Cancer Flashcards
most common causes of death in US
1st: heart disease
2nd: cancer
most common sites of cancer in men
- prostate
- lung and bronchus
- colon and rectum
most common sites of cancer in women
- breast
- lung and bronchus
- colon and rectum
What is cancer?
- A collection of diseases which share
common characteristics: - Uncontrolled cell proliferation
- Insensitivity to anti-growth signals
- Prevention of cells to self-destruct through apoptosis
- Limitless replicative potential
- Sustained angiogenesis
- Tissue invasion and metastasis
Cancer develops when…
a normal cell becomes abnormal
cancer often involved the malfunction of what?
- genes that control cell growth, cell division, or
cell death - Activation of proto-oncogene
- down-regulation of tumor-suppressor gene
What do Onco-genes do?
essentially put the “brakes” on apoptosis and cause normal cells to reproduce relatively unchecked
What does tumor suppressor gene provide?
- inhibitory signals that lead to the cessation of cell division and DNA transcription
- Mutations in these genes are considered a loss of function –> genomic instability and the
potential for cancer initiation
Sequence of events necessary for successful metastatic spread:
- Detachment and escape from primary tumor site
- Invasion of surrounding tissues and penetration into circulatory or lymphatic channels and survival without detection
- Invasion and colonization at a distant site.
- Once invasion of a new site occurs, persistent survival in this environment, and subsequent angiogenesis for further proliferation, require additional mechanisms and capabilities
Cancer causes - risk factors?
- Genetic factors
- physical carcinogens
- chemical carcinogens
- biological carcinogens
Genetic factors
up to 10% of all cancers can be caused by inherited genetic changes
physical carcinogens
UV and ionizing radiation
chemical carcinogens
asbestos, tobacco smoke, arsenic, aflatoxin
biological carcinogens
- Infections from certain viruses, bacteria, and parasites
- Human papilloma virus (HPV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), and Helicobacter
pylori (H. pylori)
Categories of drugs used to treat cancer
- Chemotherapy
- Immunotherapy
- Target therapy
- Anti-hormonals
- Often used in combinations and come in the form of liquid or pills
- Each has a diverse target with a distinct mechanism of action (MOA)
- Many have a narrow therapeutic index (TI)
Main goal of chemotherapy
- Eliminate the cancer cells without affecting normal tissues
- Cytotoxic drugs affect both normal and cancerous cells
- Aim for a favorable therapeutic index
cost of chemotherapy
- one of the most expensive medical conditions
- patents and survivors of cancer are more likely to have financial toxicity than those without cancer
- CAR-T cell therapy is $475,000 for one treatment
What can limit the dose of chemotherapy
- Toxicity
- Poor selectivity of drugs for cancer cells versus normal cells means both healthy and cancerous cells are affected
Which tissues are often the cause of dose-limited toxicities
- Bone marrow
- GI tract (primarily the mucosal lining)
- Skin
- Germinal cells (sperm & ova)
- Hair follicles
(tissues with high growth rates)
Implications for physical therapy
- A clear understanding of the complex and ever-changing use of chemotherapeutics and supportive medications is one of the most challenging parts of working with people with cancer
- Important to understand the clinical aims, MOA, and adverse effects of antineoplastic agents to provide optimal care
- A comprehensive rehabilitation program can improve a person’s ability to tolerate
a more aggressive treatment regimen
Common Toxicities - Myelosupression
- inhibition of bone marrow cells resulting in fewer red blood cells, white cells, and/or platelets
- Neutropenia, Thrombocytopenia, Anemia
Neutropenia
- Low white bloods cell count
- Increased risk of infection
Thrombocytopenia
- Low platelet count
- Bruising, nosebleeds, and/or bleeding gums
- Malaise, fatigue, and weakness
Anemia
- Low red blood cell count
- Vague symptoms: tiredness, weakness, SOB, decreased activity tolerance
Common toxicities: GI system
- Diarrhea
- Nausea, vomiting
