Principles of cancer (1) Flashcards
Cell division cycle
The cell goes through different phases as it divides (G0, G1, S, G2, and M phase)
this is important to consider because some drugs will be non specific (kill the cells at any point of the cycle), but some drugs will be cell cycle specific- and only kill drugs when they are at a certain point in the cycle
Micrometastasis
metastasis that cannot be detected by imaging
responsible for relapse
This is why we need to give chemotherapy systemically
(because there may be metastasis in places we are not aware of)
If we could pick up on these, we could treat cancer even better
Mechanism of metastasis (4)
- Hematogenous spread
-cells of primary tumor penetrate into blood vessels, spread through blood stream - Lymphatic spread
-cells of a primary tumor penetrate into lymphatic vessels - Cerebrospinal dissemination
-cells of primary tumor penetrate CSF directly or reach CSF through blood stream (cross BBB) - Trans-abdominal spread
-cells of primary tumor penetrate other organs within the abdominal cavity
Warning signs for adults (CAUTION)
C - change in bowel habits (colorectal cancer)
A - a sore that dose not heal (skin cancer)
U - unusual bleeding or discharge (lymphoma/leukemia)
T - thickening or lump in breast or elsewhere (breast cancer)
I - indigestion or difficulty swallowing (esophageal/throat cancer)
O - obvious change in wart or mole (skin cancer)
N - nagging cough or hoarseness
Warning signs for pediatrics (CHILDREN)
C - continued unexplained weight loss
H - headaches with vomiting in the morning
I - increased swelling or persistent pain in bones/joints
L - lump/mass in abdomen, neck or elsewhere
D - development of whitish appearance in the pupil of the eye
R - recurrent fevers not caused by infections
E - excessive bleeding/bruising
N - noticeable paleness or prolonged tiredness
What is the number 1 type of cancer in kids?
Leukemia
____________ must be staged prior to ________________
Solid tumors must be staged prior to initiation of treatment
(stages provide prognosis and guide treatment)
Solid tumor staging
Stage 1 - localized tumor
Stage 2 - spread to local lymph node near mass
Stage 3 - spread to distant lymph node away from mass
Stage 4 - spread with lymph node involvement + metastases
3 treatment modalities of cancer
- Surgery
- Radiation
- Chemotherapy
Surgery
Treatment of choice for most early stage solid tumors
Local treatment only
Usually combined with radiation and/or chemotherapy (to make sure all cancer cells are removed)
-The goal is to remove the tumor with negative margins (remove all cancer cells)
May be palliative (not necessarily curative in late stages)
Neoadjuvant vs adjuvant therapy with surgery
Surgery is usually combined with chemotherapy and/or radiation to ensure negative margins (removal of all cancer cells)
This can be done before, or after the surgery …
Neoadjuvant therapy is when the chemo/radiation is done prior to surgery
Adjuvant therapy is when the chemo/radiation is done after surgery
Radiation
Local treatment only
Usually combined with surgery and/or chemotherapy
May be palliative (not necessarily curative in late stages)
Radio-sensitizing chemotherapy is used to radiosensitize the tumor
Radiosensitizing chemotherapy
Low doses of chemotherapy given to radiosensitize a tumor (make cancer cells more vulnerable to radiation therapy)
Agents commonly used:
Cisplatin
Fluorouracil
Gemcitabine
Chemotherapy for solid tumors
Administered to eradicate cancer cells - systemic circulation (good to get rid of metastasis)
Can be given orally, intravenously, or intrathecally
Given as a regimen - different agents that are used throughout a cycle
-a cycle is the block of time during which the regimen is given
-the cycle is usually 21 days - different drugs part of the regimen will be given throughout and then there will be a period of time during which no chemotherapy is given (chemo kills normal cells too, so we hold therapy and wait for counts to normalize then start the cycle again)
-usually for solid tumors patient undergoes 4-6 cycles on average
How does chemotherapy differ for hematologic malignancies? (leukemia)
The terminology differs - instead of cycles, there is … induction, consolidation, and maintenance therapy
More aggressive up front
In general chemotherapy works best during which time?
