module 15: chemotherapy + cytotoxic agents

surgery: excellent for solid tumours

radiotherapy: best for blood cancers and localized tumours because it attacks everything

chemotherapy: most efficient for disseminated and localized cancers because the drugs circulate the bloodstream

a cure is defined as a 5-year disease-free interval following the treatment

if ever a cancer was to come back, let's say after 6 years, we would consider it a new tumor rather than the first tumor that just never died,

the severe toxicity it produces

- chemotherapy could cure all cancers, but since its so toxic it often kills the patient before the cancer

G0 = resting phase, cell is not dividing, can last for days, most of our cells are in this phase

G1 = synthesis of components needed for DNA synthesis

S = synthesis of DNA (DNA is replicated to have 2 copies)

G2 = synthesis of components needed for mitosis

M = mitosis

skin, hair, GI, sperm

ratio of dividing cells versus resting cells

- basically how many cells are in G0, and how many are in the cycle

- the higher the growth factor, the more cells are dividing

important because chemotherapy targets the cells that are dividing

- leaves those in G0 intact

- the higher the growth factor, the more you're killing: but remember tutors are highly dividing

- chemotherapy is also most efficient versus high growth factor fraction cancers, least efficient for solid tumours

loss of hair, infertility, nausea, vomiting and neutropenia, risks of infection, immunosuppression.

to cure cancer = need to kill 100% of cancer cells

- difficult to do without killing the patient

small tumors are rapidly dividing so chemo most efficient here BUT we cannot detect these, once they are bigger, they are less dividing, so chemo is less efficient

too early = relapse

too late = unnecessary significant toxicity

- hard to measure how many cells are left, no way to know when 100% of tumor cells are gone

1st order kinetics

- same chemo dose must be given each time

- same % of cancer cells killed each time (ex:50%)

- every time you get chemo, it is killing less and less

- continue to approach 0 but never gets there's in absolute

every round the person becomes weaker and it kills less cells, so the risk benefit becomes worse and worse over time

immune system doesn't offer much help with cancer

- chemo is an immunosuppressants

- some cancers like leukemia and lymphomas affect immune system too

toxicity to healthy cells

lack of effective early detection

drug resistance

poor response of solid tumors

limited Rx access to tumor cells

heterogeneity of tumor cells

cancer cells are super similar to healthy cells

- chemo Tx have low selectivity (unlike antimicrobials)

dose-limiting toxicity

- doses that could cure the cancer would kill the patient

smallest detectable cancers = around 1 billion cells

- except cervical cancer vis Pap smear

cancer screening and prevention still recommended

- detection at 1 billion better than 1 trillion

anticancer Rx create selection pressure

- drug-sensitive cells killed

- indirect resistance develops over time

- tumor cells keep mutating

mitigation

- like antimicrobial strategies, combine Rx to decrease resistance

p-glycoprotein is a pump that protect us from harmful substances

cancer cells get a mutation where they have an extra p-glycoprotein, meaning they get good a getting rid of any chemo molecules that would kill them

mitigation: use P-glycoprotein inhibitors to increase anticancer Rx efficacy

large tumors are less sensitive to chemo

- smaller growth fraction

- more repair + resistance mechanisms

mitigation: debunking, via radiation or surgery

- decreased tumor size

- increased growth fraction

- cells in G0 phase re-enter cell cycle

barrier impede Rx access

- ex: blood brain barrier, meninges

with larger tumors

- poor vascularization

- harder to access centre of tumor

heterogeneity decreases chemotherapy sensitivity

- multiple resistance mechanisms

- varying growth rates

- larger tumors = more heterogeneity

intermittent chemo, combination chemo, optimizing dosing and delivery

cytotoxic drugs are administered intermittently (not continuously)

- works best when healthy cells recover faster than cancer cells

max efficacy from combination of cytotoxic drugs

- less resistance development

- more cancer cells killed/round

- more potential anticancer effect

choose drugs with

- additive anti-cancer effect

- different mechanisms

- independent efficacy

- non-overlapping dose-limiting toxicities (toxicity that would kill the patient if we gave them more), you want to like "spread out" the toxicity

frequency and time of admin are crucial

- certain chemo drugs are phase specific

- ex: cytarabine is S phase specific, only kills the cells in S phase

better to give small doses multiple times per day rather than one large dose

- studies with mice showed giving the large dose killed 100% of them

- was able to affect cells at different time points because given at different time throughout the day

