Therapeutics Spring Final!!!!

Front 1

Types of lung Cancer

Back 1

1) Non-Small Cell Lung Cancer (NSCLC)

2) Small Cell Lung Cancer (SCLC)

Front 2

Non-Small Cell Lung Cancer (NSCLC)

Back 2

1) slower growing
2) surgery is 1st line in early stages
3) lower sensitivity to chemo
4) better survival
5) presents in lung periphery

Front 3

Small Cell Lung Cancer (SCLC)

Back 3

1) very aggressive
2) very chemo and XRT sensitive
3) clear relationship to smoking
4) Death occurs in 2-4 months without treatment
5) presents centrally

Front 4

NSCLC histologic subtypes

Back 4

1) non-squamous: most common in non-smokers, lung periphery

2) Squamous cell carcinoma: slower growing, smoking, bleeding

Front 5

Risk Factors for Lung Cancer

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1) Smoking
2) asbestos (synergistic with smoking)
3) Radon (2nd leading cause)
4) Occupational carcinogens
5) Diet
6) Co-existing lung disease
7) genetic/familial factors

Front 6

EGFR Mutations

Back 6

1) common in Asians and Caucasians
2) patients with this mutation should receive EGFR inhibitor first line
3) PREDICTIVE biomarker

Front 7

KRAS mutations

Back 7

1) associated with cigarette smoking
2) associated with shorter survival, poor prognosis
3) lack of benefit from platinum or vinorelbine chemo
4) prognostic and predictive biomarker

Front 8

EML4-ALK Mutation

Back 8

1) seen in younger men, non-smokers
2) drives cancer cell growth and proliferation
3) patients with this mutation should receive crizotinib as first line
4) Predictive biomarker

Front 9

Clinical Presentation of Lung Cancer

Back 9

1) Persistent cough
2) Dyspnea
3) Chest Pain/discomfort
4) Hemoptysis
5) Hoarseness
6) Generalized weakness
7) Weight Loss
8) clubbing

Front 10

Clinical Presentation of SCLC --Regional Metastases

Back 10

1) evident tumor at diagnosis
2) distal atelctasis (collapse lung) or post obstructive pneumonia
3) pleural or pericardial effusions
4) hoarseness/dysphasia

Front 11

Clinical Presentation of SCLC -- Distant Metastases

Back 11

1) tendency for early metastases
2) CNS preferential site (headache, double vision)

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Paraneoplastic Syndromes in lung cancer

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**clinical S/Sx that develop at other sites in the body not associated with tumor; more common in SCLC**

1) SIADH: (SCLC) - euvolemic, hypo-osmolar hyponatremia w/ normal kidney & adrenal function
Treatment: free water restriction & demeclocycline

2) Hypercalcemia: (NSCLC) - due to parathyroid hormone like substance
Treatment: fluids, IV bisphos

Front 13

NSCLC Staging

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TNM

T: tumor size
N: nodal involvement
M: metastasis

Front 14

SCLC Staging

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Limited Disease (confined to 1 hemithorax and regional lymph nodes; curative intent)

Extensive Disease (extends beyond, rarely curable)

Front 15

Prognosis of Lung Cancer

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1) Stage
2) Performance status
3) Gender (females more favorable)
4) Age (<60)
5) CNS involvement
6) Weight loss

Front 16

Goals of Treatment of NSCLC

Back 16

Early Stage Disease: cure, using chemo and radiation

Advanced Stage Disease: Palliative

Front 17

Treatment of Stage I NSCLC

Back 17

Surgical resection - TREATMENT OF CHOICE

Front 18

Treatment of Stage II & III (locally advanced)

Back 18

Treatment dependent on ability to resect tumor and surgical margins

may use neoadjuvant/adjuvant chemo and/or radiation

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Chemo option for NSCLC Stage IA and IB

Back 19

not recommended

Front 20

Chemo option for NSCLC Stage II and IIIA

Back 20

adjuvant cisplatin-based chemo

Cisplatin & Vinorelbine

Carboplatin/Paclitaxel (intolerant to cisplatin)

Front 21

Drugs that can be used with Cisplatin/Carboplatin in NSCLC

Back 21

1) Etoposide
2) Vinblastine
3) Docetaxel
4) Gemcitabine
5) Irinotecan
6) Pemetrexed

Front 22

Chemo Options for NSCLC Stage IIIB (unresectable)

Back 22

Platinum based chemo + radiation

1) Cisplatin + Etoposide
2) Cisplatin + Vinblastine

Front 23

Treatment of Advanced Stage Disease (Stage IV NSCLC)

Back 23

*not curable - prolong survival*
*not resectable if disseminated

Platinum based doublet regimen

Front 24

Drugs that can be used with Cisplatin/Carboplatin in Advanced Stage NSCLC

Back 24

1) Etoposide
2) Vinorelbine
3) Paclitaxel/Docetaxel
4) Gemcitabine
5) Irinotecan
6) Vinblastine

