Thoracic Malignancies



Thoracic Malignancies





NON SMALL CELL LUNG CANCERS

Helena A. Yu

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
















Pathology


Adenocarcinoma of the lung (ADCL, 72%); most common subtype, ↑ incidence, located peripherally, scar tissue, a/w hypertrophic osteoarthropathy, histology formerly known as BAC reclassified as minimally invasive ADCL, IHC: +TTF1, −p63


Squamous cell lung cancer (SQCLC), 25%: Centrally located mass but incidence in peripheral lesions increasing, strongly a/w smoking, a/w hypercalcemia 2° to PTHrP release, IHC: −TTF1, +p63 (p63 isoform p40 w/˜Sn & ↑ Sp) (Lancet Onc 2012;13:418)


Other: Adenosquamous lung cancer (ADSQLC, 1%): Important to r/o in small biopsies revealing SQCLC w/discordant clinical findings (eg, never-smoker), molecularly similar to ADCL; large cell (2%): Typically poorly differentiated, dx of exclusion, a/w gynecomastia



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 Oncol 2011;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%, ROS1 Fusions 2%, may confer Sn to crizotinib, MET Amp 2% (JCO 2011;29:abstr 7506; JCO 2012;30:863; JCO 2012;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)





































Prognosis: OS at 5 y (%)


Stage

IA

IB

IIA

IIB

IIIA

IIIB

IV


Clinical

50

36

25

19

7

2

2


Pathological

73

58

46

36

24

9

–



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 (JCO 2006;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

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Jun 19, 2016 | Posted by in ONCOLOGY | Comments Off on Thoracic Malignancies

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