Drug Therapy

Question 1

The following are three categories of factors that can affect a person’s response to drug therapy.

Answer 1

1 Pharmacologic factors
2 Disease-related factors
3 Patient-related factors

Question 2

Pharmacologic Factors that can affect a person’s response to drug therapy.

Answer 2

Combination versus
single agent
Dose intensity
Dose density
Dose reduction/delay
Drug-drug interactions

Question 3

Disease-Related Factors that can affect a person’s response to drug therapy.

Answer 3

Tumor burden
Rate of tumor growth
Doubling time
Hormone receptor status
Drug resistance

Question 4

Patient-Related Factors that can affect a person’s response to drug therapy.

Answer 4

Comorbidities
Performance status
Age
Sex
Hepatic/renal/gastrointestinal function
Genetics
Body size

Question 5

Combination Therapy

Answer 5

Combining multiple types of drugs can increase the maximum cell kill and provide broader coverage to overcome resistant cell lines. These drugs should be used at optimum schedules and doses and given at consistent intervals for maximum benefit.

Question 6

The following are characteristics of drugs that are often used in combination therapy:

Answer 6

Are active as a single agent

Have different mechanisms of action that are synergistic

Have different dose-limiting toxicities

Have different patterns of resistance

Question 7

How does chemotherapy stop the growth and division of cells?

Answer 7

Chemotherapy targets the phases of the cell cycle to stop the growth and division of cells, ultimately leading to cell death.

Chemotherapy agents can be cell cycle-specific or nonspecific.

Question 8

How do cell cycle-specific agents exhibit their effect on the cell?

Answer 8

Cell cycle-specific agents exhibit their effect on the cell during a certain phase of the cell cycle. These agents are usually not effective during the resting phase (G0). These drugs are also best administered in frequent, divided doses, or as a continuous infusion to increase the amount of time the cancerous cells are exposed to the chemotherapy agent during the specific phase of the cell cycle.

Question 9

How do cell cycle-nonspecific agents exhibit their effect on the cell?

Answer 9

Cell cycle-nonspecific agents work on the cell in any phase, including the resting phase. The drug is taken into the cell and may linger until the cell attempts to divide, causing cell death at that time. This means that apoptosis of the cell may not occur immediately. These drugs are often given intermittently to allow normal cells time to repair. Increased doses of these drugs increase the number of cells killed, which increases toxicities.

Question 10

How is bone marrow affected by chemotherapy?

Answer 10

The bone marrow is the space within bones where blood cells are made, including platelets, red blood cells (RBCs), and white blood cells (WBCs). The bone marrow is an area of the body with rapid turnover of the cells and is affected more profoundly by chemotherapy, causing suppression of the creation of new cells in the bone marrow. As a result, the patient can become deficient in one or several of these cell types.

Question 11

How are WBCs affected by chemotherapy?

Answer 11

WBCs help to protect the body from foreign invaders and coordinate the immune system. Chemotherapy can cause a decrease in neutrophils, the most common granulocytic WBC, which can lead to neutropenia and leave the patient at an increased risk for serious infection.

Question 12

How are platelets affected by chemotherapy?

Answer 12

Platelets help blood to clot. Chemotherapy may cause a decrease in platelets, known as thrombocytopenia. This increases the patient’s risk of bruising and bleeding, even during everyday activities like shaving.

Question 13

How are RBCs affected by chemotherapy?

Answer 13

RBCs carry oxygen throughout the body. Chemotherapy may cause a decrease in RBCs, causing anemia, which may lead to fatigue, poor concentration, headaches, dizziness, cold intolerance, and shortness of breath.

Question 14

Chemotherapy-Induced Nausea and Vomiting (CINV)

Answer 14

Question 15

CINV can result in the following:

Answer 15

Dehydration
Fatigue
Changes in electrolyte balance
Aspiration pneumonia
Inability to eat or drink
Fear of receiving future chemotherapy treatments

Question 16

Acute CINV

Answer 16

Occurs within the first 24 hours of treatment; however, it can often be managed or even prevented. This is predominantly the result of the peripheral pathway.

