Oncology Flashcards
What are some of the most common cancers in Canada?
- Lung
- Colorectal
- Pancreas
- Breast
- Prostate
What is the meaning of cancer incidence?
Number of new cases diagnosed with cancer in a specific period
What is the meaning of rates with respect to frequency of cancer in a population?
Divide number of cancer patients by 100,000
For rates to be comparable over time, statistics are adjusted for age (ASIR)
What is the meaning of cancer prevalence?
It is the total number of people with cancer at a specific time (snapshot)
At what age are most cancers diagnosed?
Most cancers diagnosed between 50-84 yo
What are some non-modifiable risk factors for cancer?
- Age (over 50)
- Sex
- Genetics (ex. BRCA+)
What are some modifiable risk factors for cancer?
- Smoking
- Sun exposure
- Alcohol consumption
- Physical inactivity
- Diet (ultra-processed foods)
- Obesity
- Vaccination (HPV, hepatitis)
- Minimizing exposure to radiation (healthcare), outdoor/indoor air pollution, radon gas
What is cancer?
A generic term used to describe a large number of neoplastic diseases affecting various parts of the body
Cancer cells are abnormal human cells and can arise from any cell type
What are some characteristics of cancer cells?
Exhibit uncontrolled growth
- Malignant cels unresponsive to normal feedback
Ability to invade surrounding tissue
Exhibit decreased cellular differentiation
- Malignant cells generally are not capable of performing the physiologic functions of their tissue of origin
Ability to metastasize
What are the most common sites for metastasis?
Liver, lung, bone, and brain (LLBB)
Well perfused
Do metastatic cancer growths adopt characteristics of their host tissues?
No, metastatic growth retains the characteristics of the original cancer tissue
What are some characteristics of benign tumours?
- Some degree of growth control
- Encapsulated (non-invasive)
- Localized
- Differentiated cell
- Slow growth
- Non-reccurent
What are some characteristics associated with malignant tumours?
- Uncontrolled growth
- Invasive
- Metastatic
- Atypical (anaplastic, less differentiated)
- Aggressive (faster growth)
- Recurrent
What does tumour grading refer to?
Helps determine aggressiveness and it is based on degree of differentiation of malignant cells ans secondarily on estimated growth rate
The less differentiated and more actively dividing cells = higher grade (more aggressive)
What does tumour staging refer to?
Helps determine extent of disease based on size of primary lesion (T), presence of lymph node involvement (N), and presence of identifiable metastases (M)
What is the TNM staging system for?
It is used to stage cancers (extent of disease)
T: Tumour size
N: Are lymph nodes involved?
M: Is the cancer metastasizing?
Review slide 25
Does prognosis improve with a higher TNM stage?
No, prognosis worsens with higher stage
Why is cancer grading and staging important?
Important for:
- Prognosis
- Treatment planning
- Exchnage of information
- Evaluation of treatment
What are the different types of cancer biomarkers?
Diagnostic
Prognostic
Predictive
Pharmacodynamic/Response
What is the utility of predictive biomarkers in cancer?
Identify patients likely to benefit from a specific treatment
ex. Breast cancer: estrogen receptor, progesterone receptor, and HER2, PD-L1 are types of biomarkers used to identify potential treatments
What are the four main cancer treatment modalities?
- Surgery
- Radiation
- Cytotoxic & Targeted Therapies
- Immunotherapy
What is the utility of surgical treatments for cancer?
Most effective cancer treatment for solid tumours
Largely ineffective for metastasized or liquid cancers
Often not feasible for very large tumours (need to use chemo to shrink tumour before surgery)
What is the utility of radiation treatments for cancer?
Rapidly dividing cells are very sensitive to ionizing radiation (cancer cells preferentially destroyed due to higher growth rate)
What is the utility of drug treatments for cancer?
Utilized for disseminated/metastasized cancers and for treatment of micrometastatic disease
Utilized primarily for hematologic cancers
What is the utility of immunotherapies for cancer?
Engage the patient’s own immune system to destroy cancer cells
In general, how do cytotoxic drugs in cancer work?
Traditional chemotherapy
Interfere with or damage DNA
In general, how does targeted drug therapy in cancer work?
Block, inhibit, attack specific proteins that are involved in the molecular processes driving tumour cell growth
ex. hormone therapies, Mabs, TKIs
In general, how does immunotherapy in cancer work?
They activate the patient’s immune system against a cancer
ex. vaccines, CAR-T cell engagers
What is growth fraction?
aka mitotic rate
Number of cells in cell cycle (in process of dividing)/total number of cells in the tissue
How does the growth fraction change as the tumour enlarges?
Higher growth fraction early in tumour growth
Growth fraction decreases as tumour gets larger as cells are farther away from blood vessels and nutrient supply (also accumulation of toxins)
What is the general MOA of cytotoxic drugs?
Interfere with synthesis or function of DNA/RNA causing apoptosis
Cross-linking and DNA strand breaks, leading to abnormal base pairing, inhibiting transcription of DNA to RNA, and stopping protein synthesis and cell division
Primarily effects rapidly dividing cells which do not have time for DNA repair
Review slide 38 and 39 for when in the cell cycle different chemotherapy agents are most effective
What are some characteristics of cell cycle specific chemotherapy drugs?
Most effective in tumours with high growth fraction
Effective against cells in process of division
What are the two types of cell cycle specific chemotherapy drugs?
Phase-specific agents (most effective in multiple repeated doses)
Phase non-specific agents (can inflict damage to rapidly dividing cells at anypoint in the cell cycle)
What are some characteristics of cell cycle non-specific chemotherapy drugs?
Some activity against resting cells (effects are dose dependent)
Used in large tumours with low growth fraction
What are goals of therapy associated with systemic chemotherapy?
- Cure cancer, and eliminate all known tumour cells
- Improve survival (tumour control and delay time to recurrence)
- Palliation (reduce tumour-related symptoms, improve QOL, some tumour control)
What is the response rate endpoint with respect to monitoring tumour size following chemotherapy?
It is tumour size after treatment
- Complete response (undetectable tumour)
- Partial response (30-90% reduction in size)
- Stable disease (no tumour shrinkage)
- Progressive disease (tumour growth observed)
What is the gold-standard clinical endpoint for chemotherapies?
Overall survival
Surrogate endpoints for survival:
- Progression-free survival
- Disease-free survival
- Relapse-free survival
When is induction chemotherapy used?
It is primary treatment (first strategy to tackle cancer)
Usually applied in hematologic malignancies
OR
Advanced disease (unable to operate)
When is adjuvant chemotherapy used?
aka preventative chemotherapy
Given after primary tumour is controlled by local treatment (surgery or radiation)
The patient is clinically free of cancer, but they are at risk of relapse, so adjuvant chemo is used to destroy undetectable cells
When is consolidation chemotherapy used?
Treatment of subclinical, residual disease after induction chemotherapy has produced a complete remission
ex. given following treatment of leukemia to ensure cancer control
When is neo-adjuvant chemotherapy used?
Used to improve efficacy of local treatment (surgey or radiation) by reducing tumour burden and destroying undetectable cancer cells that may have metastasized early
Adjuvant therapy may or may not follow neoadjuvant treatment & syrgery/radiation
What is the utility of maintenance chemotherapy?
Usually lower dose and used to decrease recurrence or progression rate
Used in curative and non-curative settings
What is the utility of salvage chemotherapy?
Treatment of relapsed (recurrent after previous control) or refractory (unresponsive to treatment) disease
What is the utility of local chemotherapy?
Deliver chemotherapy to relatively inaccessible sites and provide high local concentrations while avoiding systemic toxicity
What is conditioning chemotherapy before stem cell transplants?
High doses of cytotoxic drugs given that are lethal to bone marrow, and then rescued with a stem cell transplant and WBC growth factor support
What is the purpose of conditioning chemotherapy before stem cell transplants?
The goal is to overcome resistance of tumour to chemotherapy
What is lymphodepleting therapy before CAR T-cell therapy?
Reduce the number of existing lymphocytes in the patient’s body to make space for the infused CAR-T cells to effectively expand and fight cancer cells
What are some common chemotherapy toxicities?
- Bone marrow suppression (risk of infections)
- Mucositis, stomatitis (GI tract, rapidly dividing cells)
- Hair loss or thinning (alopecia)
- Nausea or vomitting (need to use anti-emetics like ondansetron)
- Fatigue
Review slide 53
What are the two ways chemotherapy drugs can be combined?
Sequential (move from one drug to another)
Concurrent (multiple drugs at once)
Review slide 56 for principles of chemotherapy
What are some factors to consider before combining chemotherapy drugs?
- Show clinical activity against the tumour alone, and synergistic together
- Different MOA (more effective)
- Minimally overlapping toxicities
- No cross resistance between drugs
How are chemotherapies initially dosed?
