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