Sweatman - Lung Cancer Rx Flashcards
(57 cards)
1
Q
Why is the division between NSCLC and SCLC no longer used?
A
- Histologic subtype of NSCLC now has to be reported due to advent of targeted therapy
- EGFR mutations are extremely rare in large cell, small cell, and pure squamous carcinomas
1. Evident in significant # of adenocarcinomas - Bevacizumab associated w/high risk of bleeding in squamous lung cancers -> only approved for use in non-squamous NSCLC
2
Q
About what % of NSCLC are squamous vs. adenocarcinoma?
A
- 50% adenocarcinoma
- 30% squamous
3
Q
How does the EGF receptor work? How does it “malfunction?”
A
-
Normal cell (A): ligand-induced receptor activation leads to receptor dimerization and trans-phosphorylation of 2 tyrosine residues
1. Transduced to nucleus via signalling, and nuclear transcription can lead to cell growth, proliferation, and avoidance of apoptosis -
Cancer cells (B): proliferative pathway gains func via 1) receptor amplification, 2) mutation, or 3) trans-location
1. Chromosome rearrangement can lead to: the transcriptional activation of proto-oncogenes or creation of fusion genes encoding chimeric proteins w/transforming properties
4
Q
How do TKI’s INH EGFR? What are the 4 NSCLC resistance mechs?
A
- TKI INH the phosphorylation step, and absence of proliferative signal leads to apoptosis -> this should lead to a clinical anti-tumor response
- Resistance mechs (see attached image):
C. Drug binding site (T790M) mutation
D. Amplified MET (hepatocyte growth factor receptor, HGFR) phosphorylates ERBB3 (circumventing drug presence)
E. HGF activates P13K/Akt via MET, independent of ERBB3 and EGFR
5
Q
What is an anti-apoptotic IC mech of resistance to TKI’s?
A
- Polymorphisms in apoptosis genes: downstream of EGFR
1. Example: BIM polymorphism -> absence of pro-apoptotic BH3 domain in 15% of East Asians (predictive of significantly shorter survival than patients with “normal” BIM)
6
Q
What is a pro-proliferative IC mech of resistance to TKI’s?
A
- KRAS and BRAF muts can render anti-EGFR drugs (Mab’s or TKI’s) ineffective due to proliferative path constitutively active DOWNSTREAM of drug-induced blockade
- Genotyping for mutation can be a deciding factor NOT to treat with Mab, e.g., Cetuximab
7
Q
What is the EML4-ALK translocation?
A
- Family of abnormal (pro-malignant) fusion genes
1. Echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) genes
2. Activates the MEK/ERK pathway and cell proliferation (drug for it now) - 2-7% of NSCLC -> more prevalent in non-smokers, pts w/hx of light smoking, & pts w/adenocarcinomas
8
Q
Why can blocking VEGF be helpful? Problematic?
A
- Proliferating tumors need blood supply, which is maintained by cells sensing oxygenation via HIF-1, and the release of VEGF
-
Potential downsides:
1. Reduce distribution of concurrent chemo
2. Induce proliferation of more aggressive cells (green in image) that have capacity to spread to other organs
9
Q
Why is human variation so critical when it comes to anti-cancer drugs, like TKI’s?
A
- Metabolism may be influenced by several host factors, including bioavailability and host pharmaco-genetics
- Variation in the germline constitution of individual patients can have significant impact on response to tx and degree of toxicity
- By inhibiting their target kinases, these agents extinguish crucial downstream signalling pathways involved in normal cell growth
- Host tissues can also influence efficacy of kinase inhibitors by secreting factors, e.g., HGF, in a paracrine fashion
10
Q
Which mutations are more common in non-smokers?
A
- EGFR (45%)
- EML4-ALK
- HER2
- hMSH2 (40%)
- Not only smokers get lung cancer
11
Q
Why is genetic testing of adenocarcinomas so important?
A
- Actionable mutation in 60% of patients
- Data used to either:
1. Treat according to guidelines based on EGFR results (KRAS and ALK too)
2. Offer enrollment in clinical trials targeting other ID’d mutations (BRAF, MET)
12
Q
What are the existing genetic testing guidelines?