Question 17

Delayed CINV

Answer 17

Occurs 24 hours or more after the chemotherapy treatment. The mechanism is different than acute nausea and vomiting; it is often under-recognized and under-managed. It is predominantly the result of the central pathway.

Question 18

Breakthrough CINV

Answer 18

Occurs despite the use of antiemetic medication.

Question 19

Anticipation CINV

Answer 19

A conditioned response to the sights, sounds, or smells remembered from past experiences of severe nausea and vomiting.

Question 20

Chemotherapy drugs, both oral and IV, are scored based on the likelihood the agent will cause nausea and vomiting. This is called the emetogenic potential. What are the scores?

Answer 20

High Risk Agents
Cause nausea and vomiting in more than 90% of people who do not receive antiemetic medications

Moderate Risk Agents Cause nausea and vomiting in 30%–90% of people who do not receive antiemetic drugs

Low Risk Agents
Cause nausea and vomiting in 10%–30% of people who do not receive antiemetic drugs

Minimal
Cause nausea and vomiting in less than 10% of people who do not receive antiemetic drugs

Question 21

What is alopecia

Answer 21

Alopecia, or hair loss, can have a significant psychosocial impact on patients with cancer and serves as a constant reminder that they have cancer. Alopecia is often considered one of the “hallmark” symptoms that patients often associate with chemotherapy. Alopecia is not a side effect of all chemotherapy agents.

The degree of hair loss can range from slight thinning of hair to complete hair loss. The scalp hair is affected more than body hair. Hair loss generally starts to appear 7-10 days after chemotherapy begins, and the severity can depend on the drug, drug dosage, and schedule.

As hair loss occurs, the scalp can be very sensitive to touch, even painful. The scalp becomes more susceptible to weather conditions and sun exposure. Hair loss can be reversible, although the hair may be a different color and texture when it grows back.

Question 22

What is neurotoxicity?

Answer 22

Neurotoxicity is when damage to the nervous system occurs. Damage to the nervous system can be temporary or permanent. If temporary, it can take a significant time to return to baseline.

Question 23

Central neurotoxicity

Answer 23

Damage occurs to the brain or spinal cord, which manifests as more systemic symptoms like dizziness or gait changes.

Question 24

Peripheral neurotoxicity

Answer 24

Damage occurs to the peripheral nerves, which manifests within the periphery and can appear as numbness, tingling, or pain in the hands and feet.

Question 25

Some chemotherapy agents can cause damage to the heart, or cardiotoxicity. Cardiotoxicity could occur as follows:

Answer 25

Damage to the muscle of the heart, which causes the heart to be less efficient when pumping (like congestive heart failure), resulting in oxygen not being delivered to tissues of the body; this may lead to shortness of breath and fatigue. This is most often seen in high cumulative drug doses.

Acute changes that may occur in the heart rate or rhythm

Question 26

Renal toxicity occurs when there is damage to the kidneys. This damage can be temporary or permanent. Renal toxicity can result in a fluid and electrolyte imbalance. A patient’s kidney function will be monitored throughout treatment via blood testing and monitoring urine output, weight, and fluid status.

Renal toxicity can manifest as follows:

Answer 26

Precipitation, where molecules of the drug become unstable and separate, causing crystals or particles to form that are difficult for the kidney to excrete

Direct damage to the kidney by the drug

Question 27

How does targeted therapy work?

Answer 27

Unlike chemotherapy that targets the DNA within the cancer cell, targeted therapies have an effect on selective molecular pathways. The targets for these agents are genetic changes within cancer cells that control how the cells divide, grow, or spread.

Not all tumors have known targets or have targets with approved drugs. Patients would need testing prior to treatment to determine if their specific cancer has any treatable targets. Targets can vary even within the same cancer type. For example, some types of breast cancer can be treated with targeted agents, and others cannot.

Question 28

How do small-molecule inhibitors work?

