1. Osteogenic sarcoma protocol
Professor Bruce Morland
Birmingham, UK

2. Osteosarcoma Disease of children and young adults1
Most common between ages of years1
Incidence: per 100,000 population in Europe2
Affects approximately 450 patients under 24 years of age in the U.S. each year3
Estimated 1,135 new cases every year in Europe4
Relapse rate in newly diagnosed patients can be as high as 30%1
Most recurrences occur as lung metastases5
1. Meyers PA, Gorlick R. Pediatr Clin North Am 1997;44(4): Bone sarcomas: ESMO Clinical Practice Guidelines. Ann Oncol 2014; 25(3): iii113-iii Mascarenhas L et al. SEER AYA Monograph 2002;8: (Table 8.1). 4. Stiller CA et al. Eur J Cancer 2013;49: Grimer RJ. Lancet Oncol 2005:6:85-92.

3. History of osteosarcoma treatment
Before the 1970s patients underwent amputation and no chemotherapy
Long term overall survival was <20%
Introduction of chemotherapy in the early 1970s significantly improved outcomes
By the mid 1980s long term overall survival up to 50-60%
Some studies showed better rates, but overall little significant improvement for over three decades
Before the 1970s when patients underwent amputation with no chemotherapy the long term overall survival was <20%. By the mid 1980s, following the introduction of chemotherapy, long term overall survival was up to 50-60% [Anninga 2011/P2432/Col1/Para 1/L8-12 & Fig1]. Some studies showed better rates, but overall there has little significant improvement for over three decades [Anninga 2011/P2432/Col1/Para 1/L11-12 & Fig1].
A meta-analysis of chemotherapy studies showed a 5 year overall survival of 60% with a 2-drug chemotherapy regimen compared with 66% for 3-drug regimen (p=0.04) [Anninga 2011/P2439/Discussion/Para 2/L5-6]. There was no benefit of adding a fourth drug [Anninga 2011/P2440/Col1/Para 1/L2-6].
Most investigators agree that treatment has reached a plateau [Meyers 2009/P1035/Col2/Para 1/L6-10].
References
Anninga JK, Gelderblom H, Fiocco M et al. Chemotherapeutic adjuvant treatment for osteosarcoma: Where do we stand? Eur J Cancer 2011;47(16):
Meyers PA. Muramyl tripeptide (mifamurtide) for the treatment of osteosarcoma. Expert Rev Anticancer Ther 2009;9:
Anninga JK et al. Eur J Cancer 2011;47(16):

4. Minimal improvement in osteosarcoma survival since 1980s
Historical:
Surgery alone
Introduction of chemotherapy
Attempted refinement of chemotherapy
Long term survival in localised high-grade osteosarcoma increased substantially from 10-20% when surgery as a single treatment was the only option, up to 50-60% in the mid 1980s following the introduction of chemotherapy in However, since then no substantial further improvement has been observed and a plateau has been seen for more than two decades [Anninga 2011/P2432/Col1/Para 1/L8-12].
Results of the cooperative group trial conducted by the Children's Oncology Group suggest that the addition of ifosfamide to multi-agent chemotherapy did not enhance overall survival or event free survival, but the addition of Mepact to multi-agent chemotherapy increased 6-year overall survival from 70% to 78% (p=0.03) for localised disease compared to chemotherapy alone [Meyers 2008/P633/Abstract/Results/L2-4].
References
Anninga JK, Gelderblom H, Fiocco M et al. Chemotherapeutic adjuvant treatment for osteosarcoma: Where do we stand? Eur J Cancer 2011;47(16):
Meyers PA, Schwartz CL, Krailo MD et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival-a report from the Children's Oncology Group. J Clin Oncol. 2008;26(4):633-38
Adapted from: 1. Anninga JK et al. Eur J Cancer 2011;47(16): 4

5. Osteosarcoma: 5-Year Survival in Europe
Stiller CA et al. Eur J Cancer 2006;42:

6. Osteosarcoma: 5 year survival (SEER data)
The Surveillance, Epidemiology, and End Results (SEER) Program of the US National Cancer Institute (NCI) collects and publishes cancer incidence and survival data from population-based cancer registries
Smith MA et al JCO 2010;28(15):

7. How are patients treated today?
85% of patients can now have their tumour removed without amputation due to1:
Better imaging techniques
Greater surgical skill
Responsiveness of tumours to chemotherapy
Advances in biomedical engineering
Chemotherapy involving doxorubicin, cisplatin, high dose methotrexate and ifosfamide (+/- etoposide) administered before and after surgery2
Actually no formal proof that giving chemotherapy pre- operatively improves outcome1
The concept originally stemmed from the need for time to construct endoprosthesis3
1. Abed R, Grimer R. Cancer Treatment Reviews 2010; 36: Bone sarcomas: ESMO Clinical Practice Guidelines. Ann Oncol 2014; 25(3): iii113-iii Gorlick R, Meyers PA. J Pediatr Hematol Oncol, 2003;25:840-1

