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

SMALL CELL LUNG CANCER

Helena A. Yu and M. Catherine Pietanza

Epidemiology

• SCLC accounts for 13–15% of all lung CAs, seen almost exclusively in smokers, majority w/extensive stage disease at dx (60–70%)

Pathology

• Dx based primarily on light microscopy w/confirmatory IHC

• IHC: +TTF-1, +CD56, +chromogranin, +synaptophysin (75% w/≥1 NE marker)

• Rarely can coexist w/SQCLC, ADCL, other histologies

Etiology and Clinical Manifestations

• Nearly exclusively seen in smokers, related to both smoking duration & intensity

• Most common presentation is large hilar mass w/bulky mediastinal LAD

• Sx: Fatigue, cough, dyspnea, wt loss, debility, hemoptysis

Molecular Biology

• Mts: p53 (75–90%) (Oncogene 1991;6:1775), SOX2 Mts/amp (Nat Genet 2012;44:1111), FGFR1 amp (Nat Genet 2012;44:1104)

• Cytogenetics: Loss of heterozygosity (LOH) at chrom 9p, 10q (PTEN) (Cancer Res 1997;57:400), deletion 3p (Cell 1996;85:17), loss of Rb gene function (13q14) (PNAS 1997;94:6933)

• Expression: Activation of telomerase, upregulation of c-kit (Clin Canc Res 2004;10:8214), c-myc (Oncogene 2006;25:130), bcl-2

Workup, Staging, Prognosis

• After tissue dx w/u includes imaging of chest, liver/adrenals, & CNS

• Poor prognostic factors include poor PS, wt loss, continued smoking, male sex, presence of paraneoplastic syndrome, elevated LDH

Management—Limited Stage

• In rare cases, surgical resection may be curative for clinical stage 1 disease (5-y survival 40–50% for path stage 1–2 disease) (J Thorac Oncol 2009;4:1049), nodes need to be confirmed negative prior to resection, pts require (neo)adjuvant chemoRT

• Concurrent chemoRT w/an OS benefit (NEJM 1992;327:1618), ORR of 80–90%, 50–60% w/CR

• Dose: 45 Gy twice daily better than ∼45 Gy daily (NEJM 1999;340:265), survival benefit for adding RT w/cycle 1 or 2 (J Clin Oncol 1993;11:336)

• Plat/etoposide is chemotherapy of choice, plat/etoposide = plat/irinotecan, although irinotecan seldom used in US, as ↑ tox (JCO 2009;27:2530), CIS = carboplatin (JCO 2012;30:1692)

Management—Extensive Stage

• Highly responsive to chemotherapy/RT, but relapses common, ORR 60–80%, CR in 15–20%

• Survival benefit to combination chemo, plat-based regimen typically used (↑ RR & improved survival), CIS/etoposide used 1st line based on efficacy & tox, ↑ RR but no difference in survival w/CIS vs. carboplatin

• Recommend 4–6 cycles of induction chemo, followed by observation

• No benefit to maintenance, ≥3 drug combos, alternating/sequential regimens

• Elderly pts: If PS adequate, proceed w/standard plat doublet chemo

Prophylactic Cranial Irradiation (PCI)

• Significant rate (17–38%) of CNS “failure” despite systemic response, CNS failure rate ∼80% over 2 y

• PCI w/in 4–8 wks after completion of chemo, MRI brain before proceeding

• LS-SCLC: After CR or significant regression to chemo ↓ brain mets, ↑ OS w/PCI (NEJM 1999;34:476)

• ES-SCLC: If tumor response to chemo, ↓ brain mets, ↑ OS w/PCI (NEJM 2007;357:664)

• Total dose of 25–30 Gy, can abbreviate if not PR or in ES-SCLC

• Toxicities: Fatigue, alopecia, neurocognitive impairment

Management—Relapsed Disease

• Median survival after relapse 2–6 mos

• Prognostic factors: PS, tumor extent, time to relapse

• Sensitive disease: Initial PR/CR to Rx, progression ≥3 mos after last d of initial tx, high likelihood of response to additional Rx

• Refractory disease: Progression after ≤3 mos or lack of response during initial Rx, chance of response to additional Rx <10%

• In late relapse (≥6 mos), significant responses w/reinduction w/1st-line chemo

• Combination therapies w/↑ RR, ↑ tox w/o survival benefit

• In pts w/adequate PS, 2nd-line chemo vs. best supportive care improves OS & QoL

• Topotecan: Only agent approved in 2nd-line setting, phase III data vs. cyclophosphamide, adriamycin (doxorubicine), vincristine (CAV) (cyclophosphamide, doxorubicin, vincristine) w/similar RR, PFS, OS but improved control of sx (JCO 1999;17:658), oral topotecan compared to BSC w/improved QoL (JCO 2006;24:5411)

• Amrubicin studied in phase 3 trial vs. topotecan (no ↑ OS, but ↑ ORR, PFS, sx control) (JCO 2011;29s:abstr7000), phase 2 in refractory SCLC: ORR 21%, mPFS 3 mos (JCO 2010;28:2598)

• Other agents: Based on smaller, single arm phase 2 studies, irinotecan, temozolomide (CCR 2012;18:1138), paclitaxel, docetaxel, vinorelbine, GEM

Targeted Therapy

• No improvements in survival w/standard Rx over last 20 y, no FDA-approved targeted agents

• Ongoing studies: Inhibitors of IGF-1R, PI3K/Akt/mTOR, Hedgehog, PARP, HDAC, Notch, Bcl-2

• Angiogenesis inhibitors tested w/o clear efficacy (thalidomide, Bev, sorafenib)

• Immunotherapy: Vaccine trials, ipilimumab studies ongoing