Chapter 62: Oncology II

Tretinoin

AKA All-trans, Retonoic Acid, ATRA MOA: decrease proliferation and increase differentiation of acute promyelocytic leukemia (APL) cells First-line therapy for APL Boxed Warnings -RA-APL differentiations syndrome, leukocytosis, pregnancy Side Effects -leukocytosis, RA-APL differentiation syndrome, QT prolongation, NVD, skin/mucous membrane dryness, hyperlipidemia, GI bleeding Unique Concerns -retinoids (vitamin A analogues) -safety issue — concern in pregnancy -Retinoic Acid-Acute Promyelocytic Leukemia (RA-APL) differentiation syndrome: fever, dyspnea, weight gain, edema, pulmonary infiltrates, pericardial or pleural effusions — treat with dexamethasone

ALK Inhibitors

ALK (anaplastic lymphoma kinase) gene translocation —> abnormal tyrosine kinase that is always "on" —> NSCLC (occurs in ~5% of NSCLC patients) Tyrosine kinase inhibitor Crizotinib (Xalkori) Ceritinib (Zykadia) Alectinib (Alecensa) Pharmacogenomics: must be ALK mutation positive to use Warnings -hepatotoxicity, bradycardia, interstitial lung disease, QT prolongation, ocular toxicities (crizotinib), pancreatitis (ceritinib), myalgia and photosensitivity (alectinib) Side Effects -skin rash, NVD, edema, hyperglycemia (ceritinib)

CAR T-Cell Gene Therapy

Axicabtagene Ciloleucel (Yescarta) MOA: the first gene therapy approved for cancer (large B-cell lymphoma). Anti-CD19 CAR T-cell therapy involves collecting lymphoma cells. These cells are then re-infused back into the patient to find and attack the lymphoma cells Boxed Warnings -cytokine release syndrome (CRS) -neurological toxicities Unique Concerns -cytokine release syndrome (CRS) and neurological toxicities. Restricted in REMS program to patients who have not responded to or who have relapsed after at least 2 other kinds of treatment

VEGF inhibitors

Bevacizumab (Avastin) Bevacizumab-awwb (Mvasi) Ramuirumab (Cyramza) MOA: vascular endothelial growth factor (VEGF) or VEGF receptor — inhibits growth of blood vessels Boxed Warnings -severe/fatal bleeding, GI perforation, surgical wound dehiscence (splitting open) Side Effects -hypertension, proteinuria, nephrotic syndrome, heart failure, thrombosis Notes -use 0.22 micron filter for ramucirumab -impairs wound healing — do not administer for 28 days before or after surgery -monitor blood pressure and proteinuria prior to each dose

Metastatic Breast Cancer Treatment

Breast cancer metastases are often located in the bone, lungs, liver and brain Hormone treatment or a HER2 inhibitor will still be used, if ER/PR or HER2 positive Primary chemotherapy drugs used for breast cancer: -capecitabine, carboplatin, cyclophosphamide, docetaxel, paclitaxel, doxorubicin and methotrexate CKD4/6 inhibitors are sometimes used in combination with hormone treatment (targeted treatment) -Palbociclib (Ibrance) -Abemaciclib (Verzenio) -Ribociclib (Kisqali)

BMI calculation

Dubois and Dubois Equation: BSA (m2) = 0.007184 x (height cm)^0.725 x (weight kg)^0.425 Mosteller Equation: BSA (m2) = square root [ (height cm) x (weight kg)/3600] Average BSA adult men: 1.9 Average BSA adult women: 1.6

Prostate Cancer Overview

Early, non-metastatic prostate cancer can be treated with surgery, radiation, hormonal treatment or watchful waiting -prostate cancer might not be treated, especially in an elderly man with a slow-growing tumor Diagnosis: -digital rectal exam (DRE( -prostate-specific antigen (PSA) — increases in most prostate cancer - a level >4 ng/ml can indicate prostate cancer The primary hormone which is blocked is testosterone — hormonal treatments are called androgen deprivation therapy (ADT) — also called chemical castration -ADT is achieved with either a a gonadotropin releasing hormone (GnRH) agonist (alone) or a GnRH antagonist (initially taken with an antiandrogen) Metastatic prostate cancer that has failed to respond to ADT is called "castration resistant" and may be treated with chemotherapy

Definition of adjuvant therapy

Eg radiation and/or chemotherapy Given after surgery in an attempt to eradicate residual disease and decrease recurrence

Definition of neoadjuvant therapy

Eg radiation or chemotherapy Can be used before surgery to shrink the tumor in order to make resection more likely to reach all or most tumor cells Commonly, the primary treatment is surgery to remove the bulk of the tumor, if the cancer is resectable

Asparaginase

Erwinaze — derived from Erwinia chrysanthem Pegaspargase (Oncaspar) -modified form of L-asparaginase (derived from E. coli) and conjugated with polyethylene glycol Contraindications -bleeding, thrombosis or pancreatitis with prior asparaginase treatment Side Effects -leukocytosis, APL differentiation syndrome, NVD, GI bleeding, stomatitis, electrolyte imbalance, acute vasomotor reactions (lightheadedness, dizziness, or hypotension), fatigue, edema, HA, insomnia, anxiety, infection Unique Concerns -deprives leukemia cells of asparagine, which is an essential amino acid in leukemia -the pegylated form (pregaspargase) allows for less frequent dosing (every 2 weeks) and less allergic reactions -monitor: fibrinogen, PT, aPTT, LFTs

Rating systems to assess the patient's physical functioning

Karnofsky ECOG (Easter Cooperative Oncology Group)

