CHEMOTHERAPY IN

BONE CANCERS

CHEMOTHERAPY IN

BONE CANCERS

Prof. V. Vedhamoorthy. MD DM

Professor and HeadDepartment of Medical Oncology

MMC, Chennai-3.

INTRODUCTIONINTRODUCTION

• CHEMOTHERAPY IN

• Osteogenic sarcoma• Ewing’s sarcoma• Multiple myeloma• Bone lymphoma• Other bone primaries

OSTEOGENIC SARCOMAOSTEOGENIC SARCOMA

• Impact of chemo in osteogenic sarcoma

1. 5 years survival with surgery alone was less than 20%

• Addition of chemotherapy as adjuvant increased the 5 year survival more than 80%

2. Chemo as neo-adjuvant increased the percentage of limb conservative surgery

3. Addition of chemo

• Delayed the development of lung metastasis

• Number of metastasis are fewer

• Metastesectomy chances are improved

• Increased the survival

• Drugs effective in osteogenic sarcoma

1. Adriamycin

2. Methotrexate

3. Cisplatinum

4. Ifosfamide

• Combination of drugs is the best

• To increase the cell kill

• To overcome drug resistance clones

• Drug combination may be 3 or 4 drugs

• Example• Adriamycin, Cisplatinum, Ifosfamide• Adriamycin, Methotrexate, Ifosfamide

• SITUATION - 1

• Osteogenic sarcoma • Limited to the bone of its origin• Smaller in size • Fit for immediate limb conservative surgery

• 26 year male

• Osteosarcoma of upper end of left tibia

• X- ray chest

• Normal

• CT chest

• Normal

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Limb conservative surgery

Combination chemo administered as adjuvant

6 courses

• PRINCIPLE OF ADJUVANT CHEMO

• To sterilize distant micro metastasis• To reduce distant relapse• To increase disease free interval• To improve overall survival

• ADVANTAGES OF ADJUVANT CHEMO

1. Primary surgical treatment is executed immediately

2. Patient is mentally happy

3. Risk of progression and dissemination are avoided

4. Risk of development of drug resistance is avoided

• DISADVANTAGES OF ADJUVANT CHEMO

1. Delay in care of distant micro metastasis

2. Risk of dissemination during surgical procedure is high

3. Clinical response of drug is not assessed

• SITUATION - 2

• Osteogenic sarcoma • Limited to the bone of its origin• Larger in size • Not fit for immediate limb conservative surgery

• 25 year old male

• Osteosarcoma of lower end of left femur

• X-ray chest

• Normal

• CT chest

• Normal

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3 courses of combination chemo as neo-adjuvant

Limb conservative surgery

3 courses of adjuvant chemo

• Pain and swelling reduced after 3courses of neo-adjuvant chemo

Underwent limb conservative surgery

X-ray after limb conservative surgery

Patient ambulant after limb conservative surgery

• PRINCIPLES OF NEO-ADJUVANT CHEMO

1. To reduce the size of the primary tumor

2. Making the tumor amenable for limb conservative surgery

• ADVANTAGES OF NEO-ADJUVANT CHEMO

1. Distant micrometastasis is taken care immediately

2. Size and vascularity of the tumor is reduced, hence dissemination risk is minimized during surgery

3. Clinical response is assessed

• DISADVANTAGES OF NEO-ADJUVANT CHEMO

1. Delay in the primary surgical treatment

2. Patient is psychologically upset

3. Risk of progression and dissemination of the disease is high

4. Development of drug resistance is increased

• ASSESSMENT OF RESPONSE OF NEO-ADJUVANT CHEMO

• Symptoms

• The size of the tumor is reduced• Pain is lessened

• X-ray, CT, MRI

• Size of the tumor is reduced• Margins become more clear and defined• Soft tissue infiltration recedes

• Thickness of cortical involvement is not altered

• Technetium 99 Bone scan

• Size is reduced• Intensity of the hot spot decreased

• Angiogram

• In very good response • Arterial phase and capillary mess are reduced

• In intermediate response• Arterial phase alone is reduced

• In poor response• No change in arterial phase and capillary mess

• Thallium bone scan and PET scan

• Both give biological response directly

• In good response – because of heavy necrosis, uptake is reduced

• In poor response – because of no much change in viable cancer cell volume, uptake is not altered

• Pathological response

• Grade I• Volume of viable cancer cells is not altered

• Grade II• Minimal reduction of viable cancer cells

• Grade III• Good reduction of viable cancer cells

• Grade IV• Complete disappearance of viable cancer cells, replaced by necrosis

• SITUATION – 3

• Osteogenic sarcoma• Limited to the bone of its origin• Presence of pathological fracture

(seen in less than 1%)

• X-ray left femur

• OS of lower end

• Pathological fracture

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Fractured segments are kept in alliance

