SOFT TISSUE SARCOMAS :

OVERVIEW AND

ROLE OF RADIATION THERAPYMayur Mayank

12.09.2014

Introduction• Heterogeneous group of Rare malignancies• Arise from Connective tissue• Can occur at any anatomic site• Median age of diagnosis – 65 years• Age at presentation varies with the histological

subtype• Children : Embryonal Rhabdomyosarcoma • Young adults : Synovial sarcoma • Elderly : Pleomorphic high-grade sarcoma, liposarcoma, and

leiomyosarcoma

T1 weighted image T2 weighted image

Introduction• Aetiology – Mostly unknown• Few environmental and genetic factors have been

attributed in the causation• Environmental factors :• Radiation exposure • Chemical exposures (Vinyl chloride, dioxin, arsenical

pesticides, and phenoxyherbicides) • Immunosuppression• Lymphedema (Stewart-Treves syndrome)• Viruses (Human immunodeficiency virus, Human Herpes

virus type 8)

Introduction• Genetic factors :• Li-Fraumeni syndrome • Werner syndrome• Neurofibromatosis type 1 - Malignant peripheral nerve

sheath tumors• Familial adenomatous polyposis (Gardner syndrome) -

Abdominal desmoid tumors

Histological Classification• WHO Histological classification of soft Tissue Sarcomas• Benign • Intermediate - Locally aggressive• Intermediate - Rarely metastasizing• Malignant

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

Site of predilection• Sites :• Most commonly seen in

Extremities• Lower limbs > Upper limbs

Clinical features• Depends on the site of tumor• Most commonly presents as a painless mass• Can be associated occasionally with pain• Ca have features of neuro vascular compromise

(depending on the extent of tumor)

Diagnosis• FNAC – Not adequate• Biopsy is preferred – Either Incisional biopsy or CT

guided core biopsy• Diagnostic biopsy should be performed carefully with the

subsequent definitive resection in mind• Tumor cells can potentially seed a biopsy tract or incision,

thereby necessitating removal of tracts and skin incisions at the time of surgical resection • Biopsy approach should not transgress an uninvolved

compartment or joint as this would create a situation where a much more radical resection would need to be performed

Diagnosis• Tumor specific translocations :

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 tumors or small (<5 cm) high-grade lesions• CT of the abdomen and pelvis : Myxoid liposarcoma

(predilection for spread to the retroperitoneum)

Imaging Workup• PET CT• Role is not defined• Used in cases of recurrence• Also used for follow up purposes (With monitoring of SUV

values)• Potential utility to help distinguish malignant peripheral

nerve sheath tumors from benign neurofibromas in patients with neurofibromatosis

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

Patterns of spread• Haematogenous spread :

• Lungs• Bone• Liver • Brain

• Lymphatic spread :• Rarely• Seen in :

• Epithelioid sarcoma (20% to 35%) • Clear cell sarcoma (10% to 18%)• Rhabdomyosarcoma (20% to 25%)• Cutaneous angiosarcoma

Grading systems• Grading systems :

• National Cancer Institute (NCI) grading system – USA• Comprises of

• Histology• Necrosis• Mitosis / HPF

• Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system – France• Comprises of :

• Tumor differentiation• Mitotic count• Tumor necrosis

Grading Systems

NCI GRADING SYSTEM FNCLCC GRADING SYSTEM

Staging• AJCC 7th edition• Based on • Size of tumor • Extent of tumor (Superficial / Deep)• Lymph node status• Presence or absence of metastasis• Grade of tumor

Staging• Drawbacks of AJCC staging system :• Does not account for

• Histologic subtype • Tumor site

• Nor does it stratify for tumor size >5 cm.

