Soft tissue sarcoma

Soft tissue sarcoma- Dr Kiran

1. MANAGEMENT OF SOFT TISSUE SARCOMA DR KIRAN KUMAR BR

2. Natural History STS can occur anywhere in the body. The most common site of presentation is an extremity , specifically the thigh. The approximate distribution of STS sites at presentation is extremity, 60% (lower extremity, 45%, upper extremity, 15%); trunk, 15% to 20%; retroperitoneum, 10% to 15%; and head and neck, 8%. Perez and Brady’s 6 TH

3. Clinical presentation Extremity:- M.C symptom:- a painless swelling. Other symptoms – d/t involvement of surrounding structures. Pain  due to invasion of neurovascular structures. Distal edema  pressure effect on vascular structures. Joint compliants  restriction of joint movements and bone # can occur . Perez and Brady’s 6 TH

4. Retroperitoneal:- Usually asymptomatic until reaching large sizes. I dentified on imaging for unrelated complaints. May present with Nonspecific abdominal pain Palpable abdominal mass. Anorexia and Chronic subacute intestinal obstruction with subsequent weight loss. Perez and Brady’s 6 TH

5. Patterns of spread Local spread : Tends to invade longitudinally along musculoaponeurotic planes Rarely transgress fascial boundaries or invade bone Compresses surrounding normal tissue to form a pseudocapsule – Contains a compression zone and a reactive zone The Reactive zone consists of edema, inflammatory cells and tumor cells Perez and Brady’s 6 TH

6. LN SPREAD STS rarely spread to lymph nodes 1.8% to 3.7% of lymph node involvement at the time of initial presentation. Notable lymph node involvement rates have been demonstrated for epithelioid sarcoma (20% to 35%), clear cell sarcoma (10% to 18%), rhabdomyosarcoma (20% to 25%), and cutaneous angiosarcoma (10% to 15%). 23% of patients had metastatic disease at presentation. The single most common site of distant metastasis (34%) lung, Bone(24%),liver(16%),brain(2%). Retroperitoneal sarcoma and intra-abdominal visceral sarcomas  1 st site is Liver . Perez and Brady’s 6 TH

7. Imaging workup MRI is the preferred modality T1 weighted images – For disease extent T2 weighted images – For peritumoral edema CT scan Not good soft tissue delineation Chest CT scan is recommended to rule out pulmonary metastases for all cases except low-grade tumour's or small (<5 cm) high-grade lesions CT of the abdomen and pelvis : Myxoid liposarcoma (predilection for spread to the retroperitoneum) Perez and Brady’s 6 TH

8. CT MRI(T1) Perez and Brady’s 6 TH MRI Scan vs CT Scan ( Demas et al. compared MRI and CT for STS lesions in the extremity and reported that for 23% of cases, the MRI scans showed tumor involvement in muscles that appeared normal on CT scan)

9. Imaging Workup PET CT Used in cases of recurrence Also used for follow up purposes. Potential utility to help distinguish malignant peripheral nerve sheath tumors from benign neurofibromas in patients with neurofibromatosis. the detection of malignant transformation in neurofibromatosis. the presence of regional or distant metastases the response to initial (i.e., neoadjuvant) treatment as a surrogate to prognosticate on future outcome. Gunderson

10. Investigation: Following appropriate imaging assessment, the standard approach to diagnosis consists of multiple core needle biopsies. However, an excisional biopsy may be the most practical option for < 3 cm superficial lesions. ( Excisional biopsy should be avoided, especially for lesions >3 cm in size, as the contamination of surrounding tissue planes may require the definitive resection to be more extensive.)- DEVITA An open biopsy may be another option in selected cases. A biopsy may underestimate the tumor malignancy grade. Therefore, when preoperative treatment is an option, radiological imaging [PET] may be useful, in addition to pathology, in providing the clinician with information that helps to estimate the malignancy grade ESMO-2018