BSA (intended to maximize dose while limiting ADRs)
Flat dosing (mg/kg)
How are chemotherapies dosed on an ongoing basis?
Usually based on toxicity/tolerability concerns which may present reduced efficacy
WBC growth factors (G-CSF) are often used to increase low WBC levels to improve tolerability of high dose chemotherapy
How is chemotherapy scheduled?
Planning dose interval depends on the following:
- Recovery of host tissue toxicity
- Tumour growth rate
- MOA of drug (cell cycle specificity)
How long is chemotherapy used in patient?
Adjuvant: Once patients get through a prescribed number of cycles
Advanced disease: Given until evidence of disease progression or as long as toxicity can be managed
What are some reasons why chemotherapy sometimes fails?
Main reason is drug resistance (inherent or acquired)
Toxicity to normal cells (dose limiting=efficacy limiting)
Patient co-morbidities limit effective dosing
First order kinetics of cell kill (constant percentage of cells killes, not constant number. Therefore will never acheive 100% cell kill)
How long can you treat? (tolerability concerns)
Failure to detect in an earlier stage (tumour burden is too high, growth fractions are low = less sensitive to chemo, compromised patient, perfusion to tumour is low)
What is tumour cell heterogeneity?
Spontaneous genetic mutations occur in tumour cell populations without exposure to drugs
Larger tumour masses have more mutations and a higher probability of drug-resistant cell lines
What are the three mechanism by which drug resistance can develop?
De novo: abnormal p53 suppressor gene in some cases
Selected: Resistant cells in a heterogenous population become predominant
Acquired: cells develop mechanisms of drug resistance
What are some cellular mechanisms by which drug resistance can develop?
- Enzymes to inactivate drug
- p-glycoprotein (pupmp drug out of cell)
- Enzymes to repair drug damage to DNA
- Mutation in protein receptor
- Another molecular pathway becomes dominant
Are endocrine therapies in cancer considered to be targeted therapies?
Yes, endocrine cancer therapies were the first true “targeted therapy”
What is the utility of endocrine therapies in the treatment of cancer?
Useful for hormone-sensitive cancers:
- Prostate cancer
- Breast cancer
- Uterine (endometrial) cancer
What are some examples of endocrine therapies that interfere with estrogen?
Estrogen receptor antagonists:
- Tamoxifen (SERM)
- Fulvestrant
Aromatase antagonists:
- Anastrazole, Letrozole
- Exemestane
Estrogen production inhibiton:
- GnRH analogues (ex. leuprolide)
- Megestrol
What are some examples of endocrine therapies that interfere with testosterone?
Testosterone receptor antagonists:
- Bicalutamide
Testosterone production inhibtion:
- GnRH (ex. leuprolide)
- Cyproterone
- Abiraterone
What are the two broad classes of targeted cancer drugs?
Small molecule compunds (nibs)
- ex. imatinib, dasatinib
Monoclonal antibodies (mabs)
- ex. rituximab, trastuzumab
What is the general MOA of small molecule targeted therapies for cancer?
Interfere key protein pathways within a cancer cell that are essential to disease progression
What is the general MOA of monoclonal targeted therapies for cancer?
Block extra-cellular proteins or receptors outside the cell that are involved in essential cancer cell functions
May also be used to deliver toxins to the cancer cell
Review slides 71 and 72 for targeting growth signalling pathways to kill cancer cells
Review slide 74 for biomarker-targeted drug selection
What are the five main types of immunotherapy for cancer?
- Cellular therapy
- Immunomodulators
- Oncolytic virus therapy
- Monoclonal antibodies
- Cancer treatment vaccines
What is the role of T-cell checkpoint regulation in cancer?
T-cells are regulated via complext inhibitory (checkpoint) and activating signals
Tumours can dysregulate ihibitory checkpoint signals, and inhibit the immune response to tumour growth
What is the general MOA of PD-1 inhibitors?
PD-1 inhibitors block PD-1/PD-L1 interaction (immune inhibition interaction) between tumour cells and T cells, thereby restoring T-cell mediated immunity
Review slide 79 for CAR T-cell therapy
How are immunotherapy toxicities different from usual drug toxicities?
Affect multiple organ systems from excess immune mediated effects (dermatological, diarrhea/colitis, hepatoxicity, thyroid, pituitary)
Requires prompt assessment
- interruption of therapy
- steroids, infliximab
- tocilizumab
Life-threatening
- Cytokine release syndrome
- Immune effector cell-associated neurotox syndrome
Review slide 81 for review of future directions with targeted therapies
In what types of cancers is endocrine therapy used?
Breast, endometrial, ovarian, uterine, and prostate cancer
What are the three hallmark treatments for breast cancer?
- Tamoxifen (SERM)
- Aromatase inhibitors (Anastrozole, Letrozole, Exemestane)
- Goserelin acetate (GnRH agonists)
What are some characteristics of tamoxifen?
Tamoxifen is a SERM
Estrogen antagonist in breast tissue
Estrogen agonist in endometrium (concern about endometrial cancer)
What is the utility of tamoxifen in breast cancer treatment?
Adjuvant (curative) in premenopausal women for ER+ or PR+ breast cancers
Metastatic (palliative) treatment in premenopausal women for ER+ or PR+ breast cancers
Also used for breast cancer in men
What is the MOA of tamoxifen?
It is a selective estrogen receptor modulator (SERM)
Tamoxifen inhibits estrogen-induced cell proliferation via receptor blockade
What are some non-breast cancer indications for tamoxifen?
Also used in gynecological cancers (recurrent or progressive, must be ER+ or PR+)
Used in sarcomas (recurrent desmoid tumours or aggressive fibromatosis)
What is the benefit of tamoxifen in breast cancer outcomes?
Tamoxifen therapy shows increases in 10-year survival and disease-free survival rates
What is the dose of tamoxifen?
20mg once daily
Is tamoxifen the most appropriate endocrine therapy for postmenopausal women with ER+ and PR+ breast cancer?
No, aromatase (anastrozole, letrozole) are used preferentially in post-menopausal women due to better outcomes compared to tamoxifen
What are some common side effects associated with tamoxifen use?
Know for exam
Menoapause-like due to estrogen blockade
- Flushing, hot flashes
- Skin rash
- Fluid retention
- Nausea
- Mood changes
- Vaginal discharge or dryness
Can OTC estrogen-containing products be used to treat some of the side effects of tamoxifen?
No, do not give any OTC estrogen products as it goes against the MOA of tamoxifen (SERM)
What are some serious side effects associated with tamoxifen?
- DVT, PE, strokes
- Uterine cancer (if they start bleeding again, cramping)
- Risks are higher among postmenopausal women and women over 50 (use aromatase inhibitors instead)
Why are CYP interactions important with tamoxifen?
Tamoxifen metabolized into active moeity (endoxifen) via CYP 2D6
Avoid concomittant use with inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine) as they may decrease levels of the active form of tamoxifen (endoxifen)
Avoid grapefruit juice
What is the impact of tamoxifen on warfarin?
May increase the risk of bleeds, therefore adjust warfarin doses accordingly
What is the MOA of aromatase inhibitors?
Prevents conversion of androstenedione to estrone
AND
Prevents conversion of testosterone to estradiol
Can aromatase inhibitors be given to premenopausal women?
Yes, but also must be on ovarian control to limit ovulation
What are some cancer indications for aromatase inhibitors?
Used in post-menopausal women in both adjuvant and metastatic breast cancer settings
Used in post-menopausal women due to lower breast cancer recurrence
Also sued in gynecological cancers (recurrent or progressive, hormone receptor positive endometrial and ovarian cancers)
Review slide 108 for comparison of aromatase inhibitors
What are some ADRs associated with aromatase inhibitors?
- Hot flashes and flushing
- Hypertension
- Osteopenia and osteoporosis (significant concern among women with osteoporosis, and may use instead of tamoxifen)
- Weakness, arthralgia
- Fatigue
- Less risk for DVT than tamoxifen
- Nausea/Vomiting
What are some indications for GnRH agonists (Goserelin acetate) in cancer?
Adjuvant breast: Used for ovarian function supression for premenopausal women at high risk for reccurent breast cancer and have ER+/PR+ disease to combine with aromatase inhibitor
Metastatic breast: Use as a bridge to oophorectomy in premenopausal women
What is the most commonly diagnosed cancer among men?
Prostate cancer
Responsible for just under 10% of cancer deaths
Incidence is strongly correlated with age
Incidence is strongly correlated with age (growth of abnormal cells in a man’s prostate)
What are some symptoms associated with prostate cancer?
