This document discusses several dilemmas in treating soft tissue sarcomas including whether repeat histopathology is needed at recurrence, options for first line chemotherapy including ifosfamide/doxorubicin vs doxorubicin alone vs olaratumab plus doxorubicin. It also discusses considerations for first line treatment in elderly populations and non-anthracycline regimens. Other topics covered include toxicities of pazopanib seen in Indian patients, use of trabectidin beyond its FDA approved indication, analysis of the eribulin approval, and role of histology-directed and immunotherapy approaches. Multidisciplinary care is emphasized as mandatory for optimal sarcoma management.

1. Management of advanced/
metastatic soft tissue sarcomas
Dr Sameer Rastogi
MD, DM Medical Oncology (TMH)
Assistant Professor, AIIMS
Email samdoc_mamc@yahoo.com

2. Dilemmas in treating soft tissue
sarcomas
• Histopathology
• First line ? I +A vs single agent A vs Olaratumab +A
• First line in elderly population and Non doxo regimen
• Toxicities of pazopanib and evidence in India
• Trabectidin – use goes beyond FDA approved indication
• Eribulin – my take
• Histology and drugs (n now immunotherapy) are not
limited

3. Multidisciplinary care
• Mandatory in all cases
• Pathologists, radiologists, surgeons, radiation
oncologist, medical oncologists and paediatric
oncologists, nuclear medicine specialists, organ-
based specialist, plastic surgeon
• NCCN-- patients with sarcoma should be managed,
but not necessarily treated, by a multidisciplinary
panel who have heavy experience

4. • Compared sarcoma unit’s histopathology
reports with referring reports on 349
specimens
• Diagnostic agreement was found only 256/
349 cases (73.4%)
• Further supported NICE guidelines that all
cases of sarcoma should be reviewed by bone
and soft tissue specific pathologist
Thway et al. Sarcoma.
Volume 2009 (2009), Article ID 741975

5. Histopathological review by expert
pathologist
• Over 1 year 2016 -2017
• N=97 patients (outside biopsy report vs AIIMS)
• Major discrepancy -37%, Minor discrepancy
24%
Discordance of histo-pathological diagnosis of patients with soft tissue sarcoma referred to
tertiary care center.
Sameer Rastogi, Aditi Aggarwal, Kamal Raj Soti et al.
Journal of Clinical Oncology 2017 35:15_suppl, 11064-11064

7. Metastatic setting – histology
directed treatment
• Desmoid, DFSP, PVNS, Chordomas- Imatinib
• Non adipocytic STS- Pazopanib
• Angiosarcoma- Weekly pacli, Gemcitabine,
antiangiogenic drugs, propanolol
• IMFT- ALK inhibitor
• SFT, ASPS, Desmoids- VEGFR inhibitors
• Dedifferentiated liposarcoma – CDK inhibitors
• PEComas and MPNST – mTOR inhibitors
• Liposarcoma and leiomyosarcoma (eribulin for
lipo and trabectidin for both lipo and leiomyo)

8. Dilemmas in treating soft tissue
sarcomas
• Repeat histopathology- Is it needed at recurrence
• First line ? I +A vs single agent A vs Olaratumab +A
• First line in elderly population and Non doxo regimen
• Toxicities of pazopanib and evidence in India
• Trabectidin – use goes beyond FDA approved indication
• Eribulin – my take
• Histology and drugs (n now immunotherapy) are not limited
• Whom not to treat?

9. Doxorubicin vs Ifosfamide/ ifosfamide
equivalents plus doxorubicin
• EORTC 62012-Ifosfamide plus doxo vs
doxorubicin
• PICASSO III -Palifosfamide plus doxorubicin vs
doxorubicin
• SARC 021 – Evofosfamide plus doxorubicin vs
doxorubicin Judson, I et al. Lancet oncol, 2014;15:415-423
Ryan et al. J Clin Oncol 2016 34:3898-3905
Tap et al. Lancet oncol, 2017;18:1089-1103

10. Combination vs single agent
doxorubicin
Trial name Response
rate (%)
PFS (months) OS (months) %
leiomyosarcomas
EORTC 62012 26 vs 14
(p=0.006)
7 vs 4.6 months
(P=0.002)
14.3 vs 12.8
(P=0.76)
24%
PICASSO III 28.3 vs 19
(p=0.047)
6 vs 5.2 months
(p= 0.19)
16.9 vs 15.9
(p=0.74)
30%
SARC 021 28 vs 18
(p=0.003)
6.3 vs 6 months
P= (0.09)
18.4 vs 19
(NS)
35%
AIIMS
Sarc.clinic
6 months 16 months SS-22%
Judson, I et al. Lancet oncol, 2014;15:415-423
Ryan et al. J Clin Oncol, 2016 34:3898-3905
Tap et al. Lancet oncol, 2017;18:1089-1103
Rastogi et al J Clin Oncol 36, 2018 (suppl; abstr e23561)

