basis of medical cancer therapy rebecca roylance senior lecturer in medical oncology
TRANSCRIPT
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
1012
1010
108
106
104
102
Time
Nu
mb
er
of c
ells
su
rviv
ing
M
T
Fractional Cell Kill Hypothesis
C C C CC
Classes of Drug
• Alkylating agents• Platinum compounds• Anthracyclines• Antimicrotubule agents• Antimetabolites• Topoisomerase II inhibitors
G0
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
Qu
ickTim
e™
an
d a
TIF
F (U
nco
mp
resse
d) d
ecom
pre
sso
rare
nee
de
d to
see th
is p
ictu
re.
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
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
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
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
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
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
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)
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
GIST
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
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