UWORLD Chapter 61: Oncology

What is the mechanism of action for taxanes (paclitaxel)?

They inhibit the depolymerization of tubulin (which stabilizes microtubules to pull apart sister chromatids) during the M phase of the cell cycle

What are the main safety concerns with all taxanes?

Peripheral neuropathy

Hypersensitivity reactions (anaphylaxis)

What is the main safety concern with docetaxel specifically?

Severe fluid retention

What premedications should be given before taxane (paclitaxel) doses to prevent hypersensitivity reactions?

Systemic steroids (dexamethasone)

Diphenhydramine

An H2RA (famotidine)

What are proto-oncogenes? How are they manipulated or mutated to cause cancer?

These genes are involved in normal cell division. Mutated forms are called oncogenes (HER2 and EGFR are examples) that promote cancer cell growth

What are DNA repair genes? How are they manipulated or mutated to cause cancer?

These are genes that fix mistakes in DNA prior to DNA replication in the cell cycle. Mutations in this gene prevents cell repair, allowing more errors to accumulate within a cell.

What are tumor suppressor genes? How are they manipulated or mutated to cause cancer?

Examples are the BRCA1 and BRCA2; they normally regulate cell division. When these genes are inactivated by a mutation, cells can grow uncontrollably.

What external factors can cause cancer?

Tobacco use

excessive alcohol intake

poor diet

low physical activity

environmental exposures like sunlight, radiation, chemicals, or viruses

What are internal factors that can cause cancer?

Hormones

inherited genetic mutations

older age

What is the ABCDE mnemonic for warning signs of melanoma?

A - Asymmetry, half of the mole doesn't match the other

B - Border, edges of the mole are irregular or notched

C - Color, isn't the same throughout

D - Diameter, larger than 6 mm or the size of a tip of a pencil eraser

E - Evolving, mole is changing in size, color, shape, or bleeding/itching

What are screening recommendations for breast cancer in females?

- <45 years of age: no screening or optional yearly mammogram

- 45 - 54 years: yearly mammogram

- 55 or more: screening mammogram every 2 years or continue yearly screenings

What are screening recommendations for cervical cancer in females?

25-65 years - Cervical cell analysis

- Pap smear every 3 years

- HPV test every 5 years

- Pap smear plus HPV test every 5 years

What are the screening recommendations for colorectal cancer? At what age should screening begin?

At age 45 or age 40 for increased-risk patients:

--yearly fecal occult blood test

--flexible sigmoidoscopy every 5 years

--colonoscopy every 10 years

What are the screening recommendations for lung cancer in males and females?

Screen at 50-80 years with an annual low dose CT scan of the chest in patients that currently smoke or used to smoke at least a 20 pack per year smoking history

What are the screening recommendations for prostate cancer in males?

Individualized decision

If screening, prostate specific antigen (PSA) blood test +/- digital rectal exam (DRE)

What does CAUTION stand for in cancer warning signs?

C: Change in bowel or bladder habits

A: A sore that does not heal

U: Unusual bleeding or discharge

T: Thickening or lump

I: Indigestion or difficulty swallowing

O: Obvious change in a wart or mole

N: Nagging cough or hoarseness.

What does the acronym TNM stand for, in regards to cancer staging?

T - Primary tumor size and location

N - Lymph node involvement

M - Evidence of metastasis

What are tests, screenings, or information collected to diagnose cancer?

- History & physical

- CBC & CMP

- Biopsy: removal of tissue sample to identify cancer cells

- Imaging tests: visualizes internal body structures (X-ray, MRI, PET scan, CT scan)

- Biomarker (tumor marker) tests: detects genes, proteins or other substances released by cancer cells

- Genetic tests: identifies specific cancer genes or mutations

What is neoadjuvant therapy for cancer?

Therapy used before the primary treatment to shrink the cancer or tumor

Usually radiation or chemotherapy

What is primary cancer treatment?

Aims to completely remove or eliminate cancer cells; any treatment modality can be used, but surgery (to remove the bulk of the tumor) is a common primary treatment for respectable cancers

What is adjuvant therapy in cancer treatment?

Additional cancer treatment AFTER primary treatment occurs to eradicate residual disease and decrease occurrence

What are the four types of treatment response?

