What is the aim of chemotherapy (4)
Eradicate a cancer (over or covert)
Prevent the death of the patient
Prolong the life of the pt / palliative care (DEC sx /make life better)
Cancer is an accumulation of ________ (2) and is a _______ process
What is the phenotypic change of cancer?
Cancer is an accumulation of GENETIC ALTERATIONS and is a multi-step process
Transformation - change to the malignant phenotype
What are the phases of the cell cycle?
(describe the basic fxn of each)
How do tumor cells differ?
Phases of the cell cycle: G0, G1, S, G2, M
G0 = non-dividing
G1= Synthesis of compenents needed for DNA synthesis
S = DNA synthesis
G2 = synthesis of components needed for mitosis
M = mitosis
Tumor cells have survival advantage over the surroudning cells;
CONTINUED CELL DIVISION occurs until the cancer becomes clinically detectable
Describe the growth curve of cancer cells:
Approx how many cell divisions turn a subclinical tumor to a clinically detectable tumor?
What two important factors allow for further growth of the tumor?
what is the underlying
A cell gains the ability to continually divide/unchecked division and goes a period of latent growth prior to clinical detection =subclinical/latent phase
It is YEARS (believed ~30 doublings = 1 billion cells) before a cancer becomes of "clinical growth" and person will have some symptoms
Because the DNA is inheritably unstable ---> further mutations will allow for two important factors:
1. Clones that gain the ability to metastasize
2. Clones that gain the ability to be chemoresistant (biggest reason why chemotherapy will fail the patient = drug resistance)
these gains evolve by chance, random, spontaneous events - most likely before medicaiton has even begun
What is tumor heterogenity?
Tumor cell heterogeneity = although cancers look similar under the microscope, the cells can be categorized w/respect to a # of different characteristics -
Examples: growth fraction (dividing cells / total cell number) metastatic potential and process
Resistance / sensitivit to chemotherapy
some of the cells may have the capability to metastasize, some may be sensitive to chemotherapy others resistance
Also, neoplastic cells may be in different parts of the cell cycle (some could be actively dividing while others aren't)
What are the steps to the metastatic process? (4)
When does this process usually occur?
From primary site of cancer --> distant organs via hematogenous process or other processes = metastatic
1. Clonal evolution - produce cells that gain this ability
4. Growth in the distant metastatic site
this usually cocurs during the latent or subclinical phase of tumor growth
(example if a person has breast cancer that has metastasize to the liver, the person has metastatic breast CA to the liver but does not have both breast CA and liver CA)
What is the TNM classification of cancer staging?
What are the three basic stages?
What are the predictive prognosis based on based on the TNM?
TNM classifies the stage of cancer / extent of disease at the time of diagnosis
Determines prognosis and treatment
1- cancer localized to the organ of origin
2- cancer localized to the organ of origin with spread to the regional draining lymph nodes
The stage assess the RISK THAT THE CANCER MAY HAVE UNDERGONE THE METASTATIC PROCESS during the subclinical or latent period of growth
Prognosis: Local > local-regional > metastatic
Metastatic rate: local-regional > local
What accounts for the majority of failure of chemotherapy?
How can we determine the ability of chemotherapy to cure a tumor?
Malignant cell resistance to chemotherapy accounts for the failure of chemotherapy to completely eradicate a malignant process. Resistance to chemotherapy could occur at any time during the natural history of a cancer
The ability of chemotherapy to cure is inverseley proportional to the tumor burden (Skipper Hypothesis)
the more # of tumor cells = the least likely to cure
What are some types of cancer treatments (4):
Surgery to remove all cancerous cells
Chemotherapy - drugs given to patients w/malignant process
Other localized therapies - embolization (cut off blood supply), radiofrequency ablation, regional organ perfusion
What is chemotherapy designed to do?
What are the different possible outcomes?
How can you asses the response to chemotherapy (4):
Chemotherapy are drugs developed/designed/selected to KILL mammalian cells; reduce the total body cancer burden by killing cancer cells
Complete eradication? pt will be cured (all cells sensitive to chemo)
Incomplete? life of the patient may be prolonged (some or all cells resistant to chemo); unless you can find OTHER chemo drugs that pt could be sensitive to, patient won't be cured
Assessment of response to chemotherapy:
cat scan to obtain baseline, give TX + new cat scan....
partial remission (>50% redution + no new lesions)
stable dz - no new growth
progression of disease - bigger or new sites
What is the effect of chemotherapy on non-neoplastic / healthy cells?
