Chemotherapy from a clinical perspective Flashcards
why is it predictive that incidences of cancer will rise despite the advancement in treatment
aging population where older patients are kept alive longer - cancer is an aging disease
What kills patients with cancer
- local complication of tumour (blocking blood vessel, airway or bowel)
- systemic complication of cancer (infection, cachexia and paraneoplastic syndromes)
- direct complication of the treatment (neutropenic sepsis, bleeding and renal failure)
- 90% = Metastasis
metastasis require _ treatment
systemic treatment
what are the types of cancer treatment
- Surgery
- Radiotherapy
- supportive therapy (analgesia, anti-emtics, psychological support for symptoms control)
- Systemic therapy (chemotherapy, immunotherapy and targeted agents
what are some Chemotherapy drugs and what do they do (big picture)
Alkylating agents, anti-metabolites, platimums, topoisomerase inhibitors and tubulin-binding agents
- target DNA replication,
- antiproliferative agents
- Non-selective normal tissue toxicity
what makes an effective chemotherapy drug
Drug reaches the tumour cell - don’t metabolise early
Sufficient quantities of active component enter the cell
Tumour cells are sensitive to the drug before resistance emerges
Normal tissue must be able to tolerate and recover (efficacy vs tolerabilty
What is ‘combination’ treatment in chemotherapy
○ Can combine 2+ chemo drugs (which work in different ways) and can also be combined with radiotherapy
○ Several different drugs, each independently active against a given disease (Each drug should have: A different mechanism of action + A different dose-limiting toxicity)
○ As a result: Each drug is given at full dose, the rate of cell kill increases (addressing tumour heterogeneity), The chance of emergence of a drug-resistant clone decreases
what is taken into consideration when patients need chemoterapy
- Patients’ fitness and co-morbidity
- Kidney/liver/ bone marrow function - look at RBC and WBC count as well as platelets
(Drugs needs to be metabolised (liver) and filtered out (kidneys)) - In advanced disease consider quality vs. quantity life
What can be done, using chemotheray, towards a curaive intent
High dose/Radical chemotherapy (Germ cell tumour/lymphomas)
Neo-adjuvant Chemo + surgery/ Radiotherapy (Oesophageal, ovarian, lung and breast)
Surgery + Adjuvant Chemo (ovarian, lung, colorectal, breast)
T/F chemo is only used with curative intent
False - Palliative chemo can be used to prolong survival
Explain the proportional cell kill models
○ Within tumour different populations of cells; some continually proliferating cells; resting cells;
○ Growth of tumour depends on the actively growing fraction of the tumour: growth fraction and the tumour doubling time
○ Tumours are detectable at a critical mass = 10-9 cells = 1 g
○ Chemo going to have max effect on the actively proliferating cells so if high growth fraction = high chemo sensitivity
○ BUT that also means affect organs with high growth fraction e.g. bone marrow and gi mucosa
○ Types of cancers can influence number of chemo cycle
how are systemic chemotherapeutic agents classified (broadly)
- Mechanism of action
- Source/origin
- Cell cycle phase specificity
how are chemotherapy further classified when they effect cell cycle
Cell cycle active (phase specific)
Cell cycle active (phase non-specific)
Non- cell cycle active (e.g corticosteroids)
How was chemotherapy discovered
Blood + Bone marrow in yellow cross gas (mustard) poisoning)
○ Soldiers exposed to yellow cross gas (mustard gas) had aplastic bone marrow
○ Those who survived had a transient reduction in the white blood count
○ Suggested use of similar agent for treatment of leukaemia
○ Lead to the development Nitrogen mustard - mustine (Alkylating agents)
how do alkylating agents work
Alkylation - transfer of one alkyl group to naother molecule
- Transfer an alkyl group to the N7 of guanine residues in DNA via production of reactive ethyleneimonium and carbonium ions
-This mechanism of toxicity is also responsible for the ability of some alkylating agents to perform as anti-cancer drugs in the form of alkylating antineoplastic agents, and also as chemical weapons such as mustard gas.
Alkylated DNA _
- either does not coil or uncoil properly, or cannot be processed by information-decoding enzymes.
- This results in cytotoxicity with the effects of inhibition the growth of the cell, initiation of programmed cell death or apoptosis.
- However, mutations are also triggered, including carcinogenic mutations, explaining the higher incidence of cancer after exposure
How do antimetabolites work
- Disrupting the building blocks of DNA
= Methotrexate an enzyme inhibitior which inhibits dihydrofolate - Have to give folic acid to rescue normal tissue to restore folate stores
- These block thymidine and purine synthesis
Blocking thymidine and purine synthesis causes what
- Folic acid undergoes reduction to first, dihydrofolate and then tetrahydrofolate, by the enzyme dihydrofolate reductase ( DHFR)
(DHFR is the primary target of the folic acid analogue MTX). - Tetrahydrofolate is a purine precursor
- TS (thymidylate synthase) catalyses the conversion of dUMP (deoxyuridine monophosphate) to dTMP (deoxythymidine monophosphate) using 5,10-CH2THF (5,10 methylenetetrahydrofolate) [ which is essential to the TS reaction] and therefore thymidine synthesis.
