Term
A patient presents with newly diagnosed lung cancer that is metastatic to both the brain and the spine.
What treatment modalities do you think may be appropriate for this patient? |
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Definition
All three modalities may be appropriate:
Surgery: for brain metastasis if single lesion; for primary tumor or spine metastasis if an emergency condition (compressing the spinal cord or lung tumor compressing superior vena cava)
Radiation: may be appropriate for brain metastases (whole brain radiation), spine metastasis if painful, possibly to primary tumor if particularly large or bulky in an emergency condition
Chemotherapy: appropriate for widespread and metastatic disease |
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Term
A new chemotherapy drug is approved that works by inhibiting histone production. Histones are proteins required for DNA synthesis.
Is this new drug cell-cycle specific or cell-cycle nonspecific?
If cell-cycle specific, in which phase does it have its action? |
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Definition
| Cell-cycle specific, works in G1 phase. |
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Term
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Definition
Disease caused by uncontrolled division of abnormal cells in a part of the body
• Uncontrolled cell proliferation
• Decreased cellular differentiation
• Inappropriate ability to invade surrounding tissues
• Ability to establish new growth at ectopic sites |
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Term
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Definition
So how does cancer develop? We have both endogenous factors, which are already in the body, and exogenous factors, which are outside of the body, that cause genomic instability, leading to either activation of cancer promoter genes or inactivation of tumor suppressor genes. And the activation of tumor promoter genes or inactivation of tumor suppressor genes is what leads to disturbance of growth and clonal expansion, loss of differentiation, or invasion and ectopic survival of these cells in other parts of the body.
Some endogenous factors may include existing gene mutations associated with cell growth, cancer, or a family history of cancer. Exogenous factors are wide and range from smoking status, level of activity, occupational exposures, diet, alcohol use. There are many, many exogenous factors.
Now if we look at the bottom half of the slide, this shows the progression of normal epithelium into an invasive carcinoma. So all solid tumors really start off as being normal epithelium. From there, the epithelium can turn into what we call hyperplasia or adenoma. And what hyperplasia is it's an enlargement of a portion of tissue just due to increased cell growth of normal cells. Adenomas are benign tissue growth.
However, adenomas or hyperplasia can lead to what's called dysplasia. And dysplasia is the presence of abnormal growth or abnormal development or maturation of cells. And this part of the process of normal epithelium to invasive carcinoma is often reversible.
So you can see there the carcinomas in situ. They're very variable in being able to cause invasive carcinoma or not. And as was said, these can often be excised at this point or reversible. However, there are times when dysplasia does lead to invasive carcinoma and perhaps also metastasis at distant sites. |
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Term
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Definition
This next slide basically shows what is a normal tumor growth curve. And it's a theoretical model of tumor growth. The green line on the slide shows the overall relationship between the percentage of actively dividing cells, the length of the cell cycle, and the rate of cell loss. And on the x-axis, we have time. And on the y-axis, we have the number of tumor cells.
So initially, as you can see, growth is very slow due to the small number of cancer cells that are actively dividing. However, over time, this growth increases rapidly and exponentially. And then as the tumor enlarges, growths slows and eventually reaches a plateau just due to the limitation of available nutrients that are required for additional growth.
Tumors are generally considered clinically detectable at 1.10 to the nine cells or one billion cells. And as you can see, by the time the tumor is detectable, the large majority of growth has already occurred. And just for reference, the lethal tumor burden is generally considered to be one kilogram. |
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Term
| Cancer Treatment Modalities |
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Definition
• Surgery
• Radiation
• Chemotherapy |
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Term
| Surgery Treatment for Cancer |
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Definition
- Remove localized tumor with adequate margin of normal tissue
• Removal of lymph nodes may be necessary
- Metastatic disease
• Local control
• Single site of metastasis
- Emergencies
- Prevention
• Breast cancer
• Colon cancer |
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Term
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Definition
• Delivers energy to kill malignant cells in a pre-specified region
- Damages cancer cell by ionizing atoms of DNA chain
- Causes double-stranded breaks leading to cell death
• May be combined with surgery and/or chemotherapy
• Can treat localized metastatic disease |
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Term
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Definition
Useofchemicalsubstancestocausecelldeath • Cancers with faster rates of growth
• Metastatic disease
• Neoadjuvant
-Larger area of disease at diagnosis
- “Shrink” tumor for possible surgical resection
• Adjuvant
- Given after localized treatment to prevent recurrence
- Eradicates clinically undetectable/micrometastatic disease |
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Term
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Definition
- Cure
• No evidence of disease
- Control
• Stabilize disease • Prolong survival
- Palliation
• Relief of symptoms |
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Term
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Definition
This next slide and graph depicts chemotherapy and tumor growth in relation to how often and when and the modalities and goals of when we're giving chemotherapy. So the red line on this slide depicts tumor growth. And if we look at the green line, the light blue line, and the dark blue line, each peak of these lines depicts an administration of chemotherapy.