• All of these factors are predictive of survival

Prognostic Factors• Poor Prognostic factors :

- Age > 50 years - Size > 8 cm - Vascular invasion - Local infiltration - Tumour necrosis - Deep location - High grade tumors - Recurrent disease - Certain histological subtypes eg. non-liposarcoma histology

Management• Treatment goals • Complete eradication of tumor • Optimal function preservation • Minimal treatment-related toxicities

Management• Surgery• Radiation Therapy• Chemotherapy

Surgery• Appropriate surgical resection is a prerequisite for

curative treatment of STS.• Various surgical modalities used :• Marginal resection or Excisional biopsy• Wide resection• Radical resection or Amputation

Surgery• Marginal resection • Simple removal of the tumor with its pseudocapsule• “Shell-out”• Commonly performed when the diagnosis of STS is not

suspected. • Local recurrence rates range from 42% to 93%.

• Microscopic tumor cells can extend beyond the pseudocapsule and up to several centimeters beyond palpable gross tumor

• It is not an appropriate treatment

Surgery• Wide resection • Conservative surgery (CS) • Limb-sparing surgery • Function-sparing surgery

• 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• Moderately high local recurrence rates : 25% to 60%

Surgery• Radical resection • Removal of all of the muscles and neurovascular structures

within the compartment where the tumor resides or amputation• Local recurrence rates are much lower : 0% to 18%. • The cost of loss of limb (or loss of an entire compartment) is

high

Surgery• Mostly unplanned excision (shell-out) with resulting

positive margins are done• It is important to perform a definitive re-excision in these

situations• As part of the re-resection

• Incisions• Biopsy tracts• Drain sites• Any tissues contaminated by the first surgery

• Ideally, the biopsy site should be excised en bloc with the definitive surgical specimen

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 chemo-RT • Rates of amputation fell to <10% as postop RT

became widely used after limb-sparing surgery

NCI Trial 1982• 43 patients with high-grade STS of the extremity were

randomized • Amputation or • Conservative Surgery and postoperative external beam RT (60 to

70 Gy)

• Patients in both treatment arms received postoperative doxorubicin, cyclophosphamide, and methotrexate • Local recurrence rates :

• 0% (0 of 16) - Amputation• 15% (4 of 27) – Conservative surgery and RT (p = .06)

• There was no significant difference in survival rates

Need for Radiation Therapy after Conservative Surgery

Study Treatment arms Local recurrence

Overall survival or Disease free

survival

Pisters et alMSKCC 1996n = 164(Extremity + Trunk)

High grade (n=119)CS versus CS + BRT

30% vs 9%(p=0.0025)

5 year DFSCombined for all

patients81% vs 84%

(p=0.65)Low grade (n=45)

CS versus CS + BRT26% vs 36%

(p=0.49)

Yang et alNCI 1998n = 141(Extremity)

High grade (n=91)CS versus CS +

EBRT(Both arms received

chemotherapy)

19% vs 0%(p=0.003)

10 year OS74% vs 75%

(p=0.71)

Low grade (n=50)CS versus CS +

EBRT

33% vs 4%(p=0.016)

10 year OS92% vs 92%

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 • Locally recurrent disease following initial wide excision• Tumor location that would not be amenable to subsequent salvage

surgery

Indications for Radiotherapy• Pre Operative• Unresectable disease• Resectable disease but resection will lead to significant

functional loss

Radiation Therapy• Planning and Simulation• Positioning :

• Depends on the site of the primary lesion• A limb should be positioned to allow treatment with as many

potential beam angles as possible• The limb should be positioned as far away from the trunk (for upper

extremities) or from the opposite limb (for lower extremities) as possible

• Proper immobilization devices should be used depending on the site of the primary

• The position should be reproducible• A custom cast is highly recommended for almost all scenarios

Radiation Therapy Volumes• Conventional :

• Phase I• GTV : Reconstructed from pre-op imaging.• CTV : Consider compartment at risk of microscopic spread. Should include

biopsy site, drain site and scarGTV + 5 cm longitudinally. Radially 2 cm expansion of GTV

• PTV = CTV + 5-10mm (depending on departmental set up) or 1 cm beyond scar

• Phase II• CTV : 2 cm longitudinal and radial expansion of the GTV

• Strip of tissue should be spared laterally (if possible) : To decrease the risk of lymphedema

Radiation Therapy Volumes• Pre operative • Based on RTOG Sarcoma Working Group consensus

(2011) • GTV : Gross tumor delineated by the T1 post gadolinium

MRI• CTV : For intermediate to high grade sarcoma > 5cms

• GTV + 3-cm margins in the longitudinal directions and 1.5-cm margins radially.

