1
Q
Vesicant Chemos
A
Anthracyclines (Adria)
Act-D
Vincas (vincristine, vinblastine, vinorelbine)
Mitomycin-C
(Cisplatin)
2
Q
Need dose adjustment for hepatic function
A
Anthracyclines (adriamycin) Act-D Texans (taxol, taxotere) Vinca alkaloids (vincristine, vinblastine, vinorelbine) Irinotecan 5-FU Gemcitabine MTX
3
Q
What chemos cause alopecia?
A
Taxol (taxotere not as much) Adriamycin/doxil not as much Cyclophosphamide Etoposide Vinca alkaloids 5-FU
4
Q
What causes CNS toxicity with Ifosfamide?
…Hemorrhagic cystitis?
A
Chloracetaldehyde (methylene blue)
Acrolein (Mensa)
5
Q
3 hour taxol infusion
A
More neurotoxicity
6
Q
24 hour taxol infusion
A
More myelosuppresion
7
Q
Taxol before cisplatin
A
Less myelosuppresion
8
Q
Which chemos require dose reduction for kidney function?
A
Platinums Bleomycin Melphalan Topotecan Mitomycin-C Hydroxyurea Capecitabine Cytoxan MTX Ifosfamide Alimta
9
Q
Topoisomerase I Inhibitors
A
Topotecan
Irinotecan
10
Q
Topoisomerase II inhibitors
A
Etoposide
Adriamycin
Mitoxantrone
11
Q
Which chemos cause secondary malignancies?
A
Etoposide Cytoxan Cisplatin Melphalan Ifosfamide
12
Q
Calvert’s formula
AKA AUC
A
Carboplatin (4-6)
Dose = AUC * (GFR+25)
GFR is a function of weight
13
Q
Vinca alkaloids:
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
A
Vincristine, Vinorelbine
- Prevent microtubule polymerization (M-phase specific)
- Constipation/ileus, alopecia, peripheral neuropathy (ataxia, foot drop, muscle wasting), leukopenia; SIADH, ARDS
- Not much nausea, VESICANT; vincristine can cause autonomic neuropathy
*Hepatic excretion/dose adjustment
14
Q
Taxol
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
A
Taxane
- Stabilizes microtubules, preventing cell division (M phase specific)
- Myelosuppresion (increased with 24 vs 3 hour infusion), neurotoxic (increased with 3 hour vs 24 hour infusion), hypersensitivity (cremphor), alopecia, asymptomatic bradycardia, cough/dyspnea/pneumonitis
- Premed with H2 blockers, H1 blocker and dexamethasone
*Hepatic dose reduction
15
Q
Cytoxan/Cyclophosmamide
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
A
Traditional alkylator - nitrogen mustard
- Interstrand DNA cross links (N-7 on guanine) (cell cycle non-specific)
- Myelosuppresion, SIADH, alopecia, secondary malignancy, hemorrhagic cystitis at high doses, cardiotoxicity (myocyte necrosis or myopericarditis), N/V, pulmonary fibrosis
- Require activation in liver —> CANNOT USE IP
Renal dose adjustment
16
Q
Ifosfamide
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
A
Traditional alkylator - nitrogen mustard
-Interstrand DNA crosslinks (N-7 on guanine) (cell cycle non-specific)
-Hemorrhagic cystitis, myelosuppresion, neurotoxicity (CNS), renal failure,
Fanconi syndrome, N/V, constipation, alopecia, hepatotoxicity, SIADH
-PRODRUG; CNS toxicity more likely with low albumin, older age
*Renal/hepatic dose adjustment
17
Q
Melphalan
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
A
Traditional alkylator - nitrogen mustard
- DNA Interstrand crosslinks (N-7 on guanine)
- myelosuppresion, alopecia, mucositis, diarrhea, interstitial pneumonitis/pulmonary fibrosis
- Renal dose adjustment, secondary malignancies
18
Q
Methotrexate
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
A
Antimetabolite - folate antagonist
- Inhibits dihydrofolate reductase (DHFR) (S phase specific)
- leukopenia, interstitial pneumonitis, alopecia (at high doses), stomatitis/mucositis, hepatotoxicity and renal toxicity
- High dose crosses BBB; leukovorin rescue
*Hepatic and renal dose adjustment
19
Q
Pemetrexed
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
