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6. Recent Advances. in soft tissue sarcoma
- 1. MANAGEMENT OF METASTATICSOFT MANAGEMENT OF METASTATIC SOFT TISSUE SARCOMA AND RECENT TISSUE SARCOMA AND RECENT ADVANCES ADVANCES Dr. G. Anitha Dr. G. Anitha PG in Surgical oncology PG in Surgical oncology Department of Surgical oncology Department of Surgical oncology Government Royapettah Hospital Government Royapettah Hospital PROF R. RAJARAMAN UNIT
- 2. METASTATIC STS METASTATIC STS 50% develop metastases 50% develop metastases Most common Site of Most common Site of metastases: lung metastases: lung Other sites: liver, lymph nodes Other sites: liver, lymph nodes
- 3. Myxoid liposarcoma Myxoidliposarcoma is an exception is an exception which metastatize to areas containing which metastatize to areas containing fat fat Isolated soft tissue masses in pelvis, Isolated soft tissue masses in pelvis, retroperitoneum, mediastinum, retroperitoneum, mediastinum, paraspinal and subcutaneous soft paraspinal and subcutaneous soft tissue and bone marrow tissue and bone marrow are hallmark are hallmark of this subtype of this subtype
- 4. Soft tissue sarcomaswith Soft tissue sarcomas with predilection for predilection for lymph node lymph node mets mets Rhabdomyosarcoma Rhabdomyosarcoma Clear cell sarcoma Clear cell sarcoma Epitheloid sarcoma Epitheloid sarcoma Synovial sarcoma Synovial sarcoma Angiosarcoma Angiosarcoma Incidence of nodal metastases is < 3%
- 5. PRESENTATION PRESENTATION Synchronous in30% Synchronous in 30% 80% present within 2 years 80% present within 2 years Usually asymptomatic until imaging Usually asymptomatic until imaging reveals metastases reveals metastases Occasionally endobronchial involvement Occasionally endobronchial involvement leads to stridor, atelectasis or leads to stridor, atelectasis or postobstructive pneumonia postobstructive pneumonia
- 6. Median survival: 12 months Median survival : 12 months 2yr survival: 20%- 25% 2yr survival: 20%- 25% Exception is Exception is alveolar soft part alveolar soft part sarcoma sarcoma where the survival is where the survival is prolonged even with metastases prolonged even with metastases
- 7. Treatment is individualised Treatmentis individualised based on based on patient factors patient factors disease factors disease factors limitations imposed by prior treatment limitations imposed by prior treatment
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- 9. SURGICAL RESECTION OFPULMONARY METS SURGICAL RESECTION OF PULMONARY METS Surgical resection is the Surgical resection is the cornerstone of treatment cornerstone of treatment 3yr overall survival rate of 30%- 54% 3yr overall survival rate of 30%- 54% 5yr overall survival rate of 25% - 5yr overall survival rate of 25% - 38% 38%
- 10. 40%- 80%will have recurrence 40%- 80% will have recurrence after after resection resection Repeat resection can be done Repeat resection can be done Chemotherapy has no survival benefit Chemotherapy has no survival benefit in patients with pulmonary mets in patients with pulmonary mets irrespective of resection irrespective of resection
- 11. CRITEREA FOR PATIENTSELECTION CRITEREA FOR PATIENT SELECTION The primary tumour is controlled The primary tumour is controlled or controllable or controllable There is no extrathoracic disease There is no extrathoracic disease Adequate predicted postoperative Adequate predicted postoperative pulmonary reserve pulmonary reserve Complete resection of all disease Complete resection of all disease appears possible appears possible Resection can be done even if there are multiple ipsilateral or bilateral mets
- 12. CONTRAINDICATIONS FOR RESECTION CONTRAINDICATIONSFOR RESECTION Poor pulmonary reserve indicated by Poor pulmonary reserve indicated by predicted postop FEV1 <0.8L or <35% predicted postop FEV1 <0.8L or <35% predicted postop DLCO <40% predicted postop DLCO <40% hypercarbia >45mm hypercarbia >45mm hypoxemia <60mm hypoxemia <60mm Presence of hilar and mediastinal Presence of hilar and mediastinal lymphadennopathy lymphadennopathy Presence of malignant pleural effusion Presence of malignant pleural effusion