Answer 28

Small-molecule drugs can penetrate the cell membrane and affect targets inside a cell. Small-molecule inhibitors are generally designed to interfere with enzymatic activity of the target protein.

Question 29

The following are several types of small-molecule inhibitor drugs used for cancer treatment:

Answer 29

Tyrosine kinase inhibitors (TKIs)

Proteosome inhibitors

Matrix metalloproteinases

Heat shock protein inhibitors

Apoptosis

Question 30

Tyrosine Kinase Inhibitors (TKIs)

Answer 30

Protein kinases are simply enzymes that modify other proteins and play an important role as secondary messengers. Intracellular signal transduction inhibitors, such as TKIs, stop messages that tell the cells to divide and grow from reaching the nucleus.

Tyrosine kinase genes are found on the majority of human chromosomes, making them a good potential target because of their abundance. Although normal cells have receptor tyrosine kinases (RTKs), most RTKs identified in oncology have low activity or expression in normal tissue and are hyperactivated or upregulated in cancerous cells, reducing the impact of TKIs on normal cells.

Question 31

What are the side effects of TKIs?

Answer 31

TKIs frequently lead to rash, fluid retention, nausea and vomiting, diarrhea, and fatigue, depending on the receptor to which they bind.

Question 32

What are mammalian target of rapamycin inhibitors

Answer 32

mTOR inhibitors are another type of small molecule. These inhibitors prevent mTOR from activating signaling pathways involved in angiogenesis and cell growth. Although mTOR is found in normal cells, it is highly active in some cancers, including kidney cancer.

Question 33

What are the side effects of mTOR inhibitors?

Answer 33

mTOR inhibitors commonly cause rash, asthenia (weakness or lack of energy), mucositis, nausea, edema, anorexia, anemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, elevated liver enzymes, elevated serum creatinine, and low platelet and WBC counts.

Question 34

What are monoclonal antibodies?

Answer 34

Unlike small molecule inhibitors, monoclonal antibodies (mAbs) are considered large molecule drugs and exert their effect outside the cell. mAbs recognize and bind to specific proteins (antigens), such as transmembrane receptors or extracellular growth factors, on the surfaces of cells. Once the mAb is attached to the protein on the cell surface, it locks that receptor from being activated, which prevents whatever action the receptor controls.

Question 35

How does hormone therapy work?

Answer 35

Hormones are chemical messengers that act on certain cells. Some cancers are hormone-sensitive or hormone-dependent for growth. Hormone therapy blocks or reduces the number of hormones in the body, which leads to a slowing or stoppage of tumor growth for cancers that rely on hormones for growth. Hormone therapy is often referred to as endocrine therapy.

Question 36

Hormone therapy can do the following:

Answer 36

Interfere with the release of hormones

Block other hormones that trigger the production or release of target hormones

Block hormone receptors

Destroy the hormone entirely

Question 37

What are two of the most commonly used hormone therapies in cancer treatment?

Answer 37

Antiestrogens and androgen

Question 38

Antiestrogen hormone therapy

Answer 38

These cancers will be noted as estrogen receptor-positive and/or progesterone receptor-positive. Antiestrogen therapy helps to reduce the concentration of estrogen and progesterone to deprive the cancer cells of these hormones, which help the cancer to grow. Treatment with antiestrogen therapy can be highly dependent on whether the patient is pre- or postmenopausal.

Question 39

Androgen hormone therapy

Answer 39

Androgens are hormones (testosterone and dihydrotestosterone) that are required for prostate function. These hormones also play a role in prostate cancer growth. These hormones bind and activate the androgen receptor, which activates genes that promote prostate cell growth. In some cases, patients treated with androgen deprivation therapy can become resistant to hormone therapy and have what is called “castration-resistant” or “hormone-refractory” prostate cancer.