So we'll start at the bottom with the green line. This shows early surgical removal of a primary tumor. And as you can see, we go down on this graph. So we already have a decrease, a large decrease, in the number of cancer cells that may be remaining in the body.
Administering chemotherapy will remove any persistent secondary tumors. And as we can see, the total duration of therapy does not have to be as long when chemotherapy alone is used. And our goal is to get it down to a number of zero cancer cells.
Now we'll move on to the light blue line. And as you can see, chemotherapy administration is started very soon or right at the time of diagnosis. We have more intensive and frequent treatment. And this leads to adequate dosing and a successful kill rate of any tumor cells in the body. So both the dark green light line and the light blue line are examples of curative chemotherapy.
The dark blue line is an example of either control or palliative chemotherapy. So as you can see, the number of administrations of chemo is less, and it is less frequent. So we may be able to prolong survival for a period of time with control, or we're basically just trying to help with any symptoms in the palliative setting.
A caveat to looking at this graph or using this graph is that a lot of solid tumors have a non-constant growth rate. And simply, growth rates vary significantly among the tumor types. There are some tumors that are more responsive to chemotherapy than others. And also, response to chemotherapy varies quite a bit among patients. But in general, starting chemotherapy treatment as early as possible and maintaining consistent chemotherapy is very important, as well as not stopping treatment too soon before all cancer cells have been eliminated if our goal is indeed cure of the tumor or cure of the cancer. |
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Term
| Oncology Pharmacologic Options |
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Definition
• Chemotherapy
- Cell cycle specific
- Cell cycle nonspecific
• Biologic therapy
• Targeted therapy
- Hormone therapy
- Small molecule inhibitors
- Monoclonal antibodies
• Immunotherapy |
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Term
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Definition
• Phases of replication and division for both normal and neoplastic cells
• Some chemotherapy agents exert their cytotoxic effect on cells that are in a certain phase of the cycle
- Cell cycle specific
• Some chemotherapy agents exert their effect without respect to cells’ phase in the cycle
- Cell cycle nonspecific |
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Term
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Definition
We take a closer look at the cell cycle itself, which you may remember from your biology class. We'll start by talking about the G1 phase. And this is the first phase that occurs when a cell starts to divide or cell starts to sort of decide that it's going to divide. G1 is a phase of protein synthesis.
And in this phase, enzymes that are needed for DNA synthesis are made. From there, the cell goes into the S phase, or the synthesis phase. And in this part, duplicate copies of DNA are made. From there, the cell moves to the G2 phase. This is also a phase of protein synthesis, and proteins needed for that actual division of the cell are made.
At this G2 phase, the cell also checks for any errors that may have been made during the duplication of chromosomes and fixes these errors. When the G2 phase is complete, the cell then moves into the M phase or mitosis, which is the actual division of the cell, the DNA, and the cell contents themselves. From the M phase, the cell can move back into the G1 phase and divide again, or it can move into the G0 phase, and we call this cell cycle arrest
So the cell will not divide any more, and it will carry on its specialized functions within the body. So generally, there are three types of cells. There are those that are always fully differentiated and carry on normal cell function. And these are cells that remain in the G0 phase and never divide. And then we have cells that are continually proliferating and dividing, so constantly going through this cell cycle.