Men and breast cancer risk

Less than 1% of breast cancer occurs in males Klinefleter syndrome increases breast cancer risk in men -normally males have one X and one Y chromosome -Klinefelter syndrome is a congenital condition in which males have one Y chromosome and 2 or more X chromosomes — they produce more estrogen than typical for males

Treatment goals

Remission (with a curative intent) Palliative (primary intent is to provide comfort, support, and control of symptoms)

Recommendations for reducing the risk of developing skin cancers

Seek shade — especially between 10AM and 4 PM Slip on a shirt — tightly woven fabrics are best Slop on sunscreen — use a broad-spectrum sunscreen with an SPF of at least 15-30 and reapply every 2 hours Slap on a hat — wear a hat with at least 2"-3" brim Wrap on sunglasses — to protect the skin around the eyes and help prevent cataracts

Aromatase Inhibitors

Used for hormone-positive breast cancer in POST-MENOPAUSAL women MOA: aromatase inhibitor— blocks conversion of androgens to estrogen Anastrozole (Arimidex) -oral Letrozole (Femara) -oral Exemestane (Aromasin) -oral Contraindications -pregnancy Side Effects -hot flashes/night sweats, arthralgia/myalgia, lethargy, fatigue, N/V, rash, hepatotoxicity, hypertension, dyslipidemia Notes -higher risk of osteoporosis due to decreased bone mineral density — consider Ca and vitamin D supplementation, weight bearing exercise, DEXA screening -higher risk of CVD compared to SERMs

Definition of partial response

= at least 50% of the tumor was eliminated, but some was not

Definition of complete response

= treatment has destroyed all known tumors

Antiandrogens

Hormonal therapy for prostate cancer First Generation MOA: competitively inhibits testosterone from binding to prostate cancer cells -only used in combination with a GnRH agonist Bicalutamide (Casodex) -oral Flutamide -oral -causes more diarrhea than others in class Nilutamide (Nilandron) -oral -can cause night blindness -disulfiram reactions (avoid alcohol) Boxed Warnings -hepatotoxicity (flutamide), interstitial pneumonitis (nilutamide) Contraindications -use in women, especially in pregnancy (bicalutamide), severe hepatic impairment (flutamide, nilutamide) Side Effects -hot flashes, gynecomastia, edema, asthenia, hepatotoxicity Second Generation -unlike first, does not cause an upregulation in the expression of androgen receptors, and can be used as a single treatment Enzalutamide (Xtandi) -oral Contraindications -pregnancy (partner to use effective contraception) Warnings -seizures Side Effects -hypertension, peripheral edema, hot flashes, fatigue

Androgen Biosynthesis Inhibitor

Hormonal therapy for prostate cancer MOA: interferes with a specific CYP-17 enzyme involved in the synthesis of steroid hormones in the testes and adrenal gland to decrease testosterone production Must be taken with prednisone to cause negative feedback on the production of aldosterone and prevent symptoms of hyperaldosteronism (hypertension, fluid retention and hypokalemia) A irate tone (Zytiga) -oral Contraindications -pregnancy Side Effects -mineralocorticoid excess: fluid retention, increased BP, hypokalemia (reduce excess with concurrent prednisone) -hepatotoxicity, hyperglycemia, increased TGs, hypophosphatemia, hot flashes Avoid concurrent use with strong CYP3A4 inducers — if used with a strong CYP3A4 inducer, dose adjustment required

Gonadotropin-Releasing Hormone Agonists

MOA: GnRH Agonists — also referred to as luteinizing hormone releasing hormone (LHRH) agonists — reduce testosterone through a negative feedback mechanism — they cause an initial surge in testosterone, followed by a gradual reduction -the initial surge can cause symptoms of "tumor flare," including bone pain and difficulty urinating -to prevent tumor flare, an antiandrogen is given for several weeks in conjunction with the start of a GnRH agonist Leuprolide (Lupron Depot, Eligard) Goserelin (Zoladex) Histrelin (Supprelin LA, Vantas) Triptorelin (Trelstar) Contraindications -pregnancy -breastfeeding Side Effects -hot flashes, impotence, gynecomastia, bone pain, injection site pain, osteoporosis, shrunken testicles, anxiety, peripheral edema -first few weeks of treatment: bone pain, difficulty urinating -QT prolongation, dyslipidemia, hyperglycemia -loss of muscle mass Notes -decreased bone density — supplement with calcium/vitamin D, use weight bearing exercises, DEXA screening may be given to identify if treatment (eg with a bisphosphonate) would be useful -leuprolide and goserelin can be used to treat breast cancer in women (by ovarian ablation) Tumor Flare: give with concurrent antiandrogen (eg bicalutamide) for several weeks

Topoisomerase II Inhibitors

MOA: block the coiling and uncoiling of double-stranded DNA during the G2 phase — this causes single and double strand breaks in the DNA and prevents religation (sealing the DNA strands back together again) of single strand breaks Etoposide IV (Toposar) -infusion rate-related hypotension — infuse over at least 30-60 minutes -IV Preparation: prepare solution to a concentration ≤ 0.4 mg/ml to avoid precipitation (due to poor water solubility) -use non-PVC IV bag and tubing due to leaching of DEHP Etoposide Phosphate (Etopophos) -does not have solution concentration limits like etoposide (primarily used if the concentration needs to be ≥ 0.4 mg/ml) -helpful in patients with fluid retention Etoposide Capsules (VePesid) -refrigerate capsules -etoposide IV:PO ratio is 1:2 (50% bioavailability) -doses >200 mg need to be given in divided doses due to reduced bioavailability Boxed Warnings -myelsuppression Side Effects -hypersensitivity reactions, anaphylaxis, secondary malignancies Bleomycin -MOA: blocks topoisomerase II and intercalating agent -due to risk of anaphylactoid reactions, a test dose should be given -may premedicate with acetaminophen to decrease incidence of fever or chills -not myelosuppressive -maximum lifetime dose of 400 units due to pulmonary toxicity Boxed Warnings -pulmonary fibrosis, anaphylaxis Side Effects -hypersensitivity reaction, pulmonary reactions (including pneumonitis, which may progress to pulmonary fibrosis), mucositis, hyperpigmentation, fever, chills, N/V (mild)