The drug is taken up by both cancer and normal cells. The effect of the drug on the normal cells is responsible for the TOXICITY / side effects of the drug
The MOA of the drug is responsible for the lethal effect on the neoplastic cell = cytotoxicity (may or may not be responsible for side effects of the drug)
What are examples of chemocurable cancers?
disseminated testicular CA, some lymphomas, some leukemia's and hodgkin's diseaes
Chemocurable cancers never develope resistance to chemotherapy
What are the two categories of chemotherapies?
Cell cycle specific
Cell cycle non-specific
What are the phases of drug development? (4)
1. Preclinical testing - drug co are responsible; lots of pre-work
background info, compared to what's currently available; needs to meet a need
2. Phase I clinical trials - determine dose and dose limiting toxicity
3. Phase II clinical trials - determine activity
4. Phase III clinical trials - determine efficacy
What does scheduling refer to? (4)
What effect does scheduling have on cytotoxicity and toxicity?
Effective cancer treatment require the repeated cyclical administration of drug/s
Scheduling refers to:
Dose (mg/M^2 of body surface area), route of administration (most IV), frequency of administration and cycle length (21-28 day intervals to allow for pt to recover from side effects of drug tx)
There is both: schedule dependent cytotoxicty (the efficacy of cancer cell kill depends critically on the schedule of drug administration) and scheduled dependent toxicity (the types of side effects the patient experiences dependent upon the schedule)
(frequency of neoplastic cell death / side effects)
What are the constitutional toxicities of chemotherapy (4):
N/V (meds for it -usually develop within hours)
Loss of appetite (varies)
Fatigue (most of patients - cyclical; expected and varies)
Except for N/V, most are NOT acute in onset
What are the toxicities due to the effect of chemotherapy on normal dividing cells? (5)
Transient myelosuppression - temp depression of the blood cell counts resulting from killing of bone marrow precursor cells; 10-14 days
Temporary hair loss (varies) - 2 to 3 weeks
GI Tox -mucositis or sore mouth, diarrhea / enteritis; due to an effect of the drug on the normal dividing cells of the oral and small intestinal mucosa; ~ 1 week after treatment
Sterility (esp women close to menopause; drug dependent, no INC incidence of birth defects try to avoid pregnancy during tx)
Second neoplasms (not common)
Mostly NON-TARGETED therapy
What drugs could be given to counter nausea and vomiting? (5)
What are some critical side effects?
(only side effect that could happen WHILE you're getting chem)
Dexamethasone (SE: elevated surgars-careful in diabetics, feeling excess energy, flushing; reversal of sleep/wake cycle)
Prochlorperazine (extrapyramidal side effects); compazine
Lorazepam (esp for anticipatory component)
5-HT3 receptor antagonist (ondansetron, granisetron) Block 5-HT3 receptors located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema
SE: QT prolongation occurs in a dose-dependent manner; cases of Torsade de Pointes have been reported. AVOID ONDASETRON in patients with congenital long QT syndrome; constipation in 9% of pt, H/A and diarrhea could also occur;
Neurokinin 1 receptor antagonist in area postrema (aprepitant) - effective in acute and delayed n/v for highly emetogenic chemotherapy regimnes (effective for pre, acute and delayed n/v, and with highly emetogenic regimens)
requires pre-medication assessment of the emetogenic potential of the cytotoxic regimen
What are some types of stomatitis supportive care? (3)
What should be considered?
Stomatitis = inflammation of the mucus membranes of the oral cavity --> grey-white painful patches
Palliative care with mouth rise: diphenhydramine, maalox/mylanta, viscous lidocaine, +/- glucocorticoids (prednisone)
Possible tx for oral fungal infections/THRUSH: Nystatin oral suspension swish and swallow
Freq requires narcotic pain medication
Condier effect on oral intake (fluid and caloric)
What are supportive care for enterititis? (3)
What are important considerations? (2)
Anti-diarrheal agents AFTER infectious etiology excluded *including c. diff diarrhea* (assay for c. diff toxin):
Loperamide (imodium), diphenoxylate, atropine (lomotil) after infectious etilogy excluded
Octreotide (IV or subcu) in severe cases
What organ specific toxicity does anthracyclines carry?
