Osteosarcoma from anatomy to management

1. OSTEOSARCOMA
By
Dr. Ayush Garg

2. Introduction
• Osteosarcoma is the fifth most common malignancy
• Bone tumours are rare cancers
• Osteosarcoma (35%)
• Chondrosarcoma (30%)
• Ewing sarcoma (16%)
• 3–5% of childhood and 1% of adult cancers
• Bimodal age- Early adolescence and age >65 years
• Male predilection- 1.2:1

3. Etiology
• The etiology of osteosarcoma is unknown
• Could be due to rapid bone growth
• Peak incidence- during the adolescent
growth spurt
• Most have complex, unbalanced
karyotypes:
• Highest frequency of loss of heterozygosity
(LOH) is for chromosomes 3q, 13q, 17p
and 18q

4. Risk factors:
• Hereditary:
• Li–Fraumeni
• Retinoblastoma
• Rothmund–Thomson syndrome
• Bloom, and Werner syndromes
• Multiple hereditary exostosis

5. Risk factors:
• Non‐hereditary:
• Prior radiation exposure (latency period >10 years)
• Paget disease
• Polyostotic fibrous dysplasia
• Chronic osteomyelitis
• Osteochondromas
• Enchondromas
• Sites of bone infarcts
• Sites of metallic implants
• Chemotherapy: Alkylating agents has been implicated with
secondary osteosarcoma

6. • Osteosarcoma has a
predilection for involvement
of the metaphysis of long
bones (areas of greatest
increase in bone length)
• Most common sites:
• Knee (distal femur or proximal
tibia)
• Proximal humerus
• Mid and proximal femur
• Other bones

7. Clinical Features
Local
Painful, firm mass

8. Clinical Features
Metastatic
• Most commonly spread to lung
• Bone is second most common site
• Skip metastases via the medullary
canal also occur
• Lymphatic spread is rare
• Metastases often occur within 2
years of initial diagnosis

9. Diagnostic work up
Plain x-ray of the
affected bone
Demonstrates
destruction of the
normal trabecular
bone with lytic and/or
sclerotic lesions,
osteoid formation
under the periosteum
(Codman triangle)

10. Diagnostic work up
• Biopsy of primary site for diagnosis and staging:
• Core needle biopsy:
• Safe direct path to tumour mass is possible from skin
• Lower cost and morbidity
• Open (surgical) biopsy:
• Short longitudinal incision in line with projected surgical approach for
resection
• Meticulous haemostasis
• Lactate dehydrogenase (LDH), alkaline phosphatase

11. • MRI- know the extent of the
lesion, evaluate any soft tissue
component, and involvement of
joint, nerves, and vasculature
• The entire affected bone should be
imaged to evaluate for the
presence of skip lesions.
• Skip metastases are well
recognized in osteosarcoma but
occur infrequently, with <5%
incidence

12. Metastatic work up
• CT scan of the chest and bone scan to evaluate
pulmonary and bone metastases
• Positron emission tomography (PET) scan can be used
as an alternative for systemic staging

13. Differentiating Ewing’s from
Osteosarcoma
Osteosarcoma Ewing sarcoma
Sclerotic lesion Lytic, destructive lesion
Metaphysis Diaphysis
Sunburst pattern (periosteal
new bone formation)
Onion skin effect

14. Differentiating Ewing’s from
Osteosarcoma
Osteosarcoma Ewing sarcoma
Sclerotic lesion Lytic, destructive lesion
Metaphysis Diaphysis
Sunburst pattern (periosteal
new bone formation)
Onion skin effect

15. Pathology
• Conventional (intramedullary) – high grade and 90%
• Chondroblastic
• Fibroblastic
• mixed subtypes
• small cell
• Telangiectatic
• malignant fibrous histiocytoma
• multifocal- worse prognosis
• Surface
• Parosteal- low grade
• Periosteal- intermediate grade
• high-grade surface
• Extraosseous osteosarcoma- rare, associated with prior radiation
exposure

16. Staging

17. Tumor 8 cm or less in greatest
dimension

18. Tumor more than 8 cm in
greatest dimension

19. Discontinuous tumors in the
primary bone site

20. Lung‐only metastases Metastases to other distant
sites, including lymph nodes

21. Prognostic factors
Prognostic
factors
Tumor related Host related Environment
related
Essential Location
Size
Extent of disease
Grade
Stage
Tumor response to
NACT
Age Residual disease
after resection
Additional LDH
ALP
Gender
Performance
status
Management by a
multidisciplinary
sarcoma team
Local recurrence

