Lung Flashcards
Epidemiology -4
2nd most common CA in US,
most common CA death,
worldwide smoking->80% burden male, 50% burden female,
15% 5 yr OS
K-ras mutation -3
exclusive to smokers;
overall freq in NSCLC 10-30%,
predicts resistance to EGFR TKIs
EGFR mutation -3
activate pathway -> inc cell proliferation, motility, and invasion;
overall freq in NSCLC 10-15%;
reported as (+) for mutation AND specific mutation
Are K-ras and EGFR mutations mutally exclusive? -1
yes
EML4-ALK -2
fusion oncogene,
independent driver of CA cell proliferation in 4-8% NSCLC
EML4-ALK clinical features
adenocarcinoma (97%), no/light smoking hx, younger age (median 52 yrs)
Risk factors - smoking
90% of deaths due to smoking (primary and passive),
2-10% occur in never smokers (women >men),
risk dec after cessation -> 80-90% dec after 15yr,
women higher risk than men at same exposure
risk factors - other than smoking -6
radon,
XRT,
asbestos,
occupation/environment (petroleum, nickel, arsenic, vinyl chloride, etc),
diet (low beta carotene, vit e),
coexisting lung dz,
genetic predisposition (metabolism of carcinogens, nucleotide excision repair)
pathophysiology SCLC -7
13-17% of lung CA,
most aggressive if left untreated,
clear smoking relationship,
paraneoplastic sx common,
initially highly sens to chemo-XRT-
-systemic dz, 60-70% present w/ detectable mets,
death in 2-4mo w/o tx
pathophysiology NSCLC
80-87% of lung CA, slower growing, moderately sens to XRT, low sens to conventional chemo– 50% present w/ mets
NSCLC types
adenocarcinoma 37-47% - most common type in non-smokers
squamous 25-32% - better prognosis than adeno
large cell 10-18% - poorly differentiated, dx of exclusion
prevention
no known effective method of chemoprevention
smoking cessation
screening -4
prevention (smoking cessation) is preferred over screening.
risk of second primary cancer 1-2%/yr NSCLC, 2-14% SCLC
spiral CT - saves lives, catches 49% stage I, 50% false (+), expensive
CXR-no benefit
screening - national lung screening trial (NLST) -3
CXR vs low dose CT
NN to screen to prevent one death 320 in CT arm
all-cause mortality dec by 6.7% in CT
signs and sx -6
cough (most common 45-75%, more in squamous and SCLC b/c in central airway),
wt loss,
dyspnea,
chest pain,
bronchitis with hemoptysis,
horseness,
others (bone pain, wheezing, pneumonitis, pleural/pericardial effusion, dysphagia, fatigue, clubbing)
lab abnormalities -2
hypercalcemia,
heme (anemia, leukocytosis, thrombocytosis)
syndromes and paraneoplastic syndromes -13
Horner's sx, SVC sx, Pancoast's sx --- para: SIADH, ectopic Cushing's sx, hypercalcemia, Eaton-Lambert, hypertrophic pulmonary osteoarthropathy, clubbing, dermatomyositis, acanthosis nigrans, hypercoag (DVT, PE, DIC, TTP), cachexia
metastasis sites -5
lymph nodes,
brain,
bone,
liver,
adrenal glands
diagnosis
H&P–labs: (CBC, electrolytes (Ca++), LFTs, albumin ->mostly assessing mets dz)–imaging: CXR, CT, PET (for surgical candidates), MRI (if mediastinal or chest wall invasion OR if brain mets in SCLC), bone scan, location of primary tumor correlates with histology–tissue: (depends on location): sputum cytology, bronchoscopy, transthoracic needle bx, thoracentesis, IHC staining (distinguishes mesothelioma vs lung adenocarcinoma)– other testing: PFTs (surgical eligibility), BMBx if indx
diagnosis – molecular studies and biomarkers
only send in non-squamous UNLESS never smokers OR small bx specimen
EGFR, EML4-ALK, ROS1, K-ras, ERCC1, RRM1 predict response
staging SCLC -2
limited stage (30-40%) one hemithorax, regional LN contained in a single radiation port
extensive stage (60-70%) everything else
staging NSCLC -4
TNM predicts survival
T: size, invasiveness
N: location of nodal mets-worse opposite side of body OR far reaching on same side such as supraclvicular nodes
M:
treatment - SCLC - general points -4
5yr OS 5%.
very sens to XRT and chemo.
