Pharmacy Exam Review

Oncology

Last updated on: May 6th, 2020

Background

  • Most of the classic chemotherapy agents can be broken down into two categories, however we don’t have to memorize which chemotherapy is cycle specific or not unless you are an oncology specialist.
    • Cell Cycle Specific & Cell Cycle Non-specific (Targeted therapies are usually better tolerated, because they target specific receptors or proteins on a tumor cell, they don't focus on the cell cycle at all.)
    • The bulk of targeted therapies fall into two categories: Monoclonal Antibodies (IV) & Tyrosine Kinase Inhibitors (PO usually).
  • Most chemo agents are dosed on Body Surface Area (BSA,). This helps make the dose of a drug less sensitive to outliers (like extreme obesity, or amputee). 
    • Most doses are in unit mg/m2
    • g: give 80mg/m2 of oxaliplatin to a patient whose BSA is 2.0. In this case, the total dose would be 160mg.
  • Warning signs of cancer: Change in bowel/bladder habit; A sore that does not heal; Unusual bleeding/discharge; Thickening or lump in breast or other area; Indigestion, difficulty swallowing; Obvious change in wart/mole; Nagging cough or hoarseness
  • Tumor Lysis Syndrome (TLS): when chemo kills those cancerous cells, the content spill out. What lives inside our cells? Potassium, phosphate, and uric acid. The high potassium levels cause heart arrhythmias. The uric acid and phosphate crystallize in the kidneys and cause acute renal failure, this further raises the potassium and leads to an emergency state called TLS.
  • Adverse effect of chemotherapy
    • classic cytotoxic chemotherapy doesn't do good at discriminating healthy cells from cancerous cells. Some healthy cells that divide more rapidly than others. E.g: GI tract, hair follicles, bone marrow. This is where most side effects of classic chemotherapy come from: anemia, hair loss, sores/ulcers in the mouth and esophagus (mucositis), nausea/vomiting. 
    • Low WBCs open up to infections (suffice it to say: low neutrophils = low immune system), low platelets introduce bleeding risk, and low RBCs leave patients suffering anemic and tired. 
  • Colorectal cancer: Colonoscopy, signoidoscopy @ age 50: yearly fecal occult blood test (gFOBT), fecal immunochemical test (FIT).

 

Anthracyclines

  • Drugs (mnemonic: all ends with “rubicin”): Daunorubicin (Cerubidine), daunorubicin liposomal (DaunoXome), doxorubicin (Adriamycin), doxorubicin liposomal (Doxil), epirubicin (Ellence), idarubicin (Idamycin), mitoxantrone (Novantrone)
  • SE: very effective but limited by cardiac toxicity (consider cardioprotective agent dexrazoxane -Zinecard), red urine/body secretion (all anthracyclines are bright red in color, just like rifampin can cause urine, tears, and other secretions to look like cherry fruit smack, mitoxantrone has blue urine). Severe tissue damage w/ extravasation (antidote- dexrazoxane (Totect)). Hand-foot syndrome (higher incidence w/ liposomal products)
  • There is lifetime dosing limit (again, in mg/m2) for each anthracycline to limit cardiac toxicity.

 

Platinum-based

  • Drugs (mnemonic: all ends with -platin): cisplatin (Platinol), carboplastin (Paraplatin), oxaliplatin (Eloxatin).
  • Major adverse effects: myelosuppression, nephrotoxic - vigorous hydration, use mannitol to avoid renal failure, electrolyte waste (correct with ion supplements), amifostine (Ethyol) is used prophylactically as antidote to prevent nephrotoxicity caused by cisplastin.
  • Dosing is based on the amount of exposure (AUC – area under curve). AUC is determined by "amount going in" and "amount going out.", so dosing is largely determined by kidney function, and we use CrCl as a proxy. Just remember that carboplatin is the only drug dosed off of AUC.
  • The Calvert Formula: Dose = (CrCl + 25)(AUC)

 