And then third, there are cells that are not currently dividing but may still enter into the cell cycle. And all three of these types of cells occur in both normal tissue and in cancerous tissue. So cell cycle specific chemotherapy agents-- these work most well on cells that are rapidly dividing or cells that have a very high turnover rate. |
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Term
| Cell Cycle Specific Chemotherapy |
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Definition
Rapidly dividing cells or cells with high turnover rate
• Includes non-malignant cells
- Bone marrow → myelosuppression
- Gastrointestinal tract → nausea, vomiting
- Hair follicles → alopecia
Plateau of killing effect
• After a certain dose, further dose increases will not result in increased cell death
Time and frequency of exposure important |
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Term
| Cell Cycle Nonspecific Chemotherapy |
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Definition
• Act at any phase of the cell cycle
• Depend on cell proliferation for activity
- Same toxicities as cell cycle specific
- Long-term effects • Fertility • Secondary cancers
• Linear killing effect
- Increasing the dose increases the fraction of cell kill |
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Term
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Definition
This next slide contrasts the dose-response curves between cell cycle specific chemotherapy on the left and cell cycle nonspecific chemotherapy on the right. So as we can see, with cell cycle specific agents, we reach this plateau of killing effect at a certain dose.
And if you were to continue to increase the dose any more, it wouldn't lead to any further cancer cell kill. However, on the right, with cell cycle nonspecific chemotherapy, we can still see this linear kill effect. So as we increase the dose of the chemotherapy, we have a linear increase in the amount of cell kill until basically all of the cancer cells are killed within the body. |
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Term
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Definition
This graph shows where certain specific chemotherapy classes have their action within the cell cycle. And the agents that we'll be talking about today, if we start in the M phase, we'll be talking about the vinca alkaloids and the taxanes. And that's on the top of the slide of the M phase. We'll also be talking about some of the S phase chemotherapy medications, particularly the antimetabolites.
And then lastly, we'll also talk about cell cycle nonspecific medications. And those are the ones in the middle of the graph, the alkylating agents, nitrosoureas, and some of the anti-tumor antibiotics |
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Term
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Definition
- Intrinsic resistance
• “Innate” resistance without exposure to drug
- Acquired resistance
• Resistance develops through selection after drug exposure |
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Term
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Definition
• Achieve maximum cell kill
• Broad coverage for intrinsically resistant cells
• Prevent development of resistance
• Choose agents with:
- Activity as single drug
- Different mechanisms of action
- Different resistance patterns
- Different toxicities
• Goal: optimal doses at optimal intervals |
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Term
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Definition
• Commonly known as “salvage therapy”
• Potentially curative combination chemotherapy after initial therapy failure or recurrence
- Attempt to overcome resistance • Different agents • More agents • Higher doses
- Usually more toxic
• Mostoftenusedinleukemiaorlymphoma
- May mean either a second attempt or last attempt for cure |
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Term
A patient is scheduled to receive a combination chemotherapy regimen consisting of cisplatin and gemcitabine.
Which most important adverse effects and toxicities would you counsel this patient about? |
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Definition
General toxicities: myelosuppression, if experience a fever go to ER right away!
Cisplatin: high risk of nausea/vomiting, making sure the patient is drinking A LOT of fluid throughout the day, neuropathy possible over time.
