Lung Cancer

lung cancer

is the most deadly cancer in the US

23%

Only _____ of all ppl diagnosed with lung cancer will survival 5 yrs or more, but if it is caught before it spreads, the chance for 5 yr survival improves dramatically.

65%

Close to _____ of all new lung cancer dx are among ppl with NO tobacco exposure or only past tobacco exposure.

risk factors for lung cancer

-80-90% of cases caused by 1st or second hand cig smoking

-asbestos

-family hx

-asthma/COPD

rarely

Lung cancer is ________ dx when pts present with s/s.

detect earlier to reduce mortality

What is the goal with screening and prevention of lung cancer?

Annual low-dose CT scan

- Age ≥ 50 with ≥ 20 pack year smoking history

- SMOKING CESSATION (as quickly as possible)

- Only ~6-13% of eligible individuals are actually screened

Symptoms from Primary Tumor in lung cancer

• Cough

• Chest pain

• Hemoptysis

• SOB/wheezing

• Pleural effusion

• Fatigue

• Anorexia

• Weight Loss

s/s from regional/metastatic spread

• Superior vena cava syndrome (can compress the vena cava -> can affect the amount of blood that gets back to the heart)

• Hoarseness

• Horner syndrome

• Bone pain

• Hepatomegaly

2

Dx of lung cancer is ____ steps.

Visualization and pathologic assessment

What are the 2 steps of dx with lung cancer?

visulization

-chest X-ray (CXR)

-CT scan

-PET scan

biopsy

pathologic assessment for lung cancer

broncoscopy

can be done if tumor is central not peripheral

Small Cell Lung Cancer (SCLC)

• ~20% of lung cancer

• Faster growing rate

• Frequently associated with paraneoplastic syndromes

• Distinguished by small neoplastic cells

Non-Small Cell Lung Cancer (NSCLC)

• ~80% of lung cancer

• Slower growth rate than SCLC

squamous cell, adenocarcinoma, and large cell

What are the 3 main types of non-small cell lung cancer (NSCLC)?

Adenocarcinoma

• ~50% of lung cancers

• Most common histology in non-smokers

• Slower growing at early stage

• Metastasize from small tumor

• Worse prognosis than squamous

squamous cell

• ~30% of lung cancers

• Higher incidence with smoking and males

• Occur centrally

• Double approximately every 120 days

• Slower to metastasize

large cell

• Undifferentiated epithelial tumor

• Occur in the periphery of lung

• Often large, bulky tumors

• Similar metastases to adenocarcinoma

• Poor prognosis

small cell carcinoma

• ~15% of all lung tumors

• Occur in major bronchi and periphery

• Very aggressive and rapid growing

• 60-70% have extensive disease at diagnosis

• Secrete peptide hormones

• Often associated with paraneoplastic syndromes

paraneoplastic syndromes

s/s that occur away from the primary tumor and not associated with direct tumor involvement

tests beginning at stage IB in NSCLC

- PD-L1 expression

- EGFR gene mutations

- ALK rearrangements

- RET

stage IV biomarker testing

-EGFR

-ALK

-ROS1

-BRAF

-NTRJ1/2/3

-MET exon 14 skipping

-RET

-HER2

-NRG1

-PD-L1

stage 1 NSCLC

T1-2a

N0

M0

stage 2 NSCLC

T1-3

N0-2a

M0

stage 3 NSCLC

T1-4

N0-3

M0

stage 4 NSCLC

any T

any N

M1

limited disease and extensive disease

staging SCLC:

limited disease (stage 1-3)

tumor is confined to single hemothorax and can be treated by a single radiation port

extensive disease (stage 4)

any disease outside of this area

prognosis of lung cancer

• Without treatment, pts with early stage NSCLC will die within 10-11 months

• Only 18% of patients with lung cancer are alive 5 years or more after diagnosis

• Prognosis dependent on stage at diagnosis

67%

localized 5 yr survival in NSCLC

40%

regional 5 yr survival in NSCLC:

12%

distant 5 yr survival in NSCLC:

34%

localized 5 yr survival in SCLC:

20%

regional 5 yr survival in SCLC:

4%

distant 5 yr survival SCLC:

approach to lung cancer tx

1) surgery

2) radiation

3) systemic therapy (chemo/targeted therapies)

surgery (neg margins)

What is the primary tx in stage 1 NSCLC?

cure

What is the goal in stage 1 NSCLC?

favorable

The prognosis in stage 1 NSCLC is __________

cure

What is the goal in stage 2 NSCLC?

surgery with adjuvant systemic therapy (if nodal involvement) and radiation if pos margins/adjuvant targeted therapy based on tumor markers

