3. Ewing Sarcoma
Epidemiology
• Second most common primary bone tumor.
accounting for approximately 2% of childhood
malignancies.
• About 200 per year in US.
• Most in the 2nd decade of life.
• Slight male predominance,
• Less commonly (about 30%), in the soft tissue
(i.e., extraosseous) anywhere in the body(GI
tract, the kidneys, the adrenal gland, the lung. ).
4. • Ewing sarcoma family of tumors includes
-Askin tumors (Ewing sarcoma arising in the
chest wall) and
- Histologically differentiated peripheral
primitive neuroectodermal tumors.
- Extraosseous Ewing sarcoma
- PNET of bone.
• The 2013 WHO classification proposed that the
phrase Ewing sarcoma be used to refer to this
family of tumors.
5. Biology and Molecular Genetics
• The cell-of-origin is unknown but is presumed to
arise from a mesenchymal stem cell.
• These tumors characteristically have recurrent
chromosomal translocations, in almost all cases.
• Of Ewing sarcoma tumors, 85% harbor t(11;22)
(q24;q12), resulting in the fusion of the EWSR1
and FLI1 genes.
• Another 10% to 15% of tumors are associated
with t(21;22) (q22;q12), which generates the
EWSR1-ERG fusion gene.
6. Clinical Presentation and Natural History
• Localized pain and swelling in the affected bone.
• Other nonspecific symptoms such as fever, decreased
appetite, and weight loss, in advanced disease.
Distribution:
• Ewing sarcoma is equally distributed between
extremity and axial sites with the pelvis/sacrum (22%),
proximal femur (10%), shoulder girdle (12%), and ribs
(8%) being the most common locations.
• Ewing sarcoma often arises in the diaphysis with
metaphyseal extension.
7. • 25% are metastatic at the initial diagnosis.
• The most frequent site - the lungs, followed by
the bones, and bone marrow.
• Other sites, such as the lymph nodes, the
liver, or the brain, are relatively rare.
8. Osteosarcoma
Epidemiology
• Most common primary, malignant bone tumor in
children and adolescents, accounting for 4% of all
childhood cancers.
• In the United States, approximately 400 new
cases per yr.
• Slightly more prevalent in males and in African
Americans.
• The majority of osteosarcomas are sporadic.
9. • Previous exposure to ionizing radiation and
alkylating agents.
• Patients older than 40 years who develop
osteosarcoma also have Paget disease of bone.
• Osteosarcoma is also associated with several
cancer predisposition syndromes, including
- hereditary retinoblastoma,
- Li- Fraumeni syndrome (LFS), and
- Rothmund-Thomson syndrome (RTS).
10.
11. Clinical Presentation and Natural History
• Pain and soft-tissue swelling ( pain before a mass appear).
• Pathologic fracture (5% to 10%).
• Systemic symptoms such as fever, weight loss, and malaise are
generally absent.
• A physical examination usually demonstrates a firm, tender mass
and restricted range of motion in the affected extremity.
Distribution
• metaphyseal region of the long bones.
• The extremity as primary site of disease in 80% of patients, (in
descending order) the distal femur, proximal tibia, and proximal
humerus.
• Unlike Ewing sarcoma, osteosarcoma rarely affects the axial
skeleton.
• Approximately 20% of patients with osteosarcoma present with
clinically detectable metastatic disease, most frequently to the
lungs and less often to bones.
12. • Osteosarcoma is broadly classified into three histologic subtypes
A) Intramedullary
• High-grade intramedullary osteosarcoma is the classic or conventional
form comprising nearly 80% of osteosarcoma. It is a spindle cell tumor
that produces osteoid or immature bone.
• Low-grade intramedullary osteosarcoma comprises less than 2% of all
osteosarcomas
B) Surface
• Parosteal and periosteal osteosarcomas are juxtacortical or surface
variants.
• Parosteal osteosarcomas are low-grade lesions accounting for up to 5% of
all osteosarcomas. The most common site is the posterior distal femur.