- 13. PROGNOSTIC FACTORS PROGNOSTIC FACTORS Disease free interval > 1 year Disease free interval > 1 year Number of nodules < 3 nodules Number of nodules < 3 nodules Low grade histology Low grade histology Complete resection Complete resection Favourable factors Unfavourable factors Age > 50yrs Histologies like liposarcoma, MPNST
- 14. TYPE OF SURGICALRESECTION TYPE OF SURGICAL RESECTION Wedge excision with Wedge excision with negative margin negative margin adequate for isolated adequate for isolated pulmonary mets pulmonary mets Lobectomy or Lobectomy or pneumonectomy if mets pneumonectomy if mets is adjacent to is adjacent to pulmonary artery , vein, pulmonary artery , vein, or major bronchus or major bronchus
- 15. APPROACHES FOR UNLATERALMETS APPROACHES FOR UNLATERAL METS VATS Vs Thoracotomy VATS Vs Thoracotomy Advantages of VATS Advantages of VATS: less pain : less pain short hospital stay short hospital stay reoperation is reoperation is easi easier er Dis advantages: lesions < 5mm will be missed Only solitary peripheral lesions are amenable
- 16. APPROACHES FOR BILATERALMETS APPROACHES FOR BILATERAL METS Staged thoracotomy Staged thoracotomy (4-8 weeks interval) (4-8 weeks interval) Median sternotomy Median sternotomy Adv: Less postop pain Adv: Less postop pain Dis adv: Exposure Dis adv: Exposure suboptimal suboptimal Clamshell approach Clamshell approach Adv: execellent exposure Adv: execellent exposure Disadv: more postop pain Disadv: more postop pain
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- 18. Probe is introducedinto the tumour under image guidance High frequency alternating current is transmitted through tip Excitation of molecules Heating of tissues Coagulative necrosis
- 20. INDICATIONS FOR RFA INDICATIONSFOR RFA Elderly patients Elderly patients Poor surgical candidates Poor surgical candidates Other options have been Other options have been exhausted exhausted
- 21. PRE REQUISITES PRE REQUISITES Number of lesions should be < 4 Number of lesions should be < 4 Size of lesion should be < 3cm in diameter Size of lesion should be < 3cm in diameter Lesion should not be adjacent to hilar or Lesion should not be adjacent to hilar or vascular structures vascular structures Emphysematous blebs should not be Emphysematous blebs should not be present around the lesion present around the lesion
- 22. COMPLICATIONS COMPLICATIONS Pneumothorax (mostsignificant) Pneumothorax (most significant) Pleurisy Pleurisy Hemorrhage Hemorrhage Fistula Fistula Infection Infection Effusion Effusion
- 23. STEREOTACTIC BODY RADIOTHERAPY STEREOTACTICBODY RADIOTHERAPY Focussed radiation beams are delivered Focussed radiation beams are delivered exclusively around tumour nidus exclusively around tumour nidus High dose RT in single session or few High dose RT in single session or few fractionated sessions fractionated sessions Can be given both with curative and Can be given both with curative and palliative intent palliative intent Indicated in tumours < 5 cm and in Indicated in tumours < 5 cm and in patients who are poor candidates for patients who are poor candidates for surgery surgery
- 24. CONTRAINDICATIONS CONTRAINDICATIONS Lesions closeto airways Lesions close to airways Centrally located tumours Centrally located tumours Lesions close to mediastinal Lesions close to mediastinal structures structures
- 26. A high potentbiological dose of radiation is delivered to the tumor. Multiple radiation beams directed to the tumor.
- 27. Fiducial markers implantedinto the tumor.
- 28. Respiratory gating technology Respiratorygating technology Fiducials act as localizing and tracking devices. Accurate and precise tumor localization at the time of radiation simulation.