Gemcitabine: flu-like symptoms for 2 to 3 days after treatment that should resolve. |
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Term
| Cell Cycle Specific Chemotherapy Classes Antimetabolites |
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Definition
Methotrexate, Gemcitabine, Pemetrexed, Cytarabine,
Fluorouracil, Fludarabine, Cladribine, Pentostatin, others |
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Term
| Cell Cycle Specific Chemotherapy Classes Microtubule agents |
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Definition
• Taxanes
- Docetaxel,Paclitaxel
• Vinca Alkaloids
- Vincristine,Vinblastine,Vinorelbine |
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Term
| Cell Cycle Specific Chemotherapy Classes Topoisomerase I inhibitors |
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Definition
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Term
| Cell Cycle Specific Chemotherapy Classes Topoisomerase II inhibitors |
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Definition
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Term
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Definition
• Chemicalthatinhibitstheuseofametabolite that is part of normal cell function
• Oftensimilarinstructuretothemetabolite
- Non-functional analog
• Haltcellgrowthanddivisionbyinterferingwith DNA/RNA synthesis (S phase)
- Analogs of purine and pyrimidine DNA/RNA base pairs • Adenine-thymine • Guanine-cytosine • Uracil |
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Term
| Antimetabolite Classes Folate antagonists (inhibit purine synthesis) |
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Definition
| • Methotrexate • Pemetrexed • Pralatrexate |
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Term
| Antimetabolite Classes Pyrimidine analogs |
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Definition
• Cytarabine
• Gemcitabine • Fluorouracil • Capecitabine • Azacitidine
• Decitabine |
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Term
| Antimetabolite Classes Purine analogues |
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Definition
• Cladribine
• Clofarabine
• Fludarabine
• Mercaptopurine • Pentostatin
• Thioguanine |
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Term
| Antimetabolite (other class) |
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Definition
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Term
| Antimetabolites Mechanism |
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Definition
• Similar base is incorporated into DNA (or RNA) strand during replication (or transcription) instead of natural base
• Antifolates inhibit formation of purines
- Inhibits lengthening of DNA or RNA strand
- Arrest of replication leads to cell death |
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Term
| Antimetabolite Toxicities |
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Definition
• Myelosuppression
• Mucositis/stomatitis
- Ulceration in mouth or gastrointestinal tract
• Nausea/vomiting
- Low to moderate risk
• Alopecia
- Dose dependent |
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Term
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Definition
• May affect all three cell lines
1. White blood cells → neutropenia 2. Red blood cells → anemia
3. Platelets→thrombocytopenia
• Most common “dose-limiting” toxicity of cytotoxic chemotherapy
- Side effect serious enough to prevent an increase in dose
- Dose-reduction often required |
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Term
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Definition
• Riskofinfectionrisesastheabsoluteneutrophil count (ANC) decreases below 1,000
- Severity, duration, frequency
• Neutropeniareducesoreliminatesnormal symptoms of infection
- Except fever
• Febrileneutropenia
- Temperature >100.4 oF for 1 hour (or single temperature of 101 oF) and ANC less than 500 (or less than 1,000 and expected to fall)
- Oncologic emergency |
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Term
Antimetabolite Specific Toxicities
• Nephrotoxicity with high doses |
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Definition
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Term
Antimetabolite Specific Toxicities
• Diarrhea
• Hand-foot syndrome
• Cardiac vasospasm |
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Definition
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Term
Antimetabolite Specific Toxicities
• Skin rash |
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Definition
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Term
Antimetabolite Specific Toxicities
• Neurotoxicity • Rash |
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Definition
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Term
Antimetabolite Specific Toxicities
• Fever
• Flu-like symptoms |
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Definition
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Term
| Microtubule Agents: Taxanes |
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Definition
• Microtubulesplayarolein migration of chromosomes to opposite sides of the cell in mitosis
• Taxanespromoteassembly of microtubules then stabilize them to inhibit movement
- Arrests the process of mitosis (M phase)
- Inhibits DNA, RNA, and protein synthesis |
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Term
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Definition
This slide depicts, more closely, the actual taxane mechanism. So if we look on the left, we see that the microtubules are attached to the chromosomes and are pulling the chromosomes to opposite sides of the cell.
Microtubules are made up of alpha-tubulins and beta-tubulins. And, basically, it's the assembly and disassembly of these tubulins that causes the movement of the microtubules and the movement of chromosomes to opposite sides of the cell.