A
- Routine testing recommended for EGFR muts and ALK rearrangements in ALL ADENOCARCINOMAS
1. Not recommended in pure squamous cell tumors due to very low diagnostic yield - DNA sequencing is the method used in most EGFR studies -> discordance of up to 28% b/t 1o tumors and distant metastases
- Fluorescence in situ hybridization (FISH) preferred and FDA-approved choice for ALK gene rearrangement testin
13
Q
What is the current recommendation for preventive scans for smokers?
A
-
Smokers (55-80 y/o) with >30-pack history and those who have quit in the last 15 years should get low-dose CT scans of lungs to look for possible tumors
1. 2 previous reviews found insufficient evidence to support annual screenings - Small risk of radiation exposure from low-dose scans outweighed by benefits of detecting abnormal growths early and intervening w/tx
14
Q
What are the standard tx plans for SCLC and NSCLC?
A
- SCLC: metastasis early, so radiation/chemo the only option
-
NSCLC: sx resection if no metastasis (early stage)
1. Chemo/radiation used in adjuvant, neo-adjuvant or maintenance role to:
a) reduce bulk of the tumor (facilitating sx) and eradicate early micrometastases OR
b) prevent growth or metastasis
2. Pre-op chemo may delay potentially curative sx -> metastasize very early, most commonly spreading to adrenals, liver, brain, and bone
15
Q
What are the standard tx options for SCLC?
A
- Etoposide + Cisplatin or Carboplatin
OR
- Cisplatin + Irinotecan
- Cisplatin + Etoposide + Ifosfamide
- Cyclophosphamide + Doxorubicin + Etoposide
- ”” + Vincristine
- Cyclo + Doxo + Vincristine
- Cyclo + Etoposide + Vincristine
16
Q
What are the standard tx options for NSCLC?
A
- Cisplatin AND Paclitaxel, Gemcitabine, Docetaxel, Vinorelbine, Irinotecan, or Pemetrexed (commonly a taxane)
- Pemetrexed maintenance: for pts w/stable or responding disease after 4 cycles of nonpemetrexed-platinum combo therapy)
- Based on appropriate genetic markers, TKI’s and VEGF inhibitors may also be used:
1. EGFR TKI’s for pts w/EGFR+ genetic test
2. Bevacizumab (pts w/non-squamous histo, no brain metastases, and no hemoptysis)
3. Erlotinib: first-line tx for locally advanced or metastatic NSCLC after failure of at least 1 prior chemo regimen, or for maintenance tx of “” that has not progressed after 4 cycles of platinum-based first-line chemo
17
Q
What is the MOA for Cisplatin and Carboplatin?
A
Form DNA intrastrand crosslinks and adducts
18
Q
What is the MOA for Cyclophosphamide?
A
Pro-drug of active alkylating moiety
19
Q
What is the MOA for Docetaxel?
A
Microtubule stabilizer inhibiting depolymerization
20
Q
What is the MOA for Doxorubicin?
A
Intercalator, free radical generator, topo II INH
21
Q
What is the MOA for Etoposide/VP-16?
A
DNA-topo II complex stabilizer
22
Q
What is the MOA for Gemcitabine?
A
DNA polymerase inhibitor via incorporation of triphosphate form during DNA synthesis
23
Q
What is the MOA for Ifosfamide?
A
Intra- and interstrand crosslinker
24
Q
What is the MOA for Irinotecan?
A
DNA-topo I complex stabilizer
25
What is the MOA for Paclitaxel?
Microtubule stabilizer inhibiting depolymerization
26
What is the MOA for Pemetrexed?
DHFR inhibitor
27
What is the MOA for Topotecan?
DNA-topo I complex stabilizer
28
What is the MOA for Vincristine/Vinorelbine?
Microtubule inhibitor; tubules disintegrate into spiral aggregates/protofilaments
29
What is a big clinical issue, and often the dose-limiting toxicity for most of the anti-cancer drugs?
Myelosuppression
30
What are the Carboplatin AE's?
- Allergic (platinum) reactions
- Dose-related myelosuppression; cumulative anemia
- Dose-related N/V
- Blood chemistry dyscrasia, _INC hepatic enzymes_, BUN, and creatinine
31
What are the Cisplatin AE's?
