General and extremity soft tissue sarcoma

Question 1

What is the most common type of sarcoma?

Answer 1

The most common type of sarcoma is soft tissue sarcoma (STS), accounting for ∼80% of sarcomas. The remainders arise from bone.

Question 2

Where does STS originate?

Answer 2

STS originates from the primitive mesenchyme of the mesoderm, which gives rise to muscle, fat, fibrous tissues, blood vessels, and supporting cells
of the peripheral nervous system.

Question 3

How many different histologic subtypes of STS have been identified?

Answer 3

> 50 histologic subtypes of STS have been identified.

Question 4

What are the 6 most common types of STS?

Answer 4

The most common types (∼75%) of diagnosed STS are:

1. Undifferentiated pleomorphic sarcoma (previously called malignant fibrous histiocytoma)
2. Liposarcoma
3. Leiomyosarcoma
4. Myxofibrosarcoma
5. Synovial sarcoma
6. Malignant peripheral nerve sheath tumor (MPNST)

Question 5

Appx how many cases of STS are diagnosed annually in the United States? How many deaths occur?

Answer 5

∼12,400 cases/yr of STS are diagnosed in the United States, with ∼5,000 deaths/yr.

Question 6

What are the 3 most common sites of STS?

Answer 6

The 3 most common sites of STS are the extremity (60%), retroperitoneal (15%), and trunk/H&N (10% each).

Question 7

What % of extremity STS involves the LE?

Answer 7

67% of extremity STS involve the LE.

Question 8

What % of LE STS is at or above the knee?

Answer 8

75% of LE STS is at or above the knee.

Question 9

What are the chromosomal translocations seen for (1) synovial sarcoma, (2) clear cell sarcoma, (3) EWS/PNET, and (4) alveolar RMS?

Answer 9

Chromosomal translocations:

1. Synovial sarcoma: t(X, 18) SY18-SSX (SY18-SSX1, SY18-SSX2 or SY18-SSX4)
2. Clear cell sarcoma: t(12, 22) EWSR1-ATF1
3. EWS/PNET: t(11, 22) EWSR1-FLI1—most common chromosomal translocation
4. Alveolar RMS: t(2, 13); t(1, 13) PAX-FOXO1 (PAX3-FOX01 or PAX7-FOX01)

Question 10

Name 4 genetic syndromes associated with sarcoma and the type of sarcoma associated with each of these syndromes.

Answer 10

Genetic syndromes associated with sarcoma and their type:

1. Gardner (a subtype of FAP) (desmoid tumors)
2. Retinoblastoma (osteosarcoma and STS)
3. NF-1 (neurofibromas, MPNSTs, GISTs, giant cell lesions, RMSs, and glomus tumors)
4. Li-Fraumeni (osteosarcoma, RMS, and STS)

Question 11

Are there any environmental risk factors associated with STS?

Answer 11

Environmental risk factors may include RT exposure (e.g., RT, radiocontrast agent Thorotrast), and chemicals (e.g., chlorophenols in pesticides/herbicides, vinyl chloride to produce PVC, dioxin). However, most STS are not known
to be associated with specific environmental hazards.

Question 12

What is the RR of secondary sarcoma in children who rcvd RT?

Answer 12

According to the Childhood Cancer Survivorship Study, RT is associated with an RR of 3.1 for developing a secondary sarcoma. (Henderson TO et al.,
JNCI 2007)

Question 13

What is Stewart–Treves syndrome?

Answer 13

Stewart–Treves syndrome is an angiosarcoma that arises from chronic lymphedema, most often as a complication of Tx for breast cancer.

Question 14

What role do viral infection and immunodeficiency play in sarcoma development?

Answer 14

Human herpes virus 8 plays a key role in the development of Kaposi sarcoma. And EBV has been associated with smooth muscle tumors in
immunocompromised pts. (Deyrup AT et al., Am J Surg Pathol 2006)

Question 15

What is the median age at Dx of STS?

Answer 15

The median age at Dx of STS is 45–55 yrs.