Monoclonal antibodies
  • Drugs (end in “mab”): cetuximab (Erbitux), trastuzumab (Herceptin), tositumomab (Bexxar), alemtuzumab (Campath), rituximab (Rituxan). (“tu” means tumor).
  • MOA: refine antibody from “sources” and distill them down until we are left with many copies of the same antibody. Include many types: VEGF inhibitors, HER2 inhibitors, EGFR inhibitors, CD inhibitors, etc.
  • Main side effect: infusion reaction (your body may detect those source antibodies as foreign objects), your immune system hyper up, you may get anaphylaxis or SJS.
  • Stop infusion and administer IV steroids or Benadryl. Infusion can be restarted at half of the previous rate, if patient reacts again, do not re-challenge them with the drug, try another therapy. Pre-medicate with diphenhydramine, or steroid like methylprednisolone would make a lot of sense. Choices like ondansetron, dexamethasone, and aprepitant, would make wrong answer choices.
  • Rastuzumab (Herceptin) is an antibody target HER2 receptor, often used in breast has high rate of cardiotoxicity; bevacizumab (Avastin), an antibody directed at VEGF can cause hypertension, proteinuria, and even GI perforation. 
 
Tyrosine Kinase Inhibitors (TKIs)
  • Drugs (all end with “nib”): Imatinib (Gleevec), erlotinib (Tarceva), lapatinib (Tykerb®).
  • MOA: targeted therapy, act on a gene level by inactivating cell signaling cascades. Cell expression has on-off switches, of which the cancerous cells are mutate and stuck in the "on" position, so the cell is unable to shut the factory down and lead to uncontrolled growth. Include many types: BCR inhibitors, EGFR (endothelial growth factor) inhibitors.
  • Most given by PO, get rid of the inconvenience of traveling to infusion center.
  • Toxicities: every TKI can cause rash and diarrhea, 3A4 substrate (hepatic toxicity), hypothyroidism, QT prolongation.
  • Risk of drug interactions, particularly with acid-suppressing agents.
 
SERMs (selective estrogen receptor modulators)
  • Drugs: tamoxifen (Novaldex), raloxifene (Evista), fulvestrant (Faslodex), toremifene (Fareston)
  • MOA: block estrogen in breast, but act as agonist in other tissues (e.g: bone, endometrium).
  • SE: menopausal symptoms (vaginal bleed, hot flash, mood changes), DVT/PE, hypertension, skin changes.
  • BBW: thromboembolic events, ↑uterine/endometrial cancer (tamoxifen).
  • DI: avoid strong 2D6 inhibitors (Paxil, Prozac, Zoloft, Cymbalta, Amiodarone) with tamoxifen, they block conversion of tamoxifen to its active metabolite.
  • Fulvestrant: IM each buttock on day 1,15,29 and then q monthly thereafter.

 

Aromatase inhibitor (po)
  • Drugs: anastrozole (Arimidex), exemestane (Aromasin), letrozole (Femara)
  • MOA: Prevents conversion of active estrogen and inhibits cell growth, use only in patients done with menopause.
  • SE: menopausal symptoms, higher risk of osteoporosis (↓bone density) and higher risk of CVD compared to SERMs.
  • Advantages over SERMs: NO hyperglycemia, or endometrial cancer.

 

Antiandrogens (po)
  • Drugs: bicalutamide (Casodex), enzalutamide (Xtandi), flutamide, nilutamide
  • SE: GI toxicity & visual disturbance(flutamide), night blindness (nilutamide), gynecomastia, hepatoxicity, ↓ libido, impotence, hot flashes
 
Luteinizing hormone-releasing hormone (LHRH) agonist
  • Drugs: leuprolide (Lupron), goserelin (Zoladex).
  • MOA: ↓ testosterone made by testicles, (initially increase androgen/estrogens, followed by a negative feedback loop resulting in suppressed production of gonadotropin, LH, FSH). They are also referred as gonadotropin-releasing hormone (GnRH) agonist.
  • Commonly used for prostate cancer.
  • SE: gynecomastia, ↓ bone density, initial surge can cause a disease flare (metastatic bone pain, can start an anti-androgen prior to LHRH).
 
Alkylator
  • Drugs: cyclophosphamide (Cytoxan), ifosfamide (Ifex), carmustine, busulfan, procarbazine 
  • MOA: Cross link DNA, prevent cell replication in “M” phase.
  • Warnings: hemorrhagic cystitis (cyclophosphamide, ifosfamide: give mesna (Mesnex) to prevent, and ensure hydration), pulmonary toxicity (busulfan, carmustine, lomustine), myelosuppression/alopecia/ neurologic toxicity, skin pigmentation.
 