So, as you can see, taxanes bind to the beta-tubulin and they prevent depolymerization, so it prevents this disassembly of the microtubule. So it arrests the microtubule where it is in the cell, and prevents any further movement of the chromosomes to opposite sides of the cell. |
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Term
Has Toxicities:
• Myelosuppression
• Hypersensitivity reactions
• Peripheral neuropathy
• Edema/fluid retention
• Nausea/vomiting • Low incidence |
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Definition
Taxanes
• Peripheral neuropathy • Paclitaxel > docetaxel
• Edema/fluid retention • Docetaxel |
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Term
| Microtubule Agents: Vinka Alkaloids |
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Definition
• Inhibit microtubule formation
• Mitotic spindle cannot form
• Prevents mitosis from occurring (S phase into M phase)
• May also interfere with nucleic acid synthesis |
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Term
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Definition
| This slide depicts the vinca alkaloid mechanism. It's thought that the vinca alkaloids interacts with the central portion of the beta-tubulin subunit, which is the same unit that the taxanes attach to, and prevent any polymerization into microtubules. So the microtubule structure cannot form and, therefore, we can't have separation of the chromosomes or the cell into two separate cells. |
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Term
Has Toxicities:
• Myelosuppression • Usually mild
• Constipation
• Peripheral neuropathy
• Nausea/vomiting • Minimal risk |
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Definition
Vinka Alkaloid
• Peripheral neuropathy: Vincristine > vinblastine > vinorelbine |
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Term
| Chemotherapy-Induced Peripheral Neuropathy |
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Definition
- Sensory neuropathy
• Disruption of microtubule function interferes with axonal transport
• Numbness and burning
• Starts from extremities of body
(feet and hands) and can extend to legs or arms
- Dependent on cumulative dose of chemotherapy agent
- Motor neuropathy possible
• Progressive muscle weakness
• Paclitaxel, vincristine |
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Term
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Definition
-Nitrogen mustards
• Cyclophosphamide, ifosfamide, chlorambucil, others
- Nitrosoureas
• Carmustine, lomustine
- Platinum complexes
• Cisplatin, carboplatin, oxaliplatin
- Antitumor antibiotics • Doxorubicin, others |
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Term
| Alkylating Agents Mechanism |
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Definition
- First “discovered” chemotherapy • WWII mustard gas
- Positively charged electrophilic molecules
• Covalently bind alkyl group (R - CH2+) to nucleophilic sites on DNA (nitrogen on guanine)
• Make cross-links between or within DNA strands leading to breaks
• Cause mispairing
• Inhibit replication and transcription |
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Term
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Definition
So, ultimately, alkylating agents inhibit replication of DNA and transcription of RNA. This slide depicts, more closely, the actual mechanism of alkylating agents. So I've highlighted the alkyl group on this particular nitrogen mustard. And, as you can see, it's this alkyl group that binds to the DNA.
And then we also have, on this nitrogen mustard, a second chloride. So we have a second alkyl group on the other side of the molecule, which can bind to a second DNA base. And this is what causes this cross-link in the DNA strand, which inhibits replication from continuing.
Cells do have repair mechanisms that can excise these errors. However, especially with giving these chemotherapy agents over time, any excessive DNA damage or DNA cross-linking can initiate apoptosis-- or death of the cell-- if the level of DNA damage exceeds the repair capacity. And this is obviously the goal of what we want in giving chemotherapy-- to be able to kill these cancer cells. |
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Term
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Definition
- All contain platinum element
• “Platin” suffix
- Form DNA cross-links in similar way to nitrogen mustards
- Renal function
• Caution with use of cisplatin
• Carboplatin dosed based on creatinine clearance |
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Term
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Definition
- Also called “natural products”
• Initially isolated from plants, fungi, or bacteria • Newer semisynthetic or synthetic compounds
- Anthracyclines
• Doxorubicin, daunorubicin, idarubicin
• Products of fungus Streptomyces percetus
• Several modes of action • Intercalation of base pairs (cell cycle nonspecific) • Inhibit topoisomerase I and II (involved in DNA unwinding and repair → S and G2 phase) |
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Term
Has toxicities:
• Myelosuppression
• Nausea/vomiting
• Nephrotoxicity
• Require aggressive preventative oral or intravenous hydration • Neuropathy
• Cardiac
• Dose-limiting toxicity, close monitoring required |
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Definition
Alkylating Agents
• Myelosuppression
• High incidence, may be severe with nitrogen mustards
• Nausea/vomiting
• Moderate to high risk with platinum agents
• Nephrotoxicity
• Ifosfamide, cyclophosphamide • Cisplatin
• Require aggressive preventative oral or intravenous hydration • Neuropathy
• Platinum agents
• Oxaliplatin (cold-induced) • Cardiac
• Anthracyclines
• Dose-limiting toxicity, close monitoring required |
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Term
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Definition
So, like I said, we'll talk a little bit more about chemotherapy-induced nausea and vomiting-- CINV-- in and of itself. There are numerous pathways that can lead to the sensation of nausea and vomiting after a patient has received chemotherapy. The most implicated pathway with regards to CINV is through the stomach or through the intestine.