When cells are moving faster through growth phases -
this occurs before 10^5 is reached
As the tumor gets bigger, (reaches 10^9 when you can clinically detect it) - at this point it is getting big and may get into surrounding tissue and metastasize - chemo will not work as well
And if you allow it to keep growing (without treatment) , the tumor will eventually plateau - it will outgrow the nutrient and blood supply there, and it will metastasize
Solid tumors are pretty slow growing in general (double in 2-3 months) compared to leukemia/lymphoma (double in days) - which is why the therapy for those is more aggressive
Cell kill hypothesis
Chemotherapy works to kill cancer cells, each cycle kills ~90%, but never reaches zero cancer cells
The hypothesis is you give multiple cycles, it will get less and less and then eventually the immune system takes care of what’s left
But there are flaws with this hypothesis
-assumes all cancers are equally responsive to chemo
-assumes that metastases do not occur
-assumes that resistance to chemo does not exist
Because of these limitations this hypothesis is not used much anymore - focus on the size/staging to figure out course of action when patient is diagnosed
Cell phase specific vs non cell phase specific chemo administration considerations
Cell cycle phase specific chemo…
-only kills cells when they are in a particular phase of the cell cycle
-Schedule dependent dosing … give continuous infusions or multiple repeated doses - so that the agent is available in the body for longer period of time - whenever the cells go into that specific phase (since they won’t all be there at the same time)
Cell cycle phase non specific chemo…
-has cell killing activity in multiple phases
-Dose dependent dosing … give larger doses
Factors that effect response to chemotherapy (6)
- Tumor burden (larger tumor)
- Cancer cell heterogenicity (homogenous populations of cells are easier to kill)
- Drug resistance (can be due to inherited gene or mutations can occur during therapy)
- Dose response
- Location of disease
- Patient specific factors
Why are larger tumors harder to kill with chemotherapy?
Because they move through the growth phases at a slower rate when it is larger (chemo works best when cells are rapidly moving through growth phase - so may need to add radiation to shrink)
What are the 2 ways that dose response can be adjusted?
Dose Intensity…
-increase dose delivered over a certain period of time (e.g. 60 mg over 3 days versus 90 mg over 3 days)
Dose density
-shortening interval between doses (e.g. every 14 days versus every 21 days)
Note - these are only used for very aggressive cancers
How can location of disease effect chemotherapy response?
There are tumor sanctuary sites - places tumors hide where there are lipophilic barriers that are hard for chemo agents to cross - preventing optimal treatment
e.g. BBB, testicles (in men)
Which patient specific factors can effect response to chemotherapy?
Factors that effect ability to optimize dosing regimen
-comorbidities, end organ dysfunction, age
Genetic mutations (e.g. breast cancer HER2 - more responsive to anthracycline based regimens)
Genetic polymorphisms - can result in life threatening toxicities (due to inability to metabolize drugs)
(ex: DPD 5-FU metabolism, TPMT thiopurine metabolism, UGT1A1 irinotecan metabolism)
What are the 3 main routes of administration of chemo?
Oral, intravenous, intrathecal
Oral chemotherapy considerations
-can be done at home, preferred by patients
-but regimens can be complicated - hard to ensure compliance, missed doses can occur
-medications can be hard to obtain (require specialty pharmacy)
Note- there is a common misconception that oral therapy is less dangerous/better tolerated than parenteral and that is NOT true (it is just as bad)
Intravenous chemotherapy considerations
Takes time, need to drive to infusion center and have someone to drive you there
Different drugs have specific diluent and tubing compatibilities (chemo agents stick to certain types of tubing - non PVC tubing or glass container may be needed)
Patients need to have IV access… (so that you don’t have to prick the patient every day)
-peripheral access is only short term - central is needed
-2 options: PICC or subcutaneous implantable port
PICC - peripherally inserted central venous catheter
-lasts up to 6 months
Subcutaneous implantable port
-preferred option
-device implanted under skin, can be left in for many years, easier access
(just looks like a little bump on chest)
Intrathecal chemo administration considerations
This is used if there is a metastasis here or in patients with leukemia or lymphoma (which are likely to spread to the CNS)
Given as a lumbar puncture (withdraw some CSF prior to administration)
Note - some agents can NOT be given IT … this can be fatal
Which chemo agents CAN be given IT? (4)
Methotrexate
Cytarabine
Hydrocortisone
Dexamethasone
Which chemo agent can NOT be given IT?
Vincristine
(will cause death if given intrathecally)
Why are steroids given with the IT chemo regimen?
Sometimes steroids can help kill cancer cells
But particularly with the IT administration they are given to help prevent swelling of the meninges with chemo administration (which can result in headache, nausea, and vomiting)
What is extravasation?
Leakage of vesicants from the vein into the surrounding vasculature
(vesicants are agents that can cause severe tissue damage if extravasation occurs)
This is why we use central and not peripheral lines
Which chemo agents are vesicants? (6)
Anthracyclines
Actinomycin D
Vinca alkaloids
Mitomycin C
Nitrogen mustards
Taxanes
How is extravasation managed if it occurs?