Topoisomerase I Inhibitors

MOA: block the coiling and uncoiling of the double-stranded DNA helix during S phase — causes single and double strand breaks in the DNA and prevents religation (sealing the DNA strands back together again) of single strand breaks Irinotecan (Camptosar) -Acute cholinergic symptoms: flushing, sweating, abdominal cramps, diarrhea (treat with atropine) -Delayed diarrhea: treat with loperamide (up to 24 mg/day) -Pharmacogenomics: patients homozygous for the UGT1*28 allele are at increased risk for neutropenia and delayed diarrhea Topotecan (Hycamtin) Boxed Warnings -myelosuppression -use only when ANC >1500 cells/mm3 and platelets >100,000 cells/mm3 (topotecan) -diarrhea (early and late) — irinotecan Side Effects -N/V/D, alopecia, diarrhea, abdominal pain

Leukocyte Cluster of Differentiation (CD) Antigens Inhibitors

MOA: cluster of differentiation (eg CD20, CD22, CD30, CD38) antigens expressed on cell surface of hematopoietic cells — binds to antigens expressed on specific hematopoietic cells and causes cell death. -used to treat certain hematologic malignancies, such as non-Hodgkin's lymphomas, Hodgkin's lymphoma, multiple myeloma Rituximab (Rituxan) Ofatumumab (Arezerra) Obinutuzumab (Gazyva) Boxed Warnings -hepatitis B reactivation, progressive multifocal leukoencephalopathy (PML) -serious skin reactions (SJS/TEN), severe/fatal infusion-related reactions (rituximab) Side Effects -rash, peripheral edema, hypertension, renal impairment, tumor lysis syndrome Notes -check hepatitis B panel prior to administration -can cause severe infusion-related reactions (urticaria, hypotension, angioedema, bronchospasm, hypoxia, anaphylaxis) Unique Concerns -premedicate with diphenhydramine, acetaminophen, steroid — slowly titrate rate of first infusion to lower risk of infusion reaction -pharmacogenomics: test for B-cell antigen CD20 — must be CD20 positive to use Brentuximab Vedotin (Adcetris) -conjugated to MMAE, a microtubule inhibitor -Boxed Warnings: progressive multifocal leukoencephalopathy -Contraindications: concurrent use with Bleomycin -side Effects: myelosuppression, neuropathy, pulmonary toxicity, hepatotoxicity, infusion-related reactions, SJS/TEN -unique concerns: CD30 antigen must be positive for use Blinatumomab (Blincyto) -Bispecific antibody targeting CD19 on B-cells and engaging CD3 on T-cells causing lysis of Bcells -Pharmacogenomics: CD19 and CD3 antigens must be positive for use -Boxed Warnings: cytokine release syndrome, neurotoxicity -Side Effects: myelosuppression, hepatotoxicity, leukoencephalopathy, tumor lysis syndrome Daratumumab (Darzalex) -anti-CD38 monoclonal antibody -Pharmacogenomics: CD38 antigen must be positive for use -premedicate with systemic steroid, acetaminophen and diphenhydramine -side effects: myelosuppression, infusion-related reactions

Platinum-Based Compounds

MOA: cross-link DNA and interfere with DNA synthesis and cell replication Cisplatin -highest incidence of nephrotoxicity and CINV -nephrotoxicity, ototoxicity (both cumulative) — doses are usually limited ≤ 100 mg/m2/cycle -nephrotoxicity: monitor renal function, intake/output, Mg and K (levels may decrease) and ensure adequate IV hydration (1-2L) before each dose -Amifostine (Ethyol): chemoprotectant that can be given prophylactically to prevent nephrotoxicity -Ototoxicity: perform audiograms at baseline and before each dose -Highly emetogenic Carboplatin -myelosuppression in dose-relegated -dosed for adults are commonly calculated by target AUC using the Calvert Formula: -total carboplatin dose (mg) = (Target AUC) x (GFR + 25) where: -AUC can range from 2-8 mg/ml x min -GFR is commonly "capped" at 125 ml/min Oxaliplatin -acute sensory neuropathy: occurs 1-7 days after administration and can be exacerbated by exposure to cold, including drinking cold beverages Boxed Warnings -anaphylactic-like reactions — risk increases with repeated exposure — caution when >6 cycles of carboplatin are used -renal toxicity, ototoxicity, doses >100 mg/m2/cycle must be confirmed with prescriber (cisplatin) -myelosuppression (carboplatin and cisplatin) Contraindications -pre-existing renal impairment, hearing impairment (cisplatin) -myelosuppression (Cisplatin and carboplatin) Side Effects -peripheral neuropathy (cumulative, dose-related), myelosuppression, increased LFTs -N/V (cisplatin, carboplatin)