And, as you remember, chemotherapy can cause damage to these cells in the GI tract. And this leads to the release of serotonin. Serotonin in the GI tract then transmits to the centrally acting chemoreceptor trigger zone in the brain. And then, from there, it goes to the vomiting center, which is actually what causes the vomiting reflex in patients.
The serotonin pathway is what most often leads to acute nausea and vomiting, so either nausea or vomiting that occurs within 24 hours after receiving chemotherapy. And we have serotonin-- or 5-HT3 antagonists, as you can see are circled on the slide here-- and we use these to prevent this mechanism of nausea or vomiting.
Dopamine is a second neurotransmitter that's released, both in the GI tract, but also centrally in the brain. And this circle shows that inhibitors of dopamine, as well as histamine antagonists and cannabinoids, work centrally to inhibit transmission of the serotonin or dopamine to the vomiting center and to try to prevent vomiting from occurring.
Sometimes, higher cortical centers involving memory and anticipation can lead to nausea and vomiting, especially if a patient has previously experienced nausea and vomiting with a previous cycle of their chemotherapy. And benzodiazepines are most effective in inhibiting this type of transmission to the vomiting center.
I will note that one pathway not listed in this slide involves the centrally-acting substance P. Substance P and its associated NK1 receptors are located primarily in the brain. And these can be activated later in regards to when the chemotherapy was administered.
So substance P and NK1 are associated with delayed CINV. And this is delayed meaning more than 24 hours after receiving chemotherapy. And we have, on the market, NK1 antagonists that work to inhibit this type of transmission to the vomiting center. |
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Term
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Definition
- Acute
• Within first 24 hours after treatment
- Delayed
• Beyond 24 hours after treatment
- Anticipatory
• Prior to receiving subsequent cycle of chemotherapy
• Conditioned response
- Breakthrough or refractory
• Preventative medications not effective
Level 4>90%, Level 3 30-90%, Level 2 10-30%, Level 1 <10% |
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Term
|
Definition
- Prevention!
• High-risk agents: NK-1 antagonist + 5HT3 antagonist + steroid
• Moderate-risk agents: 5HT3 antagonist + steroid
• Low-risk agents: 5HT3 antagonist or steroid
• Minimal-risk agents: medication not needed
- Breakthrough
• 5HT3 antagonists, dopamine antagonists, anticholinergics
• Multiple medications and routes of administration
- Anticipatory
• Benzodiazepines |
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Term
|
Definition
- The use of living organisms or derived substances for treatment
• Usually to activate the immune system
- Most laboratory-derived or synthesized
• Cytokines
• Cancer vaccines
• T-cell therapies
• Monoclonal antibodies |
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Term
| Biologic Cancer Therapies: Cytokines |
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Definition
Interferon alfa
• Multifunctional cytokine
- Binds to receptor on cell surface → gene transcription → produces IL-4
- IL-4 induces T helper cells→stimulate B cells to produce antibodies and detect foreign antigens
• Previously used for renal cell carcinoma
• Still used in melanoma after excision
-Interleukin-2
• Unknown exact mechanism for antitumor effect
- Causes enhancement of lymphocyte cytotoxicity
- Induces natural killer cell activity
• Used in renal cell carcinoma and melanoma |
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Term
| Biologic Cancer Therapies |
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Definition
Vaccine therapy
-Bacillus Calmette-Guérin (BCG)
• Livetuberculosisvaccine
• Instilledintobladderfortreatmentof superficial bladder cancer
• Inducesstronglocalizedimmune response to kill cancer cells
Autologous cellular immunotherapy
-Sipuleucel-T
• Antigen-presentingcellscollectedfrom patient’s blood
• Cells“activated”inlaboratorysetting with antigen present in prostate tissue (PAP) plus growth factor
• Activatedcellsinfusedbackintopatient |
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Term
Has Toxicities:
• Flu-like symptoms
• Hypersensitivity reactions
• Myelosuppression
• Capillary leak syndrome
- IL-2 due to increased blood vessel permeability
• Cytokine release syndrome
- T-cell therapies due to systemic inflammatory response |
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Definition
| Biologic Therapy Toxicities |
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Term
A patient has heard about new targeted treatments for cancer and wants to avoid the “bad” side effects of chemotherapy.
