BONE SARCOMA. esmo.org

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1 BONE SARCOMA Stefan Bielack Cooperative Osteosarcoma Study Group COSS Klinikum Stuttgart Olgahospital Pädiatrie 5 (Onkologie, Hämatologie, Immunologie) s.bielack@klinikum-stuttgart.de esmo.org

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

4 Bone Sarcoma: Current Therapeutic Strategies Osteosarcoma standard approach Ewing Sarcoma standard approach imaging/biopsy imaging/biopsy neoadjuvant chemotherapy surgery ADR DDP MTX IFO neoadjuvant chemotherapy surgery/radiotherapy VCR IFO/CYC DOX ActoD ETO adjuvant chemotherapy plus surgery for primary mets adjuvant chemotherapy prim. pulm. mets: plus (surgery), adjuvant lung RT? HDT?

5 Osteosarcoma WHO classification 2013 Conventional - chondroblastic - fibroblastic - osteoblastic - various unusual subtypes Teleangiectatic Small cell High grade surface Parosteal Periosteal Low grade central

6 Osteosarcoma Epidemiology incidence: age: 2-3/million/year adolescence sex: m:f ca. 1.4:1 site: metaphyses of long bones distal femur, prox. tibia, prox. humerus, prox. fibula

7 Osteosarcoma Incidence peaks in AYA Studies performed in AYA Knowledge derived from AYA Benchmark for outcomes = AYA Best served population = AYA (?)

8 Adult vs. pediatric osteosarcoma Adult More vs. pediatric axial osteosarcoma Proportion of axial tumors higher Adult vs. pediatric osteosarcoma More secondary osteosarcomas More secondary all primary 2nd cancer with Paget s

9 Adult vs. pediatric osteosarcoma Treatment - Assumptions the same treatment principles should apply but adults don t tolerate pediatric protocols

10 Adult vs. pediatric osteosarcoma Adults 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? patients 50 years

11 Young adults Treatment usually feasible (MTX?) Older adults > (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

12 Osteosarcoma: Overall Survival patients 50 years

13 survival Osteosarcoma: Overall Survival 1,0 0,8 localized limb (n=2,017) localized extremity 0,6 0,4 axial or / and primary metastatic 0,2 axial or metastatic (n=444) 0, years Bielack et al., Cancer Treat Res 2009; based on n= 2,464 COSS osteosarcomas

14 Osteosarcoma Metastases Is imaging sensitive and specific?

15 Osteosarcoma: Chest-CT Lesion-size not sufficient to distinguish mets

16 Osteosarcoma: Chest-CT Mets may present atpically

17 CT finds small lesions, but is non-specific Met No mets

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

19 Osteosarcoma- primary mets surgery & survival COSS: Kager et al., J Clin Oncol 2003

20 Osteosarcoma (Lung-)Metastases 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

21 Osteosarcoma Standard approach since early/mid 1980s imaging/biopsy neoadjuvant chemotherapy surgery HD-MTX ADR (=DOX) DDP IFOS??? adjuvant chemotherapy plus surgery for primary mets benefit of additional agents??????

22 SURGERY OF THE PRIMARY TUMOR: WHEN?

23 Timing of surgery & event-free survival n 5-year EFS p POG* delayed 45 61%.8 immediate 55 69% COSS** delayed 1, %.404 immediate % *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)

24 SURGERY OF THE PRIMARY TUMOR: WHICH TECHNIQUE? Surgical margins (Enneking et al., 1981) radical wide marginal intralesional

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

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29 Is limb-salvage always the best option? An open question! Extremity function Better after limb-salvage than after amputation (not: rotation plasty) Some limb-salvage drawbacks Local recurrence risk More long-term pain Higher complication rate More revisions (more hospital episodes, secondary amputations) Some reassuring words Most patients adjust well to either type of surgery QoL often rather good

30 Radiotherapy for inoperable osteosarcoma? Journal of the Royal College of Surgeons of Edinburgh 1955

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32 Osteosarcoma local therapy Take 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 selected inoperable lesions studies with proton / heavy ion radiotherapy ongoing

33 Osteosarcoma: Overall Survival patients 50 years Are things getting better?

34 Osteosarcoma: 5-year survival rates 70 Europe (EU & others) 70 North America Stiller et al., Eur J Cancer 2006 Mirabello et al., Cancer 2009

35 Osteosarcoma standard approach imaging/biopsy neoadjuvant chemotherapy surgery ADR DDP MTX IFO adjuvant chemotherapy plus surgery for primary mets MTX DOX DDP IFO Does it matter how many of these drugs are used?