• Periosteal osteosarcomas are intermediate-grade lesions most often
involving the femur followed by the tibia.
• High-grade surface osteosarcomas are very rare accounting for 10% of all
juxtacortical osteosarcomas.
C) Extraskeletal
• Extraosseous osteosarcoma is rarely encountered and usually occurs after
exposure to radiation
13. PREOPERATIVE EVALUATION AND
STAGING STUDIES
• CBC, ESR, CRP can be helpful in ruling out
infection.
• Alkaline phosphatase and LDH are sometimes
elevated in skeletal sarcomas; creatinine and
calcium levels are also useful chemistry tests.
• Serum and urine immunoelectrophoretic
analyses can assist in excluding myeloma, and
a basic urinalysis can be used to screen for
genitourinary health.
14. PLAIN X-RAY OF THE BONE
• The bone affected
• Site- Epiphysis, Metaphysis , Diaphysis
• Type of lesion- Lytic/Sclerotic/mixed
• Margin
• Matrix
• Periosteal reaction
• Soft tissue component
• Fracture
15. • Ewing sarcoma-On plain films, a lytic or mixed lytic–
sclerotic lesion is usually identified in the bone.
- A multilamellar periosteal reaction (i.e., onion skin
appearance ) and lifting of the periosteum(i.e.,
Codman triangle), or less frequently, radiating bone
spicules, may be present.
• Osteosarcoma- on a radiograph, a mixed lytic and
sclerotic appearance, periosteal new bone formation
with lifting of the cortex and the formation of the
Codman triangle, and ossification of the soft tissue in a
radial or sunburst pattern.
16. Computerized Tomography
• proven utility in studying axial primary sites and juxtacortical lesions
• accurate determination of intraosseous and extraosseous extension
• more accurate than MRI in determining the response to induction
chemotherapy
• predicting pathologic fracture risk- more accurate
• tumor reossification, and fracture healing are best evaluated by CT.
Magnetic Resonance Imaging
• tumor involvement and extent within the marrow
• provides details of soft-tissue extension
• Relation with neuro-vascular bundle
• Skip lesion
17.
18. • A technetium-99m whole-body radionuclide bone scan should be
obtained to detect bone metastases.
• FDG PET/CT :
- highly sensitive in screening for bone metastases
- useful predictor of outcome, similar to histologic response, after
induction chemotherapy.
- Studies evaluating the utility of FDG PET/CT in osteosarcoma staging
show that it is more sensitive and accurate than a bone scan in
detecting bone metastases.
- Furthermore, the results of several studies suggest that changes in the
metabolic tumor activity as assessed by PET/CT during therapy correlate
with the percentage of tumor necrosis at the time of definitive
surgery.
19. • CT chest - to evaluate for pulmonary metastases.
- Finding one or more pulmonary (or pleural) nodules of at
least 1- cm diameter or three or more nodules of at least
0.5-cm diameter generally indicates definite pulmonary
metastases and may not require a biopsy.
- Fewer or smaller lesions may or may not represent
metastatic disease; therefore, confirmation by resection
may be indicated
• Bilateral bone marrow sampling is required to complete
the staging of all patients regardless of primary site or
tumor size. Microscopically detectable bone marrow
metastases occur in less than 10% of patients and are
associated with a poor prognosis.(Ewing sarcoma only)
20. Biopsy
• Biopsy is key step in the diagnosis of a musculoskeletal tomours.
• When should the biopsy be done ?
- As a rule all suspected malignancies and benign aggressive lesions should be
biopsied.
- Biopsy diagnosis is necessary prior to any surgical procedure or fixation of primary
site.
• Who should do the biopsy ?
- Biopsy should be done by the operating surgeon or the operating team.
- Biopsy is optimally performed at a center that will do definitive management
21. • Guidelines- for a biopsy :
• Decide the part of the lesion that should be biopsied
• Position the point of entry along the planned incision of the definitive surgery.
• Track should be the shortest way to the lesion .
• Must not violate more than one compartment.
• Away from the neurovascular bundle.