How would you explain to the patient:
If he/she is a candidate for targeted therapy
Pros and cons of targeted therapy |
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Definition
A patient is only a candidate for targeted treatment if the cancer itself has a mutation or process that can be targeted by a drug.
Targeted treatments still have side effects and toxicities; they just differ from conventional chemotherapy toxicities.
Immunotherapy carries risk of serious autoimmune effects.
Hypersensitivity reactions with monoclonal antibodies.
May still experience fatigue, flu-like symptoms.
If oral therapy, it requires more responsibility on the part of the patient to take the medication correctly and be adherent, also still requires close monitoring for side effects and toxicities.
Cost. |
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Term
|
Definition
- Drugs“targeted”topathwaysandphysiology unique to cancer cells
• Receptors, gene mutations, angiogenesis
- Hormone therapy
• Breast cancer
• Prostate cancer
- Small molecule inhibitors
• Also known as tyrosine-kinase inhibitors (TKIs) • Newer oral chemotherapy
- Monoclonal antibodies |
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Term
|
Definition
So let's look more closely of the mechanism of action of small molecule inhibitors. So I've talked about TKI or Tyrosine Kinase Inhibitor. So a tyrosine kinase inhibitor is a pharmaceutical drug that does just what its name says. It inhibits tyrosine kinases. Tyrosine kinases, as you can see in this depiction, are enzymes that are responsible for the activation of many proteins in the cell by signal transduction cascades. The proteins are activated by adding a phosphate group to the protein. And this is the step that most TKIs or Tyrosine Kinase Inhibitors inhibit.
So as you can see on this slide, the tyrosine kinase basically then works as an on/off switch, depending whether it's phosphorylated or not phosphorylated. And our TKI inhibit the tyrosine kinase from being phosphorylated. And what this essentially does is keeps the tyrosine kinase in it's off switch, so that all these downstream cascading signaling effects can not occur and eventually leads to either decrease growth of the cell, apoptosis of the cell, decreased angiogenesis, all of these different secondary effects. |
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Term
Has toxicities:
• Generally less myelosuppression
• Minimal to low nausea/vomiting
• Most common:
• Diarrhea
• Rash/skin reactions
• Hypertension
• Liver function |
|
Definition
Small Molecule Inhibitor
• Unique to receptor being targeted!
• Hypertension
- Vascular endothelial growth factor (VEGF) inhibitors |
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Term
|
Definition
• Bindtospecifictarget on antigen binding site
1. “Mark”cellfor destruction by immune system
2. Drugconjugateis internalized by the cell leading to cytotoxicity
3. Blocktargetoncelland inhibit pathway
• Similar to small molecule inhibitors |
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Term
|
Definition
| Rituximab (Rituxan®) Ofatumumab (Arzerra®) |
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Term
|
Definition
|
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Term
|
Definition
|
|
Term
| EGFR: colorectal, head/neck |
|
Definition
|
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Term
|
Definition
|
|
Term
| HER2/neu: breast, gastric |
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Definition
|
|
Term
| VEGF: multiple solid tumors |
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Definition
|
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Term
|
Definition
|
|
Term
| PD-1: multiple solid tumors |
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Definition
|
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Term
|
Definition
And we'll start with rituximab, because this is very widely used in practice. Rituximab is a monoclonal antibody that is directed against the CD20 antigen that occurs on the surface of B lymphocytes. And as you can see that CD20 antigen is circled on those B lymphocytes on the picture on this slide.
Rituximab binds to this antigen on the cell surface and then it activates complement dependent B cell cytotoxicity and also to human Fc receptors. And basically what it does is, it mediates cell killing through an antibody dependent cellular toxicity. So rituximab marks these B cells with the CD20 antigen for destruction by the immune system leading to apoptosis of these cells. |
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Term
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Definition
Ado-Trastuzumab Emtansine Mechanism of Action
A second example of a mechanism of action of a monoclonal antibody is the example of ado-trastuzumab emtansine. This is a very interesting monoclonal antibody. It is targeted to the HER2 antibody, which we see in breast cancer. And this agent is used specifically in breast cancer. However, the monoclonal antibody is also conjugated to the drug emtansine. So this cell then incorporates the emtansine into the cell itself. And the emtansine then works as a microtubule inhibitor.
