Soft Tissue Sarcomas

Safia K. Ahmed, MD
Mayo Clinic Arizona

April 26, 2023

Disclosures
• None
Learning Objectives
• Review the natural history, diagnosis, workup, treatment, and
prognosis of extremity and retroperitoneal soft tissue sarcomas
(STS)

• Appreciate the nuances of extremity and retroperitoneal STS

treatment, particularly as they relate to radiation therapy

• Discuss existing and new data regarding the management of

extremity / trunk and retroperitoneal STS
Outline
• Overview
• Incidence
• Histopathology
• Natural history
• Clinical evaluation & diagnostic workup
• Staging

• Literature Review & Treatment Approach

• Extremity & trunk STS
• Retroperitoneal STS
Overview
Incidence & Distribution
• Estimated 13,000 new STS cases will be diagnosed in 2023
• < 1% of all cancers
• 15-20% of pediatric cancers
Head & Neck, 10%

Upper Extremity,
25%
Thigh:
44% of all
Trunk, 30%
extremity STS
Extremity,
60% Lower
Extremity, 75%
Risk Factors
• Sporadic (most common) • Chronic edema
• Stewart-Treves Syndrome
• Genetic alterations
• NF-1 • Environmental
• RB • Vinyl chloride
• Li Fraumeni • Phenoxyacetic acid
• Familial polyposis • Arsenic
• Radiation • Burns, foreign implants,
scars (rare)
Histopathology
• >100 different histologic subtypes

Pleomorphic Sarcoma Angiosarcoma GIST

Liposarcoma Rhabdomyosarcoma Solitary Fibrous Tumor

Leiomyosarcoma Myxofibrosarcoma Fibrosarcoma

MPNST Desmoid Tumor Osteosarcoma

Synovial Sarcoma Synovial sarcoma Ewing sarcoma

75% of STS cases

Histopathology
Translocations
Alveolar rhabdomyosarcoma t(2,13) or t(1,13)
Myxoid liposarcoma t(12,16)
Synovial sarcoma t(X;18)
Ewing sarcoma t(11,22)
Immunostains
Leiomyosarcoma Desmin, h-caldesmon, smooth muscle or muscle specific actin
Pleomorphic liposarcoma S100
Angiosarcoma CD31, CD34, ERG
GIST CD117 (c-kit), DOG1
Rhabdomyosarcoma Myogenin, myo-D1, myoglobulin
Natural History
• Along longitudinal tissue planes
• Within compartment
• Compresses/distorts adjacent soft tissues
• Tumor can be well beyond mass
Natural History
• Lymph node involvement uncommon (5%)
• Exception: “CARE” (15-20%)
• Clear cell sarcoma
• Angiosarcoma
• Rhabdomyosarcoma
• Epithelioid sarcoma

• Distant spread commonly to lungs

• 10% at diagnosis
• Myxoid liposarcoma: Spine & extrapulmonary metastases (obtain
whole body MRI)
Clinical Presentation
Extremity
• Enlarging painless mass
• Functional limitations
• Symptoms associated with
compression of local structures
• Pain
Retroperitoneal
• Incidentally discovered
• GI symptoms
• Pain
• Neurologic symptoms
• Musculoskeletal symptoms
Diagnostic Workup: Imaging
Extremity Retroperitoneal
• X-ray • CT abdomen-pelvis
• MRI • MRI for evaluation of muscle
invasion or neural foramina
• CT chest invasion
• CT abdomen-pelvis if tumor • CT chest
involves groin
• PET
• PET
Diagnostic Workup: Biopsy
• Core needle biopsy

• Incisional biopsy
• Ideally by surgeon who will do definitive resection
• Longitudinal in extremity
Staging
Extremity & Trunk STS
Multidisciplinary Care by Sarcoma Specialists
Low Grade STS Treatment
Surgery Alone Considered
• Primarily for superficial
tumors, <5 cm, treated
with wide R0 resection
• Local recurrence (LR): <15%
• Survival: >90%
Radiation Indications
• Positive margins
• LR s/p prior surgery alone
(with re-resection)
• Location not amenable to
salvage surgery
Baldini et. al., JCO, 1999
Cahlon et. al., Ann Surg, 2012
High Grade (Grade 2 & 3) STS Treatment
• Limb salvage surgery (LSS) + RT

• LR <15%

• Survival varies by size and grade

Inadvertent Excisions
• Common phenomena
• Generally smaller and subcutaneous tumors
• Inappropriate skin incision common
• Residual disease in 24-74% of cases
• Treatment is LSS + RT, i.e. like a de novo diagnosis
• Similar local control and survival to those with primary
management
Alamanda et. al. J Surg Oncol, 2012
Fiore et. al., Ann Surg Oncol, 2006
Venkatesan et. al., ESJO, 2012
LSS Considerations & Challenges
• Vascular involvement
• Joint involvement
• Tissue planes
• E.g., adjacent bone; removal of
periosteum?; need for fixation?
• Functional loss
• Need for plastic surgery
Treatment Evolution
Preoperative vs.
Amputation Postoperative RT