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37 Might results be improved by increasing dose or doseintensity?

38 MRC BO06 EORTC KM plot of overall progression-free survival survival G-CSF? n(risk) Regimen n(risk) 1245 (50) 169 (39) 93 (8) 45 (1) 21 Regimen (64)169(46)112(17) (44) 175 (41) (2) 68 (7) (5) 4958 (1) 32 (3) (0) Regimen 2252(55)185(56)117(15) 91 (5) 76 (4) 55 (1) 45 (0) Time Time from from randomisation randomisation (months) (months) CDDP+Dox CDDP+Dox+GCSF Regimen 1 Regimen 2 All patients and timed from randomisation All patients and timed from randomisation EOI: Lewis et al., JNCI 2007

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40 Osteosarcoma: Dose / Dose-Intensity importance remains unproven G-CSF for interval compression not useful

41 Response to preop chemo biopsy surgical specimen

42 Osteosarcoma: Response & Survival survival 1,0 0,8 grade 2 grade 1 grade 3 0,6 grade 4 grade 5 0,4 grade 6 0,2 0,0 Salzer-Kuntschik Grades years

43 Can outcomes be improved for poor responders?

44 European and American Osteosarcoma Study European and American Osteosarcoma Study COG Childrens Oncology Group Oncology Group COSS Cooperative Osteosarcoma Study Group Cooperative Osteosarcoma Study Group EOI EOI European Osteosarcoma Intergroup European Osteosarcoma Intergroup SSG SSG Scandinavian Sarcoma Group Scandinavian Sarcoma Group eligible: 40 years at osteosarcoma diagnosis

45 Design and eligibility Biopsy-proven diagnosis of resectable osteosarcoma REGISTER MAP (induction) Surgery Histological response assessment Poor RANDOMIZE Good 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

46 EURAMOS1-POOR RESPONSE: Design Induction MAP AP MM x2 Primary tumor resection wk 1-10 wk 11 Poor Response R MAP AP MM MAPIE AP MM wk A MM A MM AP MM IE M Ai M IE M AP MM IE M Ai MM wk 12-40

47 Poor Response - MAPIE vs. MAP 55% (49%-60%) 53% (46%-58%)

48 MAPIE more toxic than MAP Grad III/IV non-hematological toxicity p= Secondary leukemia 8/307 vs. 2/308

49 EURAMOS-1 Poor Response : Conclusion Adding ifosfamide and etoposide to MAP is associated with additional morbidity and has no effect on survival outcomes.

50 Might results be improved by bisphosphonates?

51 Zoledronate added to chemo: Randomized French trial suggests potential inferiority!

52 Might results be improved by immunotherapy?

53 Design and eligibility Design and eligibility Biopsy-proven diagnosis of Biopsy-proven diagnosis of resectable osteosarcoma resectable osteosarcoma REGISTER MAP (induction) Surgery Histological response assessment Histological response assessment Poor Good RANDOMIZE RANDOMIZE MAP MAPIE MAP MAPifn MAP MAPIE MAP MAPifn Randomization Good response Good response <10% viable tumor <10% Assessment viableby tumor reference pathologist if possible Assessment by reference pathologist if possible Age 5 yrs Age 5 yrs No disease progression If mets, complete removal feasible No disease progression Recovery from prior therapy If mets, complete removal feasible Randomization 35 days post-op Written informed consent Recovery from prior therapy Randomization 35 days post-

54 EFS - intention to treat EFS Event-Free Survival Good Responders randomisation Event-Free Survival - Good Responders randomisation - intention to treat intention-to-treat population intention-to-treat population N MAP MAPifn MAP MAP (n=358) (n=358) MAPifn MAPifn (n=357) (n=357) Events, n (%) n (%) (26%) (23%) 3 year EFS EFS 74% 74% (69%-79%) 77% 77% (72%-81%) Hazard ratio* (95%CI) 0.82 ( ) Hazard p-value ratio* (95%CI) 0.82 p=0.201 ( ) p-value p= Time from randomisation (months) 77% at 3yr 74% at 3yr 358 (32) 318 (38) 231 (13) 167 (5) 106 (3) 58 (1) (25) 323 (41) 235 (9) 184 (4) 112 (0) 62 (2) 22 MAP MAPifn Bielack et al., J Clin Oncol 2015 *Cox model adjusted for data center, metastases status, site and location of tumor on bone