- Stomatitis –> Inflammation and ulceration of the oral mucosa
- Mucositis –> Painful inflammation or ulceration of the mucus membranes anywhere in the GI tract
Common Toxicities: Integumentary
Hand Foot Syndrome
What is hand foot syndrome
- Pain, redness, peeling of the skin on palms and/or soles of the feet
Treatment for hand-foot syndrome
- Adjusting does of chemotherapy or changing the drug
- May reduce efficacy of cancer treatment
Integumentary - Management
- Corticosteroid creams
- Skin moisturizers
- Pain relievers: oral or topical
- Avoid activities that cause friction on palms
or soles
Common Toxicities: Nervous System
- Chemotherapy-Induced Peripheral Neuropathy (CIPN)
- Common, potentially debilitating and dose-limiting side effect of cancer treatment that
may occur when chemotherapeutic agents damage the peripheral nerves - Pathophysiology is poorly understood
Symptoms of chemotherapy-induced peripheral neuropathy
- Begin in the hands and feet and move proximally
- Pain, burning, tingling, numbness, electric shock, pins and needles, temperature sensitivity
- Affect ADLs and QoL
- Can persist months to years after completion of chemotherapy
Chemotherapy- Induced Peripheral Neuropathy results in ….
- Deficits in sensory, motor and/or autonomic functions
- Sensory symptoms develop first – “glove and stocking” distribution –> Numbness, tingling, altered touch sensation, impaired vibration, paresthesias, dysesthesias induced by touch and warm or cool temperatures, painful sensations including spontaneous burning, shooting or electric-like pain
- Motor symptoms – less frequent than sensory –> Distal weakness, gait and balance disturbances, impaired movements
Chemotherapy- Induced Peripheral Neuropathy results in ….
- Deficits in sensory, motor and/or autonomic functions
- Sensory symptoms develop first – “glove and stocking” distribution –> Numbness, tingling, altered touch sensation, impaired vibration, paresthesias, dysesthesias induced by touch and warm or cool temperatures, painful sensations including spontaneous burning, shooting or electric-like pain
- Motor symptoms – less frequent than sensory –> Distal weakness, gait and balance disturbances, impaired movements
Chemotherapy- Induced Peripheral Neuropathy results in ….
- Deficits in sensory, motor and/or autonomic functions
- Sensory symptoms develop first – “glove and stocking” distribution –> Numbness, tingling, altered touch sensation, impaired vibration, paresthesias, dysesthesias induced by touch and warm or cool temperatures, painful sensations including spontaneous burning, shooting or electric-like pain
- Motor symptoms – less frequent than sensory –> Distal weakness, gait and balance disturbances, impaired movements
CIPN - PT Management
- Balance training
- Strength training
- Interactive sensory-based activities
- Endurance training
CIPN PT Management Outcomes
improved static and dynamic balance, reduction in CIPN symptoms, decreased postural sway, increased QOL, decreased pain, increased lower
extremity strength, improved TUG and BB
Common Toxicities: Cancer-Related Fatigue
- An unusual, persistent, subjective sense of tiredness related to cancer or cancer treatment that interferes with usual functioning
- Likely the result of many causes
What is PT most effective with?
Treating fatigue
Diagnostic criteria for Cancer related fatigue
- Period of 2 weeks or longer within the preceding month during which significant CRF or diminished energy was experienced each day along with additional CRF-related symptoms
- Results in significant distress or impairment of function
- Clinical evidence suggesting CRF = consequence of cancer or cancer therapy
- CRF is not primarily a consequence of a concurrent psychiatric condition (major
depression)
Cancer Related Fatigue PT management
- Nonpharmacological Interventions = EXERCISE
- Aerobic, resistance, multimodal with higher intensity
- Timing: safe and effective during treatment, post-treatment and survivorship
General principles for treating CRF
- 60% to 85% of maximal HR
- At least 30 minutes, 3 times per week working up to a least 150 minutes of moderate or 75
minutes of vigorous activity (ACSM guidelines for patients with cancer)
How do Alkylating Agents work?