LSS + RT
Reduced Dose &
Hypofractionated
Preoperative RT
LSS + RT for High Grade Extremity STS
NCI, 1982 MSKCC, 1993 NCI, 1998

NO SURVIVAL DIFFERENCE

Harrison et. al., IJROBP, 1993

Rosenburg et. al., Ann Surg, 1982
Yang et. al., JCO, 1998
Preoperative vs. Postoperative RT

Preoperative RT Postoperative RT
- Wound complications - Wound complications
(35%) (17%)
- <15% LR
- RT dose (50 Gy) - Similar OS - RT dose (≥60 Gy)
- Treatment volume & DFS - Treatment volume
(tumor + margin) (op bed + margin)
- Risk of fibrosis, edema, - Risk of fibrosis, edema,
range of motion range of motion
limitations (16-32%) limitations (23-48%)

Davis et. al., Radiother Oncol, 2005

O’Sullivan et. al., Lancet, 2002
Innovative Preoperative RT Strategies
• Preoperative RT preferred for most situations
• Local control outcomes are excellent for most extremity STS
• <15% LF
• Acceptable toxicities and functional outcomes

• How can we advance local therapies?

• RT dose deintensification
• Hypofractionation
Preoperative RT Dose Deintensification
• Myxoid liposarcoma most radiosensitive STS subtype
• <5% local failure rate
• ≥50% pCR in >78% cases

• Tumor volumes shrinks during or after RT

Chowdhry et. al., Sarcoma, 2018

Gao et. al., CTOS 2021
Guadagnolo et. al., IJROBP, 2008
DOREMY
• Phase II, 79 patients, 36 Gy / 18
fractions
• Primary endpoint: ≥50%
histologic treatment effect
• 91% of patients
• Median follow up: 25 months
• No local relapses
• 17% wound complication rate
• 14% late grade 2+ toxicity
• RT dose deintensification is
efficacious and safe for
myxoid liposarcoma
• Optimal dose in tumors with
“high” round cell component
• 75% of tumors with ≤5%
round cell component
Lansu et. al., JAMA Oncol, 2021
Hypofractionated Preoperative RT
Oncologic outcomes Toxicities

Quicker turnaround to
surgery

DISADVANTAGES ADVANTAGES

HYPOFRACTIONATION
 Hypofractionated Preoperative RT
Study Dose / N Median Follow- Wound Local Overall
Fractionation Up (months) Complications Control Survival
Kosela-Paterczyk et. al., 25 Gy / 272 35 32.4% 81% 72%
Eur J Surg Oncol, 2014 5 fx @ 3 yr @ 5 yr

Conventional fractionation: 50 Gy in 25 fractions

EQD2 with 25 Gy in 5 fractions: 40 Gy

Insufficient dose suboptimal local control

 Hypofractionated Preoperative RT
Study Dose / N Median Follow- Wound Local Overall
Fractionation Up (months) Complications Control Survival
Kosela-Paterczyk et. al., 25 Gy / 272 35 32.4% 81% 72%
Eur J Surg Oncol, 2014 5 fx @ 3 yr @ 5 yr
Kalbasi et. al., 30 Gy / 52 29 32% 94.3% NR
Clin Cancer Res, 2020 5 fx @ 2 yr

EQD2 = 50 Gy
 Hypofractionated Preoperative RT
Study Dose / N Median Follow-Up Wound Local Overall
Fractionation (months) Complications Control Survival
Kosela-Paterczyk et. al., 25 Gy / 5 fx 272 35 32.4% 81% 72%
Eur J Surg Oncol, 2014 (EQD2 = 40 Gy) @ 3 yr @ 5 yr
Kalbasi et. al., 30 Gy / 5 fx 52 29 32% 94.3% NR
Clin Cancer Res, 2020 (EQD2 = 50 Gy) @ 2 yr
Pennington et. al., 28 Gy / 8 fx 116 71 10% 89% 82%
Am J Clin Oncol, 2018 (EQD2 = 35 Gy) @ 3 yr @ 3y
Parsai et. al., 30 Gy / 5 fx 16 10.7 31.2% 100% NR
Adv Radiat Oncol, 2020 (EQD2 = 50 Gy) @ 1 yr
Bedi et. al., 30 Gy / 5 fx 32 36.4 25% 100% 82.2%
Adv Radiat Oncol, 2022 (EQD2 = 50 Gy) @ 3 yr
Guadagnolo et. al., 42.75 Gy / 15 fx 120 24 31% 93% 91%
Lancet Oncol, 2022 (EQD2 = 50 Gy) @ 2.5 yr @ 2 yr
Mayo Clinic (accruing) 42.75 Gy / 15 fx 120 -- -- -- --
(EQD2 = 50 Gy)
RT Treatment Principles: Simulation
• Custom immobilization
• Soft tissue reproducibility
• Fixation to prevent rotation
• Soft tissue contact with immobilization device