systemic chemo backbone at all stages if pt can tolerate,
surgery has no role (except rare T1/T2 NO MO),
dose intensity DOES NOT improve outcomes
treatment -SCLC - Limited stage -3
curative intent (rate = 20%),
40% 2yr OS,
cisplatin 60mg/m2 D1-etoposide 120mg/m2 D1-3 WITH XRT (70 Gy total) x4-6 cycles (NO MAINTENANCE)
(can use carbo but fewer studies) WHEN U CAN USE CIS U SHOULD
treatment -SCLC - limited stage OR extensive stage - maintenance tx -1
No value
treatment -SCLC - extensive stage –chemo -5
survival w/o tx 5wks w/ tx 9-11mo,
2yr OS <5%:
Rarely curable,
cisplatin with etoposide OR irinotecan q3-4wks x4-6 cycles (can use carbo);
3 drug regimens NOT superior to 2.
several regimens.
elderly or debilitated very poor prognosis - BSC or less toxic regimen (no tx if PS >2)
treatment -SCLC - extensive stage –chest XRT -1
does not inc OS but use in palliation
treatment -SCLC - extensive stage –cranial XRT -2
brain mets - give PRIOR to chemo if symptomatic, AFTER if not
NO brain mets - give px if response achieved in chest to inc 1yr OS 13 to 27%
treatment -SCLC - Limited stage –cranial XRT -2
offer for pts who obtain CR,
inc 3yr OS 15 to 21%
treatment -SCLC - second line tx
THINK INTERVAL OF TIME
clinical trial preferred
relapse (>3mo since chemo) ORR 20-30%
refractory (<10%)
combo regimens should contain non-cross resistant agents from initial chemo
routine gcsf to maintain dose intensity NOT beneficial, may be harmful, DO not use if receive thoracic XRT
treatment -SCLC - time to relapse <2-3 mo, PS 0-2
ifosfamide,
taxane,
topoisomerase inhibitor,
gemcitabine,
temozolomide
treatment -SCLC - time to relapse >2-3 mo to 6 mo, PS 0-2
topotecan PO of IV (cat 1), irinotecan, CAV, taxane, vinorelbine, gemcitabine, PO etoposide, temozolomide
treatment -SCLC - time to relapse >6 mo, PS 0-2 -1
repeat initial regimen
treatment -SCLC - time to relapse >2-3 mo to 6 mo, PS 0-2 - topotecan (cat 1) -4
median survival 26 vs 13 wks,
grade IV neutropenia 32%-38%;
PO dose 2.3mg/m2 x5d, IV dose 1.5mg/m2 x5d
bioaval 60%
treatment -SCLC - elderly or severely ill -2
worse prognosis.
DO not use oral etoposide as initial tx; greater tox, poorer QOL, shorter OS
treatment -NSCLC - resectable (Stage I, II, IIIA) -4
surgery initial TOC.
XRT: if inoperable can use with curative intent.
adjuvant XRT: do not use in Stage I or II w/ neg margins (inc death), modest benefit in Stage III
adjuvant chemo: SOC in Stage II and IIIA, improves 5yr OS from 43-54% to 51-69%
treatment -NSCLC - resectable (Stage I, II, IIIA) - adjuvant chemo regimens -2
cisplatin 50mg/m2 D1,8, vinorelbine 25mg/m2 wkly q28d x 4 cycles (others with same drugs) (cat 1) (cis based preferred)
carbo AUC 6 paclitaxel 200mg/m2 D1 q21d x4 (for those not able to tolerate cis)
treatment -NSCLC - resectable (Stage I, II, IIIA) - is stage IIIA dz controversial?? -1
YES
treatment -NSCLC - UNresectable (Stage IIIB, IV) - Stage IIIB goal, regimen, duration and ADR -4
stage IIIb = just big enough to not be able to cut out
goal of downstaging for resection
cisplatin-based chemo (w/ etoposide or vinblastine) +XRT (cat 1)
duration of tx should not exceed 8 cycles
1/4 pts will have grade 3-4 esophagitis
treatment -NSCLC - UNresectable (Stage IIIB, IV) - Stage IV - general comments -4
TWO QUESTIONS.
- WHAT IS PS?
- WHAT IS HISTOLOGY? (MOLECULAR TESTING IF APPROPRIATE?)
formal palliative care involvement-> inc QOL, dec depression, inc OS 8.9->11.6mo
OS inc 6-8wk with chemo vs best supportive care and inc 1yr from 24 to 40%
PS 3-4: no benefit from tx
optimal platinum-based regimen unclear
optimal duration 4-6 cycles
Prognosis by stage -5
RESECTABLE
IA >70%, IB 60%
IIA 50%, IIB 30-40%
IIIA 10-30%
UNRESECTABLE
IIIB 10 to 14 mo
IV 4 to 12 mo
treatment -NSCLC - UNresectable (Stage IIIB, IV) - Non-squamous EGFR mutation (+) -2
erlotinib 150mg daily; For PS 0-4
can use for PS 3-4 UNLIKE WITH CHEMO
treatment -NSCLC - UNresectable (Stage IIIB, IV) - Non-squamous EML4-ALK mutation (+) OR ROS-1 mutation (+) -3
crizotinib 250mg bid;
ORR 55% at 8 wks; 1 yr OS 74%, 2yr OS 54%
can use for PS 3-4 UNLIKE WITH CHEMO
crizotinib toxicities -2
65% visual disturbances (light to dark accommodation difficulties),
inc LFTs in up to 15% (7% grade 3/4)
treatment -NSCLC - UNresectable (Stage IIIB, IV) - Non-squamous EGFR mutation (-) OR unknown -5
PS 0-1
TWO QUESTIONS.