What is the primary tx in stage 2 NSCLC?

stage 2 NSCLC

tumor up to 7cm in size; involvement in ipsilateral peribronchial or ipsilateral hilar lymph nodes (N1) and no distant metastasis

platinum doublet preferred regimen (nonsquamous)

Cisplatin + pemetrexed x 4 cycles (21 day cycles)

platinum doublet preferred regimens (squamous)

-Cisplatin + gemcitabine x 4 cycles (21 day cycle)

-Cisplatin + docetaxel x 4 cycles (21 day cycle)

carboplatin

If a pt is unable to tolerate cisplatin or has comorbidities taking platinum doublet you may substitute with __________

Cisplatin MOA

• Platinum alkylating agent

• Binds with DNA to form intrastrand crosslinks that cause changes in the conformation of the DNA and affect DNA replication

• Cell-cycle non-specific

IV; dose based on BSA; irritant/vesicant -> extravasation

What is the admin of Cisplatin?

preferred in pt with good performance status

Cisplatin place in therapy:

AEs of Cisplatin

• Boxed Warnings

- Myelosuppression

- Nausea/Vomiting

- Peripheral neuropathy

- Nephrotoxicity

• Electrolyte abnormalities (hypomagnesemia, hypokalemia)

• Ototoxicity

• Hypersensitivity

• Pre-hydrate with 1L NS prior to infusion

• Ensure urine output >100 mL/hr for 1st 24hrs

• Hold if significant changes to SCr

How do you deal with the nephrotoxicity of Cisplatin?

Carboplatin MOA

• Platinum alkylating agent

• Binds with DNA to form intrastrand crosslinks that cause changes in the conformation of the DNA and affect DNA replication

• Cell-cycle non-specific

IV; dosed based on AUC (Calvert Equation)

What is the admin of Carboplatin?

AEs of Carboplatin

• Boxed Warnings

• Administered by experienced physician

• Myelosuppression

• Vomiting (highly emetic if AUC >4)

• Hypersensitivity Reaction

• Nephrotoxicity

• Peripheral neuropathy

• Electrolyte abnormalities

(hypomagnesemia, hypokalemia)

• Structural analog of cisplatin → high cross reactivity

• Less renal toxicity, neuropathy than cisplatin → better for patients with poorer

performance status

Carboplatin place in therapy:

Pemetrexed (Alimta) MOA

• Antifolate agent that inhibits DNA synthesis

- Inhibits thymidine synthase, DHFR and glycinamide ribonucleotide formyltransferase

IV; dosed based on BSA; avoid use if CrCl < 45

Admin of Pemetrexed (Alimta):

should only be used in pts with non-squamous cell carcinoma

Pemetrexed (Alimta) place in therapy:

AEs of Pemetrexed (Alimta)

• Neutropenic Sepsis

• Skin reactions

• N/V

• Nephrotoxicity

• Avoid NSAIDS with therapy (decrease clearance of pemetrexed)

- Folic acid 1mg beginning 7 days prior to first dose and continuing 21 days after last dose

- B12 1mg (1000mcg) IM every other cycle, beginning 7 days prior to first dose

How do you prevent neutropenic sepsis with Pemetrexed (Alimta)?

prevent with dexamethasone 4mg BID x 3 days starting Day 1

How do you prevent skin reactions with Pemetrexed (Alimta)?

Gemcitabine MOA

• Antimetabolite- Pyrimidine analog

• Inhibits DNA polymerase and ribonucleotide reductase activity

• S-phase specific

IV

What is the admin of Gemcitabine?

used in pts with squamous cell carcinoma

What is Gemcitabine's place in therapy?

AEs of Gemcitabine

(very easy to tolerate usually no problems)

• Myelosuppression

• Flu-like syndrome/Fever (tx with APAP)

• Rash (tx with topical steriods)

• Increase in LFTs

• Proteinuria/hematuria

• Nausea/vomiting (low emetic potential)

• Peripheral edema

Doxetaxel MOA

• Antimicrotubule agent that bind to tubulin

- Promote microtubule assembly and interfere with microtubule

disassembly

- Disrupts mitosis

• Taxane plant derivative

-IV

-Hypersensitivity reactions

• Premedicate with steroid and antihistamine

-Avoid use with hepatic impairment (BBW)

Admin of Doxetaxel:

AEs of Doxetaxel

• Boxed Warnings:

- Neutropenia

- Fluid retention

- Hypersensitivity reaction

- Use in patients with hepatic dysfunction

• Peripheral neuropathy

• N/V/D

• Hair loss

• Nail changes

• Mouth sores

treat with dexamethasone 8mg BID x 3 days starting Day -1 to lower risk

How do you treat fluid retention BBW with Doxetaxel?

