Principles of chemotherapy
1. Introduction
Cancer = malignant neoplasm = class of diseases in which a group of cells
display
- Uncontrolled growth: division beyond the normal limits
- Invasion: intrusion on and destruction of adjacent tissues
- Sometimes metastasis: spread to other locations in the body via
lymph/blood
3 points important/needed to talk about malignant neoplasm
3 malignant properties of cancers differentiate them from benign tumors
which are self-limited and do not invade/metastasize
Benign tumors can also cause problems
- Meningioma’s: in the brain -> causes damage => life threatening
It is not because it is benign that there is no danger!!
Cancer
- Mutations can tell us about prognosis, cancer treatment, …
- Caused by abnormalities in the genetic material of the transformed cells
- These abnormalities may be due to the effects of carcinogens
o Tobacco smoke: over 70 known carcinogens
o Radiation: can provoke mutations in cells
o Chemicals – asbestos: can cause lung cancer
o Infectious agents - HPV: expect to lower HPV because of the
vaccines
- Other cancer promoting genetic abnormalities may occur random through
errors in DNA replication/inherited -> present in all cels from birth
1.1 Chemotherapy
- Affects cell division
- Tumours with high growth fractions -> more sensitive to CT because as a
larger proportion of the targeted cells are undergoing cell division at any
time
- Malignancies with slower growth rates tend to respond to CT much more
modestly -> tend to respond to CT with much more modest effects
- Ki67 marker given by pathologist -> if it is very high score => a lot of
differentiated cells = aggressive diseases
- Drugs affect younger tumors (=more differentiated) more effectively
because mechanisms regulating cell growth are usually still preserved
- Always need of a pathologist before talking about cancer => make the
diagnosis
- With succeeding generations of tumor cells -> differentiation is typically
lost -> growth less regulated + tumors less responsive to most CT agents
- All CT regimens require that the patient be capable of undergoing the
treatment
- Performance status often used as a measure to determine whether a
patient can receive CT or whether dose reduction required
1
, - Only a fraction of the cells in a tumor die with each treatment = fraction
kill => need of repeated doses administered to continue to reduce the
size of the tumor
- Current CT regimens apply drug treatment in cycles with the frequency +
duration of treatments limited by toxicity to the patient
- The dosage from phase I clinical trials based on the toxicity => that is how
they saw which dosage is the best!!
- ECOG performance status: in ideal situation you need 0/1 to give a
standard CT treatment
- Karnofsky scoring: developed mainly for clinical trials so everywhere
around the world they are speaking about the same things with %
o 100% = perfect health
o 0% = death
- GOAL
o Cure (testicular cancer)
o Prolong survival (metastatic breast cancer)
o Radiosensitization (head and neck cancer, cervical cancer)
Negative point: more side effects than CT
Patients with head an neck cancer get cetuximab (anti-EGFR)
through IV -> in clinical trials they saw a lot of necrosis but
radiation is really important for treatment so this is a
problem!!