- Difficulty urinating
- Dribbling after urination
- Need to urinate often
- Pain and blood during urination
- Difficulty having or maintaining erection
- Pain of stiffness in the lower back, hips, and pelvis (esp. if prostate cancer has metastasized)
What are some risk factors for prostate cancer?
- Older age (over 65yo)
- Black men > White men
- Family history
- Obesity
What are some treatment options for prostate cancer?
Hormone therapy (cornerstone therapy, everyone is on this)
Watchful waiting if detected early (track growth of cancer with blood tests, rectal exams, and biopsies)
Radiation therapy (commonly used)
Radical prostatectomy (remove whole prostate gland)
Chemotherapy
What are the four main types of prostate cancer therapies?
- GnRH agonists
- GnRN antagonists
- CYP17 inhibito
- Antiandrogens
What is the efficacy of hormone therapies in prostate cancer?
Androgen Deprivation Therapy
Cornerstone of prostate cancer therapy
Objective tumour response 80-90%
What is the goal of androgen deprivation therapy in prostate cancer?
Reduce serum testosterone to castrate levels to reduce prostate growth
What are some characteristics of GnRH treatment of prostate cancer?
ex. Leuprolide acetate, goserelin acetate
Cause down-regulation of HPA axis
Initial flare of symptoms must be treated with bicalutamide for 14-30 days
Reduces serum testosterone as much as bilateral orchiectomy
What is the utility of GnRH agonist treatment in prostate cancer?
Used in prostate cancer either as neo-adjuvant and/or adjuvant treatment with a max therapy duration of 3 years
What is the MOA of GnRH agonist therapy?
GnRH initially promotes increased release of LH and FSH, and down-regulate the GnRH receptors which ultimately reduces LH and FSH production = less testosterone
Treat flare with bicalutamide
What is the MOA of GnRH antagonist therapy?
Blocks GnRH receptors, which reduces production of LH and FSH = lower testosterone
No flare, rapid decrease
What is an example of a GnRH antagonist used in prostate cancer therapy?
Degarelix
What are some ADRs of androgen deprivation therapies?
Urinary symptoms (10-15%)
Gynecomastia
Hot flashes (40-80%)
Decreased libido, ED (90-100%)
Fatigue, weight gain, loss of muscle mass
What is the indication for abiraterone?
Metastatic castration sensitive prostate cancer in combo with prednisone and androgen deprivation therapy
Metastatic castration-resistant prostate cancer in combination with prednisone
Why does abiraterone need to be used with prednisone?
To limit ADRs caused by reduced cortisol production which inturn causes increased mineralocorticoids
High mineralocorticoids=hypertension, low K+, edema
Review slide 125
What is the MOA of abiraterone?
Blocks androgen production in testes, adrenal glands, and tumour
What are some examples of androgen receptor blockers?
Bicalutamide and Flutamide
Enzalutamide and Apalutamide (additional testosterone lowering effects)
What is the utility of monoclonal antibodies in cancer treatment?
Mabs are a type of targeted drug therapy
These drugs recognize and find specific proteins on cancer cells
They work in different ways to kill the cancer cell or stop it from growing
What are the meanings of the most common substems (Mab naming convention) for monoclonal antibody targets?
-ci(r)=circulatory system
-li(m)=immune system
-t(u)=tumour
-os=bone
ex. Bevacizumab (targets the circulatory system)
What are the meanings of the most common suffixes (Mab naming convention) for mAb targets?
-ximab=chimeric
-zumab=humanized
-mumab=fully human
What are some characteristics of humanized mAb with respect to their composition?
Small, but critical parts of the CDR binding region is from non-human sources, but the larger heavy and light chains are human-derived
Generally contains more than 90% human sequence
What are some characteristics of chimeric mAb with respect to their composition?
The antbody tail (non-CDR binding regions) are of human sequence
Generally contain more than 65% of human sequence
What conditions are treated with humanized monoclonal antibodies?
Treatment of colrectal cancer, breast cancer, leukemia, allergy, autoimmune disease, transplant rejection, and RSV
What is the benefit of fully humanized mAbs?
In general, the more similar a mAb is to human sequences the less likely it is to elicit an immune reaction (decrease infusion reactions)
What are some cell surface antigen targets for mAbs used to treat cancer?
CD20
EGFR
HER2
What is a plasma protein target for mAbs used to treat cancer?
VEGF
What are some indications for mAb cancer therapies?
Hematologicial malignancies
Solid tumours
Although most mAbs are administered IV, which ones can be given also subcut?
Rituximab and daratumumab
What is the most common example of combining mAb therapy in cancer?
Pertuzumab and trastuzumab in HER2+ breast cancer
Both mAbs target the HER2 receptor and when combined they have greater efficacy and toxicity
A taxane is also used with this mAb combination therapy
What are some adverse events associated with mAbs?
May elicit a number of immune-mediated and other reactions and ADRs
Infusion reactions are common (derma, GI, endocrine, other inflammatory)
What is the most common ADR associated with IV mAb therapy?
Infusion reactions
Develop within 30 minutes to 2 hours after infusion
Majority of reactions follow either the first or second exposure
What are some signs/symptoms associated with infusion reactions?
- Fever and/or shaking chills
- FLushing and/or itching
- HR and BP alterations
- Dyspnea or chest discomfort
- Back or abdominal pain
- NVD
- Various types of skin rashes
What is a severe infusion reaction associated with IV mAbs?
Cytokine release syndrome is an acute systemic inflammatory syndrome characterized by fever and multiple organ dysfunction
occurs most often after immunotherapy for blood cancers
What are some characteristics of follicular lymphoma?
Second-most common type of non-Hodgkin lymphoma
Vast majority of patients treated will see initial response to therapy with 40-80% demonstrating a complete response
Conventional therapy is not curative, and most pts. will ultimately develop progressive disease
What is the benefit of Anti-CD20 mAbs in the treatment of follicular lymphoma?
Superior treatment response and overall survival when they are combined with conventional chemo in patients with follicular lymphoma
What anti-CD20 mAbs are used to treat follicular lymphoma?
Rituximab or obinutuzumab
They can be used in combo with chemotherapy regimens
What are the four mechanisms by which anti-CD20 mAbs are useful in treating follicular lymphoma?
- Complement-dependent toxicity (B-cell)
- Antibody-dependent cellular toxicity (B-cell)
- Antibody-dependent phagocytosis (macrophage)
- Direct cell death (B-cell)
Why is EGFR a potential target for cancer therapies?
Members of the HER family are overexpressed, dysregulated, or mutated in many human tumours (colorectal, head and neck, and small cell lung cancers)
What EGFR-targeted therapies are used in EGFR+ colon cancer?
Cetuximab and Panitumumab
What is the MOA of cetuximab in colon cancer?
Prevent dimerization of EGFR, which in turn prevents cancer proliferation, angiogenesis, metastasis, and inhibition of apoptosis
What is the specific indication for Cetuximab in colon cancer?
Locally advanced unresectable or metastatic, non-mutated colorectal cancer
What is the main difference between cetuximab and panitumumab in the treatment of colon cancer?
They have similar efficacy and same target
Cetuximab is chimeric (significant immune response), while panitumumab is a completely human mAb (preferred due to reduced immune responses)
What are VEGF inhibitors?
Antibodies that bind to and neutralize VEGF have been employed to decrease VEGF signalling in patients with malignancy
What is the most commonly used VEGF inhibitor?
Bevacizumab
What is the MOA of bevacizumab?
Humanized mAb that binds to circulating VEGF plasma proteins, and prevents activation of VEGF receptors
What are some indications associated with bevacizumab?
Advanced colorectal (lots of pts.)
Advanced ovarian and cervical (with chemo)
Recurrent glioblastoma
In combination with atezolizumab in advanced cancer
What are some ADRs associated with bevacizumab?
- HTN
- Bleeding (common reason why some MDs do not prescribe bevacizumab)
- Cerebral and myocardial infarction
- Proteinuria (monitor before each dose/cycle)
What are the appropriate targeted mAb treatments for left-sided colon tumours?
Use EGFR inhibitors (Cetuximab or panitumumab) in combo with chemo
What are the appropriate targeted mAb treatments for right-sided colon tumours?
Can use either EGFR inhibitors or VEGF inhibitors
Bevacizumab is favoured (VEGF inhibitor)
What is the MOA of ramucirumab?
Inhibit VEGF2 (high affinity to this subtype)
What is the main indication for ramucirumab?
Advanced gastric cancer and gastroesophageal adenocarcinomas
What are some common ADRs seen with ramucirumab?
Infusion reactions are common
HTN, diarrhea, bleeding
What proportion of breast cancers are found to be HER2+?
20% of breast cancers overexpress HER2
A high level of HER2 overexpression determined by staining is a strong predictive factors for HER2-targeted agents
What anti-HER2 mAbs are used in HER2+ breast cancer?