used in pts with squamous cell carcinoma

Doxetaxel place in therapy:

If PD-L1 >1%

- atezolizumab (Tecentriq) for 1 year

• Improved disease-free survival at 2 yrs (74.6% vs 61%) and 3 yrs (60% vs 48.2%)

- Pembrolizumab (Keytruda) for 1 year

if EGFR mutation

osimertinib (Tagrisso) for up to 3 years

- Improved disease-free survival at 2 years (89% vs 52%)

if ALK rearrangement

alectinib (Alecensa) for up to 2 years

if RET gene fusion

selpercatinib (Retevmo) for up to 3 years

Immunotherapy

Pembrolizumab (Keytruda); Atezolizumab (Tecentriq) ;

Duravulmab (Imfinzi), Cemiplimab-rwlc (Libatyo)

Immunotherapy MOA

• PD-1 immune checkpoint inhibitor

• Blocks PD-L1 and PD-L2 on tumor cells from binding to PD-1 receptors on T-cells

• Prevent T-cell suppression and induce antitumor response

IV and no premeds needed

Admin of immunotherapy:

limit DDIs, can be used regardless of PD-L1 status

Immunotherapy place in therapy:

AEs of Immunotherapy

• Immune-mediated toxicities→ treat with high dose corticosteroids

- Skin rash

- Colitis

- Hepatitis

- Thyroid dysfunction

• Fatigue

LFT, thyroid funct, GI s/s, and skin reactions

What do you monitor with Immunotherapy?

hold dose of immunotherapy and resume once s/s resolve

managing grade 1 immunotherapy AE:

prednisone 0.5-1 mg/kg until AE resolved then slowly taper off; hold immunotherapy

managing grade 2-3 immunotherapy AE:

steroids and consider adding infliximab (Remicade-TNF alpha inhibitor); discontinue immunotherapy

managing grade 4 immunotherapy AE:

Osimertinib (Tagrisso) MOA

• EGFR tyrosine kinase inhibitor

• Blocks cell migration, proliferation and survival

oral and 80 mg qd

Admin of Osimertinib (Tagrisso):

• NSCLC with EGFR mutation

• If discovered prior to first-line systemic therapy: use prior to platinum doublet.

• If discovered during first- line systemic therapy: use after completion of systemic therapy

Osimertinib (Tagrisso) place in therapy:

AEs of Osimertinib (Tagrisso)

• Interstitial lung disease

- Hold therapy if patient develops worsening cough, SOB, pleural effusion or pulmonary infiltrates

• QTc prolongation/cardiomyopathy

- Baseline EKG and echocardiogram prior to therapy

• Diarrhea (most common ADE)

• Skin rash

• Pulmonary embolism

• Electrolyte abnormalities

Alectinib (Alecensa) MOA

• ALK tyrosine kinase inhibitor

• Used in patients with ALK-EML4 translocation (3-5% of NSCLC pts)

oral and 600 mg BID (4 caps BID)

Admin of Alectinib (Alecensa):

AEs of Alectinib (Alecensa)

• Hepatotoxicity

• Monitor liver function every 2 weeks

• Reduced renal function

• Constipation

• Myalgia

- Monitor CPK every 2 weeks for first month

• Fatigue

• Rash

• Cough → Interstitial Lung Disease

• Bradycardia

Selpercatinib (Retevmo) MOA

• Anti-RET kinase inhibitor

• Additional VEGFR inhibition

• Used in patients that are RET-fusion positive

oral and weight based dosing

Selpercatinib (Retevmo) admin:

• NSCLC with RET-fusion positive

• Use in early stage resulted in improved event-free survival at 2 years (92% vs

61%)

Selpercatinib (Retevmo) place in therapy:

AEs of Selpercatinib (Retevmo)

-Hemorrhage

• Hold 7-14 days around major surgery

-Hepatotoxicity

-Hypersensitivity Reaction

• Fever, rash (SJS), arthralgias

-Hypertension

-Pulmonary toxicity (Pneumonitis)

-QTc prolongation

• Can increase QTc >60 msec from baseline

cure; prevent progression

Stage III NSCLC goal:

- Surgery (if operable disease)

- Neoadjuvant and/or adjuvant chemotherapy

- Chemoradiation

- Consolidation Therapy

• Unresectable disease with no progression after chemoradiation

What is the tx for stage 3 NSCLC?

stage 3 NSCLC

T1-3, N1-2 involvement or T4, N0 and no distant metastasis

- Platinum-doublet PLUS immunotherapy x 4 cycles (preferred)

- Platinum-doublet x 4 cycles

Neoadjuvant Chemotherapy for stage 3 NSCLC