- 29. ADVANTAGES ADVANTAGES Can beused in patients with Can be used in patients with emphysema and COPD emphysema and COPD Patients who are extensively Patients who are extensively pretreated with chemotherapy which pretreated with chemotherapy which affects the pulmonary reserve affects the pulmonary reserve High local control rate is achieved High local control rate is achieved Minimal complications Minimal complications
- 30. There isno current consensus There is no current consensus about the optimal dosage about the optimal dosage Though better local control and Though better local control and low toxicity are observed in various low toxicity are observed in various trials, assessment of survival is trials, assessment of survival is not well studied not well studied Future trials are expected in this Future trials are expected in this regard regard
- 31. CHEMOTHERAPY CHEMOTHERAPY Single agent Singleagent doxorubicin doxorubicin is the reasonable is the reasonable first line option for palliative chemo first line option for palliative chemo For patients who progress or relapse after For patients who progress or relapse after response to doxorubicin, response to doxorubicin, ifosfamide ifosfamide is is indicated as 2 indicated as 2nd nd line drug line drug Single agent chemo is better than Single agent chemo is better than combination chemo combination chemo Various trials revealed no survival benefit Various trials revealed no survival benefit with combination chemo with combination chemo Gemcitabine Gemcitabine and and docetaxel docetaxel combination combination is useful in leiomyosarcomas is useful in leiomyosarcomas
- 32. OTHER PALLIATIVE MEASURES OTHERPALLIATIVE MEASURES Endobronchial laser debulking to Endobronchial laser debulking to establish airway patency in tumours establish airway patency in tumours obstructing main stem bronchus obstructing main stem bronchus EBRT for low grade hemoptysis EBRT for low grade hemoptysis Bronchial artery embolization for Bronchial artery embolization for severe hemoptysis severe hemoptysis
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- 34. NEWER DIAGNOSTIC MODALITIES NEWERDIAGNOSTIC MODALITIES Molecular genetic testing Molecular genetic testing Conventional cytogenetic analysis Conventional cytogenetic analysis FISH FISH RT-PCR RT-PCR Molecular imaging Molecular imaging Optical imaging Optical imaging
- 35. MOLECULAR GENETIC TESTING MOLECULARGENETIC TESTING Sarcomas with specific genetic alterations Sarcomas with specific genetic alterations (simple karyotype) (simple karyotype) chromosomal translocations chromosomal translocations point mutations point mutations Sarcomas with non specific genetic Sarcomas with non specific genetic alterations alterations (complex unbalanced karyotypes) (complex unbalanced karyotypes)
- 37. Useful indiagnosis of certain Useful in diagnosis of certain subtypes of STS where morphological subtypes of STS where morphological and IHC findings are equivocal and IHC findings are equivocal To predict prognosis To predict prognosis Identification of fusion genes aid in Identification of fusion genes aid in developing targeted therapies developing targeted therapies
- 38. MOLECULAR IMAGING MOLECULAR IMAGING Imaging the key molecules and molecular Imaging the key molecules and molecular events that are fundamental to the events that are fundamental to the development and progression of cancer development and progression of cancer Nuclear based imaging techniques are Nuclear based imaging techniques are used mainly PET scan used mainly PET scan F18 labelled FLT (deoxy fluoro thymidine) F18 labelled FLT (deoxy fluoro thymidine) PET is currently under investigation for PET is currently under investigation for STS STS
- 39. F18 FLUORO DEOXYTHYMIDINE PET SCAN F18 FLUORO DEOXY THYMIDINE PET SCAN F18 labelled FLT F18 labelled FLT FLT monophosphate FLT monophosphate Thymidine kinase activity is more in Thymidine kinase activity is more in malignant cells malignant cells Uptake corresponds to proliferation index Uptake corresponds to proliferation index Useful in evaluating response to therapy Useful in evaluating response to therapy rather than in diagnosis rather than in diagnosis Thymidine kinase
- 40. Useful in evaluatingresponse to therapy rather than in diagnosis
- 41.
- 42. OPTICAL PROBE OPTICAL PROBE Fluorochromescan be fluorescent proteins or Quantum dots which are nanoparticles
- 43. NEAR INFRA REDOPTICAL IMAGING NEAR INFRA RED OPTICAL IMAGING Consists of imaging hardware for visualisation if near infrared light couple with iv injected chemical probes that allow in vivo detection of specific protease activity
- 44. OPTICAL IMAGING OPTICAL IMAGING Useful to detect micrometastases Useful to detect micrometastases Response assessment after Response assessment after chemotherapy chemotherapy Aids in developing targeted therapies Aids in developing targeted therapies Recently tried in detection of Recently tried in detection of microscopic residual sarcoma during microscopic residual sarcoma during surgery surgery Currently this modality is under trial in mouse model
- 45. Cancer 2012;000:000–000. VC2012 American Cancer Society Exogenously administered cathepsin-activated probes can be used for image-guided surgery to identify microscopic residual NIR fluorescence inthe tumor beds of mice . The presence of residual NIR fluorescence was correlated with microscopic residual sarcoma and local recurrence. The removal of residual NIR fluorescence improved local control.