• The joint should never be violate.
• Needle biopsy is not recommended for skull base tumors.
• Fresh tissue may be needed for molecular studies and tissue banking.
22. Biopsy sites
• Clavicle – parallel to the long axis of the clavicle.
• Scapula – over the line joining from supero-lateral
part of acromiom to inferior and medial angle
• Proximal humerus .
23. Biopsy sites
• Distal humerus – posterior arm in midline.
• Pelvis –
• Femur
• ( never through rectus femoris )
24. Biopsy sites
. Proximal tibia
What part of the tumour should be biopsied?
Periphery of the tumour should be biopsied
Soft tissue component is representative as
that of the bone
Calcified areas should be avoided, lytic areas are more
representative
25. Principles of an open biopsy technique
1 . Incision - smallest longitudinal incision
transverse incisions are contraindicated
2 . Do not raise the flaps.
3 . Cortical window
26. • 4 . Use knife or the curette to avoid crushing of the tissue.
• 5 . Obtain enough tissue – send the tissue for frozen analysis.
• 6 . Culture the biopsy
• 7 . Meticulous hemostasis – to prevent postoperative haematoma
plug the cotical window
• 8 . Use drains only if necessary
27. • IHC- More than 95% of Ewing sarcomas express CD99 (encoded by
the MIC2 gene) on their cell membranes.
• Although CD99 staining is not pathognomonic and may be seen in a
variety of tumors, including synovial sarcoma, mesenchymal
chondrosarcoma, and B-cell and T-cell leukemia/lymphoma.
• Cytogenetic & molecular studies: The rapid identification of EWSR1
gene rearrangements by performing reverse transcription–
polymerase chain reaction assays or fluorescence in situ
hybridization assays on fresh, frozen, or paraffin-embedded
specimens is useful for expeditiously discriminating between Ewing
sarcoma.
28.
29.
30.
31.
32.
33. Treatment of Ewing sarcoma
• Prior to the routine use of chemotherapy, nearly all
patients with newly diagnosed Ewing sarcoma
developed distant metastatic disease and ultimately
died.
• These observations underscored the nearly universal
presence of occult micrometastatic disease in patients
with Ewing sarcoma.
• Early single-institution studies & co-operative group
trials established the efficacy of vincristine,
doxorubicin, actinomycin-D, and cyclophosphamide
(VACA) in Ewing sarcoma.
34. • Neoadjuvant chemotherapy offers several
potential advantages, including
(1) immediate treatment not only of presumed
“micrometastatic disease,” but also of the
primary tumor, so as to make local control easier
and/or safer;
(2) time for the patient and family to plan and
consider various limb salvage versus amputation
options; and
(3) the opportunity to assess histologic response to
chemotherapy, so as to guide adjuvant
treatment.
35. IESS-I
• North American Intergroup Ewing Sarcoma Study
(IESS-I): role of doxorubicine and WLRT.
• newly diagnosed disease - 342 eligible patients -
three arms:
VAC plus doxorubicin (VACA);
VAC with whole lung radiation; or
VAC;
• UK Children’s Cancer Study Group & French
Society of Pediatric Oncology- same results.
36. IESS-II
• Subsequent trials- changing the dosing strategy in
VACA and adding ifosfamide or ifosfamide/etoposide
(IE).
• The second Intergroup Study (IESS-II)
- Newly diagnosed localized nonpelvic disease - 214
eligible patients- two different VACA schedules.
- The intensive schedule- higher doses of doxorubicin
and cyclophosphamide given in 3 weekly cycles.
- The protracted schedule- lower doses of these agents
and exposure of the cyclophosphamide was distributed
across 6 sequential weeks.
• Results- all outcome measures (relapse-free, disease-
free, and overall survival) were superior for patients
randomized to the intensive arm.
37. North American Intergroup trial INT-0091
• The most definitive trial on the role of IE.
• Newly diagnosed Ewing sarcoma – 398
patients localized disease
• either standard therapy with vincristine,
doxorubicin, and cyclophosphamide (VDC)
administered every 3 weeks or VDC cycles
alternating every 3 weeks with IE cycles.