Angiogenesis inhibitor
  • Drugs: Bevacizumab (Avastin), “ci” for circulatory.
  • MOA: Limits tumor's blood supply
  • SE: GI perforation (can be fatal), impaired wound healing, bleeding, thrombosis, nephrotic syndrome.
  • Bevacizumab binds vascular endothelial growth factor, high cost, debatable use

 

 Folate antimetabolites
  • Drugs: methotrexate (Trexall), Pemetrexed (Alimta)
  • MOA: block enzymes involved in folic acid cycle, block purine and pyrimidine synthesis during S phase.
  • SE: hepatic and renal toxicity, hand-foot syndrome (red tender palms and soles)
  • Require folic acid (po) and B12 inj before, during treatment, and pre-medicated w/ dexamethasone to reduce toxicities (mucositis, hematologic, diarrhea, dermatologic).
  • Warnings: myelosuppression, hepatotoxicity, all folate antimetabolites are associated with nephrotoxicity (Maintain hydration)
  • DI: clearance ↓ by NSAID, salicylates, beta-lactams, probenecid.

 

Purine Analog antimetabolites
  • Drugs: Azathioprine (Imuran), 6-mercaptopurine (6-MP, Purinethol), fludarabine (Fludara), cladribine (Leustatin), pentostatin (Nipent)
  • MOA: Inhibits purine synthesis
  • AZA is prodrug of 6-MP
  • SE: Myelosuppression, undergoes 1st pass metabolism by xanthine oxidase which can be inhibited by allopurinol (require dose adjustment)

 

 Pyrimidine analog antimetabolites
  • Drugs: Fluorouracil (5-FU, Efudex-topical for wrinkles, Carac-topical for psoraisis), Capecitabine (Xeloda), gemcitabine, cytarabine.
  • Give 5-FU with leucovorin to ↑ efficacy.
  • Test for DPD, DPD testing: dihydropyrimidine dehydrogenase deficiency can ↑ toxicity.
  • Capecitabine: prodrug of 5-FU.
  • ↑ INR significantly due to 2C9 inhibitors, require warfarin dose adjustment

 

Retinoids (vitamin A analogues)
  • Decrease cell proliferation and promote apoptosis
  • Many SE: preg cat X, differentiation syndrome.
  • Drugs: tretinoin, alitretinoin (Panretin), bexarotene (Targretin)

 

Interleukins
  • Stimulates immune system to target cancer cells
  • Aldesleukin (Proleukin, IL-2)
    • Given only @ hospital ICU, can cause capillary leak syndrome (hypoTN, decreased organ perfusion), induce sepsis-like state, bacterial endocarditis.
    • Only given to pts w/ normal cardiac/pulmonary functions
  • Denileukin (Ontak)
    • Unique MOA: binds IL-2 receptor on T-lymphocytes

 

Immunomodulator
  • Decrease angiogenesis
  • SE: preg cat X, all specialist must enroll in RevAssist/STEPS program, neutropenia, thrombocytopenia
  • Drugs: Thalidomide (Thalomid), lenalidomide (Revlimid)

  

Vinca alkaloids
  • Drugs: vincristine (Vincasar), vinblastine (Velban), vinorelbine (Navelbine)
  • MOA: Inhibits microtubule function during M phase.
  • SE: myelosuppression, dose-dependent nerve damage (neuropathy), vesication when extravasated.
  • Vincas are potent vesicants, IV only, do not administer intrathecally-fatal!
 
Taxanes
  • Drugs: Paclitaxel (Taxol), Docetaxel (Taxotere), carbazetaxel.
  • MOA: Inhibits microtubule function (dysfunctional microtubule bundling) during M phase.
  • Elimination is reduced if given after administration of cisplatin or carboplatin. Give taxanes first.
  • SE: infusion related hypersensitivity reaction: pre-medicate w/ dexamethasone, Benadryl), peripheral neuropathy, fluid retention, myelosuppression.

 

Gonadotropin releasing hormone (GnRH) agonist

Abarelix (plenaxis depot)

  • injectable gonadotropin-releasing hormone antagonist.
  • It is primarily used in oncology to reduce the amount of testosterone made in patients with advanced symptomatic prostate cancer for whom can't have LHRH agonist

Trelstar® (triptorelin)

  • The palliative treatment of advanced prostate cancer

 

Topoisomerase inhibitors

  • Drugs: irinotecan (Camptosar), etoposide (VePesid)
  • MOA: blocks coiling and uncoiling of DNA helix during S phase (topoisomerase I) and G2 phase (topoisomerase II).
  • Warnings: acute cholinergic symptoms, delayed diarrhea.