o Palliation: for pain control in bone metastasised prostate cancer
- Cellular level of action – interaction with cell cycle: direct cell death
- Rapidly growing tumors: more sensible
o Small cell lung cancer: very aggressive tumors -> neuro-endocrine
tumor -> very sensitive to irradiation and CT -> if you cannot cure it,
they will react to palliative therapy => rapidly growing tumors is a
con but it can also be something positive for CT
Different schemes of CT depending on the cancer and patient
Hallmarks of cancer
- A set of functional capabilities acquired by human cells as they make their
way from normalcy to neoplastic growth states
- All situations that can lead to cancer
- Only be knowing these hallmarks and their mechanisms that a lot of
treatment comes from
1.2 Toxic chemotherapy – side effects
- Linked to mechanism of action
- Toxicity depends on
o Dosing and schedule: dose limiting toxicity (DLT)
o Patient: different from patient to patient
o Diseases
- Palliative patients always looking out for the quality of life <-> treatment
for cure we will always take an aggressive treatment with toxicity if it will
cure the patients and explain very well what will happen
- Not always related to the class of drugs
2
, - Combination therapy: different toxicity profiles of the different drugs,
sometimes difficult to judge which one is the cause
- Interactions with ADL (=activities of daily living)
- CTCAE TOX criteria: grading of the side effects (toxicity) developed for
clinical trials but also used in hospitals
- Side effects
o Infection, oral hygiene, nausea and vomiting
o Loss of appetite, change of taste, constipation and diarrhoea
o Sore mouth and throat, hair loss, fatigue, infertility and sex and
peripheral neuropathy
1.3 Toxicity chemotherapy – secondary leukemia
- After CT
- Secondary leukemia => bad prognosis
- FAB classification: categorizes AML into 7 distinct subtypes based on
morphology and phenotype – pathological
- Secondary to alkylating agents
o 5-7 years after R/
o First dysplastic syndrome
o FAB M1/M2 (classification leukemia)
o Chromosome alterations on chr5/7 in 60%-90%
- Secondary to topoisomerase II inhibitors
o 2-3 years after R/
o FAB M4/M5 (classification leukemia)
o Translocation chr11
2. Cellular kinetics
Daughter cells formed as a result of mitosis -> 3 subpopulations
1. Cells that are non-dividing and terminally differentiated
2. Cells that are continually proliferating
3. Cells that are resting but may be recruited into the cell cycle
All 3 populations exist simultaneously in tumors
Cell cycle specific (CCS) drugs
2.1 Cellular kinetics
- Agents that are cell-cycle-phase-nonspecific have a linear dose-response
curve
o The greater the dose of drug, the greater is the fraction of cell kill
- Cell-cylce-phase-specific drugs -> plateau with respect to cell killing ability
o Cell kill will not increase with further increase in drug dosage
2.2 Tumor kinetics
- Rate of growth of a tumor
o The proportion of actively dividing cells = growth fraction
o The length of the cell cycle = doubling time
o The rate of cell loss
- Sigmoid-shaped growth curve
o Tumor doubling time varies with tumor size (=with time)
3
1. Introduction
Cancer = malignant neoplasm = class of diseases in which a group of cells
display
- Uncontrolled growth: division beyond the normal limits
- Invasion: intrusion on and destruction of adjacent tissues
- Sometimes metastasis: spread to other locations in the body via
lymph/blood
3 points important/needed to talk about malignant neoplasm
3 malignant properties of cancers differentiate them from benign tumors
which are self-limited and do not invade/metastasize
Benign tumors can also cause problems
- Meningioma’s: in the brain -> causes damage => life threatening
It is not because it is benign that there is no danger!!
Cancer
- Mutations can tell us about prognosis, cancer treatment, …
- Caused by abnormalities in the genetic material of the transformed cells
- These abnormalities may be due to the effects of carcinogens
o Tobacco smoke: over 70 known carcinogens
o Radiation: can provoke mutations in cells
o Chemicals – asbestos: can cause lung cancer
o Infectious agents - HPV: expect to lower HPV because of the
vaccines
- Other cancer promoting genetic abnormalities may occur random through
errors in DNA replication/inherited -> present in all cels from birth
1.1 Chemotherapy
- Affects cell division
- Tumours with high growth fractions -> more sensitive to CT because as a
larger proportion of the targeted cells are undergoing cell division at any
time
- Malignancies with slower growth rates tend to respond to CT much more
modestly -> tend to respond to CT with much more modest effects
- Ki67 marker given by pathologist -> if it is very high score => a lot of
differentiated cells = aggressive diseases
- Drugs affect younger tumors (=more differentiated) more effectively
because mechanisms regulating cell growth are usually still preserved
- Always need of a pathologist before talking about cancer => make the
diagnosis
- With succeeding generations of tumor cells -> differentiation is typically
lost -> growth less regulated + tumors less responsive to most CT agents
- All CT regimens require that the patient be capable of undergoing the
treatment
- Performance status often used as a measure to determine whether a
patient can receive CT or whether dose reduction required
1
, - Only a fraction of the cells in a tumor die with each treatment = fraction
kill => need of repeated doses administered to continue to reduce the
size of the tumor
- Current CT regimens apply drug treatment in cycles with the frequency +
duration of treatments limited by toxicity to the patient
- The dosage from phase I clinical trials based on the toxicity => that is how
they saw which dosage is the best!!
