BONE TUMOURS

Dr. Abhilash GavarrajuJR-II

NORMAL BONE

m

Anatomic regions of long bones relate to the growth plate and include the epiphysis, which is the region between the growth plate and the nearest joint; the diaphysis, which is the shaft region of the bone between the two growth plates; and the metaphysis, which is the region of bone adjacent to the growth plate on the diaphysial side.

INTRODUCTION•Malignant tumours that arise from the

skeletal system are rare, representing 0.001% of all new cancers.

•In 2010, an estimated 2650 new cases and 1460 related deaths were expected.

•Osteosarcoma, Chondrosarcoma and Ewing’s Sarcoma are the most common comprising 35%, 30% and 16% of cases respectively.

CLASSIFICATIONHistological type Malignant tumors

Hematopoietic Myeloma, Reticulum cell sarcoma

Chondrogenic Primary, Secondary, Dedifferentiated, Mesenchymal

Osteogenic Osteosarcoma, Parosteal OS

Idiopathic Ewing’s, Malignant GCT, Adamantinoma, Fibrous Histiocytoma

Fibrogenic Fibrosarcoma

Notochordal Chordoma

Vascular Hemangioendothelioma, Hemangiopericytoma

ENNEKING STAGING SYSTEM

•IA (G1, T1, M0) : Low grade intracompartmental

•IB (G1, T2, M0) : Low grade extracompartmental

•IIA (G2, T1,M0) : High Grade intracompartmental

•IIB (G2, T2, M0) : High Grade extracompartmental

•IIIA (G1/2, T1, M1) : Intracompartmental, any grade with metastasis

•IIIB (G1/2, T2, M1) : Extracompartmental, any grade with metastasis

TNM AND AJCC STAGING•Primary Tumor (T) Tx – Primary cannot be assessed T0 – No evidence of primary T1 – Tumor </= 8 cm T2 – Tumor > 8 cm T3 – Discontinuous tumor in primary bone

site

•Regional Lymph Nodes (N) Nx – Regional LN’s cannot be assessed N0 – No regional LN metastasis N1 – Regional LN metastasis

•Distant Metastasis (M) Mx – Distant mets cannot be assessed M0 – No distant mets M1a – Lung only M1b – Other distant sites

•Histological Grade (G) Gx – Grade cannot be assessed G1 – Well differentiated – low grade G2 – Moderately differentiated – low

grade G3 – Poorly differentiated G4 - Undifferentiated

Stage T N M Grade

IA T1 N0 M0 G1,2 low grade, Gx

IB T2 N0 M0 G1,2 low grade, Gx

T3 N0 M0 G1,2 low grade, Gx

IIA T1 N0 M0 G3,4 high grade

IIB T2 N0 M0 G3,4 high grade

III T3 N0 M0 G3

IVA Any T N0 M1a Any G

IVB Any T N1 Any M Any G

Any T Any N M1b Any G

OSTEOSARCOMA

•It is the MC malignant bone tumour.•Histological hallmark – Production of

malignant osteoid.

•“Osteosarcoma, which is a true cancerous degenration of bone, manifests itself in the form of a white or reddish mass, lardaceous and firm at an early stage of the disease; but presenting at a later period, points of softening, cerebriform matter, extravasating blood, and white or straw coloured fluid of a viscid consistence in its interior”

Introduction

•Most commonly causes patients to die from pulmonary metastatic disease.

•Most arise as solitary lesions within the fastest growing areas of the long bones of children.

•Top 3 affected areas – Distal Femur, Proximal Tibia, Proximal Humerus.

•Synchronous Osteosarcoma – Multiple sites may become apparent within a period of 6 months.

•Metachronous Osteosarcoma – Multiple sites may be noted over a period longer than 6 months.

•Multifocal OS when occurs tends to be in patients younger than 10 yrs.

Epidemiology

•Incidence slighly higher in blacks and males.

•Incidence increases steadily with age, increasing more dramatically in adolescence, corresponding with the growth spurt

Etiology

•Exact cause in unknown•Rapid bone growth is a predisposing

factor•Typical location in the metaphyseal area

adjacent to the growth plate of long bones.

•Radiation exposure is the only known environmental risk factor.

•Genetic predisposition

Pathophysiology•Can occur in any bone, usually in the

extremities of long bones near metaphyseal growth plates

•Other significant locations are Skull and Jaw and Pelvis

•Variants – Conventional types(Osteoblastic, Chondroblastic, Fibroblastic), Telangiectatic, Multifocal, Parosteal and Periosteal

Clinical Features and Physical Examination

•MC symptom – Pain, particularly pain with activity

•Often, there is a history of trauma•Telangiectatic type – MC associated with

pathological fractures•Pain may result in a limp•Lung mets and respiratory symptoms

indicate extensive involvement•Palpable mass may or may not be present•Decreased range of motion