22. Poor factors
• Location
• Axial tumors as compared to extremity
• Increased number of anatomic bone segments involved
• Extraosseous extension
• Extension into the spinal canal or involvement of the great vessels
• Size > 9cm (AJCC 8th edition)
• Presence of and location of metastases at diagnosis
• Bone mets > Lung mets
• Multiple lung lesions> Solitary lung mets
• Presentation as pathological fracture
• Grade 2 and 3

23. • Poor response to neoadjuvant chemotherapy
• Elevated enzyme markers (LDH, alkaline phosphatase)
• Age <14 and >40 years old
• Male
• KPS<70
• Positive margin resection
• Treatment type (i.e. amputation, combination therapy with
chemotherapy, radiation and surgery) has been associated
with poor prognosis
• Unresectable tumors

24. TREATMENT OPTIONS
SURGERY RADIOTHERAPY CHEMOTHERAPY

25. Treatment
• Treatment sequence for intermediate- and high-grade
osteosarcoma is NACT→ surgery (limb-sparing) →
adjuvant chemotherapy.
• With this approach, 60% to 70% of patients without
overt metastases at diagnosis are expected to be long-
term survivors
• Isolated lung metastases have an overall survival of
35% to 40% and <20% in extensive metastatic disease

26. Surgery
• Mainstay of surgical management is the complete en
bloc resection of tumor
• Limb-sparing resections with maintenance of function
preferred over amputation
• Contraindications to limb-sparing surgery include
• Nerve or Vascular
Encasement
• Presence of Large,
Biopsy-related Hematoma
• Pathologic Fracture

27. Radiotherapy
• Historically, radiation has been used for the treatment
of osteosarcoma
• Due to improved results with chemotherapy and
surgery combined, RT is rarely used
• Indications for RT
• Incompletely resected tumors with positive margins
• Unresectable tumors
• Palliation of symptoms

28. Radiotherapy
• Adjuvant radiation has been used to improve outcomes
in patients with incomplete resections of pelvic tumors
• Postoperative radiation therapy can be used when
negative margins cannot be obtained, particularly when
there is microscopic dural involvement.
• Whole lung irradiation- 20Gy in 10 fractions in adults

29. Radiotherapy techniques
Simulation and Field Design: Conventional RT
• Include entire surgical bed + scar + 2 cm margin, if possible
• Spare 1.5–2 cm strip of the skin in extremity to prevent edema
• Bolus on scar may be considered as indicated
• Try to exclude the skin over anterior tibia, if possible, due to
poor vascularity

30. Radiotherapy techniques
Simulation and Field Design: Conformal RT
• Patient position- As per location of disease
• Immobilization- Thermoplastic cast/ Vac Lok
• CT/MRI data for treatment planning
• 3D planning- pre and post surgical imaging
• 2 cm margin for axial tumors
• 4-5cm for extremity tumors

31. RT Dose
• 60 Gy- microscopically involved margins
• 66 Gy- macroscopic residual disease
• 70 Gy- inoperable tumors

32. SBRT
• Pre-op: CTV to include region of microscopic disease up to 1 cm
from GTV
• Post-op: CTV 0–1 cm expansion of GTV/surgical bed based on
the extent of resection and location adjacent to critical structures
• PTV: 2–3 mm on CTV with modern immobilization/IGRT
• 40 Gy in 5 fractions

33. IORT
Intraoperative radiation therapy has been used to deliver dose
directly to close or involved surgical margins.

34. • Proton particle therapy has
been used in an attempt to
escalate radiation dose,
particularly in unresectable
tumors
• Radionuclide therapy with
rhenium, strontium, and
samarium has been used for
palliation of extensive bone
metastases

35. ECI- Extra corporeal irradiation
• Extracorporeal irradiation is a rare
method used in the management of
malignant bone tumors
• Surgery performed 4 weeks after
completion of NACT
• The affected bone segment was resected,
irradiated extracorporeally with a dose of
50 Gy and reimplanted

36. • The sealed bone segment was sent for ECI on the Linear
Accelerator, which is located in the adjacent block.
• The bone segment was placed on the treatment couch and
immobility was ensured.
• Every segment was irradiated with a single session dose of
50 Gy prescribed at mid plane using 6 MV X-rays.
• Two parallel opposed AP-PA were used. Radiation field size
was chosen which adequately covered the segment.
• After the completion of ECI, the bone segment was
returned to operation theatre without any delay.

