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See slides from Robin

What is Chemotherapy

  • Objectives:
    1. To outline concepts of cytokinetics and cell cycle, pharmacokinetics and pharmacodynamics.
    2. To outline concepts of strategies of chemotherapy delivery eg combination chemotherapy and sequencing
    3. To introduce the concept of drug resistance

Normal vs malignant cell??

  • “Normal” cells age and die, via processes known as cell senescence and apoptosis.
  • Malignant cells are “immortal” and often have defects in apoptosis, and require chemotherapy to interfere with DNA replication and mitosis in order to inhibit growth of the neoplasm.

Types of Malignant Cells

  • Malignancies : composed of cells of 3 types:
    1. Actively Dividing Cancer Cell
    2. Resting Cell with potential to divide
    3. Non-dividing cell that has lost the potential for replication
  • Q&A. The actively dividing malignant cell constitutes the smallest cellular component of most tumours

Actively dividing malignant cell

  • These actively dividing cells undergo many complex metabolic processes to facilitate division
  • Interference with any of these steps may lead to cell death.
  • The use of chemotherapy attempts to antagonise or disrupt one or more of these steps in the actively dividing cell.
  • With so many metabolic targets to attack, the actively dividing malignant cell is the most drug sensitive component of a neoplasm.

Barriers to successful chemotherapy

  • Unfortunately, normal cells in the body are also dividing and undergoing these same metabolic steps.
  • Drugs directed toward the malignant dividing cell may also affect normal dividing tissue.
  • Normal tissues with a significant component of actively dividing cells are also susceptible to the effects of cytotoxic chemotherapy
  • Q&A. The following normal tissues have significant components of actively dividing cells and is/are susceptible to the side effects of cytotoxic chemotherapy: Bone marrow, GI mucosa, Hair
    • Reduction of bone marrow to below 10% of normal values can cause the death of the patient. If levels get low, bone marrow transplant/transfusion can be used (usually obtained from stem cells of patient themselves or a close relative)

Tumour Growth Model

  • Tumours are said to follow a Gompertzian model of growth.
  • The GOMPERTZIAN model of Tumour Growth predicts that the larger the tumour, the smaller the proportion of its cells that are actively dividing.
  • Therefore, larger tumours are more resistant than smaller tumours, to drugs directed at dividing cancer cells.
  • One important principle of cytotoxic drug delivery is to start treatment early, when there is a lower bulk of disease,with a larger proportion of cells that are actively dividing and “in-cycle”.
  • Also, smaller tumours have fewer cells, and are therefore less likely to have cells with mutations that make them drug resistant.

The resting malignant cell

  • The second type of cell accounting for a significant component of a neoplasm is the resting malignant cell, which has the potential to divide, but is not doing so at that moment.
  • These cells use fewer metabolic processes and therefore offer fewer targets for cytotoxic drugs.
  • Resting Malignant cells are classically considered to be more resistant to chemotherapy.

The resting malignant cell

  • Drugs that kill these resting malignant cells must either effect common metabolic processes or damage the structure of basic cellular components.
  • Q&A. Drugs capable of killing resting malignant cells are likely to have more widespread toxicity to normal tissues?

The non-dividing malignant cell

  • Finally, all malignancies contain a component of neoplastic cells that have lost the ability to divide.
  • eg mature-appearing granulocytes in patients with Chronic Myeloid Leukaemia (CML)
  • or malignant cells that are dead or dying.
  • These non-dividing cells, together with nonmalignant stromal or support cells, constitute most of the mass of a tumour
  • These non-dividing cells can cause symptoms due to their bulk, for example by pressure
  • they are not as dangerous as other cancer cells, because they are not growing, invading or spreading.
  • Non-dividing cancer cells are not a major target of cytotoxic chemotherapy

The CELL CYCLE

  • The “cell cycle” model has provided a theoretical basis for drug therapy aimed at cancer cells that are dividing or retain the ability to divide.
  • The ‘cell-cycle’ model describes all human cells as going through an orderly series of stages or ‘phases’ during replication.

Cellcycle.PNG

The proliferative state of the cell

  • All malignant cells with the ability to divide are in one of these phases outlined.
  • Non-dividing cells with the potential to divide are considered to be resting in G0, which is in equilibrium with the actively cycling cells
  • The length of time a cell stays in G0 (the resting state), and the length of time it takes to move through the cell cycle, define the “proliferative state” of the cell.
  • A short resting stage and a brief time needed to pass through the cycle indicate a rapidly proliferating cell.
  • In contrast, a long G0 and a long time to pass through the cell cycle imply a very slowly proliferating cell.
  • This model helps us think about 3 general properties of anti-tumour drugs: cell cycle dependency, phase specificity, and proliferation dependence.