11. Immuno histo chemistry

12. Gunderson Cytogenic abnormalities

13. Gunderson

14. WHO Classification Benign Do not recur locally, and those that do recur usually are not locally invasive and can be cured with complete surgical excision. Intermediate, locally aggressive soft tissue tumors often recur locally and are associated with a locally infiltrative growth pattern. Do not have any potential to metastasize but typically require wide excision with a margin of normal tissue for good local control. WHO 2013

15. Intermediate rarely metastasizing tumors Often locally aggressive but in addition can occasionally give rise to distant metastases. The risk of metastasis, usually to lymph nodes or lung, is typically less than 2%, but is not reliably predictable based on histology Malignant potential for local invasion and recurrence, have a significant risk of distant metastasis, ranging in most instances from 10% to 100%, depending on histological type and grade. Some low-grade sarcomas have a metastatic risk of only 2% to 10%, but these tumor types may progress to more aggressive tumors WHO 2013

16. Histologic Diagnoses Malignant Fibrous Histiocytoma (MFH) Undifferentiated pleomorphic sarcoma. Myxofibrosarcoma With inflammation Angiomatoid malignant fibrous histiocytoma Low-grade Fibromyxoid Sarcoma ( Fibrosarcoma ) Sarcomas of Fibrous Tissue Sarcomas of Blood and Lymph Vessels Angiosarcoma Hemangiosarcoma Lymphangiosarcoma Epithelioid Hemangioendothelioma Hemangiopericytoma Kaposi’s Sarcoma Sarcomas of Peripheral Nervous Tissue Malignant Peripheral Nerve Sheath Tumor ( Neurofibrosarcoma ). Malignant granulosa cell tumour Primtive neuroectodermal tumour .(PNET) Sarcomas of Unknown Tissue Synovial Sarcoma Monophasic Biphasic Alveolar Soft Part Sarcoma Epithelioid Sarcoma Unclassified Sarcoma Extraskeletal Sarcomas of Bone Extraskeletal Osteosarcoma Extraskeletal Chondrosarcoma Extraskeletal Ewing’s Sarcoma (PNET) Dermatofibrosarcoma Protruberans Desmoid Fibromatosis Nodular Fasciitis SOFT-TISSUE SARCOMA WHO 2013

17. Leiomyosarcoma GI GU Skin Vessel Other Sarcomas of Smooth Muscle Liposarcoma Atypical Lipomatous Tumor Myxoid Liposarcoma Cellular Myxoid Liposarcoma Dedifferentiated Liposarcoma Pleomorphic Liposarcoma Sarcomas of Adipose Tissue Sarcomas of Skeletal Muscle Embryonal Rhabdomyosarcoma Botryoid RMS Spindle cell RMS Alveolar Rhabdomyosarcoma Pleomorphic Rhabdomyosarcoma Soft-tissue Tumors of Melanocytic Tissue Melanoma of Soft Parts AKA - Clear Cell Sarcoma WHO 2013

18. Histological subtypes Most common subtypes : High-grade pleomorphic sarcoma Liposarcoma Leiomyosarcoma Synovial sarcoma Malignant peripheral nerve sheath tumor

19. Grading Under histological grading , the two most important criteria appear to be the mitotic index and the extent of tumor necrosis . The two systems most favoured by pathologists are those designated as the French Federation of Cancer Centres Sarcoma Group ( FNCLCC) [tumour differentiation , mitotic count and necrosis ] The National Cancer Institute ( NCI) [tumor histology and amount of tumor necrosis ]

20. FNCLCC GRADING SYSTEM

21. NCI GRADING SYSTEM

22. Staging AJCC 8 th edition Based on Size of tumor Extent of tumor (Superficial / Deep) Lymph node status Presence or absence of metastasis Grade of tumor