37. Whole Lung Irradiation
• For lung mets, give whole
lung RT (1.5/15 Gy), or
consider resection if <4
mets.
• If residual mets after whole
lung RT, may boost to 45 Gy.

38. Complications of RT
• Joint fibrosis with decreased range of motion
• Bone weakening and fracture
• Loss of allograft
• Secondary malignancy
• Abnormal bone and soft tissue growth and development
• Permanent weakening of the affected bone, scoliosis
• decreased range of motion due to fibrosis or joint involvement

39. Complications of RT
• Vascular changes resulting in greater sensitivity to infection
• Fracture
• Lymphedema
• Skin discoloration
• Telangiectasia
• Osteoradionecrosis

40. Chemotherapy
• Chemotherapy is indicated prior to wide local excision in
high‐grade osteosarcoma
• Adjuvant chemotherapy should be given after surgery
• Neoadjuvant therapy is given for two cycles followed by four
cycles of adjuvant chemotherapy
• Cisplatin + doxorubicin are the mainstays of therapy:
• Cisplatin 100–120 mg/m2 IV + doxorubicin 60–75 mg/m2 IV over
48‐hour continuous infusion every 3 weeks + G‐CSF
Advantage of NACT
• Limb-sparing surgery and ultimately, functional outcome
can be improved

41. MSKCC T10 regimen EURAMOS I
(AOST 0331)

42. Clinical evidences
Trial name Results
Local disease
Eilber et al . (1987) Established role for adjuvant chemotherapy in patients
with localized high‐grade osteosarcoma
POG 8651
Goorin et al . (2003)
Established that survival was similarly improved by either
pre‐ or post‐surgical chemotherapy
Established a benchmark outcome for future studies
ISG/OS‐1
Ferarri et al . (2012)
Adding ifosfamide to methotrexate + cisplatin +
doxorubicin (MAP) from the preoperative phase does not
improve the good responder rate and increases
haematological toxicity
Ifosfamide should only be considered in patients who
have a poor histological response to MAP

43. Clinical evidences
Trial name Results
Adjuvant systemic treatment
Link et al . (1986) 2‐year relapse‐free survival was significantly higher in
patients with osteosarcoma of the extremity receiving
adjuvant chemotherapy versus those on observation
Lewis et al . (2007) Dose intensification of cisplatin + doxorubicin resulted in
increased dose received and a statistically significant
increase in good histological response rate, but not in
increased progression‐free or overall survival
Meyers et al . (2008) Adding ifosfamide to MAP did not enhance event‐free or
overall survival for patients with osteosarcoma
Adding MTP to the same regimen resulted in a
statistically significant improvement in OS and a trend
toward better event‐free survival

44. Clinical evidences
Trial name Results
Advanced and metastatic disease
OS‐86/OS‐91
Daw et al . (2006)
Compared ifosfamide + cisplatin + doxorubicin +
high‐dose methotrexate to the same agents at similar
doses, but with substitution of cisplatin with carboplatin
Established role of cisplatin given improvement in OS
Bacci et al . (2003) Confirmed the prognosis of patients with metastatic
osteosarcoma of the extremity remains poor, despite the
use of aggressive treatment with combination
chemotherapy and surgery
Goorin et al . (2002) Combination of etoposide + high‐dose ifosfamide is
effective induction chemotherapy for patients with
metastatic osteosarcoma

45. Follow up
• History, physical exam, chest X‐ray and imaging of the
primary site:
• Every 3 months for Years 1 and 2
• Every 4 months in Year 3
• Every 6 months in Years 4 and 5
• Annually upto 10 years
• Blood work as clinically indicated

46. Conclusion
• Osteosarcoma is the most common primary malignant
bone tumour (about 45% of all bone tumours)
• Bimodal age distribution: adolescence and sixth decade
• Risk factors include genetic, non hereditary and
alkylating agents induced
• Often presents as a firm, painful mass, adjacent to
bone
• Most common sites are the distal femur, proximal tibia
and proximal humerus