• Avoid
• Lower extremity: Contralateral extremity
• Upper extremity: Torso, head
• Ensure patient comfort
• MRI with contrast in treatment position
RT Treatment Principles: Simulation
Proximal Extremity Mid-Extremity Distal Extremity
RT Treatment Principles: Dose
Preoperative RT
• 50 Gy in 25 fx
• Hypofractionation on trial or in
certain circumstances where
conventional fractionation is not
possible
• Discuss with patient the
absence of long term-follow
up data
Postoperative RT
• Fungating tumor, extremely
painful tumor, or high risk of
wound complications
Initial volume: 45 – 50 Gy
Boost: 16 - 20 Gy
Total dose: 60-68 Gy (1.8-2 Gy/fx)
*Negative margins: 64 Gy (60-66 Gy)
*Positive margins: 66-68 Gy
DeLaney et. al., IJROBP, 2007
RT Treatment Principles: Preoperative RT Volume
• GTV: From T1 contrast and/or T2 images
• CTV: Along direction of muscle fibers, path
of least resistance, anatomically
constrained (bone, compartment, etc.)
• Longitudinal: 3-4 cm
• Radial: 1.5 cm
• CTV should include all peritumoral edema (T2 image)
• PTV: 0.5 – 1.0 cm
RT Treatment Principles: Preoperative RT Volume
• Phase II, 79 patients
• 50 Gy / 25 fx preoperative RT
• Grade 2 or 3 tumors:
• <8 cm: 2 cm longitudinal, 1 cm
radial
• ≥8 cm: 3 cm longitudinal
• Median follow up 3.6 years
• 2-year local control: 94%
• Grade 2+ late toxicity: 10.5%
Significant reduction in toxicities suggest
smaller target volumes appropriate.
Confirmatory data are awaited
Wang et. al., JCO, 2015
RT Treatment Principles: Postoperative RT Volumes
• Initial Volume • Boost Volume
• Operative bed • CTV
• Fuse preop MRI with CT • Longitudinal: 2 cm
• Postoperative changes, surgical • Radial: 1.5 cm
clips, scar, and drain sites
• PTV: 0.5 – 1.0 cm
• CTV
• Longitudinal: 3-4 cm
• Radial: 1.5 cm
• PTV: 0.5 – 1.0 cm
RT Treatment Principles: Treatment Planning
• 3D and IMRT used
• Important to spare strip of skin
• Bone dose
• Lower fracture risk if
• Maximum dose <59 Gy
• Mean dose <37 Gy
• V40 Gy < 64%

Dickie et. al., IJROBP, 2009

RT Treatment Principles: Treatment Planning
• IMRT advantages
• Decrease dose to normal tissues (bone, soft tissue)
• Increase conformity
• IMRT disadvantages
• Higher dose to full circumference of limb
• Cost
• Potential dose to other parts of body (head with proximal
upper extremity STS treatment)
• Proximal thigh tumors- IMRT advantageous (spare genitals)
RT Treatment Principles: Treatment Planning
NCIC Trial: Preop Arm RTOG 0630 PMH
IMRT (%) 0% (100% 3D) 75% 100% (flap sparing)
Local Recurrence 7% (3-yr) 11.4% (2-yr) 11.8% (5-yr)
Grade 2+
Fibrosis 31.5% 5.3% 9.3%
Edema 15.1% 5.3% 11.1%
Joint stiffness 17.8 3.5% 5.6%

Local control similar between modalities. Late

toxicities appear to be lower with IMRT O’Sullivan et. al., Lancet, 2002
O’Sullivan et. al., Cancer, 2013
Wang et. al., JCO, 2015
RT Treatment Principles: Example Case

• CTV confined to
compartment
• CTV includes
vasculature
• CTV does not
include bone
RT Treatment Principles: Example Case

PTV can be cropped

3-5 mm from skin
RT Treatment Principles: Example Case

• Bone max: 54 Gy
• Bone V40 Gy = 42%
• Bone mean = 34 Gy
Retroperitoneal STS
Overview
• Common histologies: Liposarcoma (60%)
& leiomyosarcoma (20%)

• Patterns of failure:
• Predominately LR: 50-80%
• Distant recurrence to lung and liver
• Poor outcomes:
• 5-year overall survival: 30-60%
Treatment Challenges
Surgery
• Resectable to R0
• Proximity to critical organs,
major neurovascular
structures
• Functional loss
RT
• Large tumor size
• Normal tissue sensitivities
• Kidney resection plans?
Kidney function status?
• Postoperative RT dose
exceeds bowel tolerance
• Patient’s GI symptoms
Treatment Approach
• Surgery is the mainstay and only curative treatment
• Role of RT has been debated for many years