A
AKA Alimta
Antimetabolite - folate antagonist
-Inhibits three enzymes in folate metabolism (thymidylate synthase, DHFR, glycinamide ribonucleotide formyltransferase)
-Fatigue, myelosuppression, rash, ocular toxicity
-Give with folate and B12
*renal and hepatic dose adjustment
20
Q
Fluorouracil (5-FU)
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
A
Antimetabolite - pyrimidine analog
- Inhibits thymidylate synthase (S phase specific)
- Myelosuppresion, mucositis, hand-foot, diarrhea, skin discoloration, nail changes, cerebellar ataxia, cardiac ischemia
- Give following HD; Efudex cream for vulvar; crosses blood-brain barrier
*Hepatic dose adjustment
21
Q
Capecitabine (Xeloda)
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
A
Antimetabolite - pyrimidine analog
- Prodrug of 5-FU —> inhibits thymidylate synthase (S phase specific)
- hand-foot, diarrhea, N/V, rash, mucositis
- Renal dose adjustment
ORAL form of 5-FU - converted intracellularly more efficiently in tumor cells than normal
22
Q
Gemcitabine
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
A
Antimetabolite
- Inhibits DNA replication (but not S phase specific)
- Leukopenia, thrombocytopenia, N/V, mucositis, flu-like syndrome, edema; radiation recall, rare ARDS/pulmonary toxicity
- Prodrug
*Hepatic dose adjustment
23
Q
Cisplatin
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
A
Platinum
- Intrastrand DNA crosslinks (N-7 of guanine) (cell cycle non-specific)
- Very emetogenic, nephrotoxic, neurotoxicity (ototoxicity), hypomag/K, myelosuppression
- HYDRATION with Mg and K
*Renal dose adjustment
24
Q
Carboplatin
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
A
Platinum
- Intrastrand DNA crosslinks (N-7 of guanine) (cell cycle non-specific)
- myelosuppression (esp thrombocytopenia), N/V
- AUC
*Renal dose adjustment
25
Oxaliplatin
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
Platinum
- Intrastrand DNA crosslinks (N-7 of guanine)
- Neuropathy (cold), hepatotoxicity
- Colon cancer
*Renal dose adjustment
26
Bleomycin
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
Antitumor antibiotic
- Inhibits DNA synthesis/repair (G2 specific)
- Pulmonary fibrosis, hyperpigmentation, NOT myelosuppresive or emetogenic
- Requires metal ion cofactor - primarily copper, but also nickel, manganese and cobalt
*Check DLCO; max dose 400U
27
Dactinomycin/Act-D
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
Antitumor antibiotic
- Intercalates into DNA and inhibits transcription of RNA (cell cycle non-specific but most active in G1)
- Nausea, diarrhea, alopecia, hyperpigmentation, mucositis/stomatitis, myelosuppresion, hepatotoxicity, radiation recall dermatitis
- Vesicant
*Hepatic dose adjustment
28
Mitomycin-C
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
Antitumor antibiotic
- Inhibits DNA synthesis
- CHF (doses > 30 mg/m2), fever, alopecia, N/V, myelosuppresion, nail changes, HUS
*Renal dose adjustment
29
Etoposide/VP-16
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
Epidophyllotoxin (from the Mandrake plant)
- Topoisomerase II inhibitor (S-G2 specific); also binds tubulin
- Myelosuppression, mucositis, N/V, alopecia, secondary malignancy (MLL 11q23 leukemia 1-3 years), vasospastic angina
- Hypotension 2/2 polysorbate 80; irritant
* Renal and hepatic dose adjustment*
* Risk of leukemia increases after cumulative dose of > 2000
30
Irinotecan
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
- Topoisomerase I inhibitor
- Diarrhea (severe), neutropenia, N/V, cholinergic rxn (rhinitis, salivation, diaphoresis, flushing), alopecia, hepatotoxicity
- Prodrug?