Workup•Labs - LDH, ALP (Prognostic Significance) - CBC, Platelets - LFT, KFT, Electrolytes - UrinalysisMost lab studies relate to the use of

chemotherapy - Elevated ALP at diagnosis are more likely to

have pulmonary metastasis - In patients without mets, those with an

elevated LDH are less likely to do well than are those with a normal LDH

•Imaging Studies1. Plain films – CODMAN’S TRIANGLE SUNBURST

APPEARANCE 2. CT – Primary Lesion and Chest ;

Delineate the location and extent of the tumor and is critical for surgical planning

3. MRI – Assess extent of disease and soft tissue masses and skip lesions; Single most important study for accurate surgical staging

4. Tc99 Bone Scan5. ECHO/MUGA Scan

Diagnostic Procedures

•Biopsy and Wide Resection are the two main procedures performed

•Incisional biopsies or core needle biopsies are the MC types of biopsies performed

•Wide resection is the goal for patients in whom primary tumor resection is contemplated`

Osteosarcoma Management

•A complete radical, surgical, en bloc resection of the cancer, is the treatment of choice in osteosarcoma

•About 90% of patients are able to have limb salvage surgery, complications particularly infection, prosthetic loosening and non-union or local tumor recurrence may cause the need for further surgery or amputation

•Standard therapy is a combination of limb salvage orthopedic surgery and a combination of chemotherapy

Surgery Classification of Surgical Procedures for Bone Tumors

Margin Local-limb sparing Amputation

Intralesional Curettage or debulking

Debulking amputation

Marginal Marginal excision Marginal amputation

Wide Wide local excision Wide through bone, amputation

Radical Radical local resection Radical disarticulation

Limb Sparing SurgeryPrerequisites & method• No major neurovascular tumor involvement

• Wide resection of the affected bone, with a normal muscle cuff in all directions

• En bloc removal of all previous biopsy sites and potentially contaminated tissue

• Resection of bone 3 to 4 cm beyond abnormal uptake, as determined by CT or MRI and bone scan

• Resection of the adjacent joint and capsule – expandable endoprosthesis

• Adequate motor reconstruction, accomplished by regional muscle transfers

Limb-sparing Surgery - Steps

Operation1. Resection of tumor2. Skeletal reconstruction3. Soft tissue and muscle transfers:

▫ Cover and close the resection site & to restore motor power

▫ Distal tissue transfers are not used because of the possibility of contamination

Limb Sparing SurgeryContraindications• Major Neurovascular involvement• Pathologic fractures

▫ Spread of tumor cells via the hematoma beyond accurately determined limits- risk of local recurrence increases

▫ If a pathologic fracture heals after neoadjuvant chemotherapy, a limb-salvage procedure can be performed successfully

• Inappropriate biopsy sites▫ Contamination of normal tissue planes and compartments

• Infection• Skeletal immaturity

▫ The predicted leg-length discrepancy should not be greater than 6 to 8 cm▫ Upper extremity reconstruction is independent of skeletal maturity

• Extensive muscle involvement

Chemotherapy for Bone Sarcomas

• Before routine use of systemic chemotherapy for the therapy of osteosarcoma, fewer than 20% of patients survived more than 5 years - recurrent disease developed in 50% of patients, almost exclusively in the lungs, within 6 months of surgical resection

• Findings of randomized clinical studies completed in the 1980s comparing surgery alone to surgery followed by chemotherapy demonstrated conclusively that the addition of systemic chemotherapy improved survival in patients presenting with localized high-grade osteosarcoma

• Four most important drugs used for the treatment of osteosarcoma include high-dose methotrexate (HD-MTX), adriamycin (ADM), cisplatin (CDDP), and ifosfamide (IFOS)

Considerations for Presurgical and Postsurgical Chemotherapy

Timing of Chemotherapy

Advantages Disadvantages

Preop

Early institution of systemic therapy against micrometastases

High tumor burden

Reduced chance of spontaneous emergence of drug-resistant clones in micrometastases

Increased probability in the selection of drug-resistant cells in primary tumor, which may metastasize

Reduction in tumor size, increasing the chance of limb salvageProvides time for fabrication of customized endoprosthesis

Delay in definitive control of bulk disease; increased chance for systemic dissemination

Less chance of viable tumor being spread at the time of surgery

Psychological trauma of retaining tumor

Individual response to chemotherapy allows selection of different risk groups

Risk of local tumor progression with loss of a limb-sparing option

Postop

Radical removal of bulk tumor decreases tumor burden and increases growth rate of residual disease, making S phase–specific agents more active

Delay of systemic therapy for micrometastases

Decreased probability of selecting a drug-resistant clone in the primary tumor

No preoperative in vivo assay of cytotoxic response

Possible spread of viable tumor by surgical manipulation

Which Is Optimal?Pediatric Oncology Group Study POG-8651

•45 patients of osteosarcoma were randomly assigned to presurgical chemotherapy, and 55 patients were randomly assigned to immediate surgery

•No difference observed among the two arms of the study

•Rates of limb salvage and survival same in both arms

Goorin AM, Schwartzentruber DJ, Devidas M 2003

Why Favor Pre-operative Chemotherapy?