 

Supportive care of chemotherapy

 Chemo-induced nausea and vomiting (CINV)
  • How it’s occurred? Neurotransmitters of concern: serotonin, dopamine, neurokinin, and histamine, which are released from the cells that have been damaged from chemotherapy, stimulate nerves/brain to induce nausea.
  • Background on the mechanism: Serotonin released GI tract cells stimulate the vagal nerve, which hits the chemoreceptor trigger zone (CTZ) of the brain. Chemotherapy can directly stimulate the CTZ on its own. The CTZsends a message to the vomiting center in the medulla, this makes you vomit. Some chemotherapy disrupts your vestibular apparatus directly, leading to a sensation of motion sickness.
  • Low emetogenic risk: dexamethasone (Decadron) 8 mg or 1st generation 5HT3 antagonist (1 drug)
    • Usually use Decadron because it has no mineralocorticoid activity, so high doses are less likely to result in fluid retention. 
  • Moderate emetogenic risk: 5HT3 antagonist + dexamethasone. (2 drugs)
  • Severe emetogenic risk: NK1 antagonist + 5HT3 antagonist + dexamethasone (3 drugs), dexamethasone: 8mg IV or 12mg PO before chemo (Treatment dose is higher: 10-20mg IV/PO Q4-6h) followed by 8mg po qd 2-4 days.
  • High emetogenic drugs: cisplatin (Platinol), cyclophosphamide (Cytoxan),
  • 2nd line: cannabinols (dronabinol (Marinol-CIII, refrigeration), nabilone (Cesamet, CII, BID room temp)): ↑appetite, euphoria.
  • Dopamine-blocking agents (phenothiazines): such as metoclopramide, SE of DA blockers: EPS, worsen movement disorders (lead to Parkinson-like syndromes), sedating and cause cognitive dysfunction; droperidol (Inapsine) is a sedative, anti-psychotic used to reduce nausea and vomiting caused by surgery or other medical procedures.
  • Other phenothiazines: chlorpromazine (Thorazine), promethazine (Phenergan): marked drowsiness, impaired mental abilities, avoid other CNS depressants.
5HT3 antagonist
  • MOA: ↓serotonin levels in the GI tract.
  • Drugs: granisetron (Kytril IV, Sancuso weekly patch), dolasetron (Anzemet IV/PO), palonosetron (Aloxil), ondansetron (Zofran, IV/IM/PO/ODT)
  • Palonosetron has longest half-life makes the convenience of 1 single dose, also it’s a second generation and doesn’t have QT prolongation.
  • Drug interaction: 5HT3 blocker contraindicated with Parkinson drug apomorphine.
Neurokinin-1 receptor blocker (NK1 antagonist)
  • Drugs: Emend(IV: fosaprepitant as a single dose and PO: aprepitant 3-day course), rolapitant (Varubi)
  • Drug interaction: A common adjustment in oncology is reducing the dose of dexamethasone if a patient is also receiving Emend.

 

Anemia
  • Treat with Erythropoiesis stimulating agent (ESA), however very strict usage criteria in cancer patients because it can shorten survival and increase tumor progression. (prescriber no longer need to enroll ESA APPRISE oncology program since 2017 FDA feel they are adequately informed).
  • Majority use in CKD because kidney supplies erythropoietin. Only used in Hgb <10, the goal is to lessen blood transfusion, stop around 10 or 11.
  • ESAs are never used prophylactically, only for palliative care, not for cure.
  • Takes 2-6 wks to work, don’t expect it to work overnight
  • SE: HTN, stroke, thrombosis VTE, arrhythmia, CV death
  • Review normal levels: Hgb: 12-16 g/dL (female), 13-18 (male); Hct: 36-46% (F), 37-49% (M).
  • Drugs
    • Epoetin alfa (Procrit, Epogen): dosed in units, subQ several times weekly
    • Darbepoetin (Aranesp): mg/kg SC q 2-3 weeks (less frequent dosing), don’t shake, clear and colorless

 