• These margins can be truncated if they extend beyond the compartment or into an intact fascial barrier, bone, or skin.

• Peri tumoral edema on T2 MRI should be included within the CTV

• PTV : CTV + 0.5 cm to 1 cm margin (Depending on institutional protocol)

Radiation Therapy Volumes• Post operative :• CTV :

• Pre operative GTV seen on the MRI and Surgical bed• All the tissues handled during the surgery including the incision and

any drain sites. • 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

• 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

Radiation Therapy Doses• Pre operative• 50 Gy in 25 fractions (2 Gy/ fractions)• Additional boost of 16 to 20 Gy (delivered in 1.8 to 2 Gy/

fraction) in cases of close or positive margins

Radiation Therapy Doses• Post operative• 60 to 66 Gy (1.8 – 2 Gy/ fraction) : Negative margins • 66 to 68 Gy (1.8 – 2 Gy/ fraction ) : Positive margins

• The first course of treatment is typically treated to a dose of 45 to 50 Gy and the balance of the dose is either given in one reduced field or split about evenly between two reduced fields.

Radiation Therapy Toxicity• Acute toxicity :• Skin erythema • Skin desquamation • Wound complications • Localized alopecia• Fatigue

Radiation Therapy Toxicity• Chronic Toxicity :• Edema • Subcutaneous fibrosis• Decreased muscle strength • Decreased range of motion and pain• Bone fracture • Peripheral nerve damage

TIMING OF RADIATION THERAPY

PRE OPERATIVE OR POST OPERATIVE ???

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

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

Closed early after interim significant difference

Updated Results of NCI Trial 2002 • 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

• 5 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 mortalityLocal recurrence lower after pre operative Radiation therapy

Annals of Surgical OncologyMay 2010, Volume 17, Issue 5, pp 1367-1374

Are large CTV Expansions necessary ?• 2 Prospective Randomised controlled trials are

addressing this issue

• VORTEX Trial : Volume Of post-operative RadioTherapy given to adult patients with eXtremity soft tissue sarcoma

• RTOG 0630 : A Phase II Trial of Image guided pre operative Radiotherapy for Primary Soft tissue sarcomas of the extremity

RTOG 0630 – CTV margins• CTV for Intermediate-to-High Grade Tumors ≥ 8 cm:• Include gross tumor and clinical microscopic margins.• Typically CTV = GTV and suspicious edema (defined by MRI

T2 images) plus 3 cm margins in the longitudinal (proximal and distal) directions. • If this causes the field to extend beyond the compartment,

the field can be shortened to include the end of a compartment. • The radial margin from the lesion should be 1.5 cm

including any portion of the tumor not confined by an intact fascial barrier or bone or skin surface.

RTOG 0630 – CTV margins• CTV For All Other Tumors: • Include gross tumor and clinical microscopic margins.• Typically CTV = GTV and suspicious edema (defined by MRI

T2 images) plus 2 cm margins in the longitudinal (proximal and distal) directions. • If this causes the field to extend beyond the compartment,

the field can be shortened to include the end of compartment. • The radial margin from the lesion should be 1 cm

including any portion of the tumor not confined by an intact fascial barrier or bone or skin surface.

Newer Approaches• Hypofractionation• Hyperthermia• Proton Therapy• Image Guided Radiation Therapy• Stereotactic Body Radiation Therapy (SBRT)

Conclusions• Soft tissue sarcomas are a heterogeneous group of

tumors, management of which is difficult• They have a high risk of local recurrence and have a

high metastatic potential• Multi disciplinary approach is warranted for the proper

management of soft tissue sarcomas• The lesser radical surgical approach with adjuvant

radiation therapy has improved the quality of life of patients remarkably

Conclusions• The newer techniques of Radiation therapy with the

reduction in the volumes of radiation therapy give an advantage of adequate tumor dosage with less toxicity• More studies with newer modalities are warranted to

achieve better results

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