Question 16

What is the most common presentation of STS?

Answer 16

The most common presentation of STS is a painless mass.

Question 17

What is the DDx of a painless mass of the extremity?

Answer 17

Painless mass of the extremity DDx: STS, primary or metastatic carcinoma, lymphoma, melanoma, desmoid tumor, and benign lesions (lipoma, lymphangioma, leiomyoma, neuroma, schwannoma, etc.)

Question 18

What % of M0 STS have +LNs at Dx?

Answer 18

∼2.6%–10.8% of STS have +LNs at Dx. (Brennan et al., Management of Soft Tissue Sarcoma 2013)

Question 19

Which types of STS have an increased risk of LN mets?

Answer 19

STS types that have an increased risk of LN mets:
1. Clear cell sarcoma
2. Angiosarcoma
3. RMS
4. Epithelioid sarcoma
(Mnemonic: CARE)

Question 20

What is the most common site of DM from STS?

Answer 20

The most common site of DM from STS is to the lung (70%–80%). Retroperitoneal and intra-abdominal visceral sarcomas also tend to metastasize to the liver.

Question 21

What factors are associated with an increased risk of LR in pts with STS?

Answer 21

Pt/tumor factors associated with an increased risk of LR in pts with STS:

1. Grade
2. Size
3. Age
4. Margin status
5. Histology
6. Site

Question 22

Name 6 prognostic factors for survival in pts with STS.

Answer 22

Factors associated with an increased risk of decreased survival in pts with
STS:
1. Grade
2. Size
3. Deep location (superficial/deep to fascia)
4. Site (extremity vs. trunk/RP) or (distal vs. proximal)
5. LN involvement
6. Age (young better than old)
(Baldini EH ASTRO Review 2015)

Question 23

What dose of RT can be used for KS?

Answer 23

Doses of 15 Gy for oral lesions, 20 Gy for lesions involving eyelids, conjunctiva, and genitals, and 30 Gy for cutaneous lesions have been shown to be sufficient to produce an objective response of 92%. (Kirova YM et al., Radiother Oncol 1998)

Question 24

What is an appropriate workup for a painless mass?

Answer 24

H&P including exam of the primary site and draining LN regions, CBC/BMP/LFTs, chest imaging, MRI +/– CT primary site, and core Bx or incisional Bx placed along planned resection axis.

Question 25

What are the changes in TNM stage in AJCC 8th edition (2017) compared to 7th edition (2011)?

Answer 25

A greater emphasis is placed on the anatomic primary site of the STS, which has implications for LR and metastatic Dz. Superficial vs. deep location has
been removed as part of T stage criteria.

Head and Neck
T1: ≤2 cm
T2: >2 and ≤4 cm
T3: >4 cm
T4a: Invasion into: orbit, skull base/dura, central compartment viscera,
facial skeleton or pterygoid muscles
T4b: Invasion into: brain, prevertebral muscle, carotid artery encasement,
or CNS spread
N1: Regional LN mets
M1: Mets

Trunk and Extremities
T1: ≤5 cm
T2: >5 and ≤10 cm
T3: >10 and ≤15 cm
T4: >15 cm
N1: Regional LN mets
M1: Mets

Abdomen and Thoracic Visceral Organs
T1: Organ confined
T2a: Invades serosa/visceral peritoneum
T2b: Beyond serosa
T3: Invades another organ
T4a: Multifocal (2 sites)
T4b: 3–5 sites
T4c: >5 sites
N1: LNs
M1: Mets

Question 26

What are the AJCC 8th edition (2017) stage groupings with TNM and grade for STS?

Answer 26

Head and Neck
No AJCC group staging at this time

Trunk and Extremities
Stage IA: T1, N0, Grade 1, Grade X
Stage IB: T2–T4, N0, Grade 1, Grade X
Stage II: T1, N0, Grade 2–3
Stage IIIA: T2, N0, Grade 2–3
Stage IIIB: T3–T4, N0, Grade 2–3
Stage IV: N1 or M1

Abdomen and Thoracic Visceral Organs
No AJCC group staging at this time

Question 27

The French Federation of Cancer Centers Sarcoma Group system, recognized by the AJCC Staging Manual, is determined by what 3 parameters?