• Important survival implications of histological response to such therapy

• Good responders have better prognosis

• Greater than 90% necrosis and less than 90% necrosis in tumor histology after chemotherapy differentiate good and poor responders after 10 to 12 weeks of preoperative chemotherapy

• Easy surgical resectability

Evidence of Response to Chemotherapy• Clinical: pain, alkaline phosphatase (AP) levels

decrease. The tumor shrinks, especially if significant matrix is not present

• Radiology:increased ossification of tumor osteoid, marked thickening and new bone formation of the periosteum and tumor border

• Angiography: vascularity decreases markedly

Summary of Chemotherapy• In nonmetastatic high-grade osteosarcoma -adjuvant

chemotherapy with HD-MTX and at least two other drugs among the four most-active drugs in osteosarcoma can be expected to lead to a 75% 5-year survival among good histologic responders (greater than 90% necrosis) and 55% among poor histologic responders (less than 90% necrosis)

• Timing of chemotherapy does not improve survival, though it does help in prognostic stratification of patients

Chemotherapy Regimes•First Line Therapy

(Primary/NACT/Adjuvant)1. Cisplatin-Doxorubicin Cis – 100mg/m2 i.v D1 Dox – 25mg/m2 i.v D1-3 (3 cycles NACT surgery on D63 3

cycles Adjuvant)2. Cisplatin-Ifosfamide-Epirubicin Cis – 100mg/m2 i.v D1 Epi – 90mg/m2 i.v D1 Ifos – 2g/m2 i.v over 2 hrs D2-4 (3 cycles NACT and 3 cycles Adjuvant)

3. Doxorubicin-Dacarbazine Dox – 15mg/m2 D1-4 Dacarex – 250mg/m2 D1-4 4. MAID Dox – 15mg/m2 D1-4 Ifos – 2g/m2 D1-3 Dacarex – 250mg/m2 D1-4 Mesna – 2.5 mg/m2 D1-4

5. Etoposide-Ifosfamide

•Methotrexate

- High dose Mtx 8-12g/m2 along with leucovorin

- Pretreatment creatinine should be atleast 70ml/min

- Alkalization of urine before High Dose Mtx

- Mtx is dissolved in 5%D with final conc of about 1g/100ml.

- Leucovorin rescue 24 hrs after the start of Mtx 15-25mg P.O every 6 hrs for atleast 10 doses

•Second Line Therapy1. Docetaxel-Gemcitabine Doce – 75-100mg/m2 i.v D8 Gem – 675mg/m2 D1,8

2. Cyclophosphamide-Etoposide Cyclo – 500mg/m2 D1-5 Etop – 100mg/m2 D1-5

3. Cyclophosphamide-Topotecan Cyclo – 250mg/m2/dose Topo – 0.75mg/m2/dose Each given as 30 min infusion daily x 5

days

•High dose Samarium-153 ethylene diamine tetramethylene phosphonate

(153Sm-EDTMP) for relapsed or refractory disease beyond 2nd line therapy

1,3,4.5,6,12,19 or 30 mCi/kg

ROLE OF RADIOTHERAPY• RT does not play a major role• Typically a 2 cm margin is used for axial tumors

which can be extended to 4-5 cm for extremity tumors

• 60Gy in 2Gy fractions is typically used for microscopically involved margins

• Macroscopic residual disease – 66Gy• Inoperable tumors – 70Gy• RT can be given concurrently but is usually

delivered after chemotherapy• IORT and Proton therapy have also been used• RT is extremely beneficial in patients requiring

palliation of metastatic bony sarcomas; tumors at axial sites, which are unresectable and advanced inoperable lesions of the pelvis or extremitites.

Radiotherapy• Traditionally considered radio resistant• Generally not used in the primary

treatment• Used for patients who have refused

definitive surgery, require palliation, or have lesions in axial locations

• Tumors of axial skeleton and facial bones are treated by a combination of limited surgery and radiotherapy, because the goals of treatment are functional and cosmesis preservation

• In the post operative setting when residual disease is present (margin +ve, LVI)

Palliative Setting

•Metastatic and recurrent osteosarcomas have poor prognosis

•Various combinations of the 4 drugs have been tried but 5-year survival rates have been in the range of 20%

Radiotherapy- Guidelines• Appropriate imaging studies to define tumor location

correlated with surgical pathologic findings • Physical fluoroscopic simulation or computed tomography–

based virtual simulation • Patient immobilization and/or stereotactic localization• Megavoltage conventional external-beam delivery• High radiation dose with appropriate fractionation• Large radiation field/volumes with "shrinking field" techniques

to reduce volumes beyond threshold doses for microscopic disease

• Beam-shaping devices (mounted shielding or multileaf collimation)

• Beam modifiers for contour shape—compensating filters, wedges, or dynamic wedge or beam segmentation with or without intensity modulation