- even with a lower total dosage, you get a higher % of cells killed because you wait for them to get into the proper cell phase to attack them

choice of admin route can increase efficacy and decrease toxicity

- intra-arterial = excellent for localized tumors

- intrathecal = bypass blood brain barrier

- intraccavitary = lung pleura cancers

- directly into bladder = bladder cancer

bone marrow suppression

digestive tract injury

nausea + vomiting

tumor lysis syndrome

neutropenia: leads to increased infections (most dangerous)

thrombocytopenia: leads to increased bleeding

anemia

low WBCs: serious complication of chemo

- severity and time depends on anticancer Rx

- lack of neutrophils prevents early signs of infection

- fever = infection

management

- stay home to avoid infection

- if infected, initiate IV antibiotics immediately

- manage with Colony-Stimulating factors (stimulate development of WBCs)

avoid any procedures that increase bleeding risks - even vigorous toothbrushing

favour acetaminophen over aspirin

manage with platelet transfusions

less frequent since RBC lifespan = 120 days

management

- for cure: blood transfusion

- for palliation: Epoetin

diarrhea

- consequences: impairs absorption

- Loperamide PO produces effective constipation to counter

stomatitis/oral mucositis (inflammation of oral mucosa)

- consequences: ulceration decreases eating, speaking, swallowing

- prevention: good oral hygiene + bland diet, bland diet

- management:

- mild: magic mouthwash + antihistamine

- severe: systemic opioid analgesics

- extreme: withhold chemo

- hematologic cancers: Palifermin (for solid tumors it would promote tumor growth, so only blood cancers)

direct GI toxicities

chemoreceptor trigger zone stimulation

tumor lysis syndrome

no, some have severe/low/moderate/minimal emetogenic

- but some drugs work better for the cancer the patient has, and since nausea+ vomiting isn't life threatening, sometimes they have to do the severe ones

consequences

- discomfort leading to decrease adherence

- malnutrition/dehydration

manage with antiemetics prophylaxis

- combination > monotherapy

- best for highly emetogenic chemo: aprepitant + dexamethasone + ondansetron

occurs when tumor cells release their contents into the bloodstream

- because tumor cells are killed, all their internal contents are released in the vicinity

- when some gets released in the bloodstream....BAD

- efflux of K+ -> hyperkalemia -> arrythmias EKG abnormal

- release of nucleic acid -> hyperuricemia -> uric acid crystals -> acute renal failure -> fluid depletion (fever, vomiting, nausea)

- hyper phosphatemia -> calcium phosphate imbalance (causes seizures + dysrhythmias) -> acute renal failure -> fluid depletion (fever, vomiting, nausea)

can manage hyperuricemia with Allopurinol -> can prevent further complications (ex: Gout)

alopecia: begins within a week/recovers 1-2 months post-Tx

reproductive toxicity:

- potential irreversible sterility in men -> sperm banking

- teratogen only during 1st trimester -> resume Tx after week 18

extravasation injuries

- concerns antineoplastic Rx called "vesicants"

- severe tissue toxicity if in contact with tissues

- admin via central IV line only by specially trained HCPs

most anti-cancer drugs are carcinogenic - produce more tumor or more mutations because they promote a lot of division and killing of cells.

positive benefit-risk analysis: only worth it if chances of either:

1 - cure

2 - prolongation of life

3 - palliation

measurable objectives to track success/failure:

- decrease tumor size or neoplastic blood cells

- growth inhibition

factors predicting positive chemo outcome:

- good patient general health (ex: Karnovsky Scale)

- the higher the patient is on the scale, the better their chance of surviving through chemo longer

largest class of anticancer drugs: all affect cell cycle in some way

- pay attention to their dose-limiting toxicities

50% cell-cycle phase specific

- most often S-phase/some M-Phase: admin via prolonged infusion or multiple doses because increased # of cells exposed during appropriate dose

