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Principles of chemotherapy
Ann De Becker
Klinische Hematologie
UZ Brussel
2 30-4-2014
History
Paul Ehrlich (1854-1915)
1909 Arsphenamine for syphilis treatment
Definition:
Use of any drug to cure any disease
Antineoplastic/cytotoxic treatment
Origin in warfare
Mustard gas in WW II: pancytopenia
First trial reported in sept 1946:
Nitrogen mustard therapy for Hodgkin’s disease,
lymphosarcoma, leukemia and certain allied and
miscellaneous disorders – Goodman & Gilman
Chemotherapy: goal
Attacks tumour at cellular level
Interference with cellular replication
impact on one/several phases of cell cycle
Chemotherapy use:
Cure
Palliate
Adjuvant
Neo-adjuvant
3 30-4-2014
The cell cycle
5 phases:
G0: resting phase (hours-days)
G1: preparation for DNA synthesis (18-30h)
S: generation of complete copy of
genetic material (18-20h)
G2: cell prepares for mitosis (2-10h)
M: mitosis, cell splits in 2 (30-60 min)
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The cell cycle
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Growth fraction:
# proliferating cells
# G0 cells
Higher growth fraction =
higher chemosensitivity
Cancer cell kinetics – Log Kill
Howard E Skipper: tumour models –
mouse L1210 leukemia model
Skipper-Schabel-Wilcox model: a given
dose of a given drug will kill the same
percentage not the same number of
cancer cells = Log Kill Model
Log Kill Model assumes exponential
growth of tumour
e.g. leukemia
6 30-4-2014
Log Kill Model
7 30-4-2014
Cancer cell kinetics: other models
Exponential cancer cell growth:
Delbrück-Luria
Bacterial growth/resistance
Resistent clone within tumor
Combination chemotherapy
Goldie – Coldman
Multiple drug resistance within tumour
Sequential administration of different
chemotherapeutic drugs
8 30-4-2014
Cancer cell kinetics: other models
Gompertzian model:
Tumour growth pattern not explained by
dormancy+exponential cell growth
Solid tumours
Doubling time increases with tumour growth
Homeostatic model: target size, when reached
slower growth en less chemosensitive, when
small rapid growth to reach target size and
more chemosensitive
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Drug development
Screening / selection of molecules,
substances candidate for drug
development
Preclinical development (≈ 5y)
Clinical development (≈ 5y)
Phase I: dose finding, pharmacokinetics,
effect on biological target, antitumour activity
Phase II: antitumour activity, effect on
biological target, dose-response, toxicity
Phase III: therapeutic benefit, risk/benefit
ratio
10 30-4-2014
Chemotherapy classes
Alkylating agents:
Direct DNA damage, non phase specific
Nitrogen mustards:
chlorambucil, cyclofosfamide, ifosfamide,
melphalan
Nitrosureas:
carmustine (BCNU)
Alkyl sulfonates:
busulphan
Triazines:
dacarbazine
Ethylenimines:
thiotepa
11 30-4-2014
Chemotherapy classes
Antimetabolites:
Substitute for normal building block
S-phase
cladribine
cytarabine
fludarabine
gemcitabine
hydroxyurea
5-FU
6-MP
metotrexate (antifolate)
12 30-4-2014
Chemotherapy classes
Antitumoral antibiotics:
Anthracyclines:
topo II inhibitor, DNA intercalation
Non phase specific
daunorubicin, doxorubicin, epirubicin, idarubicin
Other:
bleomycin
mitoxantrone
13 30-4-2014
Chemotherapy classes
Topoisomerase inhibitors:
Topoisomerase I inhibitors:
topotecan, irinotecan
Topoisomerase II inhibitors:
etoposide (VP16), teniposide
Platinum derivatives:
cisplatinum
carboplatinum
oxaliplatinum
14 30-4-2014
Chemotherapy classes
Mitotic inhibitors
Metaphase arrest, chromosomal damage,
microtubule disruption
Taxanes:
paclitaxel, docetaxel
Vinca alkaloids:
vinblastine, vincristine, vinorelbine
Miscellaneous:
L-asparaginase
15 30-4-2014
Chemotherapy and cell cycle
16 30-4-2014
Chemotherapy: administration
Intravenous
Per os
Intrathecal
Lumbar puncture
Ommaya reservoir
Intra-arterial
Intraperitoneal
Topical
Subcutaneaous
Intramuscular
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Chemotherapy dosage
Weight
Body surface area (BSA)
18 30-4-2014
Chemotherapy: general principles
Remission-induction
Consolidation
Combination chemotherapy
Different mode of action
Different toxicity profile
Different resistance mechanisms
Maximize chance of lasting remission/cure
19 30-4-2014
Chemotherapy: common toxicities
Nausea, vomiting
Infertility
Myelosuppression
Mucositis, diarrhea
Alopecia
Secondary tumours/leukemias
Alkylating agents
After 5-7 years, preceding MDS
Topoisomerase II inhibitors
After 2-3 years
20 30-4-2014
Cytarabine
Purine analogue
cell cycle phase specific
IV or IT administration
Corner stone of AML treatment
Activity in other hemato malignancies
Penetration in CSF after IV infusion
CSF levels 40-50% of plasma level
High dose (2-3g/m²) can overcome
cellular resistance by altering transport
of drug into the cell
21 30-4-2014
Cytarabine: toxicity
Myelosuppression
Stomatitis
Conjunctivitis
Hand-foot syndrome
CNS:
Cerebellar syndrome
Onset 3-8 days after initiation of high dose
Dysarthria, dysdiadochokinesia, dysmetria,
ataxia
22 30-4-2014
Cyclophosphamide
Alkylating agent
Formation of mustards following metabolic
activation
Cross linking of DNA strands
(non Hodgkin’s) Lymphoma
High dose:
Stem cell mobilisation
Conditioning HCT
IV/PO administration
23 30-4-2014
Cyclophosphamide: toxicity
Myelosuppression
Hemorrhagic cystitis
acrolein metabolite, onset 24h to several
weeks
high dose
hydration!