• Multiple fields to be treated per day

Dose and Volume Considerations

• Entire clinical and radiographic extent of tumor plus a generous margin for microscopic or subclinical extension of disease

• Irradiated field should encompass at least the volume of tissue that would be resected, plus an allowance of approximately 2 cm in total for patient movement

• Extremity fields should be planned with a strip of tissue deliberately out of the beam to allow for lymphatic and venous return and to decrease morbidity

• Shrinking field volume technique is recommended

Shrinking Field TechniqueEntire bone treated up to 40 Gy in 2 Gy Fractions at 5 fractions per week

Field reduction to cover tumor volume with margin up to 66-70 Gy

Newer Techniques Of Radiotherapy

3-D Conformal Radiotherapy

IMRT

Particle beam radiotherapy

CHONDROSARCOMA

Introduction•Mesenchymal origin•Predominantly made of cartilage•2nd MC primary malignant tumour of bone•Different types – Conventional (90%) Dedifferentiated Clear Cell Mesenchymal Juxtacortical Secondary

Pathophysiology and Genetics

•Primary – Arise de novo•Secondary – Arise from preexisting

cartilage Occur in Ollier disease, Mafucci

Syndrome, Multiple hereditary exostosis, Paget’s disease, Radiation Injury

•High proliferation rate on Ki-67 IHC•Loss of heterozygosity at many loci

Histological Grading•Grade I (Low Grade)•Grade II (Intermediate)•Grade III (High)

•10-15% of Grade II lesions metastasize•>50% of Grade III lesions metastasize

•Dedifferentiated chondrosarcomas are more aggressive than Grade III chondrosarcomas

Epidemiology• Conventional chondrsarcomas account for nearly

80-90% of all chondrosarcomas and 20-27% of all primary bone sarcomas

• Predilection for axial skeleton• Pelvis and ribs – 45% Ilium – 20% Femur – 15% Humerus – 10%• Dedifferentiated chondrosarcomas (10%) –

Femur is the MC site involved• Clear cell variant - <5%; predilection for ends of

long tubular bones involving epiphysis; proximal femur f/b proximal humerus

Clinical Presentation•Deep, dull achy pain•Nocturnal Pain•Joint restriction if tumor is close to the

joint•>50% of patients with dedifferentiated

chondrosarcomas present with pathological fractures

•Mean interval from pain to diagnosis is 19.4 months for Grade I and Grade II and 15.5 months for Grade III lesions

Plain Radiographs

•Typical appearance – Discrete calcification

•Usually large >5cm•Endosteal scalloping•Cortical thickening•Perpendicular periosteal new bone

formation that has a sunburst appearance•Stippled or punctate calcification

MRI, CT, Bone Scan and USG

•It is the INVESTIGATION of choice•Helps delineate extent of soft tissue

involvement•MRI also helpful for confirming or

diagnosing recurrence at a surgically treated site

•CT may be useful for subtle calcifications and improves visualization of bony destruction

Biopsy

•Directed at areas that may harbour foci of high grade tumor

•FNAC• Core Biopsy – Tru-Cut biopsy or Core

Needle biopsy•Risk of seeding of the biopsy tract is high

so procedure should be done meticulously

Treatment•RT and CT play limited roles•Diffuse mets is an indication for systemic

RT or CT•May be useful in dedifferentiated

chondrosarcoma•Surgery with clear margins remains the

primary treatment•Complete wide surgical excision is the

preferred method

Role of RT•No Level 1 evidence exists for RT in

chondrosarcoma•RT indicated to improve on high local

rates after incomplete resection of high risk tumors

•Doses of 50Gy preop and 60-66Gy postop for close or positive margins are typically used

•>70Gy dose is needed for definitive treatment

NCCN Recommendations•Base of Skull Tumors - Postop therapy or RT for unresectable

disease - >70Gy• Extracranial sites - Preop RT (19.8-50.4Gy) may be

considered if positive margins are likely f/b Postop RT with 70Gy in R1 resection and 72-78Gy in R2 resection

- Postop RT 60-70Gy in high grade lesions with positive margins

- High dose therapy with specialized techniques recommended

Outcome and Prognosis

•Grade I – 90% survival at 5 yrs•Grade II – 81% survival at 5 yrs•Grade III – 29% survival at 5 yrs•Overall 5 yr survival rate for conventional

chondrosarcomas is 48-60%•Dedifferentiated chondrosarcoma is

highly lethal, 10% survival rate after one year

EWING’S SARCOMA

Introduction•2nd MC primary tumor of bone in childhood

•ESFT include Ewing’s Sarcoma, Peripheral PNET, Neuroepithelioma, Atypical Ewing’s and Askin Tumor

•Ewing Sarcoma tumors include Ewing sarcoma, Askin tumor and peripheral PNET

•MC combination – EWS exon 7 fused to FLI1 exon 6 occurs in 50-64% of tumors

Etiology•Thought to arise from cells of the neural

crest, possibly mesenchymal stem cells

•Exact origin in unknown

•MC translocation – t(11;22)