- Cause cell death through transfer of their alkyl groups to various cellular constituents
- May cause inhibition of DNA replication and transcription, mispairing of DNA, or DNA strand breakage.
- Work in all phases of the cell cycle
Dose limiting side effect of alkylating agents
myelosupression
other side effects of alkylating agents
nausea/vomiting, alopecia, infertility, leukemia (!)
What are platinum analogs?
- Commonly classified as alkylating agents, but do
not technically alkylate DNA - Activated forms of these drugs react with
nucleophilic sites on DNA to form cross-links and
decrease replication
How do platinum analogs work?
- Covalently binds to DNA and produce
intrastrand (>90%) and interstrand (<5%) cross-links –> inhibition of DNA synthesis and inhibition of transcription - Tend to cause a variety of neurologic
complications
Antimetabolites
- Structural analogs of naturally occurring substances in the body
How do Antimetabolites exert damage?
- Incorporating directly into DNA or RNA
- Competing for binding sites on enzymes
- Inhibit cell growth and proliferation in S phase of the cell cycle
How do Topoisomerase Inhibitors work?
- Topoisomerase family of enzymes alter the supercoiling of double-stranded DNA
- A transient cut is formed in one or both strands of the DNA, allowing the supercoiled DNA to relax ahead of the replication fork as replication progresses
- Regulation of DNA supercoiling is essential to transcription and replication.
- Topoisomerase inhibitors bind to topoisomerase I or topoisomerase II and limit the ability of DNA to repair itself resulting in cell death
Who does colorectal cancer often affect?
- Affects men and women of all racial and ethnic groups
- Most frequently diagnosed in individuals >50 years old
- ~ 1:24 men and 1:25 women will develop colorectal cancer in the US
Patients with chemotherapy for colorectal cancer often receive multiple drugs with what advantages?
- Suppression of drug resistance
- Increased cancer cell death rates
- Reduced systemic toxicity
How do anthracyclines
- Multiple mechanisms of action
- Inhibit topoisomerase II and prevent repair of DNA during replication causing DNA strand breaks
- High affinity for binding to DNA and insert themselves between DNA base pairs causing additional DNA breaks.
- Metabolized in the liver to form reactive oxygen species (e.g., oxygen free radicals), adding to both the cytotoxicity and adverse effect profile
How do plant alkaloids work?
Cell cycle specific (active in M phase of the cell cycle)
How do taxanes work?
- Interfere with the G2 phase of the cell cycle
- Arrest the cells that are in mitosis
What are receptor tyrosine kinases?
proteins responsible for the activation of
signaling cascades important for many cellular functions, such as cell signaling and growth –> in some cases, RTKs become dysregulated and lead to cancer
What are Tyrosine Kinase Inhibitors and how do they work? (targeted therapy)
- TKI block the actions of RTKs to help in the management of certain types of
cancer –> Small molecule drugs and can more easily enter the cell to reach their target - NOT cell cycle dependent
how do Monoclonal Antibodies work? (targeted therapy)
- Not cell cycle dependent
- Make the cancer cell more visible to the immune system
- Neutralize growth factors that are required by cancer cells thereby inhibiting tumor
expansion - Deliver “toxic cargo” to the cancer cells
how do monoclonal antibodies make the cancer cell more visible to the immune system
- The immune system doesn’t always recognize cancer cells, mAbs can be directed to attach to
cancer cells in order to “mark” them for destruction via antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC)
How do monoclonal antibodies deliver “toxic cargo” to the cancer cells?