- Complete response: the cancer responded to treatment & can't be detected

- Partial response: a substantial reduction in cancer burden, but it is still present

- Progressive disease: cancer has grown or is worsening

- Stable disease: cancer is not improving nor is it worsening

What kinds of cells does chemotherapy traditionally target?

Chemotherapy (cytotoxic) kill cancer cells by interfering with cell division and DNA replication. Because of this, they normally target rapidly dividing cells (GI tract, hair follicles, and bone marrow)

What is the G1 phase of the cell cycle? Which chemotherapy agents work at this phase?

- G1 phase: growth phase to prepare for DNA/RNA/proteins for cell division

- Agent: Pegaspargase

What is the S phase of the cell cycle? What chemotherapy agents work during this phase?

- DNA replication

- Antimetabolites: methotrexate, fluorouracil (5-FU) or capecitabine

- Topoisomerase inhibitors: irinotecan, topotecan

What is the G2 phase of the cell cycle? What chemotherapy agents act here?

- Growth phase to prepare DNA/RNA/proteins for cell division

- Etoposide and Bleomycin

What is the M phase of the cell cycle? What chemotherapy agents work here?

- Mitosis, cell divides into 2 daughter cells

- Taxanes: Paclitaxel, Docetaxel

- Vinca Alkaloids: Vincristine, Vinblastine

Which chemotherapy agents are cell cycle nonspecific?

- Alkylating agents: cyclophosphamide, ifosfamide

- Anthracyclines: doxorubicin, daunorubicin

- Platinum compounds: cisplatin, carboplatin, oxaliplatin

What is Mosteller's formula and what is it used for?

BSA (m^2) = square root {(Ht in cm x Wt in kg)/3600}

What is the calvert formula and what is it used for?

Dose (mg) = AUC x (GFR + 25).

*Max GFR 125 ml/min

- used to dose carboplatin

What is the mechanism of action for alkylating agents (cyclophosphamide, etc)?

Cross links DNA strands, which inhibit DNA and protein synthesis and result in cell death.

What is the main safety concern with cyclophosphamide and ifosfamide?

Hemorrhagic cystitis caused by the toxic metabolite acrolein in which concentrates in the bladder. Main symptoms of this are hematuria and dysuria.

How do you prevent and/or treat hemorrhagic cystitis that is caused by cyclophosphamide/ifosfamide?

- Prevention: Adequate hydration, Mesna (a chemoprotectant) used prior to all ifosfamide doses and high cyclophosphamide doses (>1 gram/m^2)

- Treatment: Bladder irrigation with normal saline

What is the main safety concern with Busulfan?

Pulmonary toxicity, which manifests as pulmonary fibrosis

What are the main safety concerns with Carmustine?

Pulmonary toxicity which manifests as pulmonary fibrosis

Neurotoxicity and/or seizures (treat with anti seizure meds)

What is the mechanism of action for platinum based compounds (cisplatin, etc.)?

Cross links DNA, interfering with DNA synthesis and cell replication, which results in cell death.

What are the 4 main safety concerns with all platinum based compounds, but particularly more common with cisplatin?

- Hypersensitivity reactions (anaphylaxis)

- Nephrotoxicity

- Ototoxicity

- Peripheral neuropathy

How is the nephrotoxicity that can occur with platinum based agents prevented?

- Adequate hydration

- Amifostine (a chemoprotectant) reduces cumulative renal toxicity that occurs with cisplatin

- Limit cisplatin doses per cycle to

What notable safety concern is only seen with oxaliplatin and not other platinum based compounds?

Acute sensory neuropathy exacerbated by cold temperatures and consuming cold things.

What is the mechanism of action of anthracyclines (doxorubicin)?

- Intercalation (inserts itself between DNA base pairs)

- Inhibition of topoisomerase 2

- Creation of oxygen free radicals that damage cells

What are the main safety concerns with anthracyclines?

- Cardiotoxicity (decreased LVEF)

- Red discoloration of bodily fluids

What is Mitoxantrone and what is its main safety concern?

- An anthracenedione (cousin to anthracyclines)

- Blue discoloration of sclera and bodily fluids

How is doxorubicin cardiotoxicity reduced?

1. Track cumulative lifetime dosing

2. Lifetime max doxo dose is 450-550 mg/m2

3. Monitor LVEF w/ echo or MUGA

4. Dexrazoxane (Zinecard)may be given as chemoprotectant w/ doses > 300 mg/m2

What is the mechanism of action for irinotecan?

