1) Chemotherapy has improved survival rates for osteosarcoma dramatically over the past 30 years from less than 20% to between 40-60% through the use of effective combination chemotherapy and neoadjuvant treatment. 2) Key trials showed that neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy improved relapse-free and overall survival compared to surgery alone. 3) The combination of doxorubicin and cisplatin administered every 3 weeks is now considered the standard first-line chemotherapy regimen based on results from large cooperative trials.

1. Chemotherapy in Adult
Osteosarcoma
Presenter: Dr. Krushna Chaudhari
Moderator: Dr. Mansi Sharma

2. Introduction
• Most common primary bone tumour of children
and young adults
• Median age of occurrence : 20 years
(> 65 year age : Secondary to Paget's disease of bone)
• 3 Types –
– Intramedullary
– Surface
– Extraskeletal

3. Introduction
• High grade intramedullary OS – Conventional form
(80% of OS are high grade intramedullary OS)
• Low grade intramedullary OS – Uncommon entity
(<2% of all OS)
• Juxtacortical/Surface variant:
• Parosteal OS – Low grade lesions
• Periosteal OS – Intermediate grade lesions
Conversion of low grade parosteal OS to high grade OS has
been reported in 25-40% cases

5. The current management strategy
NACT Sx
ADJ
CT
For newly diagoned

6. Natural history of treatment
• The survival of patients with malignant bone sarcomas has
improved dramatically over the past 30 years, largely as a
result of the use of effective chemotherapy.
• Previously 80 to 90 percent of patients with bone
sarcomas developed metastases despite achieving local
tumor control, and died of their disease.
• It was surmised (and subsequently demonstrated) that
subclinical metastatic disease was present at the time of
diagnosis in the majority of patients and that
chemotherapy can successfully eradicate these deposits if
initiated at a time when disease burden is low.

7. No Adjuvant treatment

8. CT Agent Response rates
Adriamycin 15%
CDDP 17%
High dose MTX 20%
IFOSFAMIDE 20%
• 1960-1970’s – Trials of single agent chemotherapy
•Early trials identified cisplatin (DDP), doxorubicin
(DOX), and high-dose methotrexate (HD-MTX) as the
most active agents.

9. Combination chemotherapy
• Due to the disappointing results with single agent
chemotherapy, various agents were tried in
combination.
• With use of combination chemotherapy five-year
survival rates rose from less than 20 percent to
between 40 and 60 percent.
• Two subsequent randomized studies conducted in the
1980s demonstrated a significant relapse-free and
overall survival benefit for adjuvant chemotherapy that
persisted over time

10. Adjuvant Chemotherapy
MIOS Trial:
• Aim – To determine whether intensive multi-agent adjuvant
chemotherapy improves the chances of relapse-free survival
in patients with non metastatic high-grade osteosarcoma of
the extremity as compared with concurrent controls.
• 36 patients were randomly assigned to adjuvant
chemotherapy(BCD+HDMTX+DOX+CDDP) or to observation
without adjuvant treatment
• At 2 yrs the actuarial relapse-free survival was 17 percent in
the control group, and 66 percent in the adjuvant-
chemotherapy group (P<0.001)

11. MIOS TRIAL
At 2 Years, RFS – Observation arm – 17%
Adjuvant chemo arm – 66%

12. TIMING OF CHEMOTHERAPY???
ADJUVANT VS NACT

13. Neoadjuvant Chemotherapy
• The concept of neo adjuvant chemo in OS evolved
from early attempts at limb salvage surgery at
Memorial Sloan Kettering
• As fabrication of the prosthesis required 2-3 months
pts were treated with chemotherapy
• This concept first introduced by Rosen, not only
facilitated surgical resection but also allowed for
histological evaluation of response to treatment

14. Pros
• ??limb-salvage surgery is facilitated by
presurgical chemotherapy
• It immediately treats micrometastatic disease
and the primary tumor.
• Identification of risk groups by evaluating
pathologic responses of primary tumors after
resection

15. Cons
• It exposes a large tumor burden to potentially
marginally effective chemotherapy, which may
encourage development of distant metastases
from chemotherapy-resistant cells.

16. Neoadjuvant v/s adjuvant chemo
• Younger than 30 yrs
• Patients with Non metastatic OS who were assigned randomly to
immediate surgery or pre surgical chemotherapy
• 100 pts (45 to immediate chemo, 55 to immediate Sx)
• 5 yr EFS 69% for immediate surgery and 61% for pre surgical
chemotherapy
• The treatment arms had similar incidence of limb salvage (55%
for immediate surgery and 50% for pre surgical chemotherapy)

17. POG 8651

18. POG 8651:

19. • Advantages of Neoadjuvant chemotherapy:
- Similar rates of OS/DFS and limb salvage surgery
- More time for planning of surgery
- Response to chemotherapy can be assessed
POG 8651