What organ specific toxicity does bleomycin carry?
what organ specific toxicity does cis-DDP carry?
Myelosuppression is usually what type of toxicity?
What cells are affected/what could be expected?
Dose-limiting toxicity (for most drugs) = limits the amout of drug that can be given
Cells affected: WBC, RBC, platelets
WBC - not acute
Polys, bands (immature), ANC (note segmented neutrophils)
Hemoglobin (RBC is usually affected minimally and severe anemia req transfusions as a result of administration of anti-cancer drug is unusual)
Platelets - not acute
platelets and total WBC, PMN and band count generally fall 10-14 days following administration of drug because the effect of chemo is usually not on the formed elements but rather on the precursor cells of hte platelets and teh WBC is temporarily halted.
~ 3rd week, bone marrow is back to normal --> blood counts usually recover btw days 21 - 28 days following administration of chemo
There is cyclical fall / rise in the total WBC, PMN and band count.
Drug is administered day 1
How can is the absolute neutrophil count determined?
What is the importance of ANC?
When should critical precautions be taken?
ANC (absolute neutrophil count) =
total WBC (fraction of PMN + fraction of bands)
If ANC falls below 500, the pt is at an increased risk for infection from endogenous bacteria
Low WBC --> bacteremia!
*Pt with fever > 38.5/100.5 + ANC < 500 --> HOSPITALIZE, start on broad spec antibiotics until ANC > 500
Could neutropenia be prevented?
What precautions could be given?
Neutropenia CANNOT be prevented
The duration of neutropenia could BE SHORTENED with the administration of filgrastim (daily subcu injections) or peg-filgastim (every 3-4 week adim) when started 24 hours after chem adm = colony stimulating factors
CSF are usually not given when the pt is already neutropenic; best results when given within 24 hours of therapy
Infection precautions are required- handwashing!! low bacterial diet!
Although PMN count is usually affected more than platelet count, when should we expect the platelet count to fall?
When should we take precautions/actions towards improving platelet count/what should be avoided?
When should we expect platelet count to recover?
Platelets may fall between day: 10-14
Recover: 21-28 days
When platelet count falls below <10,000 OR patient is bleeding --> platelet transfusions are usually given to maintain platelet count about this threshold
AVOID: apsirin and other non-steroidal anti-inflam agents!
No safe pharmacologic agents to raise and support count
Megakaryocyte growth factors (interlukein-11 / Oprelvekin), can decrease the freq of platelet transfusiosn after chemo BUT major side effects include fluid retention and atrial arrhythmias
NOT used often in supportive care of the cancer pt due to to expense and toxicity
Normal platelet count: 150,000/mm3
When can neutropenia be expected?
What is the nadir?
Generally occurs 10-14 days after last dose of chemo (some agents are delayed and seen 4-6 weeks after chemo)
Nadir = lowest neutrophil count
What type of anemia could be observed with myelosuppression related to chemotherapy?
What types of treatment are available?
Anemia --> deficiency of RBC due to myelosuppression (chemotherapy toxicity) -- NORMOCYTIC anemia
SX: fatigue, dyspnea, tachycardia, or none
TX: usually no treatment but could be given-
Erythropoietin and iron (avoids transfusion)
Daropoietin and iron (avoids transfusion)
Blood transfusion (best, quick fix but could come w/risk)
Risks of erythropoetic stimulating agents (shortens time to progression and dec survival, thromboembolic events, benefits include imporved RBC count and avoid transfusions -- is this an approrpiate trade off? safe but not used to simply Improve the RBC count)
What are vesicants?
How do they work?
What are examples of vesicants? (4)
Vesicant = agent that causes tissue blistering / blister agent / vesicatory
some drugs are vesicants
Highly reactive chemicals that combine with proteins, DNA and other cellular components --> cellular changes immediately after exposure
Examples: vincristine, vinblastine, doxorubicin, daunorubicin
What is cumulative toxicity?
Toxicity seen with some drugs, which damage a particular organ a small amount and with each administration of the drug, the toxicities accumulate and becomes irreversible -- until the organ cannot function properly b/c too much of it has been damaged
examples are those associated with anthracycline, bleomycin and cis-DDP