Cell cycle dependency

  • Some drugs only kill cells that are actively dividing, ie. cells that are in the ‘cell-cycle’ and not those in G0. These drugs are considered to be cycle-dependent.
    • e.g. Antimetabolites (like hydroxyurea) interfere with DNA synthesis which is necessary for cell division.
  • Agents that kill dividing cells (in the cellcycle) and resting cells (in G0) are considered to be cycle-independent.
    • e.g. Alkylators (like cyclophosphamide) damage existing DNA and interfere with cellular function.

Phase Specificity

  • Some cytotoxic drugs are most active against cells in particular phases of the cell cycle.
    • eg. Ara-C (cytarabine), which must be incorporated into DNA to be active and only kills cells that are in the process of DNA synthesis, S phase, when the drug is administered.
  • Some drugs that are cycle-dependent are not phase–specific, i.e. the drug will work when the cell is in the cell-cycle, but it doesn’t matter what phase the cell is in when the drug is given.
  • Q&A: Some cycle-independent drugs may be phase specific.
    • Eg. actinomycin D (a cycle-independent drug), binds to and damages DNA regardless of whether the cell is dividing or not, but the lethal consequences of the binding are specific to those cells in G2 phase.

Proliferation Dependence

  • Proliferation-dependent drugs are most active against the cells dividing fastest: cells that spend the shortest time in G0, and take the least time to divide.
  • Surprisingly, proliferation-dependent drugs include some that are cycle-dependent eg. hydroxyurea) and some that are cycle–independent (eg. cyclophosphamide).
  • Proliferation-independent drugs, which kill both rapidly-dividing cells and slowlydividing cells, can also include drugs that are either cycle-dependent (eg. 5-fluorouracil), or cycle-independent (eg. nitrogen mustard).

Cytokinetics in action

  • A knowledge of cytokinetics helps researchers predict which drugs will be active in which tumours and how best to administer them.

Long infusion vs short infusion

  • Prolonged administrations of low doses make sense for phase-specific drugs being used in slowly proliferating tumours.
  • This will maximise the number of the cells exposed to the drug in the most sensitive phase of cell-cycle.

Drug sequencing

  • If several drugs are being used together, what is the best order to give them in?
  • A frequently used approach is to start with cell cycle–independent drugs that damage tumour cells regardless of whether they are dividing.
  • Cycle-dependent drugs can then be given a few days or weeks later, when the remaining tumour cells are repairing the damage caused by the first lot of drugs.
  • This repair process requires DNA synthesis and cell division, which renders the remaining cells susceptible to cycle-dependent drugs
  • The ideal time for the next dose of chemotherapy is when the normal cells have recovered, but the tumour cells have not.

The limitations of the Cytokinetic Model

  • The cytokinetic model is useful to characterise cancers and drugs.
  • However, it does not take into account the biology of the patient in whom the actual cancer resides and the biology of the specific drug in that patient.
  • That is where pharmacokinetics comes in

Pharmakokinetics

  • What is it?
    • It is the measurement of drug parameters in a patient after administration in a specific dose, route, and schedule.
  • A pharmacokinetic study typically involves measurements of drug and metabolite concentrations in plasma and urine.
  • Pharmacologists use these measurements to work out the routes and patterns of drug metabolism and clearance.
  • The initial half-life of a drug is how long it takes the plasma concentration to fall by 50% from its peak level.
  • Most of this fall is usually due to re-distribution from the plasma to other compartments, not metabolism, elimination or excretion.
  • The terminal half-life is usually due to drug metabolism, elimination, and excretion from the body.
  • These measurements help determine how a drug is handled within the body and what effect organ dysfunction or other drugs may have on its metabolism and effects

Pharmacokinetics vs Pharmacodynamics

  • Pharmacokinetics does not predict anti-tumour effects or toxicity
  • this is what pharmacodynamics does.
  • Pharmacodynamics is the discipline that links drug pharmacokinetics with cytokinetics and cytotoxicity in both tumour and normal tissues.