- mAbs can be conjugated or linked to anticancer drugs, radioisotopes, or biologic response
modifiers so that when the antibodies bind with antigen-bearing cells, they deliver their load directly to the tumor - Activate the immune system to fight cancer by targeting Cytotoxic T- Lymphocyte Antigen
4 (CTLA-4) or PD-1
Women have a BLANK risk of developing breast cancer
1 in 8 lifetime risk
what is present in the majority of breast cancers
- estrogen receptors
what plays in an important role in many treatment regimens
- The modulation of estrogen levels
- Direct – anti-estrogens
- Indirect –aromatase inhibitors
- Most ER+ breast cancers don’t overexpress HER2
What works by blocking the estrogen receptor
tamoxifen
(typically pre menopausal, after you’ve gone through chemo)
What inhibits the production of aromatase thereby reducing estrogen levels?
Exemestane
How are estrogens synthesized
- From cholesterol
- Secreted primarily by the ovaries
- Contributions from placenta, adipose tissue, and adrenal glands
What does estrogen stimulate?
- Stimulates development and maintenance of female characteristics and sexual reproduction
- The breast and uterus, which play central roles in sexual reproduction, are two of the main targets of estrogen, but estrogen also acts on the brain, bone, liver, and heart
How do aromatase inhibitors work?
- Block growth of “estrogen sensitive“ tumors by lowering estrogen levels
- Premenopausal Women –> AIs unable to effectively block the larger amounts of estrogen produced by the ovaries
- Postmenopausal Women –> Almost complete suppression of estradiol secretion by adipose and breast tissue
what are aromatase inhibitors associated with?
- Majority of side effects are mild to moderate
- Compared to tamoxifen, AIs are associated with a decreased risk of endometrial cancer and thromboembolic events and increased rates of fractures (osteoporosis)
things about prostate cancer
- Prostate cancer is the most common cancer in men; 2nd leading cause of cancer- related deaths in American men
- A man’s lifetime risk of prostate cancer is 1:8
What increases the risk of prostate cancer
- Family History increases risk (1st degree relatives) –> BRCA1 and BRCA2 increase risk, but these account for a very small percentage of
prostate cancer - When prostate cancer develops, the PSA level > 4
Does prostate cancer typically cause symptoms?
- not initially
- By the time symptoms occur, the disease may have spread
- Symptoms include decreased urinary stream, increased urinary frequency, hematuria,
bladder/bowel incontinence, bone pain
Androgen Production
- Androgens are often necessary for prostate cancers to grow
- Testosterone and dihydrotestosterone (DHT) are the most abundant androgens in men
- Testosterone sources: testes (80-90%) and adrenal glands (10-20%)
- Treatment of advanced prostate cancers usually involves some form of surgical or chemical castration to lower androgen levels
how do anti-androgens work?
Inhibit testosterone from binding to its receptor –> blocking its effects in the body and preventing the stimulation of cell growth in prostate cancer
Lifetime risks of developing lung cancer
1:16 men
1:17 women
what accounts for most lung cancer cases and deaths
- Cigarette smoking: about 80%
- Second hand smoke is the 3rd most common cause of lung cancer
What is epidermal growth factor receptor
- Belongs to the HER family that includes
EGFR (HER 1), HER2, HER3, and HER4 - EGFR – 1st receptor proposed as a target
for cancer therapy
How is epidermal growth factor receptor activated?
through genetic mutations, genetic amplification, or both –> Changes are closely related to the
occurrence, progression, and prognosis of non-small cell lung cancer (NSCLC)
Common EGFR mutations in NSCLC
- 10 - 35% of patients with NSCLC have somatic changes in the kinase domain of their EGFR gene
- The most common EGFR mutations include short in-frame deletions in exon 19 and a point mutation in exon 21 at codon 858 –> Together these account for 86% of the EGFR mutations detected
- Activating EGFR mutations in NSCLC pts are more common in women, nonsmokers, and those of Asian ethnicity
What do patients harboring activation EGFR mutations have?
an increased response to some EGFR TKIs
initial overall response to EGFR TKIs
- initially high for patients with EGFR mutations but almost all pts develop resistance
