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