Trastuzumab and Pertuzumab
What is the MOA of trastuzumab?
Blocks HER2 dimerization
What is the MOA of Pertuzumab?
Blocks heterodimerization of HER2
What is a serious ADR associated with Trastuzumab/Pertuzumab therapy?
Cardiotoxicity (low LVEF)
Chemo is also cardiotoxic, so be cautious when using in combo with EGFR inhibitors
What is the benefit of drug/toxin mAb conjugates?
mAbs are used to deliver a drug or toxin to a specific site, which is especially beneficial for cell killing in cancer therapy
What is trastuzumab emtansine?
It is an antibody-drug conjugate composed of trastuzumab, a thioether linker, and the antimicrotubule agent DM1
See slides 174-176
What is enfortumab vedotin?
It is an antibody-drug conjugate that targets a protein (Nectar-4) highly expressed in urothelial carcinomas
The released drug induces cell cycle arrest and apoptosis of Nectar-4 expressing cells
See slide 178
What are some examples of biosimilar mAbs used in cancer?
Ruxience is the biosimilar of Rituxan
Zirabev is the biosimilar of Avastin
What pathway is inhibited when EGFR is inhibited?
Tyrosine kinase pathways
What are growth factors?
They are chemicals produced by the body that control cell growth
What is the role of growth factors with respect to cancer?
Some growth factors are responsible for cell differentiation, while others control cell division or apoptosis
How do growth factors affect cellular pathways?
Growth factors bind to cell-surface receptors which then sends a signal to the inside of the cell
This signal sets off a chain of complicated chemical reactions
See slide 186
What are the main types of growth factors?
Epidermal growth factor (EGF) - controls cell growth
Vascular endothelial gorwth factor (VEGF) - controls blood vessel development
Platelet derived endothelial growth factor (PDGF) - controls blood vessel development and cell growth
Fibroblast growth factor (FGF) - controls cell growth
What are cancer growth blockers?
A cancer growth blocker is a targeted drug that blocks the growth factors that trigger cancer cells to divide and grow
What are the main types of cancer growth blockers?
- Tyrosine kinase inhibitors (TKIs)
- Proteasome inhibitors
- mTOR (mechanistic target of rapamycin inhibitors)
- Hedgehog pathway blockers
What is the naming convention for small molecule cancer drug based on their MOA?
-tinib = Tyrosine kinase inhibitors
-zomib = Proteasome inhibitor
-ciclin = Cyclin-dependent kinase inhibitor
-parib = Poly ADP-ribose polymerase inhibitor (PARP inhibitor)
-irolimus = Mammalian target of rapamycin (mTOR inhibitor)
What is the pioneer tyrosine kinase inhibitor drug?
Imatinib
What is the MOA of tyrosine kinase inhibitors?
Block tyrosine kinases which are responsible for sending growth signal in cells (blocking them stops the cell from growing and dividing)
Can tyrosine kinase inhibitors block more than one type of cancer growth blockers?
Yes, they are called multi-TKIs (tyrosine kinase inhibitors)
See slides 199 and 200
See slide 201 for examples of tyrosine kinase inhibitors
What are some examples of TKI-EGFR inhibitors for non-small cell lung cancer (NSCLC)?
Erotinib, Gefitinib, Afatinib
Osimertinib (given when pt has developed resistance to 1st line EGFR inhibitors)
What are TKI-ALK inhibitors?
They are a type of tyrosine kinase inhibitors (anaplastic lymphoma kinase)
How do TKI-ALK inhibitors work?
Block anaplastic lymphoma kinase enzyme
They only work in patients with cancer cells that have an overactive version of ALK (often have ALK fusion gene, affects young non-smokers)
What are some examples of TKI-ALK inhibitors?
- Crizotinib (1st line)
- Alectinib, Brigatinib, Ceritinib (2nd line)
- Lorlatinib (3rd gen)
What are some ADRs associated with ALK inhibitors?
GI toxicities (NVD)
Elevated LFTs (monitor CBC and LFTs and adjust dose accordingly)
Less commonly, pneumonitis
What are some examples of TKI-ROS1 inhibitors?
Crizotinib and Entrectinib
What are some examples of TKI-HER2?
Lapatinib, Neratinib, Pyrotinib, Tucatinib
Tucatinib is the most popular oral HER2 inhibitor
What is the role of VEGF in angiogenesis?
VEGF is the master regulator of angiogenesis (unregulated in many tumours, invasion, and metastasis)
See slide 212
What is the MOA associated with axitinib?
VEGF inhibitor
What is the indication for axitinib?
Metastatic renal cell cancer (can be used as a single agent or in combo with pembrolizumab)
What are some common ADRs associated with axitinib?
HTN, bleeding, impaired wound healing
What is a serious ADR associated with axitinib?
Reversible posterior leukoencephalopathy syndrome (RPLS)
- Headaches
- Seizures
- Lethargy
- Confusion
- Blindness
What is the MOA of sunitinib and pazopanib?
multi-TKI, but primarily VEGF
What is the indication for both sunitinib and pazopanib?
Both agents: Metastatic renal cell carcinoma
Sunitinib: GI stromal cancer, pancreatic neuroendocrine tumour
What are some ADRs associated with sunitinib and pazopanib?
- Nausea, diarrhea
- Hand foot skin reaction
- Discoloration of nails or hair
- Hypothyroidism
- HTN, QTc prolongation, reduced LVEF
- Bleeding
What is the indication for sorafenib?
Metastatic hepatocellular carcinoma (TKI-VEGF inhibitor)
What is the indication for regorafenib?
GI stromal tumour, hepatocellular carcinoma (TKI-VEGF inhibitor)
What are some ADRs associated with sorafenib and regorafenib vs. other TKI-VEGF inhibitors?
- less GI compared to sunitib
- less hand-foot skin reaction than sunitinib
- Severe rash, mild skin discolouration
- HTN
- Bleeding
What are some indications for lenvatinib?
Thyroid cancer, hepatocellular adenoma, renal cell carcinoma, endometrial cancer
For advanced endometrial cancer, give with pembrolizumab
What are some characteristics of lenvatinib+pembrolizumab treatment of advanced endometrial cancer?
Very toxic regimen (fatal ADRs do occur, Grade 3 and above ADRs occured in 90% of pts)
Used in patients who test negative for MSI-H or dMMR (genetic test)
What are some ADRs associated with lenvatinib?
N/V, skin rashes, diarrhea or constipation, HTN (common), oral mucositis (avoid magic mouthwash), appetite loss, fatigue
What mutation is responsible for most cases of chronc myelogenous leukemia (CML)?
BCR-ABL fusion gene is the result of an abnormal chromosome called the Philadelphia chromosome
See slide 221
What are some examples of BCR-ABL inhibitors (also a type of tyrosine kinase inhibitors)?
Imatinib, Dasatinib, Nilotinib, Bosutib, Ponatinib
What mutations are responsible for a significant number of melanomas?
Mutations in the BRAF gene are responsible for around half of melanomas
Drugs called BRAF inhibitors treat these melanomas by targeting the faulty gene, but they quickly develop resistance
What are some examples of BRAF inhibitors used in BRAF positive melanoma?
Vemurafenib, dabrafenib, and encoafenib
Are BRAF inhibitors used alone in treatment of BRAF+ melanoma?
No, they are used in combo with mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors for melanoma
How do MEK inhibitors work?
Another type of targeted cancer drug, and it targets the MEK protein
By blocking the MEK protein, it slows down the growth of cancer cells
What are some examples of MEK inhibitors?
- Trametinib
- Cobimetinib
- Binimetinib
What are the usual BRAF-MEK inhibitor combo therapies for treating melanoma?
Dabrafenib+trametenib
Vermurafenib+cobimetinib
Encorafenib+binimetinib
What is the benefit of using combo BRAF-MEK inhibitor therapy in melanoma?
Inhibition of melanoma is synergistic and the combination delays drug resistance
Tolerability is also improved
What are some ADRs associated with MEK inhibitors?
Fewer cutaneous squamous carcinomas
Acneiform rash
Cardiotoxicities
Ocular toxicity
What is the MOA of proteasome inhibitors in cancer therapy?
Help inhibit proteasomes (break down unutilized proteins into building blocks for new proteins)
Proteasome inhibitors cause a buildup of unnecessary proteins, and this causes the cancer cells to die.
What are some examples of proteasome inhibitors used in cancer therapy?
Bortezomib (subcut), Carfilzomib (IV), Ixazomib (PO)
What is the indication for bortezomib?
Multiple myeloma
What are some ADRs associated with proteasome inhibitors?