- WHAT IS PS?
- WHAT IS HISTOLOGY? (MOLECULAR TESTING IF APPROPRIATE?)
#1-4 (cat 1) 1. platinum based doublet. cis/pac = carbo/pac = cis/doce = cis/gem. None clearly superior. Carbo/pac less toxic. Doce usually given 2nd line.
- Carbo AUC 6, pac 200mg/m2, bev 15mg/kg D1 q3wk x4-6c ->bev q3wk x6c (MAINTENANCE) (don’t use if hemoptysis)
- cis 75, pem 500 D1 q3wk
- nab-paclitaxel-carbo = pac-carbo (less PN)
- PS 0-1 (only cat 2B): cis 10, vinorelbine 25-30 D1,8 q3wk x6c +cetux 400 D1, then 250 qwk until progression or tox
treatment -NSCLC - UNresectable (Stage IIIB, IV) - Non-squamous EGFR mutation (-) OR unknown PS 2 OR squamous
PS 2
TWO QUESTIONS.
- WHAT IS PS?
- WHAT IS HISTOLOGY? (MOLECULAR TESTING IF APPROPRIATE?)
platinum based doublet OR single agent
CONTROVERSIAL
treatment -NSCLC - UNresectable (Stage IIIB, IV) - Squamous PS 0-1
TWO QUESTIONS.
- WHAT IS PS?
- WHAT IS HISTOLOGY? (MOLECULAR TESTING IF APPROPRIATE?)
DO NOT test EGFR or ALK unless never smoker OR small tissue bx
- platinum based doublet (cat 1)
Cis-etop +XRT in IIIB - (cat 2B) cis 80, vinorelbine 25-30 D1,8 q3wk x6c +cetux 400 D1, then 250 qwk until progression or tox
example platinum-based doublets
carbo AUC 6, pac 200-225 over 3hr D1 q3wk cis 75, doce 75 D1 q3wk pac 135 over 24h D1, cis 75 D2 q3wk cis 100 D1, gem 1000 D1,8,15 q4wk cis 100 D1, vinor 25 D1,8,15,22 q4wk cis 80 D1, irino 60 D1, 8,15 q4wk carbo AUC 6 D1, nab-pac 100 D1,8,15 q3wk
treatment -NSCLC - UNresectable (Stage IIIB, IV) - continuation maintenance
CONSIDER IF NON-PROGESSORS AFTER 4-6 CYCLES
con’t one agent used in 1st line –to progression or poor tolerability
1. bev
- cetux
- pem (OS 11->13.9mo)
- erlot (OS 11->12mo) (EGFR mutation (+) in practice)
treatment -NSCLC - UNresectable (Stage IIIB, IV) - switch maintenance
CONSIDER IF NON-PROGESSORS AFTER 4-6 CYCLES
switch to different agent
1. erlot
- pem 500 q3wks NONSQUAMOUS ONLY (OS 10.3->15.5mo)
- (cat 2B) doce 75 q3wks SQUAMOUS ONLY (inc PFS and dec subsequent tx BUT same OS vs delayed doce given as 2nd line, so inc OS vs best supportive likely)
pemetrexed maintenance AE, >or= grade 3
fatigue (5%), neutropenia (3-4%), anemia (5%)
treatment -NSCLC - UNresectable (Stage IIIB, IV) - second line -4
- If erlotinib or crizotinib 1ST LINE consider EGFR (-) regimen
- doce (USE IN SQUAMOUS) inc 1yr OS >30% over best supportive, vinor, or ifos (reason to save for 2nd line)
- pem (nonsquamous only) = doce AND is less tox SO USE
- erlotinib, prolongs OS by 2 mo
docetaxel maintenance AE
19% grade 4 neutropenia, 1% FN
ORDER OF MOLECULAR TESTING -3
EGFR (20% pts) -> IF (-) THEN
ALK4-EML (5-8% pts)
THOUGH OFTEN DONE AT SAME TIME
IS EGFR IHC HELPFUL?
WHY OR WHY NOT?
NO
ONLY MUTATION RECEPTORS AFFECT CARCINOGENESIS -> IHC DOES NOT DETECT RECEPTOR MUTATION
treatment -NSCLC - UNresectable (Stage IIIB, IV) - third line -1
erlotinib, prolongs OS by 2 mo