Pharmacodynamics- AUC

  • The AUC is the area under the curve of drug concentration versus time since administration.
  • The AUC is usually estimated by taking serial blood samples after giving the drug and measuring how its plasma concentration falls.
  • For some well-characterised drugs in normal patients, the AUC and pattern of clearance can be estimated with fewer samples. eg, limited sampling at 1 or a few time points may be sufficient.
  • For drugs with very predictable renal excretion, the AUC can be estimated accurately without measuring drug concentrations: knowing the drug dose, patient surface area, and creatinine clearance are sufficient to estimate the AUC

AUC

  • Some cytotoxic drugs that have toxicity/cytotoxicity directly related to the AUC.
  • eg Carboplatin, Busulphan
  • Carboplatin-related thrombocytopenia can be predicted by AUC, and drug dose accordingly calculated.
  • Busulphan hepatotoxicity also correlates with

AUC

Total dose in mg (not mg/m^2) = Target AUC x (GFR + 25)

  • The GFR can either be measured directly eg from a 24-hour urine collection or from a nuclear medicine Technetium study, or it can be estimated with the Cockcroft- Gault Formula
  • Most cytotoxic drugs follow first order kinetics i.e. given dose of given drug kills a fixed proportion of the sensitive cells, not a fixed number of cells.
  • For example, if a given dose kills 99% of cells, then a typical 1 cm^3 tumour containing 10^9 cells would be reduced by 99% to 10^7 cells (i.e. 1% of 10^9). We would expect the next dose to reduce the number of cells from 10^7 cells to 10^5 cells, and the next dose from 10^5 to 10^3 cells.
  • Thus, in its simplest form, a therapeutic plan could be to give successive doses until the tumour has disappeared.

Case 1

  • 46 year old woman
  • Lumpectomy 3cm tumour
  • Node positive (3/18 nodes)
  • All visible tumour has been removed
  • Surgical margins clear
  • Does she warrant chemotherapy?
    • Yes, adjuvant chemotherapy, curative intent

Adjuvant Chemotherapy

  • Many cancers recur despite optimal surgery. This is because of micrometastatic disease that has spread before the primary cancer was eradicated.
  • The aim of post-operative adjuvant chemotherapy is to improve cure rates, recurrence rates and overall survival.
  • Adjuvant chemotherapy is well-established for early breast cancer, NSCLC and early colorectal cancer.Becoming more commonly offered for bladder cancer

Case 2

  • 58yr old man
  • Stage 3A Lung Cancer
  • Technically difficult to operate
  • What should he receive?
    • Chemoradiation, with curative intent
      • well-established for treating locally advanced Head & Neck cancers. This approach is also used in locally advanced lung cancer.

Case 3

  • 42 year old woman
  • Large inflammatory breast cancer
  • Technically difficult to resect
  • What should happen first?
    • Neoadjuvant chemotherapy

Neoadjuvant Chemotherapy

  • Neo-adjuvant chemotherapy is commonly used for women with locally advanced breast cancer.
  • Giving chemotherapy first may also facilitate less mutilating surgery to be done eg for soft-tissue sarcomas and laryngeal cancer.

Case 4

  • 35 yr old woman
  • Stage III cervix cancer
  • Uterus in-situ
  • Receives a small amount of wkly cisplatin during her radiation course
  • (an amount not cytotoxic in its own right)
  • RADIOSENSITIZING CHEMOTHERAPY
  • eg Chemotherapy being used as a radiosensitizer. For example weekly cisplatin increases the effectiveness of radiation therapy for cervix cancer

Case 5

  • 22yr old man
  • Metastatic non-seminoma (testicular cancer)
  • Lung, liver, lymph node,brain mets
  • Is he curable?
    • Yes, primary chemo is curative in itself. Might resect testis/other sanctuary sites

Case 6

  • 67yr old man
  • Pancreatic cancer with multiple liver metastases,significant pain, still has good performance status
  • Is this curable?
    • No
  • Should he receive chemotherapy?
    • Yes, palliative intent

Palliative chemotherapy

  • The goals of palliative chemotherapy are to improve length and quality of life, by shrinking the tumour, but without realistic hope of cure.
  • Chemotherapy for most metastatic solid tumours is palliative
  • Eg- capecitabine for metastatic colon cancer; mitoxantrone or docetaxel for hormone-refractory advanced prostate cancer; and gemcitabine for advanced pancreatic cancer

Types of Chemotherapy Agents

  • Antimetabolites
  • Natural products (antimicrotubule agents and epipodophyllotoxins)
  • Alkylating Agents
  • Antitumour Antibiotics

Antimetabolites

  • Mechanism of Action: These drugs are S phase specific and inhibit DNA or RNA synthesis by interfering with purine or pyrimidine synthesis.
  • Cytarabine
  • Fludarabine
  • Hydroxyurea
  • 6-mercaptopurine
  • 6-Thioguanine
  • Methotrexate
  • 5-Fluorouracil
  • Floxuridine
  • Capecitabine
  • Gemcitabine