- Allergic (platinum) reactions
- Dose-related, severe **nephrotoxicity**, myelosuppression and N/V
- Significant **ototoxicity** (tinnitus and occasionally deafness) reported in children
32
What are the Cyclophosphamide AE's?
- Blood dyscrasias -\> anemia, infection
- Renal compromise, **hemorrhagic cystitis** (Mesna is protective), N/V, rashes
- _Amenorrhea, infertility_
- Monitor for 2o malignancies
- **Pulmonary fibrosis**
33
What are the Docetaxel AE's?
- **INC mortality in NSCLC**
- _Edema_ (give steroids)
- Contraindicated with INC bilirubin/ALK/phos, AST/ALT
- Dose-limiting neutropenia
- **Sensory neuropathy**
34
What are the Doxorubicin AE's?
- Myelosuppression, **CHF** (cumulative dose exposure manner: 450 mg/sq m max cumulative dose), hepatic disease
- 2o malignancies
- Extravasational necrosis
- N/V
35
What are the Etoposide/VP-16 AE's?
- Myelosuppresion, infection
- **Dose-limiting hematologic toxicity**
- N/V, diarrhea
- _Alopecia_
36
What are the Gemcitabine AE's?
- Myelosuppression, infection
- _Arthralgia_, drowsiness, fatigue
- N/V
- _Alopecia_
- **Sensory peripheral neuropathy (10%)**
37
What are the Ifosfamide AE's?
- Alopecia
- N/V
- Blood dyscrasia -\> infection
- _Neurotoxicity_
- **Hematuria renal failure (\<10%)**
38
What are the Irinotecan AE's?
- Myelosuppression
- Diarrhea
- Asthenia
- Fever, pain
- Weight loss
39
What are the Paclitaxel AE's?
- Taxane hypersensitivity
- Myelosuppression
- **Myalgia/arthralgias**
40
What are the Pemetrexed AE's?
- Myelosuppression and GI toxicities, esp. when combined with Cisplatin vs. NSCLC
- Elevated LFT's and serum creatinine
41
What are the Topotecan AE's?
- Myelosuppression and GI toxicities
- _Hyperbilirubinemia_
42
What are the Vinblastine/Vinorelbine AE's?
- Myelosuppression
- **Neuropathic toxicity** (less so w/Vinorelbine)
- Neutropenia (Vinorelbine)
- **Intrathecal admin of Vinca alkaloids is fatal**
43
What are the TKI's approved for treating NSCLC?
- **ALK**
1. Crizotinib: + HGFR
2. Ceritinib: ALK intolerant to Crizotinib
- **EGFR**
1. Afatinib
2. Erlotinib
3. Gefitinib
44
What are some of the pitfalls associated with the oral route of administration of the TKI's?
- _Food_ may impact bioavailability: reflected in dosing instructions
- Extensive hepatic metabolism (_except Afatinib_), and predominantly fecal elimination
- Substrates for CYP3A4/5 and P-gp (_except Crizotinib_)
1. Other isoforms vary by drug
- Inhibitors of CYP3A, and to varying degrees, other isoforms
- **Drug-drug interactions are possible**
45
What are some of the (un)common TKI side effects?
- **Common**:
1. _EGFR_: diarrhea, N/V, dermatologic, elevated hepatic enzymes, opthalmic (except Afatinib)
1. _ALK_: constipation, diarrhea, N/V
- **Uncommon**:
1. _Gefitinib_ - renal
2. _Ceritinib_ - fatigue, DEC hemoglobin, hyperglycemia (but no opthalmic, unlike Crizotinib)
46
What are the *rare* AE's with the TKI's? How should pts be counseled about these?
- Bradyarrhythmia and/or QT prolongation
- Severe rash and Steven Johnson Syndrome (SJS)
- GI hemorrhage or perforation
- Hepatotoxicity and hepatic failure
- Interstitial lung disease, pneumonia, PE
- Corneal ulceration, perforation, keratitis
- _Counseling_:
1. Avoid pregnancy -\> use appropriate contraception
2. Immediately report new CV or pulm sxs
3. Immediatley report bullous, blistering, or exfolative dermatologic symptoms
47
What do you see here?
