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CHEMOTHERAPY IN ORTHOPAEDICS

Dr . SUDHEER KUMAR

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INTRODUCTION

• Surgical resection remains the mainstay of treatment in musculoskeletal tumors

• But it is difficult to treat a patient with a certain high grade tumors by surgery alone.

• Adjuvant modalities like CHEMOTHERAPY & RADIOTHERAPY play an essential part in the integrated management of these patients

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WHAT IS CHEMOTHERAPY

Chemotherapy  is the treatment of cancer with one or more cytotoxic anti-neoplastic drugs as part of a standard regimen

Treatments like radiation and surgery are considered local treatments as they usually target the cancer directly

Chemotherapy differs from surgery or radiation in that it’s almost always used as a systemic treatment

chemotherapy drugs are used today either alone or in combination with other drugs or treatments

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Goals of chemotherapy

Curative intent: Though cure may be the goal, it

doesn’t always work out that way

Control:to shrink any cancerous tumors and/or stop the cancer from growing and spreading

Palliation: at an advanced stage, drugs may be used to relieve symptoms.

to improve the quality of life but not treat the disease itself

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TYPES OF CHEMOTHERAPY

• Neo adjuvant chemo therapy• Adjuvant chemotherapy• Palliative• Intra arterial

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Neo adjuvant chemo therapy• Before surgery• Kills micro metastasis• Kills tumor emboli at the time of surgery• Decreases drug resistant clones in micro metastasis• Decreases tumor size

• Less chance of viable tumor spread at surgery

DISADVANTAGES• High tumor burden• Loss of limb sparing option• Drug resistant cells may metastasize• Delay in control of bulk disease• Increased chance of systemic dissemination

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ADJUVANT CHEMOTHERAPY

• After surgery• Improved survival rates for patients• Decreased bulk and specific agents more active • Decreased drug resistance

DISADVANTAGES• As delay of systemic therapy-micro metastasis chance to

establish• No pre op in vivo assay• Spread of tumor by surgery may have occured

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PALLIATIVE CHEMOTHERAPY

• When not combined with surgery• Poor general condition• Not willing for surgery• Disease free state for many months• Improves 5yr. Survival rate• Destroys microscopic foci• Prevents metastasis in 60%.• Disease free in 40%• Decreases tumor size• Short cyclical course decrease toxic effects• Combination of drugs increases interval between drugs—

decreases toxicity

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INTRA ARTERIAL

• Pre-op chemo administered directly into arterial supply of tumor

• This gives a very high dose of chemotherapy to the tumour, but less to the rest of the body

• Pre-op angiogram– Arterial supply– Tumor extent– Neo vascularisation

• Catheter preferably in the feeder vessel or proximal to first tumor vessel

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MECHANISM OF ACTION

 Most chemotherapeutic drugs work by impairing mitosis (cell division), effectively targeting fast-dividing cells (both

normal cells and cancer cells)

This means normal cells are damaged and this results in side effects

Cell cycle:a series of steps that both normal cells and cancer cells go

through in order to form new cells

The cell cycle has 5 phases

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Cell cycle

G0 phase (resting stage): Depending on the type of cell,G0 can last from

a few hours to a few years

G1 phase:lasts about 18 to 30 hours

S phase: lasts about 18 to 20 hours

G2 phase: lasts from 2 to 10 hours

M phase (mitosis): lasts only 30 to 60 minutesSome drugs specifically attack cells in a

particular phase of the cell cycle

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DRUGS • ALKYLATING AGENTS

– Cyclophosphamide, melphalan, ifosfamide• ANTIMETABOLITES

– Methotrexate,5fluorouracil• VINCA ALKALIODS

– vincristine• ANTIBIOTICS

– Doxorubicin, bleomycin• MISCELLANEOUS -cisplatin

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DRUG TOXICITY• BONE MARROW

– suppression • LYMPHORETICULAR TISSUE

- Suppression of immunity• GIT

• Stomatitis, vomiting• SKIN

• Alopecia• GONADS

– Oligospermia, amennorrhoea,mutation

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DRUG TOXICITY

• FETUS– Abortion, teratogenesis

• HYPERURICEMIA– Gout ,ureteric stones

• NEUROPATHY• CARDIOMYOPATHY• CYSTITIS

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ASSESSMENT OF TUMOR RESPONSE