Sindelar et. al., Arch Surg, 1993

Treatment Approach
• If RT is pursued, preoperative RT is preferred
• Advantages: Tumor identifiable, tumor displaces bowel,
margin improvement, lower radiation dose (50 Gy)

• Postoperative RT: Discouraged

• Rarely can achieve adequate therapeutic dose (60-66 Gy)
because bowel falls into treatment area, normal tissue dose
constraints below prescription dose, higher GI toxicity
STRASS
266 patients, primary diagnosis
74% liposarcoma
Median follow up: 43.1 months
Surgery only
R
Preoperative RT + surgery
Median dose: 50.4 Gy

Primary endpoint: Abdominal recurrence free survival (ARFS)

• Progressive disease
• Tumor or patient becomes inoperable
• Macroscopically incomplete resection
• Peritoneal sarcomatosis at time of surgery
• LR
Bonvalot et. al., Lancet Oncol, 2020
STRASS

All Population Liposarcoma

Bonvalot et. al., Lancet Oncol, 2020
STRASS
• Serious adverse events
• Preoperative RT + surgery: 24%
• Surgery only: 10%

“Preoperative radiotherapy should not be

considered as standard of care treatment for
retroperitoneal sarcoma.”

Bonvalot et. al., Lancet Oncol, 2020

STRASS
In the appendix…

All Population
Surgery Preoperative RT + S
Local Recurrence (N) 39 17
Liposarcoma
Surgery Preoperative RT + S
Local Recurrence (N) 30 11

Bonvalot et. al., Lancet Oncol, 2020

STRASS VS. STREXIT
• STREXIT: Prospectively maintained database, 727 patients
• STREXIT patients 1:1 propensity matched analysis to STRASS

ARFS HR (95% CI)

Preoperative RT + surgery
Liposarcoma (N=321) 0.61 (0.42-0.89)
Well-differentiated liposarcoma & G1-2 0.63 (0.40-0.97)
dedifferentiated liposarcoma (N=266)

Callegaro et. al., Annals of Surgery, 2022

Current Treatment Approach
• Multidisciplinary discussion for all cases

• De novo diagnosis
• Consider preoperative RT if surgical margins (along
vasculature, muscle, bone, etc.) anticipated to be close or
positive, and patient can tolerate preoperative RT
• Especially for liposarcoma

• Abdominal recurrence diagnosis

• Favor preoperative RT, especially if multiple recurrences
RT Planning: Simulation
• Upper and lower body immobilization
• Oral contrast (especially for upper abdominal tumors)
• IV contrast
• 4D scan for tumors superior to iliac brim
• Consider gaiting if motion >1 cm

• For psoas muscle invasion, fuse MRI

RT Planning: Contouring
• Create GTV using contrast and MRI (if applicable) scans
• Create iGTV
• CTV: 1.5 cm longitudinal and radial expansion
• 0 cm expansion at liver, bone, and kidney
• 0.5 cm expansion at bowel interfaces
• If tumor extends into inguinal canal, add 3 cm distally
• PTV: 0.5 -1.0 cm expansion
Baldini et. al., IJROBP, 2015
RT Planning: Contouring

• 50 Gy / 25 fx or
50.4 Gy / 28 fx
• IMRT
RT Planning: SIB to High-Risk Margins

56.25 Gy / 25 fx

Phase I/II Trial of Pre-Operative Image Guided Intensity Modulated

Proton Radiation Therapy (IMPT) or Photon (IMRT) with
Simultaneously Integrated Boost to the High-Risk Margin for
Retroperitoneal Sarcomas
Clinicaltrials.gov, NCT01659203
Conclusions
• STS are a diverse group of tumors best managed by a
multidisciplinary team of sarcoma specialists
• Extremity & trunk STS
• Can avoid RT in small, superficial, low-grade tumors resected
with wide R0 margins
• High-grade tumors: preoperative RT + LSS
• Preoperative RT: 50 Gy / 25 fx
• Myxoid liposarcoma: 36 Gy / 18 fx
• Hypofractionated preop RT increasing in popularity
Conclusions
• Retroperitoneal STS
• De novo diagnosis
• Multidisciplinary discussion: Evaluate surgical margins,
probability of tumor recurrence
• Preoperative RT likely beneficial for liposarcoma histology
• Recurrent diagnosis
• Consider preoperative RT
• Preoperative RT: 50 Gy / 25 fx or 50.4 Gy / 28 fx
• Consider SIB to high-risk margins
Questions & Discussion
ahmed.safia@mayo.edu