soft tissue sarcomas radiation therapy
DESCRIPTION
Overview and Role of Radiation Therapy in Soft Tissue SarcomaTRANSCRIPT
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SOFT TISSUE SARCOMAS :
OVERVIEW AND
ROLE OF RADIATION THERAPYMayur Mayank
12.09.2014
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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
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T1 weighted image T2 weighted image
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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)
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Introduction• Genetic factors :• Li-Fraumeni syndrome • Werner syndrome• Neurofibromatosis type 1 - Malignant peripheral nerve
sheath tumors• Familial adenomatous polyposis (Gardner syndrome) -
Abdominal desmoid tumors
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Histological Classification• WHO Histological classification of soft Tissue Sarcomas• Benign • Intermediate - Locally aggressive• Intermediate - Rarely metastasizing• Malignant
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Histological subtypes• Most common subtypes :• High-grade pleomorphic sarcoma• Liposarcoma• Leiomyosarcoma• Synovial sarcoma• Malignant peripheral nerve sheath tumor
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Site of predilection• Sites :• Most commonly seen in
Extremities• Lower limbs > Upper limbs
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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)
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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
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Diagnosis• Tumor specific translocations :
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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)
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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
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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
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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
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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
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Grading Systems
NCI GRADING SYSTEM FNCLCC GRADING SYSTEM
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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
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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
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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
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Management• Treatment goals • Complete eradication of tumor • Optimal function preservation • Minimal treatment-related toxicities
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Management• Surgery• Radiation Therapy• Chemotherapy
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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
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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
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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%
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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
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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
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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
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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
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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%
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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
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Indications for Radiotherapy• Pre Operative• Unresectable disease• Resectable disease but resection will lead to significant
functional loss
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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
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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
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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)
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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
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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
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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.
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Radiation Therapy Toxicity• Acute toxicity :• Skin erythema • Skin desquamation • Wound complications • Localized alopecia• Fatigue
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Radiation Therapy Toxicity• Chronic Toxicity :• Edema • Subcutaneous fibrosis• Decreased muscle strength • Decreased range of motion and pain• Bone fracture • Peripheral nerve damage
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TIMING OF RADIATION THERAPY
PRE OPERATIVE OR POST OPERATIVE ???
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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
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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
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Closed early after interim significant difference
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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
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• 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
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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
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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.
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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.
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Newer Approaches• Hypofractionation• Hyperthermia• Proton Therapy• Image Guided Radiation Therapy• Stereotactic Body Radiation Therapy (SBRT)
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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
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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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THANK YOU !!!