•It has been found that relatives of patients with Ewing’s sarcoma have an increased incidence of neuroectodermal and stomach malignancies

Epidemiology

•Incidence higher in whites by 9 times

•Incidence peaks in late teenage years

•Overall 27% cases occur in first decade, 64% in 2nd decade and 9% in 3rd decade

Signs and symptoms

•Localized pain•Back Pain (indicates paraspinal or

retroperitoneal tumor)•Palpable mass•Fever and Weight Loss (Systemic sympts)

Histology and IHC•Ewing sarcoma are small, round, blue cell

tumors. They can be nor differentiated, as reflected in rosette formation

•IHC markers include MIC2 (12E7) antigen (CD99), which is characteristic but NOT pathognomonic

•Muscle, lymphoid, and adrenergic markers should be negative.

Diagnosis•CBC, Blood Cultures, CRP, ESR, LDH•Cytogenetic and molecular studies•Histology•Plain Radiography•CT•MRI•Bilateral Bone Marrow Biopsy•Chest CT Metastatic •Whole Body MRI Work up•FDG-PET (in suspected

cases)

Treatment•Lasts 6-9 months and consists of

alternating courses of 2 regimes•VAC/IE V – 2mg/m2 i.v A – 75mg/m2 iv bolus infusion daily C f/b Mesna – 1200mg/m2 daily I – 1800mg/m2 daily for 5 days with

Mesna E – 100mg/m2 daily for 5 days with

Mesna•Patients often develop episodes of fever

and neutropenia

Chemotherapy Regimes• VAI Vinc – 1.5mg/m2 i.v D1,8,15,22 Adria – 30mg/m2 i.v D1,2,43,44 Ifos – 3000mg/m2 i.v D1,2,22,23,43,44 Actinomycin D – 0.5mg/m2/d x 3 i.v D22,23,24

• VIDE Vinc – 1.5 mg/m2 i.v D1 Ifos – 3000 mg/m2 i.v D1,2,3 Dox – 20mg/m2 i.v D1,2,3 Etop – 150mg/m2/d x 3 i.v D1,2,3 Followed by Mesna Prophylaxis and G-CSF

support

•Currently, an open study within the Children’s Oncology Group (AEWS1031) is evaluating the efficacy of adding vincristine, topotecan, and cyclophosphamide to the interval compressed 5-drug backbone for patient with nonmetastatic Ewing sarcoma (NCT01231906)

Advantages of Induction Chemotherapy•Evaluation of the effectiveness of the

regime•Shrinkage of the soft tissue mass•Surgeons can achieve better margins•Bone healing which takes place during

chemotherapy diminished the risk of pathological fracture if RT is used later

•Response rates are as high ass 90%

Role of Surgery•For definitive therapy, limb salvage surgery

is preferable over amputation, but amputation may be an option for younger patients with lesions of the fibula, tibia and foot

•In older patients, lesions of the proximal fibula, ribs, scapula, clavicle and wing of the iliem are easier to resect

•Lesions of the bones of the hands and feet may be resectable with a ray resection

•No randomized study has been performed to define whether local control is better accomplished with surgical resection or radiotherapy

Radiation Therapy

• Fields encompassing the primary tumor with a 3- to 5-cm margin

• >60 Gy if primary radiotherapy is being used

• 55.8 Gy for gross and 45 Gy for microscopic residual disease after primary treatment

Results of Therapy•Addition of CT to local therapy increased

survival from <10% to >40% at 5 yrs for patients with localized disease at diagnosis

•SEER data confirms gradual improvement in survival over time

•IESS-I reported addition of Doxorubicin improved local control

•The first CCG/POG intergroup study showed an improvement in survival in the intensified arm for patients with localized disease and large primary or pelvic tumors

•Early RT is preferable to late RT post chemotherapy

High Dose Therapy with Stem Cell rescue• Invetigational megatherapy and stem cell

rescue using high-dose CT with and without total-body irradiation

• Increasingly accepted for patients with metastatic disease or recurrence in Europe

• Different regimes – melphalan, etoposide, busulfan, carboplatin and thiopeta

• Compartmental irradiation to doses upto 54Gy and high dose CT and stem cell rescue reported a 5 yr survival rate of 54%

Radiation Induced Sarcoma• Secondary sarcomas arising in irradiated normal

bone: from 5% to 10% at 20 years from diagnosis• Doses greater than 60 Gy :excess risk of

secondary bone sarcomas• Risk of developing a secondary bone tumor in the

irradiated field was negligible at doses below 48 Gy

• The treatment of radiation-associated sarcoma is wide resection, when possible, combined with adjuvant chemotherapy