• All patients received the same duration of
therapy and the same cumulative dose of
doxorubicin.
38. • Results- statistically significant difference in 5-
year EFS (54% for patients randomized to VDC
versus 69% for patients randomized to VDC/IE).
• The addition of IE to VDC did not improve
outcomes for patients with metastatic disease at
initial presentation.
• This result established VDC/IE as a new North
American standard of care for patients with
newly diagnosed localized Ewing sarcoma.
39. COG protocol AEWS0031
• 568 eligible patients
• Newly diagnosed localized Ewing sarcoma.
• standard therapy with VDC/IE cycles alternating every
3 weeks or to the experimental arm with VDC/IE cycles
alternating every 2 weeks.
• Results:greater 5-year EFS (73% versus 65% for patients
randomized to the standard arm).
• This trial established interval compressed VDC/IE as a
new standard approach for patients with localized
Ewing sarcoma.
40. Chemotherapy for Recurrent Ewing
Sarcoma
• Historically, patients with recurrent Ewing sarcoma had
few systemic options.
- retreated with chemotherapy combinations used as
part of initial therapy.(delayed relapse)
- gemcitabine with docetaxel
- Campothecin-based regimens are currently the most
active available chemotherapy regimens for patients
with relapse.(topotecan with
cyclophosphamide/irinotecan and temozolimide)
• Currently,clinical trials of novel agents or may be
treated with a number of salvage chemotherapy
regimens.
41. High-dose Therapy Followed by Stem Cell
Transplant
• High-dose therapy followed by stem cell
transplant (HDT/SCT) has been evaluated in
patients with localized as well as metastatic
disease.
• HDT/SCT has been associated with potential
survival benefit in patients with non-metastatic
disease. However, studies that have conflicting
results for metastatic disease.
42. Local control after NACT in Ewing
sarcoma
• The inclusion of 12 to 15 weeks of NACT f/by local control
(Sx/RT/Sx+RT) has become standard practice, regardless of
tumor size, location, or stage, unless the tumor causes an
immediate threat to survival, such as spinal cord
compression or cardiopulmonary compromise.
• For decades, radiotherapy was the standard local treatment
modality, but surgery is now the preferred modality if a
complete resection is feasible.
• A prospective randomized trial comparing surgery and
radiotherapy as local control modality for Ewing sarcoma at
any primary site has never occurred.
43. • Cooperative intergroup studies- there was no significant effect of local
control modality (surgery, RT, or surgery plus RT) on OS or EFS rates.
• The CESS 86 trial,
- radical surgery
- resection + RT resulted in better local control rates (100% and 95%,
respectively) than
- definitive RT (86%),
there was no improvement in RFS or OS
• In the INT-0091 study,
-surgery or RT alone (25%), but
-surgery plus RT(10.5%) local failure.
-The 5-year EFS rate was also not significantly different.
• The combined analysis of 1058 patients treated in the CESS 81, CESS 86,
and EICESS 92 trials showed that the rate of local failure was significantly
lower after surgery (with or without postoperative RT) than after definitive
RT (7.5% vs. 26.3%, respectively; P = .001),
44. • Decisions about local control should take into account
- initial location & resectability,
- functional outcome,
- long-term morbidity,
- risk of late-onset secondary malignancies in
tissues exposed to high-dose radiotherapy, and
- patient preference.
- initial tumor response to chemotherapy.
45. Limb salvage or amputation ?
• Depends upon the - 1. margins of excision that can be achieved.
- 2. whether this will allow the preservation of sufficient
structures that are useful.
.
46. Aims of limb salvage surgery in bone tumours
• To eradicate the disease
• Retain the integrity of the skeletal system
• Preservation of the limb with useful function
• For a LSS to be a viable alternative , it should meet 2 important criteria
• 1 . Local control of the tumour
• 2 . Maintenance of the functional status that is an improvement over the
amputation or the fitting of the prosthesis
47. Guidelines for limb salvage resection
1. No major neurovascular involvement
2. Wide resection of the affected bone, with a
normal muscle cuff in all directions.