20. Initial trials assessing good- and poor-
responder groups revealed that
• Those with more than 90% necrosis after
neoadjuvant chemotherapy had a greater
than 90% 5-year event-free survival.
• For patients with poor histologic response,
considered to be less than 90% necrosis, the
5-year survival was only 50% to 60%

21. Role of Doxorubicin and Cisplatin

22. Cooperative German/Austrian/Swiss
Osteosarcoma study group (COSS)
• COSS 80
• COSS 82
• A series of trials from the German/Austrian/Swiss
Cooperative Osteosarcoma Study Group (COSS)
has clarified the use of cisplatin and doxorubicin
in osteosarcoma.
• In the COSS-80 trial, patients were randomized
to chemotherapy with doxorubicin and
methotrexate in all patients and either cisplatin
or BCD. Outcomes were similar between arms.

23. COSS 80/ COSS 82

24. COSS 80/ COSS 82
• COSS 80:
– MAP vs MA – BCD : Similar Outcomes
• COSS 82:
– MAP vs MBCD :
• Inferior disease free survival in M BCD arm
• Even though patients with poor response were shifted
to adramycin/cisplatin arm, the survival remained poor
for this arm – suggesting role of early doxorubicin.
– MFS of the study arm of COSS-82 45% at 5 years vs. 68%
for the control arm with primary use of ADR and CDDP, p
less than 0.05

25. Will altering therapy in patient with
poor necrosis benefit ????
• An initial attempt to alter therapy indicated a
benefit for those who had poor
necrosis.However, longer follow-up of these
patientsand additional studies by other
investigators have not been able to reproduce
that result
Winkler K (COSS-82) with salvage chemotherapy based on histological tumor
response. J Clin Oncol. 1988;6:329–337.
Meyers PA, . Chemotherapy for nonmetastatic osteogenic sarcoma: The Memorial
Sloan-Kettering experience. J Clin Oncol. 1992;10:5–15.

26. Role of HDMTX in osteosarcoma
• Majority of the protocols in Osteosarcoma
used High Dose methotrexate
• HDMTX has shown benefit in age<40years
• Role of HDMTX has been questioned in a few
trials
• Various trials have been done with conflicting
results

27. • In an Italian trial patients were given either
200mg/m2 or 2 gm/m2 as multi agent chemo
and similar results were obtained
• Similarly UK children cancer study group
conducted comparing 2 doses of MTX – 690
mg/m2 v/s 7.5 gm/m2 and found similar
outcomes.
Role of HDMTX in osteosarcoma

28. INT 0133 TRIAL
• The Italian Sarcoma Group conducted a randomized trial evaluating the
role of ifosfamide both in neoadjuvant and adjuvant phases of therapy.
• Patients with localized osteosarcoma were randomized to receive
methotrexate, cisplatin, and doxorubicin with or without ifosfamide
preoperatively.
• Patients randomized to not receive ifosfamide preoperatively could have
ifosfamide added postoperatively if they had a poor histologic response to
neoadjuvant chemotherapy without ifosfamide.
• Of 246 randomized patients, the proportion of patients with a good
histologic response and event-free survival were similar between
randomized groups.
• Given increased hematologic toxicity associated with the ifosfamide arm,
the authors concluded that ifosfamide should be reserved for the adjuvant
setting in patients with poor histologic response to neoadjuvant therapy
without ifosfamide

29. Role of Ifosfamide: INT-0133

30. INT-0133

31. • Results of INT-0133 , reporting on event-free
survival, suggested an interaction between the
experimental strategies that precluded statistical
analysis.
• However, additional follow-up and use of an
overall survival end point suggested no evidence
of such an interaction, and a significant
improvement in overall survival was observed for
patients receiving mifamurtide, regardless of
chemotherapy regimen.
• The addition of MTP to chemotherapy improved
6-year overall survival from 70% to 78% (P = .03).

32. • Mifamurtide has been approved in Europe for
the treatment of patients with osteosarcoma
• mifamurtide is unavailable in the United
States.
• This study did clearly establish the lack of
benefit of the addition of ifosfamide

34. European OS intergroup trial
• Doxorubicin/cisplatin vs MIOS protocol:
- Doxorubicin/ cisplatin found much better in terms of
recurrence free survival
• Same Group compared 3 weekly schedules of
Doxorubicin/cisplatin with 2 weekly schedule:
- 2 weekly schedule – Good histological response
but OS/PFS same – similar arms

35. • Since doxo / cis is small duration of chemo and asso
with less side effects MIOS chemo not used any more

36. EOI
• six cycles [18 weeks] of doxorubicin 25 mg/m2
on days 1-3 and cisplatin 100 mg/m2 on day 1
Vs
MIOS regimen

37. Equivalent results in both the groups
• Good histopathological response (> 90% tumour
necrosis)- about 29% with both regimens and was
strongly predictive of survival.
• Overall survival was 65% at 3 years and 55% at 5
years in both groups (hazard ratio 0.94 [95% CI
0.69-1.27]).
• Progression-free survival at 5 years was 44% in
both groups (hazard ratio 1.01 [0.77-1.33]).