Answer 27

Differentiation, mitotic activity, and extent of necrosis

Question 28

Under what circumstances are PET, CT, or MRI potentially useful in the workup of STS?

Answer 28

FDG-PET: may be useful for staging, prognostication and grading as well as to determine response to chemo
CT abdomen/pelvis: myxoid/round cell liposarcoma, epithelial sarcoma, angiosarcoma, and leiomyosarcoma
MRI of total spine: myxoid/round cell liposarcoma
MRI brain: alveolar soft part sarcoma or angiosarcoma

Question 29

What is the primary Tx modality for STS?

Answer 29

Sg is the primary Tx modality for STS.

Question 30

What is the LR rate after Sg alone for STS?

Answer 30

LR after Sg alone depends on the extent of resection. Based on limited, historical data for all STS LR is 93% after simple excision, 73% after local excision → wide excision, 60% after wide excision, and 8% after amputation, where LR defined as failure to control the primary. (Gerner RE et al., Ann Surg 1975)

Question 31

What prospective trial examined Sg alone in selected pts?

Answer 31

MDACC treated T1 (<5 cm), any grade STS with limb-sparing surgery (LSS) alone if R0 resection (74 pts). They found that LR at 10 yrs was 10.6% and that the vast majority of recurrences occurred in high-grade tumors.
(Pisters PW et al., Ann Surg 2007)

Question 32

What is the LR rate and DFS after primary RT alone for STS?

Answer 32

2-yr LR is 66% and 2-yr DFS is 17% after primary RT alone for STS. (Lindberg RD et al., Proc Natl Cancer Conf 1972)

Question 33

Sg alone is adequate for which pts with STS of the extremity?

Answer 33

According to the NCCN, pts with low-grade extremity STS (stage I) s/p surgical resection with appropriate margins do not require adj therapy. Consider RT for margin <1 cm or LR.

Question 34

What are the management options for a pt with stage II or III resectable STS?

Answer 34

Stage II or III resectable STS management options:

1. Sg → RT +/– chemo
2. Preop RT +/– chemo → Sg → +/– adj chemo
3. Preop chemo → Sg → adj RT +/– chemo

Question 35

What is the evidence that a LSS approach of local excision with PORT yields equivalent outcomes compared to amputation alone in the management of high-grade extremity STS?

Answer 35

The NCI trial randomized 43 pts with high-grade extremity STS to amputation vs. LSS + RT. Randomization favored limb sparing (2:1). 4 of 27
pts in the RT group had +SMs. There was no difference in 5-yr DFS (78% amputation vs. 71% RT) or OS (88% vs. 83%). There were 4 LRs in the LSS group vs. none in the amputation group. (Rosenberg SA et al., Ann Surg
1982)

Question 36

What studies support the use of adj RT following LSS in high- and lowgrade STS?

Answer 36

There have been 2 RCTs that have evaluated the impact of adj RT after LSS in STS:

Yang et al. from the NCI, randomized pts with STS of the extremity treated with LSS to adj EBRT (63 Gy) vs. no RT. (JCO 1998) Pts with high-grade STS rcvd adj Adr/cyclophosphamide. For high-grade pts, 10-yr LC
significantly favored RT (100% vs. 78%), but there was no difference in 10-yr DMFS or OS. For low-grade pts, LC favored the RT arm (96% vs. 67%), but there was also no difference in DMFS or OS.

Pisters et al. randomized (in the operating room) pts with high- and low-grade STS who had a complete resection to iridium-192 brachytherapy implant (42–45 Gy) over 4–6 days vs. no RT. (JCO 1996) For high-grade pts, 5-yr
LC favored the RT arm (89% vs. 66%), but there was no LC benefit to RT for low-grade pts. DSS was not significantly impacted by RT.

