basis of medical cancer therapy rebecca roylance senior lecturer in medical oncology

Basis of Medical Cancer Therapy

Rebecca Roylance

Senior Lecturer in Medical Oncology

Background

• Chemotherapy

• Radiotherapy

• Endocrine Therapy

• Biological Therapy

‘Ideal’ Cancer Treatment

• Highly efficacious

• Highly tumour specific

• Minimal toxicity

Chemotherapy

• Efficacious

90% cure occurs in only 10% of cancers

• Completely non-specific

• Marked toxicity

Historical Background

• 1940s alkylating agents were identified as by-product of secret gas production

marrow & lymphoid hypoplasia• Used leukaemia/lymphomas - pub 1946• Folic acid lead to proliferation of leukaemic

cells

antifolates e.g. methotrexate

Mechanism

• Principle of treatment - tumour growth fraction– Malignant cells do not divide more quickly

than normal cells– Bigger population of cells dividing

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Fractional Cell Kill Hypothesis

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Classes of Drug

• Alkylating agents• Platinum compounds• Anthracyclines• Antimicrotubule agents• Antimetabolites• Topoisomerase II inhibitors

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M

G2 G1

SMETHOTREXATE

HYDOXYUREA

CYTOSINE ARABINOSIDE

ANTHRACYCLINES

VINCA

ALKALOIDS

TAXANES

PHASE NON-SPECIFIC

Alkylating agents

Cisplatin

Nitrosoureas

Antibiotics

Alkylating agents

e.g. Cyclophosphamide• Covalently link to structures in nuclei acids

inter- or intra-DNA strand cross-linking

impairs DNA replication• More lethal if occurs during S-phase

Platinum Drugs

e.g. Cisplatin, carboplatin, oxaliplatin• Platinum drugs bind to DNA

intra-strand cross-linking predominantly• Conformational change in DNA - making

repair of the damage difficult

Anthracyclines

e.g. Doxorubicin, epirubicin, mitoxantrone• Bind tightly to DNA and deform its structure• Intercalate DNA causing single-stranded and

double stranded breaks• Produce intracellular free radicals - contribute

to toxicity

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Metaphase

Anaphase

Vinca alkaloidsprevent microtubuleassembly

Taxanes prevent microtubule disassembly

Mitotic block

Dihydrofolatereductase

Dihydrofolate(FH2)

Tetrahydrofolate(FH4)

Thymidinemonophosphate

Deoxyuridinemonophosphate

METHOTREXATEBlocks here

Folinic acidBypasses block

Combination Chemotherapy

• Only use if effective alone• Non-overlapping toxicity• Each drug used at optimal dose and schedule• Synergistic action• Different effects cell cycle

Uses of chemotherapy

• Cure– Induction– Adjuvant– Primary (neoadjuvant)

• Palliation

Neoadjuvant chemotherapy

Taken from Biology of Cancer

Clinical Trials

• Phase I - determine optimal dosage

• Phase II - assess tumour response

• Phase III - large randomised studies assess improvement in survival

Endocrine therapy

• Efficacious – Breast– Prostate

• Fairly specific• Minimal toxicity

Historical Background

• 1896 case report of oophorectomy in breast cancer by Beatson

• Postulated a link between ovaries and proliferation of breast cells

• 33 yr old women lump L breast• 12cm at presentation - breast removed but

cancer advanced oophorectomy

• pt survived for further 4 years

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Taken from BJC 2004 90(1) S2-6

Tamoxifen

• 1969 development of tamoxifen as a contraceptive

• SERM - selective oestrogen receptor modulator

• 1973 licenced for use in breast cancer

• 1980s clinical trials demonstrated a benefit in overall survival

Further Oestrogen modulation

• Aromatase inhibitors– Steroidal e.g. exemestane– Non-steroidal e.g. arimidex

• Anti-oestrogen e.g. fulvestant

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Mechanism of action of fulvestrant

Taken from BJC 2004 90(1) S2-6

Biological Therapy

• Efficacious– But less than expected, mechanisms not

fully understood• Specific• Minimal toxicity

• cf trastuzumab (herceptin)

Biological Therapy

• Monoclonal antibodies

• Small molecule inhibitors

HER2/ERBB2

• 1987 - amplified and overexpressed in 25-30% breast cancers

• Associated with poor prognosis• No natural ligand• Activation results in heterodimerisation• Many downstream substrates

FISH amplification of

HER2

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HER2 IHC

Trastuzumab (Herceptin®)

• Humanised monoclonal antibody to HER2 receptor

• Infusion related reaction - chills, fever, rash - rarely repeated

• Cardiac toxicity - especially if given in association with anthracyclines

• ?why - cross reactivity with cardiac muscle

Clinical trials - metastatic

• 2001 Phase III clinical trial showed in combination with chemotherapy in metastatic setting:

• Improved response rate 50% vs 32% (p<0.001)

• Decreased one year mortality 22 vs 33% (p=0.008)

Clinical trials - adjuvant

• 2006 - 4 trials >10000 women• Interim analysis resulted in stopping trials

early• Decreased risk of relapse - 50%• Survival advantage of 2.5%

NEJM 2005 353 1659-72 & 1673-84

Other targeted monoclonal antibody therapies

Target Drug UseVEFR Bevacizumab colorectalEGFR Cetuximab colorectalCD20 Retuximab B cell NHLCD52 Alemtuzumab CLL

HER2 Pertuzumab clinical trials

Small molecule therapy

Receptor Drug Use

KIT Imatinib (Gleevec) GIST

EGFR Erlotinib (Tarceva) NSCLC

Gefitinib (Iressa) NSCLC

HER1,2 Lapatinib Breast

RTK Sunitinib (Sutent) RCC

Imatinib (Gleevec)

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GIST

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Pre Post

Can understanding the basic biology of cancerimprove the treatment…..?

Copyright ©2001 by the National Academy of Sciences

Sorlie, Therese et al. (2001) Proc. Natl. Acad. Sci. USA 98, 10869-10874

The future

• Understanding the genetic pathways of cancer development

• Treatment will be tailored to individual patients

• Aim of making it much more effective and less toxic