CDK4/6 Inhibitors

MOA: cyclin-dependent kinase (CDK4/6) inhibitors — inhibits downstream signaling and tumor growth Palbociclib (Ibrance) Abemaciclib (Verzenio) Ribociclib (Kisqali) Side Effects -neutropenia, anemia, nausea, diarrhea, fatigue, alopecia, blurred vision -risk of thromboembolic events Notes -avoid with CYP3A4 inhibitors or inducers (Palbociclib) -avoid or reduce dose with CYP3A4 inhibitors or inducers (Abemaciclib)

EGFR Inhibitors

MOA: epidermal growth factor receptor inhibitors— inhibits growth factor from binding to surface of tumor cell and promoting cell growth -used to treat certain solid tumors, such as colon cancer Cetuximab (Erbitux) Panitumumab (Vectibix) Boxed Warnings -severe/fatal infusion-related reactions, cardiac arrest (cetuximab) -dermatologic toxicities (panitumumab) Side Effects -acneiform rash, serious skin toxicities (SJS/TEN), ocular toxicities, infusion-related reactions, NVD, Mg and Ca wasting Notes -rash usually occurs within 1st 2 weeks of treatment — rash from an EGFR inhibitor indicates that a patient is expected to have a better response to the drug. Advise patients to avoid sunlight, use sunscreen. Topical emollients, including topical steroids, and antibiotics can be given prophylactically to reduce skin damage (and avoid the need for dose reduction) and for rash treatment Unique Concerns -premedicate 1st dose with diphenhydramine -use 0.22 micron filter -pharmacogenomics: test for EGFR gene expression and KRAS mutation. EGFR positive expression correlates with better response rates in NSCLC — must be KRAS wild type to use. KRAS mutation predicts poor response to treatment in colorectal cancer -NSCLC = non-small cell lung cancer

HER2 Inhibitors

MOA: human epidermal growth factor receptor 2 (HER2) — inhibits growth factor from binding to surface of tumor cell and promoting growth -used to treat certain solid tumors, such as breast cancer Trastuzumab (Herceptin) Trastuzumab-dkst (Ogivri) Pertuzumab (Perjecta) Ado-Trastuzumab Emtansine (Kadycla) Trastuzumab conjugated to a microtubule inhibitor Boxed Warnings -heart failure, embryo-fetal death and birth defects (avoid pregnancy x 7 months after receiving) -severe infusion-related reactions and pulmonary toxicity (trastuzumab) -hepatotoxicity (ado-trastuzumab emtansine) -ado-trastuzumab emtansine and conventional trastuzumab are NOT interchangeable Side Effects -infusion-related reactions, NVD, alopecia -ado-trastuzumab emtansine: myelosuppression, hepatotoxicity, neuropathy, pulmonary toxicity Notes -use 0.22 micron filter for ado-trastuzumab emtansine -pharmacogenomics: test for HER2 gene expression — must have HER2 overexpression to use -monitor LVEF (using echocardiogram or MUGA scan) at baseline and during treatment

Proteasome Inhibitors

MOA: inhibit proteasome, which help to regulate intracellular protein homeostasis by inhibiting cell cycle progression and inducing apoptosis Bortezomib (Velcade) -SC administration has less neuropathy than IV administration -an antiviral (acyclovir, valacyclovir) can be used to prevent herpes reactivation (zoster and simplex) Contraindications -hypersensitivity to boron or mannitol, intrathecal administration (fatal) Side Effects -peripheral neuropathy, psychiatric disturbances, insomnia, weakness, paresthesias, arthralgias/myalgias, cardiotoxicity, pulmonary toxicity, hypotension, thrombocytopenia, neutropenia, NVD, tumor lysis syndrome Carfilzomib (Kyprolis) -premedicate with dexamethasone and fluids -increased alkaline phosphatase correlates with increased efficacy Side Effects -peripheral neuropathy (but less than bortezomib), fatigue, pulmonary toxicity, acute renal failure, tumor lysis syndrome, hepatotoxicity, anemia, thrombocytopenia, NVD, pyrexia, cardiotoxicity

Pyrimidine Analog Antimetabolites

MOA: inhibit pyrimidine synthesis during S phase — an active metabolite (F-UMP) is incorporated into RNA to replace uracil and inhibits cell growth, while another active metabolite (5-dUMP) inhibits thymidylate synthetase Fluorouracil, "5-FU" (Adrucil) -Efudex, Carac, Tolak, and Fluoroplex are topical formulations used for actinic keratosis, Efudex also used for basal cell carcinoma -leucovorin given with fluorouracil to increase the efficacy of fluorouracil — helps fluorouracil bind more tightly to its target enzyme, thymidylate synthetase -Pharmacogenomics: dihydropyrimidine dehydrogenase (DPD) deficiency increased risk of severe toxicity Capecitabine (Xeloda) -2 divided doses 12 hrs apart, given with water within 30 min after a meal -oral prodrug of fluorouracil -Pharmacogenomics: dihydropyrimidine dehydrogenase (DPD) deficiency increases risk of severe toxicity Boxed Warnings -significant increase in INR during and up to 1 month after treatment, monitor INR frequently (capecitabine) Contraindications -severe renal impairment (CrCl < 30 ml/min) (capecitabine) Side Effects -hand-foot syndrome, diarrhea, mucositis, cardiotoxicity, photosensitivity, dermatitis Notes -uridine triacetate (Vistogard) can be given as an antidote for overdose or severe or early toxicity due to DPD deficiency Cytarabine conventional (called "ara-c") -Cytarabine Syndrome: fever, flu-like symptoms, myalgia, bone pain, rash -Cytarabine liposomal (DepoCyt) — for intrathecal administration Boxed Warnings -myelosuppression, hepatotoxicity and GI toxicities (conventional) -chemical arachnoiditis (N/V, HA, fever) is common and can be fatal if untreated — give dexamethasone (liposomal formulations) Side Effects -pulmonary toxicity, encephalopathy, hand-foot syndrome, neuropathy, conjunctivitis (higher doses require use of steroid eye drops) Gemcitabine (Gemzar) -infusion rate affects efficacy and toxicity — infuse per institutional protocol -side effects: myelosuppression, flu-like symptoms, hepatotoxicity, pulmonary toxicity