- HepB or Herpes zoster reactivation
- Neutropenia
- Thrombocytopenia
- Peripheral neuropathy (more common with bortezomib)
- Diarrhea
What viral infection do proteasome inhibitors increase the risk of reactivation?
Herpes zoster and herpes simplex reactivation
Antiviral prophylaxis is recommended for seropositive patients
What are some of the functions of the mTOR protein?
Produces cyclins that triggers cell growth
Promote angiogenesis
These two functions make cancer cells grow and produce new blood vessels to support the growth
How can mTOR inhibitors slow down cancer proliferation?
Inhibit growth and angiogenesis
What is an example of a mTOR inhibitor used in cancer?
Everolimus
What is the hedgehog pathway?
This pathway is responsible for proper embryonic development, and normally goes dormant in adulthood
What is the utility of the hedgehog pathway blockers in cancer treatment?
In some people, hedgehog pathway proteins are reactivated.
Hedgehog pathway blockers are designed to switch off the proteins and stop the growth of the cancer
What is an example of a hedgehog pathway blocker?
Vismodegib (Erivedge) is an example of a hedgehog pathway blocker
It is used to treat basal cell skin cancer that is spreading
Can hedgehog pathway blocker be used safely in pregnant women?
No, because the embryo relies on the hedgehog pathway to develop properly
Therefore, use effective contraception during and after vismodegib therapy (M&F teratogen)
What are some ADRs associated with hedgehog pathway blockers?
GI effects, loss of taste, alopecia, arthralgia
What are PARP inhibitors?
poly-ADP-ribose polymerase (PARP)
They inhibit enzymes that otherwise repair damaged DNA. Therefore the inhibition of PARP results in decreased cell viability (esp in those that have other mutated DNA repair mechanisms, ex. mutated BRCA genes)
See slide 246
What are some general indications for PARP inhibitors?
Gynecological, breast, and prostate cancers with BRCA+ gene mutation
What are some examples of PARP inhibitors?
Niraparib and Olaparib
What are some indications associated with Naraparib?
Advanced or recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer and responsive to platinum-based chemo
What are some indications associated with Olaparib?
Patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer with BRCA+ and respond to platinum-based chemo
What types of breast cancer can be treated with Olaparib?
Early stage, high risk BRCA+ and HER2- for adjuvant treatment
What types of prostate cancer can be treated with Olaparib?
Metastatic castration resistant prostate cancer with BRCA or ATM mutations
Use with abiraterone/prednisone due to ACTH inhibition
What types of prostate cancer can be treated with Niraparib?
Metastatic castration resistant prostate cancer with BRCA+ and use with prednisone
What is the role of cyclins in cell division?
Progression through different phases of the cell cycle is controlled by cyclins
They activate cyclin-dependent kinases (CDKs)
How does cancer affect cyclin mediated cell functions?
Cancer may dysregulate cyclin-dependent kinases (CDKs) and force them through the G1 checkpoint despite genetic damage
How do cyclin-dependent kinases inhibit cancer growth?
Inhibitors of CDKs can stop cancer growth and induce senescence
What are some ADRs associated with CDK inhibitors?
Neutropenia, stomatitis, nausea, fatigue that is usually mild
What are the four main CDK 4/6 inhibitors?
- Abemaciclib
- Palbociclib
- Ribociclib
What is the administration schedule for Abemaciclib?
Continuous, only continuous CDK inhibitor
What is the administration for non-Abemaciclib CDK inhibitors?
3 weeks on, then 1 week off
What is the indication for abemaciclib?
HR+, HER2-, node positive, early stage breast cancer as adjuvant with aromatase inhibitors
What is the indication for palbociclib?
1st line in metastatic (HR+, HER2-) in combo with aromatase inhibitors
Do not use in early stage breast cancer
What is the indication for ribociclib?
1st line in metastatic (HR+, HER2-) in combo with aromatase inhibitors
can use in early stage breast cancer, unlike palbociclib
What are some ADRs associated with abemaciclib?
Diarrhea (85%)
Neutropenia (23%)
Increased creatinine (98%)
What are some ADRs associated with palbociclib?
Neutropenia (55%), which is why this regimen is discontinuous
Diarrhea (26%)
What are some ADRs associated with ribociclib?
Neutropenia (61%), which is why this regimen is discontinuous
Diarrhea (35%)
QTc prolongation
What CYP enzyme are CDK inhibitors a substrate for?
CYP 3A4 substrate
What is chronic lymphocytic leukemia (CLL)?
It is the most common adult leukemia
It is a slow progressing cancer, but its clinical course is variable
What biomarker is present in most chronic lymphocytic leukemia patients?
Nearly all patients have increased BCL2 expression in CLL cells
What is the impact of BCL2 proteins?
They are anti-apoptotic proteins that are overexpressed in patients with CLL
What is the impact of BCL2 inhibitors?
They block anti-apoptotic BCL2 (b-cell lymphoma-2) protein, which should restart cell apoptosis in malignant cells
See slide 255
What is the most effective BCL2 inhibitor?
Venetoclax
What is a serious ADR associated with BCL2 inhibitors like Venetoclax?
Tumour lysis syndrome (rapid cancer cell death, increased cell components in blood, may overwhelm electrolyte balance and the kidneys)
How is risk of tumour lysis syndrome (TLS) reduced when taking a BCL2 inhibitor like Venetoclax?
A dose ramp-up period (dose escalation every week during the first few months of therapy)
Prophylactic hydration to ease the load on the kidneys and electrolyte balance
What is the indication for BCL2 inhibitors like Venetoclax?
Newly diagnosed Acute Myeloid Leukemia (AML) in patients who are 75 years or older
OR
Have comorbidities that preclude use of intensive chemotherapy (use with azacitidine)
What is the general MOA of cancer immunotherapies?
They target the patients immune system and enhances its response to cancer
Help the immune system get around some of the immune system evasion by cancer cells
What is different about the response to immunotherapies compared to other types of cancer therapies?
Patients who respond to immunotherapy may have a more durable response
What are some types of cancer immunotherapies?
- Monoclonal antibodies
- CAR T-cell
- Cytokines
- Treatment vaccines
- BCG
- TLR agonists
Review slide 263 (slide 3) for T-cell targets for cancer immunotherapies
What are the two main types of immunotherapy agents available in Canada?
CTLA4 inhibitor (controls T-cell proliferation at an early stage)
PD-1/PD-L1 inhibitor (controls activation of T-cell and takes off the brakes from the immune system)
What are some examples of CTLA4 inhibitors?
Ipilimumab
What are some examples of PD-1 inhibitors?
Pembrolizumab
Nivolumab
What are some examples of PD-L1 inhibitors?
Durvalumab
Atezolizumab
Avelumab
See slide 264 (slide 3) for CTLA4 inhibitor visualized MOA
What are some indications for CTLA4 inhibitors?
- Melanoma (Ipilimumab mono, Ipilimumab+Nivolumab)
- Kidney cancer (Ipilimumab+Nivolumab)
- Small Cell lung cancer (Ipilimumab+Nivolumab)
See slide 265 (slide 3) for visualized MOA for PD-1 and PD-L1 receptors
See slide 266 (see slides 1) for PD-1 inhibitor indications
See slide 266 (see slides 2) for PD-L1 inhibitor indications
What are the dosing intervals for cancer immunotherapies?
Q2w, q3w, q4w, q6w
How are cancer immunotherapy doses adjusted to mitigate toxicity?
Doses are not reduced for toxicity, either hold or give a full dose
Review slide 267 (slide 1) for different cancer immunotherapy regimens
What is the impact of immunotherapies in treating metastatic melanoma?
Low survival rates with chemotherapy
For patients that saw some response with the immunotherapies, a significant improvement in long-term survival rates was seen (ex. ipilimumab shows 3 year survival rate of 22%, which is more than 1-2% seen with chemo)
What is key to the success of immunotherapies?
Better biomarker identification, which should help healthcare teams identify patients more accurately who are durable responders
What is a paradigm shift seen with advanced NSCLC therapy?
Significant improvement in survival in the pembrolizumab arm (immuotherapy) vs. chemo
Review slide 272 (slide 1) for comparison of chemo and immunotherapy ADRs
What are some risk factors for developing ADRs from cancer immunotherapies?
- Personal/Family history of autoimmune diseases
- Tumour filtration
- Concomitant medications and occupational exposures
What are some ways that ADRs from cancer immunotherapies can be mitigated?
- HCP and Patient Education
- Patient Reporting
- Call-Back Program
What baseline variables are measured before initiation of cancer immunotherapies?
- Physical examination
- Laboratory tests
- Imaging (rule out metastases before initiation of immunotherapy)
When are lab tests/evaluations performed when the patient is in the treatment phase with cancer immunotherapies?
