Principles of chemotherapy

Ann De Becker

Klinische Hematologie

UZ Brussel

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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

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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

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Log Kill Model

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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

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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

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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

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Chemotherapy classes

Antimetabolites:

Substitute for normal building block

S-phase

cladribine

cytarabine

fludarabine

gemcitabine

hydroxyurea

5-FU

6-MP

metotrexate (antifolate)

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Chemotherapy classes

Antitumoral antibiotics:

Anthracyclines:

topo II inhibitor, DNA intercalation

Non phase specific

daunorubicin, doxorubicin, epirubicin, idarubicin

Other:

bleomycin

mitoxantrone

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Chemotherapy classes

Topoisomerase inhibitors:

Topoisomerase I inhibitors:

topotecan, irinotecan

Topoisomerase II inhibitors:

etoposide (VP16), teniposide

Platinum derivatives:

cisplatinum

carboplatinum

oxaliplatinum

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Chemotherapy classes

Mitotic inhibitors

Metaphase arrest, chromosomal damage,

microtubule disruption

Taxanes:

paclitaxel, docetaxel

Vinca alkaloids:

vinblastine, vincristine, vinorelbine

Miscellaneous:

L-asparaginase

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Chemotherapy and cell cycle

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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)

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Chemotherapy: general principles

Remission-induction

Consolidation

Combination chemotherapy

Different mode of action

Different toxicity profile

Different resistance mechanisms

Maximize chance of lasting remission/cure

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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

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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

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Cytarabine: toxicity

Myelosuppression

Stomatitis

Conjunctivitis

Hand-foot syndrome

CNS:

Cerebellar syndrome

Onset 3-8 days after initiation of high dose

Dysarthria, dysdiadochokinesia, dysmetria,

ataxia

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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

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Cyclophosphamide: toxicity

Myelosuppression

Hemorrhagic cystitis

acrolein metabolite, onset 24h to several

weeks

high dose

hydration!

Mesna

bladder irrigation

Alopecia

SIADH

Cardiotoxicity (high dose)

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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

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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

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Cisplatinum

Platinum derivative/alkylating agent

Cross linking DNA

IV administration

Lymphoma (DHAP)

Toxicity:

Myelosuppression

Ototoxicity

High frequency hearing loss

Usually irreversible

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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

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Specific toxicities

Anthracyclines:

Cardiotoxicity

Bleomycin:

Hypersensitivity

Pulmonary toxicity

Vinca alkaloids:

Peripheral

neuropathy

Busulphan

Hepatic (VOD)

L asparaginase:

Coagulation

Hypersensitivity

Pancreatitis

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Response assessment Hematology

Disease specific

Laboratory evaluation (blood, marrow)

Molecular analysis, cytogenetics

Imaging: (PET-)CT / MRI

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Response assessment Oncology

Disease specific

Integration of PET-CT

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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

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Chemotherapy resistance mechanisms

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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

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Future perspectives: targeted therapy

Tyrosine kinase inhibitors

Bcr-abl: imatinib, dasatinib, nilotinib, bosutinib

Flt3 inhibitors

Bruton kinase inhibitors

ibrutinib

Monoclonal antibodies

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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

…

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Future perspectives: personalized

therapy?

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