Gonadotropin Releasing Hormone Antagonist

No initial surge in testosterone concentration — an antiandrogen is not needed Hormonal therapy for prostate cancer Degarelix (Firmagon) -SC injection Contraindications -pregnancy Side Effects -similar to GnRH agonist, plus hypersensitivity reactions Osteoporosis Risk: consider calcium, vitamin D supplementation, weight bearing exercise, DEXA screening No tumor flare: antiandrogen not needed

Taxanes

MOA: inhibit the function of microtubules during the M phase Paclitaxel (Taxol) -HSR: premedicate with diphenhydramine, steroid, H2RA Docetaxel (Taxotere) -HSR: premedicate with steroids for 3 days, starting 1 day prior to docetaxel -causes severe fluid retention (characterized by pleural effusion, cardiac tamponade and/or edema) — premed with dexamethasone -some formulations contain alcohol and may cause symptoms of alcohol intoxication Cabazitaxel (Jevtana) -HSR: premedicate with diphenhydramine, steroid, H2RA Paclitaxel albumin-bound (Abraxane) -no premedication required Boxed Warnings -severe hypersensitivity reactions (except Abraxane), myelosuppression -fluid retention (docetaxel) Side Effects -peripheral sensory neuropathy, myalgias, arthralgias, hepatotoxicity, alopecia (less with cabazitaxel) Notes -hypersensitivity reactions are due to the solvent systems, not the taxane -to maintain solubility, paclitaxel contains polyoxyl35/polyethylene castor oil (Cremophor EL) — docetaxel contains Polysorbate 80 -Abraxane is paclitaxel bound to albumin without a solvent system — only isolate case reports of allergic reaction, no need to premedicate -use non-PVC bag and tubing (except Abraxane)

Vinca Alkaloids

MOA: inhibit the function of microtubules during the M phase Vincristine (Vincasar PFS) -not myelosuppressive -often "capped" at 2 mg/dose regardless of the calculated mg/m2 dose — higher doses may be associated with increased risk of neuropathy -major substrate of CYP3A4 — when given with azole antifungals there is a high risk of severe toxicities (peripheral neuropathy, seizures, paralytic ileus) Vinblastine -myelosuppressive Vinorelbine (Navelbine) -myelosuppressive Vincristine liposomal (Marqibo) -not interchangeable with vincristine Boxed Warnings -vesicants -for IV administration only (intrathecal administration is fatal) Side Effects -peripheral sensory neuropathy (paresthesias), autonomic neuropathy (gastroparesis, constipation), SIADH Notes -to prevent inadvertent administration intrathecally, it is recommended to prepare vincristine in a small IV bag (a piggyback) rather than in a syringe Vincristine is associated with more CNS toxicity (neuropathy) than the other vinca alkaloids Vinblastine and Vinorelbine are associated with more bone marrow suppression (myelosuppression) than vincristine

Folate Antimetabolites

MOA: interfere with the enzymes involved in the folic acid cycle, blocking purine and pyrimidine biosynthesis during S phase Methotrexate (Trexall, Otrexup, Rasuvo, Xatmep) -doses used for cancer are much higher than doses used for RA or psoriasis -if given intrathecally, use only the preservative-free formulations of MTX Boxed Warnings -myelosuppression and aplastic anemia, renal dm age, hepatotoxicity* (fibrosis and cirrhosis with long-term use), interstitial pneumonitis, dermatologic reactions (SJS/TEN), GI toxicity (nausea, diarrhea, oral stomatitis (with mucositis), immunosuppression, tumor lysis syndrome, teratogenicity/fetal death -renal impairment or ascites requires dose adjustments or discontinuation *hepatotoxicity is more of a concern with chronic use of methotrexate for RA, especially when taken incorrectly (taken daily in error, instead of once-weekly dosing) Side Effects -nephrotoxicity (dose related), hepatotoxicity (more common with chronic use for autoimmune disease), nausea, diarrhea, stomatitis, mucositis, dizziness, sedation, hand-foot syndrome Unique Concerns -"High dose" methotrexate (≥500 mg/m2) requires leucovorin (folinic acid) "rescue" -"Moderate dose" MTX (100-499 mg/m2) may require leucovorin rescue -levoleucovorin (Fusilev) is also available as the (L) isomer (the active biologic moiety) of leucovorin and is doses at 1/2 the dose of leucovorin — monitor MTX levels and renal function daily and continue leucovorin until level is ≤ 0.05-0.1 micromolar -hydration and IV sodium bicarbonate must be given to alkalization the urine and decrease risk of nephrotoxicity caused by high doses — ensure patient does not have 3rd spacing prior to the drug (ascites, pleural effusions, severe edema) because this will delay drug clearance -Glucarpidase (Voraxaze) will rapidly lower MTX levels that remain high despite adequate hydration and urinary alkalization (with bicarb) -drug interactions: NSAIDs, salicylates, beta-lactate, PPIs, sulfonamide abx, probenecid — all decrease clearance of MTX -IV drug solution is yellow Pemetrexed (Alimta) -to decrease risk of side effects, give folic acid, vitamin B12, and dexamethasone -Side Effects: nephrotoxicity, hepatotoxicity, dermatologic toxicity (premedicate with dexamethasone) Pralatrexate (Folotyn) -to decrease risk of side effects, give folic acid and vitamin B12 -Side Effects: nephrotoxicity, hepatotoxicity