- ECOG performance status: in ideal situation you need 0/1 to give a
standard CT treatment
- Karnofsky scoring: developed mainly for clinical trials so everywhere
around the world they are speaking about the same things with %
o 100% = perfect health
o 0% = death
- GOAL
o Cure (testicular cancer)
o Prolong survival (metastatic breast cancer)
o Radiosensitization (head and neck cancer, cervical cancer)
Negative point: more side effects than CT
Patients with head an neck cancer get cetuximab (anti-EGFR)
through IV -> in clinical trials they saw a lot of necrosis but
radiation is really important for treatment so this is a
problem!!
o Palliation: for pain control in bone metastasised prostate cancer
- Cellular level of action – interaction with cell cycle: direct cell death
- Rapidly growing tumors: more sensible
o Small cell lung cancer: very aggressive tumors -> neuro-endocrine
tumor -> very sensitive to irradiation and CT -> if you cannot cure it,
they will react to palliative therapy => rapidly growing tumors is a
con but it can also be something positive for CT
Different schemes of CT depending on the cancer and patient
Hallmarks of cancer
- A set of functional capabilities acquired by human cells as they make their
way from normalcy to neoplastic growth states
- All situations that can lead to cancer
- Only be knowing these hallmarks and their mechanisms that a lot of
treatment comes from
1.2 Toxic chemotherapy – side effects
- Linked to mechanism of action
- Toxicity depends on
o Dosing and schedule: dose limiting toxicity (DLT)
o Patient: different from patient to patient
o Diseases
- Palliative patients always looking out for the quality of life <-> treatment
for cure we will always take an aggressive treatment with toxicity if it will
cure the patients and explain very well what will happen
- Not always related to the class of drugs
2
, - Combination therapy: different toxicity profiles of the different drugs,
sometimes difficult to judge which one is the cause
- Interactions with ADL (=activities of daily living)
- CTCAE TOX criteria: grading of the side effects (toxicity) developed for
clinical trials but also used in hospitals
- Side effects
o Infection, oral hygiene, nausea and vomiting
o Loss of appetite, change of taste, constipation and diarrhoea
o Sore mouth and throat, hair loss, fatigue, infertility and sex and
peripheral neuropathy
1.3 Toxicity chemotherapy – secondary leukemia
- After CT
- Secondary leukemia => bad prognosis
- FAB classification: categorizes AML into 7 distinct subtypes based on
morphology and phenotype – pathological
- Secondary to alkylating agents
o 5-7 years after R/
o First dysplastic syndrome
o FAB M1/M2 (classification leukemia)
o Chromosome alterations on chr5/7 in 60%-90%
- Secondary to topoisomerase II inhibitors
o 2-3 years after R/
o FAB M4/M5 (classification leukemia)
o Translocation chr11
2. Cellular kinetics
Daughter cells formed as a result of mitosis -> 3 subpopulations
1. Cells that are non-dividing and terminally differentiated
2. Cells that are continually proliferating
3. Cells that are resting but may be recruited into the cell cycle
All 3 populations exist simultaneously in tumors
Cell cycle specific (CCS) drugs
2.1 Cellular kinetics
- Agents that are cell-cycle-phase-nonspecific have a linear dose-response
curve
o The greater the dose of drug, the greater is the fraction of cell kill
- Cell-cylce-phase-specific drugs -> plateau with respect to cell killing ability
o Cell kill will not increase with further increase in drug dosage
2.2 Tumor kinetics
- Rate of growth of a tumor
o The proportion of actively dividing cells = growth fraction
o The length of the cell cycle = doubling time
o The rate of cell loss
- Sigmoid-shaped growth curve
o Tumor doubling time varies with tumor size (=with time)
3