11. • Fully monoclonal antibody against PDGFRα expressed in
tumour cells and stroma.1
• Inhibits tumor cell proliferation, angiogenesis, enhances
activity of doxorubicin in preclinical model.
• FDA approval on the basis of randomized phase 2 trial.2
1. Tonra J et al. AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics International
Conf., PA USA Nov 2005
2. William Tap et al. Lancet 2016

12. Olaratumab +doxo vs doxo (n=133)
Objective response rates – 18% vs 12% (p value =0.3)

14. Olaratumab plus doxorubicin (why doubts?)
• Phase 2 randomized trial
• Disproportionate PFS and OS benefit
• Lack of correlation between pharmacodynamic marker of
PDGFR alpha inhibition and drug efficacy
• ANNOUNCE study awaited in next 2 years (phase 3)
William Tap et al. Lancet 2016
https://clinicaltrials.gov/ct2/show/NCT02451943

15. Dilemmas in treating soft tissue
sarcomas
• Repeat histopathology- Is it needed at recurrence
• First line ? I +A vs single agent A vs Olaratumab +A
• First line in elderly population and Non doxo regimen
• Toxicities of pazopanib and evidence in India
• Trabectidin – use goes beyond FDA approved indication
• Eribulin – my take
• Histology and drugs are not limited

16. First line of chemotherapy (any
alternative to doxorubicin??)
• Elderly ?
• Patients with low ejection fraction
• Is gemcitabine/ docetaxel more effective in
Leiomyosarcoma

17. Seddon et al. Lancet 2017

20. • The end point of progression free rate is unique (PFR)
for a phase 3 trial
• PFR at 3 months and 6 months showed no correlation
with overall survival (OS) in a recently conducted meta
analysis1
• Leiomyosarcoma analysis was subgroup analysis and
should be taken with caution as it was not powered for
this
1. J Clin Oncol. 2016 May 1;34(13):1469-75

21. The first line for elderly
• Have different preferences
• Might have more toxicities
• Quality of life needs to be reasonably good

23. PFS in per protocol population

24. Key secondary endpoints

25. Ethical/ other dilemmas I can think of
• Repeat histopathology- Is it needed at recurrence
• First line ? I +A vs single agent A vs Olaratumab +A
• First line in elderly population and Non doxo regimen
• Toxicities of pazopanib and evidence in India
• Trabectidin – use goes beyond FDA approved indication
• Eribulin – my take
• Histology and drugs are not limited

26. `
Rastogi S, Sankhala KK and Chawla SP. Recent Advances in Advanced Sarcoma Therapy: Medical Oncologist’s Perspective
. SM J Orthop. 2016; 2(3): 1040.

27. No cross over was permitted
Quality of life assessment was
done and reported

28. PALETTE Trial

29. PALETTE Trial

30. Toxicities of pazopanib
Toxicities * Grade 3 and 4
Fatigue 13%
Hypertension 7%
Diarrhoea 5%
Vomiting 3%
Rash 1%
*Graaf et al. Lancet 2012/ PALETTE trial

31. Pazopanib toxicity in Indian Patients
• Literature is limited regarding pazopanib toxicity in
Indian patients with STS
• Data presented (n=28) in ESMO Asia 2017 suggested
hand foot syndrome was the most common toxicity
• Data presented at ICON 2018 (n=43), suggested only
11% patients could be escalated to 800 mg dose
Aparna Sharma, Rastogi S et al.Pazopanib toxicity in a metastatic sarcoma cohort
: Are Indian patients different? Annals of Oncology (2017) 28 (suppl_10)
Atul sharma ,Rastogi S et al. Poster ICON 2018.

32. Variables Number
Mean duration of
Pazopanib intake
4.4 months
Overall Response
rates
13.9 %
Median PFS 5.2 months
Median OS Not reached

34. • 59 year lady with pain abdomen
• Multiple liver lesions
• Biopsy suggestive of Epitheloid hemangioendothelioma
• Received thalidomide +cyclophosphamide outside
Outliers and exceptional responders

35. Started on pazopanib 400mg
Pazopanib
plus propanolol

36. Case 2
Started on pazopanib 400mg

37. Ethical dilemmas I can think of
• Repeat histopathology- Is it needed at recurrence
• First line ? I +A vs single agent A vs Olaratumab +A
• First line in elderly population and Non doxo regimen
• Toxicities of pazopanib and evidence in India
• Trabectidin – use goes beyond FDA approved indication
• Eribulin – my take
• Histology and drugs are not limited

38. • N=270
• 3 weekly schedule vs weekly schedule
• Median PFS 3.3 months vs 2.3 months
• 2007 – Approval from European Medical Agency
• No FDA approval till 2015
Demetri et al. Journal Clin Oncol, 2009.

