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Pulmonary > Drugs for Lung Cancer > Flashcards

Drugs for Lung Cancer Flashcards

1
Q

Name the drugs used in NSCLC

A
  1. Cisplatin
  2. Docetaxel
  3. Gemcitabine
  4. Paclitaxel
  5. Pemetrexed
  6. Vinorelbine
  7. Irinotecan
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2
Q

Name the drugs used in SCLC

A
  1. Doxorubicin
  2. Etoposide, VP-16
  3. Methotrexate
  4. Topotecan
  5. Cisplatin
  6. Carboplatin
  7. Ifosfamide
  8. Irinotecan
  9. Cyclophosphamide
  10. Vincristine
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3
Q

Name the drugs used in Adenocarcinoma

A
  1. Afatinib
  2. Bevacizumab (approved only for use in non-squamous NSCLCs)
  3. Crizotinib
  4. Erlotinib
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4
Q

Distinguish driver vs. passenger mutations?

A

Driver: mutations that are critical for cell growth or survival

  • inactivation will result in cell death or differentiation into a normal phenotype

Passenger: mutations that are not critical for cell growth or survival

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5
Q
A
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6
Q

Discuss TK receptors activation in normal cells

A
  • ligand binding to receptor results in dimerization and tyrosine residue trans-phosphorylation
  • transduction to nucleus
  • effects on nuclear transcriptoin can lead to cell growth, prolifeartion, and avoidance of apoptoic events
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7
Q

Discuss TK receptors activation in cancer cells

A
  • RTKs activation via gene amplification, and nucleotide changes such as mutations lead to structural alterations in encoded proteins.
  • Chromosome rearrangement leads to malignancy via the transcriptional activation of proto-oncogenes OR the creation of fusion genes
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8
Q

What are the mechanisms for TKI resistane?

A
  • Mutation in ATP binding site for TKIs
  • Polymorphisms in apoptosis gene (e.g. BIM)
    • abscence of pro-apoptotic BH3 domain in 15% of East Asian population
    • predictive of significantly shorter progression-free surival when compared to patients wtihotu BIM
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9
Q

What can lead to independent proliferative signals continuing, with or without TKI

A

KRAS or BRAF mutations

  • KRAS mutations can render anti-EGFR drugs (Mabs or TKIs) ineffective becuase the proliferative pathway remains constitutively active DOWNSTREAM of the drug-induced blockade
  • Most mutations occur at codons 12 and 13
  • GENERALLY a negative response predictor to targeted therapy of **lung cancer and colorectal cancer **
    • many downstream target proteins; some mutations in NSCLC correlate with inhibtion of cell cycel activation/progression
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10
Q

EML4-ALK Translocation

A

EML4 (echinoderm microtuble-associated protein-like 4) and ALK (anaplastic lymphoma kinase) fusion produces an oncogene that occurs in lung cancers that leads to activation of the MEK/ERK pathway and **cell proliferation. **

  • family of abnormal (pro-malignant) fusion genes
  • detectable in 2-7% of all NSCLC
  • more prevalent in nonsmokers, in patients with a history of light smoking, and in patients with adenocarcinoma
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11
Q

VEGF

A

Proliferating solid tumors maintain blood supply by cells sensing oxygenation via hypoxia inducible factor (HIF-1) and the release of VEGF

Blocking formation of new blood vessels is an attractive target with some downsides

  • reduce the distribution of concurrent chemo
  • induce accumulation of more aggressive cells that have an increased capacity to spread to other organs
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12
Q

Describe inter-patient variation in drug PKs with orally administered targeted agents

A

Orally administered kinase inhibitors (e.g. EGFR and ALK TKIs) must be absorbed in stomach and SI before entering circulatory system. Metabolism of drugs may be influened by several host factors including bioavailability.

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13
Q

Do only smokers get lung cancer?

A

NO! Certain mutations are more common in smokers whereas others are more common in never-smokers

  • EGFR mutations are more common in never-smokers
  • KRAS mutations are more common in smokers
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14
Q

Discuss Genetic Testing

A

National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) recommend routine testing for EGFR mutations and ALK rearrangements in all adenocarcioms.

  • due to very low diagnostic yield of testing pure squamous cell tumors, this is not recommended
  • DNA sequencing is method used in most EGFR studies
  • FISH is a preferrsed choice for ALK gene rearrangement testing
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15
Q

Describe the general treatment plan for SCLC and NSCLC

A
  • SCLC: metastasis occurs early so chemotherapy/radiation is the only option
  • NSCLC: surgical resection if there has been no metastasis (early stage disease)
  • Metastasize very early, spreading most commonly to the adrenals, liver, brain and bone
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16
Q

What is the most common reigmen for SCLC?