MTOR inhibitors

MOA: mammalian target rapamycin (mTOR) inhibitors — inhibit downstream regulation of vascular endothelial growth factor (VEGF) reducing cell growth, metabolism, proliferation and angiogenesis Everolimus (Afinitor, Afinitor, Disperz) -tablet, tablet for oral suspension -Zortress — for transplant -CYP3A4 major substrate Contraindications -hypersensitivity to rapamycin derivatives Side Effects -mouth ulcers/stomatitis, rash, interstitial lung disease, dyslipidemia, hyperglycemia, myelosuppression, rash, pruritus, hand-foot syndrome, stomatitis, fatigue, NVD, peripheral edema, interstitial lung disease, renal impairment, increased LFTs Temsirolimus (Torisel) -injection -CYP3A4 Major substrate -premed with diphenhydramine -use non-PVC bag and tubing due to leaching of DHEP Contraindications -moderate to severe hepatic impairment Side Effects -dyslipidemia, hyperglycemia, myelosuppression, interstitial lung disease, acute hypersensitivity reactions (polysorbate 80 solven system), NVD, peripheral edema, renal impairment

CTLA-4 Inhibitor

MOA: monoclonal antibody that binds to the cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) receptors, which effectively removes the "brake" from T-cell activation. Induces antitumor responses through increased T-cell recognition of cancer cells Ipilimumab (Yervoy) -REMS program Boxed Warnings -fatal immune-mediated reactions (enterocolitis, hepatitis, dermatitis, endocrinopathy, neuropathy) Side Effects -pneumonitis, nephrotoxicity, ocular toxicity, rash Notes -immune-mediated toxicities may require interruption or permanent discontinuation of treatment and administration of steroids

Immunomodulators

MOA: oral agents that block angiogenesis and kill abnormal cells in the bone marrow while stimulating the bone marrow to produce normal healthy cells. Usually indicated for multiple myeloma These agents cause severe birth defects and patients must not become pregnant while using these drugs All 3 have strict REMS programs Lenalidomide (Revlimid) Pomalidomide (Pomalyst) Thalidomide (Thalomid) Boxed Warnings -fetal risk/pregnancy, thrombosis (DVT/PE), hematologic toxicity (lenalidomide) Contraindications -pregnancy Side Effects -neutropenia, thrombocytopenia, constipation, NVD, fatigue, fever, cough, pruritus, rash, arthralgias, back pain, peripheral edema, DVT/PE -neuropathy, confusion, somnolence (thalidomide) -hypercalcemia (pomalidomide)

PD-1 Inhibitors

MOA: programmed death receptor-1 (PD-1) inhibitors — when the programmed cell death (PD-1) receptor binds the PD-L1 ligand, the end result is decreased T-cell activation. PD-1 inhibitors are monoclonal antibodies that selectively inhibit PD-1 activity. This allows T-cell activation. Activated T-cells are capable (to some extent) of recognizing cancer cells as "non-self" or foreign and activating the immune system against them (antitumor responses) Pembrolizumab (Keytruda) Nivolumab (Opdivo) Atezolizumab (Tecentriq) Side Effects -immune-mediated toxicities including: colitis, hepatoxicity, pulmonary toxicity, nephrotoxicity (pembrolizumab), thyroid disorders, myocarditis, encephalitis, endocrinopathies, rash, weakness Unique Concerns -immune-mediated toxicities may require interruption or permanent discontinuation of treatment and treatment with steroids

SERMs

MOA: selective estrogen receptor modulators (SERMs) - estrogen antagonist in breast tissue, raloxifene is also an estrogen agonist in bone Used for hormone-sensitive breast cancer Tamoxifen (Soltamax) — FIRST LINE -tablet -prodrug converted via CYP2D6 to the potent metabolite endoxifen — do not use with 2D6 inhibitors, which will block the conversion Fulvestrant (Faslodex) -IM injection Toremifene (Firestone) -oral -alternative option with a slow CYP2D6 metabolizer or if a drug interaction is present Raloxifene (Evista) -oral -for breast cancer prophylaxis (NOT TREATMENT) -increased bone density, and is indicated for osteoporosis prevention and treatmetn in postmenopausal women who require breast cancer prophylaxis Boxed Warnings -increased risk of uterine or endometrial cancer (tamoxifen) -increased risk of thromboembolic events (tamoxifen, raloxifene) -QT prolongation (toremifene) Contraindications -do not use with warfarin (tamoxifen) -history of DVT/PE (tamoxifen, raloxifene) -pregnancy and breastfeeding (raloxifene) -QT prolongation -hypokalemia -hypomagnesemia (toremifene) Side Effects -hot flashes/night sweats, vaginal bleeding/spotting, vaginal discharge/dryness/pruritus, decreased libido, edema, weight gain, hypertension, mood changes, amenorrhea, arthralgia/myalgias, cataracts (tamoxifen), decreased bone density — supplement with calcium/vitamin D (tamoxifen) Notes -tamoxifen is teratogenic — contraception should be used in premenopausal women. Raloxifene is also unsafe in pregnancy, but is only used in postmenopausal women The usual primary treatment for hot flashes/night sweats is estrogen — cannot be used -fluoxetine and paroxetine, which are used off label, are 2D6 inhibitors and cannot be used -instead, venlafaxine is preferred for hot flashes/night sweat relief