39. Cross over to trabectidin was not permitted

40. 4.2 vs 1.5 months

42. Progression free survival

43. Continued..

44. Grade 3 -4 toxicities of trabectidin
Toxicities profile (Grade
¾)
Trabectidin Dacarbazine
Neutropenia 37% 21%
Anemia 14% 12%
Thrombocytopenia 17% 18%
SGPT/ SGOT elevation 39% 1%
CPK elevation 5.3% 0.6%
Rhabdomyolysis 1.2% 0
Extravasation

45. Case 1
• 58 year gentleman baseline presentation 2016
• Metastatic leiomyosarcoma visceral
• After ifosfamide and adriamycin
• After gemcitabine and docetaxel
• After pazopanib PR progressive disease1
• Now started on trabectidin
1. Mehta, V., Rajawat, M., Rastogi, S., Phulware, R. H., & Mezencev, R. (2018). LMS of the
stomach with metastasis to the liver: a case report with review of the literature. Future Science OA,

47. • Multicentre, open label, phase 2 trial.
• Trabectidin (n=39) vs best supportive care (n=37)
• Primary end point progression free survival
Kawai et al. Lancet Oncology 2015. Volume 16, No. 4, p406–416

48. Trabectidin in translocation related
sarcomas
5.6 months vs 0.9 months

50. Trabectidin in mesenchymal
chondromsarcoma
• 37 year old gentleman
• Jan 2016 – Metastatic pelvic mesenchymal
chondrosarcoma
• Post Ewings like protocol PR  PD
• No option Jan 2017 –progressive diease (new nodules
in lungs and bones
• Started on trabectidin based protocol

52. Ethical dilemmas I can think of
• Repeat histopathology- Is it needed at recurrence
• First line ? I +A vs single agent A vs Olaratumab +A
• First line in elderly population and Non doxo regimen
• Toxicities of pazopanib and evidence in India
• Trabectidin – use goes beyond FDA approved indication
• Eribulin – my take
• Histology and drugs are not limited

53. • Background –
• Microtubule dynamics inhibitor/vascular remodelling/
reverses EMT transition.
• 3 month PFR was 32% in LMS
47% in Liposarcoma
Schöffski et al. Lancet 2016. Volume 387, No. 10028, p1629–1637

56. PFS- 2.6 months vs 2.6 months

58. Maggioni et al. Cardiology 2007;107:97–102
Rastogi S, Gupta V. Eribulin approval in advanced
liposarcoma – successful drug or a weaker methodology?.
Indian J Med Paediatr Oncol 2017

59. Ethical/ Other dilemmas I can think of
• Repeat histopathology- Is it needed at recurrence
• First line ? I +A vs single agent A vs Olaratumab +A
• First line in elderly population and Non doxo regimen
• Toxicities of pazopanib and evidence in India
• Trabectidin – use goes beyond FDA approved indication
• Eribulin – my take
• Histology and drugs are not limited

60. Metastatic setting – histology
directed treatment
• Desmoid, DFSP, PVNS, Chordomas- Imatinib
• Non adipocytic STS- Pazopanib
• Angiosarcoma- Weekly pacli, Gemcitabine,
antiangiogenic drugs, propanolol
• IMFT- ALK inhibitor
• SFT, ASPS, Desmoids- VEGFR inhibitors
• Dedifferentiated liposarcoma – CDK inhibitors
• PEComas and MPNST – mTOR inhibitors
• Liposarcoma and leiomyosarcoma (eribulin for
lipo and trabectidin for both lipo and leiomyo)

61. Rastogi S et al. Journal of Global Oncology 2018 Jul;(4):1-7. doi: 10.1200/JGO.18.00007

62. ASPS – patient 1.. scalp with lung and bone metastasis
progressive disease on 1st line
2016 vs 2018 status
On sunitinib 37.5mg per day – Recist Stable disease (DFI 2 years)

63. Patient 2 = Gluteal ASPS with lung metastasis
on Sunitinib

64. Patient 2 = Gluteal ASPS with lung metastasis
on Sunitinib

65. Metastatic
angiosarcoma
April 2017
June 2018
s/o complete remission
Treated on
Ppnl
+vinblastine+Methotrexate
(Pasquier et al ebiology
2016)

66. Metastatic ASPS patient PD on TKIs
Ppnl+meth
+vinbl

67. Immunotherapy in Soft tissue
sarcomas and LMS
• Sarc 028 study – 7 out of 40 patients had
objective response rate (UPS, LPS, SS)
• In SARC 028 no patient with leiomyosarcoma
had any response (n=10)
• In two stage design- First stage 12 patients
with uLMS were taken and treated with single
agent nivolumab. No patient responded.
Tawbi et al. SARC 028 Lancet 2017
George et al. Cancer 2017;123:3285‐90

68. Combination immunotherapy
• Nivolumab and nivolumab plus iplimumab
• 38 patients in both arms
• 2/38 (5%) response in single agent nivolumab
and 6/38 (16%) in the combination arm
Sandra P D’Angelo et al. Lancet oncol 2018

69. Ethical/ Other dilemmas I can think of
• Repeat histopathology- Is it needed at recurrence
• First line ? I +A vs single agent A vs Olaratumab +A
• First line in elderly population and Non doxo regimen
• Toxicities of pazopanib and evidence in India
• Trabectidin – use goes beyond FDA approved indication
• Eribulin – my take
• Histology and drugs are not limited

70. Thanks
especially department of medical oncology,
pathology, surgical oncology, orthopedics,
radiology, palliative care, radiation oncology