23. EXTREMITY SARCOMA AJCC 8TH

24. Soft Tissue Sarcoma of the Head and Neck AJCC 8TH

25. Abdomen and Thoracic Visceral Organs Gastrointestinal Stromal Tumor AJCC 8TH

26. AJCC 8 TH (ESMO)

27. AJCC 8 TH (ESMO)

28. Prognostic Factors for Survival and Local Recurrence The most powerful predictor for DFS and OS is the TNM stage of the tumor. Five-year DFS rates for stages I, II, and III STS are 86%, 72%, and 52%, respectively. Grade. Tumor size, depth, and site. Poor Prognostic factors : - Age > 50 years - Size > 8 cm - Vascular invasion - Local infiltration - Tumour necrosis - Deep location - High grade tumors - Recurrent disease Perez and Brady’s 6 TH

29. Significant predictors for LR include positive margins of resection, presentation with locally recurrent disease, older age, and head and neck or retroperitoneal location. Patients who present with locally recurrent disease are at higher risk for LR (25% to 47%) Perez and Brady’s 6 TH

30. Management and Outcome for Soft Tissue Sarcomas of Extremity and Trunk

31. SURGERY First intervention Most effective treatment to ensure cure. Function preservation Adequate Oncologic clearance Perez and Brady’s 6 TH

32. Marginal resection - simple removal of the tumor with its pseudocapsule. ( LR-42% to 93%) Radical resection- removal of all of the muscles and neurovascular structures within the compartment where the tumor resides or amputation. ( LR-0% to 18%) Wide resection ( conservative surgery (CS) limb-sparing surgery, or function sparing surgery)- It involves en bloc removal of tumor with a rim of normal tissue varying in width from about 1 cm to several centimeters depending on anatomic constraints. ( LR- 25% to 60%) Perez and Brady’s 6 TH

33. Radiation Therapy Historically, all patients underwent amputation for extremity sarcomas NCI randomized study demonstrated that high grade lesions could be treated with limb-sparing surgery with concurrent adjuvant RT. Rates of amputation fell to <10% as postop RT became widely used after limb-sparing surgery Perez and Brady’s 6 TH

34. Conservative Surgery and Radiation Therapy Perez and Brady’s 6 TH

35. Wide resection/CS combined with pre- or postoperative radiation therapy (RT) is the current standard of care for most high-grade STS. Most low-grade STS of the extremity and trunk is wide excision alone. Perez and Brady’s 6 TH

36. TIMING OF RADIATION THERAPY PRE OPERATIVE OR POST OPERATIVE ???

37. Preoperative Versus Postoperative EBRT: Recently, examination of data from 27,969 patients with extremity STS in the NCDB identified both preoperative and postoperative RT as factors associated with increased OS. However, that data showed that preoperative RT was predictive of achieving R0 resection. In a phase III randomized study conducted by the Canadian Sarcoma Group, local control and progression-free survival (PFS) rates were similar in patients receiving either preoperative or postoperative RT in patients with localized primary or recurrent disease. However, preoperative RT was associated with a greater incidence of acute wound complications (35% vs 17% for postoperative RT), especially in lower-extremity tumors (43% vs 5% for upper extremity tumors). Late-treatment–related side effects were more common in patients receiving postoperative RT, which is believed to be related to the higher RT dose (66 vs 50 Gy for preoperative RT) and the larger treatment volume. NCCN 2018

38. Updated Results of NCI Trial 2005 Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma Davis AM, Radiotherapy Oncol.2005 Apr;75(1):48-53 Post-op RT associated with worse fibrosis as well as joint stiffness (although not statistically significant). Outcome: Grade 2+ fibrosis pre-op RT 31% vs. post-op RT 48% (p=0.07) Edema, and joint stiffness also more severe in post-op arm Joint stiffness and fibrosis worse with larger field size

