Cancer therapy strategies - Standard therapies Flashcards
Cancer therapy types
- hormone therapy
- surgery
- bone marrow transplantation
- chemotherapy
- targeted therapy
- radiation therapy
- immunotherapy
Surgery in cancer treatment -> prevent cancer
- Preventive or prophylactic surgery is used to minimize the risk of developing certain types of cancer
- Removal of precancerous conditions, that make them more likely to develop into cancer
- Removal of atypical moles to prevent skin cancer
- Removal of polyps to prevent colon cancer
- Removal of breast tissue and ovaries in patients with BRCA1 or BRCA2 mutations
ABCDEs of melanoma:
- asymmetry (irregular shape)
- border (irregular border)
- color (multiple colors)
- diameter (>6mm in diameter)
- evolving (change in size, shape or color)
Surgery in cancer treatment -> diagnose and stage cancer
Surgery can be performed to collect biopsy samples from the tumor or sentinel lymph nodes
-> incisional biopsy – part of the tumor is cut out
-> excisional biopsy – the entire tumor is cut out. A margin of healthy tissue is usually removed at the same time
Evaluation of cancer type and metastatic state can influence the treatment strategy
Surgery in cancer treatment -> remove cancer
- completely remove the tumor or cancerous tissue
- most effective at an early stage in cancer development
- avoid the cut through the tumor to minimize cancer cells scattered and spread to other structures
- surgical margin: area around the tumor which consist of normal tissue
Surgery in cancer treatment -> relieve symptoms
Palliative surgery is used to relieve symptoms and improve the quality of life
- evaluation of the extent of the disease
- control of loco-regional spread
- control of discharge or hemorrhage
- control of pain
- surgical reconstruction or rehabilitation
Risk-benefit evaluation is necessary
Surgery in cancer treatment -> lower the chance of recurrence
- Radical surgery: remove other nearby normal structures including muscles, nerves and lymph nodes
- e.g. radical mastectomy removes all of the breast along with chest muscles and lymph nodes under the arm
- Can minimize cancer recurrence
Surgery in cancer treatment -> Repair damaged tissue
- Surgery is used to repair tissue that is damaged by cancer or cancer treatments
- Reconstructive: medically indicated
- Cosmetic: rebuild the body shape
Surgery in cancer treatment -> Support other treatments
- Provide direct access to blood vessels (e.g. by a central venous catheter)
- place a special pump that is used to deliver chemotherapy drugs
Surgery in cancer treatment -> Support body function
- Surgeries that help with body functions such as breathing and getting enough nutrition
- Examples: tracheostomy or gastrostomy
Radiation therapy
- Ionizing radiation carries sufficient energy to detach electrons from atoms or molecules, thereby ionizing them
How penetrating?
- paper: stops alpha rays
- thin aluminium: stops beta rays
- thick lead: stops gamma, X rays
- water or concrete: stops neutron rays
EXTERNAL BEAM RADIATION THERAPY
* Therapy using ionizing radiation delivered by a linear accelerator
* Temporary
* High speed particles collide with a target inside the machine
* Photons are released and targeted to the patient
* Electrons and protons are alternative types of radiation, but less commonly used
INTERNAL RADIATION THERAPY
* Brachytherapy: Seeds that contain a radiation source are placed near the tumor
* Temporary or permanent
* Systemic radiation therapy: radioactive drugs that circulate through the body
* Examples: iodine-131, radium-223
How does radiation damage cancer cells
-> Ionizing radiation works by damaging DNA of cells leading to cellular death
INDIRECT
- Radiation hits water molecules and other organic molecules in the cell
➜ production of free radicals like hydroxyl (HO) and superoxide (O2–)
- Short lived and rapidly interact with biomolecules
- Most important ROS are generated in 2 nm distance from DNA
DIRECT
- Less common
- Heavier particles like protons rely on direct DNA damage
Hypoxia leads to radiation therapy resistance ➜ less formation of radicals like superoxide
- Direct and indirect DNA damage by radiation causes single and double strand breaks
- Double-stranded DNA breaks are much more difficult to repair increasing the probability that cells will undergo cell death
- Dividing cells are more sensitive to radiation therapy than differentiated normal tissue
- Cancer cells are more sensitive in G2/M phases of the cell cycle than in G1/S
- Total dose of radiation is fractionated
- Fractionation regimens are individualized between different radiation therapy centers and even between individual oncologists
- Typical fractionation schedule for adults is 1.8 to 2 Gy per day, five days a week
Fractionation of radiation therapy
- Fractionation is based on the “4R”-principle: biological factors influencing the response of a tumor and normal tissues
REPAIR (few hours)
* normal cells recover, less time for repair in tumor cells leads ➜ error-prone
REASSORTMENT/REDISTRIBUTION (few hours)
* tumor cells that are in a relatively radio-resistant phase cycle into a sensitive phase