And as we learned the microtubule inhibitor stops the formation of the polymerization of the microtubules and ultimately leads to cell death. So we have a target that then leads to the incorporation of a cytotoxic chemotherapy into a specific cell that is expressing the HER2 antigen. |
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Term
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Definition
And then the last example is of cetuximab. Cetuximab is an EGFR or an Epidermal Growth Factor Receptor inhibitor. It binds specifically to this EGFR receptor and competitively inhibits the binding of Epidermal Growth Factor or EGF and other ligands to this receptor.
And as we saw with TKIs, binding to this EGFR blocks phosphorylation and activation of the TKI which results in inhibition of cell growth, induction of apoptosis, and decreased growth factor production. So all of these things are inhibited by inhibiting the EGFR receptor. So cetuximab is basically just a monoclonal antibody that works like a TKI. |
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Term
| Monoclonal Antibody Toxicities |
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Definition
• Hypersensitivity
• Flu-like symptoms
• Generally minimal myelosuppression
- Exception: T-cell depleting antibodies or cytotoxic conjugates
• Minimal nausea/vomiting
• Unique to targeted receptor
- More common: • Rash • Hypertension (VEGF) |
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Definition
Muriune- most likely to cause a hypersentitivity rxn- Tositumomab, Ibritumomab
Human- least likely to cause a hypersensitivity rxn- Panitumumab |
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Definition
- Verycommonwith endothelial growth factor (EGFR) inhibitors
• Small molecule or monoclonal antibody • Cetuximab, panitumumab • Erlotinib
- “Acneiform”
- Often a marker of response |
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Term
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Definition
- Type of targeted therapy specific to the immune system
- Assists the patient’s own immune system to recognize tumor cells as foreign
• Tumors are often able to evade detection by immune cells
- Also known as “checkpoint inhibitors” • CTLA-4 inhibitors: ipilimumab
• PD-1 inhibitors: nivolumab
• PD-L1 inhibitors: atezolizumab |
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| Immunotherapy Mechanism of Action |
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Definition
- CTLA-4
• Present on T-cell, switches T-cells “off”
- PD-1
• Present on T-cell
• When binds to PD-L1 on tumor cell causes downregulation of T-cell and death |
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Term
Has Toxicities:
• Adverseeffectsduetoenhancedimmune response
• May occur anywhere in the body
• Colitis, hepatitis, hypo/hyperthyroidism, adrenal insufficiency, pneumonitis
• Serious: myocarditis, encephalitis |
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Definition
So with all of these targeted cancer therapies that we've talked about, I do want to mention that the future of cancer chemotherapy in treating cancer is really moving toward precision medicine. And according to the Precision Medicine Initiative, the definition of precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person.
And this approach allows doctors and researchers to more accurately predict which treatment and prevention strategies for a particular disease will work in which groups of people. So it's in contrast to a "one size fits all" approach that we generally see with our conventional chemotherapy agents.
So now, disease treatment and prevention strategies are being developed for a particular, specific patient based on what sort of tumor mutations or environment they may have within their molecular profiling on this cells. So as you can see, on the left, we have all of these patients who have received molecular profiling.
We try to determine if there is any specific environment in the tumor or targets that we can target with specific drugs. And based on the targets that occur in that particular cancer, each patient gets a specialized medication that targets that receptor that is causing their cancer to occur. So it's a very exciting time in the treatment of cancer and in chemotherapy. |
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Term
| Conventional chemotherapy |
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Definition
• Cytotoxic to all rapidly-dividing cells
• Typical chemotherapy side effects of
myelosuppression, nausea, vomiting
• Intravenous therapy administered on specific schedule by trained staff
• Generally less expensive |
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Definition
• Specific to cancer with a targetable ligand or mutation
• Generally minimal myelosuppression or nausea/vomiting
• Side effects unique to target
• Oral options
- Requires more patient responsibility
• Generally more expensive |
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