39. 5 studies (1 RCT and 4 retrospective cohort) -1098 patients Localized, resectable, STS. Comparis5 studies (1 RCT and 4 retrospective cohort) -1098 patients Localized, resectable , STS. Comparison of pre operative versus and post operative Radiaotherapy Outcome: Local recurrence better in pre operative group (HR = 0.6, Significant) Survival : Pre operative - 76% vs Post operative - 67% • Conclusion: Delay in surgical resection for pre operative Radiation therapy does not increase mortality Local recurrence lower after pre operative Radiation therapy Annals of Surgical Oncology May 2010, Volume 17, Issue 5, pp 1367-1374

40. Indications for Radiotherapy Post Operative : All Deep seated tumors All High grade tumors Intermediate grade tumor, size >5cm Low grade tumors : Positive or close (<1cm) resection margins . Tumor location that would not be amenable to subsequent salvage surgery Recurrent disease following initial wide excision Pre Operative Unresectable disease Resectable disease but resection will lead to significant functional loss Perez and Brady’s 6 TH

41. Radiation Therapy Techniques

42. Radiation Therapy Positioning the Patient: the limb is positioned as far away from the trunk (for upper extremities) or from the opposite limb (for lower extremities) as possible. Perez and Brady’s 6 TH

43. Target Volumes and Treatment Fields Preoperative Radiation Therapy: Fusion of the diagnostic MRI and planning CT for optimal target definition is strongly encouraged. GTV is defined as the gross tumor delineated by the T1 postgadolinium MRI. Clinical target volume (CTV) is defined as the GTV plus 3-cm margins in the longitudinal directions and 1.5-cm margins radially. PTV: CTV plus 5 to 10 mm

44. Postoperative Radiation Therapy The CTV should encompass all the tissues handled during the surgery including the incision and any drain sites. (Postoperative changes seen on MRI help define the operative bed.) An additional longitudinal margin of 2 to 4 cm and a radial margin of 1.5 to 2 cm is generally added to the operative bed to form the CTV. The PTV is typically CTV plus 5 to 10 mm. A second (and sometimes third) course field reduction is typically used in the postoperative setting. CTV margins for the reduced field(s) vary and can include about 2 cm on the operative bed or on the initial GTV. ( Baldini et al. found no recurrences in 36 patients with resection margins ≥1 cm compared to an actuarial 10-year LR rate of 13% (4 of 38) for those with margins <1 cm .) Perez and Brady’s 6 TH

45. Perez and Brady’s 6 TH

46. NCCN 2018

47. NCCN 2018

48. Are large CTV Expansions necessary ? 2 Prospective Randomised controlled trials are addressing this issue VORTEX Trial : V olume O f post-operative R adio T herapy given to adult patients with e X tremity soft tissue sarcoma RTOG 0630 : A Phase II Trial of Image guided pre operative Radiotherapy for Primary Soft tissue sarcomas of the extremity

49. Results: Two hundred sixteen patients were randomized, 108 in each arm. Tumor/normal tissues were collected from 206 randomized and 301 registered patients. Median follow-up was 4.8yr (C and R). The 5-year local recurrence free survival (LRFS) rates were; for C: 86% and for R: 84%. For C the 5-year overall survival was 72% and for R 67%. There were no statistical differences between the arms in late radiation toxicity grade 2+ at 2 years. Conclusion: There was no difference in limb function at 2 years between control and research arms. Because of the small number of events it was not possible to state whether or not the research arm was inferior for LRFS.

50. Doses The standard dose for preoperative external-beam RT is 50 Gy delivered in 2-Gy fractions. In the situation of positive margins, a postoperative external-beam RT boost of 16 to 20 Gy (delivered in 1.8- to 2-Gy fractions) is sometimes delivered. For postoperative external-beam RT, treatment usually commences about 4 to 6 weeks following surgery and once the wound is fully healed. Recommended total doses are 60 to 66 Gy (delivered in 1.8- or 2-Gy fractions) for the case of negative margins and 66 to 68 Gy for positive margins Perez and Brady’s 6 TH