*Hepatic dose adjustment
31
Topotecan
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
Camptothecin
- Topoisomerase I inhibitor (M phase specific)
- leukopenia/thrombocytopenia, N/V (mild), alopecia, mucositis, myalgia/arthralgia, rash, increased LFTs
*Renal dose adjustment
32
Adriamycin/Doxorubicin
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
Anthracyclines
- Inhibit topoisomerase II, inhibits RNA/DNA synthesis (cell cycle non-specific)
- Myelosuppresion, cardiac toxicity - CHF at doses > 450/550 mg (get pre-treatment MUGA), radiation recall, secondary malignancies (1-3 years), N/V, red urine/tears, mucositis, VESICANT
- Requires IRON; dexrazoxane chelates iron and reduces cardiomyopathy risk; also use for extravisation; DOES NOT CROSS PLACENTA
*Hepatic dose adjustment
33
Doxil/liposomal doxorubicin
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
Anthracyclines
- Inhibits topo II, DNA/RNA synthesis (cell cycle non-specific)
- Less alopecia, myelosuppresion, nausea/vomiting, cardiotoxicity BUT MORE hand-foot syndrome (PPE), mucositis and infusion rxns; radiation recall dermatitis
- Irritant rather than vesicant
*Hepatic dose adjustment
34
Chemos effected by drug efflux pump
Doxorubicin, etoposide, vinca alkaloids, taxanes, topotecan, MTX
35
Skipper-Schabel-Wilcox Model (AKA Log-Kill Model)
Constant exponential rate of tumor cell growth (constant doubling time) therefore, cell should be killed at a constant exponential rate
36
Gompertzian Model
Cell growth is not constant —> initial tumor growth is first order, however later growth is much slower as tumor enlarges; therefore, log-kill greater for smaller tumors than larger ones
37
Norton-Simon Hypothesis
Smaller tumors regrow at a higher growth fraction
**idea of increased intensity or sequential therapy/dose-dense schedule
38
Goldie Coldman Hypothesis
Populations of cells within a tumor are capable of randomly mutation and becoming resistant to chemotherapy —> occur at 1 in 10^6 (tumor is not yet detectable)
**To avoid resistance, use non-cross-resistant chemotherapy or alternating
39
Hexalan (Altretamine)
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
Alkylator
- DNA crosslinker or anti-metabolite (cell-cycle non-specific)
- myelosuppresion, N/V, neuropathy, renal toxicity, ataxia/seizures/mood disorder
- Prodrug requires metabolism in liver
40
Taxotere (docetaxel)
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
Taxane
- Stabilizes microtubules, preventing cell division (M phase specific)
- Myelosuppression (more than taxol), hypersensitivity, edema/fluid retention (2/2 polysorbate 80), less alopecia
- Premed with dexamethasone to decrease edema
*Hepatic dose reduction
41
Radiation recall chemotherapy
Anthracyclins
Act-D
Gemcitabine
(Etoposide)
42
Bevacizumab/Avastin
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
Humanized monoclonal antibody
- Binds to VEGFA and prevents binding to the VEGFR - decreases angiogenesis
- Hypertension, headache, delayed healing, thrombosis, fistulas
- Hold for proteinuria
43
Bortezomib/Velcade
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
Small molecule inhibitor
- proteosome inhibitor - promotes apoptosis
- peripheral neuropathy, thrombocytopenia, N/V/D, rash, sudden cardiac death
- not really used in GYN
44
Cetuximab (IMC-C225)
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
Chimeric monoclonal antibody
- Binds to extracellular EGFR, blocking tyrosine kinase activity
- Nausea, rash, allergy
- Not used in GYN
45
Erlotinib/Tarceva
Small molecule inhibitor
- Inhibits EGFR tyrosine kinase leading to cell cycle arrest and inhibition of angiogenesis
- Diarrhea, rash, interstitial lung disease
- Not used in GYN
46
Evrolimus/Afinitor
Small molecule inhibitor
- mTOR inhibitor —> mTOR is downstream in PI3K pathway and regulates cell growth and proliferation
- Rash, stomatitis, infections, edema, fatigue
- Endometrial cancer trials
47
Ipilimumab/Yervoy
Immune checkpoint inhibitor
- Monoclonal antibody to CTLA-4, binding and preventing interaction of T cell CTLA-4 with tumor cell CD80 and CD86
- ‘itises (dermatitis, pneumonitis, enteritis/colitis, etc), inflammatory demyelinating polyneuropathy
- Used in cervix cancer clinic trials with PDL-1 inhibitors; approved for melanoma
48
Nivolumab/Opdivo
Immune checkpoint inhibitor
- monoclonal antibody to PD-1 on T cells, preventing interaction with PDL-1 on tumor cells
- ‘itises (dermatitis, pneumonitis, GI-itises, thyroiditis, iris inflammation), fatigue, weakness, cardiac arrhythmia
- Clinical trials in GYN; approved in melanoma, lung cancer, urothelial
49
Pembrolizumab/Keytruda
Immune checkpoint inhibitor