Alkylating Agents

MOA: work by cross-linking DNA strands and inhibiting protein synthesis and DNA synthesis Cyclophosphamide (Cytotaxan) Ifosfamide (Ifex) Carmustine (BiCNU, Gliodel Wafer) -use non-PVC bag and tubing Dacarbazine -protect from light (decomposed drug turns pink) Procarbazine (Matulane) -MAOI, avoid interacting drugs/foods Altretamine (Hexalen) Bendamustine (Bendeka, Treanda) Busulfan (Myleran, Buselfex) Lomustine (Gleostine) -fatal toxicity occurs with overdosage. Do not dispense more than one dose at a time. Both healthcare provider and pharmacist should emphasize to patient that only one dose of lomustine is taken every 6 weeks Mechlorethamine (Mustargen, Valchlor topical gel) Melphalan (Alkeran, Evomela) Temozolomide (Temodar) Boxed Warnings -myelosuppression -hemorrhagic cystitis (ifosfamide, cyclophosphamide) -pulmonary toxicity (carmustine) -neurotoxicity (ifosfamide) -hepatic necrosis (dacarbazine) Warnings -severe skin reactions, including SJS/TEN, reactivation of infections, including HBV, CMV, TB, HSV, hepatotoxicity (bendamustine) Side Effects -pulmonary toxicity (busulfan, carmustine, lomustine) -SIADH (cyclophosphamide) -mucositis, moderate-high emetic potential, alopecia, secondary malignancies, neurotoxicity Mitomycin -free radical formation and alkylation -Vesicant, do not extravasation. antidote is Dimethyl sulfoxide (DMSO) and cool compresses -Mitomycin IV solutions are hazy blue in color and can make the urine blue-green Boxed Warnings -bone marrow suppression, hemolytic uremic syndrome Contraindications -thrombocytopenia, coagulopathy, bleeding Side Effects -leukopenia, thrombocytopenia, N/V, fatigue, alopecia, mucous membrane toxicity, cystitis or dysuria (from intravesical administration into bladder) **cyclophosphamide and ifosfamide produce a metabolite, acrolein, that concentrates in the bladder and can cause hemorrhagic cystitis -the chemoprotectant MESNA (Mesnex) inactivates this toxic metabolite in the bladder without interfering with the cytotoxic efficacy -ifosfamide is always dispensed with mesna. High doses of cyclophosphamide may require mesna

Anthracyclines

MOA; work by intercalating into DNA, inhibiting topoisomerase II and creating oxygen-free radicals that damage cells Cardiotoxicity is associated with all anthracyclines and is manifested as cardiomyopathy and heart failure -risk for cardiotoxicity is related to the total cumulative anthracycline dose the patient has received over their lifetime Anthracyclines are strong vesicants — except for the Liposomal formulations Doxorubicin (Adriamycin) Daunorubicin Epirubicin (Ellence) Idarubicin (Idamycin PFS) Valrubicin (Valstar) -only used as bladder instillation, but can have systemic toxicity Boxed Warnings -myocardial (cardiovascular) toxicity, vesicant, myelosuppression, secondary malignancy -hepatotoxicity (daunorubicin), reduce dose if impairment (except valrubicin) -renal impairment (daunorubicin, idarubicin) Contraindications -pre-existing myocardial insufficiency, severe hepatic impairment Notes -potent vesicants (tissue necrosis if extravasated) -drug is red, and causes red urine discoloration -doxorubicin: do not exceed 450-550 mg/m2 (total lifetime cumulative dose) -Dexrazoxane (Totect) for extravasation, (Zinecard) for cardioprotection at higher doses Daunorubicin and cytarabine liposomal (Vyxeos) Doxorubicin liposomal (Doxil, Lipodeox50) -liposomal formulations are not interchangeable with non-liposomal formulations Boxed Warnings -myocardial (cardiovascular) toxicity, infusion-related reactions, myelosuppression Side Effects -hand-foot syndrome Mitoxantrone -an anthracenedione, related to anthracyclines -irritant with vesicant-like properties -drug is blue and causes blue urine discoloration -BBW: myocardial (cardiovascular) toxicity, myelosuppression, secondary malignancy

Skin cancer overview

Most common cancer in the US Risk factors: -history of UV light -exposure (sun or tanning beds) -light skin that burns easily -light hair color -immunosuppressant drugs or diseases (includes many transplant drugs) -past history of sin cancer 3 types: -Basal cell -Squamos cell -Melanoma Basal and squamos cell are common and very survivable if treated early Melanoma is much less common but often metastasizes and accounts for ~75% of all skin cancer-related deaths

Lung cancer overview

Most common type of cancer worldwide 3 main types: -Nonsmall cell (~85%) -Small cell (~10-15%) -Carcinoid ( <5%) Smoking causes ~80% of lung cancers. The other 20% is attributed to radon, asbestos fibers, and exposure to various types of chemicals and pollution A chronic cough with dyspnea can indicate lung cancer Typical treatment includes: surgery, followed by radiation and/or chemotherapy drugs Lung cancer is categorized in stages from I to IV according to severity of disease

Breast cancer overview

The top risk factor for developing breast cancer is being female Modifiable risk factors: overweight (in postmenopausal women), low physical activity, poor nutrition, tobacco use Breast self exams are not used for screening — but they can help women identify a change in the look or feel of the breast or nipple, or nipple discharge which would warrant follow-up screening Breast imaging studies -Mammograms — beginning at age 40 or 45, roughly every year or 2 -if anything looks suspicious, a diagnostic mammogram with more images can be taken -an ultrasound is useful to differentiate between a benign fluid-filled cyst or the needle during a biopsy -high risk women can receive a MRI exam, in addition to the annual mammogram -biopsy follows an abnormal result BRCA1 and BRCA2 genes normally suppress tumor growth -increased risk of getting breast cancer with these mutations The HER2/NEU (typically referred to as HER2) oncogene promotes breast tumor growth -approximately 20% of breast tumors over-express HER2 on cell surface, which makes the tumor grow quickly