55 Interferon treatment Starting interferon Duration of interferon Time from randomisation to starting interferon cumulative incidence 271 (76%) report starting ifn 82 (23%) report never starting, main reason is refusal (63) Time from starting to stopping Ifn 234/271 stopped ifn (55%) completed ifn (45%) terminated early 44 Toxicity 25 Progression 17 Refusal 20 Other - 37 still on ifn at data freeze N Median start = 5.4 months (95% CI ) months from randomisation 353 (219) 132 (51) 79 (0) 72 (1) 62 4 no ifn data yet 0.00 N Median duration ifn 14.9 mo (IQR ) months from starting ifn 270 (67) 202 (24) 163 (116) 39 (26) 8 Bielack et al., J Clin Oncol 2015

56 EURAMOS-1: Conclusions Evidence from EURAMOS-1 does NOT support adaptation of postoperative chemotherapy based on histological response!

57 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: , 1992) Prospective, randomized clinical trial POG/CCG INT 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

58 INT 0133 Meyers et al., J Clin Oncol 26: , 2008 n = 662 localized resectable osteosarcoma; end points EFS & overall survival EFS overall survival regimen 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% no statistical evidence of interaction proportional hazards regression analysis P =.102 (EFS),.60 (overall survival) EFS overall survival regimen 4-year 6-year 4-year 6-year A-/B- no MTP 63% 61% p=.08 78% 70% p=.03 A+/B+ MTP 69% 67% 84% 78%

59 MTP: Regulatory situation MTP licensed for nonmetastatic osteosarcoma MTP not licensed

60 MTP Interpretation by EURAMOS Group Efficacy data not sufficient => Not a part of standard osteosarcoma treatment.but some others seem to see things differently

61 Ewing Sarcoma Third most common bone sarcoma Age Adolescence < 15 J. ca. 2 / Mio / yr J. ca. 5 / Mio / yr m > f 1.5:1 Ethnicity rare in Asians, Africans Abb. aus: Arndt & Crist, N Engl J Med 1999

62 Ewing Sarcoma ((EI)CESS 81-92) Overall and Event-Free Survival OAS 3y.: / y.: / y.: / EFS 3y.: / y.: / y.: /-.0382

63 Prognostic importance of translocation-type? EWS/ERG EWS/FLI1 From: Bielack et al, New Engl J Med 2004

64 n = 565 n = 119 Conclusion: differences of EWS-FLI1 fusion architecture not useful as independent prognostic markers with current treatment regimens

65 Not everything that looks somewhat like Ewing is Ewing Undifferentiated small round blue cell EWSR1-negative Ewing s-like tumors CIC-DUX4 t(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

66 BCOR-CCNB Patients (n=26) Age: median 13.1 years ( ) 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%

67 Patients (n=7) Age: median 33 years (15-44) 6 soft tissue, 1 bone 5/7 lung mets at diagnosis CIC-DUX4 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)

68 Ewing Sarcoma ((EI)CESS 81-92) Overall and Event-Free Survival OAS 3y.: / y.: / y.: / EFS 3y.: / y.: / y.: / Can the outlook for patients with Ewing Sarcoma be improved by treatment intensification?

69 Ifo vs. CYC +/- etoposide

70 HR-group: Etoposide? YES (EVAIA) NO (VAIA)

71 49 weeks of standard chemotherapy doxorubicin, vincristine, cyclophosphamide, dactinomycin or experimental therapy with these four drugs alternating with courses of ifosfamide and etoposide

72 p=0.005 localized metastatic

73 Conclusion: treatment intensification / diversification beneficial in localized (HR) disease not beneficial for metastatic disease

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75 p= % 65% p= % 77%

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

77 EURO-E.W.I.N.G R1 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 Aug 10;32(23):2440-8

78 EURO-E.W.I.N.G R1 Le Deley et al., J Clin Oncol Aug 10;32(23):2440-8

79 . HDT-PBSCT or conventional chemo for localized HR-disease? primary pulm. mets?

80 EE99-R2Loc Scheme L O C A L VIDE VIDE VIDE VIDE VIDE VIDE T H E R A P Y VAI R VAI: vincristine actinomycin D, ifosfamide x 7 VAI VAI VAI VAI VAI VAI VAI VAI BuMel BuMel:Busulfan-Melphalan x 1 with stem cell rescue Presented by: Jeremy Whelan, ASCO 2016

81 Benefit of BuMel on Event-Free Survival ITT analysis BuMel, 3-y EFS= 67% Benefit largely related to prevention of metastases metastases Cumulative incidence of metastases (competing risk approach) VAI, 3-y EFS=53% HR = 0.64 (95%CI, ) p= HR = 0.59 (95%CI, ) p= 0.02 Presented by: Jeremy Whelan, ASCO 2016