Question 37

What RCT compared preop RT vs. PORT for extremity STS, and what did it show?

Answer 37

The NCIC trial randomized pts with extremity STS to preop RT (50 Gy/25 fx + 16–20 Gy boost for +SMs) vs. PORT (50 Gy/25 fx + 16–20 Gy boost). The initial field was a 5-cm proximal and distal margin, and boost
was a 2-cm proximal and distal margin. The primary endpoint was major wound complications. The trial closed after accruing 190 pts b/c of significantly greater acute wound complications with preop RT (35%)
vs. PORT (17%), with the highest rates of complications in the ant thigh (45%). 6-wk function was better with PORT. (O’Sullivan B et al., Lancet 2002)

At median f/u of 6.9 yrs, there was no difference in LC (93% preop RT vs. 92% PORT), RFS (58% vs. 59%), or OS (73% vs. 67%). Predictors for outcome included surgical margin status for LC and size and grade for RFS and OS. (O’Sullivan B et al., Proc ASCO 2004) The decision regarding preop vs. postop therapy was driven by toxicity profiles.

At a longer f/u endpoint of 2 yrs, PORT was associated with worse fibrosis and joint stiffness (grade 2 fibrosis was 32% vs. 48%, p = 0.07). (Davis AM et al., Radiother Oncol 2005)

Question 38

What are the advantages and disadvantages of preop RT compared to PORT for the management of extremity STS?

Answer 38

Advantages of preop RT for Tx of extremity STS:

1. Lower RT dose
2. Smaller Tx volume
3. Improved resectability
4. Margin-negative resections
5. Better oxygenation of tumor cells
6. Fewer long-term toxicities

Disadvantages of preop RT for Tx of extremity STS:
1. Increased acute wound complications

Question 39

What is the benefit of adding adj chemo for high-grade extremity STS after Sg?

Answer 39

The updated sarcoma meta-analysis collaboration (SMAC) included 1,953 pts with STS s/p WLE +/– adj doxorubicin-based chemo. Chemo improved LC
(OR 0.73), DMFS (OR 0.67), and OS (HR 0.77). Doxorubicin + ifosfamide better than doxorubicin alone (11% vs. 5% absolute OS improvement). (Pervaiz N et al., Cancer 2008)

Question 40

Should adj chemo be used in all high-grade STS pts?

Answer 40

This is controversial. Adj chemo is toxic and its survival benefits are marginal in most STS, therefore, it should not be adopted as standard practice, regardless of histology or tumor size. It may be considered for pts
with large, high-grade tumors; +SMs or gross residual Dz, synovial sarcoma, or myxoid liposarcoma (chemosensitive histologies in metastatic setting).
However, a pooled analysis of the 2 EORTC-STBSG adj chemo trials in high-grade STS (both negative trials; only 1 trial included in SMAC metaanalysis) failed to identify tumor size or histologic subgroups that benefit
from adj chemo. Poor quality of initial Sg was the most important prognostic factor for utility of chemo. (Le Cesne et al., Ann Oncol 2014)

Question 41

Which pts with extremity STS should be treated with neoadj therapy?

Answer 41

Neoadj RT, chemo, or CRT are reasonable options for all pts with stage II or III extremity STS, though Sg → adj therapy is also an option for these pts.
Neoadj therapy is the preferred option in pts with stage II or III extremity STS when Dz is only potentially resectable or the risk of adverse functional
outcomes is high (e.g., in pts who require extensive resection such as disarticulation, amputation, or hemipelvectomy).

Question 42

Cite 2 studies that demonstrate the efficacy of aggressive neoadj sequential CRT for large extremity STS.

Answer 42

The Harvard retrospective study (DeLaney TF et al., IJROBP 2003) and RTOG 9514 (Kraybill WG et al., Cancer 2010) are 2 studies that demonstrate the efficacy of neoadj sequential chemo-RT-chemo-RT-chemo for large extremity STS

Question 43

What were the results of RTOG 9514 study of neoadj sequential chemoRT for STS?