"Natural” Products

  • Mitosis Inhibitors:(e.g. the vinca alkaloids)
  • Mechanisms of Action: These drugs bind to tubulin preventing polymerisation to form microtubules, and cause interruption of the mitotic spindle and transport function in nerves. These drugs are often labelled spindle poisons.
  • Vinca Alkaloids affect mitosis (i.e. are M-phase specific). In contrast to the antimetabolites, they are not analogues of normal metabolic intermediates. Structurally, they are composed of two multi-ring units (vindolene and catharanthine), linked together by a carbon bridge.
  • Topoisomerase I inhibitors:(e.g. the camptothecin derivatives)
    • Mechanisms of Action: These are S-phase specific drugs. Topoisomerase is an enzyme that relaxes supercoiled DNA to allow the process of replication to begin by inducing a strand break, uncoiling and then repair of the break. Inhibitors bind to the enzymes stabilising the strand break and arresting DNA replication.
  • Camptothecin Derivatives
    • Topotecan
    • Irinotecan

Alkylating agents

  • Mechanism of Action:
  • Alkylating agents induce cross-linking of DNA and single strand breaks by covalent linking of reactive metabolites that are electron deficient.
  • They are generally phase-specific (G2/M and G1/S).
  • Eg.
    • Mechlorethamine (Nitrogen Mustard)
    • Oxazaphosphorines
      • Cyclophosphamide
      • Ifosfamide
    • Melphalan (L-PAM)
    • Chlorambucil

Antitumour Antibiotics

  • Mechanism of Action : acts as an intercalating agent which binds with DNA to block RNA production.
  • Antitumour antibiotics include:
    • Bleomycin
    • Anthracyclines: Doxorubicin (Adriamycin)
    • Daunorubicin
    • Idarubicin
    • Mitoxantrone
    • Dactinomycin (Actinomycin D)
    • Plicamycin

Combination Chemotherapy

  • The use of cancer chemotherapeutic agents in combination is well established.
  • The knowledge of cell kinetics and the pharmacology of antitumour agents have allowed the researchers to develop combinations that maximise tumour cell kill and minimise toxicity.
  • The basic principles are to use:
    • agents that are active,
    • in doses as close as possible to those used in single-agent therapy
    • agents with different mechanisms of action
    • agents with different or minimal overlapping toxicities
  • Disadvantages:
    • Increased toxicity
    • Increased cost
    • difficulty giving adequate doses of each drug
    • drug interactions
  • Q&A: Which solid tumours are curable with systemic cytotoxic therapy?
    • Germ cell tumours
    • Hodgkin’s disease
    • Non-Hodgkin’s Lymphoma
    • Trophoblastic Tumours
  • Which solid tumours are highly responsive to chemotherapy? (higher than 50% response rate)
    • Breast cancer
    • Ovarian cancer
    • Small cell lung cancer
    • Head and Neck Cancer
    • Urothelial cancer

New notes

  • People are living longer with cancer
  • Rehab benefits cancer patients, slowing catabolism
  • Metastasis: go from original site to somewhere else
    • Can be many years later: they look like they've been cured, but then the cancer appears years later
  • Need to consider how much QoL is lost by being on chemotherapy for a long time
  • Except lymphoma and some germ cell tumours (e.g. testicular cancer), if a cancer has left its primary site it means you will die - it will chase after you
  • Patterns in metastasis are changing with time. E.g. breast cancer now spreads to the brain because chemotherapy is very effective but doesn't cross the BBB
  • Peritoneal seeding is becoming quite common due to
    • E.g. can die of a bowel obstruction from prostate cancer because of peritoneal seeding and adhesions
  • "Cancer pain" is not adequate - need to say how it's being caused
    • Neuropathic pain, ischaemia, venous congestion, lymphatics
  • Liver is a common site for mets: 1) vascular with a dual blood supply 2) filtration system, pulls mets out of blood
    • Large liver: don't like sitting at an angle in bed so their ribs don't stick in as much
    • May have lots of symptoms or no symptoms
  • Hepatic mets can cause Squashed Stomach Syndrome (SSS)
  • Jaundice: pruritis and scratching
  • Lung second most common met site due to vascularity and filtration down to small vessel size
    • If you get symptoms, you do very badly (replaced a lot of your lung)
  • Stridor: upper airway obstruction
  • Pleuritic pain: sharp with inspiration; pleural friction rub
  • SVC obstruction: Pemberton's sign works because you increase venous return
  • Chylous effusion: due to lymphatic obstruction
  • Recurrent laryngeal nerve palsy - hoarseness and aspiration. Aspiration is a common cause of death. Need to be able to close over larynx so that you don't die of aspiration. Also occurs if cranial nerves are compromised. Neck is often fine, but the disease is in the chest.
  • Pancoast syndrome
    • Local pain around rib
    • Brachial plexus involvement - T1 distribution neuropathic pain; T1 weakness
  • Note locked-in syndrome in cancer