38. Interval compression to dose
intensification
• EOI evaluated
• DOXO/CIS 2 weekly with G-CSF support vs 3
weekly
• Better histological response -50 vs 36%
• Simillar OS and PFS
Lewis IJ, Nooij MA, Whelan J, et al. Improvement in histologic response but not
survival in osteosarcoma patients treated with intensified chemotherapy: A
randomized phase III trial of the European Osteosarcoma Intergroup. J Natl
Cancer Inst. 2007;99:112–128.

39. EUROMAS TRIAL
• The first European-American osteosarcoma study 1 sought to clarify further the
role of IE in patients with newly diagnosed resectable osteosarcoma.
• All patients received neoadjuvant chemotherapy with MAP, which has become a
consensus standard neoadjuvant chemotherapy regimen for patients with newly
diagnosed osteosarcoma.
• Patients with a good histologic response (<10% viable tumor) were eligible for
randomization evaluating the role of adjuvant interferon (see the following).
• Patients without a good histologic response to neoadjuvant chemotherapy (≥10%
viable tumor) were eligible to be randomized to receive ongoing adjuvant
chemotherapy with MAP or to receive ongoing adjuvant chemotherapy with MAP
with the addition of IE.

40. EUROMAS 1
2260 patients were registered from 325 sites
in 17 countries.
2260 patients were
registered from 325 sites
in 17 countries.

44. Comparison of MAPIE versus MAP in
patients with a poor
response
• Median follow-up was 62・1 months
• EFS- 153 in the MAP group vs 154 in the MAPIE group
• Deaths- 101 in the MAP group vs 92 in the MAPIE group
• MAPIE was associated with more frequent grade 4
• Non-haematological toxicity than MAP (35 [12%] of 301 in
the MAP group vs 71 [24%] of 298 in the MAPIE group).

45. • The POG conducted a trial for patients with newly
diagnosed metastatic osteosarcoma in which all
patients received two courses of IE prior to
surgical resection of the primary tumor.
• The overall response rate after two courses of IE
was 59%. This study design allowed histologic
response of the primary tumor to be assessed,
with 65% of patients having at least 90% tumor
necrosis after two cycles of IE.

46. • The French SFOP OS94 trial sought to determine whether doxorubicin
could be replaced by ifosfamide and etoposide in the management of
patients with newly diagnosed localized osteosarcoma.
• Patients were randomized at study entry to receive neoadjuvant
chemotherapy with high-dose methotrexate in all patients and either
doxorubicin or IE.
• Adjuvant therapy was determined by histologic response to neoadjuvant
chemotherapy. The primary end point was histologic necrosis at the time
of surgery.
• Among 234 evaluable patients, there was a significantly higher rate of
good histologic necrosis in patients randomized to IE compared to
doxorubicin.
• These results demonstrate the activity of IE in this setting, though must be
viewed in light of the fact that patients in the comparator arm received
doxorubicin without cisplatin.

48. • There were 56% good responders in the
etoposide-ifosfamide arm versus 39% in the
doxorubicin arm (pvalue = 0.009).
• No statistically significant difference in EFS
and OS.

49. • N=45
• Epirubicin 90 mg/m(2), cisplatin 100 mg/m(2) on day 1 and
ifosfamide 2.0 g/m(2)/day with an equivalent dose of
mesna on days 2-4, repeated every 21 days. Six cycles of
this combination regimen were administered (3 cycles prior
to surgery and 3 cycles postoperatively).
• Complete n good histological response-26% ,37%
• The 5-year disease-free and overall survival rates were
41.9% (95% CI 33.6-50.2) and 48.2% (95% CI 39.6-56.8).
• The most prominent grade 4 toxicity was neutropenia
occurring in 32% of patients

50. Metastatic disease at presentation
• In trials ,long-term survival rates in Metastatic
setting
For CT+Sx vs Sx (48% and 5%, respectively).

53. Sorafenib in RROS
• In a phase II trial of the Italian Sarcoma Group (n = 30),
sorafenib (VEGFR inhibitor) demonstrated activity in
patients with relapsed and unresectable high-grade
osteosarcoma after failure of standard multimodal
therapy.
• In patients >14 years
• The PFS at 4 months (primary endpoint) was 46%.
• Median PFS and OS were 4 months and 7 months,
respectively.
• Partial response and stable disease were seen in 8%
and 34% of patients, respectively, and were durable for
6 months or more in 17% of patients.

54. Relative contraindications
to a limb salvage effort
• Major neurovascular involvement
• Very immature skeletal age
• Infection
• Lack of reconstruction (e.g., very distal anatomic
location) or soft tissue coverage options
• Contamination secondary to biopsy technique
and complications,
• Inability to obtain oncologically acceptable
margins,
• Pathologic fracture.

55. THANK YOU