3. En bloc removal of all previous biopsy sites and
potentially contaminated tissues.
4 . Resection of bone 3 to 4 cm beyond abnormal uptake, as determined by CT or MRI and bone
scan
5. Resection of adjacent joint and capsule.
6 . Adequate motor reconstruction and soft tissue coverage
48. Contraindications to limb sparing surgery
1 . Major neurovascular involvement
2 . Pathological fracture - risk of local recurrence
3 . Inappropriate biopsy sites
4 . Infection
5 . Leg length discrepancy should not be more than 6 to 8 cms
.
49. Stages of limb salvage surgery
• 1 . Resection of the tumour ( stage 1 )
• 2 . Skeletal reconstruction ( stage 2 )
• 3.Soft tissue and muscle transfer ( stage 3 )
50. • Indications of adjuvant RT:
- R1 resection (dose of 50.4 Gy at 1.8 Gy per
treatment fraction)
- R2 resection doses of 55.8 Gy at 1.8 Gy per
treatment fraction.
- Ro resection but a poor histologic response to
preoperative chemotherapy
- Other primary that negatively impact local or
overall disease control include the size of the
tumor (≥8 cm) and the pelvic site of the
disease.
51. • Adjuvant chemotherapy for 28 to 49 weeks
depending on the type of regimen and the
dosing schedule (category 1).
• Progressive disease following primary
treatment is best managed with RT and/or
surgery to primary site followed by
chemotherapy or best supportive care.
54. • Chemotherapy plays little role in the
management of patients with low-grade or
surface osteosarcoma.
• Historically, there was controversy about the
role of chemotherapy in the management of
patients with high-grade osteosarcoma.
55. Evolution of chemotherapy in
Osteosarcoma
• Prior to 1960, no systemic treatment tried
• Disappointing results with only surgical Rx
• In 1960s, single agent chemotherapeutic
drugs tried
• 15-20% response rates
• Only partial responses
57. Combination chemotherapy..
• Due to the disappointing results with single
agent chemotherapy, various agents were
tried in combination.
• Improvement in survival rates with use of
combination chemotherapy
58. Randomized Trials using adjuvant
chemotherapy
MIOS study
– BCD+HDMTX+DOX+CDDP vs no treatment
– 66 % vs 17% favoring adjuvant Rx
UCLA group
65 patients
BCD+HDMTX+DOX+CDDP (intra arterial
CDDP)vs no treatment
43% vs 28% in favor of adjuvant Rx
59. MIOS study
• Multi-Institutional Osteosarcoma Study (MIOS).
• newly diagnosed localized extremity-high-grade
osteosarcoma – 36 patients.
Osteosarcoma localized
BCD+HDMTX+DOX+CDDP
observation
CT group 66%
Control group 17%
2 yr survival
60. • These results confirmed the significant impact
of chemotherapy on outcomes of high-grade
osteosarcoma, and this trial established a new
standard of care for this disease.
61. Neoadjuvant vs adjuvant treatment
• POG (Pediatric Oncology Group) 8651
o 1986 to 1993
o To compare neo adjuvant vs adjuvant treatment
100 p
< 30 years
Osteosarcoma
Non metastátic
High grade
45 p surgery- Chemo
55 p Chemo- Surgery
62. Neoadjuvant vs adjuvant: results
EFS OS 5
yr
IMMEDI
ATE Sx
61% 76%
PRE OP
CT
69% 79%
P NOT SIGNIFICANT
Limb
conservation
50%
55%
63. • Demonstrating that timing of surgical
resection did not impact outcomes.
• Neoadjuvant chemotherapy-became more
widespread- allows more time for surgical
planning and to assess the extent of histologic
necrosis in response to neoadjuvant
chemotherapy.