of the cell cycle before the next fraction is given
REPOPULATION (5-7 weeks)
* Increase in cell division
* Effective suppression of tumor cell repopulation
* Accelerated repopulation (rapid multiplication of surviving clonogens) may contribute to local failure
REOXYGENATION (hours to few days)
* Tumor cells that are hypoxic are more radio-resistant
* Reoxygenation between fractions, improving tumor cell death
Side effects
- Radiation therapy is painless
- Side effects from radiation are usually limited to the area of the patient’s body that is
under treatment
ACUTE
- Akin reddening
- fatigue
- delayed wound healing
- hair loss in treatment area
- muscle aches
CHRONIC
- swelling
- skin thickening
- joint stiffness
Rare:
- bone fractures
- sterility
- secondary tumors
Goals of chemotherapy
Chemotherapy in the treatment of cancer can have different goals
- curative chemotherapy: aims to eliminate all cancer cells from the body to achieve a permanent cure
- palliative chemotherapy: to relive certain symptoms, to slow down the progress of the disease or to stop it temporarily
- neoadjuvant chemotherapy: is done before surgery to shrink the tumor size and to allow less invasive surgery
- adjuvant chemotherapy: aims at cancer cells that might be left in the body after surgery and is performed to prevent recurrences
Chemotherapy - mechanisms
G1 CHECKS FOR:
- cell size
- nutrients
- growth factors
- DNA damage
G2 CHECKS FOR:
- cell size
- DNA replication completeness
M CHECKS FOR:
- spindle checkout
- specific complexes of cyclin and cyclin-dependent kinases are formed and activated at different phases of the cell cycle
Chemotherapy - Alkylating agents
- Oldest anti-cancer cytotoxics
- Mode of action: bind covalently via alkyl groups to DNA
- DNA damage -> DNA repair -> cell arrest -> apoptosis
- Damages in all cell types -> induction of DNA damage -> response only in proliferative cells
Chemotherapy - Antimetabolites
- Interferes with normal cellular metabolism of nucleic acids
- MoA: disrupts DNA/RNA metabolism/production; S-phase of cell cycle
- Deoxyuridine-monophosphate (dUMP)
- 5-Fluorouracil (5-FU)
- Folic acid
- Methotrexate (MTX) -> affinity is higher than for folate
- Hypoxanthine
- 6-Mercaptopurin
- Guanine
- 6-Thioguanine
-> Structure similarity between natural metabolite and antimetabolite
Chemotherapy - Topoisomerase inhibitors
- Topoisomerases are essential enzymes in regulating the topology of the DNA helix
- Cleave DNA strands and relaxes supercoils during replication
- Topoisomerase I: cleaves one strand of DNA
- Topoisomerase II: cleaves both strands of the DNA
Topoisomerase inhibitors:
* Form a ternary complex with DNA and topo enzyme by forming hydrogen bonds
* Prevent DNA re-ligation and therefore causes DNA damage resulting in apoptosis
* Cancer cells rely on topo enzymes more than healthy cells -> rapid replication
Chemotherapy - Anti-microtubule agents
- Disrupts M-phase of the cell cycle leading to cell arrest -> apoptosis
- Vinca alkaloids: inhibits microtubule assembly -> no M-phase
- Taxanes: binds to stabilized microtubules -> M-phase does not finish
Chemotherapeutics and cell cycle
- Different classes act on specific phases of the cell cycle
- Cytotoxic antibiotics & Topoisomerase inhibitors: G1, S and G2
- Antimetabolites: S
- Vinca alkaloids: M
- Microtubule inhibitors: M
- Taxanes: M
- Alkylating agents: G1, S, G2, M
- Fast dividing tumor cells react more efficiently to cell cycle phase dependent chemotherapeutics than low growing tumor cells
Chemotherapy- Adverse effects
- Chemotherapeutic agents have a range of adverse side-effects
- Adverse effects can be severe -> risk benefit analysis
- depend on type of medication
Most common medications affect all fast-dividing cells:
- epithelial cells in mouth, stomach and intestines -> gastrointestinal diseases
- blood system: white/red blood cells -> Anemia, immunosuppression
- Hair follicle cells -> Hair loss
- Germ cells -> infertility (short term or permanent)
- Tumor lysis syndrome
- Second primary neoplasms
Chemotherapy - Tumor lysis syndrome (TLS)
- Occurs after massive destruction of tumor cells at the same time
- Release of cellular content into the bloodstream; often in lymphomas and leukemias
- Characteristic findings: hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia
- High blood electrolyte levels lead to renal insufficiency, cardiac arrhythmias, seizures and death due to multiorgan failure
phosphates -> Hyperphosphataemia/Hypocalcaemia
lactates -> acidosis
nucleic acids -> urates -> Hyperuricaemia
potassium -> Hyperkalaemia
Chemotherapy - risk of second cancers
- Some chemotherapeutics are linked to different types of second cancers
- Alkylating agents and cisplatin; 2-10 years after treatment
- Leukemia as a secondary cancer can occur following treatment with chemotherapy
- Tend to be hard to treat -> Chemotherapy-induced myeloid leukemias have a cure rate of only 10% to 20%
Second primary malignancies
43.3 % Leukemia
23.9 % Lymphoma
7.5 % Multiple myeloma
6.0 % Uterine cancer
First primary malignancies
20.9 % Lymphoma
16.4 % Breast cancer
11.9 % Leukemia
9.0 % Colorectal cancer
9.0 % Lung cancer
