General and Extremity Soft Tissue Sarcoma
BACKGROUND
What is the most common type of sarcoma?
The most common type of sarcoma is soft tissue sarcoma (STS).
Approximately how many cases of STS are diagnosed annually in the U.S.? How many deaths occur?
~11,000 cases/yr of STS are diagnosed in the U.S., with ~4,400 deaths/yr.
What is the median age at Dx of STS?
The median age at Dx of STS is 45–55 yrs.
What are the 3 most common sites of STS?
The 3 most common sites of STS are the extremity (60%), retroperitoneal (15%), and trunk/H&N (10% each).
What % of extremity STS involves the lower extremity?
67% of extremity STS involves the lower extremity.
What % of lower extremity STS is at or above the knee?
75% of lower extremity STS is at or above the knee.
What is the most common presentation of STS?
The most common presentation of STS is a painless mass.
What is the DDx of a painless mass of the extremity?
Painless mass of the extremity DDx: STS, primary or metastatic carcinoma, lymphoma, desmoid tumor, and benign lesions (lipoma, lymphangioma, leiomyoma, neuroma, Schwannoma, etc.)
What are the 5 most common types of STS?
Most common types of STS:
1. High-grade undifferentiated pleomorphic sarcoma (previously called malignant fibrous histiocytoma) (20%–30%)
2. Liposarcoma (10%–20%)
3. Leiomyosarcoma (5%–10%)
4. Synovial sarcoma (5%–10%)
5. Malignant peripheral nerve sheath tumors (5%–10%)
How many different histologic subtypes of STS have been identified?
>50 histologic subtypes of STS have been identified.
What are the chromosomal translocations seen for (1) synovial sarcoma, (2) clear cell sarcoma, (3) Ewing sarcoma/PNET, and (4) alveolar rhabdomyosarcoma?
Chromosomal translocations:
1. Synovial sarcoma: t(X, 18) SYT-SSX
2. Clear cell sarcoma: t(12,22) EWSR1-ATF1
3. Ewing sarcoma/PNET: t(11,22) EWSR1-FLI1
4. Alveolar rhabdomyosarcoma: t(2,13), t(1,13) PAX-FOXO1A
Name 4 genetic syndromes associated with sarcoma and the type of sarcoma associated with each of these syndromes.
Genetic syndromes associated with sarcoma and their type:
1. Gardner (desmoid tumors)
2. Retinoblastoma (bone and STS)
3. NF-1 (benign neurofibromas and malignant peripheral nerve sheath tumors)
4. Li-Fraumeni (bone and STS)
Name 6 environmental risk factors for STS.
Environmental risk factors for STS:
1. Ionizing radiation
2. Thorotrast
3. Chlorophenols
4. Vinyl chloride
5. Arsenic
6. Herbicides
What virus is associated with Kaposi sarcoma (KS)?
Human herpes virus 8 (HHV-8), also known as Kaposi sarcoma–associated herpes virus (KSHV). AIDS-associated (or epidemic KS) KS is 1 of 4 subtypes of KS.
What dose of RT can be used for KS?
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, Radiother Oncol 1998)
What is the RR of secondary sarcoma in children who received RT?
According to the Childhood Cancer Survivorship Study, RT is associated with a RR of 3.1 for developing a secondary sarcoma. (Henderson TO et al., JNCI 2007)
What is Stewart-Treves syndrome?
Stewart-Treves syndrome is an angiosarcoma that arises from chronic lymphedema, most often as a complication of Tx for breast cancer.
Where does STS originate?
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.
What % of STS have +LNs at Dx?
5% of STS have +LNs at Dx.
Which 5 types of STS have an increased risk of LN mets?
STS types that have an increased risk of LN mets:
1. Synovial sarcoma (14%)
2. Clear cell sarcoma (28%)
3. Angiosarcoma (14%)
4. Rhabdomyosarcoma (19%)
5. Epithelioid sarcoma (20%)
(Mnemonic: SCARE)
What is the most common site of DM from STS?
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.
Name 5 factors associated with an increased risk of LR in pts with STS.
Factors associated with an increased risk of LR in pts with STS:
1. Age >50 yrs
2. Recurrent Dz
3. Positive surgical margins
4. Fibrosarcoma (including desmoid)
5. Malignant peripheral nerve sheath tumor
Name 5 factors associated with an increased risk of DM in pts with STS.
Factors associated with an increased risk of DM in pts with STS:
1. High grade
2. Size >5 cm
3. Deep location
4. Recurrent Dz
5. Leiomyosarcoma
WORKUP/STAGING
What is an appropriate workup for a painless mass?