MALIGNANT GIANT CELL TUMOR

Introduction•Rare benign primary tumor of the bone

accounting for about 3-5% of all primary bone tumors

•Strong tendency for local recurrence and that may metastasize to the lungs

•Usually occurs between 20-40 yrs of age•Distal Femur and Proximal Tibia are the

most common primary sites•Malignant transformation to high grade

osteosarcoma observed in rare cases

Workup•History and PE•CT is useful to define the extent of

cortical destruction•MRI is the preferred modality to assess

extension of tumors into adjacent tissue and neurovascular structures

•Chest CT to identify metastatic disease•Bone Scan•Biopsy to confirm diagnosis

Treatment•Surgery - Wide excision and intralesional curettage for

resectable tumors

- Wide excision associated with a lower risk of local recurrence than curettage

- Wide excision associated with poor functional

outcome and greater surgical complications

- Stage I and II – Curettage is TOC - Sage III and IV – Wide Excision preferred

•Radiation Therapy

- Used as primary treatment or in combination with surgery to improve local control and DFS for patients with marginally resected, unresectable, progressive or recurrent disease

- 50 to 60Gy for metastatic disease

- Increased risk of malignant transformation following RT has been noted in some studies

•Systemic Therapy - DENOSUMAB – significant activity in

unresectable or recurrent GCTB - FDA approved in June 2013 for treatment

in adults and skeletally mature adolescents with GCTB that is unresectable or where surgical resection is likely to result in severe morbidity

- Recent Phase II trial data suggested FDG-PET to be a sensitive tool for early detection of tumor response to Denosumab treatment

NCCN Recommendations•Localized Disease

- Intralesional excision with or without an affective adjuvant

- Serial arterial embolizations in extremity lesions

- Few case reports reported efficacy of INF and Peg-INF

- RT to be used in patients not amenable to above procedures

- Stable/Improved disease – Intralesional Excision is recommended

•Metastatic Disease

- Intralesional excision is recommended for resectable metastatic disease

- Denosumab, INF, RT, Observation are included as options

CHORDOMA

Introduction•Rare tumors that arise from embryonic

notochordal elements along the length of the neuraxis at developmentally active sites

•<1% of CNS tumors•Thought to arise from ectopic notochordal

elements•Slow growing but locally aggressive

tumors leading to tissue destruction and death

•Mets are recognized but are uncommon

Epidemiology

•0.2% of all CNS tumors•2-4% of all primary bone neoplasms•Sacrum (50%) > Clivus > Spine Axis•M:F = 2:1•Intracranial chordomas present in a much

younger age group than their spinal counterparts

Clinical Presentaiton• Sacrum – LBA, Lower extremity pain - Autonomic symptoms in 50% pts particularly

rectal dysfunction and urinary incontinence - Palpable sacral mass

• Intracranial – Diplopia, Headache, CN Palsies C.N VI and sensory V are MC• Lower vertebra – Pain, Bladder dysfunction,

Lower extremity weakness• Cervical vertebra – Hoarseness, Dysphagia

• Time span from symptoms to diagnosis averages 10 months

Pathology

•Conventional (Majority)

•Chondroid chordoma (5-15%) – Better prognosis

•Dedifferentiated chordoma (<5%) – More aggressive, faster growing and more likely to metastasize

Treatment

•Surgery has been the primary approach

•Complete en bloc resection with negative margins achieves local control in 70-80% cases

•If margins are positive, failure rate >70%

Radiotherapy• Considered relatively radioresistant

• >66Gy dose required

• Difficult to achieve with conventional EBRT techniques

• IMRT, SRS associated with good local control rates in cranial and extracranial chordmas

• Best results have been achieved with a combination of Surgery and High dose Proton Therapy exploiting the concept of Bragg peak

• Brachytherapy can be used for recurrent tumors of the base of skull or adjacent to the spine when a more aggressive surgical exposure is offered

NCCN Recommendations•Base of Skull - Postop RT or RT for unresectable disease

70Gy or higher

- Consider Postop RT for R0 resections

•Mobile Spine - Consider preop RT (19.8 to 50.4 Gy) and

postop RT to total dose of 70Gy (depending upon normal tissue tolerance)

Systemic Therapy•Not sensitive to chemotherapy except for

the potentially dedifferentiated portion of high grade dedifferentiated chordomas

•Phase II trial of 56 pts treated with IMATINIB, 70% has stable disease

•ERLOTINIB and LAPATINIB effective in IMATINIB resistance

•Patients with recurrence can be managed with surgery and/or RT and/or Systemic Therapy.

•The guidelines have included Imatinib with or without cisplatin or sirolimus, erlotinib, sunitinib and lapatinib (for EGFR +)

BONE METASTASES

Introduction• Common occurrence in the event of

malignancy • Third most common site of distant

metastases after liver and lung • Cause significant and debilitating pain• Pathological fracture and spinal cord

compression• Significant morbidity• Multimodality approach• Aims at alleviation of pain and prevention of

future complications• Palliative irradiation should be delivered

such that side effects should not be more distressing than the symptoms to be treated

Primary site Prevalence%

Breast 45-85

Prostate 54-85

Lung, 32-40

Thyroid 28-60

Kidney 33-40

GI 5-13

• Sites of preference of bone mets - Spine (69%) - Ribs - Pelvis (41%) - Skull (14%) - Long bones ends (25%)

• Spinal Location

Thoracic 60 to 70%

Lumbar 15 to 30%

Cervical 10 to 15%

Multiple 20 to 35%

•Types of Bone mets

• Osteolytic lesions :• Multiple myeloma• Mets from – Breast

- Kidney - Thyroid gland

• Osteoblastic lesions :• Prostate • Breast• Hodgkins disease

• Mixed lesions :• Breast

Clinical Features•Pain MC

▫ initially well-localized/ diffuse ache/ radiculopathy/ difficult movement

•Biologic Pain▫ Tumor's presence in the bone. ▫ The release of inflammatory mediators.▫ Irritation of nerve endings.

•Functional Pain

▫ Caused by the mechanical weakness of the bone.▫ loss of structural integrity in blastic lesions

•The development of functional pain is a marker for a bone at risk for fracture.

Diagnostic Evaluation•Careful History

•Physical examination including complete Neurological examination

•Routine hematological investigations including▫ Alkaline phosphatase▫ Tumor markers

PSA in prostate ca CA15.3 breast ca

▫ Serum Ca++•Biopsy must be performed to verify the

diagnosis before initiation of treatment.

Bx/ FNAC/ open Bx CT guided/ non weight bearing region

Imaging

•Plain radiography (XR)•Bone scan •Computed tomography (CT) •Magnetic resonance imaging (MRI)•PET-CT

Plain Radiographs•Most specific but least sensitive. • Inexpensive and easily obtained•Basis for the initial evaluation,

planning, and follow-up •Evaluate the structural integrity of

bone and the risk of impending pathologic fracture

• Important in decision making, plain radiography should be the first test ordered to evaluate bone pain.

•Loss of trabeculations and cortical erosion is characteristic

Bone Scan•Highlights regions of bone turnover with

areas of new bone deposition.•72% to 84% sensitive in detecting occult

bone lesions•Integral in the evaluation of a patient with

bone pain. •Detects functional changes•Not specific/ no structural detail•Radiographs required •Lytic lesions appear cold

CT Scan•Not a primary tool/ a useful adjunctive

study•3 D evaluation of bone integrity for

planning in shoulder and pelvic lesions•Extent of cortical destruction•Soft tissue component•Identify a target for needle biopsy•Bony anatomy well in the spine•No epidural extension and neural

compression•No extent of medullary involvement

MRI

•Marrow involvement•Early detection•Neural compression•Differentiates pathologic

compression # from osteoporotic compression #s of the spine.

•Difficulty differentiating infection, inflammation, and metastatic disease of bone.

•MRI is not a stand-alone study and images require correlation with plain radiographs.

PET-CT

•Unknown primary

•Multiple sites of metastatic disease.

•Although the PET imaging modality shows promise, it is currently only an investigational tool for most cancers.

•Correlation with structural imaging is required for treatment planning.

Planning

•Explain patient about the procedure•Positioning•Immobilization•Simulation•Dose prescription•Treatment•Patient care during RT.

Immobilization• No formal immobilization used• Cervical spine – head fixation• Adequate analgesia before & after RT

Position :• Most Comfortable to Pt

• Cervical vertebral mets : Supine• Thoracic vertebral mets : Prone• Lumbar vertebral mets : Prone

• If pt is not able to lie prone, can be simulated in supine position & treated from under couch

Radiation Portals• Cervical spine : Lateral portals – reduce morbidity by sparing

upper aerodigestive structures

• Thoracic spine : Direct Posterior portal

• Lumbar spine : Direct Posterior portal AP / PA portal if pt thin

• Ribs : Electron beams Tangential photon beams

Margins• Superior margin : one

vertebra above the highest involved vertebra (2-3cm)

• Inferior margin : one vertebra below the lowest involved vertebra (2-3cm)

• Width : to include transverse process on both sides

( appr. 7-8 cm)

• For long bones : Margins 2 - 3cm above and below

Depth of Prescription•To be decided with available images•Direct posterior portal – distance from skin

to Ant. Vertebral body of the involved vertebra

•AP/PA Portal – mid separation •Bilateral portal - mid separation

•Cervical spine – 3cm•Thoracic spine – 4cm•Lumbar spine – 5-6 cm

Dose Prescription

•8Gy/1#, 20Gy/5#, 30Gy/10#, 37.5Gy/15# & 40Gy/20#

(depending upon expected survival of the pt)

( Dirk Rades et al JCO, 2005 )

General Instructions• When bone mets from extremities to be

treated, important to spare a strip of soft tissue along the entire length of extremity to allow lymphatic return from distal portion of limb

• While irradiating pelvic bones - - Maximal sparing of small bowel, bladder &

rectum - Also closely monitor blood counts

• Careful documentation with simulator films, skin tattoos, photographs, portal diagrams

WIDE FIELD RT/HEMIBODY IRRADIATION•HBI – a form of Subtotal Body Irradiation

•One half of body irradiated

• Intent of Treatment – Palliative

• Indication : disseminated bony metastasis involving either half of body

•Most common primaries associated : Breast, Lung, Prostate

Types of HBI• UHBI (above umbilicus) – Skull, Cervical, Dorsal, Lumbar spine upto L3, Ribs, Sternum, Clavicle, Scapula, Upper limbs• LHBI (below umbilicus) – Lumbar spine below L3, Sacrum, Pelvis, Lower limbs• MHBI (diaphragm to obturator

foramen) Lumbosacral spine, Pelvis, Femoral

heads

Treatment Parameters• Borders

- UHBI : Upper – Air (3 cm above head) Lower – L3 / L4(Upper border of umbilicus) - LHBI : Upper – L3 / L4 Lower – 3-4 cm below patella

- MBI : Upper - D6 (domes of diaphragm) / D10 (insertion of diaphragm) Lower – Cover Obturator foramen Go lower down if overt disease present Laterally, cover whole extent of body

•Portals – Parallel opposed AP/PA•Energy – 6 MV photons•Field Size – 40 cm x 40 cm•Dose – * UHBI – 6 Gy / 1 # Prescribed at average

* LHBI – 8 Gy / 1 # mid thickness depth on

* MBI – 8 Gy / 1 # central axis

SIDE EFFECT UHBI / MBI LHBI

Nausea / Vomiting (onset in hrs, may last for days)

>80% without antiemetics

<15%

Diarrhea (onset in hrs, lasts for days)

less more

Hematological(nadir :10-14 days, lasts 4-6 wks)

likely Slightly more than UHBI

Pneumonitis(16 wks)

At >7.5 Gy / 1 #

RADIOISOTOPES

•Bone seeking isotopes P32, Sr89, Sm153, Rh186, Y90

•FDA approved Sr89-EDTMP, Sm153 EDTMP

•Radioactive tin and phosphorus : phase I/II trials

•Sr-89: metastatic hormone-refractory prostate and breast cancer

Advantages

▫ease of administration, ▫Treatment of multiple sites ▫improved therapeutic ratio due to

localization to bone▫potential to combine with CT / EBRT

•No apparent substantial difference in palliative efficacy of diff. radionucl.

•Only one reported randomized phase II trial compared Sr and Re

Bisphosphonates•First-generation compounds

▫ clodronate and etidronate

•Second-generation▫ tiludronate and pamidronate

•Third-generation ▫ risedronate and zoledronate

•Pamidronate has been shown in several studies to be effective in treating osteolytic disease, and zoledronate has proven efficacy in treating osteoblastic and osteolytic metastatic bone disease.

PRIMARY BONE LYMPHOMA

Introduction•Most primary lymphomas are of NHL type

and of DLBCL subtype•<1-2% of adult NHL and <7-10% primary

bone tumors•Majority of cases are limited disease and

occur in adults 45-60 yrs of age•Slight male predominance•EBV, HIV and HHV-6 known to be

associated •Optimal treatment is unknown•R-CHOP is commonly used regimen

Clinical Features

•Pain without antecedent trauma unrelieved by rest

•Monostotis or Polystotic disease most often in the long bones of adults

•Femur – MC location•Vertebral column and pelvis other

locations•B symptoms – Fever, Night Sweats,

Weight Loss

Diagnostic Evaluation

•Anaemia•Elevated LDH•Elevated ALP•Elevated ESR•Elevated Platelets•Elevated Calcium Level

•In a review of Primary NHL of bone, 103 of 131 reported cases were DLBCL

•Other subtypes reported to a much lesser extent

•In children, DLBCL is the MC subtype, followed by Lymphoblastic Lymphoma

•No specific immunophenotype has been reported for Primary NHL of bone

Genetics•Lima and colleagues reviewed 63 cases of

Primary DLBCL of bone by multiple modalities and found rearrangements of BCL-2 and c-MYC in a portion of their cases

•Of note, one of their cases showed a dual rearrangement of c-MYC and BCL-2, a molecular finding more classically seen in nodal DLBCL

FIBROSARCOMA

•<5% of all primary bone tumors•Mesenchymal origin•Predominance of fibroblasts without

tumor osteoid or cartilage production•Predilection for long bones•High metastatic potential•Treatment – Complete Surgical resection

and often with NACT/Adjuvant CT•RT can be used for incompletely resected

or unresectable tumors

MALIGNANT FIBROUS HISTIOCYTOMA

•<5% of bone tumors•Characterized by a mixture of spindle-

shaped fibroblastic cells in a storiform pattern and admixed with mononuclear cells with histiocytic morphology and anaplastic giant cells without tumor osteoid or cartilage production

•Complete Surgical resection is the mainstay of treatment

•Like Osteosarcoma, it has a high rate of metastases

•Known to benefit from Chemotherapy