• Clinical• Radiographic• Histological

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HISTOLOGICAL GRADING

• GRADE I– Little or no effect

• GRADE II UNFAVOURABLE– Area of necrosis(effect of chemo)+ area of viable tumor

• GRADE III– Predominant necrosis+– scattered foci of viable tumor

• GRADE IV FAVOURABLE– No viable tumor

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TAILORING OF THERAPY

• Pre surgical chemo

Responsive continue same regime

Unresponsive change chemo

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CHEMO SENSITIVITY OF BONE SARCOMAS

• Highly sensitive » Ewing's sarcoma

• Moderately sensitive

» myeloma• Relatively resistant

» osteosarcoma

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OSTEOGENIC SARCOMAGeneral treatment recommendations for patients with

osteosarcoma

low-grade osteogenic sarcoma Primary treatment includes wide excision only Chemotherapy is not typically recommended

high-grade osteogenic sarcomas

Chemotherapy is warranted for all stages

For non-metastatic osteosarcoma,

2-3 cycles of chemotherapy are typically given preoperatively; 3-4 cycles of chemotherapy are given postoperatively

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Primary, neo-adjuvant, or adjuvant therapy for metastatic disease :

Neo adjuvant setting:

drugs dose weeks

High-dose methotrexate

12 g/m2 IV given over 4h

0, 1, 5, 6, 13, 14, 18, 19, 23, 24, 37, and 38

cisplatin 60 mg/m2 iv for 2d each

2, 7, 25, and 28

doxorubicin 37.5 mg/m2/day IV for 2d each

2, 7, 25, and 28

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Adjuvant setting

drugs dose weeks

High-dose methotrexate

12 g/m2 IV given over 4h

3, 4, 8, 9, 13, 14, 18, 19, 23, 24, 37, and 38

cisplatin 60 mg/m2 IV for 2d each

5, 10, 25, and 28

doxorubicin 37.5 mg/m2/day IV for 2d each

5, 10, 25, and 28

2 cycles are given preoperatively, and 4 cycles are usually given postoperatively

For patients with particularly poor pathologic response to chemotherapy, ifosfamide and etoposide has been added to the postoperative chemotherapy regimen

Requires administration of 15 mg leucovorin every 6h for 10 doses, starting 24h after initiation of high-dose methotrexate

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Second-line therapy for relapsed or refractory disease

• Docetaxel and gemcitabine: Docetaxel 100 mg/m2 on day 1 of every 21-d cycle plus gemcitabine 675 mg/m2 on days 1 and 8

• For localized, unresectable osteosarcoma, radiation therapy can occasionally provide long-term, local control

•For localized, resectable osteosarcoma, radiation therapy is used as adjuvant therapy only when there is microscopic or gross residual disease

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EWINGS SARCOMA

• Radiosensitive & Chemosensitive• Controlled by radical RT with adjuvant chemo.• Palliative-whole lung irradiation for cough,dyspnoea due to

lung metastasis

• Phase I(weeks 0-9)

drugs dose days

Vincristine 1.5mg/m2 iv 1,22,29,36,43

Doxorubicin 75mg/m2 iv 2,44

Cyclophosphamide 500mg/m2 iv 23,30,,37

5-flurouracil 300mg/m2 iv 23,30, 37

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• Phase-2(week 10-15)drug dose days