A

Etoposide + Cisplatin or Carboplatin

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17
Q

What is the coventional treatmetn of NSCLC?

A

Revolves around CISPLATIN and one of a number of drugs, commonly a taxane, and maintenace treatment often involves a DHFR inhibitor that is a MTX analog (Pemtrexed)

  • **CISPLATIN AND paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan or pemetrexed **
  • Based upon appropriate genetic markers, TKIs and VEGF inhibitors may also be appropriate.
  • Bevacizumab can be used for patients with non-squamous histology, no brain mets, or no hemoptysis.
18
Q

Carboplatin

A

MOA: forms DNA intrastrand crosslinks and adducts

Adverse Effects

  • Allergic (platinum) reactions.
  • Dose related myelosuppresion
  • Cumulative anemia
  • Dose related N/V
  • Blood chemisry dyscrias, increased hepatic enzymes, BUN & Cr
19
Q

Cisplatin

A

MOA: platinum complexes bind and crosslink DNA → apoptosis

Adverse Effects

  • Allergic (platinum) rxns
  • Dose-related severe nephrotoxicity, mylosuppresion, and n/v
  • Significant ototoxicity (tinnitus and occasionaly deafness) reported in children
20
Q

Cyclophosphamide

A

MOA: covalently cross-links DNA strands at guanine N-7 → cell death; pro-drug that is activated in liver.

Adverse Effects

  • Blood dyscrias –> anemia/infection
  • Renal compromise, hemorrhagic cystitis (mesna is protective), n/v, rashes
  • Amenorrhea/infertility
  • Monitor for secondary malignancies
  • Pulmonary fibrosis
21
Q

Docetaxel

A

MOA: bind to B-tubulin and enhance assembly of tubulin dimers into microtubule polymers, which stabilizes existing microtubules and inhibits disassembly. The inability to depolymerize results in mitotic arrest.

Adverse Effects

  • increased mortality in NSCLC
  • edema (give steroids)
  • contraindicated with increased bilirubin/ALK phos/SGOT/SGPT
  • dose-limiting neutropenia
  • sensory neuropathy
22
Q

Doxorubicin

A

MOA: intercalation between DNA base pairs leads to ↓ DNA/RNA synthesis. Also inhibits DNAtopoisomerase II. Also chelates iron, producing free radicals that cleave DNA.

Adverse Effects:

  • mylosuppression
  • CHF
  • hepatic disease
  • secondary malignancies
  • extravasational necrosis
  • n/v
23
Q

Etoposide, VP-16

A

MOA: inhibition of topoisomerase II → induces DNA breakage. Causes cell death during the late S phase and G2 phase. Activated by dephosphorylation

Adverse Effects

  • Myelosuppresion, infection
  • Dose-limiting hematologic toxicity
  • N/V
  • diarrhea
  • Alopecia
24
Q

Gemcitabine

A

MOA: DNA polymerase inhibitor via incorporation of triphosphate form during DNA synthesis.

Adverse Effects: myelosuppresion, infection, arthralgia, drwosiness, fatigue, N/V, alopecia, sensory peripheral neuropathy (<10%)

25
Q

Ifosfamide

A

MOA: covalently cross-links DNA strands at guanine N-7 → cell death; pro-drug that is activated in liver

Adverse Effects

  • Alopecia, N/V
  • Blood dyscrasia –> infection, neurotoxicity, hematuria, renal failure (<10%)
26
Q

Irinotecan

A

MOA: DNA-topo I complex stabalizer

Adverse Effects: myelosuppresion, diarrhea; asthenia, fever, pain, weight loss

27
Q

Paclitaxel

A

MOA: bind to B-tubulin and enhance assembly of tubulin dimers into microtubule polymers, which stabilizes existing microtubules and inhibits disassembly. The inability to depolymerize results in mitotic arrest.

Adverse Effects: taxane hypersensitivity; myelosuppresion; myalgia adn arthralgia

28
Q

Pemetrexed

A

MOA: DHFR inhibitor

Adverse Effects

  • myelosuppresion and GI toxicities, especially when combined with cisplatin vs. NSCLC
  • elevated LFTs and serum creatinine
29
Q

Topotecan

A

MOA: DNA-topo I complex stabalizer

Adverse Effects: myelosuppresion and GI toxicities, hyperbilirubinemia

30
Q

Vinblastine and Vinorelbine

A

MOA: (Vinka Alkaloid) bind to B-tubulin, preventing microtubules from polymerizing, which effectively destroys them. These drugs prevent the mitotic spindle from forming by causing cell cycle arrest in metaphase.