Lab tests before every immunotherapy administration
Can ADRs from cancer immunotherapies develop after the treatment phase is complete?
Yes, which is why lab tests/evaluations are on a 3 month basis in the first year after treatment d/c, and then every 6 months
What are the most common causes of ADRs with cancer immunotherapies?
- Disease-related (most common cause of new ADR)
- Incidental event
- Immune-related adverse event (high level of suspicion, but do not automatically rule out other causes)
Review slide 274 (slide 2 and 3) for ADRs while on cancer immunotherapies
When do cancer immunotherapy ADRs manifest?
Most ADRs do not develop until 4 weeks of therapy, as the response to therapy is also delayed
Toxicities can develop weeks to months after treatment initiation
Is it common practice to dose-adjust cancer immunotherapies?
No, cannot reduce dose of immunotherapy agents, either hold off or continue dosing
What should you do if a patient experiences a Grade 1 ADR to a cancer immunotherapy agent?
Supportive care +/- withold drug
What should you do if a patient experiences a Grade 2 ADR to a cancer immunotherapy agent?
Withold drug, consider restart if toxicity resolves to Grade 1 or below
Initiate low-dose prednisone if symptoms do not resolve within a week
What should you do if a patient experiences a Grade 3/4 ADR to a cancer immunotherapy agent?
d/c drug and give high dose prednisone until toxicity resolves to Grade 1 or lower
What should you do if a patient experiences a severe/steroid-resistant ADR to a cancer immunotherapy agent?
May warrant additional immune supressive agents if ADR does not respond to steroids within 48-72h
Review slide 279 (slide 1) for immunotherapy ADR key takeaways
What are some challenges associated with administering cancer immunotherapies?
- Evaluating treatment response
- Identifying good candidates who will see enduring response
- Optimal regimen and treatment duration
- Combination or sequential therapies
- Role of host factors, comorbidities, meds
What is the general mechanism of CAR T-cell therapy for cancer?
Patient’s T-cells are genetically modified to target the patient’s specific cancer based on its biomarkers
What are some toxicities associated with CAR T-cell therapy?
- B-cell aplasia
- Cytokine release syndrome (CRS)
- Neurotoxicity
What are some characteristics of cancer-associated thrombosis?
Common complication of both disease and treatment
2nd leading cause of death in cancer patients (they are at 12-20x higher risk for VTE)
Activation of coagulation is important for tumour progression and metastasis
What are some risk factors for developing cancer-associated thrombosis?
- Patient related (age, history of VTE)
- Cancer related (stomach, pancreas, lung, GI/GU cancers pose a higher risk for thrombotic events)
- Treatment related
In what situations is LMWH used for VTE prophylaxis/treatment in cancer patients?
In patients at higher risk of bleeds, unresected GI/GU cancers, or have DIs with DOACs
Review slide 284 (slide 1)
Why are DOACs preferred for VTE prophylaxis/treatment in most cancer patients?
Despite higher bleed risk, oral formulations are easier to take and cost less to administer
Review slide 284 (slide 1)
Review slide 283 (slide 3) for anti-cancer therapies that may have drug-interactions with DOACs
How long is VTE treatment therapy in cancer patients?
6 months in most patients
May consider longer treatment duration in patients at higher clot risk (using PICC line, hormonal therapy, hemophiliac)
What is cancer-related fatigue (CRF)
Pervasive across cancer continuum
Distressing, persisting, subjective sense of physical, emotional, and/or cognitive tiredness, or exhauston related to cancer or cancer treatment
Not proportional to recent activity and interferes with usual functioning
What are some ways cancer related fatigue can be managed?
Manage precipitating factor (pain, anemia, nutritional status, anxiety, depression, insomnia, comorbid condition)
Energy conservation
Exercise with moderate intensity (ealking)
Limit naps longer than 1 hour (encourage sleep hygiene)
Reduce stress
Food and water intake
What causes chemotherapy side effects?
Side effects are a result of damage to healthy cells (bone marrow, GI epithelium, hair follicles and gonads)
Rapid turnover cells are particularly affected
Review slide 294 for chemotherapy ADRs
When are nausea and vomiting most common after chemotherapy?
Day 1-3
When is fatigue most common after chemotherapy?
Throughout entirety of treatment cycle
When are mouth sores most common after chemotherapy?
Day 5-12
When is neutropenia most common after chemotherapy?
Day 7-20
When is hair loss most common after chemotherapy?
Day 14 and ongoing for duration of treatment
What are some examples of urgent adverse events associated with chemotherapy?
- Temperature
- Shivering
- Flu symptoms
- Nose or gum bleeding that doesn’t stop
- Mouth sores that prevent eating or drinking
- Uncontrolled vomiting
- Diarrhea
- Dyspnea
- Anaphylaxis/infusion reaction
- Chest pain/irregular heart rhythm
How are urgent ADRs associated with chemotherapy addressed?
Need to contact cancer clinic/healthcare team immediately
Often occur during chemo infusion
What are some short term ADRs associated with chemotherapy?
- Nausea/vomiting
- Diarrhea/constipation
- Mucositis/stomatitis
- Myelosuppression
- Hair growth alterations
- Weight gain/loss
- Taste/smell alterations
- Fatigue
- Hepatic/renal changes
- Cardiac function changes
How are short-term ADRs associated with chemotherapy addressed?
Occur during treatment, and can be managed with symptomatic care strategies or dose adjustments
What are some long-term ADRs associated with chemotherapy?
- Infertility
- Secondary malignancies
- HF
- Osteoporosis
- Pulmonary fibrosis
- Cataracts
- Peripheral neuropathy
- Hearing loss
- Fatigue
- Endocrine abnormalities
How are long-term ADRs associated with chemotherapy addressed?
May occur months to years after treatment stopped, therefore recognition and treatment can be more difficult
What is the name of the ADR grading system used for cancer therapy toxicities?
Common Terminology Criteria for Adverse Events (CTCAE)
What are the ADR levels of the CTCAE grading system for cancer therapy toxicities?
Grade 0: none
Grade 1: mild
Grade 2: moderate
Grade 3: severe
Grade 4: life threatening
Review slide 302 for examples
What is the purpose of a common ADR grading scale for cancer therapy toxicities?
Ensure all team members can effectively communicate severity and initiate appropriate treatment options based on a more objective scale
What are some examples of local hypersensitivity reactions?
Rash, urticaria, erythema, phlebitis, pain and vein discolouration
What are some examples of systemic hypersensitivity reactions?
Bronchospasm, angiodema, hypotension, generalized rash, pruritis, and dermatitis
Are hypersensitivity reactions dose-dependent with respect to their severity?
No, reactions are not dose-related
What drugs are most commonly associated with hypersensitivity?
Taxanes, platinums, bleomycin, and mAbs
What are some preventative measure used to avoid infusion-related reactions?
Use of pre-medications (steroid, H2RAs, antihistamine and/or acetaminophen)
What are the direct cytotoxic effects associated with chemotherapy?
Reduce bone marrow production and total circulating blood cells
What is the main chemotherapy dose limiting ADR?
Myelosupression (a part of hematologic toxicity with chemo)
What are some examples of myelosupression experienced by patients on chemotherapy?
Neutropenia, thrombocytopenia, and anemia
What are some of the indirect cytotoxic effects associated with chemotherapy?
They alter the bone marrow microenvironment and interact with lymphoid cells
Is myelosuppression a permanent ADR associated with chemotherapy?
Generally reversible, but may lead to severe complications requiring hospitalization
Review slide 306 for a visual of myelosupression
What is the nadir period with respect to chemotherapy?
It is the lowest point for blood cell count
Chemo regimen and patient medical status affect how low and broad the nadir is
See slide 307 & 308
How are anemia and chemotherapy linked?
Chemotherapy can deplete hematopoetic stem cells and progenitor cells, causing dose-dependent anemia
What are some symptoms associated with chemotherapy-induced anemia?
Regular anemia sx
Fatigue, weakness, liht-headedness and dyspnea
How is chemotherapy-induced anemia treated?
Infusion of packed RBCs
ESAs are not recommended due to increased risk for thrombotic events
At what hemoglobin count do we become concerned about chemotherapy-induced anemia?
under 100-80g/L
What is the link between thrombocytopenia and chemotherapy?
Chemotherapy can inhibit platelet release or cause platelet apoptosis
These patients are at risk of bleeding
How is chemotherapy-induced thrombocytopenia managed?
Dose adjustment, treatment delays and/or platelet transfusion (not preferred, as it can impact chemo regimen efficacy)
When is the platelet nadir seen after chemotherapy?
Platelet life cyle is 8-10 days, so nadir is 14 days post-infusion
What is the definition of neutropenia?