Vincristine 1.5mg/m2 iv 1,8,15,22

Cyclophosphamide 500mg/m2 iv 2,9,16,23

5-flurouracil plus RT 300mg/m2 iv 2,9 ,16,23

Phase 3a(weeks 15-51)

drug dose days

Vincristine 1.5mg/m2 iv 1,22,29,36,43

Cyclophosphamide 500mg/m2 iv 23,30, 37, 44

5-flurouracil 300mg/m2 iv 23,30,37,44

Doxorubicin 75mg/m2 iv 2

To be repeated 4 times

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• Phase-3b(weeks 52-103)• To be repeated 6 times

drug dose days

Vincristine 1.5mg/m2 iv 1,22, 29, 36, 43

Cyclophosphamide 500mg/m2 iv 23,30,37,44

5-flurouracil 300mg/m2 iv 23,30,37,44

Dactinomycin 2mg/m2 iv 2

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MYELOMA

• Aim of RX.– Alleviating symptoms– Controlling advance of disease– Preventing complications– Palliative-relief from bony deposits,patho. #s &

spinal cord compression• Solitary lesion

– Aggressive RT• Disseminated lesion• -Rx. For symptomatic lesion• 40-50Gy in 4-5Wk

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• Chemo. Improves symptoms• Rib deposits

• 7Gy single fraction at ortho voltage

• Lower dorsal cervical spine & path. #s• 20Gy in 5 daily fractions over a week

– Spinal cord compression • 20-25 Gy at depth of cord 5 daily fractions over a

week

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General treatment recommendations for multiple myeloma

• The first decision made in the management of patients with myeloma who require systemic therapy is whether stem cell transplantation is part of the strategy

• In general, alkylator and nitrosourea therapy is deferred or reduced in patients who may require autologous stem cell collection to avoid injury to the stem cells

• A single autologous stem cell transplant has been associated with superior event-free survival compared with chemotherapy and is considered the preferred approach

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Primary therapy (transplant candidates)

• Patients who present with active (symptomatic) multiple myeloma are treated with induction therapy

• Alternative regimen: VAD REGIME

Pegylated liposomal doxorubicin 40 mg/m2plus vincristine 1.4 mg/m2 (maximum, 2.0 mg) as an IV infusion on day 1 plus  reduced-dose dexamethasone 40 mg PO on days 1-4

drugs dose days

Bortezomib  1.3 mg/m2  IVP  1, 4, 8

cyclophosphamide 300 mg/m2/day PO 1, 8, 15

 dexamethasone 40 mg PO daily  1-4, 9-12, and 17-20

28d cycle for 3-4 cycles

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Primary treatment (non-transplant candidates)

drug dose days

Melphalan 0.25 mg/kg PO  daily days 1-4;

prednisone 2 mg/kg  daily days 1-4;

thalidomide  200 mg PO daily days 1-4;

For every 6 weeks

Alternative treatment recommendations: VAD REGIME

Pegylated liposomal doxorubicin 40 mg/m2plus vincristine 1.4 mg/m2 (maximum, 2.0 mg) as an IV infusion on day 1 plus  reduced-dose dexamethasone 40 mg PO on days 1-4

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Treatment recommendations for maintenance therapyLenalidomide 10 mg/day on days 1-21 every 28d

Treatment recommendations for salvage therapy

used in patients who have relapse or primary progressive disease following stem cell transplant

• for the first 4 cycles of therapy and then 40 mg/day PO on days 1-4 thereafter, every 28d

drug dose days

Lenalidomide 25 mg/day PO  1-21

dexamethasone 40 mg/day PO  1-4, 9-12, and 17-20 

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METASTATIC BONE TUMOR

• MOST COMMON FORM• SKELETON ONE OF THE COMMONEST SITE• AXIAL SKELETON-MORE PRONE• APPENDICULAR SKELETON-RELATIVELY IMMUNE

(proximal femur metaphysis, proximal humerus)

• Essentially palliative• Aim

– Relieve symptoms-pain– Improve quality of life

• Symptomatic relief is satisfactory from RT and chemo

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• Systemic chemotherapy useful in high grade lesions of

• CHONDROSARCOMA• FIBROSARCOMA• LIPOSARCOMA• Malignant fibrous histiocytoma

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