Adverse Effects

  • Myelosuppresion
  • Neuropathic toxicity (less so with vinorelbine)
  • Neutropenia (vinorelbine)
  • Intrathecal adminstration of vinca alkaloids is fatal
31
Q

What are the two TKIs approved for use in lung cancer?

A

Erlotinib and Afatinib

32
Q

Erlotinib

A

MOA: reversible inhibitor SELECTIVE for EGFR (ErbB1)

Administration: oral on an empty stomach

  • food increases variability in drug bioavailability
  • erlotinib is a CYP substrate (3A4 > 1A2)
  • smoking increases clearence

Adverse Effects

  • diarrhea common in <50% of patients
  • interstital lung disease-type events, esp in patietns who recieved earlier chemo
  • liver and/or kidney problems (secondary to hepatic dysfunction)
  • stomach or intestinal perforation: bleeding events (inrease INR; additive with anticoagulants)
  • corneal performation/ulceration (conjunctivitis; hypertrichosis)
  • rash
33
Q

What two significant observations were shown in the Kaplan Meir survival curves for erlotinib vs. placebo

A
  1. drug produces a signfiicant survival effect, especially in short term
  2. effect is dependent upon the presence of molecular target, namely overexpression of EGFR by the tumor
34
Q

Afatinib

A

MOA: Covalent inhibitor of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4)

Administration: oral on an empty stomach

  • fod increases variability in drug bioavailability
  • p-gp substrate and inhibitor

Adverse Effects

  • diarrhea inevitable (100%)
  • rash almost inevitable (90%)
  • lower incidence of other adverse effects compared to erlotinib, but pattern similar
    • pulmonary toxicity rare (1%) but more prevalent (2%) with Asian ethnicity
35
Q

What is the most common and potentially severe adverse effect with EGFR TKIs?

A

RASH

36
Q

Discuss TKI Resistance

A

Due to mutations in the drug binding site, which lies in teh ATP binding site (highly conserved motif amongst TKIs). Mutations in the TK domain of EGFR can have profound effect on drug sensitivity.

  • mutations can either sensitize the cell to the effect of TKIs (deletion in exon 19 or point mutation L858R) or reduce the drug activity by preventign the correct orientation of the drug binding on the active site (T790M)
  • T790M indicates resistance may simply reflect outgrowth of resistant clones
37
Q

Crizotinib

A

MOA: reversible multi-kinase inhibitor, including ALK

Administration: oral on an empty stomach

  • food increases variability in drug bioavailability
  • CYP3A4 substrate and P-gp substrate and inhibitor

_Adverse Effects _

  • Common
    • GI toxicity (n/v, diarrhea, constipation) are common
    • edema (28%) and rarely QT prolongation (2%)
    • visual disorders common (62%)
  • Less Common: neutropenia, hepatic dysfunction, respiratory dysfunction
  • **NOTE: rash relatively uncommon (10%) compared to TKIs **
38
Q

What is the mutation in Crizotinib that results in drug resistance?

A

G2032R R0S1 has been shown to reduce drug activity; emergence of resistance most likely reflects an outgrowth of pre-existing tumor clones with inherent resistance at this site

39
Q

Bevacizumab

A

MOA: humanized antibody that binds VEGF and prevents it from binding to and activating VEGF receptors to produce a proliferative effect

Administation: **IV infusion **

Adverse Effects

  • HTN (arterial thromboembolism)
  • Alopecia
  • GI toxicity
  • Hemorrhage
  • Asthenia, dizziness, headache
  • Renal: proteinuria
  • Dyspnea and URI
  • Fistua formation
40
Q

What are the consequences of VEGF inhibition?

A

The presence of the drug target in the tumor does not imply its abscence in normal tissue.

  • inhibition blocks endothelial cell regeneration leading to underlying matrix exposure and thrombosis/hemorrhage
  • inhibition promotes non-physiologic apoptosis of endothelial cells and decreases deposition of teh sub-endothelial matrix, making asculature more susceptible to bleeding

LIFE THREATENING SEVERE BLEEDING IS POSSIBLE

Gastric perforation and impaired wound healing may also contribute to hemorrhage in some cases.

41
Q

Explain contraindication for bevacizumab treatment and why

A

Risk of high-grade bleeding relatively higher in patients with NSCLC, RCC, and colorectal cancer.

  • For NSCLC, risk associated wtih squamous histology, tumor location close to major blood vessels, and tumor necrosis or cavitation (baseline cavitation was the main risk factor of high-grade bleeding for patients with NSCLC)
  • Drug is believed to cause central necrosis and enlarge the tumor cavity in these patients. This, in combination wtih the immature blood vessels wtihin the cavity increases risk of bleeding

Pulmonary (10 decks)

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