Absolute neutrophil count (ANC) aka WBC count less than 1.5 cells x 10^9/L
How is chemotherapy-induced neutropenia managed?
Prophylaxis with GCSFs
What is the definition for febrile neutropenia?
Under 0.5x10^9/L or under 1x10^9/L, but projected to fall below 0.5 in the next 48 hours
AND
Fever of over 38.3 °C or over 38 °C if maintained for 1 hour
What should patients know about chemotherapy-induced febrile neutropenia?
Seek urgent medical attention
Educate patient to take all symptoms seriously
Also avoid any anti-pyrhetics (ex. Tylenol, Advil)
Infection prevention strategies
What are some risk factors for developing chemotherapy-induced febrile netropenia?
Cytotoxic agent
Dose intensity of the regimen
Concomitant chemoradiation therapy
Severity and duration of neutropenia
Patient factors
How is chemotherapy-induced febrile neutropenia treated?
Treat empirically with broad spectrum antibiotics (ideally given within 1 hour of being admitteddue to weakened immune function)
What are some empiric antibiotic choices for treating chemotherapy-induced febrile neutropenia?
Anti-pseudomonal lactam (pip-taz, cefepime, meropenem, ceftazidime)
Vancomycin (or linezolid) if there is high suspicion of gram-positive involvement
- Known MRSA carrier
- Catheter-related infection
- Skin or soft tissue infection, severe mucositis
- Hemodynamically unstable or sepsis
What are some febrile neutropenia prevention and treatment options?
GCSFs (Filgrastim and Pegfilgrastim)
They regulate release, promote proliferation and differentiaiton of myeloid cells, including neutrophils
What does primary prophylaxis for febrile neutropenia look like?
GCSFs are used empirically for patients at greater than or equal to 20% risk for febrile neutropenia
What does secondary prophylaxis for secondary neutropenia look like?
GCSFs prevent recurrence after experiencing febrile neutropenia from a previous chemo cycle
GCSFs also shorten the duration of severe neutropenia in patients who experienced neutropenia without fever in a previous chemo cycle
What is the impact of GCSF prophylaxis on WBC nadir following chemotherapy?
Lower nadir, and earlier recovery with GCSF therapy
See slide 317
When does mucositis appear after a chemotherapy infusion?
Usually presents during the neutrophil/WBC nadir (7-10 days with cytotoxics)
See slide 320 for mucositis at different severities
What are some risk factors for GIT ADRs associated with chemotherapy?
Continuous chemotherapy infusions and concurrent radiation therapy
Review slide 322 for the impact of mucositis/stomatitis on patients
Why does chemotherapy cause mucositis?
Reduce mucosa regeneration
What are the consequences of mucositis?
- Painful
- Limited nutritional intake
- Affect outcomes due to chemo dose reduction, delay, or stop treatment to manage mucositis
- Potential site for infection
How can chemotherapy-induced mucositis be prevented?
Good oral hygiene (brush teeth, avoid irritating foods, ensure dentures fit)
Salt/baking soda/normal saline rinse (avoid magic mouthwash or alcohol containing wash)
Ice chips (chew 30 min before chemo infusion, but CI in some regimens)
How is chemotherapy-induced mucositis treated?
Prescription mouth wash for pain relief (not magic mouthwash)
- Steroids
- Local anesthetics and analgesics
Fungal infection
- Nystatin
- Fluconazole (oral)
Analgesia (oral morphine)
Severe symptoms
- Hospitalization
- IV narcotics
- Parenteral nutrition
What is the most common cause of dyspepsia/heartburn in patients receiving chemotherapy?
Often an ADR of supportive care medications (ex., dexamethasone, antibiotics)
What are some examples of chemotherapy that are more likely to cause diarrhea?
Irinotecan
Capecitabine
Fluorouracil
Methotrexate
Cytarabine
High dose chemo prior to bone marrow transplant
What are some non-pharm diarrhea management tips?
Small, frequent meals and hydration
Limit caffeine, fried, greasy foods
Avoid food high in insoluble fiber
Encourage foods high in soluble fiber (bananas, applesauce)
What are some pharm diarrhea management tips for patients receiving chemotherapy?
Loperamide
Opioid analogues (reduce gut motility and fluid secretion)
Octreotide (reduces fluid secretion from the GIT, increases fluid reabsorption from the intestine)
What are the characteristics of irinotecan-induced diarrhea?
Irinotecan (occurs within 24h in 51% of patients)
Cholinergic mechanism (use atropine to treat)
May also use high dose loperamide regimen (take until diarrhea free for 12 h)
Secretory diarrhea caused by abnormal ion transport across injured intestinal mucosa
What are some ways constipation can manifest in patients receiving chemotherapy?
Supportive care treatment ADR (ondansetron, opioids)
Chemo-induced (reduction in GI motility and more fluid reabsorption from GIT)
Radiation to the GIT
What is the impact of chemotherapy on taste and smell?
Chemo may reduce appetite
May affect taste by direct taste receptor stimulation due to secretion of the drug in saliva
Taste changes persist due to damage to taste buds and psychological effects
Often described as metallic or chemical taste when chemotherapy is delivered (may use plastic utensils to help with reduced appetite)
What are some cutaneous reactions to chemotherapy?
- Photosensitivity
- Nail changes (see slide 341)
- Hyperpigmentation (see slide 342)
- Dry skin, rashes (see slide 343)
See slides 344 to 347 for Hand Foot Skin Reaction (HFSR)
What chemotherapy agent is most likely to cause Hand Food Skin Reaction (HFSR)?
Capecitabine
Usually appears in the first few cycles of therapy
How can Hand Foot Skin Reaction (HFSR) be treated?
Prevention is key, no treatment
How can Hand Foot Skin Reaction (HFSR) be treated?
Avoid exposure to heat (warm water)
Protective gloves and socks to prevent injuries
Moisturizer to hands and feet (BID)
Avoid activities that apply pressure to skin of hands and feet
Avoid fragrances (may irritate the skin)
What are some hair changes that come with being on chemotherapy?
Alopecia (scalp hair is the most common area for hair loss because it is the fastest growing hair)
Depigmentation of hair
Change of colour
Change of texture (more coarse)
Eyelash and eyebrow changes
See slides 351 to 353
What chemotherapy agents have the highest risk for alopecia?
Any cytotoxic has the potential to cause hair loss, but doxorubicin, paclitaxel, and docetaxel have very high rates of alopecia
What classes of chemotherapy agents are most likely to cause neurotoxicity?
Platinum agents
Taxanes
Vinca alkaloids
Proteosome inhibitor
Immunomodulating agents
What is the most common type of neurotoxicity experienced by patients on chemotherapy agents?
Peripheral neuropathy
What are some symptoms of peripheral neuropathy?
- Pain (constant or transient)
- Burning
- Tingling
- Loss of feeling
- Loss of dexterity
- Balance problems
What is the impact of anthracyclines to cardiovascular health?
Direct injury to the heart (acute: MI, arrhythmias; delayed: CHF)
Caused by ROS attack on heart tissue
Lifetime maximum doses to reduce cardiotoxicity
What is the impact of fluorouracil on cardiovascular health?
Second most common cause of chemotherapy-related cardiotoxicity, after anthracyclines
What is the impact of trastuzumab on CV health?
Associated with HFrEF, arrhythmias, HTN, cardiomyopathy, and death
More pronounced if used in combo with an anthracycline
Reversible with d/c of trastuzumab
What is the impact of poorly managed chemotherapy-induced nausea & vomiting?
Nausea and vomiting are the most feared side effect of chemotherapy
When uncontrolled, it can cause loss of appetite and weight loss, broken bones, and re-opening of surgical wounds in extreme cases
What are the clinical consequences of not adequately controlling CINV?
- Medical complications: electrolyte imbalances, dehydration
- Poor quality of life
- Poor adherence
- Dose reductions; treatment delays
- Poor outcomes
What is the goal of therapy for CINV?
No emesis and no/mild nausea
In general, how is CINV managed?
- For maximal benefit, intitiate anti-emetics prior to chemotherapy
- Much easier to prevent than to treat
- Scheduled anti-emetics versus PRNs
What are the different types of CINV?
Acute
- Occurs within 24 hours of treatment
- Serotonin dependent
Delayed
- Occurs 24-120h post treatment
- Substance P dependent
Anticipatory
- Occurs as a conditioned response due to past negative experience (occurs prior to chemo)
Breakthrough
- Occurs despite appropriate prophylactic anti-emetic
Review slide 374 for pathophysiology of CINV
What are some tretament-related risk factors for developing acute CINV?
- Intrinsic property of drug (emetogenecity)
- Dose, route, rate of infusion
- Repeated cycles
What are some patient-related risk factors for developing acute CINV?