Block the coiling and uncoiling of the double stranded DNA double helix during the S phase of the cell cycle. This causes single and double strand breaks in the DNA and prevents religation (sealing of DNA strands back together again) of single strand breaks.

What are the main side effects of topoisomerase 1 inhibitors (irinotecan)? What are they treated with?

- Acute diarrhea, during or immediately after infusion, plus cholinergic symptoms (eg abdominal cramping, lacrimation, salivation): treat with atropine

- Delayed diarrhea, >24 hours after infusion: treat with loperamide

What is the main side effect of topoisomerase 2 inhibitors (etoposide)?

Infusion rate related hypotension, infuse over 30-60 minutes to prevent this

What is the mechanism of action for vinca alkaloids (vincristine, etc)?

Inhibit microtubule (pulls sister chromatids apart during mitosis) formation during the M phase of the cell cycle

What are the main safety concerns with vinca alkaloids?

- Peripheral neuropathy (mainly vincristine)

- Autonomic neuropathy: example is constipation

- Paralysis and death if given intrathecally

What is the only route vinca alkaloids can be administered by and why?

Intravenous route only. These drugs are vesicants and can cause tissue death if outside of the venous cavity.

What is the maximum dose of vincristine that can be given in a single dose in prevention of peripheral neuropathy? (FIX)

2 mg

How is paralysis and death prevented with the vinca alkaloids?

Prepare in small IV bag (piggyback) that cannot be used for intrathecal administration

What are the administration instructions for paclitaxel?

Use non-PVC bag and tubing; use 0.22 micron filter

What are the two class wide side effects for taxanes and how do you monitor for them?

- peripheral neuropathy: signs and symptoms of neuropathy (extremity numbness, paresthesia, pain)

- Hypersensitivity reactions: anaphylaxis

What is a side effect specific to docetaxel?

severe fluid retention

What is the mechanism of action of pyrimidine antimetabolites?

Inhibits pyrimidine DNA synthesis during the S phase of the cell cycle. Leucovorin or it's L isomer levoleucovorin

What is given with fluorouracil to increase its efficacy?

Leucovorin or its L isomer levoleucovorin

What are the 5 main side effects/interactions with fluorouracil/capecitabine?

- Hand-foot syndrome (palmar plantar erythrodysesthesia): monitor for erythema and skin peeling

- Diarrhea

- Mucositis: monitor for painful mouth ulcers

- Dihydropyrimidine dehydrogenase (DPD) deficiency increases risk of toxicity (myelosuppression & GI)

- Drug interaction with warfarin (can significantly increase INR

What is the antidote for fluorouracil/capecitabine toxicity?

uridine triacetate within 96 hours for overdose or early onset toxicity

What can be used to manage hand-foot syndrome?

-reduce friction or exposure to heat to hands and feet

-use cold compresses

-use emollients (Aquaphor or urea cream) to retain moisture in hands and feet

- topical steroids help lessen inflammation and pain

What is the mechanism of action for methotrexate?

interfere with the enzymes involved in the folic acid cycle, blocking purine and pyrimidine biosynthesis during the S phase of the cell cycle

What are the two main side effects with methotrexate?

- Nephrotoxicity (with high doses of > 500 mg/m2)

- GI toxicity (mucositis and diarrhea)

What drug can be used as a "rescue" for methotrexate induced toxicities or to prevent them from occurring?

leucovorin or levoleucovorin

What are other ways to prevent methotrexate induced nephrotoxicity?

- Hydration with IV sodium bicarbonate to alkalize the urine

- Avoid NSAIDs and salicylates

What is the antidote for methotrexate induced nephrotoxicity?

glucarpidase rapidly lowers methotrexate levels

What normal supplement used for methotrexate in autoimmune diseases is not effective at oncologic doses?

folic acid

How is mucositis prevented?

good oral hygiene, holding ice chips in the mouth, frequent rinsing with bland rinses (saline or sodium bicarbonate)

How is mucositis treated?

- Symptomatic treatment: viscous lidocaine 2%, magic mouthwash

- Thrush treatment: nystatin oral suspension or clotrimazole troches

What is the mechanism of action of tretinoin?

decreases proliferation and increases differentiation of acute promyelocytic leukemia (APL) cells

What is the mechanism of action of arsenic trioxide?

increases apoptosis of APL cells and damages the fusion protein promyelocytic leukemia retinoic acid receptor alpha (PML-RARA)

What is the main side effects seen with arsenic trioxide?

