Radiation Oncology/SCLC/Review

Small Cell Lung Cancer Review

Epidemiology

 * US Incidence: ~35 thousand
 * Primary risk factor: tobacco
 * Limited stage: 20-30% at diagnosis

Clinical Presentation & Workup

 * Clinical presentation: Cough and dyspnea
 * Paraneoplastic syndromes:
 * Lambert-Eaton: progressive muscular weakness similar to myasthenia gravis, but starting with proximal leg muscles, caused by autoantibody to voltage-gated calcium channels. 50% of LEMS are found to have underlying SCLC
 * Paraneoplastic encephalomyelitis: multiple neurologic deficits, caused by anti-Hu antibody that cross-reacts with SCLC antigens and neuronal RNA-binding proteins
 * Cushing's syndrome: central obesity (including moon face and buffalo hump), thin skin, hirsutism, striated skin, caused by inappropriate ACTH release
 * SIADH: hyponatremia and fluid overload, caused by inappropriate ADH release. Found in ~16% SCLC vs 2% NSCLC
 * CXR presentation: Large hilar mass with bulky mediastinal lymphadenopathy; solitary nodule ~5%
 * Pathology
 * Malignant epithelial tumor, small cells, scant cytoplasm, high mitotic count
 * In up to 30% of autopsies, areas of NSCLC differentiation, suggesting pluripotent stem cell origin
 * Immunoreactive for keratin, epithelial membrane antigen, TTF-1 and neuroendocrine markers (chromogranin A, NSE, NCAM, synaptophysin) though these alone not sufficient since they are present in ~10% of NSCLC
 * p53 positive in 90% SCLC vs. 50% NSCLC; RB LOH in 90% SCLC vs 10% NSCLC;
 * Workup
 * Chest/liver/adrenal CT
 * Head MRI (positive in 10-15%)
 * PET (optional) or bone scan (positive in 30% with no bone pain or LDH elevation)
 * Staging:
 * Limited stage: can be safely enclosed in RT portal (corresponds to Stage I-IIIB)
 * Extensive stage: metastatic disease (corresponds to Stage IV)

Limited Stage Therapy

 * Median OS 14-20 months; 2-year OS 40%; 5-year OS 15-25%
 * Chemotherapy primary therapy
 * Cisplatin/etoposide is NCCN recommended combination; cisplatin/irinotecan not superior
 * Addition of thoracic RT: improves local control and survival (meta-analysis)
 * RT used in most of the trials was 45 Gy QD
 * Chemotherapy alone intrathoracic failure: 50-90%
 * Intrathoracic control benefit: chemo-RT improved by 25% (SS)
 * Survival benefit: 3-year chemo-RT 14% vs. chemo alone 9% (SS); 5% absolute benefit
 * Excess treatment-related deaths: chemo-RT worse by 1.2% (SS)
 * Timing/duration of RT (meta-analysis)
 * Benefit for early RT in cisplatin-based concurrent trials (HR 0.6), 5-year OS 10-15% to 20-30%
 * If RT started with 30 days of chemo: 2-year OS benefit HR 0.7 (SS)
 * If duration <30 days: even more benefit
 * RT dose/fractionation
 * INT 0096 (Turisi): 45 QD vs 45 BID with concurrent cisplatin 60 mg/m2 and etoposide 120 mg/m2 Q3W
 * Survival benefit: 2-years QD 41% vs BID 47%, 5-years 16% vs 26% (SS)
 * Local failure: QD 52% vs. BID 36% (p=0.06)
 * Grade 3 esophagitis: QD 11% vs 27% (SS), no differen

Extensive Stage Therapy

 * Median OS 9-11 months; 2-year OS <5%
 * Chemotherapy primary therapy
 * No benefit to dose intensification
 * If symptomatic brain mets, whole brain RT first
 * If asymptomatic brain mets or no brain involvement, start with chemotherapy
 * If no progression on chemo, prophylactic cranial irradiation
 * RT may benefit patients in CR after chemotherapy (Yugoslavian Trial - Jeremic)
 * Cisplatin/etoposide x3 cycles. If distant CR and local CR/PR, RT 54/35
 * Median OS 11 months vs 17 months (SS)

Prophylactic Cranial Irradiation

 * Incidence: 15-20% at diagnosis, 60-80% at autopsy
 * Limited stage, in CR after induction (meta-analysis), WBRT improves local control and overall survival
 * Brain mets without PCI: 3-years ~60%
 * Brain mets with PCI: 3-years 33%, reduction of 50% (SS)
 * Survival benefit: 3-year 21% vs 15% (SS); 5% absolute benefit
 * RT dose: 25/10 noninferior to "high dose" (36/18 or 36/24), with survival benefit
 * Extensive stage, with response after induction (EORTC 08993/22993), WBRT improves local control and overall survival
 * Symptomatic brain mets without PCI: 40%
 * Symptomatic brain mets with PCI: 15%
 * Survival benefit: 1-year 27% vs 13% (SS)
 * RT dose: 20/5 used in 60%, considered reasonable given short survival