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Metastatic soft tissue sarcoma options
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.
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Metastatic soft tissue sarcoma options
- 1. Management of advanced/ metastaticsoft tissue sarcomas Dr Sameer Rastogi MD, DM Medical Oncology (TMH) Assistant Professor, AIIMS Email samdoc_mamc@yahoo.com
- 2. Dilemmas in treatingsoft 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 • Mandatoryin 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 sarcomaunit’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 byexpert 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 treatingsoft 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 singleagent 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 monoclonalantibody 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 vsdoxo (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 treatingsoft 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 ofchemotherapy (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 endpoint 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 linefor elderly • Have different preferences • Might have more toxicities • Quality of life needs to be reasonably good
- 23. PFS in perprotocol population
- 24.
- 25. Ethical/ other dilemmasI 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, SankhalaKK and Chawla SP. Recent Advances in Advanced Sarcoma Therapy: Medical Oncologist’s Perspective . SM J Orthop. 2016; 2(3): 1040.
- 27. No cross overwas permitted Quality of life assessment was done and reported
- 28.
- 29.
- 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 inIndian 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 durationof Pazopanib intake 4.4 months Overall Response rates 13.9 % Median PFS 5.2 months Median OS Not reached
- 34. • 59 yearlady with pain abdomen • Multiple liver lesions • Biopsy suggestive of Epitheloid hemangioendothelioma • Received thalidomide +cyclophosphamide outside Outliers and exceptional responders
- 35. Started on pazopanib400mg Pazopanib plus propanolol
- 36. Case 2 Started onpazopanib 400mg
- 37. Ethical dilemmas Ican 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 • 3weekly 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 totrabectidin was not permitted
- 40. 4.2 vs 1.5months
- 42.
- 43.
- 44. Grade 3 -4toxicities 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 • 58year 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, openlabel, 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 translocationrelated 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 Ican 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 monthsvs 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 dilemmasI 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 etal. Journal of Global Oncology 2018 Jul;(4):1-7. doi: 10.1200/JGO.18.00007
- 62. ASPS – patient1.. 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/ocomplete remission Treated on Ppnl +vinblastine+Methotrexate (Pasquier et al ebiology 2016)
- 66. Metastatic ASPS patientPD on TKIs Ppnl+meth +vinbl
- 67. Immunotherapy in Softtissue 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 • Nivolumaband 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 dilemmasI 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 ofmedical oncology, pathology, surgical oncology, orthopedics, radiology, palliative care, radiation oncology
Editor's Notes
- #4 Decreases the time, keep each other informed, physicians and surgeons know are on same page helping the patient, shares responsibility , Latest advances can be shared. Team progresses together..
- #10 Palifosfamide is the active metabolite of ifosfamide and does not require prodrug activation, thereby avoiding the generation of toxic metabolites Evo is a hypoxia-activated prodrug preferentially activated under hypoxic conditions to release the DNA alkylator Br-IPM
- #12 Locally advanced or metastatic soft tissue sarcomas who have not received previous anthracyclines. 59% have received previous lines of therapies.
- #15 suggesting a potential paradigm shift in the treatment of soft-tissue sarcoma. , suggesting that the inhibitory eff ect of olaratumab on tumour and stromal PDGFRα signalling might persist beyond the immediate treatment period.
- #18 Phase 3 multicentre trial
- #19 Toxicity was such that 16% of patients had to abandon gem docetaxel chemotherapy as compared to single agent doxorubicin 2%
- #28 44% were Leiomyosarcoma 12% were synovial sarcoma
- #39 either at 1.5 mg/m 2 over 24 hours every 3 weeks or at 0.58 mg/m 2 over 3 hours weekly for 3 weeks on a 28-day cycle. All patients were premedicated with dexamethasone 20 mg intravenously 30 minutes prior to trabectedin
- #45 Myelosuppression appears to be dose dependent, with median nadir at approximately 14 days. Trabectedin neutropenia seems to be largely dependent on the total dose administered, but not the duration of infusion (68). Reversible increases in serum transaminases, bilirubin, and alkaline phosphatase are also observed, and as noted above are the most important toxicity to consider with this unique agent. Significant abnormalities in the liver transaminases reaching grade 3-4 have been seen in approximately 50% of patients. The elevation generally starts 2-5 days after trabectedin administration, reaching a maximum level between days 5-9.
- #48 Preclinical evidence that it also modulates the transcription of oncogenic fusion protein in translocation related sarcomas. Synovial sarcoma, emc, dfsp, mesenchymal chondrosarcoma, myxoid liposarcoma, alveloar rhabdomyosarcoma , clear cell sarcoma, alveolar rhabdomyosarcoma.
- #54 Eribulin- mode of action is distinct from other tubulin inhibitors. Binds to specific site of growning end of
- #55 Results of this study were intriguing as it is one of the first study to show the overall survival benefit for drug in soft tissue sarcoma.