Painless mass workup: H&P, careful exam of the primary site and draining LN regions, basic labs (CBC/BMP/LFTs), CXR, CT/MRI primary site, and a schedule for core Bx or incisional Bx
What is the AJCC 7th edition (2011) TNM classification for STS?
T1: tumor ≤5 cm
T1a: superficial to superficial fascia
T1b: deep to superficial fascia
T2: tumor >5 cm
T2a: superficial to superficial fascia
T2b: deep to superficial fascia
N1: regional LN mets
M1: DMs
Note: The retroperitoneal location is always considered deep.
What grading system is used by the AJCC for STS, and how many grades are there in this system?
Historically, the AJCC used a 4-grade system but switched to the French 3-grade system in their 7th edition (2011).
What are the AJCC 7th edition (2011) stage groupings with TNM and grade for STS?
Stage IA: T1a-bN0M0, grade 1
Stage IB: T2a-bN0M0, grade 1
Stage IIA: T1a-bN0M0, grades 2–3
Stage IIB: T2a-bN0M0, grade 2
Stage III: T2a-bN0M0, grade 3, or any TN1M0, any grade
Stage IV: M1
What 2 imaging studies are recommended to evaluate a potential STS?
MRI (+/– CT scan of the primary site) and chest imaging are recommended for pts with potential STS.
What type of Bx are recommended to evaluate a concerning soft tissue mass?
Soft tissue masses should be diagnosed using either a core needle Bx (preferred) or an incisional Bx oriented so that it may be excised during the definitive surgery. Preferably, the Bx should be done by or in coordination with the surgeon who will be performing the definitive surgery.
Under what circumstances are PET, CT, or MRI potentially useful in the workup of STS?
FDG-PET: may be useful for prognostication and grading as well as to determine response to chemo
CT abdomen/pelvis: myxoid/round cell liposarcoma, epithelioid sarcoma, angiosarcoma, and leiomyosarcoma
MRI spine: myxoid/round cell liposarcoma
MRI brain: alveolar soft part sarcoma (ASPS) or angiosarcoma
TREATMENT/PROGNOSIS
What is the primary Tx modality for STS?
Surgery is the primary Tx modality for STS.
What is the LR rate after surgery alone for STS?
LR after surgery alone depends on the extent of resection. LR is 90% after simple excision, 40% after wide excision, 25% after soft part excision, and 7%–18% after amputation.
What prospective trial examined surgery alone?
MDACC treated 88 pts with T1 (<5 cm), any grade STS with limb-sparing surgery (LSS) alone if R0 resection. 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)
What is the LR rate and DFS after primary RT alone for STS?
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)
Surgery alone is adequate for which pts with STS of the extremity?
According to the NCCN, pts with low-grade extremity STS (stage I) s/p surgical resection with >1-cm margins do not require adj therapy. Consider RT if the margin is ≤1 cm.
What are the management options for a pt with stage II or III resectable STS?
Stage II or III resectable STS management options:
1. Surgery → RT +/– chemo
2. Preop RT → consideration of postop chemo
3. Preop chemo or CRT
What studies support the use of adj RT following LSS in high- and low-grade STS?
There have been 2 RCTs that have evaluated the impact of adj RT after limb-sparing surgery in STS:
Yang et al., from the NCI, randomized pts with high- and low-grade STS of the extremity treated with LSS to adj EBRT (63 Gy) or no RT. (JCO 1998) Pts with high-grade STS received adj Adr/cyclophosphamide with or without concurrent EBRT. For high-grade pts, 10-yr LC significantly favored RT (100% vs. 80%), but there was no difference in 10-yr DMFS or OS. For low-grade pts, LC favored the RT arm (95 vs. 67%), but there was also no difference in DMFS or OS. Radiation significantly decreased joint motion and worsened edema.
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 or no RT. (JCO 1996) For high-grade pts, 5-yr LC favored the RT arm (89% vs. 66%), but there was no OS difference. For low-grade pts, LC and OS were not significantly impacted by RT.
What RCT compared preop RT vs. PORT for extremity STS, and what did it show?