Front 25

Monoclonal Antibodies used in Advanced Stage NSCLC

Back 25

1) Bevacizumab - added to normal regimens

2) Cetuximab - added to cisplatin + vinorelbine

Front 26

Oral Targeted Therapy - EGFR mutations

Back 26

1) erlotinib
2) Afatinib

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Oral Targeted Therapy - ALK rearrangements

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crizotinib

Front 28

Treatment of Limited Disease SCLC

Back 28

Goal: cure using chemo and thoracic radiation

EP: etoposide + cisplatin
EC: etoposide + carboplatin

Front 29

Treatment of Extensive Disease SCLC

Back 29

EP: etoposide + cisplatin

EC: etopside + carboplatin

CI: cisplatin + irinotecan

Front 30

Cisplatin ADRs and dosing

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1) nephrotoxicity
2) Electrolyte wasting
3) Delayed N/V
4) ototoxicity

Dose: based on BSA

Front 31

Carboplatin ADRs and dosing

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1) thrombocytopenia
2) neutropenia
3) N/V

Dose: calvert equation D=(CrCl + 25) x target AUC

Front 32

Second line agents for recurrent disease of SCLC

Back 32

1) ifosfamide
2) paclitaxel/docetaxel
3) gemcitabine
4) topotecan/irinotecan
5) vinorelbine
6) CAV (cyclophosphamide, doxorubicin, vincristine)
7) enroll in clinical trial (PREFERRED)

Front 33

Relapse with SCLC <2-3 months

Back 33

1) ifosfamide
2) paclitaxel/docetaxel
3) topotecan
4) irinotecan
5) gemcitabine

Front 34

Relapse with SCLC >2-3 months

Back 34

1) Topotecan
2) Irinotecan
3) CAV (cyclophosphamide, doxorubicin, vincristine)
4) Gemcitabine
5) Paclitaxel/Docetaxel
6) oral Etopaside
7) Vinorelbine

Front 35

Relapse with SCLC > 6 months

Back 35

may repeat original regimen

Front 36

Pemetrexed (Alimta)

Back 36

MOA: antifolate antimetabolite that inhibits thymidylate synthase & dihydrofolate reductase

USE: non-squamous cell histology (NSCLC)
*locally advanced or metastatin non-squamous NSCLC*

ADRs: rash, neutropenia, stomatitis, N/V

Front 37

Pretreatment with Pemetrexed

Back 37

1) Folic Acid 400-1000mcg given 1-3 weeks prior and 1-3 weeks after

2) Vitamin B12 1000mcg IM given 1-3 weeks prior and given every 9 weeks

3) Dexamethasone 4mg PO day before, day of, and day after to prevent rash

Front 38

Bevacizumab (Avastin)

Back 38

MOA: targets VEGF

USE: in combo with platinum based doublet as 1st line therapy for advanced non-squamous cell NSCLC

ADRs: HTN, proteinuria, hemorrhage, decreased wound healing, VTE

Front 39

Cetuximab (Erbitux)

Back 39

MOA: targets EGFR

USE: with any histologic type of NSCLC but NOT FDA approved

ADRs: infusion related reactions, acneiform rash, malaise, diarrhea, N/V

Front 40

Erlotinib (Tarceva)

Back 40

MOA: EGFR inhibitor for patients with EGFR mutation

USE: first line therapy for Stage IV non-squamous NSCLC with a known EGFR mutation

ADRs: rash, diarrhea, N/V, fatigue, pruritis, conjunctivitis, infection, dry skin

**Take on EMPTY stomach**

Front 41

Drug interactions and should be avoided with Erlotinib

Back 41

Avoid H2 blockers and PPIs

Front 42

Crizotinib (Xalkori)

Back 42

MOA: selectively inhibits ALK which reduces proliferation of cells expressing this genetic alteration

USE: first line therapy in locally advanced or metastatic NSCLC that is ALK positive

ADRs: edema, diarrhea, nausea, vision disorders, QT prolongation

**take with or without food**

Front 43

Afatinib (Gilotrif)

Back 43

MOA: potent and irreversible tyrosine kinase inhibitor of EGFR, HER2, and HER4

USE: second line therapy for patients with EGFR mutation and progressed past 1st line

ADRs: diarrhea, acneiform rash, stomatitis, dry skin, decreased appetite

**take on EMPTY stomach**

Front 44

Leukemias

Back 44

hematologic malignancies characterized by an uncontrolled increase and accumulation of immature abnormal blood forming cells