- EGFR-induced rash: common and potentially severe AE
- May necessitate specific txs with steroids, antimicrobials, and oatmeal lotions
-
48
What should you do if your lung cancer pt on TKI's presents with a rash?
49
What 2 things do these graphs tell you?
- Erlotinib produces a significant survival effect, especially in the short-term
- This effect is dependent on the molecular target, in this case, EGFR overexpression by the tumor
50
How is TKI resistance related to ATP affinity?
- Muts in TK domain of EGFR can have profound effect on drug sensitivity (**ATP binding site** highly conserved among TKI's)
1. About 10-25% of NSCLS from E. Asia have somatic _activating muts_ -\> in-frame deletions in **exon 19** (point mutation that substitutes Leu-858 w/arginine; **L858R**)
A. Compromises ATP affinity and INC initial sensitivity to TKI's: erlotinib/afatinib (_opens the therapeutic window_)
2. Secondary mut (**T790M**) _closes window_ -\> restores ATP affinity to wild-type levels)
A. Detection of this mut in naive pts indicates **resistance**; may reflect outgrowth of resistant clones (can be in pts who've never had TKI's)
51
What is the theoretical resistance mutation to Crizotinib?
- **G2032R ROS1**: has been shown to reduce drug activity in in vitro kinase activity assays
- Emergence of resistance most likely reflects an outgrowth of pre-existing tumor clones with inherent resistance at this site
52
What is PD-1?
- _Programmed cell death protein_: one of the co-stimulatory signals that serve to modulate the signal (signal 1) in T-cells after initial binding of an Ag-presenting cell (APC)
1. Binding of PD-1 receptors by _PDL1 or PDL2_ leads to an INH or (-) regulatory impact on signal 1
2. Primary role is to regulate inflammatory responses in tissues by effector T cells recognizing Ag in peripheral tissues
3. Activated T cells upregulate PD-1 and continue to express it in tissues -\> inflammatory signals in tissues induce expression of PD1 ligands that downregulate the activity of T cells, _limiting colateral damage_ in response to a microorganism in that tissue
53
Nivolumab
- Very recent approval -\> _metastatic disease after failure of platinum therapy_
- Toxicity profile limited (for now) -\> common AE's similar to those for TKI's
1. Pruritis/rash, hyperkalemia/hyponatremia, DEC appetite, constipation, N/V, elevated LFT's, cough, musculoskeletal pain, respiratory infection, fatigue
- _Less common AE's_: endocrine dysfunction, immune-mediated organ destruction
- _Pt counseling_: use reliable contraception, promptly report new sxs of dermatologic, hepatic, renal, or endocrine dysfunction
54
Bevacizumab
- Humanized Ab given IV; binds VEGF and prevents receptor activation
- Common **AE's** similar to those of TKI's:
1. HTN, _hand-foot_, endocrine, GI, or neuro dysfunction, _hemorrhage_, infections, proteinuria, fatigue
- **Less common effects**: _arterial thromboembolism_, CHF, DVT, cerebral artery occlusion, pulm HTN
1. Impaired wound healing
2. **Fistula formation** in tracheoesophagus/GI tract, liver, renal pelvis, F genital tract, bronchopleural tissue
55
What is the downside of Bevacizumab?
- INH blocks endo cell regeneration leading to underlying matrix exposure, and thrombosis/hemorrhage
- INH also promotes non-physiologic apoptosis of endo cells and DEC deposition of sub-endothelial matrix, making vasculature more susceptible to bleeding
- **Life-threatening, severe bleeding is possible**
- Gastric perforation and impaired wound healing may also contribute to hemorrhage in some cases
56
Can you use Bevacizumab in the tx of squamous NSCLC?
- **NO** -\> contraindicated in these patients due to increased risk of bleeding bc _located near major blood vessels_, and necrose and cavitate
- _Baseline cavitation_ was the main risk factor of high-grade bleeding for patients with NSCLC
- Drug causes central necrosis and enlarged tumor cavitation in these patients -\> this combo w/immature blood vessels in the cavity leads to **INC risk of bleeding**
57
How does clinical staging of lung cancer affect genetic testing?