64. Customizing post operative
chemotherapy…
• Rationale of COSS 82 Protocol…
– sparing some patients the unpleasant side effects
of highly toxic drugs like doxorubicin (DOX) and
cisplatin (CDDP) by administering these drugs
postoperatively only after poor response.
– Study group received HDMTX & BCD as preop CT
and were switched to ADR/CDDP only in poor
responders
– Control group received CDDP & ADR upfront in
addition to HDMTX & BCD
65. Results of COSS 82
• withholding cisplatin/doxorubicin
preoperatively for the study group produced a
lower rate of good responses.
• 4-year MFS rate of poor responders after
salvage chemotherapy also was poor in the
study arm (41%)
• Conclusion:The active agents (doxorubicin)
should not be withheld from the initial
therapy.
66. Role of HDMTX in osteosarcoma
• Majority of the protocols in Osteosarcoma
used High Dose methotrexate
• Role of HDMTX has been questioned in a few
trials.
• Various trials have been done with conflicting
results.
67. European Osteosarcoma Intergroup trial I
• To compare two regimens:
– ADR & CDDP
vs
- ADR & CDDP & HDMTX
Results: ADR/ CDDP better than HDMTX(DFS-57% vs 41%)
68. The European Osteosarcoma Intergroup .
• 6 cycles of doxorubicin and cisplatin
Vs
chemotherapy regimen similar to the MIOS trial.
• 391-newly diagnosed localized , resectable osteosarcoma
• Results- Equal PFS and OS
• Based upon these findings, the group concluded that the shorter
regimen with doxorubicin and cisplatin is preferable to the more
complicated and longer regimen used in the MIOS trial.
• These results called into question the role of the BCD regimen used
in the MIOS trial, which has now largely been abandoned.
69. • Patients receive neoadjuvant chemotherapy with
these drugs for approximately 10 weeks and then
undergo definitive surgery, which is followed by
adjuvant chemotherapy for approximately 20
weeks.
• The exceptions to this therapy scheme in
localized disease are low-grade central and
parosteal osteosarcomas and some periosteal
osteosarcomas without high-grade features;
these variants are traditionally treated with
surgery alone.
70. Local Control
Radiation Therapy.
• Historically, osteosarcoma has been considered to
be relatively radioresistant; therefore, radiation
therapy is generally not used as a definitive
primary treatment of this disease.
• Radiation may be used as adjuvant in patients
with
- R1 resection - doses of 55 to 68 Gy with local
control rates(67% to 78%).
- R2 resection or unresectable - doses of 70 Gy
or higher. local control of 60% .
71. Surgery:
• Surgery is the mainstay of local control.
• The choice of limb salvage versus amputation
for extremity tumors depends on the location
and extent of the tumor, the ability to achieve
good surgical margins, and proximity to the
joints and neurovascular bundle.
72. • Pelvic Tumors and Unresectable Disease-
- Patients with primary tumors of the axial skeleton
generally have poor outcomes because surgery does
not provide adequate local control.
- Most pelvic osteosarcomas can be treated by
hemipelvectomy;
- however, more centrally located pelvic tumors,
especially those involving the sacrum, are
unresectable.
• Contraindications to resection are unusually
-large extraosseous extensions with sacral plexus or
major vascular involvement. In general, these tumors
best treated by chemotherapy and radiotherapy.
73. Metastatic Osteosarcoma
• The presence of metastatic disease at
presentation is associated with a poor prognosis.
• Patients with pulmonary metastasis > bone
metastases / multifocal osteosarcoma have a
dismal prognosis.
• In the absence of an available clinical trial, most
patients with metastatic disease receive MAP
chemotherapy with high-dose ifosfamide with or
without etoposide.
74. • Multiple studies have demonstrated that the removal
of all sites of metastatic or recurrent disease (e.g.,
pulmonary lesions), even after completion of
chemotherapy, can result in long-term survival.
• In a large analysis of the Cooperative Osteosarcoma
Study Group, which included more than 1,700
consecutively treated patients, the 10-year survival
probability was 40% for metastatic patients who had all
sites of metastatic disease resected
