Radiation Oncology: A Question-Based Review

General and Extremity Soft Tissue Sarcoma

Kristin Janson Redmond and Deborah A. Frassica

image 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?

~9,000 cases/yr of STS are diagnosed in the U.S., with ~3,500 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%), trunk (30%), and H&N (10%). The retroperitoneal site comprises 10%–15%.

What % of extremity STS involves the lower extremity?

75% 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, desmoids, and benign lesions (lipoma, lymphangioma, leiomyoma, neuroma)

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)

2.     Clear cell sarcoma: t(12,22)

3.     Ewing sarcoma/PNET: t(11,22)

4.     Alveolar rhabdomyosarcoma: t(2,13), t(1,13)

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.     RT

2.     Thorotrast

3.     Chlorophenols

4.     Vinyl chloride

5.     Arsenic

6.     Herbicides

What is Stewart-Treves syndrome?

Stewart-Treves syndrome is an angiosarcoma that arises from chronic lymphedema, most often as a complication of mastectomy +/− radiotherapy 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 (23%)

4.     Rhabdomyosarcoma (15%)

5.     Epithelioid sarcoma (20%)

(Mnemonic: SCARE)

With the exception of myxoid liposarcoma, what is the most common site of DM from STS?

The most common site of DM from STS is to the lung (70%–80%), except for myxoid liposarcoma, which spreads to nonpulmonary sites in 60% of mets.

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

image 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 (2009) TNM classification for STS?

1.     T1: tumor ≤5 cm

2.     T1a: superficial to superficial fascia

3.     T1b: deep to superficial fascia

4.     T2: tumor >5 cm

5.     T2a: superficial to superficial fascia

6.     T2b: deep to superficial fascia

7.     N1: regional LN mets

8.     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 (2009).

What are the AJCC 7th edition (2009) stage groupings with TNM and grade for STS?

1.     Stage IA: T1a-bN0M0, grade 1

2.     Stage IB: T2a-bN0M0, grade 1

3.     Stage IIA: T1a-bN0M0, grades 2–3

4.     Stage IIB: T2a-bN0M0, grade 2

5.     Stage III: T2a-bN0M0, grade 3, or anyTN1M0, any grade

6.     Stage IV: M1

What 2 imaging studies should be used to evaluate a potential STS?

According to NCCN 2010 guidelines, a pt with a potential STS should have MRI +/− CT scan of the primary site and chest imagingOther imaging is optional.

What type of Bx should be done to evaluate a concerning soft tissue mass?

According to NCCN 2010 guidelines, soft tissue masses should be diagnosed using either a core needle Bx or an incisional Bx oriented so that it may be excised during the definitive surgery. Either Bx should be done by or in coordination with the surgeon who will be performing the definitive surgery.

According to NCCN 2010 guidelines, under what certain circumstances are PET, CT, or MRI useful in the workup of STS?

1.     FDG-PET: may be useful for prognostication and grading as well as to determine response to chemo

2.     CT abdomen/pelvis: myxoid liposarcoma, epithelioid sarcoma, angiosarcoma, and leiomyosarcoma

3.     MRI spine: round cell liposarcoma

What is the LC of STS after excisional Bx alone?

The LC of STS after excisional Bx alone is ~20%.

image 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 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., Proceedings National 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 limb-sparing surgery 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:

1.     Yang et al., from the NCI, randomized pts with high- and low-grade STS of the extremity treated with limb-sparing surgery to adj EBRT (63 Gy) or no RT. Pts with high-grade STS rcv concurrent Adr/cyclophosphamide with EBRT. 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, but there was also no difference in DMFS or OS. (JCO 1998)

2.     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. 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. (JCO 1996)

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 positive 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 upper leg (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., Proceedings 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?

Based on the NCI trial that randomized 65 pts with extremity STS to surgery alone (either limb sparing or amputation) vs. surgery + adj chemo. There was improved DFS (92% chemo vs. 60%) and OS (95% vs. 74%) both for pts treated with limb-sparing −surgery and with amputation. (Rosenberg SA et al., Ann Surg 1982)

Which STS pts appear to benefit most from adj chemo?

The British STS adj chemo meta-analysis included 1,568 pts with STS s/p WLE +/− adj doxorubicin-based chemo. Chemo improved LC (absolute 6%), DMFS (10%), RFS (10%), and OS (4%, NSS). The largest benefit was found in pts with high-grade extremity STS. (Tierney et al., Br J Cancer 1997)

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. Rather, it should be considered on a pt-by-pt basis, taking into account pt performance status and Tx toxicities.

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

According to the NCCN, 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:

1.     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 rcv an additional 16 Gy boost postop. 5-yr LC was 92%, DFS was 86%, and OS was 44%. 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?

1.     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% rcv the full chemo course. 3-yr LRF was 18% (if amputation was considered a failure and 10% if not). 3-yr DFS was 57%, distant DFS was 64%, OS was 75%, and there was a 92% amputationfree rate. There were 5% Tx-related deaths (mostly secondary acute myeloid leukemia), and 84% of pts had grade 4 toxicity (mostly hematologic).

2.     The authors concluded that the regimen is effective, but substantial toxicity makes this approach controversial (Kraybill WG et al., J Clin Oncol 2006). 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, positive 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 limb-sparing surgery and IMRT. 51% had close or positive 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., J Clin Oncol 2008)

How long after surgery should adj RT for STS begin?

According to the NCCN, PORT for STS should begin after healing is completed, by 3–8 wks post surgery.

What dose is recommended for adj RT for STS?

According to the NCCN, adj RT for STS should be 50 Gy in 2 Gy/fx → a 10–16 Gy boost for –margins, a 16–20 Gy boost for microscopically positive margins, and a 20–26 Gy boost for grossly positive margins.

Surgery should take place approximately how long after completion of neoadj RT for STS?

According to the NCCN, surgery should take 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?

According to the NCCN, neoadj RT for extremity STS should be to 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 positive margins, and 20–26 Gy for grossly positive margins).

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

The initial RT Tx volume for STS in the adj setting includes the tumor, scar, and drainage sites + a 5–7-cm margin longitudinally and a 2–3-cm margin perpendicularly to the block/field edge. 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.

How is postop brachtherapy 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.

1.     Low dose rate: 45–50 Gy to tumor bed over 4–6 days

2.     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. (NCCN 2010)

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).

image Toxicity

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

Toxicities associated with RT for extremity STS:

1.     Short term: wound complications (5%–15% with PORT, 25%–35% with preop RT), dermatitis, recall reactions with doxorubicin and dactinomycin, epilation

2.     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?

STS Tx follow-up per the NCCN: 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.