8. First let us not forget the basics!

10. Osteosarcoma

12. Themes
Emphasis on surgical expertise with full range of reconstructive techniques
MAP chemotherapy upfront
Surgery the mainstay of recurrent disease (thoracotomy)
Role of 2nd line chemo unproven (ifos/etop)
Poor post-relapse prognosis

13. More than anything else I say today this probably saves more lives!
Get the patients to specialists EARLY
Metastatic disease at presentation is BAD news
Stage and diagnose the patient accurately
Recognise the treatment of osteosarcoma is multidisciplinary
Team members MUST communicate effectively
This MAY be facilitated by limited specialised bone sarcoma centres

14. Strategies to Improve Outcomes
Since the 1980s strategies to improve outcomes have focused on attempting to refine both pre-operative and post-operative chemotherapy e.g.
Salvage: adapt adjuvant chemotherapy based on histological response
Increase proportion of good responders
More chemotherapy
Increase chemotherapy dose intensity
Risk-adapted chemotherapy
Addition of a new agent

15. Is tumor response improved by more chemotherapy?
Thanks to Stefano Ferrari

17. Histologic response/primary chemotherapy Rizzoli/ISG experience
Primary treatment
> 90% Tumor necrosis
IOR/OS-1
MTX-CDDP I.A.
52%
IOR/OS-2
MTX-CDDP I.A.-DOX
71%
IOR/OS-3
MTX-CDDP I.V.-DOX
64%
43%
IOR/OS-4
MTX-CDDP I.A/I.V.-DOX-IFO
69%
ISG/SSG-1
MTX-CDDP I.V.-DOX-HDIFO
63%

19. How about increasing dose-intensity?

20. intermediate
low
high
EOI
Lewis 2000

21. Is dose intensification by G-CSF beneficial?
European Osteosarcoma Intergroup
Trial EOI-80931

22. Chemotherapy at standard or increased dose intensity in patients with operable osteosarcoma of the extremity - MRC BO06 EORTC 80931

23. MRC BO06 EORTC 80931

24. Conclusion:
Dose / Dose-Intensity
importance remains unproven
G-CSF for interval compression
not useful in osteosarcoma

25. Does it matter how many of these drugs are used?
MTX DOX DDP IFO
Does it matter how many of these drugs are used?

27. Personal Opinion at least 3 of these drugs should be used
MTX DOX DDP IFO
Which and how many of these drugs should be used?
Personal Opinion
at least 3 of these drugs should be used
it may not really matter which of the 3
addition of a 4th drug may not improve outcomes, but:
adding a 4th may allow to reduce cumulative toxicities
„optimal“ conventional chemotherapy remains to be defined (but will it ever be????)

28. Can outcomes be improved for poor responders?

29. “Salvage”-Question: Stats
3y EFS: good  75% poor  50%
Significance 5%
Power 80%
50  60%
needed:  randomized poor responders
  patients willing to be randomized
 > patients overall

30. European and American Osteosarcoma Study
COG Childrens’ Oncology Group
COSS Cooperative Osteosarcoma Study Group
EOI European Osteosarcoma Intergroup
SSG Scandinavian Sarcoma Group

32. EURAMOS Recruitment 04/05 – 06/11
2.260 patients
from 326 institutions
in 17 countries
Thanks to EURAMOS-CDC,
MRC London

33. Design and eligibility
Biopsy-proven diagnosis of resectable osteosarcoma
REGISTER
MAP (induction)
Surgery
Histological response assessment
Poor
Good
RANDOMIZE
MAP
MAPIE
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
Written informed consent

34. Primary tumor resection
Design
MAP
AP MM
AP MM
A MM
A MM
Induction MAP
wk 12-29
Primary tumor resection
Poor Response R
AP MM x2
MAPIE
wk 1-10
wk 11
AP MM
IE M
Ai M
IE M
AP MM
IE M
Ai MM
wk 12-40
Eligibility for randomisation
Poor histological response to induction MAP ≥10% viable tumor in resected specimen
Complete resection of primary tumor
No progression
Recovered from prior therapy
Dosing M
Methotrexate
12gm/m2 A
Doxorubicin
75mg/m2 P
Cisplatin
120mg/m2 I
Ifosfamide
14g/m2 i
9g/m2 E
Etoposide
500mg/m2
----- Meeting Notes (10/12/14 17:11) -----
This details the design for patients with a poor response as well as the doses of agents administered during the treatment.