- Lower alcohol consumption
- Younger age
- Female
- History of motion sickness
- History of N/V during pregnancy
What are some treatment-related risk factors for developing delayed CINV?
Not well characterized with many chemotherapeutic agents
What are some patient-related risk factors for developing delayed CINV?
Similar to risk factors in acute CINV
- Low alcohol consumption, younger age, femal
- History of motion sickness
- Poor control of acute CINV
What are the four drug classes that form the backbone for high emetic risk regimens?
- 5-HT3 antagonists
- NK1 antagonists
- Corticosteroids
- Olanzapine
What is the MOA of 5-HT3 antagonists?
Inhibit serotonin inhibitors located in CTZ (chemotherapy trigger zone) and within the vagal afferent fibres from the upper GI tract
What are some examples of first generation 5-HT3 antagonists?
Ondansetron, Dolasetron, Granisetron
What is the efficacy of 5-HT3 antagonists in treating CINV?
These agents used alone are effective in the first 24h (acute phase), but not on days 2-5 post chemotherapy (delayed phase)
What are some ADRs associated with 5-HT3 antagonists?
Headaches and constipation
QTc prolongation seen with higher doses, less concerning with second gen 5-HT3 antagonists (palonosetron)
What are some examples of NK1 receptor antagonists used in CINV?
Aprepitant (PO), Fosaprepitant (IV)
Combo:
Akynzeo (netupitant+palonosetron)
- NK1 receptor antagonist + 2nd gen 5-HT3 antagonist
What is a relevant drug interaction with NK receptor antagonists?
Dexamethasone requires 50% dose reduction if using with NK-1 receptor antagonists
Why are NK-1 receptor antagonists used with other anti-emetics in CINV?
Synergistic activity when NK-1 receptor antagonists are given with 5-HT3 receptor antagonists and steroids
How is Akynzeo (netupitant+palonsetron) effective in CINV?
The netupitant is good for delayed CINV, while the palonsetron is good for acute CINV
Dual mode of action (palonosetron is a 5-HT3 antagonist and netupitant is an NK-1 receptor antagonist)
What is the general MOA of NK-1 receptor antagonists?
They bind to NK-1 receptors and inhibit Substance P-mediated responses
See slide 389
What is the CINV treatment protocol with Highly Emetogenic
Chemotherapy (HEC),
including cisplatin-
based regimens?
Day 1: Akynzeo (1h before each chemo cycle) +dexmethasone 12mg
Day 2: Dex 8mg
Day 3: Dex 8mg
Day 4: Dex 8mg
What is the CINV treatment protocol with Anthracycline-cyclophosphamide (AC) and chemotherapy not
considered to be
highly emetogenic
Also includes
Carboplatin (AUC ≥4)?
Day 1: Akynzeo (1h before each chemo cycle) + Dexamethasone 12mg
No ongoing dexamethasone for days 2-4
What were some of the most common ADRs associated with Akynzeo?
Headache
Constipation
Fatigue
What is the purpose of using steroids in prevention of CINV?
Prevention of acute and delayed CINV
What is the steroid of choice for CINV prevention?
Dexamethasone
Also preferred in patients receiving radio to the brain as it may reduce cerebral edema
What are some acute ADRs associated with steroid therapy for CINV?
Insomnia, heartburn, increased BGs
What are the indications for dexamethasone in CINV?
Adjunct with Akynzeo in high emetic risk chemotherapies (non-AC and AC based regimens)
Adjunct with 5-HT3 antagonist in moderate risk (non-carboplatin)
May be used alone in low emetic risk regimens
See slide 395 for dexamethasone dosing in CINV
What is the efficacy of olanzapine in CINV?
Very effective in preventing delayed nausea
Used for breakthrough N/V
Acts on multiple receptors
What are some examples of dopamine antagonists used for CINV treatment?
Metoclopramide, prochlorperazine, haloperidol
What is the MOA of dopamine antagonists in CINV?
They block dopamine receptors in the chemotherapy trigger zone
What is the utility of dopamine antagonists in the treatment of CINV?
Used in mild, moderate, and HEC often for breakthrough symptoms
What is the most commonly used benzodiazepine used in treating CINV?
Lorazepam
What is the utility of lorazepam in CINV?
Prevent anticipatory emesis
Also used as an anti-anxiety/sleeping aid
May be used with dopamine antagonists to reduce their restlessness ADRs
Can lorazepam be used on its own to address CINV?
No, it is a relatively weak antiemetic (not as often as a single agent)
What is the utility of canabinoids in treating CINV?
Nabilone and Dronabinol are partial agonists of CB receptors and have modest antiemetic activity (limited clinical utility)
CB1 influences nausea, appetite, mood
CB2 influences pain perception, immune system
Review slide 406 for list of high/moderate emetic risk oral chemotherapy agents
Review slide 407 for list of low/minimal emetic risk oral chemotherapy agents
What drug is used to prevent emesis from oral cancer therapies?
Ondansetron 8-16mg PO daily
What are the important high emetic IV cancer agents?
AC combos
Cisplatin
What is the important moderate emetic IV cancer agent?
Carboplatin, unless AUC is over 4 (then considered to be high emetic risk)
Review slide 407 for list of low/minimal emetic risk IV chemotherapy agents
Review slide 411 for CINV treatment alogorithm based on emesis risk (very important slide to understand)
What is the high emetic risk (non-AC) CINV treatment regimen?
Day 1: Akynzeo+Dex+Olanzapine
Days 2-4: Olazapine+Dex
See slide 414
What is the high emetic risk (AC) CINV treatment regimen?
See slide 416
Day 1: Akynzeo+Dex+Olanzapine
Days 2-4: Olanzapine only
What is the (carboplatin AUC over 4) CINV treatment regimen?
Day 1: Akynzeo+Dex
Days 2-4: No additional prophylaxis
See slide 419
What is the moderate emetic risk CINV treatment regimen?
Day 1: 5-HT3+Dex
Days 2-4: No additional prophylaxis
What is the low emetic risk CINV treatment regimen?
Day 1: 5-HT3 or Dex or Dopamine antagonists (metoclopramide)
Days 2-4: No routine prophylaxis
What is the best drug for treating breakthrough CINV?
Olanzapine if not previously used as prophylaxis (increase dose or may use metoclopramide or dexamethasone instead)
Consider alternate 5-HT3 if previously using Akynzeo (CYP2D6 substrate)
See slide 426
What are some strategies to address breakthrough CINV?
- Move up to the next emetogenic level (ex. if at moderate, treat at
high) - Add one agent from a different class to the current regimen
- Switch routes/dosage forms: oral, IV, ODT, suppository, liquid
- Use of olanzapine is a good alternative
What are some treatment options for anticipatory nausea and vomiting associated with CINV?
Behavioural therapies (muscle relaxation, systematic desensitization, hypnosis)
Benzodiazepines to reduce occurrence (give the night before infusion and right before)
What are some risk factors for developing anticipatory nausea and vomiting associated with CINV?
- Age under 50
- N/V after last chemo session describes as moderate, severe, or intolerable
- Warm or hot all over after last chemo session
- Susceptibility to motion sickness
- Female
- High emetogenic chemo regimens
What are some non-pharmacological options to reduce CINV?
- Eat smaller, but more frequent meals
- Bland foods (avoid acidic or spicy)
- Caloric dense foods
- Eating foods at room temperature
What is the lifetime probability of developing breast cancer?
one in six
Top 3 type of new cancer cases and mortality from cancer
What are some risk factors for developing breast cancer?
- Female>male
- Increasing age (see slide 440)
- Hereditary (BRCA mutations and other family history)
What is the prognosis of breast cancer?
It is a progressive disease
Early detection and intervention improves survival
Larger cancers more likely to metastasize
- less than 1cm (10% risk of spreading to lymph nodes)
- 3 cm=50% risk of spread to lymph nodes
- Metastatic disease is harder to cure
What is the role of chemotherapy in breast cancer?
Used adjunctively regardless of ER/PR positive or negative
What are some risk of adjunct chemotherapy in breast cancer?
- Nausea/vomiting
- Hair loss
- Myelosupression
- Early cognitive impairment
- Amenorrhea
- Immunosuppression (may lead to severe infections)
What is the general approach for adjuvant chemotherapy in breast cancer?
Doxorubicin and cyclophosphamide (AC) followed by paclitaxel (taxane)
Also known as AC-T regimen
What is the benefit of adjuvant chemotherapy in breast cancer?
- Targets microscopic metastatic disease
- Ideally improves disease free survival and overall survival
What is the purpose of chemotherapy in patients with metastatic breast cancer?
Not curable, but can be used to prolong survival and improve QOL by reducing cancer-related symptoms
Pts. with HER2+ cancer should also be on targeted therapy (trastuzu.+pertuzu.)