51. Principles of Treatment Planning Basic tenets for treating the extremity are to “spare a strip” of the limb circumference (to prevent subsequent lymphedema and pain), to avoid treating the whole thickness of bone to high doses (to diminish risk of fracture), and to avoid treating an entire joint to high doses (to decrease joint stiffness). With IMRT, in order to achieve more dose conformality, the tradeoff is that the volume of tissue that receives a low dose is increased; for some of these cases, the entire circumference of the limb may receive some low dose. Perez and Brady’s 6 TH

52. Radiation Therapy Toxicity Chronic Toxicity : Edema Subcutaneous fibrosis Decreased muscle strength Decreased range of motion and pain Bone fracture Peripheral nerve damage Acute Toxicities skin erythema and possible desquamation in high-dose areas, problems with wound healing, localized alopecia, fatigue. Moist desquamation can be quite uncomfortable, Perez and Brady’s 6 TH

53. Pre Operative Radiation Therapy Advantages Smaller RT fields Lower RT doses Reduced treatment time Tumor down staging Radiobiological advantage Disadvantages Higher risk of major wound complications Perez and Brady’s 6 TH

54. Post Operative Radiation Therapy Advantages Complete tumor specimen is available for pathology review for determination of histology and margin status Lower risk of major wound complications Disadvantages Larger treatment volumes Higher doses More hypoxic tissue – Radiobiological disadvantage High incidence of late toxicity Perez and Brady’s 6 TH

55. Chemotherapy There is no clear evidence showing that chemotherapy, adjuvant or neoadjuvant showing significant improved OS or PFS. Drugs tried are Doxorubicin Ifosfamide Chemotherapy is effective only in Rhabdomyosarcoma Ewing’s sarcoma. ESMO 2018

56. CT –META ANALYSIS

57. Locally recurrent sarcomas Sarcomas have high local recurrence. The treatment modalities available are Radical re-excision(amputation). Limited resection with adjuvant RT(if previously not given). Brachytherapy is preferred over EBRT as it decreases dose to normal tissues.

58. Metastatic disease Chemotherapy is the main modality for treating metastatic disease. Anthracycline based regimens were found to be effective.(doxorubicin with ifosfamide and Mesna ). Recent evidence showed gemcitabine in combination with docetaxel showed increased survival. P=0.005 P=0.009

59. ESMO 2018

60. ESMO 2018

61. Management of advanced/metastatic disease • Metachronous (disease-free interval1 year), resectable lung metastases without extrapulmonary disease are managed with surgery as standard treatment, if complete excision of all lesions is feasible. • Standard ChT is based on anthracyclines as the first-line treatment [I, A]. Multi-agent ChT with adequate-dose anthracyclines plus ifosfamide may be the treatment of choice, particularly in subtypes sensitive to ifosfamide , when a tumour response is felt to be potentially advantageous and patient PS is good [I, B] • The combination of doxorubicin with an anti-PDGFRA agent, olaratumab , is option. • Gemcitabine/docetaxel combination is not generally recommended as a first-line therapy for advanced STS patients [I, D] • Imatinib is standard medical therapy for those rare patients with dermatofibrosarcoma protuberans. • Trabectedin is an option for second line and is approved for advanced previously treated STS. • Pazopanib is an option in non- adipogenic STS. • Eribulin is an option in patients with liposarcomas and LMS. • Regorafenib is an option in doxorubicin-pretreated advanced, non- adipogenic STS patients. • Crizotinib in inflammatory myofibroblastic tumours associated with ALK translocations. Sunitinib and cediranib in alveolar soft part sarcoma, where the molecular target is as yet unclear and Sunitinib in solitary fibrous tumours [IV, C] ESMO 2018

62. NCCN 2018

63. NCCN 2018

64. Fallow up Surgically-treated intermediate-/ high-grade patients may be followed every 3–4 months in the first 2–3 years, then twice a year up to the fifth year, and once a year thereafter. Low-grade sarcoma patients may be followed for local relapse every 4–6months, with chest X-rays or CT scan at longer intervals in the first 3–5 years, then annually. ESMO 2018

65. Thank You