36. MAPIE vs. MAP in Poor Responders Event-Free Survival
Gordana’s notes
RMST - interpretation of results
Because hazards are not proportional, another summary of difference between the treatments has been used. Difference is expressed in terms of Restricted Mean Survival Time; RMST is an average event-free time over a 5-year period after randomisation.
Time to first event is on average 37.5 month in MAP arm and 38.1 months in MAPIE arm, when time to 5 years from randomisation is considered. The difference in average times to first event is 0.6 months (18 days), in favour of MAPIE arm (time to first event is on average 18 days longer in MAPIE arm). The difference is not statistically significant, therefore we can conclude that there is not enough evidence to suggest that there is EFS difference between the two treatment arms.
Other points:
-lower event rate than predicted (expected/observed 3y EFS 45%/55%)
-target/observed number of events (378/300)
-consequence: need more time to reach target number of events
At the end of the talk, there is an additional slide with event prediction – time to reaching the target number of EFS events

37. MAPIE vs. MAP in Poor Responders Overall Survival

38. MAPIE more toxic than MAP
MAPIE: More grade III/IV toxicity (examples)
febrile neutropenia 73% vs. 50%
infection 83% vs. 65%
hypophosphatemia 29% vs. 19%
MAPIE: More secondary leukemias
- MAPIE ≥7/307 vs. MAP 2/308
----- Meeting Notes (10/12/14 17:11) -----
In conclusion:
1. We find no evidence of an advantage of MAPIE over MAP in terms of EFS or OS
2. Fewer MAPIE patients received the intended dose
3. MAPIE was associated with greater toxicity and a higher risk of second malignancies.

39. EURAMOS-1 Conclusions
Poor Response Adding ifosfamide and etoposide to MAP is associated with additional morbidity and has no effect on survival outcomes.
----- Meeting Notes (10/12/14 17:11) -----
In conclusion:
1. We find no evidence of an advantage of MAPIE over MAP in terms of EFS or OS
2. Fewer MAPIE patients received the intended dose
3. MAPIE was associated with greater toxicity and a higher risk of second malignancies.

40. Poor Response Continue with MAP Do NOT add IFO/ETO!
EURAMOS-1 Conclusions
Poor Response Continue with MAP Do NOT add IFO/ETO!
----- Meeting Notes (10/12/14 17:11) -----
In conclusion:
1. We find no evidence of an advantage of MAPIE over MAP in terms of EFS or OS
2. Fewer MAPIE patients received the intended dose
3. MAPIE was associated with greater toxicity and a higher risk of second malignancies.

41. Add something new?

42. Might results be improved by “immunotherapy”?

43. Design and eligibility
Biopsy-proven diagnosis of resectable osteosarcoma
REGISTER
MAP (induction)
Surgery
Histological response assessment
Poor
Good
RANDOMIZE
MAP
MAPIE
MAPifn
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
EURAMOS-1; Bielack et al., ASCO 2013

44. Primary tumor resection
Interventions
M Methotrexate 12gm/m2
A Doxorubicin mg/m2
P Cisplatin mg/m2 MA
MAP
Primary tumor resection R
MAP MA
MAP
ifn
wk 1-10
wk 11
wk 12-29 wk
Pegylated interferon -2b
Timing
Weekly after chemo until wk 104
Dosing
Starting at 0.5 μg/kg/wk s.c. (max. 50 μg) x 4 wks
if well tolerated
Escalation to 1.0 μg/kg/wk s.c. (max. 100 μg)
Protocol guidelines for

45. 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 ( )
p=0.201
*Cox model adjusted for data center, metastases status, site and location of tumor on bone

46. Interferon treatment

47. EURAMOS-1 Conclusions
Evidence from EURAMOS-1 does not support adaptation of postoperative chemotherapy based on histological response!
----- Meeting Notes (10/12/14 17:11) -----
In conclusion:
1. We find no evidence of an advantage of MAPIE over MAP in terms of EFS or OS
2. Fewer MAPIE patients received the intended dose
3. MAPIE was associated with greater toxicity and a higher risk of second malignancies.

48. Lancet Oncology Volume 17, No. 8, p1070–1080, August 2016
Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial
Sophie Piperno-Neumann, Marie-Cécile Le Deley, Françoise Rédini, Hélène Pacquement, Perrine Marec-Bérard, Philippe Petit, Hervé Brisse, Cyril Lervat, Jean-Claude Gentet, Natacha Entz-Werlé, Antoine Italiano, Nadège Corradini, Emmanuelle Bompas, Nicolas Penel, Marie-Dominique Tabone, Anne Gomez-Brouchet, Jean-Marc Guinebretière, Eric Mascard, François Gouin, Aurélie Chevance, Naïma Bonnet, Jean-Yves Blay, Laurence Brugières
Lancet Oncology
Volume 17, No. 8, p1070–1080, August 2016

