - 66% 64% 78% 71%

A+ MTP 65% 63% 82% 75%

B- IFO 60% 58% 77% 70%

B+ IFO, MTP 74% 71% 86% 81%

EFS overall survivalregimen 4-year 6-year 4-year 6-year

A-/B- no MTP 63% 61% 78% 70%

A+/B+ MTP 69% 67% 84% 78%

no statistical evidence of interactionproportional hazards regression analysis P =.102 (EFS), .60 (overall survival)

p=.08 p=.03

MTP: Regulatory situation

• MTP not licensed

• MTP licensed for nonmetastatic osteosarcoma

http://www.ema.europa.eu/home.htm

MTP

Interpretation by EURAMOS Group

Efficacy data not sufficient

=>

Not a part of standard osteosarcoma

treatment

….but some others seem to see things differently

Ewing Sarcoma• Third most common bone sarcoma

• Age

Adolescence< 15 J. ca. 2 / Mio / yr

15-19 J. ca. 5 / Mio / yr

• m > f 1.5:1

• Ethnicity

rare in Asians, AfricansAbb. aus: Arndt & Crist, N Engl J Med 1999

Ewing Sarcoma ((EI)CESS 81-92)

Overall and Event-Free Survival

EFS

3y.: 0.655 +/-.0365

5y.: 0.619 +/-.0372

10y.: 0.589 +/-.0382

OAS

3y.: 0.771 +/-.0331

5y.: 0.696 +/-.0336

10y.: 0.644 +/-.0338

EWS/ERG EWS/FLI1

Prognostic importance of translocation-type?

From: Bielack et al, New Engl J Med 2004

Conclusion:

differences of EWS-FLI1 fusion architecture

• not useful

as independent prognostic markers

with current treatment regimens

n = 565 n = 119

Not everything that looks somewhat like Ewing is Ewing

Undifferentiated small round blue cell “EWSR1-negative Ewing’s-like tumors’

• CIC-DUX4t(4;19) or t(10;19); soft tissue tumors

•BCOR-CCNB3 X-chromosomal paracentric inversion; bone and soft tissue tumors

• CIC-FOXO4 t(X;19); FUS-NCATc2 and many others and (much) more to come

Patients (n=26)

Age: median 13.1 years (5.9-25.6)

17 male, 9 female

21 bone, 5 soft tissue

2/26 lung mets at diagnosis

Immunohistochemistry

Cyclin B3+

Treatment

24/26 chemo (mostly Ewing-like)

22/26 surgery (+/- RT), 2/26 RT only

Outcome

16/26 alive in CR (mean FU 86 mo)

5 year OS/EFS 77%/68%

BCOR-CCNB

Patients (n=7)

Age: median 33 years (15-44)

6 soft tissue, 1 bone

5/7 lung mets at diagnosis

Morphology

Undifferentiated round-cell,

more atypia & pleomorphism than Ewing

Immunohistochemistry

7/7 focal & weak CD99+; 5/7 WT1+

Outcome

6/7 died (mean 14.5 months from diagnosis)

CIC-DUX4

Can the outlook for patients with Ewing

Sarcoma be improved by treatment

intensification?

Ewing Sarcoma ((EI)CESS 81-92)

Overall and Event-Free Survival

EFS

3y.: 0.655 +/-.0365

5y.: 0.619 +/-.0372

10y.: 0.589 +/-.0382

OAS

3y.: 0.771 +/-.0331

5y.: 0.696 +/-.0336

10y.: 0.644 +/-.0338

Ifo vs. CYC

+/- etoposide

HR-group: Etoposide?

YES (EVAIA)

NO (VAIA)

49 weeks of

standard chemotherapy

doxorubicin, vincristine, cyclophosphamide, dactinomycin

or experimental therapy

with these four drugs alternating with courses of

ifosfamide and etoposide

p=0.005

metastatic

localized

Conclusion:

treatment intensification / diversification

• beneficial in localized (HR) disease

• not beneficial for metastatic disease

73%

65%

p=.048

83%

77%

p=.056

EURO-E.W.I.N.G. 99

Inclusion criteria

localized tumors with either

- good histologic response to induction chemo (< 10% cells) or

- small tumors (< 200 mL) resected at diagnosis or receiving

radiotherapy alone as local treatment.

Chemo

6 VIDE+1 VAI =>

- 7 VAC with 1.5 g/m² CYC versus

- 7 VAI with 6 g/m² IFOS

Le Deley et al., J Clin Oncol. 2014 Aug 10;32(23):2440-8

EURO-E.W.I.N.G. 99 - R1

EURO-E.W.I.N.G. 99 - R1

Le Deley et al., J Clin Oncol.

2014 Aug 10;32(23):2440-8

….HDT-PBSCTorconventional chemofor• localized HR-disease?• primary pulm. mets?