Neutropenia
  • granulocyte colony stimulating factors (G-CSF) to correct low ANC, granulocyte is a fancy word for neutrophil.
  • We don't start (except Neulasta Onpro, saves patient trip going back to infusion center 2-3 days later) until after chemotherapy. Why? If we give them before or during chemo, neutrophils they stimulated are going to be killed by the chemo. 
  • Do not improve overall survival rates. Monitor patients for infection, remember we are treating neutropenia, so patients are at risk of infection.
  • SE: bone pain (ostealgia), splenic rupture(fatal).
  • Drugs
    • sargramostin (Leukine): mcg/m2daily
    • filgrastim (Neupogen): febrile neutropenia, 5mcg/kg/day, fridge, use within 24-hr if stored RT
    • pegfilgrastim (pegylated, Neulasta): longer version of filgrastim, febrile neutropenia, 6mg SC 1x each chemo cycle, fridge
  • For testing purposes, weed out the choices by noting the differences in dosing: Neupogen is mcg/kg and daily, Leukine is mcg/m2daily, Neulasta is a flat dose in mg and only given once per cycle.

 

Thrombocytopenia (TCP)
  • Platelet normal range: 150 - 450,000/MM3; Used in count < 10,000
  • Rarely used in chemo, because they stimulate production of platelet in blood and we don’t want to introduce a new drug that stimulates cell growth. Monitor for signs of clotting.
  • Drugs: oprelvekin (Neumega) – subQ; Romiplostim (NPlate) – subQ; Eltrombopag (Promacta)- unique because it's given PO.
 
Anticoagulation
  • DVT and PE are the leading causes for mortality and morbidity in cancer patients, recommends LWMH and new oral anticoagulants.
  • LMWH is contraindicated in dialysis and needs to be dose adjusted in renal failure.
  • Avoid warfarin, many drug interactions.
 
Tumor Lysis Syndrome
  • It is easier to prevent it before you treat it.
  • First hydrate aggressively to increase urine output.
  • Second use Xanthine oxidase inhibition to lower uric acid levels.
    • allopurinol
    • rasburicase (Elitek)- an enzyme chops up uric acid into metabolic byproducts
  • To treat it, stay in ICU, monitor for cardiac and electrolytes.
 
Mucositis
  • Magic mouth wash, chlorhexidine (Perioguard) rinse, saline rinse
  • Only FDA approved agent: palifermin (Kepivance), restricted use in high dose chemo

 

Hypercalcemia
  • This is the most common metabolic complication of cancer, due to bone destruction
  • Asymptomatic: avoid thiazide diuretics (increases Ca), Ca supplements, antacids. Monitor renal function to ensure Ca level doesn't get worse. 
  • First, hydration + forced diuresis (loop diuretics only, cause hypo-Ca)
  • Second, calcitonin - derived from salmon watch out for fish allergy.
  • Next, IV bisphosphonates or denosumab (Prolia)
    • Zoledronic acid (Zometa) 4mg per month IV infusion for bone metastases/tumor, multiple myeloma, contradicted in renal failure (can go with denosumab)
      •  Same drug, different brand - Reclast is indicated in osteoporosis, 5mg per yr
    • Pamidronate (Aredia)
    • denosumab (Prolia): subQ q 6-month.

 

Diarrhea
  • Sandostatin (octreotide): a synthetic hormone that is used to lower excessive growth hormone (acromegaly).
  • Off label use for diarrhea caused by cancer.

 

NAPLEX Pearls NAPLEX Pearls

At minimum level, you should focus on these for NAPLEX.

  • Anthracyclines (doxorubicin, epirubicin, daunorubicin, idarubicin) - Cardiac toxicity
  • Ifosfamide and Cyclophosphamide - Hemorrhagic cystitis
  • Cisplatin - Renal and ototoxicity

Each of the above class has cytoprotective agent as follows, they are not always used clinically, but if you can match them up with the drug used to protect against, you'll do fine.

  • Anthracyclines - Dexrazoxane
  • Ifosfamide/Cyclophosphamide - Mesna
  • Cisplatin – Amifostine

Know how to treat side effects of chemotherapy. Drugs and supportive care are written in the order of popularity. (CINV is placed at the top of supportive care, since it is such a hot topic for the exam).

Besides the above, knowing nitty-gritty details not mentioned in the pearls, you will be more than covered for NAPLEX.

 

 




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