QT prolongation

What is the mechanism of action of bleomycin?

antitumor antibiotic: inhibits DNA synthesis via DNA strand breaks

What are the side effects of bleomycin?

pulmonary toxicity and hypersensitivity reactions

What is the maximum lifetime dose suggested to prevent pulmonary toxicity in bleomycin?

400 units

What is the mechanism of action of bortezomib/carfilzomib?

inhibit proteasomes, which help regulate intracellular protein homeostasis by inhibiting cell cycle progression and inducing apoptosis

What is the main side effect seen with bortezomib/carfilzomib? How is this side effect prevented/treated?

herpes reactivation (zoster and simplex); acyclovir/valacyclovir

What is the mechanism of action for lenalidomide/thalidomide?

immunomodulators: block angiogenesis (the formation of new blood cells) and kill abnormal cells in the bone marrow while stimulating the bone marrow to produce normal healthy cells

What are the two main side effects for the immunomodulators?

- severe birth defects (need 2 negative pregnancy tests before treatment initiation)

- Thrombosis (DVT/PE)

What is the mechanism of action for Pegaspargase?

inhibits protein synthesis by depleting asparagine in leukemic cells

What is the pro of using pegylated forms or asparaginase products?

less frequent dosing and less allergic reactions

Which chemo meds are most highly known for neurotoxicity risk?

Carmustine

What are the three main side effects of cisplatin? How are they prevented?

- ototoxicity, nephrotoxicity, high emetogenicity

- amifostine; limit dose per cycle to 100 mg/m2 or less

Which chemo meds are most likely to cause mucositis?

methotrexate, fluorouracil, capecitabine

Which chemo meds are most likely to cause pulmonary toxicity?

bleomycin, busulfan, carmustine

What is the main side effect of doxorubicin and other anthracyclines?

cardiotoxicity

What is the main side effect with ifosfamide and cyclophosphamide and how is this prevented?

hemorrhagic cystitis; take mensa with all doses or ifosfamide and high doses or cyclophosphamide

What is the made side effect seen with ironotecan and how is it prevented?

diarrhea; prevent with atropine

Which chemo meds cause peripheral neuropathy and how is this prevented?

- Platinum based compounds (cisplatin; oxaliplatin): avoid cold exposure, monitor for tingling extremities

- Vinca alkaloids (vincristine): limit single dose to 2 mg

- Taxanes (paclitaxel)

Which chemo meds do NOT cause bone marrow suppression?

bleomycin, pegaspargase, and vincristine

What is myelosuppression?

Decrease in bone marrow activity resulting in fewer RBC (anemia), WBC (neutropenia), and platelets (thrombocytopenia)

What is nadir of WBC and platelets and when is it reached?

the lowest point that WBCs and platelets reach; 7-14 days after chemo administration

What is nadir of RBC and when is it reached?

occurs after prolonged treatment, lowest point that RBCs reach, due to lifespan (120 days) for RBCs

How long does it take for WBCs and platelets to recover after chemo?

3-4 weeks; hence why chemo is usually given every 3-4 weeks

When is the highest risk of infection after chemo?

The nadir period

What is neutropenia?

low absolute neutrophil count (<1000 cells/mm3)

What is severe neutropenia?

ANC < 500

What do granulocyte colony stimulating factors (G-CSFs) do? When are they given?

stimulate white blood cell production in the bone marrow. Given prophylactically after chemotherapy to reduce the duration and severity of neutropenia

What are the brand and generic names of the testable G-CSFs?

Filgrastim (Neupogen)

Pegfilgrastin (Neulasta, Neulasta Onpro: Pegylated form of filgrastin NeuLASTa a long time (extended half life)

What is the difference in frequency of dosing for filgrastin and pegfilgrastin?

Filgrastin is once daily, pegfilgrastin is once every chemo cycle

What are the main side effects and monitoring for G-CSFs?

bone pain and splenic rupture, monitor CBC with differential and upper abdominal pain

What are storage and administrative instructions for G-CSFs?

- Store in the fridge

- administer no sooner than 24 hours after chemotherapy

- Neulasta onpro is an on-body injector that delivers dose of pegfilgrastin ~72 hours after chemotherapy