Stop the infusion but do NOT remove the needle at first (there is still drug left, so if you remove the needle the drug will squirt out into the surrounding tissue and cause more harm)
–>
Disconnect the tubing and aspirate the remaining drug from IV site with empty syringe
—>
Then administer antidote (if there is one for the particular agent - there are only 2 available)
—>
Then you can remove the needle
-Avoid putting pressure on the extravasation site (can make it spread)
-Apply hot or cold compress (depending on the agent)
-Keep extremity elevated for 48 hours
-Surgical consult (if necrosis occurs)
-And pain management as needed
Management of anthracycline extravasation
Antidote is dexrazoxane
-inactivates anthracyclines
And apply COLD compresses - causes vasoconstriction (so that damage doesn’t spread)
Management of vinca alkaloid extravasation
Antidote is hyaluronidase
-enzyme that breaks down the vinca alkaloids
And apply WARM compresses - also helps break down the vinca alkaloids
What is the biggest toxicity associated with chemo?
Neutropenia (kills WBCs)
How to calculate absolute neutrophil count (ANC)?
ANC = 10 x WBCs x (segs + bands)
e.g.
WBC = 1.6 x 10^3
Neutrophils (segs) = 48%
Bands = 5%
ANC = 10 x 1.6 x (48+5) = 848
Neutropenia management
We expect some degree of neutropenia with chemo, but if ANC < 1000 then we delay the start of the next cycle (wait for counts to be above 1000 before starting again)
-note - delaying the cycle is not a good thing (and if you have to delay one cycle you will probably have to delay the next) - it is better to give smaller doses than to delay each time
WBC Nadir
WBC Nadir is the lowest point of WBC following chemo
This is usually 7-12 days following chemo and should only last 5-7 days, then come back up
So patients should feel their worst around 7 days after chemo (and this lasts 5-7 days) - they should stay away from others, wear mask, etc - the basically have no immune system at this point and are most susceptible to infection at this point
So this is why the cycle is around 21 days - you give chemo, then nadir starts (day 7) then for about another 7 days they are in their highest risk of infection (nadir lasts) - then recovery for another 7 days - then given chemo again (cycle starts over)
When should colony stimulating factors be used?
Colony stimulating factors shorten the neutropenia following chemotherapy
They can be used if…
-neutropenia lasts longer than 5-7 days
or
-patient has a 20% chance of developing febrile neutropenia
What are the 3 colony stimulating factors
- Filgrastim (brand Neupogen)
- Pegfilgrastim (brand Neulasta)
- Sargramostim (brand Leukine)
ADRs of colony stimulating factors (3)
Fever
Bone pain
Injection site reactions (with Neupogen)
Filgrastim
Brand - Neupogen
Granulocyte colony stimulating factor (GCSF)
Given as a subq injection by the patient at home daily, until ANC is above 2000
-not a good option if patient doesn’t want to stick themselves or there are non compliance concerns
Pegfilgrastim
Brand - Neulasta
PEGylated filgrastim (colony stimulating factor)
1 time dose - on body subq injector - placed on patient by nurse, set to deliver dose 48-72 hours after chemo
-it beeps when it is done delivery the dose - patient call pull it off and throw it out
-easier and preferred by most patients
Sargramostim
Brand - Leukine
Granulocyte macrophage colony stimulating factor (GM-CSF)
This is an infusion has to be done in the clinic
Rarely used for solid tumors, very potent - tends to be used for patients undergoing bone marrow transplants
Alopecia considerations
Occurs 10-14 days after chemo
Is usually reversible (hair will grow back)
Psychological component - greater in women then men
Cooling caps - used to be recommended … they vasoconstrict the hair follicle so that the chemo agent doesn’t reach it (to prevent hair from falling out) - however … they also increase the risk of CNS metastasis as a result - so they should NOT be recommended in patients
(may be used in certain cancers that are not likely to spread to CNS, but most are, so not generally recommended)
Which agents can cause alopecia?
*doxorubicin
*ifosfamide
*etoposide
*taxanes
*vinblastine
*irinotecan
methotrexate
Oral mucositis
Killing of epithelial cells occurs with chemo agents - so mouth sores are common
-can happen in mouth, throat, or GI tract
-makes it painful to eat - PEG tubes may be needed for some patients
Usually - lidocaine is used to help with symptoms
-swish and spit/swallow
-should be avoided in patients under 3 years (can be systemically absorbed and lead to seizures)
-avoid eating 60 minutes after use due to risk of impaired swallowing and aspiration