- Without thymidine, there is uracil misincorporation into dna strands during replication leading to double strand breaks during uracil excision repair-
How does 5-Fluoroouracil work
○ Activated by intracellular enzymes to 5-fluorodeoxyuridine monophosphate (FdUMP)
○ FdUMP potent inhibitor of thymidylate synthase acting at the dUMP binding site
what are the delivery methods for 5-fluorouracil
IV bolus or infusional, with highest concentrations in GI mucosa, liver and bone marrow after administration
[Toxicity profile different for bolus vs. infusional]
5-fluoroouracil used to treated
○ Extensively used for the treatment of colo-rectal cancer, also breast cancer, upper GI and head and neck cancers
what has 5-fluorouracil being replaced by in recent times
- by the oral 5-FU pro-drug (Capecitabine) as studies confirm equivalence
what is pemetrexed
Multi-targeted antifolate which inhibits thymidylate synthase, DHFR and GARFT
What is pemetrexed used to treat
Mesothelioma (+ carboplatin)
Non-small cell lung cancer
what was the toxicological issues with pemetrexed and how was it resolved
myelosuppression, hand-foot syndrome, mucositis, diarrhoea
reduced with the addition of folic acid and Vit B12
what drugs react negatively to pemetrexed
NSAIDs/aspirin
How does Cisplatin work
- Covalently binds to DNA with preferential binding to the N-7 position of guanine and adenine.
- Reacts with two different sites on DNA to produce cross-links, either intrastrand (> 90%) or interstrand (< 5%).
- Formation of DNA adducts results in inhibition of DNA synthesis and function as well as inhibition of transcription.
- Binding to nuclear and cytoplasmic proteins may result in cytotoxic effects
what has cisplatin been used to treat
-Over 90% Metastatic testicular teratoma and ovarian germ cell tumours cured by cisplatin chemotherapy combinations
Treats Ovarian, bladder, lung, Head and neck and upper GI
how does carboplatin work
- Analogue of cisplatin however is quicker in causing effect
- Lack most of the non-haematological toxicities of cisplatin however myelosuppression can be sever and is dose limiting
how did cisplatin and carboplatin fair in clinical trials/ clinical setting
- Carboplatin activity equal to cisplatin in most randomised clinical trials so far
- Many clinicians prefer to use carboplatin as easier to administer, no pre-hydration required, day-case treatment
how is carboplatin dose calculated
not by body surface but by the calvert formula
= AUC x(GFR+25)
what is carboplatin used to treated
testicular cancer, even advanced forms
What is Vinca alkaloid and what does it do
Derived from the periwinkle plant Catharanthus roseus
Inhibits tubulin polymerization, disrupts =
- the formation of the microtubule assembly
- during mitosis and arrests cell division
M – phase specific
New analogue, vinorelbine (1990s) activity in breast and lung cancer
what are the two Taxanes (antimitotic agent)
Paclitaxel and docetaxel
How does pacitaxel work and what is it used to treat
High affinity binding to microtubules, stabilisers tubulin polymerisation which results in inhibition of mitosis and cell division
(M-phase specific)
Main role in treatment of breast cancer and ovarian cancer but has activity in Lung, Head and Neck, Upper GI, Prostate, Bladder cancers
How does Docetaxel work and what is it ised to treat
- High affinity binding to microtubules, stabilisers tubulin polymerisation which results in inhibition of mitosis and cell division
(M-phase specific) - Main role in treatment of breast cancer, NSCLC and advanced prostate cancer
How do topoisomers work as a group
The DNA coiled double helix needs to uncoil its two strands in order to replicate for cell division or transcribe new proteins
Topoisomerase I and II enzymes are essential for this uncoiling and recoiling allowing DNA replication and RNA transcription to occur
Topisomerase I = causes single strand breaks and relieves torsion
Topoisomerase II = causes double strand breaks, allows the other strand to pass through and religate
how does topoisomerase I/II inhibitors work
by binding directly to the topoisomerase-DNA complex preventing the religation of DNA once it has been cut
What is Topotecan, how does it work, what does it treat and what are the toxicities surrounding there use
Topoisomerase I inhibitor
Semi-synthetic derivative of camptothecin
- Main role in of platinum resistant ovarian cancer and relapsed small cell lung cancer
- Toxicities include: myelosuppression, diarrhoea, nausea and vomiting
What is Doxorubincin
- Topoisomerase II inhibitor = Inhibits topoisomerase II by forming a cleavable complex with DNA + topoisomerase II
- Intercalates into DNA resulting in inhibition of DNA synthesis and function
- Inhibits transcription through inhibition of DNA-dependent RNA polymerase
- Formation of cytotoxic oxygen free radicals results in single- and double-stranded DNA breaks with subsequent inhibition of DNA synthesis and function.
What is the toxicity surrounding doxorubinicin
Cumulative cardio-toxicity in form of reduced left ventricular function and cardiomyopathy
- Increase risk with > 4, 50mg/m2 total dose
what are general side effects of chemotherapy
- Alopecia
- In bone marrow = anaemia, thrombocytopenia, neutropenia
- In GI = muscositis, diarrhoea, nausea and vomiting
= Drugs to reduce side effect and cold caps reduce hair loss
Regarding toxicity what specific agents cause what toxicities
Cardiotoxicity – anthracylines, 5FU
Neurotoxicity – taxanes, platinums
Nephrotoxicity - cisplatin
Haemorrhagic cystitis – ifosfamide
Lung – Bleomycin, Methotrexate
Hand and foot syndrome – 5FU
what are the lasting general side effects of chemotherapy
infertility
secondary malignacies
How could chemotherapy be improved
- Improved delivery
- Combining chemotherapy with agents to overcome resistance
- Combining chemotherapy with immunotherapy
- Developing different schedules of the same drugs
How can chemotherapy delivery be improved
Targeting the chemotherapy to the cancer cell by using antibody drug conjugates =
- Attach the cytotoxic chemotherapy to monoclonal antibodies such as HER2 (to HER2+ positive BC in ADO-trastuzumab emtansine