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- 47. TRABECTEDIN TRABECTEDIN ET743, Ecteinascidin743 ET743, Ecteinascidin 743 DNA guanine specific DNA guanine specific minor groove minor groove binding agent binding agent Proved to be effective in phase I and II Proved to be effective in phase I and II trials in advanced STS trials in advanced STS Approved 2 Approved 2nd nd line agent in line agent in myxoid myxoid round cell liposarcomas round cell liposarcomas Side effect: increase in LFT occasionally Side effect: increase in LFT occasionally
- 48. ANGIOGENESIS INHIBITORS ANGIOGENESIS INHIBITORS Angiogenic drive (VEGF)correlates with tumour Angiogenic drive (VEGF)correlates with tumour grade grade Anecdotal reports of activity with VEGFR inhibitors, Anecdotal reports of activity with VEGFR inhibitors, including sorafenib, cediranib including sorafenib, cediranib Tumour shrinkage observed in patients with Tumour shrinkage observed in patients with alveolar soft part sarcoma (ASPS alveolar soft part sarcoma (ASPS), a rare disease ), a rare disease unresponsive to chemotherapy unresponsive to chemotherapy VEGFR inhibitor VEGFR inhibitor pazopanib pazopanib active against sarcomas active against sarcomas in EORTC trial, with exception of liposarcomas in EORTC trial, with exception of liposarcomas
- 49. MDM 2 ANTAGONISTS MDM2 ANTAGONISTS MDM2 amplification + in well differentiated and MDM2 amplification + in well differentiated and dedifferentiated liposarcomas dedifferentiated liposarcomas Nutlin –a prototype had only invitro effectiveness Nutlin –a prototype had only invitro effectiveness Spiro oxindoles Spiro oxindoles (MI-219) binds to MDM2 with high (MI-219) binds to MDM2 with high affinity ; under phase I trial affinity ; under phase I trial
- 50. CDK 4 ANTAGONISTS CDK4 ANTAGONISTS CDK4amplification is present in well differentiated and dedifferentiated liposarcomas Flavopiridol, seleciclib ( pan CDK inhibitors ) PD0332991 (selective for CDK4,6 ), PI446A05 (Only available CDK4 selective inhibitor) are under phase I trial
- 51. PPAR – PPAR –γ γ AGONISTS AGONISTS Peroxisome proliferator activated Peroxisome proliferator activated receptor receptor γ γ regulates the terminal regulates the terminal differentiation of adipocytic lineage differentiation of adipocytic lineage Troglitazone, rosiglitazone used in Troglitazone, rosiglitazone used in phase II trial in high grade liposarcoma phase II trial in high grade liposarcoma There is no convincing evidence There is no convincing evidence
- 52. RECEPTOR TYROSINE KINASEPATHWAY RECEPTOR TYROSINE KINASE PATHWAY INHIBITORS INHIBITORS MYXOID LIPOSARCOMA EVEROLIMUS FORETINIB FORETINIB EVEROLIMUS
- 53. CONCLUSION CONCLUSION Lung isthe most common site of metastasis Lung is the most common site of metastasis Pulmonary metastatectomy can be done with Pulmonary metastatectomy can be done with curative intent if the primary is controllable curative intent if the primary is controllable RFA, stereotactic radiotherapy are RFA, stereotactic radiotherapy are alternatives to surgery alternatives to surgery Single agent chemotherapy is better in the Single agent chemotherapy is better in the palliative setting palliative setting Trabectedin is the approved 2 Trabectedin is the approved 2nd nd line agent in line agent in myxoid liposarcoma myxoid liposarcoma
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Editor's Notes
- #2 Extrapulmonary mets are uncommon forms of first mets and usually occurs as late manifestation of widely disseminated disease
- #9 Optimal treatment requires understanding the natural history of the disease .surgery renders the patient potentially disease free.recurrence is bços non proliferating tumor cells may not have reached detectable size at the time of initial surgical exploration
- #14 Wedge resection leads to isolation of lung parenchyma, threatening both devitalization of tissue as well as rendering residual tissue without normal airway capacity to clear secretions and avoid infections.in general, pneumonectomy should be avoided unless absoluteky necessary for achieving an R0resection in the absence of alternate therapies
- #16 With median sternotomy, exposure to hilar, postr, left lower lung fields are inadequate
- #28 The software is integrated in the 4D CT machine. And strike zone is defined (period in the breathing cycle where the tumor moves the least) at which time the radiation beam is turned on
- #36 Fusion proteins serve as aberrant transcription factors, encode tyrosine kinases,
- #37 Alveolar RMS with mets, PAX7-FOXO1 has favourable prognosis than PAX3-FOXO1
- #47 Understanding the molecular pathogenesis of STS has aided in the development of targeted therapies for some subtypes of STS Does not affect transcription of fusion gene FUS-DDIT3 but dissociate the aberrant transcription factor from its target
- #51 These agonists bind with PPAR-γ receptor and induce terminal differentiation of normal preadipocytes in human liposarcoma cell lines in vitro