50% phase non-specific

- acts on cells in all phases (including G0)

- super toxic, used as last resort

dosage + admin

- highly individualized

- administered by trained HCPs

- avoid direct contact with skin, eyes -> toxicity

guanine alkylation creates DNA miscoding and inhibits replication

- nitrogen mustard attaches itself to the 2 guanine (bifunctional) which creates a cross link

- cross link makes it difficult to unwind the 2 strands of DNA -> inhibits DNA replication as well as causing direct damage or mutation

bone marrow suppression

nitrogen mustard and bifunctional alkylating agent

- oldest and most used alkylating agent

kinetics

- prodrug available PO

- hepatic activation

indications

- solid tumors of neck, head, ovary and breast

- hodgkin and non-hodgkin lymphomas

- multiple myeloma

toxicities

- chemo induced nausea + vomiting

- bone marrow suppression

- alopecia

platinum compound and bifunctional alkylating agent

- newer drug

kinetics

- admin by IV infusion

indications

- metastatic ovarian and testicular cancer

- advanced bladder cancer

- off label: lung + head + neck cancer

toxicities: nephrotoxicity

- mitigate with hydration + diuretics

- serious CINV within hours

newest drug

- aspiring + cisplatin

different cell uptake

overcomes cisplatin resistance

molecules that inhibit the synthesis of DNA nucleotides

- mostly S-phase specific

have dose-limiting toxicities

- bone marrow suppression

- GI ulceration

ex: methotrexate, fluorouracil, mercaptopurine

folic acid analog

- inhibits the action of dihydrofolate reductase (DHFR)

- decreases thymidine levels, so decreases DNA replication and increased apoptosis

kinetics

- very polar prodrug, requires transporters for uptake

- significant renal excretion

resistance mechanisms

- decreased MTX uptake or mutated DHFR

drug-specific toxicity: nephrotoxicity

- mitigate with hydration + urine alkalinization

indications

- non-Hodgkin lymphomas, acute lymphocytic leukemia, with leucovorin rescue (osteosarcoma, head+neck cancers)

use higher doses of MTX that would technically kill the patient if used alone but leucovorin is an antidote to MTX

- cancer cells lack the transporter to uptake leucovorin

- basically only giving antidote to healthy cells

pyrimidine analog

- inhibits thymidylate synthase

- decreases thymidine levels, so decreases DNA replication and increased apoptosis

kinetics

- IV infusion admin

- easy BBB penetration

- rapid hepatic elimination

resistance mechanisms

- decreased 5-FU activation + mutated thymidine synthase

drug-specific toxicity: fatal GI ulcerations

- discontinue at 1st signs of GI toxicity

- overdose antidote = uridine triacetate

indications

- palliative therapy of solid tumors

- adjunct for breast + colorectal cancer Tx

purine analog

- inhibits DNA synthesis + cause DNA intercalation

kinetics

- prodrug; intracellular activation

- inactivated by XO and TPMT enzyme; use polymorphism tests

- allopurinol decreases XO and TPMT, so decrease 6-mercaptopurine dosage

resistance mechanisms

- decreased intracellular activation or increased TPMT activity/expression

drug-specific toxicity

- teratogenic, hepatotoxicity, interaction w/XO and TPMT inhibitors/inducers

indications

- maintenance therapy for acute lymphocytic leukemia (ALL)

M-phase specific

- inhibit microtubule function

- cells "stuck" in M-phase

- metaphase block leads to apoptosis

vincristine

- action: inhibit microtubule assembly

- kinetics: IV admin, hepatic elimination

- toxicities: peripheral neuropathy, no bone marrow suppression, minimal CINV

- used with combination Tx

- indications: Karposi's syndrome, ALL, breast + bladder cancers

paclitaxel

- action: inhibit microtubule disassembly

- kinetics: IV infusions, unknown elimination

- toxicities: peripheral neuropathy, bone marrow suppression

- used with cisplatin

- indications: 1st line for ovarian and non-small cell lung cancer