The NCI Canada trial randomized pts with extremity STS to preop RT (50 Gy in 25 fx + a 16–20 Gy boost for +surgical margins) vs. PORT (50 Gy in 25 fx + a 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 of the planned 266 pts b/c of significantly greater wound complications with preop RT (35%) vs. PORT (17%), with the highest rates of complications in the ant thigh (45% vs. 38%). 6-wk function was better with PORT. (O’Sullivan B et al., Lancet 2002) At median follow-up 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. In the long term, PORT was associated with worse fibrosis and joint stiffness (grade 2 fibrosis was 31% vs. 48%, p = 0.07). (Davis AM et al., Radiother Oncol 2005)
What are the advantages of preop RT compared to PORT for the management of extremity STS?
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
What is the evidence that a limb-sparing approach of local excision with PORT yields equivalent outcomes compared to amputation alone in the management of high-grade extremity STS?
The NCI trial randomized 43 pts with high-grade extremity STS to amputation at the joint proximal to the tumor vs. limb-sparing resection + RT. Randomization favored limb sparing (2:1). RT was 45–50 Gy → a boost to 60–70 Gy with concurrent adr/Cytoxan → high-dose methotrexate. 4 of 27 pts in the RT group had +margins. There was no difference in 5-yr DFS (78% amputation vs. 71% RT) or OS (88% vs. 83%). There was increased LR with limb sparing (0% vs. 20%). (Rosenberg SA et al., Ann Surg 1982)
What is the benefit of adding adj chemo for high-grade extremity STS after surgery?
The SMAC meta-analysis included 1,953 pts with STS s/p WLE +/– adj doxorubicin-based chemo. Chemo improved LC (HR 0.73), DMFS (HR 0.6710), and OS (HR 0.77). Number needed to treat: 17 to prevent 1 death. Doxorubicin + ifosfamide better than doxorubicin alone. (Pervaiz N et al., Cancer 2008)
Should adj chemo be used in all high-grade STS pts?
This is controversial. Adj chemo should not be adopted as standard practice, regardless of histology or tumor size. It is typically reserved for pts with large, high-grade tumors; +margins or gross residual Dz; synovial sarcoma, or round-cell liposarcoma.
Which pts with extremity STS should be treated with neoadj therapy?
Neoadj RT, chemo, or CRT are reasonable options for all pts with stage II or III extremity STS, though surgery → 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).
Cite 2 studies that demonstrate the efficacy of neoadj CRT for large extremity STS.
The Harvard retrospective study and RTOG 9514 are 2 studies that demonstrate the efficacy of neoadj CRT for large extremity STS.
What were the results of the Harvard retrospective study for STS?
The Harvard retrospective study of neoadj CRT for large STS reviewed 48 pts with >8-cm extremity STS. Pts were treated with interdigitated sequential CRT as follows: mesna/doxorubicin/ifosfamide/dacarbazine (MAID) → RT (22 Gy in 11 fx) → MAID → RT (22 Gy in 11 fx) → MAID → surgery → MAID × 3. If surgical margins were positive, pts rcvd an additional 16 Gy boost postop. 5-yr LC was 92%, DFS was 70%, and OS was 87%. Compared with historical controls, there was a significant decrease in DM and a significant increase in DFS and OS. There were 29% wound complications and 2% Tx-related deaths. (DeLaney TF et al., IJROBP 2003)
What were the results of RTOG 9514 for STS?
RTOG 9514 was a phase II trial enrolling 64 pts with ≥8-cm grade 2 or 3 STS of the extremity or torso with expected R0 resection. 44% had malignant fibrous histiocytoma, 13% had leiomyosarcoma, and 88% had STS of the extremity. Pts were treated with MAID → RT (22 Gy in 11 fx) → MAID → RT (22 Gy in 11 fx) → MAID → surgery → MAID × 3 → a 14 Gy postop boost if necessary. 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 DFS was 56%, distant DFS was 64%, OS was 71%, and there was a 92% amputation-free rate. There were 5% Tx-related deaths (mostly secondary AML), and 84% 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) Note that RTOG 9514 used a more intense version of MAID than was used in the Harvard study, which probably worsened toxicity.
What were the results of the EORTC STBSG 62871 trial regarding neoadj chemo for STS?
EORTC STBSG 62871 was a randomized phase II trial enrolling 134 pts with STS ≥8 cm or grade 2 or 3. Pts were randomized to surgery alone vs. neoadj doxorubicin/ifosfamide. PORT was given for marginal surgery, +surgical margins, or LR. There was no difference in 5-yr DFS (52% vs. 56%) or OS (64 vs. 65%), but the study was not sufficiently powered to detect a difference. (Gortzak E et al., Eur J Cancer 2001)
What were the results of EORTC 62961 regarding hyperthermia + neoadj chemo for STS?