- Monoclonal antibody against PD-1 on T cells, preventing interaction with tumor PDL-1
- itises (dermatitis, pneumonitis, GI-itises, pituitary inflammation, thyroiditis, pancreatitis, nephritis), fatigue, arthralgia
- Approved for MSI high or MMR cancers, NSCLC, melanoma, head/neck cancers; just approved for PDL-1 high cervix cancer
50
Imatinib/Gleevac
Small molecular inhibitor
- Tyrosine kinase inhibitor - designed to target Bcr-Abl fusion protein formed as a result of the PHL chromosome; also inhibits PDGF, SCR (stem cell receptor) and c-kit
- Used in GIST and CML
51
MEK inhibitors
Selumetinib, trametinib
- Inhibit MEK1/MEK2
- Used in LGSOC (clinical trial), BRAF mutated melanoma and KRAS/BRAF mutated colon cancers
52
Trastuzimab/Herceptin
- Mechanism of action
- Toxicxity
- Misc
Humanized monoclonal antibody
- Binds to extracellular Her-2 (AKA Neu, gene = ERBB2) and inhibits signaling
- Heart failure
- Serous HER2 expression uterine cancers
53
Gefitinib/Iressa
Small molecule inhibitor
- Inhibits EGFR tyrosine kinase leading to cell cycle arrest and inhibition of angiogenesis
- Rash, diarrhea, interstitial lung disease, corneal ulcer
- Lung mostly
54
Types of antiemetics
5-HT3 receptor antagonists (ondansetron, granisetron, palonosetron (aloxi))
NK1 receptor antagonists (aprepitant (emend))
Dopamine blockade (Reglan, Phenothiazine (compazine), haldol/zyprexa)
Benzodiazepine (anticipatory nausea)
Steroids (dexamethasone)
55
Amifostine/Ethyol
- Mechanism of action (cell cycle specificity)
- Toxicity
- Misc
- Free radical scavenger; binds to cisplatin metabolites and is used to treat platinum-associated toxicity; can also use for xerostomia associated with head and neck radiation
- Nausea/vomiting, hypotension, hypocalcemia, SJS
- May make chemoRT less effective; differential effects on normal/cancer cells due to different concentrations of activating alkaline phosphates energy
56
What chemos are prodrugs?
Capecitabine
Irinotecan
Ifosfamide
57
What chemos cause hand-foot syndrome (PPE)?
Doxil, 5-FU and capecitabine, docetaxel, vinorelbine
58
Which chemos are pulmonary toxic?
Checkpoint inhibitors cause pneumonitis
Bleomycin, alkylating agents (mitomycin-C), nitrosoureas can cause pulmonary fibrosis
Taxol can cause pneumonitis
Gemzar can cause an ARDS-like syndrome
59
What chemos are cardiotoxic?
Cardiomyopathy: anthracyclines (adriamycin, daunomycin)
Arrhythmia: anthracyclines and taxol (5-FU rare)
Cardiac myocyte necrosis: Cytoxan
Vasospastic angina: Etoposide
60
What chemos are GU toxic?
Kidney damage: cisplatin, MTX, nitrosoureas, mitomycin-C
| Hemorrhagic cystitis: Ifosfamide, cytoxan
61
What chemos can cause SIADH?
Vincas, high dose cytoxan, cisplatin
62
What chemos are highly emetogenic?
Cisplatin (>50 mg/m2), cytoxan (>1500 mg/m2), carbo (AUC >4)
**Treat with 5-HT3 and dexamethasone and NK-1
63
What chemos are moderately emetogenic?
Cisplatin (<50 mg/m2), cytoxan (750/1500 mg/m2), doxorubicin, MTX (>1000 mg/m2), Ifosfamide, high dose 5-FU
**Treat with 5-HT3 and dexamethasone
64
AMG386/Trebananib
Monoclonal antibody
-Binds to soluble antiopoietin 1/2 and prevents interaction with receptor Tie2
**Acts through a non-VEGF dependent angiogenesis pathway
65
Dexrazoxane
Cardioprotective agent used with adriamycin; can also use to treat Adria extravasation
-chelates iron
**Possible higher rate of secondary malignancies
66
Parp Inhibitors
- Mechanism of action
- Toxicity
- Misc
Niraparib, olaparib, rucaparib
- Inhibit single stranded DNA damage repair via nucleotide excision repair —> thus cells are dependent upon homologous recombination for repair of these lesions; more highly active in BRCA patients since they have a defect in HR
- Myelosuppression, HTN, fatigue
- “Synthetic lethality; approved for trx of BRCA mutation OC and maintenance after response to a platinum based regimen
67
What are SERMs?
- Mechanism of action
- Side effects
Tamoxifen and raloxifen
- selective estrogen receptor modulators —> block the activity of E in the breast; tam is E agonist in the uterus
- blood clots, stroke, leg swelling/pain/cramping, HA, vasomotor symptoms, fatigue, cataracts; Tam can lead to endometrial polyps/hyperplasia/carcinosarcoma; patients on raloxifene complain of worse sexual dysfunction
68
Aromatase inhibitors
- Mechanism of action
- Side effects
Anastrozole, letrozole, exemestane
- block the conversion of androgens into estrogen
- AES fewer than SERMS; heart disease, more bone loss, and more fractures; most common AE is joint stiffness or pain; can also see muscle pain, vasomotor symptoms, vaginal dryness, carpal tunnel syndrome, thinning hair, mood swings
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