Chemotherapy

Sensitivity

 

High grade tumours often sensitive to intensive chemotherapy

- OS

- Ewings

- MFH

 

Low grade often insensitive 

- Chondrosarcoma

- Parosteal OS 

 

Role

 

1.  Eradication of overt & micrometastasis

- OS 80% have micrometastasis

 

2.  Reduce tumour locally 

- makes limb salvage easier

 

3.  Improve local control

- lesser role

- local control has no real impact on survival

 

Mode of Action

 

Interferes with synthesis of

- DNA

- RNA

- Protein

 

Action

 

Non-specific

- all cells

 

Cell Cycle-specific

- proliferating cells

 

Cell Phase-specific

- portion of proliferating cells

 

Types

 

1. Alkylating agents

- Cyclophosphomide

- Cisplatin

- Ifosfomide

 

2. Antitumoural Antibiotics

- Doxorubicin

- Bleomycin

 

3. Plant Alkaloids

- Vincristine

- Vinblastine

- VP-16 (Etoposide)

- Taxol

 

4. Antimetabolites

- Purine and Pyrimidine Antagonists

- Thioguanine & Mercaptopurine

- Cytarabine & 5-FU

- Methotrexate - Folate antagonist

 

Supportive therapy

 

Responsible for much of improvements in results

 

G-CSF 

- 175 amino acid glycopn 

- developed from E.coli recombinant DNA technology

- improves recovery by reducing neutropenic period

- neutropenia can be devastating in the more aggressive protocols

- G-CSF allows the dose to be increased further and achieve higher cell kill

 

Blood Products

- when needed 

- i.e. platelets

 

N 5-formyl-tetrahydrofolate

- MTX rescue

- following very high doses

 

Leucovarin 

- MTX rescue

 

Ondansetron 

- serotonin antagonist

 

Osteosarcoma Protocol

 

MACI pre op + G-CSF support

 

MTX

- high dose

- can see dramatic response

- blocks conversion folate ->tetrahydrofolate

- can cause renal failure

- alkylate urine and hydrate +++

- leucovorin rescue

- otherwise die very quickly

- doesn't suppress bone marrow to any great degree so use after an alkylating agent

- side effects related to levels

- mucositis and ulcers / pleuritis / conjunctivitis / hepatic and renal failure

 

Adriamycin

 

Cisplatin  

- standard drug for OS

- alkylating agent 

- direct DNA damage

- SE - emesis, renal and ototoxic

 

Ifosfamide

- new generation alkylating agent

- single most effective agent against sarcoma

- activated by hepatic P450 system

 

Timing

 

Adjuvant (Postoperative)

 

Neoadjuvant (Preoperative)

 

Standard strategy is neoadjuvant

- allows assessment of response early in disease

- restaging investigations after neoadjuvant chemotherapy

- imaging, histology

 

Advantage

- improves limb salvage

- allows planning of surgery

- re-stage after chemo

- prognostic

 

Efficacy 

 

Measured by extent of tumour necrosis

- good response is > 90% necrosis

- poor response is < 90% necrosis

- response is best prognostic factor

 

Rosen in vivo response dictates outcome

- Grade 1 = no cell death

- Grade 2 = partial <90%

- Grade 3 = necrosis >90%

- Grade 4 = complete necrosis

 

1 & 2 < 50% survival

3 & 4 > 75% long term survival in OS and MFH

 

Using Cisplatin, Doxorubicin, MTX

 

Resistance 

 

Tumour cells develop cell membrane pumps to expel chemotherapy

 

Side-Effects

 

A.  Proliferating tissues

 

Most commonly

- bone marrrow

- oral & GIT epithelium

 

Effects are

- myelosuppression

- stomatitis

- mucositis

- N & V

- anorexia

- infertility

- hair loss

 

All males store semen prior to chemotherapy

Females consider egg retrieval

 

B.  Non-Proliferating Tissues

 

Less predictable effects

 

1.  Pneumonitis & Pulmonary fibrosis 2° Bleomycin

(blasts the lungs)

 

2.  Cystitis 2° Cyclophosphamide

(cills the kidneys)

 

3.  Nephrotoxicity 2° MTX & Cisplatin

 

4.  Cardiotoxicity 2° Doxorubicin

(death to the heart)

 

5.  Neurotoxicity 2° Cisplatin & Vincristine

 

Adverse effects on Surgery

 

Systemic

- neutropenia

- thrombocytopenia

- coagulopathy

 

Local

- cytotoxicity to tissue

- wound complications

- delayed bone healing

 

Results

 

Osteosarcoma

 

Improved 5 year survival from 20 - 80%

- improved ability limb salvage OT

- multi-agent treatment

- Rosen T10 protocol (MAC CAB)

- Methotrexate / Adriamycin / Cyclophosphamide / Cis-Platin / Actinomycin-D / Bleomycin

 

Pre-operatively

- 2 / 12 months

- 3 cycles 2 weeks apart

 

Restage disease

- repeat MRI

- may repeat CT Chest / Abdo & bone scan

 

Surgery

 

Post-operatively

- regimen continued for further 6-12/12

 

Ewing's Sarcoma

 

Previous treatment was surgery or radiotherapy

- dismal outlook

- < 15% 5 year survival

 

Combination with chemotherapy gives much better results

- 50% 5 year disease-free survival

- 70% 5 year overall survival

- 30% 5 year if present with metastasis

 

Multiagent neoadjuvant chemotherapy

- 3/52

- Vincristine / Actinomycin D / Cyclophosphamide / Adriamycin

- alternating with 3/52 of Iphosphamide / VP-16

 

Surgery performed when estimated that maximal response achieved

- usually at 3-4 /12

 

Malignant Fibrous Histiocytoma

 

Mainstay of treatment is resection

- multiagent neoadjuvant chemotherapy improves 5 year survival from 50% - 75%

 

Chondrosarcoma

 

Primary treatment is surgery as tumour resistant to chemotherapy

- occasionally used for palliation but effects unclear

- hormonal agents may be effective

- i.e. HGH, somatomedin

 

Childhood Rhabdomyosarcoma

 

Improved survival from 20% to 60% 5 year

- much poorer for metastatic disease

 

Adult Soft Tissue Sarcomas

 

Treat as one disease

- controversial

- no clear evidence of long-term efficacy with chemotherapy

- exception is MFH and synovial sarcoma