Mesna
bladder irrigation
Alopecia
SIADH
Cardiotoxicity (high dose)
24 30-4-2014
Metotrexate
Antifolate
Cell cycle specific (S phase)
IV or IT (12-15mg) or PO administration
High dose IV penetrates in CSF
CNS prophylaxis
Lymphoma/leukemia
Folinic acid rescue when high dose MTX
Start 24h after MTX administration
Until MTX levels < 0,05 µM/L
IV dose = PO dose
25 30-4-2014
Metotrexate: toxicity
Myelosuppression
Mucositis
Renal
cytotoxicity tubular cells
alkalinize urine (pH>7)
hydration!
Hepatic
Neurotoxicity (IT)
arachnoiditis, paralysis, seizures, coma
Pulmonary (rare)
fever, dry cough, chest pain R/corticosteroids
26 30-4-2014
Cisplatinum
Platinum derivative/alkylating agent
Cross linking DNA
IV administration
Lymphoma (DHAP)
Toxicity:
Myelosuppression
Ototoxicity
High frequency hearing loss
Usually irreversible
27 30-4-2014
Cisplatinum: toxicity
Neurologic
Peripheral neuropathy, autonomic neuropathy
Incomplete recovery
Renal
Usually reversible
Preventive measures:
Infuse over 24h
Hydration (NaCl 0,9%)!
Follow urine output (furosemide)
Avoid other nephrotoxic drugs
28 30-4-2014
Specific toxicities
Anthracyclines:
Cardiotoxicity
Bleomycin:
Hypersensitivity
Pulmonary toxicity
Vinca alkaloids:
Peripheral
neuropathy
Busulphan
Hepatic (VOD)
L asparaginase:
Coagulation
Hypersensitivity
Pancreatitis
29 30-4-2014
Response assessment Hematology
Disease specific
Laboratory evaluation (blood, marrow)
Molecular analysis, cytogenetics
Imaging: (PET-)CT / MRI
30 30-4-2014
Response assessment Oncology
Disease specific
Integration of PET-CT
31 30-4-2014
Chemotherapy resistance
Response to initial treatment?
Primary chemoresistance
Acquired chemoresistance
Multidrug resistance (MDR)
Origin of resistant cells:
Cancer stem cells
Diverge from normal tissue stem cells
Natural quiescent state
Environment mediated drug resistance
Acquisition of quiescence
Genetic changes => permanent resistance
Alter tumour microenvironment
32 30-4-2014
Chemotherapy resistance mechanisms
33 30-4-2014
Overcoming chemotherapy resistance
Different class agent
High dose therapy
Combination chemotherapy
MDR:
P-glycoprotein overexpression
Efflux pump (anthracyclines, taxanes, vinca-
alkaloids)
Verapamil/CSA & other => no benefit in trials
Nanomedicine: liposomes/nanoparticles
New generation drugs evading P-gp
miRNA
34 30-4-2014
Future perspectives: targeted therapy
Tyrosine kinase inhibitors
Bcr-abl: imatinib, dasatinib, nilotinib, bosutinib
Flt3 inhibitors
Bruton kinase inhibitors
ibrutinib
Monoclonal antibodies
35 30-4-2014
CD20 rituximab, ofatumumab, ibritumomab (+Yttrium 90)
CD30 brentuximab (+vedotin)
CD133 gemtuzumab (+ozogamycin)
CD19 blinatumomab
CD38 daratumumab
CS1 elotuzumab
Future perspectives: targeted therapy
IMiDs
thalidomide, lenalidomide, pomalidomide
Proteasome inhibitors
bortezomib, carfilzomib
Epigenetic modulators
5-azacytidine, deoxycytidine
Panobinostat, vorinostat
Vaccination:
DC vaccination
…
36 30-4-2014
Future perspectives: personalized
therapy?
37 30-4-2014
38 30-4-2014