ABCDE mnemonic

To help educate patients about suspicious skin spots —melanoma skin cancer A: asymmetry (one half of the mole does not match the other) B: border (edges are irregular, notched) C: color is not the same all over D: diameter (larger than 6 mm or the size of the tile of a pencil eraser) E: evolving (mole is changing in size, color, shape or symptoms — itching, bleeding, tenderness)

Breast cancer treatment overview

Treatment of early stage breast cancer will include some combination of surgery, chemotherapy and/or radiation The choice of hormone treatment depends on the menopausal status of the patient If a tumor expresses a high percentage of either estrogen or progesterone receptors, the tumor is referred to as hormone-sensitive, and classified as either ER+, PR+ or both (ER+/PR+) -first line for premenopausal women with hormone-sensitive cancer is tamoxifen (SERM) -NOTE: raloxifene is a SERM used for breast cancer prophylaxis -other SERMS can be used if tamoxifen cannot Premenopausal women produce estradiol, the most potential estrogen in the ovaries — postmenopausal women do not. -postmenopausal women get most of their estrogen from the conversion of androgens into estrogen -AIS reduce estrogen production by blocking the aromatase enzyme that catalyzes the conversion of androgens -AIs do not block ovarian estradiol production, which is why they are not useful treatments for premenopausal women In some circumstances, a premenopausal woman will be put not menopause by taking a gonadotropin-releasing hormone (GnRH) agonist (Goserelin or Leuprolide) -decreased LH and FSH, which suppresses ovarian estradiol production — this makes AI treatment a reasonable option HER2 -Trastuzumab (Herceptin) and other drugs in this class, bind to the HER2 receptor, preventing dimerization

Arsenic Trioxide

Trisenox MOA: increase apoptosis of APL cells and damages fusion protein PML-RAR alpha Second line therapy for acute promyelocytic leukemia (APL) Boxed Warnings -RA-APL differentiation syndrome, ECG abnormalities (AV block, QT prolongation), ECG and electrolyte monitoring Side Effects -leukocytosis, APL differentiation syndrome, NVD, GI bleeding, stomatitis, electrolyte imbalance, acute vasomotor reactions (lightheadedness, dizziness, or hypotension), fatigue, edema, HA, insomnia, anxiety, infection Unique Concerns -QT prolongation: monitor ECG, avoid concurrent QT prolonging agents, keep Mg, Ca, and K within normal range -if acute vasomotor reactions (lightheadedness, dizziness, or hypotension) occur, prolong infusions

BRAF Inhibitors

Tyrosine kinase inhibitor Vemurafenib (Zelboraf) Dabrafenib (Tafinlar) BRAF mutation —> abnormal tyrosine kinase that is always "on" —> melanoma (occurs in ~50% of melanoma patients) Pharmacogenomics: must be BRAF V600E or V600K positive to use Warnings -new malignancies such as squamos cell carcinoma and basal cell carcinoma, QT prolongation, serious skin reactions, hepatotoxicity Side Effects -skin rash, photosensitivity, NVD, peripheral edema, fatigue, arthralgia

EGFR inhibitors used on NSCLC

Tyrosine kinase inhibitors Afatinib (Gilotrif) Erlotinib (Tarceva) Gefitinib EFGR mutation —> abnormal tyrosine kinase that is always "on" —> NSCLC (occurs in ~15% of NSCLC patients) Pharmacogenomics: must be EGFR mutation positive (exon 19 or 21) to use Warnings -interstitial lung disease, hepatotoxicity, GI perforation, skin reactions (SJS/TEN), ocular toxicity (keratitis), fetal harm -diarrhea (afatinib/gefitinib) -renal impairment requires dose adjustments (afatinib) Side Effects -acneiform rash, dry skin, pruritus, NVD, mucositis Notes -acneiform rash from an EGFR inhibitor indicates that a patient is expected to have a better response to the drug. Advise patient to avoid sunlight, use sunscreen. Topical emollients, including topical steroids and antibiotics can be given prophylactically to reduce skin damage (and avoid the need for a dose reduction) and for rash treatment

BCR-ABL Inhibitors

Tyrosine kinase inhibitors Imatinib (Gleevec) Dasatinib (Sprycel) Nilotinib (Tasigna) Ponatinib (Iclusig) Bosatunib (Bosulif) BCR-ABL gene translocation (Philadelphia Chromosome) —> abnormal tyrosine kinase (occurs in ~95% of CML patients) Pharmacogenomics: must be Philadelphia chromosome (BCR-ABL) positive to use Boxed Warnings -QT prolongation (nilotinib) -vascular occlusion (strokes, MIs), heart failure, hepatotoxicity (ponatinib) Side Effects -myelosuppression, NVD, fluid retention, edema, skin rash, increased LFTs, HF, QT prolongation (dasatinib, nilotinib, bosutinib) -HBV reactivation (imatinib, dasatinib, nilotinib)

MEK 1 and 2 Inhibitors

Tyrosine kinase inhibitors Trametinib (Mekinist) Cobimetinib (Cotellic) Inhibits MEK (mitogen-activated extracellular kinase), a cell signaling protein downstream from RAF Used in combination with BRAF inhibitors in patients with BRAF V600E or V600K mutations