EE99-R2Loc Scheme

L

O

C

A

L

T

H

E

R

A

P

Y

VIDE VIDE VIDE VIDE VIDE VIDE VAI R

VAI VAI VAI VAI VAI VAI VAI VAI

BuMel

BuMel:Busulfan-Melphalan x 1 with stem cell rescue

VAI: vincristine actinomycin D, ifosfamide x 7

Presented by: Jeremy Whelan, ASCO 2016

Benefit of BuMel on Event-Free Survival

VAI, 3-y EFS=53%

BuMel, 3-y EFS= 67%

ITT analysis

Benefit largely related to prevention of metastasesmetastases

HR = 0.64 (95%CI, 0.43-0.94)p= 0.024

Cumulative incidence of metastases (competing risk approach)

HR = 0.59 (95%CI, 0.38-0.92)p= 0.02


Benefit of BuMel on Event-Free Survival

VAI, 3-y EFS=53%

BuMel, 3-y EFS= 67%

HR = 0.64 (95%CI, 0.43-0.94)p= 0.024

ITT analysisTranslates into better Overall Survival

HR = 0.60 (95%CI, 0.39-0.92)p= 0.019

VAI, 3-y OS=70%

BuMel, 3-y OS= 78%


Ewing Sarcoma (EI)CESS 81-92

Primary metastases & survival

none

Lung

Bone/bone marrow

R3

image courtesy of H. Jürgens & M. Paulussen

R2pulm

Randomization in R2pulm

R 2 VIDE x 6

VAI x 7& Whole Lung

Irradiation

(WLI)

BuMel HD x 1

VAI x 1

Randomisation

L

O

C

A

L

T

H

E

R

A

P

Y

VAI x 1

ASCO 2016, presented by Uta Dirksen

No Benefit of BuMel on Event-Free Survival

VAI+WLI, 3-y EFS=51%

BuMel, 3-y EFS= 55%

ITT analysis

HR = 0.82 (95%CI, 0.58 – 1.15)p= 0.24

Secondary metastases

Cumulative incidence of secondary metastase

(competing risk approach)

HR = 0.79 (95%CI, 0.54-1.15)p= 0.22


No Benefit of BuMel on Overall Survival

VAI+WLI, 3-y EFS=51%

BuMel, 3-y EFS= 55%

ITT analysis

HR = 0.82 (95%CI, 0.58 – 1.15)p= 0.24

No benefit on Overall Survival

HR = 0.96 (95%CI, 0.65 – 1.40)p= 0.82

VAI+WLI, 3-y OS=68%

BuMel, 3-y OS= 68%


EURO-E.W.I.N.G. 99

R 3 – Treatment schedule

Outcome in the unselected patients with primary disseminated multifocal Ewing sarcomas.

Ladenstein R et al. JCO 2010;28:3284-3291


©2010 by American Society of Clinical Oncology

Outcome according to risk groups


Does local treatment helpin this dismal situation?

none

either / or

both

Local treatment:Primary tumor & metastases

Conclusion:

• Think about local therapyeven in (widely?) metastatic disease

….

VDC/IE(interval compressed?) orVIDE ???

please wait for the results of the prospective, randomized EEC trial

Thank you, now your tricky

questions please!.

Stefan Bielack

11.05.2018A very big „Thank you“to Uta Dirksen and Jeremy Whelan for letting me use their ASCO 2016 EE99-R2 slides!

Osteosarcoma

Is (early) detection of

recurrence

worthwhile? –

and, if yes, how?

Osteosarcoma recurrence (COSS, n=576)

Survival

0 5 10 15 20

years

0,0

0,2

0,4

0,6

0,8

1,0

surv

ival

1

2 345

Bielack et al., J Clin Oncol 2009

Surgery is essentialif a 2nd CR can be achieved

Surgery, CR2 n=275

8%

71%

18%p=.038

p<.001

Surgery, no CR2 n=95

No surgery n=53

years since relapse

20181614121086420

surv

ival 1,0

,9

,8

,7

,6

,5

,4

,3

,2

,1

0,0

Recurrent Osteosarcoma

Pleural Disruption

no pleural disruption

p<.0001

7% Kempf-Bielack2005

pleura disruptedby lung mets (n=66)

Osteosarcoma: Relapse detectioncorrelates with prognosis – true effct or lead time bias?

Signs & n=105symptoms

Radiology n=301(routine follow-up)

40%

53%

p=0.003log-rank

EURELOS-Data, Sorg et al., EMSOS 2014

• local - X-ray, ultrasound, MRI, PET/CT

• lung - X-ray, CT

• bone - scintigraphy, PET/CT, WB-MRI

• others - all of the above & more

Osteosarcoma: searching for recurrencesImaging-options

local - pain, swelling

bone - pain, swelling

others - rare, often disseminated, rarelycurative options

lung - no signs or symptoms until too late

Osteosarcoma: searching for recurrencesDon‘t forget history & physical!

Randomized study in India

• 500 localized extremity sarcomas (359 “bone”)

• prognosis 3 years from randomization

Survival HR

Chest X-ray 67% 0,9

Chest-CT 66%

q 6 Mo 64% 1,2

q 3 Mo 69%

Lung mets: X-ray or CT?

More or less frequent?

early => frequently

later => less often

then => quit after 5-10 years

Bone sarcoma: Searching for recurrencesCommon strategy

Relapse-free interval & survival

Osteo Ewing

years since relapse

20181614121086420

surv

ival 1,0

,8

,6

,4

,2

0,0

34%

late n=311

(>18 months)

early n=265

(≤18 months)

p<.0001

11%

30%

7%

This happens with what is found

while we search most frequently

Osteosarcoma, solitary lung met >10 years from initial diagnosis

This is missedif we stop looking too early

Documents

BONE SARCOMA€¦ · Journal of the Royal College of Surgeons of Edinburgh 1955 Radiotherapy for inoperable osteosarcoma? Osteosarcoma local therapy T ake home messages operate ,