Answer 43

RTOG 9514 was a phase II trial enrolling 64 pts with ≥8 cm grade 2–3 STS of the extremity or torso with expected R0 resection. 44% had malignant
fibrous histiocytoma, 13% leiomyosarcoma, and 88% STS of the extremity. Pts were treated with mesna, doxorubicin (Adriamycin), ifosfamide, and dacarbazine chemotherapy (MAID) → RT (22 Gy in 11 fx) → MAID → RT (22 Gy in 11 fx) → MAID → Sg → MAID × 3 → a 16 Gy postop boost for +SMs. 91% were R0 resections, and 59% rcvd the full chemo course. 3-yr LRF was 18% (if amputation was considered a failure and 10% if not). 5-yr LRF was 22%, distant mets 28%, DFS was 56%, distant DFS was 64%, OS was 71%, and there was a 91% amputation-free rate. There were 5% Tx related deaths (mostly secondary acute myelogenous leukemia [AML]), and 83% of pts had grade 4 toxicity (mostly hematologic). The authors concluded that the regimen is effective, but substantial toxicity makes this approach controversial. (Kraybill WG et al., Cancer 2010) RTOG 9514 used a more intense version of MAID than was used in the Harvard study, which probably worsened toxicity.

Question 44

What is the optimal regimen for neoadj CRT?

Answer 44

There is no consensus as to the optimal approach to CRT. Some centers use concomitant CRT with single-agent doxorubicin, while others prefer sequential RT and an anthracycline plus ifosfamide-based chemo regimen, or RT combined with alternative chemo agents (such as gemcitabine). There are no randomized trials to define the most effective option, and Tx strategies vary widely b/t different countries and centers.

Question 45

What were the results of the MSKCC retrospective review comparing IMRT vs. conventional EBRT for extremity STS?

Answer 45

MSKCC reported a retrospective series of 319 consecutive pts with extremity STS treated with LSS and adj RT (IMRT = 51.7%, conventional EBRT =
48.3%). Tumor location, size, depth, and histology were similar. IMRT pts had higher proportions of close/+SMs, high grade histology, age >50, preop RT use, nerve manipulation, and recent Tx yrs. The 5-yr rate of LR was
improved among IMRT (7.6%) vs. conventional EBRT (15.1%), (p = 0.05), which persisted in multivariable analysis (HR = 0.46). IMRT was associated with less acute grade 2+ dermatitis (31.5% vs. 48.7%) and late grade 2+ edema (7.9% vs. 14.9%). (Folkert MR et al., JCO 2014)

Question 46

How long after Sg should adj RT for STS begin?

Answer 46

PORT for STS preferably begins after healing is completed, by 3–8 wks post Sg.

Question 47

What dose is recommended for adj RT for STS?

Answer 47

A commonly used Rx for adj RT for STS is 50 Gy in 2 Gy/fx → a 10–16 Gy boost for –SMs, a 16–20 Gy boost for microscopically +SMs, and a 20–26 Gy boost for grossly +SMs.

Question 48

Sg should take place appx how long after completion of neoadj RT for STS?

Answer 48

Sg preferably takes place 3–6 wks after completion of neoadj RT in order to decrease the risk of wound complications

Question 49

What dose is recommended for neoadj RT for extremity STS?

Answer 49

A commonly used Rx for neoadj RT for extremity STS is 50 Gy in 2 Gy/fx. If postop SMs are close/+, consider a boost using IORT (single 10–15 Gy), brachytherapy (12–20 Gy), or EBRT (10–14 Gy for close SMs, 16–18 Gy for
microscopically +SMs, and 20–26 Gy for grossly +SMs). However, the value of adding a post-operative boost is questionable (Yami A et al., IJROBP 2010).

Question 50

What are the RT Tx volumes for STS in the preop setting?