Question 40

Antiestrogen therapies may cause the following side effects

Answer 40

Arthralgias
Changes in menstrual cycle
Decreased libido
Fatigue
Hot flashes
Mood changes
Nausea
Vaginal dryness
Weight changes

Question 41

Androgen deprivation therapies may cause the following side effects

Answer 41

Bone loss or weakening
Decreased libido or ability to have sex
Diarrhea
Enlarged breasts
Fatigue
Hepatotoxicity
Hot flashes
Nausea

Question 42

How does immunotherapy work?

Answer 42

Immunotherapy uses the patient’s own immune system to control or eliminate cancer. Immunotherapy is a type of therapy that uses substances to stimulate the immune system to help the body fight cancer. Immunotherapy can either target specific cells of the immune system or affect the immune system in a more general way. Immunotherapy is very different from chemotherapy, which targets the cancer cells more directly. Immunotherapy uses the body’s own immune system to attack the cancerous cells.

Question 43

Innate Immunity

Answer 43

Innate immunity is the first line of defense. The response to a foreign invader is rapid and non-specific and only lasts for a limited amount of time. This response also does not form memory to aid in response to future invaders of the same kind.

Innate immunity includes the skin, hair, mucous membranes, and phagocytes which engulf and destroy any non-self substance they encounter. Think “innate” because these are processes or structures that our bodies just “innately” have all the time; they don’t need to be created as the result of exposure to the foreign substance.

Question 44

Adaptive Immunity

Answer 44

The adaptive immune response is the second line of defense and is a specific response that develops more slowly and forms a memory response. Adaptive immunity includes humoral (B cells and antibodies) and cell-mediated (T cells) responses.

The adaptive immune response is dependent on the presentation of an antigen to trigger the response. Think “adaptive” because the response adapts to the specific foreign substance to create a specific response and memory.

Question 45

The concept of immunoediting describes the interaction of the immune system with cancer. The following are the three phases of immunoediting:

Answer 45

Elimination: The immune system recognizes the cancer cells as foreign and destroys them.

Equilibrium: The immune system recognizes the cancer cell as foreign and keeps the growth of the cancer cell in check, but does not kill it completely. Over time, the immune system is no longer able to identify the cancer as foreign.

Escape: The equilibrium of the immune system is disrupted, and the cancer is allowed to grow and “escape” the immune response.

Question 46

For the anticancer immune response to lead to the killing of cancer cells, a series of events occur called the cancer immunity cycle. These steps include the following:

Answer 46

1. Release of cancer cell antigens as cancer cells die
2. Cancer antigens presentation by antigen-presenting cells
3. Effector T cells are primed and active to respond to the tumor antigens presented
4. Trafficking of T cells to cancer cells
5. Activated T cells infiltrate the tumor
6. T cells recognize the cancer cells
7. Killing of cancer cells, which releases more tumor antigens and the cycle starts over again

Question 47

Immune Checkpoint Inhibitors

Answer 47

These downregulate (put the brakes on) T-cell signaling to halt over-proliferation of T cells. Although this system can help to prevent the immune system from attacking healthy tissues, cancer calls can hijack these checkpoint receptors and evade the immune system, allowing them to proliferate and metastasize.

Immune checkpoint inhibitors block these checkpoints, which allows the immune system to mount a stronger response to kill cancer cells.

Question 48

Although immunotherapy can share common side effects with other cancer treatments, such as fatigue, some immunotherapy agents also have a distinct profile of side effects. What can these include?

Answer 48

These side effects often occur as the result of the immune system working too well or going into “overdrive” and causing the immune response to attack healthy tissues. This can occur through a variety of mechanisms and depends on the specific immunotherapy. irAEs can occur in any organ system of the body and occur simultaneously in multiple systems. These side effects tend to be less predictable than those occurring in patients receiving chemoptherapy, making identification difficult.

Question 49

Immune-related adverse events (irAEs) are defined as

Answer 49

discrete toxicities caused by non-specific activation of the immune system

It is important to know that irAEs can occur months, or even years, after the patient has stopped immunotherapy. A good phrase to remember is, “Once an immunotherapy patient, always an immunotherapy patient.”