82 Benefit of BuMel on Event-Free Survival ITT analysis BuMel, 3-y EFS= 67% Translates into better Overall Survival BuMel, 3-y OS= 78% VAI, 3-y EFS=53% HR = 0.64 (95%CI, ) p= VAI, 3-y OS=70% HR = 0.60 (95%CI, ) p= Presented by: Jeremy Whelan, ASCO 2016

83 image courtesy of H. Jürgens & M. Paulussen Ewing Sarcoma (EI)CESS Primary metastases & survival R2 pulm none Lung Bone/bone marrow R3

84 Randomization in R2pulm R 2 VIDE x 6 L O C A L T H E R A P Y Randomisation VAI x 1 VAI x 1 VAI x 7 & Whole Lung Irradiation (WLI) BuMel HD x 1 ASCO 2016, presented by Uta Dirksen

85 No Benefit of BuMel on Event-Free Survival ITT analysis Secondary metastases Cumulative incidence of secondary metastase (competing risk approach) BuMel, 3-y EFS= 55% VAI+WLI, 3-y EFS=51% HR = 0.82 (95%CI, ) p= 0.24 HR = 0.79 (95%CI, ) p= 0.22 ASCO 2016, presented by Uta Dirksen

86 No Benefit of BuMel on Overall Survival ITT analysis No benefit on Overall Survival BuMel, 3-y EFS= 55% BuMel, 3-y OS= 68% VAI+WLI, 3-y EFS=51% HR = 0.82 (95%CI, ) p= 0.24 VAI+WLI, 3-y OS=68% HR = 0.96 (95%CI, ) p= 0.82 ASCO 2016, presented by Uta Dirksen

87 EURO-E.W.I.N.G. 99 R 3 Treatment schedule

88 Outcome in the unselected patients with primary disseminated multifocal Ewing sarcomas. Ladenstein R et al. JCO 2010;28:

89 2010 by American Society of Clinical Oncology Ladenstein R et al. JCO 2010;28:

90 Outcome according to risk groups Ladenstein R et al. JCO 2010;28:

91 Does local treatment help in this dismal situation?

92 Local treatment: Primary tumor & metastases both either / or none

93 Conclusion: Think about local therapy even in (widely?) metastatic disease

94 . VDC/IE(interval compressed?) or VIDE??? please wait for the results of the prospective, randomized EEC trial

95 Thank you, now your tricky questions please!. Stefan Bielack A very big Thank you to Uta Dirksen and Jeremy Whelan for letting me use their ASCO 2016 EE99-R2 slides!

96 Osteosarcoma Is (early) detection of recurrence worthwhile? and, if yes, how?

97 Osteosarcoma recurrence (COSS, n=576) Survival survival 1,0 0,8 0,6 0,4 0,2 0, years Bielack et al., J Clin Oncol 2009

98 Surgery is essential if a 2 nd CR can be achieved 71% Surgery, CR2 n=275 p< % 8% Surgery, no CR2 n=95 No surgery n=53 p=.038

99 Recurrent Osteosarcoma Pleural Disruption 1,0,9,8,7,6 pleura disrupted by lung mets (n=66),5,4,3,2,1 0,0 0 p< no pleural disruption 7% Kempf-Bielack years since relapse

100 Osteosarcoma: Relapse detection correlates with prognosis true effct or lead time bias? 53% p=0.003 log-rank Radiology n=301 (routine follow-up) 40% Signs & n=105 symptoms EURELOS-Data, Sorg et al., EMSOS 2014

101 Osteosarcoma: searching for recurrences Imaging-options local lung bone others - X-ray, ultrasound, MRI, PET/CT - X-ray, CT - scintigraphy, PET/CT, WB-MRI - all of the above & more

102 Osteosarcoma: searching for recurrences Don t forget history & physical! local - pain, swelling bone - pain, swelling others - rare, often disseminated, rarely curative options lung - no signs or symptoms until too late

103 Lung mets: X-ray or CT? More or less frequent? 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%

104 Bone sarcoma: Searching for recurrences Common strategy early later then => frequently => less often => quit after 5-10 years

105 Relapse-free interval & survival Osteo Ewing 1,0,8 late n=311 (>18 months) early n=265 ( 18 months),6,4 34% 30%,2 11% 7% 0,0 0 p< years since relapse This happens with what is found while we search most frequently

106 This is missed if we stop looking too early Osteosarcoma, solitary lung met >10 years from initial diagnosis

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