EORTC 62961 randomized 341 pts with ≥5-cm, grade 2 or 3, deep and extracompartmental STS to neoadj etoposide/ifosfamide/Adriamycin (EIA) vs. neoadj EIA + deep wave regional hyperthermia. Hyperthermia resulted in improved median LRC (3.8 yrs vs. 2 yrs) and median DFS (2.6 yrs vs. 1.4 yrs). (Issels RD et al., Proc ASCO 2007)
What were the results of the MSKCC retrospective review regarding IMRT for extremity STS?
The MSKCC reported a retrospective review of 41 pts with extremity STS treated with LSS and IMRT. 51% had close or +surgical margins. IMRT was used preop in 7 pts (mean dose, 50 Gy) and postop in 21 pts (mean dose, 63 Gy). At median follow-up at 2.9 yrs, 5-yr LC was 94% regardless of margin status, DMFS was 61%, and OS was 64%. (Alektiar KM et al., JCO 2008)
How long after surgery should adj RT for STS begin?
PORT for STS preferably begins after healing is completed, by 3–8 wks postsurgery.
What dose is recommended for adj RT for STS?
A commonly used prescription for adj RT for STS is 50 Gy in 2 Gy/fx → a 10–16 Gy boost for –margins, a 16–20 Gy boost for microscopically +margins, and a 20–26 Gy boost for grossly +margins.
Surgery should take place approximately how long after completion of neoadj RT for STS?
Surgery preferably takes place 3–6 wks after completion of neoadj RT in order to decrease the risk of wound complications.
What dose is recommended for neoadj RT for extremity STS?
A commonly used Rx for neoadj RT for extremity STS is 50 Gy in 2 Gy/fx. If postop margins are close or positive, consider a boost using IORT (single 10–16 Gy), brachytherapy (12–20 Gy), or EBRT (10–14 Gy for close margins, 16–20 Gy for microscopically +margins, and 20–26 Gy for grossly +margins).
What are the initial and boost RT Tx volumes for STS in the preop setting?
According to RTOG 0630 (IGRT preop study) revision in 2009, GTV = MRI T1 plus contrast images. CTV = GTV and suspicious edema (on MRI T2) + 3-cm margin longitudinally for intermediate to high-grade tumors ≥8 cm (2 for others) and a 1.5-cm margin radially from the GTV to the CTV. CTV is limited at bone and by the compartment in which tumor arises. A 0.5-cm expansion from CTV to PTV is generally utilized.
What are the initial and boost RT Tx volumes for STS in the postop setting?
In the postop setting, the scar and drainage sites should be included in the GTV. Longitudinal margins should be 5–7 cm. The boost volume is the surgical bed + a 2-cm margin to the block/field edge. Try to spare a 1.5- to 2-cm strip of skin.
What are important dose constraints in the extremity?
Per RTOG 0630, no more than 50% of a longitudinal strip of skin/tissue should receive >20 Gy and <50% of a weight-bearing bone should receive 50 Gy.
How is postop brachytherapy performed for the Tx of high-grade STS of the extremity?
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.
Low-dose rate: 45–50 Gy to tumor bed over 4–6 days
High-dose rate: 3.4 Gy bid × 10 fx (34 Gy in 5 days)
How should pts with unresectable STS be managed?
Consider preop RT, chemo, or CRT. If still deemed unresectable, consider definitive RT, chemo, palliative surgery, observation, or the best supportive care.
What dose of RT is recommended for unresectable STS?
If possible, the dose should be ≥70–80 Gy using sophisticated Tx planning (IMRT or proton beam).
TOXICITY
What are the short- and long-term toxicities associated with RT for STS of the extremity?
Toxicities associated with RT for extremity STS:
Short term: wound complications (5%–15% with PORT, 25%–35% with preop RT), dermatitis, recall reactions with doxorubicin and dactinomycin, epilation
Long term: abnl bone and soft tissue growth and development, leg length discrepancy, permanent weakening of bone with the greatest risk of fracture within 18 mos of completion of therapy, fibrosis leading to decreased range of motion, lymphedema, skin discoloration, telangiectasias, 2nd malignancy (≤5%)
What is the recommended follow-up after Tx of STS?
Consider evaluation by occupational/physical therapy for functional restoration, H&P and chest imaging (CXR or CT chest) q3–6mos × 2–3 yrs, then q6mos for the next 2 yrs, then annually. Consider periodic imaging of the primary site (MRI, CT, or US) to assess LR.
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