Pocket Oncology (Pocket Notebook Series), 1st Ed.

NON SMALL CELL LUNG CANCERS

Helena A. Yu and Mark G. Kris

Epidemiology

• 225K lung CA cases w/160K death annually in US; 80% are NSCLC; leading cause of CA mortality, majority adv at dx (70% stage III/IV), 85% of pts will die from their disease

Etiology and Clinical Manifestations

• Cigarette smoking: 73% of all cases, ↑ w/ intensity & duration of smoking, previous RT, carcinogens: Polycyclic aromatic hydrocarbons, radon, metals, synergy w/smoking + asbestos

• Sx: 10% asx, cough/hemoptysis (central tumors), dyspnea, wt loss, hoarseness, bone pain, facial swelling/venous distension of neck & CW (SVC syndrome), shoulder pain/hand muscle atrophy (Pancoast tumor: Apical, involves brachial plexus)

Molecular Biology

• EGFR Mt: 23% all pts, 43% never-smokers w/ADCL, L858R in exon 21 (40%) & exon 19 deletions (50%) confer EGFR TKI Sn, initially described in female Asian never-smokers but also present in smokers (J Clin Oncol2011;29:2066), exon 20 insertions do not confer Sn to EGFR TKI, acquired T790M gatekeeper Mt confers EGFR TKI resistance (NEJM 2005;352:786)

• ALK Rearrangements in 6%, various ALK fusion partners, a/w never/light smoking hx w/signet-ring ADCL histology, confers Sn to crizotinib (NEJM 2010;363:1693)

• KRAS Mt: 25% of ADCL, a/w smoking (transversions: G12C, G12V) but present in 6% of never-smokers (transitions: G12D), confers EGFR TKI resistance (CCR 2008;14:5731)

• Other aberrations in ADCL: BRAF Mt 3%, RET Fusions 1%, HER2 Amp/Mt 1%, PIK3CA Mt 3%, ROS 1 Fusions 2%, may confer Sn to crizotinib, MET Amp 2% (JCO 2011;29:abstr 7506; JCO 2012;30:863; JCO2012;30:4352)

• SQCLCs: FGFR1 Amp 20%, DDR2 Mt 4%, potential Sn to dasatinib, SOX2 Amp 8%, PIK3CA Mt 4%, PTEN Mt 10%, AKT Mt 6% (Nature 2012;489:519; JCO 2012;30:abstr 7505)

Screening and Prevention

• No mortality benefit for CXR & sputum cytology screening

• Annual low-dose CT: 20% mortality benefit in Nat’l Lung Screening Trial, NNT = 320 (NEJM 2011;365;395)

• Screening recommended: Ages 55–74, ≥30 pack y, quit <15 y ago w/annual low-dose CT

• Smoking cessation: Most effective method of prev

• High risk of second primary tumors in smokers – most commonly 2nd lung 1°, no evidence for chemoprevention w/retinoids, beta-carotene

Workup and Staging

• Bx: Core needle preferred, send for histologic review w/IHC, molecular testing for all pts regardless of smoking status

• CT chest down to adrenals, bone scan or PET scan to evaluate for distant disease, MR brain for pts w/≥ stage IB disease, PFTs for symptomatic evaluation

• Mediastinal evaluation: Recommended for nodes >1 cm on CT or PET+ via mediastinoscopy, EBUS-guided bronchoscopy or endoscopy w/LN bx

• Stage I: Tumor ≤5 cm N0, Stage II: Tumor ≥5 cm N0, T1–2N1 (station ≥10; hilar/peribronchial nodes), T3N0, Stage IIIA: T3N1 or N2 (ipsilateral mediastinal nodes), T4N0–1, Stage IIIB: N3 (supraclavicular, scalene, contralateral mediastinal nodes), Stage IV: Contralateral pulmonary nodule (M1a), pleural involvement/ effusion (M1a), distant disease (M1b)

Management: Stage I to Nonbulky IIIA (cT3N1) Disease

• Surgery: Lobectomy preferred operation, preoperative FVC of >1.5 L required for lobectomy & >2 L for pneumonectomy

• RT: For nonsurgical candidates, >60 Gy, can use standard RT, SBRT, radiofrequency ablation, good outcomes in early-stage disease

• Adjuvant Chemo: ↑ OS for pathologic stage II–IIIA, CIS doublet for 4 cycles (LACE JCO 2008;26:3552), studies used CIS/vinorelbine, other doublets likely w/similar efficacy & ↑ tolerability, adjuvant TKIs: Erlotinib (EGFR-Mt) & crizotinib (ALK-fusion+) studies ongoing

• PORT: Controversial, N2 nodes, +margins w/likely benefit

Management: Bulky Stage IIIA (cN2) to IIIB Disease

• Multimodality Rx: Sequence of chemo, surgery, & RT varies

• Induction: If resectable, chemo to best response followed by resection ± RT

• Chemoradiation: Concurrent > sequential Rx (JCO 1999;17:2692) in unresectable stage III, regimens: CIS/etoposide, carboplatin/paclitaxel, CIS/vinorelbine

• Pancoast tumor: ChemoRT → Sx (T3–4, N0–1), improves resectability, ↑ OS

Management: Metastatic Disease

• Median OS: 6-mo BSC, 10-mo plat doublet, 12-mo plat doublet + Bev (NEJM 2006;355:2542), ↑ OS w/early palliative care (NEJM 2010;363:733), survival benefit w/doublet chemo in ECOG PS2 (JCO2006;26:863)

• 1st-line Tx: RR ∼30%, standard is 4–6 cycles of plat doublet ± Bev (if eligible: No hemoptysis, non-SQCLC), doublet choice: CIS/peme (non-SQCLC) vs. CIS/GEM (SQCLC) (JCO 2008;26:3543), carboplatin/paclitaxel (any histology)

• Maintenance Rx: For CR/PR/SD after 4–6 cycles of plat doublet, ↑ PFS

Continuation maintenance (d/c plat): Continue peme ↑ OS (PARAMOUNT Lancet Oncol 2012;13:247), peme + Bev ↑ PFS (AVAPERL), GEM ↑ PFS (JCO 2012;30:3516)

Switch maintenance (d/c plat doublet, switch to different agent): Peme (Lancet 2009;374:1432), erlotinib (SATURN), docetaxel (JCO 2009;27:591)

• 2nd-line Tx: RR ∼10%, doublet not better than single agent, docetaxel (JCO 2000;18:2095), GEM, 3rd-/4th-line options include vinorelbine, mitomycin/vinblastine

• Palliative RT (WBRT or SRS) for brain mets, also for symptomatic bone lesions, SVC syndrome

Targeted Therapy

• EGFR TKIs (erlotinib): Rx of choice in EGFR-Mt, ↑ PFS, improved RR/PFS compared to plat doublet in 1st-line setting (IPASS NEJM 2010;362:2380), 2nd gen. TKIs (afatinib) in clinical trials, s/e: Rash (30–50% pts, Tx: Moisturizers, abx, topical steroids), diarrhea

• Acquired resistance to EGFR TKIs (mechanisms: T790M Mt, MET Amp, SCLC transformation): Pts who d/c TKI may experience disease flare (CCR 2011;17:6298), many continue TKI, if chemo-naïve give plat doublet, clinical trial whenever possible, consider local tx if POD in single site

• Crizotinib: Rx of choice in ALK + lung CAs, s/e: GI, fluid retention, visual changes, 2nd–gen. ALK TKIs in clinical trials