Acute or Chronic

Front 45

Pathogenesis of Leukemias

Back 45

Myeloid stem cell OR lymphoid stem cell

monoclonal

Front 46

Acute Myeloid Leukemia

Back 46

Median age of diagnosis: 66 years (disease of elderly)
Males > Females

Causes:
1) Chemical exposure (benzene, pesticides)
2) Environmental Exposure (hair dyes, smoking)
3) Prior chemo (alkylating agents, Topo II inhibitors)
4) Prior radiation
5) Genetic disorders

Front 47

Clinical Presentation of AML

Back 47

**Non-specific signs/symptoms***

1) Anemia (fatigue, weakness)
2) Neutropenia (infection)
3) Thrombocytopenia (bleeding/bruising)
4) Leukemic infiltration (cutaneous/gingival infiltration of leukemic cells)
5) Leukostasis

Front 48

Diagnosis of AML

Back 48

presence of >/= 20% abnormal blasts in bone marrow

Front 49

Prognostic Factors (Better)

Back 49

1) younger age
2) not MDS or chemo induced
3) better risk of cytogenetic abnormalities

Front 50

Induction Therapy for AML

Back 50

1st cycle to eradicate all signs of leukemia

destroys all bone marrow (pancytopenia)

Front 51

Consolidation Therapy for AML

Back 51

further chemo after complete remission

eradicates any remaining leukemia and prevent relapse

Front 52

Induction therapy used in AML

Back 52

7+3 treatment

Cytarabine + Anthracycline

Day 14 bone marrow biopsy

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Consolidation Therapy used in AML

Back 53

High Dose Cytarabine

Allogeneic hematopoietic stem cell transplant

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Refractory AML

Back 54

failed induction chemo (didn't achieve CR)

Front 55

Relapse AML

Back 55

achieve CR after induction, sometime later

disease comes back

Front 56

Acute Promyelocytic Leukemia (APL)

Back 56

characterized by t(15,17) chromosomal translocation

fusion protein (PML-RAR alpha) - prevents maturation of promyelocytes in normal neutrophils

known to have fatal coagulopathy (DIC)

Front 57

DIC (fatal coagulopathy) in APL

Back 57

Increasing clotting & increase bleeding

Need to treat APL to resolve

Front 58

Induction treatment of APL
HIGH Risk (WBC >10,000)

Tolerates Anthracyclines

Back 58

ATRA (all trans-retinoic acid)
+
(7+3) daunorubicin + cytarabine

Front 59

Induction treatment of APL
HIGH Risk (WBC >10,000)

Doesn't tolerate anthracyclines

Back 59

ATRA (all trans-retinoic acid)
+
ATO (Arsenic Trioxide)

Front 60

Induction Treatment APL
LOW/INTERMEDIATE risk (WBC <10,000)

Tolerates Anthracyclines

Back 60

ATRA (all trans-retinoic acid)
+
Anthracyclines

Front 61

Consolidation Treatment for APL
HIGH Risk (WBC >10,000)

Back 61

ATRA (all trans-retinoic acid)
+
7+3 (daunorubicin + cytarabine)

Front 62

Consolidation Treatment for APL
LOW/INTERMEDIATE risk (WBC <10,000)

Back 62

ATRA (all trans-retinoic acid)
+
ATO (Arsenic Trioxide)

Front 63

All Trans-Retinoic Acid (ATRA) for APL

Back 63

MOA: overwhelms PML-RAR alpha fusion protein to accelerate differentiation of malignant promyelocytes to mature neutrophils

ADRs: leukostasis, APL differentiation syndrome

Front 64

APL Differentiation Syndrome

Back 64

Fever, Hypoxia, Weight Gain, rapidly rising WBC, pleural effusions

Treatment: Dexamethasone 10mg q12h x 3-5 days

Front 65

Arsenic Trioxide (ATO)

Back 65

MOA: induces apoptosis of abnormal cells and causes partial differentiation of abnormal cells to normal neutrophils

ADRs: fluid retention, APL differentiation syndrome, EKG abnormalities

Rx: verify Mg >2, K>4, normal EKG

Front 66

Acute Lymphoid Leukemia (ALL)

Back 66

Proliferation and expansion of immature lymphoid cells in the bone marrow, blood, and other organs

Effects B, T, and NK cells

Bimodal: children ~5yrs, late adulthood ~50yrs

Front 67

Causes of ALL

Back 67

**Exact is unknown**

Chemical Exposure
Genetic predisposition (Trisomy 21, Fanconi's anemia)
Infections (Epstein Barr, HIV)

Front 68

Clinical Presentation of ALL

Back 68

**Non-specific Symptoms**

1) Anemia - fatigue
2) Neutropenia - increased infection
3) Thrombocytopenia - increased bleeding/bruising
4) CNS manifestations
5) B Symptoms
6) Joint and bone pain

Front 69

Prognostic Factors (better prognosis)

Back 69

1) T-cell
2) BC < 30,000
3) < 30 years
4) Female
5) Achieve CR after 1 cycle
6) Normal cytogenetics