Answer 50

Historically, initial CTV = GTV + 5 cm longitudinally and 2 cm radially.
PTV = CTV + 1 cm. However, reduced volumes with image guidance were explored in RTOG 0630:
GTV = MRI T1 + contrast images.
CTV = G2–3, tumor ≥8 cm: GTV + 3-cm margin longitudinally and 1.5-cm margin radially + suspicious edema on MRI T2. G1 tumor or G2–G3 tumor <8 cm: GTV + 2-cm margin and 1-cm margin radially + suspicious
edema. CTV is limited at bone and by the compartment in which tumor arises.
PTV = CTV + 0.5 cm.

Question 51

What were the results of RTOG 0630 regarding reduced preop Tx volumes in STS?

Answer 51

RTOG 0630 (Wang D et al., JCO 2015) was a single arm phase II study (n = 79) evaluating reduced volumes for preop RT with IGRT. Compared to the NCIC SR2 trial, the late grade 2+ toxicity rate at 2 yr was significantly
improved (10.5% vs. 37%). LC was 94% with all recurrences in field. Toxicities included fibrosis (5.3%), edema (5.3%) and joint stiffness (3.5%).

Question 52

What are the initial and boost RT Tx volumes for STS in the postop setting?

Answer 52

Postop RT is delivered in two phases: initial volume includes surgical bed + margin f/b a boost volume to include the tumor bed + margin. (Haas et al.,
IJROBP 2012)
Initial CTV = Postop bed + 4 cm longitudinally and 1.5 cm radially.
Boost CTV = Resection GTV (tumor bed) + 2 cm longitudinally and 1.5 cm radially.
Resection GTV = reconstruction of primary tumor GTV using preop MRI and/or CT registered to postop CT simulation.
PTV = CTV + 0.5–1 cm

Question 53

What are important dose constraints in the extremity?

Answer 53

For 3D-CRT spare 1–2 cm strip of skin. Per RTOG 0630, no more than 50% of a longitudinal strip of skin/tissue should rcv >20 Gy and <50% of a weight-bearing bone should rcv 50 Gy. Lower risk of RT-induced bone fx
with V40 < 64%, mean bone dose < 37 Gy, and max bone dose < 59 Gy. (Dickie CI et al., IJROBP 2009)

Pathologic fx were associated with 50 Gy to the entire bone circumference, bone exposure, periosteal stripping, and periop chemo. 10-yr fx rate = 2%
when the 50 Gy IDL encompassed the entire bone circumference without other risk factors, but was 37% when all 4 Tx-related factors were present. (Bishop AJ et al., PRO 2016)

Question 54

How is postop brachytherapy performed for the Tx of high-grade STS of the extremity?

Answer 54

Catheters are placed in the operating room after tumor resection, 1 cm apart, with a 2 cm longitudinal and 1–1.5 cm circumferential margin on the tumor bed. Tx begins on or after the 6th postop day to allow for wound healing.

Question 55

How should pts with unresectable STS be managed?

Answer 55

Consider preop RT, chemo, or CRT. If still deemed unresectable, consider definitive RT, chemo, palliative Sg, observation, or the best supportive care.

Question 56

What dose of RT is recommended for unresectable STS?

Answer 56

If possible, the dose should be ≥70–80 Gy using sophisticated Tx planning (IMRT or proton beam).

Question 57

What are the short- and long-term toxicities associated with RT for STS of the extremity?

Answer 57

Short-term toxicities increased (usually reversible) with preop RT whereas late-term toxicities (usually irreversible) increased with postop RT.
Toxicities associated with RT for extremity STS:
Short-term: wound complications, dermatitis, recall reactions with doxorubicin and dactinomycin, epilation
Long-term: abnl bone and ST growth and development, leg length discrepancy, risk of fx, fibrosis, lymphedema, skin discoloration, telangiectasias, 2nd malignancy

Question 58

What is the recommended f/u after Tx of STS?

Answer 58

Consider evaluation by occupational/PT for functional restoration, H&P and chest imaging (CXR or CT chest) q3–6 mos × 2–3 yrs, then q6mos for the next 2 yrs, then annually. Consider baseline and periodic imaging of the
primary site (MRI, CT, or US) to assess LR.