49. Mifamurtide?

50. Summary: Phase I and II Studies
Mifamurtide stimulates
monocyte tumouricidal activity
the production of cytokines
the influx of activated macrophages into osteosarcoma lung nodules
Relapsed patients treated with mifamurtide had a superior disease-free and overall survival
Combining Mifamurtide with chemotherapy did not interfere with its immune activity
Mepact (mifamurtide) is not licensed for use in patients with relapsed/metastatic osteosarcoma

51. Phase III Study Design A- A+ B- B+
RANDOMI
SATION
INDUCTION
D E F I N I T I V E S U R G E R Y H I
STOLOG
CAL
EVALUAT ON
MAINTENANCE A
Cisplatin
Doxorubicin
HDMTX
Cisplatin, Doxorubicin, HDMTX A-
Cisplatin, Doxorubicin, HDMTX, MTP (Mepact)
Ifosfamide, Cisplatin, Doxorubicin, HDMTX, MTP (Mepact) A+ B- B
Ifosfamide
Doxorubicin
HDMTX
Ifosfamide, Cisplatin, Doxorubicin, HDMTX B+
The first question was a comparison of three drug chemotherapy without ifosfamide to four drug chemotherapy including ifosfamide.
The second question was whether the addition of MTP to the maintenance therapy would improve the outcome.
The objective of this design was to answer each question independently, that is to determine the efficacy of MTP by comparing the patients in both groups assigned to receive MTP (A+ and B+) to the the patients in both groups assigned not to receive MTP (A- and B-). This was the prospective design of the study. In the course of the study we the COG enrolled 662 patients with localized osteosarcoma. 20 27 36
Weeks
Regimens A and B: Doxorubicin x 6 ea (25 mg/m2/day x 3), Cisplatin x 4 ea (120 mg/m2), and Methotrexate x 12 ea (12 g/m2)
Regimen B only: Ifosfamide x 5 ea (1.8 g/m2/day x 5)
HDMTX = High-Dose Methotrexate;
Adapted from:
Meyers PA et al. J Clin Oncol 2005;23:
Meyers PA et al. J Clin Oncol 2008;26: 51

52. POG/CCG
Meyers et al
2005

53. Event-free Survival by Chemotherapy Assignment
Meyers PA et al. J Clin Oncol 2008;26:

54. Overall Survival and Event-free Survival by Mifamurtide Assignment
p=0.03, HR 0.71
(CI: 0.52, 0.96)
p=0.08, HR 0.8
(CI: 0.62, 1.00)
Meyers PA et al. J Clin Oncol 2008;26:

55. What about metastatic disease?

56. What is the best management for metastases?
Avoid getting them in the first place!
Surgery
Chemotherapy

57. Mifamurtide?
Cancer 2009;115:

59. Patient
Sex
Age
Diagnosed
Primary site
Surgery
Mets
Completed treatment
Alive
Dead
Date of 1st post op MAP
Date of first Mifamurtide
Notes IZ F 13
Jun-11
L humerus
EPR
Jul-12 A
1st patient started when drug approved. Headaches GP 12
Mar-12
R femur
Mar-13 HB 8
Apr-12
L femur
Jun-13 HE M 7 JR 14
Jun-12
R tibia
Fibula graft
Jul-13 JB
L tibia
Lung
Aug-13
DOD
Funding delayed start of Mepact. Nearly completed all Mepact doses when relpase detected BT
Sep-12
Amputation
Sep-14
Emergency amputation after first Cis/Dox dose received RJ
May-14
Prolonged wound infection post-op. MTX-induced encephalopathy after 2nd dose of Mepact NJ
Nov-13
Dec-14
3.4.14
Omitted final 2 doses of Dox for reduced FS, replaced with 2 extra doses of MTX JM
July-15
1.9.14
MTX-induced leukoencephalopathy BC 10
Oct-15
5.1.15 RM
Feb-15
Mar-16 HM
May-16
Jun-17

60. What about new agents?

61. Tyrosine kinase inhibitors M-Tor pathway inhibitors PDL-1 CAR T-cells
New agents
Zoledronate
Data from France suggesting worse outcome
Anti-GD2 MoAb
Denosumab
Tyrosine kinase inhibitors
M-Tor pathway inhibitors
PDL-1
CAR T-cells

62. Genetically chaotic tumour Combination with chemotherapy challenging
The challenges
Genetically chaotic tumour
Unlikely single pathway will be effective therapeutically
Combination with chemotherapy challenging
How to determine if the agents work
Lumps of “chalk” don’t shrink
? PFS end points, but reliable controls…..
Patients often very end stage when come to Phase I/II

63. Immune therapies may hold some promise?
Conclusions
We are stuck!
“Gold standards”
At least 3 chemotherapy drugs (+/- Mepact)
Complete surgical resection of all disease
Includes metastases
New molecularly targeted therapies likely to have limited benefit on a genetically chaotic tumour
Immune therapies may hold some promise?

64. תודה