Limb is immobilized by POP

2 courses of combination chemo

If good callus formation occurs – suggests chemo clears tumor tissue in between

fractured fragments

Proceed with limb conservative surgery

Followed by 4 more courses of adjuvant chemo

If no callus formation occurs

Suggests tumor tissue is not sterilized by chemo

Proceed with amputation

6 courses of tailored adjuvant chemo

• SITUATION – 4

• Osteogenic sarcoma

• Presence of resectable pulmonary secondary

• X-ray chest shows solitary coin shadow at right lower zone

• CT chest

• Solitary lung secondary

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Manage the primary tumor by LCS / amputation

2 courses of combination chemo

CT chest confirms no progression of pulmonary secondary

Metastesectomy

4 courses of combination chemo

• SITUATION – 5

• Osteogenic sarcoma

• Unresectable, multiple, bilateral pulmonary secondaries

• X-ray chest

• Multiple, bilateral, subpleural and basal lung secondaries

• CT chest

• Multiple bilateral lung secondaries

• Cavitating secondary left lower lobe

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Palliative combination chemo

If chemo has not given good response to primary tumor

Proceed with palliative surgical resection

• SITUATION – 6

• Osteogenic sarcoma

• Limited to the bone of its origin

• Underwent surgery and chemo

• While on follow up develops resectable pulmonary secondary

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Resect the pulmonary secondary

Observation

or

Second line chemo

• SITUATION – 7

• Osteogenic sarcoma

• Limited to the bone of its origin

• Underwent surgery and chemo

• While on follow up develops unresectable pulmonary secondary

• Option 1• Symptomatic treatment

• Option 2• Second line combination chemo

• Option 3• High dose chemo with autologous peripheral stem cell

transplant

• Newer experimental drugs

• Muramyl Triphosphate (Macrophage stimulant)

• Aerosol GM-colony stimulating factor

• Herceptin – If Her 2 over expression present

EWING’S SARCOMAEWING’S SARCOMA

INTRODUCTIONINTRODUCTION

• Second common bone primary in the paediatric age group

• Highly radio and chemo sensitive

• SITUATION - 1

• Ewing’s sarcoma

• Limited to the bone of its origin

• Size is less than 8cm

• Cured by surgery or radiotherapy

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ADJUVANT CHEMOTHERAPY

• EVOLUTION

• 1960s• Vincristine, Actinomycin-D, Cyclophosphamide

• 1970s• Intergroup Ewing’s sarcoma study -1

• Vincristine, Actinomycin-D, Cyclophosphamide, Adriamycin and pulmonary irradiation

• Intergroup Ewing’s sarcoma study -2• Vincristine, Actinomycin-D, Cyclophosphamide,

Adriamycin in escalated dose

• 1980s onwards

• Pediatric Oncology Group• Vincristine, Adriamycin, Cyclophosphamide,

alternated with Etoposide, Ifosfamide

• Every 3 weeks • 8 courses each• Covering 48 weeks• Gives longest disease free interval and overall survival

• SITUATION - 2

• Ewing’s sarcoma

• Limited to the bone of its origin

• Size is more than 8cm

• Planed for limb conservative surgery (No role for curative radiotherapy)

• 26 year old male

• Ewing’s sarcoma of right forearm

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Neo-adjuvant 3 courses of VAC / IE

Tumor size is reduced

Limb conservative surgery is done

5 more courses of adjuvant VAC / IE

• SITUATION – 3

• Ewing’s sarcoma as disseminated disease with

• Pulmonary / bone / marrow metastasis

• 16 year old boy

• Ewing’s sarcoma of left tibia

• Principle• Palliative

• Plan• Combination chemo

• Schedule• 3 drugs regimen – V Act C• 4 drugs regimen – V Act C + Adriamycin• 5 drugs regimen – VAC / IE

• Results• All the regimens give equal results of survival

• Newer approaches

• High dose chemo with autologous peripheral stem cell transplant

• Indicated in• High risk limited stage Ewing’s sarcoma• Post chemo relapse • Disseminated stage

• Newer drugs

• Topoisomerase – I inhibitor• Topotecan• Irinotecan

• Taxanes• Paclitaxel• Docitaxel

• Chondrosarcoma• Malignant giant cell tumor

• Protocol as osteogenic sarcoma

• Fibrosarcoma of bone• Malignat fobrous histiocytoma of bone• Angiosarcoma of bone

• Chemo protocol is MAID schedule • Messna• Adriamycin• Ifosfamide• D-actinomycin

• Bone lymphoma

• CHOP schedule• Cyclophosphamide• Hydroxyl doxorubicin• Oncovin• Predinisolone

• R-CHOP• Rituximab with CHOP

• Multiple myeloma

• VAD (Vincristine, Adriamycin, Dexamethasone)• Thalidomide with dexamethasone• High dose melphalan with ABMT / APSCT

CONCLUSIONCONCLUSION

• Bone lymphoma and multiple myeloma • Primary modality of treatment is chemo

• Ewing’s sarcoma • Radiotherapy and surgery are equal options

• Osteogenic sarcoma, chondrosarcoma• Surgery is the primary modality

• Role of chemo in osteogenic sarcoma as